CHaPtEr 37 Infections in the Immunocompromised Host 529
and PTLD. Other infections that have occurred are overwhelming
Rituximab bacteremia, bacterial meningitis, toxoplasmosis, PML, dissemi-
Rituximab is a chimeric murine–human mAb that targets CD20 nated amoebiasis, parvovirus infection, and nocardiosis. All
on mature B lymphocytes. It results in rapid and profound patients receiving alemtuzumab should receive PJP and herpes-
40
depletion of B cells that can last up to several months. In virus prophylaxis for a minimum of 2 months after therapy or
most adults, serum Ig levels remain largely stable, since plasma until CD4 counts are ≥200 cells/µL (Campath package insert).
cells do not express CD20. Initial trials suggested that rituximab Given the high incidence of CMV reactivation and disease,
had minimal effect on the occurrence of infections; however, prophylaxis or preemptive therapy is warranted.
more recent meta-analyses have reported a higher risk of infec-
tions, especially with repeated administration and in patients Daclizumab and Basiliximab
with underlying immune defects or concomitant significant Daclizumab and basiliximab are humanized and chimeric mAbs,
40
immunosuppression. HBV reactivation occurs, and there have respectively, that target CD25, the α chain of the IL-2 receptor
been reports of fulminant hepatitis and death after rituximab complex expressed on activated alloantigen-reactive T lympho-
treatment, particularly when used in combination therapy (e.g., cytes. They competitively inhibit IL-2 binding and prevent IL-2
rituximab with cyclophosphamide, doxorubicin, vincristine, mediated activation of lymphocytes and cytokine release. They
and prednisone [R-CHOP]). Also a reverse seroconversion are mainly used in transplantation to prevent rejection or steroid-
37
phenomenon has been described, with loss of protective HBV refractory GvHD. When used as prophylaxis for rejection in
38
surface antibodies and reactivation. Assessment of HBV status SOT, their use does not seem to be associated with an increased
before starting rituximab is recommended. To reduce the risk of risk in infections. In allo-HSCT, high rates of mortality and of
reactivation, HBV suppression with antiviral medication should be OIs (95%) have been reported in patients receiving daclizumab
considered. for steroid-refractory GvHD; however, given the high risk of OIs
Since the initial approval of rituximab, there have been over in this population in general, the actual role of daclizumab is
280 cases of PML associated with its use. Most cases have been unclear. Infections described in this setting are common bacterial,
reported in patients with hematological malignancies; however, viral (CMV, BK virus, adenovirus, HSV, RSV, influenza virus),
some have been reported in patients with autoimmune or EBV-associated PTLD, invasive fungal infections (mold and
inflammatory diseases, who take other immunosuppressants yeasts), as well as Legionella and Nocardia and NTM infections,
as well. Rituximab now carries a black box warning about the TB, and toxoplasmosis. 38
41
risk of PML and death. There have been many reports of
PJP following use of rituximab, although most patients also Natalizumab
received other immunosuppressive therapies. The need for PJP Natalizumab is a humanized IgG4 that targets the α 4 subunit of
prophylaxis with its use remains to be determined. The great- α 4 β 1 and α 4 β 7 integrins, found in lymphocytes; it inhibits their
est risk of infection appears to be related to viral reactivation, binding to cellular adhesion molecules (vascular cell adhesion
particularly in children; as usual, this is confounded by prior molecule-1[VCAM-1] and mucosal addressin-cell adhesion
or concomitant immunosuppressive medications. In children molecule-1 [MAdCAM-1]) in the central nervous system (CNS)
with immune-mediated neurological diseases, infections after and the GI tract, thereby attenuating inflammation in these
rituximab use are common; even lethal CMV disease has been tissues. 38,43 It is associated with a profound decrease in CD4,
42
reported. Other rare infections that have been described are CD8, and CD19 lymphocytes in cerebrospinal fluid (CSF), and it
enteroviral meningoencephalitis, CMV disease, disseminated is used in the treatment of multiple sclerosis and Crohn’s disease.
VZV infection, refractory babesiosis, parvovirus B19 infection, Natalizumab was temporarily withdrawn from the market in
and nocardiosis. 37 2005 after three cases of PML were reported in patients with
prolonged exposure. It has now been reintroduced with a black
Alemtuzumab box warning about the risk of PML. Based on retrospective global
Alemtuzumab is a humanized IgG1 that targets CD52 on B and surveillance data, the overall incidence of PML in natalizumab
T lymphocytes, monocytes, macrophages, and NK cells. It lyses treated patients is 1.01 cases/1000 patient-years. However, the risk
these cell populations and results in profound and sustained of PML is significantly increased in patients who have detectable
deficits in cellular and humoral immunity that lasts for several anti-JC virus antibodies before the initiation of therapy, had
months; CD4 and CD8 cell count reach their nadir approximately prolonged exposure to natalizumab (>24 months), and had
4 weeks after treatment, but median counts remain at <25% prior use of immunosuppressants (11.1 cases/1000 patients [95%
38
of baseline for approximately 9 months. Opportunistic and confidence interval (CI) 8.3–14.5]). The incidence in patients
nonopportunistic infections have been associated with its use, with no detectable anti-JC virus antibodies is calculated at 0.09
43
particularly reactivation of herpes virus (e.g., Epstein-Barr virus cases/1000 patients (95% CI 0–0.48). Increases in bacterial
[EBV], CMV, disseminated VZV) and fungal infections (e.g., and viral infections and OIs have been reported as well, but
PJP, invasive molds, and dimorphic fungi). Moreover, several most patients with these infections were receiving concurrent
cases of TB and NTM infection have been reported. The incidence immunosuppression.
of these OIs varies with the administered dose and whether it
is used as a single agent or in combination with other immunosup- Bortezomib
pressants (e.g., induction therapy [4.5%] versus treatment for Bortezomib is a dipeptide boronate proteasome inhibitor that
rejection [21%] in SOT). 37,38 When used for T-cell depletion in causes G2–M cell cycle arrest and apoptosis, which ultimately
allogeneic HSCT (allo-HSCT) it has been associated with a very impacts T-cell immunity. It is now approved for the treatment
high risk of CMV reactivation (50–85%) and disease, severe of multiple myeloma and mantle cell non-Hodgkin lymphoma.
adenovirus infection, human herpesvirus-6 (HHV-6) encephalitis, An increased incidence of herpes virus infections, in particular
respiratory viral infections that frequently progress to pneumonia, VZV infection, has been reported. The incidence in patients
530 Part four Immunological Deficiencies
with myeloma treated with bortezomib is around 13–22% and intervention are similar among those undergoing SOT. This
in relapsed/refractory mantle cell lymphoma around 10.3%, with predictable temporal pattern has enabled the institution of specific
age ≥65 years as the only predictive factor. 44 prophylactic strategies and in the development of an infection
differential diagnosis. 45
INFECTIONS IN SOLID ORGAN TRANSPLANTATION
CLINICaL PEarLS
KEY CoNCEPtS Infections in Solid-Organ Transplant Recipients
Determinants of the Risk for Infections in • Most infections occur in the first 6 months following transplantation.
Transplant Recipients • In the first month, most infections are nosocomial or are related to
surgical procedures or preexisting infection in the donor or
recipient.
• Epidemiological exposures (e.g., residing in a Histoplasma endemic
area) • Infections between 1 and 6 months following transplantation are
• Immunosuppressive drugs commonly secondary to the use of immunosuppressive drugs, with
• Antimicrobial prophylaxis a predominance of cytomegalovirus infection.
• Type of transplantation (e.g., cord transplant vs matched related donor • Infections after 6 months are usually due either to chronic viral infection,
transplantation) acquired earlier, or to chronic allograft dysfunction, necessitating
• Time after transplantation repeated courses of high-dose immunosuppression.
Despite significant improvement in the survival of SOT recipients, Infections in the First Month After Transplantation
infectious complications remain a major cause of morbidity and Infections in this period are generally associated with technical
mortality. The risk of infection is determined by the interaction complications of the surgery or have a nosocomial etiology.
of various factors, such as age of the recipient, type of transplanta- Donor-transmitted infections (e.g., Chagas disease) or reactivation
tion, invasive procedures, dose and duration of immunosup- of prior infections (e.g., colonization and infection with
pressive drugs, epidemiological exposures of both donor and multidrug-resistant [MDR] bacteria) can also occur. 45
recipient, use of antimicrobial prophylaxis, donor–recipient
serological status to certain infections (e.g., CMV infection, EBV Infections 1–6 Months After Transplantation
infection, toxoplasmosis), and ongoing viral replication (so-called Before routine antimicrobial prophylaxis, this period was typically
45
indirect effects). Assessment of a recipient’s risk for infection characterized by the presence of OIs, such as PJP and CMV
should help tailor specific prophylactic strategies and infectious infection; the incidence of these infections has been significantly
workup when an infection is suspected. reduced or delayed with TMP-SMX prophylaxis and CMV
Age is an important determinant of susceptibility to infections; prophylactic or preemptive therapy. Reactivation of latent infec-
it impacts the likelihood of prior exposures to microbial patho- tions, such as TB, Chagas disease, endemic mycoses, and cryp-
gens, either by primary infection or vaccination. History of tococcosis, can occur. Viral infections, such as those with BK
exposure can have either positive or negative effects. Older patients virus, adenovirus, RSV, HBV, and EBV, are common (Fig. 37.4).
are more likely to have encountered pathogens that can remain Invasive fungal infections, specifically Aspergillus and non-
latent and reactivate at the time of transplantation (e.g., CMV); Aspergillus mold infections, can be problematic during this period
younger patients have a higher risk of acquiring primary infections of heightened immune suppression. 45
after transplantation, and these infections tend to be more severe
than disease secondary to reactivation of a latent infection. In Infections 6 Months After Transplantation
addition, preexisting immunity can have a protective effect against This period is less well defined; patients with satisfactory allograft
clinical disease (e.g., EBV-associated PTLDs). 45 function develop more severe manifestations of community-
The type of allograft affects the specific infectious risk, usually acquired infections but have a lower risk of OIs. Patients with poor
as a result of technical factors associated with the transplantation allograft function and, therefore, increased immunosuppression
procedure, but is also inherent to the transplanted organ. For or those with ongoing chronic viral reactivation are at high risk of
example, urinary tract infections are most common after kidney OIs, such as invasive fungal infections, late-onset CMV infection,
transplantation, as a result of either catheter placement or ureteric nocardiosis, PJP, listeriosis, and EBV-associated PTLD. In addition,
stenting. BK virus is ubiquitous, but BK virus–associated trans- lung transplant recipients with chronic graft dysfunction are
plant nephropathy is most common after kidney transplantation, at high risk of recurrent bacterial pneumonia. Similarly, liver
and it is an important cause of allograft loss. Infection after liver transplant recipients with chronic graft dysfunction frequently
transplantation frequently results from leaks from biliary and develop biliary strictures and recurrent cholangitis. 45
GI anastomoses. Cardiac assist devices in heart transplant
recipients are a frequent source of infection. Tracheal anastomotic INFECTIONS IN HEMATOPOIETIC STEM
infections, particularly caused by fungi, are a significant complica- CELL TRANSPLANTATION
tion of lung transplantation. In single lung transplantations,
recurrent infections of the native lung, such as with GNB or Survival after HSCT has significantly improved during the last
fungi, can extend to the transplanted lung. In small intestine decade. Factors contributing to the increase in survival are the
transplantation, opportunistic and nonopportunistic viral infec- use of less toxic, nonmyeloablative conditioning regimens, use
tions of the GI tract (e.g., with norovirus) are common; these of peripheral blood stem cells (PBSCs) that leads to faster
can be severe and even life threatening. 45 neutrophil recovery, and use of antimicrobial preventive thera-
46
Despite all the differences in individual risk of infection, the pies. Despite these advances, infections are still a frequent cause
general patterns of infection in the absence of antimicrobial of morbidity and mortality.
CHaPtEr 37 Infections in the Immunocompromised Host 531
A B C
fIG 37.4 Disseminated Histoplasmosis in a Patient from an Endemic Area 3 Months After
a Heart Transplantation. (A) Chest X-ray with bilateral reticulonodular infiltrates. (B) Computed
tomography (CT) scan of the chest with bilateral patchy and nodular infiltrates. (C) Lung biopsy.
Gomori methenamine silver (GMS) stain shows yeast forms compatible with Histoplasma
capsulatum.
CLINICaL PEarLS
Infections in Bone Marrow Transplant Recipients
• Infections 2–4 weeks posttransplantation are usually caused by profound
neutropenia and damage to mucosal surfaces.
• Between the period of engraftment and posttransplant weeks 15–20,
OIs predominate and are commonly associated with the development
of acute graft-versus-host disease (GvHD) and its treatment.
• Serious infections occurring 4–6 months following transplantation are
seen predominantly in patients with chronic GvHD.
The risk for infection is influenced by several factors and
varies significantly between type of transplantation (autologous
vs allogeneic), stem cell source (bone marrow, PBSC, and cord
blood), degree of human leukocyte antigen (HLA) matching,
+
hematopoietic potential of the graft (number of infused CD34 fIG 37.5 Magnetic resonance imaging (MRI) scan of the brain
cells), T-cell depletion, type of conditioning (myeloablative vs of a patient with human herpesvirus-6 (HHV-6) encephalitis 36
reduced intensity vs nonmyeloablative), underlying disease, days after a matched unrelated donor hematopoietic stem cell
presence of graft rejection or GvHD, donor–recipient serological transplantation (HSCT) for diffuse large B-cell lymphoma. Flair
status to certain infections (e.g., CMV infection), and use of axial image shows bilateral medial temporal lobe edema compat-
antimicrobial prophylaxis. 47 ible with limbic encephalitis.
Autologous HSCT (auto-HSCT) refers to the patient serving
as his or her own donor to allow administration of myeloablative
chemotherapy. Because there is no risk of rejection or GvHD
and because after engraftment there is an early and progressive are associated with faster neutrophil engraftment compared with
46
recovery of cell-mediated immunity, the risk for infection is cord blood units and therefore lower rates of infection. Bacterial
much lower than in allo-HSCT. The major compromises in host infections are most common. However, when neutropenia is
defenses occur before engraftment and are usually related to prolonged, the risk of invasive fungal infection increases signifi-
neutropenia and mucosal injury. In contrast, in allo-HSCT, the cantly. Without acyclovir prophylaxis, reactivation of severe HSV
risk for infection can be divided into three periods: preengraft- infection is frequent.
ment, early postengraftment, and late postengraftment periods.
Early Postengraftment Period
Preengraftment Period The resolution of neutropenia marks the beginning of this period
The major impairments in host defenses before engraftment are and usually lasts 2–3 months (Fig. 37.5). This period is character-
neutropenia and mucosal injury. This period varies widely between ized by a progressive but slow recovery of B- and T-lymphocyte
different types of conditioning regimens and stem-cell source. function; thus viral and fungal OIs can occur. The risk of infection
In general, when ablative regimens are used, engraftment occurs is higher in patients who develop acute GvHD and therefore
any time between 15 and 45 days after transplantation and can require high dose steroids. Common bacterial infections can
47
be as short as 5–7 days with nonablative regimens. PBSC grafts still occur and are usually related to indwelling catheters or GvHD
532 Part four Immunological Deficiencies
+
−
of the gut. CMV viremia is common during this period. However, In high-risk solid-organ recipients (D /R ), in particular recipients
routine use of preemptive or prophylactic therapy has been of lung and small bowel, although preemptive therapy is an
effective in preventing life-threatening CMV disease. The risk accepted alternative, universal prophylaxis is preferred. It has
of Pneumocystis pneumonia (PCP) has also decreased since the the theoretical advantage of preventing reactivation of other
introduction of PCP prophylaxis. 47 herpes viruses and may be more likely to prevent the indirect
effects of CMV. 48,50 Recently, the development of commercially
Late Postengraftment Period available CMV- specific IFN-γ release assays, which detect CMV-
This is the period of late immune recovery and ends when the specific T cells in whole blood, may allow for more precise target-
patient regains normal immunity. In the absence of chronic ing of prophylactic strategies, beyond those currently used. 55
GvHD, this period can last up to 2 years. Viral and bacterial
infections of the respiratory tract are common during this period. Other Herpes Viruses
The development of chronic GvHD delays immune restoration HSV infection is common in both SOT and HSCT recipients
and can extend this period for many years (as long as immunosup- during the first month after transplantation. Routine use of
pressive drugs are required). Infections with encapsulated bacteria antiviral prophylaxis has successfully decreased the incidence of
are common in patients with chronic GvHD, as well as oppor- severe HSV infection. However, breakthrough mucocutaneous
tunistic viral and fungal infections, including VZV and CMV HSV infection and even disseminated disease can still occur.
infections, invasive aspergillosis and non-Aspergillus mold Reactivation of VZV infection is also common; however, acyclovir
infections, and PJP, among others. 47 prophylaxis has decreased the incidence of disseminated VZV
infection significantly. Both severe VZV and HSV infections are
INFECTIONS OF PARTICULAR IMPORTANCE IN typically treated with intravenous acyclovir. 45,46
TRANSPLANT RECIPIENTS Although EBV can cause a wide spectrum of disease, EBV-
associated PTLD is the most feared complication. The term
Cytomegalovirus Infection EBV-associated PTLD is generally used to describe a heterogeneous
CMV is one of the most important pathogens affecting transplant group of clinical syndromes associated with uncontrolled
recipients. It is widely distributed in the general population; lymphoproliferation, which can result in true malignancies
seropositivity for CMV varies in different geographical regions containing clonal chromosomal abnormalities. Early diagnosis
48
and ranges from 30% to 97%. Before widespread use of interven- requires a high index of suspicion. EBV viral load monitoring
tions aimed at reducing the incidence of CMV disease (i.e., and radiological evaluation can assist in early diagnosis. Reduction
pneumonitis, gastroenteritis, hepatitis, etc.), it occurred frequently of immunosuppression should be the initial strategy in managing
during the first 3 months after transplantation. In SOT, the highest the disease. Timing of additional therapies, such as treatment
risk for CMV disease is in patients in whom the donor is seroposi- with antivirals and rituximab and chemotherapy, remains
−
+
tive and the recipient is seronegative for CMV (D /R ). CMV controversial. 45,47
has a predilection to invade the allograft, possibly as a result of HHV-6 has been associated with disease after transplantation,
an aberrant immune response within the graft. The risk of and although a variety of clinical manifestations have been
infection varies also with the type of transplantation; recipients described, the more convincing association is with encephalitis.
of lung, small intestine, and pancreas transplants have a higher The initial presentation may be subtle with memory loss or
risk, whereas the risk in liver and kidney recipients is lower. In disorientation. However, it may progress to severe mental status
SOT, CMV infection has been found consistently to be an abnormalities and seizures. The diagnosis is established with a
independent risk factor for other infectious complications as positive PCR in the CSF, and absence of other infectious agents.
48
well as graft rejection. In HSCT, infection is usually the result Treatment is with ganciclovir or foscarnet. 47
of reactivation of endogenous virus; hence the highest risk is in
seropositive recipients. Without prophylaxis, up to 80% of Invasive Filamentous Fungal Infections
seropositive recipients will experience CMV infection after HSCT. Invasive pulmonary aspergillosis is the most common invasive
Seronegative individuals have a 30–40% chance of becoming filamentous fungal infection. Dissemination, including to the
infected when receiving unfiltered blood products or stem cells brain, can occur and should be ruled out in all transplant
from a seropositive donor. Risk factors for CMV disease are recipients. Risk factors are prolonged neutropenia, high-dose
acute and chronic GvHD, use of high-dose corticosteroids, use corticosteroids, cord blood transplantation, CMV disease, GvHD,
of cord blood, T-cell depletion, and use of mismatched or graft rejection, and lung transplantation. Manifestations of fila-
unrelated donors. 49 mentous fungi that are almost exclusively seen in lung transplant
Typically, CMV viremia precedes CMV disease by 1–2 weeks; recipients are tracheobronchitis, characterized by ulceration and
therefore close monitoring of CMV reactivation by polymerase cartilage invasion, and bronchial anastomotic infections. 51
chain reaction (PCR) assays or pp65 antigenemia allows the Monitoring serum Aspergillus galactomannan in high-risk
detection of early replication, and therefore institution of patients, as well as computed tomography (CT) imaging, can
appropriate antiviral therapy (ganciclovir, valganciclovir, or assist in the early diagnosis of invasive aspergillosis. Despite early
foscarnet) before the development of end organ disease. This diagnosis and treatment, the mortality associated with invasive
51
approach, termed preemptive therapy, has the advantage of aspergillosis, in particular in HSCT, is still high. Antifungal
effectively decreasing the incidence of early CMV disease and prophylaxis should be considered in patients in whom prolonged
limiting drug-related toxicities. In addition, a limited amount neutropenia is expected, in patients with chronic GvHD receiving
of viral replication may allow for the development of CMV-specific high-dose corticosteroids, and in lung transplant recipients.
immune reconstitution. Preemptive therapy is the preferred Voriconazole is considered the drug of choice for invasive
49
method for preventing CMV disease in HSCT and is widely aspergillosis, but newer-generation azoles, such as posaconazole
used in SOT in patients with intermediate risk for CMV disease. and isavuconazole, are good alternatives.
CHaPtEr 37 Infections in the Immunocompromised Host 533
Fusariosis, mucormycosis, and dematiaceous and other mold such adenovirus and smallpox virus. Letermovir is a new, highly
infections are increasingly recognized as significant pathogens potent anti-CMV agent with a novel mechanism of action target-
in transplant recipients. Clinical disease can be similar to the ing the viral terminase subunit pUL56, a component of the
infection caused by Aspergillus spp., with largely sinopulmonary terminase complex involved in viral DNA cleavage and packaging.
disease. Fusarium spp. frequently disseminate hematogenously Initial trials have shown that letermovir is effective in reducing
and can be isolated in blood cultures. Many of these infections the incidence of CMV infection in allo-HSCT and has been used
54
are resistant to most antifungal drugs and remain an important successfully in MDR infections. Phase III clinical trials are
cause of transplantation-related mortality. 51 currently underway. There are other antivirals in the pipeline,
but they are at much earlier stages of development. Because of
Invasive Candidiasis the scarcity of effective, nontoxic antivirals and because uncon-
Before routine use of antifungal prophylaxis, invasive candidiasis trolled viral infections correlate with a lack of cellular immunity
was the most common invasive fungal infection in transplant against viruses, several groups are working on the development
recipients. In SOT, most Candida infections occur during the of adoptive immunotherapy, which is the artificial reconstitution
first month after transplantation, usually related to the surgical of virus-specific T cells with in vitro expanded T cells.
procedure. Recipients of liver, pancreas, and small bowel are A number of small studies have now shown that virus-specific
at high risk for invasive candidiasis; lung transplant recipients T cells are effective in controlling CMV, EBV, and adenovirus
51
can develop bronchial anastomotic infections. In HSCT, most infections in transplant recipients. The translation of adoptive
Candida infections occur in the preengraftment period and are immunotherapy into the clinic has been limited by technical
associated with mucosal injury, which results from the condition- difficulties associated with the generation of viral-specific cells
ing regimen and with the widespread use of antibiotics for the that are not alloreactive, that can be produced from naïve T cells,
treatment of fever and neutropenia. Fluconazole-resistant Candida and that can be developed rapidly and in a cost-effective way.
spp. are now increasingly isolated, and echinocandins (caspo- Cells obtained from the original donor can yield long-lasting
fungin, micafungin, and anidulafungin) are now considered the immunity, but the process of generating these cells can be
52
drugs of choice in invasive candidiasis. Antifungal prophylaxis cumbersome and often not available in a timely manner. Some
reduces the incidence of invasive fungal infections after HSCT, groups have explored adoptive transfer of HLA partially matched
as well as infection-related and overall mortality. In SOT, anti- virus-specific T cells derived from third-party donors, that is,
fungal prophylaxis is recommended for high-risk liver transplant healthy individuals other than the donor of the patient’s trans-
recipients and in small bowel and lung transplant recipients. plant. Such cells yield high number of virus-specific T-cells, but
55
these cells tend to be short lived. Currently, a few international
TRANSLATIONAL RESEARCH centers have established cryopreserved banks with virus-specific
T-cell lines from normal donors, but these are still mostly for
investigational use. Significant advances continue to be seen in
oN tHE HorIZoN the field of cellular therapy, and these could become part of the
armamentarium against viruses in the next decade.
• Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus
infections remain problematic infections in both hematopoietic-stem-cell
and solid-organ transplant recipients, and medications currently available CONCLUSIONS
to treat these infections have significant associated toxicities or lack
efficacy. Immunocompromised hosts are surviving longer as antimicrobials
• Adoptive immunotherapy, in which virus specific donor-derived T cells improve and as immunosuppressant agents become less toxic.
are expanded and infused into the transplant recipient, will likely become Both monogenetic primary immunodeficiencies and the increas-
more widespread in treating these infections.
ingly specific immunosuppressant agents allow insight into host
control of specific microbes. With this knowledge, new types of
Viral reactivation and disease are still a major cause of morbidity immunodeficiencies are being recognized, such as the autoan-
and mortality among transplant recipients. CMV, EBV, and tibody cytokine disorders described above. In addition, the
adenovirus are particularly problematic once disease develops. knowledge of specific host immunity will help in developing
Preemptive strategies have substantially decreased the incidence therapies to boost host responses in the increasing challenges
of invasive CMV disease; nevertheless, a significant number of of treatment-resistant microbes.
patients still go on to develop invasive disease. Preemptive therapy Please check your eBook at https://expertconsult.inkling.com/
and treatment are limited by the toxicity associated with the for self-assessment questions. See inside cover for registration
available antivirals and their lack of efficacy against EBV and details.
adenovirus. In addition, development of resistance can complicate
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and immunological spectrum of severe combined immunodeficiency. Eur pediatric autoimmune and inflammatory CNS disease. Neurology
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CHaPtEr 37 Infections in the Immunocompromised Host 534.e1
M u L t IPLE CH o ICE Q u ES t I o NS
1. Mucocutaneous candidiasis is thought to occur due to disrup- 3. Progressive multifocal leukoencephalopathy has been described
tion of interleukin-17 (IL-17) signaling. This is observed in in the following settings EXCEPT:
all of the following immunodeficiencies EXCEPT: A. Rituximab
A. Loss of function mutations in signal transducer and activa- B. GOF STAT1 mutations
tor of transcription 3 (STAT3) causing hyper IgE syndrome C. Natalizumab
(HIES) D. Chronic granulomatous disease (CGD)
B. CD40 ligand deficiency E. Human immunodeficiency virus (HIV)
C. Gain-of-function (GOF) STAT1 mutations F. Dedicator of cytokinesis 8 (DOCK8) deficiency
D. Autoimmune polyendocrinopathy with candidiasis and 4. Photosensitivity is associated with which antifungal?
ectodermal dysplasia (APOCED)
A. Fluconazole
2. Anticytokine autoantibodies are increasingly being recognized B. Caspofungin
as causing immunodeficiency. The following are described C. Posaconazole
associations EXCEPT: D. Voriconazole
A. Anti-interferon (IFN)-γ antibodies and disseminated E. Isavuconazole
nontuberculous mycobacteria
B. Anti–GM-CSF antibodies and Cryptococcus
C. Anti-IL-17 antibodies and mucocutaneous Candida
D. Anti-IFNγ antibodies and Staphylococcus aureus
E. Anti–granulocyte macrophage–colony-stimulating factor
(GM-CSF) antibodies and Nocardia
38
Immune Deficiencies at the Extremes of Age
Jӧrg J. Goronzy, Claire E. Gustafson, Cornelia M. Weyand
Age is a major factor determining the quality and quantity of for protection against possible infections and maternal–fetal
an immune response. This age dependency, apparent throughout rejection in utero are still reflected in the newborn infant immune
life, is most obvious at the extremes of age. Both infants and system, characterized by immune-suppressive, antiinflammatory,
older adults exhibit blunted immune responses to infections and immature cellular responses to foreign antigens. Although
and vaccination. However, the underlying mechanisms for newborns and young infants lack the ability to mount effective
immune dysfunction are distinct. Infants are born with limited immune responses against many pathogens, they acquire initial
antigen exposure and an immature immune system, which, immune protection through the passive transfer of maternal
however, progressively develops throughout infancy and child- immunoglobulin G (IgG) in utero via the placenta (termed
2
hood. The mechanisms underlying the immune dysfunction in “passive immunity”) and from secretory IgA and antimicrobial
older adults are broadly termed immunosenescence. The term is factors present in maternal breast milk. Alternations in passive
reminiscent of cellular senescence, which is defined as the loss immunity (e.g., preterm birth) can lead to increased susceptibility
of the ability to proliferate as a result of an irreversible cell cycle to infections and breakdown of immune tolerance in the infant.
block. However, it is misleading to interpret immune aging only Passive immunity can be enhanced by vaccination of pregnant
as the accumulation of senescent cells, and similar to aging in mothers to promote the transfer of vaccine-specific IgG in utero.
1
general, numerous pathways are involved. The decline in immune However, within the first months of life, as maternal IgG wanes
competence is not linear. As early as age 40 years, vaccine responses and breastfeeding is discontinued, infants must actively develop
to selected vaccines (e.g., hepatitis B) start to decline. The their own innate and adaptive immune responses to initiate and
incidence rate of herpes zoster, a reactivation of latent varicella- maintain immune protection. An overview of the development
zoster virus (VZV), starts to increase at age 50 years, as does of innate and adaptive cells, as well as the repertoire of diversity
morbidity and mortality from influenza infection. A more abrupt during aging, is outlined in Fig. 38.1.
transition appears to occur in the eighth decade of life.
In terms of public health, infections are major causes of INNATE IMMUNE DEVELOPMENT
morbidity in the very young and the very old. Although child
mortality rates have dropped by almost 50% between 1990 and The innate immune system is typically considered the first line
2013, pathogenic infections are still one of the largest causes of of defense against infection. The development of the innate
infant mortality worldwide, accounting for more than 1.6 million immune system begins in utero, with all the classic innate cells
deaths a year. Vaccinations have helped change the infectious types present by the end of the first trimester; monocytes and
landscape in children and young adults, but certain vaccines, dendritic cells (DCs) are the earliest cells observed at 4 weeks’
such as those against Streptococcus pneumoniae, still have limited gestation (WG) followed by granulocytes and natural killer (NK)
3
protective capacity at both extremes of age. Susceptibility to cells at 8 WG. These innate immune cells expand in number
pathogenic infection and ineffectiveness of vaccination is even and mature during gestation; however, at birth the functionality
greater in older adults than in young infants. Moreover, during of innate immune cells is still diminished significantly compared
aging, a functional immune system is important for tissue repair with later in life.
and is of increasing importance in degenerative diseases, and it
is vital for cancer surveillance. Immunosenescence is of increasing DYSFUNCTION OF INNATE IMMUNE CELLS
importance because of the changing population demographics,
with increases in the number of individuals older than 65 years During early infancy, all cell types of the innate immune system
in both developed and developing countries. demonstrate some impairment of function, ranging from reduced
mobility to skewed cytokine production in response to innate
INFANCY AND THE GENERATION OF immune stimulation. The most significant functional limitation
AN IMMUNE SYSTEM of neonatal innate immune cells is their collective inability to kill
pathogens. Limited chemotaxis in neutrophils is accompanied by
Infants first start to develop their immune system in utero, a reduced ability to effectively kill pathogens as a result of poor
maintaining a fine balance between immunological tolerance phagocytosis and decreased secretion of neutrophil extracellular
that helps prevent proinflammatory responses in utero and the traps under inflammatory conditions, which in combination
ability to respond to foreign antigen exposure upon birth. results in decreased killing of infectious pathogens. Moreover,
Immunosuppressive regulatory pathways utilized by the fetus NK cells and plasmacytoid DCs have reduced capacity to prevent
535
536 Part four Immunological Deficiencies
Development Homeostasis Dysfunction
Innate cells
Frequency Monocytes
Dendritic cells
Natural killer (NK) cells
B cells Maturnal Ab (lgG)
Frequency Class-switched Ab
Naive/Transitional
Class switched memory
T cells
RTE
Naïve CD4 T cells
Frequency CD4 Tregs
Naïve CD8 T cells
Memory T cells
Receptor repertoire NK cells (+/- receptors)
Naïve B cells (BCR specificity)
Diversity Naïve T cells (TCR specificity)
Memory B cells (BCR specificity)
Memory T cells (TCR specificity)
Birth 1 5 30 60 80 years
Age
fIG 38.1 Innate and Adaptive Immune Cell Frequencies and Receptor Repertoire Diversity
During Aging. The frequencies of different innate and adaptive B and T cells changes over the
course of a lifetime (upper three panels). In addition to compartment size, diversity of antigen
receptors is essential for immune function. During infancy, diversity of immune populations
expands and is then maintained during adulthood (lower panel). Aging is characterized by the
general decline in diversity within naïve B- and T-cell populations. Dotted lines indicate that the
progression of these populations is either controversial or unknown.
infection through reduced cytotoxic function and lower secre- that although lymphocytes initially develop within the fetal liver
tion of interferon- (IFN-α), respectively. In addition, antigen- (≈7 WG) and then in bone marrow (≈12 WG), T-cell maturation
presenting cells (APCs) are unable to provide effective help to T occurs in the thymus, and B cells continue maturation in bone
cells because of reduced expression of costimulatory molecules marrow in utero and after birth. Over the course of gestation,
and skewed cytokine production toward more antiinflammatory, both naïve T- cell and B-cell compartments expand, reaching
T-helper 2 (Th2)–inducing cytokines, such as interleukin-6 (IL-6). absolute cell concentrations greater than that of the adults by
These combined limitations during early infancy lead to increased birth. Thus a defect in cellular generation cannot account for
susceptibility to viral and bacterial infections and also contribute the immune limitations observed in infants. However, the
to the reduced functionality of adaptive immune cells. composition of the each lymphocyte population within young
infants is distinct from that of adults. At birth, both the newborn
KEY CoNCEPtS infant T- and B-cell compartments consist mainly of naïve and
Characteristics of the Developing Innate immature cells recently migrated out of the thymus or bone
marrow (>90% of the population). Both infant T- and B-cell
Immune System repertoires have less diversity within their receptors’ antigen-
binding regions compared with those of adults. T-cell receptors
• Reduced antibacterial responses (i.e., phagocytosis, secretion of
neutrophil extracellular traps [NETs]) by neutrophils and monocytes display reduced V-J complexity and fewer amino acid additions.
• Impaired neutrophil chemokinesis (“directed movement”) In addition, B cells have decreased B-cell receptor diversity because
• Diminished capacity of antigen-presenting cells (APCs; i.e., dendritic of less affinity maturation (i.e., somatic hypermutation; Chapter
cells [DCs]) to provide proper costimulatory help to T cells 7) compared with adult populations.
• Reduced antiviral responses (i.e., interferon (IFN)-α secretion) by The increased levels of recent thymic emigrants and naïve T
plasmacytoid dendritic cells (pDCs)
cells are maintained both in the periphery and in tissues during
early infancy. Effector memory T cells can be found selectively
ADAPTIVE IMMUNE DEVELOPMENT in the lungs and gastrointestinal (GI) tract of young infants,
likely because these mucosal tissues are the earliest sites of antigen
Adaptive immune cells (T and B cells) begin to develop in utero exposure. Class-switch antibodies produced by B cells are required
around the start of the second trimester. It is important to note for mucosal protection (primarily IgA) and systemic protection
CHaPtEr 38 Immune Deficiencies at the Extremes of Age 537
(primarily IgG) through opsonization, neutralization, or antibody- The reduced antibody titers observed during infancy can be
dependent cellular cytotoxicity (ADCC). However, infants accounted for by the functional inability of infant B cells to
demonstrate significantly lower levels of IgG and IgA compared undergo class-switching from IgM to IgA or IgG upon antigen
5
with adults throughout the first year of life, in both the periphery stimulation and the poor survival of antibody-secreting plasma
and mucosae. cells within the infant bone marrow. Moreover, infant B cells
have lower rates of somatic hypermutation compared with those
INFANCY AND FUNCTIONAL DIFFERENTIATION OF of adults, which is important for affinity maturation and the
ADAPTIVE IMMUNE CELLS generation of high-affinity antibodies. Although these defects
can be partially attributed to extrinsic T-cell defects, such as
The acquisition of a mature adaptive immune system requires poor Tfh generation, intrinsic defects in infant B cells (e.g., lack
exposure to antigens for cells to form immunological memory. of costimulatory molecules and receptors to T cell–independent
Not only are infants born with limited antigen exposure and thus factors) also prevent effective antibody responses. Collectively,
little memory, infant responses to antigenic stimulation in the these neonatal B-cell defects lead to less effective and shorter-lived
T- and B-cell compartments display altered functions compared antibody responses against infectious pathogens and vaccines
with that of adults. The most striking alterations are seen within during early infancy.
the CD4 T-cell compartment, characterized by significantly
increased frequency of immunosuppressive T regulatory cells KEY CoNCEPtS
4
(Tregs; 30–40% in infants vs 1–10% in adults). These changes
accompany increased Th2 subsets and defective differentiation Characteristics of the Developing Adaptive
to effector Th1 and T-follicular helper (Tfh) cells during early Immune System
infancy. Moreover, decreased expression of Lck in infant CD4 T • High frequencies of naïve and immature T and B cells
2
cells leads to decreased T-cell activation upon antigen exposure. • Skewing of CD4 T-cell population towards immunosuppressive regula-
Altered differentiation of CD4 Th subsets and blunted T-cell tory T cells and T-helper 2 (Th2) cells
activation promotes a tolerance-inducing environment good for • Reduced functionality and memory responses of CD8 T cells to viral
controlling unnecessary responses to foreign antigen exposure infections
after birth. However, it also leads to inhibition of effective cytotoxic • Limited ability of B cells to produce high-affinity, class-switched antibod-
T cells and limits B-cell antibody responses against infectious ies in response to both T cell–dependent and T cell–independent
antigens
pathogens and to vaccination (Fig. 38.2).
Infant Adult Elderly
Host environment
Anti-inflammatory Pro-inflammatory
History of antigen exposure
Monocytes
TLR TLR TLR
INNATE
IL-10, IL-6, IL-12, TNFa,, TNFa,
IL-23 IL-1b IL-1b, IL-6
CD4 T cells TLR TCR TCR
PD-1 PD-1
CD40L Treg, Th2 CD40L Th1 CD40L Th17
ADAPTIVE B cells CD21 BCR CD21 BCR CD21 BCR
CD11c
↓CSR CSR ↓CSR
↓SHM SHM SHM
TACI TACI ↓IgG, IgA
IgM IgG, IgA
↑autoAb
fIG 38.2 Innate and Adaptive Immune Cell Functionality During Aging. The infant immune
environment is distinctly antiinflammatory characterized by altered Toll-like receptor (TLR) signaling
from monocytes, blunted T-cell and B-cell receptor (TCR/BCR) signaling, and skewing toward T
regulatory cells (Tregs). Infant B cells are incapable of class-switch recombination (CSR) or affinity
maturation via somatic hypermutation (SHM) upon antigen exposure. Altered monocyte TLR
signaling and altered function of adaptive immune cells is also observed in older adults, but with
a distinct, more proinflammatory outcome.
538 Part four Immunological Deficiencies
INFANT IMMUNE DEVELOPMENT AND CLINICaL rELEVaNCE
THE MICROBIOME Consequences of Immaturity of the Developing
One of the first environmental exposures that infants experience Immune System
is with colonizing bacteria. Within hours after birth, the infant • Increased morbidity and mortality from bacterial infections (e.g.,
intestinal tract is colonized with nonpathogenic bacteria (termed pneumococci)
“microbiome”; Chapter 14). The microbiome can reach concentra- • Increased morbidity and mortality from viral infection (e.g., influenza
10
tions of 10 bacteria per gram of stool by age 7 days, but only virus, respiratory syncytial virus [RSV])
mirrors an adult-like composition after age 2 years. Early studies • Ineffective primary vaccinations; multiple boosters required for most
in animal models demonstrated that microbial colonization is vaccines to elicit effective protection
essential for the normal development of the immune system • Susceptibility to allergy and asthma when microbiome colonization
disrupted during early infancy
6
during early infancy and throughout life. In particular, IgA,
the most abundant antibody within the GI tract, requires
the presence of colonizing bacterial for its development and
long-term maintenance. Moreover, the specific composition of
the microbiome influences the generation of innate lymphoid neutrophils, which have a short half-life, the body needs to
10
cells, CD4 T-cells subsets (e.g., Treg, Th17, Tfh), and anti- produce ≈10 cells/kg per day. Additionally, for lymphocytes,
body development. Perturbations in the infant microbiome, which are more long-lived but are also more numerous because
caused by such factors as mode of delivery, antibiotic treat- of their wider tissue distribution, the daily need is in the order
ment, and diet, may significantly alter developing immune of several billion cells. Studies in the 1960s showed that the
responses. hematopoietic tissue in bone marrow decreases with age. A similar
+
+
It has been described that babies delivered via C-section have decline is seen for the frequencies of peripheral CD34 CD45
a microbiome composition distinct from vaginally delivered hematopoietic stem cells (HSCs). In addition to these numerical
7
babies, the latter dominated by skin bacteria (e.g., Staphylococcus) differences, the functional potential of HSCs changes with age.
instead of vaginal bacteria (e.g., Lactobacillus, Prevotella). These Old HSCs exhibit a reduced capacity to regenerate the hemato-
differences correlated with an increased incidence of allergy and poietic system. Telomerase expression in peripheral HSCs is not
asthma during childhood suggesting a causal link between fully protective, and a shortening in telomeric length is seen
microbiome and susceptibility to allergies. These findings are with age, similar to differentiated mononuclear cells. Lymphoid
preliminary and more evidence is needed to support the notion differentiation potential diminishes with age in favor of myeloid
that the microbiome influences the development of the infant differentiation as a result of altered lineage specification programs
immune system. driven by DNA damage and epigenetic changes. This shift may
contribute to the clinical observation that HSC-derived leukemia
CLINICAL CONSEQUENCES FOR preferentially has a lymphoid phenotype in the young and a
CHILDHOOD VACCINATION myeloid one in older adults.
Newborn and young infants are highly susceptible to pathogenic
infection during the first months to year of life. Indeed, infections KEY CoNCEPtS
are one of the major causes mortality, accounting for more than Aging Influences Immune Cell Generation and
24% of global infant mortality. More than 1 million deaths per Population Homeostasis
year are caused by respiratory tract infections (e.g., Streptococcus
pneumoniae, Haemophilus influenzae type b, respiratory syncytial Aging influences immune cell generation and population homeostasis.
virus [RSV]) and almost the same amount by intestinal infections • Hematopoietic stem cells (HSCs) are reduced in frequency and biased
toward myeloid lineages and against lymphoid lineages.
(e.g., rotavirus, Escherichia coli). The development and distribution • Myeloid cell generation is largely intact.
of vaccines targeting these pathogens have significantly reduced • B-cell generation declines and B-cell repertoire selection is disturbed.
infant infection rates and subsequent mortality; however, vaccine • As a result of thymic involution, naïve T cells are generated from
efficacy can vary, depending on the infant’s gestational age at birth, homeostatic proliferation of peripheral T cells.
mode of vaccine delivery (oral vs intramuscular), interference • Ability to rebuild a T-cell repertoire after lymphocyte-depleting interven-
by maternal antibodies acquired through passive immunity and tions is severely compromised after mid-adulthood.
via breast milk, and immaturity of infant immune responses, as • Virus-specific effector T-cell population accumulates.
described above. Additionally, infants require multiple vaccine
boosters to elicit and maintain robust protective immunity against
infectious pathogens (Chapter 90). Better understanding of the As a consequence, lymphocyte replenishment is more affected
limitations of the human infant immune system that prevent by age than that of myeloid lineages. Peripheral neutrophil
effective immune responses, particularly at mucosal sites where numbers do not decline and are able to recover after therapy-
these pathogens initially infect, would facilitate the generation of induced depletion (e.g., chemotherapy). Furthermore, there is
better vaccines designed to overcome these limitations and induce no loss in the ability to generate robust neutrophilia in response
more rapid and robust immune protection during early infancy. to infection or other stressors.
In addition to HSC-intrinsic alterations in lineage commit-
OLDER AGE AND IMMUNE CELL GENERATION ments, defects in bloodborne factors and bone marrow niches
8
contribute to a decline in B-cell generation. As a consequence,
The immune system is in constant demand for cellular replenish- recovery after B-cell depletion (e.g., treatment with anti-CD20
ment to compensate for peripheral losses and cell death. For antibodies to treat B-cell malignancies or autoimmune diseases) is
CHaPtEr 38 Immune Deficiencies at the Extremes of Age 539
incomplete and delayed in older adults. Moreover, the frequency of VZV-specific CD4 memory T cells has been postulated to
of typical memory B cells expressing CD27 declines, whereas explain this lack in viral control mechanisms. In contrast, EBV
other B-cell subpopulations increase. In particular, a functionally and CMV infections only relapse in severely immunocompromised
distinct B-cell population that responds to Toll-like receptor individuals, but not during normal immune aging. The immune
9
(TLR) stimulation has been described. These age-associated system commits extraordinary resources to controlling CMV,
differences in B-cell selection and expansion may contribute to and CMV-specific CD8 T cells can make up a large fraction of
monoclonal gammopathies (in >5% of individuals older than 70 the entire T-cell repertoire. Whether this memory inflation has
years; Chapter 80) or increased autoantibodies with increasing age. broader implications for immune health remains a matter of
High-throughput sequencing of Ig genes has the promise to provide controversy. Expansion of the CMV-specific T cells may com-
insights into the age-associated decline in B-cell responses at the promise the size of naïve and central memory T cell repertoires;
single-cell level. Data so far have indicated that older individuals however, many of the CMV-specific CD8 T cells have the phe-
have prevaccination-expanded B-cell populations that have a notype of end-differentiated effector T cells that lack the expres-
high mutation load and are further expanded with vaccination, sion of CCR7, CD28, and CD27 and therefore do not compete
suggesting that the B-cell response in older individuals relies on for the same space as naïve cells.
+
−
the adaptation of a restricted repertoire of memory sequences. CD45RA CD28 end-differentiated T cells express negative
T-cell generation is more affected by age than any other regulatory receptors of the killer lectin-like receptor (KLR), killer
myeloid or lymphoid lineage because of the involution of the immunoglobulin-like receptor (KIR), and immunoglobulin-like
thymus. The thymus undergoes dramatic structural changes that transcript (ILT) families that appear to constrain their otherwise
10
begin during childhood and puberty. Thymopoietic niches unopposed expansion. In spite of these inhibitory receptors, these
disappear, and the numbers of thymic epithelial cells and thy- cells are competent effector T cells capable of producing inflam-
mocytes decline. In parallel, the thymic perivascular space matory cytokines and therefore possibly contributing to inflam-
+
increases. One major structural change that does not appear to mation in older adults. End-differentiated CD45RA effector T
13
be a compensatory response but, rather, is an active and regulated cells should be distinguished from exhausted CD8 T cells. T-cell
developmental step in thymic organ transformation is the exhaustion is seen with chronic stimulation by highly replicating
accumulation and infiltration of adipocytes in the perivascular viruses or tumor cells and characterized by the expression of
space. Thymic resection in children undergoing cardiac surgery inhibitory receptors programmed death 1 (PD-1), T-cell immu-
reproduces many of the T-cell repertoire changes in 20-year-old noglobulin and mucin-domain containing-3 (TIM-3), and
14
individuals that are usually seen in 70- to 80-year-olds, confirming lymphocyte activation gene 3 (LAG3). T-cell exhaustion is not
that thymic production during the growth period of childhood a general feature per se of T-cell aging.
and adolescence is important. However, throughout adulthood,
homeostatic proliferation of naïve T cells accounts for the bulk INFLAMMATION, AGING, AND THE AGING
11
of T-cell generation. For human CD4 T cells, this process is HOST ENVIRONMENT
robust, and frequencies of naïve CD4 T cells only moderately
decline with age. In contrast, the naïve CD8 T-cell compartment The aging host environment is characterized by the continuous
clearly shrinks. However, repertoire diversity (i.e., the number presence of inflammatory mediators independent of acute or
15
of different T-cell receptors [TCRs]) remains very high for both chronic disease (Fig. 38.3). Even for the healthy older adult,
naïve CD4 and CD8 T-cell subsets, suggesting that thymic activity IL-6 and tumor necrosis factor (TNF) serum levels are twofold
is not necessary to prevent holes in the repertoire once a repertoire to fourfold higher than in young adults. Low-level systemic
has formed. Strategies to reactivate thymic T-cell generation will inflammation plays an important role in the progression of several
be more important in older patients who cannot restore the age-related diseases, including Alzheimer disease, atherosclerosis,
naïve T-cell repertoire after a medical intervention, such as and cancer. Moreover, inflammatory markers are associated with
chemotherapy or bone marrow transplantation, compared with several conditions that are characteristic of older adults. IL-6
their healthy counterparts. serum concentrations have been correlated with loss of mobility
and advent of disability; increased mortality of older individuals
T-CELL POPULATION HOMEOSTASIS has been shown among those who have higher levels of TNF-α.
Increased IL-6 and cross-reactive protein (CRP) serum levels
The adaptive system responds to antigenic challenges with clonal and increased white blood cell (WBC) counts, presumably
expansion and differentiation into effector cells followed by clonal resulting from increased production of neutrophils, predispose
downsizing and persistence of long-lived memory T cells. Infec- to, and are associated with, frailty. A causative relationship may
tions therefore leave a permanent imprint on the immune system, also exist between the increased production of IL-6 or TNF-α
a mechanism on which vaccinations capitalize. However, the and the age-associated loss in muscle mass, eventually presenting
pathogen-induced clonal expansion also represents a challenge as sarcopenia. Long-lived individuals, such as centenarians, tend
to homeostatic mechanisms that are supposed to maintain a to have lower levels of proinflammatory cytokines and increased
12
balance among naïve, memory, and effector cells. This is levels of antiinflammatory mediators, such as cortisone and IL-10,
particularly evident in persisting infections where the offending supporting the concept that low-level inflammation is detrimental
pathogen cannot be cleared. Herpes virus infections are highly to healthy aging.
prevalent in an apparently healthy population without causing Production of inflammatory cytokines is driven by several
active disease, as they establish latency. Classic examples are mechanisms. Failure of the adaptive immune system leads to a
varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and less effective control of chronic viral infections as well as incom-
cytomegalovirus (CMV). The effects of these herpes viruses with plete response to exogenous challenges, resulting in increased
immune aging differ greatly; VZV tends to relapse with age, with and prolonged innate immune activation. Defective epithelial
reactivation presenting as shingles. A decrease in the frequency barrier function, as well as decline in the mucosa-associated
540 Part four Immunological Deficiencies
Defective GALT
Inflammatory mediators
Epithelial dysfunction TNF-α, IL6 Tissue degeneration
Age-associated
adipogenesis
Increase in PAMPs Senescence-associated
and alarmins gene activation
Accumulation of
effector T cells
Defective innate immunity Frailty Coronary artery disease
fIG 38.3 Inflammation in Older Adults. The schematic diagram depicts possible mechanisms
that account for the increased production of inflammatory mediators with age. These mediators
contribute to many of the age-associated diseases.
lymphoreticular tissue (MALT), results in increased leakage and signaling pathways. Low responsiveness to cytokine stimuli is
increased systemic levels of lipopolysaccharide (LPS) and innate frequently seen in those cells that have increased baseline activa-
immune activation. Failure in maintaining T-cell population tion of a signaling pathway (e.g., cells that constitutively have
homeostasis and accumulation of effector T cells also favors an increased signal transducer and activator of transcription 3
inflammatory response. (STAT3) or STAT1 phosphorylation respond less to IL-6/granu-
locyte macrophage–colony-stimulating factor (GM-CSF) or type
KEY CoNCEPtS I/II IFNs, cytokines that activate these STATs). Attenuation of
Causes for Increased Constitutive Production of signaling pathways by induction of negative feedback loops
explains, in part, the reduced responsiveness and functionality
Inflammatory Mediators With Age (Inflammation of cells of the innate immune system.
in Older Adults) Although neutrophil and monocyte/macrophage numbers
17
• Activation of the innate immune system as a result of defective epithelial remain normal, many of their functions decline with age.
barrier function Decreased chemotaxis in neutrophils delays tissue infiltration;
• Activation of the innate immune system as a result of defective adaptive reduced phagocytosis and respiratory burst compromise the
immunity ability to control bacterial infections; and TLR-induced monocyte/
• Accumulation of adipocytes producing inflammatory mediators macrophage activation is dampened in older adults. Declines in
• Accumulation and activation of T-effector cell populations responsiveness, for example, to TLR stimulation, are partly
• DNA damage-induced transcription of inflammatory cytokine genes reversible in vitro, suggesting that they are not intrinsic. Adaptive
in senescent cells
immune cells are also directly affected by the proinflammatory
environment in the aging host.
The immune system, however, is not the only source of Equally important are cell-intrinsic changes that appear to
inflammatory cytokines. Adipocytes, in part replacing muscle be a consequence of the replicative history and failures in cellular
cells in older adults, produce various inflammatory mediators. processes, such as DNA repair and autophagy. The program
Cellular senescence has also been associated with the production most obviously influenced by age is cellular senescence. In all
of cytokines. Persistent DNA damage response signaling not hematopoietic cell lineages, including stem cells, telomeric lengths
only induces an irreversible cell cycle block that is characteristic decline with age. This is of particular importance for T cells
of cellular senescence but also initiates a transcriptional program because much of their response depends on their ability to
18
to secrete numerous growth factors, proteases, and inflammatory proliferate and clonally expand. Telomeric erosion results not
cytokines, termed the senescence-associated secretory phenotype only from cumulative replicative history and DNA damage but
(SASP). 16 also from decline in the ability to express telomerase and repair
telomeric ends.
CELLULAR DEFECTS AND SENESCENCE Lymphocytes in older adults are more differentiated than
those in the young. Although most obvious for CD8 T cells,
As described so far, immune aging occurs at the system level increasing differentiation can also be noted for B cells and CD4
with organizational restructuring. Equally important are changes T cells (Fig. 38.4). Differentiation is generally driven by antigen
at the single-cell level, which are partly cell-intrinsic and partly recognition but could also occur in the absence of exogenous
caused by the host environment. The increased cytokine con- antigen under the influence of cytokines. Proliferation alone
centrations in older adults not only activate but also attenuate may be sufficient to drive initial steps of differentiation. A classic
CHaPtEr 38 Immune Deficiencies at the Extremes of Age 541
Infant Elderly
Up
TCR TCR
CD4 CD4 Down
Lck Zap70 Lck Zap70
PLC pERK DUSP6
miR-181a
T cell activation T cell activation
Internal changes
Telomere length +++ +
DNA damage + +++
Epigenetic modifications + +++
Functional outcomes
Proliferation capacity +++ ++*
T cell activation + +
Effector function + +*
+ = low ++ = normal +++ = high *controversial
fIG 38.4 Intrinsic Differences in CD4 T Cells at the Extremes of Age. CD4 T cells from infants
and older individuals demonstrate similar dysfunctions, including poor activation and reduced
effector functions, although as a result of distinct mechanisms. Signaling cartoons illustrate the
best documented defects. Moreover, infant and older adult T cells have very different internal
changes to their DNA, including telomere length, the amount of DNA damage, and epigenetic
modifications.
KEY CoNCEPtS activation of naïve T cells. Changes in cell surface molecules
Cellular Dysfunction With Age that are seen with terminal differentiation, such as the gain in
CD57 and the loss of CD27 and CD28 expression, are the most
• Exposure to aging host environment (e.g., inflammatory cytokines) striking. Of functional importance, predominantly for CD8 T
activates negative regulatory signaling loops. cells, is the gain in expression of cell surface receptors that are
• Telomeric erosion impairs proliferative competence and restraints usually only found in NK cells. Most of these receptors have
clonal expansion. inhibitory function, but some of them also stimulate. Since
• End-differentiation reduces functional plasticity. expression of these receptors on individual cells is stochastic,
• Activation of specific gene programs modifies cell function: the consequences can range from immunosuppression to
• Gene programs associated with differentiation (e.g., microRNA
[miRNA]) autoreactivity.
• Gene programs associated with T-cell exhaustion (e.g., expression
of programmed death-1 [PD-1])
• Loss of CD28 on T cells CLINICAL CONSEQUENCES OF IMMUNE AGING—
• Gain in natural killer (NK) cell–associated regulatory receptors on IMMUNODEFICIENCY, AUTOIMMUNITY, AND
T cells (e.g., killer immunoglobulin-like receptor [(KIR], killer lectin-like
receptor [KLR], immunoglobulin-like transcript [ILT]) ACCELERATED DEGENERATIVE DISEASES
• Senescence-associated gene activation (e.g., inflammatory
mediators) The most profound and most noted consequence of human
senescence is the increased susceptibility to infections. Upper
respiratory bacterial and urinary tract infections are frequent in
the older population and less contained by the innate immune
example is the acquisition of memory-like and effector phenotypes system and preexisting adaptive immunity. Not surprisingly, the
with lymphopenia-induced homeostatic proliferation. So-called immune system of an older adult is not able to induce a protective
virtual memory cells, which presumably have never seen an response to new antigens to which the individual has not been
exogenous antigen, have been identified in mouse models; clonal exposed to in the past. Clinically important examples are the
expansions are also seen within the human naïve T-cell compart- severe acute respiratory syndrome (SARS) epidemic and West
ment. Some of the changes in gene expression that are seen in Nile fever virus infection. First-time vaccinations with live viruses,
naïve T cells with age may represent partial differentiation, such for example, yellow fever virus, are associated with increased
as declines in the microRNA miR181a and changes in the expres- morbidity and even mortality in older adults. Despite annual
18
sion of phosphatases and other signaling molecules. Increased vaccination, influenza infections continue to be associated with
expression of cytoplasmic phosphatases impairs the TCR-induced high morbidity and mortality. Pneumonia caused by RSV, usually
542 Part four Immunological Deficiencies
infecting young children, is not uncommon. Immune competence that includes antigen-receptor specificities to respond to vaccina-
to chronic infections is also compromised with age. The best tion. Repertoire contraction resulting from thymic involution or
example here is the reactivation of VZV manifesting as shingles. memory inflation appears to be less severe than originally thought,
and currently explored interventions to restore thymic activity
CLINICaL rELEVaNCE may only be meaningful for selected populations, such as bone
marrow recipients. Deficiency in the antigen-presenting system
Consequences of Immune Aging and in costimulatory signals may be overcome by identifying
new adjuvants. Increasing the vaccine dose is another promising
• Increased morbidity and mortality from bacterial infections (e.g.,
pneumococci) approach. Live vaccines or self-replicating constructs that also
• Increased morbidity and mortality from viral infections (e.g., influenza, accomplish higher antigen loads may not have a sufficient safety
West Nile fever) profile in older adults. Direct targeting of signaling defects in
• Reactivation of latent virus (e.g., varicella zoster virus) older T cells resulting from increased expression of cytoplasmic
• Ineffective primary and booster vaccinations phosphatases or inhibitory cell surface receptors will be fea-
• Acceleration of degenerative diseases as a result of the production sible, as shown for checkpoint inhibitors in oncology; however,
of inflammatory mediators (e.g., atherosclerotic disease, Alzheimer such approaches need to demonstrate a much better safety
disease, osteoarthritis)
• Increased incidence of autoimmune disease (e.g., polymyalgia rheu- profile.
matica, giant cell arteritis, rheumatoid arthritis) Interventions to influence inflammation in older adults at
present needs to be nonspecific, given the multitude of underlying
mechanisms. Immunomodulatory therapy is obviously standard
Vaccinations against pneumococcal antigens, influenza strains, practice in patients with autoimmune disease who exhibit
and VZV are recommended in older adults; however, the efficacy accelerated aging and increased all-cause mortality. Calorie
of vaccination is reduced. restriction to slow immune aging to an extent that it is effective
Immune aging also predisposes for autoimmune manifestations is generally not well accepted. Statins and aspirin are being
19
and a breakdown in self-tolerance. Autoantibodies are a common routinely used to prevent cardiovascular disease; their effect may
finding in healthy older adults; many of these autoantibodies be mostly antiinflammatory. Future interventions will require
are specific for common autoantigens, such as IgG Fc or nuclear the development of mild and low-toxicity medications to reduce
components. The risk for several autoimmune diseases, most low-grade inflammation while not impairing the ability to prevent
notably polymyalgia rheumatica and giant cell arteritis, increases innate immune activation in response to harmful antigens.
with age. Although polymyalgia rheumatica predominantly
presents as an activation of innate immunity, giant cell arteritis oN tHE HorIZoN
is clearly a disease of the adaptive immune system with T
cell–dependent granulomatous inflammation in the vascular wall • Improved vaccination strategies tailored to the infant or aged immune
of midsized and large arteries. system (novel adjuvants, novel vaccine delivery systems)
The low-grade inflammation in the aging host has direct • New vaccines for pregnant females to confer passive immunity
• Manipulation of the microbiome composition to influence immune
clinical consequences in promoting frailty and sarcopenia and system development
accelerating degenerative diseases, including coronary artery • Thymic rejuvenation (e.g. with KGF, IL-7 and other mediators)
disease, osteopenia, and Alzheimer disease. Accelerated immune • Prevention of chronic infection that accelerate immune aging (e.g.
aging may be one of the reasons that autoimmune diseases, such immunization for CMV)
as rheumatoid arthritis (RA), are associated with a shorter life • Pharmacological approaches to improve T and B cell activation, clonal
expansion and differentiation
span and increased risk for cardiovascular morbidity. Inflam- • Treatment of inflamm-aging
mation as a manifestation of accelerated aging has been also
implicated in the increased morbidity and mortality of patients
with HIV infection in spite of highly active antiretroviral therapy Please check your eBook at https://expertconsult.inkling.com/
(HAART). 20 for self-assessment questions. See inside cover for registration
details.
STRATEGIES AND INTERVENTIONS ON
THE HORIZON REFERENCES
Vaccinations hold the promise for reducing increased susceptibility 1. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell
to infections in young children and older adults, but improving 2013;153(6):1194–217.
vaccine responses has proven to be a challenge. Current strategies 2. Basha S, Surendran N, Pichichero M. Immune responses in neonates.
for targeting more elusive pediatric pathogens (e.g., RSV) included Expert Rev Clin Immunol 2014;10(9):1171–84.
maternal vaccination (i.e., the mother is vaccinated during 3. Gollwitzer ES, Marsland BJ. Impact of Early-Life Exposures on Immune
pregnancy and vaccine-specific IgG is transferred in utero to the Maturation and Susceptibility to Disease. Trends Immunol
infant) and the development of infant-specific vaccine adjuvants 2015;36(11):684–96.
utilizing newer understanding of the developing infant immune 4. Simon AK, Hollander GA, McMichael A. Evolution of the immune system
system. Also, further investigations into the role of microbiome in humans from infancy to old age. Proc Biol Sci 2015;282(1821):20143085.
and immune development (or dysfunction) may open new 5. Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of
age. Nat Rev Immunol 2009;9(3):185–94.
strategies to influence immune system development to reduce 6. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune
immune deficiencies and prevent inappropriate hyperactivity. responses during health and disease. Nat Rev Immunol 2009;9(5):313–23.
In older adults, a proper T-cell response to infectious organisms 7. Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell
or to vaccines depends on the availability of a T-cell repertoire compartment. Nat Rev Immunol 2013;13(5):376–89.
CHaPtEr 38 Immune Deficiencies at the Extremes of Age 543
8. Kogut I, Scholz JL, Cancro MP, et al. B cell maintenance and function in 14. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell
aging. Semin Immunol 2012;24(5):342–9. exhaustion. Nat Rev Immunol 2015;15(8):486–99.
9. Naradikian MS, Hao Y, Cancro MP. Age-associated B cells: key mediators 15. Kanapuru B, Ershler WB. Inflammation, coagulation, and the pathway to
of both protective and autoreactive humoral responses. Immunol Rev frailty. Am J Med 2009;122(7):605–13.
2016;269(1):118–29. 16. Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the
10. Palmer DB. The effect of age on thymic function. Front Immunol senescent secretory phenotype: therapeutic opportunities. J Clin Invest
2013;4:316. 2013;123(3):966–72.
11. Goronzy JJ, Fang F, Cavanagh MM, et al. Naive T cell maintenance and 17. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation
function in human aging. J Immunol 2015;194(9):4073–80. of innate immunity. Nat Rev Immunol 2013;13(12):875–87.
12. Nikolich-Zugich J, Li G, Uhrlaub JL, et al. Age-related changes in CD8 T 18. Goronzy JJ, Weyand CM. Understanding immunosenescence to improve
cell homeostasis and immunity to infection. Semin Immunol responses to vaccines. Nat Immunol 2013;14(5):428–36.
2012;24(5):356–64. 19. Goronzy JJ, Weyand CM. Immune aging and autoimmunity. Cell Mol
13. Akbar AN, Henson SM. Are senescence and exhaustion intertwined or Life Sci 2012;69(10):1615–23.
unrelated processes that compromise immunity? Nat Rev Immunol 20. Deeks SG. HIV infection, inflammation, immunosenescence, and aging.
2011;11(4):289–95. Annu Rev Med 2011;62:141–55.
CHaPtEr 38 Immune Deficiencies at the Extremes of Age 543.e1
M u L t IPLE-CH o ICE Q u ES t I o NS
1. The developing immune system is characterized by: B. Vaccinations with live viruses (e.g., yellow fever vaccine)
A. Increased frequencies of regulatory T cells. are potentially harmful.
B. Innate immune system activation. C. Only booster, but not primary, vaccine responses are
C. Frequent presence of autoantibodies caused by tolerance impaired in older individuals.
defects. D. Vaccinations even with inactivated or component vaccine
D. Hematopoietic stem cells preferentially differentiating into carry a higher risk in older adults.
myeloid and not lymphoid lineages.
4. T cells are derived from hematopoietic stem cells that dif-
2. An inflammatory environment in older adults is: ferentiate in the thymus. Which of the following statements
A. Less pronounced in frail older adults. is correct?
B. Caused by thymic involution. A. Thymic involution leads to a rapid loss of naïve T cells.
C. Characterized by the production of cytokines from various B. Upon thymic involution, peripheral homeostatic prolifera-
cell types. tion of existing T cells to is effective to at least partially
D. Results from failure of naïve T cells to differentiate. compensate for T cell loss.
C. The thymus starts to involute after the age of 50 years.
3. The following consideration to vaccinations in older individuals D. Generation of T cells by homeostatic proliferation can
is correct: increase the T-cell receptor repertoire.
A. Annual influenza vaccinations are not always protective
and are therefore not recommended in older individuals.
39
Human Immunodeficiency Virus Infection and
Acquired Immunodeficiency Syndrome
Susan L. Gillespie, Javier Chinen, Mary E. Paul, William T. Shearer
In recent years, there has been a stabilization and possible reversal KEY CONCEPTS
of the overall growth of the global acquired immunodeficiency
syndrome (AIDS) epidemic. The number of new infections has Trends in Human Immunodeficiency Virus
steadily declined since the late 1990s, and there are fewer AIDS- (HIV) Infection
related deaths as a result of the scale-up of antiretroviral therapy • Global rates of HIV infection have stabilized, but there is great het-
(ART) since 2004. People living with human immunodeficiency erogeneity in disease incidence among countries and regions.
virus (HIV) are now living longer and healthier lives. • Although most countries had a reduction in disease incidence between
According to the Joint United Nations Programme on HIV/ 2001 and 2009, seven countries had increases in disease incidence
AIDS (UNAIDS), 36.9 million people worldwide were estimated by more than 25% over that period.
1
to be living with HIV or AIDS at the end of 2014 (Fig. 39.1). • The age demographic most affected in the developing world, that is,
New HIV infections are declining in most countries. The annual those aged 25–44 years, includes men and women who are economi-
cally productive and women of childbearing potential.
number of incident HIV infections peaked at >3 million in the • Worldwide, most infections are acquired through heterosexual contact.
late 1990s and has steadily declined thereafter. In 2014, 2 million • In the United States, African Americans and men who have sex with
people were newly infected, with approximately 1% of these men (MSM) are disproportionately infected.
infections (220 000 cases) occurring in children younger than • The numbers of infections transmitted from mother to child are declining
1
15 years of age. Globally, however, adolescents, particularly as access to prophylactic medications to prevent infection improves.
adolescent girls, are at particular risk for acquiring HIV infection.
In 2012, there were 300 000 new infections reported among
adolescents aged 15–19 years, which accounted for about 13% of HIV infection, the number of newly diagnosed infections in
of all new infections. In sub-Saharan Africa, 70% of new infections the United States has remained unchanged from 2006–14,
2
in adolescents occurred among girls. There has been a slow but approximately 40 000–50 000 per year. Within the United States,
continued reduction in the number of people dying from AIDS- there is great variability in both the geographical and demographic
related conditions worldwide. AIDS mortality peaked at 2.1 distribution of the disease, with certain segments of the American
million in 2004, and by the end of 2014, it was down to 1.2 population being disproportionately affected, specifically men
1
million deaths resulting from AIDS-related illnesses. The decline who have sex with men (MSM) and ethnic and racial minorities,
3
reflects increased access to ART and improvements in the care including African Americans and Hispanic Americans (Fig. 39.2).
and support of infected individuals. Mortality among children In the United States and other developed countries, in contrast
younger than 15 years of age has also declined as a result of the to more resource-limited parts of the world, the number of
expansion of services to prevent mother-to-infant transmission children newly infected with HIV has decreased dramatically
of HIV and an increase in access to care and treatment for as a consequence of successful interventions against perinatal
children. Although access to care and treatment services for mother-to-child transmission. In 2014, 174 children were
HIV-infected children in resource-limited settings is expanding, diagnosed with HIV infection, 73% of whom had acquired the
4
it is estimated that only 31% of children in need of life-saving infection through perinatal transmission. At the same time,
ART received it, and an estimated 150 000 children had died of new pediatric AIDS cases and AIDS deaths also have plummeted,
AIDS-related illnesses in 2014. Of concern, HIV/AIDS is the in large part as a result of powerful combinations of antiretroviral
most common cause of death among adolescents in sub-Saharan (ARV) drugs.
Africa and the second leading cause of death among adolescents
globally. HIV PATHOGENESIS
US Perspective HIV Lifecycle
The Centers for Disease Control and Prevention (CDC) estimate HIV is a lentivirus that targets CD4 T cells by specifically
that almost 1.2 million adults and adolescents were living with binding the viral Env protein to two cell surface proteins, the
HIV in the United States at the end of 2014, including 156 300 CD4 receptor, and either the CCR5 or the CXCR4 chemokine
(12.8%) whose infection was undiagnosed. Despite ongoing receptor (Fig. 39.3). Other cell targets for HIV are monocytes
prevention efforts designed to reduce the number of new cases and dendritic cells (DCs), although they present less expression
545
546 ParT fOur Immunological Deficiencies
Adults and children estimated to be living with HIV, 2014
By WHO region
Number of people, by WHO region
Eastern Mediterranean: 330 000 [200 000–460 000] Americas: 3 400 000 [2 500 000–4 400 000] Total: 36 900 000
Western Pacific: 1 400 000 [1 200 000–1 800 000] South-East Asia: 3 500 000 [3 200 000–3 700 000] [34 300 000–41 400 000]
Europe: 2 500 000 [2 200 000–2 800 000] Africa: 25 800 000 [24 000 000–28 700 000] 0 875 1,750 3,500 Kilometers
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever Data Source: World Health Organization
on the part of the World Health Organization concerning the legal states of any country, territory, city or area or of its authorities, Map Production: Information Evidence and Research (IER)
or concerning the delimitation of its frontiers or boundaries, Dotted and dashed lines on maps represent approximate border lines World Health Organization
for which there may not yet be full agreement.
© WHO 2016. All rights reserved.
fIG 39.1 Adults and children estimated to be living with human immunodeficiency virus (HIV),
2014: by World Health Organization (WHO) region, 2014.
12,000 Estimated new HIV infections in the US 2009, for the most affected subpopulations
11,4000
10,800
10,000
Number of new HIV infections 8,000 6,000 5,400
6,000
4,000
2,000 2,400 1,700 1,700
1,200
940
0
White MSM* Black MSM Hispanic MSM Black Black Hispanic White Black male Black female
heterosexual heterosexual heterosexual heterosexual IDUs IDUs
women men women women
fIG 39.2 US trends in human immunodeficiency virus (HIV) infection by race and mode of
transmission. (From Centers for Disease Control and Prevention. HIV surveillance—United States,
1981–2008. MMWR Morb Mortal Wkly Rep 2011; 60: 689–93. Atlanta, GA: US Department of
Health and Human Services, Centers for Disease Control and Prevention; 2011. (Also available
at http://www.cdc/gov/hiv/topics/surveillance/resources/reports.gov.)
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 547
The HIV Life Cycle
HIV medicines in six drug classes stop HIV at different stages in the HIV life cycle
1 Binding (also called attachment):
HIV binds (attaches itself) to receptors
on the surface of a CD4 cell.
CCR5 antagonist
2 Fusion: The HIV envelope and the CD4 cell membrane
fuse (join together), which allows HIV to enter the CD4 cell.
Fusion inhibitors
CD4 receptors
CD4 cell membrane
3 Reverse transcription: Inside the CD4 cell, HIV releases and uses
HIV RNA reverse transcriptase (an HIV enzyme) to convert its genetic material–
Reverse transcriptase HIV RNA– into HIV DNA. The conversion of HIV RNA to HIV DNA allows
HIV to enter the CD4 cell nucleus and combine with the cell’s genetic
HIV DNA
material– cell DNA.
Non-nucleotide reverse transcriptase inhibitors (NNRTIs)
Membrane of CD4 Nucleotide reverse transcriptase inhibitors (NRTIs)
cell nucleus
Integrase 5 Replication: Once integrated into the CD4 cell DNA, HIV
begins to use the machinery of the CD4 cell to make long
chains of HIV proteins. The protein chains are the building
4 Integration: Inside the CD4 blocks for more HIV.
cell nucleus, HIV releases
integrase (an HIV enzyme).
HIV uses integrase to insert
(integrate) its viral DNA into HIV
the DNA of the CD4 cell. DNA
Integrase inhibitors
CD4 cell DNA
Protease
6 Assembly: New HIV proteins and HIV RNA
move to the surface of the cell and assemble
into immature (noninfectious) HIV.
7 Budding: Newly formed immature (noninfectious)
HIV pushes itself out of the host CD4 cell. The new
HIV releases protease (an HIV enzyme). Protease
acts to break up the long protein chains that form the
immature virus. The smaller HIV proteins combine to
form mature (infectious) HIV.
Protease inhibitors (PIs)
fIG 39.3 The human immunodeficiency virus (HIV) lifecycle and stage susceptibility to antiretroviral
therapy. (From https://www.aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-
cycle.)
548 ParT fOur Immunological Deficiencies
of these receptors compared with CD4 T cells. After the virus blood. They might produce very low levels of viral RNA and
is attached to the cell, the viral membrane fuses with the cell proteins and therefore might not be detected by immunosurveil-
membrane and viral RNA enters the cytoplasm. It is transcribed lance. HIV reservoirs are established during the acute phase of
by the viral reverse transcriptase into double-stranded DNA, the infection, hence the recommendation for early intensive
which is translocated to the cell nucleus, and the virus integrase treatment to reduce the population of latently infected CD4 T
enzyme mediates its integration into the cell genome. The viral cells (nonreplicating monocytes, astrocytes, and glial cells are
proteins Tat and Nef, in addition to T-cell activation factors, other latently infected cells). Molecular mechanisms that inhibit
induce active transcription and expression of viral RNA and HIV replication from viral DNA and maintain latent infection
proteins to produce new virus particles that exit the host cell to include histone deacetylases and methyl transferases with methyla-
infect other cells. CD4-independent viral entry has been demon- tion of viral genes, especially of the long-terminal promoter
strated in B cells, astrocytes, and kidney epithelial cells; however, repeat. These epigenetic modifications can be reversed by using
efficient viral replication is not likely to occur in these cells (see T-cell activation signals.
Treatment).
HIV Entry Through Mucosal Surfaces ANTI-HIV IMMUNITY
Using dilution techniques that can precisely determine unique Immunity against HIV depends mostly on specific cytotoxic
7
virion genome sequences, it was found that about 80% of HIV CD8 T cells, which recognize and destroy infected cells. These
5
infections via heterosexual transmission start with a single virion. antiviral cells are most efficient when certain combinations of
This is remarkable, considering the high rate of mutation and human leukocyte antigen (HLA) and virus strain occur in the
diversity of viral genome sequences found in infected individuals. host, such as the presence of a cell bearing the HLA-B27 allele
In contrast, HIV transmission occurring in MSM and in intra- and infected with clade B viral strain. However, HIV infection
venous drug users is caused by several viral variants, indicating almost always results in global T-cell destruction and exhaustion.
that the multilayered epithelia of the vaginal mucosa and the Antibody responses are initially directed against the gp41 portion
6
cervical mucus are likely deterrents for lentiviral infection. of the Env protein. This response and subsequent anti-HIV
Regardless of the route of infection, the time to develop viremia antibodies become ineffective because of the rapid production
and immunological changes is similar to that of all forms of of escape mutants.
transmission. Viral replication can be detected in the germinal
center of lymph nodes within a week, and viremia is found HIV Vaccines: Basic Concepts
within 21 days of infection. The most active replication occurs Several efforts to develop an effective anti-HIV vaccine have
in the gut-associated lymphoid tissue (GALT), with massive attempted to address the genetic diversity of HIV that develops
depletion of CD4 T cells. Activation and destruction of CD4 T in the infected individual, by identifying epitopes that remain
cells are associated with an increase of serum cytokines, which relatively conserved and by inducing neutralizing antibodies as
10
might explain the flu-like syndrome that patients might experience well as cell-mediated immunity. Broadly neutralizing antibodies,
7
during acute HIV infection. Simultaneously, HIV reservoirs which target conserved Env epitopes from different strains and
become established with viral infection and integration of viral can prevent HIV from establishing infection, might develop in
DNA in resting cells. some individuals with chronic infection, offering hope for disease
prevention. Such antibodies are found to develop after approxi-
T-cell Depletion mately 2 years of infection, when many generations of escape
Progressive T-cell depletion in HIV infection is induced, in part, virions, inducing new antibody epitopes, allow the immune
by a state of chronic immune activation, which also contributes response to refine and select for best affinity. This concept suggests
7
to noninfectious complications, such as cardiovascular disease. that several booster immunizations might reproduce the process
In individuals with HIV infection, immune activation is caused in shorter time. Current approaches involve viral vectors that
by increased microbial translocation in the gut, direct Toll-like drive the expression of HIV proteins in host tissue; an example
receptor (TLR) stimulation by HIV, and coinfection with other is a canary pox virus carrying the HIV env gene. No current
pathogens. This activated state results in increased levels of inflam- vaccines have been able to induce high titers of broadly neutral-
matory cytokines, such as interleukin-6 (IL-6). Also detected is an izing antibodies against HIV Env. Of note, an unexpected,
increase of lipopolysaccharide (LPS) in blood, which, in turn, can although modest, increased rate of HIV infection was observed
also activate the coagulation cascade and promote thrombosis. in individuals immunized with an adenovirus-based HIV vaccine
Low or normal levels of T regulatory cells (Tregs) are observed compared with nonimmunized individuals and was highest in
in long-term nonprogressors, suggesting their role in anti-HIV persons who had antiadenovirus antibodies before the trial. The
immunity, especially in modulating CD8 T-cell immunity. It mechanisms explaining this increased infection rate are not clear.
has also been suggested that Tregs may play a beneficial role by Results from the RV144 clinical trial conducted in Thailand
reducing chronic immune activation. 8 showing a 31% reduction of HIV transmission demonstrated
that vaccine protection may be a reality. New vector approaches,
HIV Latency and HIV Reservoirs improving T-cell responses and achieving high titers of broadly
The most difficult problem in the efforts toward achieving a neutralizing vaccines, are being investigated to increase vaccine
cure for HIV infection is the presence of HIV reservoirs, defined efficacy (see HIV preventive vaccines).
9
as resting or nonreplicating cells infected with HIV. Anti HIV
drugs are able to efficiently suppress HIV replication; however, ROUTES OF INFECTION
when these drugs are stopped, activation of the resting cells
results in the production of new virus. Most viral DNA is detected HIV is transmitted through three routes of infection: sexual,
in memory CD4 T cells within lymphoid tissues and peripheral parenteral, and perinatal. In general, higher viral loads, lower
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 549
CD4 T-cell count, and larger viral inoculum size are all associated After approximately 1 week, the virus becomes detectable in
with a greater risk of transmission. draining regional lymph nodes. Myeloid DCs are not infected
Sexual transmission is the most common mode of infection, with HIV; rather, HIV gp120 binds to DC-specific intercellular
responsible for 70–80% of worldwide infections. Besides the adhesion molecule–grabbing nonintegrin (DC-SIGN) in the cell
factors mentioned above, recipients in penetrative intercourse membrane. The resulting complex is internalized as a phagosome
are more likely to become infected. Anal intercourse carries the and then presented on the cell surface. As there is no fusion of
greatest risk, followed by vaginal intercourse, and oral intercourse the HIV Env with the DC membrane, infection does not occur.
is the least likely to spread the virus. The presence of other Plasmacytoid DCs, in contrast, express CD4 and the coreceptors
sexually transmitted diseases, especially ulcerative lesions, such CXCR4 and CCR5 and thus become infected by the virus. Infec-
as those seen in herpes simplex or syphilis infection, increases tion leads to expression of CCR7, which acts as a homing signal
the risk of transmission. for the lymph nodes; it is in lymph nodes that the virus infects
Parenteral transmission is the second most common route CD4 T cells, and significant viral replication occurs, resulting
of HIV infection, accounting for 8–15% of all HIV infections. in detectable viremia and dissemination through lymphoid tissues.
Examples include contaminated needles used by people who Of interest, the target cells for HIV infection, CD4 T cells and
are addicted to intravenous drug use (IDU), accidental needle monocyte/macrophage cells, are also reservoirs for the virus.
sticks occurring in health care workers, improperly sterilized HIV-infected cells carry a stable provirus integrated in the cell
hospital equipment, and contaminated blood products. Use of genome, which is transcriptionally silent until the cell is activated.
contaminated needles by people addicted to IDU is the largest risk These cells can reestablish HIV viremia even after prolonged
factor for parenteral transmission. In 2013, 7% of the estimated antiviral treatment, since viral reservoirs are unlikely to be soon
47 500 new HIV infections in the United States were attributed eradicated.
11
to IDU. Although infection control efforts have greatly reduced
the risk, HIV transmission via transfusion of contaminated blood Gastrointestinal System: Early Target
products remains significant, particularly in resource-limited Within days of infection, 20% of CD4 T cells found in the GALT
settings where there is a dependence on replacement of blood are infected. Of these, up to 80% are killed, by lytic infection
by family member donors and paid blood donors and where and Fas-mediated apoptosis of both infected and noninfected
+
+
the infrastructure for routine blood screening is suboptimal. cells, mainly CD4 CCR5 memory T cells. By the time of peak
Perinatal transmission accounts for the majority of pediatric HIV viremia, 60% of the mucosal memory CD4 T cells are infected.
cases and for 5–10% of HIV infections in patients of all ages. The Because their destruction is less drastic, circulating CD4 T-cell
virus is capable of infecting the child in utero, during labor, and after counts do not reflect the magnitude of CD4 T-cell death taking
delivery through breastfeeding. Without preventive therapy, the risk place in the GALT. Following acute HIV infection, a massive
of a child contracting HIV from the mother during gestation or activation of the immune system occurs. Inadequate memory
during labor is about 15–40%. The majority of transmission events T-cell responses can lead to infection and inflammation of
occur during the passage of the fetus through the birth canal, by the entire bowel. The presence of immune activators over the
exposure of the baby to infected maternal blood, amniotic fluid, massive surface area of the bowel has been hypothesized to
12
and/or cervical and vaginal secretions. Although breastfeeding result in the profound immune activation seen in HIV. Mucosal
increases the risk of transmission of the virus from mother to Th17 cells are a preferential target for HIV, further weakening
child by another 15–29%, breastfeeding is still recommended to mucosal immunity and favoring microbial infection. The viremia
prevent morbidity and mortality related to diarrheal diseases in decreases spontaneously from as high as 10 million copies of
settings where access to replacement feeding is limited. HIV RNA per milliliter during the acute illness phase to a
stable level many orders of magnitude lower called the viral
IMMUNOPATHOGENESIS set point. It is known that higher set points of viral load and
lower T-cell counts are loosely predictive of shorter periods of
The mechanisms of immunodeficiency induced by HIV are not clinical latency. Eventually, a prolonged period of homeostasis
limited to depletion of its main target cell, the CD4 T cell; HIV between the virus and the immune system collapses, and AIDS
infection ultimately leads directly or indirectly to the impairment ensues.
6
of every arm of the immune system. The time of progression
from infection to the development of AIDS is not the same Chronic Immune Activation and Progression to AIDS
for all infected individuals, and several explanations have been After the acute stage, HIV infection induces a high degree of
proposed, including genetic resistance genes and the presence proliferation and turnover of CD4 and CD8 T cells. The massive
of low-virulence mutant viral particles. The study of long-term immune activation can be explained by the circulation of many
nonprogressor individuals has helped to define T-cell and antibody soluble factors, including TLR ligands. HIV infection appears
features associated with anti-HIV immunity in the search for to activate plasmacytoid DCs by stimulation of TLR7 to secrete
the optimal vaccine design, focusing on minimizing the escape interferon-α (IFN-) and proinflammatory cytokines, using both
14
variants and inducing persistent specific viral neutralization or TLR8 and DC-SIGN to infect these cells. In turn, stimulated
10
inhibition of replication. HIV researchers have also explored the DCs activate T cells, which are also being directly activated
role of chronic immune activation processes that are associated through TLR ligands. Bacterial products from the mucosa (e.g.,
with progression to AIDS, which also helps explain the diverse LPS) and HIV protein products, such as Nef, Env, Vif, and so
clinical impact of this viral infection in different individuals. on, are mediators of this immune activation. Other microbial
infections (viral, bacterial, or fungal) can stimulate the different
Mucosal Dendritic Cells: Myeloid Versus Plasmacytoid TLRs and result in CD4 and CD8 T-cell activation and apoptosis.
Following a mucosal inoculation of HIV, CD4 T cells are generally This rampant immune activation is thought to lead to the eventual
13
infected by CCR5-tropic virus, also called R5 or M-tropic virus. collapse of the immune system.
550 ParT fOur Immunological Deficiencies
Anti-HIV Cellular Immunity INNATE IMMUNITY
In individuals with HIV infection, the initial control of viremia Innate immunity mechanisms are characterized by their lack of
occurs with the initial expansion of HIV-specific CD8 T cells. antigen specificity and include epithelial barriers, the complement
The importance of anti-HIV cytotoxic T cells is suggested by system, phagocytes, and antigen-presenting cells (APCs). Their
the development of viral escape mutations that are driven by role in HIV pathogenesis is complex, as their function is of
immune selection pressure and evade the immunological response. most importance during acute infection but their contribution
In addition to their cytotoxicity, CD8 T cells secrete chemokines, to immune activation may be deleterious in the chronic stage.
such as RANTES and MIP-1β, which inhibit viral entry via CCR5, Studies including individuals who were exposed to HIV but did
and IFN-γ, which activates immune cells and increases HLA not develop infection have suggested that an increased innate
expression (Chapter 10). Although severely reduced in number, immune response generated in the mucosal microenvironment
IFN-γ–secreting HIV-specific CD4 T cells are present in individu- may explain the failure to develop a specific anti-HIV response. 17
als with HIV infection. The role of adaptive cellular immunity
in protection against natural infection is currently challenged, NK Cells in HIV Infection
18
since about 40–60% of noninfected but exposed individuals do NK cells are dramatically altered in HIV infection. A small subset
not present with detectable anti-HIV responses. of NK cells has been found to express both CD4 and CCR5 or
CXCR4. These NK cells can be infected by HIV and may serve
Mechanisms of T-Cell Depletion as one of the sites of latent infection or can be activated and
Three major mechanisms of T-cell depletion have been reported: contribute to the state of immune chronic activation. CCR5 and
direct lytic infection, apoptosis, and autophagy. Direct lytic inhibitory receptor expression are higher on NK cells in patients
infection is the result of massive activation of the immune system with HIV infection than in HIV-seronegative subjects. In contrast,
with production of inflammatory cytokines, as in the GALT (see there is reduced expression of surface receptors on NK cells that
Cytokines in HIV infection). induce cytotoxic activity, such as NK-cell protein 30 (NKp30),
NKp44, and NKp46. Antibody-dependent cellular cytotoxicity
Apoptosis (ADCC) is reduced in patients with HIV infection, as well as the
Increased apoptosis of T cells in HIV infection was described NK-cell responsiveness to IL-2. The expression of HLA-C–specific
early in the history of the epidemic. Several explanations have inhibitory NK-cell receptors has been found to be increased in
been offered: (i) HIV-induced apoptosis of infected cells (viral patients with HIV. Interestingly, studies of Vietnamese patients
cytopathic effect); (ii) bystander effect from HIV-infected neighbor who were exposed to HIV through IDU but were seronegative
cells releasing viral proteins; (iii) death of HIV-specific effectors showed that the NK cells of these patients not only secreted greater
following their migration to infected sites; (iv) perturbation of quantities of chemokines compared with those of the controls
proapoptotic signaling molecules on immune cells secondary but they also had greater direct cytotoxicity. Genetic studies have
to the chronic immune activation; and (v) destruction of HIV- suggested that inheritance of particular killer inhibitor receptor
19
infected cells by immune effectors. (KIR) alleles with their HLA ligands delays disease progression.
Late HIV infection is associated with the dominance of a The two subsets of DCs, myeloid and plasmacytoid, play an
syncytia-inducing form of the virus. Syncytia formation (cluster- additional role in HIV infection by stimulating innate immune
ing of CD4 T cells and membrane fusion) occurs through the responses, such as the type 1 IFNs, against HIV via plasmacytoid
interaction of HIV Env and CD4/CXCR4 on neighboring cells. DCs. DCs may have opposing roles, with myeloid DCs acting as
These cells are more prone to undergoing apoptosis through a reservoirs and favoring HIV dissemination and plasmacytoid DCs
15
Fas-dependent pathway. Most of the HIV proteins have been inhibiting HIV replication by cytokine secretion. In fact, low levels
implicated at one time or another in HIV-induced apoptosis. of plasmacytoid DCs correlate with high viral loads, low CD4
T-cell counts, opportunistic infections, and disease progression.
Autophagy
Autophagy is a process by which cytoplasm and organelles Cytokines in HIV Infection
are sequestered and directed toward lysosomal pathways and The dysregulation of the immune system produced by HIV infection
16
histone deacetylase. This process has been implicated in both includes significant perturbation in the balance of Th1 and Th2
the prevention and induction of apoptosis, reflecting common cytokine levels. The Th1 cytokines IL-2, TNF-α, IFN-γ, and IL-12
regulatory factors shared by both (e.g., tumor necrosis factor decrease during HIV infection, whereas the Th2 cytokines, IL-10,
[TNF]–related apoptosis inducing ligand [TRAIL], FADD, DAPk, and IL-4 increase or remain normal; levels of proinflammatory
ceramide, and Bcl-2). HIV Env has been shown to be a stimulus cytokines, such as IL-1, IL-6, and IL-8, also increase. Viral replication
for autophagy in uninfected CD4 T cells via its interaction with in HIV-infected T cells and monocytes is induced by IL-2, IL-7,
CXCR4. Inhibition of the autophagic pathway prevents Env- and IL-15, as well as by the proinflammatory cytokines. These
induced cell death in uninfected cells in vitro, demonstrating cytokines appear to induce viral replication by activating the host
that this mechanism contributes to the loss of uninfected cells. cell, a requirement for HIV productive replication. Some cytokines,
such as IL-10, decrease HIV production, likely by inhibiting the
Anti-HIV Humoral Immunity synthesis of the activating cytokines and by decreasing the expres-
After establishment of HIV infection, neutralizing antibodies sion of CCR5 and other chemokine receptors. In addition, the HIV
are produced; however, the virus quickly mutates to avoid them, long terminal repeat (LTR) promoter contains sequences that bind
such that the host continues to respond to evolving viral mutants. cellular factors that are activated as a response to cytokine binding,
The fact that antibodies can be effective in protecting hosts from such as nuclear factor (NF)-κB and AP1. IFN-α and IFN-β have
HIV infection has been demonstrated in macaques and in a activity against HIV, although their role of these cytokines in vivo is
20
humanized mouse model of HIV infection. not well established and may have only an adjuvant effect. Their
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 551
activity might favor HIV infection, as shown by the upregulation CLINICaL PEarLS
of CCR5 by IFN-α, which can facilitate viral entry. Chemokines
inhibit HIV infection by competing for viral binding sites. The α Acute Infection Is an Opportunity for Early
chemokine stromal cell–derived factor 1 (SDF-1) competes with Human Immunodeficiency Virus (HIV) Diagnosis
lymphotropic HIV strains for binding to CXCR4, whereas the β • Acute HIV infection is a nonspecific viral syndrome, often described
chemokines macrophage inflammatory protein 1-α (MIP1-α), as being similar to infectious mononucleosis.
MIP1-β, and RANTES compete with macrophage-tropic strains • Many patients present to a clinician at this stage, but most are not
for binding to CCR5. recognized as HIV infection.
• Irreparable damage to the host immune system occurs during this
stage of HIV infection resulting in chronic immune activation and the
CLINICAL FEATURES eventual collapse of the immune system.
• HIV viral latency is established during the acute infection as HIV DNA
If the HIV infection is left untreated, its natural history involves integrates with the host genome resulting. Integrated viral genetic
the progression through four clinical phases: acute retroviral material makes cure of HIV impossible even after prolonged viral
syndrome, asymptomatic or latent infection, symptomatic HIV suppression with antiretroviral therapy (ART).
infection, and finally AIDS. Each clinical phase correlates with • ART initiated during the acute infection can halt the destruction of
specific events in the interaction between HIV and the host the body’s memory T cells in the gut-associated lymphoid tissue
(GALT) and lead to better long-term outcomes for the patient.
immune system. A small percentage of patients become long-term • The practical importance of early therapy of acute infection remains
nonprogressors, and an even smaller percentage become elite in question because patients who are able to achieve and maintain
controllers (see Long-term nonprogressors/elite controllers). undetectable viral loads on ART do well despite having commenced
treatment long after their acute infection.
Acute HIV Infection
Soon after infection, unopposed by effective host immune
responses, HIV rapidly replicates and disseminates to lymphoid
tissues (see Immunopathogenesis: gastrointestinal system) and Symptomatic HIV Infection (pre-AIDS)
to the systemic circulation, with viremia reaching as high as 10 As the infection progresses, most individuals develop clinical
million copies per milliliter. Plasma viremia typically peaks in 3–4 symptoms. The ability of the immune system to contain viral
weeks after transmission, and then, as a result of the depletion replication is overcome, and the viral load begins to increase.
of susceptible CD4 T cells and HIV-specific immune responses, There is usually an inflection point in the CD4 T-cell curve
the virus load precipitously declines, followed by more gradual marking the start of a period of more rapid decline in CD4
decline for several weeks before reaching the set point. T-cell counts. As these counts fall, immunodeficiency, symptomatic
Clinically, the acute phase of HIV infection is manifested by disease, and AIDS eventually occur (Fig. 39.4).
21
a flu-like illness, referred to as acute retroviral syndrome. Two
to 4 weeks after transmission, coinciding with the period of high End-Stage HIV Infection: AIDS
plasma viremia and dissemination of virus to lymphoid organs, As the CD4 T-cell count drops to <200 cells/µL, the immune
the majority of infected individuals experience a nonspecific system’s ability to fight infection is compromised to the extent
infectious mononucleosis–like illness that lasts from a few days
to several weeks. As the host develops HIV-specific immunity,
the virus load decreases, CD4 and CD8 T cells recover, and the
symptoms of the acute infection resolve. Although up to 90% of Number of CD4 cells
+
patients seek medical care for this illness, the nonspecific nature Plasma viral titer by 1,400
of the symptoms makes diagnosis of acute infection difficult, and 10 6 PCR or bDNA assay 1,200
most newly infected individuals are not diagnosed until much Plasma viral titer by
later. The public health implications of the acute HIV infection 10 5 culture or p24 antigen 1,000
are enormous because the risk of transmission from individuals
with acute infection appears to be much higher than that from 10 4 800
those with established infection, in part because of the high Plasma viremia 3 CD4 count
viral load in the former. 10 600
Asymptomatic HIV Infection 10 2 400
The acute infection is followed by a prolonged asymptomatic 10 1 200
or latent period that may last 8–10 years in adults but is much
shorter in children. During this time, the HIV viral load fluctuates
22
around a relatively stable set point. The viral set point is a 1 5 10 12
major determinant of infectivity and risk of disease progression, Time (years)
with higher viral loads being associated with more likely viral
transmission, more rapid disease progression, and greater risk Symptoms Symptoms
of death. The host immune response is insufficient to eradicate fIG 39.4 Natural course of human immunodeficiency virus (HIV)
the infection but is enough to contain viral replication for many infection. The relationship between CD4 T-cell counts and viral
years. Although commonly thought to represent a stalemate loads over the course of infection in the absence of treatment.
between viral replication and CD4 T-cell production, this period (From Baliga CS, Shearer WT. HIV/AIDS. In: Fireman P, ed. Atlas
is actually characterized by a steady and inexorable decline of of allergy. 3rd ed. Philadelphia, PA: Elsevier Science (USA); 2005:
CD4 T cells (50–75 cells per year). p. 351–67.)
552 ParT fOur Immunological Deficiencies
TABLE 39.1 Opportunistic Infection Prophylaxis and Treatment in adolescents and adults*
risk factor agent Prophylactic Medication
CD4 cell count <200 cells/µL Pneumocystis jiroveci Trimethoprim–sulfamethoxazole (TMP-SMX) or dapsone
plus or minus pyrimethamine and leucovorin or
aerosolized pentamidine or atovaquone
Coccidioidomycosis In endemic areas: fluconazole or itraconazole
CD4 T-cell count <100 cells/µL Toxoplasma gondii TMP-SMX or dapsone plus pyrimethamine plus leucovorin
or atovaquone plus pyrimethamine plus leucovorin
Histoplasmosis In endemic areas: itraconazole
CD4 T-cell count <50 cells/µL Mycobacterium avium complex (MAC) Macrolide (clarithromycin or azithromycin) or rifabutin
Cryptococcosis In endemic areas: fluconazole or itraconazole
Purified protein derivative (PPD) >5 mm Mycobacterium tuberculosis Isoniazid (INH) + pyridoxine for 9 months; if unlikely to
induration or recent tuberculosis (TB) complete 9 month course and on highly active
contact but no active TB and no history of antiretroviral therapy (HAART): rifabutin plus
treatment for active or latent TB pyrazinamide for 2 months
Contact with chickenpox or shingles in Varicella-zoster Varicella-zoster immunoglobulins (VZIGs)
varicella-zoster seronegative individuals
Human immunodeficiency virus (HIV)–infected Streptococcus pneumoniae Pneumovax
Meningococcus—for youth attending Menactra
the military or college and consider
for unvaccinated adults
Negative anti-hepatitis B core antibodies Hepatitis B Recombivax-HB or Energerix-B
(HBc) and previously unimmunized or
underimmunized to hepatitis B
Negative anti-hepatitis A serology Hepatitis A Havrix
*For additional information see the current US guidelines at http://AIDSinfo.nih.gov.
From Baliga CS, Shearer WT. HIV/AIDS. In: Fireman P, ed. Atlas of allergy. 3rd ed. Philadelphia, PA: Elsevier Science (USA); 2005: p. 351–67.
that AIDS-defining illnesses begin to appear. On the basis of the TABLE 39.2 factors affecting
CD4 T-cell count, prophylaxis for opportunistic infections is Human Immunodeficiency Virus (HIV)
administered (Table 39.1). Without treatment, most patients will Disease Progression
succumb to opportunistic infections within 2 years of developing
AIDS. Inoculum size Higher the inoculum the faster the
disease progression
Long-Term Nonprogressors/Elite Controllers Age Infected infants have a higher risk of
Some HIV-infected patients are called long-term nonprogressors rapidly developing acquired
immunodeficiency syndrome (AIDS)
(LTNPs) because they do not progress to AIDS after a defined at any given CD4 percentage
period. One explanation for this phenomenon is the deletion Less common in adults
of 32 nucleotides in the CCR5 gene (CCR5-δ32). This deletion, Viral set point The higher the viral set point the
postulated to have originated from selective pressure exerted by faster the disease progression
the bubonic plague, is found in people of European Caucasian Broad and robust cellular These correlate with lower set points,
ancestry. The deletion renders the CCR5 receptor nonfunctional and humoral immune but what parts of these and which
responses
one is more important are unknown
and offers protection against viral infection. Other mutations Coreceptor mutations: δ32 Homozygotes for the δ32 CCR5
have been identified, such as the CCR2-64I mutation, the SDF1- CCR5, CCR2-64 l, SDF mutation fail to develop disease;
3’A mutation, and the RANTES-28 G mutation; however, these 1-3’ A heterozygotes have a much longer
mutations are found in only a minority of LTNPs. period of clinical latency
Elevated levels of messenger RNA (mRNA) for the ARV cytidine T-helper 1 (Th1) responses: Found in subsets of long-term
deaminase APOBEC3G have been found in LTNPs compared with interleukin-2 (IL-2) and nonprogressors (LTNPs)
interferon (IFN)-γ levels
noninfected controls and most patients with HIV infection. An Autoantibodies to CCR5 Found in subsets of LTNPs to also
explanation for the finding of APOBEC3G in LTNPs is that these HLA-B27, -B57, -DLR correlate with Autoantibodies
individuals are infected with a defective or less fit virus. More APOBEC3G levels Higher levels are associated with
conventional mechanisms have been proposed for LTNPs, such slower progression
as strong and broadly neutralizing antibody and/or cytotoxic Viral fitness Less fit viruses are associated with
T-cell responses. HLA-B27 and HLA-B57 have also been correlated slower disease progression
+
with LTNPs. In children, CD8 HLA-DR T-cell percentages of
<5% at 1–2 months of age have been implicated in predicting
LTNPs, presumably as a result of decreased T-cell activation and
inflammation. In a subset of LTNPs, circulating autoantibodies to A rare group of HIV-infected individuals are able to control
a conformational epitope in the extramembrane loop of CCR5 the viral load at very low levels without ART. These elite controllers
that induce downregulation of the coreceptor have been found. display high expression of the T-bet transcription factor perforin,
22
Interestingly, if the levels of those antibodies waned, the LTNPs and granzyme B. Table 39.2 summarizes factors that can affect
would be more likely to progress to symptomatic disease. HIV progression.
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 553
DIAGNOSIS AND MONITORING OF HIV INFECTION detect HIV in whole blood or oral fluid specimens and can be
used at the point of care, yielding results within 30 minutes.
Diagnostic Tests Because results of rapid tests are available quickly, individuals
The diagnosis of HIV infection depends on the detection of can learn of their results in a single appointment.
biological markers, produced either by the virus or by the infected For both EIAs and rapid tests, a negative result is conclusive
host, which appear in a chronology that is typically consistent and generally requires no follow-up testing. A common exception
among individuals. The earliest virological markers, HIV RNA is that in individuals with possible recent exposure, antibody
and HIV p24, can be measured 9–12 days and 14–19 days after tests may be negative in the window period before seroconversion,
infection, respectively. The period between infection and detection so testing should be repeated within 1–2 months. A reactive EIA
of HIV RNA is called the “eclipse period” (Fig. 39.5). or rapid test requires further testing to confirm the diagnosis
(Fig. 39.6). The Western blot assay identifies specific HIV antigens
Enzyme Immunoassays to which IgG antibodies in the patient’s serum react and histori-
Various generations of screening enzyme immunoassays (EIAs) cally has been used to confirm positive screening tests results.
are able to detect anti-HIV antibody 2–6 weeks after HIV RNA However, because Western blots do not become diagnostically
is detected. Traditionally, the period between infection and reactive until approximately 5–6 weeks after infection, nucleic
detection of HIV antibody by a particular test is referred to as acid amplification tests are now commonly used to confirm
the “window period” for that assay. The window period for new infection because they detect HIV infection well before the
generation combination EIAs has been shortened to about 2 Western blot can show positive results. The current laboratory
weeks because in addition to detecting antibody to both HIV-1 HIV testing algorithm as recommended by the CDC for serum
and HIV-2, they also detect p24 antigen. 23 or plasma specimens is shown in Fig. 39.6.
Rapid HIV EIA Tests Nucleic Acid Amplification Tests
Rapid enzyme immunoassays are the most commonly used HIV Nucleic acid amplification tests are used to detect HIV RNA or
screening tests. Rapid HIV tests are self-contained EIAs that DNA in biological samples to diagnose and/or monitor HIV
HIV RNA (plasma)
HIV antibody
HIV-1 p24 antigen
HIV infection
0 10 20 30 40 50 60 70 80 180 360 540 720
Days
Eclipse
period Acute HIV infection Established HIV infection
Viral Antibody Antibody Antibody
detection detection detection detection
nd
rd
nucleic acid 3 generation 2 generation 1st generation
test immunoassay immunoassay immunoassay
Viral
detection
4th generation
immunoassay
Seroconversion window
fIG 39.5 Sequence of appearance of laboratory markers for human immunodeficiency virus type
1 (HIV-1) infection. (From: Centers for Disease Control and Prevention and Association of Public
Health Laboratories. Laboratory testing for the diagnosis of HIV infection: Updated recommenda-
tions. Published June 27, 2014. Available at: http://dx.doi.org/10.15620/cdc.23447. Accessed
March 28, 2016.)
554 ParT fOur Immunological Deficiencies
HIV-1/2 antigen/antibody combination immunoassay
(+) (–)
Negative for HIV-1 and HIV-2
antibodies and p24 Ag
HIV-1/HIV-2 antibody differentiation immunoassay
HIV-1 (+) HIV-1 (–) HIV-1 (+) HIV-1 (–) or indeterminate
HIV-2 (–) HIV-2 (+) HIV-2 (+) HIV-2 (–)
HIV-1 antibodies HIV-2 antibodies HIV antibodies
detected detected detected
HIV-1 NAT
(+) indicates reactive test result
(–) indicates nonreactive test result HIV-1 NAT (+) HIV-1 NAT (–)
NAT: nucleic acid test Acute HIV-1 infection Negative for HIV-1
fIG 39.6 Recommended laboratory human immunodeficiency virus (HIV) testing algorithm for
serum or plasma specimens. (From http://stacks.cdc.gov/view/cdc/23447, p. 7.)
infection. HIV RNA polymerase chain reaction (PCR; Chapter KEY CONCEPTS
96) is used to quantify the virus load or the extracellular viral Other Human Immunodeficiency Virus
RNA in plasma and is also measured by using qualitative assays.
HIV RNA detection plays a valuable role in identifying early (HIV) Tests
infection before seroconversion and in confirming reactive screen- • Genotyping: helps to guide the choice of antiretroviral medications in
ing tests. Quantification of HIV RNA is also used to monitor patients with resistant virus by sequencing the viral genetic code and
the effectiveness of ART in suppressing viral replication. HIV identifying mutations that confer resistance to specific agents or classes
DNA PCR is a qualitative assay used to detect HIV viral DNA of agents.
in peripheral blood mononuclear cells. Detecting HIV DNA • Phenotyping: similar information to genotyping but not widely used;
has allowed the early diagnosis of HIV in perinatally exposed based on growing engineered viruses with a patient’s virus’ genes in
the presence of antiretrovirals to determine their resistance.
infants and is still used for this purpose in international settings. • Viral fitness: this least utilized assay is based on the phenotype assay
HIV DNA PCR is not typically available for diagnostics in the except that it grows the virus without antiretrovirals to measure its
United States, although more and more physicians are ordering intrinsic replicative capacity relative to a defined wild-type virus.
this test. All three of these assays present data as if there is only one virus
strain in the body; in reality, there are numerous viral strains at any one
Monitoring Tests time, with many more archived in cells; these assays detect the dominant
strain in the circulation, neglecting the other strains, which may account
Once infection is confirmed, specific laboratory tests are per- for up to 20% of the circulating viral particles. Given this limitation, when
formed at baseline and then periodically to monitor disease status genotyping results are utilized for changing therapy, old treatment regimens
and progression, to inform treatment decisions, and to identify and previous genotype results must be taken into consideration.
end-organ toxicity. The CD4 T-cell count is used to assess immune
function and is the most important factor in the discussion of
short-term prognosis and determining whether prophylactic Drug Resistance: HIV Genotype Versus Phenotype
medications for opportunistic infections are needed. Once a Viral resistance to ARV agents can be assessed by either HIV
patient is on ART, an increasing CD4 T-cell count also helps genotype or phenotype assays. Genotype assays, based on PCR
24
confirm the efficacy of the therapy. In children younger than and genomic sequencing, identify the presence of key mutations
5 years of age, CD4 percentage is preferred because it typically that confer anti-HIV drug resistance. Phenotype assays assess
remains stable in the setting of age-related changes in absolute the ability of HIV to replicate in vitro in the presence of ARV
CD4 count in this age group. 25 agents. The assay is performed by isolating certain key regulatory
genes from HIV, usually protease and reverse transcriptase,
HIV Viral Load inserting them into standardized viral constructs containing an
Particularly for patients on ART, plasma HIV RNA (viral load) indicator cassette, and infecting cell lines in the presence of ARV
is the most important indicator of response to therapy. Optimal agents. The results are compared against control viral isolates
viral suppression is generally defined as a viral load persistently and expressed as a fold-change in viral susceptibility. Phenotyping
below the level of detection (<20–75 copies/mL, depending on assays remain very expensive, and large studies have failed to
the assay used) and is usually achieved in 12–24 weeks of effective conclusively prove a clinical advantage of phenotype assays over
24
ART. Failure to achieve maximal viral suppression or detectable genotype assays. The phenotype assay quantifies susceptibility
virus after a period of maximal suppression may indicate virologi- and is typically used by experts evaluating individuals who have
cal failure attributable to drug resistance. accumulated resistance and failed multiple regimens.
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 555
after diagnosis to reduce morbidity and mortality and to prevent
Testing for Viral Tropism and Abacavir Hypersensitivity transmission of HIV (see also HIV prevention). Randomized
Additional assays should be performed before the initiation of controlled trials have demonstrated that ART should be initiated
specific ARV medications. A viral tropism assay should be in all patients with HIV infection, regardless of disease stage.
performed before initiation of a CCR5 antagonist. HLA-B*57:01 The urgency to initiate ART is greatest for patients with lower
testing is indicated before initiation of abacavir, as this HLA CD4 counts, in whom the absolute risk of opportunistic infections,
phenotype is associated with abacavir hypersensitivity in 5–8% non-AIDS morbidity, and death is highest. However, the START
of patients early in the course of treatment. (Strategic Timing of Anti-Retroviral Therapy) and the French
National Agency for Research on AIDS and viral hepatitis (ANRS)
TREATMENT 12136 “Temprano” trials provide the evidence that morbidity
and mortality is reduced in individuals with CD4 counts >500
Antiretroviral Therapy: Attacking HIV’s Lifecycle cells/mm at the start of ART, resulting in strong recommenda-
3
Combinations of ARV medications are used to maximally inhibit tions, from both the US HIV treatment panel and the World
HIV replication and to reduce HIV-associated morbidity and Health Organization (WHO), to initiate ART in all patients
mortality. Combination ART refers specifically to a combination regardless of CD4 cell count. In the START trial—a large,
of at least three ARV medications inhibiting the HIV lifecycle multinational, randomized controlled clinical trial with 4685
(see Fig. 39.3; Fig. 39.7). Current US guidelines recommend participants—ART-naive adults with CD4 counts >500 cells/
3
initiation of ART-naïve persons with a combination of two mm were randomized to initiate ART soon after randomization
nucleoside reverse transcriptase inhibitors (NRTIs) plus an or to wait to initiate ART until their CD4 counts declined to
3
integrase strand transfer inhibitor, a nonnucleoside reverse <350 cells/mm , or until they developed a clinical indication for
transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) therapy. Serious AIDS or non-AIDS events endpoint was reported
with a pharmacokinetic enhancer (cobicistat or ritonavir). In in 42 (1.8%) early ART participants and in 96 (4.1%) deferred
ART-experienced patients, modification of ARV regimens and ART participants (hazard ratio [HR] 0.43, favoring early ART
use of other classes of ARVs is guided, in part, by consideration [95% confidence interval (CI), 0.30–0.62; p < 0.001]). The
of a number of factors, including viral resistance patterns, majority (59%) of clinical events in the delayed ART arm occurred
3
potential side effects, available medication formulations, pill in participants whose CD4 counts were still >500 cells/mm ,
burden, frequency of dosing, tolerability, short-term and long- evidence for a benefit of immediate ART even before CD4 count
term adverse event profiles, desire for pregnancy, and desire to declines below this threshold. The TEMPRANO ANRS 12136
preserve subsequent treatment options. 24,25 study—a study of more than 2000 participants in Cote d’Ivoire,
who were randomized to immediate or deferred ART—showed
When to Start Therapy the benefit of immediate treatment over deferred treatment in
There are significant data to support treating all HIV-infected reducing a combination of all-cause deaths, AIDS diseases,
individuals with ART and starting treatment as soon as possible non-AIDS malignancies, and non-AIDS invasive bacterial diseases,
RTI PI Fusion inhibitor
Abacavir (ABC) Atazanavir (ATV) Enfuvirtide
Didanosine (ddI) Darunavir (DRV) (ENF, T-20)
Emtricitabine (FTC) Fosamprenavir
Lamivudine (3TC) (FPV)
Stavudine (d4T) Indinavir (IDV) CCR5 Antagonist
Tenofovir DF (TDF) Lopinavir (LPV) Maraviroc (MVC)
Tenofovir alafenamide (TAF) Nelfinavir (NFV)
Zidovudine (AZT, ZDV Saquinavir (SQV) Pharmacokinetic (PK) booster
Tipranavir (TPV) Ritonavir (RTV)
Cobicistat (COBI)
NNRTI
Delavirdine (DLV) Integrase inhibitor (INSTI)
Efavirenz (EFV) Dolutegravir (DTG)
Etravirine (ETR) Elvitegravir (EVG)
Nevirapine (NVP) Raltegravir (RAL)
Rilpivirine (RPV)
One-pill regimen DTG/ABC/3TC; only if HLA-B*57:01 negative
EFV/TDF/FTC
EVG/COBI/TDF/FTC
EVG/COBI/TAF/FTC
RPV/TDF/FTC (if HIV RNA <100,000 copies/mL and CD4 >200
cells/µL)
RPV/TAF/FTC (if HIV RNA <100,000 copies/mL and CD4 >200
cells/µL)
fIG 39.7 Antiretroviral (ARV) medications approved by the U.S. Food and Drug Administration
(FDA).
556 ParT fOur Immunological Deficiencies
even among participants who had baseline CD4 counts >500
3
cells/mm . Earlier ART initiation appears to increase the prob-
ability of restoring normal CD4 counts, a normal CD4/CD8
ratio, and lower levels of immune activation and inflammation, Trp62
24
as summarized in the US adult treatment guidelines. Individuals
initiating ART during the first 6 months after infection also
appear to achieve lower immune activation levels and better
immune function during ART-mediated viral suppression
compared with those who delay therapy. 25
Recommendations for initiating therapy in children have
always been relatively more aggressive compared with those for Phe43
adolescents and adults because most infected children were
26
infected perinatally and experience rapid disease progression.
The decision to initiate ART should always include consideration Arg59
of a patient’s comorbid conditions, willingness, and readiness fIG 39.8 Epigallocatechin gallate (EGCG) binding to CD4. Recent
to initiate therapy. ART may be deferred because of clinical or studies indicate that polyphenolic EGCG, a component of green
psychosocial factors, with the goal of initiating therapy as soon tea, can bind to the human immunodeficiency virus (HIV) binding
as possible once barriers to successful treatment have been site of CD4 (KD = 10 nM, as measured by nuclear magnetic
reduced. spectroscopy) and potentially interfere in viral infection by
Antiretroviral Agents interaction with three key amino acids in the D1 domain of the
CD4 molecule (tryptophan 62, phenylalanine 43, and arginine
There are more than 20 approved ARV drugs that are classified 59). (From Williamson MP, et al. Epigallocatechin gallate, the
into six classes based on their chemical structure or the viral main polyphenol in green tea, binds to the T-cell receptor, CD4.
lifecycle step that they inhibit (see Fig. 39.7). The classes of ARV J Allergy Clin Immunol 2006; 118: 1369–74.)
agents currently available include NRTIs, NNRTIs, PIs, fusion
inhibitors, integrase inhibitors, and CCR5 antagonists.
Upon start of ART in patients who are compliant and able to
Reverse Transcriptase Inhibitors, Protease Inhibitors, and tolerate the regimen, the initial CD4 T-cell count is the best
Integrase Inhibitors predictor of a successful outcome. Rapid reduction in the viral
Modified versions of cellular nucleosides, NRTIs, once triphos- load, often to an undetectable level, is one of the earliest changes
phorylated in vivo, are incorporated into the proviral DNA by following initiation of ART, reflecting the ability of combination
HIV reverse transcriptase (RT) and induce premature chain ART to rapidly suppress viral replication. Lagging behind the
termination, thereby inhibiting successful conversion of the viral drop in viral load is the rise in CD4 T-cell values. An initial
RNA to DNA. NNRTIs bind to RT and induce a conformational increase in circulating cells occurs in 3–6 months as a result
change such that RT is unable to bind with nucleotides. PIs act of a decrease in immune activation and subsequent migration
+
+
on viral protease, preventing the cleaving of the posttranslational of memory T cells (CD4 , CD45RO ) out of the lymphoid
viral polyproteins necessary for the maturation and infectivity compartment. A more gradual rise in total CD4 T cells occurs
of viral particles. Integrase inhibitors prevent strand transfer of over the course of 3–5 years with the appearance of new naïve
+
+
+
viral DNA and thus block the incorporation of the completed (CD4 , CD45RA , CD62L ) and memory T cells. Interestingly,
HIV DNA copy into the host-cell DNA. a substantial minority of patients never reach a normal level of
CD4 T cells but, instead, reach a plateau at lower levels. Primary
Fusion Inhibitors, CCR5 Blockers, and drug prophylaxis and some secondary drug prophylaxis for
Low-Molecular-Weight Inhibitors opportunistic infections may be discontinued in patients once
3
Fusion inhibitors and CCR5 antagonists inhibit HIV entry into the CD4 T-cell count reaches >200 cells/mm and is maintained
host cells. Fusion inhibitors bind to viral gp41 and block the for more than 3–6 months. Cellular and humoral responses to
conformational changes necessary to induce fusion of the viral most pathogens also recover with rising CD4 T-cell counts. Of
particle with the host cell. CCR5 antagonists bind to the CCR5 interest, a low CD4 T-cell count at the time of initiating therapy
chemokine coreceptor on host cells, inducing a conformational predicts a poor response to bacterial vaccines even after recovery
change that impedes CCR5 interaction with HIV gp120, thereby of CD4 T-cell levels, suggesting a lag in the return of naïve CD4
preventing HIV entry into host cells. T cells.
Low-molecular-weight inhibitors of HIV binding to the
CD4 molecule are a new approach. Epigallocatechin gallate, by
blocking gp120 binding to the CD4 molecule, has been shown CLINICaL PEarLS
to inhibit the infections of CD4 T cells in culture by wild-type Immunoreconstitution Inflammatory
viruses, setting the stage for a phase I/II study in humans Syndrome (IRIS)
(Fig. 39.8). 27
• IRIS is typically found 2–3 weeks after initiating antiretroviral therapy
IMMUNORECONSTITUTION AFTER THERAPY (ART).
• Patients often become profoundly ill and require hospitalization.
Return of T Cells: Memory T Cells, Then Naïve T Cells • Steroids are sometimes useful in the treatment.
• Clinicians may prevent IRIS by initiating ART only after treating
To varying degrees, the immune system is able to recover following opportunistic infections.
28
initiation of therapy, a process called immunoreconstitution.
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 557
include male circumcision and expanded use of ART in infected
Immune Reconstitution Inflammatory Syndrome individuals to prevent ongoing infection (treatment as prevention)
Immune reconstitution inflammatory syndrome (IRIS) is a or prophylactically in uninfected individuals either before or after
well-known, if incompletely understood, response in patients potential exposure to HIV to prevent acquisition of infection
29
with AIDS after initiating ART. IRIS is characterized by an (preexposure prophylaxis [PrEP] and postexposure prophylaxis).
acute paradoxical worsening of inflammatory symptoms of treated
opportunistic infections or the unmasking of previously subclini- Male Medical Circumcision
cal, untreated infections related to the recovery of immune The penile foreskin contains HIV-susceptible cells and is a
responses to opportunistic pathogens. IRIS occurs within weeks potential portal of viral entry. Randomized controlled trials in
of ART initiation as the memory and effector antigen-activated several African countries have indicated that male medical cir-
CD4 T-cell population recovers. A recent systematic review found cumcision reduces the risk of heterosexually acquiring HIV
37
28
that IRIS developed in 13% of patients after initiation of ART. infection by 50–60%. The WHO recommends male circumcision
The most predictive risk factor for the development of IRIS was as part of a comprehensive HIV prevention package; however,
a low CD4 T-cell count at the start of ART, with the incidence condom use and other prevention modalities remain important
of IRIS increasing exponentially as the CD4 T-cell count declined. in HIV prevention. There was only a modest benefit for the
IRIS develops more commonly in patients with cytomegalovirus female partners of the circumcised men. In fact, in some cir-
(CMV) retinitis, cryptococcal meningitis, progressive multifocal cumstances, the risk of transmission to women from men with
leukoencephalopathy, and tuberculosis. Studies reported that as HIV infection who have undergone circumcision may be
many as 4% of patients with IRIS died, but the proportion was increased, perhaps through exposure to infected blood attributed
much higher if the syndrome was associated with cryptococcal to resumption of sexual activity before the circumcision site has
meningitis. 29 fully healed. 37
Hyperallergenic State Associated With Preexposure Prophylaxis
Immunoreconstitution Recently, two different modalities of ART have been found to
Another complication possibly associated to IRIS is the appearance decrease acquisition of HIV when used by uninfected individuals
of asthma in children who were perinatally infected with HIV before their exposure to the virus as PrEP: topically applied ARV
30
and received combination ART since infancy. This condition medications and systemic ART. Topically applied ARVs have been
may be mediated by CD4 T-cell activation, release of Th2-type shown to block the acquisition of HIV in women from their
cytokines, and loss of Tregs and tolerance. In support of this partners with HIV infection by 35–54%. The Centre for the
31
concept, Gingo et al. reported at least a 20% prevalence of AIDS Program of Research in South Africa (CAPRISA 004) trial
asthma in adults with HIV infection compared with that of was the first double-blind randomized controlled trial demonstrat-
8.8% in the general population. In a subsequent pediatric study ing the efficacy of vaginally inserted gel containing the ARV
in which pulmonary function testing was objectively measured medication tenofovir disoproxil fumarate, compared with a
by spirometry, the following findings emerged: Nonreversible placebo gel, in preventing HIV transmission from men with
obstructive pulmonary disease was present in youth who had HIV infection to their uninfected partners. Vaginal PrEP represents
been perinatally infected with HIV and possibly in those exposed a promising intervention for preventing heterosexual transmission
to HIV but were uninfected. This pulmonary disorder contains of HIV to women. This method may be particularly effective
elements of asthma and chronic obstructive pulmonary disease because women are able to initiate and control its use to protect
(COPD) and closely resembles the asthma–COPD overlap syn- themselves from infection.
drome. Chronic infections and immune dysregulation appears
to play a significant role in this complication of HIV infection. 32 Prophylactic Antiretroviral Therapy
ARVs taken prophylactically have also been shown to be effective
PREVENTION in reducing the transmission of HIV both in MSM and in
heterosexual individuals and couples. The multinational Preex-
Prevention of Mother-to-Child Transmission posure Prophylaxis Initiative trial demonstrated that daily oral
More than 90% of children living with HIV worldwide were combination therapy with emtricitabine and tenofovir disoproxil
infected through mother-to-child transmission during pregnancy, fumarate (FTC-TDF) reduced the incidence of HIV among MSM
33
around the time of birth, or through breastfeeding. Efforts to by 44% compared with placebo. Daily oral FTC-TDF was also
prevent this transmission hold the most promise in reducing the shown to reduce HIV incidence among heterosexual individuals
number of children infected with HIV, and these efforts include (i) by 63–78% and by 73% among heterosexual discordant couples.
early identification of HIV infection in pregnant women through Despite these successful trials, preliminary results of one PrEP
routine antenatal testing; (ii) provision of ARV medications to trial have failed to show similar efficacy for preventing HIV
both the pregnant woman and her infant 34,35 ; (iii) delivery by elec- acquisition among heterosexual women.
tive cesarean section, when indicated; (iv) complete avoidance of
breastfeeding when safe and sustainable alternatives are available; Expanded Treatment With Antiretroviral Therapy
(v) widespread availability of educational programs addressing The expanded use of ART in infected individuals has been shown
HIV infection; (vi) prevention of HIV perinatal transmission; to reduce HIV transmission to uninfected partners. Both “Treat-
and (vii) HIV counseling and testing services. 35,36 ment as Prevention” and “Test and Treat” strategies involve the
use of ART in individuals who do not otherwise meet the criteria
Prevention of Sexual Transmission for ART initiation with the express purpose of reducing transmis-
Several biomedical interventions have the potential for radically sion to others. In both approaches, ART is initiated regardless
changing the patterns and rates of HIV transmission. These of CD4 count or viral load to reduce the viral load in the genital
558 ParT fOur Immunological Deficiencies
secretions of infected partners and thereby reduce HIV transmis- Association of certain major histocompatibility complex (MHC)
sion to uninfected partners. The efficacy of the “Treatment as molecules with HIV disease progression is clearly linked to the
Prevention” model is demonstrated in the multinational HIV cytotoxic T-cell responses. Unfortunately, the HIV vaccine-induced
Prevention Trials Network (HPTN 052) clinical trial that examined cytotoxic CD8 T-cell response is insufficient to halt the progression
the effectiveness of ART to prevent the sexual transmission of of acute or chronic HIV disease. This was clearly indicated in
HIV in serodiscordant couples. Serodiscordant couples (1763 the STEP clinical trial, in which the CD8 T-cell effects were the
in number) were randomly assigned to have the infected partner same between HIV-infected vaccinees and sham HIV-infected
either start ART immediately upon enrollment or to defer ART vaccinee controls. Qualities of effector and central memory CD8
until immunological or clinical criteria were met. Of 28 genetically T cells that would be protective include (i) production of cytotoxic
linked infections that occurred during the trial, only 1 infection cytokines (e.g., IFN-γ and IL-2); (ii) rapidly replicating capacity;
occurred in couples assigned to receive immediate treatment, (iii) cytotoxic potential; (iv) high affinity for HIV antigens; (v)
representing a 96% reduction in the risk of HIV transmission. inhibition of HIV replication; (vi) recognition of specific HIV
There were also fewer morbidity and mortality events in the epitopes restricted by protective HLA-B antigens; (vii) central
early-treatment group, suggesting a therapeutic benefit from memory cells with long life spans; and (viii) rapid-attack memory
early treatment as well. cells at mucosal HIV entry sites. A high-level collaboration of
The fundamental paradigm for “Test and Treat” programs is preeminent clinicians and scientists has proposed the modification
the same as that for “Treatment as Prevention” programs. “Test of the partially successful RV144 vaccine with the goal of produc-
and Treat,” however, emphasizes the need for universal voluntary ing a new HIV vaccine that will broadly neutralize HIV and
routine HIV testing and initiating ART immediately in those variants of HIV that emerge under selective pressure (Table 39.3
39
found to be positive regardless of CD4 count or viral load. and Table 39.4). These modifications include changes in the
Although the approach remains controversial, with concerns viral epitopes, vaccine adjuvants, and use of a different clade as
regarding drug resistance, increased sexual risk taking in treated the construct of the virus. The goal of this new proposal is to
individuals, and societal cost-effectiveness, this approach may, use the information of many previous HIV trials to produce an
over time, prove to be an effective prevention modality. ideal HIV vaccine that will prevent the spread of HIV infection
in children and adults.
HIV VACCINES: CLINICAL TRIALS Therapeutic Vaccines
Preventive Vaccines A therapeutic vaccine is one in which the vaccine is used after
The production of an effective HIV vaccine has been thwarted infection occurs, aiming to induce antiviral immunity to alter
by the extreme rate of mutation in the virion and the sequestration the course of disease. This would be accomplished by controlling
of the virus in impenetrable reservoirs, predominantly the viremia or reducing the viral set point in infected patients. Primate
nonreplicating CD4 T cell. More than 30 HIV vaccines have models suggest that just such a result is possible, especially with
been tested in human trials, including those with recombinant cellular immunity–inducing vaccines. To date, however, data
env gp120 proteins with adjuvants, HIV DNA plasmids, viral from human studies have not shown any conclusive benefit in
38
vectors, and prime-boost designs. These vaccines have, for the using therapeutic vaccines alone. Using a therapeutic vaccine in
most part, yielded disappointing results. Phase III trials of VAX003 combination with ART is another approach currently under
in Thailand (AIDSVAX B/E plus alum) and VAX004 in North investigation. A small study of a therapeutic vaccine in 25
America and Europe (AIDSVAX B/E plus alum) showed no individuals with HIV infection produced a 1 log 10 reduction in
protection against HIV infection. Naked HIV DNA with cytokines viral load compared with placebo-treated individuals with HIV
40
IL-15, IL-12, and chemokine receptor 005 with and without infection. However, HIV disease progression was not seen with
electroporation has not been effective. Pox virus HIV vaccines this therapeutic vaccine in limited follow-up, indicating the need
in the STEP trial of North and South Americas and the Phambili for longer follow-up and larger clinical trials before any measure
trial in South Africa (Ad5-HIV trivalent vaccine) were ineffective of success can be claimed.
in stopping HIV entry or postinfection viremia. However, the
phase III trial RV144 in Thailand (ALVAC-HIV vCP1521 + Future for HIV Vaccines
AIDSVAX gp120 B/E) showed possible protection against HIV The general pessimism that prevailed in the scientific community
infection in heterosexual men and women. 38 after the failure of the STEP vaccine trial is gradually being
In addition to the goal of developing an HIV vaccine that replaced by cautious optimism as a result of the limited success
elicits neutralizing antibodies, the search for a vaccine that of the RV144 clinical trial in Thailand. In addition, there is general
stimulates a protective CD8 cytotoxic T-cell response continues. belief that more basic research exploring vaccine design and
TABLE 39.3 Post rV144 Vaccine Combinations
Improve frequency, Magnitude, and
+
Polyfunctionality of CD4 T-Cell Improve Clade-Specific antibody Improve Durability of antibody
response to HIV-1 Envelope Products responses to gp120 response Through adjuvants
ALVAC (ZM96) +/−DNA Bivalent clade C recombinant gp120 Alum, MF59, AS01 B
NYVAC (ZM96) +/− DNA protein (strains 1086 and TV-1) construct
Ad26+/− MVA gp140 clade C trimeric protein +/− gp140 Alum, AS01 B
mosaic trimeric protein
Taken with permission from Corey et al. Immune correlates of vaccine protection against HIV-1 acquisition. Sci Transl Med 2015; 7: 310rv7. Review.
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 559
TABLE 39.4 Comparison of Immune responses That Influence VE in rV 144 Versus Past and
Ongoing Human Immunodeficiency Virus (HIV) Vaccine Trials
Immune response Identified
as a Correlate in rV144 responses in Non-rV144 Efficacy Trials responses in Vaccines in Current Development
Total IgG to V1V2 scaffold Lower in HVTN 505 compared with RV144 Higher titers in DNA/NYVAC/gp120 than RV144.
Correlates of protection in heterologous NHP challenge
studies with Ad26/Ad35 and Ad26/MVA studies
Serum IgA to gp120 (higher IgA = Higher IgA (including IgA to A1ConEnv) in HVTN 505, Administration of gp120 at onset of priming with NYVAC
lower VE) compared with RV144 and DNA/NYVAC markedly lowers serum IgA to gp120
DNA/MVA priming has lower IgA
IgG3 to V1V2 Lower in HVTN 505 and VAX003 than RV144 Under evaluation
ADCC activity Minimal ADCC in HVTN 505 ADCC correlates with protection in NHP using
Ad26 +/− trimeric gp120
High ADCC in DNA/MVA regimen
Tier 1 nAbs Higher frequency in RV144 compared with HVTN 505 Clade C regions under study
High avidity to gp120 Not measured in HVTN 505 program DNA/MVA containing regimens have high avidity. Other
Env IgG avidity with low IgA correlated with products under study
decreased risk of infection
CD4+ T cells with polyfunctional Different cytokine profile in HVTN 505 vs. RV144 DNA/NYVAC and Ad26/MVA increase prevalence and
response magnitude of Env specific CD4+ T cells
ADCC, antibody-dependent cellular cytotoxicity; Ig, immunoglobulin; nAbs, neutralizing antibodies.
Taken with permission from Corey et al. Sci Transl Med 2015 Oct 21;7(310):310rv7. doi:10.1126/ scitranslmed.aac7732.
trials in animals will lead to important clues for human study. Using viral vectors to place gene constructs within nuclear DNA
Illustration of clinical trials in antiretroviral-treated macaques that prevent HIV replication is the goal of such research. Arguably,
may be applied to humans in future by Byrareddy et al and the most advanced form of this genetic engineering to halt HIV
Nishimura et al. Monoclonal antibody specific for CD4 T cell replication is the zinc finger endonuclease approach to disrupt
surface integrin (α4β7) disrupts cellular trafficking of CD4 T specific genes necessary for the lifecycle of HIV. Adoptive transfer
cells with gastrointestinal tissue mucosal vascular addressin cell of autologous zinc finger–treated stem cells with infinite replica-
adhesion molecule (MAdCAM1). The CD4 T cell counts remained tion capacity may be an attractive future for individuals already
43
steady, CD8 T cell immunity sharply increased, and HIV replica- infected with HIV. The extraordinary experiment of HLA-
tion became undetectable for up to 2 years. 41,42 As illustrated by matched and CCR5-δ35 deletion of hematopoietic stem cell
these HIV vaccine studies in animals, understanding the immune immunoreconstitution of an patient with HIV infection (“Berlin
correlates of vaccine efficacy is an absolute requirement for Man”) is a proof of concept of molecular and genetic engineering
judging the success of an HIV vaccine. to cure HIV infection, a technique totally impractical to the
44
millions of patients with HIV infection worldwide. Nevertheless,
this “one in a million” chance experiment has demonstrated the
ON THE HOrIZON survival advantage of lymphocytes that cannot become infected
• Production of newer antiretroviral drugs, including those used for with HIV.
postexposure prophylaxis with greater specificity for interrupting events HIV, a type 1 retrovirus, contains merely 9 genes, but those
in the viral lifecycle and with fewer side effects for patients. 9 genes have so far thwarted all scientific efforts toward finding
• Investigation of new microbicidal drugs that can be safely applied a cure of its infection in humans. Optimism is warranted, however,
before exposure for protection against human immunodeficiency virus because of the enormous knowledge base the study of HIV has
(HIV) transfer.
• Development of preventive and therapeutic vaccines for HIV/acquired generated in understanding the many arms of innate and adaptive
immunodeficiency syndrome (AIDS) that induce strong viral neutralizing immunity protecting humans and the promise of a curative
antibody power and strong CD8 T-cell cytotoxic responses. treatment or vaccine for HIV. The HIV/AIDS pandemic has also
• Testing of gene construct-modified autologous hematopoietic stem brought the sobering realization that other new and potentially
cells capable of halting HIV replication. deadly pathogens may yet emerge to strike at humanity. Perhaps
no other disease has caused so much to be learned so fast. In
the developed world, HIV causes chronic infection, rather than
certain death, thanks, in large part, to the use of ARV drugs.
TRANSLATIONAL RESEARCH NEEDS More novel drugs are in development as a result of the new-found
AND CONCLUSIONS understanding of the molecular biology of HIV. HIV continues
to perplex and fascinate virologists and immunologists, and it
The quest for better ARV therapeutic agents continues, with the continues to teach humility to clinicians.
goal of greater selectivity and fewer side effects. However, the
eradication of HIV/AIDS can only be approached practically ACKNOWLEDGMENTS
with a preventive vaccine that elicits strong HIV-neutralizing
ability and generates a strong cytotoxic CD8 T-cell response Supported in part by NIH Grants HD052102, AI069536 AI36211,
specific for HIV antigens. The approach to cure with gene therapy and AI082978, and the Pediatric AIDS Fund of Texas Children’s
is perhaps the most sophisticated translational research venture. Hospital.
560 ParT fOur Immunological Deficiencies
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details. 24. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines
for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Bethesda, MD: NIH Office of the AIDS Research Advisory
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associated with reduced CD4 and enhanced CXCR4 and FAS surface transmitted infections. Annu Rev Med 2014;65:293–306.
expression levels. Retrovirology 2015;12:86. 38. Huang Y, Follmann D, Nason M, et al. Effect of rAd5-vector HIV-1
16. Campbell GR, Bruckman RS, Chu YL, et al. Autophagy induction by preventive vaccines on HIV-1 acquisition: a participant-level
histone deacetylase inhibitors inhibits HIV type 1. J Biol Chem meta-analysis of randomized trials. PLoS ONE 2015;10:e0136626.
2015;290:5028–40. 39. Corey L, Gilbert PB, Tomaras GD, et al. Immune correlates of vaccine
17. Tomescu C, Abdulhaqq S, Montaner LJ. Evidence for the innate immune protection against HIV-1 acquisition. Sci Transl Med 2015;7:310rv7.
response as a correlate of protection in human immunodeficiency virus 40. Mylvaganam GH, Silvestri G, Amara RR. HIV therapeutic vaccines:
(HIV)-1 highly exposed seronegative subjects (HESN). Clin Exp moving towards a functional cure. Curr Opin Immunol 2015;35:1–8.
Immunol 2011;164:158–69. 41. Byrareddy SN, Arthos J, Cicala C, et al. Sustained virologic control in
18. Scully E, Alter G. NK Cells in HIV Disease. Curr HIV/AIDS Rep SIV+ macaques after antiretroviral and α4β7 antibody therapy. Science
2016;13:85–94. 2016;354(6309):197–202.
19. Singh KK, Qin M, Brummel SS, et al. Killer cell immunoglobulin-like 42. Nishimura Y, Gautam R, Chun TW, et al. Early antibody therapy can
receptor alleles alter HIV disease in children. PLoS ONE 2016;11:e0151364. induce long-lasting immunity to SHIV. Nature 2017;543(7646):559–63.
20. Zhao L, Gao J, Li Y, et al. Disrupted homeostatic cytokines expression in 43. June CH, Levine BL. T cell engineering as therapy for cancer and HIV:
secondary lymph organs during HIV infection. Int J Mol Sci our synthetic future. Philos Trans R Soc Lond B Biol Sci
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expression. Blood 2011;117:3799–808.
CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 560.e1
M u LTIPLE-CHOICE Q u ESTIONS
1. Globally the segment of the population with the highest human C. Preventive vaccines
immunodeficiency virus (HIV) infection rate is that of the: D. Male circumcision
A. Adult male 4. The first lymphocyte subpopulation to return in the immu-
B. Adult female noreconstitution observed after antiretroviral treatment of
C. Adolescent male immunosuppressed patients with HIV infection is:
D. Adolescent female
A. CD4 memory cells
2. The rapid HIV diagnostic screening test (results in 30 minutes) B. CD19 memory cells
most commonly used is: C. CD4 naïve T cell
A. HIV RNA D. CD8 naïve T cell
B. Enzyme immune assay
C. HIV DNA
D. Western blot
3. Worldwide, a cure for HIV/AIDS will most likely happen
with which treatment?
A. Therapeutic vaccines
B. Combination antiretroviral therapy
40
Autoantibody-Mediated Phenocopies of
Primary Immunodeficiency Diseases
Sarthak Gupta, Sarah K. Browne
Anticytokine autoantibodies have been identified in health and There are numerous commonalities and distinctions worth
disease, with their role in pathogenesis ranging from none to highlighting among anticytokine autoantibody–associated immune
directly causal. In fact, it is becoming increasingly recognized deficiency. Shared in common is the presence of high-titer, neutral-
that neutralizing, high-titer autoantibodies cause a variety of izing anticytokine autoantibodies of the immunoglobulin G (IgG)
potentially life-threatening illnesses. Their manifestations are isotype. PAP caused by anti–GM-CSF autoantibodies appears
diverse, and their clinical presentation is generally a reflection of to be primarily a lung disease largely resulting from disruption
the cytokine pathways that are rendered functionally deficient. of GM-CSF–dependent pulmonary surfactant catabolism. In
Examples include pulmonary alveolar proteinosis (PAP) vitro studies using primary human cells and mouse work have
caused by anti–granulocyte macrophage–colony-stimulating demonstrated that anti–GM-CSF autoantibodies cause immune
1
factor (GM-CSF) autoantibodies ; disseminated nontuberculous dysfunction, largely through transcription factor PU.1, which
mycobacterial (NTM) and other opportunistic infections and may explain pulmonary and extrapulmonary infections observed
2
anti–interferon-γ (IFN-γ) autoantibodies ; chronic mucocutaneous in PAP, particularly those opportunists known to be controlled
1
candidiasis (CMC) and anti–interleukin (IL)-17A, anti–IL-17F, by neutrophils or macrophages. PAP caused by anti–GM-CSF
3,4
or anti–IL-22 autoantibodies ; and staphylococcal skin infection autoantibodies is similar to severe immune deficiency caused
5
and anti–IL-6 autoantibodies (Table 40.1). In each of these cases by anti-IFN-γ autoantibodies in that both diseases have adult
a high-titer, biologically active autoantibody has been identified onset. On the basis of broad screening for other autoantibodies,
in association with a unique clinical syndrome. Although this it appears they make high-titer neutralizing autoantibody against
list is not exhaustive, these diseases are of particular interest only one cytokine and do not demonstrate an increased frequency
1,2
in that the clinical manifestations are often similar to those in of other autoantibodies or forms of autoimmunity. Patients with
patients with genetic defects in the same cytokine-associated autoantibodies against IL-17A, IL-17F, IL-22, and CMC are differ-
pathways. The mendelian defects that confer a similar phenotype ent in that, so far, all have had an underlying primary diagnosis
to their anticytokine autoantibody counterpart also provide a of either autoimmune polyendocrinopathy with candidiasis and
3,4
strong biological rationale for establishing the autoantibodies as ectodermal dysplasia (APECED) or thymic neoplasia. Thus in
causal. Although a number of other anticytokine–autoantibody the case of APECED, a mendelian defect in the gene AIRE, which
associated syndromes such as pure red-cell aplasia (antierythro- is responsible for negative selection for autoreactive T cells in the
6
poietin autoantibodies) and severe osteoporosis in celiac disease thymus, the onset of anticytokine autoantibodies and CMC occurs
7
(antiosteoprotegerin autoantibodies) have been described, this earlier in life. Occasionally, CMC is the initial presentation of
chapter focuses on those that increase susceptibility to infection. thymoma (just as myasthenia gravis caused by antiacetylcholine
receptor autoantibodies must prompt evaluation for thymoma)
KEY CONCEPTS and highlights that for all anticytokine autoantibody–associated
Anticytokine Autoantibody–Associated Primary syndromes, the time line for development of anticytokine auto-
antibodies relative to the observation of clinical disease is largely
Immunodeficiency Diseases unknown. Additionally, patients with thymoma and APECED
can develop multiple anticytokine autoantibodies, although
• Anticytokine autoantibodies have been identified in a group of patients
with immunodeficiency diseases characterized by the development they have a proclivity for certain ones, including type I IFNs,
of high-titer, neutralizing autoantibodies to cytokines. IL-17A, IL-17F, IL-22, and, in the case of thymoma (but not
• The clinical manifestations in patients with anticytokine autoantibodies APECED), IL-12. Given the presence of multiple neutralizing
are similar to those seen in patients with genetic defects in the pathway autoantibodies, and the role of the thymus in T-cell development
of the target cytokine. that can lead to intrinsic T-cell defects that could also confer
• Immunodeficiency syndromes described include those associated with infection susceptibility, it is challenging to prove that a particular
anti– granulocyte macrophage–colony-stimulating factor (GM-CSF)
autoantibodies and pulmonary alveolar proteinosis (PAP); anti–interferon anticytokine autoantibody is the necessary and sufficient agent
(IFN)-γ autoantibodies and severe immunodeficiency; anti–interleukin of disease pathogenesis. In the case of anti–IL-6 autoantibodies,
(IL)-17A, anti–IL-17F, and anti–IL-22 autoantibodies and chronic high-titer, neutralizing anti–IL-6 IgG was demonstrated in one
mucocutaneous candidiasis (CMC); and anti–IL-6 autoantibodies and 11-month-old child with recurrent staphylococcal skin infections
staphylococcal skin infection. and low C-reactive protein-reactive protein (CRP), an IL-6–driven
• Management of these syndromes involves treating the consequences inflammatory marker. The opportunity to identify common
5
of the autoantibody (e.g., infectious manifestations, lung disease) or
targeting the autoantibody itself. clinical features around this entity is limited, since other cases
have yet to be identified.
561
562 ParT FOur Immunological Deficiencies
anticytokine autoantibody–associated Syndromes and Their Phenotypically Similar Genetic Counterparts
Comments Mutations in surfactant proteins have also been described SP-B, SP-C, or ABCA3, but are considered clinically distinct Functional testing to evaluate downstream inhibitory effects of autoantibody important, (i.e., plasma inhibition of IFN-γ–induced pSTAT1 production) Reported only in the context of APECED and thymoma so far One case reported to date
Pulmonary and extrapulmonary infections with Nocardia, Aspergillus, Proteus, Histoplasmosis, and Nontuberculous mycobacteria, tuberculosis, nontyphoidal Salmonella, Histoplasma, Penicillium, Cryptococcus, Burkholderia pseudomallei, varicella-zoster virus 2 Staphylococcus aureus
Infections Cryptococcosis 1 Candida spp.
In vitro Evidence for Biological activity Anti–GM-cerebrospinal fluid autoantibodies inhibit pSTAT-5 production, 17 PU.1 expression , MIP-1α protein production Anti–IFN-γ autoantibodies inhibit pSTAT1 production(2, 11), IFN-γ inducible gene expression 29 and IL-12p70 and TNF-α protein production 2,11 Anti–IL-17 autoantibodies inhibit IL-17–induced IL-6 4 Anti–IL-6 autoantibodies prevent IL-6–induced CRP mRNA 5
Laboratory and radiological Manifestations BAL fluid contains large foamy macrophages or monocyte-like macrophages and elevated levels of surfactant proteins Characteristic computed tomography (CT) of chest demonstrates ground-glass opacities with thickening of intralobular septae, “crazy paving.” PFTs demonstrate restrictive and diffusion defects 1 Elevated erythrocyte sedimentation rate, C-reactive protein-reactive protein (CRP), β
Clinical Manifestations PAP Insidious and progressive respiratory failure Newly described cases of isolated cryptococcal meningitis and Nocardia infection in individuals without human immunodeficiency virus (HIV) infection 17-19 Chronic infections with intracellular pathogens, particularly lymphadenitis, skin, soft tissue, and bone infections; can be multiple organisms simultaneously or sequentially; reactive dermatoses; constit
TABLE 40.1 Genetic Cytokine Phenocopies Target GM-CSF receptor α GM-CSF or β subunits Mutations in IFN-γ h IFN-γR1; IFN-γR2; STAT1; IL-12Rβ1; IL-12Rβ2; IL-12p40; NEMO; IRF8; ISG15 IL-17RA IL-17A IL-17F IL-17F IL-22 STAT3 IL-6
CHaPTEr 40 Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases 563
OVERVIEW OF PATHOPHYSIOLOGY dendritic cells (DCs), erythrocyte progenitors, and megakaryo-
cytes. The GM-CSF receptor is composed of two α and two β
The pathophysiology of infection susceptibility is generally subunits, which together bind two GM-CSF molecules with high
thought to result from a functional deficiency in the cytokine affinity and induce signal transduction and activator of transcrip-
that is being neutralized (Chapter 9). It is believed that a high- tion (STAT)–5 phosphorylation, nuclear translocation, and
titer autoantibody binds its respective cytokine target, thereby induction of master transcription factor PU.1. PAP was first
blocking downstream signaling and biological activity. For each described in 1958 by Rosen et al. as an idiopathic syndrome of
anticytokine–autoantibody pair, it has been demonstrated that respiratory failure, histopathologically characterized by alveolar
plasma or purified IgG from a patient with the anticytokine filling with acellular periodic acid-Schiff–positive proteinaceous
1
autoantibody prevents the activity of the targeted cytokine at the material. The pathogenesis of PAP has since been linked to
levels of signal transduction, gene transcription, and/or protein congenital or acquired defects in the GM-CSF signaling pathway.
expression. In the case of anti–IFN-γ autoantibodies, it appears The first clues to the etiological mechanism of PAP surfaced
−/−
8
that antibody levels may track with disease activity ; however, for in 1994 and 1995 when a GM-CSF and GM-CSF receptor
−/−
anti–GM-CSF autoantibodies, the results have been conflicting, β mice, respectively, demonstrated pulmonary disease that was
and in neither case has the question been rigorously studied. virtually identical to human PAP. Shortly thereafter, mechanisms
It is also possible, but not yet proven, that antibody-binding involving disruption of GM-CSF signaling were linked to PAP
1
avidity may influence the degree of disease severity as well. Thus in humans. Primary PAP results from mutations in either the
it may be possible to have high-titer, lower avidity anticytokine GM-CSF receptor subunits α or β and generally leads to severe
autoantibodies leading to a similar disease phenotype to low-titer, respiratory failure and usually presents early in life. Autoimmune
high-avidity anticytokine autoantibodies. PAP results from neutralizing anti–GM-CSF autoantibodies, can
The events that lead to the generation of anticytokine also cause respiratory failure, and shares the same pulmonary
autoantibodies are poorly understood and are likely disease histopathology as the primary form (Fig. 40.1). In contrast to
specific. Again, by comparing and contrasting these diseases, primary PAP, the median age of diagnosis of the autoimmune form
we may begin to understand some key factors. In the case of is 39 years, and its clinical course and severity is highly variable
pulmonary alveolar proteinosis, it appears to be linked to tobacco ranging from progressive respiratory decline to spontaneous
use and also demonstrates a male predominance, which may be resolution. A secondary form of PAP caused by qualitative or
an artifact of the historically higher rates of smoking in men, quantitative deficiency of alveolar macrophages, generally in the
particularly because no gender predilection has been observed context of hematologic malignancies, iatrogenic immunosup-
1
among nonsmokers. Although a large cohort of patients has pression, or inhaled toxins, has also been recognized.
been described in Japan, this disease is seen worldwide across Although the primary pathological process relates to impair-
all ethnicities and not within families, suggesting that if there is ment of GM-CSF–dependent catabolism of surfactant and its
a genetic component, it is a complex one. No familial clustering subsequent overaccumulation in pulmonary alveoli, there has
has been identified in over 130 cases of anti–IFN-γ autoantibodies
and opportunistic infection reported 2,9-12 ; however, the disease is
mostly seen in Asian-born Asians, suggesting that there may be
an environmental trigger in the context of a common genetic
background.
The fact that anticytokine autoantibodies are both IgG
and high-affinity autoantibodies implicates the T-helper (Th) B lymphocytes
lymphocyte–dependent processes of class switching and affin-
ity maturation. Interestingly, anti–IL-17A, –IL-17F, and –IL-22
autoantibodies appear directly linked to either the genetic AIRE
deficiency of APECED or the acquired AIRE deficiency observed
13
in patients with thymoma. In both cases, thymic-driven disease
appears to be leading to extensive B-lymphocyte dysregulation
in the form of many autoantibodies, beyond just anticytokine
autoantibodies. However, given that B cells may play a primary Alveolar
role in the development of autoimmunity in AIRE deficiency, the Th2 cell macrophage
13
mechanisms underlying B-cell autoreactivity are likely complex. GM-CSF GM-CSF
Furthermore, evidence in rheumatological mouse models suggests receptor
that peripheral B-lymphocyte lineages leading to autoantibodies
may fundamentally differ from those leading to development
14
of protective antibodies. Thus a common phenomenon of Anti-GM-CSF autoantibodies associated with
anticytokine–autoantibody production may, in fact, be a reflection pulmonary alveolar proteinosis, cryptococcal
meningitis, and nocardia infections
of a convergence of multiple differing mechanisms.
FIG 40.1 Anti– Granulocyte Macrophage–Colony-Stimulating
ANTI–GM-CSF AUTOANTIBODIES AND Factor (GM-CSF) Autoantibody Associated Pulmonary Alveolar
PULMONARY ALVEOLAR PROTEINOSIS Proteinosis (PAP). Autoimmune PAP results from impairment
of GM-CSF–dependent catabolism of surfactant and its subse-
GM-CSF is a hematopoietic stem cell (HSC) growth factor that quent overaccumulation in pulmonary alveoli due to neutralizing
binds the GM-CSF receptor, which is widely expressed on many anti–GM-CSF autoantibodies, leading to respiratory failure. Th2
cell lineages, including neutrophils, macrophage precursors, cell, T-helper cell-2.
564 ParT FOur Immunological Deficiencies
1
long been an association with opportunistic infections. Beyond a clinical response was not associated with a reduction in plasma
its role in pulmonary surfactant homeostasis, the GM-CSF or BAL concentrations of anti–GM-CSF autoantibodies, thereby
receptor is widely expressed on immune cells, including neu- providing possible support for the former mechanism. 20,21
trophils, monocytes, DCs, megakaryocytes, and erythrocyte B-cell–targeted therapy using the anti-CD20 chimeric monoclonal
progenitor cells, and influences cell differentiation, proliferation, antibody (mAb) rituximab has been used to treat a small number
and immune activation. GM-CSF has been shown in both humans of patients and has shown encouraging clinical results. 22
and mice to facilitate not only terminal differentiation of
monocytes to alveolar macrophages but also innate immune ANTI–IFN-γ AUTOANTIBODIES AND
responses, primarily via induction of transcription factor PU.1. SUSCEPTIBILITY TO INTRACELLULAR PATHOGENS
Cells isolated from bronchoalveolar lavage (BAL) fluid from
patients with autoimmune PAP show decreased PU.1 messenger IFN-γ, produced predominantly by activated Th1 cells and natural
RNA (mRNA), which is thought to be central to the pathogenesis killer (NK) cells, is central to host defense against intracellular
of PAP. PU.1 has been shown to regulate Toll-like receptor (TLR) pathogens (Chapter 26). The IFN-γ receptor (IFN-γR), expressed
signaling, adhesion, phagocytosis, and microbicidal activity, thus primarily on monocytes, is composed of two subunits in duplicate,
providing a mechanism for the increased infection susceptibility IFN-γR1 and IFN-γR2. Binding of IFN-γ to its receptor leads to
that is observed in PAP. Beyond the macrophage, defects have Janus kinase 2 (JAK2) and then JAK1 phosphorylation on the
also been shown in neutrophil adhesion, phagocytosis, oxidative intracellular portions of IFN-γR2 and -1, respectively. Subsequent
burst, and bacterial killing from both the blood of human patients STAT-1 docking, phosphorylation, homodimerization, and nuclear
−/−
with PAP and GM-CSF mouse bone marrow. 15 translocation lead to transcription of IFN-γ responsive genes.
Patients with acquired PAP are vulnerable to typical respiratory Macrophage activation, differentiation, and elaboration of inflam-
pathogens as well as opportunistic infections. Although the high matory mediators, such as tumor necrosis factor-α (TNF-α) and
incidence of respiratory infections may be partially attributable to IL-12, ensue. Defects in the IFN-γ–IL-12 axis lead to mendelian
their underlying chronic lung disease, the opportunistic infections susceptibility to mycobacterial disease as well as those caused
are generally caused by organisms controlled by macrophages, by other intracellular pathogens, including listeriosis, salmonel-
16
23
1
including Nocardia, Histoplasma, nontuberculous mycobacteria, losis, histoplasmosis, melioidosis, and penicilliosis. The list of
17
and Cryptococcus. Although Witty et al. reported eight cases genetic mutations involving this pathway that result in increased
of PAP and Mycobacterium avium complex cultured from BAL susceptibility to mycobacteria or other intracellular pathogens
16
fluid, these patients did not receive antimycobacterial drugs and continues to expand and, to date, includes mutations in IFN-γR1,
appeared to fare no worse. Furthermore, most of these infections IFN-γR2, STAT1, IL-12p40, IL-12Rb1, nuclear factor-κB (NF-κB)
were described before the recognition of anti–GM-CSF autoan- essential modulator (NEMO), IFN regulatory factor (IRF) 8,
23
tibodies as being causal, so these reports may be confounded by and IFN-stimulated gene (ISG) 15. Neutralizing autoantibodies
heterogeneity within the underlying diagnosis. against IFN-γ represent an alternative mechanism by which the
Extrapulmonary infections have been observed with some IFN-γ–IL-12 metabolic pathway is disrupted, with the first cases
9
frequency, which could be ascribed to the systemic effects of described in 2004 (Fig. 40.2). We reported 85 patients identified
2
anti–GM-CSF autoantibodies identified in serum. In support in a 6-month period, with over 130 patients reported to date, 8-12
of this systemic effect, several case reports describe patients with and this suggests that immunodeficiency caused by anti–IFN-γ
PAP who had extrapulmonary infections, including cases of autoantibodies is probably underappreciated.
central nervous system (CNS) Nocardia infection, septic arthritis, The infections in patients with anti–IFN-γ autoantibodies
perinephric abscess, and Nocardia dissemination to skin; CNS mimic many of those seen in patients with inborn errors in the
1
Aspergillus and Proteus; and disseminated histoplasmosis. IL-12–IFN-γ signaling pathways and include mycobacterial,
Recently, a few case series have reported opportunistic infections particularly nontuberculous environmental mycobacteria,
associated with high-titer neutralizing anti–GM-CSF autoantibod- nontyphoidal Salmonella, Penicillium, Histoplasma, Cryptococcus,
ies without concurrent PAP. Anti–GM-CSF antibodies have been Burkholderia pseudomallei, and additionally varicella-zoster virus
2
reported in previously healthy adults uninfected by HIV who (VZV), both dermatomal and disseminated. Infections have
had cryptococcal meningitis specifically caused by Cryptococcus been noted in all organ systems, although lymph nodes, skin,
gattii. 17,18 Neutralizing anti–GM-CSF autoantibodies were also soft tissue, and bone appear to be preferentially affected. Up to
found in five of seven patients with disseminated/extrapulmonary 50% of patients develop sterile reactive dermatoses, most com-
19
Nocardia infections. However, it remains to be seen if these monly neutrophilic dermatosis, but also erythema nodosum,
infections are the only manifestations in these patients or they pustular psoriasis, and exanthematous pustulosis.
may eventually develop PAP as seen in the two of seven cases Although patients with mendelian defects tend to present
of cryptococcal meningitis associated with anti–GM-CSF in childhood, all reported cases of patients with anti–IFN-γ
17
autoantibodies. Why the same autoantibody may have different were previously healthy adults, the vast majority of whom
clinical phenotypes is unknown. Opportunistic infections have were Asian-born Asians. A recent association with human leu-
not been reported as a complication of congenital PAP. Reasons kocyte antigen–antigen D related (HLA-DR)*15:02/16:02 and
for this could include the extreme rarity of this condition or HLA-DQ*05:01/05:02 was shown in 78 patients with anti–IFN-γ
24
limited opportunity for exposure to environmental opportunists autoantibodies, further implicating a genetic predisposition to
as a result of medical debilitation. development of disease. However, no familial clustering has been
Treatment includes whole lung lavage to evacuate the pro- observed, and Asians born outside of Asia have yet to be reported
teinaceous material contained in the alveoli. Inhaled and sub- with this syndrome, suggesting complex genetics and possibly
cutaneous GM-CSF has also been effective either by saturating an environmental contribution to autoantibody pathogenesis.
the antibody or inducing tolerance. 20,21 In two large studies, one The recent report of an American-born, Caucasian female with
using subcutaneous GM-CSF and one using inhaled GM-CSF, this syndrome also adds to the complexity of its pathogenesis. 12
CHaPTEr 40 Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases 565
and IL-17RC heterodimeric receptor complexes, ultimately
activating NF-κB. IL-22, produced by T lymphocytes and NK
cells, also signals via a heterodimeric receptor composed of
IL-22R1 and IL-10R2 subunits, expressed mainly on epithelial
B lymphocytes and other nonimmune cells. IL-17A/F and IL-22 cooperate to
induce proinflammatory cytokines involved in granulopoiesis
and neutrophil recruitment as well as antimicrobial peptides,
such as β defensins and S100 proteins, which are thought to be
important in mucosal immunity. Clinical evidence for a protective
role of IL-17 in CMC arose from the observation of this infectious
complication in diseases with varying degrees of Th17 impairment,
including STAT3-deficient hyper-IgE syndrome (HIES, or Job’s
Monocyte/ IFN-γ syndrome), dectin-1 deficiency, CARD9 deficiency, and, to a
macrophage Th1 cell lesser degree, IL-12 receptor β 1 deficiency. Strong support of
27
IFN-γ
receptor this hypothesis came via instances of two families that demon-
strated inherited susceptibility to mucosal candidiasis: one with
IL-12 an autosomal recessive mutation in IL-17RA, and another with
receptor an autosomal dominant negative mutation in IL-17F. 27
IL-12
APECED syndrome is another mendelian disorder associated
Anti-IFN-γ autoantibodies associated with with CMC. APECED, caused by mutations in the AIRE gene,
disseminated mycobacteria, salmonella, leads to a clinical triad of hypoparathyroidism, adrenal insuf-
13
fungal and varicella infections ficiency, and CMC. Other endocrine glands, including gonads,
thyroid, endocrine cells in the gut, and pancreatic islet cells, are
FIG 40.2 Anti-Interferon (IFN)γ Autoantibody Associated variably affected. Many other autoimmune phenomena, including
Susceptibility to Intracellular Pathogens. Neutralizing autoan- Sjögren syndrome, rheumatoid arthritis, hepatitis, keratitis,
tibodies against IFN-γ disrupt the IFN-γ–IL-12 metabolic pathway. vitiligo, pernicious anemia, and alopecia, as well as autoantibodies
Infections in patients with anti–IFN-γ autoantibodies mimic many to type I IFNs, have been described. The biological consequences
13
of the infections seen in patients with inborn errors in the of these anti–IFN-α autoantibodies are unclear, but autoantibodies
interleukin (IL)-12–IFN-γ signaling pathways and include myco- to other tissue antigens in autoimmune polyendocrinopathy
bacterial, nontyphoidal Salmonella, Penicillium, Histoplasma, syndrome type 1 (APS-1), such as autoantibodies to glutamic
Cryptococcus, Burkholderia pseudomallei, and varicella zoster acid decarboxylase, thyroid peroxidase, and 21-hydroxylase, are
virus. Th1 cell, T-helper cell-1.
clearly pathological. Providing explanation for the preponderance
of autoimmunity seen in APECED was the observation that the
transcriptional activity of AIRE in medullary thymic epithelial
Notable laboratory features include anemia of chronic disease cells (mTECs) promotes expression of tissue-specific genes,
and elevation in inflammatory markers, such as erythrocyte thereby facilitating intrathymic destruction of autoreactive T
sedimentation rate (ESR), CRP, and β 2 microglobulin. Immu- cells and fostering self-tolerance. 13
nologically, patients commonly demonstrate polyclonal hypergam- Unlike the above-described mendelian disorders, the mecha-
maglobulinemia, but they otherwise have normal lymphocyte nism of CMC in APECED is not directly linked to the genetic
phenotyping, including CD4 T lymphocytes, monocyte numbers, deficiency itself but, rather, to the strong genetic predisposition to
and IFN-γR1 expression. autoimmunity, which, in this case, includes production of neutral-
3,4
Treatment has focused mainly on managing the infections izing anti–IL-17A, anti–IL-17F and anti–IL-22 autoantibodies
with targeted antimicrobials. Interestingly, a severe paradoxical (Fig. 40.3). Puel et al. identified antibodies to IL-17A, IL-17F, or
inflammatory reaction similar to immune reconstitution syn- IL-22 in 33 patients with APECED, 29 of whom also had CMC,
drome, manifesting as lymphadenopathy, cavitary lung lesions, compared with healthy controls who had neither autoantibodies
4
and lytic bone lesions during antituberculosis treatment, has nor CMC. Kisand et al. found anti–IL-17A, –IL-17F, or –IL-22
been reported and should be distinguished from true failure of autoantibodies in up to 90% of 162 cases, also strongly associ-
3
25
antimicrobial treatment. In cases refractory to antiinfective ated with CMC. They also identified anti–IL-17 and anti–IL-22
agents, some have attempted to overcome the antibody with autoantibodies in two patients with thymoma and CMC, but in
IFN-γ administration or drive down antibody levels with plas- none of the 33 patients with thymoma who did not have CMC.
8
26
mapheresis and cyclophosphamide or rituximab. It is unclear There were a few instances of autoantibodies without CMC, and
what factors predict response to antimicrobials alone versus a there are many examples of CMC independent of APECED,
need for further immunomodulation; the efficacy of these immune and this suggests that autoantibodies to IL-17 and IL-22 are
modulatory approaches remains to be evaluated formally in not absolutely necessary for development of CMC. However,
clinical trials. their identification, particularly in light of the CMC disease
seen in patients with IL-17RA and IL-17F mutations, provides
ANTI–IL-17 AND ANTI–IL-22 AUTOANTIBODIES support for a causal relationship. Interestingly, thymoma tissue
AND CHRONIC MUCOCUTANEOUS CANDIDIASIS also demonstrates decreased AIRE expression, further linking
these diseases beyond a shared tendency toward autoimmunity
IL-17A and IL-17F are proinflammatory cytokines that can and anticytokine–autoantibody production. What is less clear
combine as either homodimers or heterodimers with each other however, is the exact role AIRE is playing in pathogenesis of organ-
(Chapter 9). These dimerized combinations signal via IL-17RA specific autoimmunity (including anticytokine autoantibody
566 ParT FOur Immunological Deficiencies
MANAGEMENT
Therapies directed at the syndromes of pathogenic autoantibodies
have focused either on treating the disease consequences or
B lymphocytes
targeting the autoantibody itself. Therapeutic BAL removes
proteinaceous alveolar material from the lungs of patients with
1
PAP, and antimycobacterials treat the disseminated NTM infec-
tion in patients with autoantibodies to IFN-γ. 9,29 Approaches
ranging from physical removal of the antibody, to immuno-
modulatory therapy, to induction of immune tolerance or
suppression of the population of cells that produce the pathogenic
autoantibodies have also been employed.
Epithelial PAP and disseminated NTM associated with anti–IFN-γ
IL-22 IL-22 20,21
Th17 cell cell autoantibodies have been treated with exogenous GM-CSF
receptor and IFN-γ, respectively, resulting in clinical improvement,
29
although PAP has been studied more rigorously in this regard.
IL-17A Autoantibody levels after therapy were not routinely evaluated
IL-17F across diseases, nor are they performed in a standardized fashion,
IL-17
receptor although, at least in the PAP cohorts, it appears they do not
change in response to exogenous cytokine. 20,21
Anti-IL-22, anti-IL17A and anti-IL-17F In cases that are refractory to treatment, attempts have been
autoantibodies associated with mucocutaneous made to alleviate the blockade by reducing anticytokine–
candidiasis in APECED and thymoma patients autoantibody levels. One patient with anti–IFN-γ autoantibodies
FIG 40.3 Anti–Interleukin (IL)-17 and Anti–IL-22 Autoantibodies underwent plasmapheresis and cyclophosphamide therapy in
26
Associated Chronic Mucocutaneous Candidiasis (CMC). IL- addition to antimycobacterials. Rituximab, the mouse–human
17A/F and IL-22 induce proinflammatory cytokines involved in chimeric mAb that targets the human B-cell marker CD20, is
granulopoiesis and neutrophil recruitment as well as important currently approved for treatment of B-cell lymphoma and
mucosal antimicrobial peptides, such as β defensins and S100 rheumatoid arthritis. Since B cells ultimately differentiate into
proteins. Neutralizing anti–IL-17A, anti–IL-17F, and anti–IL-22 antibody-producing cells, it has been applied to a number of
autoantibodies in autoimmune polyendocrinopathy with candidiasis autoantibody-mediated diseases, such as myasthenia gravis
and ectodermal dysplasia (APECED) syndrome is the likely (Chapter 65) and pemphigus vulgaris (a blistering skin disease
mechanism of CMC in these patients. caused by autoantibodies that recognize desmoglein 3, a kera-
tinocyte cell-surface protein; Chapter 63). Successful rituximab
22
therapy has also been reported in PAP and immunodeficiency
8
caused by anti–IFN-γ autoantibodies with a specific reduction
formation), since the syndromes diverge considerably in this of anticytokine–autoantibody titers.
regard. 13 A new approach in pure red blood cell (RBC) aplasia caused
by antierythropoietin autoantibodies is to bypass the autoantibody
ANTI–IL-6 AUTOANTIBODIES AND RECURRENT with a erythropoietin receptor synthetic peptide agonist pegine-
STAPHYLOCOCCAL SKIN INFECTION satide (Hematide; Affymax) that does not share homology with
30
the eosinophil peroxidase (EPO) ligand. Although this approach
IL-6 is produced by many immune and nonimmune cells, has not been used in cases of anticytokine autoantibodies and
including B cells, T cells, macrophages, synovial cells, endothelial immune deficiency, it underscores the range of novel treatment
cells, and hepatocytes, and is involved in both acute and chronic approaches that might be explored for anticytokine autoantibody–
inflammation, ranging from sepsis to rheumatoid arthritis. IL-6 associated syndromes.
binds a heterodimeric receptor composed of IL-6Rα and a shared
receptor chain gp130. IL-6Rα confers ligand specificity, whereas CONCLUSIONS
gp130 mediates signal transduction. IL-6 regulates the acute
phase response in the liver, with its hallmark induction of CRP Anticytokine autoantibodies have been identified in healthy
and elevated ESR. Anti–IL-6 autoantibodies were identified in normal adults as well as in those with different diseases, suggesting
a Haitian boy who had two episodes of severe staphylococcal that their occurrence may range from a normal homeostatic
cellulitis, one complicating chickenpox infection, the other mechanism, to epiphenomena, to being directly pathogenic. In
5
complicating mosquito bites. Treatment included supportive PAP, the identification of anti–GM-CSF autoantibodies came
care and antiinfective agents. Undetectable CRP, despite severe over 40 years after the initial description of the syndrome, sug-
infection, suggested impairment in IL-6 activity. STAT3 is the gesting that other currently idiopathic diseases may someday be
critical signal transduction molecule for IL-6 and IL-10, and explained by the identification of neutralizing or agonizing
autosomal dominant mutations in STAT3 also lead to recurrent autoantibodies. Furthermore, it was not intuitive that systemic
28
staphylococcal skin abscesses, suggesting a common potential autoantibodies to a hematopoietic growth factor should result
mechanism for this phenotypic profile of infection susceptibility. in disease confined mainly to the lung. The identification of
The limitations to this association are that the infections in the anti–GM-CSF autoantibodies in cryptococcal meningitis impli-
Haitian boy resolved without any apparent change in the anti–IL-6 cates the GM-CSF pathway in host defense of this infection,
autoantibody titers, and this is the only reported case to date. much as mendelian disorders have done for NTM and the
CHaPTEr 40 Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases 567
ON THE HOrIZON 9. Hoflich C, Sabat R, Rosseau S, et al. Naturally occurring anti-IFN-
γautoantibody and severe infections with Mycobacterium cheloneae and
• Anticytokine autoantibodies are an emerging mechanism underlying Burkholderia cocovenenans. Blood 2004;103:673–5.
the pathogenesis of immune deficiency in previously “healthy” adults. 10. Kampitak T, Suwanpimolkul G, Browne S, et al. Anti-interferon-
• The clinical manifestations of these diseases, like pulmonary involve- γautoantibody and opportunistic infections: case series and review of the
ment in anti–granulocyte macrophage–colony-stimulating factor literature. Infection 2011;39:65–71.
(GM-CSF) associated pulmonary alveolar proteinosis (PAP), may provide 11. Patel SY, Ding L, Brown MR, et al. Anti-IFN-γautoantibodies in
insight to signaling pathways and target cells of the involved disseminated nontuberculous mycobacterial infections. J Immunol
cytokine. 2005;175:4769–76.
• Recent discovery of many anticytokine autoantibody–associated 12. O’Connell E, Rosen LB, LaRue RW, et al. The first US domestic report of
diseases suggests that other idiopathic immunodeficiency diseases disseminated Mycobacterium avium complex and anti-interferon-
may be the result of an autoantibody affecting an as-yet unknown γautoantibodies. J Clin Immunol 2014;34:928–32.
signaling pathway or cell type. 13. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis
• Much research needs to be done on the management of patients ectodermal dystrophy. J Clin Immunol 2015;35:463–78.
with these syndromes, since besides just treating the symptomatic
consequences of the autoantibody, the autoantibody or its generation 14. Huang H, Benoist C, Mathis D. Rituximab specifically depletes short-lived
itself can now be targeted. autoreactive plasma cells in a mouse model of inflammatory arthritis.
• Profiling anticytokine autoantibodies in patients with immunodeficiency Proc Natl Acad Sci USA 2010;107:4658–63.
could help personalize their management by potentially predicting 15. Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and
disease manifestations and optimizing treatment options. neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med
2007;356:567–79.
16. Witty LA, Tapson VF, Piantadosi CA. Isolation of mycobacteria in
IFN-γ–IL-12 pathway. The observation of high-titer, neutralizing patients with pulmonary alveolar proteinosis. Medicine (Baltimore)
anticytokine autoantibodies in an expanding number of diseases, 1994;73:103–9.
7
beyond just those characterized by immune deficiency, combined 17. Rosen LB, Freeman AF, Yang LM, et al. Anti-GM-CSF autoantibodies in
with the opportunity for novel therapeutic approaches to their patients with cryptococcal meningitis. J Immunol 2013;190:3959–66.
diagnoses, mandates that their presence be not merely considered 18. Saijo T, Chen J, Chen SC, et al. Anti-granulocyte-macrophage
but rigorously sought. colony-stimulating factor autoantibodies are a risk factor for central
nervous system infection by Cryptococcus gattii in otherwise
immunocompetent patients. MBio 2014;5:e00912–14.
ACKNOWLEDGEMENTS 19. Rosen LB, Rocha Pereira N, Figueiredo C, et al. Nocardia-induced
granulocyte macrophage colony-stimulating factor is neutralized by
This work was supported by the Divisions of Intramural Research autoantibodies in disseminated/extrapulmonary nocardiosis. Clin Infect
of National Institute of Arthritis and Musculoskeletal and Skin Dis 2015;60:1017–25.
Diseases (NIAMS) and National Institute of Allergy and Infectious 20. Kavuru MS, Sullivan EJ, Piccin R, et al. Exogenous
Diseases (NIAID) of the National Institutes of Health (NIH), granulocyte-macrophage colony-stimulating factor administration for
Bethesda, MD. pulmonary alveolar proteinosis. Am J Respir Crit Care Med
2000;161:1143–8.
Please check your eBook at https://expertconsult.inkling.com/ 21. Tazawa R, Trapnell BC, Inoue Y, et al. Inhaled granulocyte/macrophage-
for self-assessment questions. See inside cover for registration colony stimulating factor as therapy for pulmonary alveolar proteinosis.
details. Am J Respir Crit Care Med 2010;181:1345–54.
22. Kavuru MS, Malur A, Marshall I, et al. An open-label trial of rituximab
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first 44 years. Am J Respir Crit Care Med 2002;166:215–35. to mycobacterial disease: genetic, immunological, and clinical features
2. Browne SK, Burbelo PD, Chetchotisakd P, et al. Adult-onset of inborn errors of IFN-gamma immunity. Semin Immunol 2014;26:
immunodeficiency in Thailand and Taiwan. N Engl J Med 454–70.
2012;367:725–34. 24. Ku CL, Lin CH, Chang SW, et al. Anti-IFN-γautoantibodies are strongly
3. Kisand K, Boe Wolff AS, Podkrajsek KT, et al. Chronic mucocutaneous associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across
candidiasis in APECED or thymoma patients correlates with Southeast Asia. J Allergy Clin Immunol 2016;137:945–8.e8.
autoimmunity to Th17-associated cytokines. J Exp Med 25. Xie YL, Rosen LB, Sereti I, et al. Severe paradoxical reaction during
2010;207:299–308. treatment of disseminated tuberculosis in a patient with neutralizing
4. Puel A, Doffinger R, Natividad A, et al. Autoantibodies against IL-17A, anti-IFN-γ autoantibodies. Clin Infect Dis 2016;62:770–3.
IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis 26. Baerlecken N, Jacobs R, Stoll M, et al. Recurrent, multifocal
and autoimmune polyendocrine syndrome type I. J Exp Med Mycobacterium avium-intercellulare infection in a patient with
2010;207:291–7. interferon-γautoantibody. Clin Infect Dis 2009;49:e76–8.
5. Puel A, Picard C, Lorrot M, et al. Recurrent staphylococcal cellulitis and 27. McDonald DR. TH17 deficiency in human disease. J Allergy Clin
subcutaneous abscesses in a child with autoantibodies against IL-6. J Immunol 2012;129:1429–35, quiz 36–7.
Immunol 2008;180:647–54. 28. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the
6. Casadevall N, Dupuy E, Molho-Sabatier P, et al. Autoantibodies against hyper-IgE syndrome. N Engl J Med 2007;357:1608–19.
erythropoietin in a patient with pure red-cell aplasia. N Engl J Med 29. Kampmann B, Hemingway C, Stephens A, et al. Acquired predisposition
1996;334:630–3. to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin
7. Riches PL, McRorie E, Fraser WD, et al. Osteoporosis associated with Invest 2005;115:2480–8.
neutralizing autoantibodies against osteoprotegerin. N Engl J Med 30. Macdougall IC, Rossert J, Casadevall N, et al. A peptide-based
2009;361:1459–65. erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med
8. Browne SK, Zaman R, Sampaio EP, et al. Anti-CD20 (Rituximab) therapy 2009;361:1848–55.
for anti-IFN-γautoantibody-associated nontuberculous mycobacterial
infection. Blood 2012;119:3933–9.
CHaPTEr 40 Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases 567.e1
M u LTIPLE-CHOICE Q u ESTIONS
1. High-titer, neutralizing autoantibodies against which cytokine 3. A previously healthy HIV-negative 34-year-old woman
is commonly seen in autoimmune polyendocrinopathy presented with few days of fever, headache, neck pain, and
candidiasis ectodermal dystrophy (APECED) syndrome? vomiting. She also reported progressively increasing exertional
A. Interferon (IFN)-α dyspnea since the past 6 months. Lumbar puncture showed
B. IFN-γ increased opening pressure. Cerebrospinal fluid (CSF) analysis
C. Granulocyte macrophage–colony-stimulating factor revealed increased white blood cell (WBC) count with lym-
(GM-CSF) phocytic predominance, low glucose, and elevated protein. The
D. Interleukin (IL)-6 CSF cryptococcal antigen was positive, and the culture grew
Cryptococcus neoformans. Brain magnetic resonance imaging
2. A 45-year-old female who moved from Taiwan to the United
States at the age of 20 years presents with disseminated (MRI) was normal. Chest computed tomography (CT) showed
Mycobacterium abscessus with pulmonary and bone lesions ground-glass opacities in both lungs. Bronchoalveolar lavage
and cervical lymphadenopathy. Autoantibodies to which (BAL) revealed periodic acid-Schiff (PAS)–positive material
cytokine may be associated with her disease? on cytology, consistent with a diagnosis of pulmonary alveolar
A. IL-17 proteinosis (PAP). Autoantibodies against which cytokine may
B. IL-22 be associated with her manifestations?
C. IFN-α A. GM-CSF
D. IFN-γ B. IL-6
C. G-CSF
D. Erythropoietin
E. IFN-γ
41
Immunological Mechanisms of Airway
Diseases and Pathways to Therapy
David B. Corry, Farrah Kheradmand, Amber Luong, Lavannya Pandit
The immunological airway diseases comprise a large and disparate include clear rhinorrhea, sneezing, postnasal drip, nasal pruritus,
group of respiratory disorders characterized by airway and and congestion, often in association with ocular symptoms, such
parenchymal inflammation that impairs sinus and lung function. as conjunctivitis and tearing. Based on symptom duration, AR is
The physiological importance of the airways, combined with now classified as “intermittent” or “persistent,” with severity of
1
the need to respond immunologically to an extremely broad symptoms noted as “mild” or “moderate to severe.” Consequently,
range of particulate and gaseous aerosols, explains much of the AR can be categorized into four groups based on the combination
diverse nature of airway immune disorders and their dispropor- of above two categories of frequency and symptom severity.
tionately large effect on human health. The allergic respiratory Patients with persistent AR typically have daily symptoms all year
tract immune disorders covered in this chapter are among the round but can also show seasonal fluctuations in the severity of
most common of all human afflictions. their symptoms. The impact of symptoms on quality of life and
Allergic disorders have a common immune phenotype com- on productivity is reflected in the “mild” and “moderate–severe”
prising highly characteristic cellular, humoral, biochemical, and categorization.
molecular components, although individual variability means
that not all these immunological features are equally expressed. KEY CONCEPTS
The most studied and visually characteristic allergic immune
cells are eosinophils and tissue mast cells, which are easily Classification of Allergic Rhinitis
seen on conventional hematoxylin and eosin (H&E) staining Frequency of Symptoms Severity of Symptoms
of pathological specimens. Eosinophils may far outnumber all
other inflammatory cells. Less obvious on histochemical staining, Intermittent Mild
but equally important to allergic diseases, are B cells that secrete Symptoms present for No presence of sleep disturbance
<4 days a week
the antibody isotypes immunoglobulin E (IgE) and IgG4, and Or for <4 weeks Or impairment of daily activities,
T-helper 2 (Th2) cells, which secrete a restricted repertoire of leisure, and/or sport
cytokines, including interleukin-4 (IL-4), -5, -9, -10, and -13, Or impairment of school or work
which coordinate and activate other allergic effector cells, such Or troublesome symptoms
as innate lymphoid cells (ILCs). Persistent Moderate-Severe
The allergic airway diseases are typically chronic and occasion- Symptoms present for Presence of sleep disturbance
ally fatal; although spontaneous remissions are not uncommon, >4 days a week
the conditions are rarely curable. Recent insights into pathophysi- Or for >4 weeks And/or impairment of daily activities,
ological mechanisms have, however, opened up new prospects leisure, and/or sport
for improved therapy. And/or impairment of school or work
And/or troublesome symptoms
CLINICAL PRESENTATION OF ALLERGIC
AIRWAY DISEASE In contrast to rhinitis, which involves inflammation and
symptoms confined to the nasal passages and mucosa, rhinosi-
Although the diverse effector cells and molecules that characterize nusitis (RS) affects both the sinuses and the nasal mucosa.
allergic inflammatory exudates may be seen at any point along Rhinosinusitis can be subdivided into acute and chronic rhino-
the respiratory tract, the functional impact of allergic disease is sinusitis (CRS), based on duration of symptoms. CRS is reported
quite different in the upper and lower airways. to affect approximately 29 million Americans and is defined by
symptoms persisting for longer than 12 weeks. Clinically, CRS
Chronic Rhinitis and Rhinosinusitis is subdivided on the basis of the presence or absence of nasal
Epidemiology and Clinical Presentation polyps. Within CRS with nasal polyps (CRSwNP), there are
The major upper airway inflammatory disorders are rhinitis and several recognized clinical subtypes, including allergic fungal
chronic rhinosinusitis. Allergic rhinitis (AR) involves inflamma- rhinosinusitis (AFRS), aspirin-exacerbated respiratory disease
tion of the nasal mucosa: it is the most common type of chronic (AERD), and cystic fibrosis. 2
rhinitis affecting approximately 50 million Americans. In different Signs and symptoms associated with RS in adults include
surveys, AR accounts for 30–70% of chronic perennial rhinitis, facial pain and pressure, headaches, nasal congestion with or
with the balance being nonallergic. Typical symptoms of AR without obstruction, frontal or post nasal drainage, generalized
571
572 ParT FIvE Allergic Diseases
malaise, loss of sense of smell (hyposmia), and cough. Of these,
nasal obstruction is the most common (81–95%), followed by
facial pain and pressure (70–85%), discolored nasal drainage
(51–83%), and hyposmia (61–69%). In contrast, symptoms in
children vary with age and require the parent or caregiver to
recognize them. Young children often present with a chronic
cough and irritability, rather than facial pain. Parents often also
report the child has halitosis and purulent nasal discharge.
Although it is more difficult to determine the prevalence of RS
in children because of overlapping symptoms with AR and viral
upper respiratory tract infections, its prevalence is inversely related
to age. 2
Diagnosis
The diagnosis of AR is based on a history of typical symptoms
and physical examination findings. Common symptoms include
postnasal drainage, sneezing, itchy nose and eyes, and clear
rhinorrhea. The frequency and effect of symptoms on sleep and
productivity should be assessed to classify the AR as intermittent
or persistent and mild or moderate–severe.
Patients suffering from AR can present with an “allergic shiner,”
a darkening of the infraorbital skin resulting from chronic venous FIG 41.1 Nasal Polyposis. Seen on this nasal endoscopy are
pooling. In some children, wiping the front of the nose with the nasal polyps (NP) emanating from the sinus cavity into the nasal
back of the hand in an upward motion (the allergic salute) creates cavity between the septum (S) and the inferior turbinate (IT) of
a persistent horizontal crease across the nasal bridge that is a a patient with chronic rhinosinusitis.
hallmark of chronic anterior rhinorrhea. Bilateral conjunctivitis
may be present in patients along with ocular involvement.
On anterior rhinoscopy with a hand-held otoscope, engorged,
boggy, and pale inferior turbinates also suggest AR. In addition,
there is often a clear discharge coating the nasal cavity. Examina-
tion of the oropharynx often reveals cobblestoning of the mucosa,
a sign of chronic postnasal drip.
Although not necessary to make the diagnosis of AR, two
tests commonly used to demonstrate IgE-mediated allergic
reactions are immediate-hypersensitivity skin testing and measure-
ment of serum allergen–specific IgE levels. Skin prick tests
correlate well with the symptoms of allergic rhinitis and with
airway responsiveness to allergens, and measuring serum allergen-
specific IgE levels provides an in vitro means of supporting a
diagnosis of AR. Compared with skin prick testing, the in vitro
3
test is more specific but less sensitive and can be more expensive.
However, serum tests may be the only practical way of detecting
allergen-specific IgE in some patients, especially those with
urticaria and eczema.
The diagnosis of CRS requires the presence of at least two
major symptoms or one major and at least two minor clinical
symptoms persisting for longer than 12 weeks, in conjunction
with objective evidence of inflammation within the sinus cavity.
The major symptoms include facial pain or pressure, nasal FIG 41.2 Coronal Sinus Computed Tomography (CT) Image
obstruction, nasal drainage, and hyposmia or anosmia. Minor From a Patient With Chronic Rhinosinusitis. The maxillary
symptoms are headaches, halitosis, fatigue, dental pain, cough, sinuses (lateral to the nasal cavity) and ethmoid sinuses (medial
and ear pain or pressure. The most specific symptom for RS is to the orbital cavities) exhibit mucosal thickening and accumulation
4
discolored nasal discharge. Since most symptoms of rhinosinusitis of obstructed secretions consistent with inflammatory changes
are nonspecific, evidence of inflammation on nasal endoscopy within the paranasal sinuses.
or imaging is also necessary to make a diagnosis of CRS. On
nasal endoscopy, inflammation is suggested by edema and/or
drainage from the middle meatus; CRSwNP is diagnosed when To make the diagnosis of AFRS, the most widely accepted
nasal polyps are visualized (Fig. 41.1). Inflammation within the diagnostic criteria include five characteristics: nasal polyps; type
sinuses may not be apparent on nasal endoscopy: in patients I (immediate) hypersensitivity to fungi; radiographic imaging
with a strong history of CRS, computed tomography (CT) of consistent with AFRS; eosinophilic mucin with evidence of fungi;
the sinuses is necessary to detect mucosal thickening and/or and lack of evidence of fungal invasion into the surrounding
fluid within the sinuses (Fig. 41.2). sinus tissue. Type I hypersensitivity to fungi can be detected by
CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 573
positive skin testing to fungal antigens or elevated serum fungal- agents potentially useful in the management of rhinitis include
antigen-specific IgE titers. Imaging consistent with AFRS is oral steroids, oral leukotriene (LT) receptor antagonists, intranasal
obtained by CT and magnetic resonance imaging (MRI). Fulfilling chromones, and intranasal ipratropium bromide. 8
the remaining criteria for AFRS requires histological examination In addition to pharmaceutical approaches, allergen immu-
and microbiology for fungi within the mucin and tissue obtained notherapy offers a means of providing long-term relief from
at the time of surgery. 5 rhinitis (Chapter 91). Two types of immunotherapy are available:
subcutaneous immunotherapy (SCIT) and sublingual immu-
KEY CONCEPTS notherapy (SLIT). An important concern associated with the
use of SCIT is anaphylaxis, whereas this risk is probably much
Diagnosis of Chronic Rhinosinusitis (CRS) lower with SLIT. The antigens for SLIT are available in both
liquid formulation, which allows for customized combinations,
Chronic rhinosinusitis
• Presence of at least two of the following symptoms: and preformed tablets. Finally, intensive home and workplace
• Facial pressure or pain remediation directed at limiting allergen exposure is potentially
8
• Nasal obstruction or congestion beneficial in those with demonstrable environmental allergies.
• Anterior or posterior nasal drainage The treatment of CRS is more controversial than that of AR. In
• Hyposmia or anosmia general, treatment can consist of either medical or surgical therapy.
• Edema or discolored drainage within the sinus cavity or middle meatus CRS is currently viewed as primarily an inflammatory, rather than
• Or CT sinus showing fluid or mucosal thickening within sinus cavities
an infectious, disorder such that antibiotics are less frequently
CrS Without Nasal Polyps CrS With Nasal Polyps advocated and have largely been replaced with intranasal and oral
No evidence of nasal polyps within Presence of nasal polyps within antiinflammatory agents, such as steroids. In addition, daily sinus
the middle meatus as noted on the middle meatus as noted irrigations with physiological saline can counteract mucociliary
nasal endoscopy in a patient on nasal endoscopy dysfunction and promote antigen clearance.
with no history of previous Future therapies for CRS are likely to include biologics aimed
sinus surgery at the key cytokines, molecules, and cells that are important in
History of nasal polyps within the type 2 inflammatory responses which characterize CRSwNP.
sinus cavity in a previously These potential therapeutic targets include IL-33, IL-25, thymic
operated patient with CRS
diagnosis stromal lymphopoietin (TSLP), IL-5, IL-4, IL-13, siglec-8, and
IgE. However, these treatment options will require a more
sophisticated classification of CRS beyond the basis of nasal
The diagnosis of AERD requires meeting diagnostic criteria polyps. Endotyping based on immunological, molecular, or
for nasal polyps and asthma, along with a history of respiratory histological characteristics represents the future of CRS classifica-
symptoms exacerbated by oral intake of aspirin or other tion. We also need to better understand the role that environmental
cyclooxygenase-1 (COX-1) inhibitors on at least two occasions, fungi play in triggering the inflammatory cascade leading to
or a positive reaction on aspirin challenge. 6 particular CRSwNP subtypes and allergic asthma. The use of
Cystic fibrosis is typically diagnosed in early childhood as a antifungals in CRS seems logical, given the strong association
9
result of pulmonary symptoms. However, the presence of nasal between CRS and fungi, including yeasts and molds. This has
polyps in anyone under 18 years should prompt an evaluation been investigated through many clinical trials, most of which
for cystic fibrosis, which is confirmed either by sweat test or by are methodologically weak, failing to specify which patients
demonstrating a mutation in the cystic fibrosis transmembrane actually have fungal infection or at least fungal sensitivity and
conductance regulator gene. lacking adequate control populations. Despite these limitations,
the existing studies suggest that topical antifungal antibiotics
Therapy (e.g., amphotericin B) are not effective, whereas systemic anti-
The most effective and widely used drugs for controlling the fungals may significantly inhibit recurrent disease. 10
nasal and ocular symptoms of AR are glucocorticosteroids and Patients with persistent symptoms despite medical therapy
antihistamines. Intranasal glucocorticosteroids (steroids) are the may benefit from functional endoscopic sinus surgery (see Video
most efficacious medication class available for the management 1 online). Outcomes of medical therapy versus sinus surgery
of AR symptoms, particularly nasal congestion, and are considered combined with intranasal steroids showed similar improvements,
first-line medical therapy. They may also improve eye symptoms. but patients with CRSwNP achieved improved asthma control
Of the numerous formulations available, mometasone furoate with medical therapy. Endoscopic sinus surgery is mandatory
demonstrates the highest antiinflammatory potency and lowest for patients with AFRS in whom the sinuses are impacted with
systemic absorption compared with other commonly used copious thick mucus requiring manual extraction and patients
intranasal steroids. However, no studies have shown any differ- presenting with serious complications of CRS, such as vision
ences in clinical efficacy among the currently available intranasal loss or intracranial extension of disease.
steroids. 7
Oral antihistamines are also highly effective against the Asthma
histamine-driven symptoms of sneezing, pruritus, and rhinor- Epidemiology and Clinical Presentation
rhea. Second-generation antihistamines are recommended over After several decades of rising incidence, asthma is now the most
first-generation formulations for their lack of sedating effects common chronic disease of childhood and one of the most
and equivalent ability to reduce AR symptoms. Intranasal anti- common disorders of adults in the United States. Although most
histamines can be as effective as oral antihistamines for control frequently diagnosed initially in childhood, asthma can be first
of allergic and nonallergic rhinitis, but neither is as effective as diagnosed at any age. The widely prevalent and incurable nature
intranasal steroids for nasal congestion. Other pharmacological of asthma will continue to assure its position as one of the most
574 ParT FIvE Allergic Diseases
costly of medical afflictions both in terms of total medical reducing inflammation. Immediate relief of bronchoconstriction
expenditure and in time lost from work and school. Asthma is and dyspnea is achieved with bronchodilating agents that activate
a lower respiratory tract disease that is characterized by dyspnea the β 2 adrenergic receptor on airway smooth muscle (β-agonists).
and other symptoms, including cough, chest tightness, chest For long-term control of asthma, the most effective agent class
pain, and wheezing. Persons with mild disease often only have is glucocorticosteroids, which reduce inflammation and suppress
a mild, chronic cough. In contrast to other obstructive lung airway constriction and dyspnea. For mild to moderate disease,
diseases, asthma symptoms are present intermittently and are bronchodilating agents and steroids are typically administered
characteristically relieved by bronchodilator and antiinflammatory by inhalation, which reduces but does not eliminate systemic
therapy. side effects. A secondary class of agents used for controlling
Patients with asthma are classified into distinct clinical subtypes bronchospasm comprises anticholinergics, which are antagonists
according to characteristic environmental or occupational of the muscarinic acetylcholine receptor. Severe disease may also
exposures that elicit disease symptoms, the presence or absence require treatment with steroids, which are given orally or
of concomitant atopy, temporal expression of symptoms, and intravenously for relatively brief periods to minimize the often-
responsiveness to antiinflammatory therapy. Respiratory viruses severe side effects, and high-dose inhaled β-agonists, often given
are the most frequently implicated causes of asthma attacks, by nebulizer.
especially in children, and tobacco smoke and air pollution are Additional antiinflammatory agents available for the treatment
other major inciting agents. A large minority of patients with of asthma include LT receptor antagonists, chromones, theophyl-
asthma have atopy, a term that reflects the production of IgE, a line, omalizumab (a monoclonal antibody [mAb] that reduces
genetic predisposition toward immediate-type immune reactions, circulating and mast cell-bound IgE), and most recently mepo-
12
and symptoms on exposure to causative environmental agents, lizumab (an anti–IL-5 antibody). Bronchial thermoplasty (BT)
such as pollens, dust mites, fungi, and insects. If atopy is present, is a relatively new bronchoscopic technique, in which heat is
patients are referred to as having extrinsic, atopic, or allergic applied to the airways via a radiofrequency catheter to ablate
asthma, whereas those without atopy are referred to as having smooth muscle cells. Although early clinical trials have been
intrinsic or nonallergic asthma. In general, airway constriction encouraging with regard to the ability of this technique to reduce
occurs and symptoms of asthma are provoked when triggering exacerbation rates, further studies are required to understand
agents are inhaled from the environment, representing the clinical the patient subgroups that are most likely to respond to these
expression of airway hyperresponsiveness (AHR)—the exaggerated novel treatments. 13
tendency of the asthmatic airway to constrict in response to
exposure to a wide variety of provocative agents. Some of these OTHER AIRWAY ALLERGIC DISEASE SYNDROMES
agents, such as viruses and pollens, are only intermittently present,
causing seasonal asthma, whereas other agents are encountered In addition to the common allergic disorders discussed above,
continuously (e.g., fungi) and cause persistent (or perennial) several other allergic airway diseases have been described:
asthma. Occupational asthma is defined as asthma acquired in although not as common, these often cause profound morbid-
the workplace, where dozens of potentially toxic agents have ity. As with asthma, these disorders are clinically heterogeneous
been identified (Chapter 49). Numerous additional clinical subsets but are believed to share a similar pathophysiology related to
of asthma can be defined according to the factor or factors that the inhalation of antigens that provoke airway eosinophil and
most often elicit attacks of dyspnea. A final category of asthma, Th2 responses. No single clinical, pathological, or radiographic
steroid-resistant asthma, refers to the condition in patients who feature is pathognomonic for these diseases, and diagnosis relies
are relatively unresponsive to antiinflammatory steroid therapy. on a constellation of findings, especially antigen exposures,
radiographic details, and histopathology. Nonetheless, all of these
Diagnosis disorders are prominently linked by the presence of eosinophils
Asthma is often recognized on clinical grounds alone, with in peripheral blood and airway tissues.
acute attacks marked by obvious dyspnea, wheezing, cough, and Under the trophic influence of IL-5, eosinophils develop from
use of accessory muscles of respiration. Such attacks typically precursor cells present largely in bone marrow. Early mature
resolve with bronchodilator therapy. Spirometry can provide eosinophils are then released into blood, where they circulate
more objective evidence of airway obstruction as assessed by for a brief period before entering the interstitium of airway
reversible decrements in the forced expiratory volume per tissues, where they can reside for long periods. Chemotactic
second (FEV 1 ) and other measures of air flow. Nonetheless, a factors that enhance the extravasation of eosinophils include
uniformly acceptable disease definition has remained elusive, complement components, eosinophil chemotactic factor-A, LTs,
at least partly because of the nonspecific nature of symptoms tumor-associated factors, and chemokines. Putative functions
and a clinical spectrum that blends with many other disease of tissue resident eosinophils range from host defense against
processes. When the clinical presentation is uncertain, bronchial parasites, such as nematode helminths, in diseases, such as tropical
provocation tests can be used to determine the presence of AHR pulmonary eosinophilia, to mediators of end-stage tissue destruc-
11
and thereby establish the diagnosis. Additional laboratory data tion and irreversible lung damage and fibrosis in other disorders,
that support a diagnosis of allergic asthma include peripheral such as acute and chronic eosinophilic pneumonia.
blood eosinophilia, elevated serum total and antigen-specific IgE The eosinophilic disorders discussed below are organized
levels, and positive skin prick test results against one or more according to whether there is an extrinsic or intrinsic cause of
allergens. the eosinophilia (Table 41.1). Inhaled or ingested extrinsic factors,
including medications and infectious agents (e.g., parasites, fungi,
Therapy mycobacteria), can trigger an eosinophilic immune response.
As with AR and RS, the therapy of asthma is generally nonspecific This may be mild and self-limiting, as in Loeffler syndrome.
and directed at improving air flow through bronchodilation and Intrinsic pulmonary eosinophilic syndromes are, by definition,
CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 575
TABLE 41.1 Eosinophilic Lung Disorders
Proposed Immune
Disease Causative agent Mechanism
Loeffler syndrome Inhaled food, T cell–mediated
infection, or hypersensitivity
medication reaction
Drug rash with Drugs: Hypersensitivity reaction
eosinophilia and sulfonamides, to drug
systemic phenobarbital,
symptoms sulfasalazine,
(DRESS) carbamazepine,
syndrome and phenytoin
Parasitic infections Strongyloides spp., T-cell and B-cell clonal
Wuchereria activation in response
bancrofti, to parasite antigens
Brugia malayi and adjuvant factors
Allergic Aspergillus Immunoglobulin E (IgE)
bronchopulmonary and immune complex
aspergillosis deposition FIG 41.3 Strongyloidiasis. The coiled larva of Strongyloides
Acute eosinophilic Fungal infections, Hypersensitivity
pneumonia cigarette smoking, response to inhaled stercoralis is seen on this Papanicolau stain of a bronchoalveolar
post–stem cell antigen (infectious or lavage sample from a patient with Strongyloides hyperinfection.
transplantation otherwise) Original magnification ×400; bar = 10 µm.
Chronic Unknown systemic- Unknown, but chronic
eosinophilic mediated process nature evident with T
pneumonia cell–mediated
granuloma production systemic steroids, may develop Strongyloides hyperinfection
Idiopathic Infections, systemic Systemic responses syndrome, in which large numbers of recently released larvae
hypereosinophilic diseases, and caused, in part, by burrow through the intestine and migrate to the lungs, causing
syndrome drugs that drive excess interleukin-5 a severe and potentially fatal lung disease that is frequently
peripheral (IL-5) production from
eosinophilia clonal expansion of Th2 complicated by sepsis (Fig. 41.3). A very similar disease, termed
cells as well as fusion Loeffler syndrome, was originally reported to be caused by the
gene FIP1L1–PDGFR larvae of Ascaris spp., but other helminths and hypersensitivity
Churg-Strauss Autoimmune Decreased regulatory responses to medications have since been etiologically implicated.
syndrome vasculitis to T-cell function with Therapy of parasite-related pulmonary eosinophilia syndromes
unknown antigen, diminished IL-10 is directed at relieving symptoms and eliminating the parasites.
associated with production
asthma DRESS Syndrome
The drug rash with eosinophilia and systemic symptoms (DRESS)
syndrome is a severe drug hypersensitivity reaction that has a
idiopathic and represent a varied group of diseases, often systemic constellation of systemic signs and symptoms, including skin
in nature. rash, fever, lymphadenopathy, and inflammation of the liver,
lung, and heart (Chapter 48). Numerous drugs have been reported
Extrinsic Eosinophilic Syndromes to cause DRESS syndrome, including sulfonamides, phenobarbital,
Tropical Eosinophilic Pneumonias sulfasalazine, and antiseizure medications, such as carbamazepine
The tropical eosinophilic syndromes are a group of clinically and phenytoin. Importantly, symptom onset may be delayed
14
similar eosinophil-predominant inflammatory disorders char- long after initiation of the drug. The therapy of DRESS syndrome
acterized by chest pain, wheezing, cough, and AHR, often in the involves discontinuing the offending medication and providing
setting of a debilitating, but transient, febrile illness. Fleeting supportive care in the setting of severe organ involvement.
lung infiltrates may be seen on chest radiographs, and labora-
tory studies often demonstrate strikingly high peripheral blood, Allergic Bronchopulmonary Aspergillosis
lung, and airway eosinophilia, as well as elevated serum IgE Allergic bronchopulmonary aspergillosis (ABPA) is a severe pul-
levels. Migrating parasites traversing the lungs are thought to be monary allergic reaction to Aspergillus antigens that is seen almost
15
responsible for most cases of tropical eosinophilic pneumonia. exclusively in the setting of preexisting asthma or cystic fibrosis.
Embolization of microfilariae (e.g., Dirofilaria spp.) or helminth Diagnostic criteria include asthma with wheezing, peripheral
eggs within the pulmonary microvasculature leads to antigen blood eosinophilia, detection of precipitating anti-Aspergillus
release and induction of a typically granulomatous allergic antibodies, elevated serum total IgE levels, and radiographic
immune reaction. Persistent or chronic, recurrent infection with evidence of fleeting pulmonary infiltrates often accompanied
etiological organisms (e.g., Strongyloides spp. Wuchereria bancrofti, by central bronchiectasis. Aspergillus spp. and other filamentous
Brugia malayi) leads to chronic inflammation that may cause fungal species can frequently be isolated from airway secretions of
parenchymal necrosis and irreversible fibrosis. In the United patients with ABPA, suggesting that active fungal growth within
States, Strongyloides spp. are the most common cause of parasitical the airways is responsible for the disease. Complications of chronic
infection and tropical eosinophilic pneumonia. Patients who ABPA include severe AHR, severe bronchiectasis, eosinophilic
are immunocompromised, including those recently prescribed pneumonia, pulmonary fibrosis, and invasive fungal disease.
576 ParT FIvE Allergic Diseases
Treatment of ABPA aims to suppress the inflammatory response the lungs. Expansion of Th2 cells and local and systemic release
to the fungus and to control bronchospasm with glucocorticoid of IL-4 and IL-5 are also frequently seen. The clonal expansion
therapy, the duration of which may be shortened by concomitant of Th2 cells in the absence of known antigen exposures, and the
use of oral antifungal agents, such as itraconazole. 15 association of idiopathic hypereosinophilic syndrome (IHES)
with a variety of chromosomal aberrations, strongly support
Acute Eosinophilic Pneumonia the concept that IHES is a myeloproliferative disorder involving
Acute eosinophilic pneumonia (AEP) is an acute, often debilitating Th2 cells, although aberrant secretion of IL-5 by both solid and
eosinophilic inflammatory syndrome that exclusively involves liquid tumors can produce very similar syndromes. Many organs
the lungs and is marked by pulmonary infiltrates, dyspnea can be affected, resulting in dysfunction or failure of the
progressing to frank respiratory failure, and fever. The diagnosis gastrointestinal (GI) tract, skeletal muscles (leading potentially
is dependent on eosinophils exceeding 25% of all inflammatory to respiratory failure), endomyocardial fibrosis, myocarditis, and
cells within the bronchoalveolar lavage (BAL) fluid. Increasing congestive heart failure. Pulmonary involvement manifests as
evidence suggests an association between AEP and respiratory obstructive airway disease, pulmonary edema, or pulmonary
fungal infections and recent-onset cigarette smoking. 16,17 AEP emboli caused by a hypercoagulable state. In addition to hype-
has also been reported following allogeneic hematopoietic stem reosinophilia, patients with IHES may have evidence of polyclonal
cell transplantation (HSCT) in the setting of graft-versus-host hypergammaglobulinemia. The diagnosis is based on the discovery
18
disease (GvHD). Prompt recognition of the disease and initiation of elevated peripheral blood eosinophilia in the setting of a
of treatment with glucocorticoids usually results in rapid radio- multisystem disorder, with evidence of aberrant Th2 responses
graphic and clinical improvement. or elevated IL-5 secretion and defined genetic mutations. The
most consistently effective therapy for IHES involves tyrosine
Intrinsic Eosinophilic Syndromes kinase inhibition, using agents such as imatinib mesylate. 20
Chronic Eosinophilic Pneumonia
This disorder presents similarly to AEP, but in a more chronic Churg-Strauss Syndrome
manner (greater than 6 weeks duration). Chronic eosinophilic Churg-Strauss syndrome (CSS), also termed eosinophilic granu-
pneumonia (CEP) can occur in isolation and/or in association lomatosis with polyangiitis (EGPA), is a necrotizing vasculitis of
with polyarteritis nodosa, rheumatoid arthritis, scleroderma, medium and small caliber vessels (Chapter 58), which is character-
ulcerative colitis, breast carcinoma, and histiocytic lymphoma. ized by airway obstruction and eosinophilia. The disease has an
Most patients have evidence of asthma and atopy. Like AEP, CEP autoimmune nature, given the presence of circulating anti-
can present with striking eosinophilic inflammation of the lung myeloperoxidase and antineutrophil cytoplasmic antibodies
(Fig. 41.4). Granulomas are occasionally seen on biopsy specimens, (p-ANCA) as seen in 60–70% of affected individuals. Because
suggesting that an antigen-driven, T cell–mediated process is CSS is seen in patients with a history of asthma and allergies
involved in the chronicity of the disease. Treatment, as for AEP, and the prominent pathological feature is necrotizing vascular
is based on steroid therapy, but unlike AEP, CEP frequently and tissue granulomas, the term “allergic granulomatosis and
relapses after discontinuation of treatment. 19 angiitis” is used synonymously. Inhaled or ingested antigens have
been proposed as causative agents in susceptible individuals.
Idiopathic Hypereosinophilic Syndrome Reports linking the syndrome with the LT inhibitors zafirlukast
This multisystem disease is characterized by the massive accumula- and montelukast in the setting of steroid withdrawal suggest
tion of eosinophils in many tissues and almost always involves that these agents may unmask preexisting CSS rather than directly
causing the disorder. Similar observations have been made with
omalizumab treatment. The vasculitis of CSS can affect the
sinuses, the central and peripheral nervous systems, the GI tract,
kidneys, and the heart. Treatment of CSS is based on the use of
systemic steroids, which leads to disease resolution in the majority
of patients. In severe steroid-resistant disease, cyclophosphamide
and other immunosuppressants may be required. 21
IMMUNOLOGICAL MECHANISMS OF ALLERGIC
AIRWAY DISEASE
All patients with major allergic airway disease syndromes include
patients who demonstrate evidence of allergic inflammation,
with elevated blood and airway eosinophilia, elevated serum
total and antigen-specific IgE levels, and positive skin prick tests.
However, not all patients demonstrate all markers of allergic
inflammation simultaneously, and some patients with apparent
allergic disease express none of these markers. Specialized testing
may also reveal predominant Th2 cytokine responses generated
FIG 41.4 Histology of Chronic Eosinophilic Pneumonia. Lung from peripheral blood mononuclear cells when stimulated with
biopsy specimen from a patient with chronic eosinophilic common allergens in vitro and the presence of Th2 cells, ILC2,
pneumonia demonstrates a confluent infiltrate with eosinophils eosinophils, and IgE-secreting B cells, and the secreted products
filling alveoli together with large, multinucleate macrophages. of these cells, within affected sinus and airway tissues. As well
Original magnification, ×200, hematoxylin and eosin stain. as the conventional causes of Th2-mediated airway inflammatory
CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 577
Antigen
IgE
FcεRI
B cell
IL-4
IL-13 Mast cell Upper airway
Histamine
Leukotrienes
Prostaglandins
cell Antigen
Th 2
Cytokines
FcεRI
IL-5
Allergic airway disease
Type 4 hypersensitivity
Eosinophil IL-4
IL-4Rα
Type 1 hypersensitivity IL-13
Lower airway
Th cell
2
FIG 41.5 Differential Importance of Allergic Immune Mechanisms According to Airway
Level. Type I hypersensitivity (left), mediated by immunoglobulin E (IgE)-primed mast cells and
eosinophils, is ultimately driven indirectly by the cytokines secreted by T-helper 2 (Th2) cells. In
contrast, type IV hypersensitivity (right) is mediated directly by Th2 cytokines, especially interleukin-4
(IL-4) and IL-13, acting through a similar receptor that includes IL-4Rα. Both immune mechanisms
are important to the expression of allergic disease at all airway levels, but type I hypersensitivity
predominates in the upper airway, whereas type IV hypersensitivity likely assumes a more
important role in the lower airway.
responses, fungal and bacterial infections also serve as distinct Th2 cells coordinate both the production of IgE antibodies and
causes of inflammation. the activation and recruitment of allergic effector cells to the
The major effector immune mechanisms of disease proposed airway. Antigen-specific IgE bound to the surface of mast cells
by Gell and Coombs in the 1960s remain essential to understand- and basophils is cross-linked upon exposure to relevant antigens,
22
ing the pathogenesis of allergic airway diseases. Although such causing cellular activation and release of preformed and newly
mechanisms probably operate to some degree in all allergic formed mediators of inflammation, such as histamine, proteases,
diseases, their relative importance appears to vary, depending LTs, numerous cytokines, and other substances. IL-4, released
on whether the disease process predominantly affects the upper primarily by Th2 cells, is an especially important regulator of
respiratory tract or the lower respiratory tract (Fig. 41.5). type I hypersensitivity reactions, as it is required for B-cell
maturation and IgE secretion.
KEY CONCEPTS There is evidence that IL-4 and IL-13 can mediate distinct
Immunopathogenesis of Allergic Airway Disease effector phenotypes in airway and tissue macrophages and
dendritic cells (DCs). Two major effector macrophage subtypes
• Gell and Coombs type 1 and type 4 hypersensitivity mechanisms include conventionally activated (M1) macrophages that arise
contribute to disease expression, especially airway obstruction. under the predominant influence of type I cytokines, especially
• Innate immune pathways involving thymic stromal lymphopoietin IFN-γ, and alternatively activated macrophages (M2) that arise
(TSLP), interleukin-25 (IL-25), and complement proteins critically under the influence of IL-4 and IL-13 in the relative absence of
contribute to the development of allergic airway inflammation. IFN-γ. M2 macrophages express a distinct gene profile that
• Environmental agents that are emerging as potentially important initiation includes high-level expression of arginase 1, Ym1, Fizz1 (RELM),
factors for allergic airway inflammation include proteases, chitin, and
endotoxin as derived from fungi, insects, and bacteria. and PD-L2. Current evidence suggests that M2 macrophages
• Fungi and viruses are further emerging as potentially important infectious promote allergic responses and that redirecting them to the M1
causes of allergic disease of the upper and lower airways. phenotype might be therapeutically useful. 23
The effect of mediator release in immediate hypersensitivity
reactions is most dramatically illustrated by the clinical syndrome
Type I (Immediate) Hypersensitivity of anaphylaxis, in which patients may exhibit profound bron-
This form of hypersensitivity involves the activation of basophils choconstriction and dyspnea accompanied by the extravasation
and mast cells that release histamine and other inflammatory of vascular solutes and fluid into the interstitium, which produces
mediators that drive the clinical features of the response. Antigen diffuse edema, bronchoconstriction, and hypotension (Chapter
recognition is via IgE antibodies, which bind through their Fc 42). Type I hypersensitivity against inhaled allergens more com-
portion to high affinity receptors (FcεRI) to arm effector cells. monly presents with symptoms of acute rhinitis.
578 ParT FIvE Allergic Diseases
TABLE 41.2 Chemoattractants
'HFOLQH )(9 ,QFUHDVH 5 Linked to the recruitment of allergic receptor
Inflammatory Cells
Chemokine
CCL1 CCR8
CCL11 CCR3
)ROORZ XS KRXUV CCL17, CCL22 CCR4
FIG 41.6 Early-Phase and Late-Phase Airway Changes Fol- CX 3 CL1 CX 3 CR1
Prostaglandin D2
CR T H 2
lowing Allergen Challenge. This schematic diagram depicts Leukotriene B4 BLT1
the two phases of bronchoconstriction typically seen after allergen
inhalation in sensitized, asthmatic subjects. Within 20–30 minutes
after allergen inhalation, the first (early) phase of bronchoconstric-
tion as assessed by either a decline in forced expiratory volume
per second (FEV 1) or increase in airway resistance (R) is seen. with neurologically mediated bronchoconstriction. How IL-13
11,25
After quickly subsiding, approximately 4–6 hours (h) later, a mediates these neurological changes is currently unknown.
second (late) phase of bronchoconstriction occurs. A second and more insidious form of airway obstruction is
physical obstruction of the airways caused by mucus and fibrin
clots that can accumulate in the airways as tenacious plugs, a
26
phenomenon that is now termed plastic bronchitis. IL-13,
Cell-Mediated Features of Immediate Hypersensitivity together with IL-9, is a trophic and differentiation factor for
Airway obstruction in allergen-sensitized asthma evolves over airway goblet cells and submucosal glands, which contribute to
several hours after allergen exposure and is seen in two distinct plastic bronchitis by promoting secretion of mucus by these
phases. The early-phase response is marked by airway constriction cells. Airway obstruction caused by plastic bronchitis is not
that becomes maximal about 30 minutes after allergen exposure immediately reversible with bronchodilators or other pharma-
and is fully resolved after approximately 2 hours (Fig. 41.6). cological agents and is consequently the major cause of death,
Approximately 50% of subjects with asthma who are tested will resulting from asphyxiation, in asthma. 27
also develop a late-phase airway response in which airway Finally, IL-4 and IL-13 further coordinate the recruitment
obstruction again develops 4–6 hours after allergen exposure. and retention of allergic effector cells to airway epithelium and
Late-phase reactions are linked to the infiltration of the airways submucosa, an arrangement that facilitates rapid responses to
with Th2 cells and eosinophils, and the accompanying broncho- inhaled allergens. Acting through a similar receptor, that includes
constriction is less reversible with bronchodilating agents than the α chain of the IL-4 receptor (IL-4Rα), IL-4, and IL-13 signal
the early-phase reactions. 24 on constitutive airway cells, such as airway epithelial cells, to
AHR is neurologically mediated through parasympathetic induce secretion of a restricted repertoire of chemoattractants
nerves, such as the vagus, and is fully reversible with broncho- or chemotactic factors that promote the immigration of allergic
dilating agents that either interrupt muscarinic parasympathetic cells expressing specific cognate receptors from the lung and
signaling directly (e.g., ipratropium bromide) or activate receptors airway microcirculation (Table 41.2). 28
(e.g., β 2 -adrenergic) that antagonize muscarinic bronchoconstric-
tive pathways. Besides its formal demonstration in the clinical Contributing Immune Mechanisms in Allergic
laboratory through bronchial provocation testing, AHR is Airway Disease
recognized clinically as episodic bronchoconstriction that is In addition to its critical role in promoting IgE secretion, IL-4
reversed with bronchodilating agents. Late-phase responses after is an important growth and differentiation factor for Th2 cells.
antigen challenge, therefore, represent a form of AHR and, in part, Both IL-13 and IL-4 activate the transcription factor signal
reveal the immunological nature of this ultimately neurological transducer and activator of transcription 6 (STAT6). In addition
phenomenon. to these closely related cytokines, all components of the IL-4/
More detailed analysis of the immunological mechanisms IL-13 signaling pathway are required for expression of experi-
underlying AHR comes from experimental models of asthma. mental allergic airway disease, especially AHR.
Studies from many species have demonstrated that AHR in the IL-5 also contributes to both immediate and cell-mediated
setting of allergic inflammation is critically dependent on Th2 hypersensitivity reactions through its role in promoting the
cells and ILC2 that have specifically been recruited to the lung. growth and differentiation of eosinophils. Although widely
Moreover, it is now clear that IL-13 is the major Th2 and ILC2 viewed as pathogenic and contributing to the expression of allergic
cytokine that mediates AHR by acting directly on constitutive airway diseases, more recent studies indicate that eosinophils
airway cells, such as airway smooth muscle cells that express are important in tissue remodeling and in controlling allergic
the IL-13 receptor. However, IL-13 does not directly induce inflammation induced by pathogens, such as fungi. 29
bronchoconstriction. Bronchoconstriction in subjects with In addition to Th2 cells, mast cells, and eosinophils, innate
asthma, expressed as episodic bouts of dyspnea, is triggered by lymphoid cells that include ILC2, natural killer (NK) cells (a
diverse exogenous factors in addition to allergens (e.g., altered type of ILC1), and γδ T cells may also contribute to allergic
temperature and humidity, pungent odors, irritating aerosols) disease expression through their ability to rapidly secrete Th2
and endogenous stimuli (e.g., extreme emotional states) with and other cytokines. 25
little apparent connection to immunological mechanisms. Numerous additional soluble mediators contribute to the
Thus rather than directly mediating airway obstruction, IL-13 expression of allergic disease. The complement system is especially
establishes the basis for responding broadly to diverse agents important, and complement proteins C3a and C5a, the major
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