Netter's Infectious Disease ( PDFDrive )

Introduction to Emerging 87
Infectious Diseases
and Pandemics

Jo Hofmann

P lagues have been described since humans began to recall Two recent reports that reviewed trends in emerging infections
their history. Despite the development of antimicrobials, identified several patterns of association: emerging infectious
vaccines, and other technologic advances, infection is a leading diseases of temperate regions tend to be associated with domes-
cause of death in the developing world, and outbreaks of infec- ticated animals, advanced agriculture, and healthcare technolo-
tious diseases continue to influence global events, even in the gies, whereas those originating in tropical regions are more
twenty-first century. The appearance of emerging infectious typically linked to human interaction with wild animals or expo-
diseases (those caused by a newly recognized agent) and reemerg- sure to insect vectors. Both reports called for renewed efforts
ing infectious diseases (those caused by a known agent that has to establish programs for surveillance and investigation of
developed enhanced pathogenicity or dramatically increased in emerging infections that focus on these associations, allocating
incidence) may be due to multiple factors, but perhaps the most resources to detect novel or reemerging infections in developing
important are the alteration of human and nonhuman ecology regions with the greatest biodiversity and interaction between
and environmental change. Despite the devastating effect that wildlife and humans.
unrecognized and unanticipated diseases may have on the
human population, the concept of “emerging infections” did not Even a partial list of emerging and remerging infections of
coalesce until the 1990s. In 1992, the Institute of Medicine the last 30 years includes pathogens too numerous for all to be
(IOM) of the National Academy of Sciences published a report covered in this section: HIV, hepatitis C (formerly non-A, non-B
that called for the establishment of programs to effectively iden- hepatitis) virus, avian and swine influenza A viruses, the SARS
tify, monitor, and respond to all infectious agents, including coronavirus, Sin Nombre virus, WNV, dengue viruses, and the
newly recognized pathogens such as human immunodeficiency agent of variant Creutzfeldt-Jakob disease; B. anthracis, Esche-
virus (HIV) and antimicrobial-resistant bacteria. The 1992 IOM richia coli O157:H7 and other enterohemorrhagic E. coli, Fran-
report recommended strengthening communicable disease sur- cisella tularensis, Vibrio cholerae O139, and Yersinia pestis; and
veillance in the United States at the local, state, and federal Cryptosporidium parvum and Cyclospora cayetanensis. In addition,
levels; establishing a comprehensive global network for infec- a number of pathogens have developed significant resistance to
tious disease surveillance; and supporting research to improve antimicrobials: Neisseria gonorrhoeae, Salmonella and Shigella
infectious disease detection and response. In 2003, the IOM species, Staphylococcus species, Streptococcus pneumoniae, Mycobac-
evaluated the progress of efforts to implement their recommen- terium tuberculosis, bacterial species responsible for healthcare-
dations and reported that the global infrastructure to support associated infections, and Plasmodium falciparum and Plasmodium
response to emerging and reemerging infections continued to vivax.
be neglected, particularly in developing regions, where many
previously unrecognized human infections first appear. The chapters chosen for this section are excellent reviews of
the epidemiology of several of these infections. In addition, they
Much has happened in the United States and globally since outline the diagnostic approach to each disease, discuss the clini-
the publication of that 1992 IOM report: burgeoning antimi- cal management of patients, and describe public health interven-
crobial resistance, the North American emergence of West Nile tions to prevent and control the infections.
virus (WNV), the intentional distribution of Bacillus anthracis,
and a vaccine campaign for a vanquished disease (smallpox) Bacillus anthracis is a zoonosis that occurs globally but is
rumored to be the next weapon of mass destruction. More extremely rare in North America and Europe. B. anthracis is
recently, widespread outbreaks of severe acute respiratory easily transmissible, is highly lethal if untreated, and has great
syndrome (SARS) and avian influenza, both initially thought to potential to cause social disruption, as evidenced by the 2001
portend the next pandemic, were upstaged when a novel bioterrorist attack. For this reason, anthrax is an excellent
swine influenza caused the first pandemic of the twenty-first example of a Category A Select Agent, as designated by the
century. Centers for Disease Control and Prevention.

The confluence of human and nonhuman ecology and envi- The influenza A virus is the prototypical reemerging zoono-
ronmental disturbance sets the stage for the prototypical emerg- sis and an agent with great pandemic potential. Although influ-
ing or reemerging infectious disease: a zoonosis, or disease enza A virus has infected mammals and birds for millennia,
caused by an agent that typically infects another species but has changes in the viral genetic structure may enable a novel influ-
made an evolutionary transition that enables it to infect humans. enza A virus to cause widespread human disease. Each novel
virus’s pathogenicity is unpredictable, and several influenza A
pandemics of varying severity have occurred since the devastat-
ing pandemic of 1918.

CHAPTER 87╇ •â•‡ Introduction to Emerging Infectious Diseases and Pandemics 529

SARS is caused by a coronavirus (SARS-CoV) that was first not occur in the Americas;, however, since the virus’s apparent
recognized during a widespread but brief global outbreak that introduction into New York City in 1999, it has spread rapidly
began in November 2002 and rapidly evaporated in July 2003. across the United States and Canada to become the most
Coronaviruses very closely related to SARS-CoV have been common arthropod-borne viral disease in North America.
isolated from bats and other mammals (notably, those traded in
live animal markets as food), and SARS is most likely a zoonotic ADDITIONAL RESOURCES
infection. The rapid, extensive global response to SARS reflects Jones KE, Patel NG, Levy MA, et al: Global trends in emerging infectious
the enormous public health resources required to deal with a
rapidly emerging infection. diseases, Nature 451:990-993, 2008. A fascinating report by a multidisci-
plinary group that evaluates emerging infectious disease “events” over the past
Worldwide, more than 2 billion people are infected with M. several decades. The authors identify factors that could more effectively target
tuberculosis. Drug-resistant tuberculosis is emerging as a signifi- resource allocation in the global effort to investigate and monitor emerging
cant threat to developing regions of the world, places already infections.
being devastated by the HIV pandemic. Where resources are Lederberg J, Shope RE, Oaks SC Jr: Emerging infections: microbial threats to
most limited, the potential public health burden, morbidity, health in the United States, Washington, DC, 1992, Institute of Medicine,
and mortality from drug-resistant tuberculosis and HIV are National Academy Press. One of the first publications to outline the concept
staggering. of “emerging infections,” and an excellent introduction to the subject. Table 2-1
(which lists emerging and reemerging pathogens) is of interest in light of which
Finally, two infections exemplify the impact of environmental agents subsequently became significant public health problems.
change on human disease: tularemia and WNV disease. Tulare- Smolinski MS, Hamburg MA, Lederberg J: Microbial threats to health: emer-
mia is classically associated with rural hunting activities and gence, detection, and response, Washington, DC, 2003, Institute of Medi-
typically manifests as oculoglandular disease; however, an cine, National Academies Press. The IOM revisits its original 1992 report
increasing number of cases of inhalational tularemia have been and evaluates the progress of response to emerging infectious diseases.
reported in suburban lawn-mowing residents of Martha’s Vine- Wolfe ND, Dunavan CP, Diamond J: Origins of major human infectious
yard, Massachusetts, where infected rabbits were imported by diseases, Nature 447:279-283, 2007. The authors define five stages in a
hunting clubs in the 1920s and 1930s. Until 1999, WNV did pathogen’s transition from animal to human hosts and discuss the factors associ-
ated with this transition; they recommend prioritization of future directions in
emerging infections research based on these factors.

Novel Influenza 88

Jo Hofmann

ABSTRACT genome; a small change in a viral strain is known as genetic drift,
whereas a less frequent but more significant change resulting
Influenza virus is a cosmopolitan ribonucleic acid (RNA) virus from genetic reassortment (mixing of genomic material between
that infects birds and mammals worldwide. When an influenza different influenza viruses infecting the same host) is called
A virus subtype that usually affects birds or animals mutates into genetic shift. The reassortment of H antigen genomic segments
a novel strain able to infect people, lack of immunity in human from avian or animal influenza A and those from influenza
populations may cause widespread and serious influenza or other viruses in a human host can result in a completely novel virus—
syndromes. Three worldwide influenza epidemics, or pandem- one against which human populations have little or no immu-
ics, of the twentieth century were caused by novel influenza A nity. If a novel influenza A virus is capable of infecting humans,
viruses of avian (bird) origin, including the devastating pandemic spreading rapidly, and causing severe infection, it has the poten-
of 1918, and a novel influenza A virus of pig (swine) origin, tial to cause a particularly lethal global epidemic (pandemic),
H1N1, caused the first twenty-first–century pandemic. The because most of the world’s human population will lack antibod-
potential for novel influenza A viruses to infect humans, cause ies against its unique H antigen (Figure 88-2).
severe disease, and spread efficiently from person to person is a
worldwide public health concern. This chapter focuses on novel Avian- or animal-origin influenza A viruses that have adapted
influenza A virus subtypes with pandemic potential. to humans have been responsible for numerous localized and
worldwide outbreaks of influenza. Swine influenza was first
GEOGRAPHIC DISTRIBUTION AND described in 1918, and an influenza A (H1N1) virus was first
MAGNITUDE OF DISEASE BURDEN isolated from pigs in 1930. Influenza A H1N1 virus has caused
Influenza is an RNA orthomyxovirus that occurs worldwide and periodic outbreaks in the North American pig population and
is capable of infecting a variety of bird and mammal species, probably circulated as a relatively stable strain from 1930
including humans. Influenza viruses include types A, B, and C; through the 1990s. Recent studies of the 2009 pandemic H1N1
however, most human influenza is caused by influenza virus viral genome have suggested that since about 1998 the viruses
types A and B. In temperate regions, influenza types A and B that circulate in North American swine have undergone a series
circulate year-round, but illness and outbreaks of influenza peak of reassortments that have incorporated genetic segments from
during the colder months (the “influenza season”). Although the avian, swine, and, possibly, human influenza A viruses.
severity and rates of influenza in the United States vary from
year to year, the Centers for Disease Control and Prevention Although the exact origin of the 2009 pandemic H1N1 strain
(CDC) estimates that in an average year, 5% to 20% of the U.S. is unknown, one theory is that it arose from Mexican swine
population will be infected with influenza, more than 200,000 populations and infected humans working with pigs early in
people are hospitalized with complications of influenza, and 2009. The first documented H1N1 infections appeared in the
about 36,000 people will die from influenza-related causes. Mexican state of Veracruz in March 2009. Influenza was subse-
quently identified across Mexico and then reached the United
The influenza virus is composed of a lipid envelope, matrix States and Canada via travelers from Mexico. The H1N1 out-
proteins, and a nuclear core that contains the eight-segment break spread globally, and a pandemic was declared by the
single-stranded RNA genome. Embedded in the viral envelope World Health Organization (WHO) in June 2009. By April
are glycoprotein spikes, known as hemagglutinin (H) and neur- 2010 the pandemic had affected 214 countries and caused nearly
aminidase (N) antigens; these antigens, especially H, are the 18,000 deaths worldwide. In the United States, the CDC esti-
primary targets for the human antibody response against influ- mates that 59 million people were infected with H1N1 from
enza (Figure 88-1). There are 16 H and 9 N antigens that vary April 2009 to April 2010, with 265,000 hospitalizations and
from strain to strain and are used to identify influenza A 12,000 deaths.
subtypes—for example, the influenza A virus responsible for the
1918 pandemic (“Spanish flu”) was an H1N1 strain, whereas Avian-origin influenza A H5N1 virus was first detected in
H2N2 was associated with the 1957 pandemic (“Asian flu”) and domestic fowl in China in 1996, and 18 human H5N1 infections
H3N2 with the 1968 pandemic (“Hong Kong flu”). (six of them fatal) were reported from Hong Kong in 1997. The
virus likely circulated in bird populations at low levels for several
Influenza A is of particular concern because the virus causes years but resurfaced in 2003, when H5N1 infections were
infection in a wide variety of birds and mammals and can mutate reported among birds and animals in South Korea, China, Hong
quickly—two characteristics that provide the virus ample oppor- Kong, and Thailand. The following year, infected birds were
tunity to mix genomic material. Influenza A viruses change identified in numerous East Asian countries (Cambodia, China,
through genetic mutation and sharing of segments of their Hong Kong, Indonesia, Japan, Laos, Malaysia, Thailand, and
Vietnam), and H5N1 was confirmed to be the cause of an out-
break of severe human respiratory disease in Vietnam. From

Hemagglutinin antigen CHAPTER 88╇ •â•‡ Novel Influenza 531
Figure 88-1╇ Structure of the influenza A virus. Neuraminidase antigen
RNA in nuclear core
Lipid envelope
Matrix protein

The influenza A virus is composed of a lipid envelope, matrix proteins, and a nuclear core
that contains the single-stranded ribonucleic acid (RNA) genome. Embedded in the viral
envelope are glycoprotein spikes, known as hemagglutinin and neuraminidase antigens.
These antigens are the primary targets for human antibody response against influenza.

2004 through 2010, several strains (or clades) of H5N1 contin- RISK FACTORS
ued to spread among domestic and wild birds, causing avian and Transmission of influenza viruses to humans occurs primarily
human influenza in 61 countries in Asia, Africa, the Mideast, through inhalation of small, contaminated respiratory droplets
and Europe. By April 2010, 495 laboratory-confirmed human or by contact of the virus with mucous membranes such as those
H5N1 infections had been reported from 15 countries in Asia, of the nasopharynx, oropharynx, or the conjunctivae. Mucosal
Eurasia, the Mideast, and Africa; these infections resulted in exposure to the virus can occur by droplets produced when
292 deaths (case-fatality rate, 59%). The occurrence of human someone with influenza coughs or sneezes, or via a contami-
H5N1 infection in an unaffected country (e.g., the United nated fomite. In general, all modes of transmission (except
States) would constitute a public health emergency, and human fomite) require close contact (i.e., within 6 feet or in an enclosed,
H5N1 virus infection is reportable to most local and state health small space) with an ill person.
departments as well as to the CDC and WHO.

Direct avian-human transmission

Avian virus

Human virus

Reassortment of influenza A virus genes can occur when a single host is infected by several viruses, all of different New reassorted virus
strains. Pigs are likely “mixing vessels” for reassortment because they can be infected with influenza A viruses
from birds, humans, and pigs. If an avian virus (red RNA) and a human virus (blue RNA) infect a pig at the same
time, reassortment could occur, resulting in a novel influenza virus (red and blue RNA). If a novel virus can infect
humans, cause serious illness, and spread from person to person, a pandemic may ensue.
Figure 88-2╇ Generation of a potentially pandemic strain of influenza A through reassortment.

532 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Before the 2009 pandemic, influenza A viruses of swine Table 88-1╇ Risk Factors for Severe or Complicated
origin were reported to cause human disease, but infections Infection with 2009 Influenza
were isolated, and human-to-human transmission was limited. A Virus (H1N1)
A 2007 review of 37 human infections with swine-origin influ-
enza found that 61% of individuals reported contact with pigs RISK FACTOR COMMENT
(typically work on a farm with swine) before the onset of their Age <5 years
illness. Although genetic evidence points to swine origin for the Risk increases with decreasing age;
influenza A H1N1 virus responsible for the 2009-2010 pan- Age ≥65 years hospitalization rate highest among
demic, the virus was not detected in pigs until after recognition children <12 months of age
of H1N1 influenza in humans. There is no evidence that H1N1 Chronic
can be transmitted to humans from properly prepared and cardiovascular Highest rate of mortality but lowest
cooked pork, ham, or other pig products. The modes of human- disease risk of infection
to-human transmission of the H1N1 virus are presumed to be
similar to those of other subtypes of influenza A, with droplet Chronic lung disease Congestive heart failure,
inhalation and contamination of mucous membranes being the atherosclerosis
primary modes. Chronic renal
disease Asthma, cystic fibrosis, chronic
According to CDC data, younger age appears to be a risk for obstructive pulmonary disease
infection with H1N1, with the highest rates of disease in persons Chronic hepatic
younger than 25 years of age, especially children younger than disease Dialysis or transplantation
5 years of age. This finding may be related to partial immunity
among older individuals, who may have been exposed to an Metabolic disease Cirrhosis
H1N1 virus before 1958. The rate of hospitalization has a Neurologic disease
bimodal distribution: the highest rates occur among children Diabetes
and young adults younger than 25 years of age and adults 50 to Hemoglobinopathies Neuromuscular, cognitive, or seizure
64 years of age. Many hospitalized patients (24% to 50%) have Immunosuppression
asthma or chronic obstructive pulmonary disease. With the disorder
exception of age over 65 years, the risk factors associated with Long-term aspirin Sickle cell anemia
more severe influenza appear to be the same as those for sea- therapy in children Human immunodeficiency virus
sonal disease (Table 88-1). Among hospitalized persons,
30% had at least one underlying medical condition typically Pregnancy (HIV) infection; malnutrition;
associated with complications of seasonal influenza (see Table receipt of organ transplant,
88-1). Deaths occur at the highest rate among persons 25 to 64 Long-term smoking chemotherapy, or long-term
years of age, in contrast to seasonal influenza, in which more Morbid obesity corticosteroids
than 90% of fatalities occur among persons 65 years of age Salicylate use in children with
or older. (body mass index influenza is associated with Reye’s
≥40) syndrome and should be avoided
Thus far, essentially all human H5N1 infections have been Increased risk for hospitalization,
acquired in areas experiencing the H5N1 epizootic (an epidemic especially in third trimester
affecting animals or birds), via direct contact with infected Possible independent risk factor
domestic birds or their contaminated environments. Human Possible independent risk factor for
exposure usually occurs during farming, slaughtering, market- hospitalization, critical illness, and
ing, or preparing poultry in the 14 days before illness onset. death
Human H5N1 infection has been reported after the consump-
tion of raw poultry products; however, properly cooked poultry Adapted from Writing Committee of the WHO Consultation on Clinical
does not pose a risk for infection. As of this writing, no infec- Aspects of Pandemic (H1N1) 2009 Influenza, Bautista E,
tions have been reported in short-term travelers to areas where Chotpitayasunondh T, et╯al: Clinical aspects of pandemic 2009 influenza
the avian H5N1 epizootic is occurring. A (H1N1) virus infection, N Engl J Med 362:1708-1719, 2010.

The median age of patients with H5N1 is 18 years; 90% are CLINICAL FEATURES
40 years of age or younger, and the case-fatality rate is greatest The incubation period for human infections caused by influenza
among persons 10 to 19 years of age. Although human H5N1 A H1N1 virus is similar to that of seasonal influenza, about 2
infection may occur year-round, more cases are reported during days (range 1.5 to 7 days). Infection with H1N1 displays a wide
winter months, a pattern also seen in avian H5N1 infections. spectrum of disease: individuals may seroconvert without evi-
Despite a widespread epizootic that has affected millions of dence of illness or may succumb to fulminant viral pneumonia.
birds in 61 countries since 1996, fewer than 500 humans have A mild influenza-like illness is reported in many (8% to 32%)
been infected with H5N1, suggesting that bird-to-human trans- patients, with cough, fever, sore throat, and rhinorrhea. Less
mission is relatively rare. Human-to-human transmission of than 2% of patients report dyspnea or symptoms of pneumonia.
H5N1 virus is even less frequent; however, clusters of influenza In contrast to seasonal influenza, gastrointestinal symptoms are
among family members have been reported from several coun- more common, especially among adults: vomiting and diarrhea
tries, suggesting possible genetic determinants of viral suscepti- are seen in about 24%. The mean duration of illness is 5 days
bility and/or spread of the virus by close human contact. (range 0 to 23 days).

Rates of hospitalization vary by country, age group, and
presence of underlying conditions; the highest rates in the
United States are seen in children younger than 5 years of
age and children and adults with conditions that put them at
risk for complications of seasonal influenza (see Table 88-1).

CHAPTER 88╇ •â•‡ Novel Influenza 533

Hospitalized patients typically have viral pneumonia with be notified of the suspected diagnosis immediately (see the dis-
hypoxemia and acute respiratory distress syndrome (ARDS). cussion of prevention and control later in this chapter).
Many patients with severe or fatal infections will develop sec-
ondary bacterial pneumonia, most commonly caused by Strep- Commercial tests for diagnosis of seasonal influenza include
tococcus pneumoniae, Streptococcus pyogenes, or Staphylococcus aureus, rapid antigen detection assays and viral isolation from respira-
and rarely myositis, rhabdomyolysis, myocarditis, or neurologic tory tract secretions, serum antibody assays, and polymerase
syndromes. Chest radiographs commonly show diffuse, mixed chain reaction (PCR) assays. Rapid antigen detection assays lack
interstitial and alveolar infiltrates, but focal or multifocal con- the sensitivity and specificity to detect or distinguish influenza
solidation can occur, especially with secondary bacterial infec- A subtypes (e.g., H5 versus H1 or H2), and isolation of novel
tion. Chest computed tomography may show multifocal lower influenza viruses can take several days and may necessitate use
lobe ground-glass opacities, air bronchograms, and alveolar of biosafety practices not available in most laboratories. Paired
consolidation. Common laboratory findings include leukopenia, acute and convalescent serum influenza antibody assays are
lymphocytopenia, and elevated serum aminotransferases, lactate useful for research purposes but do not provide rapid diagnosis
dehydrogenase, creatine kinase, and creatinine. for influenza. Currently the most rapid and accurate method for
detection of influenza A H5N1 and H1N1 viruses are real-time
The incubation period of human H5N1 infection appears to reverse transcription–PCR (RT-PCR) assays capable of detect-
be 2 to 5 days, but incubation as long as 9 days has been ing viral RNA in respiratory secretions.
reported. The infectious period (duration of shedding of H5N1
virus) is unknown; however, shedding of seasonal influenza virus Every effort should be made to obtain diagnostic specimens
begins the day before illness onset and lasts 5 to 7 days, with a as quickly as possible, as viral shedding decreases with time and
peak of viral shedding during the first 2 to 3 days of illness. Some may be affected by treatment with antiviral medication. Oro-
patients may shed virus longer, particularly young children and pharyngeal or nasopharyngeal specimens are generally accept-
severely immunocompromised persons. Most patients demon- able for outpatients with suspected H1N1, whereas oropharyngeal
strate fever, dyspnea, cough, and signs of viral pneumonia. The specimens are preferred for suspected H5N1. In moderately to
majority have abnormal chest radiographic findings at presenta- severely ill patients with lower respiratory tract disease, speci-
tion, including multifocal consolidation or interstitial infiltrates mens obtained by bronchoalveolar lavage or tracheal aspirate
that may be focal or lobar and unilateral or bilateral; serious have the highest yield, as both viruses replicate most efficiently
infections rapidly progress to ARDS, showing bilateral ground- in the lower respiratory tract.
glass opacities. Common laboratory abnormalities include leu-
kopenia, lymphocytopenia, thrombocytopenia, and elevated If a novel influenza virus infection is highly suspected, a
serum aminotransferases. Atypical symptoms include diarrhea, negative RT-PCR assay result does not rule out infection, and
headache, and, rarely, syndromes in which gastrointestinal or multiple specimens obtained over several days may further
neurologic symptoms predominate. The time from onset to increase the yield. These specimens should be obtained using a
death in fatal infections is about 10 days; death is usually caused plastic or aluminum swab tipped with synthetic material (poly-
by primary viral pneumonia, secondary bacterial pneumonia, ethylene or Dacron), and the swab should be placed directly into
and multiorgan dysfunction. Less serious upper respiratory sterile viral transport media. The PCR assay can also be per-
infection without pneumonia has been reported in children; formed on tissue samples, but formalin fixation may interfere
however, serosurveys of poultry workers indicate that asymp- with viral RNA extraction. A PCR assay that specifically detects
tomatic infections are uncommon (3% to 10%). influenza A H5 and H1 viruses is available at most state public
health laboratories and at the CDC viral diagnostic laboratory
DIAGNOSTIC APPROACH in Atlanta.
Unfortunately, both seasonal and novel influenza viruses can
cause a nonspecific illness; depending on the geographic region Note that all diagnostic procedures should be performed
or a patient’s recent travel, community-acquired bacterial or using appropriate infection control and personal protective
viral respiratory infection, dengue, leptospirosis, typhoid, tuber- equipment (PPE) (see discussion of prevention and control) for
culosis, malaria, or other causes of acute systemic or respiratory the respective novel viruses. Whereas influenza A H1N1 may
illnesses may be included in the differential diagnosis. As the be isolated using Biosafety Level 2 protocols, isolation of H5N1
influenza A H1N1 virus continues to circulate, any patient with virus requires a Biosafety Level 3 laboratory, as the live virus is
an influenza-like illness should be suspected of being infected considered to be a significant biohazard. This high level of
with this virus. biocontainment is available at a few North American laborato-
ries, including the CDC. For additional information on influ-
Human H5N1 infections are most likely to be encountered enza viral diagnostics or isolation methods, contact your local
in persons who have had contact with domestic birds in areas or state health department.
currently experiencing the H5N1 avian epizootic. Clinicians in
the United States and other unaffected countries should be alert CLINICAL MANAGEMENT AND
for possible human H5N1 infections in persons who develop a DRUG TREATMENT
serious febrile respiratory illness of unknown cause within 7 The presentation of influenza is variable, and the management
days of leaving an affected area. These patients should receive is determined by the severity of disease, not necessarily by the
rapid laboratory diagnosis and be managed with appropriate specific virus subtype. In general, mild illness is limited to symp-
infection control precautions; public health authorities should toms of an upper respiratory infection with possible gastroin-
testinal involvement. Moderate illness may include signs and
symptoms of lower respiratory tract involvement (e.g., dyspnea,

534 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

chest pain, or labored breathing), myalgias, headache, and pros- PROGNOSIS
tration and may be accompanied by exacerbation of underlying For infections with influenza A H1N1 virus, a poor prognosis
medical conditions. Severe illness is characterized by respiratory is associated with moderate to severe illness with thrombocyto-
distress and prolonged or recurrent fever and may progress to penia, metabolic acidosis, and elevated creatine kinase, creati-
respiratory failure, secondary bacterial pneumonia, and multi- nine, and lactate dehydrogenase. Case-fatality rates have been
organ failure. highest in children younger than 5 years of age, pregnant
women, and persons 65 years of age and older. Overall estimates
Most mild to moderate influenza in healthy individuals can of the case-fatality rate for H1N1 are less than 0.5%—signifi-
be managed symptomatically; however, patients infected with cantly lower than that associated with seasonal influenza.
confirmed or suspected influenza A H5N1 and those with
H1N1 who require hospitalization, exhibit signs of progressive Most patients with influenza A H5N1 virus infections develop
infection, or are at risk for complications of influenza should serious illness, and many will experience complications includ-
receive empirical antiviral therapy as quickly as possible (see ing secondary bacterial pneumonia and respiratory, renal,
Table 88-1). More than 50% of patients with influenza A H5N1 cardiac, and other organ dysfunction. Overall the case-fatality
virus infections develop progressive respiratory failure and rate for human influenza A H5N1 virus infection is high: 62%,
require intensive care and mechanical ventilation. Therefore with a range of 33% to 82% (based on case-fatality rates among
ventilatory support and prevention of nosocomial complications countries reporting more than 10 cases). The impact of regional
are frequently key elements of clinical management for severe variations in viral clade predominance, medical practices, or
influenza. resources may account for some regional variations in
case-fatality rates. As noted previously, early initiation of anti-
Two classes of drugs are effective for the treatment of influ- viral therapy with oseltamivir appears to confer a significant
enza A virus infections: adamantines (i.e., rimantadine and survival benefit.
amantadine) and neuraminidase inhibitors (e.g., zanamivir and
oseltamivir). Influenza A viral subtypes and strains may vary in PREVENTION AND CONTROL
their susceptibility to these antivirals. In the United States, Overview
resistance to adamantines or oseltamivir has been found in sea- Reducing the burden of human influenza A virus infections relies
sonal influenza A viruses and the H5N1 and H1N1 viruses. on preventing disease through immunization and chemoprophy-
Although the adamantine resistance is significant enough to laxis and minimizing the risk of disease transmission with appro-
warrant exclusive use of neuraminidase inhibitors for H5N1 and priate infection control measures and community interventions
H1N1, oseltamivir resistance appears to be sporadic. (e.g., school closure, cancellation of large crowd events, volun-
tary isolation [“social distancing”], and quarantine).
Antiviral treatment should begin as soon as possible after the
onset of symptoms, and as mentioned earlier, the neuraminidase For influenza A associated with animals, primary prevention
inhibitors are the preferred drugs for therapy. Oseltamivir is of associated human disease relies on reducing infections among
available in tablet and suspension formulations for oral use and animals and decreasing opportunities for spread of influenza A
is approved for patients 12 months of age or older; it is available virus from animals to humans. For example, controlling avian
for younger children under a U.S. Food and Drug Administra- influenza A H5N1 in epizootic countries has focused on the
tion (FDA) Emergency Use Authorization. Inhaled zanamivir is most common sources of human infection in these areas: domes-
approved for use in patients older than 6 years of age. In addi- tic birds and the poultry industry. Prevention and control rec-
tion, intravenous zanamivir and peramivir are available for life- ommendations are available for poultry and agriculture workers,
threatening influenza H1N1 by Emergency Use Authorization wildlife workers, farmers, hunters, travelers to epizootic areas,
for both adults and children who require intravenous therapy or and others at risk for contact with infected birds. In the United
in whom therapy with other neuraminidase inhibitors has failed. States, where influenza A H5N1 virus infections are expected
The recommended duration of therapy for H1N1 infection is to arrive among travelers from epizootic regions, it is hoped that
5 days. early recognition of initial infections by astute clinicians, imple-
mentation of effective infection control practices, and rapid
WHO recommends early initiation of treatment with osel- notification of public health authorities will facilitate prevention
tamivir for H5N1 infections, based on the results of several and control of person-to-person spread of H5N1. The use of
uncontrolled clinical trials that demonstrated a significant sur- chemoprophylaxis and vaccines that effectively provide protec-
vival benefit from prompt oral oseltamivir therapy. However, tion against the influenza A H5N1 virus in humans will also play
the optimal dose and duration of oseltamivir therapy for a role.
H5N1 are not yet known. WHO suggests that it may be reason-
able to use a high dose of oseltamivir (adults, 150╯mg orally Infection Control
twice daily) for a 10-day course. Combination therapy with The characteristics of novel influenza A viruses are highly vari-
amantadine may be considered in areas where the clades are able and difficult to predict. Individual strains of influenza A
susceptible, although published data to support this approach virus may differ in their ability to spread from person-to-person.
are limited to animal models; in addition, the efficacy of zana- Estimates of the secondary attack rate for influenza A H1N1
mivir or peramivir in human influenza A H5N1 virus infections virus range from 4% to 28%, depending on the circumstances;
is unknown.

Based on limited data, the use of corticosteroids or other
immunomodulators has not demonstrated effectiveness in
improving outcome in patients with influenza A virus infections;
therefore routine use of these drugs is not recommended.

CHAPTER 88╇ •â•‡ Novel Influenza 535

the basic reproduction number (the mean number of secondary for influenza for those contacts. In addition, early in a looming
infections transmitted by a single primary case in a susceptible pandemic, voluntary isolation of sick patients and quarantine of
population) ranges from 1.3 to 1.7 according to the setting, exposed contacts, combined with the suspension of certain social
similar to or slightly higher than the estimates for seasonal activities, may decrease the spread of disease. A coordinated
influenza. Nosocomial spread of both seasonal and H1N1 effort by local and national public health authorities will be
viruses has been reported. Person-to-person transmission of needed to effectively limit the spread of a novel influenza A virus
influenza A H5N1 virus appears to be limited, without well- in the United States.
documented nosocomial transmission in the absence of addi-
tional disease risk factors. However, the influenza A H5N1 virus Chemoprophylaxis
has the potential, through reassortment, to acquire the capabil- Events of previous pandemics and mathematical modeling
ity to easily spread among humans. studies suggest that early, targeted mass antiviral chemoprophy-
laxis, combined with interventions to limit social interactions,
In general, CDC and WHO recommendations for infection may arrest or delay the onset of an influenza pandemic. Neur-
control for influenza A focus on immunization of healthcare aminidase inhibitors are the preferred agents for chemoprophy-
workers and reducing the risk of respiratory droplet transmis- laxis for influenza A H1N1 or H5N1 virus infections. WHO
sion (the presumed primary mode of person-to-person spread and the CDC have developed plans that address the priorities
of influenza A viruses). Specific recommendations for any indi- for distribution and use of stockpiles of these drugs; these priori-
vidual viral strain may vary, depending on the availability of ties may differ depending on the severity of the pandemic and
effective vaccines and the degree of infectivity of a particular supplies of the drugs. The indiscriminate use of chemoprophy-
novel influenza A virus. laxis during a pandemic may be problematic as supplies dwindle
or as the pandemic virus develops resistance to available chemo-
The CDC emphasizes the following fundamental measures prophylaxis agents.
for the prevention of influenza transmission in healthcare set-
tings: promoting and administering seasonal influenza vaccine, Immunization
minimizing potential influenza A exposures in healthcare set- The H1 and N1 antigens in the viral envelope characterize the
tings, managing healthcare workers with suspected or confirmed influenza A virus and are used to determine the antigenic composi-
influenza appropriately, and using effective infection control tion of influenza vaccines. In 2007, the FDA licensed the first
measures. Due to the rapidly changing nature of influenza epi- human monovalent H5N1 vaccine in the United States for persons
demiology, the details of specific infection control recommenda- 18 through 64 years of age, and the vaccine is part of the National
tions are beyond the scope of this chapter; however, comprehensive Pharmaceutical Stockpile. After the development of a safe and
and updated recommendations for prevention and control of effective monovalent vaccine for H1N1 in 2009, the CDC Advi-
influenza are available from the many agencies (see Box 88-1). sory Committee on Immunization Practices recommended that
the 2009 pandemic strain be included in the 2010-2011 trivalent
Public Health Measures seasonal influenza vaccine; they also expanded their recommenda-
One aspect of disease prevention and control that may be over- tions for influenza vaccination to include all persons 6 months of
looked is the importance of reporting suspected communicable age and older. However, existing techniques for influenza vaccine
diseases to public health authorities. In the case of novel influ- development are time- and work-intensive and impractical for the
enza A viruses, which may cause widespread, serious illness, it rapid, large-scale production needed to supply sufficient quanti-
is extremely important that clinicians report any suspected novel ties of vaccine in the event of a severe pandemic. Future directions
influenza A virus infections to their local or state health depart- in influenza vaccine research will focus on production methods,
ment. Public health personnel can assist in the evaluation of the modes of delivery, adjuvants, and how changes in influenza anti-
patient and facilitate diagnostic and confirmatory laboratory gens may affect vaccine immunogenicity.
testing. They can also assist in the identification of any persons
with whom the patient may have been in contact during the
infectious period and can provide indicated chemoprophylaxis

Box 88-1╇ Infection Control Recommendations for EVIDENCE
Influenza A
Davey VJ, Glass RJ, Min HJ, et al: Effective, robust design of
CDC: Prevention Strategies for Seasonal Influenza in Health- community mitigation for pandemic influenza: a systematic
care Settings http://www.cdc.gov/flu/professionals/infection- examination of proposed U.S. guidance, PLoS One 3:e2606,
control/healthcaresettings.htm 2008. Using mathematical modeling, the authors assess the
effectiveness of interventions proposed to limit the spread of pandemic
WHO: Infection prevention and control in health care for influenza.
confirmed or suspected cases of pandemic (H1N1) 2009 and
influenza-like illnesses http://www.who.int/csr/resources/ Smith GJD, Vijaykrishna D, Bahl J, et al. Origins and
publications/cp150_2009_1612_ipc_interim_guidance_h1n1. evolutionary genomics of the 2009 swine-origin H1N1
pdf influenza A epidemic. Nature 459:1122-1125, 2010. An
evolutionary analysis of the 2009 human influenza A H1N1 virus
WHO: Infection control recommendations for avian influ- that discusses the possible origin of the pandemic virus.
enza in health care facilities http://www.who.int/csr/disease/
avian_influenza/guidelines/EPR_AM1_E5.pdf

536 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

ADDITIONAL RESOURCES index.html. WHO coordinates the global response to seasonal, pandemic, and
Centers for Disease Control and Prevention (CDC): Seasonal influenza: H5N1 influenza. Information on this page tracks the evolving situation and
provides access to clinical and technical guidelines for management of human
information for health professionals. Available at: www.cdc.gov/flu/ influenza A H5N1 and H1N1.
professionals. The CDC coordinates the U.S. response to seasonal, pandemic, Writing Committee of the Second World Health Organization Consulta-
and human H5N1 influenza. Information on these pages tracks the evolving tion on Clinical Aspects of Human Infection with Avian Influenza A
situation and provides access to clinical and technical guidelines and information (H5N1) Virus, Abdel-Ghafar AN, Chotpitayasunondh T, et al: Update
for professionals. on avian influenza A (H5N1) virus infection in humans, N Eng J Med
Morbidity and Mortality Weekly Report: Public health resources: state 358:261-273, 2008. An excellent and comprehensive review of the global epi-
health departments. Available at: www.cdc.gov/mmwr/international/ demiologic and clinical aspects of the ongoing outbreak of human influenza A
relres.html. The CDC’s Morbidity and Mortality Weekly Report (MMWR) H5N1 virus infections.
hosts this page of links to state and local health departments’ websites, from which Writing Committee of the WHO Consultation on Clinical Aspects of Pan-
region-specific data and contact information can be obtained. demic (H1N1) 2009 Influenza, Bautista E, Chotpitayasunondh T, et al:
U.S. Department of Health and Human Services: Flu.gov website. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection, N
Available at: www.pandemicflu.gov/index.html. A one-stop access page for Engl J Med 362:1708-1719, 2010. An excellent and comprehensive review of
federal government information regarding seasonal, pandemic, and human the global epidemiologic and clinical aspects of the recent pandemic of human
H5N1 influenza. influenza A H1N1 virus.
World Health Organization (WHO): Global alert and response: avian
influenza. Available at: www.who.int/csr/disease/avian_influenza/en/

Severe Acute Respiratory 89
Syndrome (SARS)

Eileen Schneider

ABSTRACT worldwide since early 2004. Almost all persons with SARS were
reported from China, Hong Kong, Taiwan, Singapore, or
Severe acute respiratory syndrome (SARS) first appeared in Toronto, but overall, as of December 2003, WHO had received
November 2002 and ultimately resulted in 8096 probable reports of SARS from 29 countries and regions: 8096 persons
human infections and 774 deaths worldwide. By July 2003, the with probable SARS, resulting in 774 deaths, a case-fatality rate
global outbreak was declared over. A new coronavirus, SARS- of 9.6%. In the United States, eight infections were documented
associated coronavirus (SARS-CoV), was identified as the caus- by laboratory testing, and an additional 19 probable infections
ative agent; this virus appeared to have a zoonotic origin, as were reported. The syndrome arose and vanished within several
genetically similar coronaviruses have been identified in several months, and it is unclear when or if SARS will return.
animal species. The global response to the outbreak was exten-
sive. Within a short period, the pathogen had been identified, Coronaviruses
new diagnostic tests were developed, surveillance systems were Coronaviruses are enveloped, single-stranded positive strand
created, infection control and prevention measures were insti- ribonucleic acid (RNA) viruses that infect a wide spectrum of
tuted, and transmission among humans stopped. It is unclear if mammals and birds. There are three coronavirus groups: groups
and when person-to-person SARS-CoV transmission will reap- I and II affect mammals and group III affects birds. In humans,
pear. However, procedures have been established by public coronaviruses are primarily associated with upper respiratory
health organizations, including the World Health Organization infections. During the 2002-2003 SARS outbreak, several strains
(WHO) and the Centers for Disease Control and Prevention of a coronavirus unrelated to previously described coronaviruses
(CDC), to help guide diagnosis, reporting, surveillance, and were identified and isolated from clinical samples, including
prevention. respiratory secretions, urine, and autopsy tissues. This new virus
was identified as a novel group II coronavirus and named SARS-
GEOGRAPHIC DISTRIBUTION AND associated coronavirus; of all coronaviruses, it is responsible for
MAGNITUDE OF DISEASE BURDEN causing the most severe human disease.
Background
In 2002 and 2003, a previously unknown infectious agent caused Bats have been identified as natural reservoirs of SARS-
a widespread, global outbreak of life-threatening respiratory CoV–like viruses and are most likely the natural reservoirs for
infections. The illness was called severe acute respiratory syndrome SARS-CoV; therefore SARS is a zoonosis. Studies of animal
(SARS) and was one of the first emerging infections in recent ecology and virus evolution have revealed that SARS-CoV–like
history to test the global public health response. Strategies used viruses are also present in other animals, including those com-
to prevent and control SARS helped to shape future public monly traded at live animal markets in southern China (e.g.,
health response to infectious disease emergencies such as the masked palm civet, raccoon dog, red fox). At this time, it is
2009 H1N1 influenza pandemic. SARS emerged in Guangdong unclear if these animals are susceptible hosts or carriers of
Province, China, in mid-November 2002 and was first officially SARS-CoV, but recent research indicates that the masked palm
reported to WHO in February 2003. In mid-March 2003, civet probably served as intermediate host between bats and
WHO issued an alert calling attention to several outbreaks of humans during the 2002-2003 outbreak. Sequence analyses of
severe atypical pneumonia in Hong Kong, Hanoi, and Singa- SARS-CoV have shown that SARS-CoV–like viruses that infect
pore. Many of the initial SARS infections were traced to a guest masked palm civets are very similar (genome identity >99.6%)
staying at a Hong Kong hotel, and global spread occurred to the SARS-CoV that infected humans in the 2002-2003 SARS
quickly with multiple outbreaks reported in China, Southeast outbreak, suggesting that the virus had only recently circulated
Asia, Europe, and North America. By mid-April 2003, the caus- in the masked palm civet. The increased prevalence of SARS-
ative agent was identified as a new coronavirus, SARS-CoV. An CoV immunoglobulin G (IgG) antibodies among animal traders
unprecedented global outbreak response (including the imple- compared with a control group (13% versus 1% to 3%) further
mentation of surveillance systems, epidemiologic studies, appro- supports this theory. In addition, the absence of SARS-CoV
priate infection control measures, and development of laboratory antibodies in the general population without clinical evidence
diagnostics) was swiftly initiated. In July 2003, WHO announced of SARS suggests that SARS-CoV did not widely circulate
that the SARS outbreak was over. Although a few laboratory- before the 2002-2003 SARS outbreak.
associated SARS infections were reported in Asia after the out-
break was declared over, no infections have been reported Transmission
The estimated incubation period for SARS is 2 to 10 days
(median 5 to 6 days). The virus is detected at low levels in

538 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

respiratory secretions during the initial days after the onset of occur via aerosolization during patient procedures, such as intu-
illness, and peak viral levels occur during the second week of bation and bronchoscopy. Transmission has also been docu-
illness (e.g., 10 days). This viral replication phase is followed by mented on an airplane, in an apartment complex (probably
the immune hyperreactive phase, which occurs when disease secondary to faulty plumbing and aerosolization of fecal matter),
severity increases and viral load decreases. Disease progression and among laboratory workers handling SARS-CoV. Transmis-
is variable, and not all patients progress to the final pulmonary sion of the virus has not been not reported via food-borne or
destruction phase. waterborne sources, nor from an infected patient whose fever
had resolved more than 14 days previously.
The primary route of SARS-CoV transmission is via the
respiratory tract; during close contact with an infected patient, As seen with other infectious diseases, environmental and
respiratory droplets may come into contact with mucous mem- host factors influence the risk of transmission. Although the
branes either directly or indirectly through contaminated virus was initially thought to be highly infectious, the rate of
fomites. Studies have determined that SARS-CoV can remain secondary transmission of SARS-CoV is estimated to be low to
stable on environmental surfaces for several days, although the moderate. Transmission modeling studies have estimated that
virus can be easily inactivated by disinfectants. The virus has each patient will infect an average of three persons. However,
been isolated from respiratory secretions, saliva, tears, urine, some SARS-infected patients designated as “superspreaders”
and stool. Viral shedding generally does not persist beyond have been documented to have very high secondary transmis-
4 weeks, except in stool, in which the virus can be detected sion rates (infecting an average of 36 contacts [range 11 to 74
by reverse transcription-polymerase chain reaction (RT-PCR) contacts]), a phenomenon not unique to SARS. Transmission of
for longer than a month. Isolation of the virus more than a SARS-CoV by superspreaders primarily occurred in hospital
month after the onset of illness is rare. Virus detection in settings and was associated with a greater number of close con-
nasopharyngeal specimens using quantitative RT-PCR found tacts, delayed diagnosis, older age, more severe illness, and poor
that the level typically peaks during the second week of infection control practices.
illness, often when severely ill patients are seeking medical
care. As patients improve clinically and the viral load CLINICAL FEATURES
decreases, transmission of the virus also decreases. Unlike other Severity of disease among SARS patients varies from asymptom-
respiratory viral infections, such as influenza, transmission atic infection to fatal acute respiratory distress syndrome (ARDS)
before symptom onset has not been reported. During the recent (Figure 89-1). Seroprevalence surveys have documented asymp-
SARS outbreak, transmission occurred primarily in hospitals, tomatic infection, especially among animal traders in Guang-
less so within households, and to an even lesser extent within dong, China, but overall, asymptomatic or mild disease is
communities. relatively uncommon (<1%).

RISK FACTORS SARS affects persons of all ages; however, most infections
In the 2002-2003 outbreak, the primary risk factor was contact occur among adults (median age approximately 42 to 57 years).
with a person who was infected with SARS-CoV. Twenty-one Infections among children, especially those younger than 12
percent of all reported SARS-CoV infections occurred among years of age, are uncommon. Compared with adults, the disease
healthcare workers. Nosocomial transmission of SARS-CoV is considerably less severe among children, and the outcome is
was common early in the outbreak but subsequently decreased much more favorable. Infections during pregnancy have been
significantly as a result of early diagnosis and reinforcement of documented, with an increased risk of spontaneous abortion,
infection control practices. Nosocomial spread is theorized to preterm labor, severe pulmonary disease, and death. No reports
of perinatal transmission have been noted.

Lungs Air sacs

Heart

ARDS occurs when the lungs are infected
or injured. Typically, fluid will fill air sacs
in the lungs, so oxygen can’t get to the body.
Figure 89-1╇ Mechanism of acute respiratory distress syndrome.

CHAPTER 89╇ •â•‡ Severe Acute Respiratory Syndrome (SARS) 539

Early SARS symptoms are similar to other respiratory Chest radiographs can provide valuable
infections and include headache, chills, myalgia, information. Typical early findings include
and fever, typically seen in the first week following a ground glass appearance and focal opacities
onset. This is followed by cough and shortness of or consolidations in the peripheral lower lung
breath, which typically appear in the second week fields, which often progress to bilateral patchy
Figure 89-2╇ Symptoms of severe acute respiratory syndrome. consolidations

The initial symptoms of SARS are nonspecific and consistent Initial chest radiographic findings may be unremarkable or
with an influenza-like illness. A prodrome that includes fever, indistinguishable from those of other causes of infectious pneu-
headache, chills, rigors, malaise, and myalgias occurs approxi- monia in up to 30% of patients. However, serial chest radio-
mately 1 to 2 days after exposure (Figure 89-2). Nearly all graphs and high-resolution computed tomography (CT) scans
patients report fever (with temperatures frequently exceeding may offer valuable information during evaluation of a patient
101° F), which typically precedes other prodromal symptoms with suspected SARS, as abnormalities appear in a large propor-
but can also occur after the prodrome. The elderly and those tion of patients by day 7 to 10 of illness. Typical chest radio-
with a history of chronic comorbid conditions, such as diabetes graphs have a ground glass appearance with focal opacities or
mellitus or chronic renal failure, may have atypical presentations consolidation in the peripheral lower lung fields; these focal
(e.g., lack of fever). findings often progress to bilateral patchy consolidation
(Figure 89-2). Peripheral lung involvement was a very common
Although SARS primarily affects the pulmonary system, finding in most case studies of the 2002-2003 outbreak, and
respiratory symptoms (typically including nonproductive cough pulmonary cavitation, hilar lymphadenopathy, nodular infil-
and shortness of breath) appear more often during the second trates, and pleural effusion were unusual (Figure 89-3).
week of illness. In one reported patient series, gastrointestinal
symptoms, primarily diarrhea, were prominent (73%), with Evidence of extrapulmonary dissemination of SARS-CoV
high-volume diarrhea occurring in the second week of illness. can be found by laboratory and pathologic diagnostic methods.
In a separate report, diarrhea, nausea, and vomiting were less The virus has been detected in several extrapulmonary organs,
common (<25%). Mucus and blood in stool are uncommon, and including the gastrointestinal tract, kidneys, liver, and spleen.
the diarrhea is often self-limiting. Lymphadenopathy, rhinor- Studies to improve our understanding of SARS pathogenesis
rhea, sore throat, rash, and purpura are unusual. and immune response are ongoing.

In persons with SARS, inspiratory crackles at the lung bases LABORATORY FINDINGS
and, less commonly, wheezing may be noted on auscultatory Common laboratory findings in patients with SARS include
examination. Initially a consistent finding is the paucity of aus- moderate lymphocytopenia with a low to normal white blood cell
cultatory findings relative to the degree of abnormalities dis- count (primarily caused by a decrease in T-cell lineages); mild
played on chest radiographs. By the second week of illness, thrombocytopenia; increased serum lactate dehydrogenase (i.e.,
clinical deterioration may occur, with pneumonia and hypox- more than three to five times the upper limit of normal); and
emia that necessitate hospitalization. During the 2002-2003 elevated serum hepatic transaminases. Decreased CD4 and CD8
outbreak, respiratory failure and ARDS were the most common T-cell counts can be significant: up to 30% of infected patients
reasons for admission to an intensive care unit (ICU). In several have a CD4 T-cell count of <200 cells/mm3. Elevated
studies, approximately 20% to 30% of patients hospitalized with serum creatinine phosphokinase (noncardiac) and electrolyte
SARS were admitted to an ICU; about 75% of ICU patients
required mechanical ventilation.

540 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Lymph ducts

Pathway of normal
pulmonary fluid resorption

Lymphatics

Central Veins
perivascular
and interstitial
spaces

Alveolus H2O Alveolus
Capillary
Capillary Early pulmonary edema. Hazy opacification
Hydrostatic chiefly in central lung areas (butterfly pattern)
pressure
Osmotic Surfactant layer
pressure Capillary endothelium
Basement membrane (fused)
Type I pneumocyte Alveolar
Type II pneumocyte epithelium

Thin Thick Advanced pulmonary edema.
side side Patchy consolidation distributed
Interalveolar septum chiefly in lower parts of both lungs

Figure 89-3 SARS is a cause of noncardiac pulmonary edema. The infection causes the lung’s capillaries to leak more fluid than
normal into the air sacs (alveoli).

abnormalities, including hypocalcemia, hypokalemia, hypomag- Other diagnostic methods, such as virus isolation, electron
nesemia, and hypophosphatemia, are also commonly seen in microscopy, and immunohistology, are also available but are not
SARS. routinely used because of specific technologic requirements and
safety issues (e.g., virus isolation requires a Biosafety Level 3
DIAGNOSTIC APPROACH laboratory).
It is important to note that since 2004 there has been a world-
wide absence of human-to-human transmission of SARS-CoV. The virus that causes SARS can be detected from a number
As a result, resources for the laboratory diagnosis of SARS infec- of clinical specimens including respiratory fluids and tissue (i.e.,
tion are limited, and testing is reserved for situations in which nasopharyngeal and oropharyngeal [NP/OP] swab, nasal aspi-
a high level of suspicion exists for possible SARS-CoV infection. rate, sputum, bronchoalveolar lavage [BAL] specimen or lung
In the United States, the CDC has developed guidelines for the tissue) and from serum, stool, urine, and hepatic tissue. To opti-
clinical and public health management of SARS, including spe- mize laboratory diagnosis, the type of specimen obtained and the
cific criteria and algorithms for laboratory testing (see the timing of specimen collection relative to illness onset are impor-
section on prevention and control for a detailed explanation). tant. In the 2002-2003 SARS outbreak, rapid detection of SARS
was initially hampered by several factors: diagnostic assays had
In response to the SARS outbreak, laboratory diagnostics to be developed, high-level biosafety was required for working
were rapidly developed to detect the newly identified coronavi- with the live virus, and low viral load in clinical specimens and
rus. Methods of choice currently include detection of SARS- the time required by a host to mount antibody limited the sensi-
CoV–specific antibodies in serum using enzyme immunoassays tivity of assays to detect early SARS-CoV infection.
(EIAs) or immunofluorescence assays (IFAs) and detection of
SARS-CoV RNA in clinical specimens using real-time RT-PCR. During the outbreak, studies of the first-generation quantita-
tive RT-PCR assay for detection of virus levels in respiratory
specimens found that SARS-CoV RNA was detected in less than

CHAPTER 89╇ •â•‡ Severe Acute Respiratory Syndrome (SARS) 541

50% of specimens obtained in the first 4 to 5 days of illness and its complications and preventing and treating secondary bacte-
that viral load peaked by about 10 to 12 days before gradually rial infections. During the 2002-2003 SARS outbreak, ribavirin
declining. Additional studies confirmed that after 7 to 10 days, and corticosteroids were used with little apparent success. The
RNA was detectable by RT-PCR in the majority of both respira- effectiveness of other therapeutic options, such as interferon,
tory and stool specimens. Second generation RT-PCR assays, intravenous immunoglobulin, and antiviral drugs is poorly
developed after the outbreak ended, can detect SARS-CoV understood. Several laboratories worldwide are conducting
RNA in more than 80% of respiratory specimens within the first research on SARS-CoV to improve our understanding of the
3 days of symptom onset. When upper respiratory tract speci- virus and its pathogenesis, which may lead to possible future
mens are negative, sputum and BAL specimens may be useful treatment options. Currently no effective vaccine exists.
for diagnosis, as viral loads may be greater in the lower respira-
tory tract. In stool, RT-PCR assays are able to detect SARS- PROGNOSIS
CoV RNA for more than 4 weeks after illness onset; however, Approximately 30% of patients with SARS clinically improve
virus has not been isolated from stool after the third week. within a week or two of the onset of their illness, whereas 70%
develop persistent fever and worsening respiratory symptoms
Serologic testing is a useful tool for diagnosis because it and may require hospitalization; some will be admitted to
permits detection of anti-SARS antibodies, as well as helping to an ICU. The length of hospital stays has varied, but several
confirm or exclude a SARS diagnosis and better characterize the studies have reported a median length of stay of approximately
SARS immune response. Host immune response includes the 2 weeks.
development of IgG and IgM SARS-CoV–specific antibodies as
well as anti–SARS-CoV neutralizing antibodies. Longitudinal In hospitalized patients, common complications of SARS
studies conducted after the 2002-2003 outbreak using IFA and/ include cardiovascular abnormalities (e.g., hypotension, tachy-
or EIA on specimens obtained from outbreak-related SARS cardia) and hepatic dysfunction. Deep vein thrombosis (DVT)
patients showed that in the first 7 days of illness, only about has been less common, but in one Singapore case series 30% of
15% had detectable anti–SARS-CoV IgG or IgM. However, by hospitalized patients had evidence of a DVT. Disseminated
the second week of illness, IgG was detected in approximately intravascular coagulation, acute renal failure, and neurologic
40% to 50% of patients and IgM in about 40% to 65%. More and other complications are uncommon.
than 90% of patients had detectable anti–SARS-CoV IgG by
day 28 after illness onset. This milestone is important because In the 2002-2003 SARS outbreak, poor outcome was associ-
an undetectable anti-SARS antibody in a serum specimen ated with increasing age and the presence of comorbid condi-
obtained more than 28 days after onset of illness is one of three tions (e.g., diabetes mellitus, hypertension, cardiovascular
exclusion criteria recommended by the CDC when defining an disease, chronic renal disease). Overall crude mortality rates
infection as a probable SARS case. A 3-year study that followed ranged from about 4% to 15%, with age-specific mortality rates
the progression of antibody titers in 56 patients with SARS highest among older adults. Mortality rates were higher in those
found that levels of anti–SARS-CoV IgG peaked 4 months after aged 60 years or older (43%) as compared with those younger
onset of illness, then decreased; 3 years after infection, IgG was than 60 years of age (13%). Most SARS patients who survive
still detectable in 26% of patients. Second-generation immuno- have a complete, sometimes prolonged recovery, but some
assays are being developed, some focusing on recombinant severely ill patients have reported long-term decreased pulmo-
SARS-CoV nucleoprotein antigens. However, cross-reactive nary function.
antigenic epitopes between SARS-CoV and other human coro-
naviruses (some of which are newly discovered and also cause PREVENTION AND CONTROL
respiratory illness) may complicate serologic test results and It is unclear when or if the world will experience another SARS
merit continued investigation. epidemic. In the absence of person-to-person SARS-CoV trans-
mission worldwide, recommendations have been published by
A diagnosis of SARS should not be based on a single reactive several public health organizations, including WHO and the
laboratory test. Any reactive result should be confirmed by a labo- CDC. In the United States, the CDC has developed several
ratory that participates in the WHO SARS International Refer- documents that provide guidance on surveillance, clinical and
ence and Verification Laboratory Network. Because of apparent laboratory evaluation, and reporting of suspected SARS infec-
lack of circulating SARS-CoV in humans, a single reactive sero- tions (www.cdc.gov/ncidod/sars). Being familiar with the clini-
logic test may support a diagnosis, but the positive predictive cal features of SARS-CoV disease, assessing travel history and
value of serologic testing is low, and confirmation by an experi- exposure risk, and recognizing unusual clusters of unexplained
enced laboratory is still recommended. Test results that suggest a pneumonia can help maximize early detection. In the absence
diagnosis of SARS must be evaluated in the context of clinical of person-to-person transmission, public health and healthcare
findings, exposure risk factors, and epidemiologic data. The posi- personnel should be aware of specific settings that should raise
tive predictive value of a laboratory diagnosis increases with the suspicion for SARS-CoV infection (www.cdc.gov/ncidod/sars/
collection and testing of multiple and different specimen types. absenceofsars.htm). These situations include persons who are
hospitalized for radiographically confirmed pneumonia or
CLINICAL MANAGEMENT AND ARDS without an identifiable cause and who have one of the
DRUG TREATMENT following three risk factors in the 10 days before the onset of
The clinical management of SARS primarily relies on illness:
providing supportive care for the acute respiratory illness and

542 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

• Travel to mainland China, Hong Kong, or Taiwan, or close testing and has made guidelines for laboratory personnel
contact with an ill person with a history of recent travel to working with SARS-CoV available (www.cdc.gov/ncidod/sars/
one of these areas guidance/f/pdf/app6.pdf).

• Employment in an occupation associated with a risk for Globally, SARS is one of a select few conditions that has been
SARS-CoV exposure (e.g., healthcare worker, worker in a designated as immediately reportable by International Health
laboratory that contains SARS-CoV) Regulations. The local or state health department should be
promptly notified if a suspected SARS case is identified. Prompt
• Illness in association with a cluster of cases of atypical case detection, implementation of infection control measures
pneumonia without an alternative diagnosis including patient isolation and standard and droplet precautions
(www.cdc.gov/ncidod/sars/guidance/i/pdf/i.pdf), and contact
Clinicians evaluating patients who fit one of these three cri- tracing have been shown to reduce transmission. Additional
teria should implement appropriate infection control measures, infection control measures should be instituted depending on
contact the local or state health department, and continue with the setting (e.g., healthcare, home, community) (www.cdc.gov/
a diagnostic evaluation. This evaluation should include testing ncidod/sars/guidance/i/pdf/i.pdf).
for other respiratory pathogens (e.g., influenza, respiratory syn-
cytial virus, Streptococcus pneumoniae, Legionella species). If no One critical lesson learned from the 2002-2003 SARS out-
alternative diagnosis has been made after 72 hours or if a high break is the apparent need for prompt collaboration and
index of suspicion for SARS exists, the clinician and health open communication among local, national, and international
department should consider SARS-CoV testing and contact the health agencies. Early diagnosis, timely reporting, implementa-
CDC for consultation. Currently, laboratory-acquired SARS tion of infection control measures, and continued research,
infection remains a possible scenario but a remote one, as adher- including research regarding treatment and vaccine develop-
ence to strict biosafety and laboratory policies has significantly ment, will help identify and control possible future SARS
reduced this risk. The CDC is available for consultation and outbreaks.

EVIDENCE Peiris JSM, Yuen KY, Osterhaus ADME, Stohr K: The severe
acute respiratory syndrome, N Engl J Med 349:2431-2441, 2003.
Drosten C, Günther S, Preiser W, et al: Identification of a novel One of the first published peer-reviewed articles outlining chronologic
coronavirus in patients with severe acute respiratory syndrome, N events, epidemiology, clinical presentation, management, and prevention
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peer-reviewed articles describing the laboratory methods used to identify
the new coronavirus associated with SARS. Poutanen SM, Low DE, Henry B, et al: Identification of severe
acute respiratory syndrome in Canada, N Engl J Med 348:1995-
Ksiazek TG, Erdman D, Goldsmith CS, et al: A novel coronavirus 2005, 2003. A summary of the epidemiology, clinical description, and
associated with severe acute respiratory syndrome, N Engl J Med diagnostic findings of SARS cases in Canada, which reported the highest
348:1953-1966, 2003. One of the first published peer-reviewed articles number of SARS cases outside Asia.
describing the laboratory methods used to identify the new coronavirus
associated with SARS. Shi Z, Hu Z: A review of studies on animal reservoirs of the SARS
coronavirus, Virus Res 133:74-87, 2008. A comprehensive laboratory
Peiris JSM, Chu CM, Cheng VCC, et al: Clinical progression and review of SARS-CoV–like viruses from several animal reservoirs (e.g.,
viral load in a community outbreak of coronavirus-associated masked palm civet, bats) describing the possible evolutionary progression of
SARS pneumonia: a prospective study, Lancet 361:1767-1772, SARS-CoV–like viruses in animals to SARS-CoV, which infected humans.
2003. A prospective summary of the clinical, radiologic, and virologic
progression of SARS cases from a specific community in China.

ADDITIONAL RESOURCES September 15, 2010. The CDC’s portal website on SARS; provides informa-
Centers for Disease Control and Prevention (CDC): In the absence of tion for specific groups and settings and on specific topics related to SARS.
Centers for Disease Control and Prevention (CDC): Supplement I. Infec-
SARS-CoV transmission worldwide: guidance for surveillance. Clinical tion control in healthcare, home, and community settings. Available at:
and laboratory evaluation, and reporting version 2. Available at: www.cdc.gov/ncidod/sars/guidance/i/pdf/i.pdf. Accessed September 15,
www.cdc.gov/ncidod/sars/absenceofsars.htm. Accessed September 15, 2010. This document provides infection control recommendations for different
2010. This document provides guidance for surveillance, clinical and laboratory settings, including the hospital, home, and community. Implementation of infec-
evaluation, and reporting in the setting of no known person-to-person transmis- tion control measures is critical for reducing transmission. Also included are
sion of SARS-CoV worldwide. detailed recommendations for preparedness planning, and infection control guide-
Centers for Disease Control and Prevention (CDC): Guidelines for medical lines for hospitalized SARS patients (e.g., standard and droplet precautions,
surveillance of laboratory personnel working with SARS-CoV. Available isolation), healthcare workers (e.g., nurses, emergency medical services), and
at: www.cdc.gov/ncidod/sars/guidance/f/pdf/app6.pdf. Accessed Septem- persons in the community (e.g., contacts, family members).
ber 15, 2010. This document provides key messages for laboratory workers Council of State and Territorial Epidemiologists: 2009 position statement-
working with SARS-CoV and useful links for more in-depth information, 09-ID-11: national surveillance for severe acute respiratory syndrome
including those workers with possible exposure and those who may be symptomatic (SARS-CoV). Available at: www.cste.org/ps2009/09-ID-11.pdf. Accessed
without a definitive SARS-CoV exposure. September 15, 2010. This document provides guidance on the SARS case defi-
Centers for Disease Control and Prevention (CDC): Severe acute nition, clinical description, surveillance, and reporting for state and territorial
respiratory syndrome. Available at: www.cdc.gov/ncidod/sars. Accessed epidemiologists in the United States.

CHAPTER 89╇ •â•‡ Severe Acute Respiratory Syndrome (SARS) 543

World Health Organization (WHO): SARS—how a global epidemic was World Health Organization (WHO): WHO guidelines for the global surveil-
stopped. Available at: http://whqlibdoc.who.int/wpro/2006/9290612134_ lance of severe acute respiratory syndrome (SARS)—updated recommendations,
eng.pdf. Accessed September 15, 2010. A detailed WHO summary docu- October 2004. Available at: www.who.int/csr/resources/publications/
ment describing the historical events of the 2002-2003 SARS outbreak. WHO_CDS_CSR_ARO_2004_1.pdf. Accessed September 15, 2010.
WHO guidelines for SARS, covering clinical laboratory criteria for global
World Health Organization (WHO): Severe acute respiratory syndrome. surveillance of SARS, guidance on how to approach suspected SARS patients
Available at: www.who.int/topics/sars/en. Accessed September 15, 2010. during the interepidemic period, how to conduct global surveillance during an
WHO’s primary website for SARS, with links to several helpful websites and outbreak, and international reporting of a SARS case.
documents.

Multidrug-Resistant Tuberculosis 90

Christopher Edward Spitters

ABSTRACT inhaled; the mycobacteria are ingested by macrophages and in
most cases are killed or sequestered in granulomata. Some
The World Health Organization (WHO) estimates that more organisms, though, traverse the pulmonary lymphatics to the
than 2 billion people are infected with Mycobacterium tuberculosis right side of the heart, where they can disseminate via the blood-
worldwide; most of these infections occur in low-income areas stream to the lungs and other organs. Ingestion of infectious
where tuberculosis is a leading cause of death among persons organisms, particularly of M. bovis via unpasteurized dairy prod-
affected by the human immunodeficiency virus (HIV) pandemic. ucts, accounts for a small proportion of cases.
The global control of tuberculosis is a major public health chal-
lenge, and the emergence of drug-resistant strains of M. tuber- In the vast majority of cases (approximately 90% to 95%),
culosis (particularly strains resistant to multiple antituberculosis primary tuberculosis infection is controlled by the immune
drugs) presents a significant threat to efforts to address this system, and no disease occurs either at the time of infection or
challenge. Although resources for the diagnosis and effective later in life. In 5% to 10% of infections, however, either the
treatment of multidrug-resistant and extensively drug-resistant primary infection progresses or latent infection reactivates to
M. tuberculosis are available in most high resource settings, these produce active disease either in the lungs or in extrapulmonary
resources are lacking in regions where the burden of tubercu- sites. The risk of developing tuberculosis disease after infection
losis is the greatest. Advances in diagnostics and therapeutics, is increased by immunosupression (e.g., HIV, tumor necrosis
effective implementation of disease surveillance and control factor-a blockers, certain malignancies), diabetes mellitus,
programs, and general strengthening of health care systems are tobacco smoking, end-stage renal disease, silicosis, gastrectomy,
needed to control the global threat of multidrug-resistant and various forms of malnutrition and malabsorption.
tuberculosis.
In the United States, tuberculosis is most commonly caused
GEOGRAPHIC DISTRIBUTION AND by M. tuberculosis, and active disease is initially treated with a
MAGNITUDE OF DISEASE BURDEN combination of four different first-line agents (i.e., isoniazid,
Tuberculosis occurs in virtually every corner of the globe. WHO rifampin, pyrazinamide, and ethambutol or streptomycin) to
has estimated that more than 2 billion people worldwide have avoid the development of resistance to any single drug (Table
tuberculosis, and most cases occur in resource-poor areas where 90-1). Drug resistance occurs when isolates of M. tuberculosis are
tuberculosis is a leading cause of death among persons affected less susceptible to antituberculosis agents, a spontaneous event
by the HIV pandemic (Figures 90-1 and 90-2). The global driven by genomic mutations that affect the cellular targets of
prevalence of drug-resistant strains of tuberculosis varies greatly, these drugs (Table 90-2). Resistance to rifampin (which inhibits
but overall about 5% of all infections are resistant to multiple ribonucleic acid [RNA] polymerase) is conferred by a highly
drugs, with approximately 500,000 new cases worldwide each conserved mutation in the gene for RNA polymerase, whereas
year (Figure 90-3). In the United States, where approximately isoniazid resistance can be caused by mutations at multiple sites
15,000 cases of tuberculosis are reported each year, about 10% in the genome.
to 15% are isoniazid resistant, 1% to 2% are resistant to mul-
tiple drugs, and 10% of multidrug-resistant infections are exten- Drug resistance can emerge when treatment is incorrectly
sively drug resistant (i.e., 10 to 20 cases per year). prescribed or administered or when the drugs fail to reach the
affected site in adequate concentrations. The average frequency
RISK FACTORS of a drug-resistance mutation is about 1 in 106 to 108 mycobac-
Tuberculosis in humans is caused by a closely related group of teria; therefore the greater the mycobacterial burden, the greater
acid-fast bacilli that includes M. tuberculosis, Mycobacterium bovis, the opportunity for development of resistance mutations (see
M. bovis BCG, Mycobacterium africanum, Mycobacterium microti, Table 90-2).
Mycobacterium canetti, and Mycobacterium pinipedii. M. tuberculosis
and M. bovis are the most common causes of human tuberculosis Typical pulmonary tuberculosis with a cavitary lesion results
worldwide. Mycobacteria are typically transmitted through the in a total mycobacterial burden of about 109 organisms; there-
air by respiratory particles 1 to 5╯µm in diameter (droplet fore a patient with cavitary disease may harbor 10 to 1000
nuclei); these particles are produced when a person with active, organisms resistant to a given drug (Figure 90-4). Consequently,
infectious respiratory (including laryngeal) tuberculosis coughs, patients with visible acid-fast bacilli from a sputum specimen
sneezes, speaks, or sings. Infection occurs when the particles are and those with cavitary lesions on chest radiography carry the
highest risk for the emergence of drug resistance if treated inap-
propriately or if adherence is poor. If adherence to initial therapy
was good and a relapse of drug susceptible tuberculosis occurs,
the mycobacteria typically remain fully susceptible; however,
relapses of previously drug-resistant disease often show develop-
ment of further resistance to previously effective drugs. If an
individual with fully susceptible tuberculosis receives isoniazid

CHAPTER 90╇ •â•‡ Multidrug-Resistant Tuberculosis 545

Pacific Atlantic
Ocean Ocean

Estimated new TB Indian
cases (all forms) per Ocean
100,000 population

0-24
50-49
50-99
100-299
Ն300
No estimate

Figure 90-1╇ Estimated new tuberculosis infections per 100,000 population, 2008. (From World Health Organization [WHO]: Global
tuberculosis control: a short update to the 2009 report, Geneva, Switzerland, 2009, WHO Press.)

Pacific Atlantic
Ocean Ocean
HIV prevalence
in new TB cases, Indian
all ages (%) Ocean

0-4
5-19
20-49
Ն50
No estimate

Figure 90-2╇ Estimated HIV prevalence in new tuberculosis infections, 2008. (From World Health Organization [WHO]: Global tuberculosis
control: a short update to the 2009 report, Geneva, Switzerland, 2009, WHO Press.)

Pacific Atlantic
Ocean Ocean

*Australia, Democratic 0-Ͻ3 Indian
Republic of the Congo, 3-Ͻ6 Ocean
Fiji, Guam, New Caledonia, 6-Ͻ12
Solomon Islands and Qatar 12-Ͻ18
reported data on combined Ն18
new and previously treated No data
cases. available*
Subnational
data only

Figure 90-3╇ Proportion of multidrug-resistant tuberculosis among new tuberculosis infections, 1994-2009. (From World Health
Organization [WHO]: Multidrug and extensively drug-resistant TB [M/XDR-TB]: 2010 global report on surveillance and response, Geneva,
Switzerland, 2010, WHO Press.)

546 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Table 90-1╇ First-line Antimycobacterial Agents

Dosing

Adult Pediatric

AGENT DAILY INTERMITTENT DAILY INTERMITTENT
Isoniazid (MAXIMUM DOSE) (MAXIMUM DOSE) (MAXIMUM DOSE) (MAXIMUM DOSE)
Rifampin 10-20╯mg/kg (300╯mg)
5╯mg/kg (300╯mg) 15╯mg/kg BIW or TIW (900╯mg) 10╯mg/kg (600╯mg) 20-40╯mg/kg (900╯mg)
Pyrazinamide 10╯mg/kg (600╯mg) 10╯mg/kg BIW or TIW (900╯mg) 10╯mg/kg BIW or TIW
15-30╯mg/kg (2000╯mg)
Ethambutol 15-30╯mg/kg 50╯mg/kg BIW (4000╯mg) or (900╯ mg)
(2000╯mg) 30╯mg/kg TIW (3000╯mg) 15-30╯mg/kg (2000╯mg) 50╯mg/kg BIW (4000╯mg) or
Streptomycin
15-25╯mg/kg 50╯mg/kg BIW (4000╯mg) or 12-15╯mg/kg (1╯g) 30╯mg/kg TIW (3000╯mg)
(1600╯mg) 30╯mg/kg TIW (3000╯mg) 50╯mg/kg BIW (4000╯mg) or

12-15╯mg/kg (1╯g)* 12-15╯mg/kg (1╯g)* 30╯mg/kg TIW (3000╯mg)
12-15╯mg/kg (1╯g)

*Consider lowering maximum dose in patients >65 years of age to 750╯mg
BIW, Twice weekly; TIW, three times weekly.

Table 90-2╇ Mechanism of Action and Frequency of Resistance Mutations in Mycobacterium tuberculosis

AGENT TARGET COMMON RESISTANCE MUTATIONS FREQUENCY
Isoniazid 10−6
Mycolic acid synthesis katG
Rifamycins inhA 10−8
RNA-dependent RNA Others
Pyrazinamide polymerase rpoB 10−6
Ethambutol 10−5
Streptomycin Mycolic acid synthesis pncA 10−6
Mycolic acid synthesis embB
Amikacin and kanamycin Ribosome; protein synthesis rpsL
Ethionamide rrs
Fluoroquinolones Ribosome; protein synthesis Rrs
Mycolic acid synthesis inhA
DNA-gyrase gyrA

Adapted from Centers for Disease Control and Prevention (CDC): Tuberculosis training module 3. Drug resistance.

monotherapy, mycobacteria expressing isoniazid-resistant muta- may contribute to the acquisition of drug resistance (Table
tions proliferate; among those isoniazid-resistant mutants, 1 in 90-3). These factors include the following:
106 to 108 will also be resistant to rifampin. If such a patient is
subsequently treated with rifampin alone, then mutants resistant • Exposure to someone with documented drug-resistant
to isoniazid and rifampin will be selected, generating multidrug- disease, or exposure in an area or setting with a high preva-
resistant mycobacteria. lence of drug resistance

Multidrug resistance is defined as resistance to at least isonia- • Prior treatment for tuberculosis, especially with extensive
zid and rifampin; extensive drug resistance occurs when M. disease; or if the treatment was not directly observed,
tuberculosis is resistant not only to isoniazid and rifampin, but potentially inappropriately prescribed, interrupted, or if
also to fluoroquinolones and one or more of the second-line patient adherence is questionable
injectable agents (i.e., amikacin, kanamycin, capreomycin). This
definition was chosen because the highest rate of tuberculosis • Poor or no improvement with therapy
treatment failures and mortality has been observed in patients • Treatment for latent infection when active tuberculosis
infected with M. tuberculosis having this drug susceptibility
profile. was present
• Prolonged use of multiple drugs, fluoroquinolones, or an
Multidrug-resistant tuberculosis can be acquired through
transmission of an already resistant organism (“primary” multi- injectable drug for an unspecified pulmonary process
drug resistance) or through inappropriate treatment of a previ- At the clinical level, failure to improve with initial standard
ously acquired, susceptible organism (“secondary” multidrug four-drug therapy is suggestive of drug resistance, misdiagnosis,
resistance). In evaluating a patient with suspected or confirmed drug malabsorption, nonadherence, or overwhelming infection.
tuberculosis, it is important to elicit any history of factors that In low resource settings, clinical management protocols prompt
suspicion of drug resistance if sputum smears are still positive
after 2 months of therapy.

CHAPTER 90╇ •â•‡ Multidrug-Resistant Tuberculosis 547
M. tuberculosis becomes drug-resistant by acquiring mutations that affect a cellular
Spontaneous mutations target of the drug; these mutations develop spontaneously as the bacilli proliferate,
develop as bacilli with rifampin, isoniazid, and pyrazinamide resistance arising at a rate of 1 bacilli
proliferate to >108 in 108. As a result, even before treatment, there is a population of bacilli that
are drug resistant.
I
RP

Drug Mutation Rate Drug-resistant mutants in INH
Rifampin 10-8 large bacterial population RIF
PZA

Isoniazid 10-6 I Multidrug therapy; no bac- Treatment with three
Pyrazinamide 10-6 RP teria resistant to all 3 drugs effective drugs kills all
the bacilli; however,
Spontaneous mu- I I INH I I single-drug therapy,
tations develop as II IR III (e.g., isoniazid alone)
bacilli proliferate I selects for isoniazid-
to >108 I I resistant M. tuberculosis.

I

I II II INH
RIF

III

II INH IR IR IR Monotherapy: INH-resistant
III
IR IR IR IR bacteria proliferate
I
IR IR IR The isoniazid-resistant M. tuberculosis multiply and spontaneous mutations
arise, resulting in acquisition of resistance to a second drug (rifampin). Treatment
with isoniazid and rifampin can lead to selection of multidrug-resistant bacilli
IR IR IR that may acquire additional resistance, ultimately leading to extensively

INH resistant bacteria INH monoresistant resistant M. tuberculosis.
multiply to large numbers mutants killed, RIF-resistant,
mutants proliferate → MDR TB

Figure 90-4╇ Schematic mechanism of emergence of drug resistance in Mycobacterium tuberculosis.

Table 90-3╇ Risk Factors for Drug Resistance in CLINICAL PRESENTATION
Tuberculosis The initial clinical presentation of multidrug-resistant tubercu-
losis is largely indistinguishable from that of infection with
History of Large bacillary load with extensive disease drug-susceptible M. tuberculosis. Tuberculosis may manifest as
tuberculosis Lack of conversion of cultures to negative an organ-specific or systemic disease, and the diagnosis is based
(TB) on a constellation of clinical, radiographic, and mycobacterio-
during therapy logic findings. Pulmonary involvement, which is present in 70%
No history of No or little improvement or worsening of to 80% of patients in most settings, is characterized by a produc-
tuberculosis tive cough, fever, night sweats, fatigue, anorexia, and weight loss
symptoms (constitutional symptoms). Chest pain, dyspnea, and hemoptysis
Nonadherence or intermittent ingestion or are also common features. Clinical manifestations of extrapul-
monary tuberculosis include constitutional symptoms and pain
absorption of regimen or dysfunction corresponding with the affected site; about one
No or poorly supervised directly observed third of individuals with extrapulmonary infection have concur-
rent pulmonary involvement.
therapy
History of an inappropriate treatment Physical findings can include cachexia, cervical or regional
lymphadenopathy, abnormal auscultatory findings correspond-
regimen ing to lung consolidation or pleural effusion, pulsus paradoxus,
Exposure to a person with documented hepatosplenomegaly, peritonitis, spinal tenderness or gross
gibbus deformity, meningismus, and neurologic deficits.
drug-resistant TB
Residence in or travel to a region with Suggestive standard chest radiographic findings include
single or multiple areas of upper zone consolidation, upper
high rates of drug-resistant TB zone fibronodular opacities, cavitation, mediastinal and/or
Residence or work in a setting in which hilar adenopathy, and pleural effusion, occurring alone or in

drug-resistant TB is documented
Treatment of pulmonary disease with a

prolonged course of multiple medicines,
fluoroquinolone, or an injectable agent
for more than a few weeks
Previous treatment for latent TB infection
when signs of active TB disease were
not recognized

548 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

combination. Computed tomography (CT) is more sensitive for are relatively low. Consequently, the diagnosis of extrapulmo-
characterizing pleural abnormalities and detecting pulmonary nary tuberculosis often hinges on exclusion of other diagnoses,
infiltrates, cavitation, and lymphadenopathy. Imaging for extra- the patient’s epidemiologic risks, clinical presentation, histo-
pulmonary tuberculosis includes CT or magnetic resonance pathologic results, and response to therapy.
imaging (MRI) with contrast, depending on the suspected site
of infection. Typical findings include ring-enhancing lesions in Drug resistance is determined by cultivation of M. tuberculo-
lymph nodes, brain, or other tissues; multiple hypodense lesions sis, followed by drug susceptibility testing using liquid and/or
in liver and/or spleen; fluid collections (e.g., paraspinous abscess, solid media. Growth occurs more rapidly in liquid media, but
ascites, basilar meningitis); bone destruction; and obstructive solid media can quantify the in vitro degree of drug resistance.
lesions (e.g., bronchial compression, lateral ventricular enlarge- Most laboratories in high resource settings use liquid media for
ment, hydronephrosis). Whereas radiographic studies (standard growth of M. tuberculosis and initial screening for resistance to
chest radiography, CT, and MRI) may be useful in identifying first-line drugs (see Table 90-1). To confirm and quantify drug
the site and extent of disease, these technologies may be limited resistance and to screen for resistance to second-line drugs,
or unavailable in low resource settings. specimens are inoculated onto solid media plates impregnated
with clinically relevant concentrations of single drugs. This
DIFFERENTIAL DIAGNOSIS technology is slowly becoming available in parts of the develop-
The differential diagnosis for tuberculosis is broad: pulmonary ing world where the need is greatest, but the vast majority of
tuberculosis may mimic an acute or chronic pneumonic process multidrug-resistant infections are primarily diagnosed by clini-
caused by bacteria, viruses, fungi, nontuberculous mycobacteria, cal recognition of treatment failure and persistence of visible
malignancy, sarcoidosis, or rheumatologic disease. Tuberculosis acid-fast bacilli on serial specimens of expectorated sputum.
should be considered in the evaluation of fever of unknown
origin and in chronic inflammation of unknown cause (e.g., Nucleic acid amplification techniques that identify mutations
meningitis, peritonitis, and osteomyelitis). In the absence of highly correlated with phenotypic resistance have become available
mycobacteriologic or molecular evidence of tuberculosis, it is for testing on initial growth or even on patient specimens. Using
generally wise to consider further studies to reasonably exclude such assays, it is possible to identify M. tuberculosis and detect
these non-TB diagnoses before committing to empirical antitu- rifampin resistance within a single working day. Because rifampin
berculosis therapy. monoresistance is extremely unusual, detection of rifampin resis-
tance mutations is highly suggestive of multidrug resistance. These
DIAGNOSTIC APPROACH techniques have been adapted for use in low resource settings
The laboratory diagnosis of pulmonary tuberculosis relies mainly where they can accelerate the detection of drug resistance before
on the demonstration of acid-fast bacilli on smear and culture of the availability of phenotypic drug susceptibility results.
sputum. The sensitivity of sputum smear examination is enhanced
by the use of concentrated specimens and fluorochrome staining. MANAGEMENT AND THERAPY
Smear results are generally available within 24 hours, whereas In the United States and other areas where the rates of antituber-
cultures typically require 2 to 4 weeks to demonstrate growth of culosis drug resistance are low to moderate, standard treatment
bacilli, which is typically confirmed as M. tuberculosis complex of fully susceptible tuberculosis consists of an initial daily regimen
using nucleic acid hyridization. Of all infections ultimately con- of isoniazid, rifampin, pyrazinamide, and ethambutol. As soon as
firmed as pulmonary tuberculosis, about 90% will have M. tuber- drug susceptibilities are available and the M. tuberculosis is shown
culosis isolated or identified from culture of a respiratory specimen. to be susceptible to isoniazid and rifampin, ethambutol can be
In the United States, 33% to 50% of patients with culture- discontinued. After 8 weeks of therapy, pyrazinamide is discon-
confirmed pulmonary tuberculosis will have negative sputum tinued, and isoniazid and rifampin are continued to complete 6
smears. Therefore when clinical suspicion for tuberculosis is months (26 weeks) of therapy. Treatment can be administered
high and alternative diagnoses are reasonably excluded or daily, thrice weekly, or twice weekly (with appropriate dosage
deemed unlikely, the absence of acid-fast bacilli on sputum smear adjustments) after the initial 2 weeks of therapy. However, some
should not dissuade the initiation of empiric treatment. Some studies show increased rates of relapse when intermittent therapy
settings may have M. tuberculosis nucleic acid amplification is used during the initial phase in infections with heavy bacillary
testing for sputum specimens, with a sensitivity exceeding 90% load. Treatment is extended to 9 months if cavitary disease is
in smear-positive specimens and approaching 70% in smear- present and sputum cultures are still positive at 8 weeks; up to 9
negative specimens. Consequently, these tests are most useful for months for bone and joint disease; and from 9 to 12 months for
excluding the diagnosis in smear-positive patients in whom central nervous system or meningeal involvement.
infection with nontuberculous mycobacteria is suspected.
Treatment for drug-resistant tuberculosis varies depending
The diagnosis of extrapulmonary tuberculosis uses the col- on the resistance patterns. For isolated isoniazid resistance,
lection of relevant fluids or tissues for pathologic examination treatment options include the following:
and mycobacterial studies. The histopathologic hallmark of
tuberculosis is the presence of necrotizing granulomata. For • Rifampin, pyrazinamide, and ethambutol for 6 months or
fluid or tissue from extrapulmonary sites, the sensitivities of • Rifampin and ethambutol (with or without a fluoroquino-
acid-fast bacilli smear (25% to 50%) and culture (50% to 70%)
lone) for 12 months
For isolated pyrazinamide resistance (or for any course of
treatment using only isoniazid and rifampin), therapy should be

CHAPTER 90╇ •â•‡ Multidrug-Resistant Tuberculosis 549

extended to 9 months. Resistance to rifampin alone is extremely toxic agents over the course of months to years resembles cancer
rare, but when present the standard approach is to give isonia- chemotherapy more than it does treatment of an acute infec-
zid, pyrazinamide, and ethambutol for 2 months, followed by tious disease. Adverse drug reactions necessitating alteration of
isoniazid and ethambutol for 16 months. treatment occur in about 20% of patients with fully susceptible
tuberculosis.
Regimens for Multidrug Resistance
The treatment of multidrug-resistant tuberculosis involves pro- Although the adverse effects associated with individual anti-
longed use of less proven and more toxic drugs. Clinical trials tuberculosis drugs have been extensively described (Table 90-4),
in this area are limited, and treatment recommendations are the frequency of adverse effects related to treatment with regi-
drawn from observational studies and expert opinion. The stan- mens primarily consisting of second-line agents for multidrug-
dard approach to treatment of laboratory confirmed drug resis- resistant disease has not been well documented. Despite the lack
tance includes the following: of reports, the incidence of adverse effects in this setting is likely
to be high, and the options for regimen alteration are limited.
• Always treating drug-resistant tuberculosis in consultation Consequently, knowledge of the nature, cause, and management
with an expert in the field of adverse effects of first- and second-line antituberculosis drugs
is essential for successful management of tuberculosis, particu-
• Never adding fewer than two drugs to a failing regimen larly in the setting of multidrug resistance.
• Continuing any first-line drug to which the M. tuberculosis
Another key principle in evaluation of reported adverse
is susceptible effects is to discriminate between nuisance and dangerous
• Adding an injectable to which the isolate is susceptible effects. The former generally do not merit regimen alteration,
• Adding a fluoroquinolone (e.g., moxifloxacin, levofloxacin) whereas the latter generally do. Finally, when an adverse effect
• Adding cycloserine, ethionamide, and/or para-aminosalicy- has multiple agents as its potential cause (e.g., liver injury in the
setting of standard first-line regimens, rash with any drug), it is
late as necessary to achieve a five- or six-drug regimen often wisest to stop all agents and then subsequently reintroduce
• Considering use of linezolid, amoxicillin-clavulanate, clo- them serially once the effect has improved or resolved. In some
instances (e.g., severe disease) it may be necessary to impose an
fazimine, and/or imipenem if the drug-resistance profile alternative holding regimen while the former process is under-
(or patient drug intolerance) is extensive enough to exclude taken (e.g., streptomycin, ethambutol, and moxifloxacin in the
an adequate regimen using the previously mentioned setting of liver injury).
drugs
• Administering an injectable for 6 months and oral Adjunctive Surgical Therapy
agents for 18 to 24 months after sputum culture becomes Surgical excision of focal disease (e.g., lung nodules, affected
negative lobe or lymph nodes) can reduce bacillary load and subsequent
In general, a drug to which M. tuberculosis shows decreased chances of treatment failure or relapse. Surgery is often consid-
susceptibility is discontinued. Some experts, however, may still ered as adjunctive therapy when the benefit of a procedure (e.g.,
use high-dose daily or intermittent isoniazid or continue eth- wedge resection or lobectomy) outweighs the risks (e.g., intra-
ambutol on a daily or intermittent basis even when initial find- operative mortality, bronchopleural fistula or reduced lung
ings indicate resistance. In such cases, the drugs are only stopped capacity). Surgical management of multidrug-resistant tubercu-
when final susceptibility results indicate high-level resistance or losis should generally be referred to or conducted in consulta-
the patient is intolerant of the treatment regimen. If an isolate tion with a center with significant experience and expertise in
shows decreased susceptibility to all injectable agents or fluoro- this practice.
quinolones, many experts would proceed with the injectable and
fluoroquinolone agents to which the isolate shows the greatest Monitoring Treatment
susceptibility. Although a meta-analysis of randomized clinical trials on directly
observed therapy (DOT) has shown no significant impact of
Adjunctive Corticosteroids DOT on treatment outcomes, historical case series suggest that
For tuberculosis involving the pericardium, meninges, or central programmatic implementation is associated with increased
nervous system, systemic corticosteroids are routinely recom- treatment completion and decreased drug resistance in com-
mended during the initial 1 to 2 months of therapy; corticoste- munities. While work remains to be done to better specify the
roids can also be considered if an inflammatory mass compromises elements of treatment support that are most important for good
vital structures. Although their use should be limited to condi- clinical and public health outcomes, DOT remains a public
tions for which there is objective evidence of benefit, systemic health standard of care for treatment of tuberculosis, especially
corticosteroids need not be inappropriately feared in the setting in the setting of multidrug resistance. DOT not only ensures
of tuberculosis treatment when concurrent effective therapy is administration of prescribed therapy for the benefit of com-
being administered. munity disease control but also provides a regular venue for
detecting adverse effects, assessing response to therapy, and
Drug Adverse Effects encouraging perseverance with drug regimens that are typically
Compared with therapy for other bacterial infections, treatment difficult to tolerate.
of multidrug-resistant tuberculosis with multiple potentially

550 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Table 90-4╇ Adverse Effects of Antituberculosis Drugs

Typical Causative Agents

SYSTEM EFFECT FIRST LINE SECOND LINE MANAGEMENT OPTIONS
Gastrointestinal Gastritis, nausea, vomiting
PZA Ethionamide Small predose snack or meal
Central nervous Liver injury RIF PAS Proton pump inhibitor
system INH FQN If severe, discontinuation
Paresthesias — Linezolid Antiemetic or motility agent
Renal Asthenia PZA Ethionamide Interrupt therapy if transaminases >3 times
Integument Depression INH
Endocrine Sleep disturbance, agitation, RIF Ethionamide ULN with symptoms or >5 times ULN
without symptoms
tremulousness INH Any Follow resolution with serial challenge
Development or worsening Increase pyridoxine dose
INH Cycloserine Consider discontinuation if severe
of movement disorders Reassurance
Seizures — FQN Time dose for later in the day
Vision changes Antidepressant medication
Hearing and/or vestibular — — Discontinuation if severe
Discontinuation if severe
changes INH Cycloserine
Ethionamide Discontinuation if severe
Psychosis INH —
Uremia High-dose pyridoxine, antiseizure medication,
Interstitial nephritis EMB Streptomycin discontinuation
Noninflammatory pruritus INH Amikacin
Urticaria — Kanamycin Interruption and ophthalmologic examination
Acneiform rash Capreomycin with observation for recovery
Maculopapular rash INH
Hypothyroidism — Cycloserine Discontinuation
RIF Streptomycin Can progress despite interruption and can be
INH —
INH irreversible
Any — Consider a different injectable agent if
INH Any
RIF Cycloserine treatment options are limited
Any Discontinuation and consult a psychiatrist
Any Discontinuation
— Discontinuation
Ethionamide
PAS Diphenhydramine
Discontinuation and diphenhydramine
Topical therapy
Consider discontinuation if severe
Discontinue, follow resolution with serial drug

challenge
Levothyroxine

EMB, Ethambutol; FQN, fluoroquinolone; INH, isoniazid; PAS, para-aminosalicylate; PZA, pyrazinamide; RIF, rifampin; ULN, upper limit of normal.

Standard monitoring for tolerance and response to therapy but there is greater support for its use in the context of treat-
beyond DOT should include monthly standardized symptom ment failure. In practice, these studies tend to be limited to
evaluation, weight check, comprehensive metabolic panel and patients with suspected malabsorption (e.g., HIV enteropathy,
complete blood count, thyroid-stimulating hormone and/or inflammatory bowel disease, diabetic enteropathy), drug-drug
thyroxine levels (if the patient is receiving ethionamide or para- interactions that result in suboptimal serum levels of antituber-
aminosalicylate), assessment of visual acuity and color discrimi- culosis drugs, treatment failure in the absence of drug resistance,
nation (if receiving ethambutol), audiogram and vestibular and use of particular agents (e.g., cycloserine).
assessment (while receiving injectable agents), and periodic
(e.g., quarterly) radiographic examination. For patients with In low resource settings, routine culture, bloodwork, and
pulmonary disease, serial sputum examinations should be con- radiography are often eliminated from monitoring protocols
ducted (e.g., weekly until smear negative, then monthly through and tests to detect serum drug levels are not available.
the end of treatment). For extrapulmonary tuberculosis, myco-
bacteriologic monitoring is not feasible, warranting greater Prognosis and Posttreatment Follow-Up
attention to clinical and radiographic responses to therapy. Published studies vary widely in reported rates of case fatality,
Experts disagree on the benefit of routine pharmacokinetic treatment response, and cure. High-income nations with full
studies to evaluate drug absorption and targeted blood levels, access to second-line drugs, DOT, and, if appropriate, surgical

CHAPTER 90╇ •â•‡ Multidrug-Resistant Tuberculosis 551

therapy show long-term cure rates that approach 90% to 95%. or macrolides should also be anticipated and managed in
In less developed settings where drug resistance may be exten- patients being considered for use of this rifamycin.
sive, treatment resources limited, and HIV co-infection more • Immune reconstitution inflammatory syndrome, caused by
common, case-fatality rates can exceed 50% and long-term cure an exuberant immune response to mycobacterial antigens,
rates vary from 25% to 75%. In a South African outbreak of may occur during tuberculosis treatment. Immune recon-
extensively drug-resistant tuberculosis among HIV-infected stitution is most often characterized by the return of con-
individuals, the case-fatality rate was 98%; contributing factors stitutional symptoms and apparent worsening of disease.
included delays in diagnosis, immunosuppression, and lack of Although this syndrome may occur in persons not infected
access to effective drugs. Efforts to provide sustainable with HIV, it is seen most commonly several weeks follow-
community-based treatment for multidrug-resistant tuberculo- ing initiation of antiretroviral therapy in severely immuno-
sis in high-burden settings (e.g., Peru) appear to show early suppressed, HIV-infected individuals being treated for
success, with cure rates approaching those seen in high-income, tuberculosis.
low-burden countries.
PREVENTION AND CONTROL
Posttreatment surveillance for fully susceptible tuberculosis is Isolation
generally not conducted, given the high probability of cure (95% Although isolation for pulmonary tuberculosis is unusual in low
to 98%) and low probability (2% to 5%) of relapse. Relapse resource settings, in the United States, isolation of patients for
usually occurs within 12 to 24 months of completion of treat- suspected pulmonary tuberculosis is standard and generally dis-
ment. Failure and relapse rates following treatment for multi- continued once the patient has adhered to at least 2 weeks of
drug resistance vary by setting, being as low as 10% to 20% in medication, has demonstrated clinical improvement, and shows
high resource settings and as high as 25% to 50% in low resource no or decreased bacilli on sputum smears. In multidrug-resistant
settings. Because of these higher relapse rates, experts in high pulmonary tuberculosis, the goal is to eliminate rather than
resource settings generally favor active follow-up after comple- control disease transmission; therefore affected patients typi-
tion of treatment for multidrug resistant tuberculosis. Typically, cally remain in isolation until sputum cultures demonstrate no
follow-up for pulmonary disease includes serial symptom evalu- growth of M. tuberculosis. Patients with extrapulmonary disease
ation, standard chest radiography, and sputum examination in whom pulmonary tuberculosis has been reasonably excluded
during the period when relapse is most likely to occur (e.g., at 4, do not merit isolation unless they are undergoing an invasive
8, 12, 18, and 24 months after treatment completion). procedure that is likely to aerosolize organisms.

Co-infection with HIV Management of Exposed Contacts
An HIV test should be a standard component of every baseline About 30% of household contacts to an individual with infec-
evaluation for active tuberculosis in all patients not previously tious pulmonary tuberculosis will become infected. In the
known to be co-infected. A comprehensive review of the man- absence of intervention, about 5% to 10% of those exposed will
agement of co-infection with multidrug-resistant tuberculosis develop active tuberculosis in their lifetime. Latent infections
and HIV is beyond the scope of this text. However, several key can be detected by a tuberculin skin test (TST) or interferon-γ
principles should be noted when evaluating or treating any HIV- release assay (IGRA); a positive TST or IGRA result in a person
infected patient for tuberculosis: exposed to tuberculosis is associated with an increased risk of
•â•‡ The presentation of pulmonary tuberculosis can be atypical, subsequent active tuberculosis.

particularly with severe immunosuppression (e.g., CD4 Latent infections are usually treated to prevent progression
<200): to active tuberculosis, and persons known to have been exposed
• On standard chest radiography, hilar and mediastinal ade- to someone with infectious pulmonary tuberculosis are usually
evaluated for latent tuberculosis infection (LTBI) and treated if
nopathy, lower zone opacities, and diffuse micronodular they are infected. However, in the setting of a possible exposure
(miliary) opacities are more common in severely immuno- to multidrug-resistant tuberculosis, no clinical trials or observa-
suppressed patients. tional studies have assessed the benefits of LTBI treatment.
• Acid-fast bacilli smears of sputum are more likely to be For contacts of multidrug-resistant tuberculosis with LTBI,
negative. all efforts should be made to recover information regarding
• Extrapulmonary disease is more common. prior evaluations for tuberculosis in order to assess the likeli-
• Rifampin resistance may be present in patients previously hood of a prior infection with a susceptible organism as com-
treated with rifabutin for prophylaxis of Mycobacterium pared with recent acquisition of infection from exposure to
avium complex and in patients previously treated for TB multidrug-resistant disease. For contacts of a patient with
with intermittent rifamycin administration. multidrug-resistant tuberculosis, United States–born individu-
• The toxicities and interactions associated with antiretrovi- als with a new diagnosis of LTBI, children (especially under 5
ral therapy and prophylaxis for opportunistic infections years of age), or individuals with a newly positive TST or IGRA
may overlap with those associated with antituberculosis are more likely to have multidrug-resistant LTBI. Conversely,
drugs. a positive TST or IGRA result in previously untested older
• Regimens should be tailored with potential drug-drug patients who were born in, or lived for extended periods
interactions between rifamycins and anti-retrovirals in
mind. Drug-drug interactions between rifabutin and azoles

552 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

in, tuberculosis-endemic regions is much less likely to reprsent • Limitations of existing tools for diagnosis and evaluation
multidrug-resistant LTBI. And finally, immunocompetent con- of treatment (radiography, sputum smear and culture,
tacts of individuals with multidrug-resistant disease with posi- TST)
tive TST or IGRA results prior to exposure are at negligible
risk for multidrug-resistant LTBI. Nevertheless, once a decision • Limited efficacy of bacille Calmette-Guérin (BCG) vaccine
has been made that multidrug-resistant LTBI is likely, most (used in infants to prevent disseminated and meningeal
experts recommend using the two most effective oral drugs disease in most high incidence countries)
(typically, two of the following three drugs: pyrazinamide, eth-
ambutol, and moxifloxacin) to which the organism is susceptible. • Impact of HIV infection on transmission and progression
Recommended duration of therapy is 6 to 12 months, and some to active disease
experts will consider a 6- to 12-month course of moxifloxacin
alone if the source is infected with M. tuberculosis resistant to (or Consequently, strategies that would benefit efforts to control
the contact is intolerant of) pyrazinamide or ethambutol. In the tuberculosis and prevent further emergence of drug resistance
United States, many experts recommend frequent surveillance include the following:
of contacts of individuals with multidrug-resistant tuberculosis
using symptom evaluation and standard chest radiography for • Ensuring infrastructure that supports cost-effective control
24 months (e.g., 4, 8, 12, 18, and 24 months after exposure was methods by expanding the DOTS coverage
interrupted). Evaluation of close contacts of individuals with
tuberculosis should be conducted in collaboration with the local • Preventing HIV transmission and mitigating the associ-
public health agency responsible for tuberculosis control. ated population-level immunosuppression, especially in
tuberculosis-endemic regions
FUTURE DIRECTIONS
Previously, multidrug-resistant tuberculosis tended to occur in • Addressing the needs of other special groups (e.g., incar-
regions where access to first-line drugs was sufficient but control cerated, indigenous)
programs were too poorly funded or insufficiently strong to
ensure adherence to therapy and standardized practices. Gener- • Strengthening health systems infrastructure
ally, these have been low- to middle-income countries (e.g., • Engaging the private sector in implementation of interna-
former Soviet Republics, Argentina), where treatment practices
vary widely and treatment frequently occurs within the private tional standards for TB care
medical sector (e.g., India) (see Figure 90-2). More recently, the • Promoting advocacy, community involvement, and social
spread of multidrug and extensive drug resistance has been
fueled by HIV-associated immunosuppression and consequently mobilization surrounding TB prevention, treatment, and
plays an increasing role in tuberculosis morbidity in sub-Saharan control
Africa. • Developing and implementing simple, robust, and afford-
able assays for detection of tuberculosis and drug
Over the past decade, WHO and its international partners resistance
have increased emphasis on identifying, treating, and controlling • Discovering, testing, and implementing safe, new drug
transmission of multidrug-resistant tuberculosis as part of an regimens that will effectively treat both drug-susceptible
overall strategy for global tuberculosis control. A strategic and drug-resistant strains
element of this global plan to STOP TB is known as “DOTS”, • Developing more effective vaccines that protect against
a program that calls for the commitment of political and financial acquisition of infection and/or progression to active disease
resources; use of quality mycobacteriology for TB diagnosis; use Such efforts form the key elements of the Global Plan to
of standardized treatment regimens with appropriate supervision STOP TB. This initiative will require the commitment of polit-
and support for adherence; ensurance of an adequate supply of ical will and financial and human resources at global, regional,
antituberculosis drugs; and program monitoring and evaluation. and local levels, as well as cooperation among aid and nongov-
Challenges toward this end include developing a sustainable ernmental organizations, national governments, and the aca-
capacity for sputum culture and drug susceptibility testing; demic and private biomedical sectors.
ensuring access to high-quality first- and second-line drugs and
adequate infection control for healthcare workers and HIV- EVIDENCE
infected patients; and avoiding pitfalls associated with potential
amplification of drug resistance by use of standardized retreat- Chan ED, Strand MJ, Iseman MD: Multidrug-resistant
ment protocols in the absence of drug susceptibility testing. tuberculosis (TB) resistant to fluoroquinolones and
streptomycin but susceptible to second-line injection therapy
Significant barriers to the overall control of tuberculosis has a better prognosis than extensively drug resistant TB, Clin
include the following: Infect Dis 48:e50-e52, 2009. A retrospective cohort study of
treatment for multidrug-resistant and extensively drug-resistant
• Inadequate infrastructure for implementing existing tech- tuberculosis.
nology, especially in low resource settings Gandhi NR, Moll A, Sturm AW, et al: Extensively drug-
resistant tuberculosis as a cause of death in patients co-infected
• Long duration of regimens for treatment for latent and with tuberculosis and HIV in a rural area of South Africa,
active infections Lancet 368:1575-1580, 2006. Describes an outbreak of almost
universally fatal, extensively drug-resistant tuberculosis among
HIV-infected individuals in KwaZulu-Natal, South Africa.

CHAPTER 90╇ •â•‡ Multidrug-Resistant Tuberculosis 553

Kwon YS, Kim YH, Suh GY, et al: Treatment outcomes for ADDITIONAL RESOURCES
HIV-uninfected patients with multidrug-resistant and Blumberg HM, Burman WJ, Chaisson RE, et al: American Thoracic
extensively drug-resistant tuberculosis, Clin Infect Dis 47:496-
502, 2008. A retrospective review of 155 patients treated for Society/Centers for Disease Control and Prevention/Infectious Diseases
multidrug-resistant and extensively drug-resistant tuberculosis; body Society of America: treatment of tuberculosis, Am J Respir Crit Care Med
mass index, surgical resection, and use of at least four effective drugs 167:603-662, 2003. Comprehensive guidelines addressing pharmacology and
improved outcome. use of antituberculosis drugs, treatment regimens for drug-susceptible and drug-
resistant tuberculosis, patient monitoring, and treatment of tuberculosis in special
Lew W, Pai M, Oxlade O, et al: Initial drug resistance and situations. These guidelines serve as the standard for tuberculosis management
tuberculosis treatment outcomes: systematic review and in the United States.
meta-analysis, Ann Intern Med 149:123-134, 2008. Reviews the Centers for Disease Control and Prevention (CDC): Emergence of Myco-
impact of drug resistance profiles and treatment regimens on bacterium tuberculosis with extensive resistance to second-line drugs—
outcome; found higher relapse rates and further drug resistance for worldwide, 2000-2004, MMWR Morb Mortal Wkly Rep 55:301-305, 2006.
initially resistant infections. Short duration of rifampin use and An initial CDC and WHO report on laboratory surveillance to describe the
nonuse of streptomycin and pyrazinamide were associated with poorer global emergence of extensively drug-resistant tuberculosis.
outcomes. Centers for Disease Control and Prevention (CDC): Notice to readers:
revised definition of extensively drug-resistant tuberculosis, MMWR
Volmink J, Garner P: Directly observed therapy for treating Morb Mortal Wkly Rep 55:1176, 2006. Revised case definition for extensively
tuberculosis (review). Cochrane Library, Issue 1, Oxford UK, 2009, drug-resistant tuberculosis.
Wiley & Sons. A meta-analysis of 11 studies with more than 5000 Chan ED, Iseman MD: Multidrug-resistant and extensively drug-resistant
participants that detected no significant difference in clinical outcomes tuberculosis: a review, Curr Opin Infect Dis 21:587-595, 2008. Review of
when DOT was compared with self-administration or when DOT the current status of global multidrug-resistant tuberculosis: diagnostics, treat-
given at a clinic was compared with DOT given by a family member ment recommendations, and implications for disease control.
or community health worker. The authors conclude that the data Curry International Tuberculosis Center: Drug-resistant tuberculosis: a sur-
from low-, medium- and high-resource settings provide no assurance vival guide for clinicians, ed 2, San Francisco. 2008, Curry National Tuber-
that DOT compared with self-administration of treatment has any culosis Center and California Department of Public Health. An outstanding
quantitatively important effect on cure or treatment completion in manual for clinical management of multidrug-resistant tuberculosis.
people receiving treatment for tuberculosis. Harkan TJ, Condos R: Management of multidrug-resistant tuberculosis. In
Rom WN, Garay SM, eds: Tuberculosis, New York, 2004, Lippincott Wil-
Weis SE, Slocum PC, Blais FX, et al: The effect of directly liams and Wilkins, pp 729-738. Reviews principles and recommendations for
observed therapy on the rates of drug resistance and relapse in chemotherapy in patients with multidrug-resistant tuberculosis.
tuberculosis, N Engl J Med 330:1179-1184, 1994. A retrospective Tuberculosis Coalition for Technical Assistance: International standards for
study that demonstrated a reduction in relapse and drug resistance tuberculosis care (ISTC), ed 2, The Hague, 2009, Tuberculosis Coalition
following implementation of DOT in Tarrant County, Texas, in the for Technical Assistance. A coalition of the CDC, the American Thoracic
late 1980s. Society, the International Union against Tuberculosis and Lung Disease, the
Dutch Tuberculosis Foundation, and WHO formed to draft 21 standards for
Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE: Eleven addressing diagnosis, treatment, and public health responsibility for tuberculosis.
years of community-based directly observed therapy for These standards describe a consensus level of care that all practitioners, public
tuberculosis, JAMA 274:945-951,1995. A retrospective study that and private, should seek to achieve in managing tuberculosis.
demonstrated high treatment completion rates and a decline in World Health Organization: Treatment of Tuberculosis Guidelines, ed 4,
tuberculosis when community-based DOT was implemented in Geneva, 2010, World Health Organization. Guidelines for diagnosis, treat-
Baltimore. This occurred in the face of a national increase in ment, and monitoring of TB in resource-limited settings.
tuberculosis in the 1980s, especially in areas with similar rates of World Health Organization (WHO): STOP TB Partnership website. Avail-
medical and social factors. able at: http://www.stoptb.org/. Accessed April 20, 2010. A partnership of
international organizations, individual countries, donors, and nongovernmental
organizations whose mission is to control and ultimately eliminate tuberculosis.
World Health Organization Tuberculosis Program: Extensively drug-
resistant tuberculosis. Available at: www.who.int/tb/challenges/xdr/en/
index.html. Accessed April 20, 2010. Surveillance data and global program
planning to control extensively drug-resistant tuberculosis.

West Nile Virus Disease 91

Grant L. Campbell, J. Erin Staples, James J. Sejvar, and Marc Fischer

ABSTRACT animals has been reported in all states except Alaska and Hawaii.
The highest incidence of WNV disease is in the western moun-
Before 1999, West Nile virus (WNV) received little attention tain and plains states (Figure 91-4). In more recent years the
outside Africa, Asia, and Europe, where WNV is an endemic, virus also has been detected in the Caribbean and Central and
mosquito-borne cause of febrile illness and sporadic encephali- South America.
tis. After the dramatic emergence of WNV in New York City
in 1999, the virus spread westward across the United States, PUBLIC HEALTH IMPORTANCE
resulting in the largest outbreaks of serious WNV disease ever WNV is the most common cause of arthropod-borne viral
reported. From 1999 through 2009, 29,681 cases of WNV (arboviral) disease in the United States and Canada. Most
disease were reported in the United States, including 12,208 human WNV infections are asymptomatic. Approximately 20%
infections affecting the central nervous system (neuroinvasive of infected people develop an acute systemic febrile illness
disease) and 1,167 deaths. Over the past decade, much has been (WNV fever), and less than 1% develop neuroinvasive WNV
learned about the virology, ecology, transmission, epidemiology, disease (i.e., encephalitis, meningitis, or acute flaccid paralysis)
and clinical manifestations of WNV. This review highlights (Figure 91-5). In the United States, WNV surveillance data are
these new developments, which provide a platform for further reported to the Centers for Disease Control and Prevention
research into the prevention and control of WNV disease. (CDC) through ArboNET, an Internet-based arbovirus surveil-
lance system managed by the CDC and state health depart-
ETIOLOGY AND TRANSMISSION ments. From 1999 through 2009, 29,681 cases of WNV disease
WNV is a ribonucleic acid (RNA) flavivirus that is related anti- were reported to ArboNET, including 12,208 (41%) cases of
genically to St. Louis encephalitis and Japanese encephalitis neuroinvasive WNV disease and 17,473 (59%) cases of WNV
viruses. WNV is transmitted to humans primarily through the non-neuroinvasive disease; there were 1,167 (4%) associated
bite of infected mosquitoes (Figure 91-1). The predominant deaths. Reports of neuroinvasive WNV disease are considered
vectors worldwide are Culex mosquitoes, which feed primarily the most accurate indicator of WNV activity in humans, owing
from dusk to dawn and breed mostly in peridomestic standing to the substantial associated morbidity and mortality and the
water or pools created by irrigation or rainfall. Mosquitoes presumed completeness of reporting by clinicians and laborato-
become infected with WNV by feeding on a host that can sustain ries. In contrast, WNV fever likely is underdiagnosed and
infectious levels of viremia, serving to amplify the virus. Birds are underreported, as people with mild illness may not seek medical
the most important amplifying hosts of WNV; they infect care, or clinicians may not suspect or confirm WNV disease.
feeding mosquitoes, which then transmit the virus to humans Assuming that there were 140 human WNV infections for each
and other mammals during subsequent feeding. Viremia usually reported neuroinvasive WNV disease case, an estimated 1.7
lasts fewer than 7 days in immunocompetent persons, and WNV million human WNV infections occurred in the United States
concentrations in human blood are generally too low to infect from 1999 through 2009, including approximately 340,000 cases
mosquitoes, making humans incidental or “dead-end” hosts. of WNV non-neuroinvasive disease.
However, person-to-person transmission can occur through
blood transfusion and organ transplantation. Intrauterine trans- RISK FACTORS
mission and probable transmission via human milk also have In endemic areas of the northern hemisphere, the risk of WNV
been described but appear to be uncommon. Percutaneous infec- infection is higher during the warmer months when mosquitoes
tion and aerosol infection have occurred in laboratory workers, are active and more abundant, typically July through October
and an outbreak of WNV infection among turkey handlers also (Figure 91-6). Although people of all age groups appear to be
raised the possibility of aerosol transmission (Figure 91-2). equally susceptible to WNV infection, the risk of neuroinvasive
WNV disease increases with age (Table 91-1). In addition,
GEOGRAPHIC DISTRIBUTION among patients with neuroinvasive WNV disease, adults 50
WNV activity has been reported in Europe and the Middle years of age or older have substantially higher case-fatality rates
East, Africa, India, parts of Asia, and Australia (in the form of and are more likely to be reported as having encephalitis or
Kunjin virus, a WNV subtype) (Figure 91-3). WNV was first meningoencephalitis, compared with children or younger adults
detected in North America in 1999, after which it rapidly spread (18 to 49 years of age).
across the United States and northward into Canada. In the
United States, WNV activity in mosquitoes, birds, or other Solid organ transplant recipients also are at significantly
higher risk of severe illness. With the exception of increased age

CHAPTER 91╇ •â•‡ West Nile Virus Disease 555

Enzootic
cycle

West Nile virus (WNV) is transmitted in an enzootic cycle between Culex mosquitoes
and amplifying vertebrate hosts, primarily birds. WNV concentrations in human blood
are generally too low to infect mosquitoes, making humans incidental or “dead-end” hosts.

Figure 91-1╇ West Nile virus transmission cycle.

Primary Mode of Transmission Mosquito bite In utero
Secondary Modes of Transmission Transplantation

Transfusion

Breastfeeding Laboratory
Figure 91-2╇ West Nile virus transmission to humans.

556 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

If any West Nile virus Human WNV
activity has been docu- infections*
mented in a country, Nonhuman
including only sporadic, WNV activity†
focal, or regional activity, No WNV activity
the entire country is
colored in.
*Includes human disease
cases and humans testing
positive for WNV-specific
antibodies in serosurveys.
These areas may have
also reported nonhuman
activity.
†Includes animal
and arthropod data.

Figure 91-3╇ Reported West Nile virus activity by country* as of 2009.

0.00 Figure 91-4╇ Average annual incidence per 100,000
0.01-0.49 population of West Nile virus
0.50-0.99 neuroinvasive disease by county of
1.00-1.49 residence, United States, 1999 to
1.5-1.99 2008. (Adapted from Lindsey NP, Staples
Ն2.00 JE, Lehman JA, Fischer M: Surveillance for
human West Nile virus disease—United
States, 1999-2008, Centers for Disease

Control and Prevention Surveillance

Summaries, April 2, 2010. MMWR 2010;59

(No. 55-2.)

Neuroinvasive disease* (~1%) CLINICAL FEATURES
Non-neuroinvasive disease (~20%) The incubation period for WNV disease is typically 2 to 6 days
but ranges from 2 to 14 days and can be up to 21 days in immunoÂ

CHAPTER 91╇ •â•‡ West Nile Virus Disease 557

Incidence by Year Month of Illness Onset
1.5 50
Cases per 100,00 population
Cases per 100,00 population

Percentage (%)
1 40
30

0.5 20

10

0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 0 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Year Month

Average Annual Incidence by Age Group
1.5

1

0.5

0 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70ϩ
Age Group in Years

Figure 91-6╇ Epidemiologic characteristics of West Nile virus neuroinvasive disease in the United States, 1999 to 2009. (Adapted from
Lindsey NP, Staples JE, Lehman JA, Fischer M: Surveillance for human West Nile virus disease—United States, 1999-2008, Centers for
Disease Control and Prevention Surveillance Summaries, April 2, 2010. MMWR 2010;59 (No. 55-2) and West Nile Virus Activity—United

States, 2009. MMWR 2010;59:769-772.)

Table 91-1╇ Epidemiologic Features of West Nile Virus Neuroinvasive Disease Cases Reported in Children and
Adults, 1999 to 2007*

╯ CHILDREN (<18╯YR OLD) ADULTS (18-49╯YR OLD) ADULTS (≥50╯YR OLD)
N = 443 N = 3634 N = 7004
Median cases per year (range)
Median incidence† per year (range) 49 (1-137) 377 (4-1057) 826 (15-1879)
Clinical syndrome (%) 0.07 (0.00-0.19) 0.28 (<0.01-0.78) 0.92 (0.02-2.32)
â•… Encephalitis or meningoencephalitis
â•… Meningitis 163 (37) 1230 (34) 4160 (59)
â•… Acute flaccid paralysis‡ 208 (47) 1847 (51) 1640 (23)
â•… Unspecified neuroinvasive disease (<1) (<1)
Fatality (%) 5 (1) 23 (15) 37 (17)
Hospitalized§ (%) 67 (15) 534 1167 (14)
(1) (88)
3 (1) 48 (79) 949

166/206 (81) 1255/1585 2941/3344

*Includes cases reported as encephalitis, meningoencephalitis, meningitis, and/or acute flaccid paralysis (AFP) with age data.
†Incidence per 100,000 persons.
‡Includes cases reported as AFP only (not those reported as encephalitis or meningitis with AFP). Data available only from 2004 to 2007.
§Includes data from 2004 to 2007 only.

damage of anterior horn cells, and may progress to respiratory Most women known to have been infected with WNV during
muscle paralysis, necessitating mechanical ventilation. Guil- pregnancy have delivered infants without evidence of infection
lain-Barré syndrome can be distinguished from anterior horn or clinical abnormalities. In the best-documented, confirmed
cell disease by clinical manifestations and electrophysiologic congenital WNV infection, the mother developed neuroinva-
testing. Rarely, cardiac dysrhythmias, myocarditis, rhabdomy- sive WNV disease during the twenty-seventh week of gestation,
olysis, optic neuritis, uveitis, chorioretinitis, orchitis, pancre- and her neonate was born with cystic lesions in brain tissue and
atitis, and hepatitis have been described in patients with WNV chorioretinitis. One infant who apparently acquired WNV
disease. infection through breastfeeding remained asymptomatic.

558 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

DIAGNOSTIC APPROACH CLINICAL MANAGEMENT
WNV disease should be considered in any person with a febrile Management of WNV disease is supportive. Patients with
or acute neurologic illness who has had recent exposure to severe meningeal symptoms often require pain control for head-
mosquitoes, blood transfusion, or organ transplantation, espe- aches and antiemetic therapy and rehydration for associated
cially during the summer months in areas where WNV activity nausea and vomiting. Patients with WNV encephalitis require
has been reported in birds, animals, mosquitoes, or humans. close monitoring for the development of elevated intracranial
The diagnosis of WNV disease should also be considered in any pressure and seizures, and patients with WNV encephalitis or
infant born to a mother infected with WNV during pregnancy poliomyelitis should be monitored for inability to protect their
or while breastfeeding. Guidelines for the evaluation of fetal and airway. Acute neuromuscular respiratory failure may develop
neonatal WNV infections are available at www.cdc.gov/mmwr/ rapidly, particularly in patients with prominent bulbar signs, and
preview/mmwrhtml/mm5307a4.htm. In a patient with sus- prolonged ventilatory support may be required. In patients hos-
pected neuroinvasive WNV disease, other arboviruses (e.g., La pitalized with WNV disease, standard infection control precau-
Crosse, St. Louis encephalitis, eastern equine encephalitis, and tions are recommended. Although various drugs have been
Powassan viruses) also should be considered in the differential evaluated or empirically used for WNV disease, none has shown
diagnosis. specific benefit to date. Information regarding ongoing clinical
trials for treating WNV disease can be found at www.cdc.gov/
Routine clinical laboratory studies are generally nonspecific ncidod/dvbid/westnile/clinicaltrials.htm.
in WNV disease. In patients with neuroinvasive WNV disease,
cerebrospinal fluid (CSF) examination generally shows lympho- PROGNOSIS
cytic pleocytosis, but neutrophils may predominate early in the Most patients who develop WNV fever or meningitis recover
course of illness. Brain magnetic resonance imaging scans are completely, although some experience prolonged fatigue and
frequently normal, but signal abnormalities in the basal ganglia, other nonspecific symptoms. Patients who recover from WNV
thalamus, and brainstem may be seen in patients with WNV encephalitis or poliomyelitis often have residual neurologic
encephalitis. Abnormalities may also be observed in the deficits. Among patients with neuroinvasive WNV disease,
anterior spinal cord in patients with WNV poliomyelitis. the overall case-fatality rate is approximately 10%, but it is
Clinical features and electrodiagnostics can help differentiate significantly higher in WNV encephalitis and poliomyelitis
WNV poliomyelitis from WNV-associated Guillain-Barré than in WNV meningitis or fever, in which case-fatality rates
syndrome. are very low.

Serology continues to be the cornerstone of the laboratory PREVENTION AND CONTROL
diagnosis of WNV infection. Serum and, if indicated, CSF WNV infection can be prevented by avoiding exposure to
should be tested for WNV-specific immunoglobulin M (IgM) WNV-infected mosquitoes and by systematic screening of blood
antibody. If serum is collected within 8 days of illness onset, the donors for WNV infection. Coordinated mosquito-control pro-
absence of detectable WNV-specific IgM does not rule out the grams in areas with enzootic WNV transmission can reduce the
diagnosis of WNV infection, and the test may need to be abundance of mosquito vectors. People who live in areas with
repeated on a later sample. Enzyme immunoassays for WNV- WNV-infected mosquitoes should apply insect repellent to skin
specific IgM currently are available commercially and through and clothes and avoid being outdoors during peak mosquito-
local or state public health laboratories. The presence of feeding times (usually dusk to dawn for WNV vectors). The
WNV-specific IgM in blood or CSF provides good evidence of most effective repellents for use on the skin are N,N-diethyl-
recent WNV infection but may also result from cross-reactive methyl-toluamide (DEET) and picaridin. Products containing
antibodies after infection with other flaviviruses. Plaque- DEET or permethrin also can be applied to clothing. The
reduction neutralization tests performed in reference laborato- American Academy of Pediatrics recommends using formula-
ries, including some state public health laboratories and the tions of no more than 30% DEET on infants and children and
CDC, can help determine the specific infecting flavivirus and not using DEET on infants younger than 2 months of age. In
can confirm acute WNV infection by demonstrating a fourfold the United States, systematic screening of the blood supply for
or greater change in WNV-specific neutralizing antibody titer WNV infection was implemented in 2003. Nevertheless, health-
between acute- and convalescent-phase serum samples collected care providers should remain vigilant for possible WNV trans-
2 to 3 weeks apart. Because WNV-specific IgM can persist in mission through blood transfusion or organ transplantation.
some patients’ serum for more than 1 year, the presence of Any suspected WNV infections temporally associated with
WNV IgM occasionally may reflect past rather than recent blood transfusion or organ transplantation should be reported
WNV infection. promptly to public health authorities.

Viral cultures and nucleic-acid amplification tests (NATs) for Pregnant women should take the aforementioned precau-
WNV RNA can be performed on serum, CSF, and tissue speci- tions to avoid mosquito bites. Products containing DEET can
mens that are collected early in the course of illness and, if
results are positive, can confirm WNV infection. Immunohis-
tochemistry (IHC) can detect WNV antigen in formalin-fixed
tissue. Negative results of these tests do not rule out WNV
infection. Viral culture, NAT, and IHC can be requested through
state public health laboratories or the CDC.

CHAPTER 91╇ •â•‡ West Nile Virus Disease 559

be used in pregnancy without adverse effects. Although WNV Several vaccines against WNV are licensed for use in horses.
probably has been transmitted through human milk, such trans- Human WNV vaccines are not yet available, but several candi-
mission appears rare, and no adverse effects on infants have been date vaccines are being evaluated.
described.

EVIDENCE older) were classified as neuroinvasive WNV disease, cases of
neuroinvasive WNV disease were more often reported as encephalitis or
Bode AV, Sejvar JJ, Pape WJ, et al: West Nile virus disease: a meningoencephalitis, and the case-fatality rate was substantially higher.
descriptive study of 228 patients hospitalized in a 4-county region
of Colorado in 2003, Clin Infect Dis 42:1234-1240, 2006. The O’Leary DR, Kuhn S, Kniss KL, et al: Birth outcomes following
authors reported the results of the largest study to date of patients West Nile virus infection of pregnant women in the United
hospitalized with WNV disease, including neuroinvasive disease and States: 2003-2004, Pediatrics 117:e537-e545, 2006. The authors
WNV fever. Older age, diabetes mellitus, and alcoholism were associated reported the results of a study of birth outcomes among 77 women
with an increased risk of development of WNV encephalitis. Older age, diagnosed with WNV infection during pregnancy, identified through a
encephalitis, immunosuppression, a need for mechanical ventilation, and voluntary national registry. No adverse birth outcomes resulting from
a history of stroke were associated with fatal outcome. maternal WNV infection were conclusively demonstrated. Although
larger studies would be useful, the results suggest that congenitally
Hayes EB, Sejvar JJ, Zaki SR, et al: Virology, pathology, and acquired WNV infections are uncommon and that birth outcomes in
clinical manifestations of West Nile virus disease, Emerg Infect Dis women infected during pregnancy are usually normal.
11:1174-1179, 2005. This concise review of WNV disease focused on
clinical features, pathogenesis, pathology, laboratory diagnosis, clinical Pealer LN, Marfin AA, Petersen LR, et al: Transmission of West
management, prognosis, vaccine development, and future prospects. Nile virus through blood transfusion in the United States in 2002,
N Engl J Med 349:1236-1245, 2003. The results described in this
Iwamoto M, Jernigan DB, Guasch A, et al: Transmission of West landmark article confirmed transmission of WNV via blood transfusion,
Nile virus from an organ donor to four transplant recipients, N which accelerated the implementation of national guidelines for screening
Engl J Med 348:2196-2203, 2003. This landmark article described the of the blood supply for WNV. The results also indicated that the
first four recognized cases of WNV transmission via solid organ incubation period of WNV disease can be prolonged in immunosuppressed
transplantation. The sole organ donor, a trauma victim, probably persons.
acquired the infection via transfusion of WNV-infected blood products, a
conclusion that prompted the issuance of national guidelines concerning Sejvar J, Curns A, Welburg L, et al: Neurocognitive and
surveillance for blood donors with possible WNV viremia. functional outcomes in persons recovering from West Nile virus
illness, J Neuropsychol 2:477-499, 2008. The authors assessed
Lindsey NP, Hayes EB, Staples JE, Fischer M: West Nile virus quality-of-life indices and neurocognitive performance in 54 persons who
disease in children, United States, 1999-2007, Pediatrics had returned to independent living at 18 months after hospitalization
123:e1084-e1089, 2009. The authors described the epidemiologic for acute WNV disease. Over 20% of patients had persistent objective
features of pediatric WNV disease cases reported to the CDC from 1999 neurologic signs (e.g., tremor, parkinsonism, or limb weakness), and a
through 2007 and compared features of pediatric and adult majority reported subjective functional impairment or diminished quality
neuroinvasive WNV disease. The clinical syndromes and severity of of life. However, no significant neurocognitive impairments were
reported cases of pediatric neuroinvasive WNV disease were similar to identified.
those reported for cases in young adults (aged 18 to 49 years). In
contrast, a larger proportion of cases in older adults (aged 50 years or

ADDITIONAL RESOURCES summary, including information on epidemiology, clinical features, diagnostic
American College of Physicians: Physicians’ Information and Education testing, prevention, surveillance, and public health reporting, with links to state
and some local public health department websites.
Resource (PIER): West Nile virus disease. Available at: http:// Centers for Disease Control and Prevention (CDC): West Nile
pier.acponline.org/physicians/public/d951/d951.html. Accessed Febru- virus: updated information regarding insect repellents. Available
ary 24, 2010. An authoritative and user-friendly online tool for clinicians, first at: www.cdc.gov/ncidod/dvbid/westnile/repellentupdates.htm. Accessed
published in 2004 and since updated periodically. February 24, 2010. A brief, information-rich summary of the current state-
Centers for Disease Control and Prevention (CDC): West Nile virus: infor- of-the-art of repellent use in the prevention of mosquito-borne diseases; includes
mation and guidance for clinicians. Available at: www.cdc.gov/ncidod/ links to several additional useful resources.
dvbid/westnile/clinicians. Accessed February 24, 2010. A concise online

Anthrax 92

Benjamin D. Moser, Sean V. Shadomy, and Theresa L. Smith

ABSTRACT because of advancements in industry, agriculture, and laboratory
risk-prevention practices. In 2001, a surge of cases in the United
Anthrax, caused by Bacillus anthracis, is a devastating disease for States occurred surrounding bioterrorist attacks (11 cutaneous,
both humans and animals. Naturally occurring anthrax occurs 11 inhalation).
worldwide; however, it no longer causes substantial disease in
humans and animals in the United States. Anthrax most often RISK FACTORS
manifests as cutaneous, inhalation, or gastrointestinal disease. Anthrax infection in humans occurs naturally secondary to
The three forms of anthrax have different clinical presentations infection in animals. However, anthrax resulting from bioter-
associated with the route of infection and the organism’s effect rorist activities has increased the potential risk of anthrax occur-
on the affected organ system. Once diagnosed, anthrax is aggres- ring in individuals previously not at risk.
sively treated with an antimicrobial regimen consisting primar-
ily of ciprofloxacin or doxycycline, often as part of a multidrug Worldwide, anthrax results from contact with infected
antimicrobial regimen, and appropriate supportive care. Prog- animals or animal products, including those of animal origin
nosis for survival is relatively high for treated anthrax in both such as leather drumheads, brushes, or yarn. Cutaneous and
cutaneous (<1% mortality when treated) and gastrointestinal gastrointestinal anthrax outbreaks typically result from butcher-
forms (0% to 29% mortality); however, inhalation anthrax, even ing, slaughtering, or handling infected animals or from the
when treated early and aggressively, has a lower survival rate consumption of undercooked meat.
(55% in 2001). Prevention and mitigation of this disease depends
on the control of anthrax in animal populations, the restriction Anthrax may also be an occupational disease affecting veteri-
or decontamination of animal products, and the response of narians and farmers likely to contact or handle infected animals
public health authorities to bioterrorism events. or their carcasses. Laboratory workers are also at increased risk
when working with samples containing anthrax spores. Indus-
GEOGRAPHIC DISTRIBUTION trial anthrax exposures leading to inhalation anthrax result from
Anthrax is a zoonotic disease that has been reported worldwide. the inhalation of spores aerosolized by processing of animal
Epizootic in many African, Asian, and Central American coun- hides, hair, and wool. In the 1950s and 1960s, 80% of U.S.
tries and sporadically reported in southern and eastern Europe, anthrax cases were related to the production of textiles with
anthrax is responsible for major losses of livestock in endemic imported goat hair. Inhalation anthrax, or woolsorter’s disease,
areas such as Iran, Iraq, Turkey, Pakistan, South America, and decreased after improvements in industrial hygiene, immuniza-
sub-Saharan Africa. Anthrax is relatively uncommon or not tion, proper disinfection of imported materials, and the decline
present in the countries of North America and northern Europe; in the importation of contaminated raw materials.
however, sporadic epizootic outbreaks are still reported in live-
stock and wild herbivores and remain potential threats to human Sporadic cases of inhalation and cutaneous anthrax occurred
health. from 2006 to 2008 in persons using contaminated imported
animal hides for drum making. This included two cases of cuta-
DISEASE BURDEN neous anthrax in a drum maker and a family member. Both
Anthrax cases in humans are typically related to animal anthrax cutaneous and inhalation anthrax have been associated with the
outbreaks. True disease burden, however, is impeded by under- playing or handling of goatskin drums containing B. anthracis
diagnosis and underreporting of both human and animal cases, spores.
especially in the developing world. In Zimbabwe, as a result of
political instability and armed conflict that impeded anthrax B. anthracis is a Centers for Disease Control and Prevention
control initiatives, an estimated 10,000 human cases occurred (CDC) category A select agent and is considered to be one of
from 1978 to 1987. In countries with significant epizootic the most serious biowarfare or bioterrorism agents. It was used
anthrax, several hundred cases occur yearly. by the Germans during World War I against livestock and the
Japanese during World War II in Manchuria. The United States
Human cases of anthrax in the United States are rare. From and Britain conducted research on weaponized anthrax during
1951 to 2000, 410 cases of anthrax were identified, and a major- and after World War II, and nations such as the Soviet Union
ity of these cases were cutaneous. Total disease burden drasti- and Iraq continued research into more recent decades. Anthrax
cally declined from the later half of the 1950s (125 cutaneous, poses a threat as a bioterrorist weapon because of its ability
six inhalation) to the 1990s (one cutaneous; no inhalation) to be easily disseminated or transmitted into the environment,
its resulting high mortality rate, its potential for causing
social disruption, and the demands it places on public health
preparedness.

CHAPTER 92╇ •â•‡ Anthrax 561

CLINICAL FEATURES Clinical Presentation
Microbiology Human anthrax has three major clinical forms; cutaneous, inha-
lation, and gastrointestinal (Figure 92-1). Cutaneous anthrax is
B. anthracis, the causative agent of anthrax, is a large, gram- a result of introduction of spores via the skin, inhalation anthrax
positive, nonmotile, spore-forming, rod-shaped bacterium. It via the respiratory tract, and gastrointestinal anthrax via inges-
grows optimally at 37° C on many culture media. The virulence tion through the gastrointestinal tract. Cutaneous anthrax is
of B. anthracis depends on three plasmid-mediated factors: the most common naturally occurring infection caused by
edema toxin, lethal toxin, and a poly-d-glutamic acid capsule. B. anthracis.
The pX01 plasmid encodes for the three exotoxin components:
edema factor, lethal factor, and protective antigen (PA); and the CUTANEOUS ANTHRAX
pX02 plasmid encodes the antiphagocytic poly-d-glutamic acid Cutaneous anthrax develops after transcutaneous introduction
capsule. Edema factor combines with PA to form edema toxin, of B. anthracis spores. Over 90% of cutaneous anthrax lesions
causing edema and inhibiting neutrophil function. Lethal factor occur in exposed areas such as the face, neck, arms, and hands.
combines with PA to form lethal toxin, which causes macro- The lesion begins as a small, painless, but often pruritic papule,
phage apoptosis, disrupts cytokine signaling, and causes shock developing 5 to 7 days after infection (range 1 to 12 days) and
and death. The combined effects of edema toxin and lethal toxin enlarging to create a central vesicle or bulla. The vesicle rup-
include local necrosis and edema in cutaneous anthrax, and tures or erodes, leaving an underlying necrotic ulcer over which
hemorrhagic mediastinal necrosis, hypoxic insult, and pleural the characteristic black eschar develops. Satellite vesicles and
edema in inhalation anthrax. B. anthracis is susceptible to a ulcers may also form. Edematous swelling of the surrounding
variety of antimicrobial agents including penicillin, chloram- tissues is present, often with regional lymphadenopathy and
phenicol, tetracycline, erythromycin, streptomycin, and the
fluoroquinolones (see treatment section).

Oropharyngeal anthrax

Gastrointestinal anthrax Inhalation anthrax with mediastinal
lymphadenopathy
Cutaneous anthrax Inhalation anthrax with mediastinal widening
Figure 92-1╇ Clinical forms of anthrax.

562 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

lymphangitis. Systemic symptoms, including fever, malaise, and of the oropharyngeal epithelium. Edematous lesions occur on
headache, can accompany the cutaneous lesion. the epithelium and progress to necrotic ulcers with a pseudo-
membrane. Profound edema develops in the oropharynx and
INHALATION ANTHRAX neck. Pharyngitis, cervical lymphadenopathy, and fever follow.
Inhalation anthrax develops after the inhalation of anthrax The intestinal form develops after infection of the gastric or
spores. Alveolar macrophages phagocytize the spores and trans- intestinal mucosa. The infected intestinal segments become
port them to mediastinal lymph nodes, where the spores germi- edematous, lesions may become necrotic and ulcerated, and
nate, multiply, and release toxins, resulting in hemorrhagic draining mesenteric lymph nodes become infected and enlarged.
necrosis of the thoracic lymph nodes and hemorrhagic medias- The incubation period of gastrointestinal anthrax is estimated
tinitis (Figure 92-2). Necrotizing pneumonia may also develop. to be 1 to 6 days.
The incubation period for inhalation anthrax is generally esti-
mated to be 1 to 7 days but was reported to be as long as 42 Patients may present with fever, nausea and vomiting,
days in the 1979 outbreak in Sverdlovsk, and inhalation anthrax anorexia, or abdominal pain; symptoms may progress to
has developed up to 58 days and 98 days after experimental hematemesis and bloody diarrhea, and patients may develop
aerosol exposure in nonhuman primates. abdominal swelling as a result of voluminous, hemorrhagic
ascites. In less severe cases, only mild diarrhea and abdominal
The course of inhalation anthrax may be biphasic. First-stage pain develop.
clinical signs and symptoms are nonspecific and include low-
grade fever, malaise, fatigue, myalgia, and nonproductive cough. BACTEREMIC DISSEMINATION AND MENINGITIS
The condition may mimic other illnesses such as influenza. The After infection at the primary site of infection, the disease may
second stage of acute illness begins 2 to 3 days later with sudden progress with bacteremia, toxemia, and dissemination to other
onset of severe dyspnea and hypoxemia. Patients become hypo- organ systems, resulting in shock and death. Anthrax meningitis
tensive, diaphoretic, and cyanotic. may develop after initial infection with any of the three primary
forms of disease and has been rarely reported in the absence of
GASTROINTESTINAL ANTHRAX any other associated primary form of the disease.
Gastrointestinal anthrax develops after the consumption of
undercooked meat contaminated with B. anthracis. There are DIAGNOSTIC APPROACH
two clinical forms of gastrointestinal anthrax: oropharyngeal Diagnosis of anthrax currently depends on culture and isolation
and intestinal. The oropharyngeal form develops after infection of B. anthracis, which remains the gold standard for laboratory

Anthrax
Bacillus anthracis spores

Infected Bacillus anthracis spores in alveoli
pulmonary-associated
lymph nodes
Figure 92-2╇ Inhalation anthrax.

CHAPTER 92╇ •â•‡ Anthrax 563

confirmation of the diagnosis, or the detection of B. anthracis Box 92-1╇ Differential Diagnoses of Cutaneous
deoxyribonucleic acid (DNA) or antigens or of antibody Anthrax
responses against B. anthracis. Serologic diagnosis is possible
through use of an enzyme-linked immunosorbent assay (ELISA) Toxin-Related
to detect immunoglobulin (IgG) antibodies against PA and also • Brown recluse spider bite
through the detection of capsule-specific antibodies, which has
been used successfully for retrospective confirmation of anthrax Bacterial
in humans. Use of serology requires paired acute and convales- • Rickettsial pox
cent sera. Diagnostic specimens, especially for culture, should • Syphilis
be obtained before initiation of antimicrobial therapy, as the • Ecthyma gangrenosum
organisms may be rapidly cleared once effective antimicrobial • Ulceroglandular tularemia
therapy has been initiated. • Tularemia
• Tropical ulcer
In the United States, the Laboratory Response Network • Plague
(LRN), established by the Association of Public Health Labo- • Typhus
ratories and the CDC, provides laboratory capacity for confir- • Glanders
matory diagnosis of anthrax. • Rat-bite fever
• Leprosy
DIFFERENTIAL DIAGNOSIS • Staphylococcal cellulitis
Cutaneous Anthrax • Streptococcal cellulitis
In an appropriate epidemiologic setting, the presence of an • Cutaneous tuberculosis
eschar with extensive edema disproportionate to the size of the • Atypical mycobacteria
lesion and the presence of gram-positive rods and few polymor- • Cat-scratch disease
phonuclear leukocytes on Gram stain are strongly suggestive of
cutaneous anthrax. The following diagnostic tests should be Drug-Induced
performed on patients with suspected cutaneous anthrax: • Heparin or Coumadin necrosis

• For vesicular lesions, two swabs of vesicular fluid from an Autoimmune Disorders
unopened vesicle—one for Gram stain and culture, the • Antiphospholipid syndrome
second for polymerase chain reaction (PCR) • Pyoderma gangrenosum

• For eschars, the edge should be lifted and two swab samples Viral
rotated underneath and submitted—one for Gram stain • Varicella zoster
and culture, the second for PCR • Orf and milker’s nodules
• Herpes simplex
• For ulcers, the base of the lesion should be sampled with • Vaccinia
two saline-moistened swabs and submitted—one for Gram
stain and culture, the second for PCR Fungal
• Aspergillosis
In addition, a full-thickness punch biopsy of a papule or • Mucormycosis
vesicle including adjacent skin should be submitted in 10%
formalin for histopathology and immunohistochemical staining. Protozoa
In patients not undergoing antimicrobial therapy or who have • Cutaneous leishmaniasis
been undergoing therapy for less than 24 hours, a second biopsy
specimen should be submitted for Gram stain, culture, and Tumor
PCR. Box 92-1 lists the diseases that should be considered in • Melanoma
the differential diagnosis of a blackened eschar lesion. • Squamous cell carcinoma
• Basal cell carcinoma

Other
• Eczema
• Trauma
• Burns

Inhalation Anthrax compared with 376 controls with CAP or ILI revealed the
Confirmatory testing should be performed on specimens from following:
patients being evaluated for inhalation anthrax including patients
with a known exposure or clear epidemiologic link to exposure • The most accurate predictors of inhalation anthrax were
who are manifesting symptoms of inhalation anthrax (see discus- mediastinal widening or pleural effusion on chest x-ray
sion of prevention and control). Because the window of oppor- examination, and one or both of these findings were 100%
tunity for successful treatment is narrow once symptoms appear, sensitive for inhalation anthrax and 72% and 96% specific
it is important to distinguish potential inhalation anthrax cases when compared with CAP or ILI controls, respectively.
from more common disorders such as community-acquired
pneumonia (CAP), influenza, and influenza-like illnesses (ILIs). • Clinical signs more frequently associated with inhalation
Analysis of the clinical characteristics predictive of inhalation anthrax than with CAP or ILI included shortness of breath,
anthrax using data from 47 historical cases of inhalation anthrax nausea, vomiting, altered mental status, pallor or cyanosis,

564 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Box 92-2╇ Differential Diagnoses of Inhalation Box 92-3╇ Differential Diagnoses of Gastrointestinal
Anthrax or Oropharyngeal Anthrax

Bacterial Gastrointestinal
• Pneumonic tularemia • Foodborne illness
• Q fever • Acute appendicitis
• Psittacosis • Ruptured viscus
• Legionnaires’ disease • Diverticulitis
• Community-acquired pneumonia • Dysentery
• Necrotizing enteritis caused by Clostridium perfringens
Fungal
• Histoplasmosis Oropharyngeal
• Coccidioidomycosis • Vincent’s angina
• Ludwig’s angina
Viral • Streptococcal pharyngitis
• Influenza • Parapharyngeal abscess
• Community-acquired pneumonia
• Influenza-like illnesses (e.g., rhinovirus, adenovirus, and Other
• Malignancy
parainfluenza virus infection)
Box 92-3 lists the diseases that should be considered in the
Other differential diagnosis of hemorrhagic gastroenteritis or oropha-
• Malignancy ryngeal lesions suspected to be gastrointestinal anthrax.

and hematocrit greater than 45%. In contrast, symptoms CLINICAL MANAGEMENT AND
more suggestive of an ILI included rhinorrhea or sore TREATMENT
throat. Antimicrobial therapy should be initiated immediately after
laboratory or clinical suspicion of anthrax because of the rapid
Widening of the mediastinum secondary to mediastinitis is a progression of disease. Public health and state health depart-
classic finding in inhalation anthrax. Other thoracic imaging ments should be promptly notified.
abnormalities seen with inhalation anthrax include pulmonary
infiltrates or consolidation and pleural effusion. Diagnostic Ciprofloxacin, doxycycline, and penicillin G procaine are
testing of patients with suspected inhalation anthrax should approved by the Food and Drug Administration (FDA) for the
include the following: treatment of anthrax, including inhalation anthrax. As inducible
β-lactamases may be present, initial use of β-lactam antimicro-
• Blood cultures obtained before antimicrobial therapy bial agents is not recommended.
• Pleural fluid, if present, for Gram stain, culture, and
Treatment for uncomplicated, naturally occurring cutaneous
PCR anthrax is as follows:
• Cerebrospinal fluid in patients with meningeal signs, for • Ciprofloxacin (500╯mg orally twice daily in adults; 10 to 15╯mg/

Gram stain, culture, and PCR kg every 12 hours [not to exceed 1╯g/day] in children), or
• Acute and convalescent serum samples for serologic testing • Doxycycline for 5 to 7 days as follows:
• Pleural and/or bronchial biopsy specimens for immuno-
• Adults: 100╯mg orally twice daily
histochemistry, if other test results are negative • Children >8 years old and >45╯kg: 100╯mg every 12 hours
Box 92-2 lists the diseases that should be considered in the • Children >8 years old and ≤45╯kg: 2.2╯mg/kg every 12
differential diagnosis of a respiratory syndrome.
hours
Gastrointestinal Anthrax • Children ≤8 years old: 2.2╯mg/kg every 12 hours
Information regarding reliability of diagnostic testing is limited
for gastrointestinal anthrax. Culture from stool frequently does With supportive antimicrobial susceptibility profiles, penicil-
not yield B. anthracis, but Gram stain or culture of oropharyn- lin V (500╯mg orally every 6 hours) or amoxicillin (500╯mg
geal lesions or ascitic fluid may be positive. Blood cultures may orally three times daily) may be used to complete treatment. For
also be positive if collected before initiation of antimicrobial more severe cutaneous cases with systemic involvement, exten-
therapy. Diagnostic testing of patients with suspected gastroÂ

CHAPTER 92╇ •â•‡ Anthrax 565

results, penicillin G (4 to 6 million units four times daily) may The approved second-line antimicrobial agent recommend for
be used to complete the 7- to 10-day treatment. For cases of PEP is as follows:
cutaneous anthrax with a risk for potential aerosol exposure, the • Levofloxacin (500╯mg orally once daily in adults; 16╯mg/kg/
duration of antimicrobial therapy should be 60 days to provide
a full course of postexposure prophylaxis (PEP). day div q12h, with each dose not to exceed 250╯mg, in chil-
dren ≥6 months of age)
Patients with inhalation anthrax typically seek medical care Levofloxacin is considered a second-line antimicrobial agent
late in the course of the illness. Therefore first-line antimicro- for PEP when medical issues such as tolerance or resistance may
bial treatment should be immediately initiated in patients with call for its use, as safety data on extended use of levofloxacin in
suspected anthrax. The failure of single-drug therapy has been any population for more than 28 days are limited.
reported for the treatment of inhalation anthrax, thus providing Gastrointestinal anthrax manifests rather quickly, after an
rationale for a multidrug approach. Early clinical data for the incubation period of at most 1 week. There are few studied cases
treatment of inhalation anthrax cases resulting from the 2001 of gastrointestinal anthrax; therefore, the treatment regimen is
bioterrorism event suggest that intravenous treatment with two the same as suggested for inhalation anthrax. The duration of
or more antimicrobial agents improves survival. The multidrug treatment should be determined by clinical response to therapy
treatments are ciprofloxacin (400╯mg twice a day) plus one or and would not be as prolonged as recommended for inhalation
two of the following antimicrobials: doxycycline, rifampin, van- anthrax.
comycin, penicillin, ampicillin, chloramphenicol, imipenem,
meropenem, and clindamycin. PROGNOSIS
Cutaneous anthrax has had case-fatality rates as high as 20%
Patients may be switched from intravenous treatment to oral without appropriate treatment; however, with antimicrobial
therapy typically after 14 to 21 days or after their condition is therapy the case-fatality rate is less than 1%. Gastrointestinal
stable. A total duration of treatment of 60 days (combination of anthrax has an estimated untreated mortality ranging from 25%
intravenous and oral therapy) should be applied. Chest tubes or to 60%; however, with appropriate treatment the mortality is
thoracentesis should be used to drain pleural effusions as sup- lower (0% to 29%). Inhalation anthrax, if untreated, is usually
portive therapy in all inhalation anthrax cases. fatal. Antimicrobial therapy can be successful, especially if initi-
ated early in the course of disease; however, even with early
Corticosteroids have also been suggested as adjunctive initiation of treatment, five of the 11 patients with inhalation
therapy for some patients with inhalation anthrax because of anthrax (45%) associated with the 2001 bioterrorism event in
toxin-related morbidity, including patients with extensive the United States died.
edema, respiratory failure, and meningitis and patients with
cutaneous anthrax with extensive edema involving the head PREVENTION
and neck. Prevention of human anthrax is primarily dependent on the
control of the disease in animals, especially livestock. Annual
Anthrax immunoglobulin derived from persons immunized immunization of livestock in areas of enzootic anthrax is
with Anthrax Vaccine Adsorbed (AVA) is available from the recommended.
CDC, through state and local health departments, under an
Investigational New Drug (IND) protocol for the treatment of Animal anthrax cases and outbreaks should be reported to
persons with confirmed cases of life-threatening anthrax. It was agriculture and public health officials. Affected premises or areas
used as a part of the successful clinical treatment of an inhalation should be quarantined and any further slaughter, butchering,
anthrax case in 2006, but its use in the treatment of a subsequent and marketing of infected animals or their parts prevented.
inhalation anthrax case in 2008 did not prevent a fatal outcome. Antimicrobial treatment of affected animals and immunization
Clinicians and laboratorians should contact their state and local of all susceptible livestock on affected and surrounding premises
health departments to request anthrax immunoglobulin from is recommended. Carcasses of animals that die of anthrax,
the CDC. bedding, and other contaminated material should be incinerated
completely. If that is not possible, carcasses of infected animals
After an exposure to aerosolized B. anthracis spores, either should be deeply buried with a covering of chloride of lime
bioterrorism-related or naturally occurring, a full-course PEP mixed with soil; however, anthrax outbreaks have recurred
regimen of 60 days of antimicrobial agent therapy plus three where carcasses have previously been buried.
doses of AVA is recommended. Three oral antimicrobial agents
have been approved by the FDA and are recommended by the For humans, AVA (BioThrax, BioPort, Lansing, Michigan)
CDC for PEP. The first-line antimicrobial agents for adults and is the only anthrax vaccine licensed for use in the United States.
children are as follows: The vaccine is recommended for persons with an occupational
• Ciprofloxacin (500╯mg orally twice daily in adults; 10 to risk, who work in high-risk industries such as those that process
imported animal hides, hair, and wool, where industrial hygiene
15╯mg/kg every 12 hours [not to exceed 1╯g/day] in children). standards and restrictions are insufficient to prevent exposure to
The CDC recommends ciprofloxacin as the first-line drug for anthrax spores; for veterinarians and others who potentially
PEP in pregnant women and nursing mothers. handle infected animals in areas with a high disease incidence;
• Doxycycline: and for laboratory workers who encounter large quantities or
• Adults: 100╯mg orally twice daily.
• Children >8 years old and >45╯kg: 100╯mg every 12 hours
• Children >8 years old and ≤45╯kg: 2.2╯mg/kg every 12

hours
• Children ≤8 years old: 2.2╯mg/kg every 12 hours

566 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

concentrations of B. anthracis cultures. Recently the Advisory against the potential risks and the effectiveness of the disinfection
Committee on Immunization Practices (ACIP) updated the pro- method verified by appropriate quality control analysis.
visional recommendation for the use of anthrax vaccine in
persons considered to be at risk for exposure to aerosolized B. Improvements in industrial hygiene, immunization of at-risk
anthracis spores to include emergency responders, in addition to workers, and a decrease in the use of imported, contaminated
the previously mentioned recommended populations. Vaccine raw materials resulting from restrictions on the importation of
should be administered in 5 intramuscular injections at 0 and 4 potentially contaminated products of animal origin, have limited
weeks and at 6, 12, and 18 months. To maintain effective immu- industrial anthrax exposure.
nity, a booster injection is recommended annually.
Anthrax has plagued humans and animals for centuries.
CONTROL Anthrax persists throughout the world and continues to cause
Because of the resistance of the spore, disinfection of materials outbreaks, although these outbreaks are now less common in
contaminated with B. anthracis is complicated. A variety of the developed world. As experienced in the 2001 bioterrorist
procedures including those using dry heat, steam under pressure, activities in the United States, intentionally caused anthrax
formaldehyde soaking or vapor exposure, ethylene oxide gas remains a great risk.
exposure, hypochlorite solution soaking, and gamma-irradiation
are measures that have been effectively used to decontaminate Appropriate identification methods and treatment regimens
materials or areas affected by anthrax. The potential benefits must be quick and effective in their approach toward anthrax,
associated with the disinfection method should be weighed because both are essential in improving patient outcomes.
Understanding the etiology and epidemiology of anthrax facili-
tates an appropriate public health response in the treatment of
cases, in the control of outbreaks, and in limiting the effects of
intentional exposure.

EVIDENCE antigen immunoglobulin G and lethal factor, Clin Infect Dis
44:968, 2007. Study involving a natural anthrax case with further
Guarner J, Jernigan JA, Shieh WJ, et al: Pathology and analysis of the anthrax vaccine.
pathogenesis of bioterrorism-related inhalational anthrax, Am J
Pathol 163:701, 2003. Characterizes anthrax as a bioterrorism weapon Stern EJ, Uhde KB, Shadomy SV, Messonnier N:
and indentifies the pathology and pathogenesis of the infection. Conference report on public health and clinical guidelines
for anthrax [conference summary]. Emerg Infect Dis [serial
Holty JE, Bravata DM, Liu H, et al: Systematic review: a century on the Internet]. 2008 Apr [Accessed March 14, 2011].
of inhalational anthrax cases from 1900 to 2005, Ann Intern Med Available from http://www.cdc.gov/eid/content/14/4/e1.htm. Summary
144:270, 2006. Anthrax review. of updated CDC recommendations for prophylaxis and treatment of
anthrax.
Jernigan DB, Raghunathan PL, Bell BP, et al: Investigation of
bioterrorism-related anthrax, United States, 2001: epidemiologic FDA: Supplemental New Drug Approvals NDA 20-634/S-047,
findings, Emerg Infect Dis 8:1019-1028, 2002. Important paper 20-635/S-051, 21-721/S-015. 2008. [Accessed March 14, 2011].
regarding the 2001 anthrax events in the United States. Available from http://www.fda.gov/downloads/Drugs/
EmergencyPreparedness/BioterrorismandDrugPreparedness/
Meselson M, Guillemin J, Hugh-Jones M, et al: The Sverdlovsk UCM133682.pdf. Notification from the FDA regarding the approval
anthrax outbreak of 1979, Science 266:1202-1208, 1994. Discussion of the use of levofloxacin for postexposure prophylaxis of inhalation
of a classic outbreak of anthrax. anthrax.

Walsh JJ, Pesik N, Quinn CP, et al: A case of naturally acquired
inhalation anthrax: clinical care and analyses of anti-protective

ADDITIONAL RESOURCES 1998, Plenum, pp 95-107. An overview of the many aspects of anthrax disease,
Beatty ME, Ashford DA, Griffin PM, et al: Gastrointestinal anthrax: review control, and epidemiology.
Quinn CP, Turnbull PCB: Anthrax. In Hausler WJ, Sussman M, eds: Topley
of the literature, Arch Intern Med 163:2527-2531, 2003. A review of articles and Wilson’s microbiology and microbial infection, ed 9, London, 1998,
on gastrointestinal anthrax. Edward Arnold, p 799. A very thorough anthrax overview.
Brachman PS: Inhalation anthrax, Ann N Y Acad Sci 353:83-93, 1980. A Sirisanthana T, Brown AE: Anthrax of the gastrointestinal tract, Emerg Infect
classic paper on inhalational anthrax. Dis 8:649-651, 2002. An overview of gastrointestinal anthrax.
Brachman PS, Kaufmann AF: Anthrax. In Evans AS, Brachman PS, eds:
Bacterial infections of humans: epidemiology and control, ed 3, New York,

Tularemia 93

Jo Hofmann

ABSTRACT reported from Martha’s Vineyard, Massachusetts, where hunting
clubs imported infected rabbits from enzootic areas in the 1920s
Tularemia is a zoonotic bacterial infection that occurs through- and 1930s. From 2000 through 2008, the Centers for Disease
out the Northern hemisphere; it is caused by several subspecies Control and Prevention (CDC) received 1133 reports of human
of the gram-negative coccobacillus Francisella tularensis. A wide tularemia, approximately 126 infections per year (Figure 93-2).
variety of animals can be infected with F. tularensis, and the Although the global incidence of tularemia has decreased mark-
bacteria can also be carried by insects. Human F. tularensis infec- edly over the past 50 years, periodic outbreaks continue to
tion is acquired through contact with infected animals, by the occur, especially in Northern Europe and Eurasia. These out-
bite of an infected insect, or through inhalation or ingestion of breaks have been associated with drinking spring water,
the bacteria, which are highly infectious. Thus tularemia is a hunting, and other outdoor activities, and some have involved
human disease associated with outdoors activities, especially hundreds of cases of tularemia. Although rare in humans, tula-
among hunters and trappers, and may be an occupational disease remia occurs in a wide variety of animals and is maintained in
of landscape workers and gardeners. The severity of tularemia an enzootic cycle with rodents and lagomorphs. Other animals,
depends on the infecting subspecies of F. tularensis, the mode of such as cats and nonhuman primates, may serve as incidental
disease transmission, and the size of the infecting inoculum. The hosts. Outbreaks, or epizootics, of tularemia periodically occur
spectrum of human F. tularensis ranges from mild, localized in animal populations and may herald outbreaks of human
infection to life-threatening sepsis. Although F. tularensis is an disease.
uncommon human illness in the United States, because it is
highly infectious, is easily transmissible, and causes severe or RISK FACTORS
fatal illness, it is considered a potential agent of bioterrorism. The animals most commonly associated with transmission of
tularemia to humans in the United States include lagomorphs
GEOGRAPHIC DISTRIBUTION AND (rabbits and hares) and rodents (voles, squirrels, muskrats, and
MAGNITUDE OF DISEASE BURDEN beavers). Although animals are the primary reservoir of F. tula-
Tularemia, also known as rabbit fever or deer fly fever, is a zoo- rensis, the infection can also be transmitted by insect bites (espe-
nosis caused by a highly infectious, aerobic, gram-negative coc- cially those of ticks or deer flies) or by contact with bacteria in
cobacillus, F. tularensis. The natural reservoir for F. tularensis is the environment. Francisella tularemia tularensis is a hardy organ-
small mammals such as rodents or rabbits. The bacterium is ism that can survive for extended periods in water, mud, and
found throughout host animals in most of North America and frozen animal carcasses. Tularemia has been reported after skin
Eurasia. In the United States, tularemia is most commonly or mucous membrane contact with contaminated animals or
caused by two subspecies of F. tularensis: F. tularensis subsp tula- their environment, ingestion of contaminated food or water, and
rensis (type A, which is subdivided into subtypes A1a, A1b and inhalation of aerosolized bacteria (Figure 93-3). Activities asso-
A2), and Francisella tularensis subsp holarctica (type B). In Europe ciated with risk of tularemia include hunting, trapping, dressing,
and Eurasia, F. tularensis subsp holarctica is the primary cause of eating, or handling infected animals; activities that result in
tularemia. Human tularemia was first described in the United exposure to infected insects; farming or gardening with machin-
States in 1910 as “deer fly fever,” and the causative agent (at that ery that may aerosolize the carcasses of infected animals; and
time known as Bacterium tularense) was identified after an out- handling F. tularensis in a laboratory without appropriate per-
break of a plaguelike illness of ground squirrels in Tulare sonal protective equipment. Although inhalational tularemia
County, California, in 1911. In 1924 a United States Public does occur, the bacteria are not known to spread from person
Health Service physician, Edward Francis, identified B. tularense to person.
as the cause of human deer fly fever. To honor his contributions
to the understanding of this organism, the bacterium was sub- During and after World War II, several countries (including
sequently renamed Francisella tularensis. Japan, the former Soviet Union, and the United States) con-
ducted research into the use of F. tularensis as a biologic weapon.
In the United States, human tularemia is rare but has been More recently, most countries have suspended their biologic
documented in every state except Hawaii. Tularemia was much weapons research and destroyed their weapon stockpiles.
more common in the early part of the twentieth century than it However, as a highly infectious bacteria that can be easily mass
is now (Figure 93-1). Since 2000, most cases of tularemia have produced and aerosolized, with the potential to cause severe or
been reported from rural areas of the United States where infec- fatal illness, F. tularensis continues to be designated a Category
tion of host animals is common (or enzootic), such as Arkansas, A Bioterrorism Agent by the CDC.
Kansas, Nebraska, and Missouri. In addition, many cases are
Recent CDC analyses of laboratory-documented human
tularemia reported in the United States from 1964 through

568 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Cases 1000 Figure 93-1╇ Reported tularemia, United
900 States, 1950 to 2008. (From
800 Centers for Disease Control and
700 Prevention (CDC): Tularemia
600 statistics. Available at:
500 www.cdc.gov/tularemia/Tul_
400 Statistics.html.)

300 1950
200 1955
100 1960
1965
0 1970
1975
1980
1985
1990
1995
2000
2005

Year
Tularemia was much more common in the early part of the 20th century than it is now.

Figure 93-2╇ Reported cases of tularemia by county of
residence, United States, 2000 to 2008.
(From Centers for Disease Control and
Prevention (CDC): Tularemia statistics. Available
at: www.cdc.gov/tularemia/Tul_Statistics.html.)

One dot placed randomly within county of residence of each reported case

2004 found that infections tend to be acquired during the infections were associated with multiple exposures or landscap-
warmer months (72% occurred from May through September) ing activities.
and are geographically diverse (type A1 infections cluster toward
the eastern United States, type A2 infections occur toward the CLINICAL FEATURES
west, and type B is primarily clustered through the southern and The clinical presentation and severity of tularemia vary accord-
central western areas of the country). Men constitute the major- ing to the infecting type or subtype of F. tularensis, the size of
ity of infections (74%), and younger age appears to be a risk for the bacterial inoculum, and the initial site of inoculation. The
infections with type A, compared with type B (median age 38 incubation period for tularemia is about 3 to 7 days (range 1 to
versus 50 years) (Figure 93-4). Overall, 6% of infections occurred 14 days). The clinical spectrum of tularemia is quite variable,
among persons with an immunocompromising condition (e.g., ranging from localized infection to life-threatening systemic
malignancy, organ transplant, or human immunodeficiency illness; forms include ulceroglandular, glandular, pneumonic,
virus [HIV] infection). A source of infection was reported for typhoidal, oculoglandular, pharyngeal, and septic syndromes
42% of the cases, and in this subgroup, direct animal contact (Figure 93-5). After entry of F. tularensis via skin or mucous
accounted for about half of all infections (47% of type A and membranes, the bacteria disseminate to local lymph nodes and
53% of type B). Among persons with infection associated with subsequently spread via the bloodstream to additional lymph
animal contact, 53% of type A infections were attributed to nodes and organs, primarily the spleen, liver, kidney, lungs, and
lagomorphs and 30% to cats. No persons with type B infection pleura. Regardless of the form of infection, untreated tularemia
reported lagomorph contact; those infections were linked to may become chronic, with fever, malaise, weight loss, and ade-
either rodents (33%) or cats (22%). Tularemia attributed to nopathy lasting months.
insects accounted for 44% of type A infections and 29% of type
B infections; among infections resulting from insect bites, tick Tularemia most commonly manifests as ulceroglandular or
exposure (87%) was reported more commonly than contact with glandular disease (about 60% to 80% of infections) that follows
deer flies. A small proportion of types A (8%) and B (18%) entry of the bacteria into disrupted skin from contact with an

CHAPTER 93╇ •â•‡ Tularemia 569

Francisella tularensis infects many different animal species;
transmission to humans in the United States occurs most
commonly from contact with infected rabbits, rodents,
or domestic cats.

Human infection can also occur from tick and deer fly
bites or through ingestion of contaminated food or water.

Figure 93-3╇ Transmission of Francisella tularensis.

Cases 80
70
60
50
40
30
20

10 Male

0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Female
5-year age group

Tularemia is more common in males, possibly because of a greater likelihood of exposure through
hunting and landscaping. Tularemia occurs in persons of all ages, but is most common in children.

Figure 93-4╇ Reported tularemia by age and gender, United States, 2000 to 2008. (From Centers for Disease Control and Prevention [CDC]:
Tularemia statistics. Available at: www.cdc.gov/tularemia/Tul_Statistics.html.)

infected animal or via the bite of an infected insect. A papule may develop an eschar; the involved lymph nodes may become
appears at the site of inoculation, and, similar to other presenta- fluctuant and suppurate. In glandular tularemia, a less common
tions of tularemia, the skin lesion is usually accompanied by the form, a skin or mucosal lesion is not apparent.
abrupt onset of symptoms of a systemic disease: chills, fever,
headache, malaise, and myalgias. The skin lesion becomes pus- About 15% of infected persons have pneumonic tularemia,
tular and tender with local lymphadenopathy, then ulcerates and which may result from inhalation of bacteria or by hematoge-
nous spread from another site. Typical signs and symptoms

570 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

Pneumonic syndrome:
lobar or patchy pneumonia
with hilar lymphadenopathy

Ulceroglandular syndrome: Mental status Septic
ulcer at the site of inoculation Fever changes shock

Oculoglandular Acute
syndrome: respiratory
unilateral distress
conjunctivitis syndrome

Disseminated Abdominal pain
intravascular
coagulation

Septic syndrome: nonspecific, systemic Diarrhea
febrile illness that may be complicated
by septic shock and multiorgan dysfunction

Glandular syndrome:
local lymphadenopathy

Figure 93-5╇ Syndromes associated with human tularemia.

include fever and a nonproductive cough with substernal DIAGNOSTIC APPROACH
and/or pleuritic chest pain. In early pneumonic tularemia, chest The nonspecific findings associated with the many forms of
radiographs may show diffuse peribronchial infiltrates that tularemia may pose a diagnostic dilemma, especially with typhoi-
progress to patchy or lobar involvement with pleural effusions dal, pneumonic, or septic disease. Pneumonic tularemia may
and perihilar lymphadenopathy. However, many patients dem- mimic other causes of atypical pneumonia (e.g., Mycoplasma,
onstrate systemic findings alone and lack significant pulmonary Legionella, or Chlamydophila pneumonia, Q fever). Typhoidal
involvement. In one study in which volunteers were intention- tularemia can be indistinguishable from the innumerable causes
ally exposed to aerosolized tularemia, up to 75% had no pulmo- of prolonged fever without an apparent source (e.g., invasive
nary signs or symptoms at the onset of illness. Despite these bacterial, mycobacterial, fungal, and parasitic infections; rheu-
findings, pneumonic tularemia can rapidly progress to severe, matologic disorders; malignancies). An atypical presentation of
multilobar pneumonia, acute respiratory distress syndrome ulceroglandular tularemia may suggest another localized bacte-
(ARDS), and death. rial or herpes virus infection, and glandular disease can be mis-
taken for a variety of bacterial, mycobacterial, fungal, parasitic,
Less common presentations of tularemia include typhoidal and viral infections that cause chronic fever and lymphadenopa-
(a systemic illness that does not involve specific organs or lymph thy. Clinical suspicion may be heightened in enzootic areas when
nodes and lacks an obvious site of inoculation), oculoglandular a patient has ulceroglandular tularemia, especially in the setting
(inoculation of the conjunctiva with mucosal ulceration and of an epizootic, but most clinicians in the United States lack
local lymphadenopathy), and oropharyngeal (ingestion of bac- familiarity with any presentation of tularemia. Factors that may
teria followed by oropharyngeal mucosal ulceration and local signal an intentional release of F. tularensis include clusters of
lymphadenopathy). Although rare, sepsis is the most serious severe, atypical pneumonia or acute febrile illness that rapidly
form of tularemia, a systemic illness that may rapidly progress progress if untreated or tularemia that occurs in urban areas or
to shock, multisystem organ failure, and death. among persons without obvious risk factors.

Laboratory findings in tularemia are nonspecific and may Preferred specimens for the detection or isolation of F. tula-
include leukocytosis, thrombocytopenia, and hyponatremia, as rensis include biopsy specimens from an ulcer, lymph node, or
well as abnormalities associated with multi-organ dysfunction
including elevated serum aminotransferases and creatine kinase.

CHAPTER 93╇ •â•‡ Tularemia 571

other affected tissue; fluid aspirates; or tissue swabs or scrapings. Ciprofloxacin has not been approved by the Food and Drug
The organism is very rarely isolated from blood. F. tularensis Administration (FDA) for treatment of tularemia in children
requires a cysteine-enriched growth medium, and the bacteria younger than 18 years of age. More severe tularemia may require
are infrequently identified by Gram stain or isolated from a longer course of treatment.
routine cultures of skin or mucosal lesions, blood, sputum,
respiratory secretions, or lymph node or pleural aspirates. In the event of an intentional release of tularemia, the initial
Although isolation of F. tularensis from a clinical specimen is empirical therapy for adults and children would be streptomycin
considered the gold standard for a diagnosis of tularemia, clini- or gentamicin (depending on availability) for 10 days; alterna-
cal laboratories must be alerted that tularemia is suspected so tively, ciprofloxacin (for 10 days), doxycycline, or chlorampheni-
that they can use appropriate growth media and biosafety mea- col (for 14 to 21 days) can be given, with the caveat that
sures. Antimicrobial susceptibility testing should be performed chloramphenicol should not be administered to pregnant women.
only at an experienced microbiology laboratory.
PROGNOSIS
Detection of an elevated acute antibody titer against F. tula- Even with appropriate and timely administration of antimicro-
rensis provides a presumptive diagnosis of tularemia, whereas a bial therapy, complications of tularemia may occur. Involved
fourfold rise in antibody titers in paired acute and convalescent lymph nodes may suppurate and require surgical drainage. More
serum specimens is diagnostic. Convalescent blood specimens severe forms of infection can be complicated by disseminated
should be drawn at least 28 days after the onset of illness. intravascular coagulation, rhabdomyolysis, and renal and hepatic
Methods used to detect antibody include enzyme-linked immu- failure. Before the availability of antimicrobials, fatality rates of
nosorbent assay (ELISA) and microagglutination and tube 5% to 60% were reported for tularemia, depending on the
agglutination, which detect both immunoglobulin M (IgM) and infecting type and syndrome; however, more recent reviews
IgG. However, isolation of the organism or demonstration of a describe case fatality rates ranging from 4% to 9%. Factors asso-
fourfold increase in antibody titers may not be timely enough ciated with a poor outcome include increasing age, underlying
for clinical or public health management of tularemia. More medical conditions, delayed or inappropriate antimicrobial
specialized methods, available at local, state, and federal public treatment, and typhoidal or pneumonic disease. Although F.
health laboratories, include direct fluorescent antibody, poly- tularensis type A is classically associated with more severe disease
merase chain reaction assays or immunohistochemical staining than infections caused by type B, a recent investigation of the
of clinical specimens; these methods can provide a rapid, pre- molecular diversity of F. tularensis using pulsed field gel electro-
sumptive diagnosis of tularemia, enabling appropriate patient phoresis and multivariate logistic regression analysis found that
management and public health interventions. subtype A1b appears to the most lethal form of tularemia, fol-
lowed by types B, A1a, and A2, in decreasing order of lethality.
CLINICAL MANAGEMENT AND
DRUG TREATMENT PREVENTION AND CONTROL
Rapid administration of appropriate antimicrobial therapy is the Overview
only treatment for tularemia. No controlled clinical trials have Prevention of tularemia relies on minimizing the potential for
evaluated the duration of therapy required for cure or the effi- contact with F. tularensis, especially in enzootic areas. Hunters,
cacy of different antimicrobial regimens. A literature review of trappers, and others in contact with wild animals should wear
case series and reports has suggested that bactericidal aminogly- gloves when handling these animals. Wild-animal meat should
cosides appear to have the highest cure rate and the lowest always be cooked thoroughly before consumption, and drinking
incidence of relapse, compared with the bacteriostatic agents untreated water should be avoided. Anyone engaged in outdoor
tetracyclines and chloramphenicol. Ciprofloxacin has also been activities should dress to avoid insect bites (e.g., long sleeves
used in the treatment of tularemia in both adults and children, with long pants tucked into socks), use effective insect repellent
but experience with this antimicrobial is limited. For years, the (e.g., N,N-diethyl-m-toluamide [DEET] or picaridin), and
drug of choice for tularemia was streptomycin, an aminoglyco- perform frequent tick checks if outdoors for prolonged periods
side that must be given intramuscularly. However, as of this of time. When performing landscaping or gardening, consider
writing, streptomycin is no longer produced in the United wearing a dust mask and avoid activities that could aerosolize F.
States, and availability of this drug is extremely limited. In the tularensis, such as mowing over sick or dead animals.
absence of streptomycin, gentamicin is the recommended
therapy for tularemia in all adults, including pregnant women F. tularensis is one of the most highly infectious microorgan-
(3.0 to 5.0╯mg/kg/day, administered intravenously or intramus- isms that laboratory workers may encounter; inoculation with
cularly in a single dose or two or three divided doses for 7 to as few as 10 organisms can cause infection. Clinical laboratories
14 days), and children (3.0 to 7.5╯mg/day administered intrave- should always be alerted before they receive a specimen from
nously or intramuscularly in three divided doses for 7 to 14 a patient suspected to have tularemia. A detailed discussion
days). The dose of aminoglycoside should be adjusted for renal of laboratory safety is beyond the scope of this chapter;
insufficiency. As alternatives to an aminoglycoside, adults and however, whereas most microbiologic procedures involving
children may be treated with oral doxycycline (doxycycline F. tularensis can be performed using biosafety methods common
should not be used in children younger than 8 years of age to most clinical laboratories, some procedures require a
unless no alternative therapy is available) for 14 days, and adults greater level of biosafety conditions available to few nonresearch
may be treated with 10 days of doxycycline or ciprofloxacin.

572 SECTION IX╇ •â•‡ Emerging Infectious Diseases and Pandemics

laboratories. Laboratory workers exposed to F. tularensis should EVIDENCE
be monitored for fever and/or provided with chemoprophylaxis
for tularemia. Dennis DT, Inglesby TV, Henderson DA, et al: Tularemia as
a biological weapon: medical and public health management,
Immunization JAMA 285:2763-2773, 2001. A comprehensive article on the
Infection with tularemia is thought to confer lifelong immunity, history, clinical management, and public health response to tularemia
although repeat infections have been reported. A variety of vac- when used as a biologic weapon.
cines have been developed to prevent tularemia; however, cur-
rently there are no effective human vaccines available for the Feldman KA, Stiles-Enos D, Julian K, et al: Tularemia on
civilian population in the United States. Martha’s Vineyard: seroprevalence and occupational risk,
Emerg Infect Dis 9:350-354, 2003. The only reported outbreaks
Chemoprophylaxis of pneumonic tularemia in the United States occurred on Martha’s
In the event of an intentional release of F. tularensis, chemopro- Vineyard, Massachusetts, in 1978 and 2000. This study evaluated
phylaxis may be effective in preventing the development of the risk of exposure to F. tularensis among landscape employees.
tularemia if given within the incubation period. The recom-
mended treatment for children and adults (including pregnant Kugeler KJ, Mead PS, Janusz AM, et al: Molecular
women) is oral doxycycline or ciprofloxacin for 14 days. In other epidemiology of Francisella tularensis in the United States, Clin
high-risk exposure situations (e.g., exposed laboratory workers, Infect Dis 48:863-870, 2009. A CDC review of more than 500
animal handlers in contact with animals known to have tulare- cases of human and animal tularemia reported from 1964 to 2004,
mia), chemoprophylaxis may be indicated. Chemoprophylaxis of with an in-depth look at the epidemiology of subtypes of F. tularensis
persons in contact with someone who has tularemia is not indi- as determined by pulsed-field gel electrophoresis.
cated, as F. tularensis is not transmitted from person to person.
Staples JE, Kubota KA, Chalcraft LG, et al: Epidemiologic and
molecular analysis of human tularemia, United States,
1964-2004, Emerg Infect Dis 12:1113-1118, 2006. An earlier
analysis of the same cases of tularemia as reported by Kugeler, with
more focus on the epidemiology of human infections.

Infection Control ADDITIONAL RESOURCES
As noted earlier, tularemia is not transmitted from person to Centers for Disease Control and Prevention (CDC): Emergency prepared-
person; therefore in healthcare settings, standard precautions
(frequent hand hygiene with soap and water or alcohol-based ness and response: tularemia. Available at: www.bt.cdc.gov/agent/
hand sanitizers; gown and eye protection [i.e., goggles or face tularemia/index.asp. CDC website for information on tularemia as a potential
shield] during activities that may generate splashes or aerosols agent of bioterrorism.
of respiratory or other body fluids) alone are recommended for Centers for Disease Control and Prevention (CDC): Tularemia. Available
infection control for patients infected with tularemia. at: www.cdc.gov/tularemia. CDC website for tularemia and F. tularensis.
Includes information for the public and public health and clinical professionals.
Public Health Measures Penn RL: Francisella tularensis (tularemia). In Mandell GL, Bennett JE,
The importance of reporting suspected communicable diseases Dolin R, eds: Mandell, Douglas, and Bennett’s principles and practice of infec-
to public health authorities may be overlooked by busy clini- tious diseases, ed 7, Philadelphia, 2009, Elsevier Churchill Livingstone.
cians. Although highly infectious, F. tularensis cannot be spread Infectious diseases textbook chapter with comprehensive information about all
from person to person. However, prompt recognition of clusters aspects of tularemia.
of human or animal tularemia may prevent further cases of University of Minnesota Center for Infectious Disease Research and
illness or reveal an intentional release of bacteria. It is important Policy (CIDRAP): Tularemia. Available at: www.cidrap.umn.edu/cidrap/
that clinicians report any suspected cases of human tularemia to content/bt/tularemia/index.html. CIDRAP is a collaborative center of the
their local or state health department. Public health personnel University of Minnesota that focuses on emerging global challenges to public
can facilitate diagnostic and confirmatory laboratory testing and health, including preparedness and response to events such as bioterrorism and
assist in the identification of potential exposures. pandemic influenza. The site has extensive information about tularemia, includ-
ing a comprehensive review of the subject that is updated frequently.

Index

Note: Page numbers followed by f, t, and b indicate figures, tables, and boxed material, respectively.

A Acquired immunodeficiency Aeromonas hydrophila infection, 85, 94
Abdomen syndrome. See HIV/AIDS. Aeromonas infection, in travelers,

acute, differential diagnosis of, 252, Acrodermatitis chronica atrophicans, 390-393
253f 432 Africa, meningococcal disease in, 24,

cross-sectional anatomy of, 264f, Activated protein C, for 27, 204
265f meningococcal disease, 26 African Americans

Abdominal abscess. See Active immunization, 3 genital herpes in, 311
Intraabdominal abscess. Acute abdomen, differential diagnosis HIV/AIDS in, 319
trichomoniasis in, 303
Abdominal guarding, in peritonitis, of, 252, 253f AIDS. See HIV/AIDS.
287 Acute ascending cholangitis, 245-249, Airway obstruction, foreign body, 155
Alanine aminotransferase
Abdominal pain 247f in hepatitis A, 61
in appendicitis, 239-240, 241f, Acute disseminated encephalomyelitis, in hepatitis B, 67
287 Albendazole
in cholangitis, 245, 246, 247f 43 for alveolar echinococcosis, 499
differential diagnosis of, 252, 253f vaccine-related, 386-387, 387f, for cysticercosis, 483-484
in hepatic echinococcosis, 492 for giardiasis, 461, 461t
of liver abscess, 268, 271f 415 for hydatid cyst, 260, 261, 496,
in peritonitis, 287 vs. rabies, 415
Acute flaccid paralysis, 29 497, 498
Abdominal surgery, abscess formation differential diagnosis of, 31-32 in PAIR, 497
after, 262, 263, 267. See also Acute postinfectious measles perioperative, 496
Intraabdominal abscess. for lymphatic filariasis, 511, 511t,
encephalomyelitis, 43
Abortive poliomyelitis, 29 Acute respiratory distress syndrome 512-513, 512t
Abreva, for herpes labialis, 114 for roundworms, 471-473, 472t,
Abscess (ARDS)
blastomycosis and, 229, 229f 473t
anorectal, 278-285. See also chemical pneumonitis and, 155 for trichinellosis, 503
Anorectal abscess; Fistula in novel influenza and, 533 Allergic fungal rhinosinusitis, 165
ano. pathogenesis of, 538f Allergic reactions, 7
in severe acute respiratory to mumps vaccine, 49-50
appendiceal, 240f, 266 skin testing for, in sinusitis, 166
brain, 455 syndrome, 538, 538f Allergic rhinitis, sinusitis and, 162,
Acyclovir
in meningitis, 208, 209f 165
sinusitis-associated, 163f, 170 for genital herpes, 316-317, 316t Alopecia
epidural, in meningitis, 208, 209f for herpes simplex virus infection,
horseshoe, 280-281, 282f black dot, 102
intraabdominal, 262-267, 263f- 113, 113t differential diagnosis of, 103
meningeal, 211 in syphilis, 352, 354f
266f. See also Intraabdominal resistance to, 316 Alpha fetoprotein, in hepatitis B, 67
abscess. for varicella zoster virus infection Alphaviral polyarthropathy, 422t. See
liver. See Liver abscess. for prophylaxis, 59
lung for treatment, 57-58, 58t also Arbovirus infections.
in aspiration pneumonia, 153 Adamantanes, for influenza, 36 Alvarado score, 241, 242, 242t
in hospital-acquired pneumonia, Adefovir, for hepatitis B, 67-68, 406 Alveolar echinococcosis, 498-500,
Adenoviral pharyngoconjunctival
144f fever, 179 499f, 500f
muscle, 292-294, 293f Adenovirus infection Alveolar hemorrhage, radiography in,
osteomyelitis and, 218f pharyngeal, 177, 179
peritonsillar, 179-180, 179f pulmonary, 158t, 160 141f
psoas, in pyomyositis, 292-294, Adolescents, immunizations for, 3. Amantadine, for influenza, 36, 157
See also Children.
293f Adoption, international, hepatitis B from novel viruses, 534
skin/soft tissue, 83, 87-93. See also screening for, 65 Amastigotes, in Chagas disease, 522,
Aedes mosquitoes
Skin infections; Soft tissue arbovirus infections and, 419-420, 523f
infections. Amebiasis, 452-457
subdural, in meningitis, 208, 209f 420t, 421f
Acid-fast bacillus staining lymphatic filariasis and, 505 brain abscess in, 455
of nontuberculous mycobacteria, yellow fever and, 383, 419-420, clinical features of, 452-455, 453f
120 diagnosis of, 455-456
technique for, 122f 421f dysentery in, 390-393, 453, 454f

574 Index

Amebiasis (Continued) Anal wink, 278 Anthrax (Continued)
epidemiology of, 452 Anaplasmosis, human granulocytic, vs. prevention of, 565-566
etiology of, 452, 453f prognosis of, 565
hepatic, 455 Lyme disease, 432 risk factors for, 560
liver abscess in, 268-272, 270f, Ancylostoma duodenale, 467t, 470f. See treatment of, 135t, 564-565
454-455, 455f, 456. See also
Liver abscess. also Hookworms. Anthrax Vaccine Adsorbed, 565-566
pericardial, 455 Anemia, hemolytic, in mycoplasma Antibiotics
pleuropulmonary, 455
prevention of, 457 pneumonia, 147f for anthrax, 564-565
in travelers, 390-393, 391f Aneurysm, left ventricular, in Chagas for appendicitis, 242-243
treatment of, 456-457, 456t for arthritis, 342
disease, 524, 524f for atypical pneumonia, 149-151,
Amikacin Anogenital warts, 71-74, 327-333. See
adverse effects of, 550t 149t-151t
for hospital-acquired pneumonia, also Genital warts; Human for bacterial pneumonia, 133-134,
142t papillomavirus infection.
for Mycobacterium abscessus infection, Anopheles mosquitoes 134t
121 control of, 378 for bacterial vaginosis, 363-364,
for tuberculosis, resistance to, 546, lymphatic filariasis and, 505
546t, 547f. See also malaria and, 373 364t
Tuberculosis, Anorectal abscess, 278-285 for bites, 85
multidrug-resistant. clinical features of, 278 for cellulitis, 84-85
cryptoglandular origin theory of, for chancroid, 366-367, 366b
Amine test, for bacterial vaginosis, for chlamydia, 341-342, 341t
362, 363t 278, 279f for cholangitis, 247
etiology of, 278, 279f for COPD exacerbations, 184,
Amoxicillin fistula formation and, 282-284. See
for anthrax, 564 186f
for chlamydia, 341, 341t also Fistula in ano. for cystitis, 225
Haemophilus influenzae resistance to, history for, 278 for diphtheria, 7
17 horseshoe, 280-281, 282f for diverticulitis, 254, 254t
for Lyme disease, 433t intersphincteric, 279, 280f, 281, for endocarditis, 193-196,
for otitis media, 21, 175, 175f, 176
prophylactic, for dental procedures, 281f 194t-196t
199, 200t ischioanal, 279, 280-281, 280f, for epididymitis, 341-342
for sinusitis, 168, 169, 169t for erysipelas, 84-85
for streptococcal pharyngitis, 181 281f for giardiasis, 460-461, 461t
for typhoid fever, 397, 397t, 398t location of, 279-280, 280f for gonorrhea, 300, 347-349, 348t
management of, 279-282 for granuloma inguinale, 369,
Amoxicillin-clavulanate pathogenesis of, 278, 279f
for leptospirosis, 428t, 429 perianal, 279-280, 280f, 281f 369b
for otitis media, 175, 175f physical examination of, 278-279 for HACEK organisms, 191, 196t
for sinusitis, 168, 169t supralevator, 279, 280f, 281-282, for Haemophilus influenzae
for tuberculosis, 549
281f meningitis, 17, 18
Amphotericin B types of, 279-282, 280f, 281f for hospital-acquired pneumonia,
for blastomycosis, 233, 233t Anorectal advancement flap, for
for coccidioidomycosis, 234, 234t 140-143, 142t
for histoplasmosis, 232-233, 233t rectovaginal fistulas, 284 for impetigo, 79
for primary amebic Anorectal chlamydia, 338, 339f Jarisch-Herxheimer reaction and,
meningoencephalitis, 446 Anorectal lymphogranuloma
359, 361, 429
Ampicillin venereum. See Lymphogranuloma for leptospirosis, 427, 428t, 429
for endocarditis, 195t venereum. for liver abscess, 270
Haemophilus influenzae resistance to, Anthelmintics, 471-473, 472t, 473t for Lyme disease, 433, 433t
17 Anthrax, 560-566 for lymphogranuloma venereum,
for meningitis, 211 bacteremic dissemination in, 562
for pneumococcal disease, 21 in bioterrorism, 560 342
prophylactic, for dental procedures, clinical features of, 561-562, 561f for meningitis, 211-212
199, 200t cutaneous, 561-562, 561f, 563, 564t for meningococcal disease, 25-26,
diagnosis of, 562-563
Ampicillin-sulbactam differential diagnosis of, 563-564, 211-212
for endocarditis, 195t, 196t for necrotizing soft tissue
for hospital-acquired pneumonia, 563t, 564t
142, 142t disease burden from, 560 infections, 99, 276
gastrointestinal, 561f, 562, 564, for nontuberculous mycobacterial
Amylase, in mumps, 49
Anaerobic cellulitis, 100 564t infections, 120-121, 121t
Anal sphincter, examination of, geographic distribution of, 560 for osteomyelitis, 219t, 220
inhalation, 561f, 562, 562f, 563- for otitis media, 174-176, 175f
278-279 for pancreatic abscess, 265-266
564, 564t for pelvic inflammatory disease,
intestinal, 562, 564, 564t
meningitis in, 562 341-342
oropharyngeal, 561, 561f, 562, 564, for peritonitis, 289-290
for pertussis, 13
564t for pneumococcal disease, 21
postexposure prophylaxis for, 565 for pneumonia, 151t

INDEX 575

Antibiotics (Continued) Antipyretics, for influenza, 36 Arcanobacterium haemolyticum
prophylactic, for prosthetic heart Antiretroviral therapy, for HIV pharyngitis, 177, 179, 181
valves, 199, 200t
for pyelonephritis, 225-226 infection, 323-325, 323b-325b, ARDS. See Acute respiratory distress
for pyomyositis, 292, 293-294 324f, 324t, 325t syndrome (ARDS).
resistance to. See Antimicrobial Antituberculosis agents, 544, 546t,
resistance. 548-552 Argyll-Robertson pupil, in
for sinusitis, 168-170, 169t adverse effects of, 549, 550t neurosyphilis, 355
for staphylococcal nasal dosage of, 546t
colonization, 90, 91 regimens for, 549 Artemether-lumefantrine, for malaria,
for staphylococcal skin infections, resistance to, 544-546, 546t, 547f. 379t
90-91
for streptococcal pharyngitis, See also Tuberculosis, Arterial blood gas analysis, in
181-182, 181t multidrug-resistant. hospital-acquired pneumonia,
for streptococcal toxic shock Antiviral agents 140, 141f
syndrome, 99 for genital herpes, 316-317, 316t
for syphilis, 359-361, 360t for hepatitis B, 67-68, 406 Artesunate, for malaria, 378
for traveler’s diarrhea, 392, 392t, for hepatitis C, 408 Arthralgia, in mumps, 48-49
393 for influenza, 36 Arthritis
for tularemia, 151, 571 for chemoprophylaxis, 37
for typhoid fever, 397-398, 397t, for novel viruses, 534, 535 chlamydial, 339
398t for poliomyelitis, 32 gonococcal, 345-346, 346f. See also
for urinary tract infections, 225-226 for rabies, 415-416
for varicella zoster virus infection Gonorrhea.
Antifungal agents for prophylaxis, 59 in mumps, 48-49
for aspergillosis, 170 for treatment, 57-58, 58t reactive chlamydial, 339, 342
for dermatophytoses, 102-108 Aortitis, in syphilis, 357f in rubella, 52
for endemic mycoses, 232-234, Aphthous stomatitis syndrome, 178 septic
233t, 234t Aphthous ulcers, vs. herpes labialis,
for primary amebic 113 Haemophilus influenzae, 16, 17
meningoencephalitis, 446 Appendectomy, 242-243 nontuberculous mycobacterial,
for sinusitis, 170 interval, 243
laparoscopic vs. open, 243 121t
Antigen assay, for endemic mycoses, negative, 242 pneumococcal, 20, 20f
232 Appendicitis, 239-243 Ascariasis
abscess formation in, 240f, 266 clinical features of, 466, 467, 467t,
Antihistamines, for sinusitis, 168 peritonitis and, 242, 243, 287,
Antimalarials, 377-378, 378t, 379t 287f 468f
Antimicrobial resistance. See also pyogenic liver abscess and, 268, 269 diagnosis of, 470
Appendix geographic distribution of, 466
specific drugs. cancer of, 240f prevention and control of, 473-474
to fluoroquinolones, 225 mucocele of, 240f risk factors for, 466
in gonorrhea, 300, 347-348 position of, 239, 241f treatment of, 470-473, 472t, 473t
in Haemophilus influenzae infections, in pregnancy, 242, 242f Ascaris lumbricoides
roundworms in, 467, 468f in appendix, 467, 468f
16-17 Arachnoid, 202 life cycle of, 467t, 468f
in HIV infection, 323 Arbovirus infections, 419-424, Aseptic meningitis, 203b, 206
in malaria, 373, 380 435-440 genital herpes–associated, 313
in meningococcal disease, 26, clinical features of, 419, 420t, 422t, Aspartate aminotransferase, in
437-438, 438f
204-206 delayed/relapsing, 422t hepatitis A, 61
in pneumonia diagnosis of, 421-422 Aspergillus sinusitis, 164, 170
differential diagnosis of, 422 Aspiration
bacterial, 127-129, 129f geographic distribution of, 419,
hospital-acquired, 142, 142f, 420t intraabdominal abscess, 263
incubation period for, 420t liver abscess, 271, 271f
142t prevention and control of, sinus, 163, 166
risk factors for, 142f 422-423 Aspiration pneumonia, 153-156
in sinusitis, 3, 169 environmental interventions for, Aspiration pneumonitis, radiography
in soft tissue infections, 276
in staphylococcal infections, 87-93. 422-423 in, 141f
immunization for, 423 Aspirin, Reye’s syndrome and, 58
See also Staphylococcal risk factors for, 419-421 Asthma, sinusitis and, 162
infections, transmission of, 419-420, 420t, Asymptomatic bacteriuria, 221, 222
methicillin-resistant. Athlete’s foot, 105-106, 105f
in tuberculosis, 544-552. See also 421f, 422 Atovaquone, for malaria, 381t
Tuberculosis, vs. rabies, 415 Atovaquone-proguanil, for malaria,
multidrug-resistant.
in typhoid fever, 397, 397t, 398t 378, 379t, 380f, 381t
Antimotility agents, for traveler’s Atypical pneumonia, 146-151. See also
diarrhea, 392
Antipruritics, for varicella, 58 Pneumonia, atypical.
Autism, MMR vaccine and, 45
Avian influenza (H5N1), 157-159,

530-536
clinical features of, 532-534
diagnosis of, 533
disease burden from, 530-531

576 Index

Avian influenza (H5N1) (Continued) Bacterial vaginosis (Continued) Bird flu. See Avian influenza (HN51).
geographic distribution of, 530-531 geographic distribution of, 362 Bismuth subsalicylate, for traveler’s
prevention and control of, 534-536 HIV/AIDS and, 320
chemoprophylaxis in, 535 in pregnancy, 363 diarrhea, 392, 393
immunization in, 535-536 prevention and control of, 364 Bites
infection control measures in, prognosis of, 364
533, 534-535 recurrence of, 364 antibiotics for, 85
public health measures in, 534 risk factors for, 362 brown recluse spider, 84
reporting of, 535 treatment of, 363-364, 364b necrotizing fasciitis and, 99
risk factors for, 531-532, 532t trichomoniasis and, 303, 304 osteomyelitis and, 217t
treatment of, 533-534 rabies and, 413
Bacteriuria, asymptomatic, 221, 222 in travelers, management of, 417f
Azithromycin Bacterobilia, cholangitis and, 245 Black dot alopecia, 102
for chancroid, 366, 366b Bairnsdale ulcer. See Buruli ulcer. Black flies, onchocerciasis and,
for chlamydia, 341, 341t, 342 Balantidiasis, 463, 464t
for chlamydial pneumonia, 150, Bancroftian lymphatic filariasis. See 506-507, 507f, 510, 513
151t Black-legged deer ticks, Lyme disease
for gonorrhea, 348t Lymphatic filariasis.
for granuloma inguinale, 369, Bannwarth syndrome, 432 and, 430, 431f
369b Barber’s itch, 102 Black tar heroin, necrotizing soft
for leptospirosis, 428t, 429 Barmah Forest virus infection, 419
for lymphogranuloma venereum, Bartholinitis tissue infections and, 100, 273
342 Bladder, schistosomiasis of, 519, 519f
for Mycobacterium abscessus infection, chlamydial, 337 Blastocystis hominis infection, 464f, 465
121 gonococcal, 344, 345f. See also Blastomyces dermatitidis, 227
for Mycobacterium marinum
infection, 120, 121t Gonorrhea. culture of, 231
for mycoplasmal pneumonia, 150, Beef tapeworms, 475-480, 476t, 477f, Blastomycosis, 227-234
151t
for otitis media, 175, 175f 479t. See also Tapeworms. clinical features of, 228-229, 229f
for pertussis, 13 Bell’s palsy, yellow fever vaccine– diagnosis of, 231-232, 232f
prophylactic, for dental procedures, prognosis of, 234
199, 200t associated, 387, 387f treatment of, 135t, 233, 233t
for syphilis, 359, 360t Benzimidazoles, 471-473, 472t, Bleeding, in leptospirosis, 426-427
for traveler’s diarrhea, 392, 392t Blindness, in onchocerciasis, 505, 512
for typhoid fever, 397, 397t 473t Blood-brain barrier, 202
for hydatid cyst, 497-498 Blood donation, malarial
B Benznidazole, for Chagas disease,
Babesiosis, vs. Lyme disease, 432 chemoprophylaxis and, 381
Bacillary diarrhea, in travelers, 524-525 Blood–cerebrospinal fluid barrier,
Bi-undulating meningoencephalitis.
390-393 202
Bacille Calmette-Guèrin, for See Tick-borne encephalitis. Blueberry muffin syndrome, 52, 53f
Bichloroacetic acid, for genital warts, Boils. See Furuncles.
nontuberculous mycobacterial Bone
infections, 122 331, 332t
Bacillus anthracis, 560, 561 Bile duct cancer, 246f biopsy of, in osteomyelitis, 216f
Bacteremia Bile duct stones, cholangitis and, hydatid cyst in, 492, 493-495
Haemophilus influenzae, 15-18, 16 Bone scan, in osteomyelitis, 214,
in hospital-acquired pneumonia, 245-249, 246f
Biliary decompression, for cholangitis, 216f, 217
144f Bordetella pertussis, 11, 12
Bacterial meningitis, 19-22, 20f, 247-249, 248f, 249f Borrelia burgdorferi, 430
Biliary disease, pyogenic liver abscess Borrelial lymphocytoma, 432
202-212, 203b, 205t, 210t. See Borrelioses, 430-433
also Meningitis. in, 268-272 Brain, hydatid cyst of, 495
Bacterial pneumonia, 127-135. See Biliary obstruction Brain abscess
also Pneumonia, community-
acquired bacterial. cholangitis and, 245-249, 246f amebic, 455
aspiration, 153-154, 154t mechanisms of, 245, 246f in meningitis, 208, 209f
Bacterial vaginosis, 305t, 362-364, BinaxNOW malaria test, 377 sinusitis-associated, 163f, 170
363f, 363t Biopsy Brain herniation, after lumbar
chlamydia and, 336 bone, in osteomyelitis, 216f
clinical features of, 306f, 362 in endemic mycoses, 231, 231f, puncture, 208
diagnosis of, 305, 306f, 362-363 Brain surgery, meningitis after, 203b,
differential diagnosis of, 363t 232f
disease burden with, 362 jejunal, in giardiasis, 459f, 460 206, 209, 211
epidemiology of, 362 liver, in hepatitis A, 61 Branhamella catarrhalis, in otitis
lung, in endemic mycoses, 231,
media, 172, 173
231f, 232f Breakbone fever, 419
muscle, in trichinellosis, 503, 503f Breastfeeding, HIV transmission via,
nail, in dermatophytoses, 109
in necrotizing soft tissue infections, 319
Bronchiectasis, cough in, 132f
275-276 Bronchitis, chronic, exacerbations of,
skin, in dermatophytoses, 109
Bioterrorism 183-186, 184f-186f
anthrax in, 560 Bronchoalveolar lavage, in ventilator-
tularemia in, 567, 570, 571
associated pneumonia, 140

INDEX 577

Bronchoscopy, in hospital-acquired Carbuncles, 83, 87-93. See also Cefoxitin (Continued)
pneumonia, 140, 141f Staphylococcal skin/soft tissue for Mycobacterium abscessus
infections. infection, 121
Brown recluse spider bites, 84
Brudzinski’s sign, 16, 207, 207f clinical features of, 88-90, 88f, 89f Cefpodoxime
Brugia malayi, 505, 506t. See also diagnosis of, 90 for gonorrhea, 347-348, 348t
pathogenesis of, 87-88 for otitis media, 175, 175f
Lymphatic filariasis. prevention and control of, 91 for sinusitis, 169, 169t
Brugia timori, 505, 506t. See also risk factors for, 88
treatment of, 88f, 90-91 Ceftazidime, for hospital-acquired
Lymphatic filariasis. Cardiac hydatid cyst disease, 258, pneumonia, 142t
Buboes
260f, 492 Ceftizoxime, for gonorrhea, 347-348,
in chancroid, 365-367, 365f Cardiac transplantation, in Chagas 348t
in lymphogranuloma venereum,
disease, 525 Ceftobiprole, for staphylococcal skin/
339, 339f, 340 Cardiac valve surgery, endocarditis soft tissue infections, 91
Bulbar palsy, yellow fever vaccine–
and, 197-199, 197t, 198f, 199f Ceftriaxone
associated, 387, 387f Cardiomyopathy, in Chagas disease, for cellulitis, 84
Bulbar paralytic poliomyelitis, 31 for chancroid, 366b
Bull-neck appearance, in diphtheria, 522, 523-524, 524f, 525 for chlamydia, 341
Cardiovascular syphilis, 356, 357f for diverticulitis, 254t
6, 6f Carditis. See Endocarditis. for endocarditis, 194t, 195t
Bullous impetigo, 78-79 Cat bites for epididymitis, 341
Bull’s-eye rash, in Lyme disease, 430, for gonorrhea, 300, 347-348, 348t,
antibiotics for, 85 349
431f necrotizing fasciitis and, 99 for hospital-acquired pneumonia,
Bursitis osteomyelitis due to, 217t 142, 142t
Catheter-associated urinary tract for leptospirosis, 428t, 429
cellulitis and, 83, 84, 84f for Lyme disease, 433, 433t
olecranon, 83, 84, 84f infections, 222, 224, 224f, 226 for meningococcal disease, 25, 27
Buruli ulcer, 117-122 Catheter drainage. See Drainage. for otitis media, 175, 175f
clinical features of, 117-118, 118f, Catheters, for fistula in ano, 284f for pneumococcal disease, 21
Cavernous sinus thrombosis, sinusitis- prophylactic, for dental procedures,
119f 199, 200t
diagnosis of, 119-120 associated, 163f, 170 for sinusitis, 169, 169t
prognosis of, 122 Cavitation for syphilis, 359, 360t
treatment of, 120-121, 121t for typhoid fever, 397, 397t
C in aspiration pneumonia, 153
Café coronary syndrome, 155 in hospital-acquired pneumonia, Cefuroxime
Calabar swelling, 507f, 508, 509, 512 for diverticulitis, 254t
Calculi, biliary, 246f 144f for gonorrhea, 347-348, 348t
cholangitis and, 245-249 CD4+ count for Lyme disease, 433t
Calymmatobacterium granulomatosis, for otitis media, 175, 175f
in HIV infection, 320, 320f
367 treatment guidelines and, 323, Cellulitis, 76, 81, 83-85, 83f, 83t
Campylobacter erysipelas, 82 323b, 324t, 325t anaerobic, 100
Campylobacter jejuni infection, in crepitant, 100. See also Soft tissue
in SARS, 539 infections, necrotizing.
travelers, 390-393, 391f Cefazolin Haemophilus influenzae, 15-18
Cancer nonpurulent, 76
for cellulitis, 84 purulent, 76, 83, 84f
appendiceal, 240f for diverticulitis, 254t staphylococcal, 87-93. See also
bile duct, 246f for endocarditis, 194t Staphylococcal skin/soft tissue
cervical, 71-74, 327-333. See also prophylactic, for dental infections.

Cervical cancer. procedures, 199, 200t Centor Score, 180, 180t
colorectal, vs. diverticulitis, 255, Cefdinir, for otitis media, 175, Central European encephalitis. See

264-265 175f Tick-borne encephalitis.
HIV infection and, 322, 323 Cefepime, for hospital-acquired Cephalosporins
human papillomavirus–associated,
pneumonia, 142t for chlamydia, 341
71-74 Cefixime for diverticulitis, 254t
Kaposi’s sarcoma, 322, 323 for endocarditis, 193-196,
liver, hepatitis B and, 68 for gonorrhea, 347-348, 348t
lung, cough in, 132f for sinusitis, 169, 169t 194t-196t
tongue, vs. blastomycosis, 228, for typhoid fever, 397, 397t for gonorrhea, 300, 347-348, 348t,
Cefotaxime
229f for diverticulitis, 254t 349
Candidiasis for gonorrhea, 347-348, 348t for Lyme disease, 433, 433t
for Lyme disease, 433, 433t for meningitis, 211
cutaneous, 107-108 for meningococcal disease, 25, 27 for meningococcal disease, 25, 26,
esophageal, HIV-related, 323 for typhoid fever, 397, 398t
oral, HIV-related, 321 Cefotetan, for chlamydia, 341 211
vaginal, 221, 305t, 306f Cefoxitin
for chlamydia, 341
differential diagnosis of, 363t for diverticulitis, 254t
Canker sores, 113 for gonorrhea, 347-348, 348t
Capreomycin, adverse effects of, 550t