TREATMENT APPROACHES 93
• There is severe toxaemia and bacteraemia • Reducing the duration of diarrhoea by 50% Treatment approaches
• The patient is unable to take oral medication • Reducing the duration of Vibrio excretion to one day
IV drugs of choice are ceftriaxone and ciprofloxacin. Recommended antibiotics are given orally when the
vomiting stops – doxycycline, ciprofloxacin, norfloxacin or
Campylobacter infection azithromycin. Antimicrobial resistance to tetracyclines is
reported to be increasing in some areas.
Campylobacter jejuni is the most commonly isolated
species. C. jejuni is a commensal of the gastro-intestinal Non-bacterial pathogens
tract of a wide range of animal hosts, including poultry,
cattle and sheep. Common sources of infection are un- Amoebiasis
dercooked meat, poultry and unpasteurised milk. Other
sources include occupational exposure of farmers and Entamoeba histolytica accounts for 40-50 million cas-
laboratory workers, via the perinatal route and blood es of colitis or extra-intestinal disease annually. About
transfusions. 40 000 deaths occur worldwide each year.
Campylobacter infection is self-limiting. This acute Transmission is by means of ingestion of amoebic cysts
illness is characterised by peri-umbilical abdominal via contaminated food and water. The parasite exists
cramps and diarrhoea, which may be bloody. Patients in two forms, cysts (infectious) and trophozoites (which
can also present with clinical manifestations mimicking cause invasive disease).
pseudo-appendicitis and colitis. Acute-onset compli-
cations include cholecystitis, peritonitis, pericarditis and The ingested cysts pass through the stomach to the
myocarditis. Late-onset complications include reactive small intestine where they excyst in the digestive sys-
arthritis and Guillian-Barré syndrome. The diagnosis of tem to form trophozoites. The trophozoites invade and
Campylobacter is established by stool culture. penetrate the mucous barrier of the colon, causing tis-
sue destruction, increased intestinal secretion and ulti-
Treatment mately bloody diarrhoea.
Fluid and electrolyte replacement should be the fo- About 90% of E. histolytica infections are asympto-
cus of therapy. Antibiotics are not necessary for most matic. Symptoms range from mild diarrhoea to severe
cases of C. jejuni gastro-enteritis. dysentery and fulminant amoebic colitis. Complications
include extra-intestinal infections, amoebic liver abscess
In patients with severe disease or at risk of severe dis- and amoeboma.
ease, such as the elderly, pregnant and immunocom-
promised patients, antibiotic therapy is warranted. Diagnosis is best accomplished by a combination of
serology or antigen testing with identification of para-
The first-line drugs of choice include azithromycin and sites in stool or intestinal sites (ALA).
ciprofloxacin. Erythromycin is no longer used as first-line • Stool microscopy – demonstration of cysts or tropho-
therapy due to its toxicity and potential interactions.
Resistance to macrolides, fluoroquinolones and tetracy- zoites suggests intestinal amoebiasis. A minimum of
clines, has been described worldwide and continues to three specimens on separate days detects 85-95% of
increase. infections.
• Serology – antibodies are detectable within five to
Cholera seven days of acute infection.
• Positive serology cannot distinguish between acute
Cholera is a vastly underreported disease. It is reported and previous infection and should be combined
to cause three- to five-million cases, with 100 000 deaths with stool microscopy.
annually. Cholera is endemic in Africa and Asia. • Negative serology is helpful for exclusion of disease.
• Antigen testing – sensitive, specific and rapid. Uses
Vibrio cholerae is transmitted via contaminated water monoclonal antibodies to detect E. histolytica de-
and food. The organisms pass through the acidic gastric rived Gal/GalNAC lectin in stool.
environment to colonise the small intestinal epithelium by
means of pili and haemagglutinins. Treatment
Following colonisation, V. cholerae produces the Antimicrobial therapy for E. histolytica infection is al-
cholera toxin, which activates cAMP in the intestinal ways advised, even in asymptomatic cases, due to the
mucosa, leading to increased chloride secretion and potential risk of developing invasive disease and spread
decreased sodium absorption. This produces a massive to family members. The goal of antimicrobial therapy is
fluid and electrolyte loss. Cholera is characterised by se- to eliminate the invading trophozoites and to eradicate
vere watery diarrhoea with flecks of mucus, “rice water intestinal carriage of the organism.
stools” and vomiting. Massive volume and electrolyte
losses can lead to metabolic acidosis. Laboratory diag- The treatment of choice is metronidazole or tinida-
nosis is by means of stool microscopy and culture. zole. A 10-day course of metronidazole eliminates intra-
luminal infection in many cases, but a second agent is
Treatment warranted, if available.
The mainstay of therapy is fluid and electrolyte replace- Giardiasis
ment. Antibiotics serve as an adjunct to appropriate re-
hydration and have two beneficial effects: Giardia lamblia/duodenalis/intestinalis causes epi-
demic and sporadic diarrhoea. The prevalence in the
developing world is around 20-30%. It occurs in areas
HANDBOOK OF GENERAL MEDICINE VOL 1
94 TREATMENT APPROACHES
with poor sanitary conditions and insufficient water- The T-lymphocytic response is important in controlling the
treatment facilities. infection, as evidenced by increased disease severity in HIV-
infected patients with CD4+ counts <100 cells/microL.
Transmission is via faecal-oral spread in contaminated
food and water. The parasite occurs in two forms; cyst Asymptomatic infections occur in 30% of all childhood
(infectious) and trophozoite. Following cyst ingestion, cryptosporidiosis. The symptoms include secretory diar-
excystation occurs in the proximal small bowel with the rhoea and malabsorption. Immunocompromised hosts
release of trophozoites. with CD4+ <100 cells/microL, have a more protracted
and severe disease. Extra-intestinal manifestations in
The pathogenesis of diarrhoea and malabsorption is AIDS patients include cholecystitis, cholangitis, hepatitis,
not fully understood. It is assumed to be a result of both pancreatitis and respiratory involvement.
intestinal malabsorption and hypersecretion.
The illness usually resolves without therapy in 10-14
Giardiasis has variable severity: days in immunologically healthy people and can persist
• 50% of those infected clear the infection in the ab- or relapse after initial therapy.
sence of clinical symptoms Diagnosis is by means of stool microscopy. Microscopy is
• 5-15% of those infected shed the cysts asymptomati- also performed on duodenal aspirates, bile secretions and
respiratory secretions. Modified acid-fast stains that stain
cally the oocysts from red to pink are used.
• 35-45% of those infected have symptomatic infection
Other examinations, such as histopathological exami-
Acute giardiasis presents with diarrhoea, steatorrhoea nation, serology and real-time PCR, can be done.
and weight loss.
Treatment
Initial diagnosis should consist of stool microscopy.
Giardia is excreted intermittently. Detection of 50-70% Immunologically healthy patients usually have a sponta-
is achieved with a single specimen and 90% detection neous recovery within a few weeks and parasitological
with three specimens. cure within a few months without any specific therapy.
Immuno-assays have greater sensitivity than stool Initiation of HAART for immune reconstitution is an
microscopy and can be used in circumstances where important part of therapy for HIV-infected patients.
microscopy cannot provide a definite diagnosis. Other Clinical resolution may occur, but it is unclear whether
tests are duodenal biopsy, serology and real-time PCR. organisms are completely eliminated. In patients with
cryptosporidiosis and HIV infection, the prognosis with-
Treatment out immune restoration is generally poor.
Fluid and electrolyte replacement and antimicrobial Blastocystis hominis infection
therapy are indicated for symptomatic patients only.
There is controversy regarding whether B. hominis rep-
Drugs of choice are metronidazole and tinidazole or al- resents a commensal or true pathogen. The estimated
bendazole as an alternative. prevalence is 30-50% in developing countries and 5-10%
in developed countries.
Recurrent diarrhoea following treatment may be due
to recurrent infection or antimicrobial resistance. Residu- The mode of transmission is not fully understood. Fae-
al lactose intolerance and other small bowel absorptive cal-oral transmission has been postulated.
deficiencies should be excluded.
Blastocystsis spp. are often found in association with
The options for treatment of recurrent disease include: other potential pathogens. The pathogenicity or the ef-
• Longer courses of the original drug, e.g. metronida- fect of specific therapy is not well understood and some
authors have suggested that Blastocystis spp. are more
zole for 10 days instead of five days likely to be pathogenic if more than five organisms per
• Higher dose of the original drug (not well studied in oil immersion field are detected.
children) Symptoms include watery diarrhoea, abdominal
• Using a combination regimen, e.g. albendazole plus cramps, bloating, flatulence, urticaria and fatigue.
Diagnosis is made by means of stool microscopy.
metronidazole
Treatment
Cryptosporidiosis
Blastocystis causes a self-limiting infection, with cases
Cryptosporidium parvum is described as a parasitic in- resolving within three days without any specific therapy.
fection causing diarrhoea and malnutrition in young Asymptomatic patients do not require treatment. Symp-
children in developing countries. It is a chronic, life- tomatic patients should have stool microscopy to ex-
threatening illness in immunocompromised patients, clude other potential pathogens. If no other pathogen
mainly those with HIV infection. Diarrhoeal infection, is identified, therapy for Blastocystis should be adminis-
usual self-limiting, is spread via faecal-oral contamina- tered with observation for a clinical response which
tion in countries with increased crowding and poor sani- may be due to elimination of Blastocystis or another
tation. undetected pathogen. Drugs of choice are metronida-
zole or co-trimoxazole.
The pathogenesis of C. parvum is not well understood.
Transmission occurs via spread from an infected person,
animal or from a faecally contaminated food or water
source. Ingestion of only a few (10-50) oocysts can lead
to severe disease, and persistent infection, particularly
in immunodeficient patients.
The immune response associated with cryptosporidi-
osis involves the cellular and humoral components.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 95
Antibiotic-associated diarrhoea Treat mild to moderate disease with metronidazole Treatment approaches
and severe disease with vancomycin.
Clostridium difficile
If there is no clinical improvement:
C. difficile is a causative agent of antibiotic-associated • Oral vancomycin
colitis. It is spread in hospital environments via hands, • Fidaxomicin (Fidicid) can be used in patients who
clothing, medical instruments, etc. The infection is ac-
quired through colonisation of the intestinal tract via the cannot tolerate vancomycin
faecal-oral route. The incidence of C. difficile-associated • Tigecycline IV 100 mg loading dose, then 50 mg
diarrhoea (CDAD) increased fourfold per 100 000 pa-
tients between 1991 and 2003. The incidence in individu- 12-hourly
als over 65 years increased 10-fold. Among hospitalised • Treat critically ill patients with fulminant or refractory
patients, the incidence increased from three to 12 per 1
000 patients between 1991 and 2002 to 25 to 43 per 1 000 disease with oral vancomycin plus metronidazole IV
patients during 2003 and 2004. Recurrence is defined by complete abatement of
C. difficile infection symptoms while on appropriate
In North America and Europe between 2003 and therapy, followed by subsequent reappearance of
2006, C. difficile infections were observed to be more diarrhoea after treatment has been stopped.
frequent, severe, refractory to standard therapy and Treat first recurrence or relapse with:
more prone to relapse (see Table 1). These were attrib- • Oral metronidazole or vancomycin
uted to the new hypervirulent strain designated NAP1/ • Alternative oral fidaxomycin
BI/027. Treat second recurrence or relapse as follows:
• Tapering or pulsed oral vancomycin therapy is rec-
Table1. Risk factors ommended
• Alternative oral fidaxomycin
• Antibiotics, clindamycin, fluoroquinolones, broad-spectrum
penicillins and cephalosporins Further reading
• Gastric acid suppression – proton pump inhibitors and 1. Majowicz SE, Musto J, Scallan E, et al. The global burden of non
histamine-2 receptor antagonists typhoidal Salmonella gastroenteritis. Clin Infect Dis. 2010;50:882.
• Cancer chemotherapies due to their antimicrobial effect 2. Kachrimanidou M, Malisiovas N. Clostridium difficile infection. Crit
on the GI tract Rev in Microbiology. 2011;37:178-187.
• GI surgery and haematopoietic stem-cell transplantation 3. Anilrudh A, Johnson S, et al. Current state of C. difficile treatment
options. Clin Infect Dis. 2012;55(Suppl2):S71-6.
C. difficile produces two potent exotoxins, toxins A and
B, that mediate colitis and diarrhoea. Toxin A is an en- 4. Gastrointestinal infections. www.uptodate.com. 2013.
terotoxin which causes inflammation leading to intestinal
fluid secretion and mucosal injury. Toxin B is a cytotoxin HANDBOOK OF GENERAL MEDICINE VOL 1
which mediates colonic mucosal damage. The toxins
bind to receptors on intestinal epithelial cells, leading to
inflammation and diarrhoea.
The hypervirulent strain, NAP1/BI/027, produces an ad-
ditional toxin, the binary toxin.
The spectrum of disease ranges from colitis to fulmi-
nant colitis and toxic megacolon. Cardinal symptoms
are watery diarrhoea with lower abdominal pain and
high fever. Leukocytosis (WBC >15 000/microL) is usually
a common clinical sign.
Laboratory diagnosis requires demonstration of C. dif-
ficile toxins or detection of toxigenic C. difficile organ-
ism. Real-time PCR detects toxin A and B genes and it is
highly sensitive and specific.
Other available tests:
• Enzyme immuno-assays (EIA) for toxins A and B
• EIA for C. difficile glutamate dehydro-genase
• Cell cytotoxicity assay and anaerobic culture
Treatment
The initial step in treating CDAD is cessation of the incit-
ing antibiotic. Treatment is indicated in patients who are
symptomatic and have a positive diagnostic test. Empiric
therapy can be administered pending the results of diag-
nostic testing if clinical suspicion is high. Treatment is not in-
dicated in asymptomatic patients with positive toxin assay.
96 TREATMENT APPROACHES
Chronic kidney disease: prevention,diagnosis
and management
B Rayner Screening
MBChB, FCP, MMed, PhD Symptoms of CKD usually only develop in stage 4 or
5. Given the high prevalence, opportunistic screening
Emeritus Professor, Division of Nephrology and Hypertension, needs to be undertaken in all patients. However, there
Department of Medicine, University of Cape Town, Cape Town are certain groups of patients that are considered at
higher risk and screening should be mandatory (see
About one in 10 people have chronic kidney disease Table 2).
(CKD), and in South Africa, there has been a 57% in-
crease in death due to kidney disease.1 This is mainly Screening is inexpensive. A urine dipstick together
driven by a burgeoning epidemic of chronic diseases with serum creatinine and calculated eGFR, will detect
of lifestyle, namely type 2 diabetes and hypertension, most people with CKD. Further testing may include ul-
and HIV-associated nephropathy (HIVAN). Currently, trasound, and/or a CT-scan of the kidneys in certain
approximately 10% and 40% of the adult population circumstances, e.g. a family history of polycystic kidney
have diabetes and hypertension respectively, and disease.
there are 6.8 million people living with HIV at risk of de-
veloping HIVAN. The intersection of HIV and chronic dis- Table 2. Risk factors for CKD
ease of lifestyle multiplies the risk of CKD.2
Risk factors for CKD
Patients with CKD are at very high risk for cardio- Family history, e.g. polycystic kidney disease
vascular disease (CVD),3 and patients with CVD are Diabetes
at risk for CKD. This means patients with CKD must be Hypertension
evaluated for CVD, and vice versa. It is important to Obesity
note that most patients with CKD die of CVD before HIV-positive
reaching end-stage, and it is essential to focus on both Regular NSAIDs/analgesics
managing the underlying CKD, as well as implementing Recurrent UTI (reflux)
aggressive strategies to prevent CVD. Kidney stones
Increasing age (>65 years)
This overview of CKD is limited in its scope and pre- Vascular disease
sents the key elements of prevention, diagnosis and
management. Causes and diagnosis
Definition The commonest causes of CKD in South Africa are listed
in Table 3, with hypertension and diabetes being the
Chronic kidney disease is currently defined in terms of the most common identifiable causes.5 Unfortunately, the
estimated glomerular filtration rate (eGFR) that is calcu- very late presentation of many patients with end-stage
lated from the serum creatinine and adjusted for age, sex CKD makes causation challenging to assign. Further-
and race of the patient.4 Table 1 shows the stages of CKD. more, these data reflect patients accepted onto dialy-
sis in South Africa, and because of selection criteria in
CKD may occur in stages 1 and 2 if there are urine the public sector, there is under-reporting of diabetes
abnormalities (haematuria/proteinuria) or changes in and HIVAN.6
structure, e.g. cysts or scars. However, in practice, CKD
is considered significant if there is a persistent reduction Table 3. Most commonly reported causes of end-stage
in eGFR <60 ml/min over three months. There are cer- CKD in South Africa
tain provisos in interpreting the eGFR. The kidney func-
tion must be stable, and creatinine-based eGFRs may Cause % of the total
be inaccurate; for example, if there is severe wasting or Hypertensive kidney disease 34.7
muscle inflammation. If there is concern about the ac- Cause unknown 32.4
curacy of the eGFR, 24-hour urine for creatinine clear- Diabetic kidney disease 15.2
ance or an isotope-based GFR is recommended. Glomerular disease 9.9
Cystic kidney disease 3.0
Table 1. Stages of CKD Obstruction and reflux 1.7
Stage Description eGFR (ml/ Prevention of CKD
min/1.73m2)
1 Kidney damage with normal A healthy lifestyle is one of the most important aspects
function ≥90 of preventing CKD. This includes, but is not limited to,
2 regular exercise, cessation of smoking, low salt intake,
3a Kidney damage with mild ¯ in GFR 60-89
3b Moderate ¯ in GFR 45-59
4 Moderate ¯ in GFR 30-44
5 Severe ¯ in GFR 15-29
Kidney failure <15
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 97
fresh fruit and vegetables, reduction of refined carbo- also been shown to prevent progression of nephropa- Treatment approaches
hydrate and saturated fats, and weight loss. thy, as well as preventing heart failure in diabetics, and
should be considered an adjunct to ACE inhibitors/ARBs
The practitioner should be actively screening pa- in patients with diabetic kidney disease provided eGFR
tients for hypertension and diabetes, which should be is >30 ml/min.7
managed appropriately according to local guidelines.
Patients should be encouraged to be tested for HIV. If The SA Hypertension Practice Guidelines recommend
positive, treat with antiretrovirals as this prevents the de- a blood pressure target of <140/90 mmHg, while other
velopment of HIVAN. guidelines suggest a lower target of <130/80 mmHg.8,9
Hypertension is difficult to control in patients with CKD,
Nephrotoxic drugs should be avoided, or carefully and patients often require more than three different
monitored if medically indicated. For example, patients classes of antihypertensives. BP in CKD is driven by
receiving long-term tenofovir for HIV, proton pump inhi- three key elements – activation of the renin-angioten-
bitors for reflux, or lithium for bipolar disorders should sin system and sympathetic nervous system combined
have their kidney function tested at baseline and regu- with salt and water overload. The choice of antihyper-
larly after that. tensive therapy is directed at controlling these three
pathophysiological processes. ACEi/ARBs are often the
However, in the author’s experience, the major prob- backbone of therapy, then diuretics, calcium-channel
lem is often the use or abuse of NSAIDs and other anal- blockers and ß- and a-blockers should be considered.
gesics. In over 35 years of assessing a patient with CKD, Regarding diuretics, thiazide and thiazide-like diure-
two critical scenarios occur time and again. Firstly, pa- tics are less effective if eGFR <45 ml/min and should be
tients with chronic gout receive regular NSAIDs without substituted with loop diuretics often in high doses – for
addressing and treating the underlying causes of hyper- example, furosemide 40 mg twice daily, increasing to
uricaemia. Secondly, patients with severe hypertension 240 mg twice daily in advanced CKD.
often take regular NSAIDs to relieve their headaches,
rather than taking their antihypertensives to control their For CVD protection, the LDL cholesterol needs to be
blood pressure (BP). NSAIDs in the context of a weak <1.8 mmol/L, and with statins and/or ezetimibe.10 Aspirin
kidney are particularly harmful. is not routinely advised unless for secondary CVD pro-
tection.
Management of CKD
Diet
Ideally, a specialist should evaluate all patients with
CKD, but this is not always possible, given the critical With advancing CKD, especially CKD 4 and 5, it is impor-
shortage of nephrologists in South Africa. However, tant to involve a specialist dietician in the management
once the patient has CKD 3b, referral is strongly rec- of patients. Briefly, there is a need to restrict phosphate,
ommended. Referral should also be considered if the Na+ and K+ intake, and eat adequate but good-quality
cause of CKD is uncertain, there is significant proteinuria protein to prevent malnutrition (commonly seen due to
(see the chapter on proteinuria), and there is a progres- nausea-induced loss of appetite).
sion of CKD.
Although the majority of patients with CKD require
Prevention of progression and CVD protection strict Na+ restriction to control BP and prevent fluid over-
load, a small percentage of patients are salt-wasting
Preventing the progression of CKD is of vital importance. and require liberalisation of Na+ intake. These patients
The economic cost of treating end-stage CKD is exorbi- usually have BPs that are <120/80 mmHg and are not on
tant and many state patients do not receive life-saving any antihypertensives.
dialysis. It is essential to understand that even slowing
progression by 5 ml/year can lead to >10 years of dial- Anaemia
ysis-free life.
Patients with CKD commonly have anaemia, and this
The patient with CKD must focus on a healthy lifestyle is due to a combination of erythropoietin deficiency
and avoid taking NSAIDs and other nephrotoxic drugs. and relative Fe++ deficiency. Others causes include B12/
Paracetamol and tramadol are the safest drugs to use folate deficiency, chronic blood loss due to uraemic
for pain relief, but paracetamol is not without any risk. gastritis and chronic inflammation. Correcting anaemia
ACE inhibitors (ACEi) and angiotensin receptor block- can significantly improve wellbeing.
ers (ARB) prevent progression of CKD, especially if pro-
teinuria is present. After instituting either an ACEi or ARB, If anaemia is suspected, a full blood count with per-
kidney function and K+ need to be checked within a centage hypochromasia, ferritin and Fe++ saturation,
week in case there is a sudden deterioration in kidney should be ordered. Administer B12 and folate in the first
function due to undiagnosed renal artery stenosis or de- instance. In CKD Fe++ deficiency is defined differently
velopment of hyperkalaemia. However, up to 20% re- due to suppression of its availability. Ideally, the ferritin
duction may occur after starting these drugs and should should be >200 µgm/L and saturation >20%. The per-
not prompt cessation of therapy. Hyperkalaemia is a centage of hypochromic red cells >6% is also indicative.
particular issue in diabetic kidney disease and may ne- Fe++ should be supplemented orally in the first instance
cessitate stopping the ACEi/ARB, but increasingly neph- to achieve these targets, but invariably intravenous
rologists are using ion exchange resins, such as sodium Fe++ is required. If the Hb remains below 10 gm % after
polystyrene sulfonate, in low doses, e.g., 15 gm three achieving the Fe++ targets and no other cause is identi-
times per week to control the K+. SGLUT2 inhibitors have fied for the anaemia, then erythropoietin is usually pre-
HANDBOOK OF GENERAL MEDICINE VOL 1
98 TREATMENT APPROACHES
scribed to achieve a target of 10-12 gm %. The normali- Depression
sation of the Hb with erythropoietin, especially with high
doses, may increase the risk of CV events.11 Mental illness, especially depression, is common in pa-
tients with CKD, and this should be assessed from time to
Bone health time, and appropriate treatment instituted.
In advanced CKD, the kidney has a limited ability to Preparation for dialysis
excrete phosphate, and there is reduced conversion and transplantation
of cholecalciferol to active vitamin D in the kidney, re-
ducing calcium absorption and mineralisation of bone. It is crucial that patients with advanced CKD be re-
The net effect is increased phosphate and low calcium ferred to a nephrologist before reaching the end stage.
that stimulates parathyroid hormone (PTH) (and FGF- This should ideally occur at CKD stage 3b, but is man-
23) to promote excretion of phosphate and mobilise datory at stage 4. Patients presenting with end-stage
Ca++ from bone. This results in secondary hyperparathy- CKD requiring urgent dialysis have a poorer prognosis,
roidism and, combined with vitamin D deficiency, caus- with excess mortality in the first year. Early referral often
es renal osteodystrophy and increased CV events. This leads to delayed progression of CKD and enables plan-
usually becomes a clinically relevant issue at CKD stage ning – for example, the timeous insertion of a Tenchkoff
3b, and it is necessary to monitor Ca++, phosphate, alka- catheter for peritoneal dialysis or the creation of an A-V
line phosphatase, and PTH. Treatment is to reduce phos- fistula for haemodialysis. In some circumstances, a pre-
phate intake, the use of phosphate binders (e.g., cal- emptive live-related or live-unrelated transplant can
cium carbonate 1-2 tablets with meals, or sevelamer) be performed before starting dialysis. In the frail elderly,
and initially use cholecalciferol 50 000 units weekly. If conservative treatment may be strongly considered
secondary hyperparathyroidism is not controlled, active as dialysis has not been shown to prolong life. All these
vitamin D can be used (alfacalcidol at an initial dose of complex issues need to be discussed with the patient
0.25 µgm) and in severe cases a calcimimetic (cinacal- and family so that an informed choice can be made.
cet at an initial dose of 30 mg daily). Parathyroidectomy
must also be considered in the late phases where the Conclusion
glands are autonomous, and both calcium and phos-
phate are elevated. There is a high risk of vascular cal- CKD is a common problem affecting about 10% of the
cification that may be fatal. population. Early recognition and treatment can delay
and prevent the progression of the disease and adverse
Acidosis cardiovascular outcomes, which have significant impli-
cations for the health of the individual and economic
The kidney plays the principal role in the maintenance of implications for healthcare providers. Detection and
acid-base balance, and in CKD stages 4 and 5 metabol- prevention should be managed by primary care prac-
ic acidosis may develop due to failure to excrete H+ ions. titioners, but with advancing CKD, especially stages 3b
The acidosis can be associated with muscle-wasting, and beyond, management is increasingly complex and
bone disease, hypo-albuminaemia, inflammation, the these patients need to be referred to nephrologists or
progression of CKD, and increased mortality. Adminis- specialist physicians.
tration of Na+ bicarbonate, if bicarbonate concentration
is <22 mmol/L, may decrease muscle-wasting, improve References
bone disease, and slow the progression of CKD. How-
ever, if the serum bicarbonate concentration exceeds 1. Mayosi BM, Fisher AJ, Lalloo UG, et al. The burden of non-communi-
24 mmol/L, this might be associated with the exacerba- cable diseases in South Africa. Lancet. 2009; 374: 934-947.
tion of cardiovascular disease. If acidosis is corrected, it
must be done cautiously with careful monitoring. 2. Ekrikpo UE, Kengne AP, Bello AK, et al. Chronic kidney disease in
the global adult HIV-infected population: a systematic review and
Drugs and the kidney meta-analysis. PLoS One. 2018;13(4):e0195443.
The kidney excretes many drugs, and if a drug and its 3. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van
metabolites are excreted by the kidney, dose modifi- der Velde M, Astor BC, et al. Association of estimated glomerular
cation needs to be undertaken, based on the stage of filtration rate and albuminuria with all-cause and cardiovascular
CKD. This is especially important for drugs with a narrow mortality in general population cohorts: A collaborative meta-anal-
therapeutic/toxic index. Monitoring of drug levels may ysis. Lancet. 2010;375(9731):2073-81.
be necessary (e.g. aminoglycosides, lithium). Patients
should avoid nephrotoxic drugs wherever possible. 4. Levin A, Stevens PE. Summary of KDIGO 2012 CKD Guideline: Be-
NSAIDs are a significant problem, causing progression of hind the scenes need for guidance, and a framework for moving
CKD, the increase of salt and water excretion resulting forward. Kidney Int. 2014 Jan;85(1):49-61.
in uncontrolled BP and risk of heart failure, and danger-
ously high K+ levels. Over-the-counter herbal medica- 5. Davids MR, Jardine T, Marais N, Jacobs JC. South African Renal
tions should be avoided as they often contain multiple, Registry Annual Report 2016. http://sa-renalsociety.org/.
active components with unknown pharmacokinetic
data or toxicity studies. 6. Kilonzo KG, Jones ESW, Okpechi IG, et al. Disparities in dialy-
sis allocation: An audit from the new South Africa. PloS One.
HANDBOOK OF GENERAL MEDICINE VOL 1 2017;12:e0176041.
7. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progres-
sion of kidney disease in type 2 diabetes. New England Journal of
Medicine. 2016;375(4):323-34.
8. Seedat YK, Rayner BL, Veriava Y. South African hypertension practice
guideline 2014. Cardiovascular Journal of Africa. 2014;25(6):288-94.
9. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the
prevention, detection, evaluation, and management of high
blood pressure in adults: A report of the American College of Car-
diology/American Heart Association Task Force on Clinical Practice
Guidelines. Hypertension. 2017.
TREATMENT APPROACHES 99
10. Klug E, Raal FJ, Marais AD, et al. South African dyslipidaemia guide- Treatment approaches
line consensus statement: 2018 update. A joint statement from
the South African Heart Association (SA Heart) and the Lipid and
Atherosclerosis Society of Southern Africa (LASSA). S Afr Med J.
2018;108(11b):973-1000.
11. Mc Causland FR, Claggett B, Burdmann EA, et al. Treatment
of anemia with darbepoetin before dialysis initiation and clini-
cal outcomes: Analyses from the trial to reduce cardiovascular
events with aranesp therapy (TREAT). Am J Kidney Dis. 2018;S0272-
6386(18):31087-4.
HANDBOOK OF GENERAL MEDICINE VOL 1
100 TREATMENT APPROACHES
Proteinuria – what does it mean?
B Rayner phritis and should prompt further evaluation and refer-
ral. Standard dipsticks do not detect micro-albuminuria
MBChB, FCP, MMed, PhD or small quantities of albumin.
Emeritus Professor
Because the level of albumin detection by dipstick is
Division of Nephrology and Hypertension, Department concentration-dependent, the level of positivity may
of Medicine, University of Cape Town, Cape Town be affected by this. For example, concentrated urine in-
creases the positivity of the dipstick, while conversely, di-
Proteinuria or albuminuria is an inexpensive tool for luted urine reduces it. In the past, one used 24-hour urine
the evaluation of both the cardiovascular and renal to quantitate proteinuria, but this was abandoned due to
systems. It is a cardinal sign of kidney disease and pro- impracticability and substituted for the albumin- or pro-
gressive kidney damage, and cardiovascular mortality, tein-to-creatinine ratio that uses the creatinine to correct
stroke and heart attack.1 It has even been touted to re- for the concentration of albumin/protein in the urine. Both
place cholesterol as a marker for people at high cardio- are highly predictive of the 24-hour urine estimation. Test-
vascular risk. The presence of albuminuria, even in very ing should preferably be done on the first voided speci-
small quantities (micro-albuminuria), signifies a patient men in the morning to standardise the result, as posture
with silent, but modifiable, risks. Opportunistic screen- may affect albuminuria. Testing should be deferred in the
ing with a simple dipstick test should be undertaken at case of recent strenuous exercise or an urinary tract infec-
every consultation, as well as determination of the uri- tion. Ideally, at least three specimens obtained on sepa-
nary albumin/creatinine ratio in patients at high risk for rate occasions are needed, and two positives out of three
both cardiovascular and kidney disease, along with the confirm the presence of albuminuria. Table 1 details the
estimated glomerular filtration rate (eGFR), and staging classification of albumin-to-creatine ratio (ACR).
of chronic kidney disease.
In general, the albumin-to-creatinine ratio (ACR) is pre-
Understanding urine-testing ferred over the protein-to-creatinine ratio (PCR); it is more
sensitive and accurate as it does not detect other pro-
The kidney is composed of millions of glomeruli that fil- teins in the urine. The reader should be aware that the
ter the urine, allowing electrolytes, urea, creatinine and ACR is unfortunately reported in different units by South
other wastes to pass freely through, but at the same African laboratories, namely mgm/mmol and mgm/gm,
time forming a barrier to albumin, immunoglobulins, and and this is a cause of significant confusion. In this article,
red cells. It is composed of multiple capillary loops that the ACR is reported in mgm/mmol (to convert to mgm/
are lined by endothelial cells, supported by a basement gm, multiply by 10). The PCR is a cheaper test to perform
membrane and podocytes. Any disease affecting the and often used by nephrologists when the patient pre-
endothelium, basement membrane or podocyte may sents with high levels of proteinuria. Occasionally, a pa-
allow leakage of albumin (as well as bigger molecules tient may have a very high PCR with minimal albumin on
like globulin and/or red cells) into the urine. dipstick or ACR. This is a clue to the presence of monoclo-
nal gammopathy or myeloma as light chains (globulin)
A dipstick test can detect both albumin and blood in are freely filtered by the glomerulus.
the urine. It is usually quantified as absent, 1+, 2+ and
3+. The presence of albumin in the urine is almost al- Interpreting the ACR
ways abnormal and indicative of kidney disease, and
a patient at high cardiovascular risk. Albuminuria and The prevalence of micro-albuminuria and macro-albu-
haematuria are suggestive of underlying glomerulone- minuria is 8.36% and 1.68% of the population respec-
Table 1. Interpretation of the ACR according to level
Stage Level (mg/mmol)* Dipsticks& Common causes Response
Normal <3 Negative - -
Micro-albuminuria 3-30 Negative/trace DM, HT, ED Manage CV risk, ACEi/ARB for DM
Macro-albuminuria
Mild 30-70 +# DM, HT, GN, other Consider referral, manage CV risk,
ACEi/ARB
Moderate 70-200 ++# DM, GN, HIVAN, Refer
other
Severe >200 +++# DM, GN, HIVAN, Refer
other
* – for mgm/gm, multiply by 10; & – the presence of albuminuria and haematuria is suggestive of GN or other kidney diseases; # – estimated result,
DM – diabetes mellitus, HT – hypertension, HIVAN – HIV-associated nephropathy, GN – glomerulonephritis, ACEi – ACE inhibitor, ARB – angiotensin
receptor blocker
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 101
tively,2 and given the high prevalence, sensitivity and gan damage, such as left ventricular hypertrophy and in Treatment approaches
specificity of the test, makes it an ideal screening tool diabetic incipient kidney disease.
in patients with diabetes, hypertension, high cardio- The detection of micro-albuminuria should instigate a full
vascular risk, and kidney-disease risk. The interpretation assessment of the patient for cardiovascular risk (for ex-
of the ACR should always be considered in conjunction ample, screening for hypertension, diabetes and dyslipi-
with the level of albuminuria (see Table 1) and eGFR daemia) and underlying kidney disease. The majority of
(see Figure 1).3 Any patient in the red or yellow zones in patients will have a normal renal function, but in a small
Figure 1 or with moderate to high levels of albuminuria percentage, the eGFR will be below 60 ml/min, and this
(Table 1) should ideally be referred to a nephrologist or should prompt referral to a specialist (see Figure 1).
specialist physician.
In those with normal kidney function, the general prac-
Micro-albuminuria titioner should focus on prevention of cardiovascular risk
through lifestyle changes, especially stopping smoking
Micro-albuminuria is the presence of small quantities of and pharmacological treatment. The BP should be tar-
albumin in the urine – usually below standard dipstick de- geted to <140/90 mmHg, according to the South Afri-
tection. It represents leakage of albumin into the urine as can Hypertension Guidelines.7 Other guidelines suggest
a result of endothelial dysfunction in the glomerulus, but <130/80 mmHg, if well tolerated.8 ACEi/ARBs are the
it is now recognised as a marker of generalised endothe- preferred drugs of choice, but in diabetics ACEi/ARBs
lial dysfunction and CV risk. For example, in the HOPE are compelling indications for treatment as they pre-
study which included people >55 years, with a history of vent both progression of diabetic kidney disease, and
cardiovascular disease or diabetes with one other risk lower cardiovascular events and mortality (especially
factor, micro-albuminuria was present in 32.6% of those with ACEi). The LDL cholesterol should be targeted to
with diabetes and 14.8% in those without at baseline.4 <1.8 mmol/L with the use of statins, according to the
Micro-albuminuria was associated with a doubling of South Africa Lipid Guidelines.9 Diabetic control needs to
mortality in all groups, and an 83% increase for the risk be optimised, according to the Society for Endocrinol-
of myocardial infarction, stroke and heart failure.5 Treat- ogy Metabolism Diabetes of South Africa Guidelines10
ment with the ACE inhibitor ramipril resulted in a signifi- and consideration given to SGLUT-2 inhibitors that are
cant reduction in cardiovascular events and mortality, now shown to prevent progression of chronic kidney dis-
particularly in the micro-albuminuria group.6 Furthermore, ease in diabetics.11
a meta-analysis of 21 studies done in the general popu-
lation showed a linear relationship between albuminuria The ACR should be monitored, and if normalised, it is
and cardiovascular mortality.1 The reason for this relation- associated with improvement in both renal and cardio-
ship is probably the association of micro-albuminuria with vascular outcomes. If the ACR increases despite these
major cardiovascular risk factors – smoking, hypertension, measures, a referral is warranted.
diabetes, dyslipidaemia and high-sensitivity CRP. Within
the hypertensive population, it is a predictor of target or- Macro-albuminuria
Persistent albuminuria categories Macro-albuminuria has been defined as an ACR
Description and range >30 mgm/mmol and defines the presence of overt kid-
ney disease. The author has arbitrarily classified macro-
A1 A2 A3 albuminuria into mild (30-70 mgm/mmol), moderate
(70-200 mgm/mmol) and severe (>200 mgm/mmol)
Normal to Moderately Severely (see Table 1). Common causes of kidney disease in rela-
mildly increased increased tion to albuminuria are shown in Table 1. Patients with
severe macro-albuminuria are also likely to have under-
increased lying nephrotic syndrome, i.e. the additional presence
of oedema, high cholesterol and hypo-albuminaemia.
ACR* ACR* ACR*
<30 mg/g These patients are at even higher risk of progression
30–300 mg/g >300 mg/g of kidney disease and cardiovascular events. The ap-
<3mg/mmol proach is very similar to that described under micro-
3–30 mg/mmol >30 mg/mmol albuminuria. ACEi/ARBs are mandatory to lower albu-
minuria and prevent the progression of kidney disease
G1 Normal or high ≥90 unless contra-indicated. SGLUT-2 inhibitors should also
be considered in diabetics unless the eGFR is <30 ml/min.
per G2 Mildly decreased 60 –89 Cardiovascular protection should focus on lifestyle
range changes, lowering BP and LDL cholesterol to target and
optimise diabetic control.
1e.G73F2Rm2)ca-tedegsorciriepsti(omln/amindn G3a Mildly to moderately 45–59 Refer
decreased Refer All patients with moderate to severe macro-albuminuria
should be referred for specialist treatment. Patients with
G3b Moderately to 30–44 Refer Refer mild macro-albuminuria can be handled by experienced
severely Refer general practitioners as outlined, but if the eGFR is <60 ml/
decreased Refer min, referral is recommended for further evaluation.
Refer
G4 Severely 15–29 Refer HANDBOOK OF GENERAL MEDICINE VOL 1
Refer
decreased
G5 Kidney failure <15
Green – low risk (if no other markers of kidney disease, no CKD); yellow –
moderately increased risk; orange – high risk; red – very high risk; A1, A2,
A3 – categories of albuminuria; G1, G2, G3a, G3b, G4, G5 – categories
of eGFR.
Adapted from Levin A, Stevens PE. Summary of KDIGO 2012 CKD Guide-
line: Behind the scenes, need for guidance, and a framework for mov-
ing forward. Kidney Int. 2014 Jan;85(1):49-61.
Figure 1. Assessing risk and referral in relation to ACR
and eGFR
102 TREATMENT APPROACHES
Summary
The presence of albuminuria signifies a patient with silent
but modifiable risk factors for chronic kidney disease and
cardiovascular risk. All patients should undergo oppor-
tunistic dipstick-testing of their urine for detection of
overt albuminuria, and if positive, should have an ACR
and eGFR performed. Further investigation, manage-
ment and referral will depend on the level of ACR and
eGFR. Patients with high cardiovascular risk, signified by
the presence of hypertension, diabetes, dyslipidaemia,
smoking or overt cardiovascular disease, should under-
go an ACR for detection of micro-albuminuria to detect
a major additional risk factor for cardiovascular mortal-
ity, myocardial infarction, stroke and heart failure, and
chronic kidney disease in diabetics. Aggressive cardio-
vascular risk protection should be undertaken.
REFERENCES
1. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van
der Velde M, Astor BC, Woodward M, et al. Association of esti-
mated glomerular filtration rate and albuminuria with all-cause and
cardiovascular mortality in general population cohorts: A collabo-
rative meta-analysis. Lancet. 2010; 375(9731):2073-81.
2. Centers for Disease Control and Prevention. Chronic Kidney Dis-
ease Surveillance System – United States. website. http://www.cdc.
gov/ckd
3. Levin A, Stevens PE. Summary of KDIGO 2012 CKD Guideline: Be-
hind the scenes, need for guidance, and a framework for moving
forward. Kidney Int. 2014 Jan;85(1):49-61.
4. Gerstein HC, Mann JF, Yi Q, Zinman B, et al. HOPE Study investiga-
tors. Albuminuria and risk of cardiovascular events, death, and
heart failure in diabetic and nondiabetic individuals. JAMA. 2001;
25;286(4):421-6.
5. Yusuf S, Sleight P, et al. Heart Outcomes Prevention Evaluation
Study investigators. N Engl J Med. 2000 Jan;342(3):145-53.
6. Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. N Engl J Med. 2000; 342(3):145-53
7. Seedat YK, Rayner BL, Veriava Y. South African hypertension practice
guideline 2014. Cardiovascular Journal of Africa. 2014;25(6):288-94.
8. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Den-
nison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/
APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detec-
tion, evaluation, and management of high blood pressure in adults:
A report of the American College of Cardiology/American Heart
Association task force on clinical practice guidelines. Hypertension.
2017.
9. Klug E, Raal FJ, Marais AD, Smuts CM, et al. South African dyslipidae-
mia guideline consensus statement: 2018 update. A joint statement
from the South African Heart Association (SA Heart) and the Lipid
and Atherosclerosis Society of Southern Africa (LASSA). S Afr Med J.
2018;108(11b):973-1000.
10. SEMDSA 2017 Guidelines for the Management of Type 2 diabetes
mellitus. JEMDSA 2017;22:S1-S192
11. Wanner C, Lachin JM, Inzucchi SE, Fitchett D, et al. EMPA-REG OUT-
COME investigators. Empagliflozin and clinical outcomes in patients
with type 2 diabetes mellitus, established cardiovascular disease,
and chronic kidney disease. Circulation. 2018;137(2):119-129.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 103
Management of chronic daily headaches Treatment approaches
EB Lee Pan to the different headache conditions.1-4 This second
phase is important as appropriate management of the
MBChB MMed Neurology (Stellenbosch) episodic form of headaches will help prevent relapse
into the chronic daily headaches form.
Neurologist and ICT Clinical Consultant;
Acting Head of Department of Neurology, Table 1. Chronic daily headache (long-duration)
Groote Schuur Hospital, Cape Town criteria and types
Some primary headaches have both an episodic and a >= 15 headache days/month
chronic form. This applies to the two commonest head-
aches, i.e. tension-type headaches and migraines, as >= 4 hours >= 3 months
well as to headaches less frequently seen, such as prima-
ry stabbing headaches or paroxysmal haemicrania.1-4 Plus features of the headaches below:
Other primary headaches are by nature only chronic,
such as haemicrania continua or new daily persistent • Chronic tension-type headache (CTTH)
headaches (NDPH). Chronic daily headaches are also
separated into short (<4 hours) – or long (>4 hours) – • Chronic migraine (CM)
duration types.1-4 However, the chronic, short-duration
types (e.g. cluster or stabbing type) are rare and do not • Medication-overuse headache (MOH)
form part of this paper. This article aims to focus on the
common chronic headache types, often grouped as • (Haemicrania continua)
chronic daily headaches (CDH).1-4
• (New daily persistent headache)
Secondary headaches, such as medication-overuse
headaches or post-traumatic headaches, may also Many patients with episodic tension-type headaches
present as chronic headaches. Note that other second- and migraine do not present to medical services as they
ary chronic headaches, such as idiopathic intracranial cope with self-medication and home remedies. The es-
hypertension, are not included in chronic daily head- calating and disabling nature of chronic daily head-
aches. To make things more complicated, patients aches makes the patient more likely to seek medical
with chronic daily headaches may have more than attention. Medical services may not optimally manage
one underlying type of headache. For example, many these patients, and if they do not resolve the chronic
patients with migraines also have tension-type head- daily headache, patients continue to suffer. They keep
aches; or patients with post-traumatic headaches may looking for solutions and may seek alternative remedies
also develop medication-overuse headaches.1-4 Apart and move to different practitioners. For the practising
from medication-overuse headache, it is unlikely that a clinician, the general practitioner’s surgery is often the
patient will have multiple other types of chronic head- first point of contact. Therefore, it is essential for GPs to
ache at the same time.4 be able to recognise and manage this scenario.
Chronic daily headache is not a part of the current Prevalence
classification of headaches (International Headache
Society) as it is not one specific condition. It does, how- Most studies place the prevalence of CDH at about
ever, remain a handy descriptive term covering several 3-5% of the general population, with women about
different types of headaches as described above, the double that at 8-9%.1,4,7 Studies in Africa are limited, but
commonest of which are: chronic tension-type head- go as low as 1.7%.5 These figures are study-dependent
ache (CTTH), chronic migraine (CM) and medication- and therefore also country- and population-linked.
overuse headache (MOH).1-4 Chronic migraine is also Looking at the prevalence of the most frequent causes
known as “transformed migraine” to highlight how it dif- of chronic daily headache, tension-type and migraine
fers from episodic migraine.1 Chronic daily headache is headache are listed as the second and third most prev-
commonly defined as a headache occurring >=15 days alent medical conditions, after dental caries. However,
of the month, for at least three months (see Table 1) as stated, not all these patients go on to chronic forms,
and lasting four hours or longer, although many will last but the prevalence of chronic tension-type and chronic
much longer.1,2,3,4 This practical term allows clinicians to migraine headaches is nevertheless very high. Chronic
manage a group of disorders without having to tease migraine has been estimated as affecting as much as
out a specific headache disorder, although this will be- 2% of the world’s population.6
come useful as the chronic daily headache recedes.
Fortunately, the chronic daily headaches comprising Around 40% of patients attending a specialised head-
the group have been studied together, and most of the ache clinic meet chronic daily headache diagnostic
different subtypes can be managed with the same prin- criteria, of which the majority (80%) are women. In some
ciples. Later, more specific treatments can be applied of these clinics, about 60% of patients suffer from CM,
20% from CTTH, and up to 20% may meet NDPH crite-
ria. Most (80% in some clinics) of these patients, overuse
symptomatic medications. MOH can involve 50-80% of
tertiary headache-clinic patients.3 Note that population
studies cannot be generalised from headache clinics,
HANDBOOK OF GENERAL MEDICINE VOL 1
104 TREATMENT APPROACHES
and these percentages cannot be extrapolated to the Pathophysiology
general population.
Since CDH is not a disease entity, pathophysiology of the
Regarding the prevalence of other, long-duration, underlying disorders and their chronic versions has been
CDH subtypes, NDPH is rare (0.1%), whereas the prev- the focus of studies. However, the exact mechanisms
alence of CM (1.5-2%) and CTTH (2.5-3%) is higher.7 In remain elusive.9 CTTH is thought to be secondary to a
contrast to data from specialised clinics, only around a separate (from an episodic tension-type headache),
quarter to a third of CDH subjects in the general popu- central, sensitisation process which leads to a reduction
lation overuse analgesics; CDH subjects with analgesic in pain inhibition.3,9 Although there is far more research
overuse comprise 1.1% to 1.9% of the general popula- in CM, a similar increased cortical excitability has been
tion.7 Apart from the general population and head- proposed.3 Again, this is different from the mechanisms
ache clinics, emergency units also see a fair share of in episodic migraine and explains why both chronic
headache patients, with figures of 1-3% of all visits being conditions can be treated in similar ways. Importantly,
due to headaches.8 clinicians should understand that chronic headache
is a pathophysiological state and not a psychological
No local prevalence data are accessible, but 26% of all one. Migraine also has a well-established genetic com-
neurology referrals to Groote Schuur hospital (a tertiary ponent, as well as environmental influences, whereas in
academic hospital in Cape Town) in 2014 were for head- CTTH the genetic influence is less clear.10 However, the
aches, most of which were CDH (unpublished data). genetics of the chronic versions are not well studied,
and may still be a possible factor.
Impact on society
Management
Studies of the impact of CDH on society are limited,
but there is extensive documentation of the effects of Diagnosing headaches and the chronic daily head-
migraine and chronic migraine on patient health, the ache is not difficult, but require a minimum skill set (see
economy and the work environment. The high frequen- Table 2). The first is sufficient time. The nature of head-
cy of migraine and tension-type headaches and their aches delivers patients who are keen to talk – mostly
impact on society will be mirrored by their chronic ver- about how bad their current headaches are, what rem-
sions, although separating the individual influences of edies they have tried and what concerns them. Unrav-
the components of these headaches is not always pos- elling this requires experience and skill, but even then, it
sible. Migraine on its own is ranked 19th by the World can often only be achieved with sufficient time. By con-
Health Organization as a cause of “years lived with disa- trast, while a comprehensive neurological screening is
bility”.3 CDH patients are particularly vulnerable to MOH important, it can be completed in about five minutes.
and consume large quantities of analgesics which have The overall time for a consultation is likely to be in the or-
no health benefits. If not correctly managed, they also der of 30 minutes, with a range of 20 to 40 minutes and
repeatedly access of healthcare workers and services many times, even longer. The neurological screening
without any benefit. must include a rapid, confident, fundoscopic examina-
tion. Examination of the head and neck is essential, and
Diagnostic issues cranial nerves cannot be skipped. The motor examina-
tion should include power, reflexes and gaits, and sen-
Headaches are diagnosed on a clinical basis, with sory examination can be downgraded, but not entirely
the history being adequate for most primary head- omitted either. Co-ordination should also be included.4
aches.1-4 The challenge is to extract the relevant de-
tails from the history, which is often layered with many Table 2. Clinical skills for managing headache patients
distracting features which the patient feels are more
important. Table 1 shows the simple criteria for CDH, Tight time management
and since migraine and tension-type headache are
the two commonest precursors to it, there is no need Positive and realistic aproach
to study rare headache syndromes. As described in
the introduction, many patients will present in the CDH Quick good fundoscopy
stage and obtaining the primary underlying head-
ache details may be more challenging at that time. Quick neurology screen
While assessing CDH is a good start and sufficient for
initiating management, the longer-term goal is to de- Confident and reassuring assessment
termine the underlying conditions and manage these,
to reduce the risk of re-entering the CDH syndrome. Empathy
Many patients and doctors are keen on brain-imaging,
but this has been shown to be of limited value in the vast Addressing underlying factors
majority of cases where an adequate history and exami-
nation have been performed, no red flags are found Stress and medication overuse are common precipi-
and a satisfactory primary or MOH headache diagnosis tating causes of CDH. These elements add significantly
has been made.4 This is promoted on both major US and to the complexity and duration of the history. Under-
UK headache websites. It does not mean that a differ- standing, and empathising with, the patient experienc-
ent underlying pathology has been excluded, but this ing stress, anxiety or depression requires experience,
can in most cases be deferred and reviewed later, in skill and patience.2,3 Patients with medication-over-
the light of new findings or inadequate response. use headaches (MOH) will have been previously told
that their reliance on painkillers should be reduced or
HANDBOOK OF GENERAL MEDICINE VOL 1 stopped and they will often minimise or even deny their
current use of analgesics.
TREATMENT APPROACHES 105
The second main, parallel aim is to screen for impor- effective and available in South Africa include topira- Treatment approaches
tant causes of secondary headaches, which may re- mate, gabapentin, fluoxetine, levetiracetam and me-
quire further consideration. Clues to possible serious mantine.2,4 Valproate is also effective, but with its cur-
causes are typically referred to as “red flags”.4 These are rent disfavour in women of childbearing age, as well
listed in Table 3. as its potential to cause weight gain, it is less popular.
Botulinum toxin type A has also been shown to be suc-
Table 3. Red flags cessful, and sometimes a short course of prednisone is
used.2,4 Response after withdrawal varies and may take
Older onset age (e.g. >50 years) several weeks, although most patients start improving
within a few weeks.2,3 Studies suggest that benefit can
Thunderclap headache still be gained up to two months. Nevertheless, these
treatments are not short-term ones, and the aim is to
Systemic illness or immunosuppression continue for two to three months before considering
tapering.1 While drug withdrawal is best done abruptly,
Associated pregnancy some patients may need anti-emetics (10-20 mg meto-
clopramide/10 mg prochlorperazine/4-8 mg ondanse-
Associated with cough or other valsalva manoeuvre tron).2 Some chronic migraine patients may also need a
NSAID,2 although care should be taken to avoid this, if
Meningism or papilloedema or focal neurology possible. Note that withdrawal of certain drugs, such as
opiates, may require a more controlled and monitored
Other suspicious features approach. Psychiatrists often have more significant ex-
perience in this procedure, and they may also be need-
The presence of potentially ominous features in a pa- ed for depression or more complex anxiety cases.
tient with headaches raises the suspicion of a bad sec-
ondary headache and reduces the threshold for further Non-pharmacological management should not be
investigations or referral. This list is not exhaustive. neglected.2,4 Success with the above medications is lim-
ited and psychosocial stresses may play an important
Diagnosing the original episodic headache type(s) is role in the aetiology of the CDH. Patients with chronic
often helpful, as this may influence the choice of treat- headaches who are going through drug withdrawal
ment.2 However, most patients have MOH (see Table 4) and experience ongoing stresses are vulnerable to re-
and underlying CM, CTTH or both. This means that with- lapse. Lifestyle modifications, including regular, healthy
drawal of analgesia is indicated.1,2,3 meals and improved sleep hygiene, are recommend-
ed, and reducing or ceasing caffeine will aid drug
Table 4. Criteria for drug usage in medication-overuse withdrawal.2 Better management of stress, anxiety and
headaches depression may require the assistance of therapists,
counsellors or psychiatrists.2,4 Patients also often feel
Analgesics: >15 days/month the need to play an active role in their treatment, and
Combination analgesics/opiates/triptans/ergotamine: meditation, muscle-stretching, and time out are useful
>10 days options. Other alternatives include physiotherapy, Pi-
lates, yoga or similar activities. Finally, once the chronic
The patient’s cooperation is paramount, therefore headache issue is resolved, attention needs to focus on
convincing the patient that all the analgesics tried the underlying headache, such as migraine or tension-
to date have not succeeded in alleviating the head- type headache, to optimise the episodic versions. See
aches, is important. Once that is clear, the patient also Figure 1 for the algorithm of managing CDH.
needs to be told that analgesics are widely known to
cause rebound headaches. When to refer
This implies that the withdrawal of analgesia is likely Patients with “red flags” clearly need appropriate re-
to be accompanied by an increase in headaches views and tests.4 If these cannot be performed at the
before relief is achieved and this is where both non- primary or secondary level, then patients should be
pharmacological and pharmacological treatments referred with the appropriate urgency, depending on
are needed to help the patient cope.1,2,3 Some patients the suspected condition. Primary headaches, including
cannot tolerate an abrupt cessation and tapering is an CDH, can be managed at the primary level with vary-
alternative.2,3 Although some suggest withdrawal should ing degrees of success. Where management attempts,
be done in isolation, others start prophylaxis simultane- as described, have failed, referral may be considered.
ously.2 Various agents used in headache prophylaxis However, the overall success rate in chronic head-
have been trialled, although the groups are generally ache is limited and some patients are intractable, with
small and not comparable. Some are mixed and some or without continued analgesic overuse.2 Patients also
favour chronic migraine or medication-overuse pa- need to understand that the aim of therapy is not to
tients.2,4 Low doses of amitriptyline have been shown to stop all future headaches, but to move them back to
reduce the duration and severity of CM for 8-16 weeks their baseline state of acute episodic headaches, at
and also to be useful in CTTH.2,11,12 This low-cost medica- which point additional therapies may be considered.
tion is also the first-line choice in a low-resource envi- Public neurology clinics in South Africa exist in tertiary
ronment, and can be effective. However, patients may
be put off by the side effects, and to minimise these, HANDBOOK OF GENERAL MEDICINE VOL 1
start with a low dose of 10 mg (even 5 mg if the patient
is very sensitive) and increase slowly as needed usual-
ly to <50 mg, although some studies go up to 100 mg.
Some only need 10 to 25 mg. Other drugs shown to be
106 TREATMENT APPROACHES
Episodic headache Headache Chronic headache
Consider RED FLAGS
Other Investigate further? CDH
headache
<4 hours >= 4 hours
types Cluster CTTH
headache CM
Other MOH
Other
MOH
STOP ALL
ANALGESICS
Pharmacological Non-pharmacological
Amitriptyline Lifestyle changes
or topitamate Stress management
Physiotherapy or other
or other
CDH – chronic daily headache; CTTH – chronic tension-type headache; CM – chronic migraine; MOH – medication-overuse headache
Figure 1. Algorithm for managing chronic daily headaches (long duration >=4hours).
hospitals only, and owing to demand, these clinics are tion of headache prevalence and disability worldwide. Cephalal-
often unable to accept all primary headache referrals. gia. 2007;27:193-210.
In such cases, the telephonic discussion of selected cas- 6. Natoli JL, et al. Global prevalence of chronic migraine: A system-
es may be more appropriate. In private practice, there atic review. Cephalalgia. 2010:30(5):599-609
is also a waiting period to access neurologists, as well 7. Pascual J. Epidemiology of chronic daily headache. Curr Pain
as cost constraints. Therefore, training more staff with Headache Rep. 2001:5(6):529-536
regard to this condition at the primary and secondary 8. Cerbo R. Primary headache in emergency departments: Preva-
levels would be a useful step towards lowering health- lence, clinical features and therapeutic approach. J Headache
care costs effectively. Pain. 2005;6(4):287-289
9. Srikiatkhachorn A. Pathophysiology of chronic daily headache.
REFERENCES Current Pain and Headache Reports. 2001:5(6):537-44
10. Ulrich V, et al. The relative influence of environment and genes in
1. Silberstein S. Chronic daily headache. JAOA. 2005:105(S2):S23-S29 episodic tension-type headache. Neurology. 2004;62(11):2065-9
2. Dodick D. Chronic daily headache. N Engl J Med. 2006:354:158-65 11. Castells ET, et al. Use of amitriptyline for the treatment of chronic
3. Ahmed F. Chronic daily headache. Ann Indian Acad Neurol. tension-type headache. Review of the literature. Med Oral Patol
Oral Cir Bucal. 2008 Sep1;13(9):E567-72
2012:15(S1):S40-S50 12. Couch JR. Amitriptyline in the prophylactic treatment of migraine
4. Yancey JR. Chronic daily headache: Diagnosis and management. and chronic daily headache. Headache. 2011;1(1):33-51.
Am Fam Physician. 2014: 89(8):642-648
5. Stovner LJ, et al. The global burden of headache: A documenta-
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 107
Alzheimer's disease Treatment approaches
M West 1. Diagnosis of AD Yes
2. Complicated?
MBChB, FCPsych (SA)
No
Senior Specialist, Department of Psychiatry and Mental
Health, University of Cape Town, Cape Town Appropriate
intervention
S van Heerden (see text)
MBChB, MMed (Psych), FCPsych (SA) 3. Cholinesterase inhibitor
Senior Specialist, Department of Psychiatry, Response?
University of Stellenbosch, Stellenbosch
Intolerable No Yes
JA Joska
4. Switch Maintenance
MBChB, MMed (Psych), FCPsych (SA), PhD medication treatment
Associate Professor, Department of Psychiatry and Mental 5. Optimise dose and duration
Health, University of Cape Town, Cape Town
6. Response? Yes
DJ Stein No
MBChB, FRCPC, PhD, DPhil (Stell) Maintenance
treatment
Professor and Head, Department of Psychiatry and Mental
Health, University of Cape Town, Cape Town 7. Reassessment
Alzheimer’s disease (AD), first identified and associated 8. Memantine
with neurofibrillary tangles and plaque formation by the Conservative management
psychiatrist Alois Alzheimer, is the most common of the Care for the caregiver
major neurocognitive disorders (“dementias”) of the
elderly.1 Although this degenerative disorder has long Figure 1. Algorithm for pharmacotherapy
been considered essentially untreatable, increased un- of Alzheimer’s disease (AD)
derstanding of the basic neuroscience of the disorder,
the recent introduction of new medications for the diagnosis is crucial. Fortunately, there is increasing evi-
symptomatic treatment of AD, and the development of dence that the diagnosis of AD can reliably be made
biomarker technologies have resulted in growing hope using such criteria as those provided by DSM-5 (see Ta-
that more effective pharmacotherapeutic manage- bles 1 and 2).7
ment will be found.2
Diagnosis is made on the basis of defining criteria, and
A growing recognition of potential contributing caus- the removal of confounds. It is important to exclude poten-
es, and knowledge of the underlying neurobiology of tially reversible causes of or contributors to dementia, such
AD has led to a recognition of the importance of diag- as syphilis, vitamin B12 deficiency, hypothyroidism, and nor-
nosing early cognitive changes, and to the possibility of mal pressure hydrocephaly. Structural imaging, in addition
primary and secondary prevention strategies.3 This area to a thorough clinical assessment, may be a valuable tool
comprises a major arena of interest for research, and to confirm the diagnosis of AD.8
already has important clinical implications insofar as it
raises awareness of the importance of early diagnosis. While AD develops and progresses over time, it is con-
Furthermore, cholinesterase inhibitors (CEIs) may also
be useful in the management of other dementias, such HANDBOOK OF GENERAL MEDICINE VOL 1
as vascular dementia, dementia with Lewy bodies, and
Parkinson’s disease with dementia.4,5
The management of a patient diagn osed with Alz-
heimer’s disease should be a collaborative approach,
including care assessments and plans, family interven-
tions, social support and caregiver support. Carers have
higher rates of depression, substance abuse, and physi-
cal illness.6 It is therefore important to determine the
needs of caregivers and to help meet them.
STEP 1: DIAGNOSIS OF ALZHEIMER’S DISEASE
A diagnosis of AD can only be confirmed on autopsy, on
the basis of the pathognomonic tangles and plaques.
However, given advances in treatment, early clinical
108 TREATMENT APPROACHES
venient to consider its course in stages. Pre-syndromal use in non-aggressive agitation. As a class, the atypical
disease is called mild cognitive impairment (MCI), and antipsychotics may be effective – however the effect
refers to the presence of an amnestic or non-amnestic size is modest.14 The effect appears most pronounced
syndrome that does not impair daily function. In mild for risperidone and olanzapine.15 International guide-
AD there is short-term memory impairment, which may lines suggest cautious use of atypical antipsychotics
be accompanied by symptoms of anxiety and depres- for severe agitation, at the lowest effective dose, pro-
sion. Moderate AD is characterised by worsening neuro vided the expected benefits outweigh the risks.16 Cau-
cognitive features, accompanying neuropsychiatric tion should be exercised in patients with cardiovascular
symptoms (hallucinations, delusions, agitation, aggres- disease, electrolyte derangements, long QTc-interval or
sion), and disturbance of sleep patterns. Severe AD is concomitant prescription of drugs known to lengthen
characterised by prominent cognitive decline, loss of QTc.13 Long-term use of antipsychotics should be avoid-
ability to perform basic activities of daily living and mo- ed – regular re-evaluation and individual risk-benefit
tor signs (such as rigidity). analysis should take place, with a maximum treatment
period of 12 weeks.17
Target symptoms of AD treatment include cognitive
symptoms and impairm ent in daily functioning, as well Antidepressants may also be helpful in Alzheimer’s
as the various associated neuropsychiatric symptoms patients, although they have been less extensively stud-
that manifest commonly during the course of the dis- ied. SSRIs (such as citalopram) and trazodone may be
order.5 Treatment should aim to maximise functional efficacious, and are better tolerated than antipsychot-
performance and quality of life, and to reduce the pe- ics.18,19 The evidence for anticonvulsants and mood-
riod of disability. stabilisers in this context (valproate, carbamazepine,
topiramate, lamotrigine, lithium) is less supportive.20,21
STEP 2: COMPLICATIONS IN DIAGNOSIS Benzodiazepines should generally be avoided, partic-
IMPACTING PHARMACOTHERAPY ularly where daily medication for agitation is needed,
and, indeed, they are associated with accelerated
Resolution of symptoms other than memory impairment cognitive decline.22,23
(e.g. agitation) may be more important for caregivers
than subtle improvements in memory. These neuropsy- b. Depression: Comorbid depression is common in pa-
chiatric symptoms of dementia (also called behavioural tients with AD in the early stages. Furthermore, in some
and psychological symptoms of dementia [BPSD]) occur patients the cognitive symptoms of depression may
freq uently, and are associated with increased disability make diagnostic differentiation from AD very difficult.
and earlier nursing-home placement.9 In this section we In both groups of patients, a trial of antidepressants is
focus on these symptoms associated with AD, discussing warranted if symptoms are severe with significant func-
the role of medications other than the cholinesterase tional impairment.24 Lower doses are needed than in
inhibitors; however, it should be noted that the cholinest- younger patients. The absence of anticholinergic ef-
erase inhibitors may be primarily indicated for some of fects makes the selective serotonin re-uptake inhibitors
the neuropsychiatric symptoms and not only for memory a particularly useful group of agents in this context, and
impairment.10 (See also Step 3.) they may prove efficacious for a broad range of symp-
toms.25,26 The elderly may be at increased risk of the
a. Agitation: It is important to rule out medical causes hyponatraemia associated with drug-induced SIADH.27
of mental status deterioration in patients with AD. For
mild agitation, non-pharmacological interventions such c. Psychosis: Psychotic symptoms may respond well to
as environmental modifications, caregiver psycho-edu- low doses of an antipsychotic agent, although, as above,
cation and behavioural methods may be effective.11,12 prescriptions should follow an individualised risk-benefit
However, a range of different medications is used for analysis.15 Caution must be advised when hallucinations
more severe agitation in Alzheimer’s, perhaps most occur in the context of Lewy body dementia, as these
commonly low doses of neuroleptic agents. The use of patients are highly sensitive to neuroleptics.28
all antipsychotics in patients with dementia is, however,
associated with increased mortality, both in the long- STEP 3: FIRST-LINE PHARMACOTHERAPY
and short-term, and apparently with higher doses.13
A Cochrane review of haloperidol concluded that it In our algorithm (Figure 1), we suggest cholinesterase
may be useful for aggression in dementia, but that it is inhibitors as the first-line choice for preserving cognitive
poorly tolerated and so not recommended for routine function in mild to moderate AD patients. A cholinergic
hypothesis of AD was first put forward in the 1970s, and
Table 1. Criteria for major neurocognitive disorder (adapted from DSM-5)
A. Evidence of significant cognitive decline from previous level of performance in one or more of the cognitive domains
(complex attention, executive function, learning and memory, language, perceptual-motor, social cognition) based on:
(1) Concern of the individual, informant or clinician; and
(2) A substantial impairment in cognitive performance (preferably documented by standardised neuropsychological
testing)
B. The cognitive deficits interfere with independence in everyday activities
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g. major depressive disorder, schizophrenia)
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 109
ultimately led to the development of these agents.29 reports, but also by improved or stabilised MMSE scores; Treatment approaches
These agents may not only improve cognitive symp- this may not be noticeable during a brief trial of treat-
toms, but may also result in improvement in associated ment. Therefore, a reasonable approach is a six-month
symptoms, including apathy, agitation, depression, and trial on the recommended or maximum tolerated dose;
psychotic symptoms.30 To date, there is no evidence if there is no evidence of improvement on bedside test-
suggesting that any one of the cholinesterase inhibitors ing or from carers, the medication should be discontin-
is more effective than another, and the choice should ued. Length of pharmacotherapy in treatment respon
be made based on cost and side-effect profile.31,32 ders must be individualised, but the cholinesterase
inhibitors certainly improve cognitive and global func-
A second class of molecule is available for more se- tioning for up to at least six months of treatment, and
vere AD. The NMDA receptor antagonist memantine has perhaps in certain cases even longer.44
been registered in Europe and the USA for more than
10 years for this indication. It has benefits for improving STEP 5: OPTIMISE DOSE AND DURATION
agitation and BPSD, as well as slowing cognitive decline
and reducing caregiver burden.33 More recently, there It is important to optimise the dose and duration of cho-
have been trials to suggest that memantine may be linesterase inhibitor treatment. The benefits of higher
introduced in earlier disease, together with cholinester- dosing are inconsistent, and may compromise drug tol-
ase inhibitors, and that together these agents may be erability.45-47 As above, an adeq uate trial period of six
well tolerated.34 months at a therapeutic dose is recommended.
An immediate barrier to the use of these agents is Donepezil is administered once daily, beginning with
the expense. Nevertheless, by decreasing behavioural a dose of 5 mg at bedtime and increasing to 10 mg
symptoms and reducing hospitalisation and placement after four weeks (particularly in patients weighing more
costs, these medications may actually be cost-effec- than 60 kg). Rivastigmine is initiated at 1.5 mg twice
tive.35,36 There is the additional benefit of the possibility daily, and increased by 1.5 mg twice daily every two to
that caregiver burden may be considerably lightened.37 four weeks to a maximum of 12 mg daily. If treatment is
missed for more than three days, it should be restarted
No good quality data exist for oestrogen replace- at the lowest daily dose and retitrated up. Galantamine
ment, vitamin E or NSAIDs in the treatment of AD.38-40 ER (extended release) is initiated at 8 mg daily, and
dose is increased to a minimum maintenance dosage
STEP 4: ASSESS RESPONSE TO TREATMENT of 16 mg daily after a minimum of four weeks. Similarly, if
missed for more than several days, it should be restarted
In order to determine response to medic ation, it is impor- at the lowest dose and titrated up to the current dose.
tant to set reasonable expectations for the patient’s re-
sponse to treatment. It may be useful to complete a scale, Caution is needed when prescribing these agents
such as the Mini Mental Status Examination (see Table 2) in to patients with sick sinus syndrome or other supraven-
order to help quantify response to medication.41 tricular cond uction defects, or when combining agents
metabolised by the P450 syst em (donepezil, galan-
Side effects of the medication should also be moni- tamine) with other medications metabolised by this
tored. Gastro-intestinal side effects are the most com- pathway.48
mon after cholinesterase inhibitors. They are dose-
related and often transient, and may be particularly STEP 6: MAINTENANCE OF TREATMENT
distressing for thin, small patients. Patients who are in-
tolerant of a particular cholinesterase inhibitor can be Reassess the patient at the end of a clinical trial of opti-
switched to another.42 mal dose and duration. Data obtained at the two-year
mark shows that some patients are still functioning at
The cholinesterase inhibitors slow the rate of decline above their expected level of deterioration when com-
of cognitive function and improve activities of daily liv- pared with untreated patients.49 Unfortunately, response
ing5, although individual patient response may be high-
ly heterogeneous and independent of stage or severity
of illness.43 Improvement may be noted by caregiver
Table 2. Criteria for major neurocognitive disorder due to Alzheimer’s disease (adapted from DSM-5)
A. The criteria are met for major neurocognitive disorder.
B. There is insidious onset and gradual progression of impairments.
C. Criteria are met for either probable or possible Alzheimer’s disease.
Probable Alzheimer’s disease is diagnosed if either of the following is present (otherwise possible Alzheimer’s disease should
be diagnosed):
(1) Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.
(2) All three of the following are present:
a. Clear evidence of decline in memory and learning, and at least one other neurocognitive domain.
b. Steadily progressive, gradual decline.
c. No evidence of mixed aetiology (ie, absence of other neurodegenerative or cerebrovascular disease, or
another neurological, mental or systemic disease likely to contribute to cognitive decline).
D. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a
substance, or another mental, neurological or systemic disorder.
HANDBOOK OF GENERAL MEDICINE VOL 1
110 TREATMENT APPROACHES
to the cholinesterase inhibitors is heterogeneous, so 2014;62(4):762-9.
some patients do markedly better than others. Further- 6. Martin-Carrasco M, Ballesteros-Rodriguez J, Dominguez-
more, these agents do not cure the disease, but rather
slow its progression. While there may be some benefit to Panchon AI, Munoz-Hermoso P, Gonzalez-Fraile E. Interven-
continuing therapy in patients with advanced disease, tions for caregivers of patients with dementia. Actas Esp
it has been suggested that cholinesterase medication Psiquiatr. 2014;42(6):300-14.
be withdrawn once the MMSE falls to less than 12.50 Sub- 7. Matsunaga S, Kishi T, Iwata N. Combination therapy with
sequent rapid deterioration following withdrawal occa- cholinesterase inhibitors and memantine for Alzheimer’s
sionally occurs, and would suggest that there was still disease: A systematic review and meta-analysis. Int J Neu-
some value in the therapy.51 In these cases, it would be ropsychopharmacol. 2014;18(5).
reasonable to restart therapy and monitor closely for im- 8. Sachdev PS, Blacker D, Blazer DG, Ganguli M, Jeste DV,
provement. This must be done as soon as possible and Paulsen JS, et al. Classifying neurocognitive disorders: The
preferably within 7-10 days. DSM-5 approach. Nat Rev Neurol. 2014;10(11):634-42.
9. Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, et al.
STEP 7: REASSESSMENT Efficacy and safety of donepezil, galantamine, rivastig-
mine, and memantine for the treatment of Alzheimer’s dis-
Should there be no response to a clinical trial of optimal ease: A systematic review and meta-analysis. J Alzheimers
dose and duration, it may be useful to reassess a num- Dis. 2014;41(2):615-31.
ber of factors. The diagnosis of AD should be reconsid-
ered; in particular, other types of dementia should be REFERENCES
excluded (although there is evidence that cholinester-
ase inhibitors may be useful in treating dementia due to 1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The glob-
other causes, such as Lewy body dementia or Parkin- al prevalence of dementia: A systematic review and meta-analysis.
son’s disease dementia).52 Alzheimers Dement. 2013;9(1):63-75 e2.
It is also important to reconsider the diagnosis of de- 2. Gandy S, DeKosky ST. Toward the treatment and prevention of Alz-
pression. Not only may patients with AD have comorbid heimer’s disease: Rational strategies and recent progress. Annu Rev
depression, but depression may result in the misdiagnosis Med. 2013;64:367-83.
of dementia (“pseudodementia”).53 A trial of antidepres-
sants may be the only way to exclude these possibilities. 3. Bensadon BA, Odenheimer GL. Current management decisions in
mild cognitive impairment. Clin Geriatr Med. 2013;29(4):847-71.
STEP 8: TREATMENT RESISTANCE
4. Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors
There is evidence that if a patient does not respond to for dementia with Lewy bodies, Parkinson’s disease dementia and
one cholinesterase inhibitor, switching to another may cognitive impairment in Parkinson’s disease. Cochrane Database
be useful.54 A switch to memantine should also be con- Syst Rev. 2012;3:CD006504.
sidered, especially in moderate to severe AD.55
5. Van de Glind EM, van Enst WA, van Munster BC, Olde Rikkert MG,
While development of several new pharmacothera- Scheltens P, Scholten RJ, et al. Pharmacological treatment of de-
peutic interventions for AD is currently underway56,57, mentia: A scoping review of systematic reviews. Dement Geriatr
symptomatic management and caring for the care Cogn Disord. 2013;36(3-4):211-28.
giver may remain the main forms of intervention for
some time. Measures to address caregiver burden, such 6. Suehs BT, Shah SN, Davis CD, Alvir J, Faison WE, Patel NC, et al.
as referral of the caregiver to an AD consumer advo- Household members of persons with Alzheimer’s disease: Health
cacy group, may be useful.58 conditions, healthcare resource use, and healthcare costs. J Am
Geriatr Soc. 2014;62(3):435-41.
ADDITIONAL READING
7. Sachdev PS, Blacker D, Blazer DG, Ganguli M, Jeste DV, Paulsen
1. National Institute for Health and Clinical Excellence. De- JS, et al. Classifying neurocognitive disorders: The DSM-5 approach.
mentia: Supporting people with dementia and their carers Nat Rev Neurol. 2014;10(11):634-42.
in health and social care: National Institute for Health and
Care Excellence; 2006 [cited 2014]. Available from: https:// 8. Harper L, Barkhof F, Scheltens P, Schott JM, Fox NC. An algorithmic
www.nice.org.uk/guidance/cg42. approach to structural imaging in dementia. J Neurol Neurosurg
Psychiatry. 2014;85(6):692-8.
2. Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS,
Tariot PN, et al. American Psychiatric Association practice 9. Sansoni J, Anderson KH, Varona LM, Varela G. Caregivers of Alz-
guideline for the treatment of patients with Alzheimer’s dis- heimer’s patients and factors influencing institutionalization of
ease and other dementias. Second edition. Am J Psychia- loved ones: Some considerations on existing literature. Ann Ig.
try. 2007;164(12 Suppl):5-56. 2013;25(3):235-46.
3. Muayqil T, Camicioli R. Systematic review and meta-anal- 10. Madhusoodanan S, Ting MB. Pharmacological management of be-
ysis of combination therapy with cholinesterase inhibitors havioral symptoms associated with dementia. World J Psychiatry.
and memantine in Alzheimer’s disease and other demen- 2014;4(4):72-9.
tias. Dement Geriatr Cogn Dis Extra. 2012;2(1):546-72.
11. Moniz Cook ED, Swift K, James I, Malouf R, De Vugt M, Verhey F.
4. Gareri P, De Fazio P, Manfredi VG, De Sarro G. Use and safe- Functional analysis-based interventions for challenging behaviour
ty of antipsychotics in behavioral disorders in elderly people in dementia. Cochrane Database Syst Rev. 2012;2:CD006929.
with dementia. J Clin Psychopharmacol. 2014;34(1):109-23.
12. Gitlin LN, Kales HC, Lyketsos CG. Nonpharmacologic management
5. Kales HC, Gitlin LN, Lyketsos CG, Detroit Expert Panel on the of behavioral symptoms in dementia. JAMA. 2012;308(19):2020-9.
Assessment and Management of Neuropsychiatric Symp-
toms of Dementia in Clinical Settings: recommendations 13. Gareri P, De Fazio P, Manfredi VG, De Sarro G. Use and safety of an-
from a multidisciplinary expert panel. J Am Geriatr Soc. tipsychotics in behavioral disorders in elderly people with dementia.
J Clin Psychopharmacol. 2014;34(1):109-23.
HANDBOOK OF GENERAL MEDICINE VOL 1
14. Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA.
Atypical antipsychotic drugs in the treatment of behavioural and
psychological symptoms of dementia: Systematic review. BMJ.
2004;329(7457):75.
15. Ballard C, Waite J. The effectiveness of atypical antipsychotics for
the treatment of aggression and psychosis in Alzheimer’s disease.
Cochrane Database Syst Rev. 2006(1):CD003476.
16. Azermai M, Petrovic M, Elseviers MM, Bourgeois J, Van Bortel LM, van
der Stichele RH. Systematic appraisal of dementia guidelines for the
management of behavioural and psychological symptoms. Ageing
Res Rev. 2012;11(1):78-86.
17. Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot
PN, et al. American Psychiatric Association practice guideline for
the treatment of patients with Alzheimer’s disease and other de-
mentias. Second edition. Am J Psychiatry. 2007;164(12 Suppl):5-56.
18. Henry G, Williamson D, Tampi RR. Efficacy and tolerability of anti-
depressants in the treatment of behavioral and psychological
symptoms of dementia, a literature review of evidence. Am J Alz-
TREATMENT APPROACHES 111
heimers Dis Other Demen. 2011;26(3):169-83. setting. Am J Health Syst Pharm. 2009;66(10):899-907. Treatment approaches
19. Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P. Anti- 45. Loy C, Schneider L. Galantamine for Alzheimer’s disease and
depressants for agitation and psychosis in dementia. Cochrane Da- mild cognitive impairment. Cochrane Database Syst Rev.
tabase Syst Rev. 2011(2):CD008191. 2006(1):CD001747.
20. Yeh YC, Ouyang WC. Mood stabilizers for the treatment of behav- 46. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer’s dis-
ioral and psychological symptoms of dementia: An update review. ease. Cochrane Database Syst Rev. 2006(1):CD001190.
Kaohsiung J Med Sci. 2012;28(4):185-93. 47. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE. Rivastig-
21. Lonergan E, Luxenberg J. Valproate preparations for agitation in mine for Alzheimer’s disease. Cochrane Database Syst Rev.
dementia. Cochrane Database Syst Rev. 2009(3):CD003945. 2009(2):CD001191.
22. Tampi RR, Tampi DJ. Efficacy and tolerability of benzodiazepines for 48. Levy RH, Collins C. Risk and predictability of drug interactions in the
the treatment of behavioral and psychological symptoms of de- elderly. Int Rev Neurobiol. 2007;81:235-51.
mentia: A systematic review of randomized controlled trials. Am J 49. Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini
Alzheimers Dis Other Demen. 2014;29(7):565-74. E, Jones R, et al. Clinical trials and late-stage drug development for
23. Verdoux H, Lagnaoui R, Begaud B. Is benzodiazepine use a risk fac- Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med.
tor for cognitive decline and dementia? A literature review of epi- 2014;275(3):251-83.
demiological studies. Psychol Med. 2005;35(3):307-15. 50. National Institute for Health and Clinical Excellence. Dementia: Sup-
24. Leong C. Antidepressants for depression in patients with dementia: porting people with dementia and their carers in health and social
a review of the literature. Consult Pharm. 2014;29(4):254-63. care: National Institute for Health and Care Excellence; 2006 [cited
25. Lyketsos CG, Lee HB. Diagnosis and treatment of depression in Alz- 2014]. Available from: https://www.nice.org.uk/guidance/cg42.
heimer’s disease. A practical update for the clinician. Dement Geri- 51. Rainer M, Mucke HA, Kruger-Rainer C, Kraxberger E, Haushofer
atr Cogn Disord. 2004;17(1-2):55-64. M, Jellinger KA. Cognitive relapse after discontinuation of drug
26. Bains J, Birks J, Dening T. Antidepressants for treating depression in therapy in Alzheimer’s disease: Cholinesterase inhibitors versus
dementia. Cochrane Database Syst Rev. 2002(4):CD003944. nootropics. J Neural Transm. 2001;108(11):1327-33.
27. Jacob S, Spinler SA. Hyponatremia associated with selective 52. Larner AJ. Cholinesterase inhibitors: Beyond Alzheimer’s disease. Ex-
serotonin-re-uptake inhibitors in older adults. Ann Pharmacother. pert Rev Neurother. 2010;10(11):1699-705.
2006;40(9):1618-22. 53. Kang H, Zhao F, You L, Giorgetta C, Sarkhel S, et al. Pseudo-de-
28. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, et mentia: A neuropsychological review. Ann Indian Acad Neurol.
al. Diagnosis and management of dementia with Lewy bodies: third 2014;17(2):147-54.
report of the DLB Consortium. Neurology. 2005;65(12):1863-72. 54. Massoud F, Desmarais JE, Gauthier S. Switching cholinesterase inhibi-
29. Ibach B, Haen E. Acetylcholinesterase inhibition in Alzheimer’s Dis- tors in older adults with dementia. Int Psychogeriatr. 2011;23(3):372-8.
ease. Curr Pharm Des. 2004;10(3):231-51. 55. Wilkinson D, Wirth Y, Goebel C. Memantine in patients with moderate
30. Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, et al. Efficacy to severe Alzheimer’s disease: Meta-analyses using realistic definitions
and safety of donepezil, galantamine, rivastigmine, and meman- of response. Dement Geriatr Cogn Disord. 2014;37(1-2):71-85.
tine for the treatment of Alzheimer’s disease: A systematic review 56. Guzior N, Wieckowska A, Panek D, Malawska B. Recent development
and meta-analysis. J Alzheimers Dis. 2014;41(2):615-31. of multifunctional agents as potential drug candidates for the treat-
31. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase ment of Alzheimer’s disease. Curr Med Chem. 2015;22(3):373-404.
inhibitors in the treatment of neuropsychiatric symptoms and func- 57. Geldenhuys WJ, Darvesh AS. Pharmacotherapy of Alzheimer’s dis-
tional impairment in Alzheimer disease: A meta-analysis. JAMA. ease: Current and future trends. Expert Rev Neurother. 2015;15(1):3-5.
2003;289(2):210-6. 58. Beinart N, Weinman J, Wade D, Brady R. Caregiver burden and psy-
32. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et choeducational interventions in Alzheimer’s disease: A review. De-
al. Effectiveness of cholinesterase inhibitors and memantine for treat- ment Geriatr Cogn Dis Extra. 2012;2(1):638-48.
ing dementia: Evidence review for a clinical practice guideline. Ann
Intern Med. 2008;148(5):379-97. HANDBOOK OF GENERAL MEDICINE VOL 1
33. McShane R, Areosa Sastre A, Minakaran N. Memantine for demen-
tia. Cochrane Database Syst Rev. 2006(2):CD003154.
34. Matsunaga S, Kishi T, Iwata N. Combination therapy with cholinester-
ase inhibitors and memantine for Alzheimer’s disease: A systematic
review and meta-analysis. Int J Neuropsychopharmacol. 2014;18(5).
35. Bond M, Rogers G, Peters J, Anderson R, Hoyle M, Miners A, et al. The
effectiveness and cost-effectiveness of donepezil, galantamine, riv-
astigmine and memantine for the treatment of Alzheimer’s disease
(review of Technology Appraisal No. 111): A systematic review and
economic model. Health Technol Assess. 2012;16(21):1-470.
36. Pouryamout L, Dams J, Wasem J, Dodel R, Neumann A. Economic
evaluation of treatment options in patients with Alzheimer’s dis-
ease: A systematic review of cost-effectiveness analyses. Drugs.
2012;72(6):789-802.
37. Masterman DL. Role of cholinesterase inhibitors in managing behav-
ioral problems in Alzheimer’s disease. Prim Care Companion J Clin
Psychiatry. 2004;6(3):126-31.
38. Maki PM, Henderson VW. Hormone therapy, dementia, and cog-
nition: The Women’s Health Initiative 10 years on. Climacteric.
2012;15(3):256-62.
39. Farina N, Isaac MG, Clark AR, Rusted J, Tabet N. Vitamin E for Alz-
heimer’s dementia and mild cognitive impairment. Cochrane Da-
tabase Syst Rev. 2012;11:CD002854.
40. Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, et al. Anti-inflam-
matory drugs and risk of Alzheimer’s disease: An updated systematic
review and meta-analysis. J Alzheimers Dis. 2015;44(2):385-96.
41. Sheehan B. Assessment scales in dementia. Ther Adv Neurol Disord.
2012;5(6):349-58.
42. Gauthier S, Emre M, Farlow MR, Bullock R, Grossberg GT, Potkin
SG. Strategies for continued successful treatment of Alzheimer’s
disease: switching cholinesterase inhibitors. Curr Med Res Opin.
2003;19(8):707-14.
43. Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M. A meta-
analysis of the efficacy of donepezil, rivastigmine, galantamine,
and memantine in relation to severity of Alzheimer’s disease. J Alz-
heimers Dis. 2013;35(2):349-61.
44. Smith DA. Treatment of Alzheimer’s disease in the long-term-care
112 TREATMENT APPROACHES
The adult patient with attention deficit
hyperactivity disorder
NN Ngcobo Neurobiological factors
MBChB Brain-imaging studies in individuals with ADHD have
found a dysfunction of dopaminergic pathways in-
Psychiatry Registrar, Department of Psychiatry, volved in reward, motivation, executive function and
Nelson R Mandela School of Medicine, attention, and the noradrenergic pathways, which are
University of KwaZulu-Natal, Durban also involved in executive function.7 Furthermore, the
response of ADHD symptoms to stimulant medications,
B Chiliza which act by enhancing dopamine and noradrener-
gic signalling, supports the belief that the pathology of
MBChB, FCPsych, PhD ADHD involves these neurotransmitters.7
Associate Professor, Department of Psychiatry, Non-genetic factors
Nelson R Mandela School of Medicine,
University of KwaZulu-Natal, Durban Environmental factors play an important role in the
aetiology of ADHD. Studies have shown that prenatal
Attention deficit hyperactivity disorder (ADHD) is one of risk factors, such as exposure to nicotine, alcohol and
the most prevalent neuropsychiatric disorders in child- drugs, maternal factors of high blood pressure, obesity
hood and often persists into adulthood.1 Diagnosis and and stress during pregnancy, are associated with an
treatment of adult ADHD can be challenging because increased risk of ADHD.4,7 Severe early deprivation and
the condition has significant comorbidity, most com- exposure to lead in childhood has also been shown to
monly mood disorders or substance abuse.2 Other chal- increase the risk of ADHD.4
lenges in diagnosis and treatment of the disorder are
the fear of possible malingering, the apprehension that Clinical features
medications may be misused, and a reluctance to pre-
scribe controlled medication for individuals with a his- Pervasive symptoms of inattention and impulsivity char-
tory of substance abuse.3 Current evidence indicates acterise ADHD in adults.8 The presentation is, however,
that in the majority of cases where ADHD persists into different from that seen in children because of a more
adulthood, it is associated with a range of clinical and significant decrease in symptoms of hyperactivity than
psychosocial impairments.4 It is therefore essential that in symptoms of inattention.7 The decreasing symptoms
practitioners have an understanding of adult ADHD in of hyperactivity may manifest as restlessness.7 The pre-
order to be able to provide appropriate management. dominant symptoms of inattention may be manifested
in problems such as remaining focused on a task, or-
Epidemiology ganising activities, following through and completing
ADHD affects 2-16% of the school-going population. It tasks, forgetfulness, keeping appointments and missing
is now widely accepted that 60-70% of patients’ symp- deadlines.7,9
toms persist into adulthood, with the prevalence of
adult ADHD from epidemiological studies estimated at Impulsivity in adult ADHD is characterised by sudden
2-5%.4,5 In the South African setting, a study conduct- decision-making without thought of consequences or
ed to explore the prevalence and treatment of adult excessive involvement in activities that have a high
ADHD, found a prevalence of approximately 3-5%. This potential for negative consequences.6,9
study, however, had limitations as the data were only
collected from the private healthcare sector – these fig- Patients may initially present with symptoms which are
ures may consequently be an underestimation.5 not core symptoms of ADHD. These include emotional
dysregulation in the form of low frustration tolerance,
Pathophysiology anger outbursts, unstable moods and irritability.9 Sec-
ondary depressive disorders associated with low self-
Genetics esteem related to their performance are also common
There is significant evidence that ADHD has a strong in these patients, leading to impaired social and occu-
genetic transmission, with high hereditability. This has pational functioning.6
been illustrated in family studies, twin studies and other
genetic studies.6,7 Family studies indicate a prevalence Adult ADHD often has serious consequences, includ-
range of 20-50% among first-degree relatives.4 Several ing interpersonal problems (e.g. social maladjustment,
genes have been identified and implicated in ADHD, premature termination of relationships and marital
however they only account for about 3% of phenotypic problems), employment and financial difficulties (e.g.
variation.7 This suggests that the genetic cause of this quitting jobs without having an alternative source of in-
disorder is a complex mechanism of a combination of come, frequent job changes, unemployment, traffic in-
gene-gene action or gene interactions with environ- fringement tickets, and lower socioeconomic status).7,9
mental risk factors.7 Table 1 illustrates the difference in the symptomology of
ADHD in children versus adults.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 113
Table 1. The difference in the symptomology of ADHD in children versus adults Treatment approaches
Symptom DSM-IV characteristics in children Typical symptoms seen in adults
Hyperactivity Talks excessively Talks excessively
Squirms and fidgets Inner restlessness
Runs/climbs excessively Feelings of being overwhelmed
Cannot play/work quietly Chooses active jobs
“On the go” Inability to enjoy quiet leisure
The subjective sensation of being “driven”
Inattention Difficulty with homework Complains that he/she reads, “but it does
Does not listen not register”
Forgetful Frustrated over the inability to organise
Loses things Poor time management
Easily distracted Problems prioritising
Misplaces belongings
Easily distracted
Prefers multi-tasking
Inefficient
Impulsivity Blurts out answers Irritable and quick to anger
Cannot wait his turn Blurts out rude/insulting thoughts
Interrupts others Impulsively changes jobs
Drives recklessly
Impulsive sexuality
Quits new projects
Miller, M. Attention deficit hyperactivity disorder: Pharmaceutical treatment updates. Optima Educational Solutions Inc. 2002
Diagnosis Differential diagnosis and comorbidities
The diagnosis of ADHD is a clinical one which should Diagnosing ADHD in adults requires careful considera-
only be made by healthcare professionals with train- tion of differential diagnoses as the clinical picture can
ing and expertise in the diagnosis of ADHD, or paedi- be clouded by frequent comorbidity, and it can be dif-
atricians and specialist psychiatrists.10 The core triad in ficult to differentiate ADHD from other psychiatric con-
the diagnostic criteria of ADHD is a persistent pattern ditions.4,12 The most frequently co-occurring conditions
of inattention or hyperactivity-impulsivity symptoms with include disorders of mood, sleep, personality, substance
clear evidence that they interfere with, or reduce the use and generalised anxiety disorders.4,7 When differen-
quality of, social, academic or occupational function- tiating from mood disorders, it is important to determine
ing. These symptoms need to have been present before whether the symptoms have been present since child-
the age of 12 years of age, therefore it is important to hood, as symptoms of ADHD are chronic, whereas with
enquire about and screen for symptoms of childhood bipolar disorder, patients tend to experience symptoms
ADHD when evaluating patients with adult ADHD. The in discrete, manic episodes.2 It is important to rule out
leading tool used in screening for adult ADHD is The a general medical condition as being the cause of
Utah Criteria for Adult ADHD. It is designed to record symptoms if a diagnosis of ADHD is suspected. Thyroid
symptoms of ADHD in childhood retrospectively, as well disease, vitamin B12 deficiency, head injury, seizure
as to give evidence of current impairment from ADHD disorders or a brain tumour can cause symptoms that
symptoms in adulthood.6,8 These symptoms also need to may mimic ADHD.2 Taking a good history of medication
be present in two or more settings.8 and substance use is also important as certain medica-
tions can have adverse effects that mimic ADHD, such
There are several other commonly used rating scales as corticosteroids, antihistamines, anticonvulsants, caf-
for screening adult ADHD. However, the WHO Adult feine and nicotine.13
ADHD Self-Report Scale (ASRS) is the best researched.10
Self-report scales are not without their challenges. A Management
study done in Eldoret, Kenya, by Atwoli et al, to de-
termine the prevalence of self-reported ADHD symp- Treatment of adult ADHD should be preceded by a
toms among university students found a prevalence of comprehensive assessment and diagnostic certainty.10
21,8%.11 This figure is significantly higher than reported in The multi-modal treatment approach includes:
other studies of similar populations. These findings high- • Psycho-education about ADHD and comorbid dis-
light that adult recall of childhood ADHD symptoms is
often unreliable, and the need for confirmation of these orders
symptoms by a collateral source of information is cru- • Pharmacotherapy for ADHD and comorbid disorders
cial. Although rating scales can add some standardisa- • Non-pharmacological interventions10
tion and a measurable element to the symptomology,
the clinical assessment is still the core in the process of The first step in treatment, following diagnosis, should
diagnosing adult ADHD.10 be psycho-education of the patient and his or her family
about the disorder. This promotes good long-term care
and also allows the patient to make more informed de-
cisions about treatment options.10 This should include
HANDBOOK OF GENERAL MEDICINE VOL 1
114 TREATMENT APPROACHES
education on the prevalence of ADHD in children and Non-stimulant medication
adults, its heritability, ADHD symptoms, frequent comor-
bidities and treatment options.4 Atomoxetine
Pharmacotherapy is the first-line treatment for adult Atomoxetine is the only non-stimulant medication ap-
ADHD; it differs from treatment in children where non- proved for adult ADHD treatment.7 This is an appro-
pharmacological therapies may be first-line. Non-drug priate alternative for adults who do not respond to stim-
interventions in the absence of medical treatment are ulant treatment or who have a medical condition that
ineffective in the adult population. However, a combi- contra-indicates the use of stimulants.10 It is indicated in
nation of pharmacological and psychosocial interven- patients with comorbid substance-use disorders, emo-
tion is associated with improved outcomes.10 tional dysregulation or social anxiety.4
Pharmacotherapy Other agents
Based on extensive data concerning safety and effica- Other choices of drugs, such as clonidine, modafinil,
cy, stimulants (methylphenidate and dexamphetamine) guanfacine, as well as the antidepressants bupropion,
are the first-line pharmacological treatment for ADHD in venlafaxine and tricyclic antidepressants, have been
children and adults. The effectiveness of stimulants was mentioned in international guidelines. They are, howev-
found in 70% of patients in various controlled studies.4 er, not registered for use in ADHD treatment in South Af-
rica. Anticonvulsants, mood stabilisers, selective seroto-
Stimulants nin reuptake inhibitors and antipsychotic drugs may be
useful in treating comorbid conditions, although they
Methylphenidate have not shown to be effective in treating the primary
symptoms of ADHD.10
Methylphenidate (MPH) reduces not only the core
symptoms of ADHD, but also improves academic per- Non-pharmacological interventions
formance, on-task behaviour and social functioning.10
There is also an improvement in self-esteem, emotional Psychotherapy
regulation, cognitive problems, occupational problems
and family functioning.4,10 Side effects of MPH are usually Pharmacotherapy alone is usually insufficient to stabilise
mild and transitory. These include headache, reduced the many challenges in adults with ADHD. Various treat-
appetite, palpitations, nervousness, initial insomnia and ment guidelines recommend a multi-modal treatment
dry mouth. The use of stimulants is contra-indicated in where psychosocial interventions are used along with
patients with psychosis, tics and hypertension, as these psychopharmacological treatments to treat comor-
conditions may be exacerbated by this medication.7 bidities and residual symptoms that cannot be treated
with medications. Psychosocial interventions can also
Stimulant medications have the potential for abuse provide support and improve the acceptance of the
due to their mechanism of action. They increase lev- diagnosis.10 The majority of evidence supports the use
els of dopamine in the human brain, which is the same of cognitive behavioural therapies (CBT).7 Mindfulness
mechanism that makes drugs of abuse exert their re- awareness therapy can also be used as a complemen-
warding effects. This risk is increased among patients tary intervention. Other psychotherapy interventions in-
with a history of substance-use disorder.7 Therefore the clude coaching, which is a structured, supportive ther-
preferred choice is an extended-release formulation apy that can be in the form of an individual or a group
with a slow rate of serum rise. It also has the benefit of session. The aim of coaching is to teach problem-solving
better adherence, fewer rebound symptoms and less skills for identified practical problems.10
frequent dosing than in the short-acting formulation.4,10
Currently, physicians often prescribe a combination Exercise
of immediate- and extended-release preparations in
adults. This is to tailor the dosage regimen to each par- Acute aerobic and longer-term exercise activities have
ticular patient’s needs.4 Combination preparations are been shown to have a positive effect on neuropsycho-
now available in South Africa, making this treatment logical function in ADHD.10
choice more affordable. The general recommended
starting dose is 1 mg/kg. However, this must be individu- When to refer
ally adjusted, based on efficacy and tolerability.10
According to The South African Society of Psychiatrists
Lisdexamphetamine guidelines, adults presenting with symptoms sugges-
tive of ongoing ADHD who have been previously diag-
Lisdexamphetamine is recommended as a second-line nosed with ADHD during childhood should be referred
treatment for adults who develop intolerable side ef- to general adult psychiatric services for confirmation of
fects to MPH. It has also been found that it has a lower diagnosis and ongoing treatment. Adults with suspect-
liability for recreational abuse, which makes the drug a ed ADHD without previous diagnosis during childhood
better choice for patients with a dual diagnosis of ADHD should be referred to and be assessed by a specialist
and a substance use disorder.10 Common side effects psychiatrist with adequate training and experience in
of lisdexamphetamine include insomnia and irritability. assessments of adults with suspected ADHD for confir-
However, dizziness, appetite suppression with weight mation of diagnosis and treatment initiation.11
loss, headache and other gastro-intestinal side effects
have also been reported.10
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 115
Recommendations/ indicators for referral to psychia- Treatment approaches
tric services also include:
• Difficulty establishing a retrospective diagnosis of
childhood ADHD
• When the clinician is unable to establish a clear
DSM 5 diagnosis of ADHD
• Significant psychiatric comorbidity
• Contra-indications to stimulant use in the patient
• Failure of first-line treatment of adult ADHD
Conclusion
Although adult ADHD diagnosis and treatment may be
viewed with apprehension, this review aims to assist with
expanding the understanding of this disorder by prac-
titioners. Diagnosis should entail an extensive psychia-
tric work-up, including exploration of the developmen-
tal history, both a retrospective and current account
of ADHD symptoms and impairment, and associated
comorbidities, before initiating treatment. Information
should not only be gathered from the patient, but also
from reliable informants.4 It is important for general prac-
titioners to be able to recognise patients presenting with
adult ADHD to allow them to be able to treat and, if
necessary, refer accordingly.
REFERENCES
1. Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence
and correlates of adult attention-deficit hyperactivity disorder. Br J
Psychiatry. 2007;190:402-9.
2. Van Schalkwyk G, Schronen J. Attention-deficit hyperactivity dis-
order in adults: A guide for the general practitioner. Official Journal
of the South African Academy of Family Practice/Primary Care.
2014 Aug;53(2):131-134.
3. McGough J. Treatment controversies in adult ADHD. Am J Psychia-
try. 2016 Oct 1;173(10):960-966.
4. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement
on diagnosis and treatment of adult ADHD: The European Network
Adult ADHD. BMC Psychiatry. 2010, 10:67-10.1186/1471-244X-10-67.
5. Schoeman R, De Klerk M. Adult attention-deficit hyperactivity dis-
order: A database analysis of South African private health insur-
ance. S Afr J Psychiat. 2017;23,a1010.
6. Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s synopsis of psy-
chiatry: Behavioral sciences/clinical psychiatry (eleventh edition).
Philadelphia: Wolters Kluwer; 2015.
7. Volkow ND, Swanson JM. Clinical practice: Adult attention deficit-
hyperactivity disorder. N Engl J Med. 2013;369(20):1935-44.
8. American Psychiatric Association. Diagnostic and statistical manual
of mental disorders (5th ed). Arlington: American Psychiatric Asso-
ciation Publishing; 2013.
9. Bukstein O. Attention deficit hyperactivity in adults: Epidemiology,
pathogenesis, clinical features, course, assessment and diagnosis.
UpToDate. Accessed December 2018 from www.uptodate.com
10. Schoeman R, Liebenberg R. The South African Society of Psychia-
trists/Psychiatry management group management guidelines for
adult attention-deficit/hyperactivity disorder. South African Journal
of Psychiatry. 2107;23(1)1-14.
11. Atwoli L, Owiti P, Manguro G, Ndambuki D. Attention hyperactiv-
ity disorder symptom self-report among medical students in Eldoret,
Kenya. African Journal of Psychiatry. 2011.
12. Davidson MA. Literature Review: ADHD in Adults: A review of the
literature. Journal of Attention Disorders. 2008 June;11(6):628-41.
13. Acton A. Attention deficit hyperactivity disorders: New insights for
the healthcare professional. Atlanta: ScholarlyEditions; 2013.
HANDBOOK OF GENERAL MEDICINE VOL 1
116 TREATMENT APPROACHES
The primary management of depression
as a chronic disease
S Mashaphu years.6 Major depressive disorder occurs more frequent-
ly in people without close interpersonal relationships
MBChB (Natal), FC Psych (SA), MMed Psych (UKZN) and those who are divorced or separated. The preva-
lence of mood disorders does not differ among races.
Specialist Psychiatrist and Lecturer, Department of Psychiatry,
Nelson R Mandela School of Clinical Medicine, Aetiology
University of KwaZulu-Natal, Durban
Neurotransmitters
Major depressive disorder has the highest lifetime preva- Serotonin is the biogenic amine neurotransmitter most
lence of any psychiatric disorder worldwide.1 Those who commonly associated with depression. Depletion of ser-
suffer from depression experience persistent feelings of otonin occurs in depression and serotonergic agents are
sadness and hopelessness and lose interest in activities effective treatments. Abnormal levels of norepinephrine
they once enjoyed. Aside from the emotional problems are also found in blood, urine and CSF of depressed pa-
caused by depression, individuals can also present with tients. Dopamine activity is reduced in depression, and
physical symptoms, such as chronic pain, neurological drugs that reduce dopamine concentrations are also
manifestations or digestive problems. Depression is in- associated with depressive symptoms.
creasingly viewed as a chronic illness, as depressed in-
dividuals experience high rates of symptom recurrence Genetic
and sustained functional impairment.2 In recognition of Numerous family, adoption and twin studies have docu-
the chronicity of the condition, special emphasis should mented the heritability of mood disorders. Most recent-
be placed on the appropriate management and long- ly, linkage studies have been used to track the segre-
term care. This paper discusses the epidemiology and gation of specific chromosomal regions within families
aetiology of depression, its impact and burden on soci- affected with depression.
ety, and its diagnosis and treatment as a chronic illness.
Psychosocial
Major depressive disorder (MDD) is a widespread, of-
ten chronic, disorder affecting the individual, his or her Stressful life events often precipitate episodes of depres-
family, and society as a whole. It incurs tremendous sion and other mood disorders. Research has demon-
social and financial costs in the form of impaired rela- strated that stressors that the patient experiences as
tionships, lost productivity, and lost income. Although reflecting negatively on his or her self-esteem are more
chronic major depression is eminently treatable, it con- likely to produce depression.4 The stress accompanying
tinues to be poorly managed and under-recognised.2 the first episode may result in long-lasting changes in the
This is particularly true in primary care settings, where brain’s biology, which may alter the functional states of
clinicians are usually the first to encounter chronic de- various neurotransmitters. As a result, a person has a
pression, but are seldom trained to distinguish depres- high risk of undergoing subsequent episodes of a mood
sion from other medical illnesses with similar symptoms.2 disorder, even without an external stressor.
In addition, due to the stigma attached to depression,
patients often characterise their symptoms as part of a Persons with certain personality disorders, e.g. bor-
physical illness or fail to report them to a clinician at all. derline and histrionic, may be at greater risk for depres-
Depression remains undiagnosed in many people, re- sion. The psychodynamic understanding of depression
sulting in different levels of incapacity, disability, and in is also based on a theory that involves four points: the
the worst-case scenario, death through suicide.3 disturbances in infant-mother relationship during the
oral phase, real or imagined loss, introjection of the de-
Incidence and prevalence parted objects and feelings of anger and hate directed
towards the self. Losing a parent at a young age is also
Mood disorders are very common, with MDD repor- associated with high rates of depression later on.
ted as the most common mental health condition in
the general population. The global prevalence of de- Diagnosis
pressive symptoms has been increasing over the past
decades, and depression has been recognised as a The Diagnostic and Statistical Manual of Mental Dis-
leading cause of disability and a major contributor to orders (DSM-5) outlines the diagnostic criteria for major
disease burdens worldwide.4 The lifetime prevalence depressive episode as follows: the duration of a mini-
rate for MDD is 5 to 17%.5 There is a two-fold greater mum of two weeks of at least five of the list of symptoms
prevalence of major depressive disorder in women than which include change in appetite, weight change,
in men. The prevalence of depression may be affected change in sleep patterns, lack of energy, feelings of
by increased awareness and the availability of online guilt, problems making decisions and recurring thoughts
mental health information in the past two decades. The of suicide. At least one of the symptoms should be either
mean age of onset of depression is 40 years, with 50% of
all patients having onset between the ages of 20 and 50
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 117
depressed mood or loss of interest or pleasure. Depres- Significant weight changes Treatment approaches
sion may occur as a single episode or may be recurrent.
A major depressive disorder occurs without a history of One of the most common signs of depression is a
a manic, mixed or hypomanic episode. Table 1 lists the change in appetite, which can be an early sign of de-
DSM-5 diagnostic criteria for major depression. pression or an imminent relapse. While loss of appetite is
a common symptom of depression, feelings of sadness
Unpacking depressive symptoms or worthlessness can make some people overeat. De-
pression can also result in emotional eating, a common
The presentation of depression may differ from individual event in which the need to eat is not associated with
to individual. Some individuals may have increased ap- physical hunger. Emotional eating is eating in response
petite, while others may have reduced appetite. Some to emotional hunger. When patients eat in response to
may sleep a lot, while others would battle to fall asleep. their emotions, the food soothes them as it changes the
The individual symptoms of depression are clustered to- chemical balance in the brain, produces a feeling of
gether to form a syndrome, which may vary in duration fullness that is more comfortable than an empty stom-
and severity and are described in detail below. ach, and temporarily improves mood through positive
association with happier times.
Depressed mood
A person with depressed mood may report feeling low Sleep disturbances
or sad or empty most of the day, especially in the morn-
ing. The sadness and low mood of a major depressive Links between sleep and depression are strong. Dis-
episode is intense and can have a major impact on turbed sleep is a very distressing symptom that has a
an individual’s physical health, as well as occupational huge impact on quality of life in depressed patients.
and social functioning. About three quarters of depressed patients have insom-
nia symptoms, and hypersomnia is present in about 40%
Anhedonia of young, depressed adults and 10% of older patients,
Anhedonia is one of the main symptoms of a major de- with a preponderance in females.4 Some patients expe-
pressive episode. It is the loss of pleasure in previously re- rience both insomnia and hypersomnia during the same
warding or enjoyable activities, which is characterised depressive episode. The symptoms cause huge distress,
by a loss of interest in hobbies, friends, work, personal and are a strong risk factor for suicide.6 Poor quality of
care, food and sex. Depression may reduce the brain’s sleep may result in exhaustion, fatigue, headaches, ir-
hedonic capacity and ability to experience pleasure ritability and poor concentration, which are commonly
or pleasure may be experienced only briefly, not long reported together. Some sleep symptoms are often un-
enough to sustain involvement in pleasurable activities. resolved by treatment, and confer a greater risk of re-
Social withdrawal, self-isolation and apathy may be lapse and recurrence.
associated with anhedonia.4
Table 1. DSM-5 diagnostic criteria for major depressive episode5
• A. 5 (or more) of the following symptoms have been present during the same 2-week period and represent a change
from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to another medical condition.
- (1) Depressed mood most of the day, nearly every day
- (2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
- (3) Significant weight loss when not dieting or weight gain (e.g. a change of more than 5% of body weight in a
month), or decrease or increase in appetite nearly every day.
- (4) Insomnia or hypersomnia nearly every day
- (5) Psychomotor agitation or retardation nearly every day
- (6) Fatigue or loss of energy nearly every day
- (7) Feelings of worthlessness or excessive or inappropriate guilt nearly every day
- (8) Diminished ability to think or concentrate, or indecisiveness, nearly every day
- (9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide
attempt or a specific plan for committing suicide
• B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of
functioning.
• C. The episode is not attributable to the physiological effects of a substance or another medical condition.
• D. There has never been a manic episode or a hypomanic episode.
Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes are substance-induced or are
attributable to the physiological effects of another medical condition. The symptoms are not better accounted for
by bereavement.
HANDBOOK OF GENERAL MEDICINE VOL 1
118 TREATMENT APPROACHES
Psychomotor agitation or retardation Recurrent thoughts of death or suicide
Psychomotor retardation is described mostly as a sub- A suicide attempt is an event that may lead to a first
jective feeling of restlessness or being slowed down. Psy- contact with a healthcare professional who should be
chomotor agitation is technically the opposite of psy- able to recognise, assess and manage a suicidal pa-
chomotor retardation, which is characterised by restless tient, as many individuals may face the prospect of
symptoms, such as skin-picking or pacing around that suicide at some time in their lives. The underpinnings of
are caused by what may be described as mental ten- suicidal thoughts and behaviour are diverse and multi-
sion. However, both psychomotor impairment and agi- faceted, involving a unique combination of biological,
tation may occur within the same underlying cause in psychosocial and cultural factors for each individual.
the same individual. The symptoms of psychomotor Common reasons for self-inflicted death that require
impairment may vary between individuals and may further exploration by the clinician include the following:
be easily confused with certain medical or neurologi- • An escape from despair and suffering
cal symptoms. These impairments may cause issues with • A relief from intractable emotional, psychological or
muscle function and speech, which can then lead to
problems with everyday tasks, such as personal groom- physical pain
ing, performing household chores, socialising and daily • A response to a stigmatising illness
communication skills. Agitation or retardation may also • A consequence of intoxication
impact negatively on occupational functioning, for ex- • A response to commanding homicidal or self-harm
ample, grabbing objects or walking up stairs may prove
difficult. There may be a possible correlation between auditory hallucinations
anhedonia, fatigue, psychomotor retardation and re- • A manifestation of bizarre or grandiose delusions
duced libido because in all four symptoms, tasks that • A declaration of religious devotion
are often viewed as “normal,” may be challenging and • A testimony of nationalist or political allegiance
overwhelming for the individual. • A means of atonement
• A means of reunification with a deceased loved one
Fatigue or loss of energy • A means of rebirth
• A method of revenge
Individuals with depression often report fatigue without • A way to protect family honour
any underlying cause. The fatigue of depression is gen-
erally associated with erratic sleeping patterns that may Unfortunately, many suicidal individuals may not spon-
lead to exhaustion. The fatigue may also fuel apathy and taneously express suicidal thoughts or plans to their health-
anhedonia because individuals with depression often care provider, and the majority of those at risk may never
feel tired and avoid participating in any activities. Sexual be asked about suicidality during clinical assessments.
activities may also be affected by the combination of
fatigue, anhedonia and psychomotor retardation. Diagnosis using rating scales
Feelings of worthlessness or excessive Depression can be reliably diagnosed and treated by
primary health physicians in the community using only
or inappropriate guilt the DSM-5 diagnostic criteria, but the routine use of
rating scales should be incorporated into daily clinical
According to Dr. A Beck, individuals with depression feel practice. The appropriate use of rating scales will help
defeated, defective, deserted and deprived.7 Most in- clinicians to document and quantify symptoms and
dividuals with depression see themselves as deficient in monitor treatment outcomes, especially during follow-
intelligence, achievement, popularity, attractiveness, up. The examples of commonly used rating scales for
health and strength. Almost all negative emotional re- depression include the Zung Self-Rating Depression
actions contribute to feelings of low self-esteem. These Scale, the Raskin Depression Scale and the Hamilton
feelings may also be linked to low libido, presumably Rating Scale for Depression (HAM-D).4
because of feeling unattractive or unworthy, and re-
duced interest in enjoyable activities, or not deserving The burden of depression
to experience pleasure.
Depression often runs a chronic course and substan-
Diminished ability to concentrate tially impairs an individual’s occupational potential and
quality of life. The World Health Organization (WHO,
and indecisiveness 2002) predicted that by the year 2020, depression will
This is generally described as feeling forgetful and hav- rank second in global disease burdens. Important fac-
ing trouble focusing. Research has suggested that pro- tors that may be contributing towards this increase in-
cessing speed, the ability to take in information quickly clude population growth, increase in MDD prevalence,
and efficiently is impaired in individuals who are de- increase in treatment cost per individual and access
pressed.8 The inability to concentrate also makes it more to treatment.9 Suicide is another global public health
difficult for patients to make even small decisions and in- problem, with mortality rates that continue to increase
decisiveness and lack of focus are some of the reasons in most countries. According to the WHO, data from the
depression has such a major social and occupational United States indicate that suicide deaths are almost
impact because affected individuals find it harder to 40% higher than homicidal deaths. The cost of treating
keep up with relationships and perform well at work.8 depression is enormous, and a deeper understanding
and effective treatment are urgently needed in order
HANDBOOK OF GENERAL MEDICINE VOL 1 to improve the composition and quality of treatment
services.
TREATMENT APPROACHES 119
Treating depression g) After remission, it is advised to continue with anti- Treatment approaches
depressants as maintenance treatment for at least 6
Treatment setting months, to prevent relapse. The antidepressant dos-
age required to achieve remission should be contin-
Major depressive episodes are treatable in 70% to 80% ued during maintenance treatment. Long-term treat-
of patients4 and the most effective approach is to in- ment is indicated in patients with recurrent episodes.
tegrate pharmacotherapy with psychosocial interven- Table 2 shows the different classes of antidepressants,
tions. Psychiatric outpatient treatment services from
various treatment centres, both in the public and pri- dose ranges and side-effect profiles. Doses are for adults
vate sectors, are widely used by patients suffering from in good medical health, taking no other medications
depression and may be convenient for those who need and aged 18 to 60 years. Doses should be adjusted in the
to balance treatment with other responsibilities. presence of a medical condition, advanced age and
any other factors, such as tolerability and side effects.
Hospitalisation may also form part of a holistic ap-
proach to treatment in some cases of depression, e.g. Psychosocial interventions
where the risk of suicide or self-harm is high, in patients
who are unable to perform daily tasks or care for them- Psychotherapy, in conjunction with pharmacotherapy,
selves, when monitoring new treatments and when is more effective than either treatment alone in the
there is a need for treatments that are only given in hos- management of major depressive disorder.
pital, such as electroconvulsive therapy. Hospitalisation
also provides patients with an opportunity to recover in Supportive therapy of indeterminate length is indi-
a safe and stable environment, away from the stressors cated for major depressive disorder when the patient is
that may have contributed to the depression. Most gen- beginning to recover, but is not yet able to engage in
eral and psychiatric hospitals offer a variety of inpatient more demanding, interactive therapy.
psychosocial interventions, from short-term emergency
treatment of acute symptoms to long-term stays for Cognitive therapy is a short-term treatment, which
those who require comprehensive care. aims to correct the negative cognitions and the un-
conscious assumptions that underlie them, particularly
Pharmacotherapy the cognitive feelings of helplessness and hopelessness
about the past, the present and the future.
The objective of pharmacotherapy is symptom remis-
sion, not just symptom reduction. Patients with residual Behavioural therapies are highly structured and aim
symptoms, as opposed to full remission, are more likely at specific, circumscribed, undesired behaviours.
to experience a relapse or recurrence of mood epi-
sodes, and to experience ongoing impairment of daily Interpersonal therapy was developed as a specific
functioning. Overall, the treatment of mood disorders is short-term treatment for non-psychotic depression in
rewarding for clinicians. outpatients, and places emphasis on ongoing, current
a) Most clinicians begin treatment with a selective ser- interpersonal issues, as opposed to unconscious, intra-
psychic dynamics.
otonin reuptake inhibitor (SSRI). Early transient side
effects include anxiety, gastro-intestinal upset and Group therapy is gaining popularity because de-
headache. Patients who do not tolerate or respond pressed patients benefit from the support of interperson-
to one SSRI may respond to another. al group interactions and positive reinforcement from
b) Venlafaxine and duloxetine are serotonin-norep- other group members.
inephrine reuptake inhibitors that may be effective
in severe or refractory cases of depression, and the Family therapy is helpful when the patient’s depres-
response rate increases with higher doses. sion is disrupting family stability, when depression is re-
c) Nefazodone has strong serotonergic properties; it lated to family events or when it is maintained by dys-
has beneficial effects on sleep and low sexual side functional family patterns.
effects.
d) Mirtazapine has antihistamine, noradrenergic and Referral to specialist mental
serotonergic actions, which translate to reduced
anxiety, sedation and weight gain. Some of the side health services
effects, such as sedation and weight gain, may be
desirable in patients with insomnia and weight loss. The majority of people with depression can be treated
e) Tricyclics are highly effective, but they require dose effectively in primary care. Those who are considered
titration and close monitoring due to anticholinergic a risk to themselves, fail to respond to treatment after
and cardiac side effects and lethality in overdose re- three months, or whose depressive symptoms worsen
mains a great concern. should be referred for specialist opinion. Patients who
f) Augmentation strategies in treatment-resistant or are referred to Mental Health Services usually want their
partially responsive patients include lithium, carba- GP to remain involved in their care.
mazepine, sodium valproate, buspirone, quetiapine
or a combination of two antidepressants, such as bu- In summary
propion and an SSRI.
The most common clinical mistake leading to an unsuc-
cessful trial of an antidepressant is the use of too low a
dose for too short a time. Unless adverse events prevent
it, the dose of an antidepressant should be raised to the
maximum recommended level and maintained for at
least six weeks before a trial is considered unsuccessful.
Alternatively, if a patient is improving clinically on a low
HANDBOOK OF GENERAL MEDICINE VOL 1
120 TREATMENT APPROACHES
Table 2. Classification, doses, safety and side effects of antidepressants10
Mechanism of action and functional Starting Standard Lethality in Side effects
classification dose dose overdose
Insomnia
Sedation Hypoten- Anticho- Nausea or Sexual Weight
and agita- sion linergic gastrointes- dysfunction gain
tion effects† tinal effects
Reuptake inhibitors mg/day
20-40
Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine (Prozac) 20 Low Moderate None or None or None or Moderate Moderate Mild
mild mild mild
Paroxetine (Paxil) 20 20-40 Low Moderate None or None or Mild Moderate Moderate Mild
mild mild
Sertraline (Zoloft) 50 50-150 Low Moderate None or None or None or Moderate Moderate Mild
mild mild mild
Fluvoxamine (Luvox) 50 100-250 Low Moderate Mild None or None or Moderate Moderate Mild
mild mild
Citalopram (Celexa) 20 20-40 Low Moderate None or None or None or Moderate Moderate Mild
mild mild mild
Escitalopram (Lexapro) 10 10-20 Low Moderate None or None or None or Moderate Moderate Mild
Selective norepinephrine reuptake inhibitors (NRIs) mild mild mild
None or None or None or
Reboxetine (Edronax)‡ 4-8 8-12 Low Mild Mild Mild None or
mild mild mild mild
None or Mild
Nonselective norepinephrine reuptake inhibitors
Desipramine (Norpramine) 25-50 100-300 High Mild Moderate Mild None or Mild
Nortriptyline (Pamelor) 25-50 75-200 High Mild mild Mild Mild mild Mild Mild
Mild None or
mild
Maprotiline (Ludiomil) 75 75-200 High Mild None or Mild Mild None or Mild Moderate
mild mild
Mixed or dual-action reuptake inhibitors
Older agents (TCAs)
Amitriptyline (Elavil) 25-50 100-300 High None or Moderate Moderate Severe None or Mild Moderate
Dothiepin (Dothep)‡ 25-50 100-300 High mild mild Mild Moderate
None or Moderate Moderate Moderate None or
Clomipramine (Anafranil) 25-50 100-250 High mild Moderate Moderate Moderate mild Mild Moderate
Imipramine (Tofranil) 25-50 100-300 High Mild Mild Moderate Moderate Mild Mild Moderate
Moderate None or
Newer agents (non-TCAs) 37-75 75-225 Moderate Moderate None or None or None or mild
Venlafaxine (Effexor) (NRI plus SRI) Moderate Moderate None or
Milnacipran (Ixel) (NRI plus SRI)‡ 50-100 100-200 Low mild mild mild mild
Moderate None or None or None or Moderate Moderate None or
Bupropion (Wellbutrin) (NRI plus DRI) 150 150-300 Low mild mild mild Mild None or mild
Moderate None or None or Mile None or
Duloxetine (Cymbalta) (NRI plus SRI) 30 30-90 Low None or mild mild Mild Mild mild mild
Mild None or None or None or
mild mild mild mild
MAOIs 15 30-90 High Moderate Mild Moderate Mild Mild Moderate Mild
Irreversible agents
Phenelzine (Nardil) 10 20-60 High Moderate Mild Moderate Mild Mild Moderate Mild
Tranylcypromine (Parnate)
Isocarboxazid (Marplan) 20 20-60 High Moderate None or Moderate Mild Mild Moderate Moderate
mild
Selegiline (Eldepryl) 10 20-40 Moderate Mild None or Mild Mild Mild Mild Mild
mild
Reversible agents 150 300-600 Low Mild None or None or Mild Mild None or None or
Moclobemide (Manerix)‡
Mixed-action newer agents 30-60 Low None or mild mild None or None or mild mild
Mirtazapine (Remeron) (5-HT2 plus 5-HT3 30 Severe Mild None or Severe
plus a2-adrenergic receptors) 30 60-120 Low mild Moderate Mild mild mild mild Mild
Mianserin (Bolvidon) (5-HT2 plus a1- None or Mild None or None or
and a2-adrenergic receptors)‡ 300-600 Low mild Moderate Mild MIld mild mild Mild
Nefazodone (Serzone) (5-HT2 receptors) 100 None or Mild None or
Trazodone (Desyrel) (5-HT2 plus 50-100 200-600 Low mild Severe Mild None or Mild mild
None or Moderate Mild
a1-adrenergic receptors) mild mild
*These doses are standard in psychiatric practice, but may not always conform to doses recommended in the Physician's Desk Reference or drug package
insert. More detailed reviews of side effects for all classes of antidepressants may be found in the Guidelines of the American Psychiatric Association 2000 and
the Agency for Health Care Policy and Research 1999. NRI denotes norepinephrine-reuptake inhibitors, TCA tricyclic antidepressant, SRI serotonin reuptake
inhibitor, MAOI monoamine oxidase inhibitor, and DRI dopamine reuptake inhibitor.
† – Symptoms include dry mouth, constipation, sweating, blurred vision, and urinary retention.
‡ – This drug is not available in the United States.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 121
dosage of the drug, this dosage should not be raised un- Treatment approaches
less clinical improvement stops before maximum benefit
is obtained. When episodes are less than two-and-a-half
years apart, prophylactic treatment for five years is indi-
cated. Episodes that have involved significant suicidal
ideation or impairment of psychosocial functioning indi-
cate the need for prophylactic treatment.
Medication and psychotherapy are often used in
combination. Some clinicians may view mood disorders
as fundamentally evolving from psychodynamic issues
and their ambivalence about the use of drugs may re-
sult in a poor response, non-compliance and probably
inadequate dosages for too short a time. Alternatively, if
clinicians ignore the psychosocial needs of a patient, the
outcome of pharmacotherapy may be compromised.
References
1. Brody DJ, Pratt LA, Hughes JP. Prevalence of depression among
adults aged 20 and over: United States, 2013-2016. NCHS data brief.
2018(303):1-8.
2. Rost K, Nutting P, Smith JL, Elliott CE, Dickinson M. Managing depres-
sion as a chronic disease: A randomised trial of ongoing treatment
in primary care. BMJ. 2002;325(7370):934.
3. Solomon A. The noonday demon: An atlas of depression. New
York: Scribner; 2000. American Journal of Health-System Pharmacy.
2002;59(21):2130.
4. Kaplan BJ. Kaplan and Sadock’s synopsis of psychiatry. Behav-
ioral sciences/clinical psychiatry. Tijdschrift voor Psychiatrie.
2016;58(1):78-9.
5. Association AP. Diagnostic and statistical manual of mental dis-
orders (DSM-5®). Arlington: American Psychiatric Association Pub-
lishing; 2013.
6. Ağargün MY, Kara H, Solmaz M. Sleep disturbances and suicidal
behavior in patients with major depression. The Journal of Clinical
Psychiatry. 1997.
7. Beck AT. Cognitive therapy of depression: Guilford Press; 1979.
8. Fried EI, Nesse RM. The impact of individual depressive symp-
toms on impairment of psychosocial functioning. PLoS One.
2014;9(2):e90311.
9. Greenberg PE, Fournier A-A, Sisitsky T, Pike CT, Kessler RC. The
economic burden of adults with major depressive disorder in the
United States (2005 and 2010). The Journal of Clinical Psychiatry.
2015;76(2):155-62.
10. Mann JJ. The medical management of depression. New England
Journal of Medicine. 2005;353(17):1819-34.
HANDBOOK OF GENERAL MEDICINE VOL 1
122 TREATMENT APPROACHES
HIV management and antiretroviral therapy
in adults – an update
CN Menezes Impact on society
MD, MMed (Int Med), Dip HIV Mang (SA), DTM&H, FCP (SA), The majority of HIV-infected individuals in Africa are be-
Cert ID (SA) tween the ages of 15 and 49 years,3 in the prime of their
working lives, and as a result, labour is affected, hinder-
Principal Specialist, Division of Infectious Diseases, ing economic progress. The reduced ability to work has
Department of Internal Medicine, pushed affected households deeper into poverty. A
Chris Hani Baragwanath Academic Hospital, good basic education ranks among the most effective
University of the Witwatersrand, Johannesburg and cost-effective means of preventing HIV, but be-
cause parents are ill and are unable to work, children
DL Reddy have taken on the added responsibility of earning an
income and providing care for the family.
MBChB, MMed (Int Med), Dip HIV Man (SA), DTM&H, FCP (SA),
Cert ID Phys (SA) Pathophysiology
Specialist, Division of Infectious Diseases, HIV-1 transmission occurs through unprotected sexual
Department of Internal Medicine, intercourse, mother-to-child transmission, contaminat-
Chris Hani Baragwanath Academic Hospital, ed needles or blood products. HIV binds to CD4-bear-
University of the Witwatersrand, Johannesburg ing cells which include T-helper cells, monocytes/mac-
rophages, microglial cells and dendritic cells. It does this
According to the World Health Organization (WHO), by attaching to the CD4 receptor and its co-receptors,
36.9 million people worldwide were living with the hu- either chemokine receptor 5 (CCR5) or chemokine re-
man immunodeficiency virus (HIV) in 2017 and of these, ceptor 4 (CXCR4), on the surface and enters the cell.
1.8 million were newly infected during that year.1 There It then releases its RNA and enzymes, reverse tran-
were approximately 940 000 HIV-related deaths globally scriptase, integrase, and protease, into the cell.4
in 2017.1 Sub-Saharan Africa continues to bear the bur-
den of HIV-1, with an estimated 68% of the HIV-1 infec- A single-stranded RNA genome is then transcribed
tions worldwide.1 into double-stranded DNA, using the reverse tran-
scriptase enzyme, and integrated into the host chromo-
South Africa had an estimated 7.2 million people living some. This viral DNA is transported into the cell nucleus,
with HIV in 2017, with 4.35 million on antiretroviral thera- and integrated into the cell’s genome by the integrase
py (ART).1 Despite having one of the highest burdens of enzyme. Using the host’s nuclear transcription process-
this epidemic, there has been a noticeable decline in
new HIV-1 infections in South Africa.2
Table 1. Drugs available in South Africa5
Drug Dosage
NRTIs
Tenofovir (TDF)* 300 mg once daily
Lamivudine (3TC) 150 mg 12-hourly or 300 mg once daily
Zidovudine (AZT) 300 mg 12-hourly
Emtricitabine (FTC) 200 mg once daily (in combination with tenofovir)
Abacavir (ABC) 300 mg 12-hourly or 600 mg once daily
Stavudine (d4T) 30 mg 12-hourly (but no longer than six months)
NNRTIs
Efavirenz (EFV) 600 mg once at night
Nevirapine (NVP) 200 mg once daily for 14 days then 200 mg 12-hourly
Etravirine (ETR) 200 mg 12-hourly
PIs
Lopinavir/ritonavir (LPV/r) 400/100 mg 12-hourly
Atazanavir (ATV) 400 mg daily (only if ART-naïve) or preferably 300 mg with ritonavir 100 mg daily
Darunavir (DRV) 600 mg 12-hourly with 100 mg ritonavir 12-hourly or 800/100 mg daily (only if PI-naïve)
InSTI
Raltegravir (RAL) 400 mg 12-hourly
Dolutegravir (DTG) 50 mg daily
NRTI – nucleoside reverse transcriptase inhibitor; *NtRTI – nucleotide reverse transcriptase inhibitor; NNRTI – non-nucleoside reverse transcriptase
inhibitor; PI – protease inhibitor; InSTI – integrase strand transfer inhibitor.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 123
es, viral proteins are produced and cleaved into active bodies. This is helpful in terms of shortening the window Treatment approaches
forms by the protease enzyme and are packaged into period, which is defined as the time between HIV infec-
new virions ready to infect more cells.4 tion and appearance of antibodies to HIV, as HIV anti-
gen is present in the blood much earlier than antibodies
Classes of available antiretroviral to HIV can be detected. A fourth-generation ELISA test
drugs that is able to detect both the antigen and antibody in
one test is available in most South African laboratories.
The five classes of antiretroviral drugs that are available
include the nucleoside reverse transcriptase inhibitors Baseline investigations prior to ART initiation – These
(NRTIs), analogues that mimic normal building blocks must include a full blood count (FBC), a liver-function
of DNA, preventing transcription of viral RNA to DNA; test, a serum creatinine, a urinalysis for proteinuria, a
non-nucleoside viral reverse transcriptase inhibitors (NN- hepatitis B surface antigen, a CD4 count, a HIV viral
RTIs), that fit into the genomic binding site of reverse load and a serum cryptococcal antigen test.5,6
transcriptase and directly inhibit its action; protease
inhibitors (PIs) that inhibit the viral protease enzyme, Laboratory monitoring on ART – In order to monitor for
therefore inhibiting the final maturation stages of HIV antiviral therapy efficacy, CD4 counts should be per-
replication, resulting in non-infective viral particles; entry formed every six months. Viral loads should be performed
inhibitors that bind to the viral gp41, the host cell CD4 or at three months, repeated at six months and then every
chemokine receptors and block the entry of the HIV into six months thereafter. A good indication of a response to
the host cell; and integrase inhibitors that block the viral ART includes a suppression of the viral load to <50 cop-
DNA integration into the host cell genome.5 The drugs ies/ml or >2 log drop from baseline in those patients with
available in South Africa by class are listed in Table 1. a very high viral load at baseline. A FBC should be per-
formed monthly for three months, then after six months
Management on zidovudine (AZT) and thereafter when clinically indi-
cated. A serum creatinine should be performed at three
Counselling months, six months, one year, and then every 12 months
In addition to pre- and post-test counselling for HIV- if on tenofovir (TDF). Fasting cholesterol and triglycerides
testing, patients should receive adherence to therapy should be performed at three months if on lopinavir/rito-
counselling and screening for opportunistic infections navir (LPV/r), then annually only in those with other car-
prior to initiation of therapy. The patient should be diovascular-risk factors.5,6 Other serum biochemical tests
taught the names of the drugs, how often they should should be carried out as clinically indicated.
be taken and their side effects, which are generally
transient and mild (see Tables 1 and 2).5,6 Indications for ART
Investigations The goals of ART are to suppress viral load, restore im-
mune function, reduce morbidity and mortality, and
Diagnosis of HIV infection - The laboratory diagnosis is prevent onward transmission of HIV.5
dependent on the detection of HIV antigen and its anti-
Early initiation of antiretroviral therapy is now widely
recommended and supported by high-quality clinical
trial evidence, given the potency, simplicity, and safety
Table 2. Acute and chronic toxicities
Anaemia5,10
• A macrocytosis is common with d4T and AZT.
• AZT can cause an anaemia.
• 3TC and FTC have been associated with a pure red cell aplasia (PRCA). Parvovirus B19 infection-induced PRCA should be
excluded by a PCR test.
Dysglycaemia5,11
• Visceral fat gain, which occurs to a similar extent with all ART classes, is associated with insulin resistance.
• Blood glucose should be assessed as part of a cardiovascular-risk assessment.
Dyslipidaemia5,11
• Associated with all classes. All PIs with the exception of unboosted ATV can cause fasting hypertriglyceridaemia and
elevated LDL-cholesterol. d4T can cause mild hypertriglyceridaemia. EFV can cause elevated total cholesterol and mild
hypertriglyceridaemia.
• Indications for statin therapy in a HIV-infected patient should be the same as in an uninfected patient, but if the patient is
receiving a PI, a switch to boosted ATV is a better option, rather than adding therapy for the dyslipidaemia. Switching the PI
to RAL is another option, but only if used in a regimen with two other fully active drugs.
• Statins have interactions with PIs that can lead to toxic concentrations, except pravastatin and fluvastatin. Atorvastatin
concentrations are significantly raised by PIs, but lower doses of 10 mg daily may be used. Lovastatin and simvastatin should
not be used as a severe rhabdomyolysis can occur.
Gynaecomastia5,11
• Bilateral or unilateral development of breast tissue in men.
• Not related to lipodystrophy.
• Associated with EFV, so patients should be switched to either NVP (only if CD4 <400), a PI or an InSTI
HANDBOOK OF GENERAL MEDICINE VOL 1
124 TREATMENT APPROACHES
Table 2. Acute and chronic toxicities (continued)
Hepatotoxicity5,13
• Commonly associated with NNRTIs. In patients starting NVP, ALT should be monitored at two, four, eight and 12 weeks after
initiation.
• Mild ALT elevations can rarely occur with NRTIs and are usually transient. ALT elevations >5xULN are significant. Prolonged
use of NRTIs, especially d4T, may cause fatty liver.
• Isolated unconjugated hyperbilirubinaemia is associated with ATV.
• Patients with underlying hepatitis B or C infection frequently experience a “flare’”of hepatitis when ART is commenced, as
a consequence of IRIS. Hepatitis B can also flare when drugs that have activity against hepatitis B (TDF, 3TC and FTC) are
discontinued or when hepatitis B resistance develops.
• Antituberculosis agents and azoles can cause hepatotoxicity.
• Hepatotoxic drugs should be discontinued at high levels of LFT abnormality or at lower levels with symptoms of hepatitis.
Patients must be assessed for features of hepatic failure.
• In selected cases, re-challenge of drugs may be attempted, but under the supervision of a specialist.
Hypersensitivity5
• Rash with NNRTIs is common, especially with NVP. There is a cross-reaction between NVP and EFV.
• If the rash is mild, the NNRTI can be continued and the rash treated symptomatically with antihistamines and topical ste-
roids.
• If accompanied by a fever, hepatitis, mucosal involvement or blistering, the NNRTI should be stopped immediately. Re-
challenge of the drug should never be attempted.
• ABC hypersensitivity occurs within the first eight weeks of use; therapy must be discontinued and never re-introduced.
Hyperlactataemia syndromes5,11
• Lactic acidosis is a fatal side effect mostly associated with d4T. Symptomatic hyperlactataemia without acidosis is more common.
• Risk factors include female gender, obesity, and NRTIs use for >6 months, peripheral neuropathy and fatty liver disease.
• Management depends on the lactate and bicarbonate concentrations:
1. Lactate <5 mmol/L and minor symptoms: NRTIs should be switched to either TDF or ABC. Symptoms and serial lactate
should be monitored until normal.
2. Lactate >5 mmol/L and bicarbonate >15 mmol/L: NRTIs should be discontinued. Admit patient. Exclude other causes.
Symptoms and serial lactate should be monitored until normal.
3. Lactate >5mmol/L and bicarbonate <15 mmol/L: NRTIs should be discontinued. Refer for urgent specialist inpatient
care. Sodium bicarbonate may be used to partially correct severe acidosis. Blood cultures should be drawn and
broad-spectrum antibiotics can be used as sepsis can mimic NRTI-induced lactic acidosis. On recovery, all NRTIs must
be avoided in all future regimens.
Lipodystrophy5,11
• Associated with long-term ART use.
• Present with fat loss (lipoatrophy, presenting as facial-, limb- and buttock-wasting) or fat accumulation (visceral obesity,
breast enlargement, buffalo hump or lipomata) or with both. Visceral fat accumulation is associated with insulin resistance
and dyslipidaemia.
• AZT and d4T associated with lipo-atrophy. PIs associated with lipohypertrophy.
• The effects can be reversed, although this may be slow, or incomplete, with antiretroviral drug substitution, such as d4T/AZT
with TDF or ABC.
• Exercise or diet may reduce abdominal fat.
• Metformin can reduce insulin resistance and cardiovascular-risk parameters, but the concurrent use of d4T may increase
the risk of lactic acidosis.
• Cosmetic surgery is an option for facial lipoatrophy or in those with prominent buffalo humps.
Nephrotoxicity5,14
• TDF can cause acute renal failure, and rarely a tubular wasting syndrome where patients may develop muscle weakness or
other muscle symptoms. Potassium and phosphate levels must be checked.
• In patients with comorbidities such as hypertension or diabetes, creatinine should also be checked at one and two months.
Nephrotoxic agents, such as aminoglycosides or NSAIDs, should generally be avoided.
• In renal failure, TDF must be stopped. With all NRTIs except ABC, the dose needs to be adjusted according to GFR.
Neuropsychiatric toxicity5,15
• Neuropsychiatric effects, such as insomnia, vivid dreams and dizziness, are commonly associated with EFV in the first few
weeks of therapy, and subside within the first four to six weeks. Psychosis may occasionally occur. EFV neurotoxicity may
manifest as a pancerebellar syndrome and is more common in women with a low BMI; concomitant use of isoniazid is a risk
factor. EFV levels should be drawn and refer to a specialist.
• If not tolerated, then the patient should be switched to NVP (only consider if CD4 <250 in women and CD4 <400 in men) or LPV/r.
• Insomnia and headache, in addition to weight gain, are known side effects of DTG
• Peripheral neuropathy is commonly associated with the use of d4T, although other causes should be excluded. Pain control
and assistance with the activities of daily living are the mainstay of therapy. Some patients may require a switch in their an-
tiretroviral therapy. For milder forms of pain, NSAIDs may be prescribed. Antidepressants, such as amitriptyline, can be used.
Anticonvulsants, such as gabapentin and carbamazepine, are also effective in reducing pain.
d4T – stavudine; AZT – zidovudine; 3TC – lamivudine; FBC – full blood count; PCR – polymerase chain reaction; PRCA – pure red cell aplasia;
ART – antiretroviral therapy; PI – protease inhibitor; ATV – atazanavir; LDL – low-density lipoprotein; EFV – efavirenz; RAL – raltegravir; NVP – nevirapine;
NNRTI – non-nucleoside reverse transcriptase inhibitor; ALT – alanine transaminase; NRTI – nucleoside reverse transcriptase inhibitor; ULN – upper
limit of normal; IRIS – immune reconstitution inflammatory syndrome; TDF – tenofovir; FTC – emtricitabine; LFT – liver-function test; ABC – abacavir;
BMI – body mass index; NSAIDs – nonsteroidal anti-inflammatory drugs; GFR – glomerular filtrate ratio; LPV/r – lopinavir/ritonavir; NSAIDs – nonsteroidal
anti-inflammatory drugs
HANDBOOK OF GENERAL MEDICINE VOL 1
LEPETTA 083 415 6431 10046T Dolutegravir 50 mg + Lamivudine 300 mg
A CLEAN AND CLEAR FIRST CHOICE1,2 + Tenofovir disoproxil fumarate 300 mg
A dolutegravir-based fixed dose combination
regimen for first-line ART in adults*1-3
A new era for first-line ART rooted in the need for a healthier future1,4
Adcock Ingram ARVs: unwavering commitment to quality and
a ordability for people living with HIV
*Women of childbearing potential should be using consistent and reliable contraception2
Caution is advised when prescribing Nuvaco to women of child bearing age as there is an associated risk of neural tube defects to children exposed to (DTG/Nuvaco) during pregnancy.
ART: antiretroviral therapy; ARV: antiretroviral
References: 1. Meintjes G, Moorhouse MA, Carmona S, et al. Adult antiretroviral therapy guidelines 2017. S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776. 2. Updated recommendations on rst-line and second-line antiretroviral regimens and
post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. Geneva: World Health Organization; July 2018 (WHO/CDS/HIV/18.18). Licence: CC BY-NC-SA 3.0 IGO. 3. NUVACO approved package insert, October 2018. 4. Dlamini N.
Health minister sees new ARV drug as breakthrough in ght against HIV. The South African National AIDS Council. 2017 Oct 2 [cited 2018 Oct 19]; Available from: http://sanac.org.za/2017/10/02/health-minister-sees-new-arv-drug-as-breakthrough-in- ght-against-hiv/.
Nuvaco lm coated tablet. Each lm-coated tablet contains Lamivudine 300 mg, Tenofovir disoproxil fumarate 300 mg, Dolutegravir sodium equivalent to dolutegravir 50 mg. Reg. No. 52/20.2.8/0949.
For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority. 2018111210108457.
Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Telephone + 27 11 635 0000. www.adcock.com
126 TREATMENT APPROACHES
of current regimens and the benefit of early therapy in Regarding NNRTI-based first-line regimens, EFV is pre-
terms of morbidity and mortality with the reduced risk of ferred. Both severe rash and hepatotoxicity are more
transmission.5-8 common with nevirapine (NVP) use with baseline CD4
cell counts above >250 cells/mm3 in women and >400
The most recent South African ART guidelines are now cells/mm3 in men. A PI may be used in first-line therapy if
in line with the WHO guideline, which recommends ini- there are contra-indications to InSTIs and NNRTIs.5-7
tiating ART regardless of CD4 count. There are specific
clinical scenarios in which ART should be deferred in pa- The two drug NRTI combinations that are recom-
tients with HIV, due to the risks of toxicity and immune mended for use with the InSTI or NNRTI include lami-
reconstitution inflammatory syndrome (IRIS).5-7 vudine (3TC) plus TDF, AZT or abacavir (ABC). Emtricit-
abine (FTC), which is similar to 3TC, and combined with
First-line therapy in an ART-naïve HIV-infected TDF in a fixed-dose combination pill or efavirenz (EFV)
patient as a triple-drug combination pill can also be used.5-7,9-10
All guidelines previously recommended a NNRTI and If TDF is unavailable or contra-indicated in patients
two NRTIs as first-line ART therapy. However, the InSTI do- with a creatinine clearance <50 ml/min, AZT should be
lutegravir (DTG) has been shown to be superior to efa- used, provided that haemoglobin >10 g/dL.9 ABC is an
virenz (EFV)-based ART in clinical trials, driven largely by option in patients with renal failure where TDF and AZT
the superior tolerability of DTG, which also has a higher cannot be used. It must not be used in patients with
barrier to resistance.5-7 DTG-based combination ART is baseline viral loads >100 000 copies/ml.5,6
available in the private sector and is already included
in the first-line regimen in the public sector in Botswana. Stavudine (d4T) may be used in the short term (three
The WHO ART guideline and the 2019 South African ART to six months) in patients with contra-indications to other
guideline for treatment of adults, which will soon be NRTIs, and then switched to ABC, AZT or TDF, depend-
rolled out, recommends use of DTG-based first-line ART ing on resolution of the anaemia or renal dysfunction,
for all men, for women and adolescent girls on effec- whilst monitoring for adverse events, such as the hyper-
tive contraception or not of childbearing potential, lactataemia syndromes and peripheral neuropathy.5,6,11
pregnant women (in second and third trimesters) and A non-TDF-based regimen must be considered if ne-
breastfeeding women.5-7 DTG may increase the risk of phrotoxic drugs are to be used, especially in the case of
neural tube defects, and should currently be avoided in multidrug-resistant TB (MDR)-TB, where aminoglycosides
periconception and in the first trimester of pregnancy.6 are used.5 The 2019 National South African ART recom-
mendations are listed in Table 3.6
Table 3. The South African national antiretroviral therapy guidelines6
First-line therapy
All new patients needing treatment, includ- TDF + FTC/3TC Contra-indications to DTG (pregnant women in
ing all men, women and adolescent girls on +DTG first trimester, women planning pregnancy or not
effective contraception or not of childbear- using reliable contraception): use EFV
ing potential, pregnant women (in 2nd and TDF + FTC/3TC Contra-indication to EFV (psychosis, shift work-
3rd trimesters) and breastfeeding women +EFV/NVP ers): use NVP
(documented consent to receive DTG in all Pre-existent liver disease or TB co-infection: EFV
women) preferred.
Contra-indication to TDF (renal disease): use AZT
Pregnant women in first trimester, women or ABC.
who wish to become pregnant and/or not Contra-indication to TDF (renal disease) and AZT
using reliable contraception (anaemia): use d4T or ABC.
Second-line therapy
Failing on a DTG-based first-line regimen AZT+3TC+LPV/r Patients with anaemia and renal disease: switch
(may require drug-resistance testing) or pa- AZT+3TC+DTG to ABC.
tients previously on a NNRTI-based first-line Dyslipidaemia or intractable diarrhoea associ-
regimen for whom DTG is unsuitable ated with LPV/r: switch to ATV/r
TDF should be added to second-line regimens if
Failing on a NNRTI-based first-line regimen hep B co-infection
and DTG is suitable (drug-resistance testing
not necessary)
Third-line therapy
Failing any second-line regimen Individualised regimen rec- Requires supervised care. Should be based
ommended by the national on genotype resistance testing and on expert
third-line committee, based on advice.
the patient’s genotype drug-
resistance profile and Stanford
score.
Regimen includes DRV and
may include InSTIs and/or ETR.
TDF – tenofovir; 3TC – lamivudine; AZT – zidovudine; FTC – emtricitabine; ABC – abacavir; d4T – stavudine; EFV – efavirenz; NVP – nevirapine;
ETR – etravirine; LPV/r – lopinavir/ritonavir; ATV – atazanavir; DRV – darunavir; InSTI – integrase strand transfer inhibitor, DTG – dolutegravir
HANDBOOK OF GENERAL MEDICINE VOL 1
300 mg Tenofovir Disoproxil Fumarate
300 mg Lamivudine
50 mg Dolutegravir
1 INSTI + 2 NRTIs = 3 in 1 combination: TLD
ONCE DAILY
A step forward in the treatment of HIV NEW
giving more people HOPE 1-4 FIXED
DOSE
A DTG based regimen may be recommended as a preferred
first-line regimen for people living with HIV initiating ART.4,5
DTG-based regimens vs. EFV/NNRTI regimens
• Offer faster viral suppression1,4,5
• Higher genetic barrier to resistance1,4,5,6
• Improve tolerability1,4,6
• Enhance treatment simplification and adherence1-5
ART= Antiretroviral therapy; EFV = Efavirenz; DTG = Dolutegravir; FDC = Fixed-dose combination;
HIV = Human Immunodeficiency Virus; INSTI = Integrase Strand Transfer Inhibitor;
NRTI = nucleoside reverse transcriptase inhibitor; NNRTI= Non-nucleoside reverse transcriptase inhibitor;
TLD = tenofovir disoproxil fumarate, lamivudine and dolutegravir
Reference: 1. Ripin D, Prabhu VR. A cost-savings analysis of a candidate universal antiretroviral regimen. Curr Opin HIV AIDS.
2017;12:403–407 2. Hill AM, Mitchell N, Hughes S, Pozniak AL. Risks of cardiovascular or central nervous system adverse events and
immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-analysis of randomized trials. Curr
Opin HIV AIDS. 2018;13:102–111 3. McCoy C, Badowski M, Sherman E, et al. Strength in Amalgamation: Newer Combination Agents
for HIV and Implications for Practice. Pharmacotherapy. 2018;38(1):86–107 4. World Health Organization. HIV/AIDS. Dolutegravir (DTG)
and the fixed dose combination (FDC) of tenofovir/lamivudine/dolutegravir (TLD). Briefing note - 30 April 2018. [cited 2018 Sept 13]
Available from: http://www.who.int/hiv/pub/arv/dtg-tld-briefing/en/ 5. World Health Organization. Policy Brief. HIV Treatment – Interim
Guidance. Updated Recommendations on First-Line and Second-Line Antiretroviral Regimens and Post-Exposure Prophylaxis and
Recommendations on Early Infant Diagnosis of HIV. July 2018. [cited 2018 Sept 13]. Available from: http://www.who.int/hiv/pub/
guidelines/ARV2018update/en/ 6. Vitoria M, Hill A, Ford N, et al. The transition to dolutegravir and other new antiretrovirals in low-
income and middle-income countries: what are the issues? AIDS 2018;32:1551–1561
S4 EMDOLTEN. Reg. No.: 53/20.2.8/0082. Each film-coated tablet contains tenofovir disoproxil fumarate 300 mg, lamivudine 300
mg and dolutegravir sodium equivalent to dolutegravir 50 mg. For full prescribing information refer to the professional information
approved by the medicines regulatory authority (10/2018). Trademarks are owned by or licensed to the Aspen Group of companies. ©
2018 Aspen Group of companies or its licensor. All rights reserved. Marketed by Aspen Pharmacare for Pharmacare Limited. Co. Reg.
No.: 1898/000252/06. Healthcare Park, Woodlands Drive, Woodmead, 2191.
ZAR-BKS-1018-2226 12/18
128
Second-line therapy in an ART-experienced Acute and chronic toxicities
HIV-infected patient
Many drug reactions are mild and self-limiting and oc-
A switch to a second-line regimen must occur once a cur in the first few weeks of therapy. These include head-
second viral load is confirmed to be >1 000 copies/ml ache, nausea and abdominal discomfort. More severe
taken one to three months apart, despite maximum ad- side effects can occur after months to years and in-
herence.5 clude anaemia, the hyperlactataemia syndromes, peri-
pheral neuropathy and lipodystrophy. If toxicity does
Guidelines currently recommend ritonavir-boosted not resolve or is severe, the drug should be substituted.
PIs with 2 NRTIs as second-line therapy in patients who The viral load must be suppressed before substituting a
were on an InSTI-based first-line regimen for >2 years (a single drug, otherwise resistance may develop to the
resistance test may be required) or patients previous- new drug, affecting future regimens. Single drug substi-
ly on a NNRTI-based first-line regimen for whom DTG is tutions can be performed safely in the first six months of
unsuitable (a resistance test is not required).5,6 Patients ART without measuring the viral load.5 Table 2 discusses
previously on a NNRTI-based first-line regimen for whom the toxicities.
DTG is suitable (resistance test not required) may be
changed to DTG, with two NRTIs as second-line thera- ART in patients with common infections
py.6 The protease inhibitors include atazanavir/ritonavir
(ATV/r), or LPV/r. Boosting with low-dose ritonavir inhibits Tuberculosis – The decision to start ART in patients with
PI metabolism, thereby increasing the PI plasma con- pulmonary or extra-pulmonary non-neurological tu-
centration and prolonging its half-life. If a patient was berculosis (TB) is based on the CD4 count.5,6 If the CD4
receiving a PI-based first-line regimen, second-line op- count is ≤50 cells/μl, the aim should be to start therapy
tions must be discussed with a specialist, as a genotype after two weeks of TB treatment. However, if the CD4
resistance test may be required.5 count is >50 cells/μl, therapy should be delayed until
after the intensive phase of TB treatment, unless the pa-
As boosted PIs are robust drugs, virological suppres- tient has other serious AIDS-related conditions. This de-
sion will likely be achieved with good adherence, even lay is expected to reduce the risk of drug interactions
if the two NRTIs used in the second-line regimen are and shared side effects of ART with TB therapy and the
compromised by resistance mutations.5 risk of IRIS. In patients with TB meningitis, ART should be
deferred until four to eight weeks after the start of TB
NRTI combinations for second-line regimens include treatment.5,6
AZT plus 3TC, or TDF plus 3TC. 3TC can be re-used be-
cause it may have selected for the M184V resistance EFV is the preferred NNRTI for use with rifampicin. NVP
mutation and is partially able to restore susceptibility to carries a higher risk of hepatitis and virological failure
AZT, d4T and TDF in the presence of thymidine analogue when used with rifampicin. The plasma concentrations
mutations (TAMs). It is also able to restore susceptibility of all boosted PIs are reduced to subtherapeutic ranges
to TDF in the presence of the K65R mutation. Certain with rifampicin. The dose of LPV/r should be doubled
combinations are contra-indicated for toxicity reasons, slowly over two weeks to 800/200 mg twice a day and
such d4T plus didanosine (ddI), or TDF plus ddI. TDF plus the patient monitored closely for hepatotoxicity. Con-
ABC are not recommended for second-line ART, as tinue these changes to LPV/r until two weeks after com-
these agents share several resistance mutations.5 pletion of TB therapy.5 DTG needs to be dosed twice
daily when used with rifampicin.6
If a patient defaults therapy, the same regimen should
be restarted, and if the viral load is not suppressed after Hepatitis B co-infection – All HIV-infected patients should
three months, a switch to a second-line regimen should be screened for co-infection with hepatitis B. The ART regi-
occur. If it was a d4T-based first-line regimen, AZT could men should include TDF and 3TC (or FTC). NVP should be
be used as a substitute. However, TDF should not be avoided in patients with hepatitis B co-infection.5,6
substituted because if the patient has pre-existing NN-
RTI and 3TC resistance, TDF resistance may result, com- If patients meet criteria for switching to a second-line
promising its efficacy in second-line therapy. If a patient ART regimen to treat their HIV, TDF and 3TC/FTC should
has defaulted NNRTI-based first-line therapy many times also be included, as an interruption has been asso-
and if they are beyond the first year of ART, then a switch ciated with life-threatening hepatitis flares. In patients
to a second-line ART should occur. This is because of the with renal dysfunction, TDF may be considered with
possibility of NNRTI resistance. Resistance testing is not dosing based on creatinine clearance. If renal function
advised if the patient has been off ART for more than worsens with TDF, 3TC monotherapy with or without pe-
four weeks, as the resistance mutations will be achieved gylated interferon-alpha should be considered if avail-
by the presence of wild-type virus.5 able under specialist care.5
Third-line therapy in an ART-experienced HIV- Malaria – In uncomplicated malaria, patients should
infected patient failing any second-line regimen be treated with artemether-lumefantrine (Coartem®). It
is safe with NNRTIs. Boosted PIs increase the plasma con-
Patients must be offered in-depth adherence counsel- centrations of lumefantrine, but a dose reduction is not
ling prior to the application for, and initiation of, third-line recommended, as the toxicity threshold of lumefantrine
drugs. These patients require care under the supervision of seems to be high. Patients with severe malaria should
a specialist. The choice of ART should be based on geno- be referred for specialist care to receive intravenous ar-
type resistance testing. These drugs are very expensive, tesunate. Quinine should be avoided in patients receiv-
but are now available in the state sector (see Table 3).5,6 ing PIs or NNRTIs.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 129
No significant interactions exist between antiretroviral Treatment approaches
drugs and the drugs for malaria chemoprophylaxis, me-
floquine or doxycycline, but mefloquine and EFV both
share neuropsychiatric side effects; therefore doxycy-
cline is the preferred choice. Atovaquone-proguanil
(Malanil®) should be avoided.5
Cryptococcal meningitis – Where possible, a serum
cryptococcal antigen should be done in patients start-
ing ART with a CD4 count <100 cells/μl, to screen for early
cryptococcal disease and to initiate pre-emptive treat-
ment if needed. In patients with cryptococcal meningitis,
ART can be started at four to six weeks after antifungal
treatment with amphotericin B and fluconazole.5,6
Immune reconstitution
inflammatory syndrome
The clinical syndromes of Immune reconstitution inflam-
matory syndrome (IRIS) are of two types. A paradoxical
IRIS occurs when paradoxical worsening of symptoms or
new manifestations of a known condition, typically an
infection, present upon immune recovery. An unmask-
ing IRIS occurs when diseases not previously suspected,
become apparent after initiation of ART. Managing
such patients can be difficult. Treatment includes path-
ogen-specific therapy and anti-inflammatory therapies,
such as nonsteroidal anti-inflammatory drugs (NSAIDs)
or corticosteroids.5,6,12
References
1. World Health Organization. HIV/AIDS. Data and Statistics. Available
at https://www.who.int/hiv/data/en/. Accessed June 2019.
2. UNAIDS World AIDS Day Report – Results. 2012. Available at: http://
www.unaids.org/en/media/unaids/contentassets/documents/epi-
demiology/2012/gr2012/JC2434_WorldAIDSday_results_en.pdf. Ac-
cessed August 2013.
3. Statistics South Africa. Mid year population estimates 2011. Avail-
able at: http://www.statssa.gov.za/Publications/P0302/P03022013.
pdf. Accessed August 2013.
4. Fanales-Belasio E, et al. HIV virology and pathogenetic mechanisms
of infection: A brief overview. Ann Ist Super Sanita. 2010;46(1):5-14.
5. Meintjes G, Moorhouse MA, Carmona S, et al. Adult antiretroviral
therapy guidelines 2017. Southern African Journal of HIV Medicine.
2017;18(1), a776.https://doi.org/10.4102/sajhivmed.v18i1.776
6. Republic of South Africa National Department of Health. 2019 Antiret-
roviral treatment clinical guidelines for the management of HIV in
adults, pregnancy, adolescents, children, infants and neonates.
7. World Health Organization. December 2018. Updated recommen-
dations on first-line and second-line antiretroviral regimens and post-
exposure prophylaxis and recommendations on early infant diag-
nosis of HIV. Supplement to the 2016 consolidated guidelines on the
use of antiretroviral drugs for treating and preventing HIV infection.
8. Cohen MS, et al. HPTN 052 Study Team. Prevention of HIV-1 infection
with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505.
9. Schowalter L, Conradie F. Approaches to tenofovir and abacavir
drug shortages in South Africa: A guide for clinicians. SAJHIVMED
2012;13(2):56-7.
10. John MA, et al. Lamivudine-induced red cell aplasia. J Med Micro-
biol. 2008; 57(8):1032-5.
11. Falutz J. Therapy insight: Shape changes and metabolic complica-
tions associated with HIV and highly active antiretroviral therapy.
Nat Clin Pract Endocrinol Metab. 2007;3(9):651-61.
12. Armstrong WS. The immune reconstitution inflammatory syndrome:
A clinical update. Curr Infect Dis Rep. 2013;15(1):39-45.
13. Jones M, Núñez M. Liver toxicity of antiretroviral drugs. Semin Liver
Dis. 2012; 32(2):167-76.
14. Scherzer R, et al. Association of tenofovir exposure with kidney dis-
ease risk in HIV infection. AIDS. 2012;26(7):867-75.
15. Kranick SM, Nath A. Neurologic complications of HIV-1 infection
and its treatment in the era of antiretroviral therapy. Continuum
(Minneap Minn). 2012;18 (6 Infectious Disease):1319-37
HANDBOOK OF GENERAL MEDICINE VOL 1
130 TREATMENT APPROACHES
Infectious diseases in returning travellers:
focus on dengue
MBM Quam infections that carry the greatest morbidity and mortal-
ity, those that pose a public health risk and those that
PhD, MScIH, BA, BS are treatable. Infection prevention and control are key
considerations for all health workers.
Epidemiology and Global Health, Umeå Centre for Global
Health Research, Department of Public Health and Clinical Figure 1. Eschar of African tick-bite fever
Medicine, Faculty of Medicine, Umeå University, Umeå
Figure 2. Chancre of East African trypanosomiasis
LH Blumberg
Figure 3. Sindbis infection showing papules with
MBBCh MMed (Micro) ID (SA) FFTM (RCPS, Glasgow) DTM&H characteristic surrounding halos
DOH DCH
Arboviruses
National Institute for Communicable Diseases, University
of Stellenbosch, Stellenbosch Arboviruses (arthropod-borne viruses) are a diverse
group of viruses that survive in nature by transmission
Infectious diseases are a significant problem in the re- from infected to susceptible hosts by certain species of
turning traveller and range from potentially life-threat-
ening diseases, such as malaria, to those that are more
common and may be less threatening, such as travel-
ler’s diarrhoea. For the majority of patients, the consid-
eration in combination with the detailed travel history,
dates of travel in relation to the onset of symptoms,
presentation of the major symptom complex, findings of
a thorough examination and a few key laboratory in-
vestigations, can rapidly clinch the diagnosis or at least
logically guide further investigation.
The physician should be aware of the incubation pe-
riods of various diseases, the geographic distribution of
the disease along with current outbreaks, and be famil-
iar with the major symptom complex of most common
travel-related infections. Mode of travel, exposures to
insects, unsafe food and/or water, unpasteurised dairy,
raw fish, animal bites and licks, fresh water bodies, caves
and sexual encounters are important considerations.
Pre-travel immunisation, comorbidities, and medica-
tions may affect occurrence and disease presentation.
The risk of contracting malaria is highest in Africa and
Oceania, followed by Asia and Latin America. Plasmo-
dium falciparum is the most prevalent species in Africa
and overall the most serious, with rapid progression to
complicated disease. The diagnosis and management
of malaria in travellers is urgent and should be consid-
ered in any traveller returning from a malaria-transmis-
sion area who presents with an acute febrile illness, ir-
respective of whether chemoprophylaxis was taken or
the season. The physician should focus initially on those
Important practice points
• Confirming a diagnosis before treatment is ideal, but must be balanced against the need to treat severe illness
• The origin of the infection may be unrelated to recent travel and consideration must always be given to alternative local
sources
• Full blood count; blood-smear examination, especially for malaria; and liver function tests are obligatory initial investigations
• Fever and eosinophilia are commonly due to acute schistosomiasis (Katayama fever)
• Skin lesions are important clues to many travel-related infections, e.g. African tick-bite fever (see Figure 1), East African trypa-
nosomiasis (see Figure 2), arboviruses (see Figure 3)
• Tick-bite fever is common in travellers in Africa, and the typical rash may be absent. Doxycycline treatment is highly effective.
• Fever, rash, myalgia and arthritis are suggestive of arboviral infections.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 131
mosquitoes, ticks, sandflies or biting midges. Most arbo- as polymerase chain reaction (PCR). An increase in an- Treatment approaches
viruses are zoonoses; primarily infections of vertebrates tibody levels between acute and convalescent sam-
other than humans. ples tested in parallel may be useful, but it may take
two to four weeks before a diagnostic rise is detected.
There are over 500 arboviruses recognised worldwide,
but only some are implicated in human disease. Some in- Treatment
fect humans only occasionally or cause only mild illness,
whereas others are of great medical importance and There are no specific antiviral agents currently in use for
can cause large epidemics with considerable mortality. the treatment of arboviral infections.
Arboviral infections Prevention
Evaluate the geographic area of origin and season, ac-
tivities and possible exposure and clinical syndrome: Highly effective vaccines have been developed against
• Systemic febrile disease several arboviruses of public health significance, includ-
• Polyarthralgic illness ing yellow fever and Japanese encephalitis.
• Haemorrhagic fever
• Encephalitides Personal prevention of mosquito bites and other vec-
tors is vital for travellers.
Broad differential diagnosis
• The majority of arboviral infections have a benign The flaviviruses are the most important group medical-
ly, and certain infections caused by viruses in this group
course; a fulminant course in some cases of yellow are sufficiently prevalent to be of global concern and
fever and dengue may pose a risk to travellers. These include yellow fever
• No specific treatment, supportive virus (YFV), dengue virus (DENV), West Nile virus, Zika vi-
• Prevention: prevention of mosquito bites/ticks; vac- rus and Japanese encephalitis virus (JEV). The dengue
cines – Jap B, yellow fever virus is the most common human pathogen in this group
of arboviruses.
Acute febrile illness
• The commonest manifestation of all arboviruses, Focus on dengue virus infections
though many infections are subclinical Dengue, once known as “dandy” fever or “break-
• Incubation period: 3-10 days bone” fever, is a self-limiting viral infection transmit-
• Non-specific presentation, prominent headache, ted by mosquito vectors to humans, which most com-
monly presents as a benign fever; however, it can be
myalgia and arthralgia life-threatening. The World Health Organization (WHO)
• Rash may be present: maculopapular common has categorised dengue as the single most important
arboviral infection, given that almost half of the world’s
Polyartharthralgic illness human population lives in countries of endemic dengue
• Chikungunya, Sindbis, Ross River transmission. The past half-century has represented an
• Typically affects small joints of hands and feet, wrist, unprecedented expansion of geographical areas of
transmission and a 30-fold increase in the number of
knees and elbows cases globally, with annual estimates reaching as many
• Joint pain, joint-swelling (synovitis) and stiffness as 390 million infections. While the currently observed
geographic expansion of dengue is multi-factorial, it
Encephalitides may include climate, virus evolution, vector distribution,
• West Nile, Japanese B encephalitis, Rift Valley fever, population growth, urban development, commercial
trade and global travel. Although most of the burden of
Ross River, Eastern Equine encephalitis disease associated with dengue is located in areas with
• Significant effects in cerebral structures – midbrain, a tropical and sub-tropical climate within the Americas
and Asia, increasing evidence suggests areas of Africa,
basal ganglia and brainstem along with some temperate regions, are also at risk for
• The spectrum of clinical manifestations and neuro- dengue transmission. The relevant mosquito vectors di-
rectly involved with dengue transmission to humans are
logical residua: coma, flaccid paralysis mosquito species Aedes aegypti and Aedes albopictus.
• CSF: lymphocyte predominance, protein ↑ Like all mosquito varieties, the Aedes vectors’ life cycle
and breeding sites are associated with water, among
Haemorraghic fever other environmental factors. Aedes aegypti, better
• Yellow fever, dengue, Rift Valley fever, TBE, West Nile, adapted to urban habitation near humans, is consid-
ered globally to be the primary vector responsible for
JE, Zika endemic and epidemic dengue transmission, especial-
• Severe dengue/DHF/DSS: endothelial cell damage ly in tropical and subtropical areas. This includes much
of the recent transmission in parts of Africa, such as the
and increased vascular permeability 2013 dengue outbreak in Luanda, Angola. The four viral
• Yellow fever; DIC, liver dysfunction agents which cause dengue, are described as dengue
Diagnosis of arboviruses HANDBOOK OF GENERAL MEDICINE VOL 1
The viraemia (virus in the body) may be short-lived and
is best demonstrated using molecular techniques, such
132 TREATMENT APPROACHES
virus serotypes DENV-1, DENV-2, DENV-3 and DENV-4 sponse; the optimal test will depend on the stage of
and are species within the genus Flavivirus, as is the vi- the illness. Before the fifth day of fever, viraemia is still
rus involved with yellow fever and Zika. While each of sufficiently present for diagnostic tests that isolate the
the four serotypes causes similar symptoms and patterns virus in cell culture, amplify the virus using reverse tran-
of disease, recovered patients do not gain long-term scriptase-polymerase chain reaction (RT-PCR), and/or
cross-serotype immunity. The role of travel in the recent detect immunological response viral antigens (usually
and ongoing expansion of dengue is underscored, giv- NS-1), using ELISA or rapid tests. From the fourth or fifth
en that dengue infections account for the second most day of fever, dengue virus itself is less likely to be present
frequent fevers among those returning from internation- in the blood, while NS-1 antigens may last longer; there-
al travel in the tropics after malaria. fore, serological assays detecting IgM and IgG anti-
bodies should be considered for dengue diagnostics.
Diagnosis IgM can be identified from approximately the fourth
day of fever, and remain present up to three months
Clinical diagnosis of dengue infection should be con- later, peaking in the second week after onset of symp-
sidered in patients who present with a fever and have toms. IgG antibodies for dengue may be scarcely de-
been in dengue-endemic areas within the past two tected at low levels toward the end of the first week
weeks. For up-to-date maps of current areas of endem- for some patients, and the second week for others, but
ic transmission, recent and ongoing outbreaks of den- may remain present life-long. While further diagnostic
gue, and those areas that potentially may have den- tools are always being developed, several rapid tests
gue transmission, clinicians, healthcare professionals, for both NS-1 antigens and IgM antibody (and both) do
and public health staff can reference the map below exist and offer a point-of-care testing option, as well as
or the online resource known as “DengueMap” (see (in combination) a longer diagnostic period. However,
Figure 4). Dengue is likely to be under-recognised and evidence suggests that equivalent laboratory ELISA as-
under-reported in Africa owing to a lack of systematic says have better sensitivities and specificities than rapid
surveillance and diagnostic testing. Outbreaks have tests. Clinicians and medical laboratory professionals
been well documented in Tanzania (Dar es Salaam), should also note that serological assays cannot provide
Kenya (Mombasa), Angola (Luanda) and Mozambique serotype-specific diagnostics and are further limited by
(Beira, Pemba) in recent years. There is no transmission potential cross-reactivity with Zika virus, past dengue
in South Africa. and other Flavivirus infection.
Confirmation of dengue is by detection of viral com-
ponents in the blood or the serological immune re-
Average of number of reported cases, 2010-2016
≥100 000 0 cases reported
10 000-99 999 No data
1 000-9 999 Not applicable
<1 000
The boundaries and names shown and the designations used on this map do not imply the expression of any option
whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or
area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent
approximate border lines for which there may not yet be full agreement. WHO. 2016.
Figure 4. Distribution of dengue worldwide, 2016
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 133
Symptoms Figure 5. Initial diffuse flushing, mottling or fleeting Treatment approaches
pinpoint eruptions
Although the majority of those persons infected with
dengue virus may exhibit no apparent illness or only Figure 6. Confluent petechial rash characterised
minimal symptoms, clinical progression of dengue vi- by a scattered pale, round area of normal skin
ruses (DENV 1-4) infecting the human body causes seri-
ous illnesses. These are currently categorised by WHO Most cases are not symptomatically apparent and do
as “Dengue” (D), “Dengue with Warning Signs” (DW) or not display any warning signs (see Table 1) for clinicians
Severe Dengue (SD), which was previously divided into to address; however, in patients with severe dengue
Dengue haemorrhagic fever (DHF) and Dengue Shock (SD), benign infections can quickly turn into a life-threat-
Syndrome (DSS). While clinical signs and symptoms of ening disease. Severe Dengue (SD), such as dengue
dengue range widely in severity from patient to patient, haemorrhagic fever (DHF), may involve multiple organ
common features include sudden onset of fever, severe bleeds, often within the gastro-intestinal tract, and the
headache, retro-orbital pain, myalgia, joint pain, rashes, internal collection or pooling of excreted fluids. In den-
leucopenia, and thrombocytopaenia. In severe disease gue shock syndrome (DSS), the most severe form of DHF,
manifestations, the human host responds pathophysi- the extensive vascular leakages progressively cause the
ologically to the DENV infection by escalating vascular patient’s pulse to become more rapid and weaken un-
permeability; therefore plasma leakage can occur, fol- til a sudden drop in blood pressure is observed, result-
lowed by the development of capillary bleeding and ing from the overall collapse of the circulatory system.
ultimately life-threatening decreases in coagulation The endurance of dengue infection confers long-lived,
functionality. serotype-specific immunity, however it increases the
Following the incubation stage, three to seven Table 1. Dengue warning signs
days after the initial infectious mosquito bite, den- • Abdominal pain/tenderness
gue infection occurs in three clinically observable • Persistent vomiting
phases: initial febrile phase, critical phase, and re- • Clinical fluid accumulation
covery phase. A three- to seven-day febrile phase • Mucosal bleeding
presents with increased body temperature (≥38.5°C), • Lethargy/restlessness
headache, vomiting, myalgia, joint pain, rash, minor • Liver >2cm
haemorrhagic manifestations, including petechiae or • Laboratory increase in haematocrit concurrent with a
bruising and sometimes a palpable liver. During the decrease in platelet count
following three to seven days known as the critical
phase, the patient may develop vascular leakage HANDBOOK OF GENERAL MEDICINE VOL 1
warning signs or haemorrhagic manifestations, which
include worsening abdominal pain, vomiting, tender
hepatomegaly, serosal effusions, mucosal bleeding,
increased hematocrit, decreased platelet levels, and
lethargy. The increased vascular permeability is brief
and reverts spontaneously to normal during the two
to three days of the recovery phase, which is cate-
gorised by rapid improvement in the patient’s symp-
toms, with the occasional exception of fatigue which
can persist for a few weeks. The period of viraemia
or infectiousness starts approximately three days after
an infectious mosquito bite, about two days before
the onset of symptoms and lasts around six to seven
days in total, including about five days after the onset
of symptoms. The rash is an important manifestation
of dengue and is variable, depending on the stage
of the illness.
Several types of skin rashes have been described. Ini-
tially, diffuse flushing, mottling or fleeting pinpoint erup-
tions may be observed on the face, neck and chest
(see Figure 5). These are transient. The second type of
skin rash is a conspicuous rash that may be maculo-
papular or scarlatiniform and appears on approxi-
mately the third or fourth day. Towards the end of the
febrile period or immediately after defervescence, the
generalised rash fades, and there is a confluent pe-
techial rash characterised by a scattered pale, round
area of normal skin (see Figure 6). There may be itching
and peeling.
134 TRETARETAMTEMNETNATPAPPRPORAOCAHCEHS ES
possible risk of severity in the case of secondary infec- 9. Frean J, Blumberg L. Tick bite fever and Q fever – a South African
tion by another DENV serotype. There are four distinct perspective. Festschrift in honour of Professor Hendrik J Koornhof. S
dengue serotypes (DENV 1-4). While one serotype may Afr Med J. 2007; 97:1198-1202.
dominate during a given transmission period, multiple
serotypes often co-circulate within in a given area. 10. Frean JA, Blumberg L, Ogunbanjo GA. Tick bite fever in South Af-
rica. SA Fam Pract. 2008; 50(2):33-35.
Management and treatment
11. Blumberg L, Frean J. Fever in the returning traveller. Infect Dis Up-
The WHO identifies the need for swift clinical and labo- date. 2016 Jun; 5(2):6-10
ratory diagnosis followed by properly supervised intra-
venous rehydration as cornerstones of dengue control 12. Frean J, Sieling W, Pahad H, Shoul E, Blumberg L. Clinical man-
from a clinical management perspective. While efforts agement of East African trypanosomiasis in South Africa: Lessons
are being made to develop and introduce a dengue learned. Int J Infect Dis. 2018 Aug 25;75:101-108. doi: 10.1016/j.
vaccine for many settings, currently available vaccines ijid.2018.08.012.
are not recommended on a population scale at this
time. Similarly, the development of antiviral medica- 13. Amarasinghe A, Kuritsky, J Letson W, Margolis H. Dengue virus infec-
tions for limiting dengue transmission and clinical dis- tion in Africa. Emerg Inf Dis. 2011 Aug;17(8):1349-1354. doi: 10.3201/
ease progression is ongoing, but as of yet unsuccessful. eid1708.101515
Therefore, clinical treatment remains confined to fluid
therapy to support critical organ function, as presently
there are no antiviral medications to treat or prevent
dengue infections. Fluid therapy should seek to replace
the minimum fluid necessary to stabilise and maintain
cardiovascular function, whether through oral rehydra-
tion in mild cases, isotonic solutions in more severe cas-
es, or even blood transfusions in extreme cases, as each
risk the development of fluid overload.
Prevention
Prevention of dengue in travellers focuses on the use
of effective insecticide repellents applied to exposed
areas of skin to prevent the daytime biting by Aedes
mosquitos.
CYD-TDV is the first dengue vaccine to be licensed,
initially in Mexico 2015, for use in individuals 9-45 years
of age living in endemic areas, and it is now licensed in
20 countries. CYD-TDV is a live recombinant tetravalent
dengue vaccine developed by Sanofi Pasteur (CYD-
TDV), given as a three-dose series on a 0/6/12-month
schedule. The vaccine is not recommended for travel-
lers, but rather for countries considering vaccination as
part of their dengue-control programme. In this case,
a “pre-vaccination screening strategy” would be the
preferred option, in which only dengue-seropositive
persons are vaccinated.
Further reading
1. Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue:
Past, present and future prospects. Clin Epidemiol. 2013;5:299-309.
2. Wilder-Smith A, Ooi EE, Horstick O, Wills B. Dengue. Lancet.
2019;393(10169):350-63.
3. Schwartz E, Meltzer E, Mendelson M, et al. Detection on four con-
tinents of dengue fever cases related to an ongoing outbreak in
Luanda, Angola, March to May 2013. Euro Surveill. 2013;18(21).
4. Wilder-Smith A, Quam M, Sessions O, et al. The 2012 dengue outbreak
in Madeira: exploring the origins. Euro Surveill. 2014;19(8):20718.
5. Wilder-Smith A, Schwartz E. Dengue in travellers. N Engl J Med.
2005;353(9):924-32.
6. Sharp TM, Moreira R, Soares MJ, et al. Underrecognition of Den-
gue during 2013 epidemic in Luanda, Angola. Emerg Infect Dis.
2015;21(8):1311-6.
7. World Health Organization. Dengue guidelines for diagnosis, treat-
ment, prevention and control: New edition. Geneva: World Health
Organization; 2009.
8. Blumberg L, Frean J. The returning traveller with fever. CME – The SA
Journal of CPD. 2005; 23(3):133.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 135
Fever of unknown origin Treatment approaches
K Pieton (Roberg) Table 1. Common diagnoses in patients with FUO
MBBCh(Wits) DA(SA) DTM&H(SA) Dip Man HIV(SA) FCP(SA) Infection *MTB, NTM, fungal, parasite
MMED(Wits) Cert ID(SA)
Malignancy Lymphoma, leukaemia, solid organ
Consultant of Infectious Diseases, Johannesburg
Auto-immune SLE, vasculitis, Sjögrens syndrome,
In 1961, Petersdorf and Beeson first defined the syn- Still’s disease
drome of fever with an unknown origin (FUO). The three
components to make this assessment were: Drugs Any!
• A temperature >38.3 °C on several occasions
• Illness duration of more than three weeks *MTB – Mycobacterium tuberculosis, NTM – non-tuberculous
• Failure to reach a diagnosis despite one week of in- mycobacteria
patient treatment.1 What other categories should I
With recent advances in diagnostic techniques, as well consider in my patient with FUO?
as the onset of new treatment (especially immunosup-
pressant) modalities, and the emergence of infections In recent years, with the development of chemo-
such as HIV, these criteria are no longer sufficient and the therapy, as well as molecular therapy targeting the im-
categories listed below should always be considered. mune system, as treatment for cancers as well as auto-
immune disease, it is vital to assess whether the patient
What temperature is considered a fever? is on any immunosuppressant treatment. Depending
on what this treatment is targeting, an infectious dis-
The body has a natural circadian temperature rhythm, with ease may be more readily considered and diagnosed.
lowest temperatures being recorded in the early hours of It is not only the treatment that may immunosuppress
the morning, and highest measured in the early evening. patients, but comorbid conditions/toxins which place
Also, measured temperatures fluctuate in females com- them at higher risk. Diabetes mellitus, HIV, malignancy
pared with males, ethnic group and age. Following over (even before receiving immunosuppressant therapy),
700 temperature measurements in 148 healthy men and smoking and alcoholism are examples (see Table 2).
women, Machowiak et al suggested that the normal tem-
perature range was 37.2 °C (am)-37.7 °C(pm).2 Remember to ask patients whether they have been ad-
mitted to hospital recently, or whether they attend a regu-
What are the most common diagnoses lar outpatient clinic. Ask whether they reside in a care facil-
in patients with FUO? ity, such as a nursing home or frail-care unit. Any of these
may place the patient at higher risk of having a healthcare-
With the availability of advanced imaging techniques, such associated infection. In these cases, consider drug-resistant
as CT, MRI and nuclear-scanning machines, and molecular bacteria that do not respond to first-line antibiotics – ESBL
infection-detection diagnostics, many more patients who (extended-spectrum beta-lactamase producers), CRE
were previously labelled as FUO now have a firm diagnosis (carbapenem-resistant enterobacteriaceae), MRSA (me-
and can receive appropriate, often life-saving treatment. thicillin-resistant Staphylococcus aureus) are possibilities.
The vast majority of patients with an FUO have an in- Recent travel is another important category to ex-
fection (such as tuberculosis or another slow-growing clude. If the patient has travelled, a detailed itinerary
organism), a malignancy, an auto-immune disease or a and vaccination, accommodation and food history
drug fever (see Table 1).3 Malignancy is often haemato may help in making a correct diagnosis.
logical – hiding in the bone marrow or another lymphoid
site. Difficult-to-diagnose infections, such as tuberculosis Table 2. FUO in certain patient groups
and non-tuberculous mycobacterial infections, as well as
fungal and parasitic infections, should be considered in Healthcare-associated
the right setting, especially when typical, broad-spectrum
antibiotics do not affect the symptoms or fever. The age HIV
of the patient may be relevant when considering auto-
immune disease – a young female with a persistent fever Neutropaenia
may have systemic lupus erythematosus (SLE), while an el-
derly patient may have temporal artery vasculitis. Always Traveller
consider any drugs the patient may be on when imaging,
infection markers and auto-immune markers are negative. The approach to a patient with FUO
In the developing world, infections remain the most likely History
cause of an FUO, compared to resource-rich countries, Any doctor investigating a patient with FUO should start
where malignancies, auto-immune diseases and drug fe- with a good history. Once the main complaint and de-
vers are commoner. Similarly, infections are the most likely tails thereof have been ascertained, ensure that the
cause of fever in children compared to adults.4 patient does not fit one of the criteria mentioned above
(recent healthcare admission, HIV, potential neutropae-
nia/immunosuppression, recent travel.5 (See Figure 1.)6
HANDBOOK OF GENERAL MEDICINE VOL 1
136 TREATMENT APPROACHES
Source: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J: Harrison's principles of internal medicine,
18th edition. New York: McGraw-Hill; 2011. www.accessmedicine.com
The McGraw-Hill Companies, Inc.
Figure 1. Suggested clinical approach for a FUO patient
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 137
Ask specifically about the following: infection. A lumbar puncture, PAP smear, sputum, stool Treatment approaches
a. Occupation and hobbies sample if appropriate, and gastro/colonoscopy may be
useful. Any lymph nodes or masses should be aspirated
• Vets, abattoir workers, hunters, teachers, cavers, or biopsied. Consider adding syphilis and other STD tests.
hikers, divers, lab and factory workers may be ex- It is wise to consult the laboratory and inform the micro-
posed to environmental or animal toxins biologist of any samples sent. Cultures should be incu-
bated for longer to ensure that fastidious/slow-growing
b. Animal and animal products organisms (such as fungi, mycobacteria and other bac-
• Household pets, including exotic animals such as teria) have a higher pick-up rate. One can also consider
reptiles, wild animals, birds molecular (PCR) and genetic tests in consultation with
specialists. A malaria screen, in the absence of recent
c. Food and drink travel history, may be a consideration in patients with
• The consumption of unpasteurised milk or eggs, fever and low platelets, as Odyssean malaria results in
fermented foods or home-pickled/-canned goods delayed diagnosis and has a high mortality rate.
may also be sources of infection
If the cause of the fever is still not apparent, a physi-
d. Sexual history cian consultation is a good place to start, and infec-
• Unprotected intercourse and the potential acqui- tious disease specialists, rheumatologists and oncolo-
sition of sexually transmitted diseases, including gists may provide valuable advice.
HIV, may present as a prolonged fever.
Should I treat empirically while awaiting results?
e. Medication, including recreational drugs If the patient is stable and shows no concerning signs of
• Any drug can cause a fever, as can recreational impending sepsis or shock, it is not necessary to start em-
drugs. Common causes of drug fever are non- piric antibiotics. This may make the hunt for a cause dif-
steroidal anti-inflammatories (NSAIDs) and antibi- ficult, as antibiotics may suppress the growth of bacteria
otics in cultures taken after even a single dose. If the patient
is unstable, septic or shows any signs of shock, or starts
f. Recent vaccination deteriorating despite ongoing investigation, a broad-
• Any vaccination may result in a fever that is usually spectrum antibiotic trial should be commenced after
not prolonged. Live vaccines may result in infec- ensuring that all urine, blood, tissue samples have been
tion in immunosuppressed individuals with vaccine collected and sent to the laboratory. The choice of an-
strain viruses causing disease. tibiotics should include a broad-spectrum antibiotic to
cover the usual causes of sepsis, plus an antibiotic, such
g. Contact with ill people as doxycycline, or a quinolone intravenously, to cover
h. Family history atypical infectious diseases agents, such as rickettsia
and Coxiella burnetti.
• Malignancy and auto-immune disease are the
most important REFERENCES
Examination 1. Petersdorf RG, Beeson PB. Fever of unexplained origin: Report on
100 cases. Medicine (Baltimore). 1961;30:1-30
A thorough and detailed examination is vital. In addi-
tion to the chest, heart, abdomen and neurological 2. Mackowiak PA, et al. A critical appraisal of 98.6 degrees F, the up-
systems, scrutinise difficult-to-reach or forgotten places per limit of the normal body temperature, and other legacies of Carl
such as the ears and sinuses, throat and tonsils, axillae, Reinhold August Wunderlich. JAMA. 1992 Sep 23-30;268(12):1578-80
perineum and genitalia. Do not forget to move and pal-
pate all joints as septic arthritis may not be noticed at 3. Ergönül O, Willke A, Azap A, et al. Revised definition of ‘fever of
first glance. Palpate the breasts. Look carefully for rash- unknown origin’: Limitations and opportunities. J Infect. 2005 Jan.
es, insect bites, masses and lymph nodes. Bedside aids 50(1):1-5
such as urine dipstick and glucose reading should also
be performed. 4. Durack DT, Street AC. Fever of unknown origin – re-examined and
redefined. Curr Clin Top Infect Dis. 1991;11:35-51
Investigations
5. Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: A clini-
Usually, history and examination findings guide investi- cal approach. Am J Med. 2015 Oct;128:1138
gations, but it may often be difficult to decide what to
do first and where to look! 6. Longo DL, Fauci AS, Kasper DL, et al. Harrisons Principles of Internal
Medicine, 18th edition. New York: McGraw-Hill; 2011.
Start with a chest radiograph, urine MC&S (microsco-
py, culture and drug sensitivity), abdominal and pelvic HANDBOOK OF GENERAL MEDICINE VOL 1
ultrasound and basic blood work-up – FBC with differ-
ential count and smear, U&E, LFT, blood cultures (three
sets, from three different sites, at least 20 minutes apart),
HIV, TB MC&S. If there is still no clue as to what the diag-
nosis is, add hepatitis studies, a cardiac ECHO, ANA/
ENA/rheumatoid factor, and consider specific tumour
markers such as prostate-specific antigen (PSA) and al-
pha-fetoprotein (AFP). A serum protein electrophoresis
(SPEP) and the skeletal survey may give clues sugges-
tive of malignancy. Further imaging may be necessary
in the form of CT or MRI, and nuclear medicine scans,
which may help differentiate between malignancy and
138 TREATMENT APPROACHES
Listeriosis: clinical manifestation and management
J Thomas es in Johannesburg) and 2015 (3 cases in Western Cape
Province).5,6 The 1977-1978 cluster was not linked to any
MBBCh, FCPath(SA) food products, since it was only in 1981 that L. mono-
cytogenes was definitively proven to be transmitted by
Head of Centre for Enteric Diseases, National Institute contaminated food. The 2015 cluster was identified ret-
for Communicable Diseases, Johannesburg rospectively, and the cluster could not be linked to any
food products.
The bacterium Listeria monocytogenes is a foodborne
pathogen causing listeriosis in humans, a severe, albeit Up until 2017, listeriosis had historically been a rare
rare, foodborne disease. This organism is an important foodborne disease in South Africa, with less than 100
foodborne pathogen of public health concern for two cases diagnosed annually. An unusual increase in cases
principal reasons: It causes severe disease (>90% of of neonatal listeriosis was noted at two academic pub-
cases require hospitalisation) with a high mortality rate lic hospitals in Gauteng Province during July and August
(20-30%) and can cause outbreaks which may be ex- 2017, prompting further investigation. It soon became
tensive, prolonged and challenging to solve.1 evident that an unprecedented and rapidly increas-
ing number of cases were being diagnosed, and whole
Although control of L. monocytogenes in food pro- genome sequencing of L. monocytogenes isolates from
duction significantly reduces the risk of food contami- patients showed that a single strain (sequence type 6,
nation, it is impossible to eradicate these bacteria from or ST6) was responsible for more than 90% of the cases
all foods. It is therefore likely that accidental contamina- countrywide. Through intensive epidemiological, labora-
tion of food occurs fairly frequently, and that consump- tory and traceback investigations, the source of the out-
tion of contaminated food is a reasonably common break was confirmed as ready-to-eat, processed meat
event. Changes in the way foods are produced, distrib- products (polony and other delicatessen-style cold meat
uted and stored have contributed to the increased risk products) manufactured at the Enterprise® Foods’ Polok-
of L. monocytogenes contaminating food and causing wane production facility. Ready-to-eat processed meat/
outbreaks. poultry products have been responsible for numerous lis-
teriosis outbreaks worldwide, and are well-known to pose
Sporadic cases (i.e. not outbreak-related) occur a high risk of disease if contaminated.
worldwide, with three to six cases per million population
per year reported from developed countries with robust Impact on society
surveillance programmes.2
Morbidity and mortality
Although most listeriosis cases are sporadic, outbreaks
are increasingly recognised worldwide. Reported out- Over 90% of listeriosis cases are severe enough to re-
breaks have been associated most commonly with quire hospitalisation. Although listeriosis is a relatively rare
unpasteurised dairy products (milk and soft cheeses), cause of foodborne disease, compared to the burden of
ready-to-eat processed meat/poultry products (sau- disease caused by enteric viruses and other foodborne
sages, deli meats [“cold meats”], salami, pâté etc.), bacteria, it has the highest mortality rate (20-30%) and
and ready-to-eat seafood (such as smoked fish or mus- typically results in a sizeable proportion of total deaths
sels). However, outbreaks have also been linked to pas- from foodborne illness. Furthermore, it is very likely that
teurised dairy products (milk, cheese and ice cream), morbidity and mortality are under-recognised in preg-
contaminated fresh produce (fruits, vegetables and nant women because listeriosis is not typically investi-
sprouts) and frozen produce (frozen corn). gated for in cases of miscarriage or unexplained stillbirth.
Notably, up to 40% of neonates who survive listeriosis suf-
In 2017 and early 2018, South Africa experienced the fer permanent neurodevelopmental sequelae.
world’s largest listeriosis outbreak caused by contami-
nated ready-to-eat, processed meat products manu- Economic loss
factured at a single production facility, with >1 000 cas-
es and at least 200 deaths.3 The high morbidity and mortality associated with listeri-
osis itself have a direct economic impact. In terms of
Listeriosis in South Africa food safety, the prevention and control of L. monocy-
togenes in the food-production environment are chal-
In the 1920s, Dr Harvey Pirie, a bacteriologist working lenging. They require food-safety expertise and routine
at the South African Institute for Medical Research, monitoring specific to the food commodities involved
described a bacterial infection among wild rodents in and the environmental survival characteristics of this
the Orange Free State. The organism was similar to one bacterium. This has cost implications for food produc-
found by Dr EG Murray in Cambridge which caused dis- ers, which are passed on to the consumer.
ease in rabbits; together, Pirie and Murray proposed the
name Listeria monocytogenes.4
The first human case of listeriosis in South Africa was
reported in 1955. Clusters of cases which likely repre-
sented outbreaks were described in 1977-1978 (14 cas-
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 139
Microbiology and pathophysiology Table 1. Risk factors for listeriosis Treatment approaches
Microbiology Pregnancy Chronic liver disease
Neonates (≤28 days) Chronic renal disease
L. monocytogenes is a Gram-positive bacterium widely Cancer (haematological Diabetes mellitus
found in the natural environment (water, soil and vege- and solid organ)
tation), as well as the intestinal tract of many mammals. HIV Alcoholism
Colonisation or transient carriage of L. monocytogenes Auto-immune disease Immunosuppressive therapy
occurs in approximately 1-10% of healthy adults.7 (cytotoxic medications,
Transplant recipients (solid corticosteroids)
The bacterium is hardy and able to grow and survive organ and bone marrow) Adults ≥65 years
in relatively adverse conditions – it can withstand heat,
freezing, drying, high salt concentrations, and relatively Listeriosis can be divided into five clinical manifesta-
high concentrations of acid and alcohol. This makes it tion categories, with varying incubation periods and
able to survive and persist in the food-processing envi- clinical presentations, as summarised in Table 2.2,13-15
ronment, survive food-processing hurdles and proliferate 1. Febrile gastro-enteritis
in food products. It can survive and grow at standard Healthy persons can develop self-limiting febrile gas-
refrigerator temperatures, which places ready-to-eat
foods that are not cooked before eating at particular tro-enteritis, particularly after consumption of a large
risk for being successful vehicles for listeriosis.8 inoculum of L. monocytogenes in contaminated food.
Illness typically occurs 24 hours after ingestion and usu-
Pathogenesis ally lasts two days. Common symptoms include fever,
watery diarrhoea, nausea, headache and arthralgia.
The main route of transmission occurs through the con- Hospitalisation following gastro-enteritis due to listeri-
sumption of contaminated food. Vertical transmission osis is more common amongst children or the elderly,
from a pregnant woman to her foetus occurs.9,10 in whom blood cultures may be positive.
2. Pregnancy-associated listeriosis
The disease develops because of the failure of cell- Maternal immunosuppression during pregnancy
mediated immunity to control the proliferation of Listeria promotes bacteraemia, with seeding to the pla-
in the liver, which leads to bacteraemia and invasion of centa. In the placenta, bacteria proliferate and are
other organs (notably, the central nervous system and protected from further immune attack, and subse-
placenta – see Figure 1).11 quently infect the foetus.
a. Disease in pregnant women
Food contaminated with Liver Brain Most infections are asymptomatic, and of those
Listeria monocytogenes
cases that do develop into clinical disease, most
Bloodstream present as a mild febrile illness. This is typically non-
specific, presenting as febrile flu-like illness (fever,
Lymph node backache, headache, myalgia, sore throat) or
sometimes febrile gastro-enteritis (fever, vomit-
Intestine ing/diarrhoea).
b. Foetal disease
Spleen Placenta and foetus Infection is typically severe and results in miscar-
riage or stillbirth in 25-35% of cases.
Source: Adapted from Cossart P, Toledo-Arana A. Listeria monocy- c. Neonatal listeriosis
togenes, a unique model in infection biology: An overview. Microbes The disease is classified as early-onset (days 1-6 of
Infect. 2008 Jul;10(9):1041-50 life) and late-onset (days 7-28), depending on the
time of symptom onset after birth. Clinical features
Figure 1. Pathogenesis of invasive Listeria mono- include sepsis, respiratory distress or pneumonia,
cytogenes infection11 and meningitis. Granulomatosis infantiseptica is
a form of neonatal disease characterised by dis-
Diagnostic issues seminated abscesses and granulomas in multiple
organs. The mortality rate is high (up to 30%), and
Clinical manifestations 40% of surviving neonates suffer severe neurologi-
cal and developmental sequelae.
L. monocytogenes causes invasive disease mainly in 3. Bacteraemia
well-defined risk groups, most of which have impaired This is the most frequent manifestation of listeriosis
cell-mediated immunity due to pregnancy, extremes of in immunocompromised persons, adults and the el-
age, cancer, underlying chronic disease or medication derly. The bacteraemia has no obvious focus, and
(see Table 1).1,2 The incidence of invasive disease is ex- usually presents as a nonspecific febrile illness; fever
tremely low in populations with no underlying disease, may be accompanied by diarrhoea, flu-like symp-
even in the elderly.12 toms, or decompensated comorbidity. There may
be a history of antecedent diarrhoea.
Healthy persons infected with L. monocytogenes do
not typically develop any symptoms. Should they de- HANDBOOK OF GENERAL MEDICINE VOL 1
velop disease, the commonest form is self-limiting febrile
gastro-enteritis. Rarely do otherwise healthy persons de-
velop invasive disease.
140 TREATMENT APPROACHES
4. Central nervous system disease clinical samples. Detection of L. monocytogenes in stool
The disease most typically manifests as meningo- samples is challenging and not routinely performed.10
Recommended microbiological investigations for the
encephalitis or meningitis, which presents similarly diagnosis of listeriosis are shown in Table 2.
to acute bacterial meningitis/meningo-encephalitis.
There may be a history of antecedent diarrhoea. In- There is no serological test to determine exposure/
volvement of the brainstem (brainstem encephalitis) infection due to L. monocytogenes in asymptomatic
is associated with cranial nerve involvement or cer- persons.
ebellar signs (ataxia, tremor), or the development of
hemiparesis. Brain abscesses can also occur. Index of suspicion and referral
5. Focal infections
These are uncommon. A wide range of focal infec- Sporadic cases of listeriosis are typically diagnosed dur-
tions has been described, including mycotic aneu- ing an investigation for suspected meningitis or systemic
rysms (mostly of the abdominal aorta), septic arthritis bacterial infection, since these clinical manifestations
(including prosthetic joint infections), endocarditis, are non-specific. In cases of miscarriage or unexplained
endophthalmitis and osteomyelitis. stillbirth, listeriosis can be investigated as a possible
cause, particularly if there is a history of preceding fe-
Diagnosis brile gastro-enteritis or flu-like illness in the pregnant
woman.
Listeriosis is diagnosed by a positive culture from a clinical
sample, or by positive polymerase chain reaction (PCR) In an outbreak setting, it is vital to think of listeriosis
testing. L. monocytogenes is not fastidious and can be in high-risk persons presenting with compatible clinical
readily cultured from clinical specimens, such as blood, features. Consider adding ampicillin to empiric bacteri-
cerebrospinal fluid (CSF), amniotic fluid, placenta, and al meningitis therapy until laboratory investigation results
others. Where there is a high clinical index of suspicion for are available, especially for neonates and persons with
listeriosis, but specimens (including CSF, blood and pla- HIV or other underlying risk factors. Consider laboratory
centa) are culture-negative, a PCR-based test may be investigations (blood cultures) for pregnant women with
of value. This may be of particular importance in cases fever and flu-like illness or febrile gastro-enteritis. Be alert
where antibiotic therapy is given before the collection of to clusters of febrile gastro-enteritis, as was seen in the
2017-2018 outbreak in South Africa.
Table 2. Clinical manifestations and laboratory investigations for listeriosis
Clinical Incubation period Clinical features Laboratory investigations
manifestation
category
Febrile gastro- Median of 24 hours Fever and non-bloody • Stool culture with a specific request for L.
enteritis (range 6 hours-10 diarrhoea; may be monocytogenes culture. This is not routinely indicated
days) accompanied by unless there is exposure to a known contaminated food
arthralgia, headache, source or a cluster of cases with suspected exposure to
or vomiting. Typically of a common contaminated food source.
1-3 days’ duration and
self-limiting. • Blood culture*
Affects both healthy
persons and those in
high-risk groups
Pregnancy- Median 21 days Can manifest as • Maternal listeriosis: Blood cultures are suggested for
associated (range 7-67 days) maternal listeriosis, febrile gastro-enteritis or nonspecific febrile flu-like illness
foetal listeriosis or in pregnant women in an outbreak setting*.
neonatal listeriosis
• Blood, CSF, amniotic fluid or placental tissue cultures as
indicated for suspected neonatal/foetal listeriosis*
Bacteraemia Median 5 days Fever; may be • Blood culture*
(range 1-29 days) accompanied
by diarrhoea, flu-
like symptoms,
decompensated
comorbidity, sepsis
Central nervous Median 10 days Protean manifestations, • Blood culture*
system (range 1-16 days) including meningitis, • CSF culture*
meningo-encephalitis,
rhombencephalitis,
cerebral abscesses
Other Variable, A wide range of • Blood culture*
depending on the infections is described. • Culture of other sample sites, depending on
site of infection
presentation (e.g. pus, tissue, synovial fluid)*
*In cases where cultures remain negative for L. monocytogenes, but there is a high index of suspicion for listeriosis, consider PCR testing.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 141
Since listeriosis is an invasive, systemic disease, almost ate reporting by the most rapid means available upon Treatment approaches
all patients require hospitalisation for intravenous anti- diagnosis, followed by a written or electronic notifica-
biotic therapy. It is uncommon for listeriosis to be diag- tion to the Department of Health within 24 hours of diag-
nosed in an outpatient setting. nosis by healthcare providers, private health laborato-
ries or public health laboratories.
Management
Prevention
Treatment
Ampicillin is considered the drug of choice for treating There are two primary strategies for preventing listeriosis:
listeriosis. Consider adding gentamicin, as available evi- reducing contamination of food products and provid-
dence suggests that it may be of benefit. For patients ing risk-reduction guidance to high-risk individuals. Such
with β-lactam allergy, cotrimoxazole is the preferred guidance includes advice on food hygiene (proper
second-line agent. Table 3 details currently recom- food storage, handling, and hand hygiene) and avoid-
mended antibiotic treatment.2,16-19 ance of at-risk food. The World Health Organization’s
five keys to safer food is a useful resource for general
There is no evidence for the optimal duration of therapy food hygiene advice.20 Additionally, the WHO advises
for listeriosis; the recommended duration of therapy ad- that pregnant women protect themselves against
vised in most international guidelines is shown in Table 4.17,19 L. monocytogenes infection by:21
Public health response Avoiding high-risk foods, i.e. foods not cooked before
Since 15 December 2017, listeriosis is a category 1 Notifi- eating. This includes smoked and lightly preserved fish or
able Medical Condition and as such requires immedi- seafood, unpasteurised milk and its products (e.g. soft
cheeses), pâté, and prepared salads from stores.
Table 3. Antibiotic treatment for invasive infection due to Listeria monocytogenes
Adults Neonates and children
Age category Ampicillin (IVI) Gentamicin (IVI)*
Recommended Ampicillin 3g IV Neonates <7 days and 100 mg/kg/day in 2 2.5 mg/kg/dose every
treatment 6-hourly with or without 12 hours
gentamicin* 3mg/kg/ <2 000 g divided doses
day IV in 3 divided 2.5 mg/kg/dose every
doses Neonates <7 days and 150 mg/kg/day in 3 8-12 hours
>2 000 g divided doses
Neonates 8-31 days and 150 mg/kg/day in 4
<2 000 g divided doses
Neonates 8-31 days and 200 mg/kg/day in 4 2.5 mg/kg/dose every
12 hours
>2 000 g divided doses
Infants >31 days and 300 mg/kg/day in 4-6 Gentamicin 7.5 mg/
children divided doses with a kg per day in 3 divided
maximum of 12 g/day doses
Treatment in the Co-trimoxazole** 20 mg Age category Co-trimoxazole (IV)
presence of confirmed trimethoprim/kg/day in Neonates <31 days
penicillin allergy divided doses 6-hourly Co-trimoxazole 8-12 mg trimethoprim/kg/day in
for 21 days Infants >31 days and divided doses 6-hourly
children
Co-trimoxazole 8-12 mg trimethoprim/kg/day in
divided doses 6-hourly
*Consider adding gentamicin. Note that gentamicin is contra-indicated in pregnancy
**Cotrimoxazole should be used with caution in pregnancy
Table 4. Recommended duration of therapy for listeriosis
Indication Duration of therapy Additional comments
Febrile gastro-enteritis Treatment not required Consider oral ampicillin/cotrimoxazole therapy for
5-7 days for high-risk group individuals known to
Bacteraemia Ampicillin IV for 21 days have ingested a food implicated in an outbreak
Meningitis and meningo-encephalitis Gentamicin can be added to ampicillin for up to
Symptomatic disease in pregnancy Ampicillin IVI (or high-dose oral 7 days
amoxicillin) for at least 14 days or
Neonatal listeriosis until delivery Gentamicin can be added to ampicillin for 3-5
Ampicillin IV for 21 days days
Focal infections Ampicillin IV for 21 days Gentamicin can be added to ampicillin for up to
7 days
Gentamicin can be added to ampicillin for up to
7 days
HANDBOOK OF GENERAL MEDICINE VOL 1
142 TREATMENT APPROACHES
Cooking meat and poultry products, including raw,
processed (e.g. ham, Vienna sausages, polony and
cold meats) and leftovers thoroughly.
Avoiding perishable foods that are past their “con-
sume before” dates.
Antenatal and HIV clinics represent ideal opportuni-
ties for targeted food safety education, not only specif-
ic to preventing L. monocytogenes exposure, but also
for avoiding exposure to other foodborne pathogens
with a propensity to cause severe disease in these risk
groups (including non-typhoidal Salmonella spp.).
References
1. Denny J, McLauchlin J. Human Listeria monocytogenes infections in
Europe – an opportunity for improved European surveillance. Euro
Surveill. 2008;13(13).
2. Charlier C, Perrodeau E, Leclercq A, et al. Clinical features and
prognostic factors of listeriosis: the MONALISA national prospective
cohort study. Lancet Infect Dis. 2017;17(5):510-9.
3. National Institute for Communicable Diseases. Listeriosis outbreak
situation report, 26 July 2018. http://www.nicd.ac.za/wp-content/
uploads/2018/07/Listeriosis-outbreak-situation-report-_26July2018_
fordistribution.pdf
4. Frean J BL, McCarthy K, Thomas J. Plague and listeriosis: Current
outbreaks and a historical South African connection. S Afr J Infect
Dis. 2018;33(1):3-4.
5. Jacobs MR, Stein H, Buqwane A, et al. Epidemic listeriosis. Report of
14 cases detected in 9 months. S Afr Med J. 1978;54(10):389-92.
6. Smith AM, Naicker P, Bamford C, et al. Genome Sequences for a
Cluster of Human Isolates of Listeria monocytogenes identified in
South Africa in 2015. Genome Announc. 2016;4(2).
7. Hernandez-Milian A, Payeras-Cifre A. What is new in listeriosis? Bi-
omed Res Int. 2014;2014:358051.
8. De Noordhout CM, Devleesschauwer B, Angulo FJ, et al. The global
burden of listeriosis: A systematic review and meta-analysis. Lancet
Infect Dis. 2014;14(11):1073-82.
9. Schlech WF, 3rd, Lavigne PM, Bortolussi RA, et al. Epidemic listeriosis –
evidence for transmission by food. N Engl J Med. 1983;308(4):203-6.
10. Allerberger F, Wagner M. Listeriosis: A resurgent foodborne infec-
tion. Clin Microbiol Infect. 2010;16(1):16-23.
11. Cossart P, Toledo-Arana A. Listeria monocytogenes, a unique model in
infection biology: An overview. Microbes Infect. 2008;10(9):1041-50.
12. Goulet V, Hebert M, Hedberg C, et al. Incidence of listeriosis and
related mortality among groups at risk of acquiring listeriosis. Clin
Infect Dis. 2012;54(5):652-60.
13. Madjunkov M, Chaudhry S, Ito S. Listeriosis during pregnancy. Arch
Gynecol Obstet. 2017;296(2):143-52.
14. Ooi ST, Lorber B. Gastroenteritis due to Listeria monocytogenes. Clin
Infect Dis. 2005;40(9):1327-32.
15. Goulet V, King LA, Vaillant V, et al. What is the incubation period for
listeriosis? BMC Infect Dis. 2013;13:11.
16. National Institute for Communicable Diseases. Listeriosis: Clinical
recommendations for diagnosis and treatment. 2017 5 December.
http://www.nicd.ac.za/wp-content/uploads/2017/12/Clinical-
guidelines_20171206_v2.pdf
17. McGill F, Heyderman RS, Michael BD, et al. The UK joint specialist
societies guideline on the diagnosis and management of acute
meningitis and meningococcal sepsis in immunocompetent adults.
J Infect. 2016;72(4):405-38.
18. Thonnings S, Knudsen JD, Schonheyder HC, et al. Antibiotic treat-
ment and mortality in patients with Listeria monocytogenes menin-
gitis or bacteraemia. Clin Microbiol Infect. 2016;22(8):725-30.
19. Van de Beek D, Cabellos C, Dzupova O, et al. ESCMID guideline:
Diagnosis and treatment of acute bacterial meningitis. Clin Micro-
biol Infect. 2016;22 Suppl 3:S37-62.
20. World Health Organization. Five keys to safer food poster. https://
www.who.int/foodsafety/publications/consumer/en/5keys_
en.pdf?ua=1
21. World Health Organization. Food safety and nutrition during preg-
nancy and infant feeding, 30 April 2008. https://www.who.int/food-
safety/fs_management/No_03_nutrition_Apr08_en.pdf
HANDBOOK OF GENERAL MEDICINE VOL 1
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