Tuberculosis in HIV-Infected Children

8/9/2019 Tuberculosis in HIV-Infected Children

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SERIES: HIV-ASSOCIATED LUNG DISEASE

Tuberculosis in HIV-infected children

Soumya Swaminathan

Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600 031, India

Nearly 5 million people (4.2 million adults and 700 000children) are newly infected with human immunodeficiency

virus (HIV) each year; more than 95% of them belong to

developing countries. It is estimated that there are 40

million people living with HIV/acquired immunodeficiency

syndrome (AIDS) worldwide and of these, 2.5 million are

children less than 15 years of age.1 HIV is lowering life

expectancy and reversing gains in child survival in some

parts of Africa.2 Paediatric HIV infection is acquired mainly

by transmission from mother to child during pregnancy,

labour or breast feeding. Perinatal transmission accounts for

>90% of infections in children and is a major concern in

most developing countries.3 Antenatal HIV prevalence

rates vary widely by region and range from 1% in India

to 2530% in some countries in south and east Africa.

Although effective interventions in the form of anti-retro-

viral drugs during pregnancy, elective Caesarean section

and avoidance of breast feeding reduce transmission to


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other opportunistic infections, it occurs throughout the

course of HIV-1 infection. Children acquire TB infection

through contact with infected adults. Children with HIV

infection are at increased risk of progression from asymp-

tomatic tuberculous infection to TB disease. Although the

proportion of HIV-infected children with TB is lower than

HIV-infected adults, the number with HIV-attributable TB isincreasing rapidly. Several studies have demonstrated

increased rates of childhood TB associated with increasing

rates of disease in HIV-infected adults in the community.9,10

In Kenya, the annual risk of TB in school children increased

sharply between 1986 and 1996 in districts with a 50% HIV

prevalence among TB patients, but this was not seen in

other districts.11

In various studies in India, 1467.5% of children with HIV

infection have been diagnosed with TB.1214 Thesefigures

vary widely, partly because of difficulties in the definitive

diagnosis of TB as some symptoms produced by HIV/AIDS

are similar to TB. There are few studies of HIV seropreva-

lence among children with TB from different parts of the

world. A studyfrom Zambia showed an HIV seroprevalence

rate of 37%15 while Madhi et al. reported HIV seropreva-

lence of 42% among children with TB in South Africa.16 In

most parts of India, HIV seroprevalence among children with

TB is low (


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than 70% of patients with TB and pre-existing AIDS but

only in 2445% of patients with less advanced HIV dis-

ease.26 In the Ivory Coast, 29% of HIV-positive children had

extrapulmonary disease which was similar to 26% in HIV-

negative children. The common extrapulmonary manifes-

tations were lymphadenopathy, pleural effusion and miliary

TB.27

Chronic weight loss, malnutrition and absence ofBacille Calmette-Guerin (BCG) scarring are more common

in HIV-infected children with TB. They are also more likely

to show cavitation and miliary TB on chest x ray while

tuberculin reactivity is significantly lower.16

In the authors experience, of 22 HIV-infected children

diagnosed with TB, the common presenting symptoms were

persistent cough or fever with failure to thrive. The most

common clinical sign was protein energy malnutrition. Only

two children had a positive tuberculin reaction. In most

children, diagnosis was based on a combination of clinical

features and radiological abnormalities (unpublished obser-

vations). The most common radiographic abnormality was

the presence of parenchymal infiltrates/opacities followed by

hilar/mediastinal lymph node enlargement. A miliary-like

picture was seen in four children; however, in three children,

the lesions persisted despite anti-TB therapy, suggesting

other diagnoses. A study from Zimbabwe showed that

lobar infiltrates, especially in the lower lobes, were more

common in HIV-positive children.28

The diagnosis of TB in children with HIV infection poses a

number of challenges. Symptoms and signs are non-specific

and mimic many infections and bacteriologic diagnosis is

uncommon. Sputum induction has been suggested as a

diagnostic method for infants and children hospitalised with

community-acquired pneumonia. Induced sputum gavehigher yields than gastric lavage or nasopharyngeal aspirate

for M. tuberculosis and Pneumocystis carinii, respectively.29

Tuberculin skin testing is of limited value as it is only positive

in a minority of children with HIV infection. Afinal diagnosis

of confirmed or probable TB is less common than in HIV-

negative children (36% vs 63%), mainly due to the over-

lapping clinical features of these two infections.30

Many children with HIV-1 infection have features of

chronic lung disease with abnormal chest radiographs, thus

making the diagnosis of pulmonary TB even more difficult.31

Furthermore, radiographic manifestations of TB overlap

with other conditions like P. carinii pneumonia (PCP),

bacterial pneumonia and lymphocytic interstitial pneumo-

nitis (LIP). In the authors series, the diagnosis of LIP was

made after children had been given a therapeutic trial of

anti-TB therapy for presumed miliary TB but did not show

clinical improvement. LIP is more likely than TB if: recurrent

respiratory infections improve slightly with antibiotics andsteroids;finger clubbing is present; and there is no response

to anti-TB therapy (Table 1). In an autopsy study in African

children dying of respiratory illnesses, Chintu et al. found

that the three most frequent findings in the HIV-positive

group were acute pyogenic pneumonia (41%), PCP (29%)

and cytomegalovirus (22%), whilst TB was seen in all age

groups irrespective of HIV status.32 Such data underscore

the urgent need for improved diagnostic tests for bacterial

pathogens, TB and PCP in resource-limited settings.

THERAPY

It is generally accepted that HIV-positive people with TB

respond as well to short-course chemotherapy as HIV-

negative people. Alhough there have been no clinical trials

in children, studies in HIV-positive adults have shown similar

sputum smear conversion and cure rates as HIV-negative

adults. For pulmonary and most forms of extrapulmonary

TB, standard 6-month chemotherapy with isoniazid (5

10 mg/kg/day), rifampicin (1012 mg/kg/day), pyrazinamide

(30 mg/kg/day) and ethambutol (1520 mg/kg/day) for the

first 2 months followed by isoniazid and rifampicin for the

next 4 months is recommended.33 Drugs may be adminis-

tered daily or thrice weekly and directly observed treat-

ment is recommended wherever possible. For meningitisand bone and joint TB, a minimum of 9 months of treat-

ment is recommended. Thiacetazone should not be used

since its use is associated with life-threatening Stevens

Johnson syndrome. Pyridoxine 10 mg daily may be given to

prevent peripheral neuropathy due to isoniazid.

Mortality rates have been reported to be higher among

HIV-infected children with TB than in those without HIV; in

one study, the mortality was 13.4% in HIV-positive and

1.5% in HIV-negative children during the course of ther-

apy.16 Palme et al. found that although adherence to

treatment was high (96%), the cure rate was 58% for

Table 1 Features helping to differentiate between miliary tuberculosis and lymphocytic

interstitial pneumonitis.

Mil iary tuberculosis Lymphocytic interstitial pneumonitis

Occurs in younger children Usually starts in second year, uncommon in infancy

Finger clubbing uncommon Finger clubbing common

Parotid enlargement rare Parotid enlargement may be present

Child is acutely ill Child is relatively well

Widespread distribution of small,

evenly-sized nodules (


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HIV-positive and 89% for HIV-negative TB patients while

mortality was six-fold higher.34 Deaths are due directly to

TB as well as other AIDS-related opportunistic infections.

Paradoxical reactions may occur during the course of anti-

TB therapy when anti-retroviral treatment restores

immune function. This reaction, also known as immune

reconstitution syndrome, occurs a few weeks after treat-ment is begun and can manifest as high fever, enlargement

of existing lymph nodes or appearance of new ones with

worsening parenchymal lesions on chest x ray. The reaction

is self-limiting and can be managed conservatively but needs

to be distinguished from a new opportunistic infection.

These reactions can occur in patients on anti-TB treatment

alone but are most common when both TB and HIV

treatment are started together.

The treatment of HIV-infected children with multi-drug-

resistant TB (MDRTB) is likely to require the use of second-

line medications and should be undertaken by an expert.

MDRTB can occur when HIV-positive children are in contact

with adult patients with drug-resistant TB, a phenomenon not

uncommon where HIV is prevalent.35 Second-line drugs

commonly employed are a combination of kanamycin with

a fluoroquinolone, e.g. ofloxacin or ciprofloxacin, ethiona-

mide, cycloserine and pyrazinamide/ethambutol. The choice

of regimen would usually depend on the drug susceptibility

pattern of the adult contact, if available.

Drug interactions can occur between HIV and TB

medications. Rifampicin induces hepatic cytochrome P-

450, resulting in lower serum concentrations of medica-

tions metabolised through this pathway. Rifampicin should

not be administered with protease inhibitors and there is

conflicting evidence of its interaction with nevripaine.Rifampicin may be substituted by rifabutin but this is not

widely available. In general, the drug combinations pre-

ferred with anti-TB therapy are a combination of two

nucleoside reverse transcriptase inhibitors (ZDV plus lami-

vudine or stavudine plus lamivudine) with efavirenz or

abacavir. More data are needed on the use of these

combinations in children.

Mycobacterium avium complex

Disseminated infection withMycobacterium aviumcomplex

(MAC) occurs almost exclusively in children and adults with

advanced HIV disease. MAC includes two closely related

species,M. aviumandM. intracellulare. They are intracellular

parasites that proliferate within macrophages; in children

with defective cell-mediated immunity, uncontrolled bac-

terial replication occurs.M. aviumare environmental sapro-

phytes and can be found in soil, water, food and animals.

The gut may be the portal of entry for the organism.

Clinical presentation can be indolent and slowly pro-

gressive. Most children are severely immunosuppressed

and present with fever, weight loss, abdominal pain and

anaemia. Night sweats, diarrhoea, malaise, neutropenia and

hepatomegaly have been described. Without treatment,

survival ranges from 9 to 11 months. The diagnosis ofM.

avium infection requires cultivation from blood or tissue;

blood cultures are usually done using the BACTEC radio-

metric system. Characteristic histological findings of acid-

fast bacilli within macrophages are highly suggestive of MAC

infection but cultures are necessary to distinguish species.

Treatment is with a combination of two or more drugs:clarithromycin 15 mg/kg daily in two divided doses or

azithromycin 10 mg/kg once daily with ethambutol 15

20 mg/kg once daily and/or rifabutin 510 mg/kg once daily.

Children treated for disseminated MAC must remain on

lifelong prophylaxis with at least two drugs.

PREVENTIVE THERAPY

Preventive therapy (chemoprophylaxis) with isoniazid is

effective in preventing progression of TB infection to disease.

Several studies have documented that 6 or 12 months of

isoniazid (INH) given to tuberculin-skin-test-positive patients

resulted in a 7083% reduction in the incidence of TB. Based

on these studies, the Centres for Disease Control currently

recommend prophylaxis for all HIV-infected individuals with

a tuberculin skin reaction >5 mm.36 It is important to

exclude active TB before preventive therapy is instituted.

There are several alternative shorter regimens such as 2

months of rifampicin and pyrazinamide, 3 months of iso-

niazid and rifampicin etc., but none have been found to be

superior to 12 months of isoniazid.

BCG vaccination

BCG is one of the most widely used vaccinations in theworld and is part of the Expanded Program of Immunization

(EPI) schedule, often being administered in the weeks after

birth. Although it is a live attenuated vaccine, the World

Health Organisation recommends that BCG should be given

to children with suspected HIV infection unless they have

symptomatic disease, because therisks of TB far outweigh

the complications of immunisation.3 While there have been

no population-based controlled studies of BCG-related

complications, there are reports of regional or disseminated

BCG disease in HIV-infected children. Hesseling et al.

reported six cases of BCG disease among mycobacterial

isolates from 49 HIV-infected children (four with regional

axillary adenitis and two with pulmonary BCG disease). All

patients were asymptomatic at birth,


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non-specific. Although treatment using standard anti-TB

regimens is effective, outcome is poor due to high mortality

rates. Wider access to anti-retroviral therapy is likely to

reduce mortality and morbidity due to TB in HIV-infected

children and adults. Research is required to identify better

diagnostic tests and treatment strategies that include both

anti-TB and anti-retroviral drugs.

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PRACTICE POINTS

HIV is the strongest known risk factor for the

development of TB

TB accelerates the course of HIV disease

Symptoms and signs are non-specific; differential

diagnosis includes PCP, bacterial pneumonia and LIP

Tuberculin test is usually negative

Standard short-course anti-TB regimens are

recommended for treatment but mortality is

higher in HIV-positive children than HIV-negative

children with TB

Paradoxical reactions may occur, especially when

anti-TB and anti-retroviral therapy are started

together

RESEARCH DIRECTIONS

Better diagnostic tests for TB, PCP, pyogenic

pneumonia.

Clinical trials of anti-retroviral with anti-TB therapy.

Clinical trials of preventive therapy for TB in HIV-

positive children.

TUBERCULOSIS IN HIV-INFECTED CHILDREN 229


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230 S. SWAMINATHAN

Tuberculosis in HIV-Infected Children

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