“Infectious diseases of poverty” (IDoP) describes infectious diseases that are more prevalent among poor and vulnerable populations, namely human immunodeficiency virus (HIV) infection, tuberculosis (TB), malaria, and neglected tropical diseases (NTDs). In 2013, 190,000 children died of HIV-related causes and there were 550,000 cases and 80,000 TB deaths in children. Children under age 5 account for 78% of malaria deaths annually. NTDs remain a public health challenge in low- and middle-income countries. This article provides an overview of the major IDoP that affect children. Clinicians must be familiar with the epidemiology and clinical manifestations to ensure prompt diagnosis and treatment.
Key points
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Poverty is inextricably linked with infectious diseases, including human immunodeficiency virus (HIV) infection, tuberculosis (TB), malaria and neglected tropical diseases (NTDs).
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Advances have been made in HIV treatment; however, access to and management of antiretroviral therapy (ART) in children still lag behind that of adults.
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TB is the leading infectious cause of mortality worldwide; poverty and young age are significant determinants of progression from TB exposure to disease.
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Malaria remains a leading cause of child mortality; access to effective preventive measures and therapy must reach vulnerable populations.
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Clinicians, both in endemic and nonendemic areas, must be familiar with the epidemiology and clinical manifestations of these infections to ensure prompt diagnosis and treatment.
Introduction
The phrase “infectious diseases of poverty” (IDoP) is used to describe infectious diseases that are more prevalent among poor and vulnerable populations. IDoP comprises (1) human immunodeficiency virus (HIV) and AIDS, tuberculosis (TB), and malaria—the “big 3” (also referred to as the “Unholy Trinity”); and (2) neglected tropical diseases (NTDs). Poverty has been inextricably linked with infectious diseases since antiquity. Poverty, acting through nongenetic heritable principles, has transformed infectious diseases into “inheritable” conditions. IDoP is seen in pockets of poverty in high-income countries as well. IDoP perpetuates poverty by leading to adverse outcomes in pregnancy, child development, and workplace productivity. Gross domestic product, an indicator of the wealth of a country, is the most sensitive surrogate measure of burden of infectious diseases in a country. Fig. 1 illustrates the positive correlation between poverty and infectious diseases. Substandard housing, lack of access to safe water and sanitation, and inadequate vector control contribute to the efficient transmission of these infections. Other social determinants (eg, gender inequality, unemployment, low educational status, poor nutrition) compound the problem. Strategies to prevent and control infectious diseases require tremendous resources. Therefore, infectious diseases have artificially divided the world into high-income as well as low- and middle-income countries (LMIC), with LMIC bearing the greatest burden of IDoP. However, with globalization and increased interconnectedness of the world, IDoP can transcend this economic divide.
This article provides an overview of IDoP that affect children with a focus on epidemiology, clinical manifestations, diagnosis, management, and prevention. IDoP account for a significant disease burden and high disability-adjusted life-years ( Table 1 ).
| Disease | DALYs, in Thousands (95% CI) |
|---|---|
| HIV/AIDS | 81,547 (75,003–88,367) |
| Tuberculosis | 49,396 (40,065–56,071) |
| Malaria | 82,685 (63,426–109,836) |
| NTDs | |
| Leishmaniasis | 3317 (2180–4890) |
| Schistosomiasis | 3309 (1705–6260) |
| Dengue | 825 (344–1412) |
| Chagas disease | 546 (271–1054) |
| Cysticercosis | 503 (379–663) |
| Other NTDs | 4724 (3525–6351) |
Introduction
The phrase “infectious diseases of poverty” (IDoP) is used to describe infectious diseases that are more prevalent among poor and vulnerable populations. IDoP comprises (1) human immunodeficiency virus (HIV) and AIDS, tuberculosis (TB), and malaria—the “big 3” (also referred to as the “Unholy Trinity”); and (2) neglected tropical diseases (NTDs). Poverty has been inextricably linked with infectious diseases since antiquity. Poverty, acting through nongenetic heritable principles, has transformed infectious diseases into “inheritable” conditions. IDoP is seen in pockets of poverty in high-income countries as well. IDoP perpetuates poverty by leading to adverse outcomes in pregnancy, child development, and workplace productivity. Gross domestic product, an indicator of the wealth of a country, is the most sensitive surrogate measure of burden of infectious diseases in a country. Fig. 1 illustrates the positive correlation between poverty and infectious diseases. Substandard housing, lack of access to safe water and sanitation, and inadequate vector control contribute to the efficient transmission of these infections. Other social determinants (eg, gender inequality, unemployment, low educational status, poor nutrition) compound the problem. Strategies to prevent and control infectious diseases require tremendous resources. Therefore, infectious diseases have artificially divided the world into high-income as well as low- and middle-income countries (LMIC), with LMIC bearing the greatest burden of IDoP. However, with globalization and increased interconnectedness of the world, IDoP can transcend this economic divide.
This article provides an overview of IDoP that affect children with a focus on epidemiology, clinical manifestations, diagnosis, management, and prevention. IDoP account for a significant disease burden and high disability-adjusted life-years ( Table 1 ).
| Disease | DALYs, in Thousands (95% CI) |
|---|---|
| HIV/AIDS | 81,547 (75,003–88,367) |
| Tuberculosis | 49,396 (40,065–56,071) |
| Malaria | 82,685 (63,426–109,836) |
| NTDs | |
| Leishmaniasis | 3317 (2180–4890) |
| Schistosomiasis | 3309 (1705–6260) |
| Dengue | 825 (344–1412) |
| Chagas disease | 546 (271–1054) |
| Cysticercosis | 503 (379–663) |
| Other NTDs | 4724 (3525–6351) |
Human immunodeficiency virus
Epidemiology
Thirty-four years into the HIV epidemic, advances in prevention and treatment have been made. However, challenges remain regarding access to and management of antiretroviral therapy (ART), particularly in LMIC. Established modes of HIV transmission are (1) sexual contact, (2) needle injuries, (3) mucous membrane exposure, (4) mother-to-child transmission (MTCT), and (5) transfusion with contaminated blood products. MTCT continues to fuel the pediatric HIV epidemic in LMIC. The use of perinatal antiretroviral drugs to prevent MTCT (PMTCT) of HIV has resulted in a dramatic decrease (to <2%) in the rate of vertical HIV transmission in the United States.
Despite these successes, progress has not been uniform worldwide. At the end of December 2013, only 23% of the 3.2 million children estimated to be living with HIV were receiving ART and in 2013 alone, 240,000 were newly infected and 190,000 (170,000–220,000) died of HIV-related causes. Poverty is related inextricably to the disparity in global coverage of ART, with LMIC reporting low coverage ( Table 2 ). Sub-Saharan Africa, with the highest proportion of people living on less than US$2 per day (see Fig. 1 ), is home to 91% of all children living with HIV.
| WHO Region | Number on ART | Percent Coverage (Range) |
|---|---|---|
| Africa region | 630,300 | 22 (20–24) |
| The Americas | 26,400 | 51 (38–62) |
| South-East Asia region | 13,900 | >95 (94–>95) |
| Eastern Mediterranean region | 1100 | 7 (5–9) |
| Western Pacific region | 13,200 | 61 (56–67) |
| Total | 684,900 | 47.2 (7–>95%) |
Clinical Manifestations
The hallmark of HIV infection is progressive depletion of CD4 T cells leading to development of opportunistic infections, AIDS, and death. In acute simian immunodeficiency virus infection, 30% to 60% of all gut-associated CD4 cells become infected, leading to profound depletion within 4 days of infection. Similar CD4 gastroenteropathy occurs with acute HIV infection, albeit at a different pace. During primary infection, HIV infects gut-associated resting and activated memory CD4 cells, leading to breach in the intestinal epithelial barrier with a loss of tight junctions, enterocyte apoptosis, local immune activation, and depletion of CD4 cells. The breach in the mucosal barrier facilitates translocation of pathogenic bacteria and microbial products from the gut lumen to the systemic circulation, leading to chronic immune activation. The time from acute infection to the development of AIDS is defined by a CD4 cell count of less than 200 cells/mm 3 or the appearance of AIDS-defining opportunistic infections or cancers ( Box 1 ) and ranges from 6 months to 25 years. However, in infants, disease progression is rapid; without treatment, 20% and 50% of perinatally infected infants will die by 3 and 24 months of age, respectively.
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Mild HIV-related symptoms
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Children with 2 or more of the conditions listed but none of the conditions listed in Moderate Symptoms category
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Lymphadenopathy (≥0.5 cm at >2 sites; bilateral at 1 site)
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Hepatomegaly
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Splenomegaly
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Dermatitis
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Parotitis
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Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media
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Moderate HIV-related symptoms
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Anemia (hemoglobin <8 g/dL [normal, <80 g/L]), neutropenia (white blood cell count <1000/μL [normal, <1.0 × 109/L]), and/or thrombocytopenia (platelet count <100 × 103/μL [normal, <100 × 109/L]) persisting for ≥30 days
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Bacterial meningitis, pneumonia, or sepsis (single episode)
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Candidiasis, oropharyngeal (thrush), persisting (>2 months) in children older than age 6 months
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Cardiomyopathy
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Cytomegalovirus infection, with onset before 1 month
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Diarrhea, recurrent or chronic
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Hepatitis
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Herpes simplex virus stomatitis, recurrent (>2 episodes within 1 year)
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Herpes simplex virus bronchitis, pneumonitis, or esophagitis with onset before 1 month
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Herpes zoster (shingles) involving at least 2 distinct episodes or more than 1 dermatome
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Leiomyosarcoma
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Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex
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Nephropathy
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Nocardiosis
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Persistent fever (lasting >1 month)
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Toxoplasmosis, onset before 1 month
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Varicella, disseminated (complicated chickenpox)
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Stage 3–defining opportunistic illnesses in HIV infection
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Bacterial infections, multiple or recurrent
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Candidiasis of bronchi, trachea, or lungs
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Candidiasis of esophagus
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Cervical cancer, invasive
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Coccidioidomycosis, disseminated or extrapulmonary
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Cryptococcosis, extrapulmonary
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Cryptosporidiosis, chronic intestinal (>1 month duration)
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Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age greater than 1 month
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Cytomegalovirus retinitis (with loss of vision)
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Encephalopathy attributed to HIV
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HSV: chronic ulcers (>1 month duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month)
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Histoplasmosis, disseminated or extrapulmonary
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Isosporiasis, chronic intestinal (>1 month duration)
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Kaposi sarcoma
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Lymphoma, Burkitt (or equivalent term)
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Lymphoma, immunoblastic (or equivalent term)
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Lymphoma, primary, of the brain
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Mycobacterium avium complex or Mycobacterium kansasii , disseminated or extrapulmonary
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Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary
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Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
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Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia
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Pneumonia, recurrent
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Progressive multifocal leukoencephalopathy
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Salmonella septicemia, recurrent
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Toxoplasmosis of brain, onset at age greater than 1 month
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Wasting syndrome attributed to HIV
Abbreviations: HIV, human immunodeficiency virus; HSV, herpes simplex virus.
HIV infection in children results in a wide array of clinical manifestations (see Box 1 ) and has a varied natural history. Early presentations of pediatric HIV infection include unexplained fevers, generalized lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, oral and diaper candidiasis, recurrent diarrhea, parotitis, hepatitis, central nervous system disease (eg, hyperreflexia, hypertonia, floppiness, developmental delay), recurrent invasive bacterial infections, and other opportunistic infections (see Box 1 ).
Diagnosis
The HIV nucleic acid test is used for diagnosis of HIV infection. The HIV nucleic acid test includes HIV DNA and RNA polymerase chain reaction (PCR) assays, and related RNA qualitative or quantitative assays. HIV culture is not used for routine diagnostic testing. Early HIV testing of all infants born to HIV-infected women is required. Infants born to women with HIV infection will be HIV antibody positive because of transplacental transfer of maternal antibodies. HIV RNA or DNA testing of an HIV-exposed infant should be performed at birth (for infants at high risk of HIV infection), at age 14 to 21 days, at 1 to 2 months, and at age 4 to 6 months. HIV infection can be excluded in a non-breastfed infant with 2 or more negative virologic tests (ie, negative RNA or DNA), one at age 1 month or older and one at age 4 months or older, or 2 negative antibody tests from separate specimens obtained at age 6 months or older. The World Health Organization (WHO) recommends that all HIV-exposed infants have HIV virologic testing at 4 to 6 weeks of age and HIV serologic testing at 9 months to identify infants with persisting HIV antibody or who have seroreverted. Furthermore, serologic testing followed by virologic testing (if seroreverted) is recommended at least 6 weeks after breastfeeding cessation in children less than 18 months of age. For infants and children greater than 18 to 24 months of age who present with symptoms consistent with HIV infection (see Box 1 ) and unknown maternal HIV status, HIV diagnosis relies on antibody tests and a confirmatory PCR test.
Management
The goal of combination ART (cART) is to suppress HIV viral replication and restore immune function. Current treatment strategies focus on timely initiation of cART regimens capable of maximally suppressing viral replication to prevent disease progression. There are emerging reports that very early cART is associated with very small proviral reservoirs and restricted HIV-specific immune responses in perinatal infection. However, when to start ( Box 2 ) and what ART regimen to start a patient on ( Table 3 ) vary from country to country. The management of patients failing first-line regimens and treatment options for multiple drug resistant HIV is complicated and should involve an expert in HIV medicine.
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WHO Guidelines on when to start ART in children
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ART should be initiated among all children younger than 10 years of age living with HIV, regardless of WHO clinical stage or at any CD4 cell count
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As a priority, ART should be initiated among all children <2 years old or with WHO stage 3 or 4 or CD4 count ≤750 cells/mm 3 or CD percentage <25% among children younger than 5 years and CD4 count ≤350 cells/mm 3 among children 5 years and older
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ART should be initiated among all adolescents (i.e., 10 to 19 years) living with HIV regardless of WHO clinical stage and at any CD4 cell count
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As a priority, ART should be initiated among all adolescents with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and adolescents with CD4 count ≤350 cells/mm 3
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US Department of Health and Human Services Guidelines on when to start ART in children
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cART should be initiated urgently in all HIV-infected children with any of the following:
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Age younger than 12 months
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Age 1 year or older (with CDC stage 3-defining opportunistic illnesses or CDC stage 3 immunodeficiency)
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Aged 1 to younger than 6 years, CD4 less than 500 cells/mm 3
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Aged 6 years or older, CD4 less than 200 cells/mm 3
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cART should be initiated in HIV-infected children aged 1 year or older with any of the following:
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Moderate HIV-related symptoms (see Box 1 )
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Plasma HIV RNA greater than 100,000 copies/mL
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CDC stage 2
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Age 1 to younger than 6 years, CD4 count 500 to 999 cells/mm 3 .
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Age 6 years or older, CD4 count 200 to 499 cells/mm 3 .
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If CD4 count is less than 350 cells/mm 3 .
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If CD4 count is 350 to 499 cells/mm 3 .
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cART should be considered for HIV-infected children aged 1 year or older with:
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Mild HIV-related symptoms (see Box 1 ) or asymptomatic and CDC stage 1
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Ages 1 to younger than 6 years, CD4 count 1000 cells/mm 3 or greater.
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Age 6 years or older, CD4 count of 500 cells/mm 3 or greater.
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Pediatric European Network for Treatment of AIDS guidelines for ART initiation
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ART is recommended
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In all children under 1 year of age;
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In all children with significant disease [WHO stage 3 or 4 or CDC stage B or C];
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In asymptomatic children over 1 year of age based on age-specific CD4 count; and
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In those with hepatitis C virus or active tuberculosis coinfection.
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ART should be considered:
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In asymptomatic children over 5 years of age at CD4 counts of 350 to 500 cells/mm 3 ;
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In children with high VL (>100,000 copies/mL);
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In asymptomatic children aged 1 to 3 years irrespective of immune status and VL;
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In sexually active adolescents, to minimize the risk of onward transmission;
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In the presence of any significant HIV-related clinical symptoms; and
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In hepatitis B virus coinfection irrespective of immune status.
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Abbreviations: ART, antiretroviral therapy; cART, combination antiretroviral therapy; CDC, US Centers for Disease Control and Prevention; HIV, human immunodeficiency virus: VL, viral load; WHO, World Health Organization.
| Organization (Source) | Age (y) | Preferred Regimen | Alternate Regimen |
|---|---|---|---|
| WHO (2013) | Children <3 y | LPV/r + ABC + 3 TC or LPV/r + AZT + 3 TC | NVP a + ABC + 3 TC or NVP a + AZT + 3 TC (ABC + 3 TC + AZT) b |
| 3–10 y (<35 kg) | EFV + ABC + 3 TC or EFV + AZT (or TDF) + 3 TC (or FTC) | NVP + ABC + 3 TC or NVP + AZT (or TDF) + 3 TC (or FTC) | |
| 10–19 y (≥35 kg) | EFV + TDF + 3 TC (or FTC) or EFV + AZT + 3 TC EFV + ABC + 3 TC | NVP + TDF + 3 TC (or FTC) or NVP + AZT + 3 TC NVP + ABC + 3 TC | |
| US HHS (2015) | Children aged ≥14 d to <3 y | 2 NRTIs + LPV/r | 2 NRTIs + NVP |
| Children aged ≥3–6 y | 2 NRTIs + EFV (or LPV/r) | 2 NRTIs + ATV/r (≥3 mo to <6 y) 2NRTIs + RAL (≥2 y) 2NRTIs + DRV/r (≥3 to <12 y) | |
| Children aged ≥6 y | 2 NRTIs + ATV/r or EFV or LPV/r | 2 NRTIs + DRV/r (≥12 y) 2 NRTIs + DTG (≥12 y and weighing ≥40 kg) | |
| PENTA (2015) | Children <1 y | ABC c + 3 TC + LPV/r Or (ABC + 3 TC + AZT + NVP) d | NNRTI backbone: AZT + 3 TC |
| Children 1–3 y | ABC + 3 TC + LPV/r Or (ABC + 3 TC + AZT + NVP) e | NRTI backbone: AZT + 3 TC | |
| Children 3–6 y | ABC + 3 TC + LPV/r or EFV | AZT + 3 TC + NVP or DRV/r or TDF + 3 TC (FTC) + NVP or DRV/r | |
| Children 6–12 y | ABC + 3 TC + ATV/r or ABC + 3 TC + EFV | AZT + 3 TC + NVP (or LPV/r or DRV/r) or TDF + 3 TC (FTC) + NVP or LPV/r or DRV/r | |
| Children >12 y | TDF + FTC + ATV/r or DRV/r or EFV or ABC + 3 TC + ATV/r or DRV/r or EFV | ABC + 3 TC + NVP or LPV/r or RAL f or DTG |
a NVP-based regimen if LPV/r is not feasible.
b As an option for children who develop tuberculosis while on ART regimen containing NVP or LPV/r. Once tuberculosis therapy is completed, a switch to initial regimen is recommended.
c Before starting abacavir (ABC), test for HLA B*5701. If positive, then ABC should not be prescribed.
d In children less than 3 years, consider adding AZT to NVP-based regimens if there is a very high viral load or central nervous system involvement until viral load has been suppressed for at least 3 months.
e Four-drug induction for infants on NVP-based therapy may be considered until viral load has been suppressed for at least 3 months, followed by 3-drug maintenance therapy.
f In rare instances (eg, transmitted resistance or toxicity), raltegravir may be used as first-line therapy in children <12 years of age.
The standard of care for monitoring treatment in HIV-infected children is routine laboratory monitoring of CD4 absolute count or percentage and HIV viral load. The WHO recommends viral load surveillance as the preferred monitoring of HIV treatment; if not routinely available, CD4 count and clinical monitoring are used.
Prevention
HIV prevention in children can be categorized into (1) primary prevention, mainly by PMTCT, and (2) secondary prevention of morbidity and mortality of HIV. PMTCT rates as low as 1% have been achieved as a result of the use of the PACTG 076 regimen, cART, and appropriate management of labor and delivery. The birth of an infected child in a high-income countries is now rare and represents systems failure and missed opportunities during pregnancy, labor, and delivery. The WHO recommends Option B+ as the main strategy to eliminate MTCT: Option B+ proposes that all HIV-infected women receive lifelong ART beginning at their first pregnancy, regardless of CD4 count. This strategy may improve maternal health through reduced morbidity and mortality, and reduce overall MTCT, especially in settings with high fertility rates. The cost effectiveness of Option B+ has been reported by several studies.
In the era of expanded access to ART, millions of children with perinatally acquired HIV infection are now living longer. However, pediatric HIV faces new challenges related to adherence, drug resistance, reproductive health planning, transition to adult medical care, and the potential for long-term complications from HIV and the treatment thereof.
Tuberculosis
Epidemiology
TB is caused by the bacillus Mycobacterium tuberculosis and is the leading infectious cause of death worldwide. Childhood TB accounts for approximately 10% to 20% of the global burden of TB disease. In 2013, there were an estimated 9.0 million incident cases and 1.5 million deaths, including 550,000 cases and 80,000 deaths among children. In the same year, TB case rates in the United States continued to decline in all age groups except among children aged 14 years or younger (0.8 cases per 100,000). Moreover, poor case ascertainment, absence of active case finding, and limited surveillance data in TB-endemic areas contribute to underestimation of global burden of pediatric TB disease. Incidence of pediatric TB is an accurate measure of ongoing transmission of TB within a community.
The natural history of TB in children can be quite different from that of adults. Duration from TB exposure to infection to disease is much shorter owing to several factors, by far the most important of which is poverty. Poverty increases a child’s risk of TB exposure through cultural practices around child care, overcrowding in school and at home, poor housing with inadequate ventilation, adults in household with comorbidities such as HIV, seasonal and environment-related exposure, and lack of public health infrastructure. After TB exposure, risk of a child developing infection is influenced by the acid fast bacilli sputum positivity of the source case, duration and intensity of exposure, infectiousness of the TB strain, coinfections, and the child’s immune and genetic makeup.
Clinical Manifestations
TB infection could be asymptomatic in children for several years. When disease occurs, signs and symptoms may be nonspecific, leading to diagnostic delay. TB disease could manifest as pulmonary or extrapulmonary. Clinical manifestations of pulmonary TB in children include fever, weight loss, cough, and night sweats. Pulmonary TB is the most common manifestation of TB in children, accounting for 60% to 80% of all cases. Manifestations of extrapulmonary TB include lymphadenopathy (67%), central nervous system involvement (13%), miliary and/or disseminated disease (5%), and musculoskeletal (4%). TB can affect any organ and presentation may be nonspecific or unusual; therefore, in TB-endemic areas physicians should have a high index of suspicion for TB. In a TB-endemic area, the use of a symptom-based diagnostic approach provided a fairly accurate diagnosis of pulmonary TB in HIV-uninfected children 3 years and older (sensitivity, 68.3%; specificity, 80.1%; positive predictive value, 82.1%). The symptom-based diagnostic approach comprised 3 well-defined symptoms at presentation: (1) persistent, nonremitting cough of greater than 2 weeks’ duration, (2) weight loss during the preceding 3 months, and (3) fatigue.
Diagnosis
Positive culture of M tuberculosis complex from gastric aspirates, sputum, bronchial lavage, pleural fluid, cerebrospinal fluid, urine, or other body fluid or tissue biopsy specimen establishes the diagnosis of TB. TB in children is usually paucibacillary; therefore, often acid fast bacilli negative on microscopy (sputum smears are positive in <10%–15% of children diagnosed with TB) and culture negative (confirmation by culture in only 30%–40% of cases). In nonendemic areas, in the absence of bacteriologic confirmation, diagnosis of TB in children is based on a triad of (1) close contact with an infectious index patient, (2) positive tuberculin skin test (TST) result, and (3) abnormal chest x-ray findings. The best specimen for diagnosis of pulmonary TB in a child with nonproductive cough is an early morning gastric aspirate obtained before ambulation or feeding; 3 gastric aspirates on 3 consecutive mornings are required. There are innovative ways of obtaining swallowed respiratory samples for TB diagnosis in children who cannot produce sputum, such as induction of sputum with aerosolized hypertonic saline and the string test. Nucleic acid amplification tests for the detection of mycobacterial DNA or RNA are in clinical use. Their sensitivities are low in paucibacillary TB, which includes most cases of childhood TB and extrapulmonary TB.
The TST is the most common method for diagnosing latent TB infection in asymptomatic patients. TST is an immune-based test driven by interferon-gamma production by T lymphocytes. Of immunocompetent children with culture-proven TB, 10% to 15% may have a negative TST initially. Moreover, previous Bacille Calmette-Guérin (BCG) vaccination or infection with nontuberculous mycobacteria may give a false-positive TST. In most high-income countries with low TB incidence such as the United Kingdom, a TST is regarded as positive with induration of greater than 5 mm in those without prior BCG vaccination and greater than 15 mm for those with prior BCG vaccination. In the United States, TST results are interpreted based on an individual’s risk of contracting TB and clinical factors: 5 mm or greater (close contacts, TB disease, immunosuppression), 10 mm or greater (increased risk of disseminated disease or increased exposure to TB disease), and 15 mm or greater (children >4 years of age with no risk factors). The WHO guidelines differ slightly, with a positive TST being greater than 5 mm for those with risk factors (eg, HIV infection, malnutrition) and greater than 10 mm for all others.
Alternate tests to TST are the in vitro T-cell–based interferon-gamma release assays (IGRA). In these assays (eg, QuantiFERON-TB Gold, T-SPOT.TB, and Gold In-Tube), interferon-gamma is produced in response to stimulation of mononuclear cells or whole blood by specific M tuberculosis antigens. These antigens are present only in M tuberculosis complex and absent from all strains of Mycobacterium bovis BCG and almost all environmental mycobacteria. They do not have significant advantages over the TST for the diagnosis of active TB disease but may be useful in excluding false-positive TST. In 2011, the WHO’s Stop TB Department published new recommendations on the use of IGRAs and TST to detect latent TB in LMIC: (1) IGRAs and TST cannot accurately predict the risk of infected individuals developing active TB disease; (2) neither IGRAs nor TST should be used for the diagnosis of active TB disease; (3) IGRAs are more costly and technically complex than TST; and (4) given comparable performance but increased cost, replacing the TST by IGRAs in resource-constrained settings is not recommended.
Management
Latent TB infection can be treated effectively to prevent progression to active TB. The following regimens are recommended by WHO: 6 or 9 months of isoniazid daily; 3 months of rifapentine plus isoniazid weekly; 3 or 4 months of isoniazid plus rifampicin daily; and 3 or 4 months of rifampicin daily. Treatment of most forms of childhood TB disease (eg, pulmonary and extrapulmonary) consists of a 6-month chemotherapy regimen with 4 drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) in the initial intensive phase, followed by 2 drugs in the continuation phase ( Fig. 2 ). For miliary, meningeal, bone/joint, or disseminated TB, treatment is extended to 9 to 12 months. Directly observed therapy is highly recommended.
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