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Once infected, children aged ≤4 years and all HIV-infected children are more likely to develop active TB disease. Usually the clinical features of TB among HIV-infected children are similar to those among children without HIV infection, although the disease usually is more severe (169Mukadi YD, Wiktor SZ, Coulibaly IM, et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cöte d’Ivoire. AIDS 1997;11:1151-8., 170Chintu C, Bhat G, Luo C, et al. Seroprevalence of human immunodeficiency virus type 1 infection in Zambian children with tuberculosis. Pediatr Infect Dis J 1993;12:499-504.) and can be difficult to differentiate from illnesses caused by other OIs. Pulmonary involvement is evident in most cases and can be characterized by localized alveolar consolidation, pneumonitis, and hilar and mediastinal adenopathy. Concomitant atelectasis might result from hilar adenopathy compressing bronchi or from endobronchial granulomas. HIV-infected children with TB are more likely to be symptomatic (with fever and cough) and have atypical findings, such as multilobar infiltrates and diffuse interstitial disease. Rapidly progressive disease, including meningitis or mycobacterial sepsis, can occur without obvious pulmonary findings. Both HIV infection and young age increase the rate of miliary disease and TB meningitis. Older HIV-infected children and adolescents have clinical features more similar to those in HIV-infected adults, with the typical apical lung infiltrates and late cavitation (171Hoffman ND, Kelly C, Futterman D. Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort. Pediatrics 1996;97:198-203.). Approximately 25% of HIV-uninfected children with TB include extrapulmonary disease as a sole or concomitant site, and HIV-infected children may have an even higher rate. The most common sites of extrapulmonary disease among children include the lymph nodes, blood (miliary), CNS, bone, pericardium, and peritoneum (169Mukadi YD, Wiktor SZ, Coulibaly IM, et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cöte d’Ivoire. AIDS 1997;11:1151-8., 172Schaaf HS, Geldenduys A, Gie RP, et al. Culture-positive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998;17:599-604., 173Khouri YF, Mastrucci MT, Hutto C, et al. Mycobacterium tuberculosis in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 1992;11:950-5., 174Chan SP, Birnbaum J, Rao M, et al. Clinical manifestation and outcome of tuberculosis in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1996;15:443-7.).

The cornerstone of diagnostic methods for latent TB infection (LTBI) is the tuberculin skin test (TST), administered by the Mantoux method. Because children with HIV infection are at high risk for TB, annual testing of this population is recommended to diagnose LTBI (AIII). Among persons with HIV infection, ≥ 5 mm of induration is considered a positive (diagnostic) reaction. However, among immunocompetent children with active TB disease, approximately 10% have a negative TST result, and HIV-infected children with TB are even more likely to have a negative result. Therefore, a negative TST result should never be relied on for excluding the possibility of TB. The use of control skin antigens at time of purified protein derivative testing to assess for cutaneous anergy is of uncertain value and no longer routinely recommended (DII).

Sensitivity to tuberculin is reduced by severe viral infections, such as wild-type measles. As a precaution, skin testing scheduled around the time of live-virus vaccination should be done at the same time as, or delayed until 6 weeks after vaccination to avoid any potentially suppressed sensitivity to the skin test (AIII).

Two-step skin testing is used for detecting boosted sensitivity to tuberculin in health-care workers and others at the time of entry into a serial testing program for occupational TB exposure. The utility and predictive value of two-step testing have not been assessed for children (with or without HIV infection), and its use is not recommended (DIII).

Recently, ex vivo assays that determine IFN-γ release from lymphocytes after stimulation by highly specific synthetic M. tuberculosis antigens have been developed to diagnose infection (175Starke JR. New concepts in childhood tuberculosis. Curr Opin Pediatr 2007;19:306-13.). QuantiFERON^®-TB Gold and QuantiFERON-TB Gold In-Tube (Cellestis Limited, Valencia, California) and the T-SPOT^®. TB assay (Oxford Immunotec, Marlborough, Massachusetts) are now Food and Drug Administration (FDA)-approved and available in the United States. These tests were more specific than the TST in studies among adults, especially among those who are BCG vaccinated. However, as with the TST, these tests are less sensitive in HIV-infected adults with advanced immune suppression (176Maunatlala C, Alexander H, Williams KL, et al. Reproducibility of an INF-γ release assay and concordance with tuberculin skin tests in people living with HIV. Int J Tuberc Lung Dis 2007; 11 (Supplement 1): S 74. Int J Tuberc Lung Dis 2007;11(Suppl 1):S74.). In addition, limited data suggest these tests, particularly QuantiFERON, might have less sensitivity for diagnosing infection in young children (177Hesseling AC, Mandalakas AM, Chegou N, et al. The impact of M. tuberculosis,/i> exposure, age and HIV infection on T-cell assays to detect M. tuberculosis infection. Int J Tuberc Lung Dis 2007;11 (Suppl 1):S225.). Their routine use for finding LTBI or diagnosing TB in HIV-infected children is not recommended because of uncertainty about test sensitivity (DIII) (175Starke JR. New concepts in childhood tuberculosis. Curr Opin Pediatr 2007;19:306-13.).

Patients with a positive test for LTBI should undergo chest radiography and clinical evaluation to rule out active disease. Diagnostic microbiologic methods for TB consist of microscopic visualization of acid-fast bacilli from clinical specimens, nucleic-acid amplification for direct detection in clinical specimens, the isolation in culture of the organism, and drug-susceptibility testing, and genotyping. Although acid-fast stained sputum smears are positive in 50%-70% of adults with pulmonary TB, young children with TB rarely produce sputum voluntarily and typically have a low bacterial load (178Starke JR. Diagnosis of tuberculosis in children. Pediatr Infect Dis J 2000;19:1095-6.). Smear results frequently are negative, even among older children who can expectorate and provide a sample (158Nelson LJ, Schneider E, Wells CD, et al. Epidemiology of childhood tuberculosis in the United States, 1993-2001: the need for continued vigilance. Pediatrics 2004;114:333-41.). Nevertheless, a positive smear result usually indicates mycobacteria, although it does not differentiate M. tuberculosis from other mycobacterial species. Mycobacterial culture improves sensitivity and permits species identification, drug-susceptibility testing, and genotyping. Confirming M. tuberculosis infection with a culture can have greater significance for HIV-infected children because of the difficulties of the differential diagnosis. Therefore, all samples sent for microscopy should be cultured for mycobacteria. Bronchoscopy will increase the likelihood of obtaining a positive smear and culture. Obtaining early-morning gastric aspirates for acid-fast-bacilli stain and culture is the diagnostic method of choice for children unable to produce sputum. A standardized protocol that includes testing of three samples obtained separately may improve the yield from gastric aspirates to 50% (179Pomputius WF, 3rd, Rost J, Dennehy PH, et al. Standardization of gastric aspirate technique improves yield in the diagnosis of tuberculosis in children. Pediatr Infect Dis J 1997;16:222-6.). Others have shown the potential utility of induced sputum (180Iriso R, Mudido PM, Karamagi C, et al. The diagnosis of childhood tuberculosis in an HIV-endemic setting and the use of induced sputum. Int J Tuberc Lung Dis 2005;9:716-26., 181Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005;365:130-4.) and nasopharyngeal aspirates (182Owens S, Abdel-Rahman IE, Balyejusa S, et al. Nasopharyngeal aspiration for diagnosis of pulmonary tuberculosis. Arch Dis Child 2007;92:693-6.) of obtaining diagnostic specimens from children in the outpatient setting.

Two commercial nucleic acid amplification kits are FDA approved for direct detection of M. tuberculosis in sputum samples with positive smear-microscopy results. One of the methods also is approved for sputa with negative microscopy. A positive result from these methods immediately confirms the diagnosis. However, when these tests are used for other specimens, such as gastric aspirates or CSF, sensitivity and specificity have been disappointing (183Delacourt C, Poveda JD, Chureau C, et al. Use of polymerase chain reaction for improved diagnosis of tuberculosis in children. J Pediatr 1995;126(5 Pt 1):703-9., 184Pierre C, Olivier C, Lecossier D, et al. Diagnosis of primary tuberculosis in children by amplification and detection of mycobacterial DNA. Am Rev Respir Dis 1993;147:420-4., 185Smith K, Starke J, Eisenach K, et al. Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction. Pediatrics 1996;97:155-60.). These assays provide adjunctive, but not primary, diagnostic evaluation of children with TB because a negative result does not rule out TB as a diagnostic possibility and a positive result, unlike culture, does not allow for drug-susceptibility testing. However, it might be useful in establishing the diagnosis of TB among HIV-infected children who have unexplained pulmonary disease when both culture and TSTs may be falsely negative.

Because of the difficulty in obtaining a specimen for bacteriologic diagnosis of TB among children, evidence for the diagnosis often involves linking the child to an adult with confirmed TB with a positive TST and an abnormal radiograph or physical examination in the child (178Starke JR. Diagnosis of tuberculosis in children. Pediatr Infect Dis J 2000;19:1095-6.). A high index of suspicion is important. Suspicion for and diagnosis of TB in HIV-infected children is further complicated by the frequent presence of preexisting or coincidental fever, pulmonary symptoms, and radiographic abnormalities (e.g., chronic lymphoid interstitial pneumonitis or coincident pulmonary bacterial infection) and the decreased sensitivity of TST in this population. Strenuous efforts should be made to obtain diagnostic specimens (three each of sputum or gastric aspirate specimens or induced sputum) whenever TB is presumptively diagnosed or when it is suspected.

Because many children do not have culture-proven TB, and the diagnosis of drug resistance may be delayed in source cases, MDR TB should be suspected in children with TB in the following situations (90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006., 186World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva. WHO/HTM/TB/2006.371. 2006., 187Schaaf HS, Gie RP, Beyers N, et al. Primary drug-resistant tuberculosis in children. Int J Tuberc Lung Dis 2000;4:1149-55., 188Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 2002;109:765-71.):

• A child who is a close contact of an MDR TB patient.
• A child who is a contact with a TB patient who died while undergoing treatment when reasons exist to suspect the disease was MDR TB (i.e., the deceased patient was a contact of another person with MDR TB, had poor adherence to treatment, or had received more than two courses of antituberculosis treatment).
• A child with bacteriologically proven TB who is not responding to first-line drugs administered with direct observation.
• A child exposed to a source case that remains smear- or culture-positive after 2 months of directly observed firstline antituberculosis therapy.
• A child born in or exposed to residents of countries or regions with a high prevalence of drug-resistant TB.

Antimycobacterial drug-susceptibility testing should be performed on the initial M. tuberculosis isolate and on subsequent isolates if treatment failure or relapse is suspected; the radiometric culture system has been adapted to perform rapid sensitivity testing. Before obtaining results of susceptibility testing or if an organism has not been isolated from specimens from the child, the antimycobacterial drug susceptibility of the M. tuberculosis isolate from and treatment history of the source case can be used to define the probable drug susceptibility of the child's organism and to design the empiric therapeutic regimen for the child.

In the United States, where TB exposure is uncommon and BCG is not routinely administered, HIV-infected infants and children should have a TST (5-TU purified protein derivitive) at 3 months of age, and children should be tested at HIV diagnosis. HIV-infected children should be retested at least once per year (AIII).

HIV-infected infants and children should be treated for LTBI if they have a positive TST (AI) or exposure to a person who has contagious TB (after exclusion of active TB disease in the infant or child and regardless of the child's TST results) (AII). Duration of preventive therapy for children should be 9 months, and the preferred regimen is isoniazid (10-15 mg/kg/day([AII]) or 20-30 mg/kg twice weekly) ([BII]). Liver function tests should be performed before start of isoniazid (AII) for HIV-infected children. The child should be further monitored if baseline tests are abnormal; the child has chronic liver disease; or medications include other potentially hepatotoxic drugs, such as acetaminophen and some antiretroviral drugs. If isoniazid resistance is known or suspected in the source case, rifampin for 4-6 months is recommended (BII). A 2-month regimen of rifampin and pyrazinamide was never recommended for children and now is not recommended for any age group because of an increased risk for severe and fatal hepatotoxicity (EII). Children exposed to drug-resistant strains should be managed by an experienced clinician, and the regimen should be individualized on the basis of knowledge about the source-case susceptibility pattern and treatment history.

A randomized, double-blind, controlled trial of isoniazid in HIV-infected children in South Africa was halted when isoniazid administered daily or twice weekly (according to the cotrimoxazole schedule) helped reduce overall mortality (hazard ratio: 0.46; 95% confidence interval (CI): 0.22-0.95; p = 0.015) (190Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ 2007;334:136.). These findings were found across all ages and CDC HIV disease classification categories and were independent of TST result; however, the study may not have been adequately powered to detect these differences. These results suggest that HIV-infected children in areas of extremely high burden of TB may benefit from isoniazid preventive therapy irrespective of any known exposure to TB, but this approach is not recommended in the United States because of the low prevalence of TB (DII).

Not applicable.

Monthly monitoring of clinical and bacteriologic response to therapy is important (AII). For children with pulmonary TB, chest radiographs should be obtained after 2-3 months of therapy to evaluate response (AIII). Hilar adenopathy might persist for as long as 2-3 years despite successful antituberculous therapy, and a normal radiograph is not a criterion to discontinue therapy. Follow-up radiographs after completion of therapy are not necessary unless clinical symptoms recur.

Common side effects associated with TB medications are listed in Table 5. Isoniazid is available as syrup, but some specialists advise against using it because the syrup is unstable and frequently causes diarrhea (DIII). Gastric upset during the initial weeks of isoniazid treatment occurs frequently and often can be avoided by having some food in the stomach when isoniazid is administered. Hepatotoxicity is the most common serious adverse effect. It includes subclinical hepatic enzyme elevation, which usually resolves spontaneously during continuation of treatment, and clinical hepatitis that usually resolves when the drug is discontinued. It rarely progresses to hepatic failure, but the likelihood of life-threatening liver damage increases when isoniazid is continued despite hepatitis symptoms. Hepatotoxicity is less frequent in children than in adults, but no age group is risk-free. Transient asymptomatic serum transaminase elevations have been noted in 3%-10% and clinical hepatitis in <1% of children receiving isoniazid; <1% of children required treatment discontinuation (192Starke JR, Correa AG. Management of mycobacterial infection and disease in children. Pediatr Infect Dis J 1995;14:455-69., 196Palusci VJ, O’Hare D, Lawrence RM. Hepatotoxicity and transaminase measurement during isoniazid chemoprophylaxis in children. Pediatr Infect Dis J 1995;14:144-8.). However, the rate of hepatotoxicity might be greater in children who take multiple hepatotoxic medications and in children who have HIV infection. Pyridoxine (150 mg/day) is recommended for all symptomatic HIV-infected children treated with isoniazid (AII). HIV-infected children on anti-TB medications should have liver enzymes obtained at baseline and monthly thereafter (AIII). If symptoms of drug toxicity develop, a physical examination and liver enzyme measurement should be repeated (AIII). Mild elevations in serum transaminases (e.g., two to three times the upper limit of normal) do not require discontinuation of drugs if other findings are normal (AII), but they do require more frequent rechecks - as often as weekly - until they resolve.

The most ominous toxicity associated with ethambutol is optic neuritis, with symptoms of blurry vision, central scotomata, and red-green color blindness, which is usually reversible and rare at doses of 15-25 mg/kg among children with normal renal function (193World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, Switzerland: (WHO/HTM/TB/2006.361). 2006.). Assessments of renal function, ophthalmoscopy, and (if possible) visual acuity and color vision, should be performed before starting ethambutol and monitored regularly during treatment with the agent (AIII). Hypothyroidism has been associated with ethionamide and periodic (e.g., monthly) monitoring of thyroid hormone serum concentrations is recommended with its use (AIII).

Major adverse effects of aminoglycoside drugs are ototoxicity and nephrotoxicity. Periodic audiometry, monitoring of vestibular function (as possible), and blood urea nitrogen and creatinine are recommended (AIII).

Secondary drugs used to treat resistant TB have not been well studied in children. These medications should be used in consultation with a TB specialist (AIII). Coadministration of pyridoxine (150 mg/day) with cycloserine is recommended (AII). Thiacetazone can cause severe and often fatal reactions among HIV-infected children, including severe rash and aplastic anemia, and should not be used (EIII).

IRIS in patients receiving anti-TB therapy during HAART has been reported in HIV-infected adults (197Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157-61., 198Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001;120:193-7., 199Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933-6.). New onset of systemic symptoms, especially high fever; expanding CNS lesions; and worsening adenopathy, pulmonary infiltrates, or pleural effusions have been reported in HIVinfected adults during HAART up to several months after the start of TB therapy. Such cases also have been reported in children (22Puthanakit T, Oberdorfer P, Punjaisee S, et al. Immune reconstitution syndrome due to bacillus Calmette-Guérin after initiation of antiretroviral therapy in children with HIV infection. Clin Infect Dis 2005;41:1049-52., 192Starke JR, Correa AG. Management of mycobacterial infection and disease in children. Pediatr Infect Dis J 1995;14:455-69., 200Zampoli M, Kilborn T, Eley B. Tuberculosis during early antiretroviralinduced immune reconstitution in HIV-infected children. Int J Tuberc Lung Dis 2007;11:417-23.) and should be suspected in children with advanced immune suppression who initiate HAART and subsequently develop new symptoms.

IRIS occurs in two common clinical scenarios. First, in patients who have occult TB before initiation of HAART, TB may have been unmasked by immune recovery after antiretroviral drug initiation. This "unmasking IRIS" or incident TB-IRIS usually occurs within the first 3-6 months after initiation of HAART, and the infectious pathogen typically is detectable. Secondly, IRIS can occur as paradoxical exacerbation of TB after initiation of HAART in a patient already receiving anti- TB treatment through a clinical recrudescence of a successfully treated infection or symptomatic relapse despite initial clinical improvement and continued microbiologic treatment success (i.e., "paradoxical IRIS"); treatment failure associated with microbial resistance or poor adherence must be ruled out.

The literature on IRIS in children consists largely of case reports and small series, so whether IRIS occurs more often in children than in adults is not clear. Persons with mild-tomoderate symptoms of IRIS have been treated symptomatically with nonsteroidal anti-inflammatory drugs while continuing anti-TB and HIV therapies. In certain cases, use of systemic corticosteroids steroids for 1-2 weeks results in improvement during continuation of TB/HIV therapies (CIII) (197Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157-61., 198Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001;120:193-7., 199Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933-6.). However, no controlled trials of the use of corticosteroids have been published. Despite the development of IRIS, TB therapy should not be discontinued.

Most children with TB respond well to medical therapy. If response is not good, then adherence to therapy, drug absorption, and drug resistance should be assessed. Mycobacterial culture, drug-susceptibility testing, and antimycobacterial drug levels should be performed whenever possible. Drug resistance should be suspected in any child whose smear or culture fails to convert after 2 months of directly observed anti-TB therapy. In the absence of initial bacteriologic confirmation of disease, failure should be suspected in children whose clinical symptoms (including failure to gain weight) fail to respond and who have radiographic evidence of disease progression on therapy. As described above, drug-resistant TB should be managed in consultation with an expert.

Risk for recurrence is rare in children with drug-susceptible TB who are treated under direct observation. If TB recurs, the child is at high risk for drug resistance and should be managed accordingly. Chronic suppressive therapy is unnecessary for a patient who has successfully completed a recommended regimen of treatment for TB (DII). Secondary prophylaxis is not recommended for children who have had a prior episode of TB. However, HIV-infected children who were treated for LTBI or TB and who again contact contagious TB should be treated for presumed latent infection, after diagnostic evalution excludes current disease.

Not applicable.