Tuberculosis in Infancy and Childhood

Tuberculosis key facts

More than 2 billion individuals worldwide are infected with the TB bacilli Each person with TB disease can infect 10-15 people in a year; 1 in 10 people will progress to TB disease in their lifetime In 2008, the global incidence was estimated at 139 cases/100,000 population with 1.8 million deaths from TB TB is the leading cause of deaths in people with HIV; 1 in 4 people with HIV die due to TB People with HIV are 20-30x more likely to develop TB than those who do not have HIV In 2008, there were an estimated 500,000 new MDR-TB cases worlwide; with 56% of cases in China, India and the Russian Federation

What is the value of a history of contact in the diagnosis of TB?

The search for a history of exposure to an adult and or adolescent with tuberculous disease should be investigated in the evaluation of a child suspected of TB The risk of TB infection is associated with intensity of contact and the number of bacilli in the sputum There is no evidence that a history of exposure to a case with TB taken singly would be strongly predictive of childhood TB. However, when taken in conjunction with other clinical data, a history of contact of exposure to a case of TB has a good positive predictive value Tuberculin skin test and chest x-ray should be done in a child with a history of contact even if asymptomatic

What are the clinical manifestations most suggestive of childhood tuberculosis disease?
The following manifestations when taken together are suggestive of TB: history of recent weight loss or failure to gain weight, cough and or wheezing > 2 weeks and prolonged, unexpected fever > 2 weeks The combination of all these 3 taken collectively has a positive predictive value of 73% Diagnostic test most recently developed have not found a place in the routine evaluation of children suspected or having TB, rather, clinical manifestations, skin test, chest x-ray and exposure to an infectious adult remain as standard diagnostic methods In addition to the signs and symptoms above, failure to respond to appropriate medications and failure to regain previous state of health 2 weeks after an infection are also suggestive of tuberculusis disease In the presence of any 3 of the 5 signs and symptoms, work up for TB disease is recommended

What is a positive tuberculin skin test when used in the diagnosis of childhood TB disease

An induration of more than or equal to 10mm is considered positive regardless of BCG status using 5 TU PPD-S or 2TU RT23 Mantoux test read at 48-72 hours An induration of more than or equal to 5mm is considered positive if any of the following are present: history of close contact with a known or suspected infectious case of TB, clinical findings suggestive of TB, chest x-ray suggestive of TB and immunocompromised conditions

What are the chest radiograph findings most suggestive of childhood TB?

The most common chest radiograph finding in childhood TB is lymphadenpathy found in the hilar and paratracheal area The most common parenchymal changes are lobar opacification, airspace, consolidation, segmental or lobar atelectasis, air trapping and pleural effusion

How can a diagnosis of childhood latent TB infection (LTBI) be made?

The diagnosis of LTBI can be made in a child with a tuberculin skin test of more than or equal to 10mm but no clinical or chest x-ray findings of TB disease or whose chest x-ray shows evidence of healed infection The primary objective of testing for latent PTB is to identify children who are at increased risk for developing tuberculous disease

When is microbiologic diagnosis of childhood tuberculosis recommended?

The diagnosis of childhood tuberculosis can be made without recourse to microbiologic identification of M. tuberculosis The yield of microbiologic studies in children is low. Children < 10 yrs have difficulty expectorating adequate sputum and also because childhood TB is paucibacillary There are however, conditions where microscopy and culture are necessary: -when MDRTB is suspected in the absence of a culture-positive index case including treatment failure -in cases when TB is strongly considered in a sick child but the diagnosis cannot be made using other criteria Multiple specimen collection, at least 3, is important in children who tend to have fewer bacilli

What is the best clinical specimen to obtain for microbiologic diagnosis?

In children 10 yrs and older sputum is the best specimen to collect In young children < 10 yrs, the use of gastric aspirate as specimen of choice for smear and culture recommended because of the difficulty of obtaining adequate sputum specimens. They swallow their sputum rather than expectorate.

What is the value of new diagnostic tests for TB

The use of new diagnostic test, in view of their limitations and because of few studies in children, high cost and limited local availability, is limited to situations where diagnosis is difficult or of urgency because of rapid results

How can a diagnosis of extrapulmonary TB be made?

To diagnose TB meningitis, CSF analysis is essential with a definitive diagnosis established by positive CSF culture. A positive PCR establishes the diagnosis but a negative result does not rule out TBM Lymph node aspiration and or biopsy with cytology and culture establishes the diagnosis of TB lymphadenitis Plain radiographs, CT scan and or MRI can be utilized to diagnose TB of the spine. Biopsy if feasible, may be done for confirmation

Spectrum of TB Exposure, infection and disease

TB exposure Exposure yes TB Infection yes TB Disease yes

Signs & Symptoms

Tuberculin Skin Test

none
negative

none
Positive (but negative in many children) negative

positive
Positive(but negative in many children) may be positive (negative or unreliable)

Chest X-ray

negative

Direct Sputum Smear Microscopy

Other Diagnostics

negative
negative

negative
(may be positive)

May be positive or negative)

(may be positive)

What is the optimal drug regimen for newly diagnosed PTB in children?

Alternative regimens

A daily intensive phase followed by three times weekly continuation phase (2HRZE/4H3R3), provided that each dose is directly observed Three times weekly dosing throughout therapy (2H3R3Z3E3/4H3R3), provided that every dose is directly observed and the patient dose does not have HIV nor living in an HIV-prevalent setting

Adjunctive Therapy
Patients with complicated forms of TB( TB meningitis, endobronchial TB and TB pericarditis) have been shown to benefit from the addition of steroids to the anti-TB drug regimen Corticosteroids are recommended in all cases of TB meningitis Prednisone 2mkd x 4 weeks, for most seriouslly ill children the dose may be increased to 4mkd (maximum dose of 60mg/day) The dose of prednisone should be gradually tapered over oneto-two weeks before finally being discontinued

Is BCG recommended to be administered to Filipino infants at birth?

BCG vaccination induces artificial primary immunity to TB for prevention of subsequent illness caused by virulent bacilli The exposure to certain varieties of mycobacteria can give rise to a cell-mediated response which opposes the protective effect of subsequent BCG vaccination. If interfence with the response to BCG occurs this way, one method to avoid this is to vaccinate early in life, before exposure to these mycobacteria. This reason is in support of our recommendation to administer BCG vaccination at birth

Tuberculosis in Special Situation

TB in Pregnancy and Lactation TB in pregnancy should be treated without delay HREZ constitute the standard treatment for pregnant women Streptomycin and other aminoglycosides should be avoided Pyridoxine (25mg/day) is recommended for those taking Isoniazid Treatment options include 2HRZE/4HR or 2HRE/7HR Breasfeeding is encouraged because only minimal amounts of the drug are excreted in breast milk Mothers with LTBI should be treated with INH x 9 months without delay

Newborns of Tuberculous Mothers

Newborn whose mother has LTBI -after birth the infant should not be separated from the asymptomatic tuberculin positive mother with a negative chest xray but should be given BCG

Newborn whose mother has TB disease

The mother who has current TB disease but has undergone treatment for 2 weeks or more is presumed to be no longer contagious at the time of delivery Possibility of congenital TB should be ruled out The newborn should be given INH x 3 mos then should undergo TST If TST is negative, INH should be discontinued If TST is positive and the baby remains asymptomatic with a negative Cxray, preventive therapy with INH should be completed for 9 mos

 Separation is recommended for a mother who has current TB disease but has not received treatment The infant should receive INH, rifampicin can be given to INH-resistant maternal TB isolate The placenta should be sent for AFB stain and TB culture and sensitivity and should be histologically examined for granulomata If initial TST turns out negative, test should be repeated after 3 months If TST turns out positive but CXray negative, INH or Rifampicin should be continued for 6 mos If the TST and Cxray of the mother are negative and she has completed her treatment, BCG should be administered to the infant while INH or Rifampicin should be discontinued

 If the mother has extrapulmonary disease such as TB meningitis, miliary, bone or joint TB, the infant must be monitored closely for possible congenital tuberculosis A newborn with congenital TB should be given quadruple Anti-TB drugs x 2mos(HRZS) + HR x 4-7 mos If congenital TB is ruled out, preventive therapy should be given, similar to cases of newborns whose mother has TB disease

Tuberculosis in Children with Liver Impairment

INH could be removed in the initial drug regimen and REZ be given for 6-9 mos In the treatment regimen without PZA, HRE must be given for two months, followed by 7 months of HR for a total of 9 mos In advanced cases of severe liver disease, only rifampicin can be used with ethambutol, fluoroquinolone, cycloserine and other injectable agents for 12 to 18 mos For severe and unstable liver disease; streptomycin, ethambutol, fluoroquinolones, and other second line drug

TB in Children with Drug-Induced Hepatitis

Hepatotoxic 1st line drugs should be discontinued or modified depending on the level of AST Drug-induced liver injury- AST level 3or more times than the upper limit of the normal in the presence of symptoms or 5x more than the upper limit in the absence of any symptoms AST of < 5x more than normal is mild toxicity; AST of 5-10x more than normal is moderate; and a level of 10x more than normal is severe

 Rifampicin should be started first If there is no increase in AST after 1 week, INH may be restarted PZA will be restarted 1 week after INH if AST is not increasing If symptoms recur or AST increases, the last drug added must be stopped If hepatitis is severe, PZA must be discontinued and replaced by ethambutol or INH and rifampicin be continued x 9 mos

TB in Children with Renal Impairment The recommended initial TB treatment regimen for patients with renal failure or severe renal insufficiency is 2mos of HRZE followed by 4mos of HR A longer dosing interval of PZA and EMB 3x a week is recommended If streptomycin must be used, the dosage is 15mg/kg, 2-3x/week, to a maximum of 1 gram per dose, and serum levels of the drug should be monitored In severe renal impairment with creatinine clearance < 10mL/min reduction of INH dose to 200mg is recommended

 Streptomycin serum concentration is allowed at 5mcg/mL and should be given 8h before dialysis Ethambutol should be given 8h before dialysis and at 25mg/kg, 3x/week when creatinine levelis between 50-100mL/min; and 2x/week when creatinine level is between 30-50mL/min PZA is recommended at the low end of 1520mg/kg and requires supplemental dosing if given before dialysis Generally, anti-TB drugs should be given after hemodialysis to avoid filtration of the drugs during the procedure

TB in Immunocompromised Children
The recommended treatment is 2HRZE followed by 4HR, if there is evidence of slow or suboptimal response, 7 HR is recommended There is an increased frequency of rifampicin resistance when CD4 cell count is <100/ul; the continuation phase should be given daily or three times a week: Once weekly INH-rifapentine in the continuation phase; twice weekly INH-RIF; or rifabutin should not be used Anti-retroviral and anti-TB therapy should not be started at the same time because of drug interactions and toxicities TB should be treated first for at least four to eight weeks