MANAGEMENT OF PEDIATRIC TUBERCULOSIS.. WHAT’S NEW?? DR. PUJA JAIN SR, PEDIATRICS,FEHJ
INTRODUCTION Tuberculosis is a single major infectious disease causing significant morbidity and mortality in children. Children account for approx 40% of all cases of tuberculosis being treated. Confirmation of the disease is difficult in children because of paucibacillary nature of the disease and difficulty in obtaining the sputum. Therefore most cases of pediatric TB are categorized as either sputum smear negative PTB or extra pulmonary TB cases, which are not recorded and reported by NTPS.
NEED FOR REVISION?? Since the publication of the Guidance in 2006, novel evidence has become available concerning the correct dosages of medicines for the treatment of tuberculosis in children. The aim of this revised guideline is to establish standards for high-quality treatment of tuberculosis in children by providing evidence-based recommendations while considering the risks and benefits, acceptability, feasibility, cost and financial implications.
GUIDING PRINCIPLES1. Do no harm Introducing changes that preserve access for those children who are sickest and most in need.2. Ensure access and equity Ensuring that all children with tuberculosis have access to treatment with fair and equitable distribution of diagnostic and treatment services.3. Promote quality and efficiency Delivering the highest standards of care within a public health approach so as to achieve the greatest health impact with the optimal use of available human and financial resources.4. Ensure sustainability Understanding the long-term consequences of change with the vision of providing continued access to anti-TB medicines for those in need.
PULMONARY TUBERCULOSIS WHEN TO SUSPECT?? Fever and cough of recent onset > 2weeks duration. Recent loss of appetite, recent loss of weight . h/o contact. Presence of risk factors- h/o measles/whooping cough ,immunocompromised states. Persistent lower respiratory infection not responding to antibiotic therapy. No role of therapeutic trial with anti-TB drugs.
TUBERCULIN TESTo 1,2,or 5TU. (RT23)o I.D , wheal of6mmo Read after 48-72hrs by palpatory / ballpoint pen method.o >10 mm induration is positiveo 72hrs-7days- positive test can still be read.o Positive test s/o tuberculosis, negative test does not rule it out.
CHEST RADIOGRAPH Chest radiograph merely localizes the site of pathology and not etiology. There are no pathognomonic radiological signs of tuberculosis. In relevant clinical setting, certain radiological lesions may strongly suggest tuberculosis and they include miliary, hilar or paratracheal lymphadenopathy with or without parenchymal involvement. Fibrocaceous cavitatory lesions.
CONT.. Rarely chest X-ray may be normal, such cases should be referred to an appropriate center for further detailed investigations if the clinical suspicion is high. In clinical practice, non-resolving chest shadows despite adequate antibiotic therapy in a symptomatic child raises the possibility of tuberculosis. all persistent radiological lesions are not necessarily due to TB. Imaging like USG and CT are helpful in estimating pleural fluid collection.
BACTERIOLOGY Demonstration of AFB from any body fluid or tissue is the gold standard for diagnosis. Sputum positivity rate is 33%. Early morning gastric aspirate after 4-6hrs overnight fasting. Induction of sputum with 3% hypertonic saline nebulization. ZN stain can reveal only >10,000 bacilli/ml. Culture methods available are- LJ media, bactec and non radiometric methods.
SERODIAGNOSTICS Non specific. Not recommended in the diagnosis of tuberculosis.
INTERFERON GAMMA RELEASE ASSAYS A newer generation of tests which measure the production of interferon gamma by the peripheral mononuclear cells have been developed to identify the patients with TB disease or latent infection. These use two antigens, early secretion antigen target (ESAT 6) and culture filtrate protein 10 (CFP10), which are specifically present only in Mycobacterium tuberculosis and not in other mycobateria or the BCG vaccine strain.
CONT.. These tests though have a principle similar to skin test but do away with the need for a repeat visit by the patient for reading purposes. Quantiferon Gold and T spot are two of the commercially available IGRAs. These are being used in place of the skin test in low prevalence countries to detect latent TB infection. However, these expensive tests do not differentiate the TB infection from disease. Its exact utility in high burden situation is still not clear.
PCR TEST PCR cannot differentiate living from dead bacilli and continues to be positive even after successful treatment. PCR is positive in 95% to 100 % of culture positive cases but only in 50% to 60% of culture negative cases. It may be false positive in 1% to 30% of cases. Thus, no decisions can be made only on the basis of PCR tests and hence these tests are not recommended in clinical practice.
TUBERCULOSIS LYMPHADENITIS Clinical correlate of diagnosis includes progressive enlargement of lymph node for more than 2 weeks, firm, minimally tender or non-tender, fluctuating, further may get matted and develop chronic sinus formation. Mantoux test is positive in a significant proportion. Fine needle aspiration cytology (FNAC)is usually adequate for accurate diagnosis and it correlates well with biopsy in >90% of cases.
CONT.. Histopathology, typically shows necrosis and epitheloid granuloma. It is important to look for AFB in FNAC specimen and it may be positive in 20-70% of patients. When FNAC is inconclusive, biopsy is necessary for confirmation of diagnosis. In children lymphadenopathy is common due to recurrent tonsillitis and upper respiratory tract infections. Reactive lymphadenitis may clinically mimic tuberculosis but do not warrant anti-TB drugs. Hence, anti-TB drugs should not be given unless the diagnosis of TB is confirmed by FNAC or histopathology.
TUBERCULOSIS MENINGITIS Typically CSF is clear, usually does not show very high cell count (under 500 cells/cumm) with lymphocytosis. Biochemical investigations reveal increased proteins and mild reduction in glucose. The typical CSF picture described above can also be mimicked by partially treated pyogenic meningitis. In such a situation, CSF can be repeated after 48-72 hours of treatment with a fresh set of broad spectrum potent antibiotics to evaluate change in clinical status as well as in CSF
CONT.. During this time, efforts are made to establish the diagnosis by collecting more evidence using PPD, chest skiagrams, and bacteriological diagnosis from appropriate samples including CSF. Many a time concomitant TB lesions elsewhere in the body co-exist and can clinch the diagnosis. Mycobacterial culture from CSF should also be attempted but CSF culture has poor sensitivity (16%) though specificity is high (90%).
CONT.. Neuroimaging is an important diagnostic modality. It may reveal one or more of the following findings: Basal meningeal enhancement; Hydrocephalus with or without peri-ventricular ooze; Tuberculoma(s); or infarcts may be seen in different areas, especially in basal ganglia. Normal CT scan does not rule out TBM and in case of strong clinical suspicion of diagnosis, a repeat follow-up CT scan after few days may show
TUBERCULOMA Often seen in older children, it may present as a focal seizure in supra-tentorial cortical lesion or with symptoms and signs of raised intracranial tension with multiple localizing signs and hydrocephalus in posterior fossa lesion. It may sometimes also be seen as a part of TB meningitis.
CONT.. Differentiation from other ring lesions,especially neurocysticercosis (NCC) is difficult incortical lesion. A ring enhancing lesion is not pathognomonic of tuberculoma. A larger lesion >20 mm, disc lesion or ring lesion with thicker rim with central nodule favors tuberculoma; while multiple, smaller, thin rim with epicentric nodule favor NCC. MR spectroscopy may help in diagnosis of tuberculoma as it shows lipid peak.
ABDOMINAL TUBERCULOSIS It may present as localized disease such as mesenteric lymphadenopathy, intestinal disease, peritoneal involvement or systemic disseminated disease presenting as hepatosplenomegaly. Large matted lymph node mass may be clinically evident and ultrasound guided biopsy may help in confirming the diagnosis.
CONT.. Echogenic thickened mesentery with lymph nodes >15mm in size. dilated and matted bowel loops. thickened omentum, and ascites. Barium follow-through examination may be suggestive of intestinal disease but is not confirmatory. Exudative peritoneal disease presents as ascites that is often clinically evident. The ascetic tap should always be done in such situations and the fluid tapped is an exudate, typically showing lymphocytic predominant cellular response with high proteins (>3g/dL
PRINCIPLES OF TREATMENT The combination regimens used to treat active disease aim to eliminate actively replicating and dormant or near-dormant mycobateria using a combination of drugs with different actions whilst preventing the emergence of drug-resistant organisms, and all being achieved with a minimum of toxicity. Bactericidal drugs that kill actively metabolizing and replicating organisms are important to achieve a rapid reduction in microbial load which leads to clinical improvement, contains disease progression and terminates transmission.
CONT.. Isoniazid (H) and rifampicin (R) are important first- line bactericidal drugs with isoniazid having the most potent early bactericidal activity. Sterilizing drugs aim to eradicate those organisms that are less active metabolically and those that are in an acidic environment in order to prevent relapse.
CONT.. Rifampicin and pyrazinamide (Z) are important first- line sterilizing drugs. Protection against emergence of drug-resistant organisms is achieved by the combination of effective early bactericidal activity to reduce microbial load combined with effective sterilizing activity of more slowly replicating organisms, and strengthened by the addition of a fourth drug such as ethambutol or steptomycin.
CONT.. The most common TB diagnostic category in children is smear-negative PTB and so the commonest regimen used in children is 2HRZ 4HR. A fourth drug is important for cure of disease with a large microbial load such as sputum smear-positive PTB or PTB with extensive parenchymal involvement, and to reduce the risk of development of drug-resistance. The recommended treatment of TB meningitis and osteoarticular TB are also under review and 12 months regimen is the preferred option.
CONT.. The WHO guidelines of 2003 included 6HE as an alternative to 4HR for the continuation phase of new patient regimens. Rifampicin is important in the continuation phase to kill slowly metabolizing organisms whilst isoniazid is less potent for bactericidal activity in that context and when combined with rifampicin, is added to provide protection against drug resistance. relapse was more common in those in the 6HE arm than for those in the 4HR. 4HR is now the only recommended option for the continuation phase.
A WORD ABOUT ETHAMBUTOL. Studies show that toxicity is related to the dose and duration of therapy. WHO-ethambutol is safe and the risk of toxicity negligible for children of all ages if the recommended dosages were adhered to. Further, the abovementioned removal of 6HE as an alternative to 4HR for the continuation phase also reduces the potential of toxicity because duration of ethambutol usage is now usually limited to the initiation phase of two months.
ROLE OF STERIODS Definite indications for concomitant steroid therapy TBM and pericarditis. Steroids are routinely not indicated in lymphadenitis and pleural effusion. They may be used in endobronchial tuberculosis or mediastinal compression syndrome due totuberculosis, pleurisy with severe distress andmiliary disease with alveolo-capillary block. Predinsone 2-4 mg/kg/d or its equivalent is used for2-4 weeks and then tapered over next 2 weeks.
RECOMMENDATIONSRecommendation 1 Given the risk of drug-induced hepatotoxicity, WHO recommends the following dosages of antituberculosis medicines for the treatment of tuberculosis in children: Isoniazid (H) – 10 mg/kg (range 10–15 mg/kg); maximum dose 300 mg/day Rifampicin (R) – 15 mg/kg (range 10–20 mg/kg); maximum dose 600 mg/day Pyrazinamide (Z) – 35 mg/kg (30–40 mg/kg) Ethambutol (E) – 20 mg/kg (15–25 mg/kg) (Strong recommendation, moderate-quality evidence)
RECOMMENDATION 2Children living in settings where the prevalence of the HIV is high or where resistance to isoniazid is high, or both, with suspected or confirmed pulmonary tuberculosis or peripheral lymphadenitis; or children with extensive pulmonary disease living in settings of low HIV prevalence or low isoniazid resistance should be treated with a four-drug regimen (HRZE) for 2 months followed by a two-drug regimen (HR) for 4 months at the following dosages
CONT.. isoniazid (H) – 10 mg/kg (range 10–15 mg/kg); maximum dose 300 mg/day rifampicin (R) – 15 mg/kg (range 10–20 mg/kg); maximum dose 600 mg/day pyrazinamide (Z) – 35 mg/kg (30–40 mg/kg) ethambutol (E) – 20 mg/kg (15-25 mg/kg) (Strong recommendation, moderate-quality evidence) High prevalence is defined as countries, sub national administrative units, or selected facilities, where the HIV prevalence among adult pregnant women is ≥1% or among TB patients is ≥5%.
RECOMMENDATION 3 Children with suspected or confirmed Pulmonary tuberculosis or Tuberculous peripheral lymphadenitis with low HIV prevalence low resistance to isoniazid children who are HIV-negative can be treated with a three drug regimen (HRZ) for 2 months followed by a two-drug (HR) regimen for 4 months
RECOMMENDATION 4 Children with suspected or confirmed pulmonary tuberculosis or tuberculous peripheral lymphadenitis living in settings with high HIV prevalence (or with confirmed HIV infection) should not be treated with intermittent regimens (that is, twice-weekly or thrice- weekly doses). (Strong recommendation, low-to-moderate- quality evidence against the use of intermittent treatment in children)
RECOMMENDATION 5 During the continuation phase of treatment, thrice- weekly regimens can be considered for children known to be HIV-uninfected living in settings with well-established directly-observed therapy (DOT). (Weak recommendation, very low-quality evidence for use of intermittent treatment in children in specific settings)
RECOMMENDATION 6 Infants (aged 0–3 months) with suspected or confirmed pulmonary tuberculosis or tuberculous peripheral lymphadenitis should be promptly treated with the standard treatment regimens, as described above. (Strong recommendation, low-quality evidence)
RECOMMENDATION 7 Streptomycin should not be used as part of first-line treatment regimens for children with pulmonary tuberculosis or tuberculous peripheral lymphadenitis. (Strong recommendation, moderate-quality evidence).
RECOMMENDATION 8 Children with suspected or confirmed tuberculous meningitis should be treated with a four-drug regimen (HRZE) for 2 months, followed by a two-drug regimen (HR) for10 months; the total duration of treatment being 12 months. The dosages recommended for the treatment of tuberculous meningitis are the same as those described for pulmonary tuberculosis. (Strong recommendation, low-quality evidence)
RECOMMENDATION 9 Children with suspected or confirmed osteoarticular tuberculosis should be treated with a four-drug regimen (HRZE) for 2 months followed by a two- drug regimen (HR) for 10 months; the total duration of treatment being 12 months. The doses recommended for the treatment of osteoarticular tuberculosis are the same as those described for pulmonary tuberculosis. (Strong recommendation, low-quality evidence)
RECOMMENDATION 10 Children with proven or suspected pulmonary tuberculosis or tuberculous meningitis caused by multiple drug-resistant bacilli can be treated with a fluoroquinolone in the context of a well-functioning MDR-TB control programme and within an appropriate MDR-TB regimen. The decision to treat should be taken by a clinician experienced in managing paediatric tuberculosis. (Strong recommendation, very low-quality evidence)
CHEMOPROPHYLAXIS Six months of chemopropylaxis is recommended for all under 6 years age contacts of an infectiouscase, irrespective of their BCG or nutritional status. PPD positive children over 6 years of age and who donot have any evidence of active disease but are planned for immunosuppressive therapy (e.g.children with nephrotic syndrome, acute leukemias, etc) may also be given the benefit of chemoprophylaxis. While there is evidence that HR combination can make the prophylaxis shorter (3months) but the group does not recommend this dueto the risk of misuse of rifampicin.