Pediatric TB Intensive Houston, Texas November 13, 2009 Treatment of Pediatric TB Jeffrey R. Starke, M.D. November 13, 2009 MANAGEMENT OF CHILDHOOD TUBERCULOSIS Jeffrey R. Starke, M.D. Professor of Pediatrics Baylor College of Medicine 1
DRUG RESISTANCE IN TUBERCULOSIS The development of drug resistance in M. tuberculosis is the result of a conspiracy among the organism, the patient, t the doctor and the healthcare system! DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS genetic loci for resistance on chromosome, unlinked resistance of drugs independent frequency of mutations at loci is known more likely to have mutations when mycobacterial population is larger : infection vs. disease 2
3
TREATMENT OF TUBERCULOSIS More bugs, more drugs! Question: When does tuberculosis infection turn into tuberculosis disease? When do we cross the threshold or using more than one drug? 4
TB DRUGS IN CHILDREN Isoniazid: [10 15 mg/kg/day] Well tolerated with few AEs Both hepatitis and neuritis are rare Better tolerated with food in stomach Poor tolerance of suspension > 5 kg Rifampin: [10 15 mg/kg/day] Well tolerated; only rare AEs Watch for contact lenses Can t use OCPs for birth control TB DRUGS IN CHILDREN Pyrazinamide: [30 40 mg/kg/day] Large pill, no standard d suspension itching > joint pain > hepatitis Ethambutol: [20 mg/kg/day] Ocular toxicity very, very rare Watch for renal disease [elimination] Now standard 4 th drug for children 5
TB DRUGS IN CHILDREN Aminoglycosides: Mostly CNS, drug-resistant resistant TB Amikacin preferred for CNS [more resistance to streptomycin] Oto- and renal toxicity possible Ethionamide: [15 mg/kg/day] Excellent drug for CNS TB Difficult-to-use dosage form GI intolerance, but less than in adults TB DRUGS IN CHILDREN Fluoroquinolones: Used for drug-resistant resistant TB or intolerance to standard drugs Few studies, mostly ciprofloxacin Dosages unknown for moxafloxacin and gatifloxacin Levofloxacin: twice daily dosing for children < 5 years of age 6
DIRECTLY OBSERVED THERAPY FOR TUBERCULOSIS means a dispassionate 3rd party is actually present when medications are taken with every dose standard of care in U.S. for treating tuberculosis disease desirable for high risk infections - newborns and infants, household contacts, HIV - infected or immune compromised TUBERCULOSIS IN CHILDREN TREATING EXPOSED CHILDREN Very high rate of infection Takes up to 3 months for the skin test to turn positive U.S. studies 10% to 20% of childhood TB cases can be prevented if children exposed in a household receive isoniazid Assume young children are infected until proven they are not 7
TREATING TB EXPOSED CHILDREN Usually treat for 8 to 10 weeks after exposure has been broken by loss of contact or treatment Must follow both the patient and the source case [sputum conversion, drug susceptibility pattern, contact] Infants:? TST or IGRA reliable if child < 6 months of age [little data] 8
TREATMENT OF LTBI IN CHILDREN 9 months of isoniazid (daily or twice weekly under DOT) is only accepted regimen INH-resistance/intolerance rifampin for 4-6 months Multidrug-resistance lid resistance consult an expert Use isoniazid unless there is documented exposure to a specific case of drug-resistant resistant TB ALTERNATIVE REGIMENS FOR LTBI INH for 6 months Rifampin for 4-6 months INH + RIF for 3-4 months 9
PEARLS OF WISDOM FOR TREATING LTBI Use INH suspension only in children 5 kg Use DOPT for: recent contacts, infants, immune compromised When children aren t tolerating INH, the problem is more often with the parent than the child Routine LFTs only for: other liver toxic drugs, liver disease, signs or symptoms of hepatitis Pyridoxine needed only for breast- feeding infants, pregnancy, poor diets TREATMENT OF TUBERCULOSIS DISEASE IN CHILDREN Pulmonary INH, RIF for 6 months + PZA for first 2 months Add EMB initially if risk of INH resistance Can be q.day or twice weekly INH-resistant: RIF+PZA+EMB for 9 months MDR - depends on susceptibility - at least 18 months CNS, Disseminated usually start with 4 drugs (INH, RIF, PZA + EMB) usual length: 9-12 months q.day initially, may use twice weekly later 10
TREATMENT RULE OF THUMB FOR CNS TUBERCULOSIS Treatment for tuberculous meningitis should be started, while the work-up is being undertaken, for any child with meningitis, no obvious cause [such as a positive Gram stain] and any of: basilar enhancement, hydrocephalus, cranial nerve abnormality, infarction, possible tuberculoma TREATMENT OF TUBERCULOUS MENINGITIS Medications Always start at least 4 anti-tb drugs 1. Isoniazid 2. Rifampin 3. Pyrazinamide 4. Ethionamide or an aminoglycoside Always start corticosteroids [4-6 weeks] 11
TREATMENT OF TUBERCULOUS MENINGITIS Other Measures Fluid/electrolyte management Airway management Seizure control Ventriculostomy or VP shunt Physical therapy TREATMENT OF LYMPHATIC TUBERCULOSIS Biggest problem is differentiating TB from NTM adenitis and Bartonella Surgical Approach 1. Fine needle aspirate 2. Incision and drainage [Not!] 3. Excisional biopsy 12
TREATMENT OF LYMPHATIC TUBERCULOSIS Can use standard anti-tb regimens Relapse/recrudescence rates are fairly high Empiric regimen for mycobacterial lymphadenitis: INH+RIF+EMB+Clarithromycin [covers TB, M. bovis, many NTM] 13
TUBERCULOSIS IN CHILDREN IMPACT OF DRUG-RESISTANCE RESISTANCE Usually must link the child with an adult case to identify it Adults with drug-resistant resistant TB are as contagious as those with susceptible disease Disease expression ess in children the same as with susceptible strains Children tolerate and respond well to second- line drugs 14
PRINCIPLES OF TREATING MDR TUBERCULOSIS IN CHILDREN Exposure: often don t treat Infection: two best available drugs Disease: usually 4 to 6 drugs, best available PRINCIPLES OF TREATING DRUG- RESISTANT TB IN CHILDREN 1. Get susceptibility pattern 2. LTBI: RIF if susceptible; if resistant to both INH and RIF, use two best drugs PZA+EMB or PZA+quinolone; 9-12 mos. 3. Disease: Need 2 cidal drugs, if possible, plus at least 2 other drugs daily therapy only INH-R: 9 months of therapy MDR: at least 12 months of therapy XDR:??? 15
25 YEAR EXPERIENCE WITH DRUG RESISTANT TB IN CHILDREN Jeffrey Starke, MD Lydia Ong, PA-C and Andrea Cruz, MD 158 patients: 65 exposure, 55 infection, 38 disease 79 MDR-TB: 41 exposure, 28 infection, 10 disease Resistance: INH 150, RIF 103, PZA 33, EMB-27 No child with exposure or infection progressed to disease All children with disease had resolution For 76% of patients, drug resistance known at onset of treatment [contact investigation] Adverse reactions very infrequent CORTICOSTEROIDS IN PEDIATRIC TUBERCULOSIS Useful when host inflammatory response is contributing to tissue damage or dysfunction meningitis endobronchial miliary with alveolar block pericardial with constriction vertebral with spinal root irritation Can use prednisone or dexamethasone 16
TREATMENT OF TB IN HIV- INFECTED CHILDREN Respond well to standard regimens Use 4 drugs initially for TB disease Length of therapy 9-12 months Rifampin drug interactions a problem *can give rifampin for 1-2 months, then change to other TB drugs *can use rifabutin [though few data for children, esp. infants] TREATING TB IN IATROGENICALLY IMMUNE SUPPRESSED CHILDREN Corticosteroids, anti-tnf antibodies, cancer chemotherapy, anti-rejection drugs Need to stop the immunosuppression as much as possible for at least 4-6 weeks, longer for anti-tnf antibodies Case-by-case basis 17
MOST COMMON REPORTED ADVERSE REACTIONS TO ANTI-TB TB DRUGS IN CHILDREN Upset stomach [all] Loose stools [INH suspension] Decreased appetite [? all] Change in behavior [? not related] Headaches [esp. INH;? Not related] Itching [PZA] Sore joints and muscles [PZA] Signs of peripheral neuritis [INH] DEALING WITH LIVER TOXICITY IN CHILDREN More common with severe TB disease, especially early on More common with underlying liver abnormality or co-administration of hepatotoxic drugs [anticonvulsants] Most common in first two months, but can occur at any time *Warn parents: Stop drugs first, call me second [child on INH alone] 18
DEALING WITH LIVER TOXICITY IN CHILDREN Check liver enzymes for vomiting, abdominal pain and/or jaundice Liver sparing regimen: ethambutol, aminoglycoside, fluoroquinolone Restart drugs one at a time; check liver enzymes after 3-5 days for each PZA is most expendable drug FOLLOW-UP EVALUATIONS FOR CHILDREN WITH TUBERCULOSIS skin test stays positive forever frequent chest x-rays unnecessary: at diagnosis, 1-2 months, end of therapy follow growth & development closely adequate nutrition routine liver enzyme monitoring not necessary routine vitamin B 6 not necessary except breast-feeding, pregnant adolescents, poor diet 19
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME [IRIS] happens in a variety of situations when severely immunocompromised patients have rapid restoration of immune function e.g.: neutropenic cancer patients with Candidemia in HIV, a/w a variety of organisms, including mycobacteria, CMV, hepatitis B and C viruses, HSV, JC virus (progressive multifocal leucoencephalopathy), Pneumocystis, Cryptococcus, leishmaniasis, cerebral toxoplasmosis Mycobacteria account for 40% of the cases IRIS AND MYCOBACTERIA So-called paradoxical reactions occur in 2% to 23% of HIV-negative adult patients receiving treatment for tuberculosis Most common features are fever and lymph node enlargement, though respiratory failure and neurologic deterioration also occur Median time is 40-90 days after TB treatment is started Abnormality is at the original site of infection in 75% of cases, at a new location in 25% Mechanism: increased tumor necrosis factor 20
IRIS AND MYCOBACTERIA In HIV-uninfected children treated for tuberculosis, paradoxical reactions are common Enlarged hilar/mediastinal lymph nodes, tuberculomas are most common Changes may be only radiographic or clinical - stridor, respiratory distress, seizures (tuberculoma) Natural history vs. immune reconstitution IRIS AND MYCOBACTERIA Definition: presentation or clinical deterioration of an opportunistic infection in HIV-infected patients as a direct result of the enhancement of immune responses to those pathogens during HAART Strongest clue is usually a temporal association (30-90 days) No specific laboratory test available Clinical judgment is important (but may be nonspecific) Can also be a worsening of the opportunistic infection due to poor compliance, poor absorption or drug resistance Can also be a new infection or condition 21
IRIS IN CHILDREN Puthanakit et al. Pediatr Infect Dis J 2006; 25:53 32/153 (21%) HIV-infected Thai children developed d IRIS after starting HAART 14/32 (44%) episodes associated with mycobacteria [3-TB, 2-BCG, 7-MAC Complex, 2-other] In 11 of 14 patients, the mycobacterial infections had not been diagnosed prior to starting HAART 7 varicella-zoster, 7HSV, 3 Cryptococcus, 1 Guillain- Barre Children who developed IRIS had significantly lower baseline CD4 lymphocyte counts PREVENTION AND TREATMENT OF IRIS Watch out! CD4 lymphocyte count < 100 cells viral load > 10 5 copies/ml? if HAART should be delayed in patients with TB Must balance risk of IRIS with risk of other opportunistic infection if CD4 count stays low and viral load stays high Adjunctive treatment - only anecdotal evidence at present Oral corticosteroids can help when severe manifestations occur ( same as TB in HIV- uninfected children!) 22