TUBERCULOSIS IN SPECIAL SITUATIONS

DR VIPUL ASSISTANT PROFESSOR TB & RESPIRATORY MEDICINE

SPECIAL SITUATIONS
PREGNANCY AND LACTATION DIABETES MELLITUS ELDERLY LIVER DISEASE HIV/AIDS CHILDREN MDR AND XDR TB

Treatment During Pregnancy

Risk to mother and fetus is far greater from untreated TB than from the drugs used to treat TB
Increased risk of spontaneous abortion Increase in perinatal mortality Small for gestational age births Increased maternal morbidity Congenital TB Increased risk of perinatal and early post-natal transmission

 Isoniazid (INH), rifampicin and ethambutol are known to be safe for administration during pregnancy There is insufficient data on the teratogenic effect of PZA Pregnant and postpartum women are at increased risk of INH induced hepatitis Supplement with pyridoxine 50mg/day Monitor for signs of hepatotoxicity during pregnancy and immediate post-partum

 SM induced ototoxicity has been reported

irrespective of period of gestation. Therefore SM should not be used during pregnancy. WHO recommends standard chemotherapy under DOTS for pregnant patients. Duration of ATT need not be modified.

MDR TB IN PREGNANCY
Almost all second line drugs are teratogenic. Pregnancy is best avoided. If required treatment should be postponed till second trimester. The decision should be based on analysis of relative risks and benefits.

Breastfeeding
Most of the TB Levels are not likely to medications are secreted lead to toxicity in the into breast milk but not infant in significant concentrations (usually < Levels will not be sufficient to protect the 1-12% of levels measured infant in the serum) Supplement mom with B6 while breastfeeding

TB AND DIABETES MELLITUS

Patients with DM are at increased risk of TBthe relative risk is 3.5 times the normal population. More in IDDM than NIDDM and those with poorly controlled DM Clinical presentation and symptoms are similar. However, TB occurs predominantly in the lower lobes with cavitory lesions

Increased susceptibility may be due to neutrophilic dysfunction and impaired cytokine production. Same SCC is given, usually effective. Strict BSL control required, Give insulins. Possible failure of sulphonylureas with Rifampicin coadministration. Prophylactic pyridoxin is indicated to prevent INH induced peripheral neuropathy

Z gives false + benedict test in urine, as well as difficult BSL control, sometimes. PAS therapy can lead to mild acidosis, misleading to ketosis , sometimes.

ATT IN ELDERLY
EPTB is more frequent than PTB SCC is effective in geriatric population, BUT : More chances of INH induced psychosis, peripheral neuropathy. More chances of R induced Pseudo-adrenal crisis and hepatotoxicity. More chances of Z induced hyperuricemia. More chances of SM induced ototoxicity and Nephrotoxicity.

TB AND RENAL DISEASE

Patients of CRD are more susceptible to TB because Immunosuppressive effect of uraemia Use of steroids Immunosuppressive drugs used in renal transplantation.

The Renal Impaired TB Patient

Patients with end stage renal disease (ESRD) have increased risk for progression to active TB disease
Risk is 10 25 times greater for persons with ESRD than in the general population

 Clinical presentation may be atypical. Pulmonary disease is the most common. Diagnosis is difficult because tests like Chest x ray, TST,ESR can give confusing results. Diagnostic value of ADA in pleural fluid is unreliable. Diagnosis is mainly on clinical grounds.

MANAGEMENT
Alteration in the doses of some ATT is required in CRF as some drugs are cleared by kidney. Increasing the dosing interval instead of decreasing the dosage of drugs is recommended.

 INH no change is required even in severely impaired patient. RIF - up to 600 mg/ day can be given in severe RF PZA 40-60 mg/kg should be given twice or thrice weekly in RF SM - Should be given as twice or thrice weekly in usual dose. EMB Should be avoided. If necessary should be given 5-10 mg/kg/day

 If CrCl <30ml/min., including hemodialysis patients, administer anti-TB treatment thrice weekly after dialysis at the following doses:
Isoniazid and rifampicin 10mg/kg PZA 25-35mg/kg EMB 15-25mg/kg

Include supplemental pyridoxine 25-50mg with the thrice weekly regimen to prevent peripheral neuropathy

TB AND LIVER DISEASE

Risk factors for ATT induced Hepatotoxicity Advanced age Extensive pulmonary TB Malnutrition Alcoholism HBV/HCV infection HIV/AIDS Acetylator phenotype

 Baseline LFT should be done in patients with chronic liver disease, HIV, HCV, pregnant, postpartum women, chronic medical conditions. Patients on ATT if develop jaundice then other diagnosis like viral hepatitis should be ruled out first.

Hepatitis
Hepatitis (asymptomatic elevation AST/ALT occurs in 20% patients on 4 drugs)
Drug induced hepatitis = AST or ALT 3 times upper limits of normal in the presence of symptoms OR >5 times if asymptomatic INH, PZA and RIF can all cause hepatotoxicity
Hepatitis from INH is age related, from PZA is dose related, and RIF is unpredictable and less common

GRADING
Grade I: ALT 51-125 IU/L Grade II: ALT 126-250 IU/L Grade III: ALT 251-500 IU/L Grade IV: ALT > 500 IU/L

TB Treatment and Hepatitis

If 3x normal with symptoms or >5x normal without symptoms:
stop all anti-TB medications and evaluate patient
refer patient to doctor for clinical evaluation

try to rule out other causes of acute liver disease

if severely ill, may start 3 non-hepatotoxic drugs after AST <2 times upper limit of normal rechallenge drugs one-by-one starting with drugs that are not hepatotoxic

REINTRODUCTION OF DRUGS
When AST levels reach less than 2 times normal, reintroduction should be tried. Restart RIF first followed by INH and PZA

TB and HIV infection the cursed duet

Immunopathogenesis

Kaufmann et al, Nature Medicine 2005

HIV TB pandemic
TB is the leading opportunistic infection in HIV infected patients Often the first indicator of immune deficiency (AIDS defining Illness) World wide 40 million HIV infected of whom15 million are co infected with TB Tuberculosis accelerates the progression of HIV infection and HIV increases the likelihood of active TB disease

Immunopathogenesis of TB-HIV
HIV infection is associated to: Decreased chemotaxis Defective granuloma formation and maintenance Impaired antigen processing and presentation Loss of CD4+ T cells
Selective clonal deletion of M. tuberculosis-specific CD4+ T cells Loss of IFN-g+/IL-2+ CD4+ T cell precedes the loss of IFNg+ /TNF-a+ CD4+ T cells

Opportunistic diseases in the course of HIV-infection

Seroconversion: Oral Candida-infection Kaposi sarcoma

CD4+
(cells/L)

Acute retroviral syndrome

Lymphoma
Pneumococcal pneumonia Dementia Oral haircell-leukoplacia

800-

Candida vaginitis ITP

Cachexia

600-

Toxoplasmosis PCP HSV

400-

Candida esophagitis

TB
2005000 2 4 6 Years after infection 8

Cryptococcosis MAC CMV

10

Pulmonary vs extra-pulmonary TB: HIV+ vs HIV-

TB diagnosis in HIV+ persons

Microbiology
Radiology TST

IGRA

Microbiological diagnosis
Microscopy, AAFB sputum staining: 1 day Culture: liquid medium (2-8 weeks), solid medium (8-18 weeks) Identification: analysis of positive cultures by molecular biology assays (2-4 weeks) Drug- sensitive assays: to INH and RFP: 2-4 weeks to other drugs: 6-8 weeks

Microbiological diagnosis
Microscopy, smear AAFB sputum: sensitivity is around 45% in HIV+ compared to 60% of HIVpatients (Hirao et al, 2007)

Probably due to the reduction of cavitation which results in a lower number of bacilli expectorated

Radiological features of HIV+ patients

cavitary TB CD4+ 510 (23%)

miliary TB CD4+ 194 (18%)

TB Pleuritis CD4+ 34 (8%)

Lange et al, Pneumologie 2004

Radiological tools
Pulmonary TB: Chest xRay: 14% of those with culture-positive TB have a normal chest xRay CT-scan: mediastinal and hilar lymph nodes HRCT (1 mm slices): interstitial lesions tree and bud appearance Extra-pulmonary TB: Radio-nuclide scans/MRI (bone, CNS) CT-scan

TST

Tuberculin skin test (TST)

Active TB disease

M. tuberculosis
Positive TST

Latent TB infection (past exposure to M.

tuberculosis)

Latent TB infection (recent exposure to M. tuberculosis) NTM BCGvaccination

Exposure to environmental mycobacteria

BCG-vaccination

TST does not distinguish among all these different clinical situations

Tuberculin skin testing

Tuberculin reactivity four fold less in HIV infection Reactivity declines with increasing immune suppression early HIV 40-70 % advanced HIV 10-30% Annual tuberculin testing for HIV infection to detect latent infection Tuberculin anergy assoc. with risk of active TB is controversial

T cell-based assays
Interferon Gamma Release Assay (IGRA)
New generation of diagnostic tests for TB that measure in vitro the interferon- release from activated T-cells in response to TB specific RD1 antigens (ESAT6, CFP10,+/-TB7.7) Commercially available IGRAs

QuantiFERON-TB Gold (QF-TB-2G), in Tube (QF-TB3G) T-SPOT.TB (TSPOT)

Treatment of TB/HIV complicated by

Optimal regimen for treatment of co-infection not defined Optimal timing of HAART unclear Drug-drug interactions Large pill burden Variable drug absorption Risk of further AIDS-defining illnesses if HAART is deferred during TB treatment Paradoxical reactions

ART drug Classes

Nucleoside reverse transcriptase inhibitors (NRTI) Non nucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors (PI) Fusion inhibitors

NRTIS
Zidovudine Lamivudine Stavudine Zalcitabine Didanosine Abacavir Tenofovir Emtricitabine

Protease Inhibitors
Indinavir Ritonavir Nelfinavir Saquinavir Amprenavir Lopinavir Atazanavir

NNRTIs
Nevirapine Delavirdine Efavirenz FUSION INHIBITORS Enfuviritide

Combinations never used

AZT+ Stavudine - antagonistic Ddi+ Stavudine Stavudine+Zalcitabine Zalcitabine+ Ddi additive toxicity Atazanavit+Indinavir Emtricitabine +lamivudine ~ resistance profile Efavirenz based regime in pregnancy

Drug interactions
Use of Rifampicin with PI / NNRTI based ART is contraindicated. NRTI are not metabolized by hepatic cytochrome P 450 enzyme system hence they can safely be used with Rifampicin based ATT Other first line ATT (SHEZ) no interactions with ART and can be used safely : SHEZ x 2 months followed by SHZx7months

 Rifabutin :less potent inducer and can be used in place of Rifampicin in ATT with PI NNTRI based ART ( equivalent bactericidal action, clinical cure rates ) Ritonavir retards Rifabutin metabolism

(levels 35 fold) toxic reactions uveitis,

neutropenia , arthralgia occur. combination

is contraindicated

ART+ ATT Recommendations

CD4 count <200cells/mm3 start TB treatment and start ART as soon as TB treatment is tolerated ( 2weeks to 2months) ZDV/3TC/EFV CD4 count 200-350cells/mm3 start TB treatment and start ART as soon as TB treatment is tolerated ( 2weeks to 2months) ZDV/3TC/EFV CD4 count >350cells/mm3 Treat TB. Monitor CD4 counts. Defer ART.

Antiretroviral therapy for HIV infection in adults and adolescents 2010 revision
HIV/TB co infection
Irrespective of CD4 cell counts, patients co infected with HIV and TB should be started on ART as soon as possible after starting TB treatment

THANK YOU