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TB Clinical Dilemmas

TB Clinical Dilemmas. To boldly go beyond the guidelines. Martin Hetzel Bristol Royal Infirmary and Avon TB clinic (Retired). Areas involved in case discussions. TB and diabetes CNS TB TB and drug addiction TB and liver disease TB and renal failure Relapse and remission in TB

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TB Clinical Dilemmas

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  1. TB Clinical Dilemmas To boldly go beyond the guidelines Martin Hetzel Bristol Royal Infirmary and Avon TB clinic (Retired)

  2. Areas involved in case discussions • TB and diabetes • CNS TB • TB and drug addiction • TB and liver disease • TB and renal failure • Relapse and remission in TB • Atypical TB (NTM) • TB in elderly patients

  3. Mr A.Y. Age 44 • Admitted 1-6/9/11 -cough breathlessness, purulent sputum and weight loss for 6 weeks. • Past history of alcoholic hepatitis and poorly controlled diabetes. Enthusiastic smoker! • Smear positive- started on Rifater and Ethambutol • Readmission 6-14/10/11- Worse symptoms -Isoniazid resistant. • Regime changed to Rifampacin/ ethambutol/pyrazinamide • 25-27/10/11 Admission with frank haemoptysis – resolved spontaneously

  4. 6/10/11

  5. 13/10/11

  6. 3/11/11

  7. Little improvement in chest x-ray after 2 month’s treatment- what would you do at this stage? • Keep going! • Nurse supervision in community for compliance (limited as outside our nurse’s territory) • Try to optimise diabetes control/ reduce alcohol consumption/ smoking by liaison with GP

  8. Mr A.Y. Age 44 • 3/11/11 & 24/11/11 clinic- Improving, still smoking, diabetes control improved • 22/12/11 Stopped pyrazinamide • Plan: continue for 1 year on rifampacin & ethambutol. Referred opthalmology, slight blurring of vision-OK • 19/1/12 & 16/2/12 Still smoking 15/ day. BM 8-10.

  9. 16/2/12 -After 5 months’ treatment-what would you do now? Follow up for at least 1 year after treatment completed. Don’t expect CXR to improve further.

  10. Practice Points • Diabetes carries relative risk for TB of 2-41 x • Often associated with slower response • Some experts recommend prophylactic pyridoxine • In patients with diabetic retinopathy we normally use moxifloxacin instead of ethambutol- shown to be equally effective in sensitive TB (Conde et al, Lancet 2009). • Cavitating TB is associated with slow response and persisting smear positive sputum due to poorer penetration

  11. Mr L W age 30 • IV drug abuse, 2003-8. On methadone since December 2010 • Prison 2010 –February 2011 • Chronic hepatitis C, • May –November 2011: treated with interferon & ribavarin

  12. Mr L W age 30 • 19/12/11: Referred to TB clinic • Cough since April and green sputum for 3 months. Milliary shadows on CXR • Generalised minor lymphadenopathy, no other signs. HIV negative, Hb 9.8 MCV 78.3, MCH 25.0 • Alkaline phosphatase 374, ALT 29 • LDH 546, Gamma GT 184, albumin 31 • Bilirubin 5 , INR 1.1 • Plan- sputum cultures ? BAL/ node biopsy

  13. 29/12/11

  14. Mr L W age 30 • Admitted 28-30/12/11 with bloody diarrhoea. Sigmoidoscopy-mild indeterminate colitis-likely infectious origin- histology normal. • Sputum (15/12/11) now reported AFB culture positive • Started on Rifater & Ethambutol; plus methadone titrated up

  15. Mr LW age 30 • 9/2/12 TB clinic • Diarrhoea settled • Feeling better but still has a cough- still smoking • Weight improving • Chest x-ray improving • No nodes or other signs • Bilirubin 9 • ALP 137↓, ALT 15, Albumin 42 • HB 11.8↑ microcytic picture as before • Fully sensitive MTB

  16. 9/2/12 Further slow resolution of nodules on CXR, and then discharged after successful treatment

  17. Practice Points • If no known liver disease, check liver function before treatment, then either rely on symptoms/ signs of hepatotoxicity or respond to >5 times upper limit of normal transaminase rise • Most patients with liver disease can be successfully treated in collaboration with hepatologists. Do not be tempted to stop treatment unless synthetic function of liver fails (albumin, INR)- monitor weekly first 2 weeks, then 2 weekly. In liver failure can use streptomycin+ ethambutol • Deranged liver function may be partly due to hepatic TB- can improve during treatment • TB can mimic iron deficiency anaemia- (ferritin normal or high) • Addicts on methadone will need increased doses due to enzyme induction from rifampacin- take care to reduce at end of treatment! • Milliary TB is usually sputum culture positive

  18. Mrs NW Age 22 • Somali- came to UK 2006. Speaks very little English. Previous contact of aunt in Somalia, 2 young children • 30/9/10 Referred by orthopaedic surgeons, sacroiliac pains for 6 months • On examination:- • Fullness of right buttock • Several areas of erythema, with sinuses discharging pus on thighs and feet • AFB from pus from right buttock- ultrasound guided aspiration (6/9/10) 15ml viscid pus obtained • Dermatology biopsy- necrotising granulomatous inflammation with single AFB on histology • MRI August 2010 showed right sacro-iliitis with extensive abscess formation extending out through pelvic foramina into right buttock muscles.

  19. Initial managment • Started on standard chemotherapy -Rifater plus ethambutol and notified; pending full results from AFB cultures. • TB nurse supervision in community • Planned for review at 2 months with repeat MRI

  20. Follow up 9/12/10 • Pain on bending and walking • Claims compliance • Fully sensitive M TB. HIV negative • On examination:- • Very large swelling of right buttock-limited fluctuance • Small sinus over left greater trochanter • Lesions on legs all apparently healed • No lymphadenopathy • Treatment changed to Rifinah

  21. Admission 30-31/12/10 • Elective admission to drain buttock abscess (delayed by wait for school holidays) • Ultrasound guided placement of drain and 850 ml pus removed

  22. 13/1/11 TB clinic Initally she felt mass had completely resolved post drainage. Now aware of some recurrence but no discomfort On examination 5 cm mass in right buttock, no sinus Continued Rifinah No further drainage attempted because she was comfortable and we presumed this was immune response.

  23. Further follow up • 3/3/11: no symptoms. • OE: Slight fullness over right sacro-illiac joint only • Plan for completing 6 months chemotherapy with MRI at end of course • 7/4/11: Pregnant, worried about MRI and declined • On examination slight non tender fullness in right sacro-illiac joint • Stopped treatment (6 months completed), with plan to discuss deferred MRI in second trimester

  24. Then not seen until… • 21/10/11 Admitted to obstetric unit with seizures. At term, ? eclampsia. • Treatment: • Magnesium • Caesarean section- healthy baby • Further seizure: • Transferred to ITU • CT head normal

  25. Lumbar puncture • Clear colourless • Total white cells 54/ mm3 • Red cells <1 • Lymphocytes 62 % • Polymorphs 38% • Gram stain, culture negative • AFB smear negative • Protein 0.17 (<0.55) • Glucose 4.3 • PCR for Enterovirus, Herpes Simplex, Varicella zoster negative

  26. Other Tests • Magnesium 0.59 • Albumin 18-20, Globulin 32 • Alkaline phosphatase 134 • Total Vitamin D 24.0 • CRP 82-28 • Hb 9.5 MCV 77.0, MCHC 25.1 • WBC 17.87-7.27 (Neutrophils 14.67) • Cryptococcus antigen negative • Toxoplasma Dye Test 64, IgM negative

  27. ITU management • MRI brain- 2 lesions in each occipital lobe compatible with tuberculomas • Rifampacin, INAH, ethambutol, pyrazinamide, dexamethasone • Phenytoin and Keppra (Levetiracetam) • 27/10/11 transferred to respiratory ward • Initial confusion but then improving • CSF PCR for MTB negative • 31/10/11 discharged on Rifater and ethambutol plus anticonvulsants (Phenytoin level in therapeutic range) • Close TB nurse supervision • Continue TB chemotherapy pending final culture results on CSF • Neurologists recommended slow withdrawal of phenytoin at 50mg/ 2 weeks and continue keppra

  28. Diagnosis? Further management? • Most probably she had previously asymptomatic CNS TB which was inadequately treated with standard regime and reactivated by pregnancy • Or are these old sterilised tuberculomas now provoking epilepsy? • Less likely other pathologies (toxoplasmosis, cysticercosis, fungal) • On relative risks we elected to assume active CNS TB and continue with 1 year of Rifinah

  29. Further problems • Complaints to TB nurses of falls at home • TB Clinic 28/11/11: On examination nystagmus and ataxia. What to do now? • ?Phenytoin toxicity or further CNS disease- • Phenytoin level 37 (10-20) (Isoniazid inhibits cytochrome P450 isoforms  CYP2C19 and CYP3A causing reduced metabolism of phenytoin, carbamazepine, diazepam) • Repeat MRI- no cerebellar or brain stem lesions • Reduced phenytoin more rapidly and stopped dexamathasone -now symptom free • 6/2/12: Slight residual ataxia on 100mg phenytoin

  30. Final outcome • Followed up until 2014 • One further admission elsewhere with fits due to poor compliance with anticonvulsants • No evidence of any residual active TB • Note CNS TB requires 1-2 years’ treatment due to poorer penetration of blood brain barrier

  31. TB and pregnancy • Untreated TB in pregnancy leads to increased risk of miscarriage/ foetal abnormality/ maternal risk. Pregnancy/ puerperium may increase risk of drug hepatotoxicity • Pregnant patients often need a lot of reassurance to have chest x-rays but strongly indicated on relative risks in suspected TB- including pregnant women with latent TB. (We defer chemoprophylaxis until after delivery) • Mantoux is safe and as reliable as usual. IGRA also appears to be reliable • Avoid streptomycin (8th nerve damage)- other standard drugs appear to be safe. (Ethionamide/ prothionamideteratogenic) • Despite warning patients not to get pregnant/ not to rely on contraceptive pill, some do still get pregnant (no adverse outcome in my experience) • Intra uterine infection of foetus rare. • Main risk to neonate is a smear positive mother- immediate chemoprophylaxis for children under age 2 then 2 mantoux tests and BCG if no conversion • Breast feeding while on chemotherapy is safe

  32. Mr K A aged 29 • Somali- came to UK in 2001. • Drug addiction support worker. Hepatitis B carrier • 2004: Hilar lymphadenopathy, small left hilar nodes on CT- then lost to follow up • April 2008: Chronic interstitial nephritis and end stage renal failure-started haemodialysis Renal Unit, Southmead • 23/9/10: Referred to TB clinic- non tender cervical nodes for 2 months

  33. Mr KA Age 29 • O.E. 2 small bilateral posterior triangle nodes and larger posterior cervical node on right. Right forearm fistula. Soft systolic murmur • Px Bisoprolol, ramipril, aluminium hydroxide, alfacalcidol • Referred to Neck lump clinic (max fax surgeons) for needle aspirate • Quantiferon IGRA positive

  34. 1/9/10

  35. 1/9/10

  36. Mr K A Age 29 • 8/11/10: Fine needle aspirate smear negative • Need to start treatment- what should we give? • Rifinah 600mg daily • Pyridoxine 10mg daily • Pyrazinamide 2000mg (25-30 mg/kg) • +Ethambutol 1700 mg (15-25mg/kg) • 3 times a week after dialysis • 2/12/10: FNA of lymph node culture positive for MTB • ? Intermittent symptoms of peripheral neuropathy

  37. 22/11/10

  38. Mr K A Age 29 • 6/1/11- Fully sensitive M TB. Successfully completed initial phase • How would you give continuation phase treatment? • Rifampacin 600mg & Isoniazid 300mg daily (hepatic metabolism)- Refused Rifinah for religious reasons (contains gelatin) • -plus continued pyridoxine

  39. Mr K A • 17/2/11: Complains of coldness and numbness in feet. • OE: No nodes, reduced vibration sense in feet • Guidelines advise against reducing isoniazid dose below 300mg- therefore increased pyridoxine to 20mg • 17/3/11: Worse numbness, walking sometimes difficult, fine touch and vibration reduced below ankles. Pyridoxine increased to 50mg

  40. Mr K A • 24/3/11: Worse neuropathy, unable to tolerate high dose pyridoxine. Therefore stopped treatment (at 5 months). Felt better since • OE. Reduced sensation in toes only • What would you do now? • Need to balance risks of further treatment toxicity versus future risk of reactivated TB from immunosuppression after renal transplant • 14/4/11: Elected to treat further with rifampacin 600mg daily and ethambutol 1700mg 3 days a week post dialysis (i.e. as if this were isoniazid resistant TB)

  41. 14/4/11

  42. Mr K A • Completed further 4 months treatment with daily rifampacin and 3 times/ week ethambutol • June 2011: neurology review: reduced power, and sensation in lower limbs and absent motor and sensory potentials on nerve conduction/ EMG. Sural nerve biopsy unhelpful but no vasculitis. Neuropathy presumed to be due to isoniazid but motor weakness and disproportionate lower limb involvement unusual

  43. BTS Guidelines on TB in renal disease • Isoniazid: Hepatic metabolism, less active compounds then renally excreted. Very little removed by dialysis. Risk of toxic levels from intermittent therapy. Neuropsychiatric side effects and also peripheral neuropathy are described in patients on dialysis • Rifampacin: Hepatic metabolism, 10% excreted in active form in urine. Inactive formylrifampacin excreted in urine, main metabolite desacetyl rifampacin is excreted in bile. • Pyrazinamide: Hepatic metabolism, 3-4% renal excretion unchanged. 45% dialysed. Possible delayed elimination and hyperuricaemia. • Ethambutol: 80% renally excreted unchanged. At standard dose of 15mg/kg excretion is substantially reduced in renal failure and occular toxicity is dose dependent • 3 times/ week ethambutol & pyrazinamide- Before or after dialysis? • Before (4-6 hours)-Reduced toxicity risk/ increased risk of reduced efficacy • After (immediately)- Avoids premature removal, increased toxicity risk

  44. Mr TS –Medicolegal referral • Pakistani man, now aged 42 • Came to UK in 2001 • May 2009 admitted to St Elsewhere’s for investigation of dry cough, fevers and night sweats. No history of TB contact • Chest X-ray/ CT showed mediastinal nodes, right pleural effusion, and diffuse lymphangitic infiltration in abdomen

  45. 4/5/09

  46. 11/5/09

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