Property of Presenter. Not for Reproduction DENVER TB COURSE: CHALLENGING CLINICAL PRESENTATIONS

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1 DENVER TB COURSE: CHALLENGING CLINICAL PRESENTATIONS Michelle Haas, M.D. Associate Director Denver Metro Tuberculosis Program Denver Public Health

2 DISCLOSURES No relevant financial relationships

3 OBJECTIVES Discuss challenging clinical presentations Identify comorbid conditions that affect TB management Review how active TB might have been prevented Review how delays in diagnosis can be minimized

4 57 year old man with DM, ESRD and coronary artery disease PATIENT 1 Grew up in Vietnam, moved to the US at the age of 40 +TST, no latent TB (LTBI) therapy recommended At pre-transplant evaluation: denies diagnosis of TB No further diagnostic evaluation or treatment

5 Several months later, he undergoes renal transplant PATIENT 1 New pleural effusion noted, attributed to volume overload No thoracentesis performed Day of renal transplant

6 PATIENT 1: HISTORY CONTINUED 5 months later admitted for cough, subjective fevers Pleural effusion, 149 cells 88% lymphocytes: Protein ratio 0.92 LDH ratio 0.6 Labelled as transudative effusion Bacterial, fungal and AFB cultures sent Treated for healthcare associated pneumonia

7 PATIENT 1: HISTORY CONTINUED Presented to care 10 days later with worsening symptoms Pleural fluid grew M. tuberculosis on day 22 IGRA+ AFB smears positive Current immunosuppressive regimen contains: Tacrolimus Mycophenolate mofetil Prednisone

8 QUESTIONS How could his active TB have been prevented? Identification of the diagnosis of latent TB and offering treatment for LTBI Very high risk for progression to active disease: Lived as a child in an area of high TB risk Diabetes ESRD What are the drug interactions to consider?

9 DRUG INTERACTIONS Immunosuppressive medication TB medication Interaction Tacrolimus Rifampin efficacy of tacrolimus Tacrolimus Optimal regimen (assuming drug-susceptible disease): Isoniazid Rifabutin Pyrazinamide Ethambutol Rifabutin efficacy of tacrolimus, less than rifampin Prednisone Rifampin efficacy of prednisone mycophenolate mofetil Rifampin efficacy of mycophenolate mofetil

10 WHAT IS THE OPTIMAL DURATION OF TB TREATMENT IN SOLID ORGAN TRANSPLANT PATIENTS No consensus regarding optimal duration One case series recommended months Case series from Spain: 10 months, 86% success rate Case series from France: 12 months, 10% without rifampin Median treatment time of 9 months with pyrazinamide and rifampin containing regimen Data on relapse is limited: 1/15 cases after 9 months of treatment at 3 years (Taiwan) 8.1% with treatment failure in French cohort Hsu, MS et al. The American Journal of the Medical Sciences, 2007; 334 (2) Munoz P, et al. Clin Infect Dis 2005;40:581 7 Garcia-Goez, JF, et al. Transplantation Proceedings, 41, (2009) Canet, E. Nephrol Dial Transplant (2011) 26:

11 TB IN RENAL TRANSPLANT Risk of TB substantially higher than in the general population Estimated at 250/100,000 when US incidence was 7/100,000 Mortality varies widely 6-30% Risk of graft rejection Disseminated disease in up to 27% Median time from transplant to development 9 months 1/3 within 12 months s/p transplant Klote M, et al. American Journal of Transplantation 2004; 4: Hsu, MS et al. The American Journal of the Medical Sciences, 2007; 334 (2) Canet E. Nephrol Dial Transplant (2011) 26:

12 PATIENT 1: CONTINUED 4 months into therapy Failure to regain weight Elevated LFTs Develops right sided chest pain and nodular density along right chest wall Eventually re-admitted

13 PATIENT 1: CONTINUED Undergoes thoracotomy with creation of an Eloesser flap for an empyema necessitans Repeat cultures for M. tuberculosis were negative Discharged on isoniazid and rifabutin Patient does not disclose he was discharged on TB medications Discovered during a clinic visit review of medications that he brought in from home

14 PATIENT 1: CONTINUED Finally gaining weight after Eloesser flap and clinically improving Successfully completed 9 months of treatment Will monitor closely for signs of relapse Eventually will go for Eloesser flap closure

15 LESSONS LEARNED Renal transplant clinic developing protocol to ensure all patients at risk for TB infection are screened Treatment of LTBI prior to transplant Additional hospital protocols in place to improve infection control Discussions with hospitalists about avoiding discharging patients with TB medications

16 SUMMARY Individuals who are immunocompromised are at risk for progression of disease Co-morbid conditions such as HIV and solid organ transplantation can complicate TB management Clinical suspicion for TB should remain high if no alternative diagnosis found Continued respiratory isolation Empiric treatment

17 HPI 60 year old man with cryptogenic cirrhosis, associated TIPS placement is admitted with fevers, cough, a chronic right sided effusion and decompensated cirrhosis (MELD 24) Started on vancomycin and cefepime for presumed HCAP New murmur identified, TTE with possible mitral valve vegetation Multiple blood cultures negative ID consulted to assist with the evaluation of culture negative endocarditis 2017 Denver Public Health

18 HPI Lived in Mexico as a child but has been living in the US for 18 years Prior admission 2 months before with sepsis and pneumonia. Found to have exudative pleural fluid, negative bacterial cultures Remote history of presenting to TB clinic several years prior, IGRA testing done at that time was negative 2017 Denver Public Health

19 6 MONTHS PRIOR DURING AN EPISODE OF GI BLEEDING HPI ADMISSION TWO MONTHS AGO WITH SEPSIS

20 Pleural fluid RBC 48,000 WBC 1,800 (73% L) Prot 2.2 LDH 279 (serum 422) Procalcitonin < 0.05 Discharged on Levofloxacin, symptoms improve HPI

21 ONE MONTH AFTER SEPSIS EPISODE HPI THIS ADMISSION

22 Pleural fluid current admission ph 7.35 Gluc 138 RBC 46,000 WBC 1,749 (78% L) Prot 2.5 (serum 4.5) LDH 215 (serum 421) ADA 2.1 (<9.4 normal) HPI AFB cultures not sent on pleural fluid

23 CBC WBC 3.0 Hct 24.8 Platelets 68 INR 2.5 Cr 0.94 HPI CONTINUED LFTs Total Bilirubin 5.0, direct 2.0 AST 50 ALT 28 Alb 1.2 Sputum 1+ AFB; Xpert (+) TB and Rifampin resistant

24 WHAT REGIMEN WOULD YOU RECOMMEND? Any additional testing? 2017 Denver Public Health

25 HPI Treatment started with levofloxacin, amikacin, EMB, linezolid and imipenem Imipenem discontinued after two weeks QTc stable at 500 MDDR-no INH resistance, confirmed rifampin resistance Phenotypic susceptibilities rifampin and pyrazinamide resistance 2017 Denver Public Health

26 CLINICAL COURSE Treatment Regimen Notes 4 weeks Levofloxacin, ethambutol, amikacin, linezolid converts cultures at one month treatment held 2 weeks developed perforated duodenum; AKI 6 weeks Levofloxacin, ethambutol restarted followed by amikacin Tolerates this well for some time; plan was to eventually stop amikacin and start linezolid 8-10 weeks 10 weeks Levofloxacin, ethambutol, amikacin TIW, linezolid TIW Levofloxacin, ethambutol, amikacin TIW bili of 12, mostly indirect, HCT 24 to19, evidence of hemolysis. Platelets decrease to 18. Linezolid felt to be contributing to anemia and thrombocytopenia 12 weeks Levofloxacin, ethambutol, amikacin TIW need for other agents? 2017 Denver Public Health

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28 CLINICAL COURSE treatment regimen notes 14 weeks Levofloxacin, ethambutol, amikacin, added clofazimine weeks weeks Levofloxacin, ethambutol, clofazimine Levofloxacin, ethambutol, clofazimine Stopped amikacin at 15 weeks Develops right shoulder pain; reduced dose of levofloxacin to 500 mg; full thickness tear of supraspinatus tendon Worsening hepatohydrothorax, ascites and anasarca, estimated 40% mortality in 3 months (MELD 30); re-admitted 2017 Denver Public Health

29 CLINICAL COURSE AND OUTCOME Chooses hospice Died 30 weeks into treatment 2017 Denver Public Health

30 SUMMARY Treatment of drug-resistant TB in the context of cirrhosis is complex Limited treatment options Significant complications 2017 Denver Public Health

31 PATIENT # 2

32 HPI 49 year old man with newly diagnosed type II diabetes who presented to an outside hospital with back pain and numbness/tingling in his legs bilaterally No fever/chills No weight loss Vitals stable, afebrile Exam without neurologic deficits

33 MRI report: - likely metastatic disease - Pathologic 80% vertebral body fracture at T3, masslike lesion with epidural extension of presumed tumor and retropulsion severe canal stenosis

34 HPI

35 HPI Lived for years in Mexico, has been in the US since 2003 No health insurance TST reportedly negative; HIV negative Underwent biopsy of T3: Fibroadipose tissue and fragments of bone with prominent granulomatous inflammation No evidence of malignancy, no AFB or fungal organisms Discharged home on the following: Dexamethasone Metformin

36 Presents again 3 weeks later with: Continued numbness and tingling of the entire bilateral LE's as well as unsteady gait Worsening right sided upper back pain IGRA positive PSA 4.76 (>4 abnormal) HPI

37 HPI Transferred to a referral center and admitted to neurosurgery Underwent debulking with T3 corpectomy, T1- T5 spinal fusion, T2-4 decompression Concern for malignancy, PET scan ordered

38 Intense FDG activity in the following: Soft tissues around the site of the T3 corpectomy Left lateral sixth rib lesion with likely pathologic fracture Prostate Right scrotum CLINICAL COURSE

39 DISCUSSION POINTS Are PET scan findings more consistent with metastatic cancer, TB or both? Is granulomatous inflammation enough to start active TB treatment in the context of a positive IGRA?

40 Excisional biopsy of left rib mass, and fluid sampling for culture Blood and fibroadipose tissue. 2 nd Rib biopsy: Bone and bone marrow with extensive infiltration by non-caseating granulomas - No mycobacterial or fungal elements noted by AFB and GMS staining CLINICAL COURSE Prostate, right medial, right lateral, left medial and left lateral core biopsies: Benign prostatic tissue with acute and chronic inflammation, foreign body giant cell reaction and abundant noncaseating granulomas

41 CLINICAL COURSE Patient was initiated on isoniazid, rifampin, pyrazinamide and ethambutol PCR for Mycobacterium tuberculosis (Mtb) was positive from spinal mass/abscess fluid a few days later. Culture positive, pan-susceptible Rib biopsy cultures negative for Mtb Urine culture negative for Mtb Sputum cultures negative for Mtb

42 COULD HIS ACTIVE TB BEEN PREVENTED? Meets criteria for TB preventative screening with IGRA: From Mexico Has uncontrolled diabetes Had been in the US for 14 years prior to developing active TB Possible barriers: Lack of health insurance leading to challenges in receiving preventative care

43 SUMMARY Substantial overlap in the presentation of TB masquerading as metastatic disease PET scan and MRI imaging was interpreted as consistent with metastatic disease Biopsy of concerning lesions with findings clearly consistent with Mtb and not malignancy Delay in initiation of TB treatment related to substantial overlap in presentation with metastatic cancer Access to TB screening and treatment several years ago may have prevented him from developing active TB