TB MORTALITY: DID TB CONTRIBUTE TO DEATH? APPLYING LESSONS LEARNED California TB Controllers Conference Rohnert Park, CA March 12, 2019 Susan Strong, Lisa Pascopella, Janice Louie AGENDA Welcome and poll Susan Strong

Research study and surveillance findings on deaths Lisa Pascopella Case study to determine TB relatedness of death Janice Louie Discussion of steps and challenges Survey Monkey TB

Mortality Poll KAHOOTS (add link) FREQUENCY OF TB-RELATED DEATH IN TB PATIENTS WHO DIE Objectives Review findings from a national study of TB death Compare to findings from TB surveillance data Discuss approaches to assess TB contribution to

death Published in Annals ATS, Vol 15 June 2018 OBJECTIVES Assess the frequency of TB-related deaths Identify risk factors for TB-related death METHODS Reviewed deaths of TB cases reported 2005-2006 TB-relatedness algorithm

Trained data abstractors 2 reviewers per case; at least 1 clinician with TB expertise 3rd reviewer to resolve disagreements Inpatient and outpatient medical and laboratory records Classification: possibly or definitely TB-related, unlikely TB RELATEDNESS AND TIMING OF DEATHS 1,304 adults who died

272 (21%) TB-unrelated deaths 90 (7%) could not be classified 942 (72%) TB-related deaths 705 (75%) TBrelated deaths

during treatment 329 (47%) TBrelated deaths within 30 days of diagnosis 371 (53%) TBrelated deaths >31 days after diagnosis 237 (25%) TBrelated deaths

before treatment TIME TO DEATH TB RELATED VS TB-UNRELATED TB unrelated TB related Days to death STUDY ALGORITHM

VS. DEATH CERTIFICATE Study algorithm/Death cert TB was not an immediate, underlying, or contributing cause of death Not TB-related death

TB-related death Totala 185 (75) 378 (45) 563 (52) Kappa = 0.21 (0.16, 0.26) Sensitivity of death certificate=55.4% (51.9,58.7) Specificity of death certificate=75.2% (69.3, 80.5)

Death certificates were not available for 10% of decedents TB was an immediate, underlying, or contributing cause of death 61 (25) 469 (55) 540 (48)

Totala 246 (23) 847 (77) 1093 (100) RISK FACTORS TB-RELATED DEATH Many risk factors for TB-related death on treatment Delayed diagnosis Extensive TB disease

Immune suppression Comorbidities Started anti-TB treatment as inpatient TBESC STUDY CONCLUSIONS 72% TB deaths were TB-related Death certificates not reliable Underestimate TB-related deaths Need medical/hospitalization records Increased death risk when TB diagnosed in hospital

WHAT DO WE KNOW ABOUT TB DEATHS IN CA? Reviewed recent surveillance data 2 types of death Dead at diagnosis Died during treatment REPORT OF VERIFIED CASE OF TUBERCULOSIS WAS TB A CAUSE OF DEATH?


30% unknown relatedness 8.4% (n= 1267) TB cases died on treatment 36% related to TB disease 1.6% related to TB therapy 41% not TB-related 21% unknown DEATHS ON TREATMENT CA TB SURVEILLANCE DATA 2010-2016 BY LHJ LHJ

Unrelated to TB disease Related to TB disease Related to TB therapy Unknown

a 40% 21% 0.5% 39%

b 43% 47% 2.8% 7% c

24% 56% 1.9% 19% d

55% 16% 0 29% e 19%


72% national study vs. 38% surveillance Diversity of responses to RVCT questions in CA Variability in methods to ascertain TBrelatedness? Role for independent review? CDPH TBCB TOOL https://www.cdph.ca.gov/Programs/ CID/DCDC/CDPH%20Document %20Library/TBCB-RVCT-DeathAlgorithm-v1.0.pdf Dead

at diagnosis Died during treatment SAN FRANCISCO TB DEATH REVIEWS Janice Louie, MD, MPH San Francisco Department of Public Health

Tuberculosis Control Program Analysis of Tuberculosis Mortality in San Francisco (2012-2017) Elgin Yalin, PHAP, CDC TB deaths (2012-17) reviewed by physicians using RVCT, medical record, and death certificates (n=57) o SF TB-death rate =0.57 per 100,000 (~3X national rate) o 43 (75%) were assessed by MDs as TB-related o Median age 81 years (range 33-99); majority male (70%), non-USA born (88%), from China, Philippines or Vietnam (84%) All had pulmonary disease

o Smear positive -39% (n=52; 88%) o Culture positive -79% (n=49; 84%)) o Nucleic acid amplification test (NAAT) positive- 72% (n=25; 44%) 20% never started on treatment o TB-related deaths associated with average shorter time on treatment compared to non TB-related deaths (57 days vs 277 days) SF DEATH REVIEW CONCLUSIONS Over of deaths in active cases were TB-related AFB smear of sputum was positive in only 40% Shorter duration of treatment was associated with death being TB-related

Further efforts to educate clinicians to recognize TB disease are needed; nearly half of fatal cases did not have NAAT performed and 20% were never started on treatment FATAL CASE REVIEW EXAMPLE: TBRELATED OR NOT? 83 year old female from China, in US since 1994 Treated for LTBI in 1994 with INH x 12 months at SFDPH History of breast cancer s/p mastectomy and chemotherapy 1979, radiation therapy 2012 with complication of pulmonary fibrosis History of Sweets syndrome Hypertrophic cardiomyopathy

Chronic hepatitis B on lamivudine Alzheimers dementia Hospitalized August 2017 Fever x 3 months, fatigue, drenching nightsweats, slight cough, dyspnea and bilateral leg pain and swelling QFT indeterminate Chest CT- nodular scarring and calcifications in the lingula and right lung apex Sputum: AFB smear negative x 3, cultures positive for M Gordonae (x2) Re-hospitalized September 2017 Fever, nightsweats, new bilateral lower extremity rash

Diagnosed with possible vasculitis: + ANCA, elevated PR3 and anti-MPO (>600) Sputum: AFB negative x 3, + GeneXp, + culture for MTBC Seen in TB clinic; RIPE started September 29, 2017 CXR AT TIME OF TREATMENT INITIATION October 19, 2018: new purpuric rash on bilateral lower extremities, itchy, fever to 100.9. TB medications held. Evaluated by Dermatology: skin biopsy shows early vasculitis vs purpuric dermatosis, possibly due

to rifampin. ESR 120, CRP 59 Patient re-challenged with rifampin-> rash returned after one dose All TB meds held Culture converted October 21, 2017 (5 weeks) November 10, 2017: Re-challenge in progress: current meds INH and EMB Noted on routine labs to have rising creatinine (0.7-> 1.5), UA with hematuria, progressively worse dypsnea Patient re-hospitalized, started on high dose steroids and rituximab. Diagnosis: RPGN and microscopic polyangiitis

November 2017: DST /PSQ of sputa: INH resistance INH d/c, patient continued on EMB, PZA and Moxi and did well, continued on prednisone 60 mg daily with slow taper January 2018: stable/slightly worsening CXR with increasing ground glass opacities bilaterally CXR Nodular thickening along the right major fissure, linear scarring, and distortion of the fissure is worse compared to prior. Groundglass nodules

in the bilateral apices likely represents subacute infection. April 2018: Meds held due to new DILI; slow re-challenge May 2018: increasing dyspnea and fatigue with new hemoptysis and fever. Patent hospitalized with finding of new RML infiltrate, diffuse GGO not consistent with

TB. RVP + metapneumovirus. Admitted to ICU, complicated by new a-fib/flutter, flash pulmonary edema. Patient became progressively hypoxic and died May 28, 2018 DEATH CERTIFICATE Death certificates

do not identify an underlying cause of death in almost 50% of cases DISCUSSION

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