NTM Lecture Series. Challenging Cases: Part 2. Property of Presenter

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1 NTM Lecture Series Challenging Cases: Part 2 Dr. Wendi Kay Drummond DO, MPH Assistant Professor of Medicine Division of Mycobacterial and Infectious Diseases Department of Medicine October 20, 2017

2 Disclosures I have no conflicts of interest to disclose.

3 Objectives Discuss the presentation and clinical evaluation of a complicated case in an immune compromised host Review some common drug reactions associated with antibiotics used to treat NTM infections and management of these drug reactions Discuss indications for surgical intervention in complex pulmonary mycobacterial infection

4 Case 1 Mr. E. is a 53 year old Vietnamese male who presented to the NJH outpatient ID clinic for evaluation in June He first presented for care in the October 2013 with new onset dry cough, shortness of breath, weakness, fever and a 30 lb weight loss. He was subsequently hospitalized.

5 Case 1 At the time of his initial presentation, he denied any significant PMH No relevant ID exposure history that I could abstract through chart review

6 Case 1 CTA Chest 10/29/13: Round mass versus infiltrate in the inferior left hilum, superior segment left lower lobe (5.3x5.1cm) Mediastinal lymphadenopathy, left tracheobronchial angle Addendum: Left supraclavicular lymphadenopathy. The appearance is suspicious for advanced bronchogenic carcinoma.

7 CT Chest 11/4/13 (status post bronchoscopy 11/1/13)

8 CT Chest 11/4/13 Mass-like density in the left hilum and left lower lobe is again identified with constriction of the branches of the left lower lobe pulmonary artery suspicious for neoplasm is again identified. There is increasing surrounding infiltrate now extending out to the periphery of the lateral left lower lobe likely representing adjacent pneumonia or possibly pulmonary infiltrate

9 Pathology Left supraclavicular lymph node biopsy 11/1/13: Special stains negative for any organisms. Pathology notable for Non-necrotizing granulomas. Bronchoscopy with BAL 11/1/13: Brushing with rare mildly atypical cells favoring reactive change. AFB and GMS stains negative for pathogens. Left upper lung bronchus biopsy: No evidence of maligancy. Bronchial wall with severe mixed inflammation and scattered multinucleated giant cells. Histology most concerning for infectious process.

10 Pathology CT-guided needle lung biopsy 11/6/13: Left lung parenchyma with multinucleated giant cells, moderately chronic inflammation and scarring. Comment: The granulomatous inflammation and chronic inflammation is most concerning for an infectious process. All AFB and GMS stains are negative for organisms. The histology would be somewhat atypical for sarcoid.

11 Clinical Course Mr. E was treated for community acquired versus post-obstructive pneumonia Based on the results of the biopsy, he was treated for sarcoidosis and was started on prednisone 60 mg daily with a taper 11/13/13-12/9/14 with some improvement in his pulmonary symptoms. Off of steroids, he developed night sweats, abdominal pain and bilateral hip pain

12 Clinical Course He was admitted to a local hospital on 1/30/14 with worsening productive cough, progressive shortness of breath, fevers (Tmax 39) He was hospitalized from 1/30/14-7/24/14

13 Clinical Course The bronchoscopy specimen (BAL) from 11/1/13 subsequently grew Mycobacterium avium intracellulare (reported 11/11/13) The left lung biopsy from 11/6/13 was smear negative, culture positive for Mycobacterium avium intracellulare (reported 11/18/13)

14 Clinical Course He developed bone pain in his upper and lower extremities with abnormal imaging suggestive of osteomyelitis and persistent fevers.

15 Question 1: What is your diagnosis? A.Sarcoidosis, complicated by infection in an immune suppressed patient on prednisone B.Pulmonary mycobacterial infection C.Pneumonia D.Disseminated mycobacterial infection E. None of the above

16 Clinical Course Diagnosis: Disseminated MAC Bone marrow biopsies notable for granulomas Positive cultures for MAC from multiple sites (blood, bone, lung, bone marrow) Bony involvement including lesions in his skull, thoracic spine, ribs, bilateral femurs, bilateral humerii, requiring IM rods (left humerus, bilateral femurs)

17 Hospital Laboratory Data HIV 1 and 2 antibody tests negative x 2 HIV viral load undetectable CD (6/4/14) Quantiferon negative Femur specimens: AFB smear positive ANA negative, ANCA negative

18 Therapeutics He was treated with multiple courses of antibiotics Once MAC was diagnosed, he was started on therapy with azithromycin, rifampin, ethambutol M/W/F, transitioned to daily therapy 2/21/14 Amikacin (IV) added: 3/19/14-3/29/14; 4/14/14-7/14/14 He was discharged on oral azithromycin, rifampin, ethambutol, and ciprofloxacin

19 Case 1 PMH: Disseminated Mycobacteria avium complex disease History of L pulmonary mass CKD (Cr 1.5) (amikacin associated nephrotoxicity) Hearing loss (amikacin associated ototoxicity) Aspiration GERD Osteomyelitis of the long bones (bilateral femurs, humerii), ribs, spine, skull involvement Pancreatitis Globus pallidus infarct Left ulnar mononeuropathy Cognitive delay

20 Case 1 PSH: ORIF bilateral femurs, humerus (May 2014) Remote history of L4-L5 surgery (MVA) 20 years ago ALL: NKDA Social History: Patient in single. He has an adult son. No prior history of tobacco use, illicit or IVDU. Rarely drank alcohol, none current. Currently residing in a rehabilitation facility. Previously ran his own business. He was born in Vietnam, but immigrated here in 1970 with his mother and step father. Grew up in Denver.

21 The Case FMH: Mother is 70 years old and lives in Florida. Half sister who is healthy. Maternal GM/GF deceased in their late 70 s, cause unknown. Biologic father s history is unknown. No known history of autoimmune disease, pulmonary disease, immune deficiency or cancer syndromes

22 The Case Environmental/ID Exposures: Basement flooded in the past with questionable mold. Frequent sauna use over the last 20 years at the gym. No history of significant domestic or international travel. Denies TB or HIV risk factors. No history of incarceration or homelessness. No pets.

23 The Case Physical Exam: Gen: well developed, mildly obese, flat affect, slow to respond to questions Neuro: decreased sensation over the 4 th and 5 th digits on his left hand and base of his R thumb. Atrophy of the dorsal aspect of his thumb. Diminished sensation from just inferior to the knees down to his toes

24 Question 2: What is the next step in your evaluation of this patient? A. Repeat a bone marrow biopsy B. IFNy autoantibody testing C. HIV antibody test D. Quantitative immune globulins E. None of the above

25 Labs: 16.0 IgG: 1714 (high) Lymph: 2.0 k/mcl (27.7%) Neutro: 4.2 k/mcl (58.4%) Monos: 0.7 k/mcl (8.9%) Eos: 0.3 k/mcl (3.8%) Basos: 0.1 k/ml (1.2%) IgA: 710 (high) IgM: 93 (normal) IgE: 13 (normal) Lymphocyte phenotyping: Abs CD8: 641 ( ) 31.7% Abs CD19: 356 (96-515) 17.6% Abs CD4: 467 ( ) 23.1% Abs CD3: 1140 ( ) 56.4% Abs CD16/56: 477 (45-523) 23.6%

26 Labs (Immmunology Evaluation) IFNγR1 expression: 8.0 (>2.1): indicating normal receptor expression IL-12RB1: expression is PRESENT (normal) Th1/Th17 assay: IFNg and IL17 CD4 Cells by Flow. Showed appropriate IFN-gamma production by CD4 T cells. IFNγ auto-antibody: PRESENT

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28 Nontuberculous mycobacteria (NTM) infections: Major Clinical Syndromes Include skin and soft tissue infections, lymphadenitis, pulmonary disease and visceral or disseminated disease Underlying immune dysfunction/abnormalities varies between these clinical entities SSTI s typically a consequence of inoculation via surgical contamination, trauma, etc in patients with normal immune systems Disseminated disease typically occurs in immune suppressed patients

29 Disseminated NTM Infections Occurs most in immunocompromised hosts Uncommon in persons not infected with the human immunodeficiency virus (HIV) Tumor necrosis factor-alpha antagonists (TNFa) Organ transplant recipients Untreated AIDS Mendelian Susceptibility to Mycobacterial Diseases (MSMD)

30 Disseminated NTM Infections MAC is the most common cause of disseminated NTM The respiratory and GI tracts are the usual portal of entry for dissemination Bacteremia

31 Clinical Features of Disseminated NTM Infections Fever, weight loss, sweating, diarrhea, generalized lymphadenopathy, generalized cutaneous lesions, diffuse abdominal tenderness, hepatosplenomegaly Signs and symptoms typically reflect major sites of infection: bone marrow, lungs, GI tract, skin lesions, multifocal osteomyelitis Disease severity and age of onset depends on the part of the pathway affected In our patient, disseminated disease including pulmonary involvement, lymph node involvement, with multifocal osteomyelitis

32 Clinical Features Anti-IFN-gamma autoantibodies in Disseminated Nontuberculous Mycobacterial Infections. J Immunol 2005; 175: They described the clinical features of 6 patients with IFN gamma autoantibodies and DMAC 4/6 with cutaneous disease 4/6 with involvement of the cervical LN 4/6 with pulmonary involvement 3/6 with bony involvement 1/6 with appendix, retropharyngeal, parapharyngeal, prevertebral 4/6 with cervical LN and lung

33 Clinical Evaluation Biopsy of tissue of clinical concern (lymph node, lung biopsy, skin biospy/i&d, bone marrow biopsy) AFB blood cultures (more than 90% of patients with disseminated MAC have positive blood cultures) Imaging Laboratory evaluation CBC with dif, CMP, CRP, ESR HIV antibody test, Lymphocyte subsets Sputum evaluation (minimum of 3)

34 Clinical Evaluation Retrospective review of medical records in adult patients with disseminated MAC 15 non-hiv infected patients Only ½ had biopsy findings consistent with MAC (granulomas) AFB smear only positive in fewer than 20% Diagnosis made by blood culture or bone marrow biopsy in 73% of patients Lai, et al.

35 Mendelian Susceptibility to Mycobacterial Disease Rare syndrome Mutations in 7 different genes identified Predisposition to disseminated infections by weakly virulent mycobacteria Nontuberculous mycobacteria (NTM) Bacillus Calmette-Guerin (BCG) vaccine Disseminated Mycobacterium bovis More virulent M. tuberculosis Salmonella (50% patients) Intracellular pathogens Nocardia, Listeria, Klebsiella, Leishmania Viruses (HHV8, VZV, CMV) Histoplasma, Coccidiodes Holland, Steven and Wu, Un-In. Lancet Infectious Disease 2015.

36 Auto-antibodies against IFN-γ Anti-cytokine autoantibodies are increasingly recognized as having a role in disease pathogenesis IgG antibodies that inhibit IFNγ binding and downstream STAT1 phosphorylation and GAF formation Usually have normal CD4+ T cells, monocytes numbers, IFNGR and IL-12 receptor expression Holland, Steven and Wu, Un-In. Lancet Infectious Disease 2015.

37 Auto-antibodies against IFN-γ Acquired, adult onset immunodeficiency (median age of 50 years) Increased susceptibility to non-tb mycobacterial and other opportunistic infections. Most common in Asia-born Asian patients. Outside Asia, more common in women, otherwise affects both sexes equally. Not associated with tuberculosis, even in TB endemic region. Slide courtesy of Neha Dunn

38 Case 2 65 year old female with a history of ulcerative colitis s/p total proctocolectomy with ileostomy; breast cancer, s/p lumpectomy, chemotherapy and radiation therapy to the right lung (upper chest) presented to the Adult Day Unit for further evaluation of Mycobacterium abscessus pulmonary infection Diagnosed with bronchiectasis in 2003 in the context of multiple episodes bronchitis Had a sputum specimen positive for Mycobacterium abscessus in 2004, but no treatment was initiated

39 Case : CT scan of the chest demonstrated a right upper lobe cavitary lesion; isolated culture positive for Mycobacterium chelonae 2013: Bronchoscopy with BAL positive for M. abscessus; follow up CT with evidence of persistent cavitary disease. Progression of cavitary disease over the next year and half on serial CT scans

40 Case 2 PAST MEDICAL HISTORY: Bronchiectasis diagnosed in 2003 Pulmonary Mycobacterium abscessus infection History of breast cancer in 1989, status post lumpectomy on the right with concomitant radiation therapy to the right upper chest as well as chemotherapy Hypothyroidism History of ulcerative colitis diagnosed in the 70s, status post total proctocolectomy with multiple revisions to her ileostomy Gastroesophageal reflux disease Cholelithiasis, asymptomatic History of bronchitis as well as multiple episodes of pneumonia

41 Case 2 PAST SURGICAL HISTORY: Total proctocolectomy as well as ileostomy with multiple revisions History of right breast lumpectomy in 1989 History of multiple ventral hernia repairs with mesh, last in 2010 Breast reduction in 2004 Oophorectomy ALLERGIES: Sulfa, PCN (Rash)

42 Case 2 SOCIAL HISTORY: She is married. She lives with her husband. They spend part of the year in Florida for the last 3 years and live in an apartment 22 years old. They spend the rest of their time in in Massachusetts. No tobacco use, occasional alcohol use and 2 glasses of wine/week. She drinks one cup of Espresso per day. She has 2 sons. No fertility issues. ENVIRONMENTAL HISTORY: No history of mold or mildew in their homes or significant exposures. No hot tub exposures or other significant water exposure. She did used to so a lot of gardening but quit approximately one year ago. Lived in New York from 2002 to 2011 in a very old apartment. OCCUPATIONAL HISTORY: She is a former speech pathologist and worked in hospital and school environments.

43 Case 2 TRAVEL HISTORY: Travelled to Peru in 2012 as well as Columbia. She was born in Brooklyn and grew up in Rhode Island. History of travel to New Zealand and Australia as well as Italy. FAMILY MEDICAL HISTORY: Mother with history of bouts of pneumonia and bronchitis. Father with history of colon cancer as well as lymphoma and hypertension. Brother with history of arthritis and lymphoma, HLAB-27 positive. She also has a son with a history of ulcerative colitis and the other son is also HLAB0-27 positive. There is no history of specific autoimmune diseases. No congenital or acquired immune deficiencies.

44 Case 2: ADU Evaluation Bronchiectasis Evaluation: ANA profile 1:40 anti-dsdna that was less than 1:10 SSA 2 SSB 2 IgM 477 (H), IgA, IgG and IgE wnl C-reactive protein 3.35 (H) Alpha 1 antitrypsin 178 normal phenotype M Sweat test wnl ANCA wnl MPO antibody wnl PR3 antibody wnl, IgG subclasses wnl HIV antibody test negative RF 14, which is upper limit of normal; anti-ccp antibody 4

45 Case 2: ADU Evaluation HRCT Chest: Cavitary disease in the right upper lobe which had mildly progressed since prior study comparison of 12/12/ dominant cavities within the right upper lobe measuring 2.2 x 2.8 cm and 2.4 x 3.1 cm. Previously noted small cavity in the posterior aspect of the right upper lobe that has filled in, though the underlying cavity is still present. Small cavity in the left upper lobe, which has increased slightly measuring 1.1 compared to 0.9. Increased volume loss within the right upper lobe, moderate bronchiectasis noticed within the pericardiac portions of the lungs, pronounced within the right middle lobe and lingula with volume loss

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48 Case 2: ADU Evaluation Bronchiectasis likely due to ulcerative colitis +/- reflux and aspiration Surgical evaluation: Recommendations for right upper lobe (RUL) and right middle lobe (RML) lobectomy and lingulectomy based on local disease, complicated cavitary disease

49 12/2014

50 Clinical Course Microbiology: Mycobacterium abscessus Cefoxitin intermediate with an MIC of 32 Amikacin intermediate with an MIC of 8 Ciprofloxacin intermediate resistance with an MIC of 2, Moxifloxacin resistant with an MIC of 4 Clarithromycin susceptible with an MIC of less than 0.25, Azithromycin susceptible with an MIC of less than 16 Linezolid intermediate with an MIC of 8 Tigecycline susceptible with an MIC of less than 0.25 Clofazimine susceptible with an MIC of less than 0.05

51 Question 3: What is your initial treatment regimen? A. Clarithromycin, Moxifloxacin, Imipenem and Amikacin B. Azithromycin, Imipenem, Clofazimine and Amikacin C. Moxifloxacin, Clofazimine, Cefoxitin and Amikacin D. Clarithromycin, Tigecycline, and Cefoxitin

52 Clinical Course Chest wall catheter placed 3 Drug therapy initiated Imipenem Transitioned to cefoxitin in the setting of fever IV amikacin developed tinnitus and hearing loss, transitioned to inhaled amikacin roughly 4 weeks into IV therapy Azithromycin Clofazimine added when received by the patient 12 weeks of IV therapy prior to lingulectomy

53 Clinical Course Culture negative by April 2015 Lingulectomy 4/30/2015 (Uncomplicated) Right Upper and Middle Lobe Lobectomy 7/28/16 (intraoperative culture positive for 10 colonies of M. abscessus Post operative course complicated by a wound infection (Right) Suspected secondary to M. abscessus, although serial wound cultures negative Wound completely healed 6 months later (managed by a wound care specialist) Follow up CT Chest 8/2016 stable Sputum specimens negative since November 2015

54 8/2016

55 Adjuvant Surgical Resection for NTM Lung Disease Treatment success rates for medical therapy alone: 45-50% MAC, 25-30% M. abscessus Disease localized to one lung or localized disease Ability to tolerate surgery Appropriate pre and post operative antimicrobial therapy Segmentectomy, lobectomy, bilobectomy, pneumonectomy Jarand, et al. CID, 2011

56 Indications for Pulmonary Resection Poor response to medical therapy/treatment failure Limit progression of disease Persistent cavitary lesions Severe focal bronchiectasis Massive hemoptysis/other complications Relief of symptoms Intractable cough Severe and/or recurrent hemoptysis

57 Patient Outcomes Review of outcomes in patients with M. abscessus who underwent adjunctive surgical resection 107 patients over 7 years Comparison of patients on medical therapy versus medical therapy + surgical treatment More surgical than medical patients converted to culture negative and remained so at a year Jarand et al. CID, 2011

58 References Honda JR, Knight V, Chan ED. Pathogenesis and Risk Factors for Nontuberculous Mycobacterial Lung Disease. Clin Chest Med 36 (2015) 1-11 Winthrop KL, McNelley E, Kendall B et al. Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease. Am J Respir Crit Care Med 2010; 182: Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175: Patel SY, Brown M et al. Anti-IFN-gamma autoantibodies in Disseminated Nontuberculous Mycobacterial Infections. J Immunol 2005; 175: Lai CC, Lee LN, et al. Emergence of disseminated infections due to nontuberculous mycobacteria in non-hiv infection patients, including immunocompetent and immunocompromised patients in a university hospital in Taiwan. J Infect Aug; 53(2):77-84 Jarand J, Levin A, Zhang L, Huitt G, Mitchell J, Daley C. Clinical and Microbiologic Outcomes in Patients Receiving Treatment for Mycobacterium abscessus Pulmonary Disease. CID 2011;52: