NTM Lecture Series. Challenging Cases: Part 1. Property of Presenter

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1 NTM Lecture Series Challenging Cases: Part 1 Dr. Wendi Kay Drummond DO, MPH Assistant Professor of Medicine Division of Mycobacterial and Infectious Diseases Department of Medicine September 27, 2018

2 Disclosures No relevant financial disclosures to report.

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: Outpatient clinic evaluation 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. No significant PMH or pertinent exposures other than sauna use at the gym

5 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.

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

7 Pathology, Lymph Node Biopsy: Nonnecrotizing granulomas, negative stains 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.

8 Pathology: Lung Biopsy, granulomatous inflammation, stains negative 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.

9 Clinical Course: Started on treatment for sarcoidosis with steroids 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, developed night sweats, abdominal pain and bilateral hip pain Admitted to a local hospital on 1/30/14 with worsening productive cough, progressive shortness of breath, fevers (Tmax 39) Hospitalized from 1/30/14-7/24/14

10 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) He developed bone pain in his upper and lower extremities with abnormal imaging suggestive of osteomyelitis and persistent fevers.

11 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)

12 Therapeutics Once MAC was diagnosed, he was started on therapy with azithromycin, rifampin, ethambutol M/W/F, transitioned to daily therapy one month later Amikacin (IV) added 1 month later He was discharged on oral azithromycin, rifampin, ethambutol, and ciprofloxacin

13 Past Medical History Disseminated Mycobacterium 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

14 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. IFN gamma auto-antibody: PRESENT

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16 Disseminated NTM Infections Occurs most in immunocompromised hosts Uncommon in persons not infected with the human immunodeficiency virus (HIV) Tumor necrosis factoralpha antagonists (TNFa) Organ transplant recipients Untreated AIDS Mendelian Susceptibility to Mycobacterial Diseases (MSMD) MAC is the most common cause of disseminated NTM The respiratory and GI tracts are the usual portal of entry for dissemination Bacteremia

17 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 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

18 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)

19 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.

20 Auto-antibodies against IFN-γ Anti-cytokine autoantibodies are increasingly recognized as having a role in disease pathogenesis IgG antibodies that inhibit IFN gamma 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.

21 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

22 Case 2: Mycobacterium abscessus pulmonary infection 65 year old female with a history of ulcerative colitis s/p total proctocolectomy with ileostomy (1989); breast cancer, s/p lumpectomy, chemotherapy and radiation therapy to the right lung (upper chest) 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

23 Case 2: Diagnosed with cavitary disease : 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

24 Case 2: Progression of cavitary disease 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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26 Case 2: ADU Evaluation Bronchiectasis likely due to ulcerative colitis +/- reflux and aspiration; radiation pneumonitis in right lung Surgical evaluation: Recommendations for right upper lobe (RUL) and right middle lobe (RML) lobectomy and lingulectomy based on local disease, complicated cavitary disease

27 12/2014

28 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

29 Management of side effects 3 Drug therapy initiated Imipenem developed fever and elevated LFTs IV amikacin developed tinnitus and hearing loss 4 weeks into therapy Azithromycin Clofazimine added when received by the patient 12 weeks of IV therapy prior to lingulectomy

30 Post operative course 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)

31 8/2016

32 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

33 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

34 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

35 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: