Goals of This Review Testable Concepts Fundamentals: Host

41a –Infections in the Neutropenic Cancer Patient and Hematopoietic Stem Cell Recipients Speaker: Kieren Marr, MD

Disclosures of Financial Relationships with Relevant Commercial Interests

• Consultant – Amplyx, Cidara, Merck and Company, Infections in the Neutropenic Cancer Patient and Sfunga Therapeutics Hematopoietic Stem Cell Recipients • Ownership Interests – MycoMed Technologies Kieren Marr, MD Professor of Medicine and Oncology John Hopkins University School of Medicine Director, Transplant and Oncology Infectious Diseases John Hopkins University School of Medicine

Goals of This Review Testable Concepts

• Immune compromised people develop “typical” • Think about the patient infections and those specific to their underlying risks – How does underlying disease impact risks? • Focus here on testable complications specific to the • Think about the treatment received host – What type of immune suppression? – Types of immune – suppressing drugs and diseases • Think about infections breaking through preventative – Recognition of specific “neutropenic syndromes” therapies • Skin lesions – A good context to test resistance and differentials • Invasive fungal infections • Think about common non‐infectious syndromes • Neutropenic colitis

Fundamentals: Host Immune Risks Classic Immunologic risks • Immune defects associated with underlying • Neutropenia malignancy (and prior therapies) – Prolonged (>10 days) and profound (< 500 cells / mm3) – AML and myelodysplastic syndromes (MDS) associated with high risks for severe bacterial and fungal • Qualitative and quantitative neutropenia infections – Lymphoma • Bacteremia, pneumonia, candidemia, aspergillosis • Functional asplenia • Infectious risks associated with biologics –or medical – CLL and multiple myeloma immune suppression • Hypogammaglobulinemia – Aplastic anemia • Severe, prolonged neutropenia

Immune modulating anti‐cancer drugs Bendamustine

• Nitrogen‐based alkylating and • Drugs that impact neutrophils antimetabolite – Many cytotoxic agents • Indolent non‐Hodgkins • Bacterial infections, fungal infections lymphomas, CLL • Drugs that impact T cells • Neutropenia and lymphopenia (months ‐ years) – Purine analogs (fludaribine, cladribine, clofarabine) and • Higher risks for infections temozolomide (bacterial, CMV, PJP, • CD4+ T cell dysfunction: Herpes viruses histoplasmosis) (CMV, VZV), intracellular bacteria, fungi (PJP, Aspergillus)

Fung et al. Clin Infect Dis 68(2): 247-55

Biological Therapies For a more robust review • Series of articles by • Generally broken into three categories European Study Group for Infections – Biological response modifiers. Exert effects in Compromised Hosts (Supplement by stimulating immune system (ex. CSFs) in Clin Microbiol and Infect 24, 2018) – Gene therapies – Targeted therapies (mAbs and small molecule enzyme inhibitors)

Key anti‐CD Monoclonal Abs Tyrosine kinase inhibitors • Common antibodies that impact B and T cells • – Rituximab (anti‐CD20) BCR –ABL Tyrosine –kinase inhibitors • B cells: CLL, lymphoma – Inhibit signal transduction through BCR‐ABL • Loss of vaccine responses, responses to encapsulated oncogene (ex. imatinib, dasatinib, nilotinib) bacteria (pneumonia). Hepatitis B reactivation, PML • CML. Think T and B cells (VZV, Hep B reactivation) – Alemtuzimab (anti‐CD52) • Aspergillosis and other IFI • T and B cell depletion for a long time (about 6 months): lymphoma, leukemia, BMT (graft vs. host disease treatment) • Autoimmune pneumonitis and colitis (infection • Herpes viruses (esp. CMV), fungal infections (PJP, Aspergillus) mimic)

Bruton’s tyrosine kinase inhibitors Checkpoint inhibitors

• Ibrutinib • Block immune checkpoints that regulate T • B cell development, macrophage cell activation / function – multiple tumors phagocytosis • Targeting PD‐1 on T cells (pembrolizumab, • Lymphoid malignancies nivolumab, cemiplimab) or PD‐L1 on (ex. CLL, lymphomas) tumor cells (atezolizumab, avelumab, durvalumab) • Single‐center review: 11% • Targeting CTLA‐4 on T cells (ipilumumab) • Fungal, bacterial infections • Induce colitis, pneumonitis Soularue et al. BMJ gut 2018 – Aspergillosis (including CNS) • Increased risks for infection in people • Autoimmune – idiopathic drug receiving concurrent steroids, TNF‐ Varughese et al. Clin Infect Dis 2018; 67(5): 687-92 targeting agents for above “toxicities”: colitis, pneumonitis Bercusson A. Blood 2018 132(18): 1985-88 Blez et al. Haematologica 2019 (in press)

Notes about fever during neutropenia • Develop a differential based on preventative drugs already in use and other syndromes (pneumonia, colitis) Neutropenic “syndromes” • Broad coverage, examination, cultures • Inpatient – outpatient management guidelines, but not testable in this setting • Duration of therapy is controversial – Cochran Database review 2019: could not make any strong conclusions regarding efficacy, safety of short vs. long course antibiotic therapy

Stern et al. CDSR 2019

Question #1 Viridans Streptococci

35 year old woman with AML day 15 after induction therapy. • Key points: neutropenia, mucositis, high‐dose cytosine Fever, chills, diffuse erythematous rash. Blood culture + GPC in chains arabinoside, fluoroquinolone Exam – 100/62, HR 120, grade 2 oral mucositis, and a diffuse, blanching, erythematous • Can present with fever, flushing, chills, stomatitis, pharyngitis rash. CXR ‐ bilateral diffuse infiltrates. She is receiving levofloxacin and acyclovir. • VGS shock syndrome: This is most consistent with infection with which of the following organisms? – After 24‐48 hours, hypotension in 1/3 of cases – Rash, shock, ARDS in 1/4 of cases (similar to toxic shock) A. Streptococcus pneumoniae • Endocarditis unusual (<10%) B. Coagulase‐negative Staphylococcus • S. mitis, S. oralis C. Enterococcus faecalis • Vancomycin D. Streptococcus mitis • Mortality high (15‐20%) E. Stomatococcus mucilaginosus

Testable contexts: Breakthrough Bloodstream Infections Question #2

• Typical patient‐ neutropenic, progressive sepsis 59 year old woman with AML with neutropenia for 25 days. She has been febrile for 6 days, and is • Recognize holes in protection, specific syndromes receiving meropenem, vancomycin, and acyclovir. – ARDS, rash, quinolones, mucositis  viridans Streptococci New skin lesions that are small, papular, and tender, with no central ulceration. – Sepsis with β‐lactams  Stenotrophomonas, ESBL A. Rhizopus spp. – Sepsis with carbepenems  KPC B. Varicella zoster virus – Lung and skin lesions  P. aeruginosa, Fungi C. Cryptococcus neoformans – Skin lesions, gram +  Corynebacterium jeikeium D. Vancomycin resistant Enterococci – Mucositis (upper, lower tract)  Fusobacterium spp., E. Candida tropicalis Clostridium spp., Stomatococcus mucilaginosis

Fungal Infections Question #3 • Candida infections – Frequent in patients not receiving prophylactic antifungals 43 yr old F with AML with fever, cough and • C. albicans, C. tropicalis nodular lung lesions 20 days after induction therapy. On meropenem, fluconazole, acyclovir. • Mucositis, colonization, neutropenia Voriconazole begun for presumed aspergillosis. CT • Acquired through GI tract or catheter scan 10 days later showed lesion doubled in size • Organisms in patients receiving azole prophylaxis with slight cavitation. ANC has risen from 25 to 800. Clinically she is improving. – C. glabrata, C. krusei A. Change voriconazole to liposomal – C. parapsilosis amphotericin B » catheter / intravenous infusates B. Change voriconazole to posaconazole • Mold infections C. Continue to follow on current therapy – Aspergillus fumigatus most common D. Add micafungin E. Bronchoscopy for diagnosis – Risk increases with duration of neutropenia or prior neutropenic episodes

Pulmonary fungal infections Skin Lesions • Candidiasis – Small, tender papules • Herpes • Aspergillus species most common – vesicular • Nodular, tracheobronchial abnormalities (sometimes • Aspergillus with ‘halo’) that enlarge before necrotizing – ulcerative, necrotic • Other filamentous fungi • Alternative microbial diagnosis (Fusarium, P. boydii) – Fusarium, Scedosporium, others – Multiple, erythematous, different – Mucormycoses stages • P. aeruginosa – Ecthyma gangrenosum

Fusarium Question #4

50‐year‐old woman with newly diagnosed • Invasive pulmonary AML developed tender, pruritic papules and plaques on her neck. She had been febrile disease with skin lesions 38.7°C for the past several days and had received a dose of G‐CSF 3 days earlier, with • Locally invasive infections rapid WBC increase (900 ANC). Most likely etiology: in neutropenic patients A. Candida albicans B. Sweet’s syndrome – Keratitis C. Aspergillus niger D. Varicella Zoster Virus – Onychomycosis E. Pseudomonas aeruginosa

Haverstock, C. et al. Arch Dermatol 2006;142:235-b-240-b.

Question #5 Neutropenic Enterocolitis • Neutropenic enterocolitis (typhlitis) 70 yr old woman with AML, neutropenic for 15 days, s/p induction chemotherapy develops fever, – Necrotizing inflammation with transmural diarrhea, and abdominal pain. Exam ‐ decreased bowel sounds and tenderness with deep palpation in her RLQ. CT shows inflammation in cecum. Levofloxacin and fluconazole prophylaxis. infection of damaged bowel wall 4 days prior to her admission for chemotherapy, she ate Chinese food with fried rice. – Mixed infection with gram‐negative, gram‐ Which is the most likely etiology? positive, anaerobic bacteria, fungi A. Norovirus – Can be accompanied by bacteremia B. Clostridioides (Clostridium) difficile • Hint: mixed, anaerobic C. Mixed anaerobic and aerobic bacteria (C. septicum, C. tertium, B. cereus) D. Candida albicans – Medical and (less often) E. Bacillus cereus surgical management

GI Infections Hepatosplenic Candidiasis • Diarrhea is a common complaint • Inflammatory response to fungi invaded by portal vasculature – Mucositis from cytotoxic therapy • Presentation after engraftment: abdominal – Tips for infections pain, increased LFTs (alk phosph), fever, leg / • Bloody, fever, abdominal pain flank pain • Colitis / enteritis • Differential: other fungi, bacteria, lymphoma – Neutropenic enterocolitis • C. albicans most common – C. difficile colitis – Amphotericin B primary therapy followed by prolonged fluconazole, echinocandins

Summary: PEARLS Thank you • Recognize typical infections associated with neutropenia and/or other immune suppression (biologic inhibitors of cellular defenses) • Predict breakthrough bloodstream pathogens based on therapy • Know specific syndromes – S. viridans sepsis –ARDS – Differential of skin lesions [email protected] – Neutropenic patients ‐ IFI • Pulmonary • Bloodstream • Hepatosplenic candidiasis – GI tract enterocolitis