Infections in Stem Cell Transplants

Infections in Stem Cell Transplants March 30, 2007 Outline • Overview of SCT • General features of selected infections – Bacterial infections – Fungal infections • Candida • Aspergillus – Viral infections • Herpes viruses • Respiratory viruses • Other—HHV6, adenovirus, BK – Other infection complications: • CAMPATH (B/T cell depletion) increased association with EBV-related PTLD Important aspects of SCT • Conditioning therapy: – myeloablative vs. non-myeloablative (GVHD encouraged, less neutropenia, and infections predominate LATE) – mucosal damage; risk of bacteremia – XRT effects: single dose (increased risk of pancreatitis, parotitis) vs. fractionated; virtually all develop diarrhea; severe mucositis • • Infusion of stem cells: autologous vs. allogeneic (HLA match important); increased risk of GVHD with allogeneic and longer engraftment/neutropenia Source of stem cells: peripheral blood (faster engraftment but more GVHD) vs. marrow vs. cord blood (longer engraftment but less GVHD) • Infection risks: – Periods of immune impairment • Neutropenia (early during engraftment) • T cell (late) • Hypogammaglobulinemia (early to late) – GVHD and therapy – Intravascular lines Pre-engraftment days 0-30 Neutropenic pathogens Gingivostomatitis Venoocclusive disease Post-engraftment days 30-100 Opportunistic infections CMV Adenovirus GVHD Late post-transplantation >100 days Herpes zoster Encapsulated organisms assoc with GVHD Figure 311-1 Phases of predictable opportunistic infections among HSCT recipients. Immune defects predisposing to infection are bordered by color (neutropenia = pink, lymphopenia = blue, and hypogammaglobulinemia = green). Barrier defects predisposing to infection are shaded in color (mucosa l breakdown = yellow, skin breakdown = silver). Contribution of defects to infections occurring with high incidence are designated by border color (for immune def ects) and/or shading (for barrier defects). (Adapted from Van Burik J-AH, Freifeld AG. Infection in the severely imunocompromised host. In: Abeloff MD, Armitage JO, Niederhuber JE, et al, eds. Clinical Oncology. 3rd ed. Philadelphia: Churchill Livingstone; 2004:942.) Downloaded from: Principles and Practice of Infectious Diseases (on 29 March 2007 11:05 AM) © 2007 Elsevier Non-infectious entities in SCT • • • • Hemorrhagic cystitis from cyclophosphamide XRT induced diarrhea ATG and fevers, chills, arthralgias Venooclusive disease—painful hepatomegaly, elevated LFTs; complicated by jaundice, ascites, MSOF; 5-10% mortality • GVHD—skin, GI tract, lungs • Pneumonitis/diffuse alveolar hemorrhage from drugs, XRT, GVHD Bacterial infections • Mucositis related-early after BMT • • Neutropenia: ANC <500; risk dependent on severity and duration of neutropenia Sites of infection in neutropenic fever: – – – – – – – Mouth/pharynx Respiratory tract Skin/soft tissue Perineal region Urinary tract Sinuses GI tract 25% 25% 15% 10% 5% 5% 5% Neutropenic enterocolitis (Typhlitis) • Fever, RLQ tenderness, diarrhea, bleeding • Polymicrobial including Pseudomonas aeruginosa and Clostridium septicum • CT: cecal inflammation, bowel wall thickening, mesenteric stranding, intraluminal air • Broad spectrum antibiotics, surgery in rare cases Specific bacterial pathogens in neutropenic host • In addition to the usual MRSA, VRE, VISA, Enteric flora, anaerobes: • • Corynebacterium jeikium– colonizes skin, catheter related bacteremia, vancomycin drug of choice Leuconostoc species—slow growing, fastidious gpc; IV catheter infections, colitis; Vancomycin resistant; susceptible to clinda, aminoglycosides, +/PCN Capnocytophaga species—gnr, colonizes oral cavity and vagina; bacteremia, meningitis; gliding growth of yellow colonies, requires CO 2 for growth; Resistant to PCN and aminoglycosides; sensitive to carbapenems, clinda, 3rd generation cephalosporins • • Rhodococcus equi—g+cb, present in soil/water; pneumonia, lung abscess, empyema, bacteremia; salmon pink colonies in 4-7days; treat with 2 abx (vanco, carbapenems, rifampin, aminoglycosides, tetracycline); PCN resistant Bacterial infections • Intravascular-catheter related – Throughout transplant, prolonged indwelling lines • Coagulase negative staph • Corynebacteria • Mycobacteria • Encapsulated organisms (GVHD and therapy) – Strep pneumo with severe, rapid sepsis • Others: nocardia (if not on bactrim prophylaxis) Fungal infections • Candida—endogenous or exogenous source; disseminated candidiasis as neutropenia resolves • Filamentous fungi – – – – Aspergillus Fusarium Zygomycetes Other moulds • PCP • Other endemic fungi – Coccidiomycosis, Histoplasmosis NOT COMMON Hepatosplenic Candidiasis • Typically does NOT present during neutropenia • Clinical presentation secondary to inflammatory response— granulomatous inflammation • After engraftment: ab pain, increased LFTs, fever, ?leg/flank pain • Differential: other fungi, bacteria, lymphoma • Radiographic changes may get worse before improving • C. albicans most common – AmphoB primary therapy followed by prolonged fluconazole Mucosal lesions • Candida, HSV, and cytotoxic drugs • Candidal lesions can be – Pseudomembranous or erythematous • Diagnosis by scraping and culture (shell vial, fungal) Antifungal resistance in Candida species Species C. guilliermondii Tolerant/resistant to Ampho B C. lusitaniae C. parapsilosis C. glabrata C. krusei C. tropicalis C. dubliniensis Ampho B Ampho B Fluconazole Fluconazole Fluconazole Fluconazole Invasive Aspergillosis • Increased over last decade • Occurs during neutropenia or later • Presentation: fever (can be blunted), cough, SOB, hemoptysis • Pneumonia, disseminated disease to skin, abdominal organs, CNS Aspergillosis Necrotic skin lesion CNS lesion Invasive pulmonary aspergillosis: Classic findings nodules and cavities Halo sign on chest CT Pneumocystis Pneumonia • Common late after BMT – Steroids, T cell depletion – Can occur earlier in patients who receive steroids in prior regimens Prophylaxis at least 6 months in patients with chronic GVHD – Twice weekly bactrim most effective – Dapsone, aerosolized pentamidine less effective Diagnosis later than with AIDS – Mortality >50% • • frothy eosinophillic honeycombed material filling alveolar space. (H&E stain) Viral infections • Almost ANY virus can cause severe illness in the immunocompromised host • Episodic infections Latent Virus CMV Seroprevalence 45-90% EBV HHV-6 HSV >90% >90% 50-90% • Latent infections that may reactivate • Reactivation occurs in seropositive patients vs. primary infection in seronegative (reduced with leukoreduced blood products-frequency of 2%) VZV BK >90% >90% Epidemiology of CMV • Infection common, disease less so (usually late) • Dependent on serostatus and prevention strategy • In patients without prevention: CMV infection Allogeneic SCT R+/D+orR-/D+ R-/DAutologous SCT R+ RCMV disease 70% 15-25% 3-5% 25-40% 3-5% 35-40% 10% 1-3% 5-7% 1-3% CMV Disease • • Viremia Pneumonia-indolent, dry cough, mild hypoxemia, fever with rapid progression to failure; interstitial pneumonitis • GI disease – Esophagitis, colitis • Encephalitis, retinitis—LESS FREQUENT CMV Prevention and Therapy • Prevention – Prophylaxis and early therapy • Induction GCV (bid) for 2 weeks then maintenance qd until day 100 • Valganciclovir safe and effective • Common complication is neutropenia; use GCSF with ANC <1000 • Therapy – Pneumonia • Ganciclovir + CMV-Ig or IVIG • Alternatives: foscarnet, cidofovir – GI • Ganciclovir HSV infection/reactivation • Reactivation is common – >70% in seropositive without prophylaxis • ACV now common for prophylaxis usually for 30 days • ACV resistance—a growing problem – Incidence 5-10% among allogeneic SCT – Increased with URD txp, GVHD, haploidentical txp – Decreased among patients treated with GCV for CMV – THERAPY: IV Foscarnet (concern for nephrotoxicity) VZV after HSCT • Reactivation may be accompanied by severe skin lesions, disseminated disease – Multidermatomal lesions – Encephalitis – Hepatitis—ab pain, transaminitis late after BMT – DIC – Can have disseminated disease WITHOUT skin lesions • Acyclovir prophylaxis effective in decreasing reactivation but at risk after discontinuation – VZV seropositive – Severe GVHD HHV-6 after SCT • HHV-6 seroprevalence >95% by age 2 – Early reactivation in 38-60% SCT recipients (mostly type B) – Clinical correlates: rash, BM suppression, delayed platelet engraftment, idiopathic pneumonitis • Best association with meningoencephalitis – Nonspecific presentation, primarily confusion – Autopsy with white matter edema and inflammation – Risk factors: URD, anti-T-cell immunotherapy • Diagnosis by CSF PCR • ACV-resistant • Treatment: ganciclovir, foscarnet, cidofovir West Nile Virus • Mosquito exposure rare among SCT • Several cases of WNV transmission via blood products • Diagnosis: serum/CSF IgM or PCR for WNV BK virus • Cause of hemorrhagic cystitis • Incidence in allogeneic >>> autologous – Cofactors: GVHD, steroids • Definitive diagnosis difficult as asymptomatic shedding common • Therapy: supportive, ? Cidofovir which is most active in vitro but renal toxicities Episodic Viral infections after SCT • Exposure determines risk • Time after SCT: no effect • Immunosuppression impacts severity of illness • Key: infection control practices can limit morbidity/mortality – Isolation procedures – Vaccination of HCW for flu – Symptomatic surveillance Virus RSV Attack rate 5-15% Parainfluenza Influenza Adenovirus 5-10% <5% <5% Rhinovirus/hMPV Measles <5% <1% RSV • Primary winter outbreaks • Up to 50% of SCT pts hospitalized with acute URI in winter • Nosocomially spread • Most present with URI, 50% progress to LRI • Treatment: Aerosolized ribavirin, ? IVIG • Early diagnosis CRUCIAL – 100% mortality if mechanical ventilation required Parainfluenza • Clinical presentation: – 87% URI only – 6% URI + LRI – 7% LRI alone • Progression to LRI more common in steroid treated patients • Copathogens in 50%, most commonly Aspergillus Influenza • Influenza A>B • URI symptoms; myalgia and malaise rare – Pneumonia in 50% • Prevention: vaccination of family, HCW; chemoprophylaxis during outbreaks • Treatment: indicated despite lack of controlled trials with neuraminidase inhibitors (zanamavir, oseltamavir) Adenovirus after SCT • More common in children • Causes enteritis, cystitis, URI, pneumonia, encephalitis, hepatitis – Poor prognosis associated with immunosuppression and lymphopenia, detection of adenovirus at >1 site, or viremia • No controlled treatment studies – Taper immunosuppression – Cidofovir most active in vitro – Ribavirin not effective in larger studies EBV • Risk for EBV-induced lymphoproliferative disease associated with T cell deficiency • Incidence post BMT high to low: – – – – T cell depleted BMT MURD + ATG (24%) T cell depleted BMT with anti-T cell ab (25%) Unmod BMT with anti-T cell ab (15%) T cell depleted BMT (5-12%) • Fever in 50%, localized cervical LAD • Less common: disseminated LAD • Treatment: wean immunosuppression, ?IFN-alpha vs. XRT vs. anti-B cell ab vs. rituximab Parasitic infections • Toxoplasmosis – Almost always reactivation and not primary infection – Occurs in 2-7% in those who are seropositive – Clinical manifestations: fever, encephalitis, pneumonitis, myocarditis An ounce of prevention for SCT patients… • Avoid sick people, kitty litter, sandboxes, reptiles. • Wash hands frequently. • Consider wearing a mask in crowded situations during. • Get immunized. Immunization recommendations for SCT • Immunity to common childhood diseases frequently lost. • Tetanus-diphtheria q10 years • At 12 months – – – – -inactivated polio H. influenza Hepatitis B (only one booster if completed prior series) Strep pneumo • At 24 months—2nd dose of Strep pneumo optional, especially in chronic GVHD • Lifelong, seasonal influenza vaccination and for household contacts • Live viruses, e.g. MMR and varicella should not be given if active GVHD or ongoing immunosuppression • HepA for those with chronic liver disease or in endemic areas Question 1 • • • • 42yo M s/p MURD SCT Day 28: skin GVHD – 1 mg/kg steroids • Day 35: +CMV antigen test; IV GCV 5mg/kg bid started Day 42: CMV Ag 0 and switched to PO Val-GCV; viral load rebounds while on maintenance What should you do: 1. 2. 3. 4. 5. Increase Val-GCV to bid Switch to IV GCV bid Switch to IV GCV qd Switch to IV foscarnet Maintain Val-GCV at current dose Answer • Rising VL occurs in 1/3 of patients on GCV – Drug resistance unusual • • • Rising VL associated with steroids for GVHD Antiviral dose is key – Continue IV induction; resistance may become issue LATE after SCT with previous GCV exposure Increase Val-GCV to bid Switch to IV GCV bid Switch to IV GCV qd Switch to IV foscarnet Maintain Val-GCV at current dose What should you do: 1. 2. 3. 4. 5. Question 2 • A 47yo male with lymphoma has been hospitalized for an allogeneic myeloablative stem cell transplant with a conditioning regimen of cyclophosphamide and total body irradiation. He is now 35 days post transplant, receiving cyclosporine, mycophenolate, bactrim, fluconazole, and acyclovir, and has received several courses of pulse steroids for GVHD. His WBC count is 3500. • Sixty days post txp, he developed gross hematuria with clots. His UA shows rare leukocytes, the nitrate test is negative, and his urine culture is negative for routine bacterial and fungal pathogens. • Cystoscopy shows diffuse hemorrhagic cystitis. Question 2 • Which is the most likely cause of hemorrhagic cystitis in this patient? • A. Cyclosporine • B. Herpesvirus type 2 • C. JC virus • D. Adenovirus • E. CMV ANSWER • Which is the most likely cause of hemorrhagic cystitis in this patient? • A. Cyclosporine • B. Herpesvirus type 2 • C. JC virus • D. Adenovirus • E. CMV Question 3 • Consultation was requested because of low-grade fever in an 18yo male from St. Louis, Missouri. He had successful remission induction for ALL with return to normal of peripheral neutrophil counts. He had become febrile while neutropenic. The fever had not responded to 5 days of ceftaz, but began to respond when amphoB was added and his neutrophil count began to rise. • Daily low grade temps of 38 began after he had been discharged on no therapy. Physical exam was unremarkable. Routine labs show a slight increase in alk phosph to 180 but no other abnormalities. • Which of the following procedures is most likely to assist with his diagnosis? Question 3 • • • • • A. B. C. D. E. CT of abdomen Bone marrow biopsy Urine histoplasma antigen Blood culture by lysis centrifugation Removal and culture of his Hickman ANSWER • • • • • A. B. C. D. E. CT of abdomen Bone marrow biopsy Urine histoplasma antigen Blood culture by lysis centrifugation Removal and culture of his Hickman Question 4 • A 63yo male underwent SCT for CML 120 days ago. He has had multiple episodes of GVHD. His ANC hovers between 750 and 1000. He has received multiple pulses of steroids as well as maintenance doses of cyclosporine. • The patient develops fever and patchy pulmonary infiltrates. He is intubated and undergoes bronchoscopy. Branched hyphae are present on wet mount of the BAL, and liposomal amphoB (5 mg/kg/day) is started. • 5 days later, the lab reports the culture is growing Pseudallescheria boydii (Scedosporium apiospermum). The patient is still febrile and the pulmonary status has deteriorated. • What should you do? Question 4 • A. Raise the dose of liposome ampho to 10 mg/kg/day • B. Switch to Bactrim • C. Switch to fluconazole • D. Switch to voriconazole • E. Switch to caspofungin Answer • A. Raise the dose of liposome ampho to 10 mg/kg/day • B. Switch to Bactrim • C. Switch to fluconazole • D. Switch to voriconazole • E. Switch to caspofungin Question 5 • 32yo WF 86 days s/p URD allogeneic PBSCT for AML in relapse develops fever to 39: – – – – – Conditioning with Cy/TBI. HSV+, CMV D-/R-, VZV+ Receiving acyclovir, fluconazole prophylaxis On prednisone taper (1mg/kg/day) for acute GVHD Pentamidine for PCP prophylaxis (allergy to bactrim) ROS: scratchy throat for 4 days, sinus congestion for 2 days, increasing headache – CXR clear Question 5 What is appropriate therapy at this time? A. Admit for sinus CT and empirical ampho B B. Admit under respiratory isolation, send nasal lavage for shell vial culture and DFA examination for respiratory viruses C. Admit, evaluate for respiratory viruses (as in B), blood culture, and start oseltamivir D. Admit, evaluate for respiratory viruses (as in B). Blood culture, and start imipenem empirically E. Admit, obtain blood for CMV antigenemia and start GCV empirically Answer What is appropriate therapy at this time? • Admit for sinus CT and empirical ampho B • Admit under respiratory isolation, send nasal lavage for shell vial culture and DFA examination for respiratory viruses • Admit, evaluate for respiratory viruses (as in B), blood culture, and start oseltamivir • Admit, evaluate for respiratory viruses (as in B). Blood culture, and start imipenem empirically • Admit, obtain blood for CMV antigenemia and start GCV empirically Late after BMT with GVHD; not on Bactrim so at risk for bactrim especially encapsulated; Signs and symptoms of respiratory virus infection so DFA and culture; reasonable risk for Aspergillosis; low risk for CMV; on prophylactic ACV so low risk for HSV/VZV Question 6 • 45yo M 110 days s/p HLA-matched PBSCT from unrelated donor presents with fever, abdominal pain, cough. • Post tx course complicated by severe GVHD requiring steroid pulse and taper (currently 1mg/kg/day) • Had C. glabrata candidemia day 28 treated with caspofungin • Currently on bactrim. • Pre-transplant serologies: – CMV D-/R-, HSV+, VZV+, toxo- Question 6 • Physical exam: Tm 38, no rash, crackles in both lung bases, tender abdomen in RUQ, no rebound • Labs: WBC 4900, AST 928, ALT 1200, total bili 1.4, alk phosph 110. • CXR with RLL atelectasis vs. basilar infiltrate. • What is most appropriate: – A. Restart caspofungin for hepatosplenic candidiasis and obtain blood culture – B. Start imipenem for acute cholecystitis, obtain RUQ US, and blood cultures – C. Obtain CT abdomen, start imipenem, caspofungin, and high dose ACV, admit to respiratory isolation – D. Obtain CT abdomen and call surgeons – E. None of the above Answer • Physical exam: Tm 38, no rash, crackles in both lung bases, tender abdomen in RUQ, no rebound • Labs: WBC 4900, AST 928, ALT 1200, total bili 1.4, alk phosph 110. • CXR with RLL atelectasis vs. basilar infiltrate. • What is most appropriate: – Restart caspofungin for hepatosplenic candidiasis and obtain blood culture – Start imipenem for acute cholecystitis, obtain RUQ US, and blood cultures – Obtain CT abdomen, start imipenem, caspofungin, and high dose ACV, admit to respiratory isolation – Obtain CT abdomen and call surgeons – None of the above Low risk for hepatosplenic candidiasis; Not on ACV and was VZV+; Post-engraftment High risk for disseminated VZV—do not need skin lesions