Pneumocystis jirovecii in solid organ transplant recipients: updates in epidemiology, diagnosis, treatment, and prevention.

PURPOSE OF REVIEW: This review highlights the epidemiology of Pneumocystis jirovecii pneumonia in solid organ transplant recipients, advancements in the diagnostic landscape, and updates in treatment and prevention. RECENT FINDINGS: The increasing use of immune-depleting agents in the context of solid organ transplantation has given rise to P. jirovecii pneumonia in this population. The use of prophylaxis has dramatically reduced risk of infection; however, late-onset infections occur after cessation of prophylaxis and in the setting of lymphopenia, advancing patient age, acute allograft rejection, and cytomegalovirus infection. Diagnosis requires respiratory specimens, with PCR detection of Pneumocystis replacing traditional staining methods. Quantitative PCR may be a useful adjunct to differentiate between infection and colonization. Metagenomic next-generation sequencing is gaining attention as a noninvasive diagnostic tool. Trimethoprim-sulfamethoxazole remains the drug of choice for treatment and prevention of Pneumocystis pneumonia. Novel antifungal agents are under investigation. SUMMARY: P. jirovecii is a fungal opportunistic pathogen that remains a cause of significant morbidity and mortality in solid organ transplant recipients. Early detection and timely treatment remain the pillars of management.

Association Between Clostridium innocuum and Antibiotic-Associated Diarrhea in Adults and Children: A Cross-sectional Study and Comparative Genomics Analysis.

BACKGROUND: A recent study from Taiwan suggested that Clostridium innocuum may be an unrecognized cause of antibiotic-associated diarrhea (AAD) and clinically indistinguishable from Clostridioides difficile infection. Our objective was to compare C. innocuum prevalence and strain between those with AAD and asymptomatic controls. METHODS: In this cross-sectional study, we collected stool from 200 individuals with AAD and 100 asymptomatic controls. We evaluated the association between AAD and C. innocuum in stool using anaerobic culture and quantitative polymerase chain reaction (qPCR). To identify strain-specific associations with AAD, we performed whole-genome sequencing of C. innocuum isolates using Illumina MiSeq and constructed comparative genomics analyses. RESULTS: C. innocuum was isolated from stool of 126/300 (42%) subjects and more frequently from asymptomatic controls than AAD subjects (50/100 [50%] vs 76/200 [38%], respectively; P = .047). C. innocuum isolation frequency was not associated with AAD in either the adult or pediatric subgroups. C. innocuum and C. difficile were frequently co-prevalent in individuals with and without diarrhea. There were no phylogenetic differences or accessory genome associations between C. innocuum isolates from AAD subjects and asymptomatic controls. CONCLUSIONS: C. innocuum was frequently isolated and at a greater frequency in asymptomatic controls than those with AAD. We did not identify strain lineages or accessory genomic elements associated with AAD. These data highlight that differentiating C. innocuum-associated diarrhea from asymptomatic colonization, and differentiating diarrhea caused by C. difficile from C. innocuum, are clinical microbiology challenges that require additional investigation to identify host-specific factors and/or biomarkers that distinguish these conditions.

Real-World Experience of Bamlanivimab for Coronavirus Disease 2019 (COVID-19): A Case-Control Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has strained healthcare systems with patient hospitalizations and deaths. Anti-spike monoclonal antibodies, including bamlanivimab, have demonstrated reduction in hospitalization rates in clinical trials, yet real-world evidence is lacking. METHODS: We conducted a retrospective case-control study across a single healthcare system of nonhospitalized patients, age 18 years or older, with documented positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, risk factors for severe COVID-19, and referrals for bamlanivimab via emergency use authorization. Cases were defined as patients who received bamlanivimab; contemporary controls had a referral order placed but did not receive bamlanivimab. The primary outcome was 30-day hospitalization rate from initial positive SARS-CoV-2 polymerase chain reaction (PCR). Descriptive statistics, including χ 2 and Mann-Whitney U test, were performed. Multivariable logistic regression was used for adjusted analysis to evaluate independent associations with 30-day hospitalization. RESULTS: Between 30 November 2020 and 19 January 2021, 218 patients received bamlanivimab (cases), and 185 were referred but did not receive drug (controls). Thirty-day hospitalization rate was significantly lower among patients who received bamlanivimab (7.3% vs 20.0%, risk ratio [RR] 0.37, 95% confidence interval [CI]: .21-.64, P < .001), and the number needed to treat was 8. On logistic regression, odds of hospitalization were increased in patients not receiving bamlanivimab and with a higher number of pre-specified comorbidities (odds ratio [OR] 4.19 ,95% CI: 1.31-2.16, P < .001; OR 1.68, 95% CI: 2.12-8.30, P < .001, respectively). CONCLUSIONS: Ambulatory patients with COVID-19 who received bamlanivimab had a lower 30-day hospitalization than control patients in real-world experience. We identified receipt of bamlanivimab and fewer comorbidities as protective factors against hospitalization.Bamlanivimab's role in preventing hospitalization associated with coronavirus disease 2019 (COVID-19) remains unclear. In a real-world, retrospective study of 403 high-risk, ambulatory patients with COVID-19, receipt of bamlanivimab compared to no monoclonal antibody therapy was associated with lower 30-day hospitalization.

Changes in Ascitic Fluid Polymorphonuclear Cell Count After Antibiotics Are Associated With Mortality in Spontaneous Bacterial Peritonitis.

Spontaneous bacterial peritonitis (SBP) is a feared complication of ascites that affects 10%-30% of hospitalized patients with cirrhosis with an associated mortality rate of approximately 20%.1-3 Although efforts have been undertaken to encourage prompt evaluation and treatment of SBP, outcomes have generally remained dismal.3 There is significant interest in identifying factors that can reliably predict mortality among individuals with SBP.

Disparities in COVID-19 Monoclonal Antibody Delivery: a Retrospective Cohort Study.

BACKGROUND: Disparities in access to anti-SARS-CoV-2 monoclonal antibodies have not been well characterized. OBJECTIVE: We sought to explore the impact of race/ethnicity as a social construct on monoclonal antibody delivery. DESIGN/PATIENTS: Following implementation of a centralized infusion program at a large academic healthcare system, we reviewed a random sample of high-risk ambulatory adult patients with COVID-19 referred for monoclonal antibody therapy. MAIN MEASURES: We examined the relationship between treatment delivery, race/ethnicity, and other demographics using descriptive statistics, binary logistic regression, and spatial analysis. KEY RESULTS: There was no significant difference in racial composition between patients who did (n = 25) and patients who did not (n = 378) decline treatment (p = 0.638). Of patients who did not decline treatment, 64.8% identified as White, 14.8% as Hispanic/Latinx, and 11.1% as Black. Only 44.6% of Hispanic/Latinx and 31.0% of Black patients received treatment compared to 64.1% of White patients (OR 0.45, 95% CI 0.25-0.81, p = 0.008, and OR 0.25, 95% CI 0.12-0.50, p < 0.001, respectively). In multivariable analysis including age, race, insurance status, non-English primary language, county Social Vulnerability Index, illness severity, and total number of comorbidities, associations between receiving treatment and Hispanic/Latinx or Black race were no longer statistically significant (AOR 1.32, 95% CI 0.69-2.53, p = 0.400, and AOR 1.34, 95% CI 0.64-2.80, p = 0.439, respectively). However, patients who were uninsured or whose primary language was not English were less likely to receive treatment (AOR 0.16, 95% CI 0.03-0.88, p = 0.035, and AOR 0.37, 95% CI 0.15-0.90, p = 0.028, respectively). Spatial analysis suggested decreased monoclonal antibody delivery to Cook County patients residing in socially vulnerable communities. CONCLUSIONS: High-risk ambulatory patients with COVID-19 who identified as Hispanic/Latinx or Black were less likely to receive monoclonal antibody therapy in univariate analysis, a finding not explained by patient refusal. Multivariable and spatial analyses suggested insurance status, language, and social vulnerability contributed to racial disparities.

Risk Factors Associated With Nephrotoxicity During Outpatient Intravenous Vancomycin Administration.

Background: Many studies have described an association between intravenous vancomycin and nephrotoxicity; however, the majority have evaluated incidence and risk factors among hospitalized patients. Outpatient administration of intravenous antibiotics is a growing practice and presents its own set of unique challenges. Objective: The aim of this study was to identify risk factors for vancomycin-associated nephrotoxicity in the outpatient setting. Methods: A case-control study of patients who received intravenous vancomycin through an Outpatient Parenteral Antimicrobial Therapy (OPAT) program was conducted. Patients were identified who developed an acute kidney injury (AKI) during treatment. The primary outcome was the incidence of AKI during treatment. Results: A total of 37 out of 130 patients (28.5%) met the criteria for AKI. AKI was more likely to occur in patients with a longer duration of therapy, higher maximum trough concentration, co-administration of a fluoroquinolone or metronidazole, and those who received another potentially nephrotoxic medication. Co-administration of a fluoroquinolone (OR = 5.96, P = 0.009, [CI: 1.59, 24.38]), any nephrotoxic medication (OR = 11.17, P < 0.001, [CI 3.14, 51.23]), and a higher maximum vancomycin trough (OR = 1.29, P < 0.001, [CI 1.17, 1.44]) were all indicative of a higher odds of an AKI. Conclusion: In this cohort, vancomycin-associated nephrotoxicity was common during outpatient intravenous antibiotic therapy. Co-administration of a fluoroquinolone, any nephrotoxic medication, and a higher maximum vancomycin trough were associated with AKI development. Further study is needed to determine how this impacts long-term clinical outcomes and what measures can be taken to reduce nephrotoxicity risk.

Kikuchi-Fujimoto disease presenting in a patient with SARS-CoV-2: a case report.

BACKGROUND: We present a yet to be described association of SARS-CoV-2 infection with Kikuchi-Fujimoto disease. CASE PRESENTATION: A 32-year-old physician with history of SARS-CoV-2 infection presented to the emergency department with 2 weeks of fever, chills, and right sided cervical lymphadenopathy. He was treated empirically for presumed folliculitis with worsening of symptoms leading to repeat presentation to the emergency department. Extensive workup was unrevealing of an infectious cause and needle biopsy of the lesion was unrevealing. An excisional lymph node biopsy revealed follicular hyperplasia with necrotic foci showing abundance of histiocytes at the edge of necrosis with CD8 predominance of T-cells. Final diagnosis was deemed to be Kikuchi-Fujimoto disease. Antibiotic therapy was discontinued, and the patient's symptoms resolved with steroid therapy and expectant management. CONCLUSIONS: This is the first report of a patient developing Kikuchi-Fujimoto disease following SARS-CoV-2 infection. Clinicians should be aware of Kikuchi-Fujimoto disease as a possibility when approaching patients with hyper-inflammatory states who present with cervical lymphadenopathy.

Newer approaches in diagnosis of diarrhea in immunocompromised patients.

PURPOSE OF REVIEW: This review will focus on the epidemiology and cause of diarrheal illness in solid organ transplant and stem-cell transplant population recipients with a specific focus on the role of advanced multiplex technology in the diagnosis of diarrhea within this patient population. RECENT FINDINGS: A wide range of infectious and noninfectious causes of diarrhea have been described in immunocompromised patients. The most common infections noted are Clostridioides difficile, norovirus, and cytomegalovirus, whereas immunosuppressive drugs and mucositis are the most common noninfectious causes of diarrhea. Historically, diagnostic evaluation has been limited to an array of single pathogen assays. Newer multiplex assays have become available that allow rapid, sensitive detection of a wide range of pathogens in a single assay. These assays have improved the number of patients with a diagnosed pathogen but may identify colonizing pathogens that are not pathogenic. Studies are needed to inform the discrimination and optimal use of these newer assays. SUMMARY: Diarrhea is a common complication in immunocompromised patients and is associated with greater morbidity and rare mortality. New diagnostics facilitate detection of recognized pathogens and may allow for improved outcomes through the use of pathogen-targeted therapy.

Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of diarrhea in the pre- and post-transplant period. Diarrhea in an organ transplant recipient may result in significant morbidity including dehydration, increased toxicity of medications, and rejection. Transplant recipients are affected by a wide range of etiologies of diarrhea with the most common causes being Clostridioides (formerly Clostridium) difficile infection, cytomegalovirus, and norovirus. Other bacterial, viral, and parasitic causes can result in diarrhea but are far less common. Further, noninfectious causes including medication toxicity, inflammatory bowel disease, post-transplant lymphoproliferative disease, and malignancy can also result in diarrhea in the transplant population. Management of diarrhea in this population is directed at the cause of the diarrhea, instituting therapy where appropriate and maintaining proper hydration. Identification of the cause to the diarrhea needs to be timely and focused.

Safety and efficacy of chronic suppressive azole therapy for endemic fungal infections in solid organ transplant recipients.

BACKGROUND: Although the research is limited, treatment guidelines recommend lifelong suppressive azole therapy for disseminated endemic fungal infection (EFI) after solid organ transplantation (SOT). Suppressive azole therapy may prevent EFI recurrence at the risk of hepatotoxicity and drug interactions. We present real-world safety and effectiveness data of chronic suppressive azole therapy for EFI in SOT recipients over a 10-year period at a single comprehensive transplant center. METHODS: A retrospective analysis was conducted of SOT recipients diagnosed with EFI from January 1, 2005, to May 1, 2015. Chronic suppressive azole therapy was defined as treatment for more than 12 months after diagnosis. Effectiveness of suppression was defined as preventing EFI reactivation. Safety endpoints included adverse reactions and drug interactions. RESULTS: Over a 10-year period, 28 SOT recipients were diagnosed with EFI: 16 histoplasmosis, 9 blastomycosis, and 3 coccidioidomycosis. Eighteen (64%) patients were treated with chronic suppressive azole therapy for a median length of 36 months (range 15-90). One patient had an adverse drug interaction requiring azole discontinuation. There were no episodes of azole-related hepatotoxicity, toxicity from antirejection medication, or EFI reactivation. CONCLUSIONS: Chronic suppressive azole therapy was safe and effective in preventing reactivation of EFI in SOT recipients.

Cytomegalovirus infection in heart transplantation: A single center experience.

BACKGROUND: Cytomegalovirus (CMV) infection remains a major complication after heart transplantation with varying prophylaxis strategies employed. We sought to determine the impact of valganciclovir (VGC) duration on the epidemiology of CMV infections after heart transplantation. METHODS: We performed a prospective cohort study of CMV donor (D) or recipient (R) seropositive heart transplant recipients from 2005 to 2012 who completed VGC prophylaxis, ranging from 3 to 12 months according to serostatus and induction immunosuppression. Univariate and multivariate logistic regression was performed. RESULTS: Among 159 heart transplant recipients during the study period, 130 (82%) were eligible for VGC prophylaxis. CMV D/R serostatus was as follows: 24% D+/R-, 30% D+/R+, and 29% D-/R+. 65% and 21% received basiliximab and thymoglobulin induction, respectively, followed by maintenance tacrolimus, mycophenolate mofetil, and prednisone. Twenty-one (16%) recipients suffered CMV infection. There was no association with comorbidities including diabetes mellitus, chronic kidney disease, or mechanical assist devices, nor were there associations with rejection, treatments of rejection, or mortality. When VGC prophylaxis duration was stratified by ≤6 vs ≥12 months, time from heart transplantation to CMV infection was delayed (median 247 vs 452 days, P = .002) but there was no difference in days from VGC discontinuation to onset of CMV infection (median 72 vs 83 days, P = .31). CMV infection occurred most frequently within 6-16 weeks of VGC cessation, and 95% of infections occurred during the 6 months post-prophylaxis period. CONCLUSIONS: Relative to ≤6 months, ≥12 months of VGC did not reduce incidence of CMV infection and only delayed time to onset. 95% of CMV infection occurs within 6 months after cessation of VGC.

Purpureocillium lilacinum tattoo-related skin infection in a kidney transplant recipient.

Purpureocillium lilacinum is an emerging pathogenic mold among immunocompromised hosts that causes cutaneous infections related to skin breakdown. We present the first reported case of P. lilacinum tattoo-related skin infection, to our knowledge. A kidney transplant recipient recently treated for acute cellular rejection presented with skin papules overlying a tattoo. Diagnosis was confirmed on culture, histology, and 18S ribosomal RNA polymerase chain reaction. The morphological features on culture characteristic of P. lilacinum included violet colonies on malt extract agar, long tapering brush-like phialides, and elliptical conidia attached in chains. P. lilacinum has intrinsic resistance to many antifungal agents including amphotericin B, but voriconazole and posaconazole have good in vitro activity. The patient was treated with voriconazole with subsequent resolution of the papules after 3 months of therapy.

Optimal strategies for the diagnosis of community-onset diarrhea in solid organ transplant recipients: Less is more.

BACKGROUND: Diarrhea, a common complication after solid organ transplant (SOT), is associated with allograft failure and death. No evidence-based guidelines exist for the evaluation of diarrhea in SOT recipients. We performed a cost analysis to derive a testing algorithm for the diagnosis of community-onset diarrhea that minimizes costs without compromising diagnostic yields. DESIGN: A cost analysis was performed on a retrospective cohort of 422 SOT admissions for community-onset diarrhea over an 18-month period. A stepwise testing model was applied on a population level to assess test costs relative to diagnostic yields. RESULTS: Over an 18-month period, 1564 diagnostic tests were performed and 127 (8.1%) returned positive. Diagnostic testing accounted for $95 625 of hospital costs. The tests with the lowest cost per decrease in the false-omission rate (FOR) were stool Clostridium difficile polymerase chain reaction (PCR) ($156), serum cytomegalovirus quantitative PCR ($1529), stool norovirus (NV) PCR ($4673), and stool culture ($6804). A time-to-event analysis found no significant difference in the length of hospital stay between patients with and without NV testing (P=.520). CONCLUSIONS: A stepwise testing strategy can reduce costs without compromising diagnostic yields. In the first-stage testing, we recommend assessment for C. difficile, cytomegalovirus, and food-borne bacterial pathogens. For persistent diarrheal episodes, second-stage evaluation should include stool NV PCR, Giardia/Cryptosporidium enzyme immunoassay, stool ova and parasite, reductions in immunosuppressive therapy, and possibly endoscopy. Although NV testing had a relatively low cost per FOR, we recommend NV testing during second-stage evaluation, as an NV diagnosis may not lead to changes in clinical management or further reductions in length of hospital stay.

Invasive fungal infection after heart transplantation: A 7-year, single-center experience.

BACKGROUND: Invasive fungal infections (IFIs) are an infrequent but major complication of heart transplantation (HT). We sought to describe the epidemiology at our institution. METHODS: A prospective cohort study of 159 heart transplant recipients was performed from June 2005 to December 2012. IFIs were defined by European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: By univariate analysis, Hispanic ethnicity was associated with IFI (P=.01, odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7-27.9). Subsequently, a multivariate logistic regression was performed adjusting for Hispanic ethnicity, age, and gender. Seventeen IFIs were identified, occurring at a median 110 days post HT (interquartile range: 32-411 days). Five IFIs (29% of IFIs and 3.1% of all HT) occurred during the HT hospitalization, with 13 IFIs during the first year (incidence 8.2%). CONCLUSIONS: The cumulative incidence was 10.7%. IFIs were associated with pre- and post-HT vancomycin-resistant Enterococcus colonization and/or infection, post-HT renal replacement therapy, anti-thymocyte globulin induction, and antibody-mediated rejection. There were no associations with diabetes mellitus, desensitization, 2R/3R cellular rejection, treatments for rejection, re-operation, neutropenia, or cytomegalovirus infection. IFIs were associated with death (P=.02, OR 3.9, 95% CI 1.3-12.1) and 1-year mortality (P<.001, OR 9.0, 95% CI 2.3-35.7), but not 3-year mortality. Associations with Hispanic ethnicity must be validated. Optimal strategies for risk reduction and prophylaxis remain undefined.

Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

Infectious diseases are important causes of morbidity and mortality in patients with cancer. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This portion of the guidelines highlights the sections on antifungal and antiviral prophylaxis. Antifungal and antiviral prophylaxis recommendations have expanded over the past few years. New agents for the treatment of fungal infections and incorporation of therapeutic drug monitoring are presented. Antiviral prophylaxis for hepatitis B and management considerations for hepatitis C and HIV have been further developed.

Diagnostic yields in solid organ transplant recipients admitted with diarrhea.

BACKGROUND: Although diarrhea is a frequent complaint among solid organ transplant recipients, the contribution of infectious etiologies remains incompletely defined. We sought to define the etiologies of diarrhea and the yields of testing at our institution. METHODS: We performed a retrospective analysis over an 18-month period of hospitalized solid organ transplant recipients. We stratified diarrhea by community onset vs hospital onset of diarrhea. RESULTS: We identified 422 admissions (representing 314 unique patients) with community-onset diarrhea, and 112 admissions (representing 102 unique patients) with hospital-onset diarrhea. The majority of community- and hospital-onset diarrheal episodes had no identified etiology (60.9% and 75.9%, respectively; P = .03), yet were also self-limited (91% and 91%, respectively; P = .894). Thereafter, the most frequently encountered infectious etiologies were Clostridium difficile infection (13.3% and 11.8%, respectively), norovirus enteritis (8.2% and 3%), cytomegalovirus disease or colitis (6.3% and 2.7%), and bacterial enterocolitis (0.9% and 0%) (P = .03). In aggregate, these entities represented 93.7% and 90.5% of the identified infectious etiologies, respectively. Protozoan causes were rarely seen. Coinfection, or the simultaneous detection of ≥2 pathogens, occurred in 8 (1.9%) and 2 (1.8%) community- and hospital-onset diarrheal admissions, respectively (P = .99). CONCLUSIONS: In solid organ transplant recipients who presented at our institution with diarrhea, approximately one-third had infectious etiologies identified, consisting predominantly of C. difficile, norovirus, cytomegalovirus, and bacterial enterocolitis. Other infectious etiologies were rare.