Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.

The Danish-American Research Exchange (DARE): a cross-sectional study of a binational research education program.

BACKGROUND: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'. METHODS: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software. RESULTS: DARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p < 0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network. CONCLUSIONS: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration.

Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially, so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer-causing strains. Organ transplant recipients should be screened for HPV-associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.

Organ donor screening practices for Strongyloides stercoralis infection among US organ procurement organizations.

BACKGROUND: Targeted donor screening for strongyloidiasis performed at the time of organ procurement can prevent this life-threatening donor-derived infection. METHOD: The Association of Organ Procurement Organizations surveyed members to determine the number of US organ procurement organizations (OPOs) performing donor screening for Strongyloides infection and their screening practices. RESULTS: All 58 OPOs responded to the survey. Only 6 (10%) currently screen donors for strongyloidiasis; most OPOs started 6-36 months before the survey and one started 6 years prior. All used risk-based criteria to determine which donors to screen, though the criteria varied among OPOs. A median of 56 donors have been screened at each OPO since initiating their screening programs, with a median of 2 infected donors (range 0-13) identified. Overall, 53 organs have been transplanted from 22 infected donors, including hearts, lungs, kidneys, and livers. Of 52 OPOs not currently screening, 20 had considered screening and one plans to start screening in the near future. Of those considering risk-based screening, most had not decided on the criteria. Uncertainty about the benefits of and guidelines for screening and misconceptions about the interpretation of test results were concerns shared by non-screening OPOs. CONCLUSION: Continued education and advocacy on the importance of targeted donor screening are needed.

Epstein-Barr Virus Neuroretinitis in a Lung Transplant Patient.

Epstein-Barr virus (EBV)-associated optic neuropathy is rare with few reported cases, mostly involving immunocompetent patients who developed optic nerve involvement after infectious mononucleosis. We describe a unique case of a patient who developed severe bilateral EBV neuroretinitis after solid organ transplant.

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Background: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit. Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events. Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%). Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.

Use of rifabutin for the treatment of a latent tuberculosis infection in a patient after solid organ transplantation.

Latent tuberculosis infection is an important problem for solid organ transplant recipients because of the frequency of its occurrence and its potential for reactivation. Because of the high mortality rate associated with active tuberculosis infections in transplant recipients, guidelines from the American Thoracic Society recommend treatment for latent tuberculosis in this population. However, the choice of treatments is often difficult because liver transplant recipients may be more sensitive to isoniazid hepatotoxicity, and rifampin has significant drug interactions with the calcineurin inhibitors used for immunosuppression. Two prior case reports described success with the use of rifabutin, a rifampin alternative, as part of a multidrug treatment regimen for active tuberculosis in posttransplant patients; however, there is no prior literature describing any experience with rifabutin for the treatment of latent tuberculosis in the posttransplant setting. We present a summary of tacrolimus drug levels and corresponding dose requirements for a single posttransplant patient during the administration of 3 different latent tuberculosis drug regimens: rifampin alone, rifampin plus ketoconazole, and rifabutin. In this patient's case, rifabutin allowed the maintenance of adequate tacrolimus levels, although an approximate 2.5-fold increase in the dose was required. Rifampin alone was associated with inadequate immunosuppressant levels, and rifampin plus ketoconazole was associated with a problematically prolonged QT interval and concerns about inadequate tuberculosis treatment.

The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial.

OBJECTIVES: Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted. METHODS: Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, clinicaltrials.gov). The primary analyses were for safety and exploratory efficacy. RESULTS: Patients in the deferasirox arm (n=11) were more likely than those in the placebo arm (n=9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P=0.1) and 90 days (82% versus 22%, P=0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P=0.06) and 18% (2/11) versus 56% (5/9) (P=0.2). CONCLUSIONS: Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis.

Risk factors for mortality in patients with mucormycosis.

Optimal clinical care and clinical investigation of patients with mucormycosis are limited by absence of controlled trials, and absence of well-defined predictors of mortality or clinical response. The Deferasirox-AmBisome Therapy for mucormycosis (DEFEAT Mucor) study was the first randomized clinical trial conducted on patients with mucormycosis, and demonstrated that adjunctive deferasirox therapy did not improve outcomes of the disease. The current study describes clinical factors from the 20 patients enrolled to identify those associated with 90-day mortality of the 11 (55%) patients who died by day 90. Age, diabetes mellitus, transplant status, or antifungal therapy were not associated with mortality. However, active malignancy or neutropenia at enrollment were associated with increased mortality. Pulmonary infection was linked with lower Kaplan-Meier survival compared to non-pulmonary infection. Higher baseline serum concentrations of iron and ferritin were also associated with mortality. No patient who progressed clinically during the first 14 days of study therapy survived; however, many patients who clinically improved during that time did not survive to 90 days. In contrast, day 30 clinical response was predictive of 90-day survival. These factors may be useful in defining enrollment randomization stratification critieria for future clinical trials, and in supporting clinical care of patients with mucormycosis.

TNF-α inhibition in the setting of undiagnosed HIV infection: a call for enhanced screening guidelines.

BACKGROUND: Despite the risks of immunosuppression, recommendations regarding screening for HIV infection prior to initiation of biologic therapies targeting common rheumatologic disorders, including inflammatory bowel disease (IBD) and inflammatory arthritides, are limited. Few cases of patients started on biologics while living with undiagnosed HIV infection have been reported. METHODS: We report three cases of patients initiated on biologics in the absence of recent or concurrent HIV screening who developed refractory disease or unanticipated complications and were later found to have undiagnosed chronic HIV infection. RESULTS: In Case 1, a 53-year-old MSM with negative HIV testing 2 years prior presented with presumed rheumatoid arthritis. He did not respond to methotrexate, so adalimumab was started. HIV testing to evaluate persistent symptoms was positive 9 months later; CD4+ T-cell count was 800 cells/µl. Antiretroviral therapy (ART) resulted in resolution of symptoms, which were attributed to HIV-associated arthropathy. In Case 2, a 55-year-old woman with injection drug use in remission and no prior HIV testing presented with hidradenitis suppurativa. She started infliximab and methotrexate therapy with good response. After she developed weight loss and lymphopenia, an HIV test was positive; CD4+ T-cell count was 334 cells/µl. Biologic hidradenitis suppurativa therapy was discontinued, with subsequent poor hidradenitis suppurativa control. In Case 3, a 32-year-old MSM with no prior HIV testing presented with presumed IBD; infliximab and steroids were started. Symptoms progressed despite IBD-directed therapy, and he was diagnosed with extensive Kaposi sarcoma with visceral and cutaneous involvement, likely exacerbated by immunosuppression. HIV testing was positive; CD4+ T-cell count was 250 cells/µl. Kaposi sarcoma initially worsened due to ART-associated immune reconstitution inflammatory syndrome. He is now improving with systemic chemotherapy and ART. HIV-associated Kaposi sarcoma is presumed to be the underlying diagnosis. CONCLUSION: All three patients had elevated risk for HIV infection, and two had final diagnoses attributed to chronic HIV infection, not warranting therapeutic immunosuppression. Screening for HIV infection prior to initiation of biologic therapy should be incorporated into clinical practice guidelines.

Pandemic (H1N1) 2009 infection in patients with hematologic malignancy.

To assess outcomes of patients with hematologic malignancy and pandemic (H1N1) 2009 infection, we reviewed cases during June-December 2009 at the University of California San Francisco Medical Center. Seventeen (63%) and 10 (37%) patients had upper respiratory tract infection (URTI) and lower respiratory tract infection (LRTI), respectively. Cough (85%) and fever (70%) were the most common signs; 19% of patients had nausea, vomiting, or diarrhea. Sixty-five percent of URTI patients were outpatients; 35% recovered without antiviral therapy. All LRTI patients were hospitalized; half required intensive care unit admission. Complications included acute respiratory distress syndrome, pneumomediastinum, myocarditis, and development of oseltamivir-resistant virus; 3 patients died. Of the 3 patients with nosocomial pandemic (H1N1) 2009, 2 died. Pandemic (H1N1) 2009 may cause serious illness in patients with hematologic malignancy, primarily those with LRTI. Rigorous infection control, improved techniques for diagnosing respiratory disease, and early antiviral therapy can prevent nosocomial transmission and optimize patient care.

Opportunistic coinfection with Pneumocystis jirovecii and Coccidioides immitis associated with idelalisib treatment in a patient with chronic lymphocytic leukaemia.

We describe a case of opportunistic coinfections with Coccidioides immitis and Pneumocystis jirovecii following treatment with idelalisib, a phosphoinositide 3-kinase inhibitor, for chronic lymphocytic leukaemia. This is the first case of pulmonary coccidioidomycosis reported in association with idelalisib. We review challenges related to diagnosis of opportunistic infections in this context. This report illustrates (1) the uncommon occurrence of two opportunistic infections concurrently or in rapid succession, (2) the importance of maintaining a broad differential diagnosis in the setting of an atypical imaging finding, slow clinical response or when immunomodulatory drugs are used, and (3) the challenges associated with non-invasive serological testing in individuals with haematological malignancy on immunomodulatory therapy.

Outcomes of immunomodulatory and biologic therapy in people living with HIV.

OBJECTIVES: Immunomodulatory drugs (IMDs) are crucial for treating autoimmune, inflammatory, and oncologic conditions. Data regarding the safety of IMDs in people living with HIV (PLWH) are limited. We describe outcomes in all PLWH prescribed these agents from 2000--2019 at two academic medical centers. DESIGN: Retrospective cohort study. METHODS: We systematically identified and reviewed charts of all PLWH receiving IMDs. We defined a treatment episode as an uninterrupted period on an IMD regimen. We quantified infections, blips (detectable plasma HIV RNA following an undetectable result), and virologic failure (progression from plasma HIV RNA <200 copies/ml to two consecutive values >200 copies/ml despite ART). RESULTS: Seventy-seven patients contributed 110 treatment episodes. Rheumatologic comorbidities were the most frequent indication. The most common IMD classes were TNF inhibitors, antimetabolites, and checkpoint inhibitors. Ninety percent of treatment episodes involved concomitant ART. Median pretreatment CD4 T-cell count was 609 cells/µl (IQR 375--861). Among 51 treatment episodes on ART with undetectable pretreatment plasma HIV RNA, HIV became detectable within 1 year in 21 of 51 cases (41.2%); there were no instances of virologic failure. Compared with other agents, treatment episodes involving checkpoint inhibitors were more likely to involve a blip (77.8 vs. 33.3%, P = 0.015). Thirteen treatment episodes (11.8%) were associated with concomitant infection; none was attributed to IMDs by the treating clinician. CONCLUSION: PLWH treated with IMDs should be monitored carefully for virologic blips and incident infections. Checkpoint inhibitors may be associated with a higher rate of viral blips, although the clinical significance is unclear.

Performance characteristics of anal cytology and human papillomavirus testing in patients with high-resolution anoscopy-guided biopsy of high-grade anal intraepithelial neoplasia.

PURPOSE: High-resolution anoscopy is colposcopy of the anus after applying 3 percent acetic acid. High-resolution anoscopy with biopsy was used as the standard for detecting high-grade anal neoplasia and was compared to detection of high-grade anal neoplasia by anal cytology, human papillomavirus testing, or the combination. METHODS: A total of 125 men who have sex with men (MSM) were enrolled from a group of MSM identified by random digit dialing: HIV-negative = 85, HIV-positive = 35, and unknown status = 5. A specimen was taken for anal cytology and human papillomavirus testing, followed by high-resolution anoscopy with biopsy of any lesions. RESULTS: Ninety-one percent of HIV-positive and 57 percent of HIV-negative MSM had anal human papillomavirus infection. In HIV-positive men the sensitivity of abnormal cytology to detect high-grade anal neoplasia was 87 percent, and in HIV-negative MSM it was 55 percent. Among HIV-negative men, 9 of 20 cases of high-grade anal neoplasia would have been missed because cytology was negative, but the addition of human papillomavirus positivity increased sensitivity for the combination to 90 percent. CONCLUSIONS: Sensitivity and specificity of anal cytology and human papillomavirus testing are different in HIV-positive and HIV-negative MSM for detecting high-grade anal neoplasia when patients have high-resolution anoscopy-guided biopsy of lesions. The optimum use of human papillomavirus testing has yet to be defined. High-resolution anoscopy is an effective tool for diagnosing high-grade anal neoplasia.

Comparison of patient- and clinician-collected anal cytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia in men who have sex with men.

BACKGROUND: Human papillomavirus (HPV)-associated anal cancer is increasing in prevalence and is more common among men who have sex with men and HIV-positive individuals than cervical cancer is among women in the United States. Cytology screening can detect the anal cancer precursor, anal intraepithelial neoplasia (AIN). Little is known about self-collected samples for AIN screening, and few community-based AIN estimates exist. OBJECTIVE: To compare the sensitivity of self-collected versus clinician-collected anal cytology specimens to detect biopsy-confirmed AIN and the prevalence estimate of AIN in a community sample. DESIGN: Cross-sectional study. Participants were mailed anal cytology self-collection kits with instructions. Clinicians repeated anal cytology and performed high-resolution anoscopy with biopsies as the diagnostic reference standard. SETTING: San Francisco, California. PATIENTS: Community-based sample of men who have sex with men. MEASUREMENTS: Prevalence of anal HPV and AIN. Sensitivity and specificity of self-collected and clinician-collected anal cytology specimens to diagnose AIN were calculated. RESULTS: Biopsy-proven AIN was diagnosed in 57% of HIV-positive and 35% of HIV-negative participants (P = 0.04), and 80% provided adequate self-collected specimens for interpretation. The sensitivity of cytology to detect AIN in HIV-positive men was 75% (95% CI, 51% to 93%) when self-collected and 90% (CI, 68% to 99%) when clinician-collected; respective values in HIV-negative men were 48% (CI, 26% to 70%) and 62% (CI, 38% to 82%). The specificity of cytology to detect AIN in HIV-positive men was 50% (CI, 22% to 78%) when self-collected and 64% (CI, 36% to 86%) when clinician-collected; respective values in HIV-negative men were 86% (CI, 71% to 94%) and 85% (CI, 72% to 93%). LIMITATIONS: The study sample was from a narrowly defined geographical area. Participants self-reported HIV status. CONCLUSION: In a community-based sample, a high proportion of HIV-positive and HIV-negative men who have sex with men have AIN. The sensitivity of cytology to detect AIN is higher for clinician-collected versus self-collected specimens and for HIV-positive versus HIV-negative men. The specificity of cytology to detect AIN is higher in HIV-negative versus HIV-positive men. However, the probability of AIN in a patient with a negative cytology result may not be low enough (23% for HIV-negative men and 45% for HIV-positive men with a patient-collected specimen) for clinicians to be comfortable recommending no anoscopy for those with a negative cytology result if done as a one-time test. These data raise the question of whether the optimal population screening strategy is cytology screening with anoscopy only for those who test positive or whether anoscopy should be recommended for everyone in these risk groups. Given limited resources and the limited number of clinicians trained in anoscopy, cytology screening may be the best current approach to identifying disease in the at-risk population.

Lack of association of Aspergillus colonization with the development of bronchiolitis obliterans syndrome in lung transplant recipients: An international cohort study.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS. METHODS: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders. RESULTS: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007). CONCLUSIONS: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.