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.

Utility of Serial Microbial Cell-free DNA Sequencing for Inpatient and Outpatient Pathogen Surveillance Among Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Background: This study characterizes the clinical utility and validity of the Karius test (KT), a plasma microbial cell-free DNA sequencing platform, as an infection surveillance tool among hematopoietic stem cell transplant (HCT) recipients, including monitoring for cytomegalovirus (CMV) and detecting infections relative to standard microbiologic testing (SMT). Methods: A prospective, observational cohort study was performed among adult HCT recipients as inpatients and outpatients. Serial KTs were performed starting with 1 sample within 14 days before HCT, then weekly from 7-63 days posttransplant then monthly from 3-12 months post-HCT. Diagnostic performance of KT versus CMV polymerase chain reaction was evaluated with positive percent agreement and negative percent agreement. Infectious events (<12 months post-HCT) were extracted from medical records. For infectious events without positive SMT, 2 clinicians adjudicated KT results to determine if any detections were a probable cause. Difference in time from KT pathogen detection and infection onset was calculated. Results: Of the 70 participants, mean age was 49.9 years. For CMV surveillance, positive percent agreement was 100% and negative percent agreement was 90%. There was strong correlation between CMV DNA and KT molecules per microliter (r 2: 0.84, P < .001). Of the 32 SMT+/KT+ infectious events, KT identified 26 earlier than SMT (median: -12 days) and an additional 5 diagnostically difficult pathogens identified by KT but not SMT. Conclusions: KT detected CMV with high accuracy and correlation with quantitative polymerase chain reaction. Among infectious events, KT demonstrated additive clinical utility by detecting pathogens earlier than SMT and those not detected by SMT.

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.

COVID-19 in vaccinated versus unvaccinated hematologic malignancy patients.

The effect of vaccination on severity of subsequent COVID-19 in patients with hematologic malignancies (HMs) is unknown. In this single-center retrospective cohort study, we found no difference in severity of COVID-19 disease in vaccinated (n = 16) versus unvaccinated (n = 54) HM patients using an adjusted multiple logistic regression model. Recent anti-B-cell therapy was associated with more severe illness.

Impact of an Innovative Endowed Chair Program on Medical Educator Recipients.

PURPOSE: Rarely do faculty members receive endowed chairs as recognition for their work as educators. In addition to the title, endowed chairholders have traditionally received discretionary income to pursue value-added work. This study assessed the impact on recipients of receiving an endowed chair for education. METHOD: The authors conducted a qualitative thematic analysis between 2018 and 2020, interviewing University of California, San Francisco, School of Medicine chairholders who had completed at least one 5-year term. Authors double-coded all transcripts, reconciled codes, applied social cognitive career theory during analysis, and identified themes through an iterative consensus-building approach. RESULTS: Twenty-three of 24 (96%) eligible faculty members from 16 departments participated. Themes identified were symbolism, resources, education and educator credibility, development, and impact. The chair was a symbol that brought recognition, indicated quality, and amplified visibility and status within the institution and externally. Receiving an endowed chair conferred credibility on recipients and empowered them in the educational domain. The resources allowed chairholders the flexibility to undertake activities that were of value to them, to mentees, and to the organization. Holding the chair facilitated professional development for self and others. Chair recipients reported impact that persisted long after their term(s) concluded. A model of impact emerged, suggesting that simply possessing the chair title led to visibility and gravitas, which, combined with resources, allowed the holder to leverage opportunities in education. CONCLUSIONS: The endowed chair is an important strategy for career development in education for the chairholder and enhances the position of education institutionally. Having a plan sharpens the focus on activities, results, and impact.

A systematic review and meta-analysis assessing the impact of droughts, flooding, and climate variability on malnutrition.

BACKGROUND: Both the World Health Organization and the Intergovernmental Panel on Climate Change project that malnutrition will be the greatest contributor to climate change-associated morbidity and mortality. Although there have been several studies that have examined the potential effects of climate change on human health broadly, the effects on malnutrition are still not well understood. We conducted a systematic review investigating the role of three climate change proxies (droughts, floods, and climate variability) on malnutrition in children and adults. METHODS AND FINDINGS: We identified 22 studies examining the effects of droughts, floods, and climate variability on at least one malnutrition metric. We found that 17 out of 22 studies reported a significant relationship between climate change proxies and at least one malnutrition metric. In meta-analysis, drought conditions were significantly associated with both wasting (Odds Ratio [OR] 1.46, 95% Confidence Interval [CI] 1.05-2.04) and underweight prevalence (OR 1.46, 95% CI 1.01-2.11). CONCLUSIONS: Given the long-term consequences of malnutrition on individuals and society, adoption of climate change adaptation strategies such as sustainable agriculture and water irrigation practices, as well as improving nutritional interventions aimed at children aged 1-2 years and older adults, should be prioritised on global policy agendas in the coming years.

HOPE in action: A prospective multicenter pilot study of liver transplantation from donors with HIV to recipients with HIV.

Liver transplantation (LT) from donors-with-HIV to recipients-with-HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single-case reports of HIV D+/R+ LT, each with limited follow-up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors-without-HIV to recipients-with-HIV (HIV D-/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016-July 2019, there were 45 LTs (8 simultaneous liver-kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D-/R+ (10 D- were false-positive). The median follow-up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)-seropositive, 13% HCV-viremic. Weighted 1-year survival was 83.3% versus 100.0% in D+ versus D- groups (p = .04). There were no differences in one-year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p > .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation.

Characteristics of High-Titer Convalescent Plasma and Antibody Dynamics After Administration in Patients With Severe Coronavirus Disease 2019.

We characterized the antibody composition of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) and the immunologic responses of hospitalized COVID-19 patients after receiving CCP or nonimmune fresh frozen plasma. Despite selection of CCP with significantly higher total immunoglobulin G than recipients, neutralizing antibody levels did not differ between donor plasma and CCP recipients.

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.

Testing deceased organ donors for infections: An organ procurement organization survey.

Organ procurement organizations (OPO) test potential deceased organ donors for infectious diseases required by policy, but many also perform testing for additional infections. The current state of donor testing in the United States is unknown. We sent an IRB approved survey to all 57 U.S. OPOs using REDCap. Descriptive statistics were performed. From the 57 OPOs, we received 46 (80.7%) unique responses with all 11 United Network of Organ Sharing regions represented. Forty of 46 (87%) OPO respondents consulted an Infectious Diseases physician when needed. Eighteen of 46 (39%) tested for West Nile virus (WNV) and 17 of 18 (94%) tested year-round. Eleven of 46 (23.9%) tested for Strongyloides infection while 17 of 46 (37%) tested for Chagas disease. All OPOs performed prospective nucleic acid testing (NAT) for HIV, hepatitis B and hepatitis C on all donors. OPO testing of additional infections has increased since prior surveys but remains variable. Standardization of organ donor infectious diseases evaluation should be considered.

The Synergistic Relationship Between Climate Change and the HIV/AIDS Epidemic: A Conceptual Framework.

Climate change and HIV/AIDS represent two of the greatest threats to human health in the 21st century. However, limitations in understanding the complex relationship between these syndemics continue to constrain advancements in the prevention and management of HIV/AIDS in the context of a rapidly changing climate. Here, we present a conceptual framework that identifies four pathways linking climate change with HIV/AIDS transmission and health outcomes: increased food insecurity, increased prevalence of other infectious diseases, increased human migration, and erosion of public health infrastructure. This framework is based on an in-depth literature review in PubMed and Google Scholar from June 6 to June 27, 2019. The pathways linking climate change with HIV transmission and health outcomes are complex with multiple interacting factors. Food insecurity emerged as a particularly important mediator by driving sexual risk-taking behaviours and migration, as well as by increasing susceptibility to infections that are common among people living with HIV (PLWHIV). Future interventions should focus on decreasing carbon dioxide emissions globally and increasing education and investment in adaptation strategies, particularly in those areas of sub-Saharan Africa and southeast Asia heavily impacted by both HIV and climate change. Environmentally sustainable interventions such as urban gardening and investing in sustainable agriculture technologies also have significant health co-benefits that may help PLWHIV adapt to the environmental consequences of climate change.

Treatment of immunocompromised COVID-19 patients with convalescent plasma.

Immunosuppressed patients such as solid organ transplant and hematologic malignancy patients appear to be at increased risk for morbidity and mortality due to coronavirus disease 2019 (COVID-19) caused by SARS coronavirus 2 (SARS-CoV-2). Convalescent plasma, a method of passive immunization that has been applied to prior viral pandemics, holds promise as a potential treatment for COVID-19. Immunocompromised patients may experience more benefit from convalescent plasma given underlying deficits in B and T cell immunity as well as contraindications to antiviral and immunomodulatory therapy. We describe our institutional experience with four immunosuppressed patients (two kidney transplant recipients, one lung transplant recipient, and one chronic myelogenous leukemia patient) treated with COVID-19 convalescent plasma through the Expanded Access Program (NCT04338360). All patients clinically improved after administration (two fully recovered and two discharged to skilled nursing facilities) and none experienced a transfusion reaction. We also report the characteristics of convalescent plasma product from a local blood center including positive SARS-CoV-2 IgG and negative SARS-CoV-2 PCR in all samples tested. This preliminary evidence suggest that convalescent plasma may be safe among immunosuppressed patients with COVID-19 and emphasizes the need for further data on the efficacy of convalescent plasma as either primary or adjunctive therapy for COVID-19.

A prospective multicenter pilot study of HIV-positive deceased donor to HIV-positive recipient kidney transplantation: HOPE in action.

HIV-positive donor to HIV-positive recipient (HIV D+/R+) transplantation is permitted in the United States under the HIV Organ Policy Equity Act. To explore safety and the risk attributable to an HIV+ donor, we performed a prospective multicenter pilot study comparing HIV D+/R+ vs HIV-negative donor to HIV+ recipient (HIV D-/R+) kidney transplantation (KT). From 3/2016 to 7/2019 at 14 centers, there were 75 HIV+ KTs: 25 D+ and 50 D- (22 recipients from D- with false positive HIV tests). Median follow-up was 1.7 years. There were no deaths nor differences in 1-year graft survival (91% D+ vs 92% D-, P = .9), 1-year mean estimated glomerular filtration rate (63 mL/min D+ vs 57 mL/min D-, P = .31), HIV breakthrough (4% D+ vs 6% D-, P > .99), infectious hospitalizations (28% vs 26%, P = .85), or opportunistic infections (16% vs 12%, P = .72). One-year rejection was higher for D+ recipients (50% vs 29%, HR: 1.83, 95% CI 0.84-3.95, P = .13) but did not reach statistical significance; rejection was lower with lymphocyte-depleting induction (21% vs 44%, HR: 0.33, 95% CI 0.21-0.87, P = .03). In this multicenter pilot study directly comparing HIV D+/R+ with HIV D-/R+ KT, overall transplant and HIV outcomes were excellent; a trend toward higher rejection with D+ raises concerns that merit further investigation.

Kidney Transplantation in HIV-positive Patients: Current Practice and Management Strategies.

BACKGROUND: HIV-positive patients had been successfully transplanted for the last 15 y and the donor pool had successfully been expanded to also include HIV-positive donors. METHODS: We aimed to evaluate the effectiveness of transplantation in HIV-positive patients and highlight some of the important issues reported in the literature. We pooled clinical data from different cohorts to show some of the common issues encountered in HIV-positive transplantation. Furthermore, we searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL to create a comprehensive table for current evidence for different issues currently encountered when transplanting HIV-positive patients. RESULTS: We included data from 19 cohort studies and reported on outcomes of the current HIV-positive transplant programs. We made recommendations based on personal experience as well as the experience reported in the literature regarding rejection, opportunistic infection, and HIV-associated nephropathy. Opportunistic infections and malignancies are not a major problem for this population group. CONCLUSIONS: HIV-positive patients encounter very specific issues after transplantation, specifically related to drug interactions and higher rejection rates. When utilizing HIV-positive donors, the recurrence of HIV-associated nephropathy in the graft kidney is an issue which can be important. Despite some issues with high rejection rates, HIV-positive patients have similar results to HIV-negative patients posttransplantation.