Clinical Focus: Chief, Immunocompromised Host Infectious Diseases

This includes the prevention, diagnosis and treatment of Infections in patients who are immunosuppressed because of:

Solid Organ Transplantation (Kidney, Pancreas, Liver, Heart, Lung, Small Bowel)
Bone Marrow (Hematopoeitic Cell) Transplants
Hematologic Malignancies
Chemotherapy for Solid Tumors
HIV who receive Chemotherapy,Solid Organ or Bone Marrow Transplants
Immunomodulators for Auto-Immune Diseases

Clinical Focus

  • Infectious Disease

Academic Appointments

Administrative Appointments

  • Co-PI, AIDS Clinical Trials Unit, Johns Hopkins University School of Medicine (2001 - 2003)
  • Co-Director, Transplant and Oncology ID Service, Johns Hopkins University School of Medicine (2003 - 2011)
  • Chief, Immunocompromised Host ID Service, Stanford University, Division of Infectious Diseases (2013 - Present)

Honors & Awards

  • Fellow of AST (FAST), American Society of Transplantation (2018)
  • Fellow of IDSA (FIDSA), Infectious Diseases Society of America (2014)
  • Sidney Finegold Outstanding Reviewer Award, Clinical Infectious Diseases Journal (2009)
  • Associate Editor, Transplant Infectious Diseases Journal (2004-2016)
  • Award for Outstanding Research, Case Western Reserve University (UHC) (1997)
  • William Dodd Robinson Award for Excellence in Internal Medicine, University of Michigan (1994)

Professional Education

  • Board Certification: American Board of Internal Medicine, Infectious Disease (1999)
  • Fellowship: Johns Hopkins University Division of Infectious Diseases (2000) MD
  • Medical Education: University of Michigan Medical School (1994) MI
  • Residency: University Hospitals of Cleveland - Case Western Reserve (1997) OH
  • Board Certification: American Board of Internal Medicine, Internal Medicine (1997)
  • Fellowship, Johns Hopkins University School of Medicine, Infectious Diseases (2001)
  • Residency, University Hospitals of Cleveland (Case Western Reserve), Internal Medicine (1997)
  • Medical School, University of Michigan, Medicine (1994)

Current Research and Scholarly Interests

My research and scholarly interests have focused on tailoring antimicrobial prophylaxis in specific highly immunocompromised hosts depending on their specific infectious disease risks. I am interested in developing diagnostic algorithms and treatment protocols that will improve the quality of care in transplant and oncology patients.

I also have an interest in training ID fellows in this very specialized area of patient care. To that end, we have started a new ICHS ID fellowship with a specialized curriculum and are developing supplemental educational materials to enhance this training, which can be implemented at other academic training centers.

All Publications

  • Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial. JAMA internal medicine Geng, L. N., Bonilla, H., Hedlin, H., Jacobson, K. B., Tian, L., Jagannathan, P., Yang, P. C., Subramanian, A. K., Liang, J. W., Shen, S., Deng, Y., Shaw, B. J., Botzheim, B., Desai, M., Pathak, D., Jazayeri, Y., Thai, D., O'Donnell, A., Mohaptra, S., Leang, Z., Reynolds, G. Z., Brooks, E. F., Bhatt, A. S., Shafer, R. W., Miglis, M. G., Quach, T., Tiwari, A., Banerjee, A., Lopez, R. N., De Jesus, M., Charnas, L. R., Utz, P. J., Singh, U. 2024


    There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC).To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms.This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration.Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days.Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline.Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade.The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of Identifier: NCT05576662.

    View details for DOI 10.1001/jamainternmed.2024.2007

    View details for PubMedID 38848477

  • Low infectivity among asymptomatic patients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test at a tertiary care center, 2020-2022. Infection control and hospital epidemiology Tayyar, R., Kiener, M. A., Liang, J. W., Contreras, G., Rodriguez-Nava, G., Zimmet, A. N., Contag, C. A., Srinivasan, K., McIntyre, K., Subramanian, A., Shepard, J., Tompkins, L. S., Pinsky, B. A., Salinas, J. L. 2023: 1-3


    We used a strand-specific RT-qPCR to evaluate viral replication as a surrogate for infectiousness among 242 asymptomatic inpatients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test. Only 21 patients (9%) had detectable SARS-CoV-2 minus-strand RNA. Because most patients were found to be noninfectious, our findings support the suspension of asymptomatic admission testing.

    View details for DOI 10.1017/ice.2023.210

    View details for PubMedID 37746805

  • Consensus position statement on advancing the standardised reporting of infection events in immunocompromised patients. The Lancet. Infectious diseases Teh, B. W., Mikulska, M., Averbuch, D., de la Camara, R., Hirsch, H. H., Akova, M., Ostrosky-Zeichner, L., Baddley, J. W., Tan, B. H., Mularoni, A., Subramanian, A. K., La Hoz, R. M., Marinelli, T., Boan, P., Aguado, J. M., Grossi, P. A., Maertens, J., Mueller, N. J., Slavin, M. A. 2023


    Patients can be immunocompromised from a diverse range of disease and treatment factors, including malignancies, autoimmune disorders and their treatments, and organ and stem-cell transplantation. Infections are a leading cause of morbidity and mortality in immunocompromised patients, and the disease treatment landscape is continually evolving. Despite being a critical but preventable and curable adverse event, the reporting of infection events in randomised trials lacks sufficient detail while inconsistency of categorisation and definition of infections in observational and registry studies limits comparability and future pooling of data. A core reporting dataset consisting of category, site, severity, organism, and endpoints was developed as a minimum standard for reporting of infection events in immunocompromised patients across study types. Further additional information is recommended depending on study type. The standardised reporting of infectious events and attributable complications in immunocompromised patients will improve diagnostic, treatment, and prevention approaches and facilitate future research in this patient group.

    View details for DOI 10.1016/S1473-3099(23)00377-8

    View details for PubMedID 37683684

  • Use of a severe acute respiratory coronavirus virus 2 (SARS-CoV-2) strand-specific assay to evaluate for prolonged viral replication >20 days from illness onset. Infection control and hospital epidemiology Ferguson, J. D., Tayyar, R., Contreras, G., Kiener, M., Zimmet, A. N., Contag, C. A., Rodriguez Nava, G., Tompkins, L. S., Shepard, J., Rosenthal, A., Subramanian, A. K., Pinsky, B. A., Salinas, J. L. 2023: 1-3


    Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) strand-specific assay can be used to identify active SARS-CoV-2 viral replication. We describe the characteristics of 337 hospitalized patients with at least 1 minus-strand SARS-CoV-2 assay performed >20 days after illness onset. This test is a novel tool to identify high-risk hospitalized patients with prolonged SARS-CoV-2 replication.

    View details for DOI 10.1017/ice.2023.105

    View details for PubMedID 37381726

  • Mycobacteria in Organ Transplant Recipients. Infectious disease clinics of North America Narsana, N., Alejandra Perez, M., Subramanian, A. 2023


    This review describes the epidemiology and risk factors of tuberculosis (TB) in solid organ transplant recipients. We discuss the pre-transplant screening for risk of TB and management of latent TB in this population. We also discuss the challenges of management of TB and other difficult to treat mycobacteria such as Mycobacterium abscessus and Mycobacterium avium complex. The drugs for the management of these infections include rifamycins which have significant drug interactions with immunosuppressants and must be monitored closely.

    View details for DOI 10.1016/j.idc.2023.04.004

    View details for PubMedID 37268476

  • Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic. Frontiers in neurology Bonilla, H., Quach, T. C., Tiwari, A., Bonilla, A. E., Miglis, M., Yang, P. C., Eggert, L. E., Sharifi, H., Horomanski, A., Subramanian, A., Smirnoff, L., Simpson, N., Halawi, H., Sum-Ping, O., Kalinowski, A., Patel, Z. M., Shafer, R. W., Geng, L. C. 2023; 14: 1090747


    The global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well-defined.We collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) phenotype.The median age was 47 years, 59.0% were female; 49.3% White, 17.2% Hispanic, 14.9% Asian, and 6.7% Black. Only 12.7% required hospitalization. Seventy-two (53.5%) patients had no known comorbid conditions. Forty-five (33.9%) were significantly debilitated. The median duration of symptoms was 285.5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86.5%), post-exertional malaise (82.8%), brain fog (81.2%), unrefreshing sleep (76.7%), and lethargy (74.6%). Forty-three percent fit the criteria for ME/CFS, majority were female, and obesity (BMI > 30 Kg/m2) (P = 0.00377895) and worse functional status (P = 0.0110474) were significantly associated with ME/CFS.Most PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.

    View details for DOI 10.3389/fneur.2023.1090747

    View details for PubMedID 36908615

    View details for PubMedCentralID PMC9998690

  • Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference. Open forum infectious diseases Walter, K. S., Kim, E., Verma, R., Altamirano, J., Leary, S., Carrington, Y. J., Jagannathan, P., Singh, U., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Andrews, J. R. 2023; 10 (2): ofad001


    The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference.We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage.Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0-40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17-208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02-1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28-.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23-1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants.Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

    View details for DOI 10.1093/ofid/ofad001

    View details for PubMedID 36751652

    View details for PubMedCentralID PMC9898879

  • Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study. eLife Hu, Z., van der Ploeg, K., Chakraborty, S., Arunachalam, P. S., Mori, D. A., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Hedlin, H., de la Parte, L., Press, K., Ty, M., Tan, G. S., Blish, C., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Butte, A. J., Singh, U., Pulendran, B., Wang, T. T., Jagannathan, P. 2022; 11


    The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

    View details for DOI 10.7554/eLife.77943

    View details for PubMedID 36239699

  • Infective endocarditis in solid organ transplant: a review. Current opinion in organ transplantation Suarez, J. F., Subramanian, A. K. 2022; 27 (4): 263-268


    PURPOSE OF REVIEW: Infective endocarditis remains an uncommon disease with significant morbidity and mortality. In the last two decades, progress has been made describing the unique aspects of infective endocarditis in solid organ transplant (SOT) recipients.RECENT FINDINGS: Incidence of infective endocarditis in SOT is higher when compared with the general population. End-stage organ dysfunction, diabetes mellitus, older age, and prior intravenous lines have been identified as risk factors predisposing to infective endocarditis in SOT. Staphylococci and enterococci represent the most frequently isolated pathogens, whereas fungi are rarely isolated. Median time from transplantation to diagnosis ranges from 33 to 66 months. Nosocomial acquisition and mural endocarditis are more common in SOT recipients with infective endocarditis. Procurement of organs from patients with infective endocarditis might be well tolerated so long as close monitoring and targeted antibiotics are given. Selected patients might benefit from heart transplantation as definitive or salvage therapy for infective endocarditis. Outcomes of infective endocarditis in SOT recipients compared with the general population might be similar; however, patient survival and graft function are reduced when recipients suffer from infective endocarditis.SUMMARY: Infective endocarditis although rare can affect donors and recipients involved in the SOT process. Recognition of the unique characteristics in the presentation, prevention, medical, and surgical therapy of this disease is essential in order to minimize adverse outcomes.

    View details for DOI 10.1097/MOT.0000000000000993

    View details for PubMedID 36354252

  • COVID-19 in the Immunocompromised Host, Including People with Human Immunodeficiency Virus. Infectious disease clinics of North America Jakharia, N., Subramanian, A. K., Shapiro, A. E. 2022; 36 (2): 397-421


    This review describes the incidence, epidemiology, and risk factors for mortality of COVID-19 in immunocompromised patients, including persons with human immunodeficiency virus. It describes various preventive measures, including vaccines and their effectiveness and the role of monoclonal antibodies for pre-exposure prophylaxis. It also reviews the different treatment options for immunocompromised individuals, including antivirals, monoclonal antibodies, and immunomodulators. Lastly, it describes the impact of COVID-19 on transplantation and continuity care of this population.

    View details for DOI 10.1016/j.idc.2022.01.006

    View details for PubMedID 35636907

  • Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Holubar, M., Subramanian, A., Purington, N., Hedlin, H., Bunning, B., Walter, K. S., Bonilla, H., Boumis, A., Chen, M., Clinton, K., Dewhurst, L., Epstein, C., Jagannathan, P., Kaszynski, R. H., Panu, L., Parsonnet, J., Ponder, E. L., Quintero, O., Sefton, E., Singh, U., Soberanis, L., Truong, H., Andrews, J. R., Desai, M., Khosla, C., Maldonado, Y. 2022


    Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries.We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1: 1 to receive placebo or favipiravir (1800mg BID Day 1, 800 mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis.From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48-1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54-1.29; sustained: HR 0.87, 95% CI 0.52-1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment.Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

    View details for DOI 10.1093/cid/ciac312

    View details for PubMedID 35446944

  • Epidemiology of invasive fungal diseases in adults with newly diagnosed acute myeloid leukemia. Leukemia & lymphoma Miranti, E., Ho, D. Y., Enriquez, K., Subramanian, A. K., Medeiros, B. C., Epstein, D. J. 2022: 1-7


    Invasive fungal diseases (IFDs) are common in patients with acute myeloid leukemia (AML), but no recent data on incidence without antifungal prophylaxis are available. We evaluated the incidence of IFDs in patients with AML undergoing induction chemotherapy at Stanford University Hospital from 2012 to 2017, for up to 12weeks after induction. We also analyzed factors associated with IFD development. Thirty-six of 240 patients (13%) developed at least one proven or probable IFD. Seventy-eight percent of the proven or probable IFDs were due to Candida or Aspergillus species. Infection due to Fusarium and Mucorales was uncommon. Absolute neutrophil count (ANC) of <500L/L at the start of induction was associated with an increased risk of IFD. One hundred and eighty-seven patients (78%) were started on systemic antifungal drugs, even without microbiologic evidence of an IFD. IFDs remain frequent in AML patients undergoing induction chemotherapy without antifungal prophylaxis.

    View details for DOI 10.1080/10428194.2022.2060504

    View details for PubMedID 35410569

  • Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Science translational medicine Chakraborty, S., Gonzalez, J. C., Sievers, B. L., Mallajosyula, V., Chakraborty, S., Dubey, M., Ashraf, U., Cheng, B. Y., Kathale, N., Tran, K. Q., Scallan, C., Sinnott, A., Cassidy, A., Chen, S. T., Gelbart, T., Gao, F., Golan, Y., Ji, X., Kim-Schulze, S., Prahl, M., Gaw, S. L., Gnjatic, S., Marron, T. U., Merad, M., Arunachalam, P. S., Boyd, S. D., Davis, M. M., Holubar, M., Khosla, C., Maecker, H. T., Maldonado, Y., Mellins, E. D., Nadeau, K. C., Pulendran, B., Singh, U., Subramanian, A., Utz, P. J., Sherwood, R., Zhang, S., Jagannathan, P., Tan, G. S., Wang, T. T. 1800: eabm7853


    A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcgammaR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcgammaR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.

    View details for DOI 10.1126/scitranslmed.abm7853

    View details for PubMedID 35040666

  • An aberrant inflammatory response in severe COVID-19. Cell host & microbe Merad, M., Subramanian, A., Wang, T. T. 2021; 29 (7): 1043-1047


    Severe COVID-19 arises from the convergence of inadequate pre-existing immunity and a host response that damages, rather than repairs, tissues. We outline clinical presentations of COVID-19 that are likely driven by dysregulated host immunity, discuss potential mechanisms underlying pathological responses, and highlight important areas for basic research on this topic.

    View details for DOI 10.1016/j.chom.2021.06.018

    View details for PubMedID 34265243

  • Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Jacobson, K. B., Rao, M., Bonilla, H., Subramanian, A., Hack, I., Madrigal, M., Singh, U., Jagannathan, P., Grant, P. 2021


    To assess the prevalence of persistent functional impairment after COVID-19, we assessed 118 individuals 3-4 months after their initial COVID-19 diagnosis with a symptom survey, work productivity and activity index questionnaire, and 6-minute walk test. We found significant persistent symptoms and functional impairment, even in non-hospitalized patients with COVID-19.

    View details for DOI 10.1093/cid/ciab103

    View details for PubMedID 33624010

  • Clinical Accuracy and Impact of Plasma Cell-Free DNA Fungal PCR Panel for Non-Invasive Diagnosis of Fungal Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Senchyna, F. n., Hogan, C. A., Murugesan, K. n., Moreno, A. n., Ho, D. Y., Subramanian, A. n., Schwenk, H. T., Budvytiene, I. n., Costa, H. A., Gombar, S. n., Banaei, N. n. 2021


    Invasive fungal infection (IFI) is a growing cause of morbidity and mortality in oncology and transplant patients. Diagnosis of IFI is often delayed due to need for invasive biopsy and low sensitivity of conventional diagnostic methods. Fungal cell-free DNA (cfDNA) detection in plasma is a novel testing modality for the non-invasive diagnosis of IFI.A novel bioinformatic pipeline was created to interrogate fungal genomes and identify multicopy sequences for cfDNA PCR targeting. A real-time PCR panel was developed for 12 genera and species most commonly causing IFI. Sensitivity and specificity of the fungal PCR panel were determined using plasma samples from patients with IFI and non-IFI controls. Clinical impact of fungal PCR panel was evaluated prospectively based on the treating team's interpretation of the results.Overall, the sensitivity and specificity were 56.5% (65/115, 95% confidence interval [CI], 47.4%-65.2%) and 99.5% (2064/2075; 95% CI, 99.0%-99.7%), respectively. In the subset of patients with an optimized plasma volume (2mL), sensitivity was 69.6% (48/69; 95% CI, 57.9%-79.2%). Sensitivity was 91.7% (11/12; 95% CI, 62.5%-100%) for detection of Mucorales agents, 56.3% (9/16; 95% CI, 33.2%-76.9%) for Aspergillus species, and 84.6% (11/13; 95% CI, 56.5%-96.9%) for Candida albicans. In a prospective evaluation of 226 patients with suspected IFI, cfDNA testing was positive in 47 (20.8%) patients and resulted in a positive impact on clinical management in 20/47 (42.6%).The fungal cfDNA PCR panel offers a non-invasive approach to early diagnosis of IFI, providing actionable results for personalized care.

    View details for DOI 10.1093/cid/ciab158

    View details for PubMedID 33606010

  • Nocardiosis in Immunocompromised Patients on Alternative Pneumocystis Prophylaxis. Emerging infectious diseases Puing, A. G., Epstein, D. J., Banaei, N., Subramanian, A. K., Liu, A. Y. 2021; 27 (10): 2734-2736


    Prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) prevents Pneumocystis jirovecii pneumonia and nocardiosis in immunocompromised patients but sometimes is avoided because of purported allergies or side effects. Of 25 immunocompromised patients receiving alternative prophylaxis in whom nocardiosis developed, 16 subsequently tolerated TMP/SMX treatment. Clinicians should consider TMP/SMX allergy evaluation and rechallenging to assess patient tolerance.

    View details for DOI 10.3201/eid2710.210620

    View details for PubMedID 34545802

    View details for PubMedCentralID PMC8462344

  • SARS-CoV-2 Neutralization Resistance Mutations in Patient with HIV/AIDS, California, USA. Emerging infectious diseases Hoffman, S. A., Costales, C., Sahoo, M. K., Palanisamy, S., Yamamoto, F., Huang, C., Verghese, M., Solis, D. C., Sibai, M., Subramanian, A., Tompkins, L. S., Grant, P., Shafer, R. W., Pinsky, B. A. 2021; 27 (10)


    We report persistent severe acute respiratory syndrome coronavirus 2 infection in a patient with HIV/AIDS; the virus developed spike N terminal domain and receptor binding domain neutralization resistance mutations. Our findings suggest that immunocompromised patients can harbor emerging variants of severe acute respiratory syndrome coronavirus 2.

    View details for DOI 10.3201/eid2710.211461

    View details for PubMedID 34296992

  • SARS-CoV-2 subgenomic RNA kinetics in longitudinal clinical samples Open Forum Infectious Diseases Verma, R., Kim, E., Martinez, G., Jagannathan, ., Rustagi, A., Parsonnet, J., Bonilla, H., Khosla, C., Holubar, M., Subramanian, A., Singh, ., Maldonado, Y., Blish, C., Andrews, J. 2021

    View details for DOI 10.1093/ofid/ofab310

  • Active surveillance of serious adverse events following transfusion of COVID-19 convalescent plasma. Transfusion Swenson, E., Wong, L. K., Jhaveri, P., Weng, Y., Kappagoda, S., Pandey, S., Pritchard, A., Rogers, A., Ruoss, S., Subramanian, A., Shan, H., Hollenhorst, M. 2021


    The reported incidence of adverse reactions following Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) transfusion has generally been lower than expected based on the incidence of transfusion reactions that have been observed in studies of conventional plasma transfusion. This raises the concern for under-reporting of adverse events in studies of CCP that rely on passive surveillance strategies.Our institution implemented a protocol to actively identify possible adverse reactions to CCP transfusion. In addition, we retrospectively reviewed the charts of inpatients who received CCP at Stanford Hospital between May 13, 2020 and January 31, 2021. We determined the incidence of adverse events following CCP transfusion.A total of 49 patients received CCP. Seven patients (14%) had an increased supplemental oxygen requirement within 4 h of transfusion completion, including one patient who was intubated during the transfusion. An additional 11 patients (total of 18, 37%) had increased oxygen requirements within 24 h of transfusion, including 3 patients who were intubated. Six patients (12%) fulfilled criteria for transfusion-associated circulatory overload (TACO).Using an active surveillance strategy, we commonly observed adverse events following the transfusion of CCP to hospitalized patients. It was not possible to definitively determine whether or not these adverse events are related to CCP transfusion. TACO was likely over-diagnosed given overlap with the manifestations of COVID-19. Nevertheless, these results suggest that the potential adverse effects of CCP transfusion may be underestimated by reports from passive surveillance studies.

    View details for DOI 10.1111/trf.16711

    View details for PubMedID 34677830

  • IMPACT OF BASELINE ALANINE AMINOTRANSFERASE LEVELS ON THE SAFETY AND EFFICACY OF REMDESIVIR IN SEVERE COVID-19 PATIENTS Goldman, J. D., Lye, D., Hui, D., Marks, K., Bruno, R., Montejano, R., Spinner, C., Galli, M., Ahn, M., Nahass, R., Elboudwarej, E., Tian, Y., McDonald, C., Tan, S., Suri, V., Hyland, R., SenGupta, D., Chokkalingam, A. P., Gaggar, A., Osinusi, A. O., Brainard, D. M., Towner, W., Munoz, J., Mullane, K. M., Hammond, S. P., Tashima, K. T., Diaz, G. A., Subramanian, A. WILEY. 2020: 279A
  • Quantifying Infection Risks in Incompatible Living Donor Kidney Transplant Recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Avery, R. K., Motter, J. D., Jackson, K. R., Montgomery, R. A., Massie, A. B., Kraus, E. S., Marr, K. A., Lonze, B. E., Alachkar, N., Holechek, M. J., Ostrander, D., Desai, N., Waldram, M. M., Shoham, S., Mehta Steinke, S., Subramanian, A., Hiller, J. M., Langlee, J., Young, S., Segev, D. L., Garonzik, J. M. 2020


    Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010-2015, categorized by desensitization intensity: none/compatible (n=260), low (0-4 plasmaphereses,n=47), moderate (5-9,n=74), and high (≥10,n=94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high intensity desensitization (p<0.001). The most common infections were UTI (33.5% of ILDKT vs 21.5% compatible), opportunistic (21.9% vs 10.8%), and bloodstream (19.1% vs 5.4%) (p<0.001). In weighted models, a trend towards increased risk was seen in low (wIRR=0.77 1.402.56 ,p=0.3) and moderately (wIRR=0.88 1.352.06 ,p=0.2) desensitized recipients, with a statistically significant 2.22-fold (wIRR=1.33 2.223.72 ,p=0.002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR=2.62 3.574.88 , p<0.001) and death-censored graft loss (wHR=1.15 4.0113.95 ,p=0.03). Post-KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.

    View details for DOI 10.1111/ajt.16316

    View details for PubMedID 32949093

  • Use of Remdesivir for Pregnant Patients with Severe Novel 2019 Coronavirus Disease. American journal of obstetrics and gynecology Igbinosa, I., Miller, S., Bianco, K., Nelson, J., Kappagoda, S., Blackburn, B. G., Grant, P., Subramanian, A., Lyell, D., El-Sayed, Y., Aziz, N. 2020

    View details for DOI 10.1016/j.ajog.2020.08.001

    View details for PubMedID 32771381

  • Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI insight Wilson, J. G., Simpson, L. J., Ferreira, A., Rustagi, A., Roque, J. A., Asuni, A., Ranganath, T., Grant, P. M., Subramanian, A. K., Rosenberg-Hasson, Y., Maecker, H., Holmes, S., Levitt, J. E., Blish, C., Rogers, A. J. 2020


    BACKGROUND: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes.METHODS: We used a luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTS: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONS: Levels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDING: A.J.R.: Stanford ICU Biobank NHLBI K23 HL125663. C.A.B.: Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687; NIH/NIAID U19AI057229-16 (PI MM Davis); Stanford Maternal Child Health Research Institute; Chan Zuckerberg Biohub.

    View details for DOI 10.1172/jci.insight.140289

    View details for PubMedID 32706339

  • A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nature medicine Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A. 2020


    There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.

    View details for DOI 10.1038/s41591-020-0944-y

    View details for PubMedID 32514174

  • A single-cell atlas of the peripheral immune response to severe COVID-19. medRxiv : the preprint server for health sciences Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A. 2020


    There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2. Here, we apply single-cell RNA sequencing (scRNA-seq) to peripheral blood mononuclear cells (PBMCs) of 7 patients hospitalized with confirmed COVID-19 and 6 healthy controls. We identify substantial reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene (ISG) signature, HLA class II downregulation, and a novel B cell-derived granulocyte population appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines, suggesting that circulating leukocytes do not significantly contribute to the potential COVID-19 cytokine storm. Collectively, we provide the most thorough cell atlas to date of the peripheral immune response to severe COVID-19.

    View details for DOI 10.1101/2020.04.17.20069930

    View details for PubMedID 32511639

  • Antibiotic Exposure and Risk for Hospital-Associated Clostridioides difficile Infection. Antimicrobial agents and chemotherapy Webb, B. J., Subramanian, A., Lopansri, B., Goodman, B., Jones, P. B., Ferraro, J., Stenehjem, E., Brown, S. M. 2020


    Background: Clostridioides difficile infection (CDI) is a healthcare-associated infection associated with significant morbidity and cost with highly variable risk across populations. More effective, risk-based prevention strategies are needed. Here we investigate risk factors for hospital-associated CDI in a large integrated health system.Methods: In a retrospective cohort of all adult admissions to 21 Intermountain Healthcare hospitals from 2006 to 2012, we identified all symptomatic (1) hospital-onset and (2) healthcare-facility-associated, community-onset CDI. We then evaluated the risk associated with antibiotic exposure, including specific agents, using multivariable logistic regression.Results: 2356 cases of CDI among 506,068 admissions were identified (incidence 46.6 per 10,000). Prior antibiotic use was the dominant risk factor - for every antibiotic day of therapy prior to the index admission, odds of subsequent CDI increased by 12.8% (95% CI 12.2-13.4%, p<0.0001). This was a much stronger association than was inpatient antibiotic exposure (OR 1.007 (95% CI 1.005-1.009, p<0.0001). Highest risk antibiotics included 2nd generation and later cephalosporins (especially oral), carbapenems, fluroquinolones, and clindamycin, while doxycycline and daptomycin were associated with lower CDI risk.Conclusions: Cumulative antibiotic exposure prior to admission is the greatest contributor to risk of subsequent CDI. Most classes of antibiotics carry some risk, which varies by drug and route. This information may be useful for antimicrobial stewardship efforts.

    View details for DOI 10.1128/AAC.02169-19

    View details for PubMedID 31964789

  • A Multicenter, Longitudinal Cohort Study of Cryptococcosis in Human Immunodeficiency Virus-negative People in the United States CLINICAL INFECTIOUS DISEASES Marr, K. A., Sun, Y., Spec, A., Lu, N., Panackal, A., Bennett, J., Pappas, P., Ostrander, D., Datta, K., Zhang, S. X., Williamson, P. R., Lyons, J., Bhimraj, A., Trotman, R., Perfect, J., Lyon, G., Vazquez, J., Piwoz, J., Marr, K., Spindel, S., Wray, D., Garcia-Diaz, J., Strasfeld, L., Nolt, D., Subramanian, A., Schaenman, J., Taplitz, R., Miceli, M., Lee, S. A., Hong Nguyen, Pannaraj, P., Hashun, R., Limaye, A., Powderly, W., Cryptococcus Infection Network Coh 2020; 70 (2): 252–61


    Cryptococcosis is increasingly recognized in people without human immunodeficiency virus (HIV).A multicenter, prospective cohort study was performed in 25 US centers. Consenting patients were prospectively followed for ≤2 years. Neurological morbidities were assessed with longitudinal event depiction and functional scores (Montreal Cognitive Assessment [MoCA]). Risks of death were analyzed using Cox regression.One hundred forty-five subjects were enrolled. Most were male (95; 65.5%) and had immunosuppression (120; 82.8%), including solid organ transplant (SOT; 33.8%), autoimmunity (15.9%), and hematologic malignancies (11.7%). Disease involved the central nervous system (CNS) in 71 subjects (49%). Fever was uncommon, documented in 40 (27.8%) subjects, and absence was associated with diagnostic delay (mean: 48.2 vs 16.5 days; P = .007). Abnormal MoCA scores (<26) were predictive of CNS disease; low scores (<22) were associated with poor long-term cognition. Longitudinal event depiction demonstrated frequent complications in people with CNS disease; 25 subjects (35.2%) required >1 lumbar puncture and 8 (11.3%) required ventriculostomies. In multivariable models, older age (>60 years) was associated with higher risks of death (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.05-4.38; P = .036), and lower risks were noted with underlying hematologic malignancy (HR, 0.29; 95% CI, 0.09-0.98; P = .05) and prior SOT (HR, 0.153; 95% CI, 0.05-0.44; P = .001).Despite aggressive antifungal therapies, outcomes of CNS cryptococcosis in people without HIV are characterized by substantial long-term neurological sequelae. Studies are needed to understand mechanism(s) of cognitive decline and to enable better treatment algorithms.

    View details for DOI 10.1093/cid/ciz193

    View details for Web of Science ID 000506801400013

    View details for PubMedID 30855688

    View details for PubMedCentralID PMC6938979

  • Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. The New England journal of medicine Goldman, J. D., Lye, D. C., Hui, D. S., Marks, K. M., Bruno, R. n., Montejano, R. n., Spinner, C. D., Galli, M. n., Ahn, M. Y., Nahass, R. G., Chen, Y. S., SenGupta, D. n., Hyland, R. H., Osinusi, A. O., Cao, H. n., Blair, C. n., Wei, X. n., Gaggar, A. n., Brainard, D. M., Towner, W. J., Muñoz, J. n., Mullane, K. M., Marty, F. M., Tashima, K. T., Diaz, G. n., Subramanian, A. n. 2020


    Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 number, NCT04292899.).

    View details for DOI 10.1056/NEJMoa2015301

    View details for PubMedID 32459919

  • Infections Related to Biologics. Infectious disease clinics of North America Ho, D. Y., Subramanian, A. K. 2020; 34 (2): xiii-xvi

    View details for DOI 10.1016/j.idc.2020.04.001

    View details for PubMedID 32444015

  • Simultaneous Coccidioidomycosis and Phaeohyphomycosis in a Kidney Transplant Recipient: A Case Report and Literature Review. Transplant infectious disease : an official journal of the Transplantation Society Puing, A. G., Couture-Cossette, A. n., Wang, A. X., Zygourakis, C. C., Cheng, X. n., Stevens, B. A., Banaei, N. n., Novoa, R. A., Ho, D. Y., Subramanian, A. n. 2020: e13365


    Advances in solid organ transplantation have improved the survival of end-stage organ disease at the expense of an increased risk for opportunistic infections. Unusual clinical presentations and the possibility of concurrent infections make diagnosing invasive fungal infection (IFI) more difficult. Here we present a case of simultaneous vertebral infection caused by Coccidioides immitis-posadasii and subcutaneous phaeohyphomycosis due to Nigrograna mackinnonii in a kidney transplant recipient. The diagnosis of both infections required invasive procedures to obtain tissue and a high index of suspicion that more than one IFI could be present. A multidisciplinary team approach for the management of immunocompromised patients with suspected or diagnosed IFI is warranted.

    View details for DOI 10.1111/tid.13365

    View details for PubMedID 32533741

  • Characteristics and outcomes of coronavirus disease patients under nonsurge conditions, northern California, USA, March–April 2020 Emerging Infectious Diseases Ferguson, J., Rosser, J., Quintero, O., Scott, J., Subramanian, A., Gumma, M., Rogers, A., Kappagoda, S. 2020


    Limited data are available on the clinical presentation and outcomes of coronavirus disease (COVID-19) patients in the United States hospitalized under normal-caseload or nonsurge conditions. We retrospectively studied 72 consecutive adult patients hospitalized with COVID-19 in 2 hospitals in the San Francisco Bay area, California, USA, during March 13-April 11, 2020. The death rate for all hospitalized COVID-19 patients was 8.3%, and median length of hospitalization was 7.5 days. Of the 21 (29% of total) intensive care unit patients, 3 (14.3% died); median length of intensive care unit stay was 12 days. Of the 72 patients, 43 (59.7%) had underlying cardiovascular disease and 19 (26.4%) had underlying pulmonary disease. In this study, death rates were lower than those reported from regions of the United States experiencing a high volume of COVID-19 patients.

    View details for DOI 10.3201/eid2608.201776

  • Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation CLINICAL TRANSPLANTATION Subramanian, A. K., Theodoropoulos, N. M., Amer Soc Transplantation 2019; 33 (9)

    View details for DOI 10.1111/ctr.13513

    View details for Web of Science ID 000489762300026

  • Impact of Pretransplant Donor BK Viruria in Kidney Transplant Recipients JOURNAL OF INFECTIOUS DISEASES Tan, S. K., Huang, C., Sahoo, M. K., Weber, J., Kurzer, J., Stedman, M. R., Concepcion, W., Gallo, A. E., Alonso, D., Srinivas, T., Storch, G. A., Subramanian, A. K., Tan, J. C., Pinsky, B. A. 2019; 220 (3): 370–76
  • Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor-Related Papulopustular Eruption JAMA DERMATOLOGY Hirotsu, K., Dang, T. M., Li, S., Neal, J. W., Pugliese, S., Subramanian, A., Kwong, B. Y. 2019; 155 (7): 848–50
  • Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: case report and review of the literature. Transplant infectious disease : an official journal of the Transplantation Society Multani, A., Subramanian, A. K., Liu, A. Y. 2019: e13118


    Treatment of symptomatic candiduria is notoriously challenging because of the limited repository of antifungals that achieve adequate urinary concentrations. Fluconazole, amphotericin B-based products, and flucytosine are established treatment options for most Candida species. Candida krusei exhibits intrinsic resistance to fluconazole and decreased susceptibility to amphotericin B and flucytosine. In transplant patients, both amphotericin B-based products and flucytosine are less desirable due to their toxicities. Other triazole antifungals are unappealing because they do not achieve adequate urinary concentrations, have multiple toxicities, and interact with transplant-related immunosuppressive medications. Echinocandins are well-tolerated but have been traditionally deferred in the treatment of symptomatic funguria because of their poor urinary concentrations but there is a small but emerging body of literature supporting their use. Here, we present a case of successful eradication of chronic symptomatic Candida krusei urinary tract infection with micafungin 150 milligrams daily in a liver and kidney transplant recipient, and we review the literature on treatment of symptomatic candiduria. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/tid.13118

    View details for PubMedID 31111613

  • Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors AMERICAN JOURNAL OF TRANSPLANTATION Kwong, A. J., Wall, A., Melcher, M., Wang, U., Ahmed, A., Subramanian, A., Kwo, P. Y. 2019; 19 (5): 1380–87

    View details for DOI 10.1111/ajt.15162

    View details for Web of Science ID 000471342300016

  • Impact of Pre-Transplant Donor BK Viruria in Kidney Transplant Recipients. The Journal of infectious diseases Tan, S. K., Huang, C., Sahoo, M. K., Weber, J., Kurzer, J., Stedman, M. R., Concepcion, W., Gallo, A. E., Alonso, D., Srinivas, T., Storch, G. A., Subramanian, A. K., Tan, J. C., Pinsky, B. A. 2019


    BACKGROUND: BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients.METHODS: We prospectively collected pre-transplant plasma and urine samples from living and deceased kidney donors and performed BKV PCR and IgG testing on pre-transplant and serially collected post-transplant samples in kidney transplant recipients.RESULTS: Among deceased donors, 8.1%(17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4%(6/39) of living donors and 8.5%(4/47) of deceased donors of recipients at our institution (p=0.50). BKV VP1 sequencing revealed identical virus between donor-recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6%vs.7.8%, p<0.001) and viremia (66.6%vs.8.9%, p<0.001) with a shorter time to onset (log-rank, p<0.001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pre-transplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (p=0.31,0.75,0.51,respectively).DISCUSSION: Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at-risk for BKV complications.

    View details for PubMedID 30869132

  • Mycobacterium tuberculosis Infections in Solid Organ Transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clinical transplantation Subramanian, A. K., Theodoropoulos, N. M., Infectious Diseases Community of Practice of the American Society of Transplantation 2019: e13513


    These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention and management of tuberculosis in the pre- and post-transplant period. The challenges of screening for both latent and active TB in the setting of transplantation are reviewed. The use of interferon gamma release assays for detection of latent tuberculosis is discussed and compared to tuberculin skin testing. Given the limitations of both testing modality, it is important to consider exposure history and chest imaging. The clinical manifestations of active tuberculosis in transplantation are covered. New recommendations for treatment of latent tuberculosis and active tuberculosis are included. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30817030

  • Incidence of Active Tuberculosis Following Hematopoietic Cell Transplantation: A Small but Real Threat. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aronson, J. R., Rezvani, A. R., Subramanian, A. n. 2019

    View details for DOI 10.1093/cid/ciz592

    View details for PubMedID 31297538

  • Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor-Related Papulopustular Eruption. JAMA dermatology Hirotsu, K. n., Dang, T. M., Li, S. n., Neal, J. W., Pugliese, S. n., Subramanian, A. n., Kwong, B. Y. 2019

    View details for PubMedID 31017625

  • Use of Alternative Agents for Prevention of Opportunistic Infections in Heart and Lung Transplant Recipients CLINICAL INFECTIOUS DISEASES Epstein, D. J., Benamu, E., Subramanian, A. K. 2018; 67 (10): 1637–39

    View details for DOI 10.1093/cid/ciy397

    View details for Web of Science ID 000450051300025

  • Liver Transplantation for HCV Non-Viremic Recipients with HCV Viremic Donors. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Wall, A., Melcher, M., Wang, U., Ahmed, A., Subramanian, A., Kwo, P. Y. 2018


    In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing (NAT). Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12 weeks post-treatment (SVR-12) with DAA-based regimens, with a median time from transplant to treatment initiation of 43 days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380 days (IQR 263-434) post-transplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30378723

  • Native Kidney Cytomegalovirus Nephritis and Cytomegalovirus Prostatitis in a Kidney Transplant Recipient. Transplant infectious disease : an official journal of the Transplantation Society Tan, S. K., Cheng, X. S., Kao, C., Weber, J., Pinsky, B. A., Gill, H. S., Busque, S., Subramanian, A. K., Tan, J. C. 2018: e12998


    We present a case of cytomegalovirus (CMV) native kidney nephritis and prostatitis in a CMV D+/R- kidney transplant recipient who had completed six months of CMV prophylaxis four weeks prior to the diagnosis of genitourinary CMV disease. The patient had a history of benign prostatic hypertrophy and urinary retention that required self-catheterization to relieve high post-voiding residual volumes. At 7 months post-transplant, he was found to have a urinary tract infection, moderate hydronephrosis of the transplanted kidney, and severe hydroureteronephrosis of the native left kidney and ureter, and underwent native left nephrectomy and transurethral resection of the prostate. Histopathologic examination of kidney and prostate tissue revealed CMV inclusions consistent with invasive CMV disease. This case highlights that CMV may extend beyond the kidney allograft to involve other parts of the genitourinary tract, including the native kidneys and prostate. Furthermore, we highlight the tissue-specific risk factors that preceded CMV tissue invasion. In addition to concurrent diagnoses, health care providers should have a low threshold for considering late-onset CMV disease in high-risk solid organ transplant recipients presenting with signs and symptoms of genitourinary tract pathology. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30203504

  • Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors TRANSPLANTATION Santoro-Lopes, G., Subramanian, A. K., Molina, I., Maria Aguado, J., Rabagliatti, R., Len, O. 2018; 102 (2): S60–S65

    View details for PubMedID 29381579

  • Use of Alternative Agents for Prevention of Opportunistic Infections in Heart and Lung Transplant Recipients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Epstein, D. J., Benamu, E. n., Subramanian, A. n. 2018

    View details for PubMedID 29771330

  • Prevention and Management of Tuberculosis in Solid Organ Transplant Recipients. Infectious disease clinics of North America Epstein, D. J., Subramanian, A. K. 2018; 32 (3): 703–18


    Solid organ transplant recipients are at an increased risk of tuberculosis and transplant candidates should be screened early in their evaluation with a detailed history, tuberculin skin test or tuberculosis interferon-gamma release assay, and chest radiograph. For latent tuberculosis treatment, isoniazid and rifamycin-based regimens have advantages and disadvantages; treatment decisions should be customized. Tuberculosis after solid organ transplantation generally occurs after months or years; early infections should raise the possibility of donor-derived infections. Tuberculosis diagnosis and treatment in solid organ transplant recipients may be complicated by protean manifestations, drug interactions, and adverse drug reactions.

    View details for PubMedID 30146031

  • False-positive QuantiFERON TB-Gold test due to Mycobacterium gordonae DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE Gajurel, K., Subramanian, A. K. 2016; 84 (4): 315-317


    We report a case of QuantiFERON TB-Gold conversion associated to Mycobacterium gordonae in an elderly male from an assisted living facility without known risk factors for tuberculosis. This knowledge of environmental mycobacteria causing positive quantiferon assays is important to avoid unnecessary treatment of false-positive latent tuberculosis, especially in the absence of well-established positive predictive value of quantiferon conversion.

    View details for DOI 10.1016/j.diagmicrobio.2015.10.020

    View details for Web of Science ID 000372768800008

  • False-positive hepatitis C virus serology after placement of a ventricular assistance device TRANSPLANT INFECTIOUS DISEASE Durand, C. M., Marr, K. A., OSTRANDER, D., Subramanian, A., Valsamakis, A., Cox, A., Neofytos, D. 2016; 18 (1): 146-149


    Ventricular assist devices (VADs) have been associated with immune activation and sensitization. We observed several cases of false-positive (FP) hepatitis C virus (HCV) antibody (Ab) tests in patients being evaluated for orthotopic heart transplant (OHT), prompting us to investigate this further.We reviewed all VAD and OHT cases at Johns Hopkins from 2005 to 2012. FP HCV serology was defined as an equivocal or low-positive HCV Ab, plus either (i) a negative recombinant immunoblot (RIBA) and/or HCV nucleic acid test (NAT), or (ii) an indeterminate RIBA and negative NAT.In 53 patients with available HCV testing, nearly 40% of patients (21/53: 39.6%) developed FP HCV Ab tests after VAD placement: 4 patients had negative NAT, 12 had negative RIBA, and 5 had an indeterminate RIBA and negative NAT. All patients with indeterminate RIBA tests had isolated reactivity to the same HCV protein, c100p/5-1-1p (NS4b protein). In 3 of 4 VAD patients who had OHT and repeat HCV Ab testing after VAD removal, repeat HCV Ab was negative (699-947 days after OHT); in 1 case, FP HCV serology persisted (5 days after OHT). Thirteen patients had OHT alone and none developed a FP HCV Ab.FP HCV Ab results following VAD placement are very common. Reversal of FP serology in several patients after VAD removal is suggestive of a possible association with the VAD hardware. Clinicians should be aware of this phenomenon, as it could lead to delays in determining eligibility for OHT and increased costs.

    View details for DOI 10.1111/tid.12483

    View details for Web of Science ID 000370449800021

    View details for PubMedID 26565742

  • Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls. AIDS (London, England) Roland, M. E., Barin, B., Huprikar, S., Murphy, B., Hanto, D. W., Blumberg, E., Olthoff, K., Simon, D., Hardy, W. D., Beatty, G., Stock, P. G. 2016; 30 (3): 435-44


    To evaluate the impact of liver and kidney transplantation on survival in HIV-positive transplant candidates and compare outcomes between HIV-positive and negative recipients.Observational cohort of HIV-positive transplant candidates and recipients and secondary analysis comparing study recipients to HIV-negative national registry controls.We fit proportional hazards models to assess transplantation impact on mortality among recipients and candidates. We compared time to graft failure and death with HIV-negative controls in unmatched, demographic-matched, and risk-adjusted models.There were 17 (11.3%) and 46 (36.8%) deaths among kidney and liver recipients during a median follow-up of 4.0 and 3.5 years, respectively. Transplantation was associated with survival benefit for HIV-infected liver recipients with model for end-stage liver disease (MELD) greater than or equal 15 [hazard ratio (HR) 0.1; 95% confidence interval (CI) 0.05, 0.01; P < 0.0001], but not for MELD less than 15 (HR 0.7; 95% CI 0.3, 1.8; P = 0.43) or for kidney recipients (HR 0.6; 95% CI 0.3, 1.4; P = 0.23). In HIV-positive kidney recipients, unmatched and risk-matched analyses indicated a marginally significant HR for graft loss [1.3 (P = 0.07) and HR 1.4 (P = 0.052)]; no significant increase in risk of death was observed. All models demonstrated a higher relative hazard of graft loss or death in HIV-positive liver recipients; the absolute difference in the proportion of deaths was 6.7% in the risk-matched analysis.Kidney transplantation should be standard of care for well managed HIV-positive patients. Liver transplant in candidates with high MELD confers survival benefit; transplant is a viable option in selected candidates. The increased mortality risk compared with HIV-negative recipients was modest.ClinicalTrials.Gov; NCT00074386;

    View details for DOI 10.1097/QAD.0000000000000934

    View details for PubMedID 26765937

    View details for PubMedCentralID PMC4957135

  • Tolerability of Fluoroquinolones in Management of Latent Tuberculosis in Liver Transplant Candidates CLINICAL INFECTIOUS DISEASES Tien, V., Robilotti, E., Callister, D., Subramanian, A., Lutchman, G., Ho, D. Y. 2015; 61 (10): 1631–U154

    View details for PubMedID 26224000

  • Tuberculosis in solid organ transplant candidates and recipients: current and future challenges. Current opinion in infectious diseases Subramanian, A. K. 2014; 27 (4): 316-321


    Tuberculosis (TB) infection in solid organ transplant recipients poses unique diagnostic and treatment challenges. Recent guidelines for prevention of donor-derived TB and updates on TB diagnostics and treatment in the transplant setting are reviewed as follows.Prevention of donor-derived TB can be optimized by careful screening of donors with risk factors for TB, with effort taken to rule out active TB in the donor, and targeted treatment of recipients. However, transmission may still occur, especially through lung allografts, given limitations of screening tests and treatment strategies. Diagnostics for latent tuberculosis infection are limited in sensitivity and have a relatively low predictive value for development of active TB. Treatment options for latent and active TB carry risks that are still being elucidated in transplant patients, such as a dysregulated inflammatory response manifested by immune reconstitution syndrome.More sensitive diagnostics in deceased donors are needed to quantify the risk of TB transmission and the risk of progression to active tuberculosis in those with latent tuberculosis infection prior to transplant. Novel TB therapies of shorter duration with less toxicity for both latent and active TB will be of great benefit to transplant patients.

    View details for DOI 10.1097/QCO.0000000000000082

    View details for PubMedID 24977684

  • Epidemiology, risk factors, and outcomes of Clostridium difficile infection in kidney transplant recipients TRANSPLANT INFECTIOUS DISEASE Neofytos, D., Kobayashi, K., Alonso, C. D., Cady-Reh, J., Lepley, D., Harris, M., Desai, N., Kraus, E., Subramanian, A., TREADWAY, S., OSTRANDER, D., Thompson, C., Marr, K. 2013; 15 (2): 134-141


    We sought to describe the epidemiology and risk factors for Clostridium difficile infection (CDI) among kidney transplant recipients (KTR) between 1 January 2008 and 31 December 2010.A single-institution retrospective study was conducted among all adult KTR with CDI, defined as a positive test for C. difficile by a cell cytotoxic assay for C. difficile toxin A or B or polymerase chain reaction test for toxigenic C. difficile.Among 603 kidney transplants performed between 1 January 2008 and 31 December 2010, 37 (6.1%) patients developed CDI: 12 (of 128; 9.4%) high-risk (blood group incompatible and/or anti-human leukocyte antigen donor-specific antibodies) vs. 25 (of 475; 5.3%, P = 0.08) standard-risk patients. The overall rate of CDI increased from 3.7% in 2008 to 9.4% in 2010 (P = 0.05). The median time to CDI diagnosis was 9 days, with 27 (73.0%) patients developing CDI within the first 30 days after their transplant, and 14 (51.8%) developing CDI within 7 days. A case-control analysis of 37 CDI cases and 74 matched controls demonstrated the following predictors for CDI among KTR: vancomycin-resistant Enterococcus colonization before transplant (odds ratio [OR]: 3.6, P = 0.03), receipt of an organ from Centers for Disease Control high-risk donor (OR: 5.9, P = 0.006), and administration of high-risk antibiotics within 30 days post transplant (OR: 6.6, P = 0.001).CDI remains a common early complication in KTR, with rates steadily increasing during the study period. Host and transplant-related factors and exposure to antibiotics appeared to significantly impact the risk for CDI among KTR.

    View details for DOI 10.1111/tid.12030

    View details for Web of Science ID 000317287900011

    View details for PubMedID 23173772

  • Mycobacterium tuberculosis Infections in Solid Organ Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Subramanian, A. K., Morris, M. I. 2013; 13: 68-76

    View details for DOI 10.1111/ajt.12100

    View details for Web of Science ID 000315907900009

    View details for PubMedID 23465000

  • Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection LIVER TRANSPLANTATION Terrault, N. A., Roland, M. E., Schiano, T., Dove, L., Wong, M. T., Poordad, F., Ragni, M. V., Barin, B., Simon, D., Olthoff, K. M., Johnson, L., Stosor, V., Jayaweera, D., Fung, J., Sherman, K. E., Subramanian, A., Millis, J. M., Slakey, D., Berg, C. L., Carlson, L., Ferrell, L., Stablein, D. M., Odim, J., Fox, L., Stock, P. G. 2012; 18 (6): 716-726


    Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCV-positive donor (HR = 2.5), and a body mass index < 21 kg/m(2) (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes.

    View details for DOI 10.1002/lt.23411

    View details for Web of Science ID 000304524000012

    View details for PubMedID 22328294

  • Fungal infection presenting as giant cell tubulointerstitial nephritis in kidney allograft TRANSPLANT INFECTIOUS DISEASE Bagnasco, S. M., Subramanian, A. K., Desai, N. M. 2012; 14 (3): 288-291


    Giant cell tubulointerstitial nephritis in the kidney allograft caused by infection is rare, and donor-transmitted infection in transplanted kidneys is also rare. In this case report, we describe an unusual histological manifestation of Candida albicans in the graft biopsy of a 53-year-old male kidney transplant recipient with decreased renal function 12 days post transplant. Several giant cells were present in the tubulointerstitial inflammation, as well as yeasts, with no evidence of rejection, and the histological diagnosis was confirmed by urine culture. Donor urine culture was positive for C. albicans, suggestive of a possible donor-transmitted infection. Prompt antifungal treatment eradicated the infection, and averted systemic spread. To our knowledge, there are no previous reports of Candida infection with giant cell tubulointerstitial nephritis in human renal allograft.

    View details for DOI 10.1111/j.1399-3062.2011.00676.x

    View details for Web of Science ID 000305076700009

    View details for PubMedID 22093412

  • Donor-derived organ transplant transmission of coccidioidomycosis TRANSPLANT INFECTIOUS DISEASE Dierberg, K. L., Marr, K. A., Subramanian, A., Nace, H., Desai, N., Locke, J. E., Zhang, S., Diaz, J., Chamberlain, C., Neofytos, D. 2012; 14 (3): 300-304


    Coccidioidomycosis in solid organ transplant recipients most often occurs as a result of primary infection or reactivation of latent infection. Herein, we report a series of cases of transplant-related transmission of coccidioidomycosis from a single donor from a non-endemic region whose organs were transplanted to 5 different recipients. In all, 3 of the 5 recipients developed evidence of Coccidioides infection, 2 of whom had disseminated disease. The degree of T-cell immunosuppression and timing of antifungal therapy initiation likely contributed to development of disease and disease severity in these recipients. This case series highlights the importance of having a high index of suspicion for Coccidioides infection in solid organ transplant recipients, even if the donor does not have known exposure, given the difficulties of obtaining a detailed and accurate travel history from next-of-kin.

    View details for DOI 10.1111/j.1399-3062.2011.00696.x

    View details for Web of Science ID 000305076700012

    View details for PubMedID 22176496

  • Actinomucor elegans as an Emerging Cause of Mucormycosis JOURNAL OF CLINICAL MICROBIOLOGY Mahmud, A., Lee, R., Munfus-McCray, D., Kwiatkowski, N., Subramanian, A., Neofytos, D., Carroll, K., Zhang, S. X. 2012; 50 (3): 1092-1095


    We report an invasive mucormycosis caused by Actinomucor elegans in a patient with refractory aplastic anemia. The organism was isolated from a necrotic skin lesion on the patient's left arm and demonstrated angioinvasive features on histopathology examination. In contrast to three cases described previously, we describe the first case of A. elegans invasive fungal infection in an immunocompromised patient. This report, along with the three previously reported cases, is convincing evidence that A. elegans is an emerging fungal pathogen capable of causing invasive mucormycosis in humans.

    View details for DOI 10.1128/JCM.05338-11

    View details for Web of Science ID 000300997800090

    View details for PubMedID 22205785

    View details for PubMedCentralID PMC3295095

  • Antimicrobial prophylaxis regimens following transplantation CURRENT OPINION IN INFECTIOUS DISEASES Subramanian, A. K. 2011; 24 (4): 344-349


    Infection remains a major cause of morbidity and mortality following transplantation, and antimicrobial prophylaxis regimens continue to improve. This review summarizes the important studies on prophylaxis following solid organ transplant (SOT) and hematopoietic stem cell transplantation (HSCT) published in the last 18 months.Many transplant centers use 100 days of antivirals to prevent cytomegalovirus (CMV) disease after SOT. Randomized trials comparing 100-day regimens to 200 days in high-risk kidney recipients and 12 months in lung transplant patients showed distinct advantages of longer duration CMV prophylaxis. Prevention of hepatitis B virus after transplant is changing as regimens with low dose or no hepatitis B immunoglobulin are being evaluated. International consensus guidelines on the prevention of infection after stem cell transplantation are summarized and newer studies on the prevention of invasive fungal infection in this population are reviewed.In organ transplantation, routine antibacterial, antiviral, and antifungal regimens need to be tailored to address donor-transmitted infections, serological risk status of recipients, and measurable antifungal drug levels. Recent studies indicate that longer duration prophylaxis for CMV may have advantages in high-risk SOT recipients. After HSCT, regimens require adjustment based on immunological risks associated with transplant type and presence of graft vs. host disease.

    View details for DOI 10.1097/QCO.0b013e328348b379

    View details for Web of Science ID 000292185700007

    View details for PubMedID 21673573

  • Provider Response to a Rare but Highly Publicized Transmission of HIV Through Solid Organ Transplantation ARCHIVES OF SURGERY Kucirka, L. M., Ros, L., Subramanian, A. K., Montgomery, R. A., Segev, D. L. 2011; 146 (1): 41-45


    On November 13, 2007, the first reported case in 20 years of HIV (human immunodeficiency virus) transmission from a Centers for Disease Control and Prevention high-risk donor (HRD) made national headlines. We sought to characterize change in the practice of transplant surgeons resulting from this rare event.We performed a survey between January 17, 2008, and April 15, 2008, assessing attitudes and practices of transplant surgeons regarding HRDs. Descriptions of changes in practice after the event were categorized, and associations between responses and regional-, center-, and physician-level factors were studied.Transplant centers in the United States.Four hundred twenty-two transplant surgeons in current practice.Changing practice following the 2007 HIV transmission event.Among surgeons who responded to the survey, 31.6% changed their practice following the event. Also, 41.7% decreased use of HRDs, 34.5% increased emphasis on informed consent, 16.7% increased use of nucleic acid testing, and 6.0% implemented a formal policy. Ranking fear of being sued or hospital pressure as important disincentives to HRD use was associated with more than 2-fold higher odds of changing practice. Ranking medical risks of HIV as an important disincentive was associated with 8.29-fold higher odds of decreasing HRD use.The most common responses to this rare event were avoidance (decreased HRD use) and assurance (increased emphasis on informed consent) behaviors rather than patient safety measures (increased use of nucleic acid testing and implementation of formal policies), suggesting that fear of legal or regulatory consequences was the biggest driver of physician decision making and that the current litigious environment is failing to protect patient interests.

    View details for Web of Science ID 000286235500014

    View details for PubMedID 21242444

  • Recommended curriculum for subspecialty training in transplant infectious disease on behalf of the American Society of Transplantation Infectious Diseases Community of Practice Educational Initiatives Working Group TRANSPLANT INFECTIOUS DISEASE Avery, R., CLAUSS, H., Danziger-Isakov, L., Davis, J., Doucette, K., van Duin, D., FISHMAN, J., Gunseren, F., Humar, A., Husain, S., Isada, C., Julian, K., Kaul, D., Kumar, D., Martin, S., Michaels, M., Morris, M., SILVEIRA, F., Subramanian, A. 2010; 12 (3): 190-194


    The American Society of Transplantation Infectious Diseases (ID) Community of Practice has established an education workgroup to identify core components of a curriculum for training specialists in transplant ID. Clinical, laboratory, and research training form the triad of components on which an additional year of ID training, dedicated to the care of solid organ and hematopoietic stem cell transplant recipients, should be based. The recommended training environment would have access to adequate numbers of transplant patients, along with qualified faculty committed to teaching specialized fellows in this area. The learning objectives for both inpatient and outpatient clinical training are presented. The laboratory component requires trainees to attain expertize in utilizing and interpreting cutting-edge diagnostics used in transplant medicine. The research component may involve basic science, and translational or clinical research individualized to the trainee. Finally, suggestions for evaluation of both the fellows and the training program are provided.

    View details for DOI 10.1111/j.1399-3062.2010.00510.x

    View details for Web of Science ID 000278315600002

    View details for PubMedID 20624259

  • Infections in Transplant and Oncology Patients Preface INFECTIOUS DISEASE CLINICS OF NORTH AMERICA Marr, K. A., Subramanian, A. K. 2010; 24 (2): XIII-XV

    View details for PubMedID 20466268

  • MELD Score Is an Important Predictor of Pretransplantation Mortality in HIV-Infected Liver Transplant Candidates GASTROENTEROLOGY Subramanian, A., Sulkowski, M., Barin, B., Stablein, D., Curry, M., Nissen, N., Dove, L., Roland, M., Florman, S., Blumberg, E., Stosor, V., Jayaweera, D. T., Huprikar, S., Fung, J., Pruett, T., Stock, P., Ragni, M. 2010; 138 (1): 159-164


    Human immunodeficiency virus (HIV) infection accelerates liver disease progression in patients with hepatitis C virus (HCV) and could shorten survival of those awaiting liver transplants. The Model for End-Stage Liver Disease (MELD) score predicts mortality in HIV-negative transplant candidates, but its reliability has not been established in HIV-positive candidates.We evaluated predictors of pretransplantation mortality in HIV-positive liver transplant candidates enrolled in the Solid Organ Transplantation in HIV: Multi-Site Study (HIVTR) matched 1:5 by age, sex, race, and HCV infection with HIV-negative controls from the United Network for Organ Sharing.Of 167 HIVTR candidates, 24 died (14.4%); this mortality rate was similar to that of controls (88/792, 11.1%, P = .30) with no significant difference in causes of mortality. A significantly lower proportion of HIVTR candidates (34.7%) underwent liver transplantation, compared with controls (47.6%, P = .003). In the combined cohort, baseline MELD score predicted pretransplantation mortality (hazard ratio [HR], 1.27; P < .0001), whereas HIV infection did not (HR, 1.69; P = .20). After controlling for pretransplantation CD4(+) cell count and HIV RNA levels, the only significant predictor of mortality in the HIV-infected subjects was pretransplantation MELD score (HR, 1.2; P < .0001).Pretransplantation mortality characteristics are similar between HIV-positive and HIV-negative candidates. Although lower CD4(+) cell counts and detectable levels of HIV RNA might be associated with a higher rate of pretransplantation mortality, baseline MELD score was the only significant independent predictor of pretransplantation mortality in HIV-infected liver transplant candidates.

    View details for DOI 10.1053/j.gastro.2009.09.053

    View details for Web of Science ID 000273427700026

    View details for PubMedID 19800334

    View details for PubMedCentralID PMC2826170

  • Mycobacterium tuberculosis in Solid Organ Transplant Recipients AMERICAN JOURNAL OF TRANSPLANTATION Subramanian, A., Dorman, S. 2009; 9: S57-S62
  • Nontuberculous Mycobacteria in Solid Organ Transplant Recipients AMERICAN JOURNAL OF TRANSPLANTATION Dorman, S., Subramanian, A. 2009; 9: S63-S69
  • Detection and treatment of Strongyloides hyperinfection syndrome following lung transplantation TRANSPLANT INFECTIOUS DISEASE Balagopal, A., Mills, L., Shah, A., Subramanian, A. 2009; 11 (2): 149-154


    Strongyloides hyperinfection syndrome has not been reported in lung transplant recipients. We describe the case of a 61-year-old Peruvian man, who received bilateral lung transplants for idiopathic pulmonary fibrosis, and subsequently developed persistent fever with pulmonary infiltrates, ventilator dependence, and pneumothoraces. Bronchoalveolar lavage (BAL) cultures for bacteria, viruses, and fungi were negative, but testing for ova and parasites from BAL fluid revealed Strongyloides stercoralis larvae on day 16 post transplant. He was successfully treated with albendazole and ivermectin, and immunosuppression was reduced. BAL fluid also grew Mycobacterium kansasii, for which he received combination anti-mycobacterial therapy. This case illustrates the importance of screening for parasitic infections before transplantation in the appropriate clinical setting, and demonstrates the utility of direct diagnostic evaluation for parasitic infections in at-risk post-transplant patients with unexplained illnesses.

    View details for DOI 10.1111/j.1399-3062.2009.00375.x

    View details for Web of Science ID 000265015600010

    View details for PubMedID 19302281

  • Renal Transplant in HIV-Positive Patients Long-term Outcomes and Risk Factors for Graft Loss ARCHIVES OF SURGERY Locke, J. E., Montgomery, R. A., Warren, D. S., Subramanian, A., Segev, D. L. 2009; 144 (1): 83-86


    In the highly active antiretroviral therapy era of improved survival for patients living with human immunodeficiency virus (HIV), chronic kidney disease now accounts for more than 10% of HIV-related deaths. The role of kidney transplant among HIV-positive patients with end-stage renal disease is under consideration, but concerns remain regarding allocation of kidneys to these patients when long-term benefit has not been firmly established. We evaluated 39,501 patients undergoing a renal transplant between January 1, 2004, and June 30, 2006, identified through the United Network for Organ Sharing national registry and found that, although long-term allograft survival is lower among HIV-positive recipients, controllable risk factors may explain this disparity. With proper donor selection and transplant recipient management, including the avoidance of prolonged cold ischemic time, use of living donors, and determination of optimal immunosuppression dosing before transplant, long-term graft survival comparable to that in HIV-negative patients can be achieved.

    View details for Web of Science ID 000262551400021

    View details for PubMedID 19153330

  • Incidence and risk factors for hepatocellular carcinoma after solid organ transplantation TRANSPLANTATION Hoffmann, C. J., Subramanian, A. K., Cameron, A. M., Engels, E. A. 2008; 86 (6): 784-790


    Solid organ transplant recipients commonly are infected with hepatitis viruses, are immunosuppressed, and have other potential hepatocellular carcinoma (HCC) risk factors.We studied de novo HCC incidence arising after transplant using U.S. registry data (223,660 recipients, 1987-2005). We used proportional hazards regression to identify HCC risk factors and calculated standardized incidence ratios (SIRs) to compare HCC risk with that in the general population.Based on 74 cases reported by transplant centers to the registry, HCC incidence was 6.5 per 100,000 person-years among kidney, heart, and lung (non-liver) recipients and 25 per 100,000 person-years among liver recipients. Hepatocellular carcinoma incidence among non-liver recipients was independently associated with hepatitis B surface antigenemia (hazard ratio [HR] 9.7, 95% confidence interval [CI] 2.8-33), hepatitis C virus (HCV) infection (HR 6.9, 95% CI 2.5-19), and diabetes mellitus (HR 2.8, 95% CI 1.2-6.6). Among liver recipients, HCC incidence was associated with advancing age (P<0.001), male sex (HR 4.6, 95% CI 1.4-16), HCV infection (HR 3.1, 95% CI 1.3-7.2), and diabetes mellitus (HR 2.7, 95% CI 1.2-6.2). Among non-liver recipients, overall HCC incidence was similar to the general population (SIR 0.8) but elevated among those with HCV (3.4) or hepatitis B surface antigenemia (6.5). Hepatocellular carcinoma incidence among liver transplant recipients was elevated overall (SIR 3.4) and especially among those with HCV (5.0) or diabetes mellitus (6.2).Hepatocellular carcinoma incidence is elevated among liver transplant recipients and subsets of non-liver recipients. These risk factors indicate the need for improved control of viral hepatitis after solid organ transplantation.

    View details for DOI 10.1097/TP.0b013e3181837761

    View details for Web of Science ID 000259594600007

    View details for PubMedID 18813102

    View details for PubMedCentralID PMC2714173

  • The high-risk donor: viral infections in solid organ transplantation CURRENT OPINION IN ORGAN TRANSPLANTATION Singer, A. L., Kucirka, L. M., Namuyinga, R., Hanrahan, C., Subramanian, A. K., Segev, D. L. 2008; 13 (4): 400-404


    Recently, four organ recipients were infected with HIV through transplantation, raising questions about current serologic testing policies. Currently, the decision to use enzyme-linked immunosorbent assay or nucleic acid testing, an expensive and time-consuming method capable of detecting more recent infections, is left up to individual organ procurement organizations. The purpose of this review was to present estimates of the window period between infection and detection by enzyme-linked immunosorbent assay and nucleic acid testing for HIV, hepatitis B virus, and hepatitis C virus; and to evaluate the impact of those infections on posttransplant outcomes.Nucleic acid testing for HIV can detect infections 12-13 days earlier than enzyme-linked immunosorbent assay; in the case of hepatitis B virus, infections are detected 21.8-36 days earlier; and in the case of hepatitis C virus, infections are detected 26-60 days earlier. Studies indicate that it is possible to manage all three infections posttransplant. HIV/hepatitis C virus coinfections seem to present the greatest posttransplant management challenges due to drug toxicities.Nucleic acid testing can reduce the window period and thus increase the probability of detecting viral infections. HIV, hepatitis B virus, and hepatitis C virus positive organs may be appropriate for use in some situations; nucleic acid testing helps patients and physicians make informed decisions about their use.

    View details for Web of Science ID 000258258500012

    View details for PubMedID 18685336

  • Should a prisoner be placed on the organ transplant waiting list? The virtual mentor : VM Cameron, A. M., Subramanian, A. K., Sulkowski, M. S., Thomas, D. L., Nelson, K. E. 2008; 10 (2): 88-91
  • West Nile virus encephalitis in a kidney transplant recipient AMERICAN JOURNAL OF TRANSPLANTATION Shepherd, J. C., Subramanian, A., Montgomery, R. A., Samaniego, M. D., Gong, G., Bergmann, A., Blythe, D., Dropulic, L. 2004; 4 (5): 830-833


    We describe a case of West Nile virus encephalitis in a 54-year-old kidney transplant recipient. The clinical course was rapid and fatal. Serial CSF samples showed an evolving mononuclear pleiocytosis and serial MRIs showed increasing signs of cytotoxic edema in her basal ganglia. Seroepidemiological testing indicated that the infection was most likely acquired from transfusion of fresh frozen plasma at the time of transplantation.

    View details for DOI 10.1111/j.1600-6143.2004.00410.x

    View details for Web of Science ID 000221223900026

    View details for PubMedID 15084182

  • Correlation of Chlamydia pneumoniae infection and severity of accelerated graft arteriosclerosis after cardiac transplantation TRANSPLANTATION Subramanian, A. K., Quinn, T. C., Kickler, T. S., Kasper, E. K., Tucker, P. C. 2002; 73 (5): 761-764


    Chlamydia pneumoniae has been associated with atherosclerosis, although its role in the process is not clearly defined. Heart transplant recipients are known to have high titers of antibodies to C. pneumoniae, and the organism has been recovered from the coronary arteries of both transplant recipients and donors. This study evaluated association between C. pneumoniae infection and accelerated graft arteriosclerosis (AGA), also known as cardiac allograft vasculopathy (CAV), after cardiac transplantation.A case-control study was performed with 54 heart transplant recipients at the Johns Hopkins Hospital. Severe cases had >50% luminal narrowing on cardiac catheterization, mild cases <50% narrowing, and controls were free of arteriosclerotic disease. Blood specimens were examined for C. pneumoniae serology and DNA detection by polymerase chain reaction (PCR) assays.For every twofold increase in geometric mean C. pneumoniae immunoglobulin (Ig)G titer, the odds ratio for severe AGA versus controls was 3.13 (P=0.03) and for mild AGA versus control patients was 1.61 (P=0.45). On Kaplan-Meier survival analysis there was a nonsignificant trend toward faster development of CAV in patients with higher C. pneumoniae antibody titers. Overall, 29% of heart transplant patients evaluated had evidence of circulating C. pneumoniae DNA by PCR, without a statistical difference between groups.C. pneumoniae IgG titer correlates with severity of allograft arteriosclerosis after cardiac transplantation. Circulating C. pneumoniae DNA is detectable by PCR in up to 30% of cardiac transplant recipients, but this does not correlate with severity of allograft vasculopathy.

    View details for Web of Science ID 000174717100018

    View details for PubMedID 11907424

  • Cutaneous zygomycosis (mucormycosis) NEW ENGLAND JOURNAL OF MEDICINE Carpenter, C. F., Subramanian, A. K. 1999; 341 (25): 1891-1891
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