The population of iatrogenic immunocompromised individuals is steadily rising as we continue to improve in our ability to manage diseases, including cancer, autoimmune disease, and end-organ dysfunction, with increasing access to novel agents and transplantation. Enhanced survivorship allows these patients to return to their home communities and lives, leading to an increased number of immunocompromised patients across all healthcare systems. However, expertise in immunocompromised host infectious diseases or transplant ID (TID) is concentrated in urban centers and often in academic settings. In this article, we review three cases to highlight common immunosuppressed groups that can be encountered in any health system: solid organ transplantation, hematologic malignancy, and autoimmune disease. The cases describe common illness scripts and key management considerations for the opportunistic pathogens highlighted. Finally, we outline high-yield references that can support clinical care of these patients for those interested, whether they be community-based general infectious diseases clinicians or infectious diseases fellows considering dedicated training in TID. The standards and expectations for immunocompromised infectious diseases training in both general infectious diseases fellowships and dedicated TID training are still being established. There are many societies and groups focused on addressing this need, and the importance of their collaboration and efforts is emphasized by our cases. Immunocompromising conditions are no longer niche, but rather an expected and substantial population of hospitalized patients everywhere. We will need the entire infectious diseases workforce, as well as further recruitment and retention of the next generation of physicians, to meet this ever-increasing demand.

People with HIV-1 have higher risk for rejection after kidney transplantation but the mechanism is poorly understood. As HIV latency promotes immune dysregulation and chronic inflammation, we evaluated whether the size of the HIV latent viral reservoir (LVR) at baseline and through 52-weeks is associated with rejection in kidney transplant recipients with HIV from donors with and without HIV. Using the intact proviral DNA assay, we found no differences in the LVR between those who experienced rejection (n = 14) versus those who did not (N = 55) regardless of donor HIV status. These data support the feasibility of HIV+ to HIV+ organ transplantation. Clinical Trials Registration. NCT03500315.

We evaluated the effectiveness of annual LTBI screening via IGRA in people with HIV in non-endemic settings over 5 years. Out of 1898 patients with at least 2 IGRAs, only 12 developed new LTBI, highlighting the low yield of universal screening. Findings support targeted screening per current guidelines.

BACKGROUND Transplanting kidneys from donors with HIV to recipients with HIV has become standard clinical practice. However, donors with HIV may have higher prevalence of viral and bacterial infections and autoimmunity that could increase allograft rejection in recipients. METHODS We included deceased kidney donors (60 with HIV and 41 without HIV) who participated in a multicenter prospective study of HIV kidney transplantation between April 2018 and September 2021. Using phage immunoprecipitation sequencing, we compared the human antibody repertoire (allergens, autoantibodies, viruses, and bacterial toxins) between donors with and without HIV and evaluated their association with recipient allograft rejection. Moderated t tests were used to assess reactivity and a multivariate logistic regression model adjusted for donor sex and kidney donor profile index assessed the association between donor adenovirus reactivity and recipient allograft rejection. RESULTS Compared with donors without HIV, donors with HIV had lower BMI and were more likely to be African American. The median number of positive autoantibodies was marginally higher among donors with HIV (499 [IQR, 357, 579]) compared with that of donors without HIV (395 [IQR, 256, 538], P = 0.058). Donors with HIV additionally had significantly higher antibody reactivity to Epstein-Barr virus and cytomegalovirus ( q < 0.05). Among all donors with and without HIV, antibodies against adenovirus were significantly associated with increased rejection among recipients, including after adjusting for false discovery ( q < 0.05) and also adjusting for demographic factors using multivariable logistic regression (odds ratio = 4.97; 95% CI = 1.89–13.61). CONCLUSION The presence of antibodies against adenovirus infection in kidney donors with HIV may be associated with allograft rejection. TRIAL REGISTRATION ClinicalTrials.gov NCT03500315. FUNDING US NIH.

Background Strongyloides stercoralis infection can be associated with high mortality in solid organ transplant (SOT) recipients, yet global practices regarding screening and management remain poorly characterized. We conducted an international survey to evaluate knowledge, screening, and management practices among healthcare workers (HCWs) involved in SOT care.Methods We performed a cross-sectional, web-based survey of HCWs caring for SOT candidates and recipients. The survey assessed provider characteristics, knowledge of strongyloidiasis, as well as screening and management practices. Descriptive statistics were used to summarize responses.Results A total of 101 HCWs responded, including 65 (64%) infectious diseases (ID) providers and 36 (36%) non-ID providers. Knowledge gaps were identified regarding transmission and mortality, particularly among non-ID providers. Overall, 85% of respondents reported screening SOT candidates for S. stercoralis; among those who screen, serology is the most commonly used method. Screening strategies varied by geographic region, with universal screening more common in endemic areas and targeted screening in non-endemic regions. Management practices, including approaches to indeterminate or negative test results, showed substantial heterogeneity.Conclusions This international survey demonstrates considerable variability in knowledge, screening, and management of strongyloidiasis among HCWs involved in SOT care. These findings highlight opportunities for improved education, clearer guidance, and greater standardization of practices related to Strongyloides infection to avoid unnecessary morbidity.

BACKGROUND:Few studies have examined pretransplant CD4 count and risk of post-kidney transplant (KT) infection in persons with HIV (PWH). METHODS:This multi-center, retrospective cohort study included adult PWH undergoing KT from 2004 to 2019. The primary outcome was infection in the first year post-KT in PWH with pretransplant CD4 < 350 cells/µL versus CD4 ≥ 350 cells/µL. Relative risk was assessed using modified Poisson modeling. Restricted mean survival time analysis was used to assess 5-year posttransplant outcomes. RESULTS:Of the 75 patients included, 27% had a pretransplant CD4 < 350 cells/µL. Those with CD4 < 350 versus CD4 ≥ 350 were more likely to be hospitalized for infection in the first year (55% versus 16%, p = 0.001). There were no significant differences in relative risk of infection in the first-year posttransplant (RR: 1.31, p = 0.053), 5-year overall survival (87.5% vs. 93%, p = 0.49) or 5-year graft loss (29.4% vs. 23.1%, p = 0.61) between groups. CONCLUSION:These findings suggest that pretransplant CD4 count alone may not reflect the true risk of post-KT infection in PWH.

BACKGROUND:Due to high prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) among people with human immunodeficiency virus (HIV), KSHV-associated disease (KAD) may be increased after kidney transplantation from donors with HIV (HIV D+) to recipients with HIV (HIV R+). METHODS:Anti-KSHV antibodies were measured in HIV R+ and donors with and without HIV (HIV D-) using a 30-antigen multiplex assay within 3 multicenter kidney transplantation studies. KSHV seropositivity was defined as reactivity to conventional KSHV antigens (≥1 ORF73 or K8.1); reactivity to expanded 5-antigen and 30-antigen panels were also reported. Risk factors were identified using modified Poisson regression. Recipients were monitored for posttransplant anti-KSHV antibody changes and KAD. RESULTS:KSHV seroprevalence was 40.6% (143/352) among HIV R+, 25.2% (33/131) among HIV D+, and 7.5% (4/53) among HIV D-. In the multivariable model, only men who have sex with men (MSM) status was associated with KSHV seropositivity (relative risk, 1.51 [95% confidence interval {CI}, 1.07-2.14] in recipients and 2.39 [95% CI, 1.03-5.53] in donors). Among 418 HIV R+ (215 HIV D+/R+, 203 HIV D-/R+), there were 5 KAD cases (incidence, 0.63 cases/100 person-years [95% CI, .26-1.52]): 3 skin-only Kaposi sarcoma (KS), 1 multicentric Castleman disease, and 1 allograft KS. The allograft KS occurred in a female HIV D+/R+ and was likely donor derived. Remaining KAD cases occurred in male HIV D-/R+ and were likely recipient KSHV reactivation or acquisition. CONCLUSIONS:In the United States, KSHV seroprevalence in donors and recipients with HIV was high, particularly among MSM. Reassuringly, KSHV-associated disease was rare and primarily attributed to recipient rather than donor-derived KSHV.

BACKGROUND:Kidney transplantation (KT) from donors with human immunodeficiency virus (HIV-1) to recipients with HIV (HIV D+/R+) is noninferior to KT from donors without HIV (HIV D-/R+) with regard to safety. However, there may be differences in posttransplant infections. METHODS:We performed a secondary analysis of the HOPE in Action KT Study (NCT02602262) comparing the time to first clinically relevant infection within 24 months posttransplantation in 99 HIV D+/R+ versus 99 HIV D-/R+. Secondary outcomes included incidence rates, infection-related death, and timing of clinically relevant infection, each stratified by donor HIV status. RESULTS:The cumulative incidence of a clinically relevant infection at 24 months posttransplantation was 73.8% (95% confidence interval [CI]: 63.1%-81.2%) for HIV D+/R+ versus 64.7% (95% CI: 53.0%-73.4%) for HIV D-/R+. Comparing time to first clinically relevant infection in HIV D+/R+ versus HIV D-/R+, the adjusted hazard ratio (aHR) was 1.44 (95% CI: 1.01-2.04) at 24 months posttransplantation; for infections associated with hospitalization, the aHR was not significantly higher (1.21 [95% CI: .78-1.86). There were no significant differences in the number of infections, death from infection, duration, or site of infection between HIV D+/R+ versus HIV D-/R+, though viral infections were numerically more common in HIV D+/R+ (40% vs 35%). CONCLUSIONS:Although there was a statistically significant association between receipt of a kidney from a donor with HIV and time to first clinically relevant infection in the 24 months posttransplantation, there were no differences in infections associated with hospitalization. These data are overall reassuring as this emerging practice expands into clinical care. Clinical Trials Registration. NCT02602262.

BACKGROUND:Lower allograft survival has been demonstrated in kidney transplant recipients without HIV whose donors have 2 apolipoprotein L1 ( APOL1 ) renal risk variants (RRVs). The effects of APOL1 RRV on kidney transplant outcomes in people with HIV have not been fully assessed. METHODS:Genomic DNA was analyzed for APOL1 RRV genotype using a probe-based assay in HIV-positive kidney transplant recipients (R + ) and their respective HIV-negative (D - ) or HIV-positive (D + ) kidney donors participating in HIV transplantation studies in South Africa (SA) and the United States (US). Allograft outcomes (time to first rejection, HIV-associated nephropathy, graft failure, or death) were compared by both donor and recipient RRV status. RESULTS:Genomic DNA was available for 21 donors with HIV and 38 HIV D + /R + recipients in the SA cohort, and 57 donors (40 D + and 17 D - ) and 119 recipients (49 HIV D + /R + and 70 D - /R + ) in the US cohort. Recipient outcomes were not associated with recipient APOL1 genotype. However, recipients whose donor carried 1 versus 0 APOL1 RRV were significantly more likely to experience a negative composite outcome ( P  < 0.02 for both cohorts independently), which led to an adjusted hazard ratio of a poor composite outcome of 2.9 (95% confidence interval, 1.1 to 7.4) and 10.1 (95% confidence interval, 2.4 to 42.7) in the SA and US cohorts, respectively. CONCLUSIONS:In two independent cohorts, the presence of 1 APOL1 RRV in a donor kidney led to significantly worse posttransplant outcomes. Further research into the interaction between the allograft environment and donor APOL1 genotype in people with HIV is required.

Kidney transplantation from donors with HIV has recently become standard clinical practice, but the plasma inflammatory profile is not well characterized. Thirty-two cytokines and chemokines were evaluated among donors with HIV (n = 63) and without HIV (n = 41). Wilcoxon rank sum test was used to compare cytokines between groups. Donors with and without HIV were generally similar in terms of characteristics, except those with HIV had a non-significantly lower kidney donor profile index, reflecting better graft survival, creatinine, and body mass index. Most cytokine and chemokine levels were similar between groups. However, median IL-8 levels were higher (p < 0.0015) in donors without HIV (32.6 pg/mL, IQR = 13.8-394.9) compared to donors with HIV (15.1 pg/mL, IQR = 8.4-35.5). There were no significant correlations between cytokine and chemokine concentrations and CD4 counts or HIV viral load. In summary, inflammatory profiles were similar or lower among donors with HIV compared to donors without HIV supporting the safety of this emerging kidney transplantation practice.

Historically, liver transplant (LT) candidates with human immunodeficiency virus (HIV) have experienced high waitlist mortality. Since the HIV Organ Policy Equity (HOPE) Act expands access to organs from donors with HIV, we assessed the impact of HOPE on LT rate and wait time for this population. We linked data from a multicenter HOPE in Action study to Scientific Registry of Transplant Recipients (February 21, 2019 to June 1, 2024) and used Poisson regression to compare transplant rates among 99 candidates willing to accept HOPE donors (HOPE candidates) to 13 495 candidates with or without HIV not listed as willing to accept HOPE donors (non-HOPE candidates) matched on transplant center. The median time to any deceased donor liver transplant (DDLT) was 2.3 months for HOPE and 1.1 years for non-HOPE candidates. Within 2 years of listing, 90.9% of HOPE versus 58.5% of non-HOPE candidates received a DDLT (P < .001). HOPE was associated with an overall 3.11-fold higher DDLT incident rate ratio (95% CI 2.48-3.88, P < .001). Stratified by model for end-stage liver disease score categories 6 to 14, 15 to 24, 25 to 34, and 35 to 40/status 1; HOPE candidates had 10.12-fold, 5.31-fold, 1.41-fold and 2.90-fold higher DDLT rates, respectively. Willingness to accept livers from donors with HIV improves access to liver transplantation for candidates with HIV.

Abstract Background Many persons with HIV (PWH) are excluded as kidney transplants (KT) recipients due to guidelines recommending pre-transplant CD4 counts > 200 cells/mL. Historically, this threshold has been suggested due to concern for increased rates of infection among patients with lower CD4 counts, however, it has not been rigorously studied and may be unnecessarily stringent leading to exclusion of otherwise acceptable organ candidates. Methods We performed a multicenter, retrospective cohort study of post-transplant infectious outcomes in PWH undergoing KT from 2004 - 2019. We defined our exposure of interest as a pre-transplant CD4 count < 350 cells/µL based on prior literature. Our primary outcome was presence of infection (outpatient or inpatient) at 1 year post-transplant. Secondary outcomes included time-to-first infection and infections requiring hospitalization. Multivariable logistic regression analysis was performed for the primary outcome, adjusting for confounding variables. Results Of the 75 patients included, 20 (27%) had pre-transplant CD4 counts < 350. There were no differences in baseline demographics (Table 1). The CD4 < 350 group was more likely to have hyperlipidemia (p 0.048), receive a protease-inhibitor based regimen (p 0.042) and to undergo living-donor organ donation (p 0.05). The CD4 ≥ 350 group was more likely to have Hepatitis C (p 0.017), receive anti-thymocyte globulin induction and experience longer warm ischemic times (p 0.008). There were no significant differences in time-to-first infection, graft loss or death (Table 2). Patients with CD4 < 350 were more likely to have mucocutaneous (p 0.003) and gastrointestinal infections (p < 0.001) and be hospitalized for infection (p 0.028). After adjusting for confounders, CD4 < 350 was not associated with an increased risk of infection in the first year post-KT (aOR 5.28; p 0.13; 95% CI: 0.61, 45.6; Table 3). Conclusion Lower pre-transplant CD4 count was not associated with an increased risk of post-transplant infection, graft-loss or death, although patients with CD4 < 350 were more likely to be hospitalized. Future studies are needed to determine if organ transplant CD4 threshold levels should be recalibrated in PWH. Disclosures Christin Rogers Marks, PharmD, Novo Nordisk: Current employee Christine Durand, MD, Gilead: Grant/Research Support|Gilead: Honoraria Jonathan Hand, MD, AstraZeneca: Grant/Research Support|Janssen: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Scynexis: Grant/Research Support Maricar F. Malinis, MD, Moderna ( concluded): Advisor/Consultant|Paratek Pharmaceuticals, Inc.: Honoraria Martha Pavlakis, MD, Merck: Advisor/Consultant|Vertex: Advisor/Consultant Douglas Krakower, MD, FluidForm Bio: Stocks/Bonds (Private Company)|Gilead: Grant/Research Support|Matchbox Health: Stocks/Bonds (Private Company)|Medscape: Funding to develop educational content|Merck: Grant/Research Support|PrEP4All: Travel to meeting on PrEP acccess Carolyn D. Alonso, MD, AiCuris: Advisor/Consultant|Cidara: Advisor/Consultant|Ferring: Travel support to present data at meeting|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant Audrey Le Mahajan, MD, AstraZeneca: Grant/Research Support

A wide variety of bacterial pathogens have been demonstrated to cause hepatic infection, leading to a range of clinical manifestations, including subclinical hepatitis, liver abscess, cholestatic hepatitis, and rarely fulminant hepatic failure. These organisms exhibit different epidemiology; some are transmitted through inhalation, others by an insect vector or animal exposure. A patient's exposure history, combined with the clinical findings and presence of hepatic dysfunction, may provide clues to the underlying diagnosis and have prognostic implications. This section will review the most important or characteristic bacterial infections involving the liver, focusing on the patterns and severity of liver dysfunction and treatment.

BACKGROUND:The incidence of atypical pneumonia among immunocompromised patients is not well characterized. Establishing a diagnosis of atypical pneumonia is challenging as positive tests must be carefully interpreted. We aimed to assess the test positivity rate and incidence of atypical pneumonia in transplant recipients. METHODS:A retrospective cohort study was conducted at the Yale New Haven Health System in Connecticut. Adults with solid organ transplant, hematopoietic stem cell transplant (HSCT), or chimeric antigen receptor T-cell, who underwent testing for atypical pathogens of pneumonia (Legionella pneumophilia, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Bordetella pertussis) between January 2016 and August 2022 were included. Positive results were adjudicated in a clinical context using pre-defined criteria. A cost analysis of diagnostic testing was performed. RESULTS:Note that, 1021 unique tests for atypical pathogens of pneumonia were performed among 481 transplant recipients. The testing positivity rate was 0.7% (n = 7). After clinical adjudication, there were three cases of proven Legionella and one case of possible Mycoplasma infection. All cases of legionellosis were in transplant recipients within 1-year post-transplantation with recently augmented immunosuppression and lymphopenia. The possible case of Mycoplasma infection was in an HSCT recipient with augmented immunosuppression. The cost of all tests ordered was $50,797.73. CONCLUSION:The positivity rate of tests for atypical pneumonia was very low in this transplant cohort. An algorithmic approach that targets testing for those with compatible host, clinical, radiographic, and epidemiologic factors, and provides guidance on test selection and test interpretation, may improve the diagnostic yield and lead to substantial cost savings.

Introduction: Triazole agents are preferred for antifungal prophylaxis (AFP) for patients (pts) with acute myeloid leukemia (AML) given their activity against the most common causes of invasive fungal infections (IFI), namely Candida spp. and Aspergillus spp. (Halpern et. al. Blood 2015). However, use of the azole antifungals voriconazole (VCZ) and posaconazole (PCZ) is sometimes limited by their side-effect profiles, including transaminase elevation, visual disturbance, QTc prolongation, and major drug-drug interactions (DDI) due to cytochrome P450 inhibition. Conversely, isavuconazole (ICZ) has comparable efficacy against yeasts and molds, with broader activity against Mucorales, and lesser unfavorable impact of the side effects imparted by VCZ and PCZ. In this study, we sought to compare complication rates and outcomes of ICZ vs VCZ amongst pts with newly diagnosed AML. Methods: We conducted a single-center, retrospective study of pts with newly diagnosed AML started on AFP with VCZ or ICZ. Patients were followed until death or IFI. Censoring occurred at Day 0 of allogenic stem cell transplant (alloHCT) due to confounding by additional immunosuppressive effects. Chi-square analysis and Wilcoxon rank-sum tests were used for categorical and continuous variables, respectively. Time-to-event analysis from AML diagnosis was performed using Kaplan-Meier method Correlation analysis used point-biserial calculation. Significance was established with a p-value <0.05. Results: In total, 295 pts were evaluated, with exclusion if AFP was received for antecedent MDS/CMML (n=11), or if there was inadequate information available (n=6). Amongst the 278 pts included, median age was 63 years (interquartile range [IQR] 52-70), with 54.3% being male and 80.6% being white. 63 pts received ICZ and 215 received VCZ as first line AFP. Although pts on ICZ were older (median 66 vs 62 years, p=0.005), there were no differences in patient baseline characteristics including sex, ethnicity, cardiac/pulmonary comorbidity, baseline ANC or CD4 count between groups. DDIs were more common for pts on VCZ than ICZ (18% vs 2%, p=0.002). Significantly more complications overall were observed for pts on VCZ (n=124, 58%) than ICZ (n=22, 35%, p=0.001), namely visual disturbance (15% vs 0%, p=0.002) and transaminase elevations (15% vs 3%, p=0.017); however, rates of CTCAE ≥grade 3 transaminase elevation were similar (4% vs 3%, p=1.0). Pts starting on ICZ had significantly more issues with insurance approval and cost-prohibition necessitating switching AFP (30% vs 1%, p<0.001). These complications led to 10 ICZ pts spending the majority of time (>50%) on VCZ, 38 VCZ pts spending the majority of time on ICZ, and 12 VCZ pts spending the majority of time on other AFP. This led to a total of 101 and 165 pts predominantly on ICZ and VCZ, respectively. To reliably evaluate events attributable to individual AFP agents, we then evaluated only pts who were only on a single agent and followed until IFI, death, alloHCT, or last known follow-up (n=129 overall; ICZ, n=41; VCZ, n=88). There were no differences in age, sex, ethnicity, ECOG PS, cardiac/pulmonary comorbidity, or baseline CD4 count between groups. VCZ pts did have a lower baseline ANC (1.2 vs 2.2 x10^3/uL), p=0.012), but there was no difference in days with ANC <0.2 or ANC <0.5 between groups. Pts on ICZ had a higher baseline QTc (452 vs 436 ms, p=0.009), although peak QTc was similar (471 vs 456 ms, p=0.123), as was mean change in QTc (9 vs 18, p=0.285). The rate of cardiac events/arrythmia on AFP were comparable. Although ICZ pts were more likely to receive less-intensive therapy (53.7% vs 18.9% , p=0.0002), the rate of proceeding to alloHCT was similar (36.6% vs 37.8%, p=1.0). In the larger cohort, the cumulative duration of neutropenia was positively correlated with IFI incidence, with correlation coefficient of 0.26 for days with ANC <0.5 and stronger at 0.45 for days with ANC <0.2. When evaluating pts on a single AFP for >50% of the study period, the rate of IFI was similar between pts receiving ICZ vs VCZ, specifically 2.4% vs 3.3% with proven IFI, 7.3% vs 6.7% with probable+proven IFI, and 15% vs 18.9% with possible+probable+proven IFI (p=0.814) Conclusions: Our study shows that ICZ is an AFP option that is associated with considerably lesser rates of transaminase elevations, visual disturbances, and DDIs, with similarly efficacious protection from IFI when compared to VCZ for pts with AML.