Razonable, Raymund R

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D + R – ) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C + NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4 + T cells, CD3 neg CD56 dim CD57 neg NKG2C pos cells, and CD3 neg CD56 dim CD57 pos NKG2C pos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D + R – LTxR.

Abstract Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

ABSTRACT Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% ( P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization. IMPORTANCE As SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

AbstractIntroductionCytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). Measuring cell‐mediated immunity (CMI) may inform the risk of CMV infection after antiviral prophylaxis and predict relapse after CMV treatment.MethodsWe serially assessed CMV CMI using the QuantiFERON‐CMV assay (QF‐CMV; Qiagen, Germantown, MD) in two cohorts of SOTRs: during valganciclovir prophylaxis and during treatment of CMV viremia. Results of CMI were correlated with post‐prophylaxis CMV infection and post‐treatment relapse, respectively.ResultsOnly one (4.2%) of 24 CMV D+/R‐ patients demonstrated positive QF‐CMV by the end of valganciclovir prophylaxis. Four (16.6%) patients developed post‐prophylaxis CMV infection; all four had undetectable QF‐CMV at end of prophylaxis. Among 20 patients treated for CMV infection, 18 (90%) developed QF‐CMV levels >.2 IU/mL by end of antiviral treatment and none developed CMV relapse. In contrast, the single patient who relapsed after completing treatment had a CMV CMI <.2 IU/ml (p = .0036).ConclusionSince CMV D+/R‐ SOTRs are unlikely to develop adequate CMV CMI while receiving valganciclovir prophylaxis, the utility of CMV CMI monitoring for risk stratification during time of prophylaxis had limited value. Conversely, CMV CMI testing may be a useful marker of the risk of CMV relapse after antiviral treatment.

AbstractBackgroundEndemic mycoses after hematopoietic stem cell transplantation (HSCT) are rarely reported. We aimed to comprehensively review the clinical presentation and outcomes of endemic mycoses in this immunocompromised population.MethodsMultiple databases were reviewed from inception through May 31, 2023 using endemic fungi as keywords (e.g., coccidioides, histoplasma, blastomyces, talaromyces, and paracoccidioides). Only hematopoietic transplants were included.ResultsThere were 16 publications on endemic mycoses after HSCT that reported nine unique cases of histoplasmosis, seven coccidioidomycosis, and two talaromycosis. No cases of paracoccidioides and blastomycoses were identified. Fifteen cases were allogeneic hematopoietic transplant recipients and three were autologous. Many were male (14/18, 77.8%) and overall median age was 50 (range 21–75) years. Among the 16 patients with coccidiodomycosis or histoplasmosis, fever, cytopenias and disseminated disease were the most common clinical presentations, with median onset of 8 or 12 months after HSCT, respectively. Likewise, the two HSCT patients with talaromycosis presented with disseminated disease at 12 and 48 months after transplantation. The vast majority were not on effective azole prophylaxis at the time of presentation, and many had recent intensification of immunosuppression. Nine of 18 patients died (50%), and all deaths occurred among patients with disseminated endemic mycoses.ConclusionEndemic mycoses among HSCT are uncommon. Onset was late, after discontinuation of azole prophylaxis, or was associated with intensification of immunosuppression. Disseminated disease was a common presentation, manifested by fever and cytopenias. Attributable mortality was high, and emphasizes the need for a high index of clinical suspicion so that prompt diagnosis and treatment is provided. image

AbstractBackgroundManagement of multidrug‐resistant (MDR) and rifampin‐resistant (RR) tuberculosis is challenging. Data on transplant recipients is limited. We reviewed published literature to examine treatment choices, outcomes, and adverse effects from MDR‐TB/RR‐TB treatment in transplant recipients.MethodsMultiple databases from inception to 12/2022 were reviewed using the keywords “drug‐resistant TB” or “drug‐resistant tuberculosis” or “multidrug‐resistant TB” or “multidrug‐resistant tuberculosis”. MDR‐TB was defined as resistance to isoniazid (H) and rifampin (R), and RR if resistant to rifampin alone. Cases without patient‐level data and reports which did not describe treatment and/or outcomes for MDR‐TB were excluded.ResultsA total of 12 patients (10 solid organ transplants and two hematopoietic cell transplants) were included. Of these, 11 were MDR‐TB and one was RR‐TB. Seven recipients were male. The median age was 41.5 (range 16–60) years. Pre‐transplant evaluation for the majority (8/12, 66.7%) did not reveal a prior history of TB or TB treatment, but 9/12 were from TB intermediate or high‐burden countries. Seven patients were initially treated with the quadruple first‐line anti‐TB regimen. Those who had early RR confirmation (5/12) via Xpert MTB/RIF assay were initiated on alternative therapies. Final regimens were individualized based on susceptibility profiles and tolerability. Adverse events were reported in seven recipients, including acute kidney injury (n = 3), cytopenias (n = 3), and jaundice (n = 2). Four recipients died, with two deaths attributable to TB. The remaining eight patients who survived had functioning allografts at the last follow‐up.ConclusionsMDR‐TB treatment in transplant recipients is associated with many complications. Xpert MTB/RIF detected RR early and guided early empiric therapy. image

AbstractNeutralizing antispike monoclonal antibody (mAb) therapies were highly efficacious in preventing coronavirus disease 2019 (COVID‐19) hospitalization. While severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants may harbor spike protein mutations conferring reduced in vitro susceptibility to these antibodies, the effect of these mutations on clinical outcomes is not well characterized. We conducted a case–control study of solid organ transplant recipients who received an antispike mAb for treatment of mild‐to‐moderate COVID‐19 and had an available sample from initial COVID‐19 diagnosis for genotypic sequencing. Patients whose SARS‐CoV‐2 isolate had at least one spike codon mutation conferring at least fivefold decreased in vitro susceptibility were classified as resistant. Overall, 9 of 41 patients (22%) had at least one spike codon mutation that confers reduced susceptibility to the antispike mAb used for treatment. Specifically, 9 of 12 patients who received sotrovimab had S371L mutation that was predicted to confer a 9.7‐fold reduced susceptibility. However, among 22 patients who required hospitalization, 5 had virus with resistance mutation. In contrast, among 19 control patients who did not require hospitalization, 4 also had virus‐containing resistance mutations (p > 0.99). In conclusion, spike codon mutations were common, though mutations that conferred a 9.7‐fold reduced susceptibility did not predict subsequent hospitalization after treatment with antispike mAb.

AbstractBackgroundCurrent guidelines recommend immunomodulators, tocilizumab or baricitinib, for the management of severe coronavirus disease‐2019 (COVID‐19) in patients with increasing oxygen requirements. Given their immunosuppressive effects, there is a concern for higher rates of infection among transplant recipients.MethodsA retrospective cohort study of transplant patients with severe COVID‐19 between April 2020 and January 2022 was performed at the Mayo Clinic. The primary outcome was incidence of secondary infections after COVID‐19 diagnosis. Secondary outcomes were 90‐day mortality, ventilatory days, and thromboembolic events.ResultsA total of 191 hospitalized transplant patients were studied, including 77 (40.3%) patients who received an immunomodulator. Overall, 89% were solid organ transplant recipients, with kidney as the most common transplanted organ (50.3%). The majority (89.0%) required oxygen supplementation on admission, and 39.8% of these patients required mechanical ventilation during the hospital course. There was no significant difference in the incidence of secondary infections between those who received or did not receive an immunomodulator (p = .984). Likewise, there was no difference in 90‐day mortality between patients who received or did not receive an immunomodulator (p = .134). However, higher mortality was observed among patients that developed a secondary infection (p < .001).ConclusionThe use of immunomodulators in transplant patients with severe COVID‐19 was not significantly associated with an increased risk of secondary infections. Secondary infections were associated with higher risk of all‐cause mortality. Future studies of larger cohorts are needed to explore the effect of immunomodulators on survival among transplant patients with COVID‐19. image