Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial.

Importance: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC). Objective: To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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 PASC. Trial Registration: ClinicalTrials.gov Identifier: NCT05576662.

Consensus position statement on advancing the standardised reporting of infection events in immunocompromised patients.

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.

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.

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.

Infective endocarditis in solid organ transplant: a review.

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.

COVID-19 in the Immunocompromised Host, Including People with Human Immunodeficiency Virus.

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.

Epidemiology of invasive fungal diseases in adults with newly diagnosed acute myeloid leukemia.

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 12 weeks 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 <500 µL/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.

Nocardiosis in Immunocompromised Patients on Alternative Pneumocystis Prophylaxis.

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.

Simultaneous coccidioidomycosis and phaeohyphomycosis in a kidney transplant recipient: A case report and literature review.

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.

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.

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 because of 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 C 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.

Impact of Pretransplant Donor BK Viruria in Kidney Transplant Recipients.

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 pretransplant plasma and urine samples from living and deceased kidney donors and performed BKV polymerase chain reaction (PCR) and immunoglobulin G (IgG) testing on pretransplant and serially collected posttransplant 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 = .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 < .001) and viremia (66.6% vs 8.9%; P < .001) with a shorter time to onset (log-rank test, P < .001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pretransplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (P = .31, P = .75, and P = .51, respectively). CONCLUSIONS: 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.

Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation.

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.

Native kidney cytomegalovirus nephritis and cytomegalovirus prostatitis in a kidney transplant recipient.

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.

Prevention and Management of Tuberculosis in Solid Organ Transplant Recipients.

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.

False-positive QuantiFERON TB-Gold test due to Mycobacterium gordonae.

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.

Tuberculosis in solid organ transplant candidates and recipients: current and future challenges.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Antimicrobial prophylaxis regimens following transplantation.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Provider response to a rare but highly publicized transmission of HIV through solid organ transplantation.

OBJECTIVE: 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. DESIGN: 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. SETTING: Transplant centers in the United States. PARTICIPANTS: Four hundred twenty-two transplant surgeons in current practice. MAIN OUTCOME MEASURE: Changing practice following the 2007 HIV transmission event. RESULTS: 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. CONCLUSION: 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.