Inpatient COVID-19 outcomes in solid organ transplant recipients compared to non-solid organ transplant patients: A retrospective cohort

Immunosuppression and comorbidities might place solid organ transplant (SOT) recipients at higher risk from COVID-19, as suggested by recent case series. We compared 45 SOT vs. 2427 non-SOT patients who were admitted with COVID-19 to our health-care system (March 1, 2020 - August 21, 2020), evaluating hospital length-of-stay and inpatient mortality using competing-risks regression. We compared trajectories of WHO COVID-19 severity scale using mixed-effects ordinal logistic regression, adjusting for severity score at admission. SOT and non-SOT patients had comparable age, sex, and race, but SOT recipients were more likely to have diabetes (60% vs. 34%, p < .001), hypertension (69% vs. 44%, p = .001), HIV (7% vs. 1.4%, p = .024), and peripheral vascular disorders (19% vs. 8%, p = .018). There were no statistically significant differences between SOT and non-SOT in maximum illness severity score (p = .13), length-of-stay (sHR: _0.91.1_1.4, p = .5), or mortality (sHR: _0.10.4_1.6, p = .19), although the severity score on admission was slightly lower for SOT (median [IQR] 3 [3, 4]) than for non-SOT (median [IQR] 4 [3–4]) (p = .042) Despite a higher risk profile, SOT recipients had a faster decline in disease severity over time (OR = _0.760.81_0.86, p < .001) compared with non-SOT patients. These findings have implications for transplant decision-making during the COVID-19 pandemic, and insights about the impact of SARS-CoV-2 on immunosuppressed patients.

     

Clinical implications of SARS-CoV-2 cycle threshold values in solid organ transplant recipients

Detection of SARS-CoV-2 viral RNA by RT-PCR assays is the primary diagnostic test for COVID-19. Cycle threshold (C_T) values generated by some of these assays provide inversely proportional proxy measurements of viral load. The clinical implications of C_T values are incompletely characterized, particularly in solid organ transplant (SOT) recipients. We conducted a retrospective chart review of 25 adult SOT recipients admitted to the Yale New Haven Health System between March 1 and May 15, 2020, analyzing 50 test results to investigate the clinical implications of SARS-CoV-2 C_T values in this population. Initial C_T values from upper respiratory tract samples were significantly higher in patients on tacrolimus, but were not associated with admission severity nor highest clinical acuity. Viral RNA was detected up to 38 days from symptom onset with a gradual increase in C_T values over time. In five patients with serial testing, C_T values <35.0 were detected >21 days after symptom onset in 4/5 and ≥27 days in 2/5, demonstrating prolonged RNA detection. These data describe SARS-CoV-2 viral dynamics in SOT patients and suggest that C_T values may not be useful to predict COVID-19 severity in SOT patients. SARS-CoV-2 C_T values may be more useful in informing infection prevention measures.     

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case–control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17–83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03–1.36), and therapy with renin–angiotensin–aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47–34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.     

COVID‐19 in solid organ transplant recipients: Initial report from the US epicenter

Solid organ transplant recipients may be at a high risk for SARS‐CoV‐2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS‐CoV‐2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty‐six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual‐organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty‐two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID‐19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID‐19 has the potential to severely impact solid organ transplant recipients.     

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience

Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti‐CDI antibiotics, respectively. Ninety‐four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT‐related adverse events (AE) occurred in 22.3% of cases, mainly comprising self‐limiting conditions including nausea, abdominal pain, and FMT‐related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT‐related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus‐seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non‐CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.     

Burden,epidemiology, and outcomes of microbiologically confirmed respiratory viral infections in solid organ transplant recipients: a nationwide,multi-season prospective cohort study

Solid organ transplant (SOT) recipients are exposed to respiratory viral infection (RVI) during seasonal epidemics; however, the associated burden of disease has not been fully characterized. We describe the epidemiology and outcomes of RVI in a cohort enrolling 3294 consecutive patients undergoing SOT from May 2008 to December 2015 in Switzerland. Patient and allograft outcomes, and RVI diagnosed during routine clinical practice were prospectively collected. Median follow-up was 3.4 years (interquartile range 1.61–5.56). Six hundred ninety-six RVIs were diagnosed in 151/334 (45%) lung and 265/2960 (9%) non-lung transplant recipients. Cumulative incidence was 60% (95% confidence interval [CI] 53%-69%) in lung and 12% (95% CI 11%-14%) in non-lung transplant recipients. RVI led to 17.9 (95% CI 15.7–20.5) hospital admissions per 1000 patient-years. Intensive care unit admission was required in 4% (27/691) of cases. Thirty-day all-cause case fatality rate was 0.9% (6/696). Using proportional hazard models we found that RVI (adjusted hazard ratio [aHR] 2.45; 95% CI 1.62–3.73), lower respiratory tract RVI (aHR 3.45; 95% CI 2.15–5.52), and influenza (aHR 3.57; 95% CI 1.75–7.26) were associated with graft failure or death. In this cohort of SOT recipients, RVI caused important morbidity and may affect long-term outcomes, underlying the need for improved preventive strategies.     

Impact of COVID-19 in solid organ transplant recipients

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exploded onto the world stage in early 2020. The impact on solid organ transplantation (SOT) has been profound affecting potential donors, candidates, and recipients. Importantly, decreased donations and the pressure of limited resources placed on health care by the pandemic also disrupted transplant systems. We address the impact of COVID-19 on organ transplantation globally and review current understanding of the epidemiology, outcomes, diagnosis, and treatment of COVID-19 in SOT recipients.     

COVID-19 in solid organ transplant recipients: A national cohort study from Sweden

Solid organ transplant (SOT) recipients run a high risk for adverse outcomes from COVID-19, with reported mortality around 19%. We retrospectively reviewed all known Swedish SOT recipients with RT-PCR confirmed COVID-19 between March 1 and November 20, 2020 and analyzed patient characteristics, management, and outcome. We identified 230 patients with a median age of 54.0 years (13.2), who were predominantly male (64%). Most patients were hospitalized (64%), but 36% remained outpatients. Age >50 and male sex were among predictors of transition from outpatient to inpatient status. National early warning Score 2 (NEWS2) at presentation was higher in non-survivors. Thirty-day all-cause mortality was 9.6% (15.0% for inpatients), increased with age and BMI, and was higher in men. Renal function decreased during COVID-19 but recovered in most patients. SARS-CoV-2 antibodies were identified in 78% of patients at 1–2 months post-infection. Nucleocapsid-specific antibodies decreased to 38% after 6–7 months, while spike-specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score.     

An early experience on the effect of solid organ transplant status on hospitalized COVID-19 patients

We compared the outcome of COVID-19 in immunosuppressed solid organ transplant (SOT) patients to a transplant naïve population. In total, 10 356 adult hospital admissions for COVID-19 from March 1, 2020 to April 27, 2020 were analyzed. Data were collected on demographics, baseline clinical conditions, medications, immunosuppression, and COVID-19 course. Primary outcome was combined death or mechanical ventilation. We assessed the association between primary outcome and prognostic variables using bivariate and multivariate regression models. We also compared the primary endpoint in SOT patients to an age, gender, and comorbidity-matched control group. Bivariate analysis found transplant status, age, gender, race/ethnicity, body mass index, diabetes, hypertension, cardiovascular disease, COPD, and GFR <60 mL/min/1.73 m² to be significant predictors of combined death or mechanical ventilation. After multivariate logistic regression analysis, SOT status had a trend toward significance (odds ratio [OR] 1.29; 95% CI 0.99–1.69, p = .06). Compared to an age, gender, and comorbidity-matched control group, SOT patients had a higher combined risk of death or mechanical ventilation (OR 1.34; 95% CI 1.03–1.74, p = .027).     

Epidemiology and long-term outcomes of cytomegalovirus DNAemia and disease in pediatric solid organ transplant recipients

Despite prevention strategies, cytomegalovirus (CMV) remains a common infection in pediatric solid organ transplant recipients (SOTR). We sought to determine the frequency, associations with, and long-term outcomes of CMV DNAemia in pediatric SOTR. We performed a single-center retrospective cohort study, including 687 first time SOTR ≤21 years receiving universal prophylaxis from 2011 to 2018. Overall, 159 (23%) developed CMV DNAemia, the majority occurring after completing primary prophylaxis. CMV disease occurred in 33 (5%) SOTR, 25 (4%) with CMV syndrome and 10 (1%) with proven/probable tissue-invasive disease. CMV contributed to the death of three (0.4%) patients (all lung). High-risk (OR 6.86 [95% CI, 3.6–12.9]) and intermediate-risk (4.36 [2.3–8.2]) CMV status and lung transplantation (4.63 [2.33–9.2]) were associated with DNAemia on multivariable analysis. DNAemia was associated with rejection in liver transplant recipients (p < .01). DNAemia was not associated with an increase in graft failure, all-cause mortality, or other organ-specific poor outcomes. We report one of the lowest rates of CMV disease after SOTR, showing that universal prophylaxis is effective and should be continued. However, we observed CMV morbidity and mortality in a subset of patients, highlighting the need for research on optimal prevention strategies. This study was IRB approved.

     

De novo coccidioidomycosis among solid organ transplant recipients 1 or more years after transplant

Solid organ transplant recipients who contract coccidioidomycosis are at risk for complicated, protracted, disseminated, and severe disease. To date, no studies have described outcomes for patients who develop coccidioidomycosis only after the first posttransplant year. This study was a joint project of Mayo Clinic Hospital, Phoenix, Arizona, and the University of Arizona/Banner University Medical Center, Tucson, Arizona. We retrospectively reviewed electronic health records for patients with a history of solid organ transplant between January 1, 1998, and October 11, 2014, who developed coccidioidomycosis after the first transplant year. We identified 91 patients. Of those, 37/91 (40.7%) had pulmonary coccidioidomycosis (29/37 [78.4%] were symptomatic); and 5/91 (5.5%) had extrapulmonary disease (all were symptomatic). One patient (1.1%) died. Coccidioidomycosis was evident in 2/91 (2.2%) patients within 3 months of antirejection treatment. Many of the patients (51/91 [56.0%]) had asymptomatic coccidioidomycosis, 27 (27.9%) of whom were followed up closely but did not receive antifungal medication and had no sequelae. Although solid organ recipients taking low‐level immunosuppression after the first posttransplant year appeared to have less symptomatic, disseminated, or fatal coccidioidal infection than historical cohorts, this remains an important infection with morbidity and mortality even after the first posttransplant year.     

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020–June 19, 2020) and late 2020 (June 20, 2020–December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46–0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.

     

Epidemiology and outcomes of medically attended and microbiologically confirmed bacterial foodborne infections in solid organ transplant recipients

Food-safety measures are recommended to solid organ transplant (SOT) recipients. However, the burden of foodborne infections in SOT recipients has not been established. We describe the epidemiology and outcomes of bacterial foodborne infections in a nationwide cohort including 4405 SOT recipients in Switzerland between 2008 and 2018. Participants were prospectively followed for a median of 4.2 years with systematic collection of data on infections, and patient and graft-related outcomes. We identified 151 episodes of microbiologically confirmed bacterial foodborne infections occurring in median 1.6 years (IQR 0.58–3.40) after transplantation (131 [88%] Campylobacter spp. and 15 [10%] non-typhoidal Salmonella). The cumulative incidence of bacterial foodborne infections was 4% (95% CI 3.4–4.8). Standardized incidence rates were 7.4 (95% CI 6.2–8.7) and 4.6 (95% CI 2.6–7.5) for Campylobacter and Salmonella infections, respectively. Invasive infection was more common with Salmonella (33.3% [5/15]) compared to Campylobacter (3.2% [4/125]; p = .001). Hospital and ICU admission rates were 47.7% (69/145) and 4.1% (6/145), respectively. A composite endpoint of acute rejection, graft loss, or death occurred within 30 days in 3.3% (5/151) of cases. In conclusion, in our cohort bacterial foodborne infections were late post-transplant infections and were associated with significant morbidity, supporting the need for implementation of food-safety recommendations.

     

Incidence and outcome of SARS-CoV-2 infection on solid organ transplantation recipients: A nationwide population-based study

Since February 21 2020, when the Italian National Institute of Health (Istituto Superiore di Sanità–ISS) reported the first autochthonous case of infection, a dedicated surveillance system for SARS-CoV-2-positive (COVID+) cases has been created in Italy. These data were cross-referenced with those inside the Information Transplant System in order to assess the cumulative incidence (CI) and the outcome of SARS-COV-2 infection in solid organ transplant recipients (SOTRs) who are assumed to be most at risk. We compared our results with those of COVID+ nontransplanted patients (Non-SOTRs) with follow-up through September 30, 2020. The CI of SARS-CoV-2 infection in SOTRs was 1.02%, higher than in COVID+ Non-SOTRs (0.4%, p < .05) with a greater risk in the Lombardy region (2.89%). The CI by type of organ transplant was higher for heart (CI 1.57%, incidence rate ratio [IRR] 1.36) and lower for liver (CI 0.63%, IRR 0.54). The 60-day CI of mortality was 30.6%, twice as much that of COVID+ Non-SOTRs (15.4%) with a 60-day gender and age adjusted odds ratio (adjusted-OR) of 3.83 for COVID+ SOTRs (95% confidence interval [3.03–4.85]). The lowest 60-day adjusted-OR was observed in liver SOTRs (OR 0.46, 95% confidence interval [0.25–0.86]). More detailed studies on disease management and evolution will be necessary in these patients at greater risk of COVID-19.     

Alternative strategies of posttransplant influenza vaccination in adult solid organ transplant recipients

Solid organ transplant (SOT) recipients are at increased risk of influenza disease and associated complications. The mainstay of prevention is the annual standard-dose influenza vaccine, as studies showed decreased influenza-related morbidity and mortality in vaccinated SOT recipients compared to those unvaccinated. Nonetheless, the immune response in this high-risk population is suboptimal compared to healthy individuals. Over the past two decades, several vaccination strategies have been investigated to overcome this inadequate immune response in SOT recipients. Howbeit, the best vaccination strategy and optimal timing of influenza vaccination remain unclear. This review will provide a detailed summary of studies of various influenza vaccination strategies in adult SOT recipients, discussing immunogenicity results, and addressing their limitations and knowledge gaps.     

Real‐life food‐safety behavior and incidence of foodborne infections in solid organ transplant recipients

Food‐safety measures are recommended in solid organ transplant (SOT) recipients. However, the actual adherence of patients in a real‐life setting and the impact on the incidence of foodborne infections remain largely unexplored. We performed a survey among SOT recipients followed at our institution, aiming to evaluate their food‐safety behavior. We assessed the incidence of microbiologically proven foodborne infections by chart review. One hundred ninety‐seven SOT recipients (kidney = 117, lung = 35, liver = 29, and heart = 16) participated in the survey. Overall, 17.7% of the participants observed all food‐safety recommendations (22.0% avoided food at risk of contamination while 67.9% applied hygiene recommendations). Patients within the first year after transplantation (odds ratio [OR] 5.42; P = .001) and females (OR 4.67; P = .001) followed food‐safety recommendations more closely. Although the majority of SOT recipients felt concerned and actively sought information on food safety (68%‐70%), only 27% were able to recognize all risks of foodborne infection in hypothetical scenarios. Incidence of proven foodborne infections was 17.9% (95% confidence interval 9.9%‐30.9%) 5 years after transplantation. Importantly, foodborne infections occurred exclusively among patients not following food‐safety recommendations. In summary, most SOT recipients eat foods that make them at risk of foodborne infections. Our results indicate that there is room for improvement in patient education, particularly later after transplantation, and reinforce current food‐safety recommendations.