COVID-19 associated fungal co-infections in Solid Organ Transplant Recipients: A single center case series

Background. During the ongoing Coronavirus disease of 2019 (COVID-19) pandemic, there have been increasing reports of viral, bacterial and fungal co-infections. Two COVID-19-associated fungal infections (CFIs) have been identified - COVID-19 associated pulmonary aspergillosis (CAPA) andCOVID-19 associated mucormycosis (CAM), but incidence and occurrence in solid organ transplant recipients (SOTRs) is limited. We describe our experience with CFIs in SOTRs with COVID-19. Methods. In a single center retrospective study at a large volume transplant center in South Florida, USA, we included adult SOTRs (>=18 years) diagnosed with COVID-19 between March 1st 2020 and January 31st 2022, with subsequent diagnosis of CFI. We collected information related to demographics, comorbidities, COVID-19 diagnosis and therapeutics, and CFI diagnostics and management. Data obtained was analyzed descriptively. Results. We identified 612 SOTRs with COVID-19, of which 23 (3.8%) were diagnosed with CFIs. The patients were predominantly male (17/23, 73.9%), with median age of 59 years (range 43-79) [Table 1]. Twenty (86.9%) were kidney transplant recipients. Majority of SOTRs had lymphopenia (18/23, 78.3%) with elevated inflammatory markers at time of COVID-19 diagnosis. They received most commonly remdesivir and corticosteroids for COVID-19, with 22 (95.6%) needing intensive care unit admission and 19 (82.6%) needing continuous renal replacement therapy. CFIs were diagnosed at median 21 days (range, 3-161) after initial COVID-19 diagnosis. Probable CAPA was diagnosed in most patients (16/23, 69.6%), with CAM noted in 1 patient [Table 2]. 34.8% (8/23) had specific fungal species identified, with elevated fungal markers noted in 95.6% (22/23). Concurrent or prior cytomegalovirus DNAemia was noted in 26.1% (6/23). Patients were followed for median 70 days (range, 19-572), with median hospitalization duration 56 days (range, 7-204). Mortality was noted in 73.9% (17/23). Table 1: COVID-19 related clinical characteristics in study patients (N=23) Table 2: CFI-related clinical characteristics in study patients (N=23) Conclusion. Fungal co-infections were noted in a small proportion of our SOTRs, with poor outcomes. Transplant physicians should have a high suspicion for early diagnosis and treatment of CFI. Further studies are needed to determine predictors for CFI and role for anti-fungal prophylaxis.

Immunogenicity and Safety of SARS-CoV-2 Vaccines and Breakthrough Infections Among Solid Organ Transplant Recipients: Systematic Review and Meta-Analysis

Purpose: The SARS-CoV-2 pandemic has had a significant impact on the field of solid organ transplant(SOT). Immunization against SARS-CoV-2 is globally available since 2021. SOT recipients represent a vulnerable group with a higher risk of infection and worse outcomes from COVID-19 compared with the general population. There is a concern for the efficacy of SARS-CoV-2 vaccination amongst SOT recipients. We aimed to assess immunogenicity, safety and breakthrough infections after SARS-CoV-2 vaccination. Method(s): We conducted a systematic review and a meta-analysis using articles from 8 databases published from January 1,2020 to July 13,2021. We included studies reporting data regarding SOT and SARS-CoV-2 post vaccine antibody response or cellular response;safety of vaccination;and SARS-CoV-2 infection after at least one vaccine dose. A meta-analysis of postvaccine antibody response and death in breakthrough infections was conducted using a random-effects model. Result(s): Initially, we identified 572 potential studies. After careful review, we included 64 studies for systematic review and 46 studies for meta-analysis. We identified 6,710 SOT recipients. Pooled incidence of antibody positivity after completion of any vaccine schedule was 28.3% (95% confidence interval[CI] 22.5-34.8%). Pooled incidence of antibody positivity after messenger RNA vaccination with 2 doses and 3 doses were 29.3%(95%CI 23.58%-35.74%) and 57.4%(95%CI 48.63-65.78%), respectively. Twelve reports on interferon-gamma response to SARS-CoV-2 spike antigen peptides showed a positivity between 30.4% and 55.0% after messenger RNA vaccines. The most common side effect after vaccination was site pain. Only 5 cases developed rejection but no graft loss. The pooled incidence of death in breakthrough infections was 17.1%(95%CI 10.2%-27.2%). Conclusion(s): Our findings show that only 29% of SOT recipients could mount antibodies after 2 doses of messenger RNA vaccines, with an improved response seen after 3 doses (57%). Even with 3 doses, the immunogenicity is still suboptimal and further studies to investigate the optimal vaccination strategies in this population are needed.

Parainfluenza Type 3 Infection in Solid Organ Transplant Recipients

Purpose: Respiratory viral infection, including COVID-19, causes significant morbidity and mortality in solid organ transplant recipients (SOTR), however, the data of parainfluenza virus (PIV) type 3 infection in this population is still limited. The aim of this study was to reveal the clinical picture of PIV type 3 infection in SOTR. Method(s): This was a retrospective cohort study, conducted between 01/01/2017 and 08/31/2021. We included adult SOTR with an active graft whose respiratory specimen, either nasopharyngeal swab or bronchoalveolar lavage, was positive for PIV type 3 via Filmarray 2.0 and Torch, BioMerieux. Lower respiratory tract infection was defined as any chest radiological abnormality. Result(s): We identified 25 patients including 14 kidney, 4 lung, 3 heart, 1 liver, and 3 combined transplant recipients (Table 1). Hospital and intensive care unit admission rate was 88% (22/25) and 16% (4/25), respectively. Lower respiratory tract infection was seen in 44% (11/25). No specific treatments for PIV type 3 were given to this cohort. Co-, secondary infection was observed in 4 (16%) SOTR with 2 Enterovirus/ Rhinovirus, 1 Fusobacterium bacteremia, and 1 Pseudomonas aeruginosa pneumonia. Only 2 (8%) died within three months after diagnosis. Conclusion(s): PIV type 3 in SOTR showed favorable outcome and no episodes of rejection occurring during follow up. Further studies should be needed to identify the risk factors for mortality.

Re-Infection with SARS-CoV-2 in Solid-Organ Transplant Recipients: Incidence Density and Convalescent Immunity Prior to Re-Infection

Purpose: The purpose of this study was to study our cohort of adult solid organ transplant recipients who had been infected with SARS-CoV-2 to describe the incidence density of SARS-CoV-2 re-infection, as well as the clinical features and convalescent immunity profile. Method(s): Incidence density was calculated as the total cases of re-infection divided by total days after initial diagnosis with active graft. We included those with initial infection diagnosed by polymerase chain reaction before or after transplantation, and cycle threshold values were obtained when possible. Two recipients had immunity evaluated in the weeks prior to re-infection, by measuring IgG antibody titer to the SARS-CoV-2 receptor binding domain and virus-specific CD4+ and CD8+ T-cell reactivity following stimulation with SARS-CoV-2 peptide pools and using activation induced marker assays. Result(s): Out of 210 infected recipients, 5 (2.4%) developed re-infection, including two that had received full mRNA vaccination, but none developed hypoxia. The incidence density was 9.4 (95% confidence interval 3.9-22.6) cases/100,000 patient days. Two cases of re-infection had participated in our immunity study and had convalescent immunity data from a blood draw approximately six months after initial infection and prior to re-infection. Both mounted virus specific CD4 T cell responses prior to re-infection (1.19% and 0.28% of total CD4 T cells) and both had reactive IgG testing (1.30 and 4.99 signal/cut off ratio). Conclusion(s): This suggests that SOT recipients infected with SARS-CoV-2 remain at high risk for re-infection even after generating reactive cellular and humoral immune responses.

Use of Monoclonal Antibodies for Treatment of Solid Organ Transplant Recipients with COVID-19: A Single Center Experience

Purpose: The risk of severe COVID-19 requiring hospitalization and death is higher in solid organ transplant recipients (SOTr). There remains limited data on the use of monoclonal antibodies and long-term outcomes in SOTr. Method(s): This is a retrospective study conducted at Jackson Health System-Miami Transplant Institute in SOTr with mild-moderate COVID-19, from November 2020 to October 2021. Bamlanivimab was used initially for outpatients with mild to moderate COVID-19 but switched to casirivimab/imdevimab on March 1, 2021, due to rising prevalence of SARS-CoV-2 variants in the Miami-Dade area. Outcomes assessed included emergency department visits, hospitalizations, allograft rejection, and death. Result(s): Ninety-two patients were treated, most commonly with casirivimab/imdevimab (74%). The median age was 51 (range, 18-81) years, with 61% male and 60% Hispanic ethnicity. Transplanted organs included 68 kidney (74%), 10 liver (10.8%), 10 heart (10.8%), and 7 lung (7.6 %). Forty-two (45.6%) had a vaccine breakthrough infection, of which 34 (80.9%) were during the delta variant predominance. The median time from positive SARS-CoV-2 test to administration of monoclonal antibody was 1 (range, 0 - 10) day. Anti-metabolite agents were decreased or held in 54.3% of cases. Median follow-up was 116 (range, 19 - 358) days. Five (5.8%) patients had an emergency department visit, 26 (28.2%) were hospitalized;of which 11 (42%) were due to worsening COVID-19 symptoms within 28-days of infusion. 63.6% (7/11) required supplemental oxygen, none required mechanical ventilation. The median hospital length of stay was 6 (range, 2-32) days and all patients were discharged alive. During follow-up, 6 (4 kidney, 2 heart;6.5%) developed biopsy proven rejection. No graft loss or death occurred in this cohort. Conclusion(s): Early use of monoclonal antibodies in SOTr is associated with favorable outcomes. Multi-center studies assessing use of monoclonal antibodies in breakthrough infections and association with allograft rejection are needed.

A Global Survey of Countermeasures Against the COVID-19 Pandemic among Solid Organ Transplant Centers

Background. Solid organ transplantation (SOT) profoundly impacts vulnerable recipients with chronic end organ diseases. The COVID-19 pandemic disrupted healthcare systems, including organ transplants. We aimed to evaluate the responses of SOT centers to COVID-19 at the beginning of the pandemic around the world. Methods. We conducted a web-based survey amongst transplant centers, sent to members of The American Society of Transplantation Infectious Diseases Community of Practice Group, between April and May 2020. The survey included basic information of each transplant center (number and types of transplants in 2019), the countermeasures employed against COVID-19 such as timing of postponing of transplantation, and management of outpatient clinics including implementation of telemedicine and screening for in-person visits. Results. A total of 65 centers from 19 countries responded (Table 1). Regarding the percentage of hospitalized patients with COVID-19 at the time of the survey, 39 (60%) centers reported < 10%, two centers reported > 80%. All centers reduced their services to some extent as shown in Table 2. Centers reported postponing living donor kidney transplant (50/58, 86%), deceased donor kidney transplant (20/57, 35%), living donor liver transplant (32/42, 80%), deceased donor liver transplant (17/41, 41%), lung transplant (20/31, 65%), heart transplant for LVAD (18/33, 55%) and non-LVAD patients (18/33, 55%). In March and April 2020, cancellation of pre- and post- transplant clinics were reported by 36/64 (56%) and 17/65 (26%) centers. Postponing clinic appointments were reported by 56/65 (86%) centers. Most institutions (54/64, 85%) used telemedicine. Screening for COVID-19 for clinic visits was done by telephone, in-person questionnaires and/or temperature checks. Conclusion. During the early phase of the pandemic, when management strategies were highly uncertain, non-urgent and living donor transplants were frequently postponed. Emergent liver transplants continued regardless. These findings could help us navigate SOT in future epidemics. Limitations included a small sample and lack of assessment of clinical outcomes from postponing SOT.

Comparison between SARS-Cov-2, non-SARS-Cov-2 Coronavirus, Influenza and RSV Infections among Solid Organ Transplant Recipients

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been raging since the end of 2019 and has shown worse outcomes in solid organ transplant recipients (SOTR). The clinical differences as well as outcomes between these respiratory viruses have not been well defined in SOTR. Methods. This is a retrospective cohort study of adult SOTR with nasopharyngeal swab or bronchoalveolar lavage PCR positive for either SARS-CoV-2, non-SARSCoV-2 coronavirus, influenza, or respiratory syncytial virus (RSV) from January 2017 to October 2020;both inpatient and outpatient. The follow up period was up to three months. Clinical characteristics and outcomes were evaluated. Development of lower respiratory tract infection (LRTI) was defined as new pulmonary infiltrates with or without symptoms. For statistical analysis, Fischer's exact test and log rank test were performed. Results. During study period, 157 SARS-CoV-2, 72 non-SARS-CoV-2 coronavirus, 100 influenza, 50 RSV infections were identified. Patient characteristics and outcomes are shown in tables 1 and 2, respectively. Secondary infections were not statistically significantly different between SARS-CoV-2 vs. non-SARS-CoV-2 coronavirus and influenza (p=0.25, 0.56) respectively, while it was statistically significant between SARS-CoV-2 and RSV (p=0.0009). Development of LRTI was higher in SARS-CoV-2 when compared to non-SARS-CoV-2 coronavirus (p=0.03), influenza (p=0.0001) and RSV (p=0.003). Admission to ICU was higher with SARS-CoV-2 compared to non-SARS-CoV-2 coronavirus (p=0.01), influenza (p=0.0001) and RSV (p=0.007). SARS-CoV-2 also had higher rates of mechanical ventilation when compared to non-SARS-CoV-2 coronavirus (p=0.01), influenza (p=0.01) and RSV (p=0.03). With time to event analysis, higher mortality with SARS-CoV-2 as compared to non-SARSCoV-2 coronavirus, influenza, and RSV (p=0.01) was shown (Figure 1). Conclusion. We found higher incidence of ICU admission, mechanical ventilation, and mortality among SARS-CoV-2 SOTR vs other respiratory viruses. To validate these results, multicenter study is warranted.

Covid-19 in hiv-infected solid organ transplant recipients: A case series

Purpose: Coronavirus disease 2019 (COVID-19) is associated with increased mortality and morbidity in immunosuppressed patients. Data on management and outcomes in HIV-infected solid organ transplant (SOT) recipients is lacking. Methods: Single center, retrospective case series of HIV-infected SOT recipients who were diagnosed with COVID-19 by nasopharyngeal reverse transcriptasepolymerase chain reaction (RT-PCR) between April to November 2020. All patients had anti-retroviral therapy (ART) induced HIV viral load suppression at diagnosis. Results: Six consecutive patients were identified (Table.1). Four patients required hospitalization;2 were managed outpatient. Four were symptomatic with fever (75%), cough (50%), dyspnea (50%) and diarrhea (25%). An increase in inflammatory markers was seen in all patients, however only 4 (66%) required supplemental oxygen. Median time of follow up was 75 (range, 14-205) days. On diagnosis, first mycophenolate mofetil was discontinued or dose decreased by half. Calcineurin inhibitors and prednisone were continued. In addition, investigational therapies hydroxychloroquine, tocilizumab, remdesivir, dexamethasone were used in 3 (50%), 1 (17%), 1 (17%), 1 (17%), respectively (Table 2). All patients were on protease inhibitor sparing ART. A decrease in CD4 count from baseline was seen at the time of diagnosis which recovered over time. Overall, 5 (83%) survived, 1 (17%) died, 1 (17%) kidney transplant recipient had biopsy-proven acute T-cell mediated rejection 9 days after diagnosis with subsequent graft loss. Secondary infections were diagnosed with positive blood or respiratory cultures in 3 (50%). Death reported was due to septic shock from a secondary infection. Three patients had a negative SARS-CoV-2 RT-PCR at a median of 25 (range, 20-56) days from diagnosis. Conclusions: We report good outcomes in this unique, high risk cohort of HIVinfected SOT recipients. Balancing a decrease in immunosuppression and monitoring graft function to avoid graft loss is extremely important. Further studies are needed to determine the cumulative effect of HIV infection and organ transplant status on the severity of COVID-19.

Sars-cov-2 versus non-sars-cov-2 infection among solid organ transplant recipients: Case control study

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been raging since the end of 2019. The clinical differences between non-SARSCoV-2 coronavirus and SARS-CoV-2 in solid organ transplant recipients (SOTR) are not well defined. Methods: This is a case control study of adult SOTR with PCR positive nasopharyngeal sample or bronchoalveolar lavage, for either SARS-CoV-2 or non-SARS-CoV-2 coronavirus, from 1/2017 to 10/2020. Follow up period was up to three months. Secondary infections were diagnosed by culture or viral PCR from a sterile specimen. Clinical outcomes were compared amongst both groups. Results: Seventy-two non-SARS-CoV-2 coronavirus and 129 SARS-CoV-2 infections were identified. Patient's demographic information and outcomes are shown in table 1 and 2 respectively. Secondary infections and ICU admissions were statistically significantly different between both groups, and higher mortality was observed in the SARS-CoV-2 group. With time to event analysis, there was trend to higher mortality with SARS-CoV-2 infection as compared to non-SARS-CoV-2 (p=0.06)(figure). Conclusions: Our study shows SOTR with SARS-CoV-2 infection may have a significant worse outcome as compared to non-SARS-CoV-2. Secondary infection was also common after this respiratory viral infection in both groups.

Clinical outcomes of solid organ transplant recipients treated with REMDESIVIR and convalescent plasma for COVID-19 at the largest transplant center in The United States

Purpose: Solid organ transplant recipients (SOTr) are at high risk for severe disease with SARS-CoV-2. Data on efficacy of potential treatment options and long-term outcomes are lacking. We describe our experience with use of remdesivir and convalescent plasma in SOTr with COVID-19. Methods: Single-center, retrospective cohort study of SOTr diagnosed with SARSCoV- 2 infection by PCR from March 1st to September 30th, 2020. Multivariate logistic regression analysis was performed based on univariate analysis to identify the risk factors for higher mortality. Results: 129 SOTr were identified (Table. 1). Median time from transplant to diagnosis of infection was 27 (IQR, 8-73) months. 48 (37.2%) and 27 (21%) patients received remdesivir and convalescent plasma, respectively (Table 2). 5/48 (10.4%) patients developed mild transaminitis that did not warrant discontinuation of therapy. No adverse effects were seen with convalescent plasma. Anti-metabolite agents were decreased or stopped in majority of the patients (81%). During follow-up, 12 (9%) patients developed clinically suspected acute rejection. Death, graft loss, and secondary infection occurred in 15 (12%), 20 (16%), and 20 (16%) recipients, respectively. RT-PCR negativity was achieved at a median of 37 (IQR, 25-41) days. Risk factors identified for high mortality were elevated creatinine (p=0.029, Odds ratio[OR] 1.5, 95% Confidence Interval[CI] 1.0- 2.1) and older age (p=0.003, OR 1.1, 95% CI 1.0 - 1.2) at the time of diagnosis. Conclusions: SARS-CoV-2 RT-PCR positive SOT recipients in our cohort had favorable outcomes. Use of remdesivir and convalescent plasma was found to be safe. Older age and elevated creatinine at the time of diagnosis were found to be risk factors for higher mortality.

Respiratory virus infections in solid organ transplant recipients: A single center experience

Background. Community acquired respiratory virus infections (RVI) are a major concern in solid organ transplant (SOT) recipients due to severe complications such as lower respiratory tract infection (LRTI), superimposed fungal and bacterial pneumonia, intensive care admission and mortality. Besides influenza and respiratory syncytial virus (RSV), there is paucity of data of RVI in SOT recipients. Table 1: Patients characteristics Table 2: Concomitant infections Methods. Retrospective cohort study of a single large transplant center was performed. Data of multiplex qualitative PCR-based respiratory viral panel (RVP) samples collected between January 2017 and December 2019 were included. It is important to mention that our institution generally performs the RSV/influenza rapid detection assay as an initial test;if negative, the multiplex PCR panel is usually done. We did not include results from the RSV/influenza rapid test in this study. Results. One hundred transplant patients with a single positive RVP were included (table 1). Transplanted organs include kidney (40%), followed by lung (33%) and liver (9%). Most common presenting symptoms were cough (52%), shortness of breath (28%) and rhinorrhea (26%). Of note fever was seen in only 24%. Most common RVI was Rhinovirus/Enterovirus (RHV/ENT) (59%), followed by non-SARS-CoV-2 Coronavirus (19%) and Parainfluenza (PIV) (14%). None of the patients had neutropenia, however, 52% had lymphocytopenia. Lung transplant patients developed LRTI in 70% of cases compared to non-lung transplant 64% (p=0.412). Multivariate analysis showed patients with PIV 3 were less likely to develop LRTI (p= 0.038). Significant Cytomegalovirus DNAemia (>137 IU/mL) was noted in 9.8% of the recipients. No proven or probable pulmonary fungal infection were noted within 3 months after diagnosis of RVI. Five patients were admitted to the Intensive care unit due to septic shock. Three patients died at 4, 5 and 35 days after diagnosis of RHV/ENT, PIV-3 and RHV/ ENT respectively. Conclusion. Most of the cases of RVI were due to RHV/ENT. Patients with PIV 3 were less likely to develop LRTI. Lung transplant recipients developed LRTI with similar incidence to non-lung recipients. Our data shows a very low mortality of 3% after RVI in our SOT cohort, which warrants larger studies.

Clinical characteristics and outcomes of patients with COVID-19 treated with convalescent plasma in Miami, Florida

Background: The Coronavirus disease of 2019 (COVID-19) global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in unprecedented mortality, impacted society, and strained healthcare systems, yet sufficient data regarding treatment options are lacking. Convalescent plasma, used since 1895 for infectious disease outbreaks, offers promise as a treatment option for COVID-19. Methods: This is a retrospective study of patients diagnosed by a nasopharyngeal swab SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR), who received convalescent plasma between April to June 2020 at two large hospitals in Miami, Florida, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma (CCP). Results: A total of 23 patients received CCP, 13 (57%) had severe COVID-19 disease, while 8 (35%) had critical or critical with multiorgan dysfunction. Median time of follow up was 26 (range, 7-79) days. Overall, 11 (48%) survived to discharge, 6 (26%) died, while 6 (26%) are currently hospitalized. All deaths reported were due to septic shock from secondary infections. 15 (65%) showed improvement in oxygen requirements 7 days post CCP transfusion. Measured inflammatory markers, c-reactive protein, lactate dehydrogenase, ferritin and d-dimer improved 7 days post transfusion in 13 (57%) patients. No adverse events due to the transfusion were reported. 10 (43.4%) patients had a negative SARS-CoV-2 RT-PCR at a median of 14.5 (range, 4-31) days after receiving convalescent plasma. Conclusion: Administration of convalescent plasma was found to be safe, with favorable outcomes in this small cohort of relatively high acuity patients. Larger studies including control arms are needed to establish the efficacy of convalescent plasma on clinical and virologic outcomes for patients with COVID-19. (Table Presented).