key: cord-0818220-2se1bita
authors: Marinelli, Tina; Ferreira, Victor H.; Ierullo, Matthew; Ku, Terrance; Lilly, Les; Kim, S. Joseph; Schiff, Jeffrey; Sidhu, Aman; McDonald, Michael; Hosseini-Moghaddam, Seyed M.; Husain, Shahid; Rotstein, Coleman; Majchrzak-Kita, Beata; Kulasingam, Vathany; Humar, Atul; Kumar, Deepali
title: Prospective Clinical, Virologic, and Immunologic Assessment of COVID-19 in Transplant Recipients
date: 2021-10-01
journal: Transplantation
DOI: 10.1097/tp.0000000000003860
sha: a6b9e63e7c22860385e3557406ac50b8aaf46f90
doc_id: 818220
cord_uid: 2se1bita

Several studies have described the clinical features of COVID-19 in solid-organ transplant recipients. However, many have been retrospective or limited to more severe cases (hospitalized) and have not routinely included serial virological sampling (especially in outpatients) and immunologic assessment. METHODS. Transplant patients diagnosed with COVID-19 based on a respiratory sample PCR were prospectively followed up to 90 d. Patients provided consent for convalescent serum samples and serial nasopharyngeal swabs for SARS-CoV-2 antibody (antinucleoprotein and anti-RBD) and viral load, respectively. RESULTS. In the 161 SOT recipients diagnosed with COVID-19, the spectrum of disease ranged from asymptomatic infection (4.3%) to hospitalization (60.6%), supplemental oxygen requirement (43.1%), mechanical ventilation (22.7%), and death (15.6%). Increasing age (OR, 1.031; 95% CI, 1.001-1.062; P = 0.046) and ≥2 comorbid conditions (OR, 3.690; 95% CI, 1.418-9.615; P = 0.007) were associated with the need for supplemental oxygen. Allograft rejection was uncommon (3.7%) despite immunosuppression modification. Antibody response at ≥14 d postsymptoms onset was present in 90% (anti-RBD) and 76.7% (anti-NP) with waning of anti-NP titers and stability of anti-RBD over time. Median duration of nasopharyngeal positivity was 10.0 d (IQR, 5.5–18.0) and shedding beyond 30 d was observed in 6.7% of patients. The development of antibody did not have an impact on viral shedding. CONCLUSIONS. This study demonstrates the spectrum of COVID-19 illness in transplant patients. Risk factors for severe disease are identified. The majority form antibody by 2 wk with differential stability over time. Prolonged viral shedding was observed in a minority of patients. Reduction of immunosuppression was a safe strategy.

More than 1 y into the pandemic, our understanding of how SARS-CoV-2 infection affects transplant recipients has increased, but many unanswered questions remain. Hospitalization is reported in 66%-87% and mortality varies widely from 3.0% to 18.7%, 1-11 depending on the population studied, increasing up to 40% in those with severe disease. 12, 13 Much of the literature remains focused toward hospitalized patients rather than the full spectrum of COVID-19 in transplant recipients and is limited by relatively short duration of follow-up for a disease, which we now understand can have a protracted clinical course. Transplant-specific complications, including allograft rejection, have not been comprehensively assessed but are of importance given that immunosuppression is frequently modified during the treatment of COVID-19.

Following SARS-CoV-2 infection, most individuals, including transplant recipients, will develop neutralizing IgG antibodies, 3, 14 and in nonimmunocompromised hosts, the presence of such antibodies is associated with a reduction of SARS-CoV-2 reinfection at 6 mo. 15, 16 An understanding of humoral response to natural SARS-CoV-2 infection in transplant recipients will be useful when interpreting vaccine response; however, factors determining the Covid Background. Several studies have described the clinical features of COVID-19 in solid-organ transplant recipients. However, many have been retrospective or limited to more severe cases (hospitalized) and have not routinely included serial virological sampling (especially in outpatients) and immunologic assessment. Methods. Transplant patients diagnosed with COVID-19 based on a respiratory sample PCR were prospectively followed up to 90 d. Patients provided consent for convalescent serum samples and serial nasopharyngeal swabs for SARS-CoV-2 antibody (antinucleoprotein and anti-RBD) and viral load, respectively. Results. In the 161 SOT recipients diagnosed with COVID-19, the spectrum of disease ranged from asymptomatic infection (4.3%) to hospitalization (60.6%), supplemental oxygen requirement (43.1%), mechanical ventilation (22.7%), and death (15.6%). Increasing age (OR, 1.031; 95% CI, 1.001-1.062; P = 0.046) and ≥2 comorbid conditions (OR, 3.690; 95% CI, 1.418-9.615; P = 0.007) were associated with the need for supplemental oxygen. Allograft rejection was uncommon (3.7%) despite immunosuppression modification. Antibody response at ≥14 d postsymptoms onset was present in 90% (anti-RBD) and 76.7% (anti-NP) with waning of anti-NP titers and stability of anti-RBD over time. Median duration of nasopharyngeal positivity was 10.0 d (IQR, 5.5-18.0) and shedding beyond 30 d was observed in 6.7% of patients. The development of antibody did not have an impact on viral shedding. Conclusions. This study demonstrates the spectrum of COVID-19 illness in transplant patients. Risk factors for severe disease are identified. The majority form antibody by 2 wk with differential stability over time. Prolonged viral shedding was observed in a minority of patients. Reduction of immunosuppression was a safe strategy. magnitude of antibody response in transplant recipients remain unclear.

In nonimmunocompromised persons, viral load (VL) kinetics and duration of viral shedding display significant heterogeneity and may correlate with disease severity and infectivity, 17, 18 but not necessarily the magnitude of immune response. 19 Prolonged shedding of SARS-CoV-2 has been documented in transplant recipients; however, an association with severity of the disease has not been established. 14 Quantitative PCR is considered the optimal method for assessing viral burden but is often substituted for the less than ideal surrogate, cycle threshold. 20 We herein present a comprehensive overview of our center's experience of COVID-19 in SOT recipients over a 12-mo period and the lessons learned regarding the clinical course, outcomes, complications, and in a subset of patients antibody response and viral shedding in the prevaccination era.

This prospective, single-center study encompassed all SOT recipients who were diagnosed with COVID-19 over a 12-mo period starting from the date our first patient was diagnosed (March 19, 2020). The University Health Network Transplant Centre performs approximately 700 solid-organ transplants annually and has comprehensive follow-up of over 6000 transplant recipients. All patients with a positive SARS-CoV-2 diagnosis are captured by the program. Inpatients and outpatients were included if they had a positive clinical nucleic acid test for SARS-CoV-2 infection on a respiratory specimen. All patients were assessed in real-time by a transplant infectious diseases physician and followed for outcomes at 30, 60, and 90 d using a standardized form with a modified version of the WHO clinical progression scale applied. 20 A subset of consenting patients provided serum at ≥14 d after COVID-19 symptom onset. Nasopharyngeal (NP) swabs were collected from consenting patients at serial timepoints postdiagnosis by nursing staff (inpatient) or were midnasal swabs that were self-collected following verbal and written instructions (outpatient). Outpatient swabs were rapidly delivered to the laboratory by courier. The study was approved by the institutional research ethics board. All patients or their delegates provided informed consent. A study overview is found in Figure S1 , SDC, http://links. lww.com/TP/C254.

Serological testing for anti-SARS-CoV-2 IgG antibody was performed using 2 different assays according to manufacturer's instructions: an anti-NP chemiluminescent microparticle immunoassay (CMIA) (Abbott Laboratories, USA) 21 and an antispike RBD electrochemiluminescent immunoassay (ECLIA) (Roche, Switzerland). Index measurements of ≥1.4 and ≥0.8 U/mL were considered positive, respectively. The sensitivity and specificity of the anti-NP assay are 100% and 99.6% and the anti-RBD assay are 98.8% and 99.98% at >14 d postsymptom onset. 22, 23 

Quantitative VL measurements were performed on viral RNA extracted from nasopharyngeal swabs using fluorogenic probe-based real-time RT-qPCR (Norgen Biotek, Canada). Two hundred eighty microliters of swab solution were processed using the QIAamp Viral RNA kit (Qiagen, Germany), following the manufacturer's instructions. The PCR assay was based on the World Health Organization SARS-CoV-2 assay, which targets the RNA-dependent RNA polymerase (RdRP) and envelope (E) genes of SARS-CoV-2. 24 Quantification was performed using the RdRP assay and an 8-point standard-curve using the kit's positive control (starting concentration: 500 000 copies/µL). The limit of quantification (LOQ) was defined as the lowest standard point consistently detected within 40 cycles during standardization. The LOQ was 50 copies/ mL. Values below the LOQ, including undetectable VLs, were set to half the LOQ, 25 copies/mL. All samples with undetectable VLs were validated for technical errors using an RNaseP endogenous internal amplification control (Norgen Biotek). The duration of viral shedding was calculated as the middle of the interval between the last positive swab (including the diagnostic swab) and the first negative swab, calculated from the time of symptoms. When the last study swab was positive, we used this time as the duration of shedding as a conservative estimate. To assess factors influencing the duration of viral shedding, we compared those who shed virus for longer and shorter than the median duration of viral shedding in our cohort.

Demographics were analyzed using descriptive statistics. Categorical variables were compared using χ 2 or Fisher's exact test. Continuous variables were compared using Mann-Whitney U test or Spearman's correlation. The multivariate model was performed using binary logistic regression including variables that had a P value of <0.1 on univariate analysis. The number of comorbidities rather than individual comorbidities was used in the multivariate model. Statistical significance was defined at the level of P < 0.05. All statistical analyses were performed using IBM SPSS (version 25) or Prism (version 9, GraphPad Software, USA). Figures were prepared using Microsoft Excel (2016) and Prism.

During the study period, 161 SOT recipients of the ~6000 patients followed at our center were diagnosed with COVID-19. All patients were followed up for a minimum of 30 d, and 136 (84.5%) were followed for the full 90 d or until death. The demographics and baseline characteristics of transplant recipients with COVID-19 are shown in Table 1 . Symptoms at presentation are shown in Table  S1 , SDC, http://links.lww.com/TP/C254. Most (65.6%) were male with a median age of 58.0 y. Kidney transplant recipients comprised 50.6% of the cohort. A variant of concern was identified in 6 patients (based on mutation screening for N501Y). 25 Immunosuppression was reduced in 66.9% of cases; most commonly, the antiproliferative was reduced with a mean dose reduction of 80.3%. Hospitalization for COVID-19 occurred in 97 (60.6%) patients and 69 (43.1%) required oxygen. In the hospital, therapies used were remdesivir (n = 32), dexamethasone (n = 55), tocilizumab (n = 2), and convalescent plasma (n = 1). A potential source of COVID-19 transmission was identified in 60.2% (n = 97) of cases, including household (n = 69, 42.9%), social (n = 11, 6.8%), occupational (n = 7, 4.3%), nosocomial (n = 8, 8.2%), and long-term care facility (LTC) (n = 1, 0.6%). Five (3.1%) patients had a history of recent travel without a specific, known, COVID-19 positive contact. There was 1 case of donor-derived SARS-CoV-2 transmission via a lung transplant recipient, which has been previously described and is henceforth excluded from analysis due to the idiosyncratic nature of this case. 26 The epidemic curve of SARS-CoV-2 infection in transplant patients mirrored the epidemic curve in Ontario, Canada (data not shown). 27 

The spectrum of COVID-19 severity is shown in Figure 1 (based on WHO severity score). Notably, 7 (4.4%) patients were asymptomatic of SARS-CoV-2 infection, including the only patient included in this cohort who had received the COVID-19 vaccination before infection (2 doses of mRNA-1273, Moderna). Outcomes by transplanted organ are shown in Table 2 ; 97/160 (60.6%) required hospitalization, and 69/160 (43.1%) needed supplemental oxygen. ICU admission occurred in 27/160 (16.9%). Two patients required extracorporeal membrane oxygenation (ECMO), only 1 of whom survived to hospital discharge, 83 d postdiagnosis. Forty-five patients (28.1%) had an acute kidney injury. Pulmonary imaging demonstrated ground-glass opacities or infiltrates in 85 of 103 (82.7%). One-third (n = 27, 31.8%) of patients with evidence of pneumonitis required ICU admission (P < 0.001) and all patients admitted to ICU had evidence of pneumonitis on imaging.

Twenty-five patients (15.6%) died, including 12 kidney, 4 liver, 8 lung, and 1 heart transplant recipient. All deaths were attributed to COVID-19. In 2 patients, gastrointestinal catastrophes (small bowel obstruction and perforated diverticulum) contributed to death. Death occurred at a median of 15 d (IQR, [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] post-COVID-19 diagnosis, and all patients were hospitalized at the time of death. Six deaths occurred 30 or more d post-COVID-19 diagnosis.

Factors significantly associated with oxygen requirement (WHO score ≥5) (on univariate analysis) included older age (P = 0.006), 2 or more baseline comorbidities (P < 0.001), hypertension (P = 0.005), diabetes mellitus (0.040), chronic kidney disease Grade 3-5 (P = 0.047); lung transplant recipient (P = 0.005); prednisone use (P < 0.001); and mycophenolic acid (P = 0.011) at the time of SARS-CoV-2 diagnosis. On multivariate analysis, factors that were associated with more severe disease were increasing age (OR, 1.031; 95% CI, 1.001-1.062; P = 0.046) and having ≥2 comorbid conditions (OR, 3.690; 95% CI, 1.418-9.615; P = 0.007). Risk factors for death included increasing age (median 66 versus 56 y; P < 0.001) and 2 or more comorbidities (P = 0.002). Although not statistically significant, lung transplant recipients had a higher incidence of death following SARS-CoV-2 infection and all, but 1 had a preexisting chronic lung allograft dysfunction.

Treatment for concomitant bacterial pneumonia was common (n = 74, 46.3%), but an etiologic agent was proven 

Several noninfectious complications were observed during acute COVID-19. Gastrointestinal complications included 1 episode each of pancreatitis in a heart transplant recipient, small bowel obstruction, and perforated diverticulitis. Coagulopathic and thrombotic complications included a case, each of renal thrombosis leading to infarction, pulmonary embolus, and retroperitoneal bleed in the setting of therapeutic anticoagulation. There were 6 episodes of allograft rejection diagnosed during the followup period, 2 each within 30, 60, and 90 d of COVID-19 diagnosis. Five cases were biopsy proven, and 1 was diagnosed clinically. Of the 107 SOT recipients whose immunosuppression regimen was altered during COVID-19, 4 patients (3.7%) experienced allograft rejection within 90 d of COVID-19 diagnosis.

To assess the humoral response to SARS-CoV-2, we measured anti-RBD and anti-NP antibodies in the serum of 60 (37.5%) patients from this cohort at ≥14 d postsymptom onset ( Table 3 ). The median time from COVID-19 symptom onset to serum collection was 40.5 d (IQR, 34.0-50.8 d). Anti-RBD was positive in 90% (n = 54) and anti-NP in 76.7% (n = 46) with median antibody levels of 66.3 U/mL (IQR, 5.7-185.0) and 3.5 U/mL (IQR, 1.1-5.7), respectively. For anti-RBD, the percent of transplant recipients who tested positive at 14-29 d, 30-59 d, and >60 d post-symptom onset were 83.3%, 87.5%, and 100%, respectively (Figure 2A) . For anti-NP, the corresponding proportions were 83.3%, 73.2%, and 57.1%, respectively ( Figure 2B ). These data suggest anti-RBD antibody levels are relatively stable in SOT recipients over the first 60 d, whereas anti-NP responses fluctuate and wane over time. Anti-NP and -RBD antibody levels were directly correlated with each other (P < 0.001) ( Figure S2 , SDC, http://links. lww.com/TP/C254).

Prednisone use at baseline was associated with both lower anti-RBD (P = 0.003) and anti-NP levels (P = 0.011) at convalescence. MPA total daily dose of >720 mg at baseline was associated with lower levels of anti-NP (P = 0.011) ( Table 2 ). There was no significant difference in antibody levels based on disease severity or treatment received.

Of the 60 patients with serology, a subset of 30 patients submitted serial nasopharyngeal swabs for VL testing (total swabs N = 159; median of 6 swabs [range [1] [2] [3] [4] [5] [6] [7] ). Of these, 13 of 30 remained outpatients. All patients had a positive diagnostic swab; in follow-up study swabs, SARS-CoV-2 VL was detected in 18/30 (60.0%) patients. The range of detectable and peak VLs are shown in Figure 3A and C, respectively. The median duration of viral shedding from symptom onset was 10.0 d (IQR, 5.5-18.0) ( Figure 3B and D). Viral load decreased over time, and only 2 patients had a calculated duration of shedding ≥30 d (6.7%) ( Figure 3B and D). Those who shed SARS-CoV-2 for <10.0 d were kidney (42.9%), liver (28.6%), lung (21.4%), and heart (7.1%) recipients. Those who shed virus for ≥10 d from symptom onset were kidney (43.8%), liver (25.0%), kidney-pancreas (12.5%), lung (12.5%), and heart (6.3%) transplant recipients. No baseline factors (sex, age [>50 y old], transplanted organ, hospitalization status, or baseline immunosuppression) were statistically associated with prolonged shedding (defined as ≥10.0 d from symptom onset; P > 0.05 for all comparisons). Furthermore, there were no differences in anti-RBD (P > 0.99) or anti-NP (P = 0.38) antibody positivity among those with or without prolonged SARS-CoV-2 shedding.

We present a large, prospective single-center study of COVID-19 with in-depth assessment and follow-up of every SOT recipient from our center over a 12-mo period and have identified several key lessons. Unlike many previous studies, which included mainly hospitalized patients, sourced data from a central registry, or retrospectively analyzed cases, we included both inpatients and outpatients who were assessed prospectively. With 90-d follow-up for most patients, we were able to accurately assess outcomes, acute and subacute complications of COVID-19, which are not fully appreciated within a shorter follow-up period. COVID-19 causes a wide spectrum of disease in transplant recipients from asymptomatic infection (4.3%) to hospitalization (60.6%), supplemental oxygen (43.1%) requirement, mechanical ventilation (22.7%), and death (15.6%). As previously demonstrated, we found the presence of comorbid conditions to be associated with poorer outcomes 1,2,6 and the highest mortality in lung transplant recipients. Household transmission is the most common source of SARS-CoV-2 acquisition in SOT recipients and the epidemic curve mirrors that of the wider community, indicating that preventative measures must focus on the wider environment beyond the individual. Rates of allograft rejection post-COVID-19 have been reported rarely. We have demonstrated allograft rejection is uncommon post-COVID-19, even in the setting of immunosuppression modification, and most episodes occur >30 postinfection. Interestingly, proven coinfections including bacteria and fungi were also uncommon.

Our study and others show that transplant recipients can mount SARS-CoV-2-specific antibodies within 2 wk of COVID-19 symptoms, and these antibodies may be durable for 2-6 mo. In a study of 18 kidney transplants, Hartzell et al demonstrated that most patients develop SARS-CoV-2-specific antibodies from day 10 postsymptom onset. 28 Boyarsky et al found that, in a cohort of 18 organ transplant recipients, at a median of 98 d pot-COVID-19 diagnosis, 78% had a reactive screening immunoassay, of which 83% had detectable anti-S1 antibodies. All patients who did not mount an antibody response received convalescent plasma or intravenous immunoglobulin for management of COVID-19. 29 We found a high rate of antibody response to both RBD and NP. Also, anti-RBD and anti-NP were correlated with each other (P < 0.0001), but anti-RBD was more durable than the latter in the months following SARS-CoV-2 infection. Seropositivity for anti-NP in our study ranged from 57.1% to 73.2% >30 d from symptom onset, which is compatible with another study finding seroprevalence of 51% at 4-8 wk postdiagnosis. 30 Consistent with the findings of Burack et al, we identified convalescent and baseline immunosuppression as factors that appear to modify the magnitude of the humoral response. 30 A major strength of our study is the analysis of viral shedding especially in outpatients. Viral loads in outpatients are challenging to capture since patients are in home isolation. However, we used a method for self-swabbing, which is has been validated to detect SARS-CoV-2 and also used in COVID-19 vaccine studies. 31, 32 Most previous analyses of viral shedding have focused on transplant recipients with severe disease requiring hospitalization. [33] [34] [35] Benotmane et al performed virological assessment on 40 kidney transplant recipients, 14, 36 where almost 3-quarters (74.4%) had peak VL occur at diagnosis, and 25% of patients showed persistent viral shedding after 30 d. In another study, 10 of 47 (21%) of SOT recipients undergoing PCR testing at least 20 d after symptom onset tested positive for SARS-CoV-2. 37 Again, the potential bias of disease severity exists as individuals with severe COVID-19 are over-represented in many studies. We observed a relatively low rate of prolonged shedding, which may be related to the inclusion of many patients with mild disease severity. Our data suggest that the current quarantine period (in Canada) of up to 20 d for a COVID-positive transplant patient suggested by public health guidelines is adequate for those with mild to moderate disease. Importantly, most of these studies, including ours, only report VL and do not confirm whether the amount of shed virus is of an infectious nature. Of note, some studies, like ours, show no relationship between NP VLs and COVID-19 disease severity. 14 Strengths of our study include a comprehensive prospective capture of all COVID-19 positive patients with low ascertainment bias, both inpatients and outpatients, as well as long-term follow-up of patients. The study was limited in that not all patients provided serum and nasopharyngeal swabs. We may not have captured all asymptomatic patients. A unique strength of our study is the determination of viral shedding in outpatients. In summary, our study provides key insights into the full spectrum of disease severity of COVID-19 in SOT recipients based on a prospective assessment of both mild and hospitalized cases couple with supporting serological and virological data. These data may also provide a sound base for comparison when assessing the effectiveness of SARS-CoV-2 vaccinations and the differential impact of SARS-CoV-2 variants.

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

COVID-19 in solid organ transplant recipients: dynamics of disease progression and inflammatory markers in ICU and non-ICU admitted patients

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Cycle thresholds among solid organ transplant recipients testing positive for SARS-CoV-2

We thank Ms. Ilona Bahinskaya and Ms. Natalia Pinzon for their assistance in study coordination.