key: cord-0844358-562xfngc
authors: Pereira, Marcus R.; Mohan, Sumit; Cohen, David J.; Husain, Syed A.; Dube, Geoffrey K.; Ratner, Lloyd E.; Arcasoy, Selim; Aversa, Meghan M.; Benvenuto, Luke J.; Dadhania, Darshana M.; Kapur, Sandip; Dove, Lorna M.; Brown, Robert S.; Rosenblatt, Russell E.; Samstein, Benjamin; Uriel, Nir; Farr, Maryjane A.; Satlin, Michael; Small, Catherine B.; Walsh, Thomas J.; Kodiyanplakkal, Rosy P.; Miko, Benjamin A.; Aaron, Justin G.; Tsapepas, Demetra S.; Emond, Jean C.; Verna, Elizabeth C.
title: COVID‐19 in solid organ transplant recipients: Initial report from the US epicenter
date: 2020-05-10
journal: Am J Transplant
DOI: 10.1111/ajt.15941
sha: 27b7ed39d5d71de4e6b510169cf1aa7b8766d3b4
doc_id: 844358
cord_uid: 562xfngc

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.

All adult (age >18 years) solid organ transplant recipients from Columbia University Irving Medical Center (CUIMC) and Weill Cornell Medicine (WCM) with a positive test for SARS-CoV-2 in an inpatient or outpatient setting between March 13, 2020 and April 3, 2020 were retrospectively assessed. Data were extracted from the electronic medical record system. All tests performed at CUIMC or WCM used reverse-transcriptase PCR via Roche 6800 platform of nasopharyngeal swab specimens to diagnose COVID-19. Lower respiratory samples were not tested. Patient characteristics, symptoms and timing of presentation, management of immunosuppression and initial antiviral treatment strategies as well as initial outcomes were characterized. This work was approved by the local institutional review boards.

Patients were categorized as having mild disease (outpatient care only), moderate disease (admission to the general inpatient floor), or severe infection (mechanical ventilation, admission to intensive care unit [ICU] or death). The median (IQR) overall time from the date of the positive SARS-CoV-2 test until death or last follow-up was 20 (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) ).

At this time, there are limited data on effective antiviral therapies against SARS-CoV-2. As such, the initial management has been to provide supportive care for patients with mild disease while generally treating those with moderate or severe disease with hydroxychloroquine if those patients were unable to enroll in clinical trials or compassionate use of investigational agents such as remdesivir. Additional therapeutic considerations included the addition of azithromycin to hydroxychloroquine, and/or tocilizumab for patients rapidly decompensating thought due to high and deleterious 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.

antibiotic: antiviral, clinical research/practice, complication: infectious, immunosuppression/ immune modulation, infection and infectious agents -viral, infectious disease, organ transplantation in general cytokine activity. IVIG infusion and bolus steroids were also considered on a case by case basis.

Regarding immunosuppressive therapy, the general approach at our centers was to moderately decrease the overall amount of immunosuppression with a particular emphasis on decreasing or stopping antimetabolite drugs such as mycophenolate or azathioprine.

This approach was based on expert opinion developed in conjunction with various organ transplant groups and transplant infectious diseases.

In one of the centers, the clinical protocol for hospitalized patients also included initial measurement of D-dimer, ferritin, procalcitonin, C-reactive protein (CRP), high sensitivity (HS)-troponin and interleukin-6 (IL-6) levels, based on their potential to identify subsequent poor outcomes. 11, 12 

Hydroxychloroquine when given at our institutions was dosed at 600 mg orally twice daily (load) on day 1, then 400 mg orally daily on days 2-5. Caution was advised in individuals with pre-existing QT prolongation or those at risk for QT prolongation. Azithromycin was dosed as 500 mg orally once on day 1, then 250 mg orally daily on days 2-5. Azithromycin was avoided if the patient's QTc interval was >500 ms at baseline or the patient was taking any concurrent QTc prolonging medications. When combined with hydroxychloroquine, QTc was re-assessed by 12-lead ECG on hospital days 2 or 3 of therapy. Tocilizumab was given as a one-time dose of either 400 mg or 8 mg/kg (maximum 800 mg) intravenously once, and a second dose was given in select cases.

Baseline characteristics are compared between groups with mild/ moderate and severe COVID-19 infection as defined above.

Continuous variables were compared with Wilcoxon rank-sum and proportions with chi-square. For purposes of this analysis, comorbidities were determined from clinical documentation in the medical record. Chronic kidney disease was defined as baseline glomerular filtration rate below 60 mL/min. The subset of patients who were hospitalized were then analyzed for a more detailed description of laboratory abnormalities, inpatient treatment and documentation of clinical outcomes. and April 3, 2020. The overall median age of the cohort was 57 years, 59% were men, 63% Caucasian race, and 42% Hispanic ethnicity (Table 1 ). There were 46 (51%) kidney transplant recipients, 17 (19%) lung recipients, 13 (14%) liver recipients, 9 (10%) heart recipients, 3 (3%) heart-kidney recipients, 1 (1%) liver-kidney recipient, and 1 (1%) kidney-pancreas recipient. The median time from transplant to COVID-19 diagnosis was 6.64 years. Three (3%) of patients were in the first month posttransplant and 13 (14%) were in the first-year posttransplant. There were no significant differences between baseline immunosuppression and disease severity.

There were 22 (24%) patients with mild disease, 41 (46%) with moderate disease, and 27 (30%) with severe disease. Advanced age was significantly associated with severe disease. However, other baseline demographics including sex, race, ethnicity, type of transplant and time from transplant did not significantly differ between these groups (Table 1) . Patients with severe disease were also more likely to have hypertension and active cancer, while other comorbidities so far described in the general population did not significantly differ between the two groups.

The median (IQR) overall follow up time from positive test until death or last follow-up, was 20 (14-24) days.

The median number of days symptom onset until the positive test for SARS-CoV-2 was four, and there was no difference between the disease groups. The most common presenting symptom reported was fever by 63 patients (70%), followed by cough in 53 (59%), dyspnea in 39 (43%), fatigue in 25 (28%), myalgias in 22 (24%), and diarrhea in 28 (31%). Dyspnea upon presentation was significantly associated with a severe clinical course, while other presenting symptoms were similar between groups (Table 1) . Fifteen (17%) reported a known exposure outside the hospital prior to diagnosis-this was almost universally to a sick family member. In addition, three patients (4%) were suspected of having nosocomial transmission, all of whom progressed to severe disease (P = .01). Seven (8%) patients who tested positive had a recently negative initial SARS-CoV-2 PCR test but were retested due to ongoing high clinical suspicion. In addition, eight of the hospitalized patients were initially diagnosed as outpatients, 3-9 days prior to hospitalization.

Sixty-eight (76%) of all patients were hospitalized. For these patients, additional clinical details including vital signs, laboratory values and outcomes are summarized in Tables 2 and 3 . Patients with severe disease had significantly higher respiratory rates (P = .01) and lower oxygen saturation (P = .01) but lower maximum temperatures (P = .03) on initial presentation than those with moderate disease.

Laboratory values at the time of hospitalization were generally similar between those who had moderate and severe disease, TA B L E 1 Baseline demographics and clinical presentation of entire cohort by disease severity (63) 40 (63) 17 (63) .59

Black 20 (22) 13 (21) 7 (26) Asian 5 (6) 5 (8) 0 (0) Other 8 (9) 5 (8) 3 (11) Hispanic ethnicity (%) 37 (42) 25 (40) 12 (44) .72

Organ transplant (%)

Kidney 46 (51) 34 (54) 12 (44) .90

Lung 17 (19) 10 (16) 7 (26) Liver 13 (14) 9 (14) 4 (15) Heart 9 (10) 6 (10) 3 (11) Heart-kidney 3 (3) 2 (3) 1 (4) Liver-kidney 1 (1) 1 (2) 0 (0) Kidney-pancreas 1 (1) 1 (2) 0 (0) Years from transplant to diagnosis, median (IQR) 6 .64 (2.87-10.61) 6.25 (2.6-10.69) 6.86 (2.87-10.16) .92

Within 1 mo (%) 3 (3) 2 (7) 1 (4) .90

Within 1 y (%) 13 (14) 8 (13) (6) 1 (4) .57

Chronic lung disease 17 (19) 11 (17) 6 (22) .65

Active cancer 3 (3) 0 (0) 3 (11) .01 BMI > 40 kg/m 2 5 (6) 3 (5) 2 (7) .63

Presenting symptoms (%) except for a lower serum albumin in the severe group (P = .048) ( Table 2 ). In one of the centers, initial inflammatory biomarkers were checked for most patients. While the median levels of all biomarkers measured at presentation were well above normal range, procalcitonin was the only marker significantly more elevated in the severe group ( Table 2 ).

All hospitalized patients had abnormal chest radiographs, most commonly characterized by bilateral opacities. As part of infection prevention efforts, computed chest tomography imaging for the management of COVID-19 was strongly discouraged and not performed.

Immunosuppressive therapy was reduced in the majority of patients. Overall, 42 patients (88%) had antimetabolite doses reduced or held, 3 (7%) had steroids decreased or held and 10 (18%) had calcineurin inhibitor doses decreased or held ( This is not surprising and is consistent with the fact that average time from transplant to infection in our cohort was almost 6 years. It is becoming increasingly evident, however, that the risk of nosocomial transmission is a major problem in this outbreak. While it is not possible at this time to be certain that our three cases of suspected nosocomial transmission were in fact hospital acquired, all of whom progressed to severe disease. The first was a heart transplant recipient who had undergone a deceased donor kidney transplant with thymoglobulin induction 5 days prior to symptoms and the second was a kidney transplant recipient undergoing inpatient treatment for antibody mediated rejection with plasmapheresis and IVIG. The third patient was a liver transplant recipient who had also been undergoing inpatient treatment for refractory rejection and was found to be positive 10 days into the admission, after initially testing negative. All were highly immunosuppressed hosts and this may have (94) Decreased or hold steroids 3/43 (7) 1/27 (4) 2/16 (13) Decrease or hold CNI 10/56 (18) 5/35 (14) 5/21 (23) Anti-viral treatment ( contributed to their disease severity. Among the many needs during a surge of SARS-CoV-2 infections, priority must be given to infection prevention and hospital epidemiology efforts. 14 Another important finding in this report is the presence of initially negative results in seven patients. While it is possible that some patients became infected after the initial negative test, most were likely false negatives that led to a delay in diagnosis.

All testing performed via nasopharyngeal swab, which is known to have variability in sensitivity. There are important implications of this delay in diagnosis, for both therapeutic and epidemiological reasons. The possibly significant rate false negative rate of nasopharyngeal swabs has likely compounded the difficulties in understanding the prevalence of COVID-19 in our community that stem from the overall low rate of testing. 17 A major limitation of this report is our current inability to evaluate the impact of transplantation on attributable hospitalizations and mortality due to COVID-19 since there has been profound deficiency in testing availability for outpatients. It is almost certain that a much larger number of transplant recipients have been infected with SARS-CoV-2 but have not been confirmed by formal testing due to milder symptoms and/or benign course as well as instructions from the hospitals and public health community to stay home and not seek testing in this circumstance. Additional delays in diagnosis may have also occurred due to initial long turnaround time of 3-5 days for testing, which has now been reduced to less than 1 day in the final 2 weeks of this cohort. Nevertheless, transplant recipients are usually closely followed and this cohort includes a number of patients who were never hospitalized. As testing continues to improve, there will be a much better understanding of the true impact of transplant recipient status and immunosuppression on COVID-19 outcomes.

At this time, there is much uncertainty in treatment strategies. 18 In both centers, after a careful assessment of the limited existing literature, hydroxychloroquine became the preferred initial therapy. While azithromycin was initially used in combination in one of the centers, this was later discouraged given the lack of evidence to support this approach. Immunomodulation is also being actively evaluated as a therapeutic approach, in particular among those patients experiencing rapid deterioration in the second week of illness. In particular, interleukin-6 receptor blockers such as tocilizumab and sarilumab are currently being explored to address the cytokine storm that has been described as a major driver of this rapid China, showed successful recovery from COVID-19 of a renal transplant patient from 12 years earlier when his immunosuppression was reduced and methylprednisolone was given. 10 In case of lung transplantation, since the main site of SARS-CoV-2 infection is the allograft with major influx of inflammatory cells, there may be a major role of high dose steroid therapy, particularly after the first several days of the illness. Additional data in this area are urgently needed.

In summary, in a 3-week period at two large academic medical centers in New York City, 90 solid organ transplant recipients were diagnosed with COVID-19, 68 (76%) of them were hospitalized and 16 patients have died thus far (18% of cohort, 24% of hospitalized patients, and 52% of ICU patients). While it is clear that the COVID-19 pandemic will leave many communities devastated, this initial report suggests that transplant recipients may be at high risk of severe disease and poor outcomes. There is an urgent need to investigate and identify the most effective antiviral strategies as well as determine the role of the immune response in order to guide appropriate immunomodulatory therapy which may be different in various solid organ transplant recipients.

We would like to thank Meredith Aull, Moury Minhaz, and Dominique

Piquant for their assistance.

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. ECV is on the

TJW has received grants for experimental and clinical antimicrobial pharmacology and therapeutics to his institution from Allergan, Amplyx, Astellas, Lediant, Medicines Company, Merck, Scynexis, and Tetraphase and has served as consultant to

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions

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