key: cord-0886470-ng39povr
authors: Varnell, Charles; Harshman, Lyndsay A.; Smith, Laurie; Liu, Chunyan; Chen, Shiran; Al‐Akash, Samhar; Barletta, Gina‐Marie; Belsha, Craig; Brakeman, Paul; Chaudhuri, Abanti; Fadakar, Paul; Garro, Rouba; Gluck, Caroline; Goebel, Jens; Kershaw, David; Matossian, Debora; Nailescu, Corina; Patel, Hiren P.; Pruette, Cozumel; Ranabothu, Saritha; Rodig, Nancy; Smith, Jodi; Sebestyen VanSickle, Judith; Weng, Patricia; Danziger‐Isakov, Lara; Hooper, David K.; Seifert, Michael
title: COVID‐19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative
date: 2021-02-11
journal: Am J Transplant
DOI: 10.1111/ajt.16501
sha: b1aceb16af8caa61184419f77d5ff5fba7f2ef28
doc_id: 886470
cord_uid: ng39povr

There are limited data on the impact of COVID‐19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID‐19 in pediatric KT patients. Twenty‐two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS‐CoV‐2 by PCR. Testing indications included symptoms and/or potential exposures to COVID‐19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID‐19‐positive patients, 16 were managed as outpatients, six received non‐ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID‐19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID‐19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID‐19 disease and excellent short‐term outcomes.

Pediatric solid organ transplant (SOT) patients are considered to be at increased risk for infection and sequelae thereof. 1, 2 With the emergence of the severe acute respiratory syndrome 2 (SARS-CoV-2, also called Coronavirus disease 2019, in December 2019 in Wuhan, Hubei Province, China 3 the pediatric transplant community faced unprecedented unknowns in providing care to the SOT population. Limited international data from early in the COVID-19 pandemic suggest that despite a predisposition toward infection, immunosuppressed children with SOT may be at relatively low risk for adverse patient and graft outcomes from COVID-19. 1, 2, 4, 5 There are multiple published case reports and case series detailing clinical descriptions, treatments, and outcomes of COVID-19 in adult SOT patients. [6] [7] [8] However, there have been no cohort studies to document the incidence of in the pediatric SOT population and only limited data available regarding the subsequent risk for short-term harm to both the graft and patient. 9 The Improving Renal Outcomes Collaborative (IROC) is a multicenter, network-based learning health system including 34 academic pediatric kidney transplant (KT) centers in the United States. The primary aim of IROC was to characterize clinical outcome data for pediatric KT patients, provide center-and network-level analytics, and inform center-based quality improvement initiatives to improve health, longevity and quality of life for pediatric KT patients and families. 10, 11 The objectives of the current study were twofold: (1) rapidly implement a web-based registry across the IROC network to describe the incidence of COVID-19 in pediatric KT patients using our existing collaborative infrastructure, and (2) describe short-term allograft and patient outcomes for pediatric KT patients experiencing COVID-19.

medications, hospitalization-related data, biopsy data, and rejection events/outcomes. These elements are processed and disseminated to centers as statistical process control charts, population management measures, and previsit planning forms to support ongoing pediatric KT care, quality improvement activities at the institutional level, and for benchmarking across the network. Demographic data in the registry included patient age, sex, and race (although race data were incomplete for some patients). Available medical data included cause of end-stage kidney disease leading to transplant, date of KT (including prior if multiple transplants), donor type (living or deceased), current nonimmunosuppression medications (e.g., ACEinhibitors), current immunosuppression drug regimen, and history of rejection episodes with grade of rejection stratified according to Banff criteria. 12,13 IROC-based research studies are permitted to use these registry data as covariates as in the current study.

To collect specific information regarding COVID-19 testing, results, and clinical outcomes, a Research Electronic Data Capture (REDCap) data collection tool was created and distributed to IROC centers ( Figure 1 ). REDCap is a secure, web-based software platform designed to support data capture for research studies. 14, 15 Entry of COVID-19 testing information into the REDCap data collection tool was voluntary for IROC centers during the study period.

Centers were encouraged to enter all patients tested rather than only those who tested positive. During the study period of April 6 to September 3, 2020, centers entered patient-level data into REDCap for COVID-19 testing results, indication(s) for testing, symptoms at the time testing (if applicable), known history of lung disease, and the provided treatment(s) for confirmed or suspected COVID-19.

Indications for testing were not mutually exclusive, thus centers can report multiple indications for testing. Additional outcome questions included the highest level of care the patient required (e.g., outpatient, inpatient wards, intensive care) and endpoints for both the allograft and patient following COVID-19 disease, such as acute kidney injury (AKI), rejection, respiratory failure, and/or death.

Each patient in the IROC registry is assigned both a unique center ID and patient ID. The center ID and IROC registry ID(s) were entered F I G U R E 1 Map of IROC centers that participated in COVID-19 study along with COVID-19 testing data in the REDCap data collection tool. Patient clinical data, including immunosuppressive and antihypertensive agent(s), were available from the IROC registry and linked to the COVID-19 testing data using patient-level, secure identifiers.

Individual centers were contacted to provide follow-up for missing data, if available, on individual patients from either the IROC registry or the REDCap data collection tool.

Linked data from the REDCap collection tool and IROC registry were analyzed to provide descriptive information on the patients entered in the database, including the number of patients tested, indication for testing, the incidence of COVID-19, and clinical outcomes. If a patient was tested and entered into REDCap tool multiple times, the individual was analyzed once. If subsequent testing revealed a positive test, or a test with symptoms was reported, those entries were prioritized. To estimate the incidence of COVID-19-positive testing using patients with a documented test result, we analyzed a subgroup of patients from centers that entered all COVID-19 testing data during the study period. Ages were calculated based on demographic data reported in the IROC registry relative to the date that testing data were entered into the REDCap database. Continuous variables were summarized using medians with interquartile ranges (IQR) and tested for differences between groups using Wilcoxon rank-sum test to accommodate the nonnormally distributed variables. Categorical variables were analyzed by Fisher's exact test due to the small number of patients with a positive test. p < .05 were considered significant results.

Analyses were conducted using SAS version 9.4 (SAS Institute, Inc).

Twenty-two IROC centers that collectively care for 2732 patients submitted COVID-19 testing data from 281 patients between April 6, 2020 and September 3, 2020 (see Figure 2 ). All centers reported using SARS-CoV-2 PCR for testing. Patient characteristics and demographics are detailed in Table 1 

To estimate the incidence of a positive COVID-19 test in our cohort, we excluded any center that did not enter all their tested transplant patients during the study period. Thirteen IROC centers caring for a total of 1686 patients entered data on all tested patients (n = 229).

The overall estimated incidence of COVID-19 at these centers was 0.6% (10/1686). The incidence of COVID-19 in tested patients at these centers was 4.4% (10/229). Five of the 10 positive patients (50%) from this subanalysis were asymptomatic.

Twenty-four patients (8.5%) tested positive for COVID-19 out of all those entered in the REDCap registry (n = 281). Treatment and outcomes data for the entire cohort are detailed in Table 3 . The None of the patients who tested positive required dialysis or experienced graft failure, and none of them experienced respiratory failure, required intubation, or died.

We report the largest cohort assembled to date of pediatric KT patients tested for COVID-19. Key findings include: (1) the overall estimated incidence of COVID-19 was 0.6% in 1686 patients from centers that submitted complete testing data, and the incidence among 229 tested patients at these centers was 4. vations extend the findings of smaller studies that SOT patients have a relatively low incidence of symptomatic COVID-19 and a low risk of short-term adverse outcomes. We also found that patients with a positive test tended to be older (median age 18.6 years compared to 14.3 years). While this study was not designed to report differences between the testing groups, this finding is consistent with the finding in the general population that the incidence of COVID-19 is higher in older children. 16 Clinically, we were unable to identify any single symptom or set is associated with poor patient and graft outcomes. A recent meta- Tables 1 and 2 and any associations should be interpreted with caution. We acknowledge that testing was not uniform across centers or for all patients. Thus, the incidence of COVID-19 may be underestimated if many asymptomatic patients in the community were not tested or if patients were tested outside of their center. This is particularly important as almost 40% of our cohort who tested positive had no symptoms of COVID-19. Additionally, the data collection tool was created early in the pandemic while clinical symptoms were still being described, so we did not collect data on loss of smell or taste as a symptom.

This symptom has been added to our data collection tool and we hope to be able to describe this more specifically in future analyses. Finally, due to lack of complete race data available in the IROC registry, we could not study the impact of racial differences on COVID-19 testing or outcomes, which may affect the generalizability of our findings.

Overall, our findings demonstrate that immunosuppressed pediatric patients are at relatively low risk for severe pulmonary disease or death due to COVID-19. We will continue to collect COVID-19

testing data as this situation continues to rapidly change, particularly with reopening of schools across the United States in fall 2020 as well as with increasing case numbers across the United States. The pediatric KT population, like many other high-risk patient populations, are familiar with periods of social distancing and the need to mitigate risk of infectious exposure during periods of highest immunosuppression (e.g., immediately posttransplant or for treatment of acute rejection)-therefore the demographic findings and positive testing rates may change with heightened COVID-19 spread. Furthermore, the IROC learning health system infrastructure provides the opportunity to monitor patients over the coming months to years following patients with a history of COVID-19. Specifically, future questions of interest include long-term complications of prior COVID-19, assessing length of viral shedding in patients with multiple positive tests, and characterizing the development of humoral immunity.

Dr. Varnell receives support from the NIH/NCATS 2KL2TR001426-05A1. Dr. Seifert receives support from NIH/NIDDK R01DK126807.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Return to school for pediatric solid organ transplant recipients in the United States during the COVID-19 pandemic: expert opinion on key considerations and best practices

COVID-19 in solid organ transplantation patients: a systematic review

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

SARS-CoV-2 infection and early mortality of wait-listed and solid organ transplant recipients in England: a national cohort study

Mild COVID-19 in a pediatric renal transplant recipient

Management of patients on dialysis and with kidney transplantation during the SARS-CoV-2 (COVID-19) pandemic in

COVID-19 and kidney transplantation: results from the TANGO International Transplant Consortium

COVID-19 infection in kidney transplant recipients

The pediatric solid organ transplant experience with COVID-19: an initial multi-center, multiorgan case series

Quality initiatives in pediatric transplantation

Multicenter data to improve health for pediatric renal transplant recipients in North America: complementary approaches of NAPRTCS and IROC

Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibodyassociated arterial lesions

Banff 07 classification of renal allograft pathology: updates and future directions

The REDCap consortium: building an international community of software platform partners

Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support

COVID-19 trends among schoolaged children -United States

How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review

The severity of COVID-19 in children on immunosuppressive medication

Coronaviruses and immunosuppressed patients: the facts during the third epidemic

Impacts of immunosuppression and immunodeficiency on COVID-19: a systematic review and meta-analysis

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality

Practical recommendations for the management of diabetes in patients with COVID-19

Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations

Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis

PEDSnet: how a prototype pediatric learning health system is being expanded into a national network

The improving renal outcomes collaborative: blood pressure measurement in transplant recipients

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative