key: cord-257408-ejhhk1iu authors: Goss, Matthew B.; Galván, N. Thao N.; Ruan, Wenly; Munoz, Flor M.; Brewer, Eileen D.; O’Mahony, Christine A.; Melicoff‐Portillo, Ernestina; Dreyer, William J.; Miloh, Tamir A.; Cigarroa, Francisco G.; Ranch, Daniel; Yoeli, Dor; Adams, Megan A.; Koohmaraie, Sarah; Harter, Diana M.; Rana, Abbas; Cotton, Ronald T.; Carter, Beth; Patel, Shreena; Moreno, Nicolas F.; Leung, Daniel H.; Goss, John A. title: The Pediatric Solid Organ Transplant Experience with COVID‐19: An Initial Multi‐Center, Multi‐Organ Case Series date: 2020-09-18 journal: Pediatr Transplant DOI: 10.1111/petr.13868 sha: doc_id: 257408 cord_uid: ejhhk1iu BACKGROUND: The clinical course of COVID‐19 in pediatric solid organ transplant recipients remains ambiguous. Though preliminary experiences with adult transplant recipients have been published, literature centered on the pediatric population is limited. We herein report a multi‐center, multi‐organ cohort analysis of COVID‐19 positive transplant recipients ≤ 18 years at time of transplant. METHODS: Data were collected via institutions’ respective electronic medical record systems. Local review boards approved this cross‐institutional study. RESULTS: Among 5 transplant centers, 26 patients (62% male) were reviewed with a median age of 8 years. 6 were heart recipients, 8 kidney, 10 liver, and 2 lung. Presenting symptoms included cough (n=12 (46%)), fever (n=9 (35%)), dry/sore throat (n=3 (12%)), rhinorrhea (n=3 (12%)), anosmia (n=2 (8%)), chest pain (n=2 (8%)), diarrhea (n=2 (8%)), dyspnea (n=1 (4%)), and headache (n=1 (4%)). Six patients (23%) were asymptomatic. No patient required supplemental oxygen, intubation, or ECMO. Eight patients (31%) were hospitalized at time of diagnosis, 3 of whom were already admitted for unrelated problems. Post‐transplant immunosuppression was reduced for only 2 patients (8%). All symptomatic patients recovered within 7 days. CONCLUSIONS: Our multi‐institutional experience suggests the prognoses of pediatric transplant recipients infected with COVID‐19 may mirror those of immunocompetent children, with infrequent hospitalization and minimal treatment, if any, required. The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve with surges in many states across the United States (US). While emphasis has been appropriately placed on social distancing, mask This article is protected by copyright. All rights reserved. Many adult centers (2) (3) (4) have suggested that transplant recipients are at particular risk for an arduous clinical course given their immunocompromised state, though highly associated comorbidities exist as confounders and appear to play a significant role in COVID-19 outcomes for the transplant subpopulation (5) . In contrast, others (6,7) have reported similar clinical manifestations and mortality in transplant recipients relative to the general population. It has also been suggested that immunosuppression may confer a clinical advantage by potentially mitigating immune-mediated lung injury and acute respiratory distress syndrome in late severe SARS-CoV-2 infection. (8) This hypothesis may be more applicable to the pediatric population as children usually receive more immunosuppression per kilogram compared to adults. As the transplant community seeks clarity regarding management and outcomes of recipients testing positive for COVID-19, experiences with adult patients currently comprise a vast majority of the literature. The few pediatric publications that do exist are limited to single case reports. (9, 10) In view of the age-dependent risk discrepancy observed in the general population (11) , age may become an influential factor for treatment selection, modification of immunosuppression, and clinical prognosis upon post-transplant SARS-CoV-2 infection. Herein we report a multi-center, multi-organ cohort analysis focused on young transplant recipients and their clinical characteristics, management, and outcomes. All solid organ transplant recipients ≤ 18 years at time of transplant with a positive test for COVID-19 between April 1, 2020 and July 20, 2020 from 5 centers (Texas Children's Hospital, Children's Hospital Los Angeles, Miami Transplant Institute, University of Colorado, and University of Texas Health Science Center at San Antonio) were included in this cohort analysis. COVID-19 positivity was determined via nasopharyngeal (NP) swab SARS-CoV-2 real-time This article is protected by copyright. All rights reserved. RT-PCR (Hologic Aptima SARS-CoV-2 RT-PCR assay). IgM and IgG total SARS-CoV-2 antibodies were detected by the Ortho Clinical Diagnostics VITROS® Immunodiagnostics Products Anti-SARS-CoV-2 Test. Data were collected via institutions' respective electronic medical record systems and were reviewed for patient characteristics, history of recent exposure, timing of presentation, symptomatology, laboratory values, immunosuppression management, antiviral treatment strategies, and clinical outcomes. Local review boards approved this crossinstitutional study. During the COVID-19 pandemic between April 1, 2020 and July 20, 2020, 5 pediatric transplant centers in the US identified 6 heart, 8 kidney, 10 liver, and 2 lung transplant recipients that were found to be COVID-19 positive post-transplant. Eight of 26 patients (31%) were hospitalized, 3 of whom were already admitted for unrelated problems. All patients with COVID-19 symptoms at the time of diagnosis recovered before manuscript submission, with full resolution of symptoms within a median of 3 days. No patient experienced progressive deterioration or death. Overall patient demographics are summarized in Table 1 . Sixteen of 26 patients (62%) were male. The median age of COVID-19 positive transplant recipients at time of transplant was 8 years (range 5 months -18 years). Nineteen of 26 (73%) were Hispanic, 5 (19%) were Caucasian, and 2 patients (8%) were African American. Seventeen of 26 patients (65%) were blood type O while 8 (31%) were Type A and 1 patient (4%) was of the AB blood group. Body mass index (BMI) ranged between 17.4 -38.8 kg/m 2 with 9 of 26 (35%) < 20 kg/m 2 , 11 (42%) between 20 -30 kg/m 2 , and 6 (23%) > 30 kg/m 2 . Eight of 26 patients (31%) had undergone kidney transplantation, 10 (38%) underwent liver transplantation, 6 (23%) were heart transplant This article is protected by copyright. All rights reserved. Two patients (8%) were exposed by a health care provider. The 26 COVID-19 positive transplant recipients had variable clinical presentations (Table 1) . The most common documented symptom was cough (n=12 (46%)) followed by fever (n=9 (35%)), dry/sore throat (n=3 (12%)), rhinorrhea (n=3 (12%)), anosmia (n=2 (8%)), chest pain (n=2 (8%)), diarrhea (n=2 (8%)), and dyspnea and headache in 1 patient each (4%). Six patients (23%) did not have any symptoms (4 kidney, 1 liver, and 1 lung recipients). Eight of the affected patients (31%) were hospitalized at the time of COVID-19 diagnosis; however, 3 patients (Nos. 3/7/8) were already admitted for unrelated problems. The remaining 5 patients (19%) were hospitalized for a median time of 3 days, with presenting symptoms including a combination of fever (n=3), cough (n=2), chest pain (n=1), diarrhea (n=1), and rhinorrhea (n=1). Eight of 26 patients (31%) were evaluated by chest x-ray (CXR) or computed tomography (CT) of the chest and only patients 8 (kidney recipient) and 15 (liver recipient) had multifocal pulmonary infiltrates consistent with COVID-19. Six patients (23%) had a decreased white blood cell (WBC) count (< 4000 per µL of blood) and 4 (15%) had low hemoglobin (<13.5 This article is protected by copyright. All rights reserved. g/dL for males, <12.0g/dL for females) and hematocrit (<41% for males, <36% for females) (1 patient had both a decreased WBC count and low hemoglobin and hematocrit); however, none of the patients presented with laboratory evidence of hepatitis or other biochemical abnormalities. There were no observed or quantified differences in severity of clinical course or treatment dependent on blood type. Twelve of 26 patients (46%) had inflammatory biomarkers measured. Of the 12, 7 (58%) had elevation of C-reactive protein (CRP) (> 1.0 mg/L) and/or ferritin (> 300 ng/mL for males, >150 ng/mL for females). In addition, 5 patients (42%) had elevation of fibrinogen (> 400 mg/dL) and/or D-dimer (> 0.5 mg/L). A smaller subset of 4 patients (15%) had serum troponin levels measured and all were within normal limits (< 0.4 ng/mL). Age among our pediatric cohort did not appear to influence clinical severity. Follow-up COVID-19 NP swab testing was available in 10 of 26 patients (38%) with 5 of 10 testing negative (median time of 13 days after initial positive test) and the other 5 remaining positive (median time of 15 days after initial positive test). Only 1 patient (No. 18) was tested for the presence of SARS-CoV-2 antibodies, which detected IgG-specific antibodies while IgM antibodies were negative indicating previous and not active infection. Of the 26 affected patients, none required supplemental oxygen or intubation (it should be noted that No. 3 is chronically ventilatory dependent - Table 1 As the morbidity and mortality associated with COVID-19 continue to impact the world, particularly in the US, SARS-CoV-2 infection among solid organ transplant recipients is inevitable. Due to immunosuppressive treatment (1) , elevated risk of co-infections during the early post-transplant period (12) , and highly associated comorbidities linked to poor outcomes (5, 13, 14) , transplant recipients are expected to be particularly susceptible to infection and a severe clinical course in the event of SARS-CoV-2 exposure. Some transplant-specific studies report significant complications and mortality, (2-4) while other analyses demonstrate similar symptomatology and mortality rates relative to the general population (6,7) . To date, the bulk of the literature examining COVID-19 following transplant is adult focused, with pediatric reports limited to single patient experiences. (9, 10) Mirroring the majority experience This article is protected by copyright. All rights reserved. of infected children in the general population (15, 16) and report of a single pediatric heart transplant recipient (9) , our multi-center pediatric transplant cohort experienced mild symptoms or lack thereof. The underpinning of milder symptomatology in children remains obscure but is likely multifactorial. Suggested reasons include a maturing immune system primed to combat novel pathogens, decreased prevalence of comorbidities established as risk factors for severe disease, frequent infections with the common cold coronaviruses potentially providing protection, healthier respiratory tracts, and a difference in the distribution and functioning of viral receptors. Though the virus manifested in various ways within our cohort, with cough being the most frequent presentation, complete resolution of symptoms occurred within a week for each patient. None of our liver recipients, nor other solid organs, experienced the described complication of COVID-19 induced hepatitis in an infant early after liver transplant (10) or multisystem inflammatory syndrome in children (MIS-C) (17) . As a hyperinflammatory response has been associated with complications and the multiorgan involvement with COVID-19, (18) inflammatory biomarkers in chronically immunosuppressed patients are of particular interest. In our cohort, initial inflammatory biomarkers were not uniformly checked, though CRP, ferritin, fibrinogen, D-dimer, and troponin were measured in certain patients (Table 1) . 58% of the measured cohort had elevation of CRP and/or ferritin while 42% had elevation of fibrinogen and/or D-dimer. All troponin levels were within normal limits. As our patients presented with mild symptoms and most recovered within days, and less than half had evaluation of serum inflammatory biomarkers, we are unable to determine the meaning and role of assessment of inflammatory biomarkers in pediatric transplant patients. More data, including serial monitoring as opposed to single measurements, are needed to assess potential predictive value. This article is protected by copyright. All rights reserved. Comorbidities associated with a severe COVID-19 clinical phenotype among adult transplant recipients, e.g. hypertension, obesity, and diabetes, (14) are less prevalent in the pediatric population. This may explain in part our cohort's mild symptoms at presentation and rapid recovery, without any patient requiring supplemental oxygen, intubation, or extracorporeal membrane oxygenation (ECMO). That being said, 6 of our 26 patients (23%) were obese (BMI > 30 kg/m 2 ) but did not experience more severe manifestations. In addition, our cohort's relatively small patient pool and ubiquitous mild symptomatology precluded firm conclusions with respect to the described disparities in clinical course severity dependent on blood type. Nonetheless, a majority of our cohort was Type O (17/26 (65%)), for which a protective effect has been attributed given its unexplained link with a milder disease phenotype. (19) It is also important to note that immunosuppression was reduced in only 2 of 26 patients (8%), with resolution of symptoms within 72 hours, suggesting that adjustment of maintenance immunosuppression may not be necessary. In fact, our experience suggests caution should be exercised when reducing immunosuppression, particularly if symptoms are mild, as renal allograft biopsy of patient No. 8 revealed moderate ACR after initially decreasing MMF and tacrolimus. We highlight the mild COVID-19 clinical course of 26 immunosuppressed pediatric transplant recipients across 5 institutions including California, Florida and Texas, unfortunate COVID-19 hotspots in the US. Our cohort suggests immunosuppression alteration may not be necessary for a complete and rapid recovery in the immediate post-infection period. Furthermore, minimal supportive therapy may be required, if symptoms remain mild. It will be critical to learn from and share our experience through the post-COVID-19 diagnosis and recovery period, with a focus on antibody kinetics and risk for re-infection, as we seek to understand the potential longterm effects of COVID-19 infection in immunosuppressed pediatric transplant patients. This article is protected by copyright. All rights reserved. COVID-19 in a pediatric heart transplant recipient: emergence of donor-specific antibodies A case of an infant with SARS-CoV-2 hepatitis early after liver transplantation. Pediatric Transplantation. Online ahead of print Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine Rates of first infection following kidney transplant in the United States COVID-19 in kidney transplant recipients Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the Screening and severity of Coronavirus Disease 2019 (COVID-19) in children in Madrid, Spain. JAMA Pediatrics Multisystem inflammatory syndrome in children (MIS-C) related to COVID-19: a New York City experience *AA-Afric a n Am e ric a n *AKI-Ac ute kidne y injury