This multicenter study consisted of a cohort of children with chronic dialysis and kidney transplantation. This study provided an important opportunity to determine the cumulative incidence of COVID-19 in this specific pediatric patient population and to compare the severity and outcomes of the disease between children on dialysis and KTx recipients. Our results revealed that both children receiving maintenance dialysis and children with a kidney transplant are at increased risk for COVID-19, but most patients in both groups develop mild forms of the disease. It is noteworthy that a high proportion of KTx recipients were asymptomatic. AKI developed in more than one-third of KTx recipients, but none of whom required dialysis or lost their graft. In the entire cohort, one child receiving HD with multiple comorbidities died from COVID-19.
It is challenging to determine and effectively compare the incidence of COVID-19 due to differences in testing strategies between countries and centers and the presence of many asymptomatic cases. The ERA-EDTA registry showed that the incidence of diagnosed COVID-19 was 1.4% in KTx recipients and 2.9% in the dialysis population at the beginning of the pandemic [5]. For children with ESKD (on dialysis or transplanted), the Spanish Pediatric Association estimated an incidence of COVID-19 of 0.61% [8]. Similarly, the Improving Renal Outcome Collaboratives (IROC) registry from the United States reported an overall incidence of COVID-19 of 0.6% among pediatric KTx recipients and 4.4% among tested KTx recipients during the study period of April to September 2020 [18]. In the present study, among the 182 prevalent children on chronic dialysis across centers in Istanbul, 17 (9.3%) were diagnosed with COVID-19 between April 1 and December 31, 2020. Similar to dialysis patients, the rate of COVID-19 was 9.2% among 384 KTx recipients during the 9-month study period. In contrast to previous reports, our study period included both the first and second waves of the pandemics. Our results also showed that 70% of COVID-19 positive patients were diagnosed between September and December 2020. Considering the overall rate of the disease was 1.2% (1-5%) around the world on the 31st of December, according to the World Health Organization [1], and lower infection rates for children than adults, our result suggests that children with RRT are at increased risk of COVID-19. This high rate of COVID-19 in children with RRT may have resulted from regional factors as well as disease-specific factors. It is known that the uremic milieu and chronic immunosuppression increase infection risk, and patients with RRT have a higher risk of exposure to COVID-19 due to their ongoing clinical care. Moreover, these patients were closely monitored and more frequently tested for COVID-19 due to an enhanced risk of severe disease. The high proportion of asymptomatic cases in our cohort supports this hypothesis. On the other hand, this study was conducted in Istanbul, the most populous city in Turkey and one of the highest-risk cities during the pandemic, contributing to the high rate of COVID-19 in our cohort.
In contrast to adults, a significant number of children with COVID-19 are asymptomatic [14]. Similar to the general pediatric population, the IROC registry reported that 37% of KTx children were asymptomatic [18]. Consistent with this report, our KTx patients developed asymptomatic disease at a rate of 41%. Fever was the most common clinical symptom associated with COVID-19 in dialysis patients, which was present in 53% of this patient population. In accordance with the current result, previous studies have demonstrated that fever accounted for about half of dialysis patients [4, 19]. On the other hand, only one-fourth of our KTx recipients had fever as a presenting symptom. The present study contributes to previous reports indicating that fewer transplant patients may present with fever [9, 20]. Our results also showed that severe respiratory symptoms were uncommon in both groups, and most symptomatic patients had mild forms of the disease. This finding is consistent with previous pediatric studies evaluating children with ESKD, mostly in heterogeneous patient populations [8, 12, 18, 21].
Our study included both outpatients and inpatients with COVID-19. The hospitalization rate among patients on dialysis was much higher than KTx recipients despite their similar disease severity. While less than one-third of KTx recipients were hospitalized, 82% of dialysis patients were admitted to the hospital. A global pediatric study from 30 different countries revealed the hospitalization rate of 60% among 113 children with kidney disease receiving immunosuppressive therapy [12]. In our cohort, the lower rate of hospitalization among the KTx population might have resulted from the greater number of asymptomatic patients. In addition, maybe the patients with a mild disease course were isolated at home since the hospitals were quite full of COVID-19 patients.
Early evidence of the pandemic revealed a high mortality rate of up to 32% in adult dialysis and transplant patients with COVID-19, strongly associated with older age and comorbidities [5, 9, 22-24]. Comparing to adults, the pediatric population had lower rates of COVID-19-associated mortality. According to a multicenter European Study, the reported mortality rate of COVID-19 is 0.7% among the general pediatric population [25]. This rate ranges from 0 to 3.5% in children with coexisting kidney disease [7, 8, 12, 21]. In our cohort of 49 children with RRT, one child on HD died from COVID-19. This case had severe comorbidities such as malignancy and immune deficiency. Our finding contributes additional evidence that patients on dialysis, especially whom with comorbidities, are at high risk of mortality due to COVID-19.
There is limited evidence regarding effective antiviral treatment in children with COVID-19. Approximately half of our patients received antiviral therapy according to the national treatment strategy. Favipiravir was given to two-thirds of these patients, and hydroxychloroquine was given to the remaining one-third. No side effects were observed with either treatment. For KTx recipients, the best strategy for immunosuppressive therapy is still unknown. It is recommended to continue their calcineurin inhibitors and prescribed dose of glucocorticoids and to stop any anti-proliferative drugs [26]. Our analysis showed that anti-proliferative agents were modified in 62% of KTx recipients, which was equally divided between withdrawal and dose reduction of antimetabolites. In addition, tacrolimus dose reduction or discontinuation were done in two cases. None of the patients experienced allograft rejection or AKI requiring dialysis. However, 36% of KTx recipients developed early-stage AKI (stage 1). In accordance with the present result, previous studies have demonstrated that COVID-19 associated AKI develops in 27% to 52% of KTx recipients [22, 23, 27-29]. Taken together, these results highlight the need for caution regarding the increased risk of developing AKI in KTx recipients.
Our study has several limitations. We did not have any control group of the general pediatric population with COVID-19 from Istanbul to compare the infection rate and disease course to minimize regional differences. Another limitation is that we could not obtain any information regarding how many children with RRT were tested for COVID-19. Lastly, some variation may have been introduced due to the multicenter design since individual centers had their own indications for hospitalization and different approaches for the immunosuppressive modifications in KTx recipients.