Long-COVID symptoms in pediatric end-stage kidney disease patients and controls: a single-center, cross-sectional descriptive study

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has profoundly impacted global health. The World Health Organization (WHO) declared a global pandemic on March 11^th, 2020, impacting all layers of national health systems worldwide. Its medical implications include acute respiratory distress syndrome (ARDS), leading to severe pneumonia and multiorgan failure⁽¹⁾, particularly in vulnerable populations such as the elderly and those with preexisting conditions like end-stage kidney disease⁽²⁾. As the pandemic progressed, so did the understanding of the multiple organ involvement of COVID-19, and evidence surfaced about the vascular, brain, heart, endocrine and kidney effects of SARS-CoV-2.

Another long-term complication of COVID-19, a condition in which children seem to be less commonly affected compared to adults, is long-COVID. This entity, also known as post-acute sequelae of SARS-CoV-2 (PASC), was recently defined as post-COVID conditions (PCCs)⁽³⁾, a broad spectrum of new, recurring or persistent symptoms or health issues that individuals may encounter four or more weeks after the initial COVID-19 infection. These symptoms can last for extended periods. The estimated percentage of children who contract SARS-CoV-2 and subsequently develop post-COVID conditions varies. A review by Zimmermann et al.⁽⁴⁾ identified 14 studies on the subject, with a prevalence of 4% to 66%, with fatigue, headache and sleep disturbances as the most frequent symptoms. This variation is likely due to differences in study design, inclusion criteria, and follow-up durations.

Different definitions for these over 60 signs and symptoms have been proposed by major healthcare bodies. The duration of symptoms is defined as between four and 12 weeks by the National Institute of Health and Care Excellence (NICE)⁽³⁾ and the CDC⁽⁵⁾, while WHO⁽⁶⁾ cites more than 12 weeks, with onset within two months after SARS-CoV-2 infection, with at least one persisting symptom. Common symptoms reported include headaches (3% to 80%), fatigue (3% to 87%), sleep disturbances (2% to 63%), concentration difficulties (2% to 81%), and abdominal pain (1% to 76%)^(4,7). There is no consensus regarding specific laboratory tests for diagnosis, except the initial confirmation of SARS-CoV-2 infection.

Long before the SARS-CoV-2 pandemic, chronic kidney disease (CKD) was a global concern, afflicting approximately 12% of adults⁽⁸⁾, with similar projections available in children⁽⁹⁾, with a reported prevalence of 15-74.7 cases/million children. Although pediatric end-stage kidney disease (ESKD) patients (below 18 years old) constitute a very small proportion of the total ESKD population (approximately 2%), the mortality rate for these patients receiving renal replacement therapy is between 30 and 150 times higher than that of the general pediatric population⁽¹⁰⁾.

Different risk factors have been proposed for PCCs/long-COVID involvement in children. The severity of initial COVID-19, older age⁽¹¹⁾, and preexisting allergies⁽¹²⁾ or other severe diseases⁽¹³⁾ have been linked to a higher risk of PCCs in children in different studies.

Patients on dialysis have a compromised immune system due to underlying disease and the treatment itself. This has been postulated to increase the risk of developing more severe forms of COVID-19 and prolonging symptoms, potentially increasing the risk of long-COVID⁽¹⁴⁾.

The aim of our study was to identify the prevalence of long-COVID in a specific population (ESKD pediatric patients) and to compare it to a control group (children admitted for COVID-19) during the same period. The two groups were followed-up at the same interval. The second focus of this study was to characterize, from a clinical point of view, long-COVID in the two groups. In addition, this evaluation will help address the impacts of the condition on affected children and their families, as well as guide discussions about child vaccination.

Patients and methodology

From 1 September 2021 to 30 April 2023, a number of 657 pediatric patients (below 18 years old) were admitted for COVID-19 to the Clinical Hospital of Infectious Disease Cluj-Napoca, Romania. During the same period, in the Nephrology, Dialysis and Toxicology Pediatric Ward of the Emergency Clinical Hospital for Children, nine patients, out of a total of 14 suffering from end-stage renal disease (ESKD) receiving dialysis, experienced an acute infection with SARS-CoV-2. The two settings represent the most important university centers for pediatric treatment in the second largest city in our country, with a regional population of 400,000 people, of whom 106,545 are in the 0-14-year-old age group, according to the National Institute for Statistics⁽¹⁵⁾. The Clinical Hospital of Infectious Diseases was the main hospital for treating COVID-19 during the pandemic, and has both adult and pediatric wards. The Nephrology, Dialysis and Toxicology Pediatric Ward of the Emergency Clinical Hospital for Children is one of five centers that perform pediatric renal replacement therapy in our country. It serves a population of roughly 4 million from the north-west and central parts of the country.

Study design

We conducted a prospective cross-sectional descriptive study of two groups of children who went through COVID-19 in the aforementioned period. We followed the STROBE checklist⁽¹⁶⁾ for cross-sectional studies in order to make the presentation of the study clearer. The first group consists of patients with ESKD receiving renal replacement therapy in the form of hemodialysis or peritoneal dialysis. We included all the patients who met the inclusion criteria: a positive SARS-CoV-2 test during the selected period. Patients who underwent renal transplantation were excluded because of their immunosuppression regimens and their relatively low exposure (three monthly follow-ups, no overnight admissions). In the control group, we included children chosen from the cohort of patients admitted to the Clinical Hospital of Infectious Diseases Cluj-Napoca, and the case definition was similar: a positive SARS-CoV-2 test during the selected period. The number of participants in the control group was chosen to match the one in the study group. From the cohort of patients with COVID-19 admitted, unmatched patients were selected by two investigators independently, using a simple random sampling technique. The selected patients were called by the main investigator and, if there was an agreement, the interview was performed. We took into consideration the nonresponse bias, and we tried to eliminate it by making repetitive calls to reach the caretaker and explain the aim of the questionnaire. The sampling bias was also targeted by our team. Both investigators responsible for the selection were aware of this risk and used the same sampling frame. The questions were translated into the native language and were addressed as accessible as possible.

We included only patients with a positive test for SARS-CoV-2, confirmed by reverse transcriptase PCR or rapid test performed due to the presence of symptoms. None of the participants presented asymptomatic infection, but this was not an exclusion criterion. The patients in the ESKD group were also admitted during the SARS-CoV-2 infection. Regarding treatment, the national protocol in use at that time was used for both groups.

Demographic data like age, sex and disease severity were collected from the medical records. To evaluate the presence of PCCs, we performed telephone interviews using a standardized follow-up data collection protocol developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Global Pediatric COVID-19 Follow-up Working Group⁽¹⁷⁾ and available at: https://isaric4c.net/. Permission to use the follow-up protocol was obtained by e-mail. The interviews took place between 1 February 2024 and 10 August 2024. The interviews were performed by two members of the team, one in each hospital, both with a lot of experience in communication.

The patients’ selection process and the inclusion criteria are illustrated in Figure 1.
 

Definition of variables

We defined “persistent symptoms” according to the guidelines cited in the introduction^(3,6) – symptoms lasting between 4 and 12 weeks or more. We used subcategories like respiratory, neurological, fatigue, sensory, sleep, dermatological, musculoskeletal, gastrointestinal and cardiovascular, following the example available in previously published literature^(8,17). Besides data on demographics, we recorded detailed symptoms like rhinitis, pharyngitis, smell and taste disturbances (loss or alterations), cough, dyspnea, chest pain, muscle pain, joint pain, fatigue, headache, rash/skin lesions, gastrointestinal symptoms (diarrhea, vomiting, abdominal pain, loss of appetite), weakness, neurological symptoms, other symptoms, including cognitive problems. The legal representative of the child gave information on the child’s emotional well-being, activities and the impact of online time on how these activities are performed, and social relationships. Parents also reported on mood and behavior changes due to COVID-19 and pandemic, stratified by the effect. A 0-100 wellness scale⁽¹⁸⁾ was used to assess health status before COVID-19 and at the time of the study, 0 being the worst possible health and 100 representing the best possible health. For this scale, the change in value was calculated using the values before onset of COVID-19 illness compared to the follow-up assessment. We also assessed the burden on the caretaker and the family, with questions regarding anxiety levels during the acute phase, depression, discrimination and received help.

Statistical analysis

Data from the interview were collected in an Excel database (Microsoft Excel 2406), being further analyzed using SPSS Statistics V.23. We used the median for summarizing continuous variables, such as age, follow-up period, or length of hospital stay. To describe the distribution of categorical variables like sex, presence of comorbidities or symptoms, frequencies and percentages were used. To better visualize the coexistence of different symptoms, heatmaps were generated. The Mann-Whitney U test was used for comparing the weight of the patients within each group, and the p-value for statistical significance was set at the level of p≤0.05. The value of weight at the time of SARS-CoV-2 infection was compared to the weight at the follow-up interview.

Results

A total of nine 0-18-year-old children in each group were included in the study, meeting the inclusion criteria: a positive test for SARS-CoV-2, from 1 September 2021 to 30 April 2023. The patients’ demographics are illustrated in Table 1.
 

We analyzed the weight and height of the patients in the two groups. For weight, there was a recorded value during the infection and one for the moment of the interview. No significant statistical difference among the same group was found between the weight of the patients during and after COVID-19. 

The preexisting comorbidities were significantly more frequent in the ESKD group, exhibiting significantly higher rates of heart disease and neurological conditions, with 77.8% of subjects in this group affected by each of these conditions. In contrast, the control group showed a much lower prevalence of these conditions, with only 11.1% affected by heart disease or food allergy. The ESKD group also reported higher rates of genetic conditions and excessive weight, each affecting 44.4% of subjects, compared to 0% in the control group.

No patient (in either group) had a history of tuberculosis, asthma, allergic rhinitis/hay fever, gut problems, hematologic or oncologic disease, immune deficiency, diabetes type 1 or 2, or rheumatologic problems.

The questionnaire also focused on psychosocial items regarding habits and behavior that might have been influenced by acute infections with SARS-CoV-2. Each item was assessed using a 1-5 scale, where 1 meant negatively influenced (the behavior appearing less), 3 meant no change, and 5 meant positive influence (the behavior appearing more often). The results are illustrated in Figure 2.
 

A total of four patients (44.4%) from the control group reported symptoms persisting for more than four weeks, with headache, eye problems, and nasal congestion lasting more than 12 months. Nausea, headache and skin rash had the highest prevalence among the control group. In the ESKD group, eight patients (88.8%) complained of symptoms persisting between four and 12 months. The most reported symptoms of ESKD were difficulty breathing, weight loss and poor appetite, musculoskeletal problems, fatigue and hypersomnia, as highlighted in Figure 3.
 

None of the patients were diagnosed with multisystem inflammatory syndrome, shock/toxic shock syndrome, pulmonary embolism, coagulopathy, Kawasaki disease, diabetes type 1 or 2 or asthma after having COVID-19. In addition, there was no record of pain in breathing, fainting, swallowing problems, diarrhea, hair loss, or changes in menstruation.

We illustrated the psychological symptoms and the parent perception of the disease in the heatmap in Figure 4.
 

Discussion

The prevalence of long-COVID symptoms is high in our study group (88.8%). In other studies, like the one published by Weinbrand-Goichberg et al.⁽¹⁹⁾, 35/197 (17.8%) of the under 20-year-old group were infected with SARS-CoV-2, and none reported persistent symptoms. However, we could not find other studies regarding the pediatric ESKD population. The lack of data regarding this subject is also a strength of this study, even though it is a descriptive study and with a small sample size. We therefore tried comparing our results with the ones of studies done on adult patients with ESKD. We found the study of Bouwmans et al.⁽²⁰⁾, published in February 2024. This study reported a prevalence of PPC of 29% in patients with chronic kidney disease stage G4/5, a 21% prevalence in dialysis patients, and a 24% prevalence in patients with kidney transplants. In addition, 69% of patients with PCC reported (very) high symptom burden.

One of the study limitations is the low number of participants; because of this, the results were interpreted with caution. The small number of cases in the study group is partially explained by the epidemiology, with a global pediatric ESKD prevalence of 15-74.7 cases/million children⁽¹⁰⁾. Other published studies, like the one of Plumb et al.⁽²¹⁾, included five UK children with CKD who tested positive for SARS-CoV-2 infection. In another study, by Marlais et al.⁽²²⁾, 18 children from 16 pediatric nephrology centers across 11 countries (i.e., Spain, Switzerland, China, UK, Germany, France, Sweden, Colombia, USA, Iran, and Belgium) suffering from COVID-19 were included. While such low numbers preclude further analysis and follow-up, data obtained from our study are comparable to those from literature. For future studies, we might take into consideration extending to other centers treating ESKD in our country.

Another limitation is the follow-up of children at arbitrary time points, with symptoms reported by parents based on the questionnaire, but without clinical assessment and objective parameters. This was done using a validated questionnaire formulated by a highly regarded group of study – ISARIC⁽¹⁷⁾, and that was previously used and yielded significant data on the subject. The time from discharge to follow-up was similar between the two groups.

As expected⁽¹⁴⁾, patients in the ESKD group are more likely to have preexisting comorbidities. Of all, we mention neurological conditions and heart disease.

From a pathogenetic point of view, the mechanisms of long-COVID are not well known. A systematic review and meta-analysis from Lopez-Leon et al.⁽²³⁾ found that the most prominent symptoms of long-COVID are commonly present in dysautonomia, a dysfunction of the sympathe­tic and/or parasympathetic autonomic nervous system. It remains unclear whether this is the direct result of the SARS-CoV-2 infection or due to the inflammatory response mediated by cytokines. This theory could explain the high prevalence of symptoms in older children. A review by Valentini et al.⁽²⁴⁾ about the relationship between COVID-19 and innate immunity in children found that the innate immune system of children generally protects younger patients from getting infected. However, children at risk or those older seem to experience an inflammatory or immunological dysregulation responsible for severe forms of COVID-19 or long-lasting symptoms.

From the persistent symptom distribution, we drew these conclusions: for the control group, the most repor­ted symptoms have a high prevalence in the 80-month-old age group. In comparison, for the ESKD group, the most “heated” age zone is 120 months. For example, in the ESKD group, skin rash and fatigue are more prevalent in certain age groups compared to others, indicating potential age-related susceptibility. Comparing the two groups, the ESKD group shows a generally higher prevalence of symptoms, especially in specific age ranges. Certain symptoms cluster together in specific age groups, suggesting that these age groups might be more vulnerable to a combination of symptoms. In both groups, younger and older individuals seem to exhibit different symptom patterns, highlighting the need for age-specific interventions. This could be explained by the fact that systemic chronic inflammation and immune dysregulation are believed to be drivers for developing long-COVID, and these are inherent to CKD patients on dialysis⁽¹⁹⁾, thus possibly elevating their risk of PASC.

One of the dimensions of long-COVID is the psycho­social aspect. The overlap between challenges associa­ted with managing ESKD as a chronic disease, needing intense family and social care, combined with the isola­tion caused by COVID-19⁽²⁵⁾, and the possible neurolo­gi­cal involvement of long-COVID could lead to a rise in anxiety and depression. This is also valid for family and caregivers. When assessing the mental health symp­toms, we observed that certain symptoms, such as difficulty expressing emotion and behavior change, are more prevalent in the control group, in specific age ran­ges, indicating potential age-related trends. In the ESKD group, symptoms like anxiety before COVID-19 and depression before COVID-19 appear more frequently in particular age groups, reflecting the additional psycho­lo­gi­cal burden that may accompany chronic illness. The ESKD group generally shows a higher prevalence of symp­toms compared to the control group. This difference may suggest that individuals with ESKD are more likely to experience mental health challenges, possibly due to the stresses associated with managing a chronic con­di­tion. In both groups, certain symptoms appear to clus­ter together within specific age ranges. For example, symp­toms related to changes in relationships or behavior may co-occur, reflecting broader patterns of psychological adjustment during and after the COVID-19 pandemic.

The analysis of health status before and after COVID-19 for both the control and ESKD groups reveals distinct patterns in how these groups were affected by the pandemic. On average, the control group experienced a slight improvement in health status. In contrast, the ESKD group showed an average decline in health status. This finding highlights the greater negative impact of COVID-19 on individuals with ESKD compared to those in the control group, who, on average, experienced more favorable outcomes. This analysis underscores the vulnerability of the ESKD group to the long-term effects of COVID-19 and the importance of targeted interventions to support their recovery.

Our findings highlight the need for further research. The results emphasize the impact long-COVID had on these patients and, after processing data, our main objective was to draw attention on the additional need for care and follow-up in these patients. Despite the high prevalence (44.4% in the control group and 88.8% in the ESKD group) of reported long-lasting symptoms in the SARS-CoV-2 infected children, this did not seem to impact the burden of disease on the children or their families. This might be due to a high impact of the disease itself. A study in Egypt⁽²⁶⁾ on the burden of disease on families taking care of a child with ESKD found that the total PedsQL™ FIM and parental health-related quality of life (HRQoL) of caregivers were lower in the ESKD population compared with other studies of caregivers of children with other chronic diseases. Future studies should focus more on the pathophysiology and immunology of post-COVID-19 sequelae, which will be essential for refining case definitions and guiding intervention trials aimed at improving long-term outcomes.

To our knowledge, this is the first study to focus on the prevalence of long-COVID in children. Moreover, this is one of the few studies^(12,20,21) to address a specific population at risk – the pediatric ESKD population – and the first to tackle long-COVID in these patients.  Another strength of the study is the design as a cross-sectional study, allowing for a wider perspective on long-COVID.

Conclusions

Our findings emphasize the need for targeted interventions and further research to understand better and address the unique challenges faced by children with chronic conditions like ESKD in the context of COVID-19. Future studies should focus on larger, more diverse populations and explore the underlying mechanisms driving the long-term effects of COVID-19. This will be crucial for developing effective treatment stra­tegies and for improving the long-term health outcomes of children who are most at risk.

Acknowledgments: We are very grateful to the parents and carers for their kindness and willingness to participate in this study. This work would not have been possible without the ISARIC Global COVID-19 follow-up questionnaire, available at https://isaric4c.net. We would like to extend our gratitude to the Global ISARIC team, the ISARIC global adult and pediatric COVID-19 follow-up working group, and ISARIC Global support center for the development of the standardized protocol for the data collection and for their generosity in sharing their work with us.

Ethics: This study was conducted in accordance with the Declaration of Helsinki and was approved by the local Scientific Research Ethics Committee (No 11972/19.05.2023). We obtained the parental consent via verbal confirmation and a consent form was afterwards sent to the parents in order to be signed and posted to the investigator.  

Autori pentru corespondenţă: Irina Bulată-Pop E-mail: irina26pop@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.