COVID-19 and anemia in children with nephrotic syndrome

Md Abdul Qader; Azmeri Sultana; Mohammed Maruf ul Quader; Jubaida Rumana; Tarannum Khondaker; Naito Kanon; Mohammed Hanif

doi:10.4103/ajpn.ajpn_30_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 5 | Issue : 1 | Page : 21-26

COVID-19 and anemia in children with nephrotic syndrome

Md Abdul Qader¹, Azmeri Sultana², Mohammed Maruf ul Quader³, Jubaida Rumana⁴, Tarannum Khondaker⁵, Naito Kanon⁶, Mohammed Hanif⁵
¹ Department of Pediatric Nephrology, Square Hospitals Ltd., Dhaka, Bangladesh
² Department of Pediatric Nephrology, Dr. M. R. Khan Sishu Hospital and Institute of Child Health, Dhaka, Bangladesh
³ Department of Pediatric Nephrology, Chittagong Medical College Hospital, Chittagong, Bangladesh
⁴ Department of Pediatric Nephrology, Asgar Ali Hospital, Dhaka, Bangladesh
⁵ Department of Pediatric Nephrology, Dhaka Shishu (Children) Hospital, Dhaka, Bangladesh
⁶ Child Health Research Foundation, Dhaka, Bangladesh

Date of Submission	18-Jul-2021
Date of Decision	07-May-2022
Date of Acceptance	12-May-2022
Date of Web Publication	28-Jun-2022

Correspondence Address:
Md Abdul Qader
18/F, Bir Uttam Qazi Nuruzzaman Sarak, West Panthapath, Dhaka-1205
Bangladesh

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajpn.ajpn_30_21

Abstract

Context: Children with COVID-19 present with less severe disease and require fewer hospitalizations than adults. Our previous study on children with renal disease and COVID-19, which included predominantly children with nephrotic syndrome, found anemia in a significant number of participants. Aims: This study aimed at evaluating the risk factors of anemia in children with nephrotic syndrome presenting with COVID-19 and the influence of anemia on hospital outcome. Methods: This case–control study was conducted at five pediatric nephrology centers in two major cities of Bangladesh. Consecutive patients with nephrotic syndrome and positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 were included as cases, and subsequently, two cases of nephrotic syndrome with negative PCR were enrolled as controls. Participants who presented between April 2020 and December 2020 were included, and demographic data, clinical features, and laboratory parameters were retrieved from hospital records for analysis. Results: A total of 22 children with nephrotic syndrome were positive with COVID-19 and subsequently, 44 children were included as control. The median age was 6.4 years in the cases and 5.2 years among the control. Most children presented with the initial episode of nephrotic syndrome. The children in the case group had a significantly lower hemoglobin level than the controls, and anemia was associated with raised inflammatory markers. In multivariate analysis, female sex and impaired renal function was associated with lower hemoglobin, but anemia did not have effect on hospital outcome. Conclusions: Anemia in children can be multifactorial. Anemia in nephrotic syndrome associated with COVID-19 does not appear to influence length of hospital stay and outcome.

Keywords: Anemia, SARS-CoV2, acute kidney injury, inflammation, nephrotic syndrome

How to cite this article:
Qader MA, Sultana A, ul Quader MM, Rumana J, Khondaker T, Kanon N, Hanif M. COVID-19 and anemia in children with nephrotic syndrome. Asian J Pediatr Nephrol 2022;5:21-6

How to cite this URL:
Qader MA, Sultana A, ul Quader MM, Rumana J, Khondaker T, Kanon N, Hanif M. COVID-19 and anemia in children with nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2022 [cited 2023 May 27];5:21-6. Available from: https://www.ajpn-online.org/text.asp?2022/5/1/21/348527

Introduction

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), was first detected in the Chinese province of Wuhan in 2019 and quickly spread worldwide.^[1] It is an inflammatory condition defined by the release of pro-inflammatory cytokines linked to neutrophil activity, with the intensity of the inflammation worsening with age.^[2] COVID-19 predominantly affects the respiratory system, but it has also been associated with a variety of cardiovascular and multisystem consequences, such as hepatic, cardiac, and kidney failure.^[3],[4] Anemia is a prevalent symptom in COVID-19 patients. It is hypothesized to be caused by suppression of viral heme metabolism through surface glycoprotein binding to the beta chain of hemoglobin and virus-induced hemoglobin denaturation.^[5],[6] Inflammation modifies iron homeostasis, such that there is increased iron acquisition and retention among macrophages and decreased bowel absorption.^[7] This decreases the amount of iron available for erythropoiesis and hemoglobin synthesis. Furthermore, anemia of inflammation (AI) has previously been defined as a combination of cytokine-mediated erythropoiesis suppression, shortened erythrocyte half-life, and decreased erythropoietin biological activity.^[8]

The presence of anemia has been proven to be a risk factor for a poor course and outcome in inflammation.^{[9],[10],[11],[12],[13]} Anemia has been linked to severe COVID-19 and poor outcomes in adult populations, according to a study.^[14] Our earlier study revealed significant anemia in children with preexisting renal disease who were admitted with a positive COVID-19 test.^[15] The objective of this study was to evaluate anemia in children with nephrotic syndrome who were infected with COVID-19. Therefore, we designed a case–control study to evaluate the risk factors for anemia in children with nephrotic syndrome and COVID-19 infection and the influence of anemia on hospital outcome.

Methods

This study is a follow-up to our prior work on the “Clinical profile and outcome of COVID-19 in children with preexisting renal disease.”^[15] In the preceding study, we found that a significant number of children had anemia while hospitalized with COVID-19. Because the majority of the participants in the previous study had nephrotic syndrome, and anemia in nephrotic syndrome is uncommon, a case–control study was designed to identify the risk factors associated with developing anemia in the COVID-19-infected children, as well as the impact of anemia on hospital course and outcome.

Detection of COVID-19

All admitted patients were tested for COVID-19 for case identification and isolation regardless of their presenting symptoms to the hospital. A trained physician, nurse, or medical technologist collected a nasopharyngeal specimen, and the specimen was transferred to the laboratory immediately. Viral RNA was extracted from the nasopharyngeal specimen within 24–48 h of collection and tested for the presence of SARS-CoV2 using the COVID-19 reverse transcription–polymerase chain reaction (RT-PCR) kit (S3104E; Sansure Biotech Inc., Changsha, Hunan, China).

Selection of case and control

This case–control study was conducted on hospitalized children admitted to Dhaka Shishu Hospital, Dhaka, Dr M R Khan Shishu Hospital and Institute of Child Health, Dhaka, Chittagong Medical College Hospital, Chittagong, Square Hospitals Ltd., Dhaka, and Asgar Ali Hospital, Dhaka, between April 2020 and December 2020. This research work included children who had been diagnosed with nephrotic syndrome either before or after admission. The reasons for hospitalization of the patients with nephrotic syndrome were severe complications of relapse or relapse associated with severe infection. Children with a positive COVID-19 RT-PCR from a nasopharyngeal swab were included as cases. Patients with nephrotic syndrome who did not have COVID-19 infection were matched 1:2 from the admitted patients with matching of admission during the study period from the same institution, taking into consideration similar exposure potential, for the control group. As a result, when considering the issue of sample distribution, an age or gender match control could not be always considered. Controls were tested for COVID-19, and all were confirmed to be negative. Controls were recruited using a convenience sampling strategy, with two consecutive COVID-19 RT-PCR negative children from the hospital record being included as control after each positive case. Children with insufficient clinical details were excluded from the study.

Data collection

Clinical parameters included presenting characteristics, anthropometry and blood pressure at presentation, degree of anemia, signs of cardiac and respiratory dysfunction, organomegaly, and any rash. For the two groups, laboratory data such as complete blood count, iron profile, renal function test, liver function test, chest radiograph, and urine analysis were studied. Data on hospital stay and management, including the use of immunosuppressive drugs, antibiotics, and need for cardiorespiratory support, were included in the analysis.

Definition of anemia

The study employed the World Health Organization criteria of anemia, which defined anemia as hemoglobin <11 g/dL in children under the age of 5, <11.5 g/dL in children aged 5–11, and <12 g/dL in children aged 12 and over.^[16] For purpose of the study, anemia was defined as hemoglobin levels <1 g/dL and categorized as no anemia, mild anemia, and moderate to severe anemia for hemoglobin values above 11 g/dL, between 9 and 11 g/dL, and below 9 g/dL, respectively.

Markers of inflammation and COVID-19

Because COVID-19 viral replication evokes inflammatory responses, resulting in monocyte and macrophage-induced cytokine and chemokines release,^[17] we studied indicators such as C-reactive protein (CRP), procalcitonin, serum ferritin, erythrocyte sedimentation rate, and interleukin-6, which have been linked to severe COVID-19^{[18],[19],[20]} to evaluate their association with the severity of anemia in patients with nephrotic syndrome and COVID-19.

Outcome measures

Various risk factors were examined for the association with anemia in patients with COVID-19 and nephrotic syndrome. Further, we evaluated whether length of hospital stay, requirements of respiratory support, and admission into intensive care unit were associated with anemia.

Statistical analysis

Data are presented using descriptive statistics, with continuous variables expressed as median (interquartile range, IQR) or mean ± standard deviation, based on the data distribution. Nonparametric Mann–Whitney U-test and Pearson Chi-square tests were used to compare demographic and laboratory characteristics between cases and controls. Multiple linear or logistic regression analysis was conducted to examine the association of risk factors with anemia among cases. Potential factors, chosen based on literature review, and examined for their association with severity and degree of anemia in COVID-19 patients, included sex; diagnosis; leukocyte, lymphocyte, and platelet counts; estimated glomerular filtration rate (eGFR); albumin; abnormalities on chest X-ray; and length of hospital stay. All tests were two-sided, and assessed at a level of significance of 0.1. SPSS Version 22.0 (SPSS Inc., Chicago, Illinois, USA) and Stata version 14.0 (Stata Corp LLC, Texas, USA).

Results

Twenty-two children with nephrotic syndrome were positive for SARS-CoV2 infections during the study period at the five centers. Their demographic and clinical characteristics are depicted in [Table 1]. Half were boys, with slight male preponderance among controls. The median (IQR) age at presentation was 6.4 (4–9) years among the cases and 5.3 (3.7–7) years among the controls.

Table 1: Baseline characteristics and course of disease in inpatients with nephrotic syndrome

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At admission 36% of the patients with COVID-19 (cases) and 53% of those without COVID-19 (controls) were in relapse of nephrotic syndrome, with or without infection. Both fever and cough were noted in 27% of the cases, while a few had only fever. The other important presenting feature was breathlessness (14%). At baseline, patients with COVID-19, when compared to controls, had lower median levels of hemoglobin (10.5 g/dL vs. 12.5 g/dL; P = 0.023) and eGFR (P = 0.049). Raised inflammatory markers were insignificantly more common among patients with COVID-19 (cases) than controls, including leukocytosis (leukocyte count >11,000/mm³; P = 0.85) and elevated CRP (>10 mg/L; P = 0.31).

About 42% of the cases had either pneumonia or pneumonia with pleural effusion in the chest radiograph. One-third of these required respiratory support, either in the form of nasal cannula or face mask [Table 1]. More than 80% of the cases and controls had good recovery within 15 days of hospital stay. Two (9%) of the 22 patients among the cases succumbed to sepsis and pulmonary edema; one patient also had septic shock.

Inflammatory indicators such as leukocytosis, neutrophilia, and raised CRP were associated with low hemoglobin levels (P = 0.025) among the cases versus controls. On bivariate analysis, lymphocytosis was linked to lower hemoglobin levels (P = 0.045) and higher eGFR (P = 0.027). Lymphocytosis was related to lower hemoglobin levels on bivariate analysis, and it remained significantly associated after adjusting for confounders such as gender, eGFR, and albumin.

As shown in [Table 2], on multiple regression, sex, a diagnosis of steroid-dependent or steroid-resistant nephrotic syndrome, lymphocytosis, thrombocytosis, and eGFR were significantly associated with degree of anemia among cases. The levels of hemoglobin were lower by approximately 2.25 g/dL among girls as compared to boys, after adjusting for other covariates (95% confidence interval [CI] −3.1,−1.4; P = 0.004). Patients with steroid-dependent or steroid-resistant nephrotic syndrome had higher hemoglobin levels, by 1.73 g/dL (P = 0.042) and 1.97 g/dL (P = 0.036), respectively, compared to the children with the initial episode of nephrotic syndrome. Children with thrombocytosis had lower hemoglobin, by 1.27 g/dL (95% CI − 2.371,−0.162; P = 0.036), in contrast to the children with normal platelet count, keeping all the covariates constant.

Table 2: Results of multiple regression analysis for the relationship between the degree of anemia and clinical parameters among the cases

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Discussion

As the pandemic progresses, with varying levels of penetration in different populations, our understanding of the disease's course and outcomes has improved tremendously. However, research on children with kidney disease was limited. Marlais et al. published a multinational study in which they looked at COVID-19 positive children who were receiving immunosuppressive therapy.^[21] Their multicenter survey included 30 children with nephrotic syndrome, whereas our study included 22 children, indicating that children were less affected and required fewer COVID-19 admissions.^[21] Adult patients with renal disease and a history of prior immunosuppressive therapy did not have an elevated risk of COVID-19 infection or severe disease due to immunosuppression, according to studies. Children and adolescents on immunosuppressants due to renal or other causes were also depicted in the studies with similar findings.^{[21],[22],[23],[24],[25]} This is consistent with our findings and could explain why children on immunosuppression due to nephrotic syndrome had a decreased number of COVID-19 positive patients.

Considering above facts, this research has specifically examined the impact of COVID-19 on children with nephrotic syndrome. Earlier research in immunocompromised children revealed a milder infection with COVID-19.^[21],[26] A systematic review found that SARS-CoV-2 infection among 43 children with idiopathic nephrotic syndrome was mild, less often required respiratory support and was not associated with death. However, the data in this analysis comes from developed countries.^[27] Among the studied children, unfortunately we lost two patients. The first patient who was a case of infrequent relapse nephrotic syndrome who presented with sepsis, circulatory shock, and renal impairment and died within 24 h of admission. The second case presented with initial episode of the disease along with pneumonia and respiratory failure. In our study, the death rate was 11%. Other studies that included children on immunosuppressive medication found that mortality ranged from 0% to 28%.^{[28],[29],[30],[31],[32]}

During the pandemic, parents were strict with their children in terms of severe home isolation and a delay in seeking medical help, which may have contributed to the deaths of those two children. During the COVID-19 pandemic, there have been instances of delayed hospitalization, as well as maltreatment or delayed treatment initiation.^[33] On the other hand, a recent Latin American study on children with multisystem inflammatory syndrome found a strong link between mortality with immunodeficiency or use of immunosuppressive medicines.^[34] Another study from the University Hospital Colorado's Department of Pediatrics found that being immunocompromised is a risk factor for admission, and that elevated CRP is linked to the requirement for critical care assistance.^[35]

Our study had an important finding of lower degree of hemoglobin in COVID-19-positive cases in comparison to controls. The findings suggest that COVID-19 in children was not involving respiratory system alone, and may have multisystem involvement including sepsis which anemia of inflammation. Multivariate linear regression analysis among the COVID-19-positive cases revealed the presence of inflammation, abnormal or elevated renal function correlated with the degree of anemia. Surprisingly, girls were at risk of lower hemoglobin in multivariate linear regression analysis. Children who were either steroid-dependent nephrotic syndrome or steroid-resistant nephrotic syndrome, had higher hemoglobin in relation to those were at their initial episode or infrequent relapse. In a systematic review among adult patients, the authors found lower level of hemoglobin in older patients and those with diabetes mellitus and hypertension but not in those with kidney disease or on immunosuppression.^[36] Another study revealed evidence of anemia in patients with heart failure.^[37] Thrombocytosis was found to be significantly associated with anemia in multivariable regression analysis, which could be a result of viral infection, although the probability of iron deficiency could not be ruled out for all of the studied children.^[38]

Important limitations of the study are the lack of investigations related to the cause of anemia and lack of evaluation of other anemia-related comorbidities. Detailed information regarding the past history of anemia and sociodemographic profile and dietary adequacy were lacking.

Conclusions

Children with nephrotic syndrome who had COVID-19 had lower hemoglobin in comparison to their peers who were admitted without COVID-19. Raised inflammatory markers and impaired kidney function were risk factors for anemia. The degree of anemia did not influence the duration of hospital stay or mortality.

Acknowledgment

We thank all the members of the Departments of Pediatric Nephrology of all five institutes who helped us providing relevant data for this study.

Ethical clearance

Ethical clearance was taken from the institutional review board of Dhaka Sishu Hospital, Chittagong Medical College Hospital, Dr M. R. Khan Sishu Hospital and Institute of Child Health and hospital ethical committee of Square Hospitals Ltd and Asgar Ali Hospital before commencement of data collection from the institute.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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