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Original Studies

Longitudinal Follow-up of Antibody Responses in Pediatric Patients With COVID-19 up to 9 Months After Infection

Oygar, Pembe Derin MD*; Ozsurekci, Yasemin MD*; Gurlevik, Sibel Lacinel MD*; Aykac, Kubra MD; Kukul, Musa Gurel MD*; Cura Yayla, Burcu Ceylan MD; Ilbay, Sare MD*; Karakaya, Jale PhD; Teksam, Ozlem MD§; Cengiz, Ali Bulent MD*; Ceyhan, Mehmet MD*

Author Information
The Pediatric Infectious Disease Journal: August 2021 - Volume 40 - Issue 8 - p e294-e299
doi: 10.1097/INF.0000000000003199
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Abstract

In detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ribonucleic acid (RNA) has been the standard approach for diagnosing novel coronavirus disease 2019 (COVID-19) since the beginning of the pandemic. Serologic tests are not recommended as the basis for diagnosing acute infection; they are recommended for surveillance purposes or in certain situations to support clinical assessments of people who present late in their illnesses, in conjunction with viral detection tests and in situations where a person is suspected to have a postinfectious syndrome caused by SARS-CoV-2 infection, such as Multisystem Inflammatory Syndrome in Children (MIS-C).1 However, methods used in RNA detection rely on the presence of the viral genome in sufficient quantities at the site where the sample is collected.2 Missing the time window of viral replication can produce false-negatives.3 Reliable and rapid serologic diagnostic methods are needed to screen SARS-CoV-2 infected people, including those who do not have symptoms. Most emerging studies describe serologic tests based on the detection of SARS-CoV-2-specific immunoglobulin (Ig) M and G, and they revealed varied results on IgM response times; some responses were as short as 4 days4 whereas others were obtained after 7–9 days.5,6 Although detecting SARS-CoV-2-specific IgA in serum has been reported in only a few studies, the results are promising in terms of early diagnosis of COVID-19 disease.7 Hence, in our study, we tested the seroconversion of IgA as a potential early detectable antibody instead of IgM. We also tested neutralization antibodies (N-Abs) and IgG in children diagnosed or suspected to have COVID-19 disease, with various disease severities and at different time intervals.

MATERIALS AND METHOD

Setting

This study was conducted from April 2020 to February 2021 at the Hacettepe University Faculty of Medicine Ihsan Dogramaci Children’s Hospital and the Ankara Health Sciences University Hospital Pediatric Infectious Disease Units. The study was approved by the Institutional Review Board and the Ankara Health Sciences University Hospital Ethics Committee (Approval number E-20/411).

Patients

Patients under 18 years old with confirmed or probable COVID-19 who were willing to give blood samples enrolled in the study. Confirmed cases were defined as SARS-CoV-2 PCR-positive cases; probable cases were PCR-negative patients who had one or more close positive-PCR household contacts and all probable cases, whether symptomatic or not, were included. All patients were evaluated upon admission for signs and symptoms of COVID-19, contact history, duration of symptoms, demographics and underlying diseases. Confirmed cases were classified as asymptomatic, mild/moderate, and severe/critical according to the classification of Dong et al, which is based on clinical characteristics, laboratory results and radiologic imaging. The classifications are described as follows: (a) asymptomatic infection, or cases with positive PCR despite the absence of the clinical or radiologic findings; (b) mild disease, or cases with symptoms of upper respiratory tract infections without pneumonia; (c) moderate disease, or cases with pneumonia; (d) severe disease, or cases with progressive respiratory disease, dyspnea, and central cyanosis and (e) critically ill, or cases with acute respiratory distress syndrome or respiratory failure, shock and organ dysfunction.8

Specimen Collection and Testing

All 84 patients were tested for SARS-CoV-2 RNA from nasopharyngeal swabs taken upon admission, and those who were negative on the first test were tested again after 24–48 hours. For detection, reverse transcriptase quantitative PCR (RT-qPCR) targeting the SARS-CoV-2 RNA-dependent-RNA-polymerase was performed using primers supplied by the National Public Health Laboratory.

Blood samples were collected from the patients after receiving informed consent from parents and children 12 years old or younger. Centrifuged and obtained sera were stored at −80°C. To determine serologic responses, the blood samples were divided into 4 groups according to the time windows in which they were obtained (0–7 days, 8–14 days, 15–39 days and ≥40 days). For symptomatic confirmed or probable cases, the onset of symptoms was marked as day 0 whereas for asymptomatic confirmed or probable cases, the date of admission was marked as day 0. The IgG values obtained for 15 days–3 months were referred to as early (early period) whereas those obtained later were referred as late (late period). Forty-eight patients’ blood samples were collected 7–9 months after day 0 for detecting late-period IgG response.

Euroimmun (received EUA from FDA) anti-SARS-CoV-2 enzyme-linked-immuno-adsorbent assay (ELISA) IgG and IgA Test Kits and the Genscript SARS-CoV-2 Surrogate Virus Neutralization Test Kit were used for detecting anti-SARS-CoV-2 IgG, IgA and N-Abs, respectively. Patient samples were thawed, mixed and diluted 1:101 in a sample buffer for the Euroimmun Anti-SARS-CoV-2 ELISA IgG and IgA test Kits whereas the dilution for the Genscript SARS-CoV-2 Surrogate Virus Neutralization Test Kit was 1:9. All the steps were carried out by trained research laboratory staff according to the instructions suggested by the manufacturers. Eighty-seven serum samples of 84 patients were analyzed for IgG and N-Abs, and 93 sera of 51 patients were analyzed for IgA measurement. For the Euroimmun SARS-CoV-2 IgA and IgG results, those <0.8 were considered negative, those between 0.8 and 1.1 were considered borderline, and those ≥to 1.1 were considered positive. The results of the Genscript SARS-CoV-2 Surrogate Virus Neutralization test, based on antibody-mediated blockage of the ACE2-spike protein-protein interaction, were interpreted as positive when the inhibition was >20% and negative when the inhibition was <20%.

Statistics

IBM SPSS software package version 26 was used for all statistical analyses. Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as the mean or median. Wilcoxon signed-rank and Kruskal Wallis tests were used for the comparison of the different groups, and a P value of <0.05 was considered statistically significant. The sensitivities of the tests were calculated according to a 95% confidence interval (CI).

RESULTS

Eighty-four patients (88% confirmed cases; 44 girls and 40 boys) ages 7–204 months (M = 115) were enrolled in the study. The patients’ demographics, underlying diseases, treatments, and interventions are shown in Table 1, and their PCR and serology positivity according to disease severity are shown in Table 2. For symptomatic patients, the symptoms lasted for 1–4 days (mean = 2.5), while asymptomatic and probable cases were all admitted on the day of diagnosis of the close household contact.

TABLE 1. - Demographic Properties of Patients According to Seropositivity
Patients IgA (%) IgG Early Period (%) IgG Late Period (%) N-Ab (%)
Age (mean), mo 120 (7–204) 115.37 (7–204) 114 (7–204) 115.37 (7–204)
Sex, F/M 27/24 46/41 25/23 46/41
Total number of samples 93 87 48 87
Total number of positive samples 76 (81.7) 84 (96.6) 46 (95.8) 84 (96.6)
Underlying disease
 None 35 (46) 59 (70.2) 36 (78.6) 59 (70.2)
 Pulmonary 13 (17.1) 22 (26.2) 7 (15.2) 22 (26.2)
 Metabolic 1 (1.3) 1 (1.2) 1 (2.2) 1 (1.2)
 Neurologic 0 1 (1.2) 1 (2.2) 1 (1.2)
 Hematologic 1 (1.3) 0 1 (2.2) 0
 Gastrointestinal 1 (1.3) 1 (1.2) 0 1 (1.2)
Antiviral
 No 74 82 44 82
 Yes 2 2 2 2
P = 0.002 P = 0.001 P = 0.001
IVIG
 No 73 (96.1) 82 (97.6) 44 (91.7) 82 (97.6)
 Yes 3 (3.9) 2 (2.4) 2 (4.2) 2 (2.4)
P = 0.082 P = 0.004 P = 0.04
MV
 No 75 (98.6) 84 (100) 45 (97.8) 75 (98.6)
 Yes 1 (1.3) 0 1 (2.8) 1 (1.3)
P = 0. P = 0.004 P = 0.04
ECMO
 No 76 (100) 84 (100) 46 (100) 76 (100)
 Yes 0 0 0 0
P = 0.05 P = 0.07 P = 0.07
MV indicates mechanical ventilation.

TABLE 2. - Seropositivity of Patients by Disease Severity and PCR Positivity
Patients IgA Neutralizing Ab IgG EEarly Period IgG Late Period
Age (mean), mo 120 (7–204) 115.37 (7–204) 115.37 (7–204) 114 (7–204)
Sex, F/M 27/24 46/41 46/41 25/23
Total number of samples 93 87 87 48
Total number of sero positive samples 75 (80.6) 81 (93.1) 81 (93.1) 46 (95.8)
PCR
 Positive 70 (93.3) 74 (91.4) 74 (91.4) 40 (90.9)
 Negative 5 (6.7) 7 (8.6) 7 (8.6) 6 (9.1)
Disease stage
 Asymptomatic 19 (25.3) 16 (19.8) 16 (19.8) 11 (23.9)
 Mild/moderate 51 (68) 61 (75.3) 61 (75.3) 32 (69.6)
 Severe/critic 5 (6.7) 4 (4.9) 4 (4.9) 3 (6.5)
P* = 0.683 P* = 0.17 P* = 0.17 P* = 0.634
p*: p values are given for disease stages.
PCR indicates polymerase chain reaction.

PCR

All 84 patients received a SARS-CoV-2 PCR test on admission, and 73 tested positive. The remaining 11 underwent a second PCR test 24–48 hours after the first test, and one patient tested positive. With a total of 74 positive patients, the sensitivity of the PCR testing was 88.4% (Table 3) on a 0–7–day time interval. All PCR-positive patients were retested 14 days after their first positive tests, and 72 tested negative. Two patients’—both overweight and with mild/moderate disease—tested PCR-negative on days 16 and 18.

TABLE 3. - Serology and PCR Sensitivity of Cases by Time Intervals
PCR IgA IgG N-Ab
Days Total number of samples Total number of positive samples Sensitivity (%, 95% CI) Total number of samples Total number of positive samples Sensitivity (%, 95% CI) Total number of samples Total number of positive samples Sensitivity (%, 95% CI) Total number of samples Total number of positive samples Sensitivity (%, 95% CI)
0–7 86 76 88.4 17 8 47.1
8–14 86 2 2.3 27 24 88
15–39 2 0 30 40 36 90 72 70 92.8 72 70 92.8
40–82 9 8 88.9 15 14 94.1 15 14 94.1
210–250 48 46 95.4
CI indicates confidence interval; IgA, immunoglobulin A; IgG, immunoglobulin G; N-Ab, neutralizing antibody; PCR, polymerase chain reaction.
Dash signifies that immunoglobulin measurements are not available on those time intervals.

IgA Findings

Serum samples for 51 of the 84 cases (92% confirmed and 8% probable) were tested for IgA response. A total of 93 serum samples were tested; 42 patients’ blood samples were tested at 2 time intervals, and 9 patients’ serum samples were tested once. During the 0- to 7-day interval, the median day was 6, 17 samples—all confirmed cases—were tested for IgA response, and 47% had detectable IgA levels. Thus, the sensitivity of the IgA test was 47.1% (95% CI) for this time interval, while the rate increased to 70% for the 0- to 10-day interval (Table 3). For the 8- to 14-day interval, 27 samples were tested. The median day for testing was 9, and IgA was detected in 89% of the cases. Thus, the sensitivity of the IgA test was 88% (95% CI) for this interval (Table 3). During the 15- to 39-day interval, 40 samples belonging to confirmed cases were tested, with 90% of them testing positive. On and after 40 days, the IgA responses for 9 cases were measured, 8 of which tested positive. The earliest that IgA levels were tested was day 4, and the latest that IgA levels were detected was day 82. The median of the first IgA-level measurement significantly differed from that of the second (P = 0.016); the median of the first was 4.75 (Min/Max = 0.08–9), and the median of the second was 7.26 (Min/Max = 0.6–9; Fig. 1A).

FIGURE 1.
FIGURE 1.:
IgA test results. A: The change in IgA levels of 46 patients, measured at 2 time intervals: the first ranged from day 4 to day 14, and the second ranged from day 21 to day 82. B: IgA response by disease severity.

Overall, IgA-type antibodies were not detected in 2 of 3 confirmed patients who were critically ill and treated with intravenous immunoglobulin (IVIG) and antiviral treatment; however, no significant difference in IgA response was observed among disease severity (P = 0.683; Fig. 1B). The IgA response sensitivity was 100%, 85.7%, 71.4% and 75% in probable, asymptomatic, mild/moderate and severe/critical cases, respectively.

IgG and N-Abs Findings (Early Period; 15 Days–3 Months)

Eighty-seven samples collected from 84 patients were tested for IgG and N-Abs responses. Blood samples collected on 15- to 39-day and ≥40-day intervals were used for measuring IgG and N-Abs. IgG and N-Abs were detected in 81 patients, 74 being confirmed cases (Fig. 2A). Neutralizing antibodies were an exact match with IgG-type antibodies (k = 1; Fig. 2A). Seven probable cases had detectable IgG and N-Abs on a 20- to 34-day time interval. In 3 confirmed patients, IgG antibodies as well as N-Abs were not detected; 2 of them, being critically ill, received antiviral and IVIG treatment, both required mechanical ventilation, and one also required extracorporeal membrane oxygenation. In terms of IgG conversion, P = 0.001, 0.004, 0.007 for antiviral, IVIG and extracorporeal membrane oxygenation requirements, respectively (Table 1). The third patient in whom IgG and N-Abs were not detected was a 16-year-old man with no underlying disease. He was asymptomatic and was not given treatment. The IgG levels for asymptomatic cases were 2.3–16.8 (Median = 9.8), for mild/moderate cases were 1.4–15.2 (Median = 10) and for severe/critical cases were 0.4–12.2 (Median = 9.6). In terms of early IgG response, there was no difference among disease severity (P = 0.17; Fig. 2B).

FIGURE 2.
FIGURE 2.:
Neutralizing antibodies, early-period and late-period IgG results. A: The correlation between N-Abs and early-period IgG results. B: Early IgG responses by disease severity. C: Early-period and late-period IgG responses. The difference between the IgG levels between the early and late periods was significant (P < 0.001). D: Late-period IgG responses by disease severity.

For all 84 patients, the sensitivity of the early-period IgG test was 95.9% (88%–99%; 95% CI). In asymptomatic cases, the sensitivity was 93.3%; in mild/moderate cases, 100%; and in severe/critical cases, 60%.

Late IgG Findings (Late-period; After 6 Months)

The IgG levels of 48 patients (25 girls and 23 boys ages 7–204 months [Median = 114]) were tested after 6 months, 41 of them being confirmed cases. Eleven of them were asymptomatic, 34 were mild/moderate and 3 were severe/critical cases. Ten patients had underlying diseases—7 had pulmonary diseases, 2 had neurometabolic diseases and 1 had osteopetrosis. Of the 46 patients who had previously tested positive for IgG, 45 had IgG levels above the determined threshold for seroconversion (Fig. 2C). One confirmed case who tested negative for IgG on day 82 had detectable IgG levels after 9 months. The mean IgG levels were 4.02 (0.19–9.09). For all 48 patients, the sensitivity of the IgG test was 97.6% (93–100%; 95% CI). Although there was no significant difference between early-period and late-period IgG levels in patients according to disease severity (P = 0.169), the difference of IgG levels between the early (Median = 11.98 [0.2–16.8]) and late period (Median = 4.02 [0.19–9.09]) was significant (P <0.001). Additionally, the late-period IgG response was not different in patients with any disease course (P = 0.634; Fig. 2D). However, according to disease severity, while the decrease of IgG levels was significant in asymptomatic and mild/moderate cases (P <0.008 and P < 0.001, respectively), the decrease in severe-critical cases was moderate (P = 0.285; Fig. 2D).

DISCUSSION

New emerging pathogens are always a major concern for public health. With a high attack rate, SARS-CoV-2 quickly led to a pandemic and killed more than one million people in 9 months.9 Asymptomatic or subclinical carriage of the virus as well as limited time sensitivity of PCR played crucial roles in the spread of the infection and hampered efforts toward its containment.

Serologic tests are useful for true surveillance of pandemics, but we need reliable serologic tests for diagnosis as well. In our study, 7 patients of 10 missed by PCR were diagnosed by serologic tests. One study of adults revealed that the seroconversion of IgM and IgA can be as early as 4 days, and 14 days for IgG.4 Other studies stated that the mean seroconversion time of IgM and IgG was 7–9 days.5,6 In a study of 87 adult COVID-19 patients, Hu et al reported that, during the 4–10 days after the onset of symptoms, the IgA kit exhibited the highest positive diagnostic rate, at 88.2%, while the IgM kit and IgG kit detection rates were 76.4% and 64.7%, respectively.10 In our study, we calculated the sensitivity of IgG and N-Abs after 14 days, and they ranged between 92.8% and 94.1% whereas the sensitivity of IgA reached 88.9% within 4–14 days after exposure. Consistent with the literature, testing for IgG and N-Abs is beneficial for diagnosing patients with negative PCR after 14 days, while testing for IgA at as early as 4 days may enable early diagnosis.11

Some studies of adults have reported that the IgG response of COVID-19 patients decreased in a couple of months.12,13 However, after a thorough search of the literature and preprints, we could not find longitudinal pediatric data on IgG response. The present study shows that SARS-CoV-2 IgG antibody levels significantly decreased after 6 months in asymptomatic and mild/moderate pediatric patients. The decline in severe/critical cases; however, was less.

Despite this overall decline, 95.8% of children remained positive up to 9 months postinfection. In our study, contrary to the studies of adults, IgG seroconversion did not differ in pediatric patients with COVID-19 depending on their disease severity9,14,15; however, the decrease of IgG levels was moderate in severe/critical cases. This fact may be attributable to the stronger stimulation of B-cells and the formation of plasma cells with a longer lifespan in severe/critical cases.16 The reasons for unsustainable antibody responses against SARS-CoV-2 and other coronaviruses are not clear, but dysregulation of early humoral responses is a probable explanation. The correlation of IgG with neutralizing antibodies and the duration of the IgG response up to 9 months after infection may be due to the unique nature of humoral responses in children.17 Although the required antibody titer for immunity against SARS-CoV-2 is unknown, the seropositivity of 95.8% of the children after 6 months gives us hope that the reinfection risk of children might be lower than expected.13,18,19

IgM and IgG seroconversion occurred in all patients between the third and fourth week of clinical illness onset, as measured in 23 patients by To et al and 85 patients by Xiang et al20,21 Thereafter, IgM levels declined, reaching low levels by week 5 and almost disappearing by week 7, whereas IgG levels persisted beyond 7 weeks. In another study involving 140 patients, the combined sensitivity of PCR and IgM ELISA directed at nucleocapsid antigen was 98.6%, compared with 51.9% with a single PCR test. During the first five and a half days of infection, qPCR had a higher positivity rate than IgM ELISA; however, after five and a half days, the opposite was true.4 Given these findings, we planned to test IgA response in the early period instead of IgM. In our study during the 0- to 7-day interval, the sensitivity of PCR testing was 88.4%. Combined use of PCR and serologic tests is important for an early and accurate diagnosis of COVID-19.

Hsueh et al proposed that the presence of underlying diseases and the use of immunosuppressive or immunomodulatory agents did not influence the dynamics of SARS-1 antibody response.22 However, in a recent study conducted on 173 patients with a mean age of 48 years, the antibody response to SARS-CoV-2—both IgG and IgA—was highest in severe cases.23 In our study, patients for whom antibodies could not be detected were mostly those who had severe disease and received antiviral or IVIG treatment. However, in 2 patients with asymptomatic or mild/moderate disease who received neither IVIG nor antiviral treatment, we could not detect IgG or IgA antibodies. These findings led us to believe that multiple factors affect serologic responses against SARS-CoV-2.

There were limitations in our study. First, we could not obtain serial blood samples from all children enrolled in the study since most of them were young and frightened. Second, we did not determine the responses to IgG before 14 days, and we could not test IgM levels since we chose to test IgA levels. Because the number of severe cases was only 4, statistical analysis may have been misleading in this group. However, the strength of this study is that it is one of few conducted in children to describe the immune response beyond 6 months according to disease severity.

CONCLUSIONS

Although serologic tests contribute positively to diagnosing COVID-19, measuring IgA levels is helpful during the subacute phase of the disease, with a relative sensitivity, and measuring IgG levels is useful during the late phase. Although in our study, IgG levels declined in asymptomatic to critically ill COVID-19 pediatric patients, 95.8% remained positive up to 9 months after infection. Since the beginning of the pandemic, it has been proposed that, in many aspects, including infectivity, disease severity and developing MIS-C, COVID-19 differs in children compared with adults.5,24 Antibody production and the duration of seroconversion are also different in children, and the duration of IgG positivity may be longer compared with adults.

ACKNOWLEDGMENTS

We are grateful to Samet Ece for his expert technical support in the laboratory.

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Keywords:

SARS-CoV-2; serology; IgG; IgA; children

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