**4. Discussion**

In the absence of more extensive and/or thorough data, it remains unclear whether PID is a predisposing or, paradoxically, a protective factor for SARS-CoV-2 infection [18]. To answer this question, more data regarding COVID-19 morbidity, clinical course and mortality in patients with PID is necessary. Our study represents the experiences of one clinical centre and as such should be regarded as a single opinion in a broader discussion. It is worth considering if immunoglobulin replacement therapy is the protective factor for a severe course of COVID-19, even if immunoglobulins available on the market during the study (June 2020–June 2021) probably did not contain significant level of anti-SARS-CoV-2 IgG antibodies. This influence may be associated with the modulatory effect of immunoglobulins on the immune system, which is used in therapy of e.g., Kawasaki disease, Guillain-Barre syndrome [19].

In an observational study conducted in Israel [20], which was published in January 2021, amongst patients with PID aged 4 months to 6 years, a total number of 20 SARS-CoV-2 infections was recorded. The majority of these cases (95%) were reported during the second wave of the pandemic, which was consistent with our results. Moreover, children receiving immunoglobulin substitution therapy constituted the majority of the infected patient population. There were no cases of severe COVID-19, none of the infected patients required hospital admission and 35% of the affected children remained asymptomatic during the course of the disease. The authors implied that the COVID-19 pandemic had little impact on patients with PID.

The observations made by researchers in Iran [21] were different. In a prospective study, based on data acquired from the national registry, it was concluded that with only 1.23-fold higher incidence of infections, patients with PID, mainly those with combined immunodeficiency and immune dysregulation, present a 10-fold higher mortality rate compared to the general population. The study included 19 children with PID in whom SARS-CoV-2 infection was confirmed using an RT-PCR test. Exposure to the virus from an unknown source or a source outside the patient's family accounted for 84.2% of the total number of cases. The results of our study were quite different, and contact with close relatives was the source of infection for many of the infected patients (*n* = 11).

The Iranian researchers showed that combined immunodeficiency (*n* = 10, all without hematopoietic stem cell transplantation or HSCT, 47.0%) was the major PID entity amongst COVID-19 positive cases, followed by humoral immunodeficiencies (*n* = 4), phagocytic defects (*n* = 2), immune dysregulation (*n* = 2), and autoinflammatory disorders (*n* = 1) [21], ergo studied population was different than ours. The discrepancies in the incidence of certain forms of PID might be a result of the relatively low number of patients in both study groups and different characteristics of the populations managed in each hospital department. It is worth mentioning that the difference between Iranian and Polish patients with PID is related to the high prevalence of consanguinity in Iran compared to Poland, and the consequent high prevalence of autosomal recessive immunodeficiency.

In an international study conducted by Meyts et al. [22] published in February 2021, 32 cases of COVID-19 were recorded in children with PID, nine of them required management in an intensive care unit (ICU) and two of them died. Among patients treated in the ICU settings there were patients with a diagnosis of chronic granulomatous disease (*n* = 1), trisomy 21 (*n* = 1), Wiskott-Aldrich syndrome (*n* = 1), nuclear factor κB mutation (NFKB2) (*n* = 1) and X-linked inhibitor of apoptosis protein (XIAP) deficiency (*n* = 1). Due to numerous comorbidities, the authors defined the connection between SARS-CoV-2 infection and the death of both patients as 'unclear'.

Throughout an observation period of 1 year, none of the patients managed by our department for PID required treatment in ICU while infected with SARS-CoV-2.

At present, the data regarding IgG anti-SARS-CoV-2 antibody synthesis in individuals with PID are insufficient.

However, the research conducted on the immunocompetent population presents some interesting information. A key factor in determining the appropriate time window for the use of serological tests is the occurrence of seroconversion. Recent publications indicate that the median IgG detection occurs 9 to 14 days after disease onset [23,24]. Peterson et al. reported that approximately 1 in 16 people lacked IgG antibodies following infection. Race/ethnicity, weight status, immunosuppressive therapy and illness severity were independent predictors of IgG antibody presence after SARS-CoV-2 infection [25].

In a study conducted by Venkatamaran et al. in India, the authors evaluated humoral immune response associated with anti-SARS-CoV-2 antibody synthesis in hospitalised patients by comparing antibody titres between children with and without PIMS-TS [26]. Almost half of seropositive children had PIMS-TS. Antibody levels may be helpful in the diagnosis and disease stratification of PIMS-TS. Nearly one-fifth of the hospitalised children tested serology positive over four months. Antibody levels in children with PIMS-TS were significantly higher in comparison to the other two groups (acute COVID-19 infection and children without PIMS-TS).

The main purpose of our study was to evaluate antibody synthesis in patients with primary immune deficiency, and so an additional comparison of antibody synthesis between this unique population and children with (both ongoing and previous) PIMS-TS was made. No difference in levels of the antibody was recorded (Figure 2). This observation requires further verification on a larger group of patients, including meticulous evaluation of synthesis and perseverance of the antibody during the acute phase of the disease and after its resolution. It is noteworthy that in one patient with a history of PIMS-TS, IgG subclass deficiency was detected twice. There was no reference, however, since no immunological studies were performed in this patient before PIMS occurred.

It is also important to note that amongst children receiving immunoglobulin substitution therapy, positive anti-SARS-CoV-2 IgG test was recorded only in individuals with infection confirmed with a PCR/antigen test or with a high probability of infection, which meant the presence of characteristic clinical symptoms and/or close contact with an

infected person. Moreover, the mean level of anti-SARS-CoV-2 IgG in this group (IVIG +) was lower than in children not receiving such treatment and proved to be statistically significant (*p* = 0.0001). This leads to the conclusion that the IgG anti-CoV antibody test results were legitimate (throughout the observation period). Another important issue is that a significant percent of the study group with relatively mild immunodefciency (= not required immunoglobulin replacement therapy at the time of the study, i.e., isolated IgG subclass deficiency) may influence the results of the study.

Furthermore, it is worth mentioning, that the control group was not a classic control group and included patients with (mostly) mild recurrent upper respiratory tract infections, without abnormalities in immunological tests, who did not meet IUIS criteria for IEI.

The most important limitation of the study was the retrospective nature of the analysis which was based on collected medical records. More precise, prospective studies, evaluating the duration of antibody response in patients with PID and a history of COVID-19 are needed.
