The outbreak of new SARS-CoV-2 variants represents a second pandemic emergency among paediatric populations. Since the second semester of 2021, epidemiological reports have confirmed that the diffusion of the Omicron SARS-CoV-2 variant in the general population is not limited to adults, highlighting the need for new studies on the incidence in young immunocompromised subjects, potentially exposed to severe complications [1].

In 2020, at the beginning of the pandemic, children seemed to have a lower incidence and milder clinical course of coronavirus disease 2019 (COVID-19), including those receiving chronic treatment with rituximab for nephrotic syndrome [2]. In April 2020, during the first pandemic wave, we prospectively followed up a cohort of 159 paediatric patients on chronic immunosuppression with the two B cell-depleting antibodies, rituximab vs. ofatumumab, due to steroid-dependent nephrotic syndrome (NCT02394119) [3] and we observed no cases of COVID-19 [2]. Such findings supported the therapeutic strategies to maintain administration of rituximab in these children during the pandemic. However, after almost 2 years, with the diffusion of the new variants characterized by faster spread also among the paediatric population, a re-analysis of COVID-19 incidence in children with nephrotic syndrome on immunosuppression was considered mandatory so as to exclude underestimating risks.

We report here an update on the incidence and clinical outcome of SARS-CoV-2 infection in paediatric and young adults with nephrotic syndrome on chronic immunosuppression. This large cohort includes 228 patients, 176 children [≤ 18 years] and 52 young adults [19–24 years]), enrolled in two randomized controlled trials comparing the safety/efficacy profile of the B cell-depleting antibodies rituximab vs. ofatumumab (NCT02394119) [3] and rituximab vs. mycophenolate mofetil (MMF) (NCT04585152) [4]. Swab tests for Sars-Cov2 were performed based on clinical signs or according to the Italian surveillance protocols, in case of close contact, or in order to obtain a Green Certificate (vaccination/exemption certificate) without vaccination for > 12 year-old.

Of the 228 subjects considered, 29 (13%) reported SARS-CoV-2 infection. Among the entire cohort, only 48 patients received regular mRNA vaccination for SARS-CoV-2 (Pfizer/BioNtech BNT162b2 or Moderna m-1273) and none reported SARS-CoV-2 infection vs. 29/180 (21%) non vaccinated individuals (p = 0.0011) (Fig. 1A). Median age of unvaccinated subjects was 9 ± 5 vs. 14 ± 6 years of vaccinated patients. Of note, one subject reported an increase to 2 g/die of proteinuria two weeks after the second dose of vaccine, but recovered in one week without treatment.

Fig. 1
figure 1

Positivity for SARS-CoV-2. A The 29 positive subjects were not vaccinated for SARS-CoV-2 at the time of infection. None of the vaccinated patients developed SARS-CoV-2 infection (p = 0.0011). B Prevalence of infection in patients receiving rituximab is statistically significant when compared to subjects receiving MMF (p = 0.03)

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No cases of relapse of the nephrotic syndrome were observed after the infection and 7/29 patients (24%) reported low or moderate positive dipsticks for 18 ± 6 days after positivity, that spontaneously recovered.

Therefore, contrary to what was reported in the first phase of the COVID-19 pandemic, the incidence of infection in a large cohort of paediatric and young patients with nephrotic syndrome receiving chronic immunosuppression has rapidly increased, in particular in the last months, as occurred in the general population. Of relevance, 9/27 (33%) positive subjects developed infection within only 6 weeks of the Omicron variant spread, from December 2021 to January 2022.

Between April 2020 and January 2022, 24 of the 112 patients on rituximab (21%) and 5 of the 48 on MMF (8%) reported COVID-19 infection (p = 0.03) (Fig. 1B). Comparing positive and negative subjects in the rituximab group, no significant differences were observed in median time since last infusion (15 months [0–56] in positive vs. 14 months [0–64] in negative subjects). Two patients reported SARS-CoV-2 infection a few days after their last infusion of rituximab. The clinical outcome was good in all cases and no patient required hospitalization: 5/24 on rituximab and 1/5 on MMF had mild symptoms, including fever (> 37 °C), cough, fatigue or gastrointestinal disorders. Median time to achieve negative swab test was 24 (7–38) and 23 (14–32) days in the rituximab and MMF groups, respectively.

The use of B cell–depleting therapies like rituximab may represent a significant risk factor compared to MMF. According to our observation, vaccination appears to be the greatest protective factor towards COVID-19. Unlike previous reports in the context of rheumatic diseases [5], no major or fatal COVID-19-related complications were reported in our patients receiving rituximab: our therapeutic scheme is limited to a single infusion of 375 mg/m2 and this strategy may protect against severe complications.

The main conclusion of the present update on COVID-19 incidence in a large cohort of paediatric and young subjects receiving immune-treatments is that therapeutic strategies need not be altered, mostly considering the benign clinical course in our cases of SARS-CoV-2 infection.

We also strongly recommend vaccination for SARS-CoV-2 at any age. In our cohort, only a minority of subjects were vaccinated (21%), mostly due to the age limit (14%) or because still on a waiting list to receive it (46%). To avoid a long wait after B-cell depletion, we suggest vaccination before rituximab infusion.