Infection prophylaxis following anti-CD20 monoclonal antibodies in childhood kidney diseases

Abstract

Anti-CD20 monoclonal antibodies (mAbs), which act as B-cell–depleting therapies, are now regarded as important treatments for a range of paediatric kidney diseases. Despite their effectiveness in achieving B-cell depletion and consequent disease remission, concerns remain regarding their side effect profile. These include infusion reactions, hypogammaglobulinaemia, and neutropenia, as well as infections. At present, the evidence supporting preventive measures such as intravenous immunoglobulin (IVIG) replacement and antibiotic prophylaxis remains inconclusive. In this review, we summarise the existing data on infection-related risks following anti-CD20 therapy and propose practical strategies to mitigate infection risk tailored to this group of children.

Graphical Abstract

A higher resolution version of the Graphical abstract is available as Supplementary information

Supplementary information

The online version contains supplementary material available at 10.1007/s00467-026-07180-2.

Introduction

Anti-CD20 monoclonal antibodies (mAbs) are a B-cell depleting therapy that depletes the B-cell population [1]. Their clinical use was first described in B-cell non-Hodgkin’s lymphoma [2]. Subsequently, they have been widely utilised in various autoimmune conditions, including rheumatoid arthritis and ANCA-associated vasculitis (AAV) [3, 4]. In paediatric nephrology, one of the main indications for anti-CD20 mAbs is steroid-sensitive nephrotic syndrome (SSNS). Multiple clinical trials established the efficacy of anti-CD20 mAbs in maintaining disease remission [5–8], and since then, they have become one of the important steroid-sparing approaches in steroid-dependent nephrotic syndrome (SDNS) [9–12]. Anti-CD20 mAbs have been increasingly utilised for other childhood kidney diseases such as steroid-resistant nephrotic syndrome, lupus nephritis (LN), AAV, antibody-mediated rejection (AMR) of graft kidney, and membranous nephropathy (MN) [13–18] (Supplementary Table 1).

Although anti-CD20 mAbs, in particular rituximab, are generally considered to be safe in children, there are valid concerns about side effects. These range from infusion reactions, infection, hypogammaglobulinaemia, neutropenia, to severe and fatal complications related to hepatitis reactivation, myocarditis and multifocal leukoencephalopathy [19–23]. Infection is a significant concern, as approximately half of the children treated with rituximab develop hypogammaglobulinaemia [24], and concurrent immunosuppression and agranulocytosis post-rituximab can also contribute to infectious complications [25]. Data pertaining to preventive measures such as intravenous immunoglobulin (IVIG) supplementation and antibiotic prophylaxis remain scarce [26]. By comprehending the mechanisms of action of anti-CD20 treatment and the infections linked to their actions, clinicians can more effectively anticipate these risks and proactively prevent and identify opportunistic infections. In this review, we summarise the current understanding on infection-related risks associated with anti-CD20 mAbs in the management of paediatric kidney diseases, and propose practical preventive strategies to mitigate the risk in this specific patient population.

Mechanism of action

Anti-CD20 mAbs target CD20 antigens expressed on B cells, mostly pre-B cells, transitional, naïve and memory B cells [1]. They are classified as type I (e.g. rituximab and ofatumumab, the latter no longer commercially available) and type II (e.g. obinutuzumab) [27]. Rituximab mediates B cell destruction through different mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and direct cell death [2]. The dosing of rituximab ranged from 375 to 1500mg/m² per treatment course, administered as 1 to 4 infusions, depending on the underlying conditions [9–11, 13–16]. The measurement of rituximab drug level does not predict treatment response or correlate with treatment toxicity [28]. At present, this medication remains off-label for paediatric use, and the optimal dosing regimen has yet to be defined by future trials. Obinutuzumab, a glycoengineered, second-generation anti-CD20 mAb, has been designed to overcome potential rituximab resistance by exhibiting a higher affinity for CD20 and enhanced B-cell depletion capacity [29]. The differences between rituximab and obinutuzumab are summarised in Table 1. Data pertaining to obinutuzumab in treating childhood kidney diseases are scarce; only a small number of retrospective data have been published among children with SDNS who were refractory or intolerant to rituximab [29, 31].

Table 1.

Characteristics of Type I and II anti-CD20 monoclonal antibodies

	Type I	Type II
Mechanism of action	Induce the aggregation of CD20 into lipid rafts	Do not induce the aggregation of CD20 into lipid rafts
	High CDC	Low CDC
	ADCC	ADCC
	ADCP	ADCP
	Direct cell death	Stronger direct cell death
	B cell depletion	B cell depletion with longer duration [29]
FDA approved for paediatric kidney disease	AAV (≥ 2 years old) [30]	——
Examples	Rituximab, ofatumumab	Obinutuzumab
Availability as biosimilars	Available for rituximab	No

CDC complement-dependent cytotoxicity, ADCC antibody-dependent cellular cytotoxicity, ADCP antibody-dependent cellular phagocytosis, AAV ANCA-associated vasculitis

Infectious complications following anti-CD20 mAbs

Rituximab impairs the immune homeostasis not only by depleting B cells, but also by disrupting B- and T-cell cross-talk. Together with neutropenia and agranulocytosis, it poses a significant risk of infections not limited to bacteria, but also viruses and opportunistic organisms. Having said that, it is difficult to measure the risk of infections caused by rituximab treatment alone because of the difference in underlying conditions and the immunosuppressive effects of other concomitant therapeutic agents. Overall, about 5% of patients develop infective complications, of which 50% require hospitalisation [32]. The incidence does not appear to increase after repeated courses or higher cumulative doses of rituximab [32]. About 80% of these infections are bacterial, with respiratory infections being the commonest presentation [32–35]. Evidence indicates that rituximab disrupts B-cell and T-cell interactions, which may also increase the risk of certain viral and fungal infections [34]. Pneumocystis Jirovecii pneumonia (PJP) is uncommon but a serious infection that was reported despite the use of antimicrobial prophylaxis [32, 36]. There is an increased risk of hepatitis B virus (HBV) reactivation following treatment with rituximab [37]. Cytomegalovirus (CMV), Epstein–Barr virus (EBV), and BK virus infections may occur in kidney transplant recipients, particularly following treatments for AMR. Importantly, attributing these infections solely to rituximab is challenging, given the frequent use of concurrent immunosuppressive therapies such as corticosteroids and plasma exchange in this setting.

In contrast, reactivations of hepatitis C and tuberculosis are reported less frequently [38–40]. Progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease of the brain caused by JC polyoma virus, was reported in adult patients with rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA) treated with rituximab-based chemotherapy, yet the risk is low [41]. Infections appear to be more prevalent in the first 6 months after rituximab administration [22], and interventions are more likely to be required before B cells repopulate [7].

On the other hand, the safety data of obinutuzumab are limited. In the largest available cohort, Dossier et al. described that only one out of the 41 children (2.44%) treated with obinutuzumab for SDNS was hospitalised for pneumonia, with a favourable outcome [42]. Nonetheless, clinicians should consider the use of obinutuzumab more cautiously, due to the longer B-cell depletion period and higher rates of neutropenia and low IgM compared to rituximab [42]. Reports of infection-related adverse events associated with the use of anti-CD20 mAbs in paediatric kidney disease from prospective studies are presented in Table 2. Corresponding data for the adult population are provided in Supplementary Table 2.

Table 2.

Reports of adverse events related to infection after anti-CD20 use in kidney disease in children from prospective studies

Study	Study Design	Disease	Anti-CD20	No. of Patients Analysed	No. of anti-CD20 courses	Regimen per Course mg/m2	Infections, episodes		Serious Infections, episodes		Upper respiratory tract infection
							anti-CD20	Control	anti-CD20	Control	anti-CD20
Brogan et al., 2022 [43]	Prospective	AAV	Rituximab	25	25	1500	105	-	9	-	41
Guigonis et al., 2008 [44]	Prospective	SDNS and SRNS	Rituximab	22	40	375–1500	NR	-	2	-	NR
Kamei et al., 2009 [45]	Prospective	Refractory SDNS	Rituximab	12	22	375–1500	NR	-	NR	-	NR
Ravani et al., 2011 [46]	RCT	NS	Rituximab	54	27	375–750	NR	NR	NR	NR	NR
Magnasco et al., 2012 [47]	RCT	NS	Rituximab	31	16	750	NR	NR	NR	NR	NR
Ravani et al., 2013 [48]	Prospective	NS	Rituximab	46	104	375–750	NR	-	3	-	NR
Iijima et al., 2014 [7]	DBRCT	FRNS and SDNS	Rituximab	48	24	1500	105	42	4a	0	NR
Ruggenenti et al., 2014 [5]	Prospective	FRNS and SDNS	Rituximab	10	10	375–750	NR	-	0	-	0c
Sun et al., 2014 [49]	Prospective	SDNS, FRNS, and SRNS	Rituximab	12	12	375–750	3	-	0	-	2
Ravani et al., 2015 [8]	RCT	SDNS	Rituximab	30	15	375	NR	NR	NR	NR	NR
Ahn et al., 2018 [50]	RCT	SDNS	Rituximab	51	35	375–750	21	4	NR	NR	NR
	Prospective	SRNS	Rituximab	23	23	375–750	16	-	NR	-	NR
Basu et al., 2018 [51]	RCT	CDNS	Rituximab	120	60	750–1500	13b	26b	2	2	4b
Takahashi et al., 2019 [52]	Prospective	FRNS and SDNS	Rituximab	22	22	1500	25	-	1	-	8
Kari et al., 2020 [53]	Prospective	SSNS	Rituximab	46	19	750	NR	NR	NR	NR	NR
Ravani et al., 2020 [54]	RCT	SDNS	Rituximab	30	15	375	NR	NR	NR	NR	NR
Ravani et al., 2020 [55]	RCT	MRNS	Ofatumumab	13	7	1500mg/1.73 m2	NR	NR	NR	NR	NR
Ravani et al., 2021 [56]	RCT	SDNS	Ofatumumab	140	140	375	NR	NR	NR	NR	NR
Ravani et al., 2021 [57]	RCT	SDNS	Rituximab	30	15	375	NR	NR	NR	NR	NR
Al Salloum et al., 2022 [58]	Prospective	SDNS	Rituximab	17	23	750–1500	NR	-	1	-	NR
Mathew et al., 2022 [59]	RCT	SSNS	Rituximab	41	21	750	86	67	2	2	64
Wang et al., 2022 [60]	3-arm RCT	FRSDNS	Rituximab	51	17	562.5–750.5	19	71	NR	NR	NR
Basu et al., 2023 [61]	Prospective	SDNS	Rituximab	119	89	750	NR	NR	NR	NR	NR
Zhu et al., 2023 [62]	RCT	FRNS and SDNS	Rituximab	29	29	775–1500	17	-	NR	-	NR
Cravedi et al., 2024 [63]	Prospective	SDNS	Rituximab	13	13	375	0	-	0	-	0
Liu et al., 2024 [64]	Prospective	SSNS	Rituximab	76	43	375	15b	NR	4	NR	10b
Nozu et al., 2024 [65]	Prospective	MRNS	Rituximab	6	6	1500	8	-	2	-	NR
Sheng et al., 2025 [66]	RCT	NS	Rituximab	24	12	1500	NR	NR	0	0	2a
Sinha et al., 2025 [67]	RCT	FRNS and SDNS	Rituximab	91	91	375–750	NR	-	5	-	NR
Billing et al., 2008 [68]	Prospective	AMR	Rituximab	6	6	375	0	-	0	-	0
Zarkhin et al., 2008 [69]	RCT	AMR	Rituximab	20	10	1500	NR	NR	NR	NR	NR
Billing et al., 2012 [70]	Prospective	AMR	Rituximab	20	20	375	NR	-	1	-	NR
Total				1278	1011		405/233	184/94	32/508	4/116	115/99
Episodes per rituximab course							1.74	1.96	0.06	0.03	1.16

Study	Upper respiratory tract infection	Lower respiratory tract infection		Urinary tract infection		Herpes simplex virus related		Gastrointestinal infection		Sepsis/bloodstream infection
	Control	anti-CD20	Control	anti-CD20	Control	anti-CD20	Control	anti-CD20	Control	anti-CD20	Control
Brogan et al., 2022 [43]	-	5	-	3	-	NR	-	3	-	1	-
Guigonis et al., 2008 [44]	-	1	-	NR	-	NR	-	1	-	NR	-
Kamei et al., 2009 [45]	-	NR	-	NR	-	NR	-	NR	-	NR	-
Ravani et al., 2011 [46]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Magnasco et al., 2012 [47]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Ravani et al., 2013 [48]	-	NR	-	1ac	-	NR	-	NR	-	NR	-
Iijima et al., 2014 [7]	NR	NR	NR	1ac	0ac	NR	NR	1ac	0ac	NR	NR
Ruggenenti et al., 2014 [5]	-	NR	-	NR	-	NR	-	0c	-	NR	-
Sun et al., 2014 [49]	-	1	-	NR	-	NR	-	NR	-	NR	-
Ravani et al., 2015 [8]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Ahn et al., 2018 [50]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
	-	NR	-	NR	-	NR	-	NR	-	NR	-
Basu et al., 2018 [51]	6b	4b	8b	0b	2b	1b	0b	3b	5b	NR	NR
Takahashi et al., 2019 [52]	-	1	-	NR	-	NR	-	NR	-	NR	-
Kari et al., 2020 [53]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Ravani et al., 2020 [54]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Ravani et al., 2020 [55]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Ravani et al., 2021 [56]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Ravani et al., 2021 [57]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Al Salloum et al., 2022 [58]	-	1	-	NR	-	NR	-	NR	-	NR	-
Mathew et al., 2022 [59]	47	1	2	NR	NR	NR	NR	5	0	NR	NR
Wang et al., 2022 [60]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Basu et al., 2023 [61]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Zhu et al., 2023 [62]	-	NR	-	NR	-	NR	-	NR	-	NR	-
Cravedi et al., 2024 [63]	-	0	-	0	-	0	-	0	-	0	-
Liu et al., 2024 [64]	NR	5b	NR	NR	NR	NR	NR	NR	NR	NR	NR
Nozu et al., 2024 [65]	-	NR	-	NR	-	NR	-	NR	-	NR	-
Sheng et al., 2025 [66]	0	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Sinha et al., 2025 [67]	-	NR	-	1	-	NR	-	NR	-	1	-
Billing et al., 2008 [68]	-	0	-	0	-	0	-	0	-	0	-
Zarkhin et al., 2008 [69]	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Billing et al., 2012 [70]	-	1	-	NR	-	NR	-	NR	-	NR	-
Total	47/32	11/182	2/20	4/135	-	0/19	-	9/105	0/20	2/135	-
Episodes per rituximab course	1.47	0.06	0.10	0.03	-	0.00	-	0.09	0.00	0.01	-

Only AEs without grade scale were included for calculation. No case related to varicella zoster virus, hepatitis B reactivation, cytomegalovirus, Epstein-Barr virus, BK virus, and death due to infection was reported from prospective studies. Therefore, the data of them are not shown

RCT randomised controlled trials, AAV ANCA-associated vasculitis, SDNS steroid dependent nephrotic syndrome, SRNS steroid resistant nephrotic syndrome, FRNS frequently relapse nephrotic syndrome, MRNS multiple drug-resistant nephrotic syndrome, FRSDNS frequently-relapsing steroid-dependent nephrotic syndrome, NR not reported

^aReported by the number of subjects

^bGrades 2–4

^cGrades 3–4

Non-infectious complications mimicking infection: rituximab-induced interstitial lung disease (RTX-ILD)

Rituximab-induced interstitial lung disease (RTX-ILD) is a non-infectious pulmonary complication that can mimic pneumonia clinically. The reported incidence of RTX-ILD is heterogeneous across studies, ranging from 0.01% to 10.0% [71]. Symptoms may occur shortly after rituximab administration, including dyspnoea, cough, and fatigue [72, 73]. The condition is typically resistant to antimicrobials, but can be treated with corticosteroids. In severe cases, patients may progress to fatal respiratory failure, and consequently a high index of suspicion is warranted [72].

Risk factors for infections

Several factors confound the effects of anti-CD20 mAbs and further increase the risk of infection in children, including neutropenia, hypogammaglobulinaemia, and concomitant use of other immunosuppressive agents. In addition, the nature of the primary disease, such as nephrotic syndrome, and the development of chronic kidney disease may also predispose children to infections [74, 75]. Notably, up to 25% of patients treated with rituximab for severe lupus nephritis developed infections, highlighting the implication of underlying disease on infection [76, 77]. Younger children are more susceptible to developing agranulocytosis and hypogammaglobulinaemia after the use of anti-CD20 mAbs [32, 78]. Early identification and modification of these risk factors may serve as an important strategy to prevent infection.

Neutropenia and agranulocytosis

Anti-CD20 mAbs result in bone marrow suppression and impair neutrophil production [22, 78, 79]. Neutropenia was described in 1.7%–41.9% and 0.6%–66.7% of children and adults respectively, while agranulocytosis was reported in 2.3%–8.3% of children after rituximab (summarised in Supplementary Tables 3 and 4). In addition, younger age at rituximab is an important associated factor of agranulocytosis [78]. Theoretically, children with neutropenia are susceptible to various types of infections, yet a significant proportion of them developed febrile neutropenia without an identified causative microorganism in a cohort by Chan et al. [32].

Hypogammaglobulinaemia

The reported rates of hypogammaglobulinaemia are heterogeneous, owing to discrepant local monitoring policies [80]. Even among prospective studies on NS, AAV, and AMR, hypogammaglobulinaemia was reported in 2.3%–91.7% of children and 3.0%–42.4% of adults (Table 3 and Supplementary Table 5). Persistent hypogammaglobulinaemia beyond 1 year post-rituximab is common, and up to 41% of children continue to experience low IgG levels 2 years after the last anti-CD20 administration [81]. In addition to young age, pre-existing hypogammaglobulinaemia prior to anti-CD20 mAbs (e.g. in SRNS with persistent nephrotic-range proteinuria) and concurrent use of immunosuppressants predispose patients to develop and/or perpetuate hypogammaglobulinaemia [24, 32, 81–85]. The significance of hypogammaglobulinaemia on infection risk remains controversial, as only a minor proportion of hypogammaglobinaemia episodes (~ 1%) eventually complicate with significant infections [32, 81, 86]. Clinical studies also observed and reported low IgM and IgA levels [43, 45, 56, 69], yet their roles in preventing infection are inconclusive [87, 88].

Table 3.

Reported rates of hypogammaglobulinemia after rituximab in children from prospective studies

Study	No. of patients analysed	No. of rituximab courses	Regimen per course mg/m2	Outcome measures		Rate of Hypogammaglobulinemia			Serious infectious episodes
						Overall	Baseline IgG levels
							Normal	Reduced
ANCA-associated vasculitis
Brogan et al., 2022 [43]	25	25	1500	Patient based	Low IgG at 18 months	11/23 (47.8%)	NR	NR	9
Childhood nephrotic syndrome
Guigonis et al., 2008 [44]	22	40	375–1500	Patient based	Low IgG at last follow-upa	8/22 (36.4%)	4/18 (22.2%)	4/4 (100%)	2
Sun et al., 2014 [49]	12	12	375–750	Patient based	Low IgG during rituximab	1/12 (8.3%)	NR	NR	0
Ravani et al., 2020 [54]	30	15	375	Patient based	Low IgG at 6–24 months	0 (0%)	0 (0%)	0 (0%)	NR
Ravani et al., 2021 [57]	30	15	375	Patient based	Low IgG at last follow-upb	8/15 (53.3%)	2/6 (33.3%)	6/9 (67%)	0
Al Salloum et al., 2022 [58]	17	23	750–1500	Patient based	Low IgG at 3 years	1/17 (5.9%)	NR	NR	1
Zhu et al., 2023 [62]	29	29	775–1500	Dose based	Low IgG during rituximab	40/95 (42.1%)	NR	NR	0
Cravedi et al., 2024 SC [63]	13	13	375	Patient based	Low IgG at 12 months	0 (0%)	0 (0%)	0 (0%)	0
Liu et al., 2024 [64]	76	43	375	Patient based	Low IgG at disease onset	1 (2.3%)	NR	1/1 (100%)	4
Nozu et al., 2024 [65]	6	6	1500	Patient based	Low IgG at last follow-upc	0 (0%)	0 (0%)	0 (0%)	2
Sheng et al., 2025 [66]	24	12	1500	Patient based	Low IgG during rituximab	11/12 (91.7%)	0 (0%)	11/11 (100%)	0
Sinha et al., 2025 [67]	91	91	375–750	Patient based	Low IgG at 18 months	13/91 (14.3%)	NR	NR	6*
Antibody-mediated rejection
Billing et al., 2008 [68]	20	20	375	Patient based	Low IgG at 24 months	6/20 (30.0%)	NR	NR	NR

SC rituximab subcutaneous injection, NR not reported

^*Number of patients

^aMedian follow-up: 9.5 months

^bUnpublished data provided upon request by investigators; at last follow-up (median follow-up 286 days)

^cPersistent hypogammaglobulinemia; 1 followed during rituximab, 5 followed for 2.5 years

Approximately 80% of children relapse after rituximab therapy and require repeated courses to maintain long-term disease control [89]. Multiple treatment courses raise concerns about the development of drug resistance and the potential impact on the long-term immunological profile of a growing child. Colucci et al. studied 27 children with NS treated with rituximab, whose follow-up exceeded 4 years from the first dose and at least 2 years from the last anti-CD20 administration [81]. At last follow-up, total, transitional and mature-naïve B cells had normalised in nearly all patients. In contrast, total memory B cells and switched memory B cells remained significantly reduced in 74% and 78% of cases respectively. IgG levels against hepatitis B virus and tetanus were also further reduced. Although revaccination could induce antigen-specific memory B cells, IgG titres remained low. Similarly, we reported lower antibody seropositivity following COVID-19 vaccination among children receiving rituximab for glomerular disease [90, 91]. More importantly, functional humoral response, measured by surrogate viral neutralisation test, was also impaired after rituximab therapy [90, 91]. Therefore, the use of anti-CD20 should be carefully considered in children during periods of active disease, which often coincide with the critical stage of immune development.

Concomitant use of immunosuppressants

In SDNS, maintenance immunosuppression with MMF is a well-studied strategy to extend relapse-free remission after anti-CD20 mAbs [89, 92]. It weakens T-cell immunity [85, 93, 94] and predisposes patients to neutropenia, which could potentiate the risk of infections. Iijima et al. reported that children receiving maintenance MMF after rituximab had a high rate of neutropenia (12.8% vs 5.1%) and agranulocytosis (5.1% vs 0%), and they were also more susceptible to infection compared to placebo (1.59 vs 0.82 episodes of infections per patient) [92]. Hogan et al. also reported a high rate of VZV infection (25%) when rituximab was used in combination with MMF in paediatric LN patients [95]. In contrast, the relationship between infection and concomitant immunosuppression could not be established in adults treated with rituximab for glomerular disease (MMF, steroids, CNI and cyclophosphamide), except azathioprine and therapeutic plasma exchange [33, 96]. For kidney transplant recipients, the combination of anti-thymocyte globulin and rituximab is associated with a high risk of infection [97, 98].

Prophylactic measures for patients on anti-CD20 mAbs

The strategies for preventing infection in children receiving anti-CD20 mAbs should extend beyond antimicrobial prophylaxis to include a comprehensive assessment of infection risk, vaccination, and the modification of risk factors.

Evaluation of infection risk prior to commencement of anti-CD20 mAbs

We recommend evaluating patients for infection risk before initiating anti-CD20 mAbs. A comprehensive history taking (including birth history, past infections, vaccination history and family history) and a thorough physical examination should be undertaken for all children contemplated for anti-CD20 mAbs. This information would guide the subsequent investigations and actions as summarised in Table 4.

Table 4.

Baseline evaluations before anti-CD20 treatment to assess infective risk

1. General assessment

• Review vaccination record • Review past medical history • Review concurrent drug history • Review travel history

2. Investigations

• Complete blood count • Immunoglobulin G, A, M • G6PD status (for use of cotrimoxazole as PJP prophylaxis) • Screening for Mycobacterium tuberculosis infection - Tuberculin skin test (TST) - Interferon gamma release assay (IGRA) • Serologic testing for (a) Hepatitis B virus (HBV) - Hepatitis B core antibody total (anti-HBc total) - Hepatitis B surface antibody (anti-HBs) - Hepatitis B virus surface antigen (HbsAg) - HBV DNA in HBsAg-positive patients (b) Hepatitis C virus (anti-HCV IgG) (c) Cytomegalovirus (CMV IgG) (d) Epstein-Barr virus (EBV IgG) (e) Human Immunodeficiency Virus (fourth-generation antigen/antibody combination test) (f) Varicella-zoster virus (VZV IgG) (g) Measles, mumps, rubella, if available • Optional: - B-cell subsets - Chest radiograph (to rule out active infection or in case of positive TB screening in high prevalence areas)

Monitoring following anti-CD20 mAbs

In our practice, we regularly monitor patients’ complete blood count and immunoglobulin G, A, and M levels 1 month after anti-CD20 mAbs administration, and every three months thereafter. While the neutropenia usually occurs early after drug exposure, hypogammaglobulinaemia may perpetuate. Consequently, we monitor immunoglobulin levels for at least 18 months and until the levels normalise. In addition, we would evaluate for neutropenia and hypogammaglobulinaemia during active infection, where active interventions may be required.

Immunisations

Ideally, children should receive all necessary immunisations prior to anti-CD20 mAbs for optimal immunogenicity, yet it is usually not feasible in most clinical scenarios due to the urgency of treatment. All vaccinations should be given at least 2 to 4 weeks prior to the administration of anti-CD20 mAbs for immunologic response to develop [99, 100]. This is highlighted by the observation that none of the patients achieved seroconversion if hepatitis B vaccine was given within 3 days before rituximab administration [101]. For patients who were given anti-CD20 mAbs during an ongoing vaccine series, seroconversion rates declined with fewer vaccine doses prior to therapy initiation, from 92.8% (95% CI 87.1–96.5) after 4 doses to merely 24.0% (95% CI 9.4–45.1) after 1 dose [102]. Available data suggest that circulating B-cell levels at the time of vaccination correlate with the antibody levels [103–105]. Thus, delaying vaccinations until B-cell reconstitution is a plausible approach to optimise vaccine responses. Pre-existing antibodies from primary immunisation were preserved in some cases treated with rituximab, since the long-lived plasma cells are theoretically unaffected by anti-CD20 mAbs [103, 106, 107]. However, other studies also reported reduced antibody titres following treatment [101, 106]. Higher or additional doses of vaccines, and adjuvanted vaccines, have been used in influenza and SARS-CoV-2 mRNA vaccines to improve immunogenicity in immunocompromised patients [90, 108]. Additional doses of SARS-CoV-2 mRNA vaccines are able to boost antibody responses following rituximab, although the attained antibody titres remained lower compared to children receiving dialysis and healthy controls [90, 109].

The use of inactivated vaccines during or after recent anti-CD20 mAbs is considered safe [110]. In general, inactivated vaccines should be administered at least 5 to 6 months after the last anti-CD20 administration and 2 to 4 weeks prior to the subsequent dose [107, 111]. In addition to diminished vaccine competency, live attenuated vaccines (e.g. measles-mumps-rubella and varicella vaccines) are contraindicated during anti-CD20 mAbs administration owing to the risk of developing severe vaccine-related infection [100]. Although these vaccines have been safely administered to selected patients on long-term immunosuppressants with preserved cellular and humoral immunity [112], such practice has not been formally evaluated in rituximab-treated patients. The desired timing of live-attenuated vaccines is 12 or more months after rituximab, after B-cells repopulate while the patient is not receiving concurrent immunosuppression [107]. In situations where immunisation is not feasible, close monitoring and patient education on vaccine-preventable diseases are essential for timely diagnosis and post-exposure prophylaxis. Vaccination of household and close contacts should be encouraged to protect immunocompromised patients [100]. In summary, clinicians should review immunisation status at diagnosis and, where feasible, timely vaccinate the patients before initiating anti-CD20 mAbs. In glomerular disease, timely vaccination is often challenging due to the need for early immunosuppression. Once anti-CD20 mAbs are administered, vaccination should ideally be deferred until B-cell repopulation to optimise immunogenicity while balancing infection risk. For children progressing rapidly to kidney failure and awaiting a kidney transplant, there is limited data on live vaccines to support the best approach. Inactivated vaccines with post-vaccination antibody titre monitoring may be considered to ensure adequate immune response. Table 5 summarises vaccination recommendations for patients receiving anti-CD20 mAbs.

Table 5.

Specific recommendations for the vaccines in patients treated with rituximab and other anti-CD20 mAbs [107, 111]

Vaccine	Vaccine type	Suggested dose	Suggested timing of vaccination in relation to rituximab	Serological testing post immunisation
Diphtheria, tetanus, polio vaccine	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
Haemophilus conjugate vaccine	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
Hepatitis B	Inactivated	Higher dose for immunocompromised people: Double dose of age should be given, total 4 doses (months 0, 1, 2, 6–12) [113]	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion Consider to delay the entire vaccine series until completion of rituximab courses	Anti-HBs at 1–2 months following completion of the vaccine series [100]
Human papillomavirus vaccine	Inactivated	Three doses for immunocompromised people [114] Months 0, 2, 6 from 9 years old onwards	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion Consider delaying the entire vaccine series until completion of rituximab courses	Not available in routine setting
Inactivated influenza Vaccine	Inactivated	Usual dose and schedule Second dose is required for children aged < 9 years who have not previously been vaccinated	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion Can receive during influenza seasons without delay to reduce complications of infections	Not available in routine setting
Measles, rubella, mumps (MMR)	Live-attenuated	Usual dose and schedule	Preferably 12 months after last infusion and 4 weeks prior to next infusion [107]	Measles, mumps, rubella IgG antibodies
Meningococcal ACWY vaccine	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
Meningococcal B vaccine	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
Pneumococcal 23-valent (PPSV-23)	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
Pneumococcal vaccine 15-valent (PCV-15)	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
Pneumococcal vaccine 20-valent (PCV-20)	Inactivated	Usual dose and schedule	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion	Not available in routine setting
SARS-CoV2-mRNA vaccine	mRNA	Additional doses for immunocompromised people, please refer to latest CDC recommendation [115, 116]	Preferably 6 months after last infusion and at least 2 weeks prior to next infusion Can receive during peak seasons without delay to reduce complications of infections	Not available in routine setting
Varicella	Live-attenuated	Usual dose and schedule	Preferably 12 months after last infusion and 4 weeks prior to next infusion [107]	Varicella IgG antibodies

Immunoglobulin replacement

Immune globulin preparations are highly purified IgG antibodies extracted from pooled plasma of qualified donors using methods that vary by manufacturer [117]. Both IVIG and subcutaneous immune globulins (SCIG) have been used in primary immunodeficiencies to reduce infections and associated complications [117]. The policy of prophylactic immune globulin replacement for post-rituximab hypogammaglobulinaemia has been adopted in some centres [118], since these patients are considered to have secondary immunodeficiency and are at risk of infections. In a large cohort study comprising 8633 adults (mean age 59.8 years), higher cumulative immunoglobulin replacement dose reduced the risk of severe infection by 2% (HR 0.98; 95% CI, 0.96–0.99; P = 0.002) [21]. Direct data extrapolation to children may not be appropriate and this measure has not been evaluated in paediatric trials. On the other hand, many patients with post-rituximab hypogammaglobulinaemia remain asymptomatic, even with very low levels of IgG [24]. IVIG preparation has a short half-life between 32 and 36 days, and therefore monthly infusion is required, resulting in repeated hospitalisations and compromised quality of life [24]. SCIG is a convenient alternative to IVIG, which allows self-administration at home after adequate training [119]. The decision of regular IVIG infusions should be made jointly with the patient and the family, balancing the potential benefits and drawbacks (Table 6). On the other hand, IgM deficiency is common after rituximab and obinutuzumab, which is a potential risk factor of severe and/or recurrent infections [42]. The use of IgM-enriched immunoglobulin, rather than IVIG or SCIG with minimal content of IgA and IgM, has been successful as an adjunctive treatment of sepsis. However, it has not been studied in detail in the context of infection prophylaxis after anti-CD20 therapy [120].

Table 6.

Comparisons of immunoglobulin replacement therapy

	Intravenous immunoglobulin	Subcutaneous immunoglobulin
Brand examples	Privigen®, Intragam Nexgen®	Hizentra®, Cuvitru®
Concentration	10%	20%
Route of administration	Intravenous	Subcutaneous
Frequency of administration	Every 4 weeks	Every 1–2 weeks
Duration of infusion	Shorter	Longer
Systemic adverse reactions	Higher	Fewer
Need for hospital visit	Yes, require medical personnel	No, self-administration at home
Need for patient and family training	No	Yes

In adult patients with AAV receiving maintenance rituximab therapy, current recommendations suggest replacing immunoglobulin intravenously at 0.4 g per kg every month if the IgG level is < 300 mg/dL with recurrent severe infections [121]. Some guidelines suggest keeping a higher level of trough IgG level in case of one or more life-threatening infections over the previous 12 months [122]. The optimal target of IgG level remains unclear [123]. An IgG level of 800 mg/dL or lower normal limit for age has been suggested to be the initial replacement target [122, 123], with monthly titration to achieve infection-free status. IVIG is generally well tolerated but can also cause adverse reactions such as infusion reactions, haemolysis and thromboembolism [124]. Of note, acute kidney injury may follow exposure to sucrose-containing immune globulin preparation, especially among patients with pre-existing kidney impairment [125]. The risk may be mitigated by pre- and post-hydration and limiting the infusion rate.

Antimicrobial prophylaxis and specific considerations

Antimicrobial prophylaxis should be personalised alongside standard preventive measures. Several factors warrant careful evaluation, including the patient’s risk factors, baseline evaluation results, the type, severity, and frequency of previous infections, as well as the costs and potential side effects of antimicrobials [75, 126]. Generally, antimicrobial prophylaxis may be considered for patients with persistent hypogammaglobulinaemia and recurrent infections, tailored to the potential pathogens based on their infection history [21]. Prophylaxis against several microorganisms and viruses is detailed in the following section and Table 7.

Table 7.

Available options of prophylaxis to specific infections [117]

Infection	Prophylaxis regimen	Renal dose adjustment	Adverse reactions	Duration of prophylaxis and monitoring
Cytomegalovirus (CMV) [127, 128]	Valganciclovir PO  < 16 years old: Daily dose = 7 × BSA (m2) × eGFR; Max 450 mg for intermediate-risk transplant recipient (donor CMV +ve to recipient CMV +ve); and Max 900  mg for high-risk transplant recipient (donor CMV +ve to recipient CMV −ve)	eGFR < 60; paediatric formula has incorporated eGFR in dose calculation	Neutropenia, nausea, diarrhoea, anaemia, hypertension	High-risk transplant recipient: 6 months Intermediate-risk transplant recipient: 3 months
Herpes simplex virus (HSV) [75]	Prevention for recurrent infections Acyclovir 80 mg/kg/day in 2 to 3 divided doses PO, max 800 mg per dose	eGFR < 25	Acute kidney failure, neutropenia, anaemia, thrombocytopenia	Until at least 6 months after last rituximab infusion
	Prevention for recurrent infections Valacyclovir 20 mg/kg (max 500 mg) BD PO	eGFR < 30	Abdominal pain, nausea, headache, nasopharyngitis, acute kidney failure, neutropenia,
Hepatitis B [129]	HBV reactivation Entecavir  > 2 years old: 0.015 mg/kg (max 0.5 mg) daily PO	eGFR < 50	Increased transaminases, glycosuria, haematuria	Until 12–18 months after last rituximab infusion, followed by 12 months of close surveillance after cessation of prophylaxis
	Tenofovir disoproxil fumarate  > 2 years old: 8 mg/kg (max 300 mg) daily PO	eGFR < 50	Nephrotoxicity, decreased bone mineral density
	Tenofovir alafenamide  > 6 years old: 25 mg daily PO	eGFR < 30	Headache, increased transaminases
	Post-exposure in anti-HBs negative patients Hepatitis B hyperimmune globulin (HBIG) 0.06 mL/kg (max 5 mL) IM as soon as possible after exposure (within 24 h of needlestick, ocular or mucosal exposure) Consider giving a second dose of HBIG 4 weeks later (due to suboptimal vaccine response)	Not required	Headache, malaise, myalgia, pain at injection site, erythema	1–2 doses
Influenza A and B [130]	Post-exposure prophylaxis Oseltamivir 10–15 kg: 30 mg daily  > 15–23 kg: 45 mg daily  > 23–40 kg: 60 mg daily  > 40 kg: 75 mg daily	eGFR < 60	Nausea, vomiting, headache, skin reactions	7 days
	Inhaled zanamivir  > 5 years old: 10 mg (two 5 mg inhalation) daily	Not required	Bronchospasm, skin reactions	7 days
Pneumocystis jirovecii [131]	Trimethoprim-sulfamethoxazole (TMP-SMX)/cotrimoxazole (suggested) 2.5–5 mg/kg (max 160 mg) TMP daily or 3 times per week PO	eGFR < 30	Hypersensitivity reactions (rashes, fever), neutropenia, hyperkalaemia, increased transaminases, kidney failure	Until at least 6 months after last rituximab infusion, or until B-cell reconstitution, whichever longer
	Inhaled pentamidine (> 5 years old) 300 mg every month, with nebulised salbutamol as pre-medication IV pentamidine  > 2 years old: 4 mg/kg (max 300 mg) every 4 weeks	Not required	Nephrotoxicity, hyper or hypokalaemia, hypoglycaemia, hypocalcaemia, arrhythmias, pancreatitis, respiratory symptoms
	Dapsone 2 mg/kg (max 100 mg) daily or 4 mg/kg (max 200 mg) weekly PO	Not required	Rash, fever, lymphadenopathy, haemolytic anaemia, increased transaminases, methemoglobinemia, neutropenia
	Atovaquone  > 2 years old: 30 mg/kg (max 1500 mg) daily PO	Not required	Nausea, diarrhoea, fever, hepatitis, rash
Tuberculosis [132]	Reactivation of latent infection (1) Isoniazid monotherapy for 6 or 9 months 10–20 mg/kg (children), 5 mg/kg (adult) (max 300 mg) daily PO (2) Isoniazid and rifapentine combination therapy for 3 months Isoniazid 2–11 years old: 25 mg/kg (max 900 mg) once weekly PO  > 12 years old: 15 mg/kg (max 900 mg) once weekly PO Rifapentine (10–14 kg) 300 mg once weekly PO (14.1–25 kg) 450 mg once weekly PO (25.1–32 kg) 600 mg once weekly PO (32.1–49.9 kg) 750 mg once weekly PO  > 50 kg 900 mg once weekly PO (3) Rifampicin monotherapy for 4 months 15–20 mg/kg (children) or 10 mg/kg (adult) (max 600 mg) daily PO (4) Isoniazid and rifampicin combination therapy for 3 months Isoniazid 10–20 mg/kg (children), 5 mg/kg (adult) (max 300 mg) daily PO Rifampicin 15–20 mg/kg (children) or 10 mg/kg (adult) (max 600 mg) daily PO	Not required	Isoniazid Peripheral neuropathy, hepatotoxicity, rash, hypersensitivity Rifapentine Anaemia, thrombocytopenia, neutropenia Rifampicin Hepatotoxicity, rash or other allergy, thrombocytopenia, gastrointestinal upset	Duration varies with the regimen (as mentioned)
Varicella zoster virus (VZV) [133]	Post-exposure prophylaxis Acyclovir 20 mg/kg/dose four times a day (max 800 mg per dose) for 7 days PO, beginning 7 days after exposure	eGFR < 25	Acute kidney failure, neutropenia, anaemia, thrombocytopenia	7 days
	Post-exposure prophylaxis Varicella immunoglobulin IM injection (VARIZIG®) 125 IU/10 kg body weight, up to a maximum of 625 IU, ideally within 96 h but can be given up to 10 days after exposure	Not required	Pain at injection site, skin rash	1 dose

Prophylaxis against specific microorganisms

Pneumocystis Jirovecii

While clinical practice is heterogeneous and evidence remains limited, in view of the high mortality of pneumocystis Jirovecii (PJP) infection, prophylaxis has been suggested in some centres for patients receiving anti-CD20 mAbs, particularly for those receiving concurrent immunosuppressants with high-dose corticosteroids [9, 15, 126, 134]. Trimethoprim-sulfamethoxazole (TMP-SMX or cotrimoxazole) is the preferred choice for prophylaxis at a dose of 5–10 mg/kg TMP component (max 160 mg TMP/800 mg SMX) daily or three times per week [135]. Similar efficacy between daily and thrice-weekly regimens was observed in childhood leukaemia [136], although some studies favoured a daily dosing regimen [136]. However, adverse effects including neutropenia and skin eruption are common, with higher incidences in daily dosing regimens. Recent evidence in the transplant population suggests that daily low-dose cotrimoxazole (2.5 mg/kg TMP) may provide adequate protection against PJP and is better tolerated [137, 138]. PJP prophylaxis is given for at least 6 months following the last anti-CD20 infusion [75, 131] and should cover the period of B-cell depletion [9]. The duration may be extended in those treated with obinutuzumab, who often experience a longer duration of B-cell depletion [42]. A high index of suspicion is warranted as late-onset PJP infections may occur even after drug discontinuation [139]. In addition, prophylactic use of cotrimoxazole was associated with a lower frequency of severe infections (predominantly respiratory tract infections) (HR 0.30; 95% CI 0.13–0.69) in an adult population with AAV [140]. Pentamidine can be used in case of cotrimoxazole allergy or intolerance and G6PD deficiency (Table 7). Other alternatives include dapsone and atovaquone.

Hepatitis B and C virus

Use of anti-CD20 mAbs is associated with high risk (> 10%) of HBV reactivation among carriers [141]. For this reason, it is advisable to check both HBsAg and anti-HBc (IgG or total) prior to therapy. High-risk patients, who are HBsAg positive or HBsAg negative/anti-HBc positive, should be additionally assessed by HBV DNA viral load. Current guidelines suggest that antiviral prophylaxis with high barrier to resistance (e.g. entecavir or tenofovir) should be initiated 1 week before or at the time of anti-CD20 mAbs initiation and continued for at least 12–18 months after the last administration [141–144]. Close surveillance for late HBV reactivation is indicated for 12 months following cessation of antiviral prophylaxis [143, 144]. In patients with negative anti-HBs (titre < 10 mIU/mL), due to suboptimal vaccine responses during anti-CD20 mAbs, precautionary measures to avoid HBV exposure are important, and passive immunisation with hepatitis B immunoglobulin can be offered within 48 h following exposure (e.g. contact with HBsAg-positive individuals via blood, mucosal or sexual routes) [113]. Rare cases of rituximab-induced hepatitis C reactivation were reported in lymphoma and rheumatoid arthritis [145]. However, there are no existing guidelines to recommend routine prophylaxis against hepatitis C infection during anti-CD20 mAbs.

Cytomegalovirus virus (CMV) and Epstein–Barr virus (EBV)

In kidney transplant recipients, CMV reactivation and CMV disease may occur following anti-CD20 therapy for AMR [38]. Therefore, it is recommended to initiate valganciclovir prophylaxis among moderate- and high-risk patients (particularly CMV donor-positive, recipient-negative pair) for 3 to 6 months, with close surveillance (CMV PCR or CMV pp65) for late-onset CMV reactivation after discontinuation of prophylaxis [127]. Notably, valganciclovir may contribute to an additional risk of developing neutropenia with concurrent rituximab administration [146]. In contrast, there is no effective prophylaxis against EBV. Regular surveillance for EBV PCR is advisable in transplant recipients after intensive immunosuppression [147]

Influenza infection

For influenza A and B, post-exposure prophylaxis (preferably oseltamivir) is indicated within 48 h of exposure to prevent influenza complications, since anti-CD20 mAbs-treated patients may not have mounted a sufficient immune response to influenza vaccine [130].

Herpes simplex virus (HSV) and varicella zoster virus (VZV)

HSV and VZV reactivation is a frequent complication following anti-CD20 therapy. In patients with recurrent HSV or VZV infections, valacyclovir or acyclovir prophylaxis can be considered until 6 months after the last dose of anti-CD20 administration [75]. Patients without immunity to varicella (VZV IgG negative) should be offered varicella zoster immunoglobulin within 96 h following exposure [133]. A 7-day course of antiviral (acyclovir or valacyclovir), beginning within 7 and 10 days post-exposure, can be considered if immunoglobulin cannot be administered within the aforementioned timeframe.

Human immunodeficiency virus (HIV)

In HIV-infected children, use of anti-CD20 mAbs is associated with clinically relevant adverse effects such as leukopenia, neutropenia and transient decline in CD4+ and CD8+ T-cell counts that potentially increase susceptibility to infections [148]. There are no specific recommendations on additional antimicrobial prophylaxis in patients with HIV after anti-CD20 mAbs. Antimicrobial prophylaxis should follow the existing recommendations for HIV disease based on CD4 count and history of infections [149].

Mycobacterium tuberculosis

Compared to anti-TNF therapies and moderate to high doses of corticosteroids, the risk of tuberculosis (TB) reactivation following anti-CD20 therapy is relatively low. In the context of childhood kidney diseases where rituximab is indicated, most children often receive concurrent immunosuppressive agents. Therefore, TB should be excluded through a thorough medical history and clinical examination in all children. Chest radiograph should be considered in children residing in high-prevalence areas or with a positive travel history. If active TB is diagnosed, anti-tuberculous treatment should be initiated prior to commencing immunosuppressants. For latent TB infection, defined as asymptomatic patients with a positive tuberculin skin test or interferon gamma release assay, appropriate treatment should be offered concurrently [150]. While rifampicin-based regimens are generally safe and associated with high treatment completion rates [132, 151], rifampicin can cause drug-drug interactions and increase the clearance of corticosteroids. Consequently, isoniazid monotherapy for 6–9 months may be considered to minimise potential drug interactions. Patients receiving isoniazid should undergo regular liver function monitoring and take pyridoxine (vitamin B6) throughout the course of treatment to prevent peripheral neuropathy [152].

Conclusion

Although anti-CD20 mAb has become an essential treatment in several immune-mediated childhood kidney diseases, its safety profile in paediatric patients has not been fully established. While immunosuppressed children are at an increased risk of infections, many of these can potentially be prevented or their risks reduced through strategies such as exposure avoidance, vaccination, antimicrobial prophylaxis, and the use of immunoglobulins when indicated. Clinicians can help mitigate the risk of serious infections associated with anti-CD20 mAbs by identifying patients with relevant risk factors and understanding the mechanisms and risks of immunosuppression. Screening and counselling should be performed prior to initiating therapy, and patients with complex exposure histories or latent infections should be referred to infectious disease specialists for further evaluation and management. Continuous risk assessments and education should be provided throughout treatment, especially during disease flares. Last but not least, education of patients and their families regarding non-pharmacological infection prevention strategies, together with vigilant monitoring for signs and symptoms of infection, remains crucial to ensuring safe and effective treatment outcomes (Table 8).

Table 8.

Practice points for minimising risk of infection for anti-CD20 mAbs in paediatric kidney diseases

Practice Points

1) Pre therapy assessment and immunisation: o Detailed evaluation on the medical history, review the indications of anti-CD20 mAbs, concurrent use of immunosuppressants, vaccination history, and travel history o Screen for active/latent infections (see Table 4), consult infectious disease specialists for complex cases o Administer necessary vaccines 2–4 weeks before anti-CD20 mAbs 2) If vaccination cannot be completed before anti-CD20 mAbs: o Surveillance for infections o Re-vaccinate at an appropriate interval after the last anti-CD20 mAbs administration, considering B-cell reconstitution 3) After anti-CD20 mAbs: o Adjust and minimise concurrent immunosuppression o Monitor complete blood count for neutropenia and agranulocytosis (may require GCSF treatment) o Antimicrobial prophylaxis (preferably cotrimoxazole if no G6PD deficiency) against Pneumocystis jirovecii pneumonia ≥ 6 months, may be extended until B-cell reconstitution o For children with persistent hypogammaglobulinaemia and recurrent or severe infections, consider prophylactic immune globulin (either intravenous or subcutaneous) o CMV prophylaxis in moderate- to high-risk transplant recipients for 3–6 months o Promote seasonal influenza vaccination (see Table 5 for caution) 4) Comprehensive education of patients and their families o Infection prevention strategies o Monitor for signs and symptoms of infection for early intervention

Key summary points

1. Anti-CD20 mAbs are increasingly used in the management of childhood kidney diseases, yet there are concerns about their side effects, especially infection.

2. A structured approach should be adopted to assess and mitigate infection risk in children receiving anti-CD20 mAbs.

3. In addition, monitoring for neutropenia and hypogammaglobulinaemia, antimicrobial prophylaxis, immunisation, and the modification of risk factors should be considered to optimise safety in children receiving anti-CD20 mAbs.

4. Further prospective, large cohort paediatric studies, particularly for new generations of anti-CD20 mAbs, are warranted to explore their infection risks and refine prophylaxis strategies.

Multiple-choice questions

Answers are provided following the references.

1. In which of the following conditions may anti-CD20 mAbs be indicated?

   • A
     Nephrotic syndrome
   • B
     ANCA-associated vasculitis nephritis
   • C
     Antibody-mediated rejection
   • D
     All of the above
   • E
     None of the above
2. Which of the followings should be screened prior to anti-CD20 mAbs?

   • A
     Immunoglobulin G (A, M)
   • B
     Complete blood count
   • C
     Hepatitis B and C serology
   • D
     Interferon gamma (or tuberculin skin test, if not receiving immunosuppression)
   • E
     All of the above
3. Which of the following is the preferred prophylaxis against pneumocystis Jirovecii?

   • A
     Trimethoprim-sulfamethoxazole
   • B
     Penicillin
   • C
     Pentamidine
   • D
     Dapsone
   • E
     Oseltamivir
4. When should we administer inactivated vaccine after anti-CD20 mAbs?

   • A
     5 to 6 months after anti-CD20 mAbs
   • B
     5 to 6 months after anti-CD20 mAbs with B cell repopulation
   • C
     1 month after anti-CD20 mAbs
   • D
     No restriction
   • E
     1 year after anti-CD20 mAbs

Supplementary information

Below is the link to the electronic supplementary material.

Declarations

Conflict of interest

The authors declare no competing interests.