Treatment of children with Kawasaki disease complicated by selective IgA deficiency using immunoglobulin preparations: a case report

Abstract

Background

Kawasaki disease (KD) was first reported by Kawasaki in Japan in 1967. Although more than 50 years have passed since then, the aetiology and long-term prognosis of this condition remain not fully elucidated. Clinically, it frequently affects the cardiovascular system, leading to complications such as coronary aneurysms, macrophage activation syndrome, or KD shock syndrome. Selective IgA deficiency (SIgAD) is a common primary immunodeficiency disorder associated with other clinical conditions, such as autoimmune diseases, pulmonary diseases, gastrointestinal diseases, allergic diseases, neurological disorders, and malignancies. However, there is a conflict between the treatment regimens for the two conditions, and selecting the appropriate treatment strategy for patients with both conditions presents a challenge.

Methods

We report the case of a 5-year-old child who was admitted to hospital with fever and, during his hospitalisation, was diagnosed with KD complicated by SIgAD. During the course of clinical treatment, the patient’s anti-IgA antibody levels were not measured; following a comprehensive assessment, the patient was treated with intravenous immunoglobulin (IVIG)(an ultra-low, IgA-depleted formulation) and aspirin.J06BAJ215

Results

On the second day of hospitalisation, the child underwent an echocardiogram: the width of the left coronary artery orifice was 0.20 cm, with a Z-score of − 1.789; the width of the right coronary artery orifice was 0.20 cm, with a Z-score of − 0.472. Following administration of IVIG, the fever gradually subsided, and the rash and conjunctival hyperaemia improved compared with previously. On the fourth day of hospitalisation, the child’s temperature returned to normal. On the sixth day of admission, the child’s cervical lymph nodes began to shrink, and the indurations, swelling and erythema in the limbs had resolved. On the seventh day of admission, the child’s conjunctival injection and strawberry tongue had virtually disappeared, the rash had largely resolved, and no enlarged cervical lymph nodes were palpable. A follow-up echocardiogram showed that the width of the left coronary artery ostium was 0.18 cm with a Z-score of − 2.406, whilst the width of the right coronary artery ostium was 0.20 cm with a Z-score of − 0.472. The child was discharged. A follow-up echocardiogram performed 16 days after discharge showed: the left coronary artery orifice measured 0.28 cm in width with a Z-score of 0.68; the right coronary artery orifice measured 0.27 cm in width with a Z-score of 1.636. A follow-up echocardiogram performed 44 days after discharge showed: the main truncus of the left coronary artery was 0.16 cm wide with a Z-score of -3.023, and the main truncus of the right coronary artery was 0.21 cm wide with a Z-score of -0.171. The child reported no discomfort.

Conclusions

Although, in this case, no allergic reactions were observed in the patient with SIgAD following IVIG treatment, this does not imply that all patients with SIgAD are suitable candidates for IVIG therapy. Given that the patient was not tested for anti-IgA antibodies, the possibility cannot be ruled out that other patients with SIgAD may have sufficient levels of anti-IgA antibodies to trigger an allergic reaction. This case report merely provides a literature-based clinical management protocol for KD complicated by SIgAD. We do not advocate a blanket rejection of existing safety guidelines for the use of immunosuppressive agents in immunodeficient patients; rather, we support the adoption of a localised clinical management strategy: implementing strict, proactive and continuous monitoring of relevant cases, with follow-up assessments conducted within a controlled inpatient setting. This will help to control the progression of KD in a timely manner and improve patient prognosis.

Introduction

KD is an acute febrile exanthematous paediatric condition characterised primarily by systemic vasculitis, which can lead to serious cardiovascular complications. Clinically, it is characterised by fever, rash, redness, and swelling of the palms and conjunctival injection, resembling the presentation of an infectious disease. SIgAD is defined as a serum IgA concentration below 7 mg/dL, whilst serum IgM and IgG levels remain normal. The author conducted a literature search in the PubMed database using the search terms ‘Kawasaki disease’ and ‘selective IgA deficiency’ and ultimately retrieved two relevant reports that met the inclusion criteria. Among these, Nishikawa et al. reported a case of a child with KD complicated by SIgAD who received pulse steroid therapy (intravenous methylprednisolone at 30 mg/kg/day for 3 consecutive days); following treatment, the child’s condition improved [1]. Anzai et al. treated a 5-year-old child with KD complicated by SIgAD with cyclosporine A (CsA, 3.0 mg/kg/day), resulting in remission of symptoms [2]. A literature retrieval revealed that there are very few case reports concerning KD complicated by SIgAD. After all, treating children who suffer from both conditions is a particularly thorny problem. Previous studies have generally reported the presence of anti-IgA antibodies in children with SIgAD, which makes them highly susceptible to severe allergic reactions following IVIG treatment. However, as IVIG is one of the recognised standard treatments for paediatric Kawasaki disease, the decision on whether to employ IVIG in children with KD complicated by SIgAD presents a dilemma.

Case presentation

A 5-year-old girl presented at the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine on 30 January 2024 with a two-day febrile illness. Two days prior to admission, the patient developed a fever without any apparent cause. The highest recorded temperature was 39.8 °C, with an average of 3–4 fever spikes per day, indicative of remittent fever. The patient was seen at a local clinic, where a complete blood count revealed: white blood cell count (WBC) 15.24 × 10⁹/L; neutrophil percentage (NEUT%) 67.10%; lymphocyte percentage (LYMPH%) 25.90%; haemoglobin (HGB) 124 g/L; platelet count (PLT) 133 × 10⁹/L; C-reactive protein (CRP) 77.3 mg/L. Diagnosis: Acute tonsillitis. The child was treated with oral cefaclor for one day. The following day, the child continued to experience recurrent fever, and was therefore admitted to the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine for treatment. The child’s birth history and family history are unremarkable. The child has a history of pneumonia. No medication that could cause selective IgA deficiency has ever been used.

On admission: temperature 38.8 °C, respiratory rate 28 breaths per minute, heart rate 110 beats per minute; other vital signs were stable. The patient was alert and able to assume a voluntary position. The pharynx was congested, with bilateral grade II tonsillar enlargement. Breath sounds were coarse in both lungs. No significant abnormalities were noted in the skin, mucous membranes or lymph nodes throughout the body, nor were any significant abnormalities found on examination of the heart, abdomen or nervous system.

Laboratory tests: Complete blood count: WBC 9.58 × 10⁹/L; NEUT% 68.30%; LYMPH% 22.10%; HGB 120 g/L; PLT 194 × 10⁹/L; CRP 105.41 mg/L; Chest X-ray: Increased pulmonary vascular markings in both lungs. Electrocardiogram: Sinus tachycardia.

The treatment process: The child was admitted with a diagnosis of acute tonsillitis. Anti-infective treatment was initiated with ceftriaxone sodium (80 mg/kg/day) in combination with oseltamivir phosphate (45 mg twice daily). On the second day of admission, the child consecutively developed rashes, conjunctival injection, strawberry tongue (Fig. 1a), a swollen superficial lymph node in the left neck measuring approximately 2.0 cm, and hard, swollen, and erythematous limbs (Fig. 1b, c). Infection markers: CRP 107.00 mg/L; procalcitonin 7.99 ng/mL; interleukin-6 113.20 pg/mL. Liver function: alanine aminotransferase (ALT) 283 U/L. Cardiac enzymes: aspartate aminotransferase (AST) 256 U/L. Immunoglobulin levels: immunoglobulin G (IgG): 7.83 g/L; immunoglobulin A (IgA): 0.02 g/L; immunoglobulin M (IgM): 1.32 g/L. Echocardiography: the width of the left coronary artery orifice was 0.20 cm, with a Z-score of − 1.789; the width of the right coronary artery orifice was 0.20 cm, with a Z-score of − 0.472 (Fig. 2a, b). Based on the above abnormal findings and clinical presentation, a detailed medical history was taken from the child’s family, who stated that no medication likely to cause SIgAD had been administered. The revised and supplementary diagnosis is as follows: (1) KD complicated by SIgAD; (2) Impaired liver function. The treatment regimen was adjusted: high-dose IVIG (National Code: XJ06BAJ215B001020104143) (2 g/kg/day) was administered in combination with aspirin (40 mg/kg/day) for high-dose anti-inflammatory therapy, alongside oral compound glycyrrhizin (3 tablets tid) for liver protection. On the third day of hospitalisation, following treatment with IVIG, the child reported no discomfort, and the fever, rash and conjunctival hyperaemia had all been alleviated. The aspirin dose was adjusted to 30 mg/kg/day. On the fourth day of the hospital stay, the child’s temperature returned to normal. On the sixth day of admission, the superficial lymph nodes in the left neck had reduced in size compared to previously, and the hardness, swelling, and erythema of the limbs had resolved; the aspirin dosage was further reduced to 3 mg/kg/day. On the seventh day of admission, the child’s conjunctival injection and strawberry tongue had resolved, most of the rashes had subsided (with some patches merging), and no lymph nodes were palpable in the left neck. Relevant medical examinations were repeated: an echocardiogram showed that the width of the left coronary artery ostium was 0.18 cm, with a Z-score of − 2.406, whilst the width of the right coronary artery ostium was 0.20 cm, with a Z-score of − 0.472. Immunoglobulins: IgG: 14.51 g/L, IgA: 0.06 g/L, IgM: 1.58 g/L. Liver function: ALT 52 U/L. Cardiac enzymes: AST 51 U/L. Complete blood count: WBC 13.63 × 10⁹/L; NEUT% 47.20%; LYMPH% 41.00%; HGB 100 g/L; PLT 570 × 10⁹/L; CRP 31.71 mg/L. The patient was discharged. A follow-up echocardiogram 16 days after discharge showed: the left coronary artery orifice measured 0.28 cm in width with a Z-score of 0.68; the right coronary artery orifice measured 0.27 cm in width with a Z-score of 1.636 (Fig. 2c, d). A follow-up echocardiogram 44 days after discharge showed: the main truncus of the left coronary artery was 0.16 cm wide with a Z-score of -3.023, and the main truncus of the right coronary artery was 0.21 cm wide with a Z-score of -0.171 (Fig. 2e); immunoglobulins: IgG: 11.68 g/L, IgA: 0.03 g/L, IgM: 1.37 g/L. However, the child experienced no discomfort after being discharged from hospital. The clinical course is shown in Fig. 3.

Fig. 1.

Clinical manifestations in a child with Kawasaki disease complicated by selective IgA deficiency. a Strawberry tongue. b Swelling, induration and redness of the hands, with rashes visible on the upper limbs. c Swelling, induration and redness of the feet, with rashes visible on the lower limbs

Fig. 2.

Imaging images of the coronary arteries in a child with Kawasaki disease complicated by selective IgA deficiency. a The ostium of the left coronary artery is 0.20 cm wide. b The ostium of the right coronary artery is 0.20 cm wide. c The ostium of the left coronary artery is 0.28 cm wide. d The ostium of the right coronary artery is 0.27 cm wide. e The main trunk of the right coronary artery is 0.21 cm wide

Fig. 3.

This diagram illustrates only the main clinical manifestations of the paediatric patient and her treatment plan. Following treatment with immunoglobulin and aspirin, the patient’s clinical condition improved. Laboratory tests showed little change in white blood cell (WBC) counts, a marked decrease in C-reactive protein (CRP), and platelet (PLT) counts

Discussion

KD, also known as cutaneous-mucosal-lymph node syndrome, is an acute, self-limiting vasculitic condition. Based on clinical symptoms and laboratory findings, KD can be classified into two types: complete Kawasaki disease (CKD) and incomplete Kawasaki disease (IKD). The diagnostic criteria for CKD include fever and the presence of at least four of the following five major clinical features: (1) non-exudative bilateral ocular conjunctival hyperaemia; (2) changes to the lips and oral mucosa, namely dry, red, chapped and congested lips, strawberry tongue, and diffuse congestion of the oropharyngeal mucosa; (3) acute non-suppurative cervical lymphadenopathy (usually > 1.5 cm in diameter); (4) polymorphic rash, including erythema and oedema around the BCG scar; (5) changes in the extremities, namely erythema of the palms and soles and indurated oedema of the hands and feet during the acute phase, and membranous desquamation around the fingernails and toenails during the convalescent phase, with or without coronary artery involvement [3]. Some studies suggest that KD is associated with SIgAD [4]. SIgAD is the most common type of primary immunodeficiency disorder. The diagnostic criteria are as follows: male or female patients aged 4 years or older with serum IgA levels below 7 mg/dL (0.07 g/L), but with normal serum IgG and IgM levels, and in whom other causes of hypogammaglobulinaemia have been ruled out [5]. Based on the relevant clinical symptoms and laboratory tests, this child can be diagnosed with CKD complicated by SIgAD.

Initially, Cunningham-Rundles et al. suggested that the serum of patients with SIgAD might contain anti-IgA non-specific antibodies, which are associated with severe anaphylactoid reactions following transfusion of blood products [6]. Subsequently, IgG and IgE antibodies directed against IgA were found to be implicated in the pathogenesis of IgA-mediated allergic reactions. Cindy J et al. found that patients with serum IgA deficiency had IgG autoantibodies directed against IgA. It is surmised that following the administration of intravenous IgG preparations containing IgA, immune complexes formed, which, by activating the complement pathway, led to complement-mediated anaphylactic shock. A W Burks et al. proposed that IgE antibodies against IgA are the cause of allergic reactions in patients [7, 8]. However, other reports have not supported a link between these antibodies and severe reactions [9]. Consequently, the role of IgG or IgE anti-IgA antibodies in anaphylactic shock among patients with IgA deficiency receiving immunoglobulin therapy remains a matter of debate. It has been reported that anaphylactic shock can still occur in patients with IgA deficiency in whom no circulating antibodies of this type or other immunoglobulins have been detected [10].

Nevertheless, virtually all Immunoglobulin preparations carry a warning advising caution when administering to IgA-deficient patients or even listing this condition as a contraindication for product administration [11]. S. Gerald Sandler et al. have suggested that, in the United States, manufacturers of immunoglobulins and other plasma derivatives have propagated largely unfounded precautionary statements in package inserts warning against use in IgA-deficient patients with a history of hypersensitivity. The ongoing cost of testing patients with adverse reactions to plasma-derived IgA and/or anti-IgA is significant. The observation that patients have fewer clinical reactions when infused with products containing lower concentrations of IgA is not evidence that IgA is the causative agent. There was a case of a patient found to have IgA deficiency and low IgG levels who received numerous IVIG infusions over many years without any reaction, despite not having been tested for anti-IgA. The manufacturing process is not limited to the removal of IgA. The process not only purifies IgG but also reduces the concentration of other plasma proteins that may also cause adverse reactions. Therefore, the presence of anti-IgA is neither a necessary nor a sufficient condition for causing an anaphylactic reaction [12].

In this case, following multidisciplinary consultation, it was agreed that the child should receive IVIG. The specific reasons for this decision are as follows: ①Case reports of anaphylactic shock occurring in patients with IgA deficiency following immunoglobulin therapy are extremely rare; this does not support the widespread excessive concern within the medical community regarding the use of blood products, including IVIG, in patients with IgA deficiency [13]. IgG therapy should never be withheld from patients with IgA deficiency solely on the basis of theoretical concerns regarding rare, serious adverse reactions. When patients require high-dose IVIG for anti-inflammatory purposes, the use of preparations with a low IgA content should be considered [11]. At the onset of the illness, the child presented with elevated CRP and transaminase levels, as well as dilated coronary artery orifices, suggesting a high likelihood of early coronary artery aneurysms (CAA), macrophage activation syndrome, or KD shock syndrome. The primary objectives of treatment during the acute phase of KD are to suppress the inflammatory response, neutralise antibodies and toxins, and minimise the risk of CAA. IVIG is currently the most effective treatment for reducing the risk of CAA in children with KD. Glucocorticoids (GC) should only be used in children with KD who do not respond to IVIG, or in those with KD who have persistently elevated inflammatory markers and concomitant CAA or peripheral vascular haemangioma; furthermore, repeated IVIG therapy and combination treatment with GC may significantly increase the risk of thrombosis within the CAA [3]. ②It has been reported that IgA plasma cells infiltrate the coronary arteries of children with KD because, when antigens enter the body via the respiratory tract, bronchus-associated lymphoid tissue mounts an IgA-dominant immune response, forming immune complexes that are then carried via the bloodstream to various parts of the body [14]. Therefore, the role of IgA antibodies in KD inflammation is very important [2]. Shingadia et al. observed a reduction in circulating IgA-expressing B lymphocytes in acute KD. They hypothesised that, as part of the KD-specific IgA response, B lymphocytes selectively migrate from the peripheral blood to target sites—primarily the arterial walls—where they ultimately differentiate into antibody-secreting plasma cells [15]. ③Qianli Zhuang and colleagues found that IVIG treatment exerts a negative regulation on serum total IgE and specific IgE. This confirms that IVIG can inhibit Ig production both in vivo and in vitro. This inhibitory effect involves all Ig subtypes and is mediated primarily via the F(ab´)₂ and Fc fragments, with the F(ab´)₂ fragment playing a more significant role [16]. S. Klaesson et al. similarly demonstrated that IVIG exerts a significant inhibitory effect on IgG- and IgM-producing B cells in vitro. IgG is the major component of immunoglobulin; the F(ab´)₂ fragment exhibits the same inhibitory effect as intact IgG, whereas the Fc fragment does not exhibit this effect [17]. ④Research indicates that the actual incidence of anti-IgA-mediated transfusion reactions caused by anti-IgA antibodies is as low as 1.3 cases per million units of blood or blood products transfused. Furthermore, in the supply of blood products for individuals with IgA deficiency, 0.5 mg/L should be the maximum permissible IgA concentration to ensure that individuals with anti-IgA antibodies do not experience adverse reactions [18]. In addition, reducing the infusion rate, desensitisation with subcutaneous immunoglobulin, or pretreating blood products with the child’s own plasma can all reduce the likelihood of an allergic reaction [19].

Therefore, the author believes that the low IgA levels in this patient’s peripheral blood may be due to the situation that the majority of B lymphocytes capable of differentiating and expressing IgA are involved in the IgA-dominant immune response associated with KD and are abnormally transported to the coronary artery wall. This is not simply a case of low IgA levels in a child with SIgAD due to the presence of anti-IgA antibodies in the body. However, as this conjecture has yet to be sufficiently substantiated by substantial experimental data or the literature, the possibility that other pathological mechanisms may be responsible for the development of this comorbidity cannot be ruled out. In addition, immunoglobulin preparations can suppress autoantibodies; this may be due to their inhibition of events associated with B-cell proliferation and the progression of the B-cell cycle [20]. It is also possible that anti-idiotypic antibodies present in the formulation may form complexes with autoreactive antibodies. Subsequently, these complexes may cross-link via immunoglobulins on the surface of B cells, thereby inducing an immunological non-response [21]. Furthermore, the child was administered intravenous human immunoglobulin manufactured by Shandong Taibang Biological Products Co., Ltd., China, in which the IgG content is not less than 95% of the total protein content. It is also possible that the rate of IgG antibody production against IgA in the patient’s body is slow, such that it forms complexes with the low dose of exogenous IgA in the preparation at an extremely low rate, allowing these complexes to be cleared from the circulatory system. Consequently, sufficient concentrations of IgG-IgA immune complexes cannot be formed, and no reaction can be triggered in the recipient [11, 21]. The Academic Committee of the Japanese Society of Paediatric Cardiology has pointed out that immunoglobulin should be administered with caution in patients with IgA deficiency [22]; therefore, during IVIG treatment, we have reduced the infusion rate (2 ml/kg/h).Following treatment, the child’s coronary artery dilation and clinical symptoms both improved, and no severe allergic reactions were observed during the course of treatment. It is worth noting that, as IgA antibodies were not tested for in this case, it is not possible to determine whether IVIG treatment would trigger an allergic reaction in patients with IgA antibodies. Furthermore, echocardiograms performed at the time of discharge and during follow-up after discharge showed Z-scores greater than 2 in both instances, suggesting that the coronary artery lesions had not yet completely resolved. For paediatric patients without CAA, low-dose ASA is discontinued eight weeks after the onset of KD [3], indicating that the recovery process from KD requires at least eight weeks. Moreover, both follow-up IgA test results were below the normal range. Given that the paediatric patient still exhibited coronary artery lesions, it is speculated that the IgA-dominant immune response associated with KD, as well as the abnormal transportation mechanism of B-lymphocytes capable of differentiating and expressing IgA, may still be present at this stage.

Conclusions

In this case, following a multidisciplinary discussion to assess the risk-benefit ratio, IVIG with a low IgA concentration was selected for the child, and the infusion rate was slowed down. This ultimately yielded good clinical results without any serious allergic reactions. This result does not imply that existing international safety contraindications should be completely disregarded; rather, it confirms that, provided the risks associated with the condition are fully assessed and reasonable measures are taken, there is no absolute contraindication to IVIG treatment for children with KD complicated by SIgAD. Consequently, this crucial therapeutic approach should not be blindly avoided due to the presence of SIgAD. Furthermore, this case conjectures that the pathological mechanism for KD combined with SIgAD may involve abnormal migration of B lymphocytes capable of differentiating and expressing IgA, driven by IgA-mediated immune responses, thereby providing a clinical rationale for future investigations into the association between these two conditions. However, as this study is a single-case report with a limited sample size, the relevant conclusions require further validation through multicentre, large-scale clinical trials. It is hoped that future in-depth research into the link between KD and SIgAD will lead to the development of targeted treatment regimens, thereby providing more precise medical care for these particular paediatric patients.

Abbreviations

KD

Kawasaki disease

SIgAD

Selective IgA Deficiency

IVIG

Intravenous immunoglobulin

WBC

White blood cell count

NEUT%

Neutrophil percentage

HGB

Haemoglobin

CRP

C-reactive protein

IgG

Immunoglobulin G

IgA

Immunoglobulin A

IgM

Immunoglobulin M

LYMPH%

Lymphocyte percentage

PLT

Platelet count

CAA

Coronary artery aneurysms

GC

Glucocorticoids

Authors’ contributions

All the authors contributed to the conception and writing of the manuscript. All the authors critically reviewed the manuscript and approved the final version.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The informed consent forms were signed by the guardians of the patients involved.

Competing interests

The authors declare no competing interests.