To the Editor

There is growing evidence that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with the development of autoimmunity diseases, including systemic vasculitis. Multisystem inflammatory syndrome in children (MIS-C) is the most frequent manifestations of childhood vasculitis after coronavirus disease 2019 (COVID-19) [1], while COVID-19-associated pediatric vasculitis with pulmonary involvement only being discussed in a few case reports [2]. Although, the pathogenesis of systemic vasculitis after COVID-19 infection is not fully understood, it is believed that the interplay of genetic and environmental factors likely to contribute. Interestingly, we found that inborn errors of immunity (IEI) may be the underlying cause of these conditions. Furthermore, the disease course, treatment outcome of pulmonary vasculitis following COVID-19 infections in children have not been fully described. Hence, 3 case studies are presented here to enable a better understanding of this complication.

Patient 1

A 6.4-year-old girl was transferred from a local hospital due to the presence of a cough with hemoptysis. She had a non-productive cough for 1 month, and 4 days prior presentation she developed blood-streaked sputum and hemoptysis. Chest CT imaging showed multiple ground-glass opacities and consolidated images distributed along the bronchovascular bundle (Fig. 1A). Medical history included allergic rhinitis and insect bite dermatitis. On examination, her breathing was steady, and scattered reddish rashes were detected on both of her lower limbs.

Fig. 1
figure 1

Chest CT images of the three pulmonary vasculitis after COVID-19 infection. (A) Chest CT of patient 1 showed multiple ground-glass opacities and consolidated images distributed along the bronchovascular bundle (Fig. 1A). (B) Chest CT of patient 2 showed subpleural nodular consolidation with cavitation and adjacent ground-glass opacification. (C, D) Chest CT of patient 3 revealed bilateral peripheral consolidations with “hole signs”; marked vascular wall thickening, luminal narrowing and multiple filling defects of bilateral pulmonary artery branches

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The patient’s white blood cell (WBC) count and C-reactive protein (CRP) levels were normal. Hemoglobin levels showed evidence of mild anemia (9.5 g/dL). Urine analysis revealed the presence of occult blood and microalbuminuria. The urine microscopic examination shown RBC was 1–2 /HP. The D-dimer level was normal (0.11 mg/L). Autoantibody tests revealed positive ANA (1:20) and p-ANCA (38.7RU/ml). A large number of hemosiderin-laden alveolar macrophages were observed in her bronchoalveolar lavage fluid (BALF), which indicated an alveolar hemorrhage and the possibility of pulmonary vasculitis. BALF cultures for bacteria, fungi, and mycobacteria were negative. A skin biopsy of a lower limb was taken, but typical inflammatory and vasculitic changes were not observed. SARS-CoV-2 testing was performed due to the high prevalence of SARS-CoV-2 infections at the time. Nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2 was positive.

The patient received intravenous methylprednisolone therapy (2 mg/kg/day) and intravenous immunoglobulin, which resulted in favorable improvement of her general condition and disease control. Subsequently, oral prednisone was weaned to maintenance doses. One week after discharge the whole exome sequencing revealed a heterozygous missense mutation (c. 1540T > C, p.Y514H) in the NOD2 gene (ACMG: Likely pathogenic, GnomAD-All-0.00004, PM1 + PM2 + PP3 + PP5), which is associated with Yao syndrome (YAOS). Currently, she has been receiving treatment for 10 months (currently, prednisone 5 mg/day maintenance therapy), and remains clinically and radiologically stable.

Patient 2

A 8.3-year-old girl referred to our department due to a persistent cough, chest distress for 18 days, and wheezing for 7 days. Simultaneously, the patient’s mother and grandmother presented with upper respiratory symptoms and positive SARS-CoV-2 antigen tests. She has a medical history of asthma, allergic rhinitis, and recurrent eczema. She did not receive a COVID-19 vaccine in the past year. On physical exam, mild wheezes were detected upon chest examination and reddish rashes were observed on her right ankle and acrotarsium. Chest CT imaging showed subpleural nodular consolidation with cavitation and adjacent ground-glass opacification (Fig. 1B). Hence, SARS-CoV-2 infection and pulmonary vasculitis were considered. Routine blood and urine tests were clinically normal. Repeated nasopharyngeal swabs for PCR testing of SARS-CoV-2 were negative, however, antibody testing was positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies. BALF cultures for bacteria, fungi, and mycobacteria were negative. The levels of serum immunoglobulin were in normal ranges. The D-dimer level was normal (0.05 mg/L). Clinical workup for autoimmune disorders were all negative. Further skin biopsies were taken, which showed thickening of vascular walls with infiltration of lymphocytes, neutrophils, histocytes, nuclear dust, and scattered extravascular red blood cells, which demonstrated small vasculitis (Supplementary Fig. 1A), the diagnose of pulmonary vasculitis arose.

She received intravenous methylprednisolone (1 mg/kg/d) therapy, followed by oral prednisone, which were effective for symptom relief and the gradual resolution of pulmonary lesions. One month after discharge the whole exome sequencing revealed a heterozygous splicing mutation (c.61 + 1G > A) in the TNFRSF13B gene (ACMG: Pathogenic, GnomAD-All-None, PVS1 + PM2), which is associated with common variable immunodeficiency (CVID). The patient received corticosteroids for a total of 6 months. Currently, treatment has been discontinued for 9 months without evidence of recurrence.

Patient 3

A 14.3-year-old girl with complaints of intermittent fatigue, cough, chest distress, and chest pain. Two months prior, she had a COVID-19 infection (positive SARS-CoV-2 PCR test) which manifested as a mild upper respiratory infection. Approximately 2 weeks after recovering from COVID-19, she developed fatigue, chest distress, and a non-productive cough. A chest CT at that time showed minor evidence of infiltrates. The patient was treated for 7 days at local hospitals (unknown administered medication), and the symptoms of cough and chest distress resolved. Twenty days prior to this presentation, she experienced fatigue, cough, and chest distress once again, in addition to chest pain. She had a history of atopic dermatitis. On examination, reddish maculopapular rashes with ulcerations and scabs were detected on her face and limbs. The patient’s routine blood and urine analysis were normal. Chest CT imaging revealed bilateral peripheral consolidations with “hole signs”, as well as marked vascular wall thickening, luminal narrowing and multiple filling defects of bilateral pulmonary artery branches, suggesting multiple pulmonary embolisms and vasculitis (Fig. 1C and D). Two consecutive nasopharyngeal swab PCR and antigen tests for SARS-CoV-2 were negative. The D-dimer level was normal (0.27 mg/L). Autoantibody tests revealed positive lupus anticoagulant, while ANA, ds-DNA and ANCA were negative. The patient underwent a skin biopsy which showed evidence of vasculitic changes: thickening and denaturation of vascular walls with infiltration of lymphocytes, eosinophils, and neutrophils, as well as small vessel occlusions (Supplementary Fig. 1B). She did not have whole exome sequencing performed. The patient received oral prednisone (initial dose of 1 mg/kg/day) combined with anticoagulant therapy, which were effective in inducing remission. Currently, she is being treated for 9 months with prednisone (now 5 mg/day maintenance dose) and remains clinically and radiologically stable.

Here, we presented 3 cases of pulmonary vasculitis following COVID-19 infection in pediatric patients. All patients had a confirmed history of SARS-CoV-2 exposure. The diagnosis of pulmonary vasculitis depends mainly on the integration of clinical manifestations, chest imaging features, and histopathological confirmation of vasculitis. Based on the alveolar hemorrhage, renal involvement, and positive P-ANCA the diagnosis of pulmonary vasculitis was made in patient 1. Patient 2 and patient 3 exhibited subpleural nodular consolidation with cavitation and adjacent ground-glass opacification on chest CT, especially the changes of vascular wall thickening and luminal narrowing, as well as the skin biopsy results of the two patients demonstrated evidence of small vasculitis, supporting the diagnosis of pulmonary vasculitis in the two patients.

The pulmonary manifestations of these 3 patients were mainly alveolar hemorrhage, ground-glass nodular infiltrations and pulmonary embolisms respectively, that consist with the typical manifestations of pulmonary vasculitis. Although hypercoagulable state and thrombosis are part of the clinical spectrum of acute COVID-19 infections, it is mainly seen in severe cases. The multiple pulmonary embolisms that occurred in patient 3 considered to be secondary to the vasculitis, due to the observed marked vascular wall thickening and luminal narrowing, and history of mild COVID-19 infection two months ago prior to the onset of symptoms.

Patient 1 was found to have a likely pathogenic heterozygous mutation (c. 1540T > C, p.Y514H) in the NOD2 gene, this mutation was previously described in a patient with Yao syndrome [3]. Although patient 1 did not exhibit characteristic manifestations of YAO syndrome, infections and/or interferon release have been described as possible triggers for the onset of NOD2-associated autoinflammatory disease (AID) [4]. Hence, the pulmonary vasculitis seen in patient 1 is likely to be a manifestation of an underling NOD2-associated AID triggered by a COVID-19 infection. Patient 2 had a history of asthma, allergic rhinitis, and recurrent eczema. Here, a pathogenic heterozygous splicing mutation (c.61 + 1G > A) in the TNFRSF13B gene was identified, which has been implicated in the CVID phenotype [5]. Interestingly, a very similar splice site variant in TNFRSF13B (c.61 + 1G > T, GnomAD-All-None) was detected in a CVID patient [6]. Although the serum immunoglobulin levels of patient 2 were in normal ranges, indeed the clinical and immunological phenotypes of CVID may be poorly defined in childhood that with gradual progression as the patients age, until full presentation in adulthood leads to diagnosis [7]. Overall, our findings suggest that SARS–CoV-2 may trigger systemic vasculitis in genetically predisposed patients.

In all 3 patients, systemic corticosteroids were administered as the single immunosuppressant, which resulted in clinical remission and marked radiographic improvements. Further follow-up is needed to elucidate the long-term prognosis especially in the context of the underling IEI condition.

In conclusion, SARS-CoV-2 infections may be a trigger for the development of pulmonary vasculitis. The coexistence of an underling IEI should be investigated in children, which is important not only in the etiology diagnosis but also to guide therapeutic interventions. In general, the short-term outcomes of pediatric cases of pediatric pulmonary vasculitis after SARS-CoV-2 infection described here were favorable. The limitation of this study was lack of lung biopsy supporting the pathological diagnosis of vasculitis. Further studies are needed to validate and expand on our findings.