Vaccines for coronavirus disease (COVID-19), which is caused by an infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been developed and used worldwide. Vaccines developed by Pfizer–BioNTech and Moderna (December 2020) and Janssen/Johnson & Johnson’s (February 2021) received emergency approval from the US Food and Drug Administration (FDA). The vaccines effectively prevented infection from the virus and decreased the severity of the viral infection. There have also been some common side effects reported, including injection site tenderness, fever, fatigue, muscle pain, and headache [1]. Little is known about the long-term effects, and rare cases showing relevance between SARS-CoV-2 vaccination and the occurrence of autoimmune diseases have been reported [2-5].

Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune disease affecting the lungs and kidneys. It accounts for 1% to 5% of all glomerulonephritis and approximately 0.5 to 1.8 cases per million Asian–European populations annually [6]. It is known that autoantibodies against antigens present in type 4 collagenous chains of alveolar and glomerular basement membranes appear and are activated by some triggering causes, such as metal dust, organic solvents or hydrocarbons, smoking, upper respiratory tract infection, and hereditary predisposition [6].

Here, we report a case diagnosed with anti-GBM disease following the Pfizer–BioNTech mRNA SARS-CoV-2 vaccination.

A 48-year-old woman without any underlying disease or medication history visited for hemoptysis that lasted seven days after her first dose of Pfizer–BioNTech mRNA SARS-CoV-2 vaccination. Her blood pressure was 135/74 mmHg, respiratory rate was 18 per minute, pulse rate was 99 per minute, and body temperature was 36.9°C at the time of her visit. The breath sound was slightly reduced, and the heart sound was regular without murmur. There were no other specific findings on physical examination.

The blood tests showed hemoglobin 7.6 g/dL, hematocrit 25.9%, leukocytes 8,870/mm³, platelets 592,000/mm³, international standardized ratio of prothrombin time (PT INR) 1.14, and activated partial thromboplastin time (aPTT) 44.9 s. The serum biochemical tests showed blood urea nitrogen of 10.4 mg/dL, creatinine of 0.51 mg/dL, estimated glomerular filtration rate of 114.07 mL/min/1.73 m², protein of 7.2 g/dL, albumin of 3.6 g/dL, AST of 19 U/L, ALT of 3 U/L as within the normal range, and C-reactive protein of 12.4 mg/dL as elevated. Urinalysis showed a specific gravity of 1.029, pH of 6.0, protein++, glucose negative, ketone+, urobilinogen+, bilirubin negative, blood+++, nitrite negative, white blood cells++, and microscopic examination showed 10–19 white blood cells, several red blood cells, and few bacteria, per high magnification field of view. The 24-h quantified urine test exhibited 496.08 mg of protein. The immune antibody tests were performed for further evaluation, and the results were as follows: c-antineutrophil cytoplasmic antibody (c-ANCA) positive (>178.0 IU/mL), antinuclear antibody (ANA) negative, anticardiolipin antibody negative, and anti-GBM antibody positive (62 U/mL).

The simple chest radiograph showed an increased shadow around the right lung field (Fig. 1). Chest computed tomography showed peri-bronchial ground glass opacities and consolidation predominantly in the right lung (Fig. 2). Bronchoscopy showed diffuse hemorrhage in the right lung, and there was no endobronchial lesion observed (Fig. 3). The renal biopsy was performed, and it showed no histo-morphological changes in light and electron microscopy (Fig. 4A, C) with some focal cellular crescent formation in light microscopy (Fig. 4B). Linear pattern diffuse IgG staining along the glomerular basement membrane was observed in immunofluorescence staining (Fig. 4D).

Figure 1. Simple chest radiograph. An increased shadow around the right lung field.

Figure 2. Chest computed tomography. Peri-bronchial ground glass opacities and consolidation predominantly in the right lung.

Figure 3. Bronchoscopy. Diffuse hemorrhage in the right lung. No endobronchial lesion was observed. (A) View from the right main bronchus. (B) View after passing the right upper lobe orifice.

Figure 4. Renal biopsy. (A) No histo-morphological changes (Light microscopy, Periodic Acid-Schiff, ×200). (B) Focal (1/9) cellular crescent formation (Light microscopy, Masson Trichrome, ×200). (C) No histo-morphological changes (Electron microscopy, ×4,000). (D) Linear pattern diffuse IgG staining along the glomerular basement membrane (Immunofluorescence staining, ×200).

Plasmapheresis was performed with intravenous methylprednisolone 500 mg for three days, followed by oral prednisolone 70 mg and cyclophosphamide 150 mg. The patient showed improvement in hemoptysis and was discharged. The antibody tests 30 days after discharge showed anti-GBM antibody negative and c-ANCA positive (5 IU/mL), a lower titer than those at admission. She is on gradual reduction of oral prednisolone and regular outpatient follow-up without recurrence of symptoms.

It is well known that autoimmune reactions can occur in association with vaccines [7, 8]. According to Rodríguez et al.’s analysis of cases with autoimmune and autoinflammatory status after SARS-CoV-2 vaccination, women accounted for 53.6% (488/910), with a median age of 48 years (IQR: 34 to 66). The mean period from vaccination to symptom onset was eight days (IQR: 3 to 14) [9]. Immune thrombocytopenia, Guillain–Barre syndrome, and myocarditis were common in newly diagnosed cases after SARS-CoV-2 vaccination [9]. Immune thrombocytopenia, psoriasis, IgA nephro-pathy, and systemic lupus erythematosus were common in cases of exacerbation or recurrence of pre-existing diseases [9]. For vaccine types, mRNA-1273 SARS-CoV-2 was found to be widely associated in both cases [9].

Some of the aforementioned diseases can also be caused by infections or other vaccines [10-12]. This suggests that a similar immunopathogenic mechanism between vaccines and infectious substances may act as a triggering factor for autoimmune diseases. This hypothesis can also be supported by the anti-idiotype immune response of antibodies against a specific antigen, which can trigger the production of a second specific antibody against the first antigen, and the second antibody produced can attach to a receptor that can bind to the first antigen [13]. It is crucial because the vaccines identified in several reports on autoimmune or autoinflammatory responses associated with previous SARS-CoV-2 vaccines have this anti-idiotype immune response as their primary mechanism [14, 15].

In addition to molecular mimetic mechanisms, mRNA vaccines can trigger a series of immunological cascades that lead to abnormal immune system activation. The synthesis of RNA chains and the inherent immunogenicity of nucleic acids are used to encode the desired antigenic protein. In this process, it is encapsulated by nanoparticles or liposomes to avoid degradation by RNase and moves into target cells through endocytosis. The mRNA is then translated into immune proteins by ribosomes [16]. However, during this process, mRNA may also bind to pattern recognition receptors inside the endosome or cytosol. Toll-like receptor (TLR) 3, TLR7, and TLR8 can recognize double-stranded RNA or single-stranded RNA chains in endosomes. In contrast, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) can detect short and long filaments of double-stranded RNA inside the cytosol. Hence, a series of activations of various pro-inflammatory substances, including type I interferon response and nuclear translocation of NF-κB, occur [17].

This signal transduction pathway is extensively studied in various autoimmune diseases [18]. The very high type I interferon response may affect mRNA translation and vaccine efficacy [19]. Increased type I interferon effect may also cause a decrease in immune tolerance [19].

It is unclear whether the SARS-CoV-2 vaccines cause autoimmune diseases, and several drugs can cause anti-GBM disease [6]. Considering the global spread of COVID-19, close monitoring and further studies would be needed.

None declared.