Anti-Melanoma Differentiation-Associated Protein-5 and Anti-Polymyositis/Scl-75 Antibody-Associated Interstitial Lung Disease Triggered by COVID-19 Vaccine: A Case Report

Interstitial lung disease (ILD) encompasses a broad category of lung pathologies with many different etiologies. Connective tissue diseases, such as dermatomyositis and systemic sclerosis, are a major contributor to ILD that can change the prognosis and management of the disease (1). The anti-melanoma differentiation-associated protein-5 (MDA-5) antibody is associated with a rapid development of ILD and a poor prognosis (2). The anti-polymyositis (PM)/Scl-75 antibody is a rare antibody that classically presents with “mechanic's hands” (cracked palmar fingertips) and lung fibrosis, and it is associated with severe ILD with a worse prognosis (3, 4). With the global pandemic caused by the SARS-CoV-2, the BNT162b2 mRNA vaccine for COVID-19 was developed with a 95% efficacy rate and a reduction in disease severity and mortality (5). During the phase II/III clinical trial, the BNT162b2 mRNA vaccine showed favorable safety profile (5). There were no cases of ILD after vaccine administration in clinical trials. Since its approval and worldwide use, there have been multiple case studies of ILD development within 2 weeks after receiving the BNT162b2 mRNA vaccine, including 4 cases with positive anti-MDA-5 antibody (6, 7).

Here, we report a case of rapidly progressive ILD with positive anti-MDA-5 and anti-PM/Scl-75 antibodies after the patient received the BNT162b2 mRNA vaccine.

A 61-year-old Hispanic woman presented to the clinic with dyspnea, dry cough, myalgias, and pleuritic chest pain 14 days after receiving her second dose of the BNT162b2 mRNA vaccine. Her symptoms began the same day she received her second dose of the vaccine. Her medical history was remarkable for well-controlled asthma with rare use of an albuterol inhaler, ulcerative colitis in remission after total colectomy with rectal mucosectomy and J-pouch ileoanal anastomosis with loop ileostomy, right breast invasive ductal carcinoma status-post bilateral mastectomy, and migraines, which were being treated with subcutaneous fremanezumab. She did not have a history of smoking.

On evaluation, her pulse oximetry remained stable at 95%. Polymerase chain reaction tests of nasopharyngeal swab samples for SARS-CoV-2 and influenza virus were negative. Initial computed tomography of the chest with contrast revealed patchy areas of atelectasis, mild subpleural fibrosis anteriorly with some apical scarring, and left lung ground-glass opacities (Figure 1A). She was initiated on azithromycin, methylprednisolone tapered dosage, inhaled fluticasone, and treated empirically for lower respiratory tract infection. The patient was referred for initial pulmonology consultation, and pulmonary function tests revealed restrictive pattern with reduced diffusion capacity for carbon monoxide (Dlco) (FEV₁/FVC = 86%, FEV₁ = 65%, FVC = 62%, total lung capacity = 68%, Dlco 63%). She was provided another course of methylprednisolone tapered dosage and encouraged to use inhaled steroids.

Despite the aforementioned treatment, the patient was admitted to outside hospital for worsening dyspnea. Repeat computed tomography of the chest revealed new bilateral patchy pulmonary infiltrate with ground-glass opacities (Figure 1B). Bronchoscopy with bronchoalveolar lavage was negative for malignant cells, bacterial culture, acid-fast bacillus smear, and fungal culture. Initial autoantibody work-up was negative (Table 1). She had video-assisted thoracoscopy surgery for wedge resection of the right upper, middle, and lower lobe as well as parietal pleura. Pathology showed nonspecific interstitial pneumonia with some fibrotic zones and patchy organizing pneumonia (Figure 2). The patient was discharged home on oxygen 2 liters/min via nasal cannula and oral prednisone, 30 mg daily, with outpatient pulmonology and rheumatology follow-up.

During the initial outpatient rheumatology evaluation, she admitted having a history of periungual erythema and episodic joint pain with swelling. On physical examination, she had abnormal nail fold capillaroscopy and erythematous rash on the lateral aspect of middle and index fingers (Figure 3). There were no signs of inflammatory arthritis at time of evaluation. Laboratory results revealed low-titer elevation of anti-MDA5 antibody and anti-PM/Scl-75 antibody (Table 1). Other pertinent markers included elevated erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, aldolase, but negative antinuclear antibodies (Table 1). Biopsy of the rash on the fingers was consistent with pernio. She was started on prednisone, 1 mg/kg, and azathioprine, 75 mg oral daily, for anti-MDA-5 and anti-PM/Scl-75–associated amyopathic dermatomyositis with ILD.

Despite being on prednisone, 1 mg/kg, for 1 week, her respiratory status continued to decline. She was readmitted to an outside hospital and started on intravenous methylprednisolone, 1000 mg, for 3 days and subsequently 60 mg every 6 hours, intravenous rituximab, 375 mg/m² every week, and intravenous immunoglobulin, 2 g/kg. Unfortunately, the patient continued to decline despite aggressive treatment, and died due to worsening respiratory failure.

We present a patient who developed rapidly progressive ILD with nonspecific interstitial pneumonia pattern on lung biopsy and positive antibodies for anti-MDA-5 and anti-PM/Scl-75 after the administration of second dose of BNT162b2 mRNA vaccine. Based on the temporal relationship of receiving the vaccine and the onset of symptoms, we consider this a case of rapidly progressive ILD triggered by BNT162b2 mRNA vaccine.

The anti-MDA-5-antibody presents with distinct cutaneous ulcerations of the digits, cracked palmar fingertips (“mechanic's hands”), little-to-no muscle involvement, and is strongly associated with rapidly progressive ILD (2). Retrospective cohort studies found low survival rates and poor response to immunosuppressive therapy for the presence of positive anti-MDA-5 antibody in rapidly patients with progressive ILD (2).

Anti-PM/Scl-75 antibodies are found in patients with polymyositis, dermatomyositis, or systemic sclerosis, with the greatest occurrence in overlap syndromes (4). Most common reported clinical manifestations are ILD, mechanic's hands, swallowing difficulty, muscle weakness, and Raynaud syndrome (4, 8). Large retrospective studies found both anti-MDA-5 and anti-PM/Scl-75 antibodies have high specificity for developing rapidly progressive ILD (4, 8).

Our patient did not have digital ulcerations but did have findings similar to mechanic's hands and significant lung involvement. Interestingly, she tested positive for both anti-PM/Scl-75 and anti-MDA-5 without any previous history of connective tissue disease. This suggests that the patient may have had an underlying predisposition for an immune reaction that was triggered by the vaccine, resulting in rapidly progressive ILD. Another possibility includes a subclinical ILD that went unrecognized and was exacerbated with vaccination. Although baseline spirometry 4 years previously showed FEV₁ postbronchodilator response >15%, we did not have access to total lung volumes or Dlco with this baseline spirometry report to confirm a concurrent underlying restrictive process.

Less commonly, inflammatory bowel diseases (IBDs) such as ulcerative colitis have extraintestinal pulmonary manifestations (9). IBD-related lung disease tends to affect large and small airways more than the parenchyma, leading to bronchiectasis and chronic bronchitis (9). Although rare, there have been cases of parenchymal involvement leading to ILD (10). These cases are often related to drug-induced ILD from IBD medications, such as sulfasalazine, mesalamine, methotrexate, and anti-tumor necrosis factor monoclonal antibodies (9). Pulmonary manifestations remain rare among extraintestinal symptoms of IBD and if related to IBD, usually present in patients with active disease (9). Given that her ulcerative colitis had been inactive for years, her pulmonary manifestations were less likely to be due to IBD.

Our patient's findings were similar to previously reported cases. The biggest difference was that most patients recovered after treatment with a combination of steroids, intravenous immunoglobulin, and rituximab. The unique features of this case include 2 positive markers with strong association for rapidly progressive ILD, which ultimately led to the patient's demise despite the similar treatment protocol. Establishing an accurate diagnosis of ILD can be challenging, and it is important to recognize its strong association with autoimmune diseases to involve rheumatology early in the course of the disease. We consider that BNT162b2 mRNA vaccine may have induced hyperactivation of immune system leading to her clinical presentation.