Rapid Progression of Acute Interstitial Pneumonia in a Patient with Low MDA-5 Antibody Titer

Introduction

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders distinguished by muscle inflammation and involvement of various extra-muscular organ systems. In IIMs, lung involvement is frequently identified, mainly in the form of interstitial lung disease (ILD), with a rate ranging from 17% to 36%. The frequency and clinical manifestations of lung involvement varies depending on the autoantibodies. For examples, anti-Jo1 and anti-PL7, the autoantibodies known to frequently accompany lung involvement, occur in 66% and 84% of IIMs, respectively [1].

Melanoma differentiation associated gene-5 antibody (MDA-5 Ab) is also an autoantibody that frequently accompanies lung involvement and is identified in approximately 10% of IIMs in adults. Unlike in other antibody-positive cases, MDA-5 Ab muscle involvement is seen only in less than 20% of cases and shows aspects of amyopathic IIMs. This antibody also shows lung involvement in adult myositis, and lung involvement in this case is more common in Asian populations (60% in Europeans and 90% in Asians) [1–4].

The manifestation of lung involvement in MDA-5 Ab is also different from that seen with other autoantibodies. The predominant chest computed tomography (CT) finding is organizing pneumonia, followed by nonspecific interstitial pneumonia. About half of cases show rapid-progress ILD, which progresses to interstitial pneumonia within several weeks to months [4]. Empirically, MDA-5 Ab-positive interstitial pneumonia is treated like other connective tissue disease ILDs. However, to date, there are not sufficient evidences for additional management and treatment in MDA-5 Ab-positive rapid-progress ILD, and the mortality rate related to ILD is high.

Here, we report a 55 year-old female patient who presented with interstitial pneumonia of unknown etiology. A relatively low titer of MDA-5 antibody was confirmed during empirical antibiotic and immunosuppressive treatment, and this patient had a good prognosis, with full recovery without sequelae.

Case Report

A 55-year-old female patient with a past history of diabetes mellitus, hypothyroidism after left thyroidectomy due to diagnosis of suspicious thyroid nodule, and post-menopausal osteopenia visited our Emergency Department (ED) for a sputum-producing cough that started a week prior and dyspnea that started the previous day. The patient’s initial vital signs showed tachycardia and low oxygen saturation in room air. Initial measurements were blood pressure, 110/70 mmHg (mean arterial pressure: 83 mmHg); body temperature, 37.2°C; respiratory rate, 21 breaths/min; heart rate, 106 beats/min; and oxygen saturation in room air, 93%. There were no specific findings in the nervous system, skin, muscle, or joints. Initial chest radiography revealed bilateral diffuse haziness, predominantly in the lower lung field. In laboratory findings, leukocytes were elevated, at 14.3×103/μL, with neutrophil dominance of 84.5%, and C-reactive protein level was elevated, at 364.56 mg/L (Table 1). Chest CT revealed multifocal ground-glass opacities (GGOs) and consolidations in both lungs, mainly in the lower lobes (Figures 1, 2).

Based on findings in the ED, it was thought to be pneumonia, and the patient was admitted to a general ward because her oxygen requirement was not high. However, on day 1 of hospitalization, pneumonia progressed rapidly, and the PaO2/ FiO2 ratio worsened to under 150 mmHg, such that a high-flow nasal cannula was needed. Shock was also confirmed. Vital signs were blood pressure, 90/55 mmHg (mean arterial pressure: 67 mmHg); body temperature, 38.2°C; respiratory rate, 28 breaths/min; and heart rate, 110 beats/min.

Suspecting acute respiratory distress syndrome (ARDS) with severe pneumonia, we transferred her to the Intensive Care Unit (ICU) and initiated antibiotics (ceftriaxone and levofloxacin) and systemic steroid therapy (initial dose: methylprednisolone 1 mg/kg). We performed bronchoscopy, and there were no specific endoscopic lesions. Because of hypoxemia, bronchial alveolar lavage could not be performed, and only bronchial washing was performed to obtain a specimen. Therefore, an appropriate sample capable of analyzing the white blood cell differential count could be obtained. In the specimen obtained through bronchial washing, the Gram stain and culture was negative; however, Streptococcus pneumoniae, Haemophilus influenzae, and parainfluenza viruses were detected using multiplex PCR.

In a multidisciplinary discussion with the Radiology Department, it was considered necessary to perform a workup for causes other than infection because of the initial chest CT finding of lower lobe dominant GGOs and consolidations with traction bronchiectasis in both basal lobes. Therefore, we conducted an additional workup, including serology.

After 10 days of ICU treatment, the oxygen supply was reduced to a PaO2/FiO2 ratio above 300, and we transferred the patient to the general ward. During treatment with steroids and antibiotics, MDA-5 (14 SI) and Mi-2a (24 SI) antibodies were detected (Table 2). We performed follow-up chest CT to confirm the changes in progress. Compared with the initial chest CT, there were increased GGOs in both upper lobes. In the bilateral lower lobes, there were decreased GGOs and consolidations; however, there was new multifocal fibrosis and air trapping (Figure 3).

We stopped using antibiotics but continued steroid treatment while the patient was in the general ward, owing to high suspicious of interstitial pneumonia with autoimmune features and radiological findings suggestive of acute interstitial pneumonia. We gradually reduced the steroid dose to prednisolone 12.5 mg. At the time of discharge, her oxygen requirement and other vital signs were normal: blood pressure, 130/80 mmHg (mean arterial pressure: 97 mmHg); body temperature, 36.8°C; respiratory rate, 18 breaths/min; heart rate, 85 beats/min; and oxygen saturation in room air, 98%. She was discharged with administration of oral steroids. In 3 months of outpatient follow-up, she continued steroid therapy, while we carefully observed symptoms and radiologic findings. She showed no new skin, muscle, and joint involvement; therefore, we did not add treatment other than steroids, in consultation with the Rheumatology Department. On chest X-ray after 2 months of steroid therapy, the diffuse haziness was markedly decreased, and on chest CTs, bilateral diffuse GGOs and consolidations were decreased (Figure 4). At the 6-month follow-up, respiratory symptoms also recovered almost fully, and chest CT showed a more recovered status, with improvement of previous air trapping (Figure 5).

Discussion

We reported interstitial pneumonia with ARDS, with a low MDA-5 titer. In this case, the patient had no noticeable findings other than respiratory symptoms. Therefore, we did not consider autoimmune antibodies, including IIMs, as a cause of ARDS from the beginning. In addition to the MDA-5 Ab-positive finding, S. pneumoniae, H. influenzae, and parainfluenza virus were detected through PCR by bronchoscopic washing. However, since the radiologic findings of this case were not inconsistent with those of infection and the culture was negative, we considered infection as the trigger factor of ILD rather than main infectious cause, as in previous reports [5,6].

MDA-5 Ab is known to have a lower prevalence of muscle involvement, compared with other myositis autoantibodies [7]. Similar to our case, there are reports of patients progressing to ARDS, with insufficient evidence of myositis. In the case of previous reports, myositis could not be suspected at first, because the patients did not show any extra pulmonary symptoms other than joint pain [8,9]. Even in our report, there were no signs of suspected myositis other than respiratory symptoms. Therefore, in pneumonia with rapid exacerbation of hypoxia of unknown cause, anti-MDA5 should be considered.

The current therapy is an empirical immunosuppressive agent consisting of corticosteroids, calcineurin inhibitors, and cyclophosphamide in MDA-5 Ab-positive ILD [10]. Fortunately, our patient had a good response of interstitial pneumonia with only corticosteroid treatment, and no respiratory sequelae were observed. A previous study reported that a low positive titer of the MDA-5 antibody indicated a good prognosis in patients with MDA-5 Ab-positive ILD, and the suggested cutoff value was 100 SI [11,12]. In our case, the titer of MDA-5 Ab was as low as 14 SI, which may be related to the treatment response. Therefore, not only the presence of antibodies but also the confirmation of the titer of antibodies are thought to be important in lung disease.

Conclusions

In ARDS, in which radiologic imaging shows interstitial damage of unclear cause, the presence of MDA-5 antibodies should be considered. In addition, as the prognosis can vary depending on the titer of MDA-5, it is necessary to check the antibody titer if atypical pulmonary invasion with rapid progressive hypoxemia is identified. Furthermore, observation of the interstitial lung damage by follow-up MDA-5 antibody testing will be necessary.