key: cord-0813178-jzdflths authors: Amiya, Saori; Fujimoto, Jun; Matsumoto, Kinnosuke; Yamamoto, Makoto; Yamamoto, Yuji; Yoneda, Midori; Kuge, Tomoki; Miyake, Kotaro; Shiroyama, Takayuki; Hirata, Haruhiko; Takeda, Yoshito; Kumanogoh, Atsushi title: Case report: Acute exacerbation of interstitial pneumonia related to mRNA COVID-19 vaccination date: 2022-01-19 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2022.01.031 sha: 50ebcb44badf3e53d084782952b37841ad368220 doc_id: 813178 cord_uid: jzdflths mRNA vaccines that protect against coronavirus disease (COVID-19) are widely used in many countries due to their high efficacy and safety profiles. Recently, some severe adverse events, such as anaphylaxis and myocarditis, were reported in healthy individuals. The safety of mRNA COVID-19 vaccines has not been adequately studied in patients with interstitial lung disease. We report two cases of acute exacerbation of pre-existing interstitial pneumonia associated with mRNA COVID-19 vaccination. In both cases, lung disease was stable prior to the vaccination. Initial responses to steroid therapy were unfavorable, and intravenous cyclophosphamide was administered in both cases. Both patients were diagnosed with vaccine-related exacerbation of interstitial pneumonia, based on laboratory results, radiological features, and the observed clinical course, which lacked other causative events. We suggest that clinicians should note the possibility of acute exacerbation of pneumonia after mRNA COVID-19 vaccination, and carefully monitor patients with interstitial lung disease. Patients with respiratory comorbidities are at increased risk of severe coronavirus disease (Aveyard et al., 2021 , Drake et al., 2020 ; hence, these individuals are primary candidates for vaccination against the disease. In a phase 2/3 trial, which included 1,478 patients with chronic pulmonary disease, the short-term safety of the BNT162b2 mRNA vaccine was established (Polack et al., 2020) . Recently, some severe adverse events associated with vaccination, such as anaphylaxis (Shimabukuro et al., 2021) and myocarditis (Bozkurt et al., 2021 , Montgomery et al., 2021 , were reported in a healthy population. The rare occurrence of adverse events requires further investigation. Little is known about the safety of the mRNA COVID-19 vaccine in patients with interstitial lung disease. We report two cases of acute exacerbation of pre-existing interstitial pneumonia related to mRNA COVID-19 vaccination. An 83-year-old man with a 13-day history of high fever and dyspnea was referred to our hospital. He received his first dose of the BNT162b2 mRNA vaccine 1 day prior to the onset of these symptoms. Three days later, his family doctor prescribed levofloxacin, but his condition worsened. Two years prior to admission, the patient was diagnosed with idiopathic interstitial pneumonia. He had no respiratory symptoms, and his radiological findings were stable, prior to vaccination ( Figure A ). He was a previous smoker, and had a history of hypertension and atrial fibrillation that had remained unchanged and were treated with candesartan and edoxaban. He reported no new chemical exposure. On admission, the patient's body temperature was 37.5ºC and he was tachypneic, with 93% peripheral oxygen saturation in room air. Blood tests revealed elevated C-reactive protein (CRP) (24.5 mg/dL), ferritin (1,976 ng/mL), Krebs von den Lungen-6 (KL-6) (1,457 U/mL), and pulmonary surfactant protein-D (SP-D) (427 ng/mL) levels. White blood cell count was 9300/uL, and the differential count was neutrophils 87.6%, lymphocytes 5.0%, and eosinophils 2.6%. Procalcitonin was within normal levels (0.135 ng/mL). Serological tests for autoimmune markers were negative. Chest radiography and CT showed bilateral diffuse ground-glass opacities ( Figure B ). Sputum and blood cultures for bacteria, fungi, and mycobacteria were negative, and polymerase 5 chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using a pharyngeal swab, was negative. Because antibiotics failed to improve symptoms, the patient was considered unlikely to have an infection at that time. He was diagnosed with interstitial pneumonia exacerbation related to mRNA vaccination based on his clinical course, laboratory results, and radiological findings. Pulsed corticosteroid therapy was initiated, with little effect. Another pulsed corticosteroid dose was administered, along with intravenous cyclophosphamide (IVCY). The patient's respiratory distress eventually improved, and oxygen therapy was discontinued 4 weeks after IVCY administration. A 65-year-old man presented to the emergency room with low-grade fever and shortness of breath. He received a second BNT162b2 mRNA vaccine 14 days prior to admission, which resulted in a low-grade fever the next day. No systemic reaction was noted after his first vaccination. Six days after his second vaccination, the patient visited his family doctor due to prolonged low-grade fever and dyspnea. Levofloxacin was prescribed to treat abnormalities in his chest radiograph. SARS-CoV-2 PCR test using a pharyngeal swab was negative. However, the patient's symptoms continued to deteriorate. Two years prior to admission, the patient was diagnosed with acute exacerbation of interstitial pneumonia and was treated with oral prednisolone ( Figure C) . Steroid therapy was gradually 6 tapered and withdrawn a year prior to admission. Subsequently, no relapse was observed ( Figure D ). He was a previous smoker with a history of very-low-risk myelodysplastic syndrome. His hemoglobin level was relatively low but stable, and regular check-ups were performed. He reported receiving no new medications or chemical exposure. On admission, he was afebrile, but his peripheral oxygen saturation was 90% on 5 Lpm oxygen support. Chest radiography and CT revealed ground-glass opacities and traction bronchiectasis extending superior to both upper lobes ( Figure E) . Serum laboratory tests showed leukopenia (1,440 /μL), with a differential of 65.2% neutrophils, 18.8% lymphocytes, and 1.4% eosinophils; anemia that was more severe than typical for the patient (5.6 g/dL hemoglobin); and elevated CRP (6.18 mg/dL), ferritin (1178 ng/mL), KL-6 (984 U/mL), and SP-D (1610 ng/mL) levels. Serologic tests for autoimmune markers were negative. Another SARS-CoV-2 PCR test, and sputum and blood cultures for pathogens were negative. Therefore, an infectious disease was considered unlikely to be the cause of symptoms. The patient was diagnosed with interstitial pneumonia exacerbation related to mRNA vaccination, based on his clinical course, laboratory data, and radiological findings. Pulsed corticosteroid therapy was initiated, with no respiratory symptom improvement. Repeated pulsed corticosteroid and IVCY therapies were initiated, which resulted in gradual recovery of the patient in a month. To the best of our knowledge, this is the first report of acute exacerbation of pre-existing interstitial pneumonia after mRNA COVID-19 vaccination. In the United states, 108 cases of interstitial lung disease in association with COVID-19 vaccination have been identified (the Centers for Disease Control and Prevention and the Food and Drug Administration, 2021). However, detailed information is unavailable, and the presence or absence of pre-existing lung disease is unknown. Hibino et al. reported nine cases of interstitial pneumonia associated with the influenza vaccine (Hibino and Kondo, 2017) . In that report, two patients had pre-existing interstitial pneumonia, and all cases were resolved after corticosteroid administration. The mean interval between symptom onset and vaccination was 2 days, which was comparable to our cases. Park et al. reported a case of BNT162b2 mRNA vaccine-related interstitial lung disease without a history of pulmonary disease (Park et al., 2022) . The acute symptom onset after vaccination and chest CT findings in that case are similar to those in our cases. The patient was responsive to steroid therapy, as with influenza vaccine-related interstitial pneumonia, while our patients were not. This difference may be due to the different vaccines the patients received or because our patients had pre-existing interstitial pneumonia. We are unable to establish the reason for the difference because we reviewed only a few cases. The etiology of mRNA vaccine-related exacerbation of interstitial pneumonia remains unknown. We speculated that the immune system contributes to the exacerbation of interstitial pneumonia. Notably, in our case, we could treat the patients using strong immunosuppressive therapy, which confirms this idea. Recently, it was reported that an innate inflammatory response could be induced by the mRNA or by SARS-CoV-2 spike protein (Caso et al., 2020 , Lu et al., 2021 , Zhao et al., 2021 . It has also been reported that cross-reactivity of spike proteins with lung surfactants and related proteins may induce pulmonary inflammation (Kanduc and Shoenfeld, 2020) . To achieve safer COVID-19 vaccination in patients with interstitial lung disease, more studies are needed to determine the reason for the exacerbation of the disease's symptoms and to identify patients at risk of experiencing adverse events. In conclusion, we encountered two cases of acute interstitial pneumonia exacerbation related to COVID-19 mRNA vaccination. Interstitial lung disease is considered a risk factor for severe COVID-19 (Aveyard et al., 2021 , Drake et al., 2020 . The benefits of vaccination outweigh the risks associated with these rare adverse events. However, clinicians should note the possibility of acute exacerbation post-mRNA COVID-19 vaccination and carefully monitor patients with interstitial lung diseases post-vaccination. Authors declare no conflict of interests. Funding Source: No sources of funding were obtained for this study. interacts with and activates TLR41. Cell Res. 2021; 31:818-20. https://doi.org/10.1038/s41422-021-00495-9. Association between pre-existing respiratory disease and its treatment, and severe COVID-19: A population cohort study Myocarditis with COVID-19 mRNA Vaccines The vaccine adverse events reporting system established by the Centers for Disease Control and Prevention and the Food and Drug Administration Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study Interstitial Pneumonia Associated with the Influenza Vaccine: A Report of Two Cases On the molecular determinants of the SARS-CoV-2 attack SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2 Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military COVID-19 vaccine-related interstitial lung disease: A case study Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine Reports of Anaphylaxis After Receipt of mRNA COVID-19 Ethical Approval statement:Informed consent was obtained from the patients for publication of this case report and accompanying image.