key: cord-1038626-fj4sdqg8
authors: Yoshimura, Yukihiro; Sasaki, Hiroaki; Miyata, Nobuyuki; Miyazaki, Kazuhito; Okudela, Koji; Tateishi, Yoko; Hayashi, Hiroyuki; Kawana-Tachikawa, Ai; Iwashita, Hiromichi; Maeda, Kazuho; Ihama, Yoko; Hatayama, Yasuyoshi; Ryo, Akihide; Tachikawa, Natsuo
title: An autopsy case of COVID-19-like acute respiratory distress syndrome after mRNA-1273 SARS-CoV-2 vaccination.
date: 2022-04-30
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2022.04.057
sha: fb7d0445097c15f9e00fa01931ec59475954852f
doc_id: 1038626
cord_uid: fj4sdqg8

We report the first case with COVID-19-like acute respiratory distress syndrome following mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. An 88-year-old woman developed dyspnea several hours after vaccination with the second dose of mRNA-1273. She was hospitalized on day 9 due to worsening dyspnea. Chest computed tomography showed bilateral ground-glass opacities and consolidations, mainly in the peripheral lung areas. Repeat polymerase chain reaction tests for SARS-CoV-2 were negative though serum level of antibodies against spike protein was elevated extremely. Her condition did not improve with high-dose corticosteroids and high-flow nasal cannula oxygen therapy; she died on day 18. Autopsy findings revealed very early-phase diffuse alveolar damage in the whole lung without other lung diseases. The clinical and pathological findings suggested vaccine-induced acute respiratory distress syndrome. Serological and pathological tests might be useful to differentiate the disease from COVID-19.

The messenger RNA (mRNA)-based vaccines BNT162b2 and mRNA-1273 were developed against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); their efficacy and safety have been reported (Baden et 

An 88-year-old Japanese woman received the first dose of the mRNA-1273 vaccine and experienced cold, dyspnea, fatigue, headache, cough, and abnormal sense of taste one to two weeks after vaccination; however, symptoms resolved spontaneously. She suffered from dyspnea, fatigue, and loss of sense of smell and taste several hours after the second dose of mRNA-1273 vaccination (day 0), which was administered 28 days after the first dose. These symptoms persisted, and dyspnea worsened on day 9, resulting in hospital admission. Her medical history revealed intake of the following maintenance medications for the past year: amlodipine, pravastatin, montelukast, dihydrocodeine, DL-methylephedrine, chlorpheniramine, zolpidem, and mecobalamin for hypertension, dyslipidemia, asthma, peripheral neuropathy, and insomnia, respectively. She had a history of a hysterectomy for uterine fibroids and no history of SARS-CoV-2 polymerase chain reaction (PCR) and rapid antigen testing with nasopharyngeal swabs were negative. We administered pulse steroid therapy (methylprednisolone, 500 mg/day on days 9-11), heparin (10,000 U/day), and ceftriaxone (2 g/day; Supplementary Figure 2 ). Hypoxia progressed without proportional signs of respiratory distress, and high-flow nasal cannula (HFNC) oxygen therapy was initiated on day 12; her oxygen levels did not improve. On day 14, we increased the methylprednisolone dose from 80 mg/day to 500 mg/day. She suffered from dyspnea and did not wish for tracheal intubation; therefore, we initiated sedation with morphine on day 15. The patient died from respiratory failure on day 18. Her sputum culture revealed normal flora, serologic markers for Mycoplasma pneumoniae and Chlamydophila pneumoniae were negative, a Legionella urinary antigen test was negative, and sputum and pharyngeal swab multiplex PCR was negative with the Autopsy was performed 88 hours postmortem because she died on a holiday and her body was placed in a cool room for 3 days. Both lungs were edematous and heavy. The cut surfaces felt solid and firm and appeared partially glittering, gray-white, brownish-red in color, with partially viscous exudate ( Figure 1A) . Histologically, the gray-white firm areas were in the proliferative stage of diffuse alveolar damage with pneumocytes, macrophages, and myofibroblastic cell proliferation ( Figure 1B) . The brownish-red areas were in the exudative stage with the presence of hyaline membranes ( Figure 1C ). The lesions were entirely immunohistochemically negative for both the SARS-CoV-2 spike ( Figure 1D ) and N protein ( Figure 1E ). An enzyme-linked immunosorbent assay and western blot for the S protein of the lung lysate also showed negative results (data not shown). PCR confirmed that SARS-CoV-2 was not present in the lung and other organs, including the heart, liver, spleen, and kidney. We did not find any significant pathological changes, such as thrombosis and myocarditis, in any of the organs examined (Supplementary Table 2 ).

To the best of our knowledge, this is the first report of an autopsy case of ARDS after mRNA-1273 vaccination. Her clinical presentation and pathological findings were similar to those of COVID-19; however, SARS-CoV-2 was not detected in the specimens, respiratory or otherwise. We tested SARS-CoV-2 PCR with nasopharyngeal swabs on day 9 and 12 and with bronchial fluid and lung specimens after death, all of which were negative.

Assessing the likelihood of a causal association between the events and the vaccine is This suggests that her body mounted a tremendous humoral immune response after vaccination. On the other hand, S protein was not detected in her lungs with various assays, and immune complex deposition of S protein and anti-S antibodies in the lung was less likely to occur. Another unlikely mechanism is that the S protein, that was locally translated from mRNA in the vaccine, traveled to the lung and induced inflammation. In this case, S protein synthesized around the local injection site might have provoked hyperinflammation in the lungs simply through a systemic immune response. The last and third hypothesis is that an occult lung disease became overt after being triggered by the vaccination. However, this is unlikely because whole lung pathological findings revealed no other diseases, such as idiopathic pulmonary fibrosis.

And her comorbidities and regular medicines, which had not been changed for a year, were unlikely to cause the ARDS.

In conclusion, mRNA-1273 vaccines induced ARDS confirmed by clinical and pathological findings. We should understand that COVID-19 vaccination is an important tool in stopping the pandemic and rarely causes severe pulmonary adverse events.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Written informed consent for publication was obtained from her family. We complied with the policy of the journal on ethical consent.

Citizen's Hospital, to which Yukihiro Yoshimura, Hiroaki Sasaki, Nobuyuki Miyata, Kazuhito Miyazaki and Natsuo Tachikawa belong, have received research funding from the three companies, Gilead Sciences, Inc., Eli Lilly Japan K.K, and Ono Pharmaceutical Co., Ltd. in the last two years that may have an interest in the submitted work.

☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☒The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Department of Infectious Disease and Respiratory Medicine of Yokohama Municipal Citizen's Hospital, to which Yukihiro Yoshimura, Hiroaki Sasaki, Nobuyuki Miyata, Kazuhito Miyazaki and Natsuo Tachikawa belong, have received research funding from the three companies

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Prime Minister's Office of Japan, Novel Coronavirus Vaccines

ARDS Definition Task Force

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In the brownish-red areas, hyaline membranes on the alveolar septa were found (C). The lesions were entirely immunohistochemically negative for both SARS-CoV-2 spike (D) and nucleocapsid protein (E)

We wish to acknowledge Dr. Shuzo Usuku, Department of Testing and Research, Yokohama City Institute of Public Health, for his help in performing multiplex PCR.