An Autopsy Case of Post-COVID-19 Interstitial Lung Disease with Acute Exacerbation

Abstract

The prognosis of patients with post-coronavirus disease 2019 (COVID-19) interstitial lung disease remains unclear. We herein report an autopsy case in which serial progression after the onset of post-COVID-19 interstitial lung disease resulted in an acute exacerbation, leading to a fatal outcome. Autopsy findings included hyaline membrane formation/interstitial inflammatory cell infiltration, suggestive of acute lesions, and severe regional fibrosis, indicating a preexisting chronic condition. In the present case, we histopathologically confirmed the acute exacerbation of post-COVID-19 interstitial lung disease.

Introduction

Coronavirus disease 2019 (COVID-19) was first reported in China in December 2019. As of June 2023, the COVID-19 pandemic is still ongoing. Virus mutations, diagnostic methods/drug development, and spontaneous infection- or vaccine-related immunity acquired by many individuals have decreased the number of patients with severe status and mortality (1).

However, many patients have corona sequelae (2). Post-COVID-19 interstitial lung disease markedly reduces the quality of life; however, its effects on the morbidity rate, treatment, and prognosis of patients have yet to be clarified (3,4).

We herein report an autopsy case in which serial progression after the onset of post-COVID-19 interstitial lung disease resulted in acute exacerbation, leading to a fatal outcome.

Case Report

The patient was a 62-year-old man with hypertension and type II diabetes mellitus. The patient had a smoking history of 60 cigarettes per day for 20 years, and his body mass index (BMI) was 27.1 kg/m². The patient had never been vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since this case occurred before the vaccination program started in Japan. Malaise and a fever developed seven days previously, and he presented to our hospital with dyspnea. The patient was hypoxemic, and chest computed tomography (CT) showed peripheral predominant ground-glass opacities (Fig. 1A). Loop-mediated isothermal amplification testing with a nasopharyngeal swab led to the diagnosis of COVID-19; thus, the patient was admitted for treatment.

Figure 1.

(A) Chest computed tomography at the time of the diagnosis. There was no emphysema, and peripheral ground-glass opacity was observed predominantly in both lungs. (B) Four days after the diagnosis. Extended ground-glass opacity and an increase in the density were noted. (C) Day 210. (D) Day 469. (E) Day 644. Images D and E revealed the progression of pulmonary fibrosis. Traction bronchiectasis and peripheral predominant cysts were noted in the right upper lobe. (F) At the time of acute exacerbation (705 days after the diagnosis). Diffuse ground-glass opacity, consolidation, and pleural effusion were observed.

Remdesivir and dexamethasone were administered for COVID-19, and endotracheal intubation and respiratory care were performed for respiratory failure (Fig. 1B). As respiratory failure related to severe inflammation was protracted, long-term steroid therapy and respiratory care were required. After 62 days, the patient was successfully weaned off mechanical ventilation; however, oxygen therapy was required thereafter. Furthermore, bacteremia with Streptococcus and Candida albicans and cerebral infarction occurred during management with mechanical ventilation; thus, antibiotic and anticoagulant therapies were administered. The patient was discharged 203 days after the diagnosis (Fig. 1C). Although long-term oxygen therapy/rehabilitation for chronic respiratory failure and steroid therapy for protracted inflammation were continued, the patient's dyspnea persisted. Chest radiography and CT revealed progression of pulmonary fibrosis (Fig. 1D, E).

The patient was diagnosed with post-COVID-19 interstitial lung disease based on the lack of abnormalities on annual chest X-ray screening before COVID-19 infection and no emphysema or fibrosis on chest CT at the time of the COVID-19 diagnosis. Furthermore, hematology did not suggest any underlying diseases that caused interstitial pneumonia, such as collagen disease or vasculitis. Chest CT showed progression of fibrosis after the onset of COVID-19. The initiation of antifibrotic therapy was considered for interstitial lung disease with progressive fibrosis; however, it was avoided because of anorexia, weight loss (a 25-kg decrease in body weight from that on admission), and a low BMI (18.7 kg/m²).

The patient was readmitted to our hospital with severe dyspnea and hypoxemia 705 days after the initial diagnosis. Chest CT revealed ground-glass opacity, consolidation, and pleural effusion (Fig. 1F). The FilmArray Respiratory Panel test, which is a rapid multiplexed molecular assay approved for the detection of viral and atypical bacterial pathogens in nasopharyngeal specimens, was negative. Blood and sputum culture test results were also negative. Under a diagnosis of acute exacerbation of interstitial pneumonia, empirical broad-spectrum antibiotics, steroid pulse therapy, and non-invasive positive pressure ventilation were administered; however, the patient died of respiratory failure after seven days.

A systemic autopsy, excluding the head, was conducted 12 h after death (713 days after the initial diagnosis). The lung weight increased (left, 602 g; right, 694 g). A marked reduction in pneumatization was observed, and honeycomb-lung-like cyst formation was detected below the pleura (Fig. 2). Histologically, severe regional fibrosis of the bilateral lungs, disappearance of alveolar structures, and a decrease in air space were noted. These findings were consistent with the fibrotic stage of diffuse alveolar damage (DAD). Even in the area where the lung structures were maintained, hyaline membrane formation, macrophages/exfoliated alveolar epithelium in the alveolar cavity, and interstitial infiltration of inflammatory cells, primarily lymphocytes, were observed, which was consistent with the findings of acute exacerbation. Destruction of the peribronchiolar vascular wall structure was also noted, suggesting angiitis involvement (Fig. 3). There were no abnormalities in organs other than the lungs, particularly the heart and blood vessels. Although the autopsy specimens were not cultured, there were no obvious findings of infection. The direct cause of death was respiratory failure related to acute exacerbation of interstitial pneumonia.

Figure 2.

Macroscopic findings of the cross sections of the lungs. (A) Left lung, (B) right lung. Cysts and congestion were observed.

Figure 3.

Microscopic findings. (A, B) Severe regional fibrosis, the disappearance of alveolar structures, and a decrease in air spaces. (C) Severe interstitial fibrosis. (D) The rupture of elastic fibers (black), the disappearance of alveolar structures, and the outgrowth of collagen fibers (light green). (E) Pulmonary congestion and edema. (F) Hyaline membrane formation (arrows). (G) An exfoliated alveolar epithelium in the alveolar cavity (arrows), and the interstitial infiltration of inflammatory cells, primarily lymphocytes. Hematoxylin and Eosin staining (A, C, E-G), Elastica van Gieson stain (B), and Elastica-Masson stain (D). Scale bars: 10 mm (A, B), 200 μm (C-E, G), and 100 μm (F).

A clinicopathological conference concluded that the patient had developed interstitial pneumonia after COVID-19, which had been exacerbated by the progression of fibrosis.

Discussion

The acute exacerbation of post-COVID-19 interstitial lung disease and histopathological findings in the autopsy of hyaline membrane formation/interstitial inflammatory cell infiltration, suggestive of acute lesions, and severe regional fibrosis, indicating a preexisting chronic condition, were confirmed in the present case.

We initially considered the possibility of the acute exacerbation of post-COVID-19 interstitial lung disease. The prognosis of patients with post-COVID-19 interstitial lung disease currently remains unclear. Lorent et al. reported non-progressive fibrous changes on CT at 12 months after discharge in 10% of patients with COVID-19 (5). According to Han et al., the complete disappearance or improvement of non-fibrous interstitial pneumonia was achieved in most patients, whereas fibrous interstitial pneumonia persisted after 1 year (no change in 77%, slight improvement in 23%) (6). Acute exacerbation of post-COVID-19 interstitial lung disease has not yet been reviewed. We therefore will discuss the risk factors for acute exacerbation in the present case with reference to acute exacerbation of idiopathic pulmonary fibrosis.

Risk factors for acute exacerbation of this disease include infections, microaspiration of gastric contents, surgery and thoracic procedures, advanced lung disease, pulmonary hypertension, a high BMI, coronary artery disease, and immunosuppressive therapy (7). In the present case, progression of post-COVID-19 interstitial lung disease was observed, but the cause of acute exacerbation was idiopathic.

Regarding the histopathology of the lungs in the present case, severe fibrosis was observed as a background factor, which was consistent with the fibrotic-stage DAD. According to previous studies (8,9), the pulmonary pathology of COVID-19 is characterized by DAD as a pathological finding of acute respiratory distress syndrome (ARDS), which has been detected in the majority of patients who died, and fibrosis ≥3 weeks after the disease onset. Roden et al. (10) examined lung tissue ≥28 days after the onset of COVID-19 and reported fibrotic changes and thrombosis in 75% and 27% of the patients, respectively. The present case did not have primary lung disease; therefore, severe COVID-19 may have induced ARDS, increasing the severity of fibrotic-stage DAD. In addition to severe regional fibrosis, the disappearance of lung structures was observed in some areas but was maintained in others, which was in contrast to the common type of interstitial pneumonia. Nakajima et al. (11) reported that fibrosis was patchy, with areas of DAD at different stages alternating with nearly normal lung parenchyma because SARS-CoV-2 invaded/infected the lungs via the respiratory tract, inducing inflammation. A similar pathogenesis was suggested in the present case. Hyaline membrane formation and interstitial infiltration of inflammatory cells were observed in areas where lung structures were maintained, which was consistent with exudative-stage DAD. This is in accordance with the acute exacerbation of interstitial pneumonia 705 days after the diagnosis.

Acute exacerbation of post-COVID-19 interstitial lung disease, as demonstrated in the present case, has not yet been histologically verified; therefore, the present results provide useful information. Furthermore, Hashimoto et al. (12) indicated that COVID-19 induces severe conditions by destroying the vascular endothelial barrier. The destruction of the peribronchiolar vascular wall structure in the present case supports this finding.

Difficulties are associated with the treatment of progressive post-COVID-19 interstitial lung disease, as demonstrated in the present case, which may represent the most important approach for preventing the onset of post-COVID-19 interstitial lung disease or the severe status of COVID-19. Vaccination needs to be promoted and inflammation attenuated in the acute stage using antiviral/neutralizing antibody therapeutics, adrenocorticosteroids, and interleukin-6 inhibitors. This management strategy will contribute to the prevention of barotrauma associated with long-term respiratory care. Furthermore, clinical trials are being conducted to investigate whether or not antifibrotic therapy inhibits the progression of fibrosis in patients with post-COVID-19 interstitial lung disease (13-16), and the results obtained will provide novel insights. Although antifibrotic therapy delays the progression of fibrosis, it is not curative. Therefore, prevention of fibrosis may be an important approach.

Conclusion

In the present case, we histopathologically confirmed the acute exacerbation of post-COVID-19 interstitial lung disease.

Consent to publish details of the case was obtained from the patient's family.

The authors state that they have no Conflict of Interest (COI).