Pulmonary Pathology of COVID-19 Following 8 Weeks to 4 Months of Severe Disease

A Report of Three Cases, Including One With Bilateral Lung Transplantation

Scott W. Aesif, MD, PhD; Alejandro C. Bribriesco, MD; Ruchi Yadav, MD; Summer L. Nugent, MD; Dmitriy Zubkus, MD; Carmela D. Tan, MD; Atul C. Mehta, MD; Sanjay Mukhopadhyay, MD

Disclosures

Am J Clin Pathol. 2021;155(4):506-514. 

In This Article

Cases

Case 1

A 46-year-old Black man with hypertension, obesity (body mass index, 36.9 kg/m2), and chronic lymphocytic leukemia (2 years in remission) sought treatment for moderate respiratory symptoms. Reverse transcriptase (RT)–PCR for SARS-CoV-2 by nasopharyngeal swab was positive (day 1). After initial management as an outpatient, he presented on day 10 with worsening dyspnea. Chest imaging showed bilateral multifocal peripheral consolidation. He was lymphopenic (total leukocyte count 3,700/μL, 13.7% lymphocytes) with elevated C-reactive protein (CRP, 19.5 mg/dL), ferritin (853.5 ng/mL), lactate dehydrogenase (401 IU/L), D-dimer (2,919 ng/mL), and fibrinogen (761 mg/dL). Despite treatment with remdesivir, convalescent plasma, and tocilizumab, he deteriorated and was intubated on day 18. Refractory hypoxia persisted despite neuromuscular blockade, airway-pressure release ventilation, and prone positioning. Given persistent hypoxemia, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was started on day 21. His lungs showed worsening diffuse airspace disease and were poorly compliant on lung-protective mechanical ventilation settings. Bilateral lower extremity deep vein thromboses were treated with anticoagulation. Nasal and oropharyngeal bleeding was managed with packing. Repeat SARS-CoV-2 testing was positive on day 23. A spontaneous right pneumothorax (day 24) required chest tube placement. Right hemothorax (day 29) required chest tube placement followed by video-assisted thoracoscopic surgery on day 31 with hemothorax evacuation. The right lung surface was gelatinous and flaccid despite intraoperative ventilation. He continued to require frequent blood transfusions for persistent bleeding from the right chest. A lung parenchymal-pleural fistula (air leak) was observed, making recruitment of potentially salvageable lung impossible. Chest computed tomography (CT) on day 35 Image 1A showed extensive airspace consolidation in the right lung, mixed airspace and ground-glass opacities in the left lung, and a loculated right hemopneumothorax. On day 38, exploratory thoracotomy showed liquefying necrosis of the right middle lobe with retained clots in the visceral pleura. Debridement of the necrotic right middle lobe was performed with suture closure of visible small airways and right middle lobe pexy with application of BioGlue (CryoLife) to mitigate loss of ventilation from bronchopleural fistulas. A spontaneous left pneumothorax occurred subsequently, requiring chest tube insertion. The next 2 weeks saw no clinical improvement, complete dependence on V-V ECMO, and persistent bilateral air leaks. Repeat SARS-CoV-2 testing was negative on day 44. He then developed renal insufficiency requiring dialysis, as well as elevated liver enzymes and shock requiring vasopressor support. Without a realistic chance of meaningful recovery, he was transitioned to comfort care and died on day 57.

Image 1.

Case 1, late complications of coronavirus disease 2019. A, Chest computed tomography coronal reformatted image (day 35) shows extensive airspace consolidation in the right lung, especially the right middle lobe. Scattered mixed airspace and ground-glass opacities are present in the left lung with a few thin-walled cysts/cavitary lesions suggesting superinfection. B, C, The surgically debrided lung tissue is completely necrotic, with "ghosts" of hyaline membranes visible within the necrotic lung (H&E, ×10 and ×20, respectively). D, Grocott methenamine silver stain showing numerous Candida organisms within the necrotic lung (×40).

Histologic examination of the debrided right middle lung lobe confirmed extensive infarct-like necrosis of the lung. Within the necrotic lung, "ghosts" of alveolar septa lined by hyaline membranes remained appreciable Image 1B and Image 1C. A few blood vessels (mainly small arteries) within the necrotic areas contained thrombi. Grocott methenamine silver staining highlighted extensive colonization of necrotic lung by budding yeast with pseudohyphae Image 1D. Culture of the lung tissue confirmed Candida albicans. Subsequent autopsy showed findings identical to the original lung specimen. While largely obscured by the extensive infarction-related necrosis, overall the pattern of lung injury was compatible with diffuse alveolar damage in the acute stage. No significant fibrosis was observed.

Case 2

A 57-year-old obese Hispanic woman with distant myocardial infarction presented with 3 days of dyspnea, cough, hypoxia, and fever (101.4°F). RT-PCR for SARS-CoV-2 by nasopharyngeal swab was positive (day 1). CRP was 169 mg/dL, creatinine was 0.76 mg/dL, and total leukocyte count was 8,000/μL. Chest x-ray showed bilateral airspace opacities. On day 4, she was started on hydroxychloroquine. Mechanical ventilation was started on day 6. At this time, she developed septic shock attributed to a urinary tract infection (Proteus spp). Over the next 4 days, she was paralyzed and proned. Convalescent plasma was administered on day 10. Despite these measures, her respiratory status continued to worsen. On day 12, she was transferred to a regional ECMO center, arriving prone on 100% fraction of inspired oxygen and positive end-expiratory pressure of 14 cm H2O. Supine O2 saturation was 80% with a Murray score of 3.8. Chest x-ray showed extensive bilateral airspace opacities. Percutaneous V-V ECMO was initiated upon arrival. Oxygen saturation improved to 98% with 4.5 L/min of flow. A course of remdesivir was started. On day 18, a second dose of convalescent plasma was administered and cytokine filter treatment performed. Enterococcus faecalis septic shock on day 20 necessitated change of ECMO circuit, including cannulas. Spontaneous bilateral hemothoraces occurred subsequently, requiring chest tube drainage on day 25. Repeat SARS-CoV-2 testing on day 38 was negative. Her respiratory status, inflammatory markers, and radiographic picture never improved. Chest CT (day 40) showed marked bilateral consolidation and moderate bilateral pleural effusions. Repeat CT on day 59 showed findings suspicious for evolving fibrotic lung disease with superimposed diffuse consolidation Image 2A. On day 74 (after 63 days of ECMO), surgical lung biopsy was performed. Shortly thereafter, the patient experienced acute deterioration in respiratory status. The goals of care were switched to comfort, and she died on day 74.

Image 2.

Case 2, late complications of coronavirus disease 2019. A, Axial chest computed tomography on day 59 showing diffusely consolidated lungs with air bronchograms as well as dilated bronchi with undulating contours suggesting traction bronchiectasis likely related to underlying fibrosis. A few small peripheral cystic changes are also noted, possibly representing early honeycombing. Right hydropneumothorax (arrow) and left pleural effusion (arrowheads) are also seen. B, Diffuse, uniform interstitial expansion with associated pneumocyte hyperplasia (H&E, ×10). C, Focal microscopic honeycomb change (H&E, ×4). D, Movat pentachrome stain (×40).

Histologic sections of the surgical lung biopsy specimen showed diffuse, somewhat mild, and relatively uniform interstitial expansion Image 2B, a pattern vaguely reminiscent of nonspecific interstitial pneumonia (NSIP). Focal microscopic honeycomb change was also present Image 2C. Foci of superimposed organizing acute lung injury, patchy interstitial lymphocytic infiltrates, and mild chronic pleuritis with fibrinous exudates were also present. The superimposed organizing acute lung injury appeared compatible with organizing DAD; however, Movat pentachrome stains demonstrated the majority of the interstitial fibrosis to be more mature collagen-type Image 2D. Definitive hyaline membranes, Masson bodies, or fibroblastic foci were not appreciated. No capillaritis/vasculitis or thromboembolic changes were observed.

Case 3

A 57-year-old man with coronary artery disease and hypertension was diagnosed by nasopharyngeal swab elsewhere with COVID-19 and subsequently developed progressively worsening hypoxic respiratory failure due to ARDS despite treatment with plaquenil, azithromycin, solumedrol, tocilizumab, and an interleukin 1 receptor blocker (anakinra). He required mechanical ventilation on day 14. His hospital course was complicated by atrial fibrillation with rapid ventricular response and high D-dimer. He was initially placed on apixaban and then switched to tissue plasminogen activator to prevent thromboembolism. Despite use of inhaled nitric oxide and proning, his oxygenation did not improve. Tracheostomy was performed on day 13 of mechanical ventilation. His course was further complicated by bacteremia (Escherichia coli and methicillin-sensitive Staphylococcus aureus). On day 54, he was placed on V-V ECMO due to worsening pulmonary parameters. Subsequent complications included pneumomediastinum, pneumothorax, and lower gastrointestinal bleed. Chest CT on day 59 revealed diffuse bilateral consolidation, a large right pneumothorax in the setting of a pleural drain, and findings suggesting bronchopleural fistula Image 3A. Following multiple negative RT-PCR tests for SARS-CoV-2, he was transferred to our institution for consideration of lung transplantation (day 74). Chest x-ray at admission revealed low lung volumes with diffuse mixed bilateral interstitial and airspace opacities, a small right pneumothorax, and bilateral pleural effusions. He underwent thorough pretransplant evaluation, including bronchoalveolar lavage, to exclude persistent viral infection. Chest radiograph on day 122 demonstrated low lung volumes with complete opacification of both hemithoraces. On day 126, he underwent bilateral sequential lung transplantation. Two and a half months following lung transplantation (day 202, approximately 7 months after his initial diagnosis), he remains hospitalized, requiring mechanical ventilation in the intensive care unit.

Image 3.

Case, 3, late complications of coronavirus disease 2019. A, Chest computed tomography coronal reformatted image (day 75) shows homogeneous diffuse bilateral consolidation with volume loss, traction bronchiectasis, and a few peripheral cystic changes likely representing early honeycombing (arrows). The findings are suggestive of an acute process superimposed on underlying fibrotic lung disease. A large right pneumothorax is seen despite the presence of a pleural drainage catheter. A few of the subpleural cystic changes communicate with the pleura, suggesting a bronchopleural fistula. B, Diffuse, uniform, and somewhat cellular interstitial expansion (H&E, ×10). C, Focal peribronchiolar metaplasia (H&E, ×10). D, Filling of the airspaces by pigmented and foamy macrophages (H&E, ×40). E, Iron (Prussian blue) stain (×10). F, Movat pentachrome stain (×10).

Histopathologic examination of the explanted lungs revealed mild diffuse interstitial chronic inflammation with diffuse, relatively uniform-appearing interstitial expansion Image 3B. This pattern again vaguely resembled NSIP. Peribronchiolar metaplasia was also present but not extensive Image 3C. This was accompanied by numerous hemosiderin-laden and foamy macrophages within the airspaces Image 3D and Image 3E. Foci of microscopic honeycomb change were also present (not shown). There was no evidence of acute lung injury or capillaritis/vasculitis. A single small vessel demonstrated some intimal fibroplasia, but no definitive evidence of a thromboembolic event was seen. Fibroblast foci were not observed, and a Movat pentachrome stain revealed most of the interstitial expansion to be composed of collagen-type fibrosis.

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