A 62-year-old man presented with acute dyspnea at rest, requiring high-flow oxygen therapy with a fraction of inspired oxygen of 80% in February 2021. A nasopharyngeal SARS-CoV-2 PCR was negative; however, the patient reported contracting a mild case of COVID-19 in December 2020, which was treated in an outpatient setting. Known comorbidities included hypertension, hyperlipidemia, and diabetes mellitus type II with a negative history of smoking and lung disease. A chest CT scan performed at admission revealed bilateral, diffuse ground-glass opacities, bronchiectasis and subpleural reticular changes consistent with pulmonary fibrosis predominantly in the middle and lower lobes (Fig. 1a, b).
Treatment with high-dose glucocorticoids was initiated, starting with 10 mg/day dexamethasone for 21 days with a switch to oral 25 mg/day prednisolone and 1,500 mg/day mycophenolate mofetil. However, therapy remained ineffective, and lung function progressively worsened (forced expiratory volume of 1.23 L [42%], total lung capacity of 3.1 L [51%] 2 weeks after admission). Imaging demonstrated a rapid decline of his condition with an acute respiratory distress syndrome pattern, upon which the patient was intubated (Fig. 1c, d). The indication of lung transplantation was established in line with previously suggested selection criteria. As a bridge to transplantation, a venovenous extracorporeal membrane oxygenation was implanted a month after admission. A week later, bilateral lung transplantation was successfully conducted.
No major postoperative complications were reported. After undergoing an intensive rehabilitative program, the patient was discharged 2 months later with steadily improving forced expiratory volume values (2.9 L [92%] in June 2021).
The lung explant was examined on grossing and sent for further histological and molecular analysis. The lungs were heavy, firm, with brownish yellowish carnification of the parenchyma, and showed signs of diffuse calcification (Fig. 2), as evidenced by a video demonstration of the macroscopic examination (see online suppl. Materials; see www.karger.com/doi/10.1159/000525457 for all online suppl. material).
As a correlate to the calcification, histology revealed extensive, diffuse interstitial dendriform ossification, comprising of lamellar bone with fatty marrow with focal hematopoiesis (Fig. 3a). Diffuse interstitial fibrosis with bronchiolar, mucinous and transitional cell metaplasia of the alveolar epithelium (Fig. 3b); traction bronchiectasis; bronchiolar mucostasis; fibrinous pleuritic; and multifocal alveolar hemorrhages were evident throughout the parenchyma. Hemosiderin-laden macrophages were a frequent finding (online suppl. Fig. 1). A proliferation of interstitial and intra-alveolar bronchiogenic giant cells exhibiting partial positivity for thyroid transcription factor 1 was observed (not shown). There were various signs of pulmonary remodeling, as evidenced by an increase of interstitial collagen and a disarray of elastic fibers, proliferative diffuse alveolar damage (DAD) and an interstitial accumulation of M2-polarized CD163+ and CD206+ macrophages (Fig. 3c) with an increased expression of phospho-ERK (Fig. 3d) and increased neoangiogenesis (CD105+ vessels) (Fig. 3e). Fibrin staining revealed sparse intra-alveolar fibrinous exudates, corresponding to residual exudative DAD without microthrombi.
Interstitial lymphocytes were predominantly T cells (ratio of CD3+ T cells to CD20+ B cells is 2:1) with an exhausted phenotype (weak PD1 positivity). Cytotoxic T cells (CD8+) and T-helper 1 subsets (Tbet+ TH1) were more frequent than T-helper 2 subsets (GATA3+ TH2) (Fig. 3f, g). T-regulatory cells (FoxP3+ Treg) and gammadelta T cells (gammadelta+) comprised 2-3% of lymphocytes. Plasma cells were polytypic; there was no plasmablast excess (no MUM1+ cells). Mast cells (as evidenced by mast cell tryptase stain) were increased.
Quantitative reverse transcriptase polymerase chain reaction for SARS-CoV-2 revealed low residual viral load in the explanted lung tissue (N-Gene: Ct [cycle threshold] value 36.5) (PCR protocol as previously described). This result was confirmed with the orthogonal method - droplet digital PCR (N1 gene: 0 copies/muL; N2 gene 0.0307 copies/muL). Immunohistochemistry for SARS-CoV-2 nucleocapsid (N)-antigen showed focal endothelial deposition in arterioles (Fig. 3h). Links of the scanned H&E sections as well as all antibody protocols can be found in online supplementary Materials.
coronal. chest CT shows extensive bilateral ground-glass opacities, reticulation, and bronchiectasis consistent with ARDS pattern. ARDS, acute respiratory distress syndrome.