Antemortem vs Postmortem Histopathologic and Ultrastructural Findings in Paired Transbronchial Biopsy Specimens and Lung Autopsy Samples From Three Patients With Confirmed SARS-CoV-2

Daniel Gagiannis, MD; Vincent Gottfried Umathum, MD; Wilhelm Bloch, MD; Conn Rother, MD; Marcel Stahl, MD; Hanno Maximilian Witte, MD; Sonja Djudjaj, PhD; Peter Boor, MD, PhD; Konrad Steinestel, MD, PhD


Am J Clin Pathol. 2022;157(1):54-63. 

In This Article

Abstract and Introduction


Objectives: Respiratory failure is the major cause of death in coronavirus disease 2019 (COVID-19). Autopsy-based reports describe diffuse alveolar damage (DAD), organizing pneumonia, and fibrotic change, but data on early pathologic changes and during progression of the disease are rare.

Methods: We prospectively enrolled three patients with COVID-19 and performed full clinical evaluation, including high-resolution computed tomography. We took transbronchial biopsy (TBB) specimens at different time points and autopsy tissue samples for histopathologic and ultrastructural evaluation after the patients' death.

Results: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed by reverse transcription polymerase chain reaction and/or fluorescence in situ hybridization in all TBBs. Lung histology showed reactive pneumocytes and capillary congestion in one patient who died shortly after hospital admission with detectable virus in one of two lung autopsy samples. SARS-CoV-2 was detected in two of two autopsy samples from another patient with a fulminant course and very short latency between biopsy and autopsy, showing widespread organizing DAD. In a third patient with a prolonged course, autopsy samples showed extensive fibrosis without detectable virus.

Conclusions: We report the course of COVID-19 in paired biopsy specimens and autopsies, illustrating vascular, organizing, and fibrotic patterns of COVID-19–induced lung injury. Our results suggest an early spread of SARS-CoV-2 from the upper airways to the lung periphery with diminishing viral load during disease.


Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease, coronavirus disease 2019 (COVID-19), emerged in late 2019, much effort has been put in a better understanding of the clinical course of the disease. While most patients have rather mild symptoms, some patients—especially those sharing risk factors such as older age, cardiovascular disease, or chronic obstructive pulmonary disease—are at risk of developing life-threatening respiratory failure.[1] Early autopsy studies conducted in China described diffuse alveolar damage (DAD) with an early edematous phase followed by hyaline membrane formation, desquamation of pneumocytes, and an increased interstitial mononuclear infiltrate.[2] In one case, Tian et al[3] reported loose intra-alveolar fibromyxoid proliferation reminiscent of organizing pneumonia (OP). In the meantime, it is widely accepted that COVID-19 follows a biphasic pattern of an initial viral response phase followed by an inflammatory second phase and that mortality is linked primarily to the development of acute respiratory distress syndrome (ARDS).1,4 Based on a meta-analysis of 131 reported autopsy cases, Polak et al[5] postulated that the main histologic patterns of COVID-19–related lung injury can be categorized into epithelial (reactive changes and DAD), vascular (microvascular damage, thrombi, and OP) and fibrotic, but these patterns may overlap and be coexistent in the same patient at a given time point. Nicholson et al[6] proposed that an initial (pre)exudative phase of DAD (0–7 days) is followed by an organizing phase (1 week to months) and might ultimately progress to fibrosis (months). A specific subtype of organizing DAD and OP with ball-like fibrin and fibromyxoid plugging, designated acute fibrinous and organizing pneumonia (AFOP), has also been described in COVID-19 autopsy cases.[7] The exact mechanisms of SARS-CoV-2–related ARDS development are not fully understood. It has been postulated that the severity of COVID-19 might correlate with a hyperinflammatory response and uncontrolled secretion of cytokines, showing similarities to cytokine releasing syndrome,[8] but cytokine levels in severe cases of COVID-19 are lower compared with those in patients with severe influenza.[9] Overlapping clinical, serologic, and imaging features between severe COVID-19 and lung manifestation of autoimmune disease, such as systemic lupus erythematosus or systemic sclerosis, have been described, and in one study, the presence of autoantibodies (antinuclear antibodies ANAs and extractable nuclear antibodies [ENAs]) was significantly associated with a need for intensive care treatment and the occurrence of severe complications.[10] This finding has now been confirmed by others and might be attributed to extrafollicular B-cell activation with excessive production of antibody-secreting cells in critically ill patients with COVID-19.[11–13] A better understanding of the pathophysiology of lung injury in COVID-19 would also shed light on the urgent question of long-term sequelae of the disease in millions of COVID-19 survivors. Despite a large number of autopsy studies that represent a snapshot of the disease at the time of death, to our knowledge no study has compared antemortem vs postmortem histopathologic and ultrastructural features of COVID-19. We report here the histopathology of transbronchial biopsy specimens and autopsy samples together with reverse transcription polymerase chain reaction (RT-PCR)– and fluorescence in situ hybridization (FISH)–based detection of SARS-CoV-2 and ultrastructural analyses from three patients with confirmed SARS-CoV-2 infection.