|Ahead of print
|Histopathological changes in lungs of patients with fatal COVID 19 infection: A series of 15 cases
Pranita Medhi1, Swagata Dowerah1, Nabajit Barman2, Mridul Singh1
1 Department of Pathology, Assam Medical College, Dibrugarh, Assam, India
2 Department of Forensic Medicine, Assam Medical College, Dibrugarh, Assam, India
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|Date of Submission||26-Aug-2021|
|Date of Decision||05-Jan-2022|
|Date of Acceptance||09-Jan-2022|
|Date of Web Publication||26-May-2022|
| Abstract|| |
Introduction: The predominant pathology noted in the lungs of patients dying of COVID-19 is reported to be diffuse alveolar damage (DAD). Other studies have identified microthrombi to be a prominent finding of lung injury in patients affected by COVID-19. We describe the lung histopathological findings in fifteen cases of COVID-19 who died from the disease with the aim of reporting the microscopic changes in the lungs of patients dying from this disease. Methods: Lung tissues from fifteen consecutive autopsy cases of COVID-19 were studied for gross and microscopic features. The case history of the deaths was noted, and the information was analyzed. The lung damage seen was graded on a semiquantitative scale on the basis of the percentage of tissue involved. Results: Gross examination of the lungs showed multiple foci of consolidation mainly in the lower lobes of the lungs as the most commonly encountered finding. The other significant pattern was congested and edematous lungs with areas of consolidation. Microscopic assessment of lung sections showed 8 out of the 15 cases showing changes of the exudative phase of diffuse alveolar damage, whereas two cases were in the proliferative phase. Hyaline membranes were one of the common findings along with intra-alveolar edema and interstitial edema. Four cases showed changes in organizing phase. Other findings were microthrombi formation, fungal abscesses, dilated and collapsed alveoli, intra-alveolar hemorrhage, and acute neutrophilic pneumonia. Conclusion: DADand interstitial pneumonitis were the most striking features in our autopsy study. Features of different phases of diffuse alveolar damage were seen to coexist in the same patient indicating the temporal heterogeneity of the ongoing lung injury in these patients.
Keywords: COVID 19, histopathology, lung autopsy
|How to cite this URL:|
Medhi P, Dowerah S, Barman N, Singh M. Histopathological changes in lungs of patients with fatal COVID 19 infection: A series of 15 cases. Indian J Pathol Microbiol [Epub ahead of print] [cited 2022 Sep 28]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=345899
| Introduction|| |
COVID-19 disease which started as a cluster of pneumonia cases in Wuhan, China caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) soon became a pandemic with a major impact on the health care system of many countries. Our ability to deal with this pandemic has been hampered by our limited knowledge of this virus. Although the virus affects all systems of the body, pulmonary damage is the dominant feature in most cases of severe COVID-19 and the primary cause of the fatal outcome.
Most respiratory viral infections present with interstitial inflammation, diffuse alveolar damage (DAD), and necrotizing bronchitis/bronchiolitis in histopathological examinations of the lung.,
SARS-CoV-2 is the seventh member of the coronavirus family identified to cause disease in humans. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. Two earlier members of the SARS-CoV-2 family, Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV infections have shown many similarities in clinical presentation. Of these, the SARS-CoV and MERS-CoV are known to cause acute DAD, pneumocyte hyperplasia, and interstitial pneumonia.,,
The predominant pathology noted in the lungs of patients dying of COVID-19 is reported to beDAD, which is the pattern of injury seen in patients with acute respiratory distress syndrome, regardless of the cause.,, Other studies have identified microthrombi to be a prominent finding of lung injury in patients affected by COVID-19, giving rise to speculation that SARS-CoV-2 has a predilection for endothelial cells.,, Most of our knowledge regarding the changes in lungs of COVID-19 patients comes from autopsy studies. However, even these are sparse in spite of a large number of fatalities, presumably because of the highly contagious nature of the infection, limited information about the disease, and lack of proper infrastructure for the appropriate handling of the infected post mortem cases in different parts of the world.
We describe the lung histopathological findings in fifteen cases of COVID-19 who died from the disease with the aim of reporting the microscopic changes in the lungs of patients dying from this disease.
| Methods|| |
Lung tissues from fifteen consecutive autopsy cases of COVID-19 were processed and analyzed under the microscope. The case history of the deaths was noted, and the information was analyzed. All the cases were confirmed for COVID-19 infection through reverse transcription-polymerase chain reaction (RT-PCR)/rapid antigen test. Post mortem examination was carried out with the use of proper personal protective equipment. Sections were taken from the lungs and fixed in 10% buffered formalin. The tissue was processed as per the standard protocol and stained with hematoxylene and eosin. The slides were assessed by two pathologists independently, and the findings were noted. In case of any discrepancy, the slides were jointly reviewed. The lung damage seen was graded on a semiquantitative scale on the basis of the percentage of tissue involved: absent (0%), rare (<5%), focal (5%–25%), multifocal (26%–50%), plurifocal (51%–75%), or diffuse (>75%).
| Results|| |
Out of a total of 15 cases, 14 were male, and only one case was female. The median age of the patients was 55 years. The youngest patient in our study was 23 years old, and the oldest was 78 years. One case was a known hypertensive with COVID pneumonitis, whereas another was a known case of type 2 diabetes mellitus with chronic kidney disease (CKD). Nine cases had clinical and radiological features of COVID pneumonitis. The remaining six patients had symptoms compatible with COVID infection (fever, cough, body ache, loss of smell, breathing difficulty) before their deaths as per the history received and cases tested positive for COVID 19 and therefore under the current prevailing scenario, the cause of death was assumed to be COVID-19. An autopsy done on the other organs of these patients did not reveal any other pathology indicating some other cause of death. Apart from the two cases with hypertension and diabetes, none of the cases had revealed any previous illness or comorbidity which could be attributed as the cause of death. All cases were doing well before the onset of these flu-like and respiratory symptoms.
Gross examination of the lungs showed multiple foci of consolidation mainly in the lower lobes of the lungs as the most commonly encountered finding (9 cases). The other significant pattern was congested and edematous lungs with areas of consolidation and frothy hemorrhagic exudates on cut sections (seen in 5 cases). Some of the specimens showed punctuate hemorrhage and areas of necrosis. One case had a contracted lung with surface nodularity, cavities, and areas of consolidation and necrosis.
Microscopic assessment of lung sections showed 8 out of the 15 cases showing changes of the exudative phase of diffuse alveolar damage, whereas two cases were in the proliferative phase [Table 1]. Hyaline membranes were one of the common findings seen in seven cases, whereas intra-alveolar edema was seen in four cases, and interstitial edema was noted in five cases. Four cases showed changes in organizing phase with variable amounts of fibrosis, myofibroblastic proliferation, and loss of alveolar cells. Microthrombi were noted in five cases. Fungal abscesses were seen in four cases. In one patient, the only finding was interstitial inflammation in otherwise normal-looking lung tissue. Dilated and collapsed alveoli were a common finding in the tissue sections. Two cases showed intra-alveolar hemorrhage. Acute neutrophilic pneumonia was seen in three cases [Figure 1] and [Table 2].
|Figure 1: Showing microscopic changes in lungs of patients with COVID-19 INFECTION a. Exudative phase of DAD with intra-alveolar exudates, hyaline membrane at places and interstitial inflammation (10 ×, H&E) b. Type 2 alveolar pneumocyte hyperplasia and intra-alveolar giant cells (10 ×, H&E) c. Neutrophilic inflammation (40 ×, H&E) d. Section showing fungi morphologically resembling candida albicans (40 ×, H&E) e. Organizing phase of DAD (10 ×, H&E) f. lung tissue in fibrotic phase (10 ×, H&E) g. extensive fibrosis with dilatation and collapse of airspaces (40 ×, H&E) h. alveolar exudates with interstitial chronic inflammation (10 ×, H&E )|
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| Discussion|| |
Different studies have noted remarkable similarities in the microscopic features of lung lesions in all three coronavirus pandemic cases of the twenty-first century. DAD has emerged as a consistent feature of COVID-19–related pulmonary pathology. Post mortem examinations conducted during the early stages of the pandemic revealed DAD with capillary congestion, microthrombosis, and thrombosis of small- to mid-sized arteries as well as pulmonary thromboembolism, suggesting the presence of vascular dysfunction in these patients.,,
The virus itself is believed to play a direct role in the pathogenesis of the pulmonary disease, binding of viral spike protein reduces angiotensin-converting enzyme 2 (ACE2) expression and causes acute lung injury, leading to the excessive production of angiotensin II which increases pulmonary vascular permeability. The vasculature of the lung also plays a crucial role as evidenced by the characteristic micro thrombosis of the capillary network of the alveoli and thrombosis of pulmonary arteries/arterioles. This is thought to result from the endothelial cell activation and damage occurring secondary to the binding of the virus to the endothelial cells via ACE 2 receptors, as well as activation of the coagulation through several procoagulant pathways induced by a dysregulated immune response or cytokine storm which occur in severe forms of the disease.,
On gross examination, the lungs usually show an increase in weight with edema and congestion; cut surfaces with irregularly distributed regions of consolidation, and in some cases, areas of hemorrhage or infarction are seen, visible thrombosis may be noted in the feeder vessels. In our study, most of the cases had multiple foci of consolidation, whereas the other notable finding was heavy, congested edematous lung with patchy consolidation. According to the literature, COVID-19 changes in the lungs can be subdivided into four main morphological stages – an early stage (day 0–1) with edema, incipient epithelial damage, and capillaritis/endothelialitis, the stage of exudative diffuse alveolar damage (DAD) (days 1–7), the organizing stage (1 to several weeks), and the fibrotic stage of DAD (weeks to months). Other authors have divided the DAD into exudative, proliferative, and fibrotic phases with other associated findings such as alveolar multinucleated giant cells and interstitial and alveolar inflammation and found bilateral DAD in the exudative and proliferative phases to be the most consistent finding.,,, In our study, although the exudative phase was the most common finding, there was a clear overlap between the different phases of DAD with many cases showing features of different stages coexisting in the same lung reflecting the temporal heterogeneity of the infection in the lungs. A total of 26% of our cases showed features of the fibrotic phase of DAD, which is generally believed to be a feature of long-standing disease. Other changes like acute neutrophilic infiltrate, most frequently a manifestation of superimposed bacterial pneumonia, and large airway inflammatory changes which include mucosal ulceration, acute and/or chronic inflammation have also been described in various cases. We also came across three cases of superimposed bacterial pneumonia and four cases of the fungal abscess. Bronchopneumonia as an indication of bacterial or less commonly fungal superinfection has been described in 32%–57% of patients in the larger autopsy series.,, It was seen in our series that the cases which presented with congested edematous lungs on gross examination mostly showed microscopic evidence of the exudative phase of DAD. The cases which were in the proliferative, organizing, or fibrotic phase had multiple foci of consolidation in the lungs. Pleura was congested in most of our cases.
Literature suggests that the exudative phase is represented by CD3-positive lymphocytes and a few plasma cells, infiltrating the interstitial space; large numbers of CD68-, CD163-, and CD206-positive macrophages are mainly found localized in the alveoli., Granulocytes are involved in vascular thromboinflammation and formation of neutrophilic extracellular traps but are not common in the alveoli unless there is superinfection.
A clinically important finding mentioned in most of the reports is diffuse or focal platelet-fibrin thrombi involving the peripheral or central pulmonary arterial vessels and capillaries in both affected and preserved lung parenchyma and these entrap many inflammatory cells including neutrophils in them.,, We observed microthrombi in one-third of our cases.
Various studies including our own have seen that the features of COVID-19 pneumonitis are nonspecific, and the lungs of these patients usually show features of DAD, which can be seen in various other conditions. However, by ruling out the presence of prior comorbidities which could present with similar histopathological picture and on the basis of the prevailing pandemic situation, the clinical context, radiological findings and positivity for COVID 19 tests, this and other similar studies have assumed the histopathological findings at autopsy to be those caused by COVID-19 infection.
It was observed that many of the cases did not attend any medical facility probably due to hesitation and the stigma associated with the disease in the initial part of the pandemic, and so thorough workup of these cases was not done antemortem. Therefore, although the symptoms suggested COVID-19 disease, these cases deteriorated at home and were rushed to the local medical facilities at the last moment and succumbed to the illness. This calls for creating greater public awareness and mandatory testing and treatment of symptomatic patients without creating a fatal delay.
| Conclusion|| |
DAD and interstitial pneumonitis were the most striking features in our autopsy study. Along with these other features like thrombi formation, alveolar dilatation and collapse, features of bacterial pneumonia, and evidence of fungal infection were also seen in some cases. However, features of different phases of DAD were seen to coexist in the same patient indicating the temporal heterogeneity of the ongoing lung injury in these patients. Histopathology of autopsy specimens is an essential tool in understanding the pathology of COVID-19 and gaining important insight into the spectrum of COVID-19 associated lung changes.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Assam Medical College, Dibrugarh, Assam
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]
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