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BRIEF COMMUNICATION  
Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 653-656
Pathological changes in COVID-19 pneumonia on limited post-mortem sampling of lung: A saga of inflammation and thrombosis


1 Department of Pulmonary Medicine, AIIMS Bhopal, Bhopal, Madhya Pradesh, India
2 Department of CTVS, AIIMS Bhopal, Bhopal, Madhya Pradesh, India
3 Department of Pathology and Lab Medicine, AIIMS Bhopal, Bhopal, Madhya Pradesh, India
4 Department of Anesthesia, AIIMS Bhopal, Bhopal, Madhya Pradesh, India

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Date of Submission21-Sep-2020
Date of Decision14-Feb-2021
Date of Acceptance06-Oct-2021
Date of Web Publication26-May-2022
 

   Abstract 


We describe three postmortem open lung-biopsy findings among patients with COVID-19 pneumonia who were on anticoagulant therapy. The spectrum of histopathological findings included lung inflammation in the form of diffuse alveolar damage (DAD) in exudative and organizing phases, with or without pulmonary artery thrombosis in different stages of evolution. This spectrum of inflammation and thrombosis may be indicative of a natural history of severe COVID-19 pneumonia or demonstrative of variation in therapeutics.

Keywords: Anticoagulation, ARDS, COVID-19, pulmonary artery, thrombi

How to cite this article:
Goyal A, Niwariya Y, Goel G, Joshi D, Saigal S, Gella DV. Pathological changes in COVID-19 pneumonia on limited post-mortem sampling of lung: A saga of inflammation and thrombosis. Indian J Pathol Microbiol 2022;65:653-6

How to cite this URL:
Goyal A, Niwariya Y, Goel G, Joshi D, Saigal S, Gella DV. Pathological changes in COVID-19 pneumonia on limited post-mortem sampling of lung: A saga of inflammation and thrombosis. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:653-6. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/653/345853





   Introduction Top


As of May 15, 2020, more than 4 million confirmed cases of COVID-19 infection, including more than 285,000 deaths, have been reported. With a fatality rate of approximately 3% and a median R0 value of 5.7, it has become a challenge for mankind in a short time span.[1] Novel coronavirus infection is a spectrum, ranging from asymptomatic or mildly symptomatic infected individuals to those with moderate and severe disease. Individuals with severe disease clinically have acute respiratory distress syndrome (ARDS) and have a happy–hypoxemic state.[2] Although this state is attributed to microcirculatory abnormalities, there is very limited data on pulmonary pathological changes in severe COVID-19 pneumonia.

Viral pneumonias are characterized by alveolar and interstitial inflammation. Severe COVID-19 infection however has intense systemic inflammation, also known as a cytokine storm. This causes endothelial damage, leading to platelet aggregation and a procoagulant state by tissue factor pathway activation.[3],[4] Such activation of the coagulation system is also described in Ebola, HIV, and dengue virus infections.[5] Although anticoagulants are being used in patients with COVID-19 pneumonia, its targets and duration remain unclear. In a study from Italy, it was reported that despite prophylactic anticoagulation, 22% of the COVID-19 patients developed deep venous thrombosis (DVT).[6] We performed a post-mortem lung biopsy in three patients with COVID-19 pneumonia, who died despite being on anticoagulant therapy.


   Case 1 Top


A 62-year-old man presented with complaints of shortness of breath and fever for the last 3 days. His chest radiograph showed bilateral peripheral opacities. [Figure 1]a His nasopharyngeal and oropharyngeal swabs were positive for RT-PCR-COVID-19. He was admitted to the COVID intensive care unit (ICU) of the hospital with an oxygen saturation of 89% on 5 L of oxygen. On the third day of admission, he failed a high-flow nasal cannula (HFNC) and was intubated. His oxygen requirement kept fluctuating between FiO2 of 0.5 and 0.8. He was ventilated for the next 10 days, after which he was tracheostomized. On day 13, he developed atrial fibrillation and cor pulmonale. The patient succumbed to his illness on day 24.{Figure 1}


   Case 2 Top


A 61-year-old man with known chronic obstructive airway disease presented with breathlessness and fever. Although he was initially stable on 2 LPM of oxygen support, he developed ARDS after 2 days of hospital admission. His chest radiograph showed bilateral peripheral consolidation [Figure 1]b. As he was not maintaining saturation on HFNC, he was intubated on day 4 of admission and developed refractory hypotension and ventricular arrhythmias. He died on day 7 of hospital admission.


   Case 3 Top


A 62-year woman presented with a history of fever for 7 days, increasing breathlessness for 2 to 3 days, and abdominal pain for 1 day. On admission, she had an oxygen saturation of 60% on room air and required FiO2 (0.7) by HFNC. Her initial chest X-ray showed bilateral peripheral lower zone predominant consolidation [Figure 1]c. A computed tomography (CT) of the abdomen was done in view of severe abdominal pain, which revealed a thrombus in the aorta below the D8 level and partial thrombus in the distal part of the superior mesenteric artery. She also received broad-spectrum antibiotics, and over the next 7 days, her oxygen requirement decreased from 0.7 to 0.28 along with significant clearing of Chest X-ray (CXR) over a week [Figure 1]d. Her abdominal pain however worsened, and a laparotomy was done on day 10 of her admission, which revealed an ileal perforation with spillage of intestinal contents into the peritoneal cavity. Postoperatively, she developed septic shock and died on day 12 after admission.


   Lung Biopsy and Histopathology Top


Lung biopsies from the lower lobe (which was the most affected part radiologically) of all three patients were taken within 1 h of death with due precautions. Consent of relatives was taken for biopsy. Tissue samples were fixed in 10% buffered formalin and processed via the standard procedure, and the sections were stained with hematoxylin–eosin and Masson's trichrome stains.

The lung tissue submitted for histopathology showed a spectrum of findings. Cases 1 and 2 showed features of proliferative and exudative phases of diffuse alveolar damage (DAD), respectively. There was a presence of subsegmental artery thrombi [Figure 2]a with extensive squamous metaplasia [Figure 2]b, prominent fibrosis, and focal collagen deposition in Case 1. There was a presence of extensive intra-alveolar and interstitial inflammatory exudate [Figure 2]c, comprising neutrophils, lymphocytes, and macrophages, suggesting a secondary infection in Case 2. Other histological features favoring DAD, such as hyaline membrane formation [Figure 2]d, type II pneumocyte hyperplasia, viral cytopathic effects in the form of nucleomegaly with binucleation, and bright eosinophilic nucleoli [Figure 2]e, and fibrin microthrombi, were seen predominantly in Cases 1 and 2.{Figure 2}

Case 3 showed the presence of organized subsegmental artery thrombi with evidence of neovascularization in the vessel wall [Figure 2]f. There was the presence of occasional lymphoid aggregate, and only a small part of the tissue showed type 2 pneumocyte hyperplasia and intra-alveolar macrophages. There were no histological features of DAD.

The clinical and pathological findings are summarized in [Table 1].{Table 1}


   Discussion Top


We have presented histopathological findings on postmortem lung biopsy in three patients who had COVID-19 pneumonia. The spectrum of histopathological findings included DAD in exudative and organizing phases, with or without pulmonary artery thrombus in different stages of evolution. This spectrum may be indicative of variation in therapeutics or natural history of severe COVID-19 pneumonia. In our limited case series, the first patient was on prophylactic anticoagulation and he had arterial thrombi in the subsegment of the pulmonary artery. The second patient was on therapeutic anticoagulation, and his histopathology was suggestive of pulmonary microthrombi. The third patient was on dual antiplatelets and unfractionated Heparin (UFH) heparin infusion. Although she had initially clinically improved, she succumbed to perforation peritonitis. Her histopathology was suggestive of DAD and pulmonary thrombus in resolution.

One of the first biopsy reports, published for COVID-19 patients by Tian et al.,[7] reported changes in early ARDS such as edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and absence of hyaline membranes. No obvious micro- or macrothrombi were seen. Two other series by Tian et al.[8] and Zhang et al.[9] reported findings of DAD such as hyaline membrane formation, fibrin exudates, intra-alveolar loose fibrous plugs, intra-alveolar organizing fibrin epithelial damage, and diffuse-type II pneumocyte hyperplasia. In a third and the largest postmortem case series of 38 patients by Carsana et al.,[10] changes in the diffuse pattern of exudative and early proliferative phases of DAD were found. The fibrotic phase was rarely seen. The peculiar histopathological findings were atypical pneumocytes (reactive atypia) and diffuse thrombosis of peripheral small vessels. There was no information available regarding the level of anticoagulation given to deceased patients in this series.

Wichmann et al.[11] reported an autopsy series of 12 patients from Germany, 4 patients died due to pulmonary embolism (PE). DAD was seen in two-thirds of patients and DVT was found in 7/12 (58%) patients in this series. On close reading of this paper, we found that two patients were on direct Xa inhibitor prophylaxis before getting infected with COVID-19; on autopsy, they did not have any evidence of either DVT, PE, or microthrombi. In this series, all four patients who were mechanically ventilated developed DVT. Only two of these mechanically ventilated patients were given Low molecular weight heparin (LMWH) prophylaxis, and they had DVT, PE, and thrombi on autopsy. Similarly, in other autopsy series by Lax et al.[12] and Creel-Bulos et al.[13] all patients with COVID-19 developed pulmonary thrombus despite prophylactic anticoagulation.

Patients with severe COVID-19 pneumonia develop lung inflammation and thrombosis. The role of immunosuppression, antiviral drugs, and anticoagulation therapy remains unclear in mortality prevention. We found more extensive thrombosis in a case where minimal anticoagulation was used, yet mortality was not prevented in others where biopsy suggested partial or complete resolution of thrombosis. The current literature demonstrates that prophylactic anticoagulation is insufficient in critically ill COVID-19 patients.[6],[12],[13],[14] Other aspects of anticoagulation, such as antiplatelets (aspirin and clopidogrel), direct Xa inhibitors, and fibrinolytics such as tissue plasminogen activator (tPA), need to be evaluated for prophylaxis and treatment of COVID-19-related coagulopathy, respectively.[15]

To conclude, the histopathological changes mentioned in this report have been well described in the current literature. However, this report provides morphological evidence that anticoagulants have a significant role in modifying the course of the disease. Because all three patients succumbed to the disease, this suggests that the pathogenesis of the disease is multifactorial and complex, with both inflammatory and coagulation cascades activated in the disease. Hence, more studies are required to explore the pathogenesis that may aid in better management of patients with severe COVID-19 pneumonia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Sanche S, Lin Y, Xu C, Romero-Severson E, Hengartner N, Ke R. High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2. Emerg Infect Dis 2020;26:1470-7.  Back to cited text no. 1
    
2.
Couzin-Frankel J. The mystery of the pandemic's 'happy hypoxia'. Science 2020;368:455-6.  Back to cited text no. 2
    
3.
Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol 2020;127:104362.  Back to cited text no. 3
    
4.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844–7.  Back to cited text no. 4
    
5.
Antoniak S, Mackman N. Multiple roles of the coagulation protease cascade during virus infection. Blood 2014;123:2605–13.  Back to cited text no. 5
    
6.
Tavazzi G, Civardi L, Caneva L, Mongodi S, Mojoli F. Thrombotic events in SARS-CoV-2 patients: An urgent call for ultrasound screening. Intensive Care Med 2020;22:1–3.  Back to cited text no. 6
    
7.
Tian S, Hu W, Niu L, Liu H, Xu H, Xiao S-Y. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020;15:700–4.  Back to cited text no. 7
    
8.
Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020;33:1007–14.  Back to cited text no. 8
    
9.
Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, et al. Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19. Ann Intern Med 2020;172:629-32.  Back to cited text no. 9
    
10.
Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: A two-centre descriptive study. Lancet Infect Dis 2020;20:1135-40.  Back to cited text no. 10
    
11.
Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann Intern Med 2020;173:268-77.  Back to cited text no. 11
    
12.
Lax SF, Skok K, Zechner P, Kessler HH, Kaufmann N, Koelblinger C, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series. Ann Intern Med 2020;173:350-61.  Back to cited text no. 12
    
13.
Creel-Bulos C, Hockstein M, Amin N, Melhem S, Truong A, Sharifpour M. Acute cor pulmonale in critically ill patients with covid-19. N Engl J Med 2020;382:e70. doi: 10.1056/NEJMc2010459.  Back to cited text no. 13
    
14.
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094–9.  Back to cited text no. 14
    
15.
Liu C, Ma Y, Su Z, Zhao R, Zhao X, Nie HG, et al. Meta-analysis of preclinical studies of fibrinolytic therapy for acute lung injury. Front Immunol 2018;9:1898.  Back to cited text no. 15
    

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Correspondence Address:
Garima Goel
Department of Pathology and Lab Medicine, AIIMS Bhopal Saket Nagar, Bhopal - 462 024, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_1158_20

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    Abstract
   Introduction
   Case 1
   Case 2
   Case 3
    Lung Biopsy and ...
   Discussion
    References

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