Lung

Infectious

Viral

COVID-19


Editorial Board Members: Carolyn Glass, M.D., Ph.D., Jefree J. Schulte, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Jijgee Munkhdelger, M.D., Ph.D.
Andrey Bychkov, M.D., Ph.D.

Last author update: 31 May 2023
Last staff update: 31 May 2023

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PubMed Search: COVID-19 lung pathology

See Also: COVID-19 colitis, COVID-19 convalescent plasma, COVID-19 kidney injury, COVID-19 placentitis, COVID-19 testing, COVID-19 viral hepatitis

Jijgee Munkhdelger, M.D., Ph.D.
Andrey Bychkov, M.D., Ph.D.
Page views in 2023: 5,715
Page views in 2024 to date: 1,523
Cite this page: Munkhdelger J, Yoshikawa A, Bychkov A. COVID-19. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorcovid.html. Accessed May 19th, 2024.
Definition / general
Essential features
  • COVID-19 is a viral infection caused by coronavirus SARS-CoV-2 that can progress to severe acute respiratory syndrome with pneumonia and acute respiratory distress syndrome
  • The disease spread rapidly and became a pandemic with > 100 million confirmed cases and over 2 million deaths worldwide by end of January 2021
  • Histologically, COVID-19 shows diffuse alveolar damage corresponding to the phase of the disease (acute to fibrotic), divided into 3 main injury patterns: epithelial, vascular and fibrotic
  • Definite diagnosis is based on detection of viral RNA by RT-PCR
Terminology
  • COVID-19 is also called novel coronavirus pneumonia
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also called 2019 novel coronavirus (2019-nCoV)
ICD coding
  • ICD-10 (emergency codes):
    • U07.1 - COVID-19 confirmed by laboratory testing
    • U07.2 - suspicious for COVID-19 with inconclusive laboratory testing
  • ICD-11:
    • RA01.0 - COVID-19 (definite)
    • RA01.1 - COVID-19 (suspected or probable)
Epidemiology
Sites
  • Upper respiratory tract in mild disease
  • Bilateral lobes of the lung in more severe disease
Pathophysiology
  • Spike surface glycoprotein of the virus binds to the host via receptor binding domains of the angiotensin converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells (J Virol 2020;94:e00127-20)
  • After a SARS-CoV-2 attaches to a target cell, the virion releases RNA into the cell, initiating replication of the virus which further disseminates to infect more cells (Cell 2020;181:271)
  • SARS-CoV-2 produces several virulence factors that promote shedding of new virions from host cells and inhibit immune response
  • Virus independent immunopathology in fatal COVID-19 (Am J Respir Crit Care Med 2021;203:192)
    • Organ injury and death in COVID-19 is immune mediated rather than pathogen mediated
    • Tissue inflammation and organ dysfunction in fatal COVID-19 do not correlate with the tissue and cellular distribution of SARS-CoV-2
Etiology
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive sense, single stranded RNA virus having close genetic similarity to bat coronaviruses (Nature 2020;579:270)
Diagrams / tables

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SARS-CoV-2

Pathogenesis of COVID-19

Epidemic timeline of COVID-19


Timeline of tissue changes

Timeline of autopsy studies

Autopsy PPE

Clinical features
  • Average time from exposure to symptom onset is 5 days (Ann Intern Med 2020;172:577)
  • Asymptomatic infection rate is 46% (J Med Virol 2020;92:2543)
  • Rare in children, about ~2 - 5% of confirmed cases, with milder symptoms and very low hospitalization rate (< 7%) (JAMA 2020;324:782)
  • Common symptoms in hospitalized patients (JAMA 2020;324:782):
    • Fever (70 - 90%)
    • Dry cough (60 - 86%)
    • Shortness of breath (53 - 80%)
    • Fatigue (38%)
    • Myalgias (15 - 44%)
    • Nausea / vomiting or diarrhea (15 - 39%)
    • Headache, weakness (25%)
  • Patients can present with nonclassical symptoms (JAMA 2020;324:782):
    • Isolated gastrointestinal symptoms
    • Isolated anosmia or ageusia (3%)
  • COVID-19 can progress to severe acute respiratory syndrome and its major clinicopathological phenotypes include pneumonia and acute respiratory distress syndrome
  • Patients who required ICU supportive care presented with acute respiratory distress syndrome, acute cardiac injury, acute kidney injury and shock; up to 15% of them had fatal outcomes (Travel Med Infect Dis 2020;34:101623)
  • Common complications among hospitalized patients (JAMA 2020;324:782):
    • Pneumonia (75%)
    • Acute respiratory distress syndrome (15%)
    • Acute liver injury (19%)
    • Cardiac injury (7 - 17%): troponin elevation, acute heart failure, dysrhythmias, myocarditis (JAMA 2020;324:782)
    • Prothrombotic coagulopathy resulting in venous and arterial thromboembolic events (10 - 25%)
    • Acute kidney injury (9%)
    • Acute cerebrovascular disease (3%)
    • Shock (6%)
  • A rare multisystem inflammatory syndrome similar to Kawasaki disease has recently been described in children (2 per 100,000 persons aged < 21 years) (JAMA 2020;324:782)
  • Post acute COVID-19 syndrome: persistent symptoms, delayed or long term complications beyond 4 weeks
    • Persistent ≥ 1 symptom was reported in 32.6 - 87.4% of cases (fatigue, joint pain, chest pain, dyspnea, cough, loss of taste / smell, headache, diarrhea) (Nat Med 2021;27:601)
Diagnosis
Laboratory
Radiology description
  • Ground glass opacities, crazy paving pattern and consolidation in bilateral lobes are common findings (Radiology 2020;295:715)
  • 15% of CT and 40% of chest radiograph findings are normal early in the disease (JAMA 2020;324:782)
  • Evolution of abnormalities occurs in the first 2 weeks after onset
Radiology images

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Chest CT images

Severe changes

Prognostic factors
Case reports
Treatment
Gross description
Gross images

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Grossing protocol

Thickened alveolar septa, thromboemboli

Patchy consolidations

Subsegmental pulmonary embolism

Microscopic (histologic) description
  • Pulmonary changes are the most significant, although nonspecific (Lancet Respir Med 2020;8:420, J Thorac Oncol 2020;15:700, Mod Pathol 2020;33:1007)
    • Findings of diffuse alveolar damage (DAD) corresponding to the phase of disease:
      • Exudative phase: hyaline membrane formation, desquamation of pneumocytes, cellular or proteinaceous exudates, alveolar hemorrhage, fibrinoid necrosis of small vessels
      • Organizing phase: interstitial and intra-alveolar proliferation of fibroblasts, lymphocytic infiltration, type II pneumocyte hyperplasia, fibrin deposition
      • Fibrotic phase: dense collagenous fibrosis, architectural remodeling
    • Lung injury patterns (Mod Pathol 2020;33:2128, Eur J Clin Invest 2020;50:e13259):
      • Epithelial (85%): DAD with varying degrees of organization, denudation, hyperplasia of pneumocytes
      • Vascular (59%): diffuse intra-alveolar fibrin, microvascular damage, (micro) thrombi, acute fibrinous and organizing pneumonia
        • More vascular changes (hemangiomatosis-like changes, thromboemboli, pulmonary infarcts, perivascular inflammation) in fatal COVID-19 cases compared to DAD of other causes (Am J Respir Crit Care Med 2022;206:857)
      • Fibrotic (22%): fibrotic DAD, interstitial fibrosis
        • Prominent ongoing fibrosis in explanted lungs, accompanied by abundant macrophage infiltration, neoangiogenesis and persistent microvascular thrombosis (Am J Clin Pathol 2022;157:908)
    • Viral infection changes:
      • Multinucleated enlarged pneumocytes with large nuclei, amphophilic cytoplasm and prominent nucleoli in alveolar spaces
      • Intranuclear inclusions
    • Bacterial pneumonia may be superimposed
  • Extrapulmonary changes (Mod Pathol 2020;33:2128):
    • Cardiovascular: mild pericardial edema, some serosanguinous pericardial effusion, mild myocardial edema, low grade interstitial infiltration of mononuclear cells, endotheliitis
      • Widespread systemic vasculitis with associated thromboemboli is not as common as initially thought (Lancet 2020;396:320)
    • Hepatobiliary: hepatic congestion, mild steatosis, patchy hepatic necrosis, Kupffer cell hyperplasia, increased number of lymphocyte predominant inflammatory cells in the portal tracts and sinusoids, endotheliitis
    • Renal: varying degrees of acute tubular injury, lymphocytic tubule interstitial infiltration, fibrin or hyaline thrombi in blood vessel, glomerular capillary dilatation, lymphocytic endotheliitis (Kidney Int 2020;98:219)
    • Gastrointestinal: epithelial damage, prominent endotheliitis, ischemic enterocolitis
    • Spleen: reduced number of lymphocytes with necrosis, atrophy, congestion, hemorrhage, infarction
    • Bone marrow: histiocytic hyperplasia, hemophagocytosis (Mod Pathol 2020;33:2139)
    • Other: cutaneous, prostatic manifestations, inflammation and clots in placenta with funisitis
Microscopic (histologic) images

Contributed by Toru Igari, M.D., Jin Takahashi, M.D. and Shinyu Izumi, M.D.
Bronchial change

Bronchial change

Squamous metaplasia

Squamous metaplasia

Acute phase

Acute phase

Hyaline membranes

Hyaline membranes

Organizing phase

Organizing phase


Organizing phase Organizing phase

Organizing phase

Organizing phase Organizing phase

Organizing phase

Fibroblastic proliferation

Fibroblastic proliferation


Lymphocytic infiltration

Lymphocytic infiltration

Pneumocyte hyperplasia Pneumocyte hyperplasia Pneumocyte hyperplasia

Pneumocyte hyperplasia

Epithelial denudation

Epithelial denudation


Epithelial denudation

Epithelial denudation

Perivascular lymphocytes

Perivascular lymphocytes

Clear cell change

Clear cell change

Multinucleation Multinucleation

Multinucleation



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Lung injury patterns


SARS-CoV-2 in lung

Cytology description
  • Bronchoalveolar lavage (BAL):
    • Inflammatory background (lymphohistiocytic, histiocytic, neutrophil predominant), virus related changes (atypical nuclei, nuclear cytoplasmic inclusion, multinucleation), nonspecific reactive changes (bronchial, alveolar, reserve cell hyperplasia) (Acta Cytol 2022;66:532)
    • Abundant activated plasma cells, as per a single case report (J Thorac Oncol 2020;15:e65)
    • Alveolar macrophages may feature nuclear clearing or intranuclear cytopathic inclusions
    • High neutrophil proportions in mechanically ventilated critically ill patients (Clin Respir J 2022;16:329)
Cytology images

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Inflammatory background

Nuclear, cytoplasmic inclusion


Multinucleated alveolar macrophage

Multinucleated giant cell

BAL ThinPrep

Positive stains
Electron microscopy description
  • Spherical particles sized 60 - 140 nm
  • Distinctive spikes on the surface (9 - 12 nm) giving virions the appearance of a solar corona, consistent with the Coronaviridae family
  • Inclusion bodies filled with virus particles in membrane bound vesicles in cytoplasm of the respiratory epithelium (N Engl J Med 2020;382:727)
Electron microscopy images

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Scanning electron microscopy

Transmission electron microscopy

Virus in epithelial cells

Molecular / cytogenetics description
Videos

Pathology of COVID-19: a pulmonary pathologist explains

Sample management

Autopsy


SARS-CoV-2 detection in tissues

Pulmonary pathology

Cardiovascular pathology


COVID-19 autopsy pathology findings

Histology of acute respiratory distress syndrome

Sample pathology report
  • Usually reported as part of autopsy findings:
    • Diffuse alveolar damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
    • Diffuse alveolar damage with changes compatible with viral infection
Differential diagnosis
Additional references
Board review style question #1

Which of the following is the main histologic finding in the organizing phase of diffuse alveolar damage in COVID-19 infection?

  1. Alveolar hemorrhage
  2. Dense collagenous fibrosis
  3. Fibrinoid necrosis of small vessels
  4. Fibroblastic proliferation
  5. Hyaline membrane formation
Board review style answer #1
D. Fibroblastic proliferation

Comment Here

Reference: COVID-19
Board review style question #2



Which of the following is the target organ affected by SARS-CoV-2 and is responsible for the major manifestation of COVID-19?

  1. Brain
  2. Heart
  3. Kidney
  4. Liver
  5. Lung
Board review style answer #2
E. Lung

Comment Here

Reference: COVID-19
Board review style question #3
Which of the following findings suggests viral infection of the lung?

  1. Alveolar hemorrhage
  2. Fibrin deposition
  3. Neutrophilic aggregation
  4. Nuclear inclusions
  5. Type II pneumocyte hyperplasia
Board review style answer #3
D. Nuclear inclusions

Comment Here

Reference: COVID-19
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