Lung
Infectious
Viral
COVID-19
Editorial Board Member: Carolyn Glass, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Topic Completed: 4 August 2020
Minor changes: 8 April 2021
Copyright: 2020-2021, PathologyOutlines.com, Inc.
PubMed Search: COVID-19[TI] lung[TIAB] pathology[TIAB]
See Also: COVID-19 convalescent plasma, COVID-19 testing, COVID-19 viral hepatitis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Cite this page: Yoshikawa A, Munkhdelger J, Bychkov A. COVID-19. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorcovid.html. Accessed April 15th, 2021.
Definition / general
- Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease caused by novel coronavirus SARS-CoV-2 that emerged in Wuhan, China at the end of 2019, resulting in a worldwide pandemic
- Infection control guidance for healthcare professionals:
- CDC (CDC: Infection Control Guidance for Healthcare Professionals About Coronavirus (COVID-19) [Accessed 4 August 2020])
- Personal protective equipment (PPE) basics (CDC: Using Personal Protective Equipment (PPE) [Accessed 4 August 2020])
- Autopsy guidelines:
- Personal protective equipment (Pathol Res Pract 2020;216:153039)
- CAP (CAP: Amended COVID-19 Autopsy Guideline Statement from the CAP Autopsy Committee [Accessed 5 February 2021])
- CDC (CDC: Collection and Submission of Postmortem Specimens from Deceased Persons with Known or Suspected COVID-19 [Accessed 4 August 2020])
- RCPath (RCPath: Briefing on COVID-19 [Accessed 7 July 2020])
- Italian experience (Virchows Arch 2020;476:821)
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
Epidemiology
- COVID-19 pandemic
- In December 2019, cases of pneumonia with unknown etiology were reported from Wuhan, Hubei Province, China to WHO (WHO: Novel Coronavirus (2019-nCoV) Situation Report - 1 [Accessed 31 March 2020])
- In January 2020, the Chinese authorities identified a novel type of coronavirus, which was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- At the beginning of February 2020, almost 10,000 cases of COVID-19 were confirmed in China and 100+ cases were detected outside of China (WHO: Novel Coronavirus (2019-nCoV) Situation Report - 11 [Accessed 31 March 2020])
- The disease spread rapidly and became a pandemic with > 100 million confirmed cases and over 2 million deaths worldwide by end of January 2021
- The United States now has the most confirmed cases (> 25 million) and confirmed deaths (> 400,000) worldwide (Reuters: Global COVID-19 Cases Surpass 100 Million as Nations Tackle Vaccine Shortages [Accessed 27 January 2021])
- Coronavirus maps:
- Person to person transmission is suspected to occur via respiratory droplets (cough, sneeze)
- The key to slowing the spread of this disease is widespread testing so that patients can be quickly identified and isolated
- More than 120 SARS-CoV-2 vaccines are under development (JAMA 2020;324:782)
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)
- 10 - 20 times higher binding affinity as compared with the SARS-CoV-1 virus (J Pathol 2020;251:228)
- 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 (medRxiv: Tissue-Specific Tolerance in Fatal COVID-19 [Accessed 27 July 2020])
- 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
Images hosted on other servers:
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)
- 97.5% of people who develop symptoms do so within 11.5 days (JAMA 2020;324:782)
- Asymptomatic infection rate 46% (J Med Virol 2020;92:2543)
- Rare in children, about 2 - 5% of confirmed cases, with milder symptoms, 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
- Distribution of severity (JAMA 2020;323:1239):
- Mild or no disease: 81%
- Severe disease: 14%
- Critical disease: 5%
- Overall case fatality rate: 2.3%
- 20 - 42% of hospitalized patients developed acute respiratory distress syndrome (JAMA Intern Med 2020;180:1, JAMA 2020;323:1061)
- Distribution of severity (JAMA 2020;323:1239):
- 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)
Diagnosis
- Diagnostic testing of SARS-CoV-2 (COVID-19)
- Nasopharyngeal swab is recommended for the specimen; oropharyngeal swab, sputum and bronchoalveolar lavage may be used alternatively (CDC: Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19) [Accessed 31 March 2020])
- Positive rates of SARS-CoV-2 PCR testing by specimen types: bronchoalveolar lavage fluid (93%), sputum (72%), nasal swabs (63%), pharyngeal swabs (32%) (JAMA 2020;324:782)
- Definite diagnosis is based on detection of viral RNA by real time RT-PCR via many available laboratory tests (CDC: Information for Laboratories [Accessed 31 March 2020])
- False negative test results may occur in up to 20 - 67% of patients depending on the quality and timing of testing
- A modeling study estimated sensitivity at 33% 4 days after exposure, 62% on the day of symptom onset and 80% 3 days after symptom onset (JAMA 2020;323:1843)
Laboratory
- Meta analysis data (Travel Med Infect Dis 2020;34:101623):
- Decreased albumin
- High C reactive protein
- High lactate dehydrogenase (LDH)
- Lymphopenia
- High erythrocyte sedimentation rate (ESR)
- D dimer elevation (J Pathol 2020;251:228)
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
Images hosted on other servers:
Chest CT images
Severe changes
Prognostic factors
- Risks of acute respiratory distress syndrome development include age (> 65 years), underlying diseases (diabetes mellitus) and secondary infection (JAMA Intern Med 2020;180:1, Intensive Care Med 2020;46:846)
- Risk factors for disease progression: male, old age (> 65 years) and smoking (J Infect 2020;81:e16)
- Risk factors for critical / mortal states, in order of strength of association (Lancet 2020;395:1054):
- Cardiovascular disease
- Respiratory disease
- Diabetes
- Hypertension
Case reports
- Infant girl with COVID-19 hepatitis (Arch Pathol Lab Med 2020 Apr 17 [Epub ahead of print])
- 44 year old man and 62 year old woman with COVID-19 pneumonia (Diagn Pathol 2020;15:73)
- 65 year old man with multiorgan failure (Hum Pathol 2020;101:82)
- 73 year old man and 84 year old woman with lung cancer and coincidental COVID-19 (J Thorac Oncol 2020;15:700)
- 76 year old woman with COVID-19 pneumonia (N Engl J Med 2020;383:380)
- 79 year old woman with residual SARS-CoV-2 in pulmonary tissues (Cell Res 2020;30:541)
- Autopsy case series (Lancet Respir Med 2020;8:420, Preprints 2020;2020030311)
Treatment
- Home management is recommended for patients with mild symptoms
- Optimal duration of home isolation is under investigation but virus is shed for an average of approximately 20 days after disease onset in hospitalized patients (Lancet 2020;395:1054)
- Patients with severe disease require hospital care
- May need oxygenation support, ranging from low dose oxygen supplement to invasive ventilation and extracorporeal membrane oxygenation (ECMO)
- Among antiviral drugs (ribavirin, favipiravir, remdesivir) undergoing clinical testing, remdesivir seems to be most promising (JAMA 2020;324:782)
- NIH COVID-19 Treatment Guidelines Panel recommends using dexamethasone in patients on ventilators and those whom require supplemental oxygen but not in other patients (Lancet 2020;395:1054, CDC: Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) [Accessed 31 March 2020], WHO: Coronavirus disease (COVID-19) Technical Guidance - Patient Management [Accessed 31 March 2020], NIH: COVID-19 Treatment Guidelines - Corticosteroids [Accessed 8 April 2021])
Gross description
- From pulmonary edema to lung consolidation (J Clin Pathol 2020;73:239)
- Increased lung weight
- Hemorrhagic changes (Mod Pathol 2020;33:2128)
- Macroscopic pulmonary emboli (Mod Pathol 2020;33:2128)
- Pleurisy (pleural inflammation) may be seen
- Purulent inflammation, if secondary infection superimposed
Gross images
Images hosted on other servers:
Grossing protocol
Thickened alveolar septae, 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, Preprints 2020;2020030311)
- 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
- Fibrotic (22%): fibrotic DAD, interstitial fibrosis
- Viral infection changes:
- Multinucleated enlarged pneumocytes with large nuclei, amphophilic cytoplasm and prominent nucleoli in alveolar spaces
- Intranuclear inclusions
- Bacterial pneumonia may be superimposed
- Findings of diffuse alveolar damage (DAD) corresponding to the phase of disease:
- 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
- Cardiovascular: mild pericardial edema, some serosanguinous pericardial effusion, mild myocardial edema, low grade interstitial infiltration of mononuclear cells, endotheliitis
Microscopic (histologic) images
Contributed by Toru Igari, M.D., Jin Takahashi, M.D. and Shinyu Izumi, M.D.
Low power
Bronchial change
Squamous metaplasia
Acute phase
Hyaline membranes
Low power
Organizing phase
Fibroblastic proliferation
Lymphocytic infiltration
Pneumocyte hyperplasia
Epithelial denudation
Epithelial denudation
Perivascular lymphocytes
Clear cell change
Multinucleation
Images hosted on other servers:
Diffuse alveolar damage
Marked alveolar hemorrhage
Lung injury patterns
Thromboemboli
Extrapulmonary
SARS-CoV-2 in lung
Virtual slides
Cytology description
- Bronchoalveolar lavage (BAL):
- 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
Cytology images
Images hosted on other servers:
BAL specimen
Positive stains
- IHC positive for SARS-CoV-2 antigen detected in pneumocytes, ciliated airway cells and upper airway epithelium in the acute phase (Mod Pathol 2020;33:2104)
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
Images hosted on other servers:
Scanning electron microscopy
Transmission electron microscopy
Virus in epithelial cells
Molecular / cytogenetics description
- ISH, including RISH and FISH positive for SARS-CoV-2 antigen detected in pneumocytes, ciliated airway cells and upper airway epithelium in the acute phase (Lab Invest 2020;100:1485, JCI Insight 2020;5:139042)
- Guidelines from CDC (CDC: Information for Laboratories [Accessed 31 March 2020])
- Diagnostic testing of SARS-CoV-2 (COVID-19)
Videos
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
- Diffuse alveolar damage due to COVID-19 is morphologically indistinguishable from other DAD causes (Histopathology 2020;77:570), including other viral pneumonias: cytomegalovirus, respiratory syncytial virus and herpes simplex virus
- Severe acute respiratory syndrome: detection of SARS virus
- Acute respiratory distress syndrome of other etiology
- Acute interstitial pneumonia: idiopathic by definition
Additional references
- WHO: Coronavirus Disease (COVID-19) Pandemic [Accessed 31 March 2020], CDC: Coronavirus (COVID-19) [Accessed 31 March 2020]
- General biosafety guideline protocol for histological and cytological samples from patients with suspected or proven COVID-19 infection (Cancer Cytopathol 2020;128:317)
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?
- Alveolar hemorrhage
- Dense collagenous fibrosis
- Fibrinoid necrosis of small vessels
- Fibroblastic proliferation
- Hyaline membrane formation
Board review style answer #1
Board review style question #2
Which is the target organ affected by SARS-CoV-2 and responsible for the major manifestation of COVID-19?
- Brain
- Heart
- Kidney
- Liver
- Lung
Board review style answer #2
Board review style question #3
Which of the following findings suggests viral infection of the lung?
- Alveolar hemorrhage
- Fibrin deposition
- Neutrophilic aggregation
- Nuclear inclusions
- Type II pneumocyte hyperplasia
Board review style answer #3
