Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2).
SARS-CoV-2 is enveloped, round or oval, often polymorphic, and 60 - 140nm in diameter. The spikes on the surface are like a royal crown, so it is named for coronavirus. Its genetic characteristics are significantly different from SARS-CoV and MERS-CoV. Current researches have indicated that the virus has more than 85% homology with SARS-like coronavirus in bats (bat-SL-CoVZC45). In isolation and in vitro culture, SARS-CoV-2 can be found in human respiratory epithelial cells in about 96 hours, while it takes about 6 days to isolate and culture in Vero E6 and Huh-7 cell lines.
Figure 1 SARS-CoV-2
The virus is sensitive to ultraviolet light and heat. Lipid solvents such as ether, 75% ethanol, chlorine-containing disinfectants, peracetic acid, and chloroform can effectively inactivate the virus, and the virus can be inactivated at 56 °C for 30 minutes, whereas chlorhexidine cannot effectively inactivate the virus.
The receptor is angiotensin-converting enzyme 2 (ACE2) in humans, and ACE2 are present mostly in the lung. Once the coronavirus enters the respiratory tract and contacts the lung epithelial cells, the spikes adhere to the ACE2, and the virus begin to replicate.
Figure 2 the binding of SARS-CoV-2 with ACE2 in human body
Sources of infection
The sources of infection are mainly patients with NOVID-19. Asymptomatic patients can also be the sources of infection.
Modes of transmission
Respiratory droplets and close contacts are the main routes of transmission, and prolonged exposure to high concentrations of aerosols in a relatively closed environment may be a transmission route. As the virus can be isolated from feces and urine, attention should be paid to aerosols or exposure to environmental contamination caused by feces or urine.
Humans are generally susceptible.
Signs and Symptoms
The incubation period is 1 - 14 days, mostly 3 - 7 days.
Main symptoms are fever, fatigue, and dry cough. Some patients have nasal congestion, runny nose, sore throat, myalgia, and diarrhea. Severe patients often develop dyspnea or hypoxemia 1 week after onset, quickly progressing into acute respiratory distress syndrome, septic shock, metabolic acidosis difficult to correct, coagulation disorders, and multiple organ dysfunction syndrome. Critical patients may be with moderate or mild fever, even without obvious fever.
Some children and neonates may have atypical symptoms, manifested by gastrointestinal symptoms such as vomiting and diarrhea or only mental weakness and shortness of breath.
Mild patients are manifested by low fever, mild fatigue, and absence of pneumonia.
In the early stage, the total count of white blood cells in the peripheral blood is normal or declined, the lymphocyte count is decreased, some patients may have increased liver enzymes, LDH, muscle enzymes, and myoglobin, and some critical patients can have increased troponin. Most patients have elevated C-reactive protein (CRP) levels and erythrocyte sedimentation rate and normal procalcitonin. In severe patients, D-dimer levels are elevated and lymphocytes in peripheral blood are progressively decreased. Increased inflammatory cytokines can be seen in severe and critical patients.
The viral nucleic acid of SARS-CoV-2 can be detected with RT-PCR or NGS in nasopharyngeal swabs, sputum, other lower respiratory tract secretions, blood, and feces. The results from lower respiratory tract specimens, such as sputum or airway extraction, are more accurate. Immediate inspection of specimens after collection should be performed.
Most specific IgM antibodies occur 3 - 5 days after onset. A 4-fold rise of IgG antibody titers in the recovery period than in the acute phase can be tested.
Multiple small patchy shadows and interstitial changes are present in the early stage, obviously in the periphery, developing into multiple ground glass opacity and infiltration shadows in the lungs. In severe cases, pulmonary consolidation can be seen. Pleural effusion is less common.
Figure 3 manifestations of COVID-19 in chest imaging
Consolidation with varying degrees is present in lungs.
Serum, fibrinous exudate, and transparent membrane formation can be seen in the alveolar cavity. Exudations are mainly composed of mononuclear cells and macrophages, and multinucleated giant cells are easily seen. Type II alveolar epithelial cells are proliferated significantly, and some cells are exfoliated. Inclusion bodies can be seen in type II alveolar epithelial cells and macrophages. Alveolar septal vascular congestion and edema, monocyte and lymphocyte infiltration, and intravascular hyaline thrombosis can be seen. Focal hemorrhage and necrosis of the lung tissue may cause hemorrhagic infarction. Organization of some alveolar exudates and pulmonary interstitial fibrosis are present.
Exfoliated epithelium of the bronchial mucosa in the lungs are seen, and mucus and mucus plug formation are visible in the cavity. Overinflation, ruptured alveolar septum, or cystic cavity formation can be seen.
Coronavirus particles can be seen in the cytoplasm of bronchial mucosal epithelium and type II alveolar epithelial cells in electron microscopy. Immunohistochemistry shows that some alveolar epithelia and macrophages are positive for SARS-CoV-2 antigens, and positive coronavirus nucleic acids are present in RT-PCR tests.
Spleen, hilar lymph nodes, and bone marrow
The size of spleen is significantly reduced, and the count of lymphocytes is obviously reduced. Focal hemorrhage and necrosis, macrophage proliferation, and phagocytosis are visible in the spleen. The count of lymphocytes in lymph nodes is declined, and necrosis can be seen. Immunohistochemistry shows that CD4+ and CD8+ T cells are reduced in the spleen and lymph nodes. Granulocytes, erythrocytes, and megakaryocytes in bone marrow are decreased.
Heart and blood vessels.
Degeneration and necrosis of myocardial cells can be seen, and mild monocyte, lymphocyte, or neutrophil infiltration is present in the interstitials. Endothelial exfoliation, intimitis, and thrombosis in some blood vessels are present.
Liver and gallbladder
Dark red, enlarged liver can be seen. Hepatocyte degeneration, focal necrosis, neutrophil infiltration, congestion of hepatic sinusoids, lymphocyte and monocyte infiltration in the portal areas, and microthrombosis are visible. The gallbladder is full and plentiful.
Exudates in the glomerular capsules, degenerated and exfoliated renal tubular epithelium, and hyaline casts can be seen. Interstitial hyperemia, microthrombus, and focal fibrosis are visible.
Congestion and edema of brain tissue and degeneration of some neurons are present. Focal necrosis in the adrenal glands is visible. Degeneration, necrosis, and exfoliation of mucosal epithelium of the esophagus, stomach, and intestines can be seen.
Considerations in epidemiology
- Travel or residence history in the epidemic areas within 14 days before onset
- Exposures to patients with fever or respiratory symptoms in the epidemic areas within 14 days before onset
- Onset in groups
- History of contacts with patients infected with COVID-19
Considerations of clinical manifestations
- Fever or respiratory symptoms
- Imaging characteristics of pneumonia mentioned above
- Normal or decreased total count of white blood cells and lymphocytes in the early stage
If one consideration in epidemiology and two considerations in clinical manifestations are present, or considerations in epidemiology are absent but 3 considerations in clinical manifestations are present, the case is suspected.
If suspected cases with one of the following pathogenic evidences, the case can be confirmed.
- Positive SARS-CoV-2 nucleic acids detected with real time reverse transcription polymerase chain reaction (RT-PCR)
- Highly homologous viral genes to known novel coronaviruses with gene sequencing
- Positive specific IgM antibodies and IgG antibodies in serum, specific IgG antibodies changed from negative to positive or with a 4-fold rise in titers in the recovery period than in the acute phase.
The clinical symptoms are mild, and pneumonia is absent on chest imaging.
Fever and respiratory tract symptoms are present, and chest imaging reveals pneumonia.
Severe cases in adults
At least one of the following are present.
- Respiratory distress, RR≥30 /minute
- In the resting state, the oxygen saturation in fingers ≤93%
- Arterial oxygen partial pressure (PaO2) / concentration of oxygen inhalation (FiO2) ≤300mmHg (1mmHg = 0.133kPa), and PaO2 / FiO2 should be adjusted according to the formula of PaO2 / FiO2 × [atmospheric pressure (mmHg) / 760] in high altitude areas (1000 meters above)
- Significant progression of lesions > 50% within 24-48 hours in chest imaging
Severe cases in children
At least one of the following are present.
- Respiratory distress, RR≥60 /minute in children aged < 2 months, RR≥50 /minute in children aged 2 - 12 months, RR≥40 /minute in children aged 1 - 5 years, RR≥30 /minute in children aged > 5 years, with the exclusion of interferes caused by fever or crying
- In the resting state, the oxygen saturation in fingers ≤92%
- Assisted respiration (groaning, nasal flaring, three concave sign), cyanosis, and intermittent apnea
- Hypersomnia and convulsions
- Apocleisis or feeding intolerance, signs of dehydration
At least one of the following are present.
- Respiratory failure and mechanical ventilation required
- Other organ failures and ICU required
Clinical alarms for severe and critical patients
- Progressive decline of lymphocytes in peripheral blood
- Progressive rise of inflammatory factors such as IL-6 and C-reactive protein in peripheral blood
- Progressive elevation of lactic acid
- Rapid progresses of intrapulmonary lesions in the short term
- Increased respiratory rate
- Poor mental response and somnolence
- Progressive elevation of lactic acid
- Bilateral or multilobar infiltration, pleural effusion, or rapid progression in the short term
- Infants aged < 3 months, or children with underlying diseases, such as congenital heart disease, bronchopulmonary dysplasia, respiratory malformations, abnormal hemoglobin, and severe malnutrition, with immunodeficiency, or immunocompromised
The mild manifestations of COVID-19 need to be differentiated from respiratory infections caused by other viruses.
Pneumonia in COVID-19 is mainly differentiated from other known viral pneumonia caused by influenza virus, adenovirus, and respiratory syncytial virus and mycoplasma pneumoniae infections. For suspected cases, rapid antigen detections and PCR nucleic acid detections should be performed to detect common respiratory pathogens.
The disease should also be differentiated from non-infectious diseases, such as vasculitis, dermatomyositis, and cryptogenic organizing pneumonia.
Determination of the treatment places according to the condition
- Suspected and confirmed patients isolated and treated in designated hospitals.
- Critical patients admitted to intensive care unit (ICU) as soon as possible.
- Bed rest, supportive treatment
- Monitors of blood routine, urine routine, CRP, biochemical indicators (liver enzyme, myocardial enzyme, renal function), coagulation function, arterial blood gas analysis, and chest imaging
- Effective oxygen therapy, including nasal cannulas, oxygen masks, transnasal high-flow oxygen therapy, and mixed hydrogen-oxygen inhalation treatment (H / 02: 66. 6% / 33. 3%)
- Antiviral therapy: α-interferon 5,000,000U twice a day, lopinavir / ritonavir 400mg / 100mg orally twice daily for less than 10 days, or ribavirin 500mg IV 2 - 3 times daily for less than 10 days, chloroquine phosphate 500mg for 18 - 65 years old adults with a body weight ≥ 50kg orally twice a day for 7 days and twice for the first and second day and once for the remaining 5 days for those with a body weight < 50kg, umifenovir 200mg orally 3 times a day for less than 10 days, can be used alone or in combination.
- Antibacterial treatment: inappropriate antibacterial drugs, especially combinations of broad-spectrum antibacterial drugs, should be avoided.
Treatment of severe and critical patients
On the basis of symptomatic treatment, active prevention of complications, treatment of underlying diseases, prevention of secondary infections, and organ function supports should be performed.
Respiratory supports include:
- Oxygen therapy
- High-flow nasal cannula oxygen therapy or non-invasive positive pressure ventilation
- Invasive mechanical ventilation
- Salvage treatment, such as lung recruitment, prone position ventilation, and extracorporeal membrane oxygenation (ECMO)
- Circulation support
- Continuous renal replacement therapy
- Convalescent plasma therapy
- Continuous blood purification
- Immunotherapy, such as tocilizumab 4 - 8mg/kg diluted with 100ml of 0.9% normal saline for severe patients with increased IL-6, cumulative administration < twice, maximum single dose < 800mg
According to the degree of dyspnea and chest imaging progress, glucocorticoids can be used within a short period of time such as 3 to 5 days as appropriate. Intestinal microecological modulators can prevent secondary bacterial infections.
Intravenous immunoglobulin in severe and critical children may be considered as appropriate.
Termination of pregnancy should be performed in pregnant women with severe or critical COVID-19, and cesarean section is preferred.
Patients often have anxiety and fear, and psychological counseling should be strengthened.
Most patients have a good prognosis, and few are severe or critical. The prognosis is poor in old adults and those with chronic underlying diseases. The clinical processes of pregnant women with COVID-19 are similar to those of patients at the same age. Symptoms in children are relatively mild.