Diagnosis and Treatment of COVID-19 Pneumonia: Chinese Clinical Guidance (7th Edition)

The novel coronavirus (SARS-CoV-2) has caused a pneumonia epidemic that emerged in Wuhan, Hubei Province, from December 2019 onward. As the epidemic spread, similar cases were detected in other Chinese cities and in many countries. Under the People's Republic of China's law on the prevention and control of infectious diseases, this acute infectious respiratory illness was categorized as a class B infectious disease and managed as a class A infectious disease. Although many preventive control and medical treatment measures were taken, the epidemic's upward trend in China could be limited to a certain degree. Later, the epidemic eased in most parts of China, but case numbers detected in other countries rose rapidly.

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With a deeper understanding of the disease's clinical and pathological features and growing experience in diagnosis and treatment, we are publishing a translation of the 7th edition of the clinical guidance to strengthen early diagnosis and treatment, increase the cure rate, reduce mortality and prevent hospital-acquired infection.

1. Etiology (the cause of the disease)

The novel coronavirus (SARS-CoV-2) belongs to the β coronavirus genus. It is an enveloped virus, round or oval in shape, measuring 60-140 nanometers (nm) in diameter. SARS-CoV-2's genetic characteristics differ from SARS-CoV-1 and MERS-CoV, with 80% similarity to SARS-CoV-1. It shows 85% homology with the SARS-like coronavirus isolated from bats, bat-SL-CoVZC45. SARS-CoV-2 can be detected in human respiratory epithelial cells in vitro for up to 96 hours, but isolation and culture in Vero E6 and Huh-7 cell lines take approximately 6 days.

Our current biochemical understanding of SARS-CoV-2 comes mainly from previous studies of SARS-CoV and MERS-CoV. SARS-CoV-2 is sensitive to ultraviolet light and heat, 30 minutes at 56 °C. It is also inactivated by lipid solvents such as ether, 75% ethanol, chlorine-containing disinfectants and chloroform. Chlorhexidine, however, has been shown to be ineffective.

Epidemiology

Epidemiology is a branch of medical science that examines the distribution and frequency of disease, accidents and health-related conditions in populations, and the factors affecting them. Its aims include collecting, interpreting and using health information to improve health and reduce disease.

Below is an epidemiological comparison of viruses that cause respiratory infections.

For COVID-19:

1. Source of infection Symptomatic and asymptomatic infected patients are sources of infection. Asymptomatic patients are thought to be the main source of its spread.
2. Route of transmission SARS-CoV-2 spreads through respiratory droplets and close contact. Aerosol, or airborne, transmission can occur when people are exposed for prolonged periods to aerosols containing high concentrations of the virus in relatively enclosed spaces.
   Note: aerosols are solid or liquid particles that can remain suspended in air. Their diameters can range from 0.003 micrometers to 100 micrometers.
3. Susceptible population People are generally susceptible to COVID-19. It is not yet clear why some have no symptoms while others develop symptoms and may experience severe disease.

Pathology

The following summary is based on a limited number of autopsy and biopsy findings.

Lungs

Different degrees of lung consolidation were observed. Alveolar cavities were filled with fibrin exudate and hyaline membrane formation. Exudative cells consisted mainly of mononuclear cells and macrophages. Multinucleated giant cells were common. Type 2 alveolar epithelial cells had proliferated substantially, and some had shed into the alveolar cavity. Inclusion bodies were present in type 2 alveolar epithelial cells and macrophages. Hyperemia and edema were common in alveolar septal regions. Mononuclear cell and lymphocyte infiltration, intravascular hyaline thrombosis, focal hemorrhage and necrosis of lung tissue were visible, and hemorrhagic infarction had occurred. Pathological features of organizing pneumonia and pulmonary interstitial fibrosis could be observed in the lung parenchyma.

Intrapulmonary bronchial epithelial cells had exfoliated, and the bronchial cavities were filled with mucus plugs. In some areas, pulmonary alveoli were hyperinflated, alveolar septa had ruptured and cystic formations had developed.

Coronavirus particles were detected in bronchial epithelium and type 2 alveolar epithelial cells by electron microscopy. Some alveolar cells and macrophages stained positive for SARS-CoV-2 antigen on immunohistochemistry. SARS-CoV-2 nucleic acids were detected by RT-PCR.

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Spleen, hilar lymph nodes and bone marrow

The spleen was substantially smaller, and its lymphocytes were severely reduced in number. Visible focal hemorrhage and necrosis were present. Macrophage proliferation and phagocytosis were also observed. Lymphocytes in the lymph nodes were also reduced and necrotic. Immunohistochemical staining showed a substantial reduction in CD4- and CD8-positive T cells in both the spleen and lymph nodes. All hematopoietic cell lineages in the bone marrow were reduced.

Cardiovascular system

Some cardiomyocytes were found to be degenerated and necrotic, and small numbers of monocytes, lymphocytes and/or neutrophils had infiltrated the myocardium. In some areas, vascular endothelial cells had detached from the vessel lining where inflammation and thrombosis had occurred.

Liver and gallbladder

The liver was characterized by increased volume, a dark red color, hepatocyte degeneration, focal necrosis with neutrophil infiltration, hepatic sinus congestion, lymphocyte and monocyte infiltration in portal areas, and microthrombus formation. The gallbladder was also substantially enlarged.

Kidney

Protein exudate was present in Bowman's capsule. The renal tubular epithelium had denatured and exfoliated, and hyaline casts had formed. Interstitial hyperemia, microthrombi and focal fibrosis could be observed.

Other organs

Brain tissue was congested and edematous, and some neurons were degenerated. Focal necrosis was present in the adrenal glands. The esophageal, gastric and intestinal epithelium showed varying degrees of denaturation, necrosis and exfoliation.

Clinical features

Clinical presentation

According to current epidemiological data, the incubation period is 1-14 days. Most patients develop symptoms within 3-7 days.

Fever, dry cough and malaise are the main manifestations. Other symptoms include nasal congestion, runny nose, sore throat, myalgia and diarrhea. Severe cases may present with dyspnea and/or hypoxemia within 1 week of onset. Some may deteriorate rapidly, progressing to ARDS, septic shock, refractory metabolic acidosis, coagulopathy and multiple organ failure (MOF). Notably, some severe cases had only a mild fever throughout the illness, and some had no fever at all.

Some children and newborns have shown atypical symptoms, such as vomiting, diarrhea and other gastrointestinal disturbances, or only mild drowsiness and shortness of breath.

Mild cases presented with low-grade fever and mild malaise, without visible findings of pneumonia.

According to our current observations, most patients have a good prognosis, while a small proportion become critically ill. The prognosis is relatively worse in older patients and those with comorbidities. COVID-19 pneumonia follows a similar course in pregnant women and patients of the same age. Symptoms in children are relatively mild.

Laboratory investigations

Routine investigations

Early in the disease, the total peripheral white blood cell count may be normal or low, while the lymphocyte count is low. Some patients have elevated liver transaminases, lactate dehydrogenase, creatine kinase and myoglobin. Troponin levels are also elevated in critical cases. CRP and ESR are elevated in most patients, while procalcitonin is generally within normal limits. Importantly, D-dimer rises markedly in severe cases and the peripheral lymphocyte count falls progressively. Inflammatory biomarkers are generally elevated in severe cases.

Etiological and serological investigations

Etiological investigations: SARS-CoV-2 nucleic acids can be detected in nasopharyngeal swabs, sputum and other lower respiratory secretions, blood and stool using RT-PCR and next-generation sequencing (NGS). Detection in lower respiratory secretions provides more accurate results. Samples should be tested immediately after collection.

Serology: IgM antibodies specific to the COVID-19 agent become positive 3-5 days after disease onset. During recovery, the IgG antibody titer is 4 times its level in the acute phase.

Chest imaging

In the early stages of the disease, patchy opacities and interstitial changes appear in the lungs, more prominently in the peripheral zones. Ground-glass appearances and widespread infiltrates develop later. Cases involving pain may show consolidation. Pleural effusion is rare.

Diagnostic criteria

Figure 1: The tests used to diagnose SARS-CoV-2 and a summary of the immune damage mechanism it causes are shown below.

There are two main types of tests for diagnosing the novel coronavirus SARS-CoV-2:

1. Polymerase chain reaction (Polymerase Chain Reaction = PCR) and
2. Rapid diagnostic tests

The PCR test screens the viral genome in a nasopharyngeal sample, a swab of the nose and throat; for this coronavirus, the genome is RNA. The procedure takes 45 - 90 minutes. It is also called a molecular diagnostic test.

Rapid diagnostic tests screen for the virus's antigens or the immune system 's antibodies against the virus. Rapid diagnostic tests can use either nasal and throat swabs or blood. Swabs are examined for viral antigens, whereas blood is examined for antibodies developed against the virus.

Figure 2: The types of coronavirus tests and the samples used can be seen below.

Suspected cases

Epidemiological history

A history of travel to Wuhan and surrounding areas, or to an area with a documented COVID-19-positive case, in the 14 days before disease onset.

A history of contact with a COVID-19-positive case, confirmed by nucleic acid detection, in the 14 days before disease onset.

A history of contact in the 14 days before disease onset with a patient who has fever and respiratory symptoms and had traveled to Wuhan and surrounding areas or an area with a documented COVID-19-positive case.

Cluster onset: 2 or more cases developing fever and/or respiratory complaints within 2 weeks in small settings such as a home, office or school.

Clinical presentation

• Fever and/or respiratory symptoms.
• The radiological findings described above for COVID-19 pneumonia.
• A normal or low white blood cell count in the early stage.

A case can be considered suspected if it meets any of the epidemiological history criteria above and any two clinical criteria. If a clear epidemiological history cannot be obtained, all three clinical criteria must be met.

Confirmed cases

Suspected cases meeting any of the following criteria are considered confirmed:

• SARS-CoV-2 nucleic acid positivity by RT-PCR
• Detection through gene sequencing of a viral gene highly homologous to SARS-CoV-2
• Positive COVID-19-specific IgM and IgG antibodies
• Chest CT findings specific to COVID-19 pneumonia

Clinical classification

1. Mild type: Mild clinical symptoms without signs of pneumonia on chest imaging.
2. Moderate type: Fever and respiratory symptoms with radiological evidence of pneumonia.
3. Severe type:
   Adults meeting any of the following criteria:
   - Shortness of breath, respiratory rate (RR) ≥ 30/min
   - Oxygen saturation at rest ≤ 93%
   - Intra-alveolar oxygen partial pressure / fraction of O2 in inspired air (PaO2/FiO2) ≤ 300 mmHg (1 mmHg = 0.133 kPa). At high altitudes, 1000 meters and above, PaO2/FiO2 should be corrected using: PaO2/FiO2×[Atmospheric pressure/760]
   Children meeting any of the following criteria:
   - Shortness of breath: RR≥60/min between 2 and 12 months; RR≥50/min below age 2; RR≥40/min between ages 1 and 5; RR≥30/min above age 5. The effects of crying and fever should be excluded.
   - Oxygen saturation at rest ≤ 92%
   - Labored breathing, sighing and retraction of accessory respiratory muscles
   - Lethargy and convulsions
   - Difficulty breastfeeding or feeding, signs of dehydration
4. Critical type:
   Patients meeting any of the following criteria:
   - Respiratory failure requiring mechanical ventilation
   - Clinical shock
   - Other organ failure requiring intensive care
   Warning signs for severe and critically severe disease
   1. Adults
   1. Progressive decline in peripheral lymphocyte count
   2. Progressive rise in inflammatory biomarkers such as IL-6 and CRP
   3. Progressive rise in lactate levels
   4. Rapid progression of pulmonary lesions
   2. Pediatric patients
   1. Increased respiratory rate
   2. Reduced mental responsiveness and drowsiness
   3. Progressive rise in lactate levels
   4. Bilateral or multilobar infiltration and pleural effusion, or rapid progression of pulmonary lesions
5. Infants younger than 3 months, children with coexisting conditions such as congenital heart disease, bronchopulmonary dysplasia, respiratory deformities, hemoglobinopathies or severe malnutrition, and children with immunodeficiency or receiving long-term immunosuppressive treatment.

Differential diagnosis

• Mild signs and symptoms of COVID-19 infection must be distinguished from upper respiratory infections caused by other viruses.
• COVID-19 pneumonia should be distinguished from other viral pneumonias, such as influenza, adenovirus and respiratory syncytial virus, and from mycoplasma pneumonia. Rapid antigen tests and/or multiplex PCR for viral agents should be used in suspected cases.
• It should also be distinguished from noninfectious diseases such as vasculitis, dermatomyositis and organizing pneumonia.

Case identification and registration

When a suspected COVID-19 case is identified, the patient must immediately be isolated in a single room for further monitoring and treatment. If the case remains suspected after comprehensive assessment, it must be reported online to the CDC within 2 hours. A sample should also be collected for COVID-19 nucleic acid testing. Meanwhile, the patient should be transferred to a designated hospital using safe transport procedures. If a suspected case has a history of close contact with someone previously diagnosed with COVID-19 pneumonia, nucleic acid testing for COVID-19 should be performed even when tests for other common respiratory pathogens are positive.

COVID-19 can be excluded if two consecutive COVID-19 nucleic acid tests are negative, with at least 24 hours between tests, and COVID-19-specific IgG and IgM remain negative 7 days after onset.

Treatment

The treatment setting should be selected according to the patient's clinical classification above.

• Suspected and confirmed patients should be isolated and treated in designated hospitals using effective isolation and protective measures.
• Critically severe patients should be admitted to intensive care units as soon as possible.

General treatment

• Patients should be placed on bed rest with supportive treatment to ensure adequate energy intake. Water and electrolyte balance should be observed and recorded. Vital signs and oxygen saturation should be monitored closely.
• Routine blood and urine tests, CRP, biochemical markers such as liver enzymes, cardiac enzymes and renal function tests, a coagulation panel, arterial blood gases and chest imaging should be monitored. Cytokine testing should be performed if possible.
• Effective oxygen treatment should be provided promptly. This includes nasal cannula, oxygen mask and high-flow nasal cannula oxygen therapy. Hydrogen-oxygen inhalation treatment (H2/O2: 66.6% / 33.3%) should be considered.
• Antiviral treatment may be tried: α-interferon, 5 million units or equivalent in adults, with 2 ml sterile water added, inhaled 2 times daily; lopinavir/ritonavir, 200 mg/50 mg/capsule, 2 capsules 2 times daily in adults, with total treatment not exceeding 10 days; Ribarvirin, recommended in combination with interferon or lopinavir/ritonavir, 500 mg per dose IV 2-3 times daily for no more than 10 days; chloroquine phosphate, 500 mg per dose 2 times daily for 7 days in adults over 50 kg, and 500 mg per dose in adults under 50 kg, 2 times daily for the first 2 days and once daily on subsequent days (3-7); and Abidol, 200 mg per dose 3 times daily in adults for no more than 10 days. Attention should be paid to possible adverse effects, contraindications, including not using chloroquine in people with heart disease, and drug interactions. Using 3 or more antiviral agents together is not recommended.
• Drugs should be stopped when intolerable adverse effects occur. Gestational age should be considered when treating pregnant women, and the drug with the least effect on the fetus should be chosen. Inappropriate antibacterial drugs, particularly broad-spectrum agents, should be avoided.

Note: Current studies have not demonstrated benefits from chloroquine and hydroxychloroquine (Plaquenil). Respiratory function has even been reported to worsen in patients taking hydroxychloroquine compared with the control group, and hydroxychloroquine use has not been reported to reduce mortality.

Treatment of severe and critically severe patients

In addition to symptomatic treatment, it is important to prevent complications effectively, treat underlying diseases, prevent secondary infections and support organ function.

• Oxygen therapy: Patients with severe illness should start oxygen support through a nasal cannula or mask, with monitoring of whether respiratory distress and/or hypoxemia improve over time.
• High-flow nasal cannula therapy or noninvasive mechanical ventilation: These should be considered in patients who do not improve with standard oxygen support. If the patient deteriorates or does not improve within a short period, 1-2 hours, despite these measures, endotracheal intubation should be performed and invasive mechanical ventilation started.
• Invasive mechanical ventilation: A lung-protective ventilation strategy should be chosen to avoid ventilator-associated lung injury: a small tidal volume, 6-8 mL/kg of ideal body weight, and low airway plateau pressure, ≤30 cm H2O. When airway plateau pressure is kept at ≤35 cm H2O, the ventilator can be adjusted appropriately for a high PEEP value. The airway should be kept warm and humid. Prolonged sedation should be avoided, and patients should be awakened as early as possible and started on pulmonary rehabilitation. Sedatives and muscle relaxants should be used appropriately in patients with synchronization problems during mechanical ventilation. If secretions obstruct the airway, sputum should be aspirated, and bronchoscopy performed when necessary.
• Rescue treatment: Lung expansion is recommended for patients with severe ARDS. Mechanical ventilation in the prone position should be performed for more than 12 hours daily. If prone mechanical ventilation is ineffective, extracorporeal membrane pulmonary oxygenation (ECMO) should be considered as soon as possible if available. Relative indications are: (1) PaO2 remaining below 80 mmHg for at least 3-4 hours with FiO2≥90%; (2) respiratory failure developing while airway plateau pressure is ≥35 cm H2O. VV-ECMO mode should be preferred, but VA-ECMO mode should be chosen if circulatory support is also needed. Gradual weaning should begin when the underlying disease is controlled and cardiopulmonary function shows signs of improvement.
• Circulatory support: Vasoactive drugs should be considered after adequate fluid resuscitation. Lactate and base deficit in arterial blood gases, urine output, blood pressure and heart rate should be closely monitored. Fluid balance should be followed carefully during treatment. If heart rate rises by 20% from baseline or blood pressure falls by more than 20% from baseline, accompanied by signs of poor skin perfusion and reduced urine output, be alert for progression to septic shock, gastrointestinal bleeding and severe heart failure.
• Renal failure and renal replacement therapy: If renal failure develops, underlying causes such as hypoperfusion and drugs should be analyzed. Fluid, acid-base and electrolyte balance should be maintained. Nitrogen balance should be considered when providing nutritional support. Renal replacement therapy should be considered in severe cases. Indications include management of fluid balance in (1) hyperkalemia, (2) acidosis, (3) pulmonary edema or fluid overload, and (4) MOF.
• Plasma therapy from recovered patients: Appropriate for rapidly progressing severe and critically severe cases.
• Blood purification treatment: This includes plasma exchange, adsorption, perfusion and blood/plasma filtration. By reducing inflammatory factors, these treatments may prevent a cytokine storm and thus reduce damage caused by the body's inflammatory response. They may be used in severe and critically severe cases during early or intermediate cytokine storms.
• Immunotherapy: Tocilizumab may be tried in patients with widespread lung lesions and high IL-6 levels. The first dose is 4-8 mg/kg. The recommended dose is 400 mg, diluted in 100 ml normal saline. Infusion should take more than 1 hour. If the first treatment is ineffective, it can be repeated at the same dose after 12 hours. The drug should not be administered more than 2 times in total, and the maximum single dose should not exceed 800 mg. Be alert for allergic reactions. It is not recommended for patients with other active infections, such as tuberculosis.
• Other treatment measures: Glucocorticoids for 3-5 days should be considered in patients with progressively worsening oxygenation indicators and an excessive inflammatory response. The daily methylprednisolone dose should not exceed 1-2 mg/kg. Keep in mind that high-dose glucocorticoids prolong coronavirus clearance. Gut microbiota balance should be maintained and secondary bacterial infections prevented. IVIG should be considered in severe and critically severe pediatric cases. Termination of pregnancy should be considered in severe and critically severe pregnant patients. Delivery should be by C/S. Psychiatric and psychological support should be provided to manage anxiety.

Discharge criteria and post-discharge precautions

Discharge criteria

• Body temperature has returned to normal for more than 3 days
• Significant improvement in respiratory symptoms
• Significant improvement in acute exudative lesions on lung imaging
• Negative nucleic acid tests on 2 consecutive occasions, at least 24 hours apart, for sputum, nasopharyngeal swabs and other respiratory samples

Patients meeting all the criteria above may be discharged.

Post-discharge precautions

• Hospitals should communicate well with primary healthcare centers about the patient and share medical details when necessary.
• Isolation precautions should continue for 14 days after discharge. The patient should not go out, should wash hands frequently, stay in a single well-ventilated room and minimize contact with family members.
• Follow-up at the hospital is recommended in week 2 or 4 after discharge.

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