Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (COVID-19)

(Trial Version 7 - Released by National Health Commission & State Administration of Traditional Chinese Medicine on March 3, 2020 - Translated by the World Health Organisation China Office)

Since December 2019, multiple cases of novel coronavirus pneumonia (NCP) have been identified in Wuhan, Hubei. With the spread of the epidemic, such cases have also been found in other parts of China and other countries. As an acute respiratory infectious disease, NCP has been included in Class B infectious diseases prescribed in the Law of the People's Republic of China on Prevention and Treatment of Infectious Diseases, and managed as an infectious disease of Class A. By taking a series of preventive control and medical treatment measures, the rise of the epidemic situation in China has been contained to a certain extent, and the epidemic situation has eased in most provinces, but the incidence abroad is on the rise. With increased understanding of the clinical manifestations and pathology of the disease, and the accumulation of experience in diagnosis and treatment, in order to further strengthen the early diagnosis and early treatment of the disease, improve the cure rate, reduce the mortality rate, avoid nosocomial infection as much as possible and pay attention to the spread caused by the imported cases from overseas, we revised the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 6) to Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7).

I. Etiological Characteristics

The novel coronaviruses belong to the β genus. They have envelopes, and the particles are round or oval, often polymorphic, with diameter being 60 to 140 nm. Their genetic characteristics are significantly different from SARS-CoV and MERS-CoV. Current research shows that they share more than 85% homology with bat SARS-like coronaviruses (bat-SL-CoVZC45). When isolated and cultured in vitro, the 2019-nCoV can be found in human respiratory epithelial cells in about 96 hours, however it takes about 6 days for the virus to be found if isolated and cultured in Vero E6 and Huh-7 cell lines. Most of the know-how about the physical and chemical properties of coronavirus comes from the research on SARS-CoV and MERS-CoV. The virus is sensitive to ultraviolet and heat. Exposure to 56°C for 30 minutes and lipid solvents such as ether, 75% ethanol, chlorine-containing disinfectant, peracetic acid, and chloroform can effectively inactivate the virus. Chlorhexidine has not been effective in inactivating the virus.

II. Epidemiological Characteristics

  1. Source of infection: Now, the patients infected by the novel coronavirus are the main source of infection; asymptomatic infected people can also be an infectious source.

  2. Route of transmission: Transmission of the virus happens mainly through respiratory droplets and close contact. There is the possibility of aerosol transmission in a relatively closed environment for a long-time exposure to high concentrations of aerosol. As the novel coronavirus can be isolated in feces and urine, attention should be paid to feces or urine contaminated environmental that leads to aerosol or contact transmission.

  3. Susceptible groups: People are generally susceptible.

III. Pathological changes

Pathological findings from limited autopsies and biopsy studies are summarized below:

1. Lungs

Solid changes of varying degrees are present in the lungs. Alveolar damage involves fibromyxoid exudation and hyaline membrane formation. The exudates are composed of monocytes and macrophages, with plenty of multinucleated syncytial cells. Type II alveolar epithelial cells are markedly hyperplastic, some of which are desquamated. Viral inclusions are observed in type II alveolar epithelial cells and macrophages. Alveolar interstitium is marked with vascular congestion and edema, infiltration of monocytes and lymphocytes, and vascular hyaline thrombi. The lungs are laden with hemorrhagic and necrotic foci, along with evidence of hemorrhagic infarction. Organization of alveolar exudates and interstitial fibrosis are partly present.

The bronchi are filled with desquamated epithelial cells, mucus and mucus plugs. Hyperventilated alveoli, interrupted alveolar interstitium and cystic formation are occasionally seen.

On electron microscopy, cytoplasmic NCP virions are observed in the bronchial epithelium and type II alveolar epithelium. NCP virus antigen positivity in some alveolar epithelia and macrophages are revealed through immunohistochemistry staining, which are positive for NCP virus nucleic acid via RT-PCR.

2. Spleen, hilar lymph nodes and bone marrow

The spleen is evidently shrunk. Lymphocytopenia and focal hemorrhage and necrosis are present. Macrophagocyte proliferation and phagocytosis are noted in the spleen. Lymph nodes are found with sparse lymphocytes and occasional necrosis. CD4+ and CD8+ T cells are present in reduced quantity in the spleen and lymph nodes, revealed by immunohistochemistry staining. Pancytopenia is identified in bone marrow.

3. Heart and blood vessels

Degenerated or necrosed myocardial cells are present, along with mild infiltration of monocytes, lymphocytes and/or neutrophils in the cardiac interstitium. Endothelial desquamation, endovasculitis and thrombi are seen in some blood vessels.

4. Liver and gall bladder

Appearing enlarged and dark-red, the liver is found degenerated with focal necrosis infiltrated with neutrophils. The liver sinusoids are found hyperemic. The portal areas are infiltrated with lymphocytes and monocytes and dotted with microthrombi. The gall bladder is prominently filled.

5. Kidneys

The kidneys are noted with protein exudation in the Bowman’s capsule around glomeruli, degeneration and desquamation of the epithelial cells of renal tubules, and hyaline casts. Microthrombi and fibrotic foci are found in the kidney interstitium.

6. Other organs

Cerebral hyperemia and edema are present, with degeneration of some neurons. Necrosis foci are noted in the adrenal glands. Degeneration, necrosis and desquamation of epithelium mucosae at varying degrees are present in the esophageal, stomach and intestine.

IV. Clinical Characteristics

1. Clinical manifestations

Based on the current epidemiological investigation, the incubation period is one to 14 days, mostly three to seven days. Main manifestations include fever, fatigue and dry cough. Nasal congestion, runny nose, sore throat, myalgia and diarrhea are found in a few cases. Severe cases mostly developed dyspnea and/or hypoxemia after one week. In severe cases, patients progress rapidly to acute respiratory distress syndrome, septic shock, metabolic acidosis that is difficult to correct, coagulopathy, multiple organ failure and others. It is worth noting that for severe and critically ill patients, their fever could be moderate to low, or even barely noticeable. Some children and neonatal cases may have atypical symptoms, manifested as gastrointestinal symptoms such as vomiting and diarrhea, or only manifested as low spirits and shortness of breath.

The patients with mild symptoms did not develop pneumonia but only low fever and mild fatigue. From current situations, most patients have good prognosis and a small number of patients are critically ill. The prognosis for the elderly and patients with chronic underlying diseases is poor. The clinical course of pregnant women with NCP is similar to that of patients of the same age. Symptoms in children are relatively mild.

2. Laboratory tests

General findings

In the early stages of the disease, peripheral WBC count is normal or decreased and the lymphocyte count decreases. Some patients see an increase in liver enzymes, lactate dehydrogenase (LDH), muscle enzymes and myoglobin. Elevated troponin is seen in some critically ill patients while most patients have elevated C-reactive protein and erythrocyte sedimentation rate and normal procalcitonin. In severe cases, D-dimer increases and peripheral blood lymphocytes progressively decrease. Severe and critically ill patients often have elevated inflammatory factors.

Pathogenic and serological findings

(1) Pathogenic findings: Novel coronavirus nucleic acid can be detected in nasopharyngeal swabs, sputum, lower respiratory tract secretions, blood, feces and other specimens using RT-PCR and/or NGS methods. It is more accurate if specimens from lower respiratory tract (sputum or air tract extraction) are tested. The specimens should be submitted for testing as soon as possible after collection.

(2) Serological findings: NCP virus specific IgM becomes detectable around 3-5 days after onset; IgG reaches a titration of at least 4-fold increase during convalescence compared with the acute phase.

3. Chest imaging

In the early stage, imaging shows multiple small patchy shadows and interstitial changes, apparent in the outer lateral zone of lungs. As the disease progresses, imaging then shows multiple ground glass opacities and infiltration in both lungs. In severe cases, pulmonary consolidation may occur while pleural effusion is rare.

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V. Case Definitions

1. Suspect cases

Considering both the following epidemiological history and clinical manifestations:

1.1 Epidemiological history

1.1.1 History of travel to or residence in Wuhan and its surrounding areas, or in other communities where cases have been reported within 14 days prior to the onset of the disease;

1.1.2 In contact with novel coronavirus infected people (with positive results for the nucleic acid test) within 14 days prior to the onset of the disease;

1.1.3 In contact with patients who have fever or respiratory symptoms from Wuhan and its surrounding area, or from communities where confirmed cases have been reported within 14 days before the onset of the disease;

or 1.1.4 Clustered cases (2 or more cases with fever and/or respiratory symptoms in a small area such families, offices, schools etc within 2 weeks).

1.2 Clinical manifestations

1.2.1 Fever and/or respiratory symptoms;

1.2.2 The aforementioned imaging characteristics of NCP;

1.2.3 Normal or decreased WBC count, normal or decreased lymphocyte count in the early stage of onset. A suspect case has any of the epidemiological history plus any two clinical manifestations or all three clinical manifestations if there is no clear epidemiological history.

2. Confirmed cases

Suspect cases with one of the following etiological or serological evidences:

2.1 Real-time fluorescent RT-PCR indicates positive for new coronavirus nucleic acid;

2.2 Viral gene sequence is highly homologous to known new coronaviruses.

2.3 NCP virus specific Ig M and IgG are detectable in serum; NCP virus specific IgG is detectable or reaches a titration of at least 4-fold increase during convalescence compared with the acute phase.

VI. Clinical Classification

1. Mild cases

The clinical symptoms were mild, and there was no sign of pneumonia on imaging.

2. Moderate cases

Showing fever and respiratory symptoms with radiological findings of pneumonia.

3. Severe cases

Adult cases meeting any of the following criteria:

(1) Respiratory distress (≧30 breaths/ min);

(2) Oxygen saturation≤93% at rest;

(3) Arterial partial pressure of oxygen (PaO2)/ fraction of inspired oxygen (FiO2)≦ 300mmHg (l mmHg=0.133kPa). In high-altitude areas (at an altitude of over 1,000 meters above the sea level), PaO2/ FiO2 shall be corrected by the following formula: PaO2/ FiO2 x[Atmospheric pressure (mmHg)/760]

Cases with chest imaging thatshowed obvious lesion progression within 24-48 hours >50% shall be managed as severe cases.

Child cases meeting any of the following criteria:

(1) Tachypnea (RR ≥ 60 breaths/min for infants aged below 2 months; RR ≥ 50 BPM for infants aged 2-12 months; RR ≥ 40 BPM for children aged 1-5 years, and RR ≥ 30 BPM for children above 5 years old) independent of fever and crying;

(2) Oxygen saturation ≤ 92% on finger pulse oximeter taken at rest;

(3) Labored breathing (moaning, nasal fluttering, and infrasternal, supraclavicular and intercostal retraction), cyanosis, and intermittent apnea;

(4) Lethargy and convulsion;

(5) Difficulty feeding and signs of dehydration.

4. Critical cases

Cases meeting any of the following criteria:

4.1 Respiratory failure and requiring mechanical ventilation;

4.2 Shock;

4.3 With other organ failure that requires ICU care.

VII. Clinical early warning indicators of severe and critical cases

1. Adults.

1.1 The peripheral blood lymphocytes decrease progressively;

1.2 Peripheral blood inflammatory factors, such as IL-6 and C-reactive proteins, increase progressively;

1.3 Lactate increases progressively;

1.4 Lung lesions develop rapidly in a short period of time.

2. Children.

2.1 Respiratory rate increased;

2.2 Poor mental reaction and drowsiness;

2.3 Lactate increases progressively;

2.4 Imaging shows infiltration on both sides or multiple lobes, pleural effusion or rapid progress of lesions in a short period of time;

2.5 Infants under the age of 3 months who have either underlying diseases (congenital heart disease, bronchopulmonary dysplasia, respiratory tract deformity, abnormal hemoglobin, and severe malnutrition, etc.) or immune deficiency or hypofunction (long-term use of immunosuppressants).

VIII. Differential Diagnosis

1. The mild manifestations of NCP need to be distinguished from upper respiratory tract infections caused by other viruses.

2. NCP is mainly distinguished from other known viral pneumonia and mycoplasma pneumoniae infections such as influenza virus, adenovirus and respiratory syncytial virus. Especially for suspect cases, methods such as rapid antigen detection and multiplex PCR nucleic acid detection should be adopted as much as possible for detection of common respiratory pathogens.

3. It should also be distinguished from non-infectious diseases such as vasculitis, dermatomyositis and organizing pneumonia.

IX. Case Finding and Reporting

Health professionals in medical institutions of all types and at all levels, upon discovering suspect cases that meet the definition, should immediately put them in single room for isolation and treatment. If the cases are still considered as suspected after consultation made by hospital experts or attending physicians, it should be reported directly online within 2 hours; samples should be collected for new coronavirus nucleic acid testing and suspect cases should be safely transferred to the designated hospitals immediately. People who have been in close contact with patients who have been confirmed of new coronavirus infection are advised to perform new coronavirus pathogenic testing in a timely manner, even though common respiratory pathogens are t