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Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition)

Since December 2019, many cases of novel coronavirus pneumonia have been found in Wuhan City, Hubei Province, and with the spread of the epidemic, such cases have also been found in other regions of China and overseas.As an acute respiratory infectious disease, the disease has been listed as a Class B infectious disease as provided by the "Law of the People's Republic of China on Prevention and Control of Infectious Diseases", and is managed as a Class A infectious disease.By employing a series of measures for prevention, control, and treatment, the upward trend of the epidemic in our nation has been contained to a certain degree, and the epidemic has eased in most provinces, but the number of cases outside China is on the rise. With thorough understanding of the clinical manifestations and pathology of the disease and the accumulation of experience in its diagnosis and treatment, we have revised the "Novel Coronavirus Diagnosis and Treatment Plan (Provisional Version 6)" to form the "New Coronavirus Pneumonia Diagnosis and Treatment Plan (Trial Version 7)", in order to further strengthen the early diagnosis and treatment of the disease, to improve the cure rate, to reduce the mortality rate, and to avoid hospital infection to the greatest extent possible, and at the same time to give a reminder to pay attention to the transmission and spread caused by imported cases.

I. Pathogenic Characteristics

The Novel Coronavirus belonging to the genus of betacoronavirus. The enveloped viral particles may appear spherical or oblong, with a diameter of 60-140nm.Its genetic characteristics are significantly different from SARS-CoV and MERS-CoV.Current research shows that it has more than 85% homology with bat SARS-like coronavirus (bat-SL-CoVZC45).When isolated and cultured in vitro, the new coronavirus 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.

Most of the understanding of the physicochemical properties of coronavirus comes from the research of SARS-CoV and MERS-CoV.The virus is sensitive to ultraviolet rays and heat, exposure to 56 °C for 30 minutes, ether solvents, 75% ethanol, chlorine-containing disinfectants, peracetic acid, and chloroform can effectively inactivate the virus. Chlorhexidine cannot effectively inactivate the virus.

II. Epidemiological Characteristics

(1) Source of infection.

At present, the source of infection is mainly patients infected by the novel coronavirus.Those who are asymptomatic but infected may also become a source of infection.

(2) Route of transmission.

The main route of transmission is respiratory droplets and close contact.There is the possibility of aerosol transmission when exposed to high concentration aerosol for a long time in a relatively closed environment.As new coronaviruses can be isolated in feces and urine, attention should be paid to aerosol or contact transmission of fecal and urine to environmental pollution.

(3) Susceptible populations.

The population is generally susceptible.

III. Pathological Changes

The pathological observations from autopsies and biopsies are summarized below.

(1) Lungs

Pulmonary consolidation of varying degrees. Intra-alveolar serous fluids, fibrinous exudate and hyaline-membrane formation are present. Exudate consists mainly of mononuclear macrophages. Multinucleated giant cells are common. Significant hyperplasia of type II pneumocyte. Some desquamation is present.

Inclusion bodies can be seen inside type II pneumocytes and macrophages. Alveolar congestion and edema can be seen. Infiltration of monocytes and lymphocytes, as well as the formation of hyaline thrombus in blood vessels, are evident. Focal pulmonary hemorrhage and necrosis. Hemorrhagic infarction can be seen. Exudate organization and pulmonary interstitial fibrosis are present in some alveoli.

Desquamation of bronchial mucosal epithelium is present. Intra-cavity mucus and mucus plugs can be seen. Overinflation, alveolar septa fracture and cyst formation are present in some alveoli.

Coronavirus particles can be seen in the cytoplasm of tracheal mucosal epithelial cells and type II pneumocytes under an electron microscope. A portion of the alveolar epithelium and macrophages contain the 2019-nCoV antigen as shown by IHC. Sample tests positive for the nucleic acid of 2019-nCoV with RT-PCR.

(2) Spleen, hilar lymph nodes and bone marrow

The size of the spleen is significantly reduced. Lymphocyte count is significantly reduced. Focal hemorrhage and necrosis are present. Macrophage hyperplasia and phagocytosis can be observed in the spleen. In the lymph nodes, the number of lymphocytes is reduced; some necrosis can be seen. A reduction of CD4+ T cells and CD8+ T cells can be detected in both the spleen and the lymph nodes by IHC. Trilineage hematopoiesis is reduced in the bone marrow.

(3) Heart and blood vessels

Degeneration and necrosis can be seen in cardiomyocytes. Interstitial infiltration of a small number of monocytes, lymphocytes and/or neutrophils can be seen. Desquamation of vascular endothelium, endothelial inflammation and thrombus formation are observed in some vessels.

(4) Liver and gallbladder

The liver appears enlarged and dark red in colour. Hepatocyte degeneration and focal necrosis are accompanied by neutrophil infiltration; hepatic sinusoidal congestion, infiltration of lymphocytes and monocytes in the hepatic portal area can be seen. Microthrombi are formed.The gallbladder appears highly filled.

(5) Kidneys

Proteinaceous exudate can be seen inside the glomerular capsule. Degeneration and desquamation of renal tubular epithelium are present. Hyaline casts can be seen. Interstitial congestion, microthrombi and focal fibrosis can be seen.

(6) Other organs. Cerebral hyperemia, edema, and degeneration of some neurons. Focal necrosis in the adrenal glands.

Variable degrees of degeneration, necrosis or desquamation of the esophageal, gastric and intestinal mucosal epithelium.

IV. Clinical Characteristics

(1) Clinical presentation.

Based on the current epidemiological investigation, the incubation period is 1-14 days, and most often between 3-7 days.

The primary presentations are fever, dry cough, and fatigue. A minority of patients have symptoms such as nasal congestion, nasal discharge, sore throat, muscle pain, and diarrhea.Severe patients often suffer from dyspnea and/or hypoxemia one week after symptom onset, and severe patients can rapidly progress to acute respiratory distress syndrome, septic shock, difficult to correct metabolic acidosis, coagulation dysfunction and multiple organ failure.It is worth noting that severe and critical patients may have moderate to low fever or even no obvious fever during the course of the disease.

Some children and infants may present with atypical symptoms such as vomiting and diarrhea, or only with malaise and rapid breathing.

Patients with the mild form of the disease present only as low fever, slight fatigue, and so forth, with no lung inflammation.

Judging from the current cases, most patients have a good prognosis and a minority are in critical condition.The prognosis of the elderly and those with chronic underlying diseases is more poor. The clinical course of COVID-19 in pregnant patients is similar to that for patients of the same age. The symptoms of children are relatively mild.

(2) Laboratory examination.

1. General Examination

In the early stage of the disease, the total number of peripheral blood leukocytes is normal or reduced, and the lymphocyte count is reduced, and some patients may have elevated liver enzyme, lactate dehydrogenase (LDH), myoenzyme and myoglobin; some critically ill patients may have elevated troponin.C-reactive protein (CRP) and erythrocyte sedimentation rate increased in most patients, and procalcitonin was normal. In severe cases, D- dimer increased and peripheral blood lymphocytes progressively decreased. Inflammatory cytokines often increase in severe and critical patients.

2. Etiologic and serologic tests

(1) Etiological testing: Use rRT-PCR and/or NGS to detect 2019-nCoV nucleic acid in nasopharyngeal swabs, sputum and other lower respiratory tract secretions, blood, and stool samples.Testing done on lower respiratory tract samples (sputum or airway suction) is more accurate. After collection, samples should be sent for testing ASAP.

(2) Serologic testing: nCoV-specific IgM antibodies usually test positive 3-5 days after the onset of symptoms; the titre of IgG antibodies is elevated by 4 times or more in the recovery phase compared with the acute phase.

(3) Chest imaging

In the early stage, there are multiple small patches and interstitial changes, most notably in the outer lung. It further develops into multiple ground-glass opacity and infiltration shadows in both lungs; and in severe cases, consolidation of the lungs may occur, and pleural effusion is rare.

V. Diagnostic Criteria

(1) Suspected cases.

Comprehensively analyze combinations of the following epidemiological history and clinical presentations:

      1. Epidemiological history

(1) Within 14 days prior to onset, had history of travel or residence in Wuhan or surrounding regions, or other communities reporting cases;

(2) Within 14 days prior to symptom onset, having had contact with patients infected with 2019-nCoV (positive nucleic acid test).

(3) Within 14 days prior to onset, had contact with patients who had a fever or respiratory tract symptoms that had come from Wuhan, its surrounding regions, or other communities reporting cases.

(4) Clustered onset (Within a span of 2 weeks, 2 or more cases with fever and/or respiratory symptoms appear in a small area, such as a family, an office, or a school class)

2. Clinical presentations

(1) Fever and/or respiratory tract symptoms;

(2) Having the imaging features of novel coronavirus pneumonia discussed above;

(3) During the early stages of the disease, white blood cell count is normal or reduced, while the lymphocyte count is normal or reduced.

Where there are any of the epidemiologic history items, and any 2 of the clinical presentions are met.

Where there is no clear epidemiological history, and at least 3 of the clinical presentations are met.

(2) Confirmed cases.

A 2019-nCoV diagnosis is confirmed if the suspected cases also have one of the following etiological or serological evidence.

    1. Positive result in real-time fluorescence RT-PCR detection of novel coronavirus nucleic acid;
    2. The sequence of the virus is highly homologues to that of 2019-nCoV.
    3. Specific IgM and IgG antibodies against 2019-nCoV test positive in the serum; IgG antibodies specific to 2019-nCoV test positive after previous negative results, or increased by more than 4 times in the recovery phase compared to the acute phase.

VI. Clinical classifications

(1) Mild form.

Clinical symptoms are minor, imaging does not show signs of lung inflammation.

(2) Regular form.

Has fever and respiratory tract symptoms, imaging shows visible lung inflammation.

(3) Severe form.

Adults who meet any one of the following:

    1. Shortness of breath, RR > 30 breaths/minute; 2. Oxygen saturation < 93% at rest
    2. Arterial oxygen partial pressure (PaO2)/ fraction of inspired oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa).

For high altitude (altitude over 1000 meters) regions, (PaO2/FiO2) should be corrected according to the following formula: PaO2/FiO2 x [ atmospheric pressure (mmHg)/760]

The patient should be managed as a severe case if lung imaging shows a substantial progression of lesions (greater than 50%) within 24-48 hours.

Children who meet any one of the following:

    1. Show shortness of breath (<2 months old, RR>60 times/min; 2~12 months old, RR>50 times/min; 1~5 years old, RR>40 times/min; 55 years old, RR>0 times/min), except the effects of fever and crying;
    2. Oxygen saturation <92% at rest.
    3. Laboured breathing (wheezing, flaring of nostrils (Nasal flaring), three concave sign), cyanosis, intermittent apnea.
    4. Lethargy, convulsions.
    5. Refusal to eat or difficulty feeding; signs of dehydration.

(4) Critical form. Meeting any of the following criteria:

    1. Respiratory failure occurs and mechanical ventilation is required;
    2. Shock;
    3. Combined failure of other organs that requires ICU monitoring.

VII. Clinical Warning Signs for Severe and Critical Cases

(1) Adults.

1. Progressive reduction of peripheral blood lymphocytes

2. Progressive increase of peripheral inflammatory cytokines such as IL-6 and C-reactive protein.

3. Progressive increase of lactate.

4. Rapid progression of lung pathologies in a short period of time.

(2) Children.

    1. Rapid breathing
    2. Lack of mental energy, lethargy
    3. Progressive increase of lactate
    4. Imaging shows bilateral or multilobe infiltration, pleural effusion or rapid disease progression within a short period of time.

5. Infants under 3 months or with underlying disease (congenital heart disease, bronchopulmonary dysplasia, respiratory malformation, hemoglobinopathies, severe malnutrition and so on), immunocompromised or immunosuppressed (long-term usage of immunosuppressants).

VIII. Differential Diagnosis

(1) Mild manifestations of 2019-nCoV infection need to be distinguished from other virus-induced upper respiratory tract infections.

(2) COVID-19 is to be distinguished from pneumonia caused by known viral agents such as influenza, adenovirus, and respiratory syncytial virus, as well as mycoplasma pneumonia. As much as possible, suspected cases should be tested for common pathogens using methods such as rapid antigen tests and multiplex PCR nucleic acid test.

(3) Furthermore, distinguish COVID-19 from non-infectious diseases such as vasculitis, dermatomyositis, and organizing pneumonia.

IX. Discovery and Reporting of Cases

When a suspected case is discovered by medical workers at the various levels or types of medical institutions, the patient should receive treatment in isolation immediately. Consultations of specialists or attending physicians should consider differential diagnosis and report the case online within 2 hours. Samples should be collected for 2019-nCoV nucleic acid testing. The suspected case should then be transferred to designated hospitals under safe transferring conditions immediately. It's recommended that patients who tested positive for other respiratory antigens be tested also for 2019-nCoV if they have had close contact with 2019-nCoV patients.

Two consecutive negative nCoV nucleic acid tests (samples taken at least 24 hours apart), and continued negativity for nCoV-specific IgG and IgM antibodies after 7 days of symptom onset can rule out the diagnosis of a suspected case.

X. Treatment

(1) Determine the place of treatment based on the patients' conditions.

    1. Suspected and confirmed cases should be treated in quarantine, in designated hospitals with effective isolation and disease control capacity. Suspected cases should be treated in individual isolation. Confirmed cases can be treated with multiple patients in the same isolation room.
    2. Patients who are severely or critically ill should be admitted to ICU as early as possible.

(2) General treatment.

1. Treatment for mild cases includes bed rest, supportive treatments, and maintenance of caloric intake. Pay attention to fluid and electrolyte balance and maintain homeostasis. Closely monitor the patient's vitals and oxygen saturation.

2. As indicated by clinical presentations, monitor the hematology panel, routine urinalysis, CRP, biochemistry (liver enzymes, cardiac enzymes, kidney function), coagulation, arterial blood gas analysis, chest radiography, and so on. Cytokines can be tested if possible.

3. Administer effective oxygenation measures promptly, including nasal catheter, oxygen mask, and high flow nasal cannula.If conditions allow, a hydrogen-oxygen gas mix (H2/O2: 66.6%/33.3%) may be used for breathing.

4. Antiviral therapies: Interferon-alpha (adult: 5 million units or equivalent can be added to 2ml sterile injection water and delivered with a nebulizer twice daily), lopinavir/ritonavir (adult: 200mg/50mg/tablet, 2 tablets twice daily; the length of treatment should not exceed 10 days), ribavirin (recommended in combination with interferon or lopinavir/ritonavir, adult: 500mg twice or three times daily via IV, the length of treatment should not exceed 10 days), chloroquine phosphate (adult 18-65 years old weighing more than 50kg: 500mg twice daily for 7 days; bodyweight less than 50kg: 500mg twice daily for day 1 and 2, 500mg once daily for day 3 through 7); umifenovir (adult: 200mg three times daily; the length of treatment should not exceed 10 days).

Pay attention to issues such as adverse drug reactions, contraindications (for example, chloroquine should not be given to patients with heart diseases), and drug interactions. Further evaluate the efficacy of current treatment regimens in clinical applications. Concurrent usage of 3 or more antiviral drugs is not recommended. Corresponding medication should be discontinued should intolerable side effects appear.

Care planning for pregnant patients should consider the stage of pregnancy, the choice of medications that minimize risks to the fetus, and whether the pregnancy should be terminated before the treatment, and inform the patient.

5. Antibiotic therapies: avoid unjustifiable or inappropriate usage of antibiotics, especially combinatory use of broad-spectrum antibiotics.

(3) Treatment of severe and critical cases.

    1. Treatment principles: on the basis of symptom management, proactively prevent and manage complications, treat underlying diseases, prevent secondary infections, and support organ functions promptly.
    2. Respiratory support:

(1) Oxygen therapy: patients with severe symptoms should be receiving oxygenation through nasal cannulas or oxygen masks. Assess the patient timely to determine whether dyspnea and/or hypoxemia have been alleviated

(2) High flow nasal cannula or non-invasive ventilation: when patients with dyspnea and/or hypoxemia do not respond to regular oxygen therapy, consider using high flow nasal cannula or non-invasive ventilation. If the symptoms do not improve or worsen within a short period of time (1-2 hours), tracheal intubation and invasive mechanical ventilation should be used.

(3) Invasive mechanical ventilation: using lung-protective ventilation strategy (LPVS), i.e. low tidal volume of 6-8ml/kg ideal body weight, and low inspiratory pressure (plateau pressure <30cm H2O) for mechanical ventilation in order to reduce ventilation-associated lung injury. Higher PEEP may be used appropriately while maintaining airway plateau pressure under 35cm H2O. Maintain airway warming and humidification. Avoid long-term sedation to facilitate early awakening and pulmonary rehabilitation treatment. Patient-ventilator asynchrony is common. Sedation and muscle relaxant should be used appropriately. Choose airtight suctioning depending on the status of airway secretions. When necessary, conduct a bronchoscopy and give treatment accordingly.

(4) Salvage therapy: for patients with severe ARDS, a recruitment maneuver is recommended.

When human resources allow, prone ventilation should be carried out for 12 hours or more every day.If prone ventilation is ineffective, extracorporeal membrane oxygenation (ECMO) should be considered ASAP if conditions allow.Indications:

When FiO2 > 90%, oxygenation index < 80mm Hg and lasting for more than 3-4 hours; airway plateau pressure > 35cm H2O. VV-ECMO is preferred for patients with respiratory failure only. VA-ECMO should be used for patients who also require circulation support.Weaning trials may be considered when the underlying diseases are controlled, and the cardiopulmonary functions of the patient show signs of recovery.

    1. Circulatory support: on the basis of sufficient fluid resuscitation, improve microcirculation, use vasoactive drugs, closely monitor the changes in the patient's blood pressure, heart rate, urine output, lactate and base excess in arterial-blood gas tests. When necessary, monitor hemodynamics using non-invasive or invasive means, including Doppler ultrasound, echocardiogram, invasive blood pressure or Pulse Contour Cardiac Output (PiCCO) monitoring. During treatment, pay attention to fluid balance strategies to avoid hypervolemia and hypovolemia.

If the patient's heart rate suddenly increased by more than 20% of the baseline value, or the blood pressure dropped by more than 20% of the baseline value, closely monitor the patient for septic shock, GI bleeding, or heart failure if symptoms like poor skin perfusion and decreased urine output are also present.

    1. Renal failure and renal replacement therapy: for severely and critically ill patients who have renal damage, actively investigate the causes of renal impairment such as poor perfusion or medication. In patients with renal failure, pay attention to fluid balance, pH balance and electrolyte balance. For nutrition support, pay attention to nitrogen balance and the supplement of calories and trace elements. Continous renal replacement therapy (CRRT) may be used for severely ill patients. Indications include: (1) hyperkalemia; (2) acidosis; (3) pulmonary edema or hypervolemia; (4) fluid management under multiple organ dysfunction
    2. Use of convalescent plasma collected from recovered patients: indicated for severely or critically ill patients with rapid disease progression. For usage and dosage, see "COVID-19 Clinical Treatment Plan Using Convalescent Plasma Collected from Recovered Patients (Provisional 2nd edition)".
    3. Blood purification treatment: techniques such as plasma exchange, plasma absorption, plasma perfusion, blood/plasma filtration may clear inflammatory cytokines, inhibit "cytokine storm", therefore reduce inflammation-induced damage to the body and can be used in the early/mid-phase treatment of severely and critically ill patients experiencing cytokine storms.
    4. Immune therapy: for patients with extensive and bilateral lung disease and severely ill patients with elevated IL-6 levels, treatment with tocilizumab may be attempted. The initial dose should be 4-8mg/kg, with the recommended dosage being 400mg. Dilute with 0.9% saline to 100ml and infuse over the course of more than 1 hour. Repeat once after 12 hours (same dosage) if the response to the first dose was poor. Maximum two cumulative doses. Single maximum dose is 800mg. Pay attention to allergic reactions. Prohibited in patients with active infections such as tuberculosis.
    5. Other treatment measures

For patients with progressively deteriorating oxygenation index, rapid imaging progression, and overactive inflammatory responses, short-term (3-5 days) glucocorticoid treatment may be used at the clinician's discretion. It's recommended that the dosage should not exceed the equivalence of methylprednisolone at 1-2mg/kg/day, since the immunosuppressive function of high-dose glucocorticoid may delay the clearance of coronavirus from the system. Xuebijing may be given intravenously at 100ml twice a day. Probiotics can be given to maintain intestinal microbiome balance and to prevent secondary bacterial infection.

IV infusion of gamma immunoglobulin may be considered for severely or critically ill children. Pregnant patients should be encouraged to terminate pregnancy, preferably with C-section.

Patients often have anxiety and fear, and psychological counseling should be strengthened.

XI. Criteria for discharge and notes after discharge

(1) Criteria for discharge

    1. Normal body temperature for 3 days or more

2. Significant improvement of respiratory symptoms

    1. Chest radiology findings show substantial improvement of acute exudative lesions.
    2. Two consecutive negative nucleic acid tests using respiratory tract samples (taken at least 24 hours apart).

Those meeting the requirements above may be released from isolation or hospital.

(2) Matters for attention after hospital discharge.

    1. Designated hospitals should communicate with primary care facilities at the patient's place of residence and share medical records. Information on the discharged patients should be forwarded to the relevant neighbourhood committees and primary care facilities in a timely manner.
    2. Discharged patients are at increased risk of acquiring other pathogens due to their reduced immune functions during recovery. It's recommended that the patients: continue to self-monitor for 14 days, wear masks, live in well-ventilated individual suites if possible, reduce close contact with family members, eat separately, practice good hand hygiene, and avoid going outside.
    3. Follow-up visits are recommended at 2 and 4 weeks after discharge.

XII. Transportation principles

Implement in accordance with the "Novel Coronavirus Pneumonia Case Transfer Program (Provisional)" released by our Commission.

XIII. Prevention and Control of Infection in Medical Establishments

Strictly follow the requirements in the "Technical Guidelines for the Prevention and Control of Novel Coronavirus Infection in Medical Establishments (1st Edition)" and "Guidelines on the Usage of Common Medical Protective Equipment in the Management of COVID-19 (Provisional)".

Copy sent to:The joint mechanism (leading group, command department) for the prevention and control of the novel coronavirus pneumonia epidemic of each province, autonomous region, and directly governed municipality, as well as for the Xinjiang Construction and Production Corps.

General Office of the National Health Commission

Distributed on March 3rd, 2020

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