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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. Under 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 exude 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 pneumocyte 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.
传
(6) Other organs. Cerebral hyperemia, edema, and
degeneration of some neurons. Focal necrosis in the adrenal glands.
Varying 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) Etiologic testing: Use RT-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:
- 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.
- Positive
result in real-time fluorescence RT-PCR detection of novel coronavirus
nucleic acid;
- The
sequence of the virus is highly homologues to that of 2019-nCoV.
- 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:
- Shortness
of breath, RR > 30 breaths/minute; 2. Oxygen saturation < 93% at
rest
- 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:
- 出现气促(<2月龄,RR>60 次/分;2~12月龄,RR> 50 次/分;1~5岁,RR>40 次/分;55岁,RR>30 次/分),除外发热和哭闹的影响;
- Oxygen
saturation <92% at rest.
- Laboured
breathing (wheezing, flaring of nostrils, three concave sign), cyanosis,
intermittent apnea.
- Lethargy,
convulsions.
- Refusal
to eat or difficulty feeding; signs of dehydration.
(4) Critical form. Meeting any of the following
criteria:
- Respiratory
failure occurs and mechanical ventilation is required;
- Shock;
- Combined
failure of other organs than require 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.
- Rapid
breathing
- Lack
of mental energy, lethargy
- Progressive
increase of lactate
- 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.
- 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.
- 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. Using 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.
- Treatment
principles: on the basis of symptom management, proactively prevent and
manage complications, treat underlying diseases, prevent secondary
infections, and support organ functions promptly.
- 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 4-8ml/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.
- 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.
- 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
- 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)".
- 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.
- 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.
- 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.
(4) Treatment by Traditional Chinese Medicine
TRANSLATOR NOTE: The section on Chinese medicine is
largely untranslated, but click here to show
XI. Criteria for discharge and notes after discharge
(1) Criteria for discharge
- Normal
body temperature for 3 days or more
2. Significant improvement of respiratory symptoms
- Chest
radiology findings show substantial improvement of acute exudative
lesions.
- 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.
- 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.
- 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.
- 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
Proofread: Qingyang Du
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