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Novel Coronavirus Pneumonia (COVID-19) Diagnosis and Treatment Guideline (UPDATED)

Around December 2019 city of Wuhan in Hubei province appear a new novel coronavirus that
slowly become epidemic and hit other province in short matter of time. This disease appear to be
acute respiratory infection category B infectious disease (based on People’s Republic of China
infectious disease prevention and treatment guideline). By taking series of preventive and
treatment measures, China epidemic outbreak can finally reach at containment level. And lot of
provinces already recovered from epidemic but incidence in overseas steadily growing in
numbers.

A) Etiology
Novel Coronavirus (SARS-CoV-2) belong to family of betacoronavirus, consist of envelope,
round or oval shape granule particles, mostly multi-shape and have round diameter 60-140nm.
Mostly having distinct characteristics with MERS-CoV. Recent research showed that novel
coronavirus having similar genetic sequence with SARS Bat virus (bat-SL-CoVZC45) up to 85%.
During cultured in vitro for 96 hours, the new coronavirus can be found in human respiratory
epithelial cells. Using Vero E6 and Huh-7 cells to incubate virus for 6 days.
For coronavirus physical and chemical properties research study comes from SARS-CoV and
MERS-CoV research studies. Virus susceptible to ultraviolet and heat (56 oC for 30 mins), diethyl
ether, 75% alcohol, chlorine disinfectant, peracetic acid and lipid solvents like chloroform most of
them have antiviral properties. Chlorine alone can’t disinfect virus.

B) Epidemiology
a. Source of infection
Currently all source infection coming from person who got infected by SARS-CoV-2.
Asymptomatic person also can spread the virus as well.

b. Route of transmission
Respiratory droplets and close proximity contact are the main route of transmission.
There is possibility of aerosol transmission in closed proximity indoor environmental if
there is long time exposure. Attention should be paid to possibility of fecal-oral
transmission since there is report detection of viral particles in fecal matter and urine of
infected person.

c. Risk population
Most people could be infected

C) Pathology
Based on limited data from autopsy, lung biopsy histology examination result;
a. Lung
Lung consolidation change. Plasma, fibrin exudate and visible detected at alveolar space;
exudation material consist of monocytes and macrophages, more easily to view multinucleated
giant cells. Type II alveolar epithelia cells proliferated, some part of cells exfoliated. Inclusion
bodies were found in type II alveolar epithelial cells and macrophages. There were hyperemia,
edema, monocyte and lymphocyte infiltration, and hyaline thrombosis in alveolus septum.
Pulmonary hemorrhage and necrosis may occur, and hemorrhagic infarction may occur. Some
alveolar exudates and pulmonary interstitial fibrosis.
Part of the epithelium of the pulmonary bronchus private membrane is exfoliated, and
mucus and private fluid thrombus can be seen in the lumen. A small number of alveoli were over
inflated, the alveoli septum was broken or cystic cavity was formed.
Under the electron microscope, coronavirus particles were found in the cytoplasm of the
epithelial cells of the bronchial film membrane and type II alveolar epithelium. The SARS-CoV-2
antigen was detected in some alveolar epithelial cells and macrophages by immunohistochemical
staining. Positive detection on nucleic acid novel coronavirus (SARS-CoV-2) using RT-PCR.

b. Spleen, hilar lymph nodes and bone marrow


The spleen was obviously become atrophy. The number of lymphocytes was significantly
reduced, focal hemorrhage and necrosis, macrophage proliferation and phagocytosis, necrosis
were observed in spleen, and the number of lymphocytes in lymph nodes was reduced.
Immunohistochemical staining showed that CD4 + T and C08 + T cells were decreased in spleen
and lymph nodes. Decrease numbers of three cell lineage (refer to red blood cells, white blood
cells, and megakaryocytes) in bone marrow.

c. Cardiovascular
Degeneration and necrosis can be seen in myocardial cells, and a few monocytes, lymphocytes
and / or neutrophils can be seen in interstitial. Some vascular endothelial exfoliated, intimal
inflammation and thrombosis occur.

d. Liver and Gallblader


Size increase and having dark red color appearance. Hepatocyte degeneration, focal necrosis with
neutrophil infiltration, hepatic sinusoidal congestion, infiltration of lymphocytes and monocytes
in the portal area, and develop microvesicular thrombosis. High gallbladder filling

e. Kidney
Exudates fluid can be seen in intracavity glomerular, See transparent tube type. Interstitial
hyperemia, microthrombosis and focal fibrosis.

f. Other organs
The brain tissue is congested and edema, and some neurons showing degenerate. Focal necrosis
can be seen in the adrenal gland. Degeneration, necrosis and exfoliation of mucosa epithelium of
esophagus, gastric and intestine in different degrees.

D) Clinical Manifestation
Based on epidemiology study assessment, overall incubation period is 1-14 days, mostly 3-7 days.
Main symptoms are fever, dry cough, and fatigue. Some patients experiencing nasal congestion,
runny nose, sore throat, myalgia and diarrhea symptoms. Severe patients mostly experienced
dyspnea/or low oxygen level (hypoxemia) 1 week after been diagnosed. Severe patients could be
developed ARDS (acute respiratory distress syndrome), septic shock, and metabolic electrolyte
imbalance that difficult to treat and blood coagulation disorder and multiple disorder organ
syndrome. Need to paid attention to severe and critical patients disease progression that could
display mild grade fever that went undetected.
Some neonates and children display atypical symptoms, overall are vomiting, diarrhea and
other gastrointestinal symptoms or only display mild unconsciousness and dyspnea.
Mild type patients only display low grade fever, mild fatigue and no pneumonia
characteristic
From the current cases perspective, lot of patients having overall good prognosis and only
some of them in critical care condition. Elderly and comorbidity patients having worse prognosis.
Maternal patients having similar clinical manifestation with their respective patients at the same
age. Children having a mild case symptom overall.

1. General examination
 Peripheral WBC (white blood cell) count decrease or normal in early period.
 Lymphopenia, increase LDH, liver enzyme, muscle enzyme and myoglobin
 Some critical patient have elevated troponin
 Most of patients elevated CRP and ESR, normal or decrease calcitonin.
 Severe patients have elevated D-dimer and continuously decrease lymphocytes.
 Increase pro inflammatory factor

2. Virology and serological test


 Virological test: use RT-PCR or/and next generation sequencing method for coronavirus
nucleic acid test by collecting sample from nostril, oropharynx, nasopharynx swab and
other respiratory tract secretion, blood, fecal matter specimen. Respiratory tract specimens
are more accurate for diagnosis.
 Serological test: SARS-CoV-2 specific IgM antibody positive occur at 3-5 days after infection.
IgG antibody elevated up to 5 times during recovery phase

3. Radiological examination
 the early stage, there were multiple small patch shadows and interstitial changes,
especially in the extrapulmonary zone
 Furthermore, multiple ground glass shadows and infiltrative shadows may develop in both
lungs.
 In severe cases, pulmonary consolidation may occur, and pleural effusion is rare

E) Diagnostic Criteria
a. Suspected Case
1. Epidemiology
 Recent travel history from Wuhan and nearby area and/or other area with confirmed
cases in span of 14 days before disease onset.
 Recent contact history with known infected person in 14 days before disease onset
 Recent contact in 14 days before disease onset with person that display fever or
respiratory symptoms from Wuhan and nearby area or area with confirmed cases.
 Clustering onset (appear 2 or more cases of fever and/or respiratory symptoms cases at
home, office, school and other public place in recent 2 weeks)

2. Clinical manifestation
 Fever and/or respiratory symptoms
 Having overall coronavirus radiological characteristic above
 Early disease onset decrease or normal white blood cells count, normal or decrease
lymphocyte count.

For people that should be suspected case need at least one of these criteria
 Having one of epidemiology criteria + 2 criteria from clinical manifestation above
 No epidemiology criteria + 3 criteria of clinical manifestation above.

b. Confirmed Case
Having one criteria for suspected cases plus fulfill one of virological or serological test below:
 RT-PCR nucleic acid test positive for SARS-CoV-2
 Gene sequencing similarity with already known SARS-CoV-2
 IgM and IgG antibody positive

F) Clinical Classification
 Mild Type
Mild symptoms and no abnormalities in radiology examination
 Common Type
Having fever, respiratory symptoms and pneumonia characteristic in radiological
examination
 Severe Type
Adult that has one of criteria below:
 Rapid breathing, RR≥ 30/minute
 During rest condition, SaO2 ≤ 93%
 PaO2/FiO2 ≤ 300 mmHg (1 mmHg = 0.133kPa)
 Radiological examination showed lesions progressed more than 50% within 24-48
hours
High altitude (1000 M above the sea) area need to re calculate based on this equation
atm pressure
PaO 2/ Fi O 2×
760 mmHg
 Children criteria
 Rapid breathing (≤2 months, RR>60 times/minute; 2-12 months, RR ≥ 50
times/minute); 1-5 years, R≥ >40 year times/minute; >5 years, RR ≥ 30
times/minute), doesn’t include influence of crying and fever.
 Resting condition SaO2 ≤92%
 Assisted breathing, cyanosis, and intermittent apnea
 Drowsiness and convulsion
 Decrease appetite and dehydration sign
 Critical type
Having one of these criteria below:
 Respiratory failure and need mechanical ventilation breathing
 Shock
 With or other organ systems failure and in need ICU for treatment

G) Severe and critical predictor guideline


 Adult
 Lymphocytes count continue to decrease
 Inflammatory factor such as IL-6 and CRP level continue to increase
 Lactic acid level keep increasing
 Intrapulmonary pathological rapidly progress
 Children
 Rapidly breathing
 Poor consciousness and drowsiness appear
 Lactic acid level keep increasing
 Radiology exam showed bilateral lung infiltration, pleural effusion or disease
rapidly progress in short amount time
 3 months old neonatal (baby) or comorbidities neonates (congenital heart disease,
bronchopulmonary dysplasia, respiratory tract deformity, abnormal hemoglobin,
severe malnutrition etc) immune deficiency (long term immunosuppressant
medication)

H) Differential Diagnosis
 Mild infection of SARS-CoV-2 should be distinguish with other cause of upper respiratory
viral infection
 SARS-CoV-2 infection need to be distinguish from other pathogen causing pneumonia
such as adenovirus, RSV (respiratory synctial virus), influenza and mycoplasma.
 Still need to differentiate with other non-infectious disease such as vasculitis,
dermatomyositis and chemical induced pneumonia.

I) Case Finding and Report


All hospitals and medical personnel after discover suspected patients need to proceed
isolation treatment and consult with hospital specialist if it still suspecting in 2 hours have to do
online report and undergo nucleic acid test PCR test. At the same time, the suspected cases
should be transferred immediately to certain approved hospital for further treatment. And SARS-
CoV-2 test still recommended in timely manner even if the common respiratory pathogens test
are positive.
If suspected cases having negative result in 2 times a row (have to be 24hr between tests)
and 7 days after disease onset the antibody of IgM and IgG result still negative then suspected
cases could be excluded.
J) Treatment
 Treatment based on disease severity condition
 Suspected and confirmed cases shall be isolated and treated in designated
hospitals with effective isolation conditions and protection conditions. Suspected
cases shall be isolated and treated in a single room. Confirmed cases can be
treated in the same ward by multiple persons
 Critical patients need to be admitted to ICU as soon as possible

 General treatment
 Bed rest and supportive treatment (intravenous fluid etc), sufficient calorie intake;
pay attention to fluid and electrolyte balance. Pay close attention to vital signs and
oxygen saturation level (SaO2)
 Based on patient condition do lab check for routine blood test, urinalysis, CRP,
biomarker (LFT, Cardiac, KFT) coagulation factor, ABG (Arterial Blood Gas), Chest
CT and X-ray. Cytokine test if needed.
 Effective oxygen therapy should be given in time, including nasal catheter, mask
and high flow oxygen therapy. If possible, it can be treated with hydrogen oxygen
mixed inhalation gas
 Antiviral treatment:
 Alpha interferon (-INF) (adult dosage every day 5,000,000 units or
equivalent dosage, add sterile water for injection 2ml every day 2 times by
inhalation)
 Lopinavir/Ritonavir: adult 200mg/50mg/tablet, 2 tablet bid, treatment course
not more than 10 days
 Ribavirin (suggestion to co administer it along with interferon or
lopinavir/ritonavir): adult 500mg bid/tid ivgtt course treatment not more
than 10 days
 Chloroquine Phosphate (adult 18-65 years old): BW> 50Kg, 500mg bid for 7
days. BW<50 Kg first and second day dosage 500 mg bid and then rest of
dosage 500 mg qd.
 Arbidol (Umifenovir): adult 200mg tid for course treatment not more than 10
days.
Every drug treatment need to pay attention for side effects and contraindications
(prohibit use of chloroquine if patients have heart condition) and interactions with
other drugs. Further evaluation of the efficacy of current drug trial for clinical
appliance. It is not recommended to use 3 or more antiviral drugs at same time
and in case of intolerable side effect should be encountered that relevant drugs
should be stopped. For treatment of pregnant women we should consider
gestational week period and choose the drugs that have less impact on fetus and
know whether to treat after termination of pregnancy.

 Antibiotic treatment: avoid inappropriate use of antibiotics especially the


combination of broad-spectrum antibiotics.
 Severe and Critical patient treatment
 Principle treatment: in accordance to symptomatic treatment, actively engage to
prevent complications and treat underlying disease and prevent secondary
infection and organ function supportive treatment

 Ventilator support
 Oxygen therapy: Severe patients should receive nasal or face masks for
oxygen therapy, and assess accordingly whether respiratory distress and / or
hypoxemia are relieved
 High flow oxygen therapy or noninvasive ventilation: for patients with ARDS
and/or hypoxemia that couldn’t be relieved on time can be considered using
high flow oxygen therapy or non-invasive ventilation. If there is no significant
improvement during 1-2 hours periods then need to do endotracheal
intubation or invasive ventilation.
 Invasive ventilation therapy: using lung protective ventilation method, low
tidal volume (6-8ml/kg ideal body weight) and low airway platform pressure
(<30cmH2O) for mechanical ventilation to reduce ventilator related lung
injury. During airway platform pressure steady <30 cmH 2O could use
appropriate high PEEP to keep airway warm and humid. Avoid sedation for
longer time and trying keep patients awake earlier to continue lung
rehabilitation. Many patients are in different situation from each other so
appropriate use muscle relaxant and sedation depend on each patient
condition. Based on airway secretion condition we can use closed
endotracheal suctioning and if necessary bronchoscopy should be carried out
for treatment accordingly.
 Rescue Therapy: for severe ARDS patients lung expansion therapy could be
considered. If there is adequate resources prone position ventilation should
be done every day for more than 12 hours. ECMO (extra corporeal membrane
oxygenation) should be consider if prone position ventilation fail to improve
patient condition. Certain criteria indicate using ECMO: (1) FiO2 > 90% SaO2 <
80mmHg undergo more than 3-4 hours, (2) airway platform pressure > 35
cmH2O.
For the first time choose VV-ECMO mode and if needed choose VA-ECMO. If
general condition is improving and cardiopulmonary function shows signs of
recovery then mechanical ventilation can be withdrawal.
 Cardiovascular support: improve microcirculation by using vasoactive drug
and closely monitor blood pressure, heart rate, urine volume as well as lactic
acid and alkali in ABG (arterial blood gas) and conduct non-invasive and
invasive hemodynamic monitoring if necessary such as ultrasound,
echocardiography and PiCCO (Pulse Countour Cardiac Output) monitoring.
Pay attention to electrolyte balance strategy to avoid excessive or insufficient.
If there is evidence showing patient’s heart rate goes up to more than 20%
above normal or BP drop 20% below normal accompany with poor skin
perfusion and low urine output then need to consider probability of SEPTIC
SHOCK, GI bleeding or Heart Failure.
 Kidney failure or renal replacement therapy: critical patients kidney injury
should be closely monitor and find the main cause of injury such as low
perfusion or drug related. We should pay attention to the balance of body
fluid, acid-base and electrolyte in the treatment of renal failure, and pay
attention to the supplement of nitrogen balance, calorie and trace minerals in
the nutritional support treatment. Severe patients can choose continuous
renal replacement therapy (CRRT). Other indications include: hyperkalemia,
acidosis, pulmonary edema or fluid overloaded, MODS (multiple organ
disorder syndrome)

 Convalescent plasma therapy: suitable for patients with rapid progressive


disease and severe critical patients.
Indication:
1. According to above patient’s criteria condition with disease course
not longer than 3 weeks; positive test for corona virus or specialist determine
that patients are having septicemia (blood stream infection)
2. Patients with rapid progressive disease or severe condition in
earlier stage or based on specialist decision to carry out plasma treatment.
3. Injection dosage based on patient condition and body weight.
Generally dosage given are 200-500 ml (4-5ml/kg BW)

Contraindications:
1. Patients with history of plasma infusion allergy or human plasma
protein product allergy.
2. Patients with history of citric acid and methylene blue allergy
3. Patients with other severe allergy
4. Unsuitable use for patients with terminal disease, irreversible MODS,
non-COVID19 related infection and physician specialist decision not to use it
on patients based on other criteria that won’t allow them to use plasma
therapy.

 Blood purification therapy: blood purification system includes plasma


exchange, absorption, perfusion, blood / plasma filtration, etc. it can clear
inflammatory factors and block "cytokine storm", in order to reduce the
damage of inflammatory response to the body, which can be used for the
treatment of severe and critical patients in the early and middle stages of
cytokine storm.
 Immunotherapy: patients with severe bilateral lung damage and lab exam
report show elevated IL-6 can choose Tocilizumab treatment. First dosage 4-
8mg/kg, recommended dosage 400 mg diluted with 0.9% saline 100ml. iv
infuse more than 1 hours; if still not improving it could add another
treatment (same dosage) after 12 hours. Cumulative times of administration
is 2 times at most and maximum dosage for single time shall not exceed 800
mg and pay attention to anaphylaxis side effect. It is contraindicate for those
with active tuberculosis infection.
 Other therapy: Glucocorticoids should be appropriately used for short-term
(3-5 days) in patients with progressive SaO 2 decline and rapid progress of lung
imaging and over activation of inflammatory response. Recommended
dosage not exceed prednisolone 1-2mg/kg/day, should take into
consideration that large dosage of glucocorticoid will delay clearance of
coronavirus due to immunosuppression; consider to give xuebijing (TCM
drug) injection 100ml bid
Consider to use intestinal microbiome regulator to keep gut bacteria balance
and prevent secondary infection.
Severe and critical children patients should consider taking intravenous
gamma globulin (IVIG).
Severe or critical pregnant patients infected with COVID-19 should consider
pregnancy terminated. C-Section prefer to be first choice.
Patients often display anxious and fear symptoms need to strengthen
psychological relief.

K) Hospital discharge and follow up


 Discharge parameters
 normal body temperature for more than 3 days
 improvement respiratory symptoms
 Pulmonary imaging showed that acute exudative lesions were significantly
improved
 Negative nucleic acid test result 2 times (24 hrs between first and second
test)
Need all 4 parameters in order for patients to be discharge from hospital

 Important follow up after discharge


 Establish communication between appointed hospital and primary medical
institutions where the patient currently live and share all patient’s related
medical history to local residence community.
 Discharge patients need mandatory continue self-isolation for 14 days after
discharge from hospital for follow up. Need to wear medical mask and stay in
private room designated for one person to reduce contact with other family
members. Keep personal hygiene procedure such as hand washing, separate
meal and avoid going out.
 Recommended to follow up during 2nd and 4th week after discharge to come
to hospital for further examination.

L) Transport guideline
According to the Novel Coronavirus Infection Case Plan for transport work (Trial
Implementation) issued by the national health and Health Commission
M) Prevention and control of infection in medical care facility
In strict conformity with novel coronavirus infection prevention and control guidelines in medical
care facility and Novel coronavirus pneumonia infection protection guidelines for the use of
common medical protective products published by China National Health Commission.