X. Treatment

1. Treatment venue determined by the severity of the disease

1.1 Suspected and confirmed cases should be isolated and treated at designated hospitals with effective isolation, protection and prevention conditions in place. A suspect case should be treated in isolation in a single room. Confirmed cases can be treated in the same room.

1.2 Critical cases should be admitted to ICU as soon as possible.

2. General treatment

2.1 Letting patients rest in bed and strengthening support therapy; ensuring sufficient caloric intake for patients; monitoring their water and electrolyte balance to maintain internal environment stability; closely monitoring vital signs and oxygen saturation.

2.2 According to patients’ conditions, monitoring blood routine result, urine routine result, c-reactive protein (CRP), biochemical indicators (liver enzyme, myocardial enzyme, renal function etc.), coagulation function, arterial blood gas analysis, chest imaging and cytokines detection if necessary.

2.3 Timely providing effective oxygen therapy, including nasal catheter and mask oxygenation and nasal high-flow oxygen therapy. If possible, inhalation of mixed hydrogen and oxygen (H2/O2: 66.6%/33.3%) can be applied.

2.4 Antiviral therapy: Hospitals can try Alpha-interferon (5 million U or equivalent dose each time for adults, adding 2ml of sterilized water, atomization inhalation twice daily), lopinavir/ritonavir (200 mg/50mg per pill for adults, two pills each time, twice daily, no longer than 10 days), Ribavirin (suggested to be used jointly with interferon or lopinavir/ritonavir, 500 mg each time for adults, twice or three times of intravenous injection daily, no longer than 10 days), chloroquine phosphate (500 mg bid for 7 days for adults aged 18-65 with body weight over 50 kg; 500 mg bid for Days 1&2 and 500 mg qd for Days 3-7 for adults with body weight below 50 kg), Arbidol (200 mg tid for adults, no longer than 10 days). Be aware of the adverse reactions, contraindications (for example, chloroquine cannot be used for patients with heart diseases) and interactions of the above-mentioned drugs. Further evaluate the efficacy of those drugs currently being used. Using three or more antiviral drugs at the same time is not recommend; if an intolerable toxic side effect occurs, the respective drug should be discontinued. For the treatment of pregnant women, issues such as the number of gestational weeks, choice of drugs having the least impact on the fetus, as well as whether pregnancy being terminated before treatment should be considered with patients being informed of these considerations.

2.5 Antibiotic drug treatment: Blind or inappropriate use of antibiotic drugs should be avoided, especially in combination with broad-spectrum antibiotics.

3. Treatment of severe and critical cases

Treatment principle:

On the basis of symptomatic treatment, complications should be proactively prevented, underlying diseases should be treated, secondary infections also be prevented, and organ function support should be provided timely.

Respiratory support:

3.2.1 Oxygen therapy: Patients with severe symptoms should receive nasal cannulas or masks for oxygen inhalation and timely assessment of respiratory distress and/or hypoxemia should be performed.

3.2.2 High-flow nasal-catheter oxygenation or noninvasive mechanical ventilation: When respiratory distress and/or hypoxemia of the patient cannot be alleviated after receiving standard oxygen therapy, high-flow nasal cannula oxygen therapy or non-invasive ventilation can be considered. If conditions do not improve or even get worse within a short time (1-2 hours), tracheal intubation and invasive mechanical ventilation should be used in a timely manner.

3.2.3 Invasive mechanical ventilation: Lung protective ventilation strategy, namely low tidal volume (6-8ml/kg of ideal body weight) and low level of airway platform pressure (<30cmH2O) should be used to perform mechanical ventilation to reduce ventilator-related lung injury. While the airway platform pressure maintained ≤30cmH2O, high PEEP can be used to keep the airway warm and moist; avoid long sedation and wake the patient early for lung rehabilitation. There are many cases of human-machine asynchronization, therefore sedation and muscle relaxants should be used in a timely manner. Use closed sputum suction according to the airway secretion, if necessary, administer appropriate treatment based on bronchoscopy findings.

3.2.4 Rescue therapy: Pulmonary re-tensioning is recommended for patients with severe ARDS. With sufficient human resources, prone position ventilation should be performed for more than 12 hours per day. If the outcome of prone position ventilation is poor, extracorporeal membrane oxygenation (ECMO) should be considered as soon as possible. Indications include: ①When Fi02＞90%, the oxygenation index is less than 80mmHg for more than 3-4 hours; ②For patients with only respiratory failure when the airway platform pressure ≥ 35cmH2O, VV-ECMO mode is preferred; if circulatory support is needed, VA-ECMO mode should be used. When underlying diseases are under control and the cardiopulmonary function shows signs of recovery, withdrawal of ECMO can be tried.

Circulatory support:

On the basis of adequate fluid resuscitation, efforts should be made to improve microcirculation, use vasoactive drugs, closely monitor changes in blood pressure, heart rate and urine volume as well as lactate and base excess in arterial blood gas analysis. If necessary, use non-invasive or invasive hemodynamic monitor such as Doppler ultrasound, echocardiography, invasive blood pressure or continuous cardiac output (PiCCO) monitoring. In the process of treatment, pay attention to the liquid balance strategy to avoid excessive or insufficient fluid intake.

If the heart rate suddenly increases more than 20% of the basic value or the decrease of blood pressure is more than 20% of the basic value with manifestations of poor skin perfusion and decreased urine volume, make sure to closely observe whether the patient has septic shock, gastrointestinal hemorrhage or heart failure.

Renal failure and renal replacement therapy:

Active efforts should be made to look for causes for renal function damage in critical cases such as low perfusion and drugs. For the treatment of patients with renal failure, focus should be on the balance of body fluid, acid and base and electrolyte balance, as well as on nutrition support including nitrogen balance and the supplementation of energies and trace elements. For critical cases, continuous renal replacement therapy (CRRT) can be used. The indications include: ① hyperkalemia; ② acidosis; ③ pulmonary edema or water overload; ④fluid management in multiple organ dysfunction.

Convalescent plasma treatment:

It is suitable for patients with rapid disease progression, severe and critically ill patients. Usage and dosage should refer to Protocol of Clinical Treatment with Convalescent Plasma for NCP Patients (2nd trial version).

Blood purification treatment:

Blood purification system including plasma exchange,absorption, perfusion and blood/plasma filtration can remove inflammatory factors and block cytokine storm, so as to reduce the damage of inflammatory reactions to the body. It can be used for the treatment of severe and critical cases in the early and middle stages of cytokine storm.

Immunotherapy:

For patients with extensive lung lesions and severe cases who also show an increased level of IL-6 in laboratory testing, Tocilizumab can be used for treatment. The initial dose is 4-8mg/kg with the recommended dose of 400mg diluted with 0.9% normal saline to 100ml. The infusion time should be more than 1 hour. If the initial medication is not effective, one extra administration can be given after 12 hours (same dose as before). No more than two administrations should be given with the maximum single dose no more than 800mg. Watch out for allergic reactions. Administration is forbidden for people with active infections such as tuberculosis.

Other therapeutic measures

For patients with progressive deterioration of oxygenation indicators, rapid progress in imaging and excessive activation of the body's inflammatory response, glucocorticoids can be used in a short period of time (three to five days). It is recommended that dose should not exceed the equivalent of methylprednisolone 1-2 mg/kg/day. Note that a larger dose of glucocorticoid will delay the removal of coronavirus due to immunosuppressive effects. Xuebijing 100ml/time can be administered intravenously twice a day. Intestinal microecological regulators can be used to maintain intestinal microecological balance and prevent secondary bacterial infections.

Child severe and critical cases can be given intravenous infusion of γ-globulin.

For pregnant severe and critical cases, pregnancy should be terminated preferably with c-section.

Patients often suffer from anxiety and fear and they should be supported by psychological counseling.

Traditional Chinese medicine (TCM) treatment

The COVID-19 belongs to plague in TCM with the etiology of epidemic factor exposure. Different regions can refer to the following plans for syndrome differentiation and treatment, according to the disease, local climate characteristics and different constitutions. Prescriptions which exceed maximum dose according to pharmacopoeia should be used under the guidance of a physician.

(1) Medical observation period

1.1 Clinical manifestation: fatigue with gastrointestinal discomfort

Recommended Chinese patent medicine: Huoxiang Zhengqi Capsule (Pill, Liquid, Oral liquid)

1.2 Clinical manifestation: fatigue with fever

Recommended Chinese patent medicines: Jinhua Qinggan Granule, Lianhua Qingwen Capsule (Granule), Shufeng Jiedu Capsule (Granule)

(2) Clinical treatment period (confirmed cases)

Qingfei Paidu Decoction

Scope of application: in accordance with the clinical observations of doctors in various locations, it is suitable for mild, moderate and severe cases, and can be used reasonably with the consideration of the actual conditions of critically ill patients.

The basic prescription: Ma Huang (Ephedrae Herba) 9g, Zhi Gan Cao (Glycyrrhizae Radix) 6g, Xing Ren (Armeniacae Semen) 9g, Raw Shi Gao (Gypsum fibrosum) (decocted first) 15-30g, Gui Zhi (Cinnamomi Ramulus) 9g, Ze Xie (Alismatis Rhizoma) 9g, Zhu Ling (Polyporus) 9g, Bai Zhu (Atractylodis macrocephalae Rhizoma) 9g, Fu Ling (Poria) 15g, Chai Hu (Bupleuri Radix) 16g, Huang Qin (Scutellariae Radix) 6g, Jiang Ban Xia (Pinellinae Rhizoma Praeparatum) 9g, Fresh ginger (Zingiberis Rhizoma recens) 9g, Zi Wan (Asteris Radix) 9g, Kuan Dong Hua (Farfarae Flos) 9g, She Gan (Belamcandae Rhizoma) 9g, Xi Xin (Asari Radix et Rhizoma) 6g, Shan Yao (Dioscoreae Rhizoma) 12g, Zhi Shi (Aurantii Fructus immaturus) 6g, Chen Pi (Citri reticulatae Pericarpium) 6g, Huo Xiang (Pogostemonis Herba) 9g.

Administration: traditional Chinese herbal pieces in decoction. One package per day. Take warm twice (40 minutes after meal in the morning and evening). One course of treatment is for three packages.

If possible, half bowl of rice soup after taking the decoction is advised. For the patients with dry tongue due to fluid depletion, one bowl of rice soup is suggested. (Note: If no fever, the dosage of gypsum should be reduced. In case with fever or high fever, the amount of gypsum can be increased. If the symptoms improve but not toally recovered, continue the second course of treatment. If the patient has a special condition or other underlying diseases, the prescription can be modified according to the actual situation in the second course. If the symptoms disappear, the drug should be discontinued.

Reference: The General Office of the National Health Commission of the people’s Republic of China The Office of the National Administration of Traditional Chinese Medicine “Notice on Recommending the Use of Qingfei Paidu Decoction in Pneumonia Treated with Integrated Chinese and Western Medicine for the COVID-19 Infection” (National Administration of Traditional Chinese Medicine Office Medical Letter [2020] No.22)

Mild case

Cold-damp constraint in the lung pattern

Clinical manifestation: fever, fatigue, generalized body aches, cough, expectoration, chest tightness and labored breathing, poor appetite, nausea, vomiting and sticky stool, pale enlarged tongue with tooth marks or light red tongue and coating which is white, thick, curd-like, and greasy or white and greasy, and soggy of slippery pulse.

Recommended prescription: Raw Ma Huang (Ephedrae Herba) 6g, Ku Xing Ren (Armeniacae Semen) 15g, Raw Shi Gao (Gypsum fibrosum) 30g, Raw Yi Yi Ren (Coicis Semen) 30g, Mao Cang Zhu (Atractylodis Rhizoma) 10g, Guang Huo Xiang (Pogostemonis Herba) 15g, Qing Hao Cao (Artemisiae annuae Herba) 12g, Hu Zhang (Polygoni cuspidati Rhizoma) 20g, Ma Bian Cao (Verbenae Herba) 30g, Gan Lu Gen (Phragmitis Rhizoma) 30g, Ting Li Zi (Lepidii/Descurainiae Semen) 15g, Hua Ju Hong (Citri grandis Exocarpium rubrum) 15g, Raw Gan Cao (Glycyrrhizae Radix) 10g.

Administration: one package daily, 400ml after decocting, and equally divide into twice, in the morning and evening.

Cold-damp obstructing the lung pattern

Clinical manifestation: low-grade fever, unsurfaced fever or no fever, dry cough with little sputum, lassitude and fatigue, chest tightness, stomach discomfort, or nausea, and loose stool. The tongue is pale or light red and coating is white or white greasy. The pulse is soggy.

Recommended prescription: Bing Lang (Arecae Semen) 10g, Cao Guo (Tsaoko Fructus) 10g, Hou Po (Magnoliae officinalis Cortex) 10g, Zhi Mu (Anemarrhenae Rhizoma) 10g, Huang Qin (Scutellariae Radix) 10g, Chai Hu (Bupleuri Radix) 10g, Chi Shao (Paeoniae Radix rubra) 10g, Lian Qiao (Forsythiae Fructus) 15g, Qing Hao (Artemisiae annuae Herba) (added later) 10g, Cang Zhu (Atractylodis Rhizoma) 10g, Da Qjng Ye (Isatidis Folium) 10g, Raw Gan Cao (Glycyrrhizae Radix) 5g.

Administration: one pack daily, 400ml after decocting, divide into twice, and half in the morning and half in the evening.

Moderate case

Damp-toxin constraint in the lung pattern

Clinical manifestation: fever, cough with little sputum or yellow sputum, chest tightness and shortness of breath, abdominal distension, and constipation with difficult defecation. The tongue body is dark-red, and tongue shape is enlarged. The cotaing is yellow greasy or yellow dry. The pulse is slippery and rapid or wiry and slippery.

Recommended prescription: Raw Ma Huang (Ephedrae Herba) 6g, Ku Xing Ren (Armeniacae Semen) 15g, Raw Shi Gao (Gypsum fibrosum) 30g, Raw Yi Ni Ren (Coicis Semen) 30g, Mao Cang Zhu (Atractylodis Rhizoma) 10g, Guang Huo Xiang (Pogostemonis Herba) 15g, Qing Hao Cao (Artemisiae annuae Herba) 12g, Hu Zhang (Polygoni cuspidati Rhizoma) 20g, Ma Bian Cao (Verbenae Herba) 30g, Gan Lu Gen (Phragmitis Rhizoma) 30g, Ting Li Zi (Lepidii/Descurainiae Semen) 15g, Hua Ju Hong (Citri grandis Exocarpium rubrum) 15g, Raw Gan Cao (Glycyrrhizae Radix) 10g.

Administration: one package daily, 400ml after decocting, and equally divide into twice, in the morning and evening.

Cold-damp obstructing the lung pattern

Clinical manifestation: low-grade fever, unsurfaced fever or no fever, dry cough with little sputum, lassitude and fatigue, chest tightness, stomach discomfort, or nausea, and loose stool. The tongue is pale or light red and coating is white or white greasy. The pulse is soggy.

Recommended prescription: Cang Zhu (Atractylodis Rhizoma) 15g, Chen Pi (Citri reticulatae Pericarpium) 10g, Hou Pu (Magnoliae officinalis Cortex) 10g, Huo Xiang (Pogostemonis Herba) 10g, Cao Guo (Tsaoko Fructus) 6g, Raw Ma Huang (Ephedrae Herba) 6g, Qiang Huo (Notopterygii Rhizoma seu Radix) 10g, Raw Jiang (Zingiberis Rhizoma recens) 10g, Bing Lang (Arecae Semen) 10g.

Administration: one package daily, 400ml after decocting, and equally divide into twice, in the morning and evening.

Severe case

Epidemic toxin blocking the lung pattern

Clinical manifestation: fever with red face, cough with little yellow and sticky sputum, or blood-stained sputum, chest tightness and short of breath, lassitude, dryness, bitterness and stickiness in the mouth, nausea and loss of appetite, difficult defecation, and scanty dark urine. The tongue is red with yellow greasy coating. The pulse is slippery and rapid.

Recommended prescription: Huashi Baidu prescription

The basic prescription: Sheng Ma Huang (Ephedrae Herba) 6g, Xing Ren (Armeniacae Semen) 9g, Sheng Shi Gao (Gypsum fibrosum) 15g, Gan Cao (Glycyrrhizae Radix) 3g, Huo Xiang (Pogostemonis Herba) (added later) 10g, Hou Po (Magnoliae officinalis Cortex) 10g, Cang Zhu (Atractylodis Rhizoma) 15g, Cao Guo (Tsaoko Fructus) 10g, Fa Ban Xia (Pinellinae Rhizoma Praeparatum) 9g, Fu Ling (Poria) 15g, Sheng Da Huang (Rhei Radix et Rhizoma) (added later) 5g, Sheng Huang Qi (Astragali Radix) 10g, Ting Li Zi (Lepidii/Descurainiae Semen) 10g, Chi Shao (Paeoniae Radix rubra) 10g.

Administration: 1-2 packages daily, decoction, 100-200ml each time, 2-4 times per day, oral administration or nasal feeding.

Blazing of both qi and ying pattern

Clinical manifestation: high fever with polydipsia, tachypnoea and shortness of breath, delirium and unconsciousness, blurred vision or accompanied with macules and papules, or hematemesis, epistaxis or convulsion of the four limbs. The tongue is crimson with little or no coating. The pulse is deep, thready and rapid, or floating, large and rapid pulse.

Recommended prescription: Raw Shi Gao (Gypsum fibrosum) (decocted first) 30-60g, Zhi Mu (Anemarrhenae Rhizoma) 30g, Sheng Di (Rehmanniae Radix) 30-60g, Shui Niu Jiao (Bubali Cornu) (decocted first) 30g, Chi Shao (Paeoniae Radix rubra) 30g, Xuan Shen (Scrophulariae Radix) 30g, Lian Qiao (Forsythiae Fructus) 15g, Dan Pi (Moutan Cortex) 15g, Huang Lian (Coptidis Rhizoma) 6g, Zhu Ye (Phyllostachys nigrae Folium) 12g, Ting Li Zi (Lepidii/Descurainiae Semen) 15g, Sheng Gan Cao (Glycyrrhizae Radix) 6g.

Administration: one pack daily, decoction, Shi Gao and Shui Niu Jiao should be decocted first, 100-200 ml each time, 2-4 times per day, oral administration or nasal feeding.

Recommended Chinese patent medicines: Xiyanping injection, Xuebijing injection, Reduning injection, Tanreqing injection, and Xingnaojing injection. Drugs with similar effects can be selected according to individual conditions, or can be used in combination according to clinical symptoms. Traditional Chinese medicine injection can be used together with TCM decoction.

Critical case

Internal blockage and external desertion pattern

Clinical manifestation: Dyspnea, panting on exertion or mechanical ventilation required, accompanied with unconsciousness and dysphoria, sweating, cold extremities. The tongue is dark and purple with thick greasy or dry coating. The pulse is floating and large without root.

Recommended presicription: Take Su He Xiang Wan or Angong Niuhuang Wan with the following decoction composed of Ren Shen (Ginseng Radix) 15g, Hei Shun Pian (Aconiti Radix lateralis praeparata) (decocted first) 10g, Shan Zhu Yu (Corni Fructus) 15g.

If there is mechanical ventilation with abdominal distension, constipation or difficult defecation, 5-10g of Sheng Da Huang (Rhei Radix et Rhizoma) can be considered. If patient-ventilator asynchrony occurs, 5-10g of Sheng Da Huang and 5-10g of Mang Xiao (Natrii Sulfas) can be used together with sedation and muscle relaxant.

Recommended Chinese patent medicines: Xuebijing injection, Reduning injection, Tanreqing injection, Xingnaojing injection, Shenfu injection, Shengmai injection, and Shenmai injection. Drugs with similar effects can be selected according to individual conditions, or can be used in combination according to clinical symptoms. Traditional Chinese medicine injection can be used together with TCM decoction.

Note: Recommended usage of TCM injections for severe and critical cases

The use of TCM injections follows the principle of starting from a small dosage and modifying based on pattern identification in the instructions. The recommended usage is as follows:

Viral infection or combined with mild bacterial infection: 0.9% sodium chloride injection 250ml with Xiyanping injection 100mg (bid), or 0.9% sodium chloride injection 250ml with Reduning injection 20ml, or 0.9% sodium chloride injection 250ml with Tanreqing injection 40ml (bid).

High fever with disturbance of consciousness: 0.9% sodium chloride injection 250ml with Xingnaojing injection 20ml (bid).

Systemic inflammatory response syndrome (SIRS) or / and multiple organ failure (MOF): 0.9% sodium chloride injection 250ml with Xuebijing injection 100ml (bid).

Immunosuppression: glucose injection 250ml with Shenmai injection 100ml or Shengmai injection 20-60ml (bid).

Convalescence

Lung-spleen qi deficiency pattern

Clinical manifestation: shortness of breath, lassitude and fatigue, poor appetite with nausea and vomiting, abdominal fullness, a sense of incomplete evacuation, and sticky loose stool. The tongue is pale and enlarged with white greasy coating.

Recommended prescription: Fa Ban Xia (Pinellinae Rhizoma Praeparatum) 9g, Chen Pi (Citri reticulatae Pericarpium) 10g, Dang Shen (Codonopsis Radix) 15g, Zhi Huang Qi (Astragali Radix) 30g, Chao Bai Zhu (Atractylodis macrocephalae Rhizoma) 10g, Fu Ling (Poria) 15g, Huo Xiang (Pogostemonis Herba) 10g, Sha Ren (AmomiFructus) (added later) 6g, Gan Cao (Glycyrrhizae Radix) 6g.

Administration: one package daily, 400ml after decocting, and equally divide into twice in the morning and evening.

Deficiency of both qi and yin pattern

Clinical manifestation: fatigue, shortness of breath, dry mouth, thirst, heart palpitation, profuse sweating, poor appetite, low-grade fever or no fever, dry cough with little sputum. The tongue is dry tongue with scanty fluid. The pulse is thready or weak and forceless.

Recommended prescription: Nan Sha Shen (Adenophorae Radix) 10g, Bei Sha Shen (Glehniae Radix) 10g, Mai Dong (Ophiopogonis Radix) 15g, Xi Yang Shen (Panacis quinquefolii Radix) 6g, Wu Wei Zi (Schisandrae Fructus) 6g, Sheng Shi Gao (Gypsum fibrosum) 15g, Dan Zhu Ye (Lophatheri Herba) 10g, Sang Ye (Mori Folium) 10g, Lu Gen (Phragmitis Rhizoma) 15g, Dan Shen (Salviae miltiorrhizae Radix) 15g, Sheng Gan Cao (Glycyrrhizae Radix) 6g.

Administration: one package daily, 400ml after decocting, and equally divide into twice in the morning and evening.

XI. Discharge criteria and after-discharge considerations

1.Discharge criteria

1) Body temperature is back to normal for more than three days;

2) Respiratory symptoms improve obviously;

3) Pulmonary imaging shows obvious absorption of inflammation,

4) Nuclei acid tests negative twice consecutively on respiratory tract samples such as sputum and nasopharyngeal swabs (sampling interval being at least 24 hours).

Those who meet the above criteria can be discharged.

2. After-discharge considerations

2.1 The designated hospitals should contact the primary healthcare facilities where the patients live and share patients’ medical record, to send the information of the discharged patients to the community committee and primary healthcare facility where the patients reside.

2.2. After discharge, it is recommended for patients to monitor their own health status in isolation for 14 days, wear a mask, live in well-ventilated single room if possible, reduce close contact with family members, separate dinning, practice hand hygiene and avoid going out.

2.3 It is recommended for the patients to return to the hospitals for follow-up and re-visit in two and four weeks after discharge.