Diagnosis and Treatment Protocol for COVID-19 Patients (Tentative 8th Edition)

Abstract

As an emerging acute respiratory infection, the coronavirus disease 2019 (COVID-19) has become a major public health emergency that threatens global health. Through active prevention, control, and treatment measures, China has essentially brought the situation within its borders under control. Only sporadic outbreaks and imported cases remain in some parts of the country. However, as the virus is still spreading across the globe, the pandemic may persist for a longer period of time, and the risk of COVID-19 re-emerging in China still lingers. In order to further observe the principles of early detection, reporting, quarantine, and treatment of COVID-19 patients, to increase recovery rates and to lower fatality rates, we have updated the Diagnosis and Treatment Protocol for COVID-19 Patients (Tentative 7th Edition) by summarizing China's recent clinical experience and referencing treatment guidelines issued by the World Health Organization and other countries. Thus, the Diagnosis and Treatment Protocol for COVID-19 Patients (Tentative 8th Edition) was developed. I. Etiological characteristics The 2019-novel coronavirus (SARS-CoV-2) belongs to the beta genus of coronaviruses. The enveloped viral particle is round or oval, with a diameter of 60–140 nm. It has five essential genes, encoding ribonucleic acid (RNA)-dependent RNA polymerase and four structural proteins of nucleoprotein (N), envelope protein (E), matrix protein (M), and spike protein (S), respectively. The nucleoprotein wraps the RNA genome to form a nucleocapsid, which is surrounded by the E protein with embedded M and the S proteins. The S protein enters the cell by binding to angiotensin converting enzyme 2. When isolated and cultured in vitro, SARS-CoV-2 can be found in epithelial cells of human respiratory tract within 96 h, while it takes about 4–6 days to isolate and culture in Vero E6 and Huh-7 cell lines. SARS-CoV-2 is sensitive to ultraviolet rays and heat. It can be inactivated under 56°C for 30 minutes, or by ether, 75% ethanol, chlorine-containing disinfectant, peracetic acid, chloroform, and other lipid solvents, but not by chlorhexidine. II. Epidemiological characteristics 1. Source of infection The source of infection is mainly patients with SARS-CoV-2 infection as well as asymptomatic infection. Patients are infectious during the incubation period and are highly infectious within 5 days after the onset of disease. 2. Route of transmission SARS-CoV-2 is spread mainly through droplets and close contacts. Contact with items contaminated by the virus can also cause infection. Prolonged exposure to high-concentration aerosols in a relatively closed environment may spread the virus through aerosols. Since SARS-CoV-2 can be isolated in feces and urine, attention should be paid to contact or aerosol transmission in an environment contaminated by the virus. 3. Susceptible population Everyone is susceptible to coronavirus disease (COVID-19). After infection or vaccination, one can develop some immunity, with unknown duration. III. Pathological changes The following are pathological changes in major organs caused by SARS-CoV-2 infection, along with the testing results (excluding underlying diseases): 1. Lungs The lungs can show consolidation in varying degrees, which is mainly manifested by diffuse alveolar damage and exudative alveolitis. The lung lesions in different regions are complex and varied, and the old and new lesions are interlaced. Serous and fibrinous exudates, in addition to formation of hyaline membrane can be found in the alveoli; the exudatives contain mainly mononuclear and macrophages, and occasionally multinucleated giant cells. Proliferation of type II alveolar epithelial cells can be observed, with shedding of some cells. Inclusion bodies are occasionally found in type II alveolar epithelial cells and macrophages. Congestion, edema, and mononuclear and lymphocyte infiltration can be seen in the alveolar septum. A few alveoli are over-inflated, with breaks of the alveolar septum or formation of cystic cavity. Part of the epithelium of the bronchial mucosa in the lungs sheds and exudates, and mucus are detected in the cavity. Mucus plug can be seen in the small bronchi and bronchioles. Pulmonary vasculitis, thrombosis (mixed thrombus, hyaline thrombus), thromboembolism, focal hemorrhage, and hemorrhagic infarction can be observed in the lungs, as well as bacterial and/or fungal infections. In the case of a longer course of disease, the organization of alveolar exudate (sarcoidosis) and pulmonary fibrosis can be seen. Under electron microscope, coronavirus particles are found in the cytoplasm of bronchial mucosa epithelium and type II alveolar epithelial cells. The antigen of the novel coronavirus can be detected by immunohistochemical staining, as well as the nucleic acid by means of PCR, in some bronchial epithelial cells, alveolar epithelial cells, and macrophages. 2. Spleen, hilar lymph nodes, and bone marrow The splenic volume is reduced, with atrophy of white pulp, decreased lymphocytes, and necrosis of some cells. Hyperemia of red pulp, focal hemorrhage, and proliferation of macrophages, accompanied by phagocytosis, can be seen in the spleen. Anemic infarction can also occur in the spleen. Lymphocyte count is reduced in lymph nodes, together with necrosis. Immunohistochemical staining shows reduced CD4+ T and CD8+ T cells in both the spleen and lymph nodes. Nucleic acid of SARS-CoV-2 may be present in lymph nodes, while the antigen can be detected by immunostaining in macrophages. Increased and decreased hematopoietic cells may be seen in bone marrow, with increased granulocyte-to-erythrocyte ratio. Hemophagocytosis is occasionally seen. 3. Heart and blood vessels Degeneration, necrosis, interstitial congestion, and edema can be found in some cardiomyocetes, with infiltration of few monocytes, lymphocytes, and/or neutrophils. Occasionally, the nucleic acid test is positive for SARS-CoV-2. Shedding of endothelial cells, and inflammation of intima or full-thickness can be observed in small blood vessels throughout the body. Mixed thrombosis, thromboembolism, and infarction in corresponding sections can be found in blood vessels. Visible thrombosis can be seen in the microvasculatures of the major organs. 4. Liver and gallbladder Degeneration and focal necrosis of hepatocytes, with neutrophil infiltration, can be seen, as well as liver sinusoid congestion, lymphocyte, and monocyte infiltration in the portal area, and microthrombosis. The gallbladder is fully expanded. Nucleic acid for SARS-CoV-2 can be detected in the liver and gallbladder. 5. Kidneys There are congestions of glomerular capillaries, and segmental fibrinoid necrosis, with proteineous exudates in Bowman's space. Degeneration of the epithelium of the proximal renal tubules can be observed, with some necrosis and shedding. Casts are seen in the distal renal tubules. There are congestion of renal interstitium, with microthrombosis. Nucleic acid test is occasionally positive for SARS-CoV-2 in kidney tissues. 6. Other organs Congestion and edema can be seen, with degeneration, ischemic changes and loss of some neurons, and occasional phagocytic phenomenon. There is infiltration of monocytes and lymphocytes in the perivascular space. Focal necrosis of adrenal gland can also be found. The epithelium of the esophagus, stomach, and intestinal mucosa shows degeneration, necrosis, and shedding to varying degrees, with infiltration of monocytes and lymphocytes in the lamina propria and submucosa, respectively. Adrenal cortex cells exhibit degeneration, focal hemorrhage, and necrosis. In the testes, the number of spermatogenic cells decreases in varying degrees, with degeneration of Sertoli cells and Leydig cells. SARS-CoV-2 can be detected in the nasopharynx, gastrointestinal mucosa, testes, salivary glands, and other organs. IV. Clinical features 1. Clinical manifestations The incubation period is 1–14 days, mostly 3–7 days. Main manifestations are fever, dry cough, and fatigue. Anosmia and/or ageusia may be presenting symptoms in some patients. A few patients have symptoms such as nasal congestion, running nose, sore throat, conjunctivitis, myalgia, and diarrhea. Severe patients often develop dyspnea and/or hypoxemia one week after the onset of the disease. In critical cases, symptoms can quickly progress to acute respiratory distress syndrome, septic shock, refractory metabolic acidosis, coagulopathy, and multiple organ failure. A very small number of patients may also have central nervous system involvement and peripheral ischemic necrosis. Severe and critically ill patients may have moderate-to-low-grade fever, or even no fever, during the course of the illness. Mild patients can be characterized by low fever, mild fatigue, anosmia, and ageusia. No pneumonia is present. Few patients may remain asymptomatic after novel coronavirus infection. Most patients have a good prognosis, with a few patients becoming critically ill, mainly in elderly patients, patients with chronic underlying diseases, women in late pregnancy or perinatal period, and obese patients. Symptoms in children are relatively mild. Some children and newborns have atypical symptoms, such as vomiting, diarrhea, and other gastrointestinal symptoms. Some children just exhibit poor response and shortness of breath. Very few children may develop multiple system inflammatory syndrome (MIS-C), which often occurs in the recovery phase, with symptoms similar to Kawasaki disease or atypical Kawasaki disease, toxic shock syndrome, or macrophage activation syndrome. Clinical manifestations may include fever with rash, non-purulent conjunctivitis, mucosal inflammation, hypotension or shock, coagulopathy, and acute gastrointestinal symptoms. Once MIS-C occurs, the condition can deteriorate rapidly. 2. Laboratory tests 2.1. General tests In the early stage of COVID-19, white cell count is often normal or decreased, while lymphocyte count is decreased. Some patients may have increased levels of liver enzymes, lactate dehydrogenase, muscle enzymes, myoglobin, troponin, and ferritin. C-reactive protein (CRP) and erythrocyte sedimentation rate is elevated in most patients, whereas procalcitonin is normal. Increased D-dimer level can be seen in severe and critically ill patients, together with progressive decrease in lymphocyte count, and increased inflammatory cytokines. 2.2. Etiology and serology tests 2.2.1. Etiology tests The nucleic acid of SARS-CoV-2 can be detected in nasopharyngeal swabs, sputum, and other specimens of lower respiratory tract, blood, feces, and urine, by means of real time reverse transcription-polymerase chain reaction (RT-PCR) and/or next generation sequencing. More accurate results can be obtained with specimens from the lower respiratory tract (sputum or tracheal aspirates). The accuracy of nucleic acid tests may be affected by multiple factors, such as the course of the illness, sampling, testing, and test kits. In order to improve sensitivity, the sampling procedure should be standardized, and specimens should be sent for testing as soon as possible after collection. 2.2.2. Serology tests The seroconversion rate within 1 week after disease onset remains very low, with regards to SARS-CoV-2-specific IgM antibody and IgG antibody. False-positive results of serology tests may be related to the test (cutoff value), the patient (presence of interfering substances, e.g., rheumatoid factor, heterophilic antibody, complement, lysozyme, etc.), or specimen preparation (hemolysis, bacterial contamination, excessive storage time, and incomplete coagulation). Serology tests cannot be used alone; they should be considered in the context of epidemiological history, clinical manifestations, and underlying diseases, in order to confirm the diagnosis. The following patients can be diagnosed through serology tests: (1) patients who are clinically suspected of COVID-19 but have a nucleic acid and patients who are in the recovery and have a nucleic acid 3. In the early stage of COVID-19, multiple small and interstitial changes are seen, mainly in may progress multiple and In severe cases, consolidation may but is In patients with can show and pulmonary 1. cases cases can be diagnosed as of the epidemiological and of the clinical of the clinical and positive SARS-CoV-2-specific IgM antibody in not clinical in not Epidemiological or in a with case within days the of contact with patients with COVID-19 or asymptomatic infection within days of the Contact with patients with fever or respiratory symptoms from with case within days of the cases or cases of fever and/or respiratory symptoms in small such as within Clinical and/or respiratory symptoms with features with or decreased white cell count and lymphocyte count in the early 2. cases cases who of the following (1) test positive for of the virus highly to the of positive tests for SARS-CoV-2-specific IgM and IgG and seroconversion of SARS-CoV-2-specific IgG antibody, or increase in IgG antibody in that in the acute Clinical 1. Mild cases The clinical symptoms are and is no of pneumonia in 2. cases Patients have fever and respiratory symptoms. 3. Severe cases patients of the (1) shortness of respiratory rate 30 in In with should be to the following of clinical symptoms, with within in the lung lesions in of the (1) fever shortness of 5 30 of fever and in respiratory distress and and and with of 4. cases one of the following (1) severe respiratory shock, and other organ patient population 1. old 2. with such as and diseases, chronic lung pulmonary disease, chronic liver disease, chronic kidney disease, and 3. of or other that to a 4. 5. pregnancy and perinatal women 6. for cases 1. (1) of hypoxemia or respiratory of or progressive decrease in lymphocyte count or increase in inflammatory such as and ferritin. increase of D-dimer and other related of of lung 2. (1) response and increase of inflammatory such as and or infiltration, or of lung disease, respiratory tract severe etc.), of and 1. The mild cases of COVID-19 be from respiratory tract caused by other 2. of COVID-19 pneumonia caused by other respiratory and through antigen tests and nucleic acid 3. Other may include such as vasculitis, and 4. in children with and mucosal damage should include Kawasaki disease. and case by should in by by or COVID-19 cannot be the case should be in a system within h, and specimens should be for nucleic acid test for SARS-CoV-2. the case should be to under the of close contact with positive test of other respiratory it is still to a test for SARS-CoV-2. COVID-19 can be in suspected cases tests are for nucleic acid of and both SARS-CoV-2-specific IgM and IgG are days after disease cases should be in a system within Treatment 1. the treatment to the and cases should be and in cases should be isolated in whereas cases can be cases should be to as soon as 2. General treatment Patients are to have and to treatment to and should be to should be tests include blood cells, blood enzymes, enzymes, and kidney blood and levels of can be should be in severe and critical cases, nasal and nasal of may be considered or of and be about with 3. clinical have under emergency no have to be in However, of some The is that with should be used early in the course of the disease, in who are risk of becoming critically with or is not It is the of with or The following can be the of which remains to be (1) 5 in for The course of treatment is to days. or with treatment to days. with as or is for for 1 and by days for to days. about and It is with or should be or with should be with the of to the pregnancy be 4. in patients with and severe and critically ill patients. the and to the Clinical Treatment Protocol of for Patients with COVID-19 (Tentative human in and severe cases with The is for cases, and for severe clinical human can be other to five in patients with lung disease and severe cases with elevated or in normal 1 the can be after the Patients should not be with with no be in patients with active such as 5. patients with progressive of and days, no should be with as is that of may viral to 6. Treatment of severe and critical cases from the of treatment should include treatment of underlying disease, of and with nasal or Severe patients with should with nasal or under close for in respiratory distress and/or nasal or should be or Patients with should be with or for should be in patients with or not Some patients have a risk of treatment with or and they should be for of symptoms and the patient not improve after a as by refractory or excessive volume or after treatment with or and should not be and should not be in patients with However, to the atypical of hypoxemia in patients with severe COVID-19, for and should be of clinical and organ is that may cause in patients. and treatment with treatment is in the of critically ill patients with is the should be considered in patients with acute respiratory distress syndrome, or In COVID-19 patients with low positive may to and should be is with in to is to the risk of aerosol while under may be and is to and active are to and pulmonary membrane membrane is patients of the following of volume of 5 with no and and h, and and 30 of shock or ill patients who the for and have no should as soon as is with poor of is most used in patients respiratory is in patients both respiratory and In patients with in the and during should be is even in patients with include volume 4–6 and should be in patients with refractory excessive consolidation in and for of with severe COVID-19 should be with and lung to to and is not ill patients with COVID-19 can be with In patients, should be after blood and should be in addition to lactate and may be to and of in order to improve Severe or critically ill patients are risk of who have elevated D-dimer level and no to should be In cases of thromboembolism, patients should be to kidney and renal In critically ill patients who develop acute kidney as and should be and and should be for renal include (1) severe acidosis, and pulmonary edema or refractory to may organ caused by by of inflammatory cytokines. It may be used in severe and critically ill patients with MIS-C in children The patients should be under with early of shock and coagulopathy, and with or atypical manifestations of Kawasaki disease, treatment for Kawasaki disease should be used with and Other Other treatment the of and to to and to bacterial infections. children with severe or critical COVID-19, can also be should be in patients with severe or critical COVID-19, by is as patients often have and and may be disease belongs to in caused by the to the different and of and the following treatment Protocol may The of should be by a Clinical and gastrointestinal or Clinical and fever clinical treatment of It is for and severe patients, and can be used in with the situation of patients in the treatment of critically ill patients. for in with of the in the and in the after with days a course of the patient can a of time after the and can to one the patient has a dry and is in the patient not have a fever, the of should be a fever or fever, the of can be the symptoms improve but not fully the course of the patient has or other underlying diseases, the of the course of treatment can be the situation and the should be the symptoms Source of the of in Treatment of COVID-19 by and by the of the of the General of the Health Mild cases and lung syndrome Clinical fever, fatigue, sore cough, loss of vomiting, and has or is and the is white or white and the is or to 30 and with one of the in the and in the and lung syndrome Clinical low or no fever, fatigue, and muscle dry cough, sore throat, dry of or accompanied by no or or and loss of diarrhea, or The is and the is and or and the is or 5 with of the in the and the other in the cases and lung syndrome Clinical fever, and sputum, or sputum, shortness of and The is red and the is or and the is or and 30 30 30 30 with of the in the and the other in the lung syndrome Clinical low fever, fever or of fever, dry cough, sputum, fatigue, and in the stomach, or The is or and the is white or and the is one with of the in the and the other in the Severe cases and syndrome Clinical fever, cough, or blood in sputum, shortness of fatigue, and in the loss of poor and The is the is and the is and 5 one or with the in across the or nasal of both and syndrome Clinical fever, shortness of and or rash, or or in the The is with or no The is and or and 30 30 30 30 and other with the in across the or with similar can be to or can be used in to clinical symptoms. can be used in with cases and Clinical or or dry and with or patients with or of patients with of and of while and muscle with similar can be to or can be used in to clinical symptoms. can be used in with of for severe and critical cases The of the of from a small and the to the of the The is as infection or mild bacterial of or of of or of of fever with of of of inflammatory response syndrome multiple organ of of of of or of period and spleen syndrome Clinical shortness of fatigue, and The is and 30 with of of the in the and the other in the of both and syndrome Clinical fatigue, shortness of dry poor low or no fever, dry cough, dry or with of of the in the and the other in the respiratory and should be as soon as to and should be the of the In patients with severe COVID-19, the and should be In critically ill patients, of is blood and in addition to should be and changes should be in patients to of should be in patients and as well as in patients with attention is for and of is in patients with may be of and after 1. who the following can be (1) of for days, in respiratory symptoms, in lung in and respiratory tract for nucleic acid of SARS-CoV-2. patients who 1 but with positive test of nucleic acid of SARS-CoV-2 for it is to a of the through antibody and viral 2. after (1) and should develop an of to and of patients. patients are to for days, in addition to of health patients are to in with is and public and close contact with and should be It is to after and are to the for the of by the issued by the Health in the of the for the and of in Health Edition) issued by the Health and the for the of in the of are to good and should be and to to and to fatigue. The of and should be should and or of the to be to fever in case of respiratory symptoms. with recent to or of exposure to or suspected cases should be for nucleic acid of SARS-CoV-2. of The General of Health and The and Treatment Protocol for is The was through in China and the are the of the

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