key: cord-0877756-ovk8oei1 authors: Yang, Qing title: Multidisciplinary, three-dimensional and individualized comprehensive treatment for severe/critical COVID-19()()() date: 2020-08-25 journal: Liver Res DOI: 10.1016/j.livres.2020.08.001 sha: 980bff62ebfcb469686daf21f8c888617665ce1b doc_id: 877756 cord_uid: ovk8oei1 Severe/critical cases account for 18–20% of all novel coronavirus disease 2019 (COVID-19) patients, but their mortality rate can be up to 61.5%. Furthermore, all deceased patients were severe/critical cases. The main reasons for the high mortality of severe/critical patients are advanced age (>60 years old) and combined underlying diseases. Elderly patients with comorbidities show decreased organ function and low compensation for damage such as hypoxia and inflammation, which accelerates disease progression. The lung is the main target organ attacked by severe acute respiratory syndrome coronavirus (SARS-CoV-2) while immune organs, liver, blood vessels and other organs are damaged to varying degrees. Liver volume is increased, and mild active inflammation and focal necrosis are observed in the portal area. Virus particles have also been detected in liver cells. Therefore, multidisciplinary teams (MDTs) and individualized treatment plans, accurate prediction of disease progression and timely interventions are vital to effectively reduce mortality. Specifically, a “multidisciplinary three-dimensional management, individualized comprehensive plan” should be implemented. The treatment plan complies with three principles, namely, multidisciplinary management of patients, individualized diagnosis and treatment plans, and timely monitoring and intervention of disease. MDT members are mainly physicians from critical medicine, infection and respiratory disciplines, but also include cardiovascular, kidney, endocrine, digestion, nerve, nutrition, rehabilitation, psychology and specialty care. According to a patient’s specific disease condition, an individualized diagnosis and treatment plan is formulated (one plan for one patient). While selecting individualized antiviral, anti-inflammatory and immunomodulatory treatment, we also strengthen nutritional support, psychological intervention, comprehensive rehabilitation and timely and full-course intervention to develop overall and special nursing plans. In response to the rapid progression of severe/critical patients, MDT members need to establish a three-dimensional management model with close observation and timely evaluation. The MDT should make rounds of the quarantine wards both morning and night, and of critical patient wards nightly, to implement “round-the-clock rounds management”, to accurately predict disease progression, perform the quick intervention and prevent rapid deterioration of the patient. Our MDT has cumulatively treated 77 severe/critical COVID-19 cases, including 62 (80.5%) severe cases and 15 (19.5%) critical cases, with an average age of 63.8 years. Fifty-three (68.8%) cases presented with more than one underlying disease and 65 (84.4%) severe cases recovered from COVID-19. The average hospital stay of severe/critical cases was 22 days, and the mortality rate was 2.6%, both of which were significantly lower than the 30–40 days and 49.0–61.5%, respectively, reported in the literature. Therefore, a multidisciplinary, three-dimensional and individualized comprehensive treatment plan can effectively reduce the mortality rate of severe/critical COVID-19 and improve the cure rate. disease progression. The lung is the main target organ attacked by severe acute respiratory syndrome coronavirus (SARS-CoV-2) while immune organs, liver, blood vessels and other organs are damaged to varying degrees. Liver volume is increased, and mild active inflammation and focal necrosis are observed in the portal area. Virus particles have also been detected in liver cells. Therefore, multidisciplinary teams (MDTs) and individualized treatment plans, accurate prediction of disease progression and timely interventions are vital to effectively reduce mortality. Specifically, a "multidisciplinary three-dimensional management, individualized comprehensive plan" should be implemented. The treatment plan complies with three principles, namely, multidisciplinary management of patients, individualized diagnosis and treatment plans, and timely monitoring and intervention of disease. MDT members are mainly physicians from critical medicine, infection and respiratory disciplines, but also include cardiovascular, kidney, endocrine, digestion, nerve, nutrition, rehabilitation, psychology and specialty care. According to a patient's specific disease condition, an individualized diagnosis and treatment plan is formulated (one plan for one patient). While selecting individualized antiviral, anti-inflammatory and immunomodulatory treatment, we also strengthen nutritional support, psychological intervention, comprehensive rehabilitation and timely and full-course intervention to develop overall and special nursing plans. In response to the rapid progression of severe/critical patients, MDT members need to establish a three-dimensional management model with close observation and timely evaluation. The MDT should make rounds of the quarantine wards both morning and night, and of critical patient J o u r n a l P r e -p r o o f wards nightly, to implement "round-the-clock rounds management", to accurately predict disease progression, perform the quick intervention and prevent rapid deterioration of the patient. Our MDT has cumulatively treated 77 severe/critical COVID-19 cases, including 62 (80.5%) severe cases and 15 (19.5%) critical cases, with an average age of 63.8 years. Fifty-three (68.8%) cases presented with more than one underlying disease and 65 (84.4%) severe cases recovered from COVID-19. The average hospital stay of severe/critical cases was 22 days, and the mortality rate was 2.6%, both of which were significantly lower than the 30-40 days and 49.0-61.5%, respectively, reported in the literature. Therefore, a multidisciplinary, three-dimensional and individualized comprehensive treatment plan can effectively reduce the mortality rate of severe/critical COVID-19 and improve the cure rate. for severe/critical patients in combination with our own experiences of diagnosis and treatment. This treatment approach has achieved good effects and significantly reduced the mortality rate while greatly improving the cure rate in severe/critical COVID-19 patients. The respiratory system is the main target organ attacked by SARS-CoV-2. The pathophysiological characteristics include diffuse alveolar injury with fibrous mucinous exudation and retention of mucous secretions in the small airways, hyaline J o u r n a l P r e -p r o o f membrane formation in the alveolar spaces, 5, 6 lung interstitial fibrosis and lung consolidation, atrophy of alveolar epithelium and cytoplasmic necrotizing bronchitis, along with diffuse alveolar hemorrhage and pulmonary hemorrhagic infarction in some cases (Table 1) . In many patients, the immune organs are also affected. Peripheral blood flow cytometry and immunohistochemistry of spleen and lymph nodes in COVID-19 patients show a significant decrease in CD4 + T and CD8 + T lymphocytes. Almost no inflammatory hyperplasia in lymph nodes or spleen is observed and the lymphocyte count and activation markers are decreased dramatically in cases succumbing to disease, suggesting that fatal cases are in an immunodepleted state (Table 1) . 4, 5 Liver damage is also observed in some severe/critical COVID-19 patients, mainly manifesting as increased transaminase, lactate dehydrogenase (LDH) and decreased serum albumin, without significant increases in bilirubin, gamma glutamyl transferase and alkaline phosphatase. The pathological manifestations include increased liver volume, 3 along with mild active inflammation and focal necrosis in the portal area, and microvascular thrombosis and focal necrosis around the central vein. 5, 7 SARS-CoV-2 particles in liver cells have also been identified in liver sections under electron microscopy (Table 1) . 8 Previous studies have shown that the spike protein of SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) to invade cells, 9 and ACE2 is expressed in multiple organs such as ileum, heart, kidney, lung, testis and the central nervous system. Clinical data from severe COVID-19 patients indicate that extra-pulmonary J o u r n a l P r e -p r o o f organs including the heart and kidneys suffer damage during COVID-19. However, according to pathology upon autopsy of deceased cases, the damage to extra-pulmonary organs is relatively mild; therefore, the main target organ of SARS-CoV-2 is the lungs (Table 1) . [3] [4] [5] [10] [11] [12] J o u r n a l P r e -p r o o f 7 Pathological features of COVID-19. A multi-disciplinary management model is tailored to the combined underlying disease profile of each patient. A "special disease responsibility system" with the seek multi-level and multi-disciplinary support; fourth, timely early warning: give timely early warning in case of disease aggravation and poor prognosis; fifth, timely treatment: provide timely treatment for critical conditions, disease progression and other urgent problems. Astute observation of the symptoms and signs in COVID-19 patients is vital. Because of the limitations in quarantine ward conditions, disease condition observations of severe cases include several aspects. Observation of the patients' basic condition, including age greater than 65 years, combined with multiple organ damage and underlying diseases is key, as these are high-risk factors for death. 1, 13 Any new or altered development of mental depression, laziness to speak, irritability and consciousness change, etc., indicate severe disease or disease progression. Any changes to vital signs, including persistent fever (for example, >38 ) or increased body temperature, heart rate greater than 100 beats/min continuously or faster than before, blood pressure lower than 90/60 mmHg or progressive decline, or mean arterial pressure lower than 70 mmHg, suggest disease progression or even shock. Similarly, respiratory symptoms must be accurately observed. Aggravated coughing, shortness of breath, decreased activity tolerance, respiratory rate greater than 30 J o u r n a l P r e -p r o o f times/min continuously or further aggravation, or blood oxygen saturation lower than 93% suggest severe disease or disease progression. During oxygen therapy, it is necessary to monitor the blood oxygen saturation and maintain SpO 2 ≥95%. Otherwise, arterial blood gas analysis needs to be performed as soon Early identification of changes in white blood cell counts is of great importance in severe/critical COVID-19 patients. Peripheral blood lymphocyte count gradually decreases to (0.3-0.4)×10 9 /L. 14 Absolute lymphocyte count is positively associated with the severity of disease, and continuous decline of lymphocytes is a sign of poor prognosis. COVID-19 patients often show increased neutrophil to lymphocyte ratio (NRL), which was more pronounced in patients who ultimately succumbed to disease. When the NRL is ≥3.13, patients should be transferred to the intensive care unit (ICU) quickly. 15 If the CD4/CD8 count decreases, the neutrophil/CD8 + T ratio (N8R) increases and the CD4 + T lymphocyte count falls to <0.25×10 9 /L, it indicates a worsening of disease and the treatment plan should be urgently adjusted, such as by administering immunopotentiation therapy. 16 Electrolyte disturbances (such as low/high potassium, low/high sodium) and acid-base imbalance (mainly metabolic acidosis, hyperlactacidemia) easily induce arrhythmia and central nervous system disorders while aggravating hypoxia and systemic dysfunctions. Once identified, these symptoms should be treated urgently to prevent poor prognosis. Chest computed tomography (CT) or X-ray is recommended for all high-risk groups with clinical early warning signs, even if they have no obvious respiratory symptoms. Patients with severe/critical COVID-19 suffer from different levels of hypoxia and respiratory failure. Unless chronic obstructive pulmonary disease is underlying, patients generally exhibit type I respiratory failure but rarely type II respiratory failure, and so they require different methods of oxygen therapy or respiratory support therapy (Fig. 1) . Theoretically, the sooner antiviral therapy is administered, the better. However Convalescent plasma from recovered patients contains specific IgM and IgG showing efficacy in terms of virus clearance and body temperature recovery. 22 Overall, convalescent plasma is understood to be safe, but its efficacy requires further study. Thymosin α1, a peptide known to enhance cell-mediated immunity, is widely used in immunocompromised or impaired groups. It has also been used in the treatment of SARS. According to clinical experiences reported in the literature, 23 COVID-19 patients may also benefit from thymosin. Inflammation storm is an important cause of disease severity in COVID-19 patients, and can lead to ARDS and multiple organ failure. 14, 17 During the treatment of severe/critical COVID-19 patients, it is necessary to closely monitor the dynamic changes in inflammatory cytokines and optimize anti-inflammatory treatment, so as to improve the prognosis of severe/critical COVID-19 patients. Patients with COVID-19 have systemic inflammatory responses and hypercoagulability, with elevated fibrin, fibrinogen, and D-dimer. 19 These increases are particularly common in patients with severe/critical COVID-19 and are associated with poor prognosis. 25 Severe/critical COVID-19 is often accompanied by a variety of basic cardiovascular and cerebrovascular diseases, and patients may be bedridden for a long time during hospitalization, all of which exacerbates the adverse consequences caused by hypercoagulability, such as venous thrombosis, pulmonary embolism, cerebral infarction, etc. Therefore, routine anticoagulation therapy for severe/critical COVID-19 patients is required, and the anticoagulation regimen should be implemented in accordance with the standard regimen for non-COVID-19 patients. 26 According to the CT imaging distribution characteristics and signs of COVID-19, GGO and consolidation of the lungs are the most common imaging characteristics. Up to 46.2% of COVID-19 patients demonstrate GGO and consolidation. 27 Such common pulmonary fibrosis changes seriously affect the prognosis in severe/critical patients; therefore, the treatment of lung consolidation and pulmonary fibrosis is of great significance in the recovery of patients. Underlying liver diseases should be actively treated during COVID-19. Liver damage in COVID-19 patients is usually reversible and can heal without any special treatment. should be followed, to maintain an appropriate negative balance and prevent excessive fluid. Albumin and blood products should be actively supplemented to maintain blood volume and plasma colloid osmotic pressure. Appropriate nutritional therapy can meet the needs of severe/critical patients and improve their immune functions. 28 By supplementing reasonable nutrients, this approach can reduce the burden on the gastrointestinal tract and heart. 3 Patients with severe/critical COVID-19 suffer the psychological stress of potentially life-threatening illness, often combined with other stressful events, such as the death of a loved one, family clustering infections, social isolation, etc. This patient group, therefore, is under great psychological pressure. 31 Studies have shown that active psychological interventions can improve patients' sleep, moods and bad behaviors, which not only improves patients' immunity, 32, 33 but can also enhance treatment compliance and improve outcome. Most severe/critical patients have suffered from different degrees of limb dysfunction and respiratory impairment; therefore, they should receive rehabilitation assessment and treatment of related dysfunctions, to reduce subsequent complications. 34 J o u r n a l P r e -p r o o f Severe/critical COVID-19 is a systemic disease that mainly involves the lungs and immune system. Severe/critical patients are mostly elderly with combined underlying diseases, and suffer from a high mortality rate. Our team has cumulatively treated 77 patients, while greatly improving the cure rate. The authors declare that they have no conflict of interest. Chinese Center for Disease Control and Prevention. 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