Characteristics and Treatment Strategies of Different Clinical Types in Patients with Corona Virus Disease 2019

Objective To describe the epidemiological and clinical characteristics of patients with Corona Virus Disease 2019 (COVID19) in Beijing. To analyze the treatment strategies especially the application of corticosteroids in patients with severe pneumonia. Methods We collected information on demographic characteristics, exposure history, clinical characteristics, treatment and outcomes of the 65 confirmed cases of COVID19 at the 5 th Medical Center of PLA General Hospital from Jan 20 to Feb 23, 2020. The final follow-up date observed was Feb 29, 2020. Results The number of patients with mild, general, severe, and critical type were 10 (15.38%), 32 (49.23%), 8 (12.31%), and 15 (23.08%), respectively. The median incubation period was 6 days. Notable outliers were 1 patient at 16 days and 1 patient at 21 days. In lymphocyte subgroup analysis, decreases in total, T, CD4, and CD8 lymphocytes were more common as the disease worsened (All P <0.05). Methylprednisolone was applied to 31 (47.69%) patients with pneumonia, including 10 (31.25%) general, 8 (100%) severe, and 13 (86.67%) critical patients, respectively. Corticosteroids inhibited Interleukin-6(IL-6) production ( P =0.0215) but did not affect T lymphocyte ( P =0.0796). There was no significant difference between patients using lower dose (≤2mg/kg.d) and higher dose (>2mg/kg.d) methylprednisolone in inhibiting IL-6 production ( P =0.5856). Thirty of 31 patients (96.77%) had stopped methylprednisolone due to improvement of pneumonia. Virus RNA clearance time lengthened with disease progression ( P =0.0001). In general type, there was no significant difference in virus clearance time between patients with (15, 12-19 days) and without (14.5, 11-18 days) ( P =0.7372) methylprednisolone use.


Introduction
In December 2019, cases of acute respiratory disease (ARD), now known as a Corona Virus Disease 2019 (COVID19) occurred in Wuhan, Hubei Province, China [1][2][3] . Recent evidence has shown that person-to-person transmission in China is increasing [4][5][6][7][8] . The virus has spread to different parts of China and other countries 9 . Presently, the laboratory-confirmed cases and recorded deaths in the world, especially in China, are still increasing at an alarming rate 9,10 . The aim of the study is to compare clinical characteristics, treatment strategies, and outcomes among different clinical types of COVID19 patients treated in a tertiary hospital in Beijing, and to analyze the treatment strategies especially the application of corticosteroids in patients with severe pneumonia.

Data collection
All laboratory-confirmed patients admitted to the 5 th Medical Center of PLA General Hospital from January 20 to February 23, 2020, were enrolled. Cases were diagnosed based on the Diagnosis and Clinical types of COVID19 included mild, general, severe, and critical types. Mild type was diagnosed as patients with mild clinical symptoms and no pneumonia on radiological imaging. General type was diagnosed as patients with fever, respiratory symptoms, and pneumonia on imaging. Severe type was diagnosed as patients with any one of the following: 1. Three patients (4.62%) were under 15 years old (the youngest one was 3 years), and 15 patients (23.08%) were over 65 years old. All 3 younger patients (all with mild type) had a quick recovery to discharge with median virus RNA clearance time of 4 days. Patients with critical type tended to be older than those with mild type (P<0.0001). There was no significant difference by gender among different clinical types (P = 1.000).
A history of recent travel to or living in Wuhan, contact with people confirmed with COVID19, and contact with people from Wuhan was documented in 55.38%, 26.15% and 7.69% of patients, respectively. Not all patients could provide their exact exposure time. There were 49 patients with complete exposure time information. The range of time from exposure to onset of symptoms (incubation period) was 0 to 21 days, with median (IQR) of 6 (4-10) days. Notably, 2 patients presented at 14 days, 1 patient at 16 days and 1 patient at 21 days.
A linear mixed model showed the relationship between clinical type or corticosteroids used and dynamic IL-6 values or T lymphocyte counts throughout the course of the disease (Table 3 and 4).
The confounding variables included age, gender, and concurrent disease. IL-6 increase and T lymphocyte decrease were more common as the disease worsened (All P<0.05). Corticosteroids did not affect T lymphocyte counts (P = 0.0796) but inhibited IL-6 levels (P = 0.0215). In patients using corticosteroids, there was no significant difference in dynamic IL-6 values or T lymphocyte counts between patients using lower dose (≤2mg/kg.d) and higher dose(>2mg/kg.d) methylprednisolone throughout the course of the disease (All P>0.05). The IL-6 levels in patients using corticosteroids decreased quickly after using corticosteroids. Whereas in patients without corticosteroids use, the decrease of IL-6 levels was later and more gradual as patients recovered (Figure 1c). The T lymphocyte count trends had a similar pattern throughout the course of disease in patients with and without corticosteroids use (Figure 1d).

Discussion
Our study included 65 COVID19 patients representing the full spectrum of clinical types. All patients, except for 16 who had no identified exposure history, were infected through human-to-human transmission. Human-to-human transmission was the major way spreading COVID19 in our study, which is consistent with recent reports [4][5][6]8 . The median incubation period was 6 days, including 2 patients at 14 days, 1 patient at 16 days and 1 patient at 21 days. Therefore, the incubation period of COVID19 is likely to be greater than 14 days. 14 days may not be long enough to rule out infection after coming in contact with infected patients. The incubation period needs to be verified with a larger population.
Fever, dry cough and bilateral patchy shadowing on chest X-ray were the most common clinical features, whereas other symptoms (ie. myalgia, fatigue, dyspnea, anorexia, diarrhea, nausea and vomiting) were observed in less than 35% of cases. Chest CT feature was more typical with bilateral ground-glass opacity. The duration of time from onset of symptoms to pneumonia was similar in different clinical types. However, the onset of symptom to virus RNA clearance time lengthened dramatically as clinical type worsened.
The laboratory abnormalities observed in this study were leucopenia, lymphopenia, elevated D-dimer, ESR, IL-6, serum ferritin, CRP, and LAC, which were related to sustained inflammatory response. All the observed abnormalities were more pronounced in critical patients than in mild ones. We also observed that COVID19 is more severe in older people as well as patients with concurrent diseases as these patients generally had weaker immune functions 19,20 . Decreased T, CD4, and CD8 lymphocytes were much more common in critical patients than in mild ones in our study. A substantial decrease in total number of lymphocytes indicates that coronavirus consumes many immune cells and inhibits the body's cellular immune function. Damage to T lymphocytes might be an important factor leading to exacerbations of patients 21 . All the evidence indicates that COVID19 might mainly act on lymphocytes, especially T lymphocytes. In this study, decreased lymphocytes, including total, T, CD4, and CD8 lymphocytes, were more common as the disease worsened.
The virus could induce a cytokine storm in the body, generating a series of immune responses. In view of the high amount of cytokines induced by SARS-CoV 22,23 , MERS-CoV 24,25 , and 2019-nCoV infections 1 , corticosteroids were commonly used to treat patients with severe illness, for a potential benefit of reducing inflammatory-induced lung injury. Some reports did not support corticosteroid treatment, because it could inhibit immune responses and virus clearance [26][27][28] . However, some studies supported the use of corticosteroids in patients with coronavirus infection, because it could reduce mortality and the need for mechanical ventilation, and shorten the length of stay in hospital [29][30][31] . In this study, methylprednisolone was applied to 47.69% of patients with COVID19, including 31.25% general, 100% severe, and 86.67% critical patients, respectively. Thirty of the 31 patients (96.77%) with methylprednisolone using had stopped methylprednisolone due to improvement of pneumonia. However, one patient died of septic shock on the 11 th day after corticosteroids were stopped. We can't exclude the correlation between septic shock and higher dose (mean dose, 4mg/kg.d, 9 days) methylprednisolone. We found that corticosteroids inhibited IL-6 production throughout the course of the disease. Meanwhile, there was no significant difference between patients using lower dose (≤2mg/kg.d) and higher dose (>2mg/kg.d) methylprednisolone. Therefore, application of lower dose corticosteroids (≤2mg/kg.d) could inhibit IL-6 production (a representative of cytokines) as effectively as a higher dose.
Some studies reported that methylprednisolone may delay virus clearance time 13,32 . In our study, all severe and most critical patients used methylprednisolone. We could not distinguish whether the lengthened virus RNA clearance time was completely due to disease progression or if it was impacted by methylprednisolone use. We could not compare the virus clearance time of using versus not using methylprednisolone in severe and critical groups due to almost all of these patients being treated with methylprednisolone. In general type, 31.25% of patients used methylprednisolone and 68.75% of patients didn't use, and the virus clearance time was similar between users and non-users. Therefore, more study is necessary to elucidate whether properly using corticosteroids delays virus clearance time among patients with COVID19.
Timely use of mechanical ventilation is a more effective treatment for patients with moderate or severe ARDS 33 . NIPPV or IPPV could open alveoli and reduce exudation, improving the PaO 2 /FiO 2 , which is the signal to stop using methylprednisolone. At the same time, preventing fluid overload and early application (AKI stage 2) of CRRT also guarantee a better prognosis.
Proper use of corticosteroids could have led to the improvement observed in this study. The following rules should be considered when using corticosteroids: 1, When to start and stop using corticosteroids should be carefully weighed. 2, Dosage should be personalized, and the duration should be short, especially in critical patients. 3. Side effects should be seriously monitored and promptly addressed.
This study has several limitations. First, only 65 patients with confirmed COVID19 in Beijing were included, thus certain subgroup analyses had limited statistical power. Second, because most patients were still hospitalized, final clinical outcomes were not available for analysis at the time of manuscript submission. We will continue to follow-up these patients in order to have a more comprehensive understanding of COVID19.

Conclusion
The incubation period of COVID19 in a few patients is likely to be greater than 14 days. Lymphocyte, especially T lymphocyte, in severe and critical patients showed a dramatic decrease. Application of lower dose corticosteroids (≤2mg/kg.d) could inhibit IL-6 production (a representative of cytokines) as effectively as a higher dose. Proper use of corticosteroids in general type patients did not delay virus clearance. For patients with moderate to severe ARDS, timely use of mechanical ventilation and CRRT guarantee a better prognosis.
General Hospital. Written informed consent was waived in light of the urgent need to collect clinical data. Tables   Due to technical limitations, Tables 1-4

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