Zhong Nanshan leads the article in medical journals: Don't misread the minimum and maximum values ​​in the incubation period

Zhong Nanshan leads article in top medical journals: Don't misread the minimum and maximum values ​​in the incubation period

On February 28 local time, a research paper entitled "Clinical Characteristics of New 2019 Coronavirus Diseases in China" led by Zhong Nanshan, a high-level expert group leader of the National Health and Medical Commission and an academician of the Chinese Academy of Engineering, was published in the top medical journal "New England Medical Journal" (NEJM). ) On the public online. The study included 1,099 patients diagnosed with new coronary pneumonia from 552 hospitals in 31 provinces (municipalities) across the country from December 11, 2019 to January 29, 2020.

There are 37 authors of the study. The authors include the National Respiratory Diseases Clinical Medical Research Center, Wuhan Jinyintan Hospital, Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Thoracic Oncology, First Affiliated Hospital of Guangzhou Medical University, and Huanggang Central Hospital. , State Key Laboratory of Organ Failure Prevention and Control of Southern Medical University, Chinese University of Hong Kong, Peking Union Medical College, Chinese Academy of Medical Sciences, State Key Laboratory of Infectious Disease Diagnosis and Treatment of the First Affiliated Hospital of Zhejiang University School of Medicine, etc. Zhongshan Nan is the corresponding author and the research team represents the Chinese New Crown Pneumonia Medical Expert Group.

Prior to February 9, local time, the paper was first published on the preprinted website medRxiv (without peer review at the same time) when it was submitted to the New England Journal of Medicine, and it attracted widespread attention.

The study showed that of 1,099 patients, 926 were non-severe and 173 were severe. Severe patients are 7 years older (median) than non-severe patients. In addition, comorbidities were more common in severe patients (38.7%) than in non-critical patients (21.0%). However, the history of exposure in critically ill and non-critically ill patients is similar.

The median incubation period of the study was 4 days (interquartile range, 2-7), and the incubation period of one patient in each of the severe and non-severe new crowns was 24 days. However, the team believes that simply assessing the population latency based on the minimum and maximum values ​​is likely to cause misunderstanding.

It is worth noting that 43.8% of patients had fever during admission, but 88.7% had fever during admission. The proportion of patients with non-fever new coronary pneumonia is higher than those with SARS-CoV (1%) and MERS-CoV (2%) infections, so if the definition of surveillance cases focuses on detecting fever, patients without fever may be missed.

Compared with SARS-CoV and MERS-CoV, the lethality of neocrown virus is lower. The mortality rate determined by the research team in this study is 1.4%, which is lower than the recent mortality rate reported by other teams. In their opinion, the reason is likely to be the difference in sample size and case inclusion criteria. They also believe that since mild and untreated patients were not included in the study, the true mortality rate may be lower. The research team also emphasized that despite the similarity between Neocoronavirus and SARS-CoV, some clinical features can distinguish neocoronax pneumonia from SARS-CoV, MERS-CoV, and seasonal influenza.

Cannot rule out the existence of "super communicators"

The research team obtained medical records of laboratory-confirmed patients with new coronary pneumonia and outpatients received by the National Health Commission from December 11, 2019 to January 29, 2020, and compiled the data. The study data deadline is January 31, 2020.

Newly diagnosed cases of neocoronary pneumonia are defined as positive high-throughput sequencing or real-time reverse transcription-polymerase chain reaction (RT-PCR) testing of nasal and throat swab samples. Only laboratory confirmed cases were included in the analysis.

The research team extracted the patient's recent exposure history, clinical symptoms or signs, and laboratory test results at the time of admission from the electronic medical record. Imaging evaluation includes chest radiography or CT, and all laboratory tests are performed according to the patient's clinical diagnosis and treatment needs. Laboratory assessments include full blood cell counts, blood chemistry analysis, coagulation tests, liver and kidney function assessments, and measurements of electrolytes, C-reactive protein, procalcitonin, lactate dehydrogenase, and creatine kinase.

According to the American Thoracic Society's Community Acquired Pneumonia Guidelines, the research team classified patients with new coronary pneumonia as severe and non-severe when they were admitted.

As of January 29, 2020, 7,736 patients with new coronary pneumonia were hospitalized in 552 research centers, and the research team obtained clinical symptom and outcome data for 1099 patients (14.2%). Wuhan Jinyintan Hospital has the largest number of patients (132 cases). There are 1,856 designated hospitals in 30 provinces, autonomous regions, and municipalities nationwide for the treatment of patients with new coronary pneumonia, and 29.7% of the hospitals included in this study.

Of the patients included in this study, 3.5% were medical staff, 1.9% had a history of wildlife exposure; 483 patients (43.9%) were residents of Wuhan. Of the patients living outside Wuhan, 72.3% had a history of contact with Wuhan residents, of which 31.3% had been to Wuhan; 25.9% of non-Wuhan residents had neither been to Wuhan nor had a history of contact with Wuhan residents.

The research team believes that the analysis shows that about 2% of patients have a history of direct contact with wildlife, and more than three-quarters of the patients are Wuhan residents, have been to Wuhan, or have a history of contact with Wuhan residents. These findings are consistent with other recent reports, including a clustered family outbreak, transmission of disease by asymptomatic patients, and a three-phase outbreak pattern. They argue that the study cannot rule out the existence of "super communicators."

In such studies, the incubation period is defined as the interval between the earliest possible date of exposure to the source of infection (wildlife or suspected or confirmed cases) and the earliest date when symptoms (ie, cough, fever, fatigue, or myalgia) occur. The median latency of the study was 4 days (interquartile range, 2-7).

The median age of patients was 47 years (interquartile range, 35-58); 0.9% of patients under 15 years of age. Women accounted for 41.9%. 43.8% of patients had fever at admission, but 88.7% had fever during admission. The most common symptoms that followed were cough (67.8%); nausea or vomiting (5.0%) and diarrhea (3.8%) were uncommon. In the entire population, 23.7% had at least one comorbidity (such as hypertension and chronic obstructive pulmonary disease). At admission, the severity of neocoronary pneumonia in 926 patients was classified as non-severe, and 173 patients were classified as severe. Severe patients are 7 years older (median) than non-severe patients. In addition, comorbidities were more common in severe patients (38.7%) than in non-critical patients (21.0%). However, the history of exposure in critically ill and non-critically ill patients is similar.

From the results of imaging and laboratory tests, 86.2% of the 975 CT scans performed at admission were abnormal. The most common manifestations of chest CT were ground glass shadows (56.4%) and bilateral lung patchy shadows (51.8%). 157 (17.9%) of 877 non-severe patients and 5 (2.9%) of 173 severe patients had no imaging or CT abnormalities.

At admission, 83.2% of patients had lymphopenia, 36.2% had thrombocytopenia, and 33.7% had leukopenia. C-reactive protein levels were elevated in most patients; elevated levels of alanine aminotransferase, aspartate aminotransferase, creatine kinase, and d-dimer were rare. Compared with non-severe patients, laboratory abnormalities, including lymphopenia and leukopenia, are more pronounced in severe patients.

During the discussion, the research team mentioned that in the early stage of the new coronary pneumonia epidemic, the diversity of symptoms, imaging results, and severity of the disease at the time of patient consultation complicated the diagnosis of the disease.

It is worth mentioning that the study also found that the incubation period of each patient in the severe and non-severe group of new crowns was 24 days.

However, the joint first authors of the paper, Guan Weijie, Liang Wenhua, Professor He Jianxing, and Professor Zhong Nanshan, emphasized in the interpretation that they carefully examined the distribution pattern of the incubation period of the entire population and found that a total of 13 cases (12.7%) with an incubation period greater than 14 days, and the incubation period Only 8 cases (7.3%) were older than 18 days.

They believe that simply assessing the incubation period of a population based on minimum and maximum values ​​can easily lead to misinterpretation.

Impaired respiratory function at admission is associated with poor outcome

The primary composite end point for patients with neocoronary pneumonia is admission to the intensive care unit (ICU), mechanical ventilation, or death. Secondary endpoints included mortality, the time from the onset of symptoms to the occurrence of the composite endpoint, and the time from the onset of symptoms to the occurrence of each component of the composite endpoint.

In this study, 67 patients (6.1%) had a primary composite endpoint event, including 5.0% in ICU, 2.3% in invasive mechanical ventilation, and 1.4% in death. Primary composite endpoint events occurred in 43 (24.9%) of the 173 critically ill patients. In all patients, the cumulative risk of the composite endpoint was 3.6%; in critically ill patients, the cumulative risk was 20.6%.

In terms of treatment, most patients (58.0%) received intravenous antibiotics, 35.8% received oseltamivir; 41.3% received oxygen inhalation, and 6.1% received mechanical ventilation; the proportion of severe patients receiving these treatments was higher than high. Severe patients received mechanical ventilation more than non-severe patients (noninvasive ventilation, 32.4% vs. 0%; invasive ventilation, 14.5% vs. 0%).

204 patients (18.6%) received systemic glucocorticoid therapy, and the proportion of severe patients receiving this treatment was higher than that of non-critical patients (44.5% vs. 13.7%). Of these 204 patients, 33 (16.2%) were admitted to the ICU, 17 (8.3%) received invasive ventilation, and 5 (2.5%) died. Five severe patients (0.5%) received external membrane oxygenation. Studies show that the median length of hospital stay was 12.0 days (mean, 12.8). During hospitalization, most patients were diagnosed with pneumonia (91.1%), followed by ARDS (3.4%) and shock (1.1%). The proportion of severe patients diagnosed with pneumonia was higher than that of non-severe patients (99.4% vs. 89.5%).

Complications, treatments and clinical endpoints

The research team mentions that, although the total number of new coronavirus-related deaths is high, the mortality rate appears to be lower than SARS-CoV and MERS-CoV. Impaired respiratory function (a major driver of disease severity) at the time of admission was associated with poor outcomes.

It is worth noting that the mortality rate determined by the research team in this study was 1.4%, which is lower than the recent mortality rate reported by other teams. In their opinion, the reason is likely to be the difference in sample size and case inclusion criteria. They also believe that since mild and untreated patients were not included in the study, the true mortality rate may be lower.

Distinguish from SARS, MERS, and seasonal flu

During the discussion, the research team pointed out that the general transmission routes of SARS-CoV, MERS-CoV and highly pathogenic influenza include respiratory droplet transmission and direct contact transmission, and the transmission route of new crown virus is likely to be the same. However, new coronaviruses have been detected in the gastrointestinal tract, saliva, and urine, and these potential routes of transmission need to be studied.

They believe that, consistent with the results of other recent studies, the research team found that the clinical features of new coronary pneumonia are similar to SARS-CoV. Fever and cough are the main symptoms, and gastrointestinal symptoms are uncommon, so it suggests that the new coronavirus has a different tendency than SARS-CoV, MERS-CoV and seasonal influenza.

The proportion of patients with non-fever new coronary pneumonia is higher than those with SARS-CoV (1%) and MERS-CoV (2%) infections, so if the definition of surveillance cases focuses on detecting fever, patients without fever may be missed. Lymphopenia is common and severe reductions are achieved in some cases.

The research team also emphasized that despite the similarity between Neocoronavirus and SARS-CoV, some clinical features can distinguish neocoronax pneumonia from SARS-CoV, MERS-CoV, and seasonal influenza.

The research team also mentioned that there are some obvious limitations of the study, including incomplete contact history and laboratory inspection records in some cases, inadequate infrastructure in non-specialized hospitals, and insufficient training of medical staff, and only estimates of records in this study Information on the incubation period of 291 patients, many patients are still hospitalized, and the outcome is unknown at the time of data cutoff.

In their limitations, they also emphasized, "We undoubtedly missed asymptomatic or home-treated mild patients, so our study cohort may represent the more serious side of neocoronary pneumonia."

Surging news reporter He Liping