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The following article is from the Chinese Epidemiology microplatform , author Chinese Journal of Epidemiology
Chinese epidemiology microplatform
Chinese epidemiology microplatform
Post exchange of academic information
Author：Gao Wenjing Li Liming
Abstract
Novel coronavirus pneumonia is spreading rapidly to the population, and both latent patients and latently infected individuals have the potential to become infectious agents by expelling the virus outside the body, but due to the insidious clinical symptoms, such infectious agents cannot be effectively identified and easily form gaps in prevention and control measures. There are studies suggesting that latent or latently infected patients may cause disease transmission, but research is still limited and nearly half of the literature is still in preprint without peer review.
There is no clear and accepted answer to the question "can an infected person transmit the virus during the latent period, and can an asymptomatic infected person transmit the virus and how efficiently? There is an urgent need to screen infected individuals in a larger group of close contacts or in the general population and to assess their risk of transmitting the disease.
Introduction
The incubation period is the period of time from the time the pathogen enters the body to the earliest clinical signs or symptoms. The inapparent infection (subclinical infection, subclinical infection, asymptomatic infection), also known as subclinical infection, is a pathogen that invades the body and causes only a specific immune response, causing no or only minor tissue damage, and therefore does not show any clinical The recessive infected person also becomes a healthy carrier (healthy carrier). Both latent patients and recessive carriers have the potential to become infectious agents by expelling virus outside the body, but due to the insidious clinical symptoms, these infectious agents cannot be effectively identified and are prone to form loopholes in prevention and control measures, thus latent patients and recessive carriers are of great epidemiological importance.
The novel coronavirus pneumonia (COVID-19) outbreak caused rapid transmission in the population in less than 3 months from the first patient admission on December 12, 2019. As of February 28, 2020, a total of 79 251 confirmed cases of novel coronavirus pneumonia and 2 835 cumulative deaths have been reported in China. Wild animals (animal hosts) are no longer considered to be the main source of infection in the current outbreak, but rather patients with novel coronavirus infection. Therefore, a large number of communities and sites in China are taking temperature measurements and timely screening of febrile patients for suspected infectious sources, and this approach has captured the main contradiction, and symptomatic infectious sources with high viral load release have been effectively controlled. However, there is a lack of evidence summarizing what the role of latent patients and latently infected individuals is for the viral transmissibility of COVID-19, and the risk assessment of such infectious agents is necessary for the current prevention and control measures to identify gaps and eventually eradicate this disease, and these 2 questions are clearly listed as urgently needed to be answered in the New Coronary Pneumonia Epidemic Emergency Research Agenda (transmission and non-pharmaceutical mitigation strategies).
This article will collate the sources of evidence published online up to February 28, 2020, which include PubMed and corresponding full-text databases, medRxiv online preprint database, according to the "COVID-19" or "2019-nCoV " keywords, 24 out of 562 publications were manually screened by reading the titles and abstracts (15 domestic and 9 foreign) for current research progress on these two issues.
Latent period
1. How long is the latency period of COVID-19?
There are many studies on the incubation period of COVID-19, and most of them consider the incubation period <14d, with the median ranging from 3 to 7d. Two studies concluded that the mean incubation period was 5.2 d. These were a retrospective analysis by the CDC in China for 10 cases at the beginning of the epidemic (95% CI: 4.1-7.0, 95% of patients within 12.5 d) and an estimate by Johns Hopkins University in the United States based on 101 confirmed cases published in 38 provinces, regions or countries (95% CI: 4.4-6.0, 97.5% of patients were within 10.5 d). Japanese researchers calculated the incubation period to be about 5 (95% CI: 2 to 14) d on average, based on data from 158 cases made available on the Web as of January 31. Korean researchers estimated the mean incubation period to be 3.6 d (median 4 d) using 24 confirmed patients. An analysis of 291 clinically confirmed cases from 31 provinces and cities in China also showed a median incubation period of 4 (IQR: 2-7) d. The Dutch researchers estimated the incubation period to range from 2.1 to 11.1 d with a mean incubation period of 6.4 (95% CI: 5.6-7.7) d based on 88 patients with a history of travel to Wuhan who were diagnosed in the early stages of the COVID-19 outbreak. Ninety-one cases in five hospitals in eastern Zhejiang Province showed a latency period of 6 (IQR: 3-8) d. Notably, the median latency period calculated from epidemiological analysis of 483 cases in Henan Province was 7 d, and the study still found that 7.45% of patients had a latency period >14 d.
2. Do patients with incubation period cause disease transmission?
On February 13, medRxiv published online a paper by Japanese scholars on a study of 26 primary-secondary case pairs, which found that the median COVID-19 case interval (serial interval, which is the time interval between the appearance of clinical disease in primary and secondary cases) was 2.6 d, much lower than the median incubation period of COVID-19 (5 d ), this study suggests that a large number of infections occur before the onset of symptoms in COVID-19 patients. The study also compared the case interval of COVID-19 with that of SARS (8.4 d), which was lower than that of SARS, explaining why COVID-19 was significantly more infectious than SARS. 95% CI:5.3 to 19.0) d, which is not less than the median incubation period.
Hong Kong scholars calculated the mean case interval of 4.4 (95% CI:2.9~6.7) d with a standard deviation of 3 (95% CI:1.8~5.8) d based on 21 transmission chains identified from publicly available surveillance data in Hong Kong. other scholars found that based on 468 pairs of confirmed COVID-19 infections reported by health departments in 18 provinces in China from January 21 to February 8 The interval ranged from 11 to 20 d, with a mean of 3.96 (95% CI:3.53-4.39) d. 12.1% of the reports showed pre-symptomatic transmission.
3. Where is the dividing line between the end of the latent period and the beginning of the infectious period?
The incubation period generally consists of a latent period and an infectious period. The latent period is the time interval between the time the virus invades the body and the time the body becomes infectious. The infectious period is the time between when an infected individual is able to transmit the virus to another susceptible person. The dividing line between the latent and infectious periods is an important evidence of disease transmission caused by latent patients and an important basis for the delimitation of close contacts. on January 30, the New England Journal published an article in which four cases were found in Germany that could have acquired infection through latent patients because three of the cases had crossed pathways with only one index patient (index patient) in the 3 d before their onset ( The index patient was diagnosed immediately after his return to China. However, in the case of the German case, Science reported on February 3 that "the information proved to be wrong" and that the researchers relied only on the information provided by the four German patients before publishing the paper, without actually talking to the index case. However, the indicated cases had "felt weak, had muscle aches, and were taking antipyretics" while in Germany, and were not "asymptomatic.
On February 24, the CDC EID (Emerging infectious diseases) journal published online two cases of familial aggregation reported by the CDC in Zhoushan, Zhejiang Province. The infection was spread among the families of these two patients. Also on the same day, February 24, the Chinese CDC published the Guidelines for Investigation and Management of Close Contacts of Novel Coronavirus Pneumonia Cases (Trial Version), which based on the infectious person-infected transmission chain analysis conducted in China, the investigation and medical observation of close contacts 4 d before the onset of the case as proposed by the WHO study on emerging diseases, and the study by Japanese scholars and based on the basic understanding of most infectious diseases. The 2 d before case onset (i.e., the last 2 d of the incubation period) was used as the time frame for investigation and judgment of close contacts.
The length of the incubation period helps to trace the source of infection and determine the route of transmission, and also determines the duration of detention, quarantine, and medical observation of close contacts. Current studies on the length of the incubation period have varying median lengths and inconsistent maximum incubation periods. In addition to the differences in the number of cases and data sources due to the obvious, more importantly, the definition of the duration of infection differs due to different epidemiological characteristics within and outside Wuhan, with early epidemic focus on history of wildlife contact, South China seafood market and related environmental contact history, but as the primary source of infection changes, history of confirmed case contact and Wuhan sojourn becomes more important. Data analysis strategies also varied, with most studies suggesting analysis according to a log-normal distribution, but others suggesting a better fit of the Weibull distribution. In addition, specific stratified analyses based on case characteristics, such as aggregated cases/disseminated cases and generational cases/continuing cases, were not seen, and the different strategies used in tracing and verifying the source of infection in these cases need to be further explored in depth in future studies. As for the question of whether latent patients cause transmission of the disease and the dividing line between the end of the latent period and the beginning of the infectious period, there are only data supporting individual cases, and research evidence around these two issues needs to be further accumulated.
Latently infected patients
Latent patients can be traced retrospectively, but when latent infected patients are infectious, they can only rely on immunological or genetic testing techniques to be informed of the infection due to their lack of obvious symptoms, and their increased difficulty for prevention and control is more significant than that of latent patients.
1. Does COVID-19 exist in recessive infected patients?
In a Jan. 24 Lancet article, five of six people in a family with a history of travel to Wuhan, Shenzhen, were symptomatic, and one 10-year-old child had no conscious symptoms, but CT showed typical COVID-19 manifestations of "pulmonary vitreous lesions", and the child was subsequently confirmed by RT-PCR to be infected with a new coronavirus. On February 6, medRxiv published an article from the Guangdong CDC in which a new coronavirus was detected in 3 cases with mild respiratory symptoms and 2 asymptomatic cases, suggesting the presence of latent infections. While Gansu CDC and Lanzhou Pulmonary Hospital published an article on February 17, among a family aggregation of 7 patients, 4 cases were asymptomatic but positive for COVID-19 specific IgM.
2. What is the distribution of occult infections in the population?
From January 29 to 31, 565 people were evacuated from Wuhan, Japan. Screening data on February 2 showed that of the 565 people evacuated from Wuhan, 8 (1.4%) were confirmed by RT-PCR. Of these 8 people, only 3 showed COVID-19 symptoms and 5 were asymptomatic recessive infections. By February 11, the investigators added an additional report, as one more person showed symptoms, leaving a 50/50 split between symptomatic and asymptomatic infections. Based on this, the researchers estimated that the proportion of likely asymptomatic infections ranged from 37.5% to 50% (95% CI: 12.5% to 87.5%) of those infected. Of the 24 early confirmed cases in Korea, 2 (8.3%) were asymptomatic. In contrast, the analysis of the Chinese CDC based on 72,314 cases showed a total of 889 asymptomatic infections, accounting for only 1.2% of the total number of cases, which differed significantly from the analysis of the Japanese and Korean data, probably because the analysis in China was based on data from the case reporting system, whereas the Japanese and Korean data were based on screening of high-risk populations.
3. What are the characteristics of recessive infected individuals and how long do nucleic acid positivity persist in vivo?
In a study of close contacts in Nanjing, Jiangsu province, 24 asymptomatic nucleic acid screen positive cases (5 cases showed fever, cough and malaise after nucleic acid diagnosis) were found, of which 12 cases (50.0%) showed typical glassy lesions on CT, 5 cases (20.8%) showed streaks in the lungs, and the remaining 7 cases (29.2%) had normal CT. The median infection period (communicable period, i.e., from day 1 of positive nucleic acid test to day 1 of consecutive negative tests) was 9.5 d (the longest infection period was 21 d in 24 asymptomatic cases).
4. Did the latent infected person cause transmission of the disease?
A February 21 JAMA study from Anyang City, Henan Province, suggests that an asymptomatic infected person who experienced 19 d from exposure to the source of infection to confirmation by nucleic acid may have caused transmission including 5 people. This is the only case study that can be retrieved regarding transmission caused by a recessive infected person.
5. Have recessive infected individuals caused superspread of the disease?
Those who transmit the virus to more than 10 people are called super spreader (super spreader), and recessive infections are in a position to become super spreader of the virus because they are insidious and difficult to detect. Currently, no scientific studies of superspreaders caused by recessive infections have been reported in the global epidemic, except for news reports of a 53-year-old male COVID-19 patient in the United Kingdom who may have caused 11 infections and a 61-year-old female patient in South Korea (case #31) who may have caused at least 11 infections (as of Feb. 19). The significance of a latently infected person as a source of infection depends on his or her distribution in the population, the amount and duration of excreted virus, and the occupation, behavior, habits, range of activity, and sanitary precautions of the latently infected person. Current studies can provide only a few clues, and the characteristics of latently infected individuals need to be further clarified. Close contacts have a higher chance of becoming latent infections than the general population, and screening for latent infections among close contacts and assessing their risk of disease transmission seems to be more efficient at this stage.
With the development of COVID-19, it is also important to know the proportion of recessive infected individuals in the general population to clarify whether an immune barrier has been established in the population. Based on the above review of the literature,
