A study of nearly 2,000 Marine recruits who went through supervised quarantine before starting basic training revealed several instances of asymptomatic transmission of SARS-CoV-2, the virus that causes COVID-19, despite the quarantine measures.
The findings have important implications for the effectiveness of public health measures to suppress transmission of COVID-19 among young adults, whether in military training, schools, or other aspects of the pandemic.
The researchers from the Icahn School of Medicine at Mount Sinai and the Naval Medical Research Center studied new Marine recruits while they were in a two-week supervised quarantine.
The study results, publishing November 11 in The New England Journal of Medicine, showed that few infected recruits had symptoms before diagnosis of SARS-CoV-2 infection, that transmission occurred despite implementing many best-practice public health measures, and that diagnoses were made only by scheduled tests, not by tests performed in response to symptoms.
“We were honored that the U.S. Navy gave us the opportunity to collaborate on studying SARS-CoV-2 in Marine recruits,” says Stuart Sealfon, MD, the Sara B. and Seth M. Glickenhaus Professor of Neurology at the Icahn School of Medicine at Mount Sinai.
“This is a difficult infection to suppress in young people, even with close supervision of their mask wearing, social distancing, and other mitigation measures.
We find that regular testing not dependent on symptoms identifies carriers who can transmit SARS-CoV-2. We hope this information helps in developing more effective measures to keep military installations and schools safe.”
The study data revealed asymptomatic spread of the virus even under strict military orders for quarantine and public health measures that most likely experienced better compliance than what would be possible in other youth settings like college campuses.
The researchers noted that daily temperature and symptom checks did not detect infections among the recruits and that the virus was largely transmitted within a given platoon group where trainees tended to be near one another.
The study focused on 1,848 study participants who were enrolled from nine different Marine recruit classes, each containing 350 to 450 recruits, between May 15 and the end of July. The participants were offered enrollment in a prospective, longitudinal study after self-quarantining at home for two weeks prior to arrival at basic training.
Once they arrived, they were required to follow strict group quarantine measures with two-person rooms for two weeks – the duration of the study period – before the start of the actual training.
The supervised group quarantine took place at a college used only for this purpose. Each recruit class was housed in different buildings and had different dining times and training schedules, so the classes did not interact.
Each weekly class was further divided into platoons of 50-60. During the study period, all recruits wore cloth masks, practiced social distancing of at least six feet, and regularly washed their hands, and each recruit had just one roommate. Most of their instruction, including exercising and learning military customs and traditions, was done outdoors. After each class finished quarantine, a deep cleaning, using bleach on surfaces, occurred in all rooms and common areas of the dormitories before the arrival of the next class.
To determine asymptomatic and symptomatic SARS-CoV-2 prevalence and transmission during supervised quarantine, participants were tested within 2 days of arrival, at 7 days, and at 14 days using a nasal swab (PCR) test authorized for emergency use by the U.S. Food and Drug Administration.
Analysis of viral genomes from infected recruits identified multiple clusters that were temporally, spatially, and epidemiologically linked, revealing multiple local transmission events during quarantine.
“The identification of six independent transmission clusters defined by distinct mutations indicates that there were multiple independent SARS-CoV-2 introductions and outbreaks during the supervised quarantine,” said Harm van Bakel, Ph.D., Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai.
“The data from this large study indicates that in order to curtail coronavirus transmission in group settings and prevent spill-over to the wider community, we need to establish widespread initial and repeated surveillance testing of all individuals regardless of symptoms.”
Insight into COVID-19 characteristics and SARS-CoV-2 transmission in military personnel has relevance to developing safer approaches for related settings composed primarily of young adults such as schools, sports, and camps.
“Our study highlights the power of Navy Medicine research to deploy and overcome many logistical hurdles during a pandemic and quickly stand up an institutional review board-approved study.
These results will improve the medical readiness of our Marines and should help inform public health policy across the Navy, Department of Defense, and society at large to decrease transmission of SARS CoV-2,” said Cmdr. Andrew Letizia, MD, Deputy Director of the Naval Medical Research Center’s infection disease directorate and lead researcher for the study.
Epidemic status & transmission characteristics of asymptomatic COVID-19 patients
Confirmed asymptomatic SARS-CoV-2 infections continue to increase
Multiple studies indicate that asymptomatic infections make up a large percentage of confirmed COVID-19 cases. A retrospective study in Beijing collected data for 262 individuals with diagnosed COVID-19 from 20 January to 10 February 2020, and 13 were asymptomatic (5.0%) .
In addition, 126 persons of German nationality were evacuated from Hubei Province to Frankfurt, Germany, on 1 February 2020. After strict screening and testing, two were confirmed to have SARS-CoV-2 infection, yet both patients were asymptomatic . A further epidemiological investigation (28 January to 9 February 2020) was conducted in clinics and communities in Nanjing, Jiangsu Province, China.
The survey screened the close contacts of patients with confirmed or suspected infections. The results of nucleic acid screening identified 24 confirmed SARS-CoV-2 carriers without any obvious symptoms. Of these, five patients developed typical symptoms during the subsequent hospitalization, while the other 19 patients remained asymptomatic .
Furthermore, the Ministry of Health, Labor and Welfare of Japan announced on 5 March 2020 that among 696 people on the ‘Diamond Princess’ cruise ship infected with SARS-CoV-2, 410 were asymptomatic . All of the above indicates that in the community there may be a large number of unidentified asymptomatic people with contagious infections (Figure 1).
Asymptomatic patients with SARS-CoV-2 infection may carry high viral loads
SARS-CoV-2 has been detected in nasopharyngeal swabs and sputum samples from asymptomatic patients . The viral load detected in asymptomatic individuals was similar to that of symptomatic patients suggesting that people without symptoms have a strong ability to transmit the virus to others .
In addition, SARS-CoV-2 has been detected in the blood and stool samples of seemingly well patients [22–24], and compared with the virus in respiratory secretions, the virus in feces may take longer to clear .
Complex incubation period in asymptomatic SARS-CoV-2 infection
In general, patients with symptoms of SARS-CoV-2 infection are admitted to hospital for detection and treatment under isolation. However, asymptomatic individuals may not be recognized by healthcare workers, and do not self-isolate or seek treatment. Bai et al.  showed that the incubation period of an asymptomatic patient was 19 days. What is more, Hu et al.  reported that the communicable period of asymptomatic COVID-19 patient may be as high as 29 days.
Transmission of SARS-CoV-2 by asymptomatic persons is implicated in crowd & family-clustered outbreaks
Multiple studies have found that there are asymptomatic SARS-CoV-2 infections in the process of crowds and family-clustered outbreaks. Among a family of six in Shenzhen who traveled to Wuhan from 29 December 2019 to 4 January 2020, five members were identified with COVID-19, including an asymptomatic 10-year-old boy .
A family of three who traveled on 22 January 2020 from Wuhan to Guangzhou, China, through the high-speed rail tested positive for SARS-CoV-2, but only one developed clinical symptoms, and the other two members had no signs or clinical symptoms . Infants also are not spared from SARS-CoV-2 infection.
The first pediatric case was confirmed asymptomatic in Singapore. The infant was part of a family transmission cluster, in which its parents and their live-in helper were symptomatic . Furthermore, asymptomatic COVID-19 patients can even become the source of infection in contagious outbreaks among families.
SARS-CoV-2 transmission from an asymptomatic infected person returning home from Wuhan on 10 January 2020 was suspected as the cause of a family cluster epidemic of five members in Anyang, China . In fact, any infected person, symptomatic or asymptomatic, may be the first to transmit SARS-CoV-2 to other members in a clustered and family-clustered outbreak.
Clinical characteristics of asymptomatic patients with SARS-CoV-2 infection
Identification & diagnosis of asymptomatic SARS-CoV-2 infection
At present, cases of COVID-19 continue to occur around the world, so the rate of asymptomatic infections cannot be accurately determined. Identification and isolation of asymptomatic patients is essential to control virus outbreaks. Various studies have shown that asymptomatic persons with SARS-CoV-2 infection are generally not discovered until after their families, relatives, friends or close contacts have symptoms that are diagnosed [11,14,21,22,26–28].
Therefore, in order to not miss any infected patients, it is best to perform screening for all close contacts of patients with confirmed or suspected infections [15,19]. The main tests used to diagnosis COVID-19 are the SARS-CoV-2 nucleic acid test (NAT) of nasopharyngeal swab samples, the SARS-CoV-2 specific serological test and chest computed tomography (CT) scanning. NAT by reverse transcription-PCR (RT-PCR) is well established as the gold standard for the diagnosis of COVID-19 , but still the test is associated with false negatives due to problems with sample collection and the operating procedures [30,31].
Therefore, for cases that are highly suspicious of COVID-19 but test negatively by NAT, diagnosis via screening with a SARS-CoV-2 specific serological test and chest CT scan may be of great value [28,32,33]. In one study of 285 COVID-19 patients with acute antibody responses to SARS-CoV-2, in 19 days after the onset of symptoms, 100% of the patients were positive for antiviral IgG.
Importantly, the seroconversion of IgG and IgM occurs simultaneously or sequentially, and the titers of IgG and IgM were found to be stable within 6 days after seroconversion .
However, if the NAT result is negative and the SARS-CoV-2 specific serological test is positive, the diagnosis still cannot be directly confirmed. It is necessary to continue to observe and conduct multiple NAT tests until either the NAT result is positive or the SARS-CoV-2 specific serological test is determined to be a false positive.
A study conducted in the USA used 1020 serum specimens that were previously tested for HSV serology by western blotting in 2018 and 2019 (prior to SARS-CoV-2 circulation) and detected one false positive using the Abbott SARS-CoV-2 IgG test . In addition, many studies on SARS-CoV-2 specific serological tests have shown that it is difficult to achieve 100% sensitivity and specificity [36,37].
Thus, for now, the diagnosis of COVID-19 remains a challenge globally. No test method is completely mature and reliable, but the combination of multiple testing methods can improve the effectiveness of screening  and avoid missed diagnoses and misdiagnoses as much as possible .
It is important to note that some patients with COVID-19 may experience only mild symptoms and signs. Kam et al.  reported a 6-month-old infant who developed a temperature of 38.5°C during hospitalization, although for only 1 h. Hoehl et al.  reported a 48-year-old German woman who experienced a mild rash and minimal pharyngitis after admission.
Therefore, persons with COVID-19 may appear essentially asymptomatic, but do experience very mild symptoms and can enter the recovery period without being detected. Therefore, at the time of consultation healthcare workers should thoroughly interview the patient for any recollection of discomfort.
Variety of people with SARS-CoV-2 infection may be asymptomatic
Asymptomatic infection is not limited to young or middle-aged adults , but also children , infants  and even the elderly . Hu et al.  showed that asymptomatic patients were relatively young, with a median age of 14 years in seven cases. In addition, asymptomatic infections were found in both males  and females .
Disease progression, changes in CT images & laboratory indicators in people with asymptomatic SARS-CoV-2 infection
In general, asymptomatic infected people do not suffer seriously, but the virus they transmit can cause others to develop severe disease .
Those with asymptomatic infections did not always show lung changes such as ground glass opacities after CT examination, and may appear normal . Yet, in other cases the typical changes in CT examination may be observed . Changes in laboratory test indicators typical of SARS-CoV-2 infection have been found in some asymptomatic patients [11,22,27], but for others, indicators are normal (Table 1) [14,19,26].
Clinical characteristics of asymptomatic patients with SARS-CoV-2 infection in recent studies.
|Study||Country (patient)||Age (years)/sex||Chronic medical illness||Clinical characteristics||Collection site and viral load||Ref.|
|Laboratory analysis||Computed tomography||Other situations|
|Chan||China||10/Male||None||Alkaline phosphatase (↑)†||GGOs||NM||Nasopharyngeal swab (NF), throat swab (40)‡, sputum (27)‡|||
|Bai||China||20/Female||NA||NOA||NOA||NOA||Nasopharyngeal swab (+)§|||
|DMs (2)#||Blood leukocyte count (↓ 2)#,††||Normal (7)#||NOA||Pharyngeal swab (+)§|||
|Hypertension (2)#||Lymphocyte count (↓ 2)#,††||GGO or patchy shadowing (12)#|
|CHD (1)#||C-reactive protein (↑ 2)†,#|
|Procalcitonin (↑ 4)†,#|
|CVD (1)#||Lactose dehydrogenase (↑ 3)†,#||stripe shadowing (5)#|
|Alanine aminotransferase (↑ 2)†,#|
|Creatinine (↑ 2)†,#|
|D-dimer (↑ 3)†,#|
|Hoehl||Germany||58/Male||NA||Anemia||NM||NOA||Throat swab (24.39 and 30.25)‡|||
|Zou||China||26/Male||NA||NM||NOA||NOA||Nasal swab (22–28)‡|
Throat swab (30–32)‡
(day 8 of admission)
|NP||Temperature rise (38.5°C in 1 h)||Nasopharyngeal swab|
(N gene 15.57; Orf1ab gene 13.73)‡
Blood sample and stool sample (+)§
|Pan||China||33/Female||NA||NOA||NOA||NM||Nasopharyngeal swab: (+)§|||
|Lin||China||61/Male||None||C-reactive protein (↓)††||Multiple|
GGOs (day 1 of admission)
|Only mild shortness of breath (1 day)||Throat swab (+)§|||
|Bai SL||China||61/Male||CHD||NM||GGOs; lesion occupying lung field (different degree)||NOA||Throat swab (+)§|||
‡CT value obtained by RT-PCR viral nucleic acid test.
§Positive by RT-PCR viral nucleic acid test but CT value was not shown.
#Number of cases with an indicator or performance.
††The indicator reduced.
CHD: Coronary heart disease; CoV: Coronavirus; CT: Computed tomography; Ct: Cycle threshold; CVD: Cerebrovascular disease; DM: Diabetes mellitus; GGO: Ground glass opacity; IQR: Interquartile range; NA: Not available; NF: No SARS-CoV-2 found; NM: Not mentioned; NOA: No obvious abnormality; NP: Not performed; RT: Reverse transcription.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291769/
Journal information: New England Journal of Medicine