Researchers at Montefiore Health System and Albert Einstein College of Medicine may have solved a mystery surrounding the novel coronavirus pandemic: Why men infected by the virus generally show more severe symptoms and are more likely than women to die from COVID-19.
In collaboration with the Kasturba Hospital for Infectious Diseases in Mumbai, India, the scientists showed for the first time that men clear the virus from their bodies slower than women and found a possible explanation: a potential male-only “reservoir” for coronavirus.
Their study was uploaded today to MedRxiv, a website created by Cold Spring Harbor Laboratory to make research quickly available to the scientific community before undergoing the usual peer review process.
It has become widely used to share information quickly during the COVID-19 pandemic.
“COVID-19 studies worldwide have consistently shown a higher incidence and greater severity of the disease in men compared with women,” says Aditi Shastri, M.D., assistant professor of medicine at Einstein, a clinical oncologist at the Montefiore Einstein Center for Cancer Care, and lead author of the Montefiore-Einstein study.
“Our collaborative study found that men have more difficulty clearing coronavirus following infection, which could explain their more serious problems with COVID-19 disease.”
The viral-clearance analysis involved 68 people (48 men and 20 women) with symptoms of COVID-19 who were examined at India’s Kasturba Hospital for Infectious Diseases, in Mumbai.
After undergoing initial nasal swab tests indicating active infection, individuals were re-tested with serial swabs until the tests turned negative, indicating the time taken to clear the coronavirus.
The women cleared the virus significantly earlier than men: a median of four days for women vs. six days for men.
Next, three Mumbai families were identified in which men and women had tested positive for coronavirus infection on swab testing.
Again, the women in all three families cleared the coronavirus earlier than male members of the same family.
Why do men have trouble shaking off their infections?
Seeking a molecular explanation, the researchers focused on how coronavirus infection occurs. To infect cells, coronaviruses must first latch onto well-known proteins, called ACE2 receptors, that sprout like tiny antennae from the surfaces of cells.
Cell types expressing copious levels of ACE2 on their surfaces would theoretically be most susceptible to infection.
The researchers consulted three independent databases with information on ACE2 expression in different tissues. They saw that the testes, along with the lungs and kidneys, were among the areas of the body with the highest ACE2 expression. By contrast, ACE2 could not be detected in tissue of the ovaries.
Dr. Shastri stresses that the novel coronavirus’ ability to infect and multiply in testicular tissue needs to be confirmed, but says it wouldn’t surprise her.
A recent study from China compared the levels and ratios of sex hormones in male COVID-19 patients vs. healthy men of the same age.
The results indicated that the COVID-19 patients had experienced impaired testicular function – evidence that the testes may be significantly affected when men develop COVID-19.
Such a COVID-19 complication could have important medical and public health implications, she notes, and deserves to be investigated by clinical trials.
The study’s Montefiore-Einstein senior authors are Amit Verma, M.B.B.S., professor of medicine and of developmental & molecular biology at Einstein and director of hematologic malignancies at Montefiore; and Ulrich Steidl, M.D., Ph.D., professor of cell biology and of medicine and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Einstein, and associate chair for translational research in oncology at Montefiore.
The study’s other senior author is Jayanthi Shastri, M.D., a microbiologist and infectious disease specialist. As director of Kasturba Hospital’s molecular diagnostic laboratory, Dr. Jayanthi Shastri led Mumbai’s effort to serially monitor and analyze coronavirus infection in individuals and their family members.
Pathogenicity
An important concern in the recent pandemic is the capability of the pathogen to establish and induce infection with different clinical manifestations in human. According to WHO report, about 82 percent of COVID-19 patients have mild symptoms and were recovered immediately. As of 20 February, there were 18264 (24%) recovered cases in China and recovery and mortality rates of the disease among severe cases in Guangdong were 26.4 % and 13.4%, respectively. Median time for onset of symptoms to recovery in mild and severe cases was 2 and 3-6 weeks, respectively. Furthermore, time interval between onset and developing severe symptoms such as hypoxia was one week (22).
In case studies that were conducted outside of mainland China, time of onset of symptom(s) to recovery was 22.2 days (95% confidence interval 18-83). Moreover, average time of onset of symptom(s) to death varies from 20.2 (95% confidence interval 15.1-29.9) to 22.3 days (95% confidence interval 18-82) (23,24). Results of a case-series study on six infants (45-days to one-year) infected with COVID-19 in China indicated mild symptoms of the disease in this age group with no need for further intensive care (25). According to WHO report, COVID-19 disease among children seems to be rare with mild symptoms, about 2.4% of total cases were reported in children and adolescents (aged under 19 years), while older cases aged over 60 years and those with a background of chronic diseases were at higher risk of developing severe disease and death (22).
Even though age is an important deterministic factor for severity of symptoms, other risk factors such as having a history of underlying diseases and/or co-infection with other infections like Influenza virus and Klebsiella may accelerate the progress of symptoms and lead to poor prognosis of the disease (26). However, findings from a study in Singapore shows that infected patients with no history of underlying diseases may also develop severe disease and need for intensive care (4).
Virulence
The virulence of a disease is usually measured on the basis of indicators such as mortality rate and disability. Compared with the previous two epidemics (SARS and MERS), the case fatality rate was lower and approximately 2% in COVID-19, and only less than 15% of patients would seek hospital services. However, the case fatality rate of SARS and MERS was 10% and 34%, respectively (18). Results of a study in China revealed the overall case fatality rate of 2.3% for COVID-19 (27) and some studies reported case fatality rate of 0.9% in Beijing (28). In another study, Jung and colleagues reported a confirmed case fatality risk of 5.3% to 8.4% for COVID-19(23). However, due to the rapid spread of COVID-19, there is a higher number of death cases in the recent pandemic (N=3043, up to 02 March 2020) compared to SARS and MERS (N=1871) (29).
There is a poor prognosis for the disease in middle and older aged patients (28). In a study on 44672 confirmed cases in China, case fatality rate was highest in the group of over 80 years (14.77%), followed by the age group between 70 to 80 years (7.96%) and no mortality was reported in age group below 10 years (30). Even though death outcome is uncommon in young people, a few deaths are reported in this age group in China and Iran.
Availability of and access to healthcare facilities has likely contributed to increase in death outcome. As a probable explanation for the difference between fatality rate in Wuhan (3%) and other provinces (0.7%) in China, death rates are likely affected by shortage in health resources due to increasing number of patient who had sought diagnosis and treatment services in the early phase of the epidemic in Wuhan (31).
Immunogenicity
Exploring and understanding the immunogenicity of COVID-19 is essential for developing the most effective treatment regimens and vaccine. However, evidence on immunogenicity of COVID-19 is limited. Study on B-cell and T-cells epitopes revealed that SARS-CoV and the virus causing COVID-19 had identical proteins (32). A few clinical trials have evaluated the efficacy of new vaccines in MERS-CoV and SARS-CoV. Results of these studies in Phase-1 showed some degree of efficacy and one of these studies has been certified to begin Phase-2 (33,34).
Absence of clinical symptoms, respiratory lesions in CT scan and two negative RT-PCR tests in two consecutive days are introduced as criteria of discharge from hospital or quarantine center in China (35). However, recent studies reported several cases of COVID-19 with clinical manifestations of the disease along with a positive test after discharging from hospital (36,37). False positive and false negative results have been reported in RT-PCR test (10,38); hence, hospitals in China have considered additional antibody test (negative IgM and positive IgG results) as a recovery criteria and discharge requirement (39). In conclusion, recurrence of COVID-19 in recovered cases highlights the necessity for development of a more effective vaccine.
Diagnosis
Pathogen of COVID-19 has been detected in upper and lower respiratory tracts in initial assessments. Moreover, viral RNA has been detected in fecal and blood samples in later studies. According to WHO guideline, laboratory diagnosis of COVID-19 is based on a positive RT-PCR test. Target gene for diagnosis may be different by country. Accordingly, target genes for screening and confirmatory assays by RT-PCR are ORF1ab and N in Chinese laboratory protocol, while RdRP, E and N are checked in Germany. Furthermore, three targets in N gene are considered in the US protocol (40).
RT-PCR is an expensive test and no access to diagnostic facility during COVID-19 pandemic advocates conducting new researches on other diagnostic approaches such as Chest CT. However, results of recent studies in China demonstrate low specificity for this diagnostic approach (41). As a critical point in diagnostic studies, accuracy of a new test is compared to the gold standard. This comparison resulted in lower values of diagnostic accuracy for the new test. On the other hand, the sensitivity and specificity of a test depend on the severity of cases, which may vary between different populations according to their type of surveillance system (42). In the mentioned study that compared CT scan with RT-PCR as a gold standard, sensitivity of CT scan was appropriate (41). However, the study population consisted of suspected cases and generalizability of the findings is questionable (43). Furthermore, the large number of hospitalized cases due to false positive results by CT scan may increase the risk of transmission to healthy people. On the other hand, RT-PCR test may be subject to some limitations, especially in the earlier phase of an epidemic, as the specialists should be trained for running related procedures and interpretation of results. Moreover, false negative results due to either low quality of specimen in use or inadequate number of organisms in the samples are introduced as main challenges (44). Results of a recent study on rapid IgM-IgG combined test revealed some limitation for RT-PCR test as a standard diagnostic method for COVID-19. The following limitations were indicated for RT-PCR test: long turnaround times, complex operation, and need for quality controlled laboratories, expensive equipment and trained specialists (38).
Surveillance The outbreak surveillance is the anticipation, early warning, prompt detection and response to unusual increase in the number of cases. Establishing a surveillance system for a new epidemic is believed to be a core intervention in controlling the disease (45). Surveillance system data provides reliable information for epidemiologists to identify weak chains of transmission and facilitates evidence-based decisions by policymakers both inside and outside the healthcare service. Moreover, updating and sharing interpretations of data with media, especially in earlier phase of an epidemic, will aid community engagement and participation in control activities and prevention of spreading rumors. Although, it may be too soon to compare the effectiveness of surveillance systems for COVID-19 epidemic in different countries, it seems that the Chinese surveillance system is highly effective as it ensures timely detection, recording, tracking, updating and sharing information on media for an outbreak with unknown origin and high burden of cases (4).
In a large number of countries, the initial focus of the surveillance system for CIVID-19 is examination of all suspected cases with symptoms of the disease (mostly fever) and all people with a travel history to China or visiting Chinese travelers or citizens it the previous two weeks. However, this type of screening program mainly relies on fever cases and those with direct flights from China, so it misses pre-symptomatic cases as well as infected travelers who are arriving from regions with high burden of disease via indirect flights, which could be a source of infection in COVID-19-free countries (46).
In a communicable disease outbreak, essential data are usually collected in parallel from different available information sources in the country including data of weekly outpatient visits to health care centers and hospital referrals with a chief complaint of fever, data of weekly inpatient fever cases and deaths with unknown origin (45). Furthermore, increase in the number of cases and deaths due to pneumonia may raise an alarm in COVID-19 free areas.
A prerequisite for establishing a surveillance system is to provide basic laboratory facilities, particularly at “point of care” (10). This system should be constantly monitored and evaluated using sensitive indicators to ensure the quality of case detection, diagnosis and management.
Detection of primary confirmed cases with poor prognosis in early phase of the epidemic without any link to confirmed cases from other regions emphasis on the insensitivity of a national and local surveillance systems and low performance of control activities against the disease in community level. In this case, it should be immediately addressed and capability and capacity of the surveillance system should be checked.
Examples of surveillance systems in different countries ( 47 )
National authorities are actively looking for cases in all provinces of China and efforts for finding additional cases inside and outside of Wuhan City have been expanded. Moreover, active and reactive case detection along with tracing close contacts have been started in medical institutions.
The Department of Disease Control in Thailand scaled up the Emergency Operations Center to Level 3 to closely monitor the ongoing situation in both national and international levels. This country has started a screening program to check for fever in all travelers who arrived from Wuhan through direct flights in airports.
Japan’s Ministry of Health requested local health governments to be aware of the respiratory illnesses in Wuhan using the existing surveillance system for serious infectious illnesses with unknown etiology. It has strengthened surveillance for undiagnosed severe acute respiratory illnesses. Quarantine and screening measures have been intensified for travelers from Wuhan at the points of entry. Furthermore, National Institute of Infectious Disease (NIID) established an in-house PCR assay for COVID-19.
Contact tracing and other epidemiological investigation are ongoing in the Republic of Korea to prevent the spread of the disease. The government has scaled up the national alert level from Blue (Level 1) to Yellow (Level 2 of the 4-level national crisis management system). Surveillance of pneumonia cases has been strengthened in health facilities nationwide and quarantine and screening measures have been enhanced for travelers from Wuhan at the points of entry.
The US centers for disease control and prevention (CDC) activated its Emergency Response System to provide ongoing support against COVID-19. Screening of passengers on direct and indirect flights from Wuhan China to the 3 main ports of entry in the United States has begun and will expand to Atlanta and Chicago in the coming days. CDC deployed a team to support ongoing investigation in the state of Washington and tracing close contacts following the first reported case of COVID-19.
Clinical Case Management
Diagnosis of COVID-19 based on clinical manifestations is complicated and initial symptoms of the disease are usually nonspecific. A large number of patients present to clinics and health centers with mild common cold symptoms such as dry cough, sore throat, low-grade fever or body aches. Patients usually go to the emergency departments if the symptoms of the clinical manifestations worsen after a few days. Because of the wide spectrum of clinical symptoms, research on biomarkers and clinical criteria predicting prognosis is of high priority to enable differentiating cases that require further interventions in the early phase of the disease (10).
No approved drug regimen has been introduced to treat infected cases so far, antiviral treatments are used to alleviate the disease symptoms. Studies on Remedesevir, as an antiviral agent, revealed its in vitro activity against the COVID-19 virus and its safety was proven in Ebola trials. Another proposed treatment is Chloroquine, an old drug for treatment of malaria, with apparent effectiveness and acceptable safety against COVID-19 associated pneumonia (48,49). Evaluating the efficacy of anti-influenza drugs such as Umifenovir and Oseltamivir against COVID-19 virus is interesting but lacks any biological plausibility. Using monoclonal antibodies has been suggested as an attractive choice among inactive prophylactic methods; however, its effectiveness has not been proven in other viral respiratory diseases and influenza, yet (50,51).
Steroids and methylprednisolone seem to be widely used in the recent pandemic. However, in case of MERS, it has been shown that the drug prolongs the presence of the virus and WHO does not recommend its use for COVID-19, except for patients with acute respiratory distress syndrome (ARDS) (52,53).
The effectiveness of other medicines and regimens such as Chloroquine, Vitamin C, and Chinese medicine, as well as Lopinavir/Ritonavir combination therapy and Remedesevir are being evaluated in China. Even though randomized clinical trials are important for improving prognosis and interrupting transmission of disease, researchers and healthcare providers should concentrate on alleviation of the disease among subgroups of patients and in different phases of the disease (54).
In addition, since the emerging virus has become a serious global concern, there is a need for rapid development of a vaccine. There are a few vaccine candidates developed in response to outbreak. However, an effective anti-viral medication or a vaccine that has been evaluated for safety and efficacy against COVID-19 is not available yet, and most vaccines are still in the preclinical testing stage (55,56,57).
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More information: Aditi Shastri et al. Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs, (2020). DOI: 10.1101/2020.04.16.20060566
