Targeted Population, Strategy, Issues and Progress to Combat COVID‐19

Introduction A COVID‐19 disease threatens the population and the economies of the countries significantly. Till now, this pandemic has affected 215 counties or territories. Unavailability of vaccine is the primary concern for the society. To avoid the spread of this disease, social isolation must be preserved and the inter and intra‐ population movement must be minimized. To reduce the possibility of transmission, the categorization of regions based on susceptibility to COVID‐19 infection is a must. Method Due to the unavailability of a large amount of paper collection for this novel COVID‐19 diseases, we used current literature available on a COVID‐19 susceptibility of the diabetic patient, human reproductivity, hemodialysis patient’s, pregnant women and meteorological factors and geographical location. Results Countries in the cold region are more susceptible to the risk of COVID‐19 transmission. There was no evidence of the spread of this disease from non‐respiratory bodies. Diabetic patients and pregnant women were found to be more susceptible to COVID‐19 infection. Anosmia was observed in the majority of the COVID‐19 infected cases in European countries. No evidence indicates COVID‐19's impact on the human reproductive system explicitly. No cases of vertical transmission of this disease have been observed until now. Conclusion All the studies available till now is the small scale study. Correlation with something always does not mean causation. There are certain factor like pollution level, temperature Diurnal temperature range, geographical factor, humidity, pollution level, wind speed, population density, medical healthcare facilities social and political factor plays a critical role in transmitting the SARS‐COV‐2 virus. Besides the adverse effects, it has taught us to shed our selfish goals and to promote the welfare of all.


Introduction
A Rapid spread of SARS-COV-2 (Severe Acute Respiratory syndrome) led to a pandemic COVID-19 (Coronavirus disease 2019). COVID-19 viral genes show 86.9% identity with the SARS-COV genome; therefore, it is known as SARS-COV-2 [1]. Zero patient of COVID-19 was found in Wuhan province of China on 8 December 2019. The global spread of SARS-COV-2, WHO declare COVID-19 as a pandemic on 1 March 2020. Globally as of 11 May 2020, there have been 4,006,257 confirmed cases of COVID-19, including 278,892 deaths reported by WHO [2].
Till now, the source of the origin of SARS-COV-2 is not known. There is an ambiguity regarding animal or human origin. Before this pandemic, all human coronavirus originated from mice or domestic animals [3]. SARS-COV-1, MERS (Middle East Respiratory Syndrome) are the previously originated respiratory syndrome, which has the same symptom as SARS-COV-2. These symptoms are associated with mild illness, severe acute respiratory syndrome distress, severe respiratory infection and death [4]. Real exposure to such disease defined by the R0 number known as reproduction or transmission rate. In 2009 for seasonal influenza, H1N1 had R0 value as 1.46 -1.48 and for COVID-19, it is reported as 2.24 -3.58 [5]. Ro between 2.24 to 3.58 shows that 2-3 people infected from every index cause.

SARS-COV-2 and Cardiovascular disease
Cardiovascular disease involves the blockage or narrowing of the blood vessel that leads to chest pain and heart attack. SARS-COV-2 attacks the human lungs and causes severe lung damage. It is suggesting the need to understand the potential mechanism of cardiovascular disease causes through SARS-COV-2.

Imbalance of Renin-Angiotensin System (RAS)
RAS is the hormone system responsible for the regulation of blood pressure and fluid balance. Spike protein of SARS-COV-2 binds the ACE-2 receptor that is homologs to ACE and the critical component of the RAS. ACE converts the Renin Hydrolyzes Angiotensinogen to Yield Angiotensin I to angiotensin II (Ang II). Ang II causes vasospasm that leads to higher blood pressure. Therefore ACE 2 binding with spike protein leads to the excessive release of Ang II, which in turn the heart loading by increasing blood pressure [7].

Cytokine storm
The fusion of spike protein and ACE 2 activates the immune response, which released pro-inflammatory cytokine. After the fusion of viral with the host cell membrane, the virus replicates it on the lung surface cell and causes lung inflammation. This infection causes downregulation of ACE 2 without affecting the ACE enzyme [15,16]. Filtration of inflammatory cells from the blood and accumulation of cytokine at the injury site causes a cytokine storm. This leads to the over-activation of the immune system and increasing the damage of myocardial cells (muscle tissue) and increasing the risk of cardiovascular disease [17,18].

Hypoxemia
It is the condition in which low arterial oxygen supply leads to the accumulation of oxygen free radical. To maintain an adequate level of oxygen, pump blood is intensified and prone to shortness of breath, rapid heart rate and myocardial infarction [19].

Stress response
In 20-30 % of COVID-19 patient severity of illness closely related to hypertension [7]. Interaction between the host cell and virus is a sophisticated process where interaction among the tissues and organs takes place.
Meanwhile, a human response like fear, anxiety increases the human stress level. Catecholamine (monoamine neurotransmitter) reacts to stress in the body and mainly released in large quantities. That causes an increase in heart rate, breathing and blood pressure level. ACE I (Angiotensin-converting enzyme Inhibitors) are the class of medicine used for the treatment of high blood pressure. It caused a decrease in blood volume, therefore less oxygen demand from the heart, which leads to lower blood pressure. Animal studies show that ACE I drugs significantly increase the ACE 2 biological activity in rat cardiomyocytes [6,20]. In the human body, it is unclear that these drugs increase the susceptibility of COVID-19. Therefore, the high blood pressure patient should not change the ACE I treatment plan without severe adverse reaction [7].

COVID-19 and testing
Early detection of COVID-19 is essential for the prevention and control of this pandemic. The patient, which showing early onset of symptoms clinical characteristic (CT (Computed Tomography) image), cannot alone diagnose the COVID-19. Nucleic acid detection-based RT-PCR test more rapid, reliable and more sensitive toward early detection of COVID-19. The test became undetectable for patient-1 after the 14-15 days and for patient-2 after the 18-20 days since the onset of symptoms. This suggested that COVID-19 disease shows different viral load kinetics in an individual patient. Therefore, the period of disease and sampling timing plays an essential role in the testing results [22]. False-negative and false-positive results are critical issues with RT-PCR. Negative results do not exclude the possibility of infection and false-positive results are the risk to the patient. Therefore, it is advisable to use a combination of CT image features and RT-PCR for the COVID-19 disease management that could reduce the inaccuracy in the results. It is advisable for all laboratories and hospitals should use standard guidelines and reporting procedures based on their public health policies to avoid any inconsistency in results. Sometimes contaminated sample leads to a false-positive or false-negative result. Therefore, the use of a sputum sample is suggested for the most accurate RT-PCR testing [23].

Reverse Transcription Polymer Chain Reaction (RT-PCR) test
Due to the shortage of laboratory-based RT-PCR molecular testing and regent's, the manufacturer has begun to sell antibody test kit that can work outside the laboratory. These test kits are based on protein detection from the SARS-COV-2 and the human respiratory specimen like blood, sputum and throat swab.

Rapid test based on antigen detection from viral body
The rapid diagnostic test detects the viral protein (antigen) presence in the COVID-19 virus from the human respiratory tract. If the antigen present in the sufficient concentration in the human respiratory sample, it binds to a specific antibody enclosed in a device and starts to replicate it. Visible lines on the test kit paper show the detection of this antigen. This test is useful for the detection of early infection. The sensitivity of the test depends upon the time from the onset of symptoms, quality of the sample type, the concentration of the antigen in the respiratory tract and precise concentration of the reagents in the kits. Typically, the visual line is detectable on the test kit within 30 minutes. Bruning et al. found that the sensitivity of this test can be expected within the range of 34-80% [24]. Based on this information, it can be expected that more than half of the COVID-19 patients will be missed by such testing. There may be a chance of false-positive and negative results. If the person is suffering from human coronavirus that causes the common cold, such a test will detect the antigen and shows the false-positive result and further treatment of such a patient might be risky. Therefore, secondgeneration test kits are required for the detection of COVID-19 in the early stage, which needs adequate

Rapid test based on antigen detection from the host body
Rapid test kits are the qualitative, immunochromatographic assay detects the IgG and IgM antibody present in the human respiratory sample. This test detects the antigen from human blood and believes that the patient has been infected from COVID-19 disease. The antibody response for all the individuals is not the same; it depends on several factors, including the severity of the disease, age, nutrition status and infection like HIV that suppress the immune system [25][26][27][28]. Figure 1 shows the antibody response with days of infection. Studies show that the majority of patients develop an antibody response in the second weak from the onset of symptoms. Therefore, this antibody kit should not use for the early body diagnosis of COVID-19. This suggests that antibody response is higher in the recovery phase, where most of the opportunities for clinical intervention transmission risk pass away. This test targets the antibody response that may also cross-react with the human pathogen, including coronavirus [27] and shows false-positive results. Eventually, the WHO does not recommend the use of this test for patient care. The testing can be continued in disease surveillance and epidemiological research [25]. A chart for the COVID-19 detection technique shown in Figure 2. Table 1 represents the clinical significance of testing results.

COVID-19 and meteorological factor
Currently, countries which are situated in the low-temperature region are suffering more from COVID-19 disease. Therefore, it is necessary to understand the effect of meteorological factors such as ambient temperature, humidity, diurnal temperature range, wind speed and geographical location of the countries.
Apart from these factors, the transmission of the virus can be affected by many other parameters such as population density, medical care quality and policymaker decision, social and political factors [31]. Wang et al. [32] found that the transmission rate of COVID-19 disease in the warm and humid region of china was less as compared to the cold region. Arajo et al. [33]  Yueling et al. [37] conducted a study in the Wuhan and try to correlate the mortality rate with diurnal temperature range (DTR), average temperature, relative humidity and air pollution (PM2.5, PM10, CO, NO2, O3, and SO2). They found that DTR positively related with the COVID-19 mortality rate and average daily temperature and relative humidity negatively associated with mortality rate. This can be justified by the previous study where respiratory disease mortality increases with a decrease in temperature [38] and heat and cold effect (related to DTR) harm the respiratory system [39]. Similar results found by Kim et al. [40], where they conducted a study on 30 East Asian countries and found that an increase in DTR increases the risk of respiratory and vascular disease that increases the mortality rate. Lower humidity or dry air causes contraction of mucociliary clearance and results in a respiratory infection [41]. So, it is essential to maintain a proper environment for the patient inside the hospitals. To avoid such risk situations in Wuhan, hospital windows were kept open for 24 hours for ventilation. Therefore, indoor meteorological factor variation could be the same as an outdoor and sudden change in temperature can be avoided [37].

COVID-19 and diabetic patient
It is known that diabetic Mellitus (disease related to a high level of sugar in the blood) is the common comorbidities in diabetic patients [42,43] and poor glycemic control in the diabetic patient causes the infection [44]. This shows that a diabetic patient is more susceptible to infection. A study was conducted on the 1382 diabetic patient with an average age of 51.5 years in Italy to access the mortality risk due to COVID-19. The first outcome of this study shows that diabetic COVID-19 patient is at high risk of ICU admission. For second outcome study was conducted on 471 people with 56.6 average age. It shows that the mortality rate was higher for COVID-19 suspected diabetic patients as compared to others [45]. Therefore, diabetic patient requires extra medical care with standard medical guidelines. no one has developed acute respiratory distress syndrome, shock and any other complication [46]. This result suggested that hemodialysis patient does not require extra medical attention. SARS-COV-2 is a novel virus;

COVID-19 and hemodialysis patient
therefore, data availability limits the further conclusion regarding hemodialysis patients.

COVID-19 and human reproductivity
Till now, there has been no evidence that SARS-COV-2 directly affect the male and female gametes. There are no reports available that suggest the presence of the virus in female reproduction tract amniotic fluid in vaginal secretions. It was found that fever affects spermatogenesis in the male reproduction system. Therefore, maybe a chance of diminishes male fertility within 72-90 days followed by COVID-19 by reducing sperm concentration [48,49]. Gametes obtained from COVID-19 patient does not require any special precaution (reducing exposure to cross-contamination of other laboratory tissues or non-infected partner) like HIV and hepatitis at laboratory scale due to lack of transmission of SARS-COV-2 through the blood or sexual content [50,51]. Currently, there are no guidelines available for a sperm donor, infected by the COVID-19. This area required further investigation to ensure the safety of preserve gametes and the safety of patients undergoing reproduction [3].

COVID-19 and Pregnancy
A study reported that severe acute respiratory syndrome was the most severe disease for pregnant women. It was found that pregnant women require mechanical ventilation 3 times more than non-pregnant women [3].
Currently, no therapies are available for the pregnant COVID-19 patient; therefore, people are using mechanical ventilation to treat the complication. A study reported that Chloroquine (CQ) does not harm pregnancy [55]. and requiring ICU admission [53]. Some study shows that due to characteristic immune response during pregnancy and potential risk form cytokine storm by COVID-19 infection, pregnant women may be infected by COVID-19 may face severe morbidity and even mortality. COVID-19 may alter the immune response at the maternal-fetal interface and affect the mothers and infants. Pregnant women more susceptible to respiratory pathogens; therefore, they may be more susceptible to COVID-19 infection than the general population. Till now, there is no evidence that infants born from the diseased COVID-19 mother have a higher mortality rate and vertical transmission of disease [3,54].

Chloroquine (CQ) and Hydroxychloroquine (HCQ)
Chloroquine and its derivative Hydroxychloroquine are antimalarial drugs. The structure of both drugs is the same and works as a weak acid. These are the widely available drugs in countries like India, where malaria is endemic. It is also used for type II diabetic treatment patients in India since 2014 [55]. A Chinese center for disease control reported that the mortality rate in diabetic patients increases by 2.3% [56]; therefore, they need extra care and attention [43]. Due to the public health, emergency lot of medication is used to cure the COVID-19 patient. Some of these medications are the use of Chloroquine and Hydroxychloroquine. A study of Chloroquine and Hydroxychloroquine was conducted in vitro. Chloroquine is the potent anti-SARS-COV-1 effects in vitro. It interferes with the binding of viral to ACE 2 exists in the lungs and heart by creating a deficiency in the glycosylation receptor at the virus surface [55,57]. It was found that the SARS-COV-2 virus also affects the ACE2 receptor. Therefore, recent study showing the use of Chloroquine and Hydroxychloroquine drugs for the treatment of COVID-19 patients. The use of these medicine affects cell signaling and produce a cytokine storm that regulates the immune system. A study reported that the standard dose of Chloroquine is highly effective in reducing the replication of the virus on the cell surface by penetrating the tissues [58,59]. Some studies found that Hydroxychloroquine is the more favorable drug for the COVID-19 patient [60]. Therefore, the question arises whether these drugs have the same effect on the COVID-19 patient in all the stages like SARS-COV-1 patient.  [67]. The risk of abnormal QTc for a male is above 450ms and in a female is above 470ms [68]. Therefore, a patient with 450-500ms QTc required ECG daily.

BCG (Bacillus Calmette Guerin) vaccine
BCG used as a vaccine against TB (tuberculosis). This vaccination is given to the children in most of the

Vaccine
Till now, there is no vaccine available for the SARS-COV-2. S1 domain of spike protein functions in the viral binding attachment of the host cell membrane; therefore, international research aimed at using the S1 domain of spike protein as a target for therapeutic anti-viral therapy for the vaccine development [3]. A total of 71 vaccines has been under review reported by WHO. Out of these 71, vaccine four vaccine has been prepared for the phase 1 trial and one vaccine has been prepared for phase 2 trial and the remaining vaccine is under clinical evaluation. Table 2 represents the details of these developed vaccines.

Asymptomatic patient
SARS-COV-2 proven exceptionally difficult due to asymptomatic and pro symptomatic spread as well as high person to person transmission. The asymptomatic person does not show any symptoms of COVID-19, including fever, shortening of breath, high heartbeat, headache, cough, sputum production, myalgia and anosmia. It is reasonable to say that asymptomatic represent a substantial contribution to disease spread [72,73]. Due to this, healthcare workers are the vulnerable population at high risk of viral transmission. In Bhilwara's district  [52]. Therefore, asymptomatic COVID-19 patient is a cumbersome task for the COVID-19 infected country. The only way to find such a patient is large scale testing.

Testing
The question comes in our mind that is testing the only strategy to control the transmission of COVID

Lockdown
India is the second-largest populated country in the world. Where community transfer would make the people panic and harm the population as well as the economy. Union government of India imposed lockdown over 1.32 billion people on 24 March 2020. It was an effort to put people in the biggest isolation. To find the effectiveness of lockdown, Raj and Prashant et al. [75] used a kinetic model theory for the qualitative understanding of the complete lockdown in India. They found that in case of complete lockdown after 60 days since the onset of lockdown, less than 4% of the population exposed to at high risk of transmission, whereas without lockdown, more than 40% of the Indian population would have got exposed to high risk of transmission. WHO report stated that most of the region of Americas like United States of America, Brazil, Canada, and Mexico comes in the category of community transfer whereas India comes in the category of a

Body temperature measurement
To at least 10 minutes for children to become acclimatized after coming from a cold environment [80]. Some patient takes antipyretics that decrease the body temperature to avoid outdoor quarantine. Interaction of such type of people in the hospital crowd may lead to the hospital staff at risk. In response to avoid such situations, a study was performed in Taiwan hospital. They made a rule of temperature checkup in the waiting area and again on the inside. During May 2020, hospital finds, out of 40887 visitors, only 5 patients were found temperature higher than 38 °C at the entrance of the hospital. However, 37 people were found to have fever inside the hospital during the second temperature measurement. Therefore, it is advisable for the hospital to takes repeated checkups of body temperature after acclimatizing to indoor. This simple strategy could play an important role in hospital prevention and control [81].

Economy
The biggest challenge for any COVID-19 affected country is to revive the economy from an unprecedented closure. It is expected that the pandemic will result in loss of skilled labor, a decrease in the pace of setting up infrastructure and even the scarcity of capital required for economic activities. The burden of high expenditure for containing the virus is going to affect the fiscal deficit target of the major countries. The temporary closure of industries, majorly MSMEs (Micro Small and Medium Enterprises), has made the workers cashless and this has led to a slump in demand. On top of this, to maintain social distancing, the restriction on agricultural activities has made the situation worse for marginal farmers.
The agricultural products sold to Mandi (Grain market) is also a major challenge and will affect the farmers strongly. To cope with COVID-19 and to practices social distancing in the workplace, countries have announced lockdown. The pandemic has resulted in a closure of factories other than those producing lifesaving drugs and other essentials. It is expected that pandemic will result in a loss of skilled laborers, as most of the workers are facing hardships and are returning to their native place. Even after the lockdown is lifted, the number of workers returning to their workplace is estimated to be low due to a lack of social security experienced in these hard times.
In a country like India, a large number of workers are daily wage laborers and are employed in the unorganized sector. Due to lockdown, these workers are facing a cash crisis and are likely to spend a very minimal amount on even the essentials. This could lead to a slump in demand, putting further strain on the economy. The lockdown has also impacted the small and marginal farmers in a big way. The agricultural activities are moving at a slow pace due to lockdown. In addition to this, due to restrictions on movements, it is difficult for farmers to sell their produce in agricultural markets. Farmers thus have to bear the excess inventory cost to their product for a more extended period. The procurement of urea and seeds required for agricultural activities have also become complicated and therefore, the farmers are likely to face a delay in their activities, which could affect the production. The farmers and workers constitute a large population of India and therefore, a major population of the country has to suffer due to the pandemic. Not only the laborers and farmers, but the pandemic has also hit the hospitality and tourism industry strongly. The hotels, taxi business, local artifacts have seen a slump in their business. It is estimated that pandemic can lead to the closure of around 50% of the small restaurants. The real estate sector is also facing difficulties in surviving. With almost no activities allowed in the real estate constructions, the industry has come to a standstill. The fact that the economy is cash-starved is making it difficult for real estate even to continue working. In these situations, the sector is expected to see a sharp decline in the demand leading to massive losses, as people are less likely to invest in properties. The lockdown has hit the aviation industry hard too. The aviation industry was already under immense pressure and losses. The halt in operations is increasing the troubles for the air carriers. The condition of the aviation industry is in such a fur moil that of the companies has announced a salary cut of up to 50% for their staff. With time, the companies might have to reduce their staff, resulting in job losses. All the industries under these strained conditions are expected to reduce their workforce leading to an unemployment crisis.
It would need both individual efforts and the government's determination to recover. While it would need considerable time to catch pace, the economy is expected to recover gradually. A behavioral change in consumer's choices is predicted to be seen concerning healthier items and organic products. International trade, tourism and transportation would require more time to scale up. Healthcare Industry has had the greatest advantage of the epidemic, although health professionals had to work for long hours, risking their own precious lives. Sanitizers, Face mask sales, have grown by more than 300%, and a behavioral change towards the use of sanitizers is expected. While we would face a high amount of loss due to the pandemic, it has given the economy a thought to work more on to date overlooked sectors, which have grown more important. COVID-19 pandemic has abrupt the supply chain between the major trading countries. In view of resuming the economic development and reducing the dependency of manufacturing products on China, the Japanese government has compiled a $2.2 billion package. This package for the help of Japanese manufacturing firms who wants to move out of China. Out of this $2 billion fund is for the manufacturing companies who want to shift their production from China to Japan and remain for the shifting of production to other countries [82]. The USA government is also previewing the support of manufacturing firms from China to other countries [83]. It

COVID-19 is a lesson for society?
Despite being a deadly menace, COVID-19 has had some positive effects too. The concept of family, quality family time, friends, relatives, etc. has seen some positivity. The pandemic has taught us to be more sensitive towards our family members and well-wishers to find out time for people who matter in our lives. The disease has prompted us to be self-sufficient and self-reliant; it has made us understand the dignity of labor, the importance that our housemaids and other menial workers hold in our lives. Conclusion SARS-COV-2 has a mortality rate of 6.78 % worldwide, which is somewhat lower than that of MERS. A Higher Climate Emergency seems very imminent now. Humankind has learned that sustainability and conservation efforts do matter. COVID-19 has taught us to shed off our welfare and work more towards the welfare of all.