Covid-19 Disease Pandemic

                                Dr. KS Dhillon

Epidemiology

It is still unknown where the covid-19 outbreak first started. A cluster of pneumonia with unknown etiology appeared in Wuhan City, Hubei Province of China in December 2019. Many of these initial patients with pneumonia visited a wet seafood market where wildlife species were sold. Virus isolation from the patients and molecular analysis carried out showed that the pathogen was a new coronavirus (CoV) and it was named 2019-nCoV.   Subsequently on 11/2/2020 WHO renamed it COVID-19 which is short for coronavirus disease 2019.

This new coronavirus is the 7th member of the Coronaviridae which is known to infect humans. CoVs are a class of genetically diverse viruses found in many host species, including birds and mammals. CoVs cause intestinal and respiratory infections in animals as well as in humans [1,2,3,4]. Coronaviruses first came into the spotlight in 2002–2003 in Guangdong Province in China where clusters of ‘atypical pneumonia’ were reported. Researchers isolated a novel CoV virus (SARS-CoV) and the disease was renamed severe acute respiratory syndrome (SARS). Further studies carried out showed that the SARS-CoV originated from bats and interspecies transmission to humans took place via an intermediate host: Himalayan palm civets or raccoon dogs (Nyctereutes procyonoides) [4,5,6]. The other well-known CoV of animal origin is the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which has a high case fatality rate, but, fortunately, it is rarely transmitted between humans.

As of 31 December 2020, 83,134,416 cases of Covid-19 have been detected. The death toll stands at 1,813,386. The figure of recovered individuals stands at 58,932,394 [7].

Many countries do not test those with mild symptoms. Li et al [8] in an analysis of the early phase of the outbreak up to 23 January 2020 estimated that 86 percent of COVID-19 infections had not been detected and that 79% of detected cases were from these undocumented infections. Studies by several authors have estimated that the numbers of infections in many countries are likely to be much higher than the reported cases [9,10]. 

The COVID-19 deaths refer to people who died after testing positive for COVID-19. These figures do not include deaths of people who die without having been tested. 

The recovery rate after COVID-19 infections is more than 95%. The time between the onset of symptoms and death ranges from 6 to 41 days and is usually about 14 days [11]. People with underlying conditions, such as a weak immune system, serious heart or lung problems, severe obesity, and the elderly are at the greatest risk of death from COVID-19 infection [12]. 

The number of deaths due to COVID-19 divided by the number of diagnosed cases within a given time interval provides the death-to-case ratio. The global death-to-case ratio is 2.2 percent (1,671,772 deaths for 75,508,468 cases) as of 18 December 2020 according to Johns Hopkins University statistics [13]. 

Infection fatality ratio (IFR) is the most important metric in assessing the death rate. The infection fatality ratio is obtained by dividing the number of deaths attributed to a disease divided by individuals infected (including all asymptomatic and undiagnosed) [14].

A peer-reviewed analysis of pre-serology data from China in March 2020 yielded an overall IFR of 0.66%. For those aged 0 to 9 years the value was 0.00161%, for those aged 50-59 years it was 0.595% and for those aged 80 and more the value was 7.8% [15]. 

In April 2020, an IFR range of 0.12–1.08% was derived from non-peer-reviewed serology surveys that showed that the IFR for COVID-19 ranges from 0.12-1.08% and that for influenza is 0.04% which makes COVID-19 deadlier than influenza by 3 to 27 times [16]. 

The CDC in the USA, in July 2020, adopted the IFR as the standard for the direct measurement for disease severity for COVID-19 and calculated that the overall 'best estimate' for planning purposes in the USA is an IFR of 0.65% [17,18].

The CDC in September 2020, computed an age-bracketed 'best estimate' for the USA of 0.003% for those aged between 0–19 years, 0.02% for 20–49 years, 0.5% for 50–69 years, and 5.4% for 70+ years [19].

Dr. Mike Ryan, director of the WHO's Health Emergencies Programme, on 6/10/2020, announced that "Our current best estimates tell us that about 10% of the global population may have been infected by this virus" [20].

Another metric that is used to assess the death rate is the case fatality ratio (CFR). The value is obtained by dividing the deaths attributed to disease by the number of individuals diagnosed to-date. 

This metric, however, can be misleading because of the delay between onset of symptom and death and also because testing focuses on individuals with symptoms, particularly on those manifesting severe symptoms [21].

Coronavirus disease 2019 (COVID-19)

Signs and symptoms

People with COVID-19 can have a wide range of symptoms ranging from mild symptoms to severe illness [22]. Symptoms usually appear 2-14 days after exposure to the virus. Some of the symptoms include:

• Fever or chills- 83% to 99%.
• Fatigue- 44% to 70%.
• Shortness of breath or difficulty breathing- 31% to 40%.
• Cough- 59% to 82%.
• Muscle or body aches- 11% to 35%.
• New loss of taste or smell- 15% to 30%.
• Coughing up sputum- 28% to 33%.
• Loss of appetite- 40% to 84%.
• Sore throat
• Headache
• Congestion or runny nose
• Diarrhea
• Nausea or vomiting

Patients with severe disease may have these signs and symptoms:

• Difficulty in breathing
• Persistent pain or pressure in the chest
• New confusion
• Inability to wake or stay awake
• Bluish lips or face
• Coughing blood
• High fever
• Kidney failure

About one in five people who are infected with the virus do not develop symptoms at any point in time. Research earlier in the pandemic suggested that the rate of asymptomatic infections could be as high as 81% [23]. A meta-analysis published in December 2020 [24], which included 13 studies involving 21,708 people, calculated the rate of asymptomatic presentation to be 17%. The asymptomatic carriers invariably do not get tested, and they can spread the disease. People also get infected from pre-symptomatic people who later develop symptoms [25]. 

Transmission of COVID-19

COVID-19 usually spreads from one person to another person mainly through the respiratory route when an infected person talks, coughs, sneezes, sings or breathes. The infection spreads when virus-containing particles are exhaled by an infected person. The viruses are carried by either respiratory droplets or aerosols and these viruses find their way into the mouth, nose, or eyes of people who are in close contact with an infected person [26,27]. During human-to-human transmission, an average of about 1,000 infectious SARS-CoV-2 virions are thought to initiate the new infection.

The closer and longer people interact, the more likely they are to transmit the disease. At close distances, larger droplets that fall to the ground and aerosols transmit the virus load, whereas at longer distances only aerosols carry the virus load. The larger droplets can also evaporate to form aerosols. The virus, however, is not known to be transmitted between rooms over long distances such as through air ducts. 

Airborne transmission occurs in crowded and less ventilated venues in indoor locations such as in restaurants, offices, choirs, nightclubs, gyms,  and religious venues. It also occurs in healthcare settings where aerosol-generating medical procedures are performed on COVID-19 patients.

The number of people that one infected person can infect varies. It has been estimated that one infected person can infect on an average between two and three other people [28]. This makes COVID-19 more infectious than influenza, but less than measles [29]. COVID-19 infections often spread in clusters, where infections can be traced back to one index person at a particular geographical location. There are also "super-spreading events", where many people are infected by one person.

Cause of COVID-19 disease

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a strain of coronavirus [30]. 

Each infected person on an average can spread the infection to 5.7 persons according to estimates by epidemiological studies.

Diagnosis of CVID-19 disease

The presence of SARS-CoV-2 is detected by real-time reverse transcription-polymerase chain reaction (rRT-PCR) [31] which detects the presence of viral RNA fragments [32]. The test detects the virus RNA but not the infectious virus. The test is usually done on respiratory samples obtained by a nasopharyngeal swab. A nasal swab or sputum sample may also be used [33,34]. Usually, the results are available within a few hours.

The specificity and sensitivity of the rRt-PCR test is not known but some authors have estimated the pooled sensitivity to rRT-PCR as 89% (95%CI: 81-94%).  False negatives are as low as 2% and as high as 37%. The false positives rates are about 5% or lower.

CT scans of the chest may be useful in the clinical diagnosis of COVID-19  in a person with a high index of clinical suspicion of infection but scans are not recommended for routine screening. In early infections, bilateral asymmetric multilobar ground-glass opacities are seen at the periphery in the posterior aspect of the lungs. 

Lung consolidation, subpleural dominance, lobular septal thickening with variable alveolar filling may appear as the disease progresses.

Prevention of COVID-19 disease

Preventive measures to reduce the chances of infection include:

• Staying at home 
• Avoiding crowded places
• Wearing a mask in public 
• Keeping distance from others
• Ventilating indoor spaces
• Washing hands with soap and water often and for at least 20 sec
• Practicing good respiratory hygiene
• Avoiding touching the eyes, nose, or mouth with unwashed hands

CDC advises individuals who are diagnosed with COVID-19 or who believe they may be infected to stay home except when getting medical care. Individuals should call ahead before visiting a healthcare provider. They must wear a mask before they enter the healthcare provider's office and when they are in any room or vehicle with another person. When coughing and sneezing the mouth and nose must be covered with a tissue. Regular handwashing with soap and water should be carried out and there should be no sharing of personal household items [35,36].

The UK medicines regulator MHRA granted regulatory approval for the first COVID-19 vaccine on 2 December 2020 [37].

COVID-19 vaccine

Ideally, a pandemic vaccine should be delivered in a single shot making it possible to stretch supplies to cover a lot of people. It should trigger no side effect more significant than a sore arm. The vaccine should be easy to ship and store.

Several vaccines have been approved by national health agencies and these include ChAdOx1 nCoV-19 by Oxford University and AstraZeneca, Tozinameran from Pfizer–BioNTech (German), BBIBP-CorV by Sinopharm (China), CoronaVac by Sinovac (China), mRNA-1273 by Moderna (USA), and Gam-COVID-Vac by Gamaleya Research Institute (USSR).

The Moderna and Pfizer vaccines are mRNA vaccines. Such vaccines contain part of the coronavirus' genetic code which is injected into the body, triggering the body to begin making viral proteins, which trains the immune system to attack the virus.

The Sinovac’s CoronaVac is an inactivated vaccine. It uses killed viral particles to expose the body's immune system to the virus without risking a serious disease response. This inactivated virus vaccine is like most other traditional vaccines produced and successfully used in the past.

The mRNA vaccines on the other hand are a new type of vaccine and there is currently no successful example of them being used in the population in the past.  

By December 2020, more than 10 billion vaccine doses had been preordered by several countries [38] with Canada leading the pack. About half of the doses were purchased by high-income countries comprising about 14% of the world's population [39].

Pfizer, Moderna, and AstraZeneca have predicted a manufacturing capacity of 5.3 billion doses in 2021, which can be used to vaccinate about 3 billion people (two doses per person). 

Because of high demand from richer countries in 2020–21, people in poorer developing countries may not receive vaccinations from these manufacturers until 2023 or 2024 [38].

On 4th February the Secretary of Health and Human Services in the USA  issued a Declaration to provide liability immunity to individuals and entities  “against any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures (Covered Countermeasures), except for claims involving “willful misconduct”[40].

Similarly, the UK government announced in December 2020 that “it had granted Pfizer legal indemnity protecting the American pharmaceutical company from civil lawsuits due to any unforeseen complications arising from problems with its COVID-19 vaccine’ [41].

The liability immunity given by the USA and UK for use of COVID-19 vaccines raises questions about the safety of the vaccines. The speed at which these vaccines are being produced and rolled out raises the risks of side effects.

The Pfizer vaccine is authorized for use in people aged 16 and older while the Moderna’s is for people 18 and older. 

According to preliminary studies, the Pfizer vaccine showed efficacy of 95% at preventing symptomatic Covid infection, starting from seven days after the second dose was administered. The Moderna vaccine was 94.1% effective at preventing symptomatic Covid-19, starting from 14 days after the second dose. The vaccine’s efficacy appeared to be slightly lower in people who are 65 years. Both vaccines appear to reduce the risk of severe Covid disease. It’s not known yet if either of the vaccines prevents asymptomatic infection with the SARS-CoV-2 virus. It is also not known if vaccinated people can transmit the virus if they do become infected but don’t show symptoms. There are announcements that China's Sinovac vaccine is 91.25% effective, according to interim data from a late-stage trial in Turkey. There are, however, no trial outcome publications as yet.

In essence, these vaccines do not prevent the disease like other vaccines such as smallpox and polio vaccines do. It is also not known how long the protection from infection lasts with COVID-19 vaccines. 

Both the Pfizer/BioNTech and the Moderna vaccines require two shots: a priming shot followed by a booster shot. The interval between Pfizer vaccine doses is 21 days and for Moderna doses is 28 days.

Each dose of Pfizer’s vaccine contains 30 micrograms of vaccine whereas the Moderna vaccine dose contains 100 micrograms of vaccine. 

Vaccines that trigger a range of transient side effects in most of the recipients are known as reactogenic.

Most of the Covid-19 vaccines that have reported data so far fall into the reactogenic category. 

The most common side effects are injection site pain, headaches, fatigue, joint pain, and muscle pain. Some people have reported fever. Side effects are more common after the second dose and in younger adults who have more robust immune systems.

To date, there have been no serious, long-term side effects with the use of these vaccines. There have been a handful of reports of people having allergic reactions (anaphylaxis) to the Pfizer vaccine. Such allergic reactions have so far not been seen with the Moderna vaccine. 

The safety of these vaccines for those who are pregnant or lactating has not been tested. 

Both of these vaccines require an elaborate cold chain, the term used to describe the conditions under which vaccines must be stored during distribution and when they are in the doctors’ offices, pharmacies, or public health clinics where they’ll be administered. 

The Moderna vaccine is far easier to use than Pfizer’s. Moderna’s vaccine must be shipped at -4 Fahrenheit whereas the Pfizer’s vaccine must be shipped and stored at -94 Fahrenheit. The former is the temperature of a regular refrigerator-freezer; the latter, however, requires special ultra-cold freezers that need to be topped up with dry ice every five days. Doctors’ offices and nearby pharmacies do not have ultracold freezers which makes it difficult for health care workers to dispense the Pfizer vaccine. After thawing, the Pfizer vaccine vial must be used within five days. The  Moderna’s vaccine is stable at fridge temperature for 30 days and at room temperature for 12 hours. The Sinovac vaccine can be stored in a standard refrigerator at 2-8 degrees Celsius

The minimum purchase order for Pfizer vaccine 975 doses. There are plenty of places where they do not need 975 doses to vaccinate people currently eligible for vaccination such as health workers and nursing home residents. The Moderna vaccine’s minimum order of 100 doses is a much more manageable number. The Moderna’s vaccine is shipped in 10-dose vials and the Pfizer vaccine is shipped in five-dose vials. 

Evaluation of hospitalized adults

In the evaluation of hospitalized patients with documented or suspected COVID-19 infections, features associated with severe illness are identified and organ dysfunction or other comorbidities that could complicate potential therapy are also identified [42]. 

Several laboratory tests are done to evaluate the patient although the prognostic value of many of the tests remains uncertain.

The following laboratory studies are usually done on a daily basis [42]:

●Complete blood count (CBC) with differential count (focus on the total lymphocyte count trend)

●Comprehensive metabolic panel including:

Alanine Aminotransferase (ALT)

Albumin

Alkaline Phosphatase

Aspartate Aminotransferase (AST)

Bicarbonate (HCO3)

Bilirubin, Total

Calcium Total (Ca)

Chloride (Cl)

Creatinine

Glucose

Potassium (K)

Protein, Total

Sodium (Na)

Urea Nitrogen (BUN)

●Creatine kinase (CK)

●C-reactive protein (CRP)

●Ferritin

The following studies are carried out every other day (or daily if elevated or in the intensive care unit):

●Prothrombin time (PT)/partial thromboplastin time (PTT)/fibrinogen

●D-dimer

The following studies are carried out at baseline and repeated if abnormal or if the clinical condition worsens:

●Lactate dehydrogenase, repeated daily if elevated

●Troponin, repeated every two to three days if elevated

●Electrocardiogram (ECG), with at least one repeat test after starting any QTc-prolonging agent. 

Hepatitis B virus serologies, hepatitis C virus antibody, and HIV antigen/antibody testing is also carried out. The presence of chronic viral hepatitis can affect the interpretation of transaminase elevations and exacerbate the hepatotoxicity of certain medical therapies. Any underlying HIV infection may change the assessment of the patient's risk for deterioration and could warrant initiation of antiretroviral therapy [42].

For all COVID-19 hospitalized patients an initial chest x-ray is essential. A chest x-ray is usually sufficient for initial evaluation of pulmonary complications and extent of lung involvement. Chest CT is not necessary for patients with COVID-19 infections. This is consistent with the recommendations of the American College of Radiology [43]. 

There are certain characteristic chest CT findings that may be seen in COVID-19 infections but these findings cannot reliably distinguish COVID-19 from other causes of viral pneumonia. 

Although acute myocardial injury has been described as a complication of COVID-19, routine ECG is not necessary for patients with COVID infections, even if troponin levels are increased and there is hemodynamic compromise with other cardiovascular findings suggestive of cardiomyopathy [42]. 

Secondary bacterial infection is not common among patients with COVID infections. If secondary bacterial infection is suspected, based on chest imaging or sudden deterioration, then two sets of blood cultures are taken and sputum Gram stain and culture done. 

Management of COVID-19

A simple clinical classification of COVID-19 patients divides the patients into 5 grades:

• Grade 0: Where the patients are asymptomatic with no clinical signs       
• Grade I : Outpatients with mild clinical symptoms with lower or upper respiratory tract infections.
• Grade II: Patients requiring hospitalization, with lobar or multilobar pneumonia with/without the need for supplemental oxygen, or refractory to initial treatment.
• Grade III: Patients requiring ICU treatment, noninvasive or invasive mechanical ventilatory support, or with acute respiratory distress syndrome and/or non-pulmonary involvement.
• Grade IV: Critical patients who need immunomodulatory therapy or with multiorgan failure and/or cytokine storm.

A.General Management Issues

1.Empiric treatment for bacterial pneumonia

Bacterial superinfection is not a prominent feature of COVID-19, hence routine administer of empiric therapy for bacterial pneumonia is not necessary in patients admitted for COVID-19 infections. However, if there is clinical suspicion of bacterial infection empirical antibiotic therapy can be started after sputum samples have been taken for gram stain and culture [42].

2.Empiric treatment for influenza during influenza season

The clinical features of seasonal influenza and COVID-19 overlap and it is difficult to distinguish between the two. If microbiologic testing confirms the presence of influenza, antiviral therapy for seasonal influenza can be started [42].

3.Prevention of venous thromboembolism 

Thromboembolic complications among hospitalized patients with COVID-19 are high according to several studies, particularly in patients who are critically ill. Pharmacologic prophylaxis for venous thromboembolism is hence recommended for all hospitalized patients with COVID-19. 

4.Avoiding nebulized medications

Whenever possible, inhaled medications should be administered by metered-dose inhaler. Nebulizers should be avoided whenever possible to avoid the risk of aerosolization of SARS-CoV-2 through nebulization.

If a nebulizer has to be used then the necessary precautions should be taken to prevent the spread of the COVID infection. 

5.Uncertainty about use of NSAIDs

There have been anecdotal reports which raised concerns about possible negative effects of NSAIDs because there were reports where a few young patients who received NSAIDs early in the course of the infection, experienced severe disease [42]. However, there have been other observational studies that have found no association between NSAID use and worse outcomes when compared with acetaminophen use or no antipyretic use [42].

The US NIH, WHO, and the European Medicines Agency (EMA), COVID-19 treatment guidelines do not recommend that NSAIDs should be avoided when clinically indicated in patients with COVID-19 infections.

B.COVID-19-Specific Therapy

Dexamethasone and other glucocorticoids 

Dexamethasone at a dose of 6mg daily for 10 days or until discharge, whichever is shorter, is usually recommended for severely ill COVID-19 patients who are on supplemental oxygen or ventilatory support. Other glucocorticoids can be used if dexamethasone is not available.  Hydrocortisone 150 mg, methylprednisolone 32 mg, or prednisone 40 mg daily may be used but data supporting the use of these alternatives are limited. These drugs are not used for the prevention or treatment of mild to moderate COVID-19 (patients not on oxygen) [42]. 

Patients on glucocorticoids should be monitored for adverse effects such as hyperglycemia and infections (bacterial, fungal, and Strongyloides infections).

Randomized trials support the use of glucocorticoids for severe COVID-19. A meta-analysis of seven trials which included 1703 critically ill COVID-19 patients (on respirator), glucocorticoids reduced the 28-day mortality as compared with standard care or placebo (327% versus 41.4% percent) and were not associated with an increased risk of severe adverse events [44]. 

In another systematic review carried out by Siemieniuk et al [45], the authors found that glucocorticoids probably reduced mortality and mechanical ventilation in patients with covid-19 when compared with standard care. The effectiveness of most interventions was, however,  uncertain because most of the randomized controlled trials were small and had important study limitations.

Benefit is usually not seen with glucocorticoids among patients who do not require either oxygen or ventilatory support.

Data on the efficacy of glucocorticoids other than dexamethasone are limited to smaller trials, many of which were stopped early because of a lack of definite efficacy [46,47]. 

Methylprednisolone has also not demonstrated a clear benefit. A randomized trial from Brazil that included 393 patients with suspected or confirmed severe COVID-19 showed that there was no difference in 28-day mortality rates with methylprednisolone compared with placebo (37% versus 38%) [48]. 

Glucocorticoids may also have a role in the treatment of refractory shock in critically ill patients with COVID-19. 

Remdesivir 

Remdesivir is an adenosine analogue. It incorporates into nascent viral RNA chains and results in its premature termination. Remdesivir has shown in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [49].

Some doctors use remdesivir for patients who are hospitalized with severe COVID-19 because there is some data that suggests that it reduces time to recovery [42]. It is used in patients requiring low-flow supplemental oxygen and it may reduce mortality in this population [42]. 

The optimal role of remdesivir, however, remains uncertain. WHO does not recommend the use of remdesivir in hospitalized patients because there is no clear evidence that the use of remdesivir improves patient outcomes for hospitalized patients (such as, mortality and the need for mechanical ventilation) [50,51]. The Infectious Diseases Society of America and the National Institutes of Health, however, suggest using remdesivir in hospitalized patients who require supplemental oxygen [52,53]. 

The Food and Drug Administration (FDA) in the USA approved remdesivir for hospitalized children ≥12 years and adults with COVID-19, regardless of disease severity [42]. On the first day 200 mg of remdesivir is given intravenously followed by 100 mg daily for 5 days. If there is no improvement and in patients, on mechanical ventilators, the drug can be given for 10 days. Remdesivir is not recommended in patients with renal impairment because in patients with renal impairment accumulation of the drug can occur and lead to toxicity. Liver enzymes should be checked before and during remdesivir administration. Potential drug interactions can occur if remdesivir is used with hydroxychloroquine or chloroquine. 

The Janus kinase inhibitor baricitinib can be used in combination with remdesivir in patients with COVID-19 who require oxygen or ventilatory support [42]. 

Convalescent plasma 

Convalescent plasma obtained from individuals who have recovered from COVID-19 contain antibodies that can provide passive antibody-based immunity. The main active component in the plasma is the neutralizing antibodies though other immune mediators may also be present.  Convalescent plasma with high level of neutralizing antibody titers appears to have clinical benefits when given in the early course of the disease. It is especially useful in individuals with deficits in antibody production (eg, those receiving anti-CD20 therapies) [54]. 

The role of convalescent plasma in patients with severe disease, however, is not clear.

Hydroxychloroquine/chloroquine 

Chloroquine and hydroxychloroquine can inhibit SARS-CoV-2 in vitro [59]. There are, however, several controlled trials that show that chloroquine and hydroxychloroquine do not provide clinical benefit for patients with COVID-19 [60-65]. The US FDA in June 2020, revoked its emergency use authorization for these agents in patients with severe COVID-19. They noted that the known and potential benefits do not outweigh the known and potential risks [66].

High doses of these drugs can lead to high mortality rates. They can produce QTc prolongation and arrhythmias.

Other agents

The use of other agents such as favipiravir, interferons, azithromycin (with or without hydroxychloroquine), lopinavir-ritonavir, ivermectin, sofosbuvir plus daclatasvir, the selective serotonin receptor blocker fluvoxamine, famotidine, colchicine, vitamin D, zinc, IL-1 inhibitors, other cytokine inhibitors, kinase inhibitors, complement inhibitors, bradykinin pathway inhibitors, and recombinant hematopoietic colony-stimulating factors, are not recommended because their efficacy has not been proven [42].

Management of Hypoxia, ARDS and Other complications

Patients who have severe disease very often need oxygenation support. High-flow oxygen is delivered via nasal cannulas. Noninvasive positive-pressure ventilation is often used. Since these are aerosol-generating procedures specific isolation precautions have to be taken. 

Some experts encourage hospitalized patients with COVID-19 to spend as much time as is feasible and safe in the prone position while receiving oxygen. There is some evidence that proning results in improved oxygenation [42].

The World Health Organization recommends titrating oxygen to a target SpO2 of ≥94 percent during initial resuscitation and ≥90 percent for maintenance oxygenation.

When patients develop acute respiratory distress syndrome (ARDS) then intubation with mechanical ventilation is necessary. 

In some patients, a tracheostomy may be needed for failed extubation, secretion management, airway edema, and in patients with neurological impairment such as that which impairs airway protection.

Prognosis

The severity of COVID-19 disease varies in different patients. In patients with mild disease, there may be few or no symptoms. The symptoms may resemble a common cold. Mild cases usually recover within two weeks. In patients with severe or critical disease recovery may take three to six weeks. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks [67]. Patients with prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital tend to have a severe course of COVID-19 and have a higher chance of transfer to ICU [68,69].

About 10% to 20% of patients with COVID infections will experience symptoms lasting longer than a month [70,71].

Many patients who were admitted to the hospital with severe disease often report long-term problems such as fatigue and shortness of breath [72]. Besides fatigue and shortness of breath, they can have long term effects such as cough, inflammation, and injury of major organs (including the lungs and heart), as well as neurological and psychological effects. They can also have cyclical bouts of fatigue, headaches, months of complete exhaustion, and mood swings. 

Screening, Containment and Mitigation of COVID-19

There are several strategies that can be used to control an outbreak of infection in a pandemic. These include screening, containment (or suppression), and mitigation. 

Screening for COVID-19

Screening aims to identify individuals who may be infected but are showing no symptoms. Many individuals with COVID-19 virus appear healthy or may only show mild symptoms. It is very important to identify infected people so that they can be kept away from others and appropriate treatment can be instituted. The importance of correctly identifying individuals with or without COVID-19 cannot be overemphasized.  Incorrectly identifying no infection in infected individuals can spread the infection and incorrectly identifying COVID-19 in healthy people could lead to unnecessary self-isolation and further investigation.

Screening for COVID-19 includes temperature checks, asking about travel history and contact with COVID-19 cases, and doing rapid virus tests. Screening can be done in person at home, workplace, clinics, hospitals, schools, and at airports. Screening can also be done on a phone and online.

Viswanathan et al [73] carried a Chochrane review to find out the effectiveness of screening for COVID-19. These were their findings:

• Questioning individuals about symptoms at airports may slightly slow, but not stop, the importation of infected people.
• Weekly or biweekly screening of healthcare workers may reduce transmission of the infection to patients and other healthcare workers in the emergency departments.
• No studies reported on negative effects of screening.
• Screening incorrectly identified between 20 and 100 out of 100 infected people as healthy.
• Screening incorrectly identified between 0 and 38 people out of 100 healthy people as infected. 
• Asking about symptoms incorrectly identified between 40 to 100 out of 100 infected people as healthy.
• Asking about symptoms incorrectly identified between 0 to 34 out of 100 healthy people as infected. 
• Temperature taking and asking history of travel and exposure to infected/suspected infected person incorrectly identified between 77 and 100 out of 100 infected people as healthy.
• Temperature taking and asking history of travel and exposure to infected/suspected infected person incorrectly identified between 0 and 10 out of 100 healthy people as infected.
• Asking about symptoms plus temperature measurement incorrectly identified between 31 and 88 out of 100 infected people as healthy.
• Asking about symptoms plus temperature measurement incorrectly identified between 0 to 10 people out of 100 healthy people as infected. 
• One study showed that 70% of infected travellers were missed when entry and exit screening was done at airports.

The authors concluded that one-time screening in apparently healthy people is likely to miss people who are infected. They were also uncertain whether combined screenings, repeated symptom assessment, or rapid laboratory tests are useful.

These studies show poor sensitivity of existing screening approaches. Hence there is a need for greater emphasis on other ways to prevent transmission. These include, face covering, physical distancing, quarantine, as well as adequate personal protective equipment for frontline workers.

Containment of COVID-19

Some of the measures taken to contain the disease include [74]:

• Trace and isolate infected individuals
• School closures
• Workplace closures
• Cancellation of public events
• Restrictions on size of gathering
• Closures of public transport
• Stay-at-home requirements 
• Restrictions on internal movement
• Restrictions on international travel

All measures contribute significantly to reducing the number of COVID-19 cases. Restrictions on international and domestic travel and stay-at-home orders appear to have been most effective in containing the disease [74]. 

Mitigation Strategies for COVID-19

Mitigation activities are actions that people and communities take to slow the spread of a new virus in a pandemic and at the same time protecting all individuals, especially those at high risk for severe illness while minimizing the negative impacts of these strategies. Generally, mitigation strategies should be acceptable, feasible, and practical. They should be implemented in a manner that minimizes both morbidity and mortality from COVID-19 [75].

Some of the mitigation strategies to consider include [75]:

1.Promoting behaviors that prevent spread

• Staying home when sick and when having had contact with COVID infected person.
• Teaching and reinforcing hand hygiene practices and respiratory etiquette
• Teaching and reinforcing the use of cloth face coverings to protect others 
• Ensuring availability of sinks, soap, hand sanitizers, paper towels and/or hand dryer
• Post posters and signs that promote behaviors that prevent spread

2.Maintaining healthy environments

• Intensify disinfection and cleaning of surfaces that are frequently touched 
• Ensure ventilation systems are operating efficiently and increase  outdoor air circulation
• Ensure that water systems are safe to use
• Modify layouts to make sure that social distance of at least 6 feet between people is kept especially for persons who do not live together
• Install physical barriers to support social distancing 
• Close communal spaces if possible
• Reduce sharing of objects

3.Maintaining healthy operations

• Protecting people who are at higher risk for severe illness from COVID-19
• Helping individuals to cope with stress and encouraging them to take time to unwind and connect with others
• Maintaining awareness of all local or state regulations
• Staggering and rotating schedules
• Avoiding mixing between groups
• Pursuing virtual events. Maintaining social distancing at events, and limiting group size
• Limiting non-essential visitors, volunteers, and activities involving external groups or organizations
• Encouraging telework and virtual meetings 
• Considering options for non-essential travel in accordance with regulators
• Implementing flexible and non-punitive leave policies
• Training staff on safety protocols
• Conducting daily health checks such as temperature screening and symptom checking
• Encouraging individuals who share facilities to adhere to mitigation strategies
• Putting in place communication systems for individuals to self-report COVID-19 symptoms, a positive test for COVID-19, or exposure to someone with COVID-19
• Putting in place communication systems to notifying local health authorities of COVID-19 cases
• Putting in place communication systems for notifying individuals of any COVID-19 exposures while maintaining the confidentiality 
• Notifying individuals of the closure of any facility 

4.Preparing for when someone gets sick

• Preparing to isolate and safely transport individuals who are sick, to their home or to a healthcare facility
• Encouraging individuals who are sick to follow CDC guidelines for caring for themselves and others who are sick
• Notifying health officials of any case of COVID-19 while maintaining the confidentiality 
• Notifying those who have had close contact with an individual diagnosed with COVID-19 and advising them to stay home and self-monitor for symptoms
• Advising individuals who are sick when it would be safe for them to discontinue home isolation
• Closing off areas used by someone who is sick. Waiting more than 24 hours before cleaning and disinfecting.

Individual and organizational responsibility for implementing and enforcing the mitigation strategies is of paramount importance.

Contact tracing 

Contact tracing is used by health authorities to determine the source of infection and to prevent further transmission.

To carry out contact tracing, clinics, laboratories, and hospitals send the names of people who have been diagnosed with COVID-19 to their local health authorities [76].

The health authorities will then ask each person with COVID-19 about people with whom they have recently had close contact. The authorities will then quickly (usually within 24 hours) alert individuals who are close contacts that they have been exposed to the COVID-19 virus. The authorities don't share the name of the person who has exposed them so that the contact tracing process can remain anonymous and confidential.

Contact tracing apps are often widely used. These apps make it faster and easier to find and notify people who've been exposed to the COVID-19 virus [76].

A close contact is an individual who's been within 6 feet (2 meters) of a person with COVID-19 within two days of the person's diagnosis. Close contacts include family, friends, co-workers and health care providers.

The close contacts are asked whether they have any symptoms and they are advised to be tested for the virus. They are given several instructions on how to reduce the risk of unknowingly spreading the COVID-19 virus to others.

For close contacts who do not have symptoms and cannot be tested, or test negative for the COVID-19 virus, doctors and the health authorities will [76]:

• Advise them to self-quarantine at home for 14 days after they were exposed. They can end the quarantine after 10 days if they don't have symptoms and cannot get tested. The quarantine can end after 7 days if they tested negative for the virus. They are, however, advised to look out for symptoms for 2 weeks.
• Advise them to keep social distance from others including family members and pets. They also have to use separate bedrooms and bathrooms. 
• Advise them to monitor their health and watch out for COVID-19 symptoms.
• Advise them to check their temperature twice a day.
• Advise them to let their doctor and health department know if they develop any symptoms.
• Advise them to send daily health updates to the doctors and the health department 

For close contacts who test positive for the virus, develop symptoms, or have symptoms but cannot be tested, the doctors and the health authorities  will [76]:

• Advise them to self-isolate and recover at home for at least 10 days if they have symptoms. They have to self-quarantine for 14 days after being exposed. People with symptoms have to isolate themselves from family and pets and also use separate bedrooms and bathrooms.
• Advise them to seek medical care if they have any emergency warning signs, such as breathing difficulty or persistent chest pain.
• Advise them to monitor their symptoms and avoid spreading the COVID-19 virus to others.

Contact tracing is a powerful tool that helps to reduce the spread of the COVID-19 virus and help control the COVID-19 outbreak.

Shortages related to the COVID-19 pandemic

The fundamental outbreak response measure for the COVID-19 pandemic is the need to increase capacity and to adapt to the healthcare needs. The European Centre for Disease Prevention and Control (ECDC) and the European regional office of the WHO have issued guidelines for hospitals and primary healthcare services for shifting of resources at multiple levels. This includes focusing laboratory services towards COVID-19 testing, canceling elective procedures whenever possible, isolating and separating COVID-19 positive patients, and increasing capabilities of the intensive care unit by training personnel and increasing the number of available ventilators and beds [77,78]. In an attempt to maintain physical distancing to protect both the patients and clinicians, in some non-emergency areas the healthcare services are provided virtually [79-81].

Capacity limitations in the standard supply chains has led some manufacturers to carry out 3D printing of healthcare material such as nasal swabs and ventilator parts [82,83]. NASA developed a ventilator for COVID-19 patients in just 37 days. It was approved by FDA in April 2020 [84]. 

Conclusion

As of 31 December 2020, 83,134,416 cases of Covid-19 have been detected and the death toll stands at 1,813,386. These numbers do not accurately reflect the actual number of cases and deaths because many go undetected especially in underdeveloped and poorer countries with large populations. Covid-19 is here to stay for some time. Presently there is no cure for the disease and there appears to be no vaccine that can prevent the infection. The economic toll brought about by this pandemic is high.

References

1. Resta S. Isolation and propagation of a human enteric coronavirus. Science. 2018;4717:978–981. 
2. Arabi Y.M. Middle East Respiratory Syndrome. N. Engl. J. Med. 2017;376:584–594. 
3. Zhong N.S. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003. Lancet. 2003;362:1353–1358. 
4. Drosten C. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med. 2003;348:1967–1976. 
5. Guan Y. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science. 2003;302:276–278. 
6. Song H.D. Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. Proc. Natl. Acad. Sci. U. S. A. 2005;102:2430–2435.
7. COVID-19 CORONAVIRUS PANDEMIC at https://www.worldometers.info/coronavirus/?utm_campaign=homeAdvegas1?
8. Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J (March 2020). "Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2)". Science. 368 (6490): 489–493.
9. "Report 13 – Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in 11 European countries". Imperial College London. 
10.  Lau H, Khosrawipour V, Kocbach P, Mikolajczyk A, Ichii H, Schubert J, et al. (March 2020). "Internationally lost COVID-19 cases". Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi. 53 (3): 454–458.
11. Fuller, Thomas; Baker, Mike (7 May 2020). "Coronavirus Death in California Came Weeks Before First Known U.S. Death". The New York Times.
12. Rothan HA, Byrareddy SN (May 2020). "The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak". Journal of Autoimmunity. 109: 102433.
13. "COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)". ArcGIS. Johns Hopkins University.
14. CDC (11 February 2020). "Coronavirus Disease 2019 (COVID-19)". Centers for Disease Control and Prevention.
15. Verity et al "Estimates of the severity of coronavirus disease 2019: a model-based analysis". The Lancet Infectious Diseases. 2020 June; 20 (6): 669–677.
16. Fox, Justin (24 April 2020). "The Coronavirus Isn't Just the Flu". Bloomberg.
17. "COVID-19 Pandemic Planning Scenarios" (PDF). CDC. 10 July 2020. 
18. Meyerowitz-Katz, Gideon; Merone, Lea (7 July 2020). "A systematic review and meta-analysis of published research data on COVID-19 infection-fatality rates". MedRxiv. 101: 138–148.
19. "COVID-19 Pandemic Planning Scenarios | CDC". 12 September 2020. Archived from the original on 12 September 2020.
20. Keaten, Jamey (5 October 2020). "WHO: 10% of world's people may have been infected with virus". AP NEWS.
21. Hauser, Anthony; Counotte, Michel J.; Margossian, Charles C.; Konstantinoudis, Garyfallos; Low, Nicola; Althaus, Christian L.; Riou, Julien (28 July 2020). "Estimation of SARS-CoV-2 mortality during the early stages of an epidemic: A modeling study in Hubei, China, and six regions in Europe". PLOS Medicine. 17 (7): e1003189.
22. "Symptoms of Coronavirus". U.S. Centers for Disease Control and Prevention (CDC). 13 May 2020.
23. Nogrady, Bianca (18 November 2020). "What the data say about asymptomatic COVID infections". Nature. 587 (7835): 534–535. 
24. O. Byambasuren, et al. Estimating the extent of asymptomatic COVID-19 and its potential for community transmission: Systematic review and meta-analysis Official Journal of the Association of Medical Microbiology and Infectious Disease Canada (2020), 10.3138/jammi-2020-0030.
25. Furukawa, Nathan W.; Brooks, John T.; Sobel, Jeremy (4 May 2020). "Evidence Supporting Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 While Presymptomatic or Asymptomatic". Emerging Infectious Diseases. 26 (7). doi:10.3201/eid2607.201595.
26. "Q&A: How is COVID-19 transmitted? (How is the virus that causes COVID-19 most commonly transmitted between people?)". www.who.int. 9 July 2020. 
27.  "Transmission of COVID-19". www.ecdc.europa.eu. 7 September 2020.
28. "Q & A on COVID-19: Basic facts". www.ecdc.europa.eu. 25 September 2020.
29. "How COVID-19 Spreads". www.cdc.gov. 5 October 2020.
30. Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, et al. (March 2020). "The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2". Nature Microbiology. 5 (4): 536–544. doi:10.1038/s41564-020-0695-z. PMC 7095448. PMID 32123347.
31. "2019 Novel Coronavirus (2019-nCoV) Situation Summary". U.S. Centers for Disease Control and Prevention (CDC). 30 January 2020.
32. "Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans". World Health Organization (WHO).
33. "Curetis Group Company Ares Genetics and BGI Group Collaborate to Offer Next-Generation Sequencing and PCR-based Coronavirus (2019-nCoV) Testing in Europe". GlobeNewswire NewsRoom.
34. Brueck H (30 January 2020). "There's only one way to know if you have the coronavirus, and it involves machines full of spit and mucus". Business Insider.
35. Centers for Disease Control and Prevention (5 April 2020). "What to Do if You Are Sick". U.S. Centers for Disease Control and Prevention (CDC).
36. "Coronavirus Disease 2019 (COVID-19) – Prevention & Treatment". U.S. Centers for Disease Control and Prevention (CDC). 10 March 2020.
37. "UK medicines regulator gives approval for first UK COVID-19 vaccine". Medicines and Healthcare Products Regulatory Agency, Government of the UK. 2 December 2020.
38. Mullard, Asher (30 November 2020). "How COVID vaccines are being divvied up around the world Canada leads the pack in terms of doses secured per capita". Nature. doi:10.1038/d41586-020-03370-6. PMID 33257891. S2CID 227246811.
39. So AD, Woo J (December 2020). "Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis". BMJ: m4750. doi:10.1136/bmj.m4750. 
40. Azar A (4 February 2020). "Notice of Declaration under the Public Readiness and Emergency Preparedness Act for medical countermeasures against COVID-19".
41. UK government grants Pfizer civil legal indemnity for COVID-19 vaccine at https://www.jurist.org/news/2020/12/uk-government-grants-pfizer-civil-legal-indemnity-for-covid-19-vaccine/. 
42. Kim AY and Gandhi RT. Coronavirus disease 2019 (COVID-19): Management in hospitalized adults at https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults. 
43. ACR Recommendations for the use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection.
44. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA 2020; 324:1330.
45. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ 2020; 370:m2980.
46. Angus DC, Derde L, Al-Beidh F, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA 2020; 324:1317.
47. Dequin PF, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA 2020; 324:1298.
48. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial. Clin Infect Dis 2020.
49. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30:269.
50. Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19. BMJ 2020; 370:m3379.
51. World Health Organization. Therapeutics and COVID-19: living guideline. https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline.
52. National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. https://covid19treatmentguidelines.nih.gov/.
53. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/.
54. Clark E, Guilpain P, Filip IL, et al. Convalescent plasma for persisting COVID-19 following therapeutic lymphocyte depletion: a report of rapid recovery. Br J Haematol 2020; 190:e154.
55. Piechotta V, Chai KL, Valk SJ, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev 2020; 7:CD013600.
56. Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA 2020; 324:460.
57. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020; 371:m3939.
58. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med 2020.
59. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020; 71:732.
60. RECOVERY Collaborative Group, Horby P, Mafham M, et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020; 383:2030.
61. NIH halts clinical trial of hydroxychloroquine https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine (Accessed on July 08, 2020).
62. WHO. “Solidarity” clinical trial for COVID-19 treatments: Update on hydroxychloroquine. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/ global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. 
63. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020; 369:m1849.
64. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med 2020; 383:2041.
65. Self WH, Semler MW, Leither LM, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA 2020; 324:2165.
66. US FDA. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. June 15, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine. 
67. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) (PDF) (Report). World Health Organization (WHO). 24 February 2020. 
68. Baranovskii, D. S.; Klabukov, I. D.; Krasilnikova, O. A.; Nikogosov, D. A.; Polekhina, N. V.; Baranovskaia, D. R.; Laberko, L. A. (19 November 2020). "Prolonged prothrombin time as an early prognostic indicator of severe acute respiratory distress syndrome in patients with COVID-19 related pneumonia". Current Medical Research and Opinion: 1–8. doi:10.1080/03007995.2020.1853510. ISSN 1473-4877. PMID 33210948. S2CID 227065216.
69.  Christensen, Bianca; Favaloro, Emmanuel J.; Lippi, Giuseppe; Van Cott, Elizabeth M. (October 2020). "Hematology Laboratory Abnormalities in Patients with Coronavirus Disease 2019 (COVID-19)". Seminars in Thrombosis and Hemostasis. 46 (7): 845–849.
70. "Living with Covid19". National Institute for Health Research. 15 October 2020. doi:10.3310/themedreview_41169.
71.  "How long does COVID-19 last?". UK COVID Symptom Study. 6 June 2020.
72. "Summary of COVID-19 Long Term Health Effects: Emerging evidence and Ongoing Investigation". University of Washington. 1 September 2020.
73. Viswanathan M, Kahwati L, Jahn B, Giger K, Dobrescu AI, Hill C, Klerings I, Meixner J, Persad E, Teufer B, Gartlehner G. Universal screening for SARS-CoV-2 infection: a rapid review. Cochrane Database of Systematic Reviews 2020, Issue 9. Art. No.: CD013718. DOI: 10.1002/14651858.CD013718.
74. Pragyan Deb ; Davide Furceri ; Jonathan David Ostry ; Nour Tawk. The Effect of Containment Measures on the COVID-19 Pandemic. IMF Working Paper. 7th August 2020.
75. Implementation of Mitigation Strategies for Communities with Local COVID-19 Transmission. Centers for Disease Control and Prevention (CDC USA) at https://www.cdc.gov/coronavirus/2019-ncov/community/community-mitigation.html  
76. William F. Marshall. Contact tracing and COVID-19: What is it and how does it work? At https://www.mayoclinic.org/diseases-conditions/coronavirus/expert-answers/covid-19-contact-tracing/faq-20488330. 
77. "Hospital readiness checklist for COVID-19". euro.who.int. 25 March 2020. 
78.  Checklist for hospitals preparing for the reception and care of coronavirus 2019 (COVID-19) patients (Report). European Centre for Disease Prevention and Control. 26 February 2020.
79. Smith, Anthony C; Thomas, Emma; Snoswell, Centaine L; Haydon, Helen; Mehrotra, Ateev; Clemensen, Jane; Caffery, Liam J (20 March 2020). "Telehealth for global emergencies: Implications for coronavirus disease 2019 (COVID-19)". Journal of Telemedicine and Telecare. 26 (5): 309–313. doi:10.1177/1357633x20916567. PMC 7140977. PMID 32196391.
80.  Ohannessian, R; Duong, TA; Odone, A (2 April 2020). "Global Telemedicine Implementation and Integration Within Health Systems to Fight the COVID-19 Pandemic: A Call to Action". JMIR Public Health and Surveillance. 6 (2): e18810. doi:10.2196/18810. PMC 7124951. PMID 32238336.
81.  Keshvardoost, Sareh; Bahaadinbeigy, Kambiz; Fatehi, Farhad (23 April 2020). "Role of Telehealth in the Management of COVID-19: Lessons Learned from Previous SARS, MERS, and Ebola Outbreaks". Telemedicine and E-Health. 26 (7): 850–852.
82. Temple J. "How 3D printing could save lives in the coronavirus outbreak". MIT Technology Review. 
83.  Tibken S. "3D printing may help supply more essential coronavirus medical gear". CNET.
84. NASA-Developed Ventilator Authorized by FDA for Emergency Use. May 1 2020 at https://www.nasa.gov/press-release/nasa-developed-ventilator-authorized-by-fda-for-emergency-use.