Reviewed by Dr. Ricardo Kotliroff
Coronavirus 2019 (COVID-19)
Recent events have shown us (again) how rapidly a new disease can take root and spread. Such events are accompanied by an explosion of clinical and epidemiological information and research. The goal of Premilife is to open whatever resources we can to help our communities, researchers and clinicians contain and manage this disease. Our resources span scientific and medical journals and textbooks, educational products, and a variety of other resources, like travel precautions from and media posts of interest to ours communities.
Premilife is a professional homeopathic remedies company dedicated to offering a wide range of complex homeopathic remedies for different diseases. Two-thirds of all diseases in the world are either still not treated adequately or not treated at all.
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Treatments success and scientific breakthroughs are more likely to occur when scientist are free to tackle problems from different angles and ways.
Most people who catch the new coronavirus SARS-CoV-2 recover at home, and some need hospitalization to fight the virus. But in a number of patients, the disease called COVID-19 is deadly. Some people are at higher risk of getting very sick from this illness. It includes older adults, people who have serious chronic medical conditions, people with compromised immune systems, people having chemotherapy or who have received chemotherapy in the last three months and people having immunotherapy, among others.
A coronavirus pandemic can overwhelm the capacity of outpatient facilities, emergency departments (EDs), hospitals, and intensive care units, leading to critical shortages of staff, space, and supplies with serious implications for patient outcomes. As a result of this new reality, we decided to support the patients interested in Premilife.com treatments and offer a 30% discount on all the homeopathic remedies on our website. We care about your health and your community, that is the reason we are providing this huge discount. In the future, we are going to send you emails with new research information about the coronavirus, so pay attention to your inbox.
Bacterial vs. viral infections: How do they differ?
Bacterial and viral infections have many things in common. Both types of infections are caused by microbes – bacteria and viruses, respectively – and spread by things such as:
- Coughing and sneezing.
- Contact with infected people, especially through kissing and sex.
- Contact with contaminated surfaces, food, and water.
- Contact with infected creatures, including pets, livestock, and insects such as fleas and ticks.
Bacteria and viruses are too tiny to be seen by the naked eye, can cause similar symptoms and are often spread in the same way, but that’s where the similarities end.
Bacteria are relatively complex, single-celled creatures, many with a rigid wall, and a thin, rubbery membrane surrounding the fluid inside the cell. They can reproduce on their own. Fossilized records show that bacteria have existed for about 3.5 billion years, and bacteria can survive in different environments, including extreme heat and cold, radioactive waste, and the human body.
Most bacteria are harmless, and some actually help by digesting food, destroying disease-causing microbes, fighting cancer cells, and providing essential nutrients. Fewer than 1% of bacteria cause diseases in people and are referred to as pathogenic bacteria.
Viruses are tinier: the largest of them are smaller than the smallest bacteria. All they have is a protein coat and a core of genetic material, either RNA or DNA.
Unlike bacteria, viruses are parasitic and require living hosts – such as people, plants or animals – to multiply. They can only reproduce by attaching themselves to cells. In most cases, they reprogram the cells to make new viruses until the cells burst and die. In other cases, they turn normal cells into malignant or cancerous cells.
Viruses may reproduce with fidelity or with errors (mutations); this ability to mutate is responsible for the ability of some viruses to change slightly in each infected person, making treatment difficult.
Also unlike bacteria, most viruses do cause disease, and they’re quite specific about the cells they attack. For example, certain viruses attack cells in the liver, respiratory system, or blood. In some cases, viruses target bacteria.
Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral infection. Some viruses, including those that cause AIDS, HPV infection, and viral hepatitis, evade these immune responses and result in chronic infections.
Perhaps the most important distinction between bacteria and viruses is that antibiotic drugs usually kill bacteria, but they aren’t effective against viruses. Viral infections require either vaccinations to prevent them in the first place or antiviral drugs inhibit their development.
Human coronaviruses were first discovered in the late 1960s.
Only 7 coronaviruses are known to cause disease in humans.
Four of the 7 coronaviruses most frequently cause symptoms of the common cold. Coronaviruses 229E and OC43 cause the common cold; the serotypes NL63 and HUK1 have also been associated with the common cold. Rarely, severe lower respiratory tract infections, including pneumonia, can occur, primarily in infants, older people, and the immunocompromised.
Three of the 7 coronaviruses cause much more severe, and sometimes fatal, respiratory infections in humans than other coronaviruses and have caused major outbreaks of deadly pneumonia in the 21st century:
- SARS-CoV was identified in 2002 as the cause of an outbreak of severe acute respiratory syndrome (SARS), provoked a large-scale epidemic beginning in China and involving two dozen countries with approximately 8422 cases and 842 deaths (fatality rate 10%). No cases had been reported worldwide since 2004.
- MERS-CoV was identified in 2012 as the cause of Middle East respiratory syndrome (MERS) began in Jordan and Saudi Arabia and has approximately 2,500 cases and 800 deaths and still causes as sporadic cases (fatality rate 35%). Cases have also occurred in countries outside the Middle East, including France, Germany, Italy, United Kingdom, and South Korea in people who had been traveling or working in the Middle East.
- SARS-CoV2 is a novel coronavirus identified as the cause of coronavirus disease 2019 (COVID-19) that began in Wuhan, China in late 2019 and spread worldwide. (fatality rate 3.4%).
Coronavirus disease 19 (COVID-19)
We must realize that in our crowded world of 7.8 billion people, a combination of altered human behaviors, environmental changes, and inadequate global public health mechanisms now easily turn obscure animal viruses into existential human threats. We have created a global, human-dominated ecosystem that serves as a playground for the emergence and host-switching of animal viruses, especially genetically error-prone RNA viruses, whose high mutation rates have, for millions of years, provided opportunities to switch to new hosts in new ecosystems. It took the genome of the human species 8 million years to evolve by 1%. Many animal RNA viruses can evolve by more than 1% in a matter of days. It is not difficult to understand why we increasingly see the emergence of zoonotic viruses, meaning that they can be transmitted to people from animals.
The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic:
- First, SARS-CoV spread from bats to palm civets (cat-like mammals) before infecting and spreading between humans.
- Second, MERS-CoV: Dromedary camels are a major animal source of MERS-CoV infection in people.
- Third, SARS-CoV-2: a new virus that is closely related to bat coronaviruses, pangolin coronaviruses, and SARS-CoV.
The earliest reported symptoms occurred on 1 December 2019, in a person who had not had any exposure to the Huanan Seafood Wholesale Market or to the remaining 40 of the first cluster detected with the new virus. Of this first cluster, two-thirds were found to have a link with the market, which also sold live animals.
The median age ranged from:
- In several cohorts of hospitalized patients with confirmed COVID-19, the median age ranged from 49 to 56 years.
- A detailed clinical and epidemiologic description of the first 425 cases reported in the epicenter of the outbreak: the city of Wuhan in Hubei province, China. The median age of the patients was 59 years, with higher morbidity and mortality among the elderly and among those with coexisting conditions (similar to the situation with influenza); 56% of the patients were male. Of note, there were no cases in children younger than 15 years of age. Either children are less likely to become infected, which would have important epidemiologic implications, or their symptoms were so mild that their infection escaped detection, which has implications for the size of the denominator of total community infections.
- In a report from the Chinese Center for Disease Control and Prevention that included approximately 44,500 confirmed infections, 87 percent of patients were between 30 and 79 years old.
- Nearly 30% of US coronavirus cases have been among people 20-44 years old, CDC report , showing that young people are getting sick, too
A) Nearly 30% of confirmed US coronavirus cases have been among people between 20–44, according to the CDC.
B) Additionally, that age group accounted for 20% of hospitalizations and 12% of ICU admissions among US cases, the CDC found.
C) While older age groups are still at more risk from COVID-19, the numbers show that lots of younger people are getting sick as well.
D) The CDC cautioned that it still doesn’t know the ages of many patients, but its findings are similar to what other countries have reported.
During the early stages, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration, as Wuhan is a transport hub in China and the infected individuals quickly spread throughout the country. On 20 January, China reported nearly 140 new patients in a day, including two people in Beijing and one in Shenzhen. Later official data shows that 6,174 COVID-19 virus-infected patients had already developed symptoms by 20 January 2020.
On 26 February 2020, WHO reported that, as new cases reported dropped in China but suddenly increased in Italy, Iran, and South Korea, the number of new cases outside China had exceeded the number of new cases in China for the first time on 25 February 2020.
Increasing numbers of cases have also been reported in other countries across all continents except Antarctica.
As of 21 March 2020, more than 287,326 cases have been confirmed, of which 8,117 were classified as serious or critical. Over 186 countries and territories have been affected, with major outbreaks in central China (81,008 total cases), South Korea (8,799 total cases), Italy (47,021 total cases), Spain (24,926 total cases), USA (19,919 total cases), Germany (21,625 total cases), and Iran (20,610 total cases).
1) Active cases 181,885 (Currently Infected Patients): 173,768 (96%) in Mild Condition and 8,117 (4%) in Serious or Critical Condition.
2) Closed cases 105,512 Cases which had an outcome: 93,617 (89%) Recovered / Discharged and 11,895 (11%) Deaths.
European Centre for Disease Prevention and Control -Situation update worldwide
Although the outbreak is likely to have started from a zoonotic transmission event associated with a large seafood market that also traded in live wild animals, it soon became clear that efficient person-to-person transmission was also occurring.
The primary mode of transmission is via respiratory droplets.
Person-to-person spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to occur mainly via respiratory droplets, resembling the spread of influenza. With droplet transmission, virus released in the respiratory secretions when a person with infection coughs, sneezes, or talks can infect another person if it makes direct contact with the mucous membranes. These droplets can land in the mouths or noses of people who are nearby or possibly be inhaled into the lungs. These only stay suspended in the air for a short time. Droplets typically do not travel more than six feet (about two meters) and do not linger in the air.
The virus is stable for several hours to days in aerosols and on surfaces, it was detectable in aerosols (a suspension of tiny particles or droplets in the air) for up to three hours, up to four hours on copper, up to 24 hours on cardboard and up to two to three days on plastic and stainless steel. Disinfection of surfaces is possible with substances such as 62–71% ethanol applied for one minute.
Some spread might be possible before people show symptoms; there have been reports of this occurring with this new coronavirus, but this is not thought to be the main way the virus spreads.
People are thought to be most contagious when they are most symptomatic (the sickest). Viral RNA levels appear to be higher soon after symptom onset compared with later in the illness.
According to a joint WHO-China report, the rate of secondary COVID-19 ranged from 1 to 5 percent among tens of thousands of close contacts of confirmed patients in China. In the United States, the symptomatic secondary attack rate was 0.45 percent among 445 close contacts of 10 confirmed patients.
How easily a virus spreads from person-to-person can vary. Some viruses are highly contagious (spread easily), like measles, while other viruses do not spread as easily. Another factor is whether the spread is sustained, spreading continually without stopping.
The virus that causes COVID-19 seems to be spreading easily and sustainably in the community (“community spread”) in some affected geographic areas.
SARS-CoV-2 RNA has been detected in blood and stool specimens. Live virus has been cultured from stool in some cases, but according to a joint WHO-China report, fecal-oral transmission did not appear to be a significant factor in the spread of infection
There have been estimates for the basic reproduction number (the average number of people an infected person is likely to infect), ranging from 2.13 to 4.82. As of 24 January 2020 the virus was reported to have been able to transmit down a chain of up to four people. This is similar to severe acute respiratory syndrome-related coronavirus (SARS-CoV).
Super-spreaders played an extraordinary role in driving the 2003 SARS outbreak and may also play a significant role in the current COVID-19 outbreak. A super-spreader is an individual who transmits an infection to a significantly greater number of other people than the average infected person.
The WHO furthermore writes that though history with SARS and MERS show that transmission through food does not happen, the possibility remains open and that meat and animal products should be cooked thoroughly as a rule of thumb (milk in developed countries is usually pasteurised).
Early information out of China, where COVID-19 first started, shows that some people are at higher risk of getting very sick from this illness. This includes:
A) Older adults: Most developed world countries have accepted the chronological age of 65 years as a definition of ‘elderly’ or older person, but like many westernized concepts, this does not adapt well to the situation in Africa. While this definition is somewhat arbitrary, it is many times associated with the age at which one can begin to receive pension benefits. At the moment, there is no United Nations standard numerical criterion, but the UN agreed cutoff is 60+ years to refer to the older population.
Older age was associated with increased mortality, with a case fatality rate of 8 and 15 percent among those aged 70 to 79 years and 80 years or older, respectively.
B) People who have serious chronic medical conditions like:
- Heart disease: A type of disease that affects the heart or blood vessels. The risk of certain heart diseases may be increased by smoking, high blood pressure, high cholesterol, unhealthy diet, lack of exercise, and obesity. The most common heart disease is coronary artery disease (narrow or blocked coronary arteries), which can lead to chest pain, heart attacks, or stroke. Other heart diseases include congestive heart failure, heart rhythm problems, congenital heart disease (heart disease at birth), and endocarditis (inflamed inner layer of the heart). Fatality rate 10.5 percent.
- Diabetes: A chronic disease associated with abnormally high levels of the sugar glucose in the blood. Diabetes is due to one of two mechanisms: Inadequate production of insulin (which is made by the pancreas and lowers blood glucose), or Inadequate sensitivity of cells to the action of insulin. Fatality rate 7.3 percent
- Lung disease: Lung disease is any problem in the lungs that prevents the lungs from working properly. There are three main types of lung disease:
1) Airway diseases – These diseases affect the tubes (airways) that carry oxygen and other gases into and out of the lungs. They usually cause a narrowing or blockage of the airways. Airway diseases include asthma, COPD and bronchiectasis. People with airway diseases often say they feel as if they’re “trying to breathe out through a straw.”
2) Lung tissue diseases – These diseases affect the structure of the lung tissue. Scarring or inflammation of the tissue makes the lungs unable to expand fully (restrictive lung disease). This makes it hard for the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often say they feel as if they are “wearing a too-tight sweater or vest.” As a result, they can’t breathe deeply. Pulmonary fibrosis and sarcoidosis are examples of lung tissue disease.
3) Lung circulation diseases – These diseases affect the blood vessels in the lungs. They are caused by clotting, scarring, or inflammation of the blood vessels. They affect the ability of the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. An example of a lung circulation disease is pulmonary hypertension. People with these conditions often feel very short of breath when they exert themselves.
Many lung diseases involve a combination of these three types. Fatality rate 6 percent.
Lung disease and cardiac complications: Cardiac complications, including new or worsening heart failure, new or worsening arrhythmia, or myocardial infarction are common in patients with pneumonia. Cardiac arrest occurs in about 3% of inpatients with pneumonia. Risk factors of cardiac events after pneumonia include older age, pre-existing cardiovascular diseases, and greater severity of pneumonia at presentation. Coronary heart disease has also been found to be associated with acute cardiac events and poor outcomes in influenza and other respiratory viral infections.
Risk Factors - Compromised immune system
People with compromised immune system are at a higher risk from the coronavirus. There are many things that can cause a weak immune system (immunosuppressed). These include: cancer treatment, treatment for autoimmune diseases, such as rheumatoid arthritis, lupus, multiple sclerosis (MS) and inflammatory bowel diseases, HIV, having an organ transplant or a bone-marrow transplant.
The total number of NK and CD8+ T cells was decreased markedly in patients with SARS-CoV-2 infection. The function of NK and CD8+ T cells was exhausted with the increased expression of NKG2A in COVID-19 patients. Importantly, in patients convalescing after therapy, the number of NK and CD8+ T cells was restored with reduced expression of NKG2A. These results suggest that the functional exhaustion of cytotoxic lymphocytes is associated with SRAS-CoV-2 infection. Hence, SARS-CoV-2 infection may break down antiviral immunity at an early stage.
Very high levels of cytokines and chemokines in the blood and lungs of SARS patients were reported on autopsy. Protein or RNA expression of IL-6, CCL2/MCP-1, and CXCL10/IP-10 was detected by IHC and RT-PCR in the lungs of patients with fatal SARS cases. Elevation of IL-6 and IL-8 during the acute phase of disease and persistent expression of CCL2/MCP-1, CXCL9/MIG, and CXCL10/IP-10 in both acute and fatal cases were consistently detected in the blood of SARS patients. Moreover, increased serum levels of CXCL10/IP-10, IL-2, and IL-6 correlated significantly with SARS pneumonitis in patients.
Chemokine receptors play a crucial role in directing inflammatory cells to the sites of infection. Previous studies have documented the importance of chemokine receptors in protection from SARS-associated disease. CCR1-, CCR2-, and CCR5-deficient mice developed severe disease and mortality without inflammatory cell recruitment to the lungs. In contrast, upregulation of chemokines MCP-1/CCL2 (CCR1), MIP-1α/CCL3 (CCR2), and RANTES/CCL5 (CCR5) in the lungs of wild-type mice coincided with pulmonary recruitment of inflammatory cells and protected the mice from mortality. The protective role of CXCR3 (CXCL9/MIG and CXCL10/IP-10) in cell-mediated viral clearance of West Nile virus (WNV) infection has been documented, where CXCR3-deficient mice exhibited significantly enhanced mortality.
In an experiments with SARS-CoV infection in senescent mice, the biphasic increased expression of chemokines (MCP-1/CCL2, MIP-1α/CCL3, RANTES/CCL5, MIG/CXCL9, and IP-10/CXCL10) and their receptors (CCR2, CCR5, and CXCR3) is coincident with the appearance of inflammatory cells in the lungs.
CD8+ T cells are not required but CD4+ T cells are important for the control of viral replication in primary SARS-CoV infection in senescent mice.
CD8+ CTLs alone are not sufficient to clear SARS-CoV in the absence of both CD4+ T cells and Abs. Depletion of CD8+ T cells alone does not affect clearance of the virus.
Taken together, these data suggest an important role for immune-mediated inflammation and chemokine recruitment of inflammatory cells in severe SARS-CoV disease.
People with cancer might be more likely to get infections because of:
Cancer patients are among those at high risk of serious illness from an infection because their immune systems are often weakened by cancer and its treatments. Most people who were treated for cancer in the past (especially if it was years ago) are likely to have normal immune function, but each person is different. It’s important that all cancer patients and survivors, whether currently in treatment or not, talk with a doctor who understands their situation and medical history.
This is because some treatments, like chemotherapy, can stop the bone marrow from making enough white blood cells. White blood cells are part of your immune system. This is most likely to happen during a course of cancer treatment, but the effects can last for some time afterwards.
Some types of cancer can also lower your ability to fight infection. This is usually cancer that affects your immune system like leukaemia or lymphoma.
The effects of coronavirus infection could be more severe for certain people with prostate cancer. These include:
- men having chemotherapy, or who’ve had chemotherapy in the last three months
- men having clinical trial drugs that affect the immune system, such as olaparib (Lynparza®) or pembrolizumab (Keytruda®).
When your ability to fight infection is lowered the symptoms of any infection can be much more severe and may become dangerous.
Infectious diseases are the second-leading cause of mortality in patients with cancer, whose immune systems are often compromised. While less than 1 percent of people who were otherwise healthy died from COVID-19, the fatality rate for people with cardiovascular disease was 10.5 percent. That figure was 7.3 percent for diabetes patients and around 6 percent for those with chronic respiratory disease, hypertension, or cancer.
At the present time, we have no specific information about the risk of COVID-19 in people with HIV.
The risk from immune suppression is not known, but with other viral respiratory infections, the risk for people with HIV getting very sick is greatest in:
People with a low CD4 cell count, and
People not on HIV treatment (antiretroviral therapy or ART).
People with HIV can also be at increased risk of getting very sick with COVID-19 based on their age and other medical conditions.
Some types of HIV medicine (in particular, lopinavir/ritonavir) are being evaluated in clinical trialsexternal icon to treat COVID-19. While there is some evidence that this type of HIV medicine might help treat infections with SARS and MERS (two other coronaviruses related to the virus that causes COVID-19), there are no data available yet from clinical trials that these drugs help people with COVID-19.
People with HIV should not switch their HIV medicine in an attempt to prevent or treat COVID-19.
If a COVID-19 outbreak happens in your community, it could last for a long time (an outbreak is when a large number of people suddenly get sick.) Depending on how severe the outbreak is, public health officials may recommend community actions to reduce people’s risk of being exposed to COVID-19. These actions can slow the spread and reduce the impact of disease.
If you are at higher risk for serious illness from COVID-19 because of your age or because you have a serious long-term health problem, it is extra important for you to take actions to reduce your risk of getting sick with the disease.
Pregnant women are particularly susceptible to respiratory pathogens and severe pneumonia, because they are at an immunosuppressive state, and physiologic adaptive changes during pregnancy (e.g., diaphragm elevation, increased oxygen consumption, and edema of respiratory tract mucosa) render them intolerant to hypoxia.
Previous epidemics of many emerging viral infections have typically resulted in poor obstetrical outcomes including maternal morbidity and mortality, maternal-fetal transmission of the virus, and perinatal infections and death.
We do not currently know if pregnant women have a greater chance of getting sick from COVID-19 than the general public nor whether they are more likely to have serious illness as a result. Pregnant women experience changes in their bodies that may increase their risk of some infections. With viruses from the same family as COVID-19, and other viral respiratory infections, such as influenza, women have had a higher risk of developing severe illness.
Literature describing 38 pregnant women with COVID-19 and their newborns in China to assess the effects of SARS-CoV-2 on the mothers and infants including clinical, laboratory and virologic data, and the transmissibility of the virus from mother to fetus reveals that unlike coronavirus infections of pregnant women caused by SARS and MERS, in these 38 pregnant women COVID-19 did not lead to maternal deaths.
At this point in the global pandemic of COVID-19 infection there is no evidence that SARS-CoV-2 undergoes intrauterine or transplacental transmission from infected pregnant women to their fetuses. Analysis of additional cases is necessary to determine if this remains true.
Any pregnant woman who has travelled in a country affected by SARS-CoV-2 within the previous 14 days or who has had close contact with a patient with confirmed SARS-CoV-2 infection should be tested with a SARS-CoV-2 nucleic acid amplification test, even if asymptomatic.
Pregnant women with laboratory-confirmed SARS-CoV-2 infection who are asymptomatic should be self-monitored at home for clinical features of COVID-19 for at least 14 days. These patients and those recovering from mild illness should be monitored with bimonthly fetal growth ultrasounds and Doppler assessments because of the potential risk for intrauterine growth restriction. Pregnant women with COVID-19 pneumonia should be managed by a multidisciplinary team at a tertiary care center. When quick Sepsis-related Organ Failure Assessment criteria are met, the patient should be transferred to an intensive care unit.
For pregnant women with confirmed infection, the choice of delivery timing should be individualised depending on the week of gestation and maternal, fetal, and delivery conditions. Whenever possible, vaginal delivery via induction of labour, with eventual instrumental delivery to avoid maternal exhaustion, should be favoured to avoid unnecessary surgical complications in an already sick patient. Septic shock, acute organ failure, or fetal distress should prompt emergency cesarean delivery (or termination if legal before fetal viability).
Newborns of mothers positive for SARS-CoV-2 should be isolated for at least 14 days or until viral shedding clears, during which time direct breastfeeding is not recommended.
In limited studies on women with COVID-19 and another coronavirus infection, Severe Acute Respiratory Syndrome (SARS-CoV), the virus has not been detected in breast milk; however we do not know whether mothers with COVID-19 can transmit the virus via breast milk.
Deaths and Risk factors assessment associated with death
The term mortality comes from the Latin word mortalitas. The mortality rate is the number of deaths within a given population in a given time period. The mortality rate is typically expressed in number of deaths per 1,000 or 100,000 individuals per year.
Definition of death-to-case ratio
The death-to-case ratio is the number of deaths attributed to a particular disease during a specified time period divided by the number of new cases of that disease identified during the same time period. The death-to-case ratio is a ratio but not necessarily a proportion, because some of the deaths that are counted in the numerator might have occurred among persons who developed disease in an earlier period, and are therefore not counted in the denominator.
The maximum incubation period is assumed to be up to 14 days, whereas the median time from onset of symptoms to intensive care unit (ICU) admission is around 10 days. Recently, WHO reported that the time between symptom onset and death ranged from about 2 weeks to 8 weeks.
Risk factors assessment associated with death in adults during the stay in an intensive care unit (ICU).
Specifically, a) being of an older age, b)showing signs of sepsis, and c) having blood clotting issues when admitted to hospital are key risk factors associated with higher risk of death from the new coronavirus.
a) Being of older age, increased age was associated with death in patients with COVID-19. The age-dependent defects in T-cell and B-cell function and the excess production of type 2 cytokines could lead to a deficiency in control of viral replication and more prolonged proinflammatory responses, potentially leading to poor outcome.
b) Showing signs of sepsis, a severe condition resulting from the presence of harmful microorganisms in the blood or other tissues and the body’s response to their presence, potentially leading to the malfunctioning of various organs, shock, and death.
Sepsis is most common and most dangerous in: Older adults, Pregnant women, Children younger than 1, People who have chronic conditions, such as diabetes, kidney or lung disease, or cancer and People who have weakened immune systems.
- a fever above 101ºF (38ºC) or a temperature below 96.8ºF (36ºC)
- heart rate higher than 90 beats per minute
- breathing rate higher than 20 breaths per minute
- probable or confirmed infection
Severe sepsis occurs when there’s organ failure. You must have one or more of the following signs to be diagnosed with severe sepsis:
- patches of discolored skin
- decreased urination
- changes in mental ability
- low platelet (blood clotting cells) count
- problems breathing
- abnormal heart functions
- chills due to fall in body temperature
- extreme weakness
Symptoms of septic shock include the symptoms of severe sepsis, plus a very low blood pressure – the organs of the body fail to receive sufficient oxygen. To be diagnosed with septic shock, you must have a probable or confirmed infection and both of the following:
- The need for medication to maintain blood pressure greater than or equal to 65 millimeters of mercury (mm Hg).
- High levels of lactic acid in your blood (serum lactate) after you have received adequate fluid replacement. Having too much lactic acid in your blood means that your cells aren’t using oxygen properly.
c) Having blood clotting issues
Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
- Coagulopathy is a condition in which the blood’s ability to coagulate (form clots) is impaired and may cause uncontrolled internal or external bleeding. Left untreated, uncontrolled bleeding may cause damage to joints, muscles, or internal organs and may be life-threatening. Coagulopathy was defined as a 3-second extension of prothrombin time or a 5-second extension of activated partial thromboplastin time.
- Disseminated intravascular coagulation (DIC) is a rare but serious condition that causes abnormal blood clotting throughout the body’s blood vessels. It is caused by another disease or condition, such as an infection like novel coronavirus, that makes the body’s normal blood clotting process become overactive. DIC may develop quickly over hours or days, or more slowly.
Sepsis is well established as one of the most common causes of DIC; development of DIC results when monocytes and endothelial cells are activated to the point of cytokine release following injury, with expression of tissue factor and secretion of von Willebrand factor.
Circulation of free thrombin, uncontrolled by natural anticoagulants, can activate platelets and stimulate fibrinolysis.
Signs and symptoms may include bleeding, bruising, low blood pressure, shortness of breath, or confusion. Complications can be life-threatening and include bleeding or multiple organ failure. DIC that develops quickly usually requires emergency treatment in the hospital.
Fibrin and fibrinogen degradation product (FDP) testing is commonly used to diagnose disseminated intravascular coagulation (DIC). The reference range of FDP levels is less than 10 mcg/mL (conventional units) or less than 10 mg/L (SI units). An fibrinogen degradation product (FDP) level of more than 40 mg/mL is considered critical.
In treating DIC, your doctor will treat the disease that is causing DIC. Your doctor may also give you medicines to prevent blood clots, or blood products such as platelets or clotting factors to stop bleeding.
- Having a high Sequential Organ Failure Assessment (SOFA) score is is a good diagnostic marker for sepsis and septic shock and is used to track a person’s status during the stay in an intensive care unit (ICU) to determine the extent of a person’s organ function or rate of failure.
The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems).
Having d-dimer greater than 1 μg/mL. A positive D-dimer result may indicate the presence of an abnormally high level of fibrin degradation products. It indicates that there may be a significant blood clot (thrombus) formation and breakdown in the body, but it does not tell the location or cause. Non-surviving patients presented higher D-dimer levels, prolonged PT, and aPTT compared with surviving patients.
The first confirmed death was on 9 January 2020 in Wuhan. The first death outside China occurred in the Philippines, and the first death outside Asia was in France. As of 13 March 2020, outside of mainland China, more than a dozen deaths have been recorded in each of Iran, South Korea, and Italy. Deaths have also been reported in North America, Australia, San Marino, Spain, Iraq and the United Kingdom.
As of 3 March 2020, WHO data shows the percentage of infected people who have died from COVID-19 is 3.4% globally (1.6% outside of China).
As of March 21, 2020 – Total death in most affected countries:
COVID-19 Fatality Rate by AGE:
The CDC’s analysis found that 31 percent of all cases, 45 percent of hospitalizations, 53 percent of ICU admissions and 80 percent of all fatalities from the virus occurred among adults aged 65 plus with the highest percentage of severe outcomes happening among those aged 85 and over.
The proportion of severe or fatal infections may vary by location. As an example, in Italy, 12 percent of all detected COVID-19 cases and 16 percent of all hospitalized patients were admitted to the intensive care unit; the estimated case fatality rate was 5.8 percent in mid-March. In contrast, the estimated case fatality rate in mid-March in South Korea was 0.9 percent. This may be related to distinct demographics of infection; in Italy, the median age of patients with infection was 64 years, whereas in Korea the median age was in the 40s.
Up to day information – live, interactive map of global coronavirus cases.
- Link: https://www.worldometers.info/coronavirus/
- Link: https://www.krqe.com/health/coronavirus/johns-hopkins-offers-live-interactive-map-of-global-coronavirus-cases/
The coronaviral genome – proteins and receptor
A complete genome sequence was obtained for a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain isolated from an oropharyngeal swab specimen of a Nepalese patient with coronavirus disease 2019 (COVID-19), who had returned to Nepal after traveling to Wuhan, China. The specimen tested positive for SARS-CoV-2 by real-time reverse transcriptase PCR (rRT-PCR) developed in the University of Hong Kong.
Sequencing was done using the Illumina MiSeq system with the Burrows-Wheeler Aligner MEM algorithm (BWA-MEM) 0.7.5a-r405 assembly method. The full genome was amplified directly from the RNA extract from the original specimen using gene-specific primers for open reading frame 1b (ORF1b) and N to produce overlapping PCR products covering the full genome. The new genome sequence was obtained by first mapping reads to a reference SARS-CoV-2 genome using BWA-MEM 0.7.5a-r405 with default parameters to generate the consensus sequence. In addition, the assembly produced by MEGAHIT 1.2.9 (de novo assembly), using default parameters, was used to cross-validate with the reference-based method as an internal control.
The final genome of sequenced SARS-CoV-2 consists of a single, positive-stranded RNA that is 29,811 nucleotides long, broken down as follows: 8,903 (29.86%) adenosines, 5,482 (18.39%) cytosines, 5,852 (19.63%) guanines, and 9,574 (32.12%) thymines.
The coronaviral genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein.
The S protein is responsible for facilitating entry of the CoV into the target cell. It is composed of a short intracellular tail, a transmembrane anchor, and a large ectodomain that consists of a receptor binding S1 subunit and a membrane-fusing S2 subunit.
Sequence analysis of the SARS-CoV-2 S protein genome showed that it was only 75% identical with the SARS-CoV S protein. However, analysis of the receptor binding motif (RBM) in the S protein showed that most of the amino acid residues essential for receptor binding were conserved between SARS-CoV and SARS-CoV-2, suggesting that the 2 CoV strains use the same host receptor for cell entry. The entry receptor utilized by SARS-CoV is Angiotensin-Converting Enzyme 2 (ACE-2).
Angiotensin-Converting Enzyme 2 (ACE-2) is a type I transmembrane metallocarboxypeptidase with homology to ACE, an enzyme long-known to be a key player in the Renin-Angiotensin system (RAS) and a target for the treatment of hypertension. It is mainly expressed in vascular endothelial cells, the renal tubular epithelium, and in Leydig cells in the testes.
ACE-2 is an Entry Receptor for SARS-CoV-2 – researches:
Based on the sequence similarities of the RBM between SARS-CoV-2 and SARS-CoV, several independent research groups investigated if SARS-CoV-2 also utilizes ACE-2 as a cellular entry receptor. Zhou et al. showed that SARS-CoV-2 could use ACE-2 from humans, Chinese horseshoe bars, civet cats, and pigs to gain entry into ACE-2-expressing HeLa cells. Hoffmann et al. reported similar findings for human and bat ACE- Additionally, Hoffmann et al. showed that treating Vero-E6 cells, a monkey kidney cell line known to permit SARS-CoV replication, with an Anti-ACE-2 Antibody (R&D Systems, Catalog # AF933) blocked entry of VSV pseudotypes expressing the SARS-CoV-2 S protein.
PCR analysis revealed that ACE-2 is also expressed in the lung, kidney, and gastrointestinal tract, tissues shown to harbor SARS-CoV. The major substrate for ACE-2 is Angiotensin II. ACE-2 degrades Angiotensin II to generate Angiotensin 1-7, thereby, negatively regulating the renin angiotensin system (RAS).
ACE-2 has also been shown to exhibit a protective function in the cardiovascular system and other organs.
How does virus jump from animals to humans?
- To enter viruses bind receptors on the host cell – like a key to a lock.
- These receptors are structurally different between humans and animals (different lock)
- Thus, animal virus do not infect humans efficiently (different key)
- In very rare events the virus changes and gains the ability to infect humans
How new coronavirus breaks into human cells?
- To infect a human host, viruses must be able to gain entry into individual human cells. They use these cells’ machinery to produce copies of themselves, which then spill out and spread to new cells.
- The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics.
- The new virus attaches to a receptor on respiratory cells called angiotensin-converting enzyme 2, or ACE2.
The analysis of public genome sequence data from SARS-CoV-2 and related viruses found no evidence that the virus was made in a laboratory or otherwise engineered.
SARS-CoV-2 is closely related to the original SARS-CoV.
Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13).
In February 2020, Chinese researchers found that there is only one amino acid difference in certain genome sequences between the viruses found in pangolins and those from human patients, implying that pangolins may have been an intermediate host.
Research institutions used this sequencing data to explore the origins and evolution of SARS-CoV-2, they analyzed the genetic template for spike proteins, armatures on the outside of the virus that it uses to grab and penetrate the outer walls of human and animal cells.
More specifically, they focused on two important features of the spike protein: the receptor-binding domain (RBD), a kind of grappling hook that grips onto host cells, and the cleavage site, a molecular can opener that allows the virus to crack open and enter host cells. The scientists found that the receptor-binding domain (RBD) portion of the SARS-CoV-2 spike proteins had evolved to effectively target a molecular feature on the outside of human cells called ACE2, a receptor involved in regulating blood pressure.
The SARS-CoV-2 spike protein was so effective at binding the human cells, in fact, that the scientists concluded it was the result of natural selection and not the product of genetic engineering.
This evidence for natural evolution was supported by data on SARS-CoV-2’s backbone — its overall molecular structure. If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness. But the scientists found that the SARS-CoV-2 backbone differed substantially from those of already known coronaviruses and mostly resembled related viruses found in bats and pangolins.
“These two features of the virus, the mutations in the RBD portion of the spike protein and its distinct backbone, rules out laboratory manipulation as a potential origin for SARS-CoV-2”.
Coronaviruses (CoVs) are the largest group of viruses belonging to the Nidovirales order, which includes Coronaviridae, Arteriviridae, and Roniviridae families. The Coronavirinae comprise one of two subfamilies in the Coronaviridae family, with the other being the Torovirinae. The Coronavirinae are further subdivided into four groups, the alpha, beta, gamma and delta coronaviruses. The viruses were initially sorted into these groups based on serology but are now divided by phylogenetic clustering.
All viruses in the Nidovirales order are enveloped, non-segmented positive-sense RNA viruses. They all contain very large genomes for RNA viruses, with Coronavirinae having the largest identified RNA genomes, containing approximately 30 kilobase (kb) genomes.
Other common features within the Nidovirales order include:
- A highly conserved genomic organization, with a large replicase gene preceding structural and accessory genes.
- Expression of many nonstructural genes by ribosomal frameshifting.
- Several unique or unusual enzymatic activities encoded within the large replicase-transcriptase polyprotein.
- Expression of downstream genes by synthesis of 3′ nested sub-genomic mRNAs. In fact, the Nidovirales order name is derived from these nested 3′ mRNAs as nido is Latin for “nest”. The major differences within the Nidovirus families are in the number, type, and sizes of the structural proteins. These differences cause significant alterations in the structure and morphology of the nucleocapsids (The nucleic acid of a virus together with the protein coat that encloses it) and virions (are defined as the complete infective virus residing outside a host cell, which includes its core of RNA, as well as the capsid).
Signs and symptoms
Asymptomatic (their frequency is unknown) or develop symptoms such as fever, cough, fatigue, shortness of breath, or muscle pain.
A WHO review of 55,924 laboratory-confirmed cases in China indicated the following typical signs and symptoms:
- Fever (99 %). fever was reported in almost all patients, but approximately 20 percent had a very low-grade fever <100.4°F/38°C
- Dry Cough (59 %), Shortness of breath or difficulty breathing (31%), Expectoration (27%)
- Fatigue (70%), Anorexia (40%), Myalgia (muscle pain) (35%).
Other, less common symptoms have included
- Pharingalgia (Pain in the pharynx).
- Nausea, Abdominal Pain, Diarreha.
- Dizziness, Headache.
- Those with more severe disease may have lymphopenia and chest imaging findings consistent with pneumonia.
Further development can lead to severe pneumonia, acute respiratory distress syndrome, sepsis, septic shock, and death. Some of those infected may be asymptomatic, returning test results that confirm infection but show no clinical symptoms, so researchers have issued advice that individuals with close contact to confirmed infected patients should be closely monitored and examined to rule out infection.
There are no specific clinical features that can yet reliably distinguish COVID-19 from other viral respiratory infections.
Spectrum of illness severity
- Mild (no or mild pneumonia) was reported in 81 percent.
- Severe disease (eg, with dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours) was reported in 14 percent.
- Critical disease (eg, with respiratory failure, shock, or multiorgan dysfunction) was reported in 5 percent.
- The overall case fatality rate was 2.3 percent; no deaths were reported among noncritical cases.
According to the WHO, recovery time appears to be around two weeks for mild infections and three to six weeks for severe disease.
Covid-19 symptoms vs. other viruses
|Aches and Pain||Sometimes||Common||Common|
|Runny or stuffy nose||Rare||Common||Sometimes|
|Shortness of breath||Sometimes||No||No|
Viral load in nasal and throat swabs
- Higher viral loads soon after symptom onset, higher in the nose
- Shedding pattern of patients infected with SARS- CoV 2 resembles that of influenza but different from SAR- CoV (peak day 10)
- Load in asymptomatic patients was similar to that of symptomatic patients, suggesting transmission potential of asymptomatic patients.
The WHO has published several RNA testing protocols for SARS-CoV-2, the virus that causes COVID-19, with the first issued on 17 January. Testing uses real time reverse transcription polymerase chain reaction (rRT-PCR). The test can be done on respiratory or blood samples. Results are generally available within a few hours to days.
Signs of pneumonia may precede confirmation of COVID-19 infection through RT-PCR.
An alternative method of diagnosis is based on clinical presentation such as looking for visual signature patterns of COVID-19 in CT scans of the lungs.
Imaging findings – Chest CT in patients with COVID-19 most commonly demonstrates ground-glass opacification with or without consolidative abnormalities, consistent with viral pneumonia.
Case series have suggested that chest CT abnormalities are more likely to be bilateral, have a peripheral distribution, and involve the lower lobes. Less common findings include pleural thickening, pleural effusion, and lymphadenopathy.
In one report of 21 patients with laboratory-confirmed COVID-19 who did not develop severe respiratory distress, lung abnormalities on chest imaging were most severe approximately 10 days after symptom onset.
However, chest CT abnormalities have also been identified in patients prior to the development of symptoms and even prior to the detection of viral RNA from upper respiratory specimens.
Even patients with asymptomatic infection may have objective clinical abnormalities. As an example, in a study of 24 patients with asymptomatic infection who all underwent chest computed tomography (CT), 50 percent had typical ground-glass opacities or patchy shadowing, and another 20 percent had atypical imaging abnormalities. Five patients developed low-grade fever, with or without other typical symptoms, a few days after diagnosis.
- By washing hands when appropriate with soap and water for at least 20 seconds, especially after blowing your nose, coughing, or sneezing, or having been in a public place. If soap and water are not available, use a hand sanitizer that contains at least 60% alcohol.
- Health organizations recommended that individuals cover their mouth and nose with a tissue when coughing or sneezing (which should then be disposed of immediately), or with a sleeve if a tissue is not available.
- Avoiding touching the eyes, nose or mouth with unwashed hands.
- Clean and disinfect your home to remove germs: practice routine cleaning of frequently touched surfaces (for example: tables, doorknobs, light switches, handles, desks, toilets, faucets, sinks & cell phones).
- To the extent possible, avoid touching high-touch surfaces in public places – elevator buttons, door handles, handrails, handshaking with people, etc. Use a tissue or your sleeve to cover your hand or finger if you must touch something. Wash your hands after touching surfaces in public places.
- Avoid crowds, especially in poorly ventilated spaces. Your risk of exposure to respiratory viruses like COVID-19 may increase in crowded, closed-in settings with little air circulation if there are people in the crowd who are sick.
- Wearing a surgical mask in public.
- Stay home as much as possible.
- Consider ways of getting food brought to your house through family, social, or commercial networks
- Consult with your health care provider for more information about monitoring your health for symptoms suggestive of COVID-19.
- Stay in touch with others by phone or email. You may need to ask for help from friends, family, neighbors, community health workers, etc. if you become sick.
- Determine who can provide you with care if your caregiver gets sick
- Know what medications your loved one is taking and see if you can help them have extra on hand.
- Monitor food and other medical supplies (oxygen, incontinence, dialysis, wound care) needed and create a back-up plan.
- Stock up on non-perishable food items to have on hand in your home to minimize trips to stores.
- If you care for a loved one living in a care facility, monitor the situation, ask about the health of the other residents frequently and know the protocol if there is an outbreak.
The use of surgical masks by those who may be infected has also been recommended, as they can limit the volume and travel distance of expiratory droplets dispersed when talking, sneezing, and coughing. The WHO has issued instructions on when and how to use masks, including:
- Masks are effective only when used in combination with frequent hand-cleaning with alcohol-based hand rub or soap and water.If you wear a mask, then you must know how to use it and dispose of it properly.
- Before putting on a mask, clean hands with alcohol-based hand rub or soap and water.
- Cover mouth and nose with mask and make sure there are no gaps between the face and the mask.
- Avoid touching the mask while using it; if you do, clean your hands with alcohol-based hand rub or soap and water.
- Replace the mask with a new one as soon as it is damp and do not re-use single-use masks.
- Remove the mask using the lace from behind (do not touch the front of mask); discard immediately and clean hands.
- Masks have also been recommended for use by those taking care of someone who may have the disease.
- Furthermore, health care professionals were advised to wear respirators at least as protective as NIOSH- certified N95, EU standard FFP2, or equivalent, in addition to other personal protective equipment.
Individuals who have been diagnosed with COVID-19 and those who suspect they have been infected have been advised by public health agencies to restrict all activities outside of the home, except for getting medical care. “Do not go to work, school, or public areas. Avoid using public transportation, ride-sharing, or taxis”. Those seeking medical care are advised to call ahead before visiting a healthcare provider.
Individuals who have recently travelled to a country with widespread transmission or who have been in direct contact with an individual diagnosed with COVID-19 have also been asked by some government health agencies to self-quarantine or practice social distancing for 14 days from the time of last possible exposure.
There are no vaccines currently available. Several organisations around the world are developing vaccines, using several different methods. By early March 2020, some 30 vaccine candidates were in development, with products by Gilead Sciences and Ascletis Pharma in Phase III clinical trials.
I think and hope that we have researches today like Maurice Ralph Hilleman (August 30, 1919 – April 11, 2005) was an American microbiologist who specialized in vaccinology and developed over 40 vaccines, an unparalleled record of productivity. Of the 14 vaccines routinely recommended in current vaccine schedules, he developed eight: those for measles, mumps, hepatitis A, hepatitis B, chickenpox, meningitis, pneumonia and Haemophilus influenzae bacteria. He also played a role in the discovery of the cold-producing adenoviruses, the hepatitis viruses, and the potentially cancer-causing virus SV40.
There are no specific antiviral medications, though development efforts are underway. Attempts to relieve the symptoms may include taking regular (over-the-counter) cold medications, drinking fluids, and resting. Depending on the severity, oxygen therapy, intravenous fluids, and breathing support may be required. Some countries require people to report flu-like symptoms to their doctor, especially if they have visited mainland China.
Several compounds, which were previously approved for treatment of other viral diseases, such as favipiravir, ribavirin, remdesivir and galidesivir, are being investigated against the coronavirus. Bruce Aylward, an assistant director-general of the World Health Organization (WHO), has stated “there is only one drug right now that we think may have real efficacy and that’s remdesivir.” Trials are in progress, and results could be available within weeks of 24 February.
Glucocorticoid drugs are man-made versions of glucocorticoids, steroids that occur naturally in your body. They have many functions. One is to interrupt inflammation by moving into cells and suppressing the proteins that go on to promote inflammation. They also help your body respond to stress and regulate how your body uses fat and sugar.
Limited role of glucocorticoids – The WHO and CDC recommend glucocorticoids not be used in patients with COVID-19 pneumonia unless there are other indications (eg, exacerbation of chronic obstructive pulmonary disease). Glucocorticoids have been associated with an increased risk for mortality in patients with influenza and delayed viral clearance in patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Although they were widely used in management of severe acute respiratory syndrome (SARS), there was no good evidence for benefit, and there was persuasive evidence of adverse short- and long-term harm.
Nonsteroidal anti-inflammatory drug NSAID
Prostaglandins are a family of chemicals that are produced by the cells of the body and have several important functions. They promote inflammation that is necessary for healing, but also results in pain, and fever; support the blood clotting function of platelets; and protect the lining of the stomach from the damaging effects of acid.
Prostaglandins are produced within the body’s cells by the enzyme cyclooxygenase (COX). There are two COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever. However, only COX-1 produces prostaglandins that support platelets and protect the stomach. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the COX enzymes and reduce prostaglandins throughout the body. As a consequence, ongoing inflammation, pain, and fever are reduced. Since the prostaglandins that protect the stomach and support platelets and blood clotting also are reduced, NSAIDs can cause ulcers in the stomach and promote bleeding.
Nonsteroidal anti-inflammatory drug, a medication that is commonly prescribed or purchased over the counter to treat the inflammation associated with conditions such as arthritis, tendonitis, and bursitis. Examples of NSAIDs include aspirin, indomethacin (brand name: Indocin), ibuprofen (brand name: Motrin), naproxen (brand name: Naprosyn), piroxicam (brand name: Feldene), and nabumetone (brand name: Relafen). People who take certain NSAIDs may have a higher risk of having a heart attack or a stroke than people who do not take these medications. This risk may be higher for people who take NSAIDs for a long time. Other major side effects of NSAIDs are gastrointestinal problems. Some 10 to 50 percent of patients are unable to tolerate NSAID treatment because of these side effects, which include abdominal pain, diarrhea, bloating, heartburn, and upset stomach.
Uncertainty about NSAID use – Some clinicians have suggested the use of non-steroidal anti-inflammatory drugs (NSAIDs) early in the course of disease may have a negative impact on disease outcome. These concerns are based on anecdotal reports of a few young patients who received NSAIDs early in the course of infection and experienced severe disease, as well as the theoretic concern that the anti-inflammatory properties associated with NSAIDs could have a negative impact on the patient’s immune response. In light of these concerns, some providers are using acetaminophen in place of NSAIDs for reduction of fever; however, the European Medicines Agency (EMA) and the WHO do not recommend that NSAIDs be avoided when clinically indicated.
Investigational agents – A number of investigational agents are being explored for antiviral treatment of COVID-19, and enrollment in clinical trials should be discussed with patients or their proxies. A registry of international clinical trials can be found on the WHO website and at clinicaltrials.gov.
Certain investigational agents have been described in observational series or are being used anecdotally based on in vitro or extrapolated evidence. It is important to acknowledge that there are no controlled data supporting the use of any of these agents, and their efficacy for COVID-19 is unknown.
Remdesivir, developed by Gilead Sciences Inc., is an investigational broad-spectrum antiviral treatment. It was previously tested in humans with Ebola virus disease and has shown promise in animal models for treating Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), which are caused by other coronaviruses.
Remdesivir is a prodrug that metabolizes into its active form GS-441524. GS-441524 is an adenosine nucleotide analog that interferes with the action of viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. It was unknown whether it terminates RNA chains or causes mutations in them.
Several randomized trials are underway to evaluate the efficacy of remdesivir for moderate or severe COVID-19. Remdesivir is a novel nucleotide analogue that has activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and related coronaviruses (including SARS and MERS-CoV) both in vitro and in animal studies. The compassionate use of remdesivir through an investigational new drug application was described in a case report of one of the first patients with COVID-19 in the United States. Any clinical impact of remdesivir on COVID-19 remains unknown.
- Chloroquine phosphate is in a class of drugs called antimalarials and amebicides. It is used to prevent and treat malaria. It is also used to treat amebiasis.
If chloroquine is shown to be effective against SARS-CoV-2, it will not be via the same mechanism by which the drug functions as an antimalarial. That’s because malaria is caused not by a virus but by a microparasite Plasmodium falciparum. Chloroquine makes it toxic for the parasite to digest its host’s hemoglobin. The clinical usefulness of chloroquine, and in some recent cases of quinine as well, has been much reduced by the evolution and spread of chloroquine resistant malaria parasites.
Chloroquine might have entirely different effects against a virus, such as, for example, disrupting the virus’s ability to enter a cell.
- Hydroxychloroquine is in a class of drugs called antimalarials. It is used to prevent and treat acute attacks of malaria. It is also used to treat discoid or systemic lupus erythematosus and rheumatoid arthritis in patients whose symptoms have not improved with other treatments and occasionally to treat porphyria cutanea tarda.
Both chloroquine and hydroxychloroquine have been reported to inhibit SARS-CoV-2 in vitro, although hydroxychloroquine appears to have more potent antiviral activity.
Use of chloroquine is included in treatment guidelines from China’s National Health Commission and was reportedly associated with reduced progression of disease and decreased duration of symptoms. However, primary data supporting these claims have not been published.
Other published clinical data on either of these agents are limited. In an open-label study of 36 patients with COVID-19, use of hydroxychloroquine (200 mg three times per day for 10 days) was associated with a higher rate of undetectable SARS-CoV-2 RNA on nasopharyngeal specimens at day 6 compared with no specific treatment (70 versus 12.5 percent). In this study, the use of azithromycin in combination with hydroxychloroquine appeared to have additional benefit, but there are methodologic concerns about the control groups for the study, and the biologic basis for using azithromycin in this setting is unclear.
Despite the limited clinical data, given the relative safety of short-term use of hydroxychloroquine (with or without azithromycin), the lack of known effective interventions, and the in vitro antiviral activity, some clinicians think it is reasonable to use one or both of these agents in hospitalized patients with severe or risk for severe infection, particularly if they are not eligible for other clinical trials.
Lopinavir-ritonavir – The combination of lopinavir and ritonavir is used with other medications to treat human immunodeficiency virus (HIV) infection. Lopinavir and ritonavir are in a class of medications called protease inhibitors. They work by decreasing the amount of HIV in the blood. When lopinavir and ritonavir are taken together, ritonavir also helps to increase the amount of lopinavir in the body so that the medication will have a greater effect. Although lopinavir and ritonavir will not cure HIV, these medications may decrease the chance of developing acquired immunodeficiency syndrome (AIDS) and HIV-related illnesses such as serious infections or cancer.
This combined protease inhibitor, lopinavir and ritonavir, has in vitro activity against the SARS-CoV and appears to have some activity against MERS-CoV in animal studies . Although the use of this agent for treatment of COVID-19 has been described in case reports, there was no difference in time to clinical improvement or mortality at 28 days in a randomized trial of 199 patients with severe COVID-19 given lopinavir-ritonavir (400/100 mg) twice daily for 14 days in addition to standard care versus those who received standard of care alone.
Tocilizumab – Treatment guidelines from China’s National Health Commission include the IL-6 inhibitor tocilizumab for patients with severe COVID-19 and elevated IL-6 levels; the agent is being evaluated in a clinical trial.
Tocilizumab (Actemra), a treatment used for adverse events related to cancer therapy, among other indications, is being explored in a phase III trial as a treatment for adult patients hospitalized with severe COVID-19 pneumonia, according to Genentech (Roche), the manufacturer of the interleukin-6 receptor antagonist.
National response measures have included containment measures such as lockdowns, quarantines, and curfews.