SYMPTOMS AND DISEASE
COVID-19 (Coronavirus Disease) is an illness caused by the virus designated 2019-nCoV (now called SARS-CoV-2), which is a novel strain of the Coronavirus group first seen in China in December 2019. This illness is similar to viral flu and therefore is called ILI (Influenza-like Illness). From the time of getting infected, it can take from 2 days to 2 weeks (incubation period) to manifest definite and recognizable symptoms.
ILI is defined as fever of 38 degC or more, with cough with onset within the last 10 days. Presenting symptoms of COVID include fever, dry cough, and sore throat which may be accompanied by fatigue, body ache, nasal congestion, running nose, loss of smell or taste, nausea/vomiting, loss of appetite or diarrhea. Many infected patients are often asymptomatic. Loss of smell and taste (salt and sweet), is a useful sign to look for in otherwise asymptomatic people with suspected exposure to COVID.
In about 4-5 days, the virus can spread and cause damage to the lower respiratory tract (bronchi and lungs) and decrease blood oxygen saturation. This manifests as breathlessness in addition to the other symptoms. Rarely neurological symptoms like dizziness, decreased alertness, disorientation, fits, or a stroke have also been seen.
Causes of Death in COVID include ARDS (Acute Respiratory Distress Syndrome) which is respiratory failure resulting from massive lung inflammation and scarring (fibrosis), decreased oxygen in the blood, and/or sepsis leading to multi-organ failure (including Heart and Kidney failure). More recent research has pointed towards involvement and damage to the endothelium (the inner lining of blood vessels) as the possible cause for severe disease and mortality. Endothelial damage causes an increased risk of blood clotting (thrombosis), as well as adverse cardiovascular effects.
The overall mortality rate from COVID-19 is around 2-3% (<1% below 50 years of age). The risk of serious disease, complications, and death is higher and seen far more in older patients (>60 years) and those suffering from other underlying medical illnesses like Diabetes, Hypertension, Cancers, and diseases of the Airway/Lungs, Heart, Kidney, Liver or Immune system.
More than 58 million people have been infected globally to date. >90% of people have mild symptoms and almost 75% of the cases have already recovered. Post recovery weakness, reduced work capacity, and shortness of breath have been seen for prolonged periods in some patients due to damage caused to the lung and blood vessels. There have been around 1.3 million deaths so far globally.
It is still uncertain as to how long immunity lasts after being infected with Coronavirus. There have been cases of re-infection within 3-6 months in cases who were COVID positive with mild or no symptoms. Children have been seen to get infected or suffer symptoms very minimally.
The WHO in February 2020, had designated COVID-19 as a “public health emergency of international concern” (PHEIC) and a pandemic indicating that international and collaborated action will be required to tackle this infection.
TRANSMISSION AND SPREAD
The SARS-CoV-2 is transmitted between humans through droplets and aerosols (smaller droplets usually<5 microns) emitted from infected individuals through coughing, sneezing, spitting, or talking. One gets exposed to these droplets by coming in direct contact with infected persons, infected surfaces, and suspended droplets in the air especially when at close proximity (about 1-2 meter/ 3-6 feet) of an infected patient. How far the droplets travel depends on many factors. Aerosols being smaller and lighter travel further and remain suspended longer in the air than larger droplets, however, aerosols also have less viral load per particle and can diffuse easily. A higher force of expulsion (as in sneezing and coughing, as compared to talking or breathing out), and more wind velocity can increase the degree of droplet transmission. The virus can remain on metal surfaces, plastic, and fabric for up to 12 hours.
Every country has taken immense measures to curtail the spread of COVID-19 and limit the number of cases and deaths. Measures include restricting flights, limiting public transport, monitoring or closing public places and institutions, imposing lockdowns and curfews, disinfecting and sanitizing common areas, and stepping up testing units and hospital facilities. However, the most important thing is for the people to follow and adhere to the advisories and recommendations of their respective governments, and take the required precautions and care without panicking.
ANTIGEN (VIRUS) DETECTION
A cotton swab sample from the nose-throat and/or mouth-throat junction (nasopharyngeal and/or oropharyngeal swab) is taken to test for the presence of the virus (antigen) in an individual. A person is said to be positive if the presence of the COVID-19 virus is confirmed in the nose or throat swab sample. The following are some of the tests used for Virus Antigen detection:
RT-PCR (Real-time Polymerase Chain Reaction) tests work by amplifying genetic fragments of the viral RNA with the help of a process called reverse transcription (conversion to DNA). Thereafter primers are added which bind to the selected DNA sequences, along with a fluorescent probe that helps in real-time antigen detection. The Ct value (cycle threshold) can give some indication about viral load and how infective a person is. Ct values above 24 usually imply a low risk of transmission. Every affected country has set up designated testing centers and reference standard laboratories for RT-PCR testing for COVID-19. It usually takes 1-2 days for getting the test results, (5-7 hours for the test plus time for transporting samples). RT-PCR has the highest sensitivity among all antigen tests and is the gold standard test for declaring a person COVID negative.
NAT (Nucleic acid Amplification Test) is also an RT-PCR test that detects the E (envelope) gene as well as the key replication enzyme RNA dependent RNA polymerase of the virus. TrueNAT is the portable form of CB-NAAT (Cartridge Based Nucleic Acid Amplification Test) used in labs. TrueNAT is compact and uses a cartridge and microchip. Therefore it gives faster results (in 1-2 hours), is cheaper, convenient to transport, and is very useful in interior areas, to set up kiosks, camps and drive-through testing facilities.
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has recently been approved with high sensitivity and specificity (96% and 98% respectively) and uses a specially adapted Cas9 protein to successfully detect the virus. The paper-strip uses cutting-edge CRISPR gene-editing technology to identify and target this genetic material of SARS-CoV-2 and can give results in less than an hour.
Antigen detection tests done by RT-PCR, CRISPR, TrueNAT, or CBNAAT are considered equivalent and do not require further confirmatory tests.
Rapid Antigen Tests (RAT) are now available, which are point of care tests giving results in under an hour. They are most economical in price and are available in the form of convenient test strip packs. The test is performed for quick and mass screening, as house-to-house testing, or in institutes, large commercial establishments, and organizations. RATs also help increase detection rates in containment zones, hot spots, and migrant clusters. RAT act by detecting the spike protein of the coronavirus. RATs are less sensitive than the conventional RT-PCR and though a positive result is taken as confirmed, a negative result could be false if viral load is low or the disease stage is early, and so will need confirmation by RTPCR. If the person is symptomatic, but negative on the RAT, a conventional RT-PCR should be performed.
COVIRAP is a recently introduced rapid test in India that uses isothermal amplification techniques (IAT) as alternatives to PCR to rapidly and efficiently accumulate nucleic acid sequences at constant temperature. The test is read with colored lines on treated paper strips dipped into the processed sample to detect the virus. It is economical, faster (under 1 hour), portable, reusable (many tests from one unit), and can be handled by relatively unskilled operators on the field. It can detect low viral loads and can be useful in early stages of infection, preventing uncontrolled spread and timely isolation. It has 94% sensitivity and 98% specificity of that of RT-PCR.
Who should be tested?
People with the presence of ILI symptoms:
When community transfer is evident, ideally all people showing ILI symptoms should be tested for COVID. However, the below categories of people must definitely be tested when showing likely COVID symptoms.
- Had known or possible contact with a lab-confirmed COVID case
- Had contact with a person returned from international travel to a COVID affected country in the last 14 days
- Is residing in a hotspot, containment zone, or building with COVID cases
- Is a migrant and returned to home-town or village in the last 14 days
- Is Hospitalized and develops ILI, or has SARI (Severe Acute Respiratory Infection)
- Is a COVID Health Care Worker (HCW)/Front line worker
People without symptoms (Asymptomatic):
People who possibly had contact with a lab-confirmed COVID positive case and are asymptomatic should be in 14-day self-isolation to observe for symptoms. The same has also been advised to asymptomatic people who have traveled in the last 14 days to a COVID affected country (or had contact with a symptomatic person who had traveled in the last 14 days to a COVID affected country). These people are tested when they develop ILI symptoms.
People living in the same household as a COVID positive case are considered High-Risk Contacts (HRC), and should be in strict isolation for 14 days. Direct Household Contacts as well as those contacts having co-morbid conditions like Diabetes, Hypertension, Cancer, or Elderly>65 years, should be tested immediately on the onset of any possible ILI symptom, or within a period of 5-10 days after their COVID positive contact developed symptoms.
Health Care Workers handling COVID positive patients should be tested if they develop symptoms. If a Health Care Worker has handled a COVID positive case without adequate protection, he/she may be tested even if asymptomatic.
Asymptomatic people are to be tested for COVID if they are due to undergo any hospital procedure or surgery. However, no emergency care should be denied to any patients on grounds of waiting for or getting positive test results. Universal precautions, personal protective equipment (PPE), isolation, and hygienic measures should be taken throughout the procedure and patient’s hospital stay.
This works by testing antibodies (IgM and IgG) to SARS-CoV-2 proteins in the blood (serological test). This is useful for screening large population groups in areas with a high number of cases to detect the extent of disease spread, and how much population has been exposed to the virus. The test being positive can imply both active symptomatic or asymptomatic infection, as well as past exposure and immunity developed to the virus. ELISA (Enzyme-Linked ImmunoSorbent Assay) is a rapid antibody test that can yield results in a few minutes.
X-ray with AI-assessment and High-Resolution Chest CT scans are also being used for the detection of COVID in several countries. Risk of severe disease and mortality is further assessed by an increase in levels of certain blood markers like neutrophil/lymphocyte ratio, CRP (C reactive protein), Lactate Dehydrogenase, D-dimer (signifies risk of thrombosis), Ferritin, Cardiac Troponin 1 and Cytokine IL-6.
There is currently no specific drug/medicine available for COVID-19. All active cases should be placed in strict isolation. Mild cases recover with symptomatic treatment (Paracetamol and Naproxen/Mefenamic acid) for fever and body ache, maintaining hydration, a nutritious diet, and clinical monitoring of symptom severity and oxygen saturation. Sometimes additional drugs for improving cough-cold symptoms may be given like Antihistamines, Montelukast, or Mucolytics like Ambroxol. Nutritional supplements including Vitamin C, D, and Zinc are often prescribed to improve general nutrition and immunity, without any specific role in treating COVID.
Some drugs which were specifically developed and approved in the past for other infections are being researched and tried in certain COVID patients and are therefore called Repurposed medicines. More clinical trials and research data is required and ongoing to confirm the generalized effectiveness in managing COVID-19, of many of the drugs mentioned below. These drugs can have side effects that need to be clinically monitored, especially when given in combination. Therefore they should be used appropriately depending on patient type, disease severity, and presence of associated medical conditions. Most importantly, none of these drugs should ever be taken without the prescription and monitoring of a qualified physician.
Oxygen therapy may be required in moderate-severe cases which can be given at home, or in health-care centers/hospitals. Serious cases may require ICU care with ventilator and life support.
Remdesivir (originally developed for the Ebola virus) and Favipiravir (an anti Flu drug) have shown effectiveness in reducing the recovery time and duration of illness in COVID patients. Remdesivir given by intravenous injection has been approved for treating all hospitalized COVID patients. The recent SOLIDARITY trial by WHO showed no significant effect of Remdesivir on reducing overall mortality, initiation of ventilation, and duration of stay in hospitalized patients. However, the ACTT1 trial (based on which USFDA approval was given) has shown an overall reduction in recovery time, and a mortality reduction in the subgroup of patients on oxygen therapy. Favipiravir is given orally and has been approved for mild-moderate COVID cases.
In some countries where the above drugs are not yet available, anti-HIV drugs like Lopinavir-Ritonavir have been tried with some success, especially when lymphocyte count is extremely low. However, this combination has not shown benefit in hospitalized COVID patients according to the WHO SOLIDARITY drug trial. Recently some early evidence has been seen with the anti-HIV drug Zidovudine but further studies are awaited.
Anti-parasitic and Antibiotic medicines
Hydroxychloroquine, an oral anti-Malaria, and anti-Rheumatoid Arthritis (RA) drug, is being used in many countries, usually with Azithromycin (antibiotic). Results have been encouraging in recent clinical studies with a reduction in viral shedding, hospitalization, ICU admission, and mortality when given early in the course of mild-moderate COVID patients, where it is recommended in some countries. Hydroxychloroquine has not shown benefit in hospitalized patients according to the WHO SOLIDARITY trial. Caution and monitoring with ECG (for QT interval prolongation or heart rhythm abnormalities) is advised, especially in elderly COVID patients with other co-morbid health conditions. Hydroxychloroquine has also been approved in a few countries to prevent symptomatic or severe COVID in exposed or infected health care workers and close/household contacts.
Ivermectin and Nitazoxanide (also anti-parasitic drugs) are also being given in certain centers (sometimes with Doxycycline), in some COVID cases. Data from large clinical studies are yet to confirm the definite place of these medicines in managing COVID, and these drugs are currently not part of standard treatment protocols.
Corticosteroids: Dexamethasone or methylprednisolone (oral/injectable), have shown effectiveness in clinical studies in reducing inflammatory lung damage and mortality in moderate-severe COVID patients on ventilators or requiring oxygen therapy. So far, only corticosteroids have been proven effective for severe or critical hospitalized COVID-19 patients. Sometimes corticosteroids may also be given via nebulizers with or without added bronchodilators.
Tocilizumab, an injectable anti-RA drug (anti-IL-6 cytokine), is being used in certain moderate-severe cases for reducing severe lung disease and symptoms caused due to a ‘cytokine storm’ (which is a damaging hyper-immune reaction with massive inflammation), however latest trial data has not been conclusive of its benefits. Itolizumab, an injectable anti-Psoriasis drug, has also now been approved for limited emergency use in moderate-severe COVID cases.
Another anti-inflammatory anti-RA drug called Colchicine has also shown some early evidence in treating hospitalized COVID patients, but more conclusive research is awaited. Recently some preliminary evidence has come in about Interferon-beta treatment in an inhalational form to prevent severe disease and lung damage in COVID patients.
Aspirin (used early as low dose in mild-moderate cases) can have protective effects on the endothelium by its anti-inflammatory and anti-platelet (anti-thrombotic) action. Low molecular weight Heparins (LMWH like Enoxaparin injected subcutaneously) are anticoagulants, used in hospitalized patients with an increased risk of thrombosis. Alternately oral anticoagulants like Apixaban, Rivaroxaban are also used especially in out-patients at thrombosis risk. Another investigational drug, Nafamostat, also an anticoagulant, is being studied for its anti-viral properties of inhibiting entry and activation of SARS-CoV-2 in human cells. The Statin group of Cholesterol-lowering drugs (like Atorvastatin) also have anti-inflammatory and antithrombotic properties that help protect blood vessels and thereby reduce endothelial damage and dysfunction. These drugs are also being further evaluated for their likely benefits as an adjunct therapy in COVID patients.
Convalescent Plasma is the non-cellular component of the blood from recovered patients which contains antibodies to the COVID virus. It is being used to treat certain severe and non-responsive cases and has helped in the recovery of some patients. However, clinical studies currently have not been able to confirm its efficacy or benefits, and more research is needed, while its large scale feasibility and effectiveness are still being ascertained. Preformed concentrated COVID antibodies (Hyper-Immune Globulin) have also been developed for treatment and short term prophylaxis.
Research labs and companies in some countries have genetically studied and sequenced the COVID virus and are engaged in fast-tracking a potential vaccine, for which clinical trials have already begun and are in various phases. The vaccine types under clinical trials include Inactivated (killed) virus, Vector (adenoviral-CoV spike protein), and Genetic (mRNA) vaccines from various companies around the world. Preliminary phase 3 results have shown the production of protective antibodies in humans with the Pfizer-BioNtech nRNA vaccine and the Oxford University AstraZeneca adenoviral vector vaccine, both given as 2 doses 21 days apart. More confirmatory data is awaited soon, following which commercialization and mass use of vaccines can be expected by early 2021.
LEVELS OF CARE
To prevent overwhelming and overloading of healthcare workers and facilities, a multi-level isolation and treatment system for COVID patients has come into play in some countries like India. Patients with mild symptoms (fever, cough, sore throat, no breathlessness, and blood oxygen saturation>95%), without ant risk factors or pre-existing medical illness, are isolated at Home (if independent room and toilet are available) or in COVID-Healthcare Centers (self-care/basic care repurposed stay centers like hostels, lodges, stadia, guest houses, etc.). These patients should self assess temperature, and oxygen saturation by a digital pulse oximeter, at-least every 4 hours and inform the over-seeing HCW.
Moderate cases (having breathlessness, or blood oxygen saturation <95%, and respiratory rate >24 breaths/min) or patients with comorbidities, are treated in COVID isolation wards in dedicated COVID Hospitals or Hospital blocks with oxygen administering facilities. Severe cases (Oxygen saturation <90%, respiratory rate> 30 breaths/min), are cared for in COVID Hospital ICUs with life support/ventilator availability.
Coronavirus is a family of viruses possessing a single-stranded RNA as the genetic material and is characterized by the presence of spiked glycoproteins on its surface. This gives these viruses the appearance of wearing a crown (or corona) and makes them distinctly identifiable under the microscope. There are many types of Coronaviruses found in humans as well as animals like bats, birds, and pigs. Four types namely the 229E, NL63, OC43, HKU1 Coronaviruses regularly circulate in humans throughout the world and cause the common viral cold.
Sometimes the Coronavirus found primarily in animals and not routinely in humans, can periodically undergo a mutation (change in its genetic material sequencing) into a new virus subspecies (strain). It can then ‘jump’ to humans, through animals that people commonly come in contact with through food products, in wet markets, farms or in various other ways.
The strain of Coronavirus seen first in Wuhan, Hubei province of China which started infecting humans in December 2019, is one such novel Coronavirus strain labeled 2019-nCoV, and the disease it causes is called COVID -19.
In 2002, a similar occurrence originated in Guangdong, China, and that Coronavirus strain was called SARS virus (Severe Acute Respiratory Syndrome). In 2012, another outbreak happened in the Middle East, where Camels were supposed to be the intermediate animals. (MERS -Middle East Respiratory Syndrome virus). The 2019-nCoV has been renamed SARS-CoV-2 in February 2020.
The current Coronavirus SARS-CoV-2 has shown some similarity with a virus that infects the Malaria-causing parasite Plasmodium vivax, suggesting a possible inverse link with fewer numbers and deaths of cases of COVID in Malaria endemic regions of the world. Similarly, a link with the immune-stimulatory and protective effect of BCG vaccine has been suggested. However, the evidence is still early and more studies and research is required and ongoing.
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