Home Features The Science of COVID-19: COVID-19 and Treatment of Adults
Moti Ramgopal, MD, FACP, FIDSA
Medical Director, Midway Immunology and Research Center
Founder, Midway Specialty Care
Associate Professor, Florida State University
Dr Moti Ramgopal, the Guyanese doctor who led the clinical trial on COVID-19 treatment given to US President Donald Trump
Since March this year, I have treated hundreds of cases of patients infected with COVID-19, but three cases in particular have aroused my curiosity about the genetic relationship of COVID-19. Do genes play a role in how severe symptoms will be?
Take the case of JT, age 61, I saw over a month ago with a history of COPD, hypertension and diabetes, who developed fatigue, body aches, cough, shortness of breath, and a temperature of 101.6 degrees Fahrenheit. His COVID test was postive.
His oxygen saturation was 94 per cent on 3.5 L. Indicators of severe disease are marked tachypnea (respiratory rate, ≥30 breaths per minute), hypoxemia (oxygen saturation, ≤93 per cent; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, 50 per cent of the lung field involved within 24 to 48 hours).
Once admitted, he started treatment with decadron, remdesivir, convalescent plasma, vitamin C, zinc and anticoagulants. With a history of diabetes and obesity, iron deteriorated, and he was enrolled into clinical trials and received several investigational drugs as well as Actemra, an immunomodulator.
30 days later, he is currently hospitalised with a tracheostomy tube and a feeding tube.
His brother PT, with diabetes, hypertension, and obesity as well as bladder cancer, was admitted two days prior to his brother’s admission with cough and a positive COVID-19 test.
PT was hospitalised for four days and discharged on oxygen after he clinically improved. PT was readmitted five days later with worsening shortness of breath and he was started on Remdesivir, Decadron, heparin and plasma. PT’s condition improved over the next three days, but then went into cardiac arrest with ventricular arrhythmia and died.
Their 82-year-old mother was infected with COVID as well, but was asymptomatic until she presented three weeks later for thromboembolic event, or a blood clot, involving her right leg. She developed ischemia, an inadequate blood supply, requiring amputation. The family decided on hospice care.
These three cases question the genetic component of COVID-19. A UK group studying more than 2200 COVID-19 patients has pinned down common gene variants that are linked to the most severe cases of the disease.
In June, one such genome-wide association study in “The New England Journal of Medicine (NEJM)” found two “hits” linked to respiratory failure in 1600 Italian and Spanish COVID-19 patients: a marker within the ABO gene, which determines a person’s blood type, and a stretch of chromosome three that holds a half-dozen genes.
A gene called IFNAR2 codes for a cell receptor for interferon. A variant of this gene raises the risk of severe COVID-19 by 30 per cent. There are genes which code proteins, that can activate an enzyme that breaks down viral RNA changes in this gene, and this activation allows the virus to flourish.
Also, genes can code for proteins to ramp-up the inflammatory response to lung damage triggered by COVID-19. Genes DPP9 and TYK2 are involved in inflammation and blocking these enzymes may be beneficial. CCR2 is a gene that encodes a receptor for cytokine proteins that play a role in inflammation. But other data points to SLC6Z20, which codes for a protein that interacts with the main cell receptor used by COVID-19 to enter cells.
The importance of recognising the genetic impact may influence treatment strategies.
It is still unknown why African-American or Hispanic patients had such a higher risk of infection, but this can be related back to pre-existing conditions. However, I would not be surprised if there is a genetic relationship that can be found.
Blood type A is associated with a higher risk of respiratory failure. COVID-19 is primarily spread from person to person through respiratory particles, probably of varying sizes, which are released when an infected person coughs, sneezes, or speaks. Because both smaller particles (aerosols) and larger particles (droplets) are concentrated within a few metres, the likelihood of transmission decreases with physical distancing and increased ventilation.
Aerosols can be generated under circumstances, such as talking, singing, or shouting indoors in poorly ventilated environments. In these situations, transmission over longer distances may occur. Respiratory transmission is probably the main mode of transmission, hence masking and physical distancing markedly decrease the chance of transmission. Under laboratory conditions, COVID-19 may persist on cardboard, plastic and stainless steel for days.
Patients can be infectious one to three days before symptom onset, and up to 40-to-50 per cent of cases may be attributable to transmission from asymptomatic or presymptomatic people. Just before and soon after symptom onset, patients have high nasopharyngeal viral levels, which then fall over a period of one to two weeks.
A patient may be positive for weeks to months, but viable virus and contact-tracing assessments suggest that the duration of infectivity is much shorter and isolation can be lifted in most patients 10 days after symptom onset if fever has been absent for at least 24 hours and other symptoms have decreased.
The clinical spectrum of COVID-19 infection ranges from asymptomatic infection to critical illness. Among patients who are symptomatic, the median incubation period is approximately four to five days, and 97.5 per cent have symptoms within 11.5 days after infection.
Symptoms may include fever, cough, sore throat, malaise and myalgias. Some patients have gastrointestinal symptoms, including anorexia, nausea and diarrhoea. Anosmia (loss of smell) and ageusia (loss of taste) have been reported in up to 68 per cent of patients and are more common in women than in men.
Risk factors for complications of COVID-19 include older age, cardiovascular disease, chronic lung disease, smoking, pregnancy, diabetes, and obesity. It is unclear whether other conditions (for example, uncontrolled HIV infection or use of immunosuppressive medications) confer an increased risk of complications, but these conditions may be associated with worse outcomes after infection with other viruses.
Laboratory findings in hospitalised patients may include lymphopenia and elevated levels of d-dimer, lactate dehydrogenase, C-reactive protein and ferritin. These inflammatory markers are important to trend during the clinical course.
Evaluation of COVID-19 is guided by the severity of illness. According to data from China, 81 per cent of people with COVID-19 had mild or moderate disease (including people without pneumonia and people with mild pneumonia), 14 per cent had severe disease, and five per cent had critical illness. Patients who have mild signs and symptoms generally do not need additional evaluation.
However, some patients who have mild symptoms initially will subsequently have precipitous clinical deterioration that occurs approximately one week after symptom onset. In patients who have risk factors for severe disease, close monitoring for clinical progression is warranted, with a low threshold for additional evaluation. If new or worsening symptoms (for example, dyspnea) develop in patients with initially mild illness, additional evaluation is warranted.
Physical examination should be performed to assess for tachypnea, hypoxemia, and abnormal lung findings. In addition, testing for other pathogens (for example, influenza virus, depending on the season, and other respiratory viruses) should be performed, if available, and chest imaging should be done. Typical findings are ground-glass opacifications or consolidation.
Hallmarks of moderate disease are the presence of clinical or radiographic evidence of lower respiratory tract disease, but with a blood oxygen saturation of 94 per cent or higher while the patient is breathing ambient air.
Indicators of severe disease are marked tachypnea (respiratory rate, ≥30 breaths per minute), hypoxemia (oxygen saturation, ≤93 per cent; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, 50 per cent of the lung field involved within 24 to 48 hours).
Remdesivir, an inhibitor of RNA-dependent RNA polymerase, has activity against COVID-19 in vitro and in animals.
In the Adaptive COVID-19 Treatment Trial 1 (ACTT-1), which involved hospitalised patients with evidence of lower respiratory tract infection, those randomly assigned to receive 10 days of intravenous remdesivir recovered more rapidly than those assigned to receive placebo (median recovery time, 10 vs 15 days); mortality estimates by day 29 were 11.4 per cent and 15.2 per cent, respectively. In another trial, clinical outcomes with five days of remdesivir were similar to those with 10 days of remdesivir.
Currently, remdesivir is recommended for the treatment of hospitalised patients with severe COVID-19, but consider data to be insufficient to recommend for or against the routine use of this drug for moderate disease – studies are ongoing.
Data from patients with COVID-19 who were enrolled in a large expanded-access programme for convalescent plasma in the United States suggested that mortality might be lower with receipt of plasma with a high titer of antibody than with receipt of plasma with a low titer of antibody; the data also suggested that mortality might be lower when plasma is given within three days after diagnosis than when plasma is given more than three days after diagnosis.
Ongoing randomised trials must be completed to determine the role of convalescent plasma.
Monoclonal antibodies directed against the COVID-19 spike protein are being evaluated in randomised trials as treatment for people with mild or moderate COVID-19 and as prophylaxis for household contacts of persons with COVID-19.
In the recovery trial, dexamethasone reduced mortality among hospitalised patients with COVID-19, but the benefit was limited to patients who received supplemental oxygen and was greatest among patients who underwent mechanical ventilation.
Clinical studies have shown that in 1703 critically able patients, glucocorticoid reduced mortality versus standard of care passivity of 32 per cent versus 40 per cent.
Dexamethasone can be given at a dose of 6 mg a day for 10 days or until discharge. Other steroids may be similarly effective, such as hydrocortisone, methylprednisolone, and prednisone.
Dexamethasone did not improve outcomes, and may have caused harm among patients who did not receive supplemental oxygen, and thus it is not recommended for the treatment of mild or moderate COVID-19.
Use of concomitant
people with COVID-19
Because COVID-19 enters human cells through the ACE2 receptor, questions were raised regarding whether the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) – which may increase ACE2 levels – might affect the course of COVID-19. However, large observational studies have not shown an association with increased risk.
Patients who are receiving ACE inhibitors or ARBs for another indication should not stop taking these agents, even if they have COVID-19.
Regeneron cov 2 antibody cocktail has shown to rapidly reduce viral load and associated symptoms and cause an antibody to spike protein that neutralises the virus. Broadly direct acting antivirals are now in clinical trials. They have been shown to inhibit replication of viral pathogens from multiple RNA virus families including SARS influenza RSV, filovirus, flavivirus to name a few.
The mechanism of antiviral activities viral error catastrophe is a concept that’s predicated on increasing the viral mutation rate beyond a biologically tolerable threshold resulting in impairment of viral fitness and activity leading to viral extinction.
There are multiple other strategies for antiviral work. Another mechanism in treatment is the role of light cytokine which belongs to the TNF family, which is secreted in high-level general viral infection by reducing the cytokine. This is associated with related lung fibrosis and cytokine storm.
Infection Control and Prevention healthcare workers must be protected from acquiring COVID-19 when they are providing clinical care. Using telehealth when possible, reducing the number of healthcare workers who interact with infected patients, ensuring appropriate ventilation, and performing assiduous environmental cleaning are critical.
PPEs used while caring for patients with known or suspected COVID-19 should include, at a minimum, an isolation gown, gloves, a face mask, and eye protection (goggles or a face shield).
Article submitted as part of the Ministry of Health’s COVID-19 public information and education programme