Dr. Idrees Marwat
COVID-19 is caused by a single stranded RNA virus. It is called severe acute respiratory syndrome Coronavirus 2, or SARS CoV 2. An attack of this virus on the human immune system still remains a conundrum.
Cov 2 morphology
While understanding the Pathogenesis, let’s first study it’s structure and the part of it’s structure responsible for attacking the human cell.
The virus has following morphological components:
1- Spikes
The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit
2- Hemagglutinin esterase (HEs) dimers
These are the glycoproteins, that certain enveloped viruses possess and use as an invading mechanism.
HEs help in the attachment and destruction of certain sialic acid receptors that are found on the host cell surfaces.
3.Envelope protein.
4.Membrane protein.
5.Lipid membrane.
6.Nucleoplasmid containing RNA.
Cov 2 Safari
The Coronavirus starts it’s journey from nose, mouth or eye’s epithelial cells, making it to the alveoli of the lungs which are responsible for exchange of gases.
Cov 2 as an appendage of the cells
Coronavirus through it’s spikes attaches with the ACE-2 receptors, which are mainly present on type II alveolar cells.
This attachment allows the virus to enter inside the cells. The virus thus injects it’s RNA, seizing the cell’s own system and commandeering the human cells to prepare it’s own RNA, hence releasing more and more RNA inside to infect other cells. Now it’s our own cells that start replicating viral RNA. The host cells are destroyed and the virus attack other cells. When they attack the cells, their capacity of synthesis of interferon is destroyed and without competition it’s RNA attacks other cells.
Normal cellular mechanism
The alveoli are lined by 2 types of cells, type I and type II, covered by the capillaries. The RBCs release their CO2 and picks up the O2.
The type I cells are thin enough and gases are exchanged easily.
The type II cells release surfactant and keeps the alveoli patent.
Symptoms due to viral attack on human cells
When the virus attaches to type II cells, their normal mechanism is destroyed.
Role of human immune system
When type II alveolar cells are infected, they release inflammatory signals which recruit macrophages (immune cells).
These macrophages release more cytokines which cause vasodilation to recruit more immune cells to the site of injury and exit the capillaries.
Stay at home
Symptoms
1.Dry cough
2.Fever
3.Flu etc
After all this, more fluid enters in the alveoli and dilutes the surfactants which cause alveolar collapse resultantly preventing the exchange of gases.
Symptoms
Pneumonia and shortness of breath
The neutrophils are recruited and release the reactive oxygen species (ROS) to destroy the infected cells.
After destruction of alveolar type I and type II cells, the alveoli are collapsed and cause acute respiratory distress syndrome (ARDS).
Symptoms
Hospitalise the patient
Dangerous for high risk patients, i.e, above 60, those with diabetes, COPD, hypertension, autoimmune diseases, on chemotherapy, on dialysis etc.
If the condition worsens further, the protein rich fluid enters the blood and reaches other areas of the body causing systemic inflammatory response syndrome (SIRS),
Note: when the immune system attacks the infected cells it also kills the healthy cells which as a consequence results in three things than hinders gaseous exchange
a. Alveolar collapse because of loss of surfactants due to destruction of type II alveolar cells.
b. Less oxygen enters the blood stream due to lack of type I cells.
c. More fluid enters the alveoli, which may cause fibrosis
Shift In ICU
Symptoms
Needs ventilator and life support
Complications may develop in untreated patients
SIRS may cause multi-organ failure and septic shock. Consequences can be fatal.
Note: In ICU
With proper care, patient May recover at any stage during this process
Effect of drugs
No vaccine available
Symptomatic and supportive treatment
1. Hydroxychloroquine and chloroquine
Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore, also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro.
The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro.
Based on PBPK models, the authors recommended a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days.
A larger study was performed by Prof. Roullete at IHU Méditerranée Infection, Marseille, France. A cohort of 1061 COVID-19 patients, treated for at least 3 days with the Hydroxychloroquine-Azithromycin (HCQ-AZ) combination and a follow-up of at least 9 days was investigated.
Key findings were:
* No cardiac toxicity was observed.
* A good clinical outcome and virological cure was obtained in 973 patients within 10 days (91.7%).
A poor outcome was observed for 46 patients (4.3%); 10 were transferred to intensive care units, 5 patients died (0.47%) (74-95 years old) and 31 required 10 days of hospitalization or more.
The authors conclude that:
“The HCQ-AZ combination, when started immediately after diagnosis, is a safe and efficient treatment for COVID-19, with a mortality rate of 0.5%, in elderly patients. It avoids worsening and clears virus persistence and contagiosity in most cases.”
2. Antivirals & Corticosteroids
A small prospective study found no evidence of a strong antiviral activity or clinical benefit. Corticosteroids are not generally recommended for treatment of COVID-19 or any viral pneumonia. The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS.
3. Ivermectin
It is a broad-spectrum anti-parasitic agent. Researchers infected cells with SARS-CoV-2, then exposed them to ivermectin. A single dose of ivermectin could kill COVID-19 in a petri dish within 48 hours, indicating potent antiviral activity, says Prof. David Jans, PhD, at Monash University in Melbourne. But experts say more testing is needed to know if it works well in humans and if it’s safe to use.
4. Use of convalescent plasma
Trials conducted on ten Covid-19 patients in China had showed significant improvement in their symptoms after convalescent plasma therapy was administered to them.
However, the opinion on application of convalescent plasma or whole blood sto-cks-still, as the mystery of Cov 2 engaging Porphyrin resultantly amassing free iron (iron overload) and also compromising O2 supply to the body tissues remain an enigma.
