COVID-19: A Clinician’s Perspective Simplified. (Part 2)
In part 2 of this article, I will discuss the different diagnostic and therapeutic strategies currently under observation for COVID 19.
Diagnosing the disease:
Before discussing the diagnostic tools available for SARS COV 2, it would be worthwhile to understand what sensitivity and specificity are concerning medical testing.
The sensitivity of a test is a measure of the true positive rate of the test i.e. how many patients, who actually have the disease, are correctly diagnosed as having the disease by the test.
The specificity of a test is a measure of its true negative rate i.e. how many suspected people, who actually do not have the disease, are correctly diagnosed as not having the disease by the test.
A general explanation is that a test can have a high sensitivity but low specificity, in which case being tested positive with the test almost certainly means you would have the disease but being tested negative does not mean you do not have the disease. Or a test can have a high specificity but low sensitivity, in which case being tested negative with the test almost certainly means you do not have the disease but being tested positive does not mean you have the disease! Usually, tests with both high sensitivity and specificity are preferred for routine laboratory examinations.
THE RT-PCR:
The hallmark test for diagnosing COVID 19 is the RT-PCR (the reverse transcription Polymerase Chain Reaction). The viral genome of SARS COV 2 is a single-stranded RNA. Hence this test is utilized in which the viral RNA is first converted into a complementary DNA strand (cDNA) using reverse transcriptase, and then the cDNA is incubated and processed in a pool of nucleotides, primers, and special DNA polymerases. The purpose of this is to synthesize a large number of DNA strands, amplifying the small sample collected from the patient.
This test is highly specific, and the sensitivity of this test is undetermined (though it is assumed to be around 66% to 80%1. A suspected patient may undergo sample collection via nasal swabs, oropharyngeal swabs, tracheal aspirate, or bronchoalveolar lavage (BAL). It is still up for debate which site yields the most accurate results, but for convenience, an upper respiratory swab (nasal or oropharyngeal) is the preferred collection site. Given correct instructions, even the patients themselves can collect nasal swab samples at home and send them to a laboratory for testing. Since there is also virus shedding in the stools of COVID-19 patients, as I have described in part 1 of this article, a stool sample can also be used to run the RT-PCR2.
The Chest CT-scan:
Another widely employed radiological test for diagnosing COVID-19 is the chest CT scan. This test is especially employed to help diagnose COVID-19 in countries such as India and Pakistan, where there are densely populated areas with rampant disease spread and an overburdened healthcare system. Due to lack of supplies and funding, the governments cannot ramp up RT-PCR testing quickly enough to match the disease transmission and are compensating with already employed diagnostic facilities like the chest CT scan.
The typical appearance of COVID-19 on a chest CT scan is of ground-glass opacities, in the peripheral and lower lung fields, and areas of lung consolidation (refer to part 1 of the article). In general, the worse the disease, the larger the areas of lung consolidation. Other visual cues also include pleural thickenings, pleural effusion, and lung honeycombing (due to pulmonary fibrosis).
The sensitivity of this test is high (about 87 to 95%) in patients with clinically severe disease but is quite low (about 50%) in patients with only mild disease2. It is best used when combined with the RT-
PCR.
USG and Chest X-ray:
Ultrasonic findings of B-lines, pleural thickenings, pleural effusions, etc., have been observed with COVID-19 patients. The test has a very low specificity and, though some studies show a sensitivity of up to 75%3, the test is highly operator dependent and not very reliable. Similarly, a chest X-ray can also be used to visualize areas of lung consolidation but its sensitivity is also quite low, approximately 59%4.
The main role of USG and chest X-rays are in determining disease progression and prognosis in already diagnosed cases.
Other lab findings:
Other findings include:
- leucopenia (a decrease in circulating white blood cells found in almost 34% of COVID 19 patients),
- leukocytosis (an increase in circulating white blood cells found in almost 24-30% of COVID-19 patients),
- increased blood concentrations of alanine aminotransferase and aspartate aminotransferase (found in 37% of patients),
- lymphocytopenia (a decrease in circulating lymphocytes found in 83% of COVID-19 patients)
- Thrombocytopenia (decrease in platelet count found in 36% of patients)
- Increased levels of Troponin (probably from the acute myocardial injury of COVID-19)
- Acute-phase proteins, like increased CRP levels which are markedly raised in patients with severe disease. 2
Treating the disease:
Supportive Oxygen Therapy:
In severe cases with large areas of lung consolidation, the patients are unable to maintain an adequate level of oxygen saturation. If the SpO2 of a COVID-19 patient falls below 93%, immediate oxygen therapy must be initiated via non-invasive methods like nasal catheters and face masks. If the patient is still unable to maintain a SpO2 of above 93%, a CPAP (continuous positive airway pressure) device is recommended. If a CPAP fails as well, then invasive oxygen delivery must be undertaken via tracheal intubation and mechanical ventilation with high PEEP (positive end expiratory pressure) values2,5–9. In simplified terms, the reasoning behind CPAP and high PEEP values is to prevent alveolar collapse (discussed in part 1 where I explained why COVID-19 causes lung consolidation and collapse by damaging surfactant production) and to hopefully recruit more and more alveoli with each breath.
Unfortunately, recent evidence suggests that even with such invasive measures to maintain SpO2, many patients who go on a ventilator do not survive.
Remdesivir:
As of the writing of this article, the only drug with robust, statistically proven clinical benefit in treating COVID-19 is Remdesivir. A trial involving 1063 patients was undertaken in several different hospitals, and it was observed that Remdesivir shortened hospital stay of patients on an average of 4 days (shorter hospital stay results in more availability of hospital facilities for newer patients) and also decreased mortality from approximately 11.9% to 7.1%10.
Remdesivir’s mechanism of action is inhibition of the viral RNA dependent RNA polymerase required for replicating the viral genome. The drug is available as an IV infusion only and the team researching Remdesivir gave participants a dose of 200 mg OD on the first day and then a 100 mg OD for up to 9 days10,11.
The known side effects of the drug include acute kidney injury and elevated liver enzymes. The drug is not recommended for use in patients whose GFR (glomerular filtration rate, a measure of kidney function) is below 30 ml/min. Other contraindications and side effects may be present but they are currently unknown and it is recommended that the drug not be used during pregnancy 11.
Chloroquine\Hydroxychloroquine:
Although these drugs have shown in vitro evidence of thwarting SARS COV 2 replication, actual data from clinical studies is lacking. It is thought that Hydroxychloroquine and Chloroquine act by:
- Inhibition of glycosylation of the ACE 2 receptor, preventing viral attachment to it.
- Raising endosomal pH, which, in broad terms, hampers the ability of the virion to replicate inside the cells.
- It has immunomodulatory effects that might help decrease the overwhelming cytokine storm in critically ill patients. 12
Dosing for chloroquine is 500mg BD for 5 to 10 days. For Hydroxychloroquine, a recommended loading dose of 400mg BD is given for the first day followed by 200mg BD for the next 4 days. The drugs are highly toxic and have a slew of side effects including anorexia, vomiting, diarrhea, arrhythmias, hemolytic anemias, and visual changes and retinal toxicities. 2,11,12
Other drugs:
Other antivirals like Lopinavir/ritonavir, Favipiravir, and Umifenovir are also being tested along with immunomodulatory compounds like Tocilizumab2,11. It is very well possible that the final proposed treatment of COVID-19 is a combination of antivirals and other drugs, like what we see with HIV.
Convalescent Plasma (CP):
It is observed that people who have already cleared the infection have, in most cases, developed a strong antibody response against the virus. It is possible to extract these antibodies containing plasma from the survivors of COVID-19 and inject it into patients with an active infection. The theory is that:
- Passive immunity will be gained via the injection of these antibodies, which will help the host immune response to fight the infection.
- Immunomodulatory effects (through very complex mechanisms) of the injected antibodies to prevent excessive inflammatory and autoimmune damage. 13
This treatment too is not universally available, in countries where COVID-19 is rapidly spreading there are a lot more patients than there are donors of CP, transfusion related reaction like anaphylaxis and mismatch are also possible, and transfusion related diseases are also a challenge like HIV, Hepatitis B, Hepatitis C, Syphilis, etc. 14
References:
1. Ai, T. et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology 200642 (2020) doi:10.1148/radiol.2020200642.
2. Pascarella, G. et al. COVID‐19 diagnosis and management: a comprehensive review. J. Intern. Med. joim.13091 (2020) doi:10.1111/joim.13091.
3. Huang, Y. et al. A Preliminary Study on the Ultrasonic Manifestations of Peripulmonary Lesions of Non-Critical Novel Coronavirus Pneumonia (COVID-19). https://papers.ssrn.com/abstract=3544750 (2020) doi:10.2139/ssrn.3544750.
4. Bernheim, A. et al. Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection. Radiology 295, 200463 (2020).
5. Guo, Y.-R. et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil. Med. Res. 7, 11 (2020).
6. Arabi, Y. M., Fowler, R. & Hayden, F. G. Critical care management of adults with community-acquired severe respiratory viral infection. Intensive Care Med. 46, 315–328 (2020).
7. Rello, J. et al. Coronavirus Disease 2019 (COVID-19): A critical care perspective beyond China. Anaesth. Crit. Care Pain Med. 39, 167–169 (2020).
8. Fan, E. et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am. J. Respir. Crit. Care Med. 195, 1253–1263 (2017).
9. Li, T. Diagnosis and clinical management of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0). Emerg. Microbes Infect. 9, 582–585 (2020).
10. Beigel, J. H. et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. N. Engl. J. Med. NEJMoa2007764 (2020) doi:10.1056/NEJMoa2007764.
11. Sanders, J. M., Monogue, M. L., Jodlowski, T. Z. & Cutrell, J. B. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA (2020) doi:10.1001/jama.2020.6019.
12. Singh, A. K., Singh, A., Shaikh, A., Singh, R. & Misra, A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab. Syndr. 14, 241–246 (2020).
13. Rojas, M. et al. Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmun. Rev. 19, 102554 (2020).
14. Zhao, Q. & He, Y. Challenges of Convalescent Plasma Therapy on COVID-19. J. Clin. Virol. 127, 104358 (2020).
