Is Hydroxychloroquine beneficial for COVID-19?

Why Anti-malarial(Hydroxychloroquine) is used for the treatment of COVID-19?


Introduction:

Malaria is a life-threatening zoonotic disease caused by the plasmodium parasite. It is transmitted from human to human through bites of a female anopheles mosquito. This disease has reported 228 million cases worldwide in 2018 out of which more than 4 lakh people have died. Almost 94% of the deaths have taken place in Africa according to WHO. Malaria causes an acute febrile illness. The disease is associated with high levels of parasitemia, which may lead to severe anemia, cerebral symptoms, renal failure, pulmonary edema, and death, depending on the susceptibility of the host. (1)
Scientists think there is a presumable pathogenic link with SARS-CoV2, not only being a respiratory illness. As it is an emerging novel Coronavirus, studies are still ongoing to understand it's actual pathogenesis which shall intern help in the treatment and discovery of its vaccine.

What is Hydroxychloroquine?

Quinine is the first recognized potent anti-malarial drug. Chloroquine and hydroxychloroquine are more synthetic versions. They are used in Rheumatic arthritis(2), Systemic lupus erythrocytosis(3) and many more diseases.

Where else Hydroxychloroquine is used?

Hydroxychloroquine is the treatment of choice as anti-microbial in chronic Q-fever endocarditis. Not only anti-bacterial, but researchers also tested for Anti-viral action in AIDS caused by human immunodeficiency virus(HIV). Hydroxychloroquine was shown to inhibit virus replication in T cells, by inhibiting the surface envelope glycoprotein 120(5).”This anti-HIV mechanism lacks cross-resistance with other antiretroviral drugs and was novel in the armamentarium of anti-HIV drugs” With a combined treatment of Hydroxychloroquine,  didanosine and hydroxyurea patients resulted with low viral load, decreased viral replication, and increased the CD4 count.

What are its magical benefits?

-Hydroxychloroquine not only treats but also proven beneficial for reducing cardiovascular risk by improving glycemic control in RA and SLE patients(6). It should be noted, better treatment of choice for type 2 diabetic Mellitus patients where better results inculcated than other drugs.
-It also was shown to be protective against thrombosis in lupus patients with antiphospholipid syndrome (APS).

-Not only that also showed a favorable effect on lipid profile in patients with rheumatic diseases(7).

What happens in COVID-19?
  • With the tip of the iceberg clinical signs of Fever, Cough and shortness of breath, there is a lot more happening inside their bodies with variable clinical severity featuring respiratory and extra-respiratory manifestations.
  • SARS-CoV-2 infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia. It mainly invades alveolar epithelial cells, resulting in respiratory symptoms with mostly upper respiratory symptoms than lower. Lower respiratory infected patients turn out to be more critical with pneumonia-like symptoms, end up in ICU when compared to cough and shortness of breath that of upper respiratory infection. 
  • The respiratory manifestations are shown in axial chest CT’s with extensive bilateral ground-glass opacities and consolidations. Also it causes inflammatory reactions leading to sepsis linked multi-organ failure evolved with dysregulated host responses.
  • In a deep-sea perspective, COVID-19 increases Interleukin-6 concentrations in critically ill patients. IL-6 is mostly pro-inflammatory and it increases during conditions like inflammatory diseases, infections, autoimmune disorders, cardiovascular diseases and some types of cancer.

Hydroxychloroquine and its role in COVID-19?

Studies have demonstrated that chloroquine and hydroxychloroquine inhibit SARS-CoV-2 in vitro with hydroxychloroquine (EC50=0.72%µM) found to be more potent than chloroquine (EC50=5.47%µM).

Hydroxychloroquine proves to regulate cytokinin, inhibit IL-1 and IL-6 in human monocyte and T-cells.  Its anti-inflammatory effect is likened to its preferential inhibition of IL-1-alpha production by monocytes and IL-6 produced by T cells and monocytes. This effect saves critical patients suffering from COVID-19 in ICU. Prolonged beneficial treatment in rheumatoid arthritis also likened to Interlukin-6.  Cytokine release syndrome(CRS), resembling similar to SARS CoV2 like fever and multi-organ dysfunction proved efficient with Hydroxychloroquine .

How Hydroxychloroquine decreases viral load?

-The precise effect is incomparable to malaria but is of considerable interest. In malaria, chloroquine accumulates in the digestive vacuole where it is thought to prevent pH-dependent detoxification of heme, which is produced upon parasitic consumption of hemoglobin to obtain free amino acids. This sequestering effect is also apparent in mammalian cells, in which chloroquine treatment leads to an increase in lysosomal pH and turning suicidal for the parasite.
-Chloroquine-induced antiviral effects include inhibition of pH-dependent viral fusion/replication and prevention of viral envelope glycoprotein as well as host receptor protein glycosylation.
-Chloroquine may also inhibit virion assembly in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-like structures.
-One of the mechanisms responsible for chloroquine-mediated effects against SARS-CoV2 is a general decrease in the ability of cells to perform clathrin-mediated endocytosis of nanosized structures due to PICALM suppression.


-As mentioned earlier chlorine exhibits host effects, independent of direct viral action, by attenuating the expression of pro-inflammatory factors and receptors that can induce acute respiratory distress syndrome, which is primarily responsible for coronavirus-associated mortality.
-Moreover, chloroquine-induced prevention of endosome–lysosome fusion is likely to interfere with general endocytic trafficking, such as membrane receptor recycling, which is thought to be required for SARS-CoV-2 cellular entry. Thus, decreasing the viral load in an affected patient.
-Studies also suggestive of anti-SARS-CoV2 activity in cell culture even when administered after viral uptake, suggesting that multiple beneficial mechanisms may be involved(9)

How effective is Hydroxychloroquine against COVID-19?

  • As per the clinical trials approved by the French ministry of health on 36 patients, out of which 22 had an upper respiratory infection, 8 had lower and 6 were asymptomatic. Ultimately, 22 patients got treated with 200mg thrice daily, showed a significant reduction of the viral carriage and much lower average carrying duration. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.
  • A day6 post-inclusion, 70% of hydroxychloroquine-treated patients were virologically cured comparing with 12.5% in the control group.

Figure 1. Percentage of patients with PCR-positive nasopharyngeal samples from inclusion to day6 post-inclusion in COVID-19 patients treated with hydroxychloroquine and in COVID-19 control patients. 
Are they other useful drugs?
  1. Azithromycin (Antibiotic) 500mg on the initial day followed by 250mg used with hydroxychloroquine has decreased the carrying duration by half. Previously, azithromycin showed beneficial in-vitro against Zika and Ebola viruses.

Figure 2. Percentage of patients with PCR-positive nasopharyngeal samples from inclusion to day6 post-inclusion in COVID-19 patients treated with Hydroxychloroquine only, in COVID-19 patients treated with Hydroxychloroquine and Azithromycin combination, and in COVID-19 control patients. 
  1. Corticosteriods - Chinese have used Corticosteriods in severe COVID-19 patients, who are assisted on ventilator support to prevent the development of ARDS. Pathological findings of pulmonary edema and hyaline membrane formation also prompt timely and appropriate use of Corticosteriods(8).
  2. Remdesivir - which is recent, analyzed by Gilead Sciences, a research-based biotech company performed trials on 53 patients who received 200mg(IV) on day 1, followed by 100mg for rest of the 9 days. 31 patients(68%) showed improvement with only 18%(6 of 34) mortality among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. Overall 13% mortality is better than 17 to 78% in china among severely affected cases.

What are the side-effects of Hydroxychloroquine?

-From minor symptoms like nausea, vomiting, skin rashes, itching, headache and visual disturbances. 
-Parenteral administration causes hypotension, confusion, cardiac arrhythmias, convulsions and cardiac arrest.
-Prolonged use in large doses causes cardiomyopathy, irreversible retinopathy and ototoxicity.
Out of 100 incidents, 43 were linked to cardiovascular by the French health officials on their experimental hydroxychloroquine trials on COVID-19 patients. (11)
I request health workers and high-risk individuals to consult a doctor before using hydroxychloroquine as a prophylactic or treatment measure.
Noteworthy info: Unlike typical pneumonia affecting particle lobe of a lung, COVID-19 effects various lobes of both lungs, based on CAT Scan of a 59-year-old patient at The George Washington University Hospital, USA.
"An ounce of prevention is worth a pound of cure"

Citations:

1.Syed A Hoda, MD, Esther Cheng, DO, Robbins Basic Pathology, American Journal of Clinical Pathology, Volume 148, Issue 6, December 2017

2.Clark P, Casas E, Tugwell P, Medina C, Gheno C, Tenorio G, et al. Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med. 1993;119(11):1067–1071.

3.Molad Y, Gorshtein A, Wysenbeek AJ, Guedj D, Majadla R, Weinberger A, et al. Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort. Lupus. 2002;11(6):356–361. doi: 10.1191/0961203302lu203ra.

4. Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol. 1993;20(5):803–808.


6. Shojania K, Koehler BE, Elliott T. Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis. J Rheumatol. 1999;26(1):195–196.

7.Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med. 1990;89(3):322–326. doi: 10.1016/0002-9343(90)90345-E.

8.Gautret, Philippe, et al. “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial.” International Journal of Antimicrobial Agents, Elsevier, 20 Mar. 2020, www.sciencedirect.com/science/article/pii/S0924857920300996.

9.Hu, Tony Y., et al. “Insights from Nanomedicine into Chloroquine Efficacy against COVID-19.” Nature News, Nature Publishing Group, 23 Mar. 2020, www.nature.com/articles/s41565-020-0674-9#ref-CR7.

10.Gautret, Philippe, et al. “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial.” International Journal of Antimicrobial Agents, Elsevier, 20 Mar. 2020, www.sciencedirect.com/science/article/pii/S0924857920300996.

11.https://thehill.com/policy/international/europe/492317-french-officials-report-heart-incidents-in-experimental

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