COVID-19 Controversies

Dr Swapnil Pawar April 5, 2020 324

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Many novel therapies have been proposed in our battle against this deadly pandemic. In this podcast, we summarise the literature available to date and present our views so you can make an informed decision while treating your patients with COVID-19.

COVID-19 Literature

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in COVID-19

Do ACE inhibitors and ARBs help or harm? It has been shown that COVID-19 uses the ACE2 receptor to gain access into cells . This has led to the hypothesis ACE inhibitors and ARBs may upregulate ACE2 expression, leading to increased predisposition to COVID-19 infection. However, according to Perico et al., the entry of the virus into the cell is a complex, tightly regulated process involving several steps. Besides, ARBs and angiotensin II compete for the same receptor; this may result in an increase in the release of angiotensin. An increase in angiotensin II levels leads to enhanced binding to the catalytic site of ACE2 receptors. An increase in binding may lead to a structural change in the ACE2 receptor that may inhibit the binding of the virus to the receptor and prevent cellular entry. This has led to the suggestion that ARBs may, in fact, reduce the extent of lung damage in patients with COVID-19 disease. Considering the conflicting theories and lack of clinical data, most guidelines, including those of the American College of Cardiology recommend the continued administration of ARBs and ACE inhibitors among patients who are currently on treatment

Hydroxychloroquine (HCQ)

Discovered in 1934, and extensively used in the treatment of malaria for decades, chloroquine may exhibit anti-viral activity through several mechanisms. It may inhibit pH-dependent steps involved in viral replication, besides inhibition of the generation and release of TNF-alpha and IL-6 (2). It may suppress cellular autophagy, leading to the inhibition of viral replication (3).

In a pilot study, patients with confirmed COVID-19 disease were randomized to receive HCQ 400 mg/d for 5 days compared to standard care. Clearance of viral nucleic acid from pharyngeal swabs occurred in 13/15 (86.7%) patients in the HCQ group and 14/15 (93.3%) patients in the control group. There was no difference between the HCQ-treated and control groups regarding the time to defervescence or progression of changes on CT imaging (4).

In a French study, 20 patients with confirmed COVID-19 disease received HCQ 600 mg/d; azithromycin was added based on the clinical situation. Sixteen patients from another center acted as controls. By day 3, 50% of HCQ-treated patients tested negative for the virus by RT-PCR compared to 6.3% in the control group; by day 6, 70% among the treated group tested negative compared to 12.5% in the control group. The addition of azithromycin seemed to augment viral clearance (5). 

However, the outcomes of six patients from the treatment group were not reported in this study. Clinical worsening occurred in three patients requiring ICU admission and one patient died, while treatment was discontinued in two other patients. There was no mortality or requirement for ICU admission in the control group. Hence, apart from early viral clearance, this study does not demonstrate any clinical benefit associated with the use of HCQ.

The use of hydroxychloroquine is currently being evaluated in several clinical trials as pre- or post-exposure prophylaxis for COVID-19 infection. No data are currently available to guide the dose or duration of prophylactic HCQ.

Lopinavir-ritonavir combination

Does specific anti-viral therapy help in COVID-19 disease?

In a recently published randomized controlled trial, Cao et al. evaluated the efficacy of the lopinavir-ritonavir combination among patients with an oxygen saturation of less than 94% while breathing room air or P/F ratio of less than 300 mm Hg. The primary endpoint was the time interval from randomization to improvement by two points on a seven-category scale or hospital discharge, whichever occurred earlier. There was no difference between the anti-viral combination and standard care in the primary outcome. No significant difference was observed in the 28-d mortality between groups. Besides, there was no difference in the number of patients with detectable viral RNA at different points of time during the course of treatment (6). This study suggests that the lopinavir-ritonavir combination may not improve clinical outcomes or reduce viral shedding in patients with COVID-19 disease.

A post-hoc analysis of patients who received treatment within 12 days of disease onset revealed reduced mortality among patients who received the lopinavir– ritonavir combination. Whether earlier treatment would favorably influence clinical outcomes needs further rigorous research.

CT imaging

Patients with COVID-19 disease have shown characteristic features on CT imaging that may help with early diagnosis and evaluation of disease progression. Peripheral and subpleural ground-glass opacities (GGO) are one of the common features. The GGO may be unilateral or bilateral (9). Thickening of interlobular septa and intralobular lines against a background of GGO may result in a typical “crazy paving” pattern. Patchy consolidation, air bronchograms, pleural thickening, and sub-pleural curvilinear lines are other CT features among patients with COVID-19 pneumonia (10).

Chest CT imaging may allow early, reliable diagnosis in patients presenting with COVID-19 pneumonia compared to RT-PCR. Ai et al. studied 1014 patients who underwent CT imaging and RT-PCR testing during a 1-month period in Wuhan, China. Among patients suspected of COVID-19 disease, RT-PCR was positive in 601/1014 (59%), while CT imaging was diagnostic in 888/1014 (88%) patients. When RT-PCR was used as the reference, chest CT revealed a sensitivity of 97%. Among 308 patients with negative RT-PCR and a diagnostic CT scan, 147 (48%) were considered to be highly likely, and 103 (33%) patients were considered to have probable COVID-19 disease (11). When serial RT-PCR and CT scans were analyzed, 60–93% of patients had an initial diagnostic CT, prior to positive RT–PCR test results.

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