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Novel Therapies and Diagnostic Tools in COVID-19

Dr Swapnil Pawar April 18, 2020 304 1


Background
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Source – JAMA Network April 2020

Remdesivir

The nucleotide analog remdesivir has in vitro activity against SARS-CoV-2. It was used on a compassionate basis in 61 patients with COVID-19 who had an oxygen saturation of less than 94% on room air or required supplemental oxygen. Remdesivir was administered intravenously in a dose of 200 mg on day 1, followed by 100 mg per day for 9 days. Clinical outcomes of 53 of the 61 patients were analyzed. At baseline, 30 patients (57%) were invasively ventilated and four patients were on extracorporeal membrane oxygenation (ECMO). The median follow-up period was 18 days. The level of the oxygen support device (ECMO, invasive mechanical ventilation, non-invasive ventilation, high-flow oxygen, or low-flow oxygen) could be scaled down in 36 patients (68%). Seventeen of 30 patients (57%) who were invasively ventilated could be extubated. Twenty-five patients (47%) had been discharged, and seven (13%) had died at the time of follow up. The mortality among invasively ventilated patients was 18% (6/34); mortality was 5% (1/19) among those who did not receive invasive ventilation. 

( Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10;NEJMoa2007016.) 

Hydroxychloroquine

Two controlled studies have already been published with the use of HCQ in COVID-19. A more rapid viral clearance was noted in a French study (2), while a pilot study from China revealed no difference between the HCQ-treated and control groups regarding the time to defervescence or progression of changes on CT imaging (3). 

In the newest study on HCQ for the treatment for COVID-19, Chen et al. conducted a randomized, parallel-group trial at the Renmin Hospital, in Wuhan, China, over a 24-day period. The study included patients with RT-PCR proven COVID-19 pneumonia who presented with a mild illness, with oxygen saturation of > 93% on air or a PaO2/FiO2 ratio of > 300 mm Hg. Patients who were critically ill were excluded from the study. In the intervention arm, HCQ was administered in a dose of 200 mg twice daily from days 1–5 of treatment, while patients in the control group received standard care. Patients in both groups received oxygen therapy, antiviral and antibacterial agents, intravenous immunoglobulin, and corticosteroids.

The study included 31 patients in each arm. The main endpoint was the time to clinical recovery, defined as normalization of body temperature, and relief from cough, for more than 72 hours. Among patients who received HCQ, the time to temperature normalization was 2.2 ± 0.4 days compared to 3.2 ± 1.3 days in the control arm, the difference being statistically significant. The time to remission of cough, 2.0 ± 0.2 vs. 3.1 ± 1.5 days, was also significantly less among HCQ treated patients. 

The authors also compared changes in CT findings between groups over a 6-day period. HCQ-treated patients showed significantly more improvement in consolidation on CT (80.6% vs. 54.8%); 61.3 patients in the HCQ group revealed a significant resolution of consolidation. In the control group, four patients progressed to severe illness, compared to none in the HCQ group. Mild adverse reactions were noted in two patients who received HCQ (4). Although a pilot study of small sample size, this study suggests a possible benefit with HCQ in patients who are less severely ill. However, we need more robust data before it may be routinely used in the treatment of patients with COVID-19. 

Previous studies on hydroxychloroquine use in COVID-19 have been of poor quality with conflicting results. Against this background, Raoult et al. reported on another cohort of 1061 patients who were treated with the hydroxychloroquine-azithromycin combination for a minimum period of 3 days and followed up for 9 days. This study is available in the abstract form (11). The mean age was of patients was 43.6 years; in 973 patients (91.7%) a “good clinical outcome” and virological cure occurred. Forty-six patients (4.3%) experienced “a poor outcome” with 10 patients requiring intensive care. Five patients (0.47%) aged between 74–95 years died, while 31 patients required 10 or more days of hospitalization. The investigators did not observe any cardiac toxicity among the study patients. A major weakness of this study, yet again, similar to previous studies by the same group, is the lack of a control arm. 

 Abstract_Raoult_EarlyTrtCovid19_09042020_vD1v.pdf [Internet]. [cited 2020 Apr 11]. Available from: https://www.mediterranee-infection.com/wp-content/uploads/2020/04/Abstract_Raoult_EarlyTrtCovid19_09042020_vD1v.pdf

Ivermectin 

The anti-parasitic agent, ivermectin, effective against several parasites, has been shown to have anti-viral activity against several viruses, including dengue viruses, the West Nile Virus, Venezuelan equine encephalitis virus, and influenza. Investigators from the Monash University in Australia demonstrated a 5000-fold reduction in viral RNA at 48 hours in cell cultures with a single dose of ivermectin. Although widely used and considered safe in humans, it remains to be seen whether the usual clinical dose will be effective in SARS-CoV-2 infection. Further pre-clinical testing and clinical trials are required to evaluate its efficacy in COVID-19. 

Convalescent Plasma

Convalescent plasma is recommended for the empirical treatment of Ebola Virus Disease (EVD) and Middle East Respiratory Syndrome (MERS). Shen et al. evaluated the effect of convalescent plasma transfusion among a series of five critically ill patients with COVID-19 pneumonia. Patients had severe pneumonia with ARDS and experienced rapid disease progression with persistent high viral loads. All were ventilated and had PaO2/FiO2 ratios less than 300 mm Hg. Convalescent plasma with a SARS-CoV-2 specific antibody (IgG) binding titer greater than 1:1000 from was derived from five donors who had recovered from laboratory-confirmed COVID-19 infection. 

The study subjects were on antiviral therapy and methylprednisolone. Following transfusion of convalescent plasma, defervescence occurred within 3 days in four patients. The SOFA scores decreased, and the PaO2/FiO2 ratios increased within 12 days. The viral loads diminished and turned negative within 12 days after transfusion. Resolution of ARDS was noted at 12 days post-transfusion; three patients were weaned off from ventilation within 2 weeks. At day 37 post-transfusion, three patients had been discharged from the hospital; the other two were in a stable clinical condition (9).  Similar to the beneficial effects noted in patients with EVD and MERS, convalescent plasma holds promise as a possible therapy, especially among patients with severe COVID-19.

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.

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. 

Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020 Feb 26;200642. 

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