COVID-19 update: April 3, 2020

It has been a long, hard week of complete lockdown in India. We have not seen a significant impact yet, it is probably too early. However, there is a disturbing trend in the number of new COVID-19 cases, although, thankfully, the mortality has remained low. Many other countries are struggling, with a seemingly uncontrollable increase in new cases in the US. However, New York city, one of the worst-hit, may have seen the worst and the curve may be flattening (1). Italy appears to be finally riding out the storm after several weeks of utter despair. At the time of writing, more than a million people have been infected all over the world, leaving a staggering trail of death. 

Let us look at some of the impactful new studies that have been published in the past week on COVID-19.

A new randomized controlled trial on hydroxychloroquine (HCQ)

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 a small sample size, this study suggests 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. 

Report from Seattle

In a case series from the US, Bhatraju et al. reported on 24 ICU patients from nine hospitals in the Seattle area. Data were available until the March 23, 2020, and patients were followed up for at least 14 days.  Comorbidities were common, including diabetes mellitus (58%), chronic kidney disease (21%), and asthma (14%). All patients presented with acute hypoxemic respiratory failure. Bilateral lung opacities were seen on the chest radiograph in 23 patients; CT-imaging was performed in 5 patients, which revealed bilateral ground-glass opacities in four patients and pulmonary nodules in one patient. 

High-flow nasal cannula was used in 10 (24%) patients, and invasive mechanical ventilation was carried out in 18 (75%) patients; five (28%) patients were prone ventilated. Vasopressors were required in 17 (71%) patients; 14 patients continued to be hypotensive for longer than 12 hours post-intubation. No patient received non-invasive ventilation or extracorporeal membrane oxygenation. Interestingly, similar to previous reports (5), ventilation was possible with relatively low driving and plateau pressures, and the respiratory system compliance was reasonably well-preserved. However, the PaO2/FiO2 ratios remained poor, with the lowest values observed on day 3 (median: 134; IQR: 108–171). Among the 18 ventilated patients, 6 patients were extubated by day 31. 

At the 14-day follow-up, 12 (50%) patients had died, while three (13%) continued to require mechanical ventilation; four (17%) were discharged from the ICU but continued to be in hospital. Five patients (21%) were discharged from hospital (6). 

Case-fatality ratio and infection fatality ratio of COVID-19

Verity et al. attempted to overcome biases in the estimation of the case-fatality ratio and infection fatality ratio in a model-based analysis. The case-fatality ratio is the proportion of all diagnosed cases (tested positive) that eventually leads to death;  the infection fatality ratio comprises of all patients with infection, including those who are asymptomatic, and hence, remain undiagnosed. Thus, the infection fatality ratio, with a larger denominator, will be lower than the case-fatality ratio. Based on this model, the best estimate of the case-fatality ratio in China was 1·38% (1·23–1·53). Mortality was substantially higher among older age groups. It was 6·4% (5·7–7·2) among those aged ≥60 years compared to 0·32% (0·27–0·38) in those less than 60 years old.  The infection fatality ratio for China was 0·66% (0·39–1·33), and increased with age (7). 

The Italian experience

Gattinoni et al., from their initial experience in Italy, note that COVID-19-related ARDS is characterized by several atypical features. Even in the face of severe hypoxemia, lung compliance remained fairly well-preserved. Among their first 16 patients with COVID-19, the respiratory system compliance was 50.2 ± 14.3 ml/cm H2O, associated with a high shunt fraction of nearly 50%. They hypothesize that the large increase in intrapulmonary shunt may be due to the loss of hypoxic pulmonary vasoconstriction and continued perfusion of non-ventilated lung tissue. The apparent response to recruitment maneuvers and prone positioning may be due to a more favorable redistribution of perfusion to better-ventilated areas of the lung, resulting from changes in gravitational forces and application of pressure. They suggest early intubation and mechanical ventilation among patients who demonstrate a high respiratory drive, characterized by forceful respiratory efforts. Forceful spontaneous efforts on non-invasive ventilation may lead to patient self-inflicted lung injury. Besides the adverse effects related to high transpulmonary pressures, the alveolar pressure may drop significantly lower than the end-expiratory pressure during vigorous spontaneous respiratory efforts. The intravascular pressure within the pulmonary blood vessels decreases proportionally; however, the pleural pressure decreases to a greater extent, thus, increasing the transmural pulmonary vascular pressure. The increase in the transmural pulmonary vascular pressure combined with increased capillary permeability results in leakage of fluid from within the capillaries and may worsen pulmonary edema (8). The authors also warn against the use of high PEEP levels in poorly recruitable lungs, which may lead to hemodynamic instability and fluid retention (5). 

Does convalescent plasma help? 

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 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 possible therapy, especially among patients with severe COVID-

Summary

  • Three controlled studies have been published so far evaluating the efficacy of HCQ in the treatment of COVID-19 infection. Initial results from small studies hold promise but need to be confirmed in larger randomized controlled studies. There are many studies currently recruiting patients with hydroxychloroquine alone and in combination with antiviral drugs.  
  • A report from Seattle, in the US, corroborates with previous findings among critically ill patients with COVID-19 pneumonia. This study revealed severe hypoxemia, requirement for mechanical ventilation, hypotension requiring vasopressors, and high mortality. 
  • Variable mortality rates are reported across the globe. This may be due to the difference in the number of patients who are tested positive, relative to the actual number of patients who are infected.  
  • The initial Italian experience suggests severe hypoxemia in spite of reasonably preserved lung compliance. The authors postulate that a large increase in the intrapulmonary shunt due to inhibition of the hypoxic pulmonary vasoconstrictor response may cause an increase in the shunt fraction. 
  • A small case series from China suggests the efficacy of convalescent plasma in severely ill patients with COVID-19 infection. 

References

1.         Harris JE. The Coronavirus Epidemic Curve Is Already Flattening in New York City [Internet]. Rochester, NY: Social Science Research Network; 2020 Mar [cited 2020 Apr 3]. Report No.: ID 3563985. Available from: https://papers.ssrn.com/abstract=3566078

2.         Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar;105949. 

3.         Chen Jun LD, Chen Jun LD. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ Med Sci. 2020 Mar 6;49(1):0–0. 

4.         Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial [Internet]. Epidemiology; 2020 Mar [cited 2020 Apr 1]. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.03.22.20040758

5.         Gattinoni L, Coppola S, Cressoni M, Busana M, Chiumello D. Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020 Mar 30;rccm.202003-0817LE. 

6.         Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, et al. Covid-19 in Critically Ill Patients in the Seattle Region — Case Series. N Engl J Med. 2020 Mar 30;NEJMoa2004500. 

7.         Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Mar;S1473309920302437. 

8.         Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017 Feb 15;195(4):438–42. 

9.         Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA [Internet]. 2020 Mar 27 [cited 2020 Apr 3]; Available from: https://jamanetwork.com/journals/jama/fullarticle/2763983

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