The COVID-19 pandemic continues to wreak death and devastation across most parts of the world. The curve may have flattened in many parts of Europe, but the worst may not yet be over for the US. We are still unclear about the trajectory in India. In the meantime, theories abound regarding mechanisms of causation of the disease, and the quest for the elusive magic bullet goes on. Let us briefly look at noteworthy information that has emerged in the past week.
The New York experience
Richardson et al. evaluated a large case series of 5,700 patients admitted to 12 hospitals under Northwell Health, the biggest health care provider in New York (1). They analyzed the clinical characteristics and outcomes of patients hospitalized over a 35-day period between March 1, 2020, and April 4, 2020. All patients tested positive for SARS-CoV-2 by RT-PCR on the nasopharyngeal sample. Patients were followed up until they were discharged alive or dead, or until the study endpoint. On April 4, 2020, the final follow-up date, 2634 (46.2%) patients were either discharged alive or dead, while 3066 were still undergoing continued treatment in hospital.
The median age of patients was 63 (IQR: 52–75) years, with a distinct male preponderance (60.3%). Common comorbidities included hypertension (56%), obesity (BMI ≥30, 41.7%), morbid obesity (BMI ≥35, 19%), and diabetes mellitus (33.8%). Lymphopenia (less than 1,000/microliter) was observed in 3387 (60%) patients. Important clinical outcomes are depicted in Table 1.
Table 1. Important clinical outcomes of the New York case series
| Dead or discharged alive at follow-up | 2634/5700 (46.2%) |
| Discharged alive | 2081/2634 (79%) |
| Dead | 553 (21%) |
| Total number of ventilated patients during the study period | 1151/5700 (20.2%) |
| Ventilated patients who were dead/discharged alive at follow-up | 320/1151 (27.8) |
| Patients who continued to be on ventilation at follow-up | 831 (72.2%) |
| Mortality among ventilated patients at follow up | 282/1151 (24.5%) |
Renal replacement therapy was required in 81 (3.2%) patients. The overall median length of hospital stay (from admission to death or discharge) was 4.1 (IQR, 2.3–6.8) days.
ACE-inhibitors and angiotensin receptor blockers
The SARS-CoV-2 binds to the ACE2 receptors to gain access into cells. This has led to the hypothesis that ACE inhibitors and ARBs may upregulate ACE2 expression, leading to increased severity of illness among COVID-19 patients (2). In contrast, inhibition of the renin-angiotensin system and increased levels of ACE2 may have a protective effect in acute lung injury (2). Investigators at the King’s College and Princess Royal University Hospitals, London, studied a cohort of 205 patients hospitalized with COVID-19 infection. Among these patients, 37 (18%) were on ACE-inhibitors (ACE-I). On serial logistic regression analysis, the primary endpoint of death or admission to the ICU occurred in 5/37 (14%) patients who were on ACE-I compared to 48/168 (29%) of patients who were not on ACE-I (odds ratio: 0.29, CI: 0.10–0.75, p <0.01). Although limited by small sample size, this study does not suggest an increase in severity of illness among COVID-19 patients who are on ACE-I (3). A possible protective effect needs to be evaluated among larger cohorts of patients.
Hydroxychloroquine
Conflicting evidence and unfulfilled promises continue with the use of hydroxychloroquine in COVID-19 infection.
A previous randomized controlled trial from China had revealed a shorter time to relief of symptoms and more rapid resolution of consolidation on CT-imaging with the use of HCQ (4). In a recent randomized controlled trial from China, HCQ was administered in a dose of 1200 mg daily for 3 days, followed by 800 mg daily for a period of 2–3 weeks. Patients in the control group received standard of care alone. The primary endpoint, viral clearance on RT-PCR at 28 days, was not significantly different between groups (85.4% Vs. 81.3%, P = 0.341). RT-PCR negativity was also similar between groups at days 4, 7, 10, 14, and 21. Relief of symptoms at 28 days was also similar; however, on post hoc analysis, after the elimination of possible confounding effects of anti-viral drugs, HCQ seemed to be more efficacious in the alleviation of symptoms.
In spite of several case series and a few controlled studies, the efficacy of HCQ among patients with COVID-19 infection remains unclear.
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 had previously demonstrated a 5000-fold reduction in viral RNA at 48 hours in cell cultures with a single dose of ivermectin (5).
A registry-based, multicenter, observational, case-controlled study was performed using prospectively collected data on patients with COVID-19 infection between January 1, 2020, and March 31, 2020. Data were collected from a registry, including 169 hospitals in North America, Europe, and Asia. For each Ivermectin-treated patient, a matched control (non-ivermectin treated) was identified using propensity-score matched criteria. Propensity matching was performed using age, gender, race or ethnicity, and the presence of comorbidities; qSOFA as used to match severity. Among 68,230 patients who were screened, 704 patients received ivermectin. The control group included 704 propensity-matched patients. Ivermectin was administered in a mean dose of 150 mcg/kg body weight. The overall mortality was significantly lower in the ivermectin-treated group (1.4% Vs. 8.5%, p < 0.0001). Among patients who were mechanically ventilated, the mortality was 7.3% in the ivermectin group compared to 21.3% in the control group (p < 0.001) (6). Adequately powered, randomized controlled trials are required to confirm possible improvement in clinical outcomes with ivermectin treatment in COVID-19 infection.
Clinical and laboratory features of fatal cases of COVID-19
Tu et al. evaluated the clinical and laboratory characteristics and complications among 25 consecutive fatal cases of COVID-19 at the Wuhan University Zhongnan Hospital. They observed higher levels of IL-6, C-reactive protein, and D-dimer among patients who died compared to those who survived. An abnormal coagulation profile was noted in all non-survivors, and 24 (96%) patients had elevated D-dimer levels. IL-6 and CRP levels were high among all non-survivors, suggesting an intense cytokine storm. These findings offer information regarding the characteristics of severe COVID-19 infection and support further investigation regarding the use of immunomodulators (7).
Prone positioning in awake, non-intubated patients
The use of the prone position in the intubated patient is well established to improve oxygenation and clinical outcomes (8). The prone position may improve oxygenation by selective redistribution of blood flow to areas of the lung that are better ventilated and allow recruitment of collapsed areas of the lung. With the increasing spread of COVID-19 across the world, there has been an upsurge of interest in positioning unintubated, spontaneously breathing patients in the prone position. The strategy of awake proning is of particular interest in patients who are hypoxic but appear reasonably comfortable at the onset of illness.
In one of the earlier studies, awake prone positioning in unintubated patients was carried out in 15 patients with acute respiratory distress syndrome of variable etiology. The prone position was well-tolerated by all except two patients. No significant change in the respiratory rate or hemodynamic parameters were noted on assuming the prone position. With the use of the same levels of FiO2 and PEEP, prone positioning resulted in an increase in the PaO2/FiO2 ratios without any change in the pH and PCO2 (9).
A recently published study evaluated the use of non-invasive ventilation or high flow nasal cannula combined with intermittent prone positioning among patients with acute respiratory distress syndrome. Two sessions of prone positioning were carried out daily, each lasting for 2 hours. Intubation could be avoided in 11 of the 20 patients studied. The authors observed that the early application of prone positioning with high-flow nasal cannula, especially in moderate ARDS with a baseline SpO2 > 95%, may reduce the requirement for intubation (10). Awake proning has also been described as part of the critical care management in a Chinese protocol for COVID-19 pneumonia (11). In light of the available evidence and anecdotal experience, the use of awake proning in unintubated patients may be a feasible option, particularly in resource-constrained settings. Patients who are hemodynamically stable and able to position themselves may be suitable candidates for awake proning.
Summary
- A large case series of COVID-19 from New York revealed important predisposing comorbidities, including included hypertension, obesity, and diabetes mellitus. More than half of the study patients remained in hospital at the time of follow-up. Among 1,151 patients who were invasively ventilated, 831 continued to be on ventilation at the completion of the study period.
- Emerging new evidence suggests that ACE-I and ARBs may not impact the severity of COVID-19 infection.
- A new randomized controlled trial re-establishes the relative lack of efficacy of HCQ in viral clearance and symptom alleviation.
- Ivermectin, an antiparasitic drug, resulted in improved survival in COVID-19 patients in a propensity-matched, registry-based study.
- An abnormal coagulation profile and increased levels of cytokines seem to characterize patients who develop severe disease.
- Prone positioning of awake, unintubated patients may improve oxygenation and reduce the requirement for invasive ventilation.
References
1. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA [Internet]. 2020 Apr 22 [cited 2020 Apr 24]; Available from: https://jamanetwork.com/journals/jama/fullarticle/2765184
2. Perico L, Benigni A, Remuzzi G. Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade. Nephron. 2020 Mar 23;1–9.
3. Bean D, Kraljevic Z, Searle T, Bendayan R, Pickles A, Folarin A, et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust [Internet]. Infectious Diseases (except HIV/AIDS); 2020 Apr [cited 2020 Apr 24]. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.04.07.20056788
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. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Apr 3;104787.
6. Patel A. Usefulness of Ivermectin in COVID-19 Illness [Internet]. Rochester, NY: Social Science Research Network; 2020 Apr [cited 2020 Apr 24]. Report No.: ID 3580524. Available from: https://papers.ssrn.com/abstract=3580524
7. Tu W-J, Cao J, Yu L, Hu X, Liu Q. Clinico-laboratory study of 25 fatal cases of COVID-19 in Wuhan. Intensive Care Med [Internet]. 2020 Apr 6 [cited 2020 Apr 24]; Available from: http://link.springer.com/10.1007/s00134-020-06023-4
8. Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159–68.
9. Scaravilli V, Grasselli G, Castagna L, Zanella A, Isgrò S, Lucchini A, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study. J Crit Care. 2015 Dec;30(6):1390–4.
10. Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020 Dec;24(1):28.
11. Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020 Mar 18;10(1):33.
