The COVID-19 pandemic has spread to 210 countries, affecting approximately 1.7 million people and resulting in more than 103,000 deaths until now. More than one-third of the world population, including India, is currently in lockdown. Although the epidemic curve has flattened in some countries, others continue to struggle. There has been an upsurge of literature on clinical experience and therapeutic interventions in the past week.
Italy has been through the most daunting health crisis, following the first report of a young man who was admitted with atypical pneumonia at a Lombardy hospital on 20th February, 2020. He reported positive for SARS coronavirus 2, followed by 36 new cases over the next 24 hours. What followed was an explosive transmission of the disease that reached catastrophic proportions.
From Lombardy, Italy
Graselli et al. reported on 1591 patients who were treated in 72 hospitals of the Lombardy ICU network between 20th February and 18th March, 2020. Among 1591 patients included, the median age was 63 (IQR: 56–70) years. The majority of patients were males (82%); 68% had comorbidities, hypertension being most common. Data on respiratory support was available in 1300 patients; among these patients, 1150 (88%) required invasive mechanical ventilation, and 137 (11%) received non-invasive ventilation. The median PEEP level was 14 (IQR: 12–16), and the median PaO2/FiO2 ratio was 160 mm Hg (IQR: 114–220). The FiO2 requirement was more than 0.5 in 89% of patients. At the time of follow-up on 25th March, 2020, data was available on 1581 patients; 405 (26%) of patients had died, 920 (58%) were still in ICU, and 256 (16%) were discharged from the ICU (1). This study clearly shows that critically ill patients with COVID-19 have a protracted and complicated clinical course with high mortality.
Coagulopathy in COVID-19
A fulminant coagulopathy can occur in patients with COVID-19 pneumonia. Endothelial dysfunction leads to excessive thrombogenesis and inhibition of fibrinolysis, resulting in a hypercoagulable state. Furthermore, hypoxia is well known to trigger the procoagulant pathway leading to venous thrombosis. Microthrombosis was observed in the pulmonary vessels on autopsy of a critically ill patient with COVID-19 (2). In a study of 183 consecutive patients with COVID-19, D-dimer and fibrin degradation products were higher, and the prothrombin and partial thromboplastin times were more prolonged among non-survivors compared to survivors. Among non-survivors, 71.4% had evidence of disseminated intravascular coagulation compared to 0.6% among survivors (3).
The incidence of thrombotic events, including acute pulmonary embolism, deep vein thrombosis, acute ischemic stroke, acute myocardial infarction, and arterial embolism was evaluated in 182 COVID-19 patients admitted to three hospitals in the Netherlands. Thrombotic events were noted in 31% of patients in this study, acute pulmonary embolism being the most common complication (82%). Increasing age and the presence of coagulopathy were independent predictors of thrombotic events (4). Clinically significant coagulopathy with the presence of antiphospholipid antibodies was reported among three patients with COVID-19 (5).
A retrospective observational study was performed in Wuhan, China, in patients with COVID-19, comparing patients who received anticoagulant therapy with unfractionated or low molecular weight heparin with those who had no anticoagulant treatment. On multivariate logistic regression analysis, patients with a SIC score (a scoring system that includes the platelet count, INR, and the SOFA score) of 4 or higher who were treated with unfractionated or low molecular weight heparin had a significantly lower 28-day mortality compared to those who did not receive anticoagulant therapy (6).
The question arises, do we anticoagulate patients with COVID-19?
In light of a high incidence of thrombotic complications among patients with COVID-19, the International Society of Thrombosis and Haemostasis (ISTH) recommends the administration of prophylactic low-molecular-weight heparin to all hospitalized patients in the absence of active bleeding, if the platelet count is more than 25,000/μl, regardless of the INR and APTT. This strategy is expected to reduce the incidence of a sepsis-like coagulopathy and prevent venous thromboembolism (7).
The cytokine storm and secondary hemophagocytic histiocytosis (sHLH)
A profound, rapidly fatal cytokine storm can occur in viral infections and culminate in sHLH, characterized by multiorgan failure. The main features of sHLH include cytopenias associated with high serum ferritin levels and severe acute respiratory distress syndrome. Mortality in COVID-19 patients has been shown to be associated with high ferritin levels, suggesting infection-related hyperinflammatory response to be the causative mechanism (8). Attenuation of the intense cytokine storm is a possible modality of treatment in COVID-19 pneumonia. Patients with COVID-19 should be screened for a hyperinflammatory syndrome with regular blood counts and serum ferritin levels. The options for cytokine inhibition include corticosteroids and intravenous immunoglobulin. A randomized controlled trial with tocilizumab, an IL-6 blocker, is currently recruiting patients in China (9).
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 (10).
Hydroxychloroquine – same investigators, new study
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.
QT prolongation with the hydroxychloroquine-azithromycin combination
Changes in the QT interval was studied in 84 patients with COVID-19 who received the hydroxychloroquine-azithromycin combination. The maximal prolongation of the corrected QT interval (QTc) was observed between days 3 and 4 of treatment. Severe QTc prolongation of more than 500 ms was observed in 11% of patients. Acute kidney injury was a predictor of prolonged QTc on multivariate analysis; baseline QTc was not a predictor of prolongation. This study suggests that the hydroxychloroquine-azithromycin combination can lead to severe prolongation of QTc, and regular monitoring is required, especially among patients with renal dysfunction.
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.
- In a retrospective observational study from Lombardy, Italy, the majority of patients admitted to the ICU were men in the older age group. The large majority of patients required invasive mechanical ventilation with relatively high mortality.
- A fulminant coagulopathy with extensive thrombosis can occur in patients with SARS-CoV-2 infection. Low-molecular-weight heparin should be considered in all hospitalized patients in the absence of active bleeding, if the platelet count is more than 25,000/μl.
- An intense cytokine storm can occur in patients with COVID-19 leading to sHLH, and multiorgan failure. Corticosteroids and intravenous immunoglobulin are therapeutic options in this setting. Tocilizumab, an IL-6 blocker, is currently being investigated.
- Remdesivir has shown in vitro activity against SARS-CoV-2. Promising results were observed in a small case series and further evaluation is required in controlled studies.
- Yet another case series from the Marseilles group claims improved clinical outcomes and effective viral clearance with the use of the hydroxychloroquine-azithromycin combination.
1. Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA [Internet]. 2020 Apr 6 [cited 2020 Apr 11]; Available from: https://jamanetwork.com/journals/jama/fullarticle/2764365
2. Luo W, Yu H, Gou J, Li X, Sun Y, Li J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). 2020 Feb 27 [cited 2020 Apr 11]; Available from: https://www.preprints.org/manuscript/202002.0407/v1
3. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844–7.
4. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Apr;S0049384820301201.
5. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 8;NEJMc2007575.
6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost [Internet]. 2020 Mar 27 [cited 2020 Apr 11]; Available from: http://doi.wiley.com/10.1111/jth.14817
7. Brady L. Stein MD. Coagulopathy Associated with COVID-19. NEJM J Watch [Internet]. 2020 Apr 6 [cited 2020 Apr 11];2020. Available from: https://www.jwatch.org/NA51254/2020/04/06/coagulopathy-associated-with-covid-19
8. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3;
9. Chinese Clinical Trial Register (ChiCTR) – The world health organization international clinical trials registered organization registered platform [Internet]. [cited 2020 Apr 11]. Available from: http://www.chictr.org.cn/showprojen.aspx?proj=49409
10. 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.
11. 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