Therapeutic strategies for critically ill patients with COVID-19

Nucleoside analogs have a broad-spectrum antiviral effect via the mechanisms of lethal mutagenesis, chain termination, and inhibition of nucleotide biosynthesis. Fabiravir and ribavirin are representative drugs of nucleoside analogs and exhibit the antiviral effect by inhibiting nucleotide biosynthesis. It has been demonstrated that the combination of fabiravir and oseltamivir in the treatment of severe influenza may accelerate clinical recovery than oseltamivir alone [14]. In addition, it has been reported that the combination of ribavirin and interferon alpha (IFN-⍺) significantly reduced the 14-day mortality of critically ill patients infected with MERS, although the 28-day mortality was not affected [15]. Ribavirin and IFN-⍺ were also used in the treatment for SARS. However, ribavirin might have side effects such as anemia and liver injury, and IFN-⍺ may not improve the patients’ outcome [16]. Therefore, the use of ribavirin and IFN-⍺ in the treatment of COVID-19 needs to be further elucidated by clinical studies.

Lopinavir/ritonavir is a protease inhibitor in the treatment of HIV infection. Lopinavir/ritonavir showed the antiviral activity by inhibiting the replication of coronavirus in vitro. It has been reported that the combination of lopinavir/ritonavir with ribavirin could lower the risk of ARDS compared with ribavirin alone [17]. Most recently, the randomized clinical trial of lopinavir/ritonavir (400 mg/100 mg, twice-daily for 14 days) in the treatment of COVID-19 by Cao et al. has shown that in hospitalized adult patients with severe COVID-19, no beneficial effect was observed with lopinavir/ritonavir treatment compared with standard care group [18]. The adverse effects of lopinavir/ritonavir treatment include anorexia, nausea, abdominal discomfort, diarrhea, or acute gastritis. Moreover, the risk of hepatic injury, pancreatitis, more severe cutaneous eruptions, as well as the drug interactions due to CYP3A inhibition has been observed in the clinical trial, which arouses concern about the use of higher or prolonged dose regimens for outcome improvement [18]. In addition, serious complications such as acute kidney injury and secondary infection were fewer than in those not receiving treatment. Future trials with severe illness might help to elucidate the possibility of benefit of lopinavir/ritonavir treatment.

Remdesivir (GS-5734) is a new nucleoside analog and has been recognized as a potential and promising antiviral drug against a wide array of RNA viruses, including SARS/MERS-CoV. It is currently under clinical development for the treatment of Ebola virus infection [19]. Remdesivir potentially inhibits the RNA-dependent RNA polymerase from MERS-CoV, reduces virus replication, decreases the virus titer in mouse lungs infected with MERS-CoV, and improves the lung tissue damage [20, 21]. The antiviral activity of remdesivir and IFN-beta was found to be superior to that of the combination of lopinavir/ritonavir and IFN-beta against MERS-CoV [22]. A randomized, controlled trial has reported that the prolonged use of remdesivir in the treatment of Ebola virus disease (EVD) is safe [19], and no adverse events have been observed [23]. As a candidate drug that has not been approved, information about the side effects of remdesivir has not been reported yet. At present, two randomized, controlled, double-blind clinical trials are ongoing to evaluate the efficacy and safety of remdesivir (200 mg loading dose on Day 1, followed by 100 mg i.v. once-daily maintenance dose for 9 days) in hospitalized patients with mild/moderate or severe COVID-19 respiratory disease [24, 25]. The results of these clinical trials may open the window for effective antiviral therapy for such an epidemic infectious disease.

Arbidol is a small indole-derivative molecule and is approved for the prophylaxis and treatment of influenza and other respiratory viral infections [26]. It also showed inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C [27]. In addition, arbidol has been reported to have antiviral activity against the pathogen of SARS, and the effect of arbidol mesylate—a derivative of arbidol, was almost five times higher than arbidol in reducing the reproduction of SARS in cells in vitro [28]. It has been claimed that arbidol was effective against 2019-nCoV in vitro [29]. A randomized multicenter controlled clinical trial of arbidol in patients with 2019-nCoV is in progress in China [30].

It is known that angiotensin-converting enzyme-2 (ACE2) as a membrane protein is a functional receptor of SARS-CoV and it can facilitate virus entry into the cells by binding to the spike (S) protein of the virus, which mediates the fusion of viral and host membranes [31‐33]. Therefore, it may be of importance to block the binding of S protein to ACE2 to treat viral infection, such as SARS-CoV [34]. Chloroquine is a 9-aminoquinoline known since 1934, the sulfate and phosphate salts of which have both been commercialized as widely used antimalarial and autoimmune disease drugs. Chloroquine also shows broad-spectrum antiviral effects [35]. It was found to be a potent inhibitor of SARS-CoV infection due to its inhibitory effect on ACE2 [36]. It has been demonstrated that 2019-nCoV enter the epithelial cells of oral mucosa via the essential receptor ACE2 [37], and chloroquine can function at both entry and post-entry stages of 2019-nCoV infection [38]. Besides the antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Recently, Wang et al. have demonstrated that chloroquine is highly effective in the control of 2019-nCoV infection in vitro and is suggested to be assessed in human patients suffering from COVID-19 [38]. In addition, the results from more than 100 COVID-19 patients have indicated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging, promoting virus negative conversion, and shortening the disease course [39]. However, attention should be paid to the potential detrimental effects of chloroquine observed in previous attempts to treat viral diseases. At present, the clinical trials to evaluate the efficacy and safety of chloroquine in the treatment of COVID-19 is ongoing [40]. The use of chloroquine in the treatment of COVID-19 should refer to the most recent announcements if any.

In addition, hydroxychloroquine is a 4-aminoquinoline derivative antimalarial drug. Hydroxychloroquine is an immunosuppressive drug with mature clinical application in the treatment of rheumatic immune diseases such as rheumatoid arthritis and systemic lupus erythematosus [41, 42]. It has been found to be more potent than chloroquine in inhibiting 2019-nCoV in vitro. Hydroxychloroquine sulfate 400 mg given twice daily for 1 day, followed by 200 mg twice daily for another 4 days is recommended in the treatment COVID-19 [43]. At present, the clinical evaluation of hydroxychloroquine in the treatment of COVID-19 is in progress [44], which might shortly provide preliminary results about the effectiveness of hydroxychloroquine.

The use of corticosteroids in the treatment of ARDS is controversial. Observational data in SARS suggest that immunomodulation with regimens of high-dose methylprednisolone might be helpful in modulating inflammatory responses and lung damage [49, 50]. On the other hand, other studies showed that use of steroids is associated with increased risk for bacterial infection, increased mortality, and even antiviral resistance in influenza-associated pneumonia or ARDS [51‐54]. Moreover, multiple studies have reported that corticosteroid treatment is associated with delayed viral shedding in hospitalized patients without significant change in 90-day mortality [55‐57]. Corticosteroid therapy in patients with MERS was shown to be not associated with a difference in mortality, but associated with delayed MERS coronavirus RNA clearance [57].The early use of parenteral glucocorticoids therapy for fever reduction and pneumonia prevention has been shown to increase the risk for critical disease or death from H1N1 infection [58].

The currently limited clinical research does not support the use of corticosteroids in the treatment of ARDS in COVID-19 patients to improve the outcome of patients. The WHO recommended that corticosteroids should not be used in the treatment of viral pneumonia or ARDS. There is no convincing proof for the therapeutic benefits of corticosteroids in the treatment of COVID-19, which still need to be demonstrated in clinical research.

Thymosin alpha-1 is a thymic peptide hormone with significant benefits in restoring the homeostasis of the host immune system [59]. It is chemically synthesized and used in diseases with impaired immune system [60]. It has been reported that the low lymphocyte count is associated with the poor prognosis of septic patients. The use of thymosin alpha-1 therapy in combination with conventional medical therapies was effective in improving clinical outcomes and reducing mortality in severe sepsis [61]. In addition, thymosin alpha-1 can enhance the immune responses of SARS patients and help to limit the spreading of SARS [62]. Therefore, although there is no clinical evidence showing the beneficial effects of thymosin alpha-1 in COVID-2019, it has been recommended to be used for some patients to enhance cellular immunity for the resistance of viral infection.

Cyclosporine A is widely used in transplantation and autoimmune disorders due to its immunosuppressive effect. Cyclophilin A as a key member of immunophilins is the cellular receptor for cyclosporine A [63]. The inhibition of cyclophilins by cyclosporine A could block the replication of coronavirus, including SARS-CoV [64]. Therefore, non-immunosuppressive derivatives of cyclosporine A might serve as broad-range CoV inhibitors applicable against emerging virus like 2019-nCoV, which still needs to be confirmed by clinical studies in the future.

There are two types of interferons (IFNs), type I IFNs and type II IFNs. It has been demonstrated that type I IFNs can inhibit the replication of both SARS and MERS-CoV [65, 66]. Kuri et al. have reported that IFN transcription was blocked in tissue cells infected with SARS-CoV and cells infected with SARS-CoV were able to partially restore their innate immune responsiveness to SARS-CoV after priming with small amounts of IFNs [67]. Moreover, in patients with severe MERS-CoV infection, the combination of IFN-alpha-2a with ribavirin was shown to improve survival [66]. Recently, the combination of remdesivir and IFN-beta was shown to have significant antiviral activity [22].

Intravenous gammaglobulin is considered as the safest immunomodulating drug available for the treatment of severe infection and sepsis. It has high titers of neutralizing antibodies against broad-spectrum virus, bacteria, and other pathogens, and can modulate the host immune responses in several ways. However, a large-scale multicenter randomized placebo-controlled trial did not show improved survival with intravenous gammaglobulin in severe sepsis [68]. Moreover, a Cochrane review showed that intravenous gammaglobulin did not reduce the mortality of septic patients [69]. Therefore, there is no convincing argument to recommend intravenous gammaglobulin in the treatment of 2019-nCoV.

One of the most important mechanism underlying the deterioration of COVID-19 is cytokine storm characterized by elevated levels of IL6, IFN- and other cytokines, which will lead to ARDS or even multiple organ failure [70]. Tocilizumab is a recombinant humanized monoclonal antibody binding to IL6 receptor and inhibiting its signal transduction. Tocilizumab has been used in the treatment for rheumatoid arthritis (RA) [71]. Moreover, tocilizumab has been reported to be effective against cytokine release syndrome induced by CAR-T cell infusion against B cell acute lymphoblastic leukemia [72]. In Diagnosis and Treatment Guidelines of NCP (trial version 7.0) [73], tocilizumab is recommended for the immunotherapy of patients with extensive lung lesions and severe cases that show an increased level of IL6 in laboratory testing. The efficacy of tocilizumab in COVID-19 patients still needs to be investigated.

Oxygen therapy, high-flow nasal cannula, and non-invasive ventilation may reduce the need of endotracheal intubation and decrease ventilator-associated complications and mortality. However, several studies have reported that the failure of non-invasive ventilation was up to 85% in which invasive ventilation was ultimately required in the treatment of severe influenza A (H1N1) in Canada [87]. Non-invasive ventilation may be effective and safe for some patients, whereas it might increase virus transmission to health care workers because of risk for infected aerosol generation. Therefore, for the treatment of 2019-nCoV, non-invasive ventilation may be used in selected patients in early stages with milder acute hypoxemic respiratory failure [88]. While for critically ill patients, the effectiveness of transitionally oxygen therapy, such as respiratory status and oxygen index (PO2/FiO2), needs to be closely monitored and it should be switched to mechanical ventilation when necessary.

High-flow nasal cannula has emerged as an alternative to non-invasive ventilation to prevent intubation and reduce mortality in patients with acute hypoxemic respiratory failure [89]. High-flow nasal cannula has been reported to significantly reduce 90-day mortality of community-acquired pneumonia compared with standard oxygen or non-invasive ventilation [89]. Hui et al. have shown that the breath dispersion distance is limited therefore lowering the risk of air transmission. However, the loose connection of the cannula with nasal obstruction can significantly increase the dispersion distance [90]. Wearing masks (particularly N95) can effectively reduce the breath dispersion distance during high-flow nasal ventilation to prevent nosocomial transmission [91, 92]. In addition, high-flow nasal cannula might increase virus transmission risk due to aerosol generation. Therefore, staff protection of health care workers is critical.

Mechanical ventilation for patients with severe ARDS should be managed with lung-protective strategies to minimize ventilator-associated lung injury and to improve survival. The approach to minimize ventilator-associated lung injury and to improve survival includes: ventilation with low tidal volumes (4 to 8 mL/kg of predicted body weight), targeting plateau pressure (< 30 cmH₂O) [93], and minimizing the inspired oxygen concentration to decrease oxygen toxicity. High positive end-expiratory pressure (PEEP) can reduce the need for high FiO2 by improving gas exchange and lung compliance, whereas too high PEEP may lead to lung overdistension and hemodynamic instability. Optimal PEEP which can be titrated by pressure–volume curve, oxygenation, stress index, electrical impedance tomography (EIT), ultrasound, and some other clinical parameters is associated with improved survival rate among severe ARDS patients [9].

Lung recruitment needs to be evaluated for mechanically ventilated patients when uncorrectable hypoxemia occurs, and lung recruitment should be executed for patients whose lungs can restore aeration. CT, EIT, ultrasound, and other bedside techniques should be used to evaluate lung recruitability before lung recruitment.

For critically ill patients managed with mechanical ventilation, excessive spontaneous breathing due to stretching may lead to lung injury. Therefore, neuromuscular relaxant may be used to control the spontaneous breathing and protect the lung.

Prone positioning ventilation is a technique that often improves oxygenation in ARDS, possibly through improvements in ventilation–perfusion matching, the uniformity of ventilation, and gravity-related atelectasis. Prone ventilation was used in mechanically ventilated SARS patients without enough data to draw any conclusion with regard to its efficacy [86]. Although prone ventilation showed no improvement in survival or organ dysfunction overall, it might be beneficial for patients with severe ARDS. A multicenter RCT demonstrated that early application of prone positioning in patients with severe ARDS resulted in decreased mortality [94]. In addition, the use of prone positioning in patients with H7N9 influenza-induced severe ARDS was shown to be related with improved oxygenation, sustained after returning to a supine position, and with decreased carbon dioxide retention [95]. Generally speaking, prone positioning ventilation for no less than 12 h daily is a relatively safe procedure that rarely worsens a patient’s respiratory status. It can be thus recommended for the treatment of 2019-nCoV-induced severe ARDS.

ECMO has become the important life-support strategy for the standardized treatment of ARDS patients. ECMO should be considered as early as possible when the lung recruitment and prone positioning ventilation show to be ineffective.

Observational studies have reported that patients with ARDS induced by H1N1 influenza showed lower hospital mortality with transfer to an ECMO center compared with matched non-ECMO-supported patients [96]. The use of ECMO also showed survival benefit in patients with severe MERS [97]. ECMO tends to improve patient outcomes when used among those with limited organ failures and good pre-morbid functional status [9]. Substantial proportion of critically ill patients with COVID-19 appear to have developed cardiac arrhythmias or shock [13], and may need ECMO support. However, for those who will develop septic shock or refractory multiple organ failure, ECMO is not suggested due to its less benefit.

ECMO is a resource-intensive, highly specialized and expensive form of life support with potential for significant complications such as hemorrhage and nosocomial infection. Therefore, the use of ECMO should be strictly limited in the treatment of COVID-19. Moreover, since the number of critically ill patients is still increasing and the resource of ECMO is finite, judgment is needed to decide when ECMO may be worthwhile and when it may not. Support with ECMO is supposed to be for the most critically ill patients in regions with extensive resources for this therapy [98].