Current State of Play in the Battle against Coronavirus: Treatments, PART 2 OF 4

In the second part in the series , we look at what Treatments have been used and the current evidence regarding these, in the battle against Coronavirus.


There have been interesting recent developments, which serve as a reminder for us, in how to interpret medical studies and information. This was recently highlighted in the case with Remdesivir. A NEJM study published in November, suggested treatment with Remdesivir, showed benefit. This was countered by the WHO releasing information from 4 studies, which showed evidence does not warrant use of the drug. So, that puts the public, the media and health practitioners in a tough position, where they must correctly evaluate and constantly update information.


Treatments

There is no specific antiviral treatment recommended for COVID-19.


The treatment is symptomatic, and oxygen therapy represents the first step for addressing respiratory impairment.

The majority of cases, will be managed as suspected Covid, and negative pressure rooms, isolation and full PPE is mandatory, with each measure adopted as early as possible.

Non-invasive (NIV) and invasive mechanical ventilation (IMV) may be necessary in cases of respiratory failure refractory to oxygen therapy. Obviously in severe and complicated cases, intensive care is needed for specialised management and monitoring. The primary role of quarantine, is to keep these important arms of treatment, open and accessible.


Concerning ARDS treatment, as Gattinoni et al. suggested, COVID-19-induced ARDS (CARDS) is not a "Typical" ARDS.[36]

This aspect of the disease is of fundamental importance and has probably negatively affected the therapeutic approach in the early stages of the pandemic. In the beginning of the pandemic, early IMV was postulated as the better strategy for addressing CARDS. However, in COVID-19 pneumonia the typical ARDS respiratory mechanics featuring reduced lung compliance cannot be found.

On the contrary, in CARDS, good pulmonary compliance can be demonstrated. As a consequence, and in contrast to what was initially believed, NIV can have a key role in CARDS therapy.

O2 Fast Challenge

In a patient with a

  • SpO2 < 93-94% (< 88-90% if COPD) or a

  • respiratory rate > 28-30 / min, or

  • dyspnoea,

The administration of oxygen by a 40% Venturi mask must be performed.

After a 5 -10 mins reassessment, if the clinical picture has improved the patient continues the treatment and undergoes a re-evaluation within 6 hours. In case of failure, the patient undergoes NIV treatment, if not contraindicated.


HFNO and Non-invasive Ventilation

In regards to HFNO or NIV, the experts' panel, points out that these approaches performed by systems with good interface fitting do not create widespread dispersion of exhaled air, and their use can be considered at low risk of airborne transmission.[37]

HFNO

Because this procedure has a greater risk of aerosolization, it should be used in negative pressure rooms.

Suggested ways to manage HFNO:

  • Indication: when it is difficult to maintain SpO2 > 92% and/or not improved dyspnoea through standard oxygen.

  • Setting: 30-40 L / min and FiO2 50-60%; adjust according to clinical response.

  • Switch to NIV if the symptomatology is not improved after 1 hour with flow > 50 L / min and FiO2> 70%.

  • HFNO can also be used for CPAP breaks and for assisted fibreoptic tracheal intubation in critically ill patients.[38]

  • Contraindication to HFNO: hypercapnic patient.

  • Medcast has several HFNO webinars for medical professionals looking for more info.

Non-invasive ventilation and Continuous Positive Airway Pressure

NIV/CPAP has a key role in managing COVID-19-associated respiratory failure.

Suggested ways for performing NIV/CPAP:

  • Interface: Helmet is preferred for minimizing the risk of aerosolization. In the case of NIV with face mask (full-face or oronasal), the use of integrated expiratory valve and non-tubes with exhalation port, and insert an antimicrobial filter on the expiratory valve is recommended.

  • Setting:

  • CPAP: start with 8-10 cmH2O and FiO2 60%

  • NIV (PSV): start with PEEP 5 cmH2O , monitor and bring to 8-10 cmH2O, FiO2 60%, PS 8-10 cmH2O

  • Management: after at least 4-6 hours, if stabilized, detach for max 1 hour and allow the intake of small quantities of fluids; during the night, NIV continuously

Intubation and Protective Mechanical Ventilation

Special precautions are necessary during intubation. The procedure should be executed by an expert operator who uses personal protective equipment (PPE) such as FFP3 or N95 mask, protective goggles, disposable gown long sleeve raincoat, disposable double socks, and gloves.

If possible, rapid sequence intubation (RSI) should be performed. Preoxygenation (100% O2 for 5 minutes) should be performed via the continuous positive airway pressure (CPAP) method. Heat and moisture exchanger (HME) must be positioned between the mask and the circuit of the fan or between the mask and the ventilation balloon.

Lung-protective ventilation. Mechanical ventilation should be with lower tidal volumes (4 to 6 ml/kg predicted body weight, PBW) and lower inspiratory pressures, reaching a plateau pressure (Pplat) < 28 to 30 cm H2O. PEEP must be as high as possible to maintain the driving pressure (Pplat-PEEP) as low as possible (< 14 cmH2O). Moreover, disconnections from the ventilator must be avoided for preventing loss of PEEP and atelectasis.

Finally, the use of paralytics is not recommended unless PaO2/FiO2 < 150 mmHg. Prone ventilation for > 12 hours per day, and the use of a conservative fluid management strategy for ARDS patients without tissue hypoperfusion (strong recommendation) are emphasized. Lung-protective ventilation can also reduce the risk of new or worsening AKI by preventing ventilator-induced hemodynamic effects.


Other Therapies

Corticosteroids

Among other therapeutic strategies, although systemic corticosteroids for the treatment of viral pneumonia or acute respiratory distress syndrome (ARDS) were not recommended, in severe CARDS these drugs are usually used.


On 16 June, the first proven lifesaving treatment for Covid-19 had been found. Dexamethasone, a widely and cheaply available steroid, was reported to have cut deaths by a third among hospital patients with covid-19 who needed ventilation and by a fifth among patients receiving oxygen only. In the chaotic, fear filled first half of 2020, this was at last an evidence based treatment from a randomised controlled trial.

Conducted by researchers at Oxford University, the ongoing RECOVERY trial involves all major hospitals in the UK. Within its first three months it reported its first policy changing result: that the widely promoted, Hydroxychloroquine was ineffective. This was swiftly followed by the Dexamethasone announcement.

In the intervention group, 2,100 patients received Dexamethasone (6 mg/day for 10 days) whereas in the control group patients (n=4,300) received standard care for the disease.[39]

Antiviral Agents

No antiviral treatments have been approved.

A recent RCT, demonstrated no benefit with Lopinavir/Ritonavir treatment compared to standard care and WHO has abandoned further studies on these drugs and recommended they are not used. [12,41]

Preclinical studies suggested that Remdesivir— an inhibitor of RNA polymerase— could be effective for both prophylaxis and therapy of HCoVs infections.[42] Despite a Study Published in NEJM by Biegel atal, Nov 2020 showing a improved recovery time of 10 days with Remdesivir, compared to 15 days in the control group, the WHO has recently recommended to not use this drug.[11] This was based on the Solidarity trials, a collection of 4 studies with 7000 patients. The pooled evidence suggested that no benefit was seen in Hospitalised Covid patients, but ongoing study is continuing.

The evidence suggested no important effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes with Remdesivir treatment.[10]

Several anti-flu drugs such as oseltamivir have been used for the treatment of COVID-19 patients[45]. Another anti-flu medication, favipiravir demonstrated a certain efficacy against SARS-CoV-2 in vitro.

A retrospective investigation showed that the broad-spectrum antiviral Arbidol can improve the discharging rate and decrease the mortality rate of COVID-19 patients.[46]


Antiviral/Immunomodulatory Drugs

Chloroquine (500 mg every 12 hours), and hydroxychloroquine (200 mg every 12 hours) were proposed as immunomodulatory therapy. In a non-randomized trial, Gautret et al.[47] showed that hydroxychloroquine was significantly associated with viral load reduction until viral disappearance and this effect was enhanced by azithromycin.

WHO recommended in July that Chloroquine and Hydroxychloroquine, showed no evidence of improved outcomes in hospitalised patients and recommended they were not used as treatment in these patients. As mentioned , the recovery trial also showed no benefit from Hydroxychloroquine.


Ivormectin has shown good results in centres. Strangely this drug has not been recommended by the WHO or governing bodies and there is serious confusion regarding this. This is a subject that requires further understanding and discussion amongst medical professionals and decision makers. It also raises serious issues regarding the direction of medicine.


In vitro and in vivo studies, indeed, have shown that macrolides may mitigate inflammation and modulate the immune system. In particular, these drugs may induce the downregulation of the adhesion molecules of the cell surface, reducing the production of proinflammatory cytokines, stimulating phagocytosis by alveolar macrophages, and inhibiting the activation and mobilization of neutrophils.[48] However, further studies are needed for recommending the use of azithromycin, alone or associated with other drugs such as hydroxychloroquine, outside of any bacterial coinfection.

Attention must be paid with the concomitant use of hydroxychloroquine with azithromycin as the association can lead to a higher risk of QT interval prolongation and cardiac arrhythmias.[49] Chloroquine can also induce QT prolongation.

Serotherapy

Antibodies taken from the blood of recovered individuals represent a therapeutic option currently under study. It is calculated that the dose of antibodies necessary for the treatment of a single patient with SARS-CoV-2, requires the removal of antibodies carried out by at least three patients recovered from the SARS-CoV-2 infection. A clinical trial has been launched (June 11, 2020) for investigating an antibody cocktail for the prevention and treatment of COVID-19.

Anticoagulant

Because COVID-19 patients have a higher incidence of venous thromboembolism and anticoagulant therapy is associated with reduced ICU mortality, it is suggested that patients should receive thromboprophylaxis. Moreover, in the case of known thrombophilia or thrombosis, full therapeutic-intensity anticoagulation (e.g., enoxaparin 1 mg/kg twice daily) is indicated.[50]

Inflammation Inhibitors

Tocilizumab is a humanized IgG1 monoclonal antibody, directed against the IL-6 receptor and commonly used in the treatment of rheumatoid arthritis.

In the US, a Phase 2/3, randomized, double-blind, placebo-controlled study on Sarilumab, another anti-IL-6 receptor antibody, is ongoing.[51]

Other similar strategies have been tested.

Anakinra is a recombinant IL-1 receptor antagonist used to treat autoinflammatory disorders . The authors of a retrospective analysis showed that in patients with moderate-to-severe ARDS, the use of anakinra induced clinical improvement in 72% of patients[52].

Targeting excessive host inflammation can be also addressed in another way. Acalabrutinib is a selective Bruton tyrosine kinase inhibitor, which regulates macrophage signalling and activation. Roschewski et al.[53] tested this agent on 19 patients hospitalized with severe COVID-19 in a prospective off-label clinical study. The proved that the treatment improved oxygenation in a majority of patients, ameliorating measures of inflammation such as C-reactive protein and IL-6.

Other Therapies

When the disease results in complex clinical pictures of MOD, organ function support in addition to respiratory support, is mandatory. Extracorporeal membrane oxygenation (ECMO) for patients with refractory hypoxemia despite lung-protective ventilation should merit consideration after a case-by-case analysis. It can be suggested for those with poor results to prone position ventilation.

Unselective or inappropriate administration of antibiotics should be avoided, although some centers recommend it, highlighting an area of concern regarding correct treatment approaches and the need for consensus and better decision making.


So What is Next ?

Of course, the last in the series on The year of the Coronavirus, will look at the quest or race to find a Vaccine. There are many complex factors in play, so make sure you check in to that post.