Dinko Anzulović Mirošević MD PhD
Correspondence: Independent scientific researcher (formerly University of Padua Cardiology Department), IFI- Via Tommaseo 50, Padua, Italy; E -mail: anzumd@yahoo.com
Abstract:
Coronavirus induced disease-2019 (COVID19, COVID) caused by coronavirus Wuhan type (Severe acute respiratory syndrome coronavirus 2019, SARS-CoV 19) has been a major global problem since the outbreak of the pandemic at the end of 2019. There is no recommended therapy for the non severe form of the disease at the moment.
The data obtained from clinical trials and observational studies suggest a possible benefit of immunomodulation and anti aggregation therapy in reducing hospitalisations and mortality due to the disease.
The therapy with low dose colchicine and aspirin is proposed for all non severe COVID patients that can tolerate it from the onset of symptoms, with addition of corticosteroids in selected patients.
Introduction :
In more than a year of coronavirus Wuhan type pandemic no therapy for non severe forms non requiring hospitalisation has been developed (1). Even with accelerated vaccination rates there will probably be continual need of efficient therapy that reduces mortality and morbidity in acute and chronic forms.
Numerous medicaments have been studied with many trials concluded or still ongoing but only a few demonstrated a clearly beneficial effect. Unfortunately, the first therapy proposed i.e. hydroxychloroquine and azithromycin showed no benefit (2,3).
From the studies performed it emerged that potentially beneficial are colchicine (4-7), aspirin (8,9) in outpatient and hospital setting and heparin (10,11), corticosteroids (12), remdesevir (13), monoclonal antibodies (14) in the hospital setting only.
The role of the outpatient therapies will be examined.
Materials and methods:
Since the first description of Coronavirus induced disease-2019 (COVID19, COVID) and identification of coronavirus Wuhan type (Severe acute respiratory syndrome coronavirus 2019, SARS-CoV 19) a peculiar feature of this pathology has been observed.
The patients usually presented a biphasic clinical status with mild to moderate respiratory and general disturbs followed in minority of cases at 10-14 days of illness by worsening of the clinical status, rapid deterioration and death. Apparently, this lapse of time is shortening and actually reported as 8-12 days in majority of cases but can be as short as 3 days (15-18).
This event happened frequently also after apparent resolution of symptoms, in apyretic patients.
It became clear that the immune response of the body and not the direct cytotoxic effect of the virus is involved. This state has been identified as “cytokine storm” and regarded early as a therapeutic target. It could be not only a cytokine overproduction but a new entity that is a mix of extreme reaction to virus antigens (19) and autoimmune (20) response that will be called hyperimmune response.
It is possible that a therapy that prevents the hyperimmune reaction could be beneficial and thus it should start with first symptoms that will allow use of lower doses with less collateral effects similar to preventing anaphylactic shock for allergic patients when exposure to allergen is unavoidable. An iodine allergic patient who needs a contrast test is a good example since established protocols with good results are reported (21).
The concept of a possible benefit for immunomodulation in non severe forms up to immunosuppression in severe forms of COVID is apparently clear.
Hypothetically there could be a clinical benefit combining immunomodulating, antiviral and antithrombotic therapy but at the moment there is a lack of data to implement an multidrug regimen based on randomized controlled trials (RCT’s) .
The mechanisms of the damage described for coronavirus Wuhan type – COVID (22), in rat coronavirus RCOV (23), and previously for influenza with lung injury (24), indicated that the injury is partly promoted by neutrophils and macrophages, and therefore could be responsive to treatment with colchicine.
The pathohistological finding of mixed neutrophil and thrombocyte aggregates (25) in microthrombosis of pulmonary vasculature, but also other districts, implicated that inhibition of both thrombocytes and neutrophils could be beneficial, thus the association of colchicine with antiaggregant like aspirin could have synergic effect.
In hospitalised patients from the first description on, some laboratory features have been identified which were associated with worse outcomes (high neutrophils count, low lymphocytes count, low thrombocytes count; high d-dimer, ferritin, cytokines). The patients with the most severe disease course have significantly more neutrophils than those with a more benign course. The threshold seemed to be approximately 7 x 109/l neutrophils (26).
These findings, although potentially useful in hospitalised patients, have difficulties to be adopted in outpatient setting because of necessary isolation of the patients. So, the clinical status is assessed at home mostly by anamnesis and self measurement of oxygen saturation and body temperature.
At the moment no therapy is recommended by major organisations (World Health Organisation-WHO, Centers for Disease Control and Prevention- CDC) for non hospitalised patients, except antipyretics (mostly paracetamol). For hospitalised patients there are recommendations for medical therapy, appearing not to be very efficient.
The criteria for hospitalisation remain clinical, oxygen saturation (SpO2) < 90% (arbitrary threshold), dyspnoea, polypnea ( > 30 breaths/minute) , shock ( WHO, CDC).
Therefore a possibly effective therapy should be developed starting from existing and available drugs.
Colchicine, first proposed by the author a year ago (27), has shown in randomised trials a significant benefit of a reduction in hospitalisations of 25% (5) and a trend towards a reduction in mortality up to 50% (4-6) that was statistically significant only in one smaller trial (4). In a large trial studying hospitalised patients taking a high dose of corticosteroids (7) this trend was not observed. The long term symptoms have not been explored by the existing trials but it is possible that they are also attenuated or eliminated by the colchicine therapy since the treated patients had fewer symptoms and hospitalisations in the acute phase. In all trials symptomatic COVID patients were treated and no analyses was done on laboratory parameters so it is not possible to know if the group of patients with neutrophilia had major benefits from immunomodulation with colchicine with respect to the patients without it. As previously said for logistic reasons only laboratory testing performed on most of the outpatients is the nasopharyngeal swab for coronavirus.
The mechanism of the drug’s action is not fully understood but it seems not to interfere with the body’s basic antiviral response and is thus not interfering with the ability of developing a good response against coronavirus Wuhan infection (28).
It seems reasonable to start the colchicine therapy with a low dose (0,5 mg q.d.) at first symptoms of clinically suspected COVID and to continue for 20 days.
This dose was extremely well tolerated in trials using colchicine for other purposes (29).
The treatment should be interrupted if diarrhoea occurs as a possible sign of toxicity. That could be a problem since some patients have diarrhoea as a symptom of covid, usually in the first days. Empirically a challenge of a few days suspension can be made with the reintroduction of the drug when the diarrhoea stops. In case the patient tolerates the therapy it should be continued and if the diarrhoea reoccurs the colchicine therapy should be terminated. In the trials where a low dose was used for long periods, very few patients interrupted therapy because of collateral effects (29).
The drug is not dialysable so patient on dialysis and end stage renal failure should be excluded from treatment.
There are no data available on the use of colchicine for COVID in paediatric population or pregnant women.
It is possible that in hospitalised patients with hyperimmune reaction different dosage could be more efficient at the price of major toxicity. In other forms of acute tissue injury caused by local cytokine hypersecretion, such as gout arthritis (27), colchicine is most efficient in the first twelve hours of the onset of symptoms. Near toxic doses are used (up to 6-10mg) in that condition and further trials would be needed for acute hyperimmune reaction of COVID that requires intensive treatment.
Aspirin (acetylsalicylic acid) is a widely used medicine, especially as antiplatelet agent. In observational studies it reduced mortality in COVID patients up to 50%, the results of randomized trials are awaited (8,9)
The pathohistological findings of thrombocytes-neutrophils agglomerates microthrombi would theoretically justify its use and also beneficial synergy with colchicine can be hypothesized.
The direct endothelial injury by virus or hyperimmune response can be responsible for platelet aggregation with a possible benefit of anti aggregation therapy.
It is reasonable to believe that in prevention of hyperimmune response low dose of aspirin is safe and efficient (75-100mg q.d. or 100mg on alternate days). For the persons intolerant of aspirin another antiaggregant can be reasonable alternative.
Corticosteroids have been a fundamental anti inflammatory and immunosuppressive therapy since their first introduction (30). Long lasting molecules like dexamethasone in high doses have demonstrated a significant reduction of mortality of 30% in critically ill patients requiring mechanical ventilation. No benefits in non severe forms have been observed until now (12).
Initially they were not recommended considering the attenuation of antiviral response (31,32) and the therapeutic success in full hyperimmune response can be a sign of importance of timing of this therapy in COVID. It can be hypothesized that adding a low dose of corticosteroid after a week or less (5-6 day of illness) of non severe disease if the symptoms haven’t been resolved in the first 3-5 days could prevent or attenuate hyperimmune response (8-14 day of illness). The idea of starting cortisone later and only in selected cases should leave antiviral capability of organism intact and act only on hyperimmune response. There are, at the moment, no data from RCT’s to support this idea.
Heparins (unfractionated-UFC and low molecular weight-LMWH) have shown contradictory results up to now, some results seem promising although some major trials have been stopped for signals of worse outcomes (10,11). Venous thromboembolism is an important feature of COVID so in the patients that are not able to walk the use of heparins or other anticoagulants is possibly beneficial. There could be a synergic effect with aspirin but at a price of major incidence of bleeding. This associations are used frequently in acute coronary syndromes with a reasonably safe result, (33) but in asset of COVID there is a lack of data to base the cost-benefit analysis.
Remdesevir, an antiviral, has been approved for treatment of severe COVID in hospital asset, on the basis of reduction of recovery time but not the mortality (13).
Ivermectin has shown some benefit in small studies but no placebo controlled trials with statistical power to detect mortality benefit had been performed yet (34). Hypothetically there could be a clinical benefit combining antiviral and immunomodulating therapy.
Antibiotics have shown no benefit in RCT’s (azithromycin) but also no harm (3).
Vitamins – supplementation during the COVID has not shown measurable benefits (35,36)
Discussion :
On the basis of the displayed data it can be concluded that the possible rational approach to the outpatient COVID therapy has to be based on drugs that have shown benefit in RCT’s and observational studies and exclude those with no effect.
Considering that major risk factors for mortality are hypertension, diabetes and obesity the patients with those conditions should be prophylactically evaluated and the best medical therapy prescribed. If there is a clinical suspect of vitamin deficiency they should be supplemented, especially with vitamin D.
The following therapeutic scheme is proposed for symptomatic non severe COVID:
To start as soon as diagnosis is made (based on confirmatory PCR or antigenic lab test or clinical presentation):
- Colchicine 0,5 mg q.d for 20 days,
- Aspirin 100 mg on alternate days, for 20 days, if not tolerated consider Clopidogrel 75 mg q.d.
- Walking at home for at least five minutes, three times a day if the patient is able to move
If the patient is still symptomatic after 5-6 days after the symptoms onset start a low dose corticosteroid and titrate according symptoms:
Hydrocortisone 10-20 mg b.i.d. up to 80 mg b.i.d.
or
Dexametasone 1-2 mg q.d. up to 6 mg q.d.
Antibiotics to be started only in case of symptoms indicating possible bacterial superinfection. The therapy of choice should be azithromycin (500mg q.d. for 3 days), the only one extensively studied for COVID since it has shown no harm in trials.
Paracetamol for symptomatic fever relief according to the best medical practice recommendations.
If there are symptoms or history of acid related gastrointestinal pathology add a proton pump inhibitor or anti H2 in prophylactic dose:
Pantoprazole 20 mg q.d.
For the patients that are not able to stand and walk consider prophylactic doses of LMWH or oral anticoagulant agent.
The patients should be monitored daily, directly or with telemonitoring, with report of general status, symptoms, body temperature and oxygen saturation.
In the case of a worsening clinical status patients should be hospitalised promptly according to the best medical practice criteria (WHO, CDC)
Conclusion:
At the current up-to-the-minute situation there is enough evidence to support the immunomodulating and antiaggregant therapy for non severe covid with the aim to reduce hospitalisations and hopefully mortality.
The therapeutic scheme of a combination of the low dose colchicine and aspirin associated with corticosteroid if necessary, explored in this article, seems to be both safe and beneficial in this setting. At best of the author’s knowledge this is the first time that such combination therapy is proposed.
The large trials should be performed to have a definite answer and to explore this and other possible combination therapies, starting with the existing, and low cost drugs that can be readily available for most of the World’s population.
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Disclaimer –author has no conflict of interest and the opinions expressed are personal.