Immunotherapies
Plasma Therapy has been successful in several other cases of viral diseases such as Ebola, Influenza H1N1, H5N1 and more importantly against the SARS and MERS Corona Viruses. Intravenous immunoglobulins (IVIG) and hyperimmunoglobulins isolated from the plasma of COVID-19 recovered patients (convalescent plasma therapy or CPT) are under investigation as sources of neutralizing antibodies against SARS-CoV-21213.
Neutralizing antibodies can stop SARS-CoV-2 replication by preventing receptor binding, wall fusion and un-coating of the virus once inside the cytoplasm 12. They also play a role in inhibiting and reversing the effects of the cytokine storm (a complex interaction between factors such as IL-6, IL-7, IL-10, G-CSF and TNF-alpha) that occurs in SARS-CoV-2. These factors cause endothelial dysfunction, coagulation and increased vascular permeability that are linked to severe symptoms 14.
There have been several cases of successful plasma convalescent therapy. Among them were 10 patients with symptoms of severe COVID-19 who were given 200ml of CP from recovered patients with titres of neutralizing antibodies of more than 1:640. The symptoms of the patients in the treatment group improved within 3 days, C-reactive protein (CRP) levels decreased, and lymphocyte counts increased. Chest imagery analysis also showed considerable resolution of pulmonary lesions in all patients. This outcome was compared to that of a historical control group consisting of 10 patients treated in the same hospitals (without CP), with the same baseline characteristics and severity of disease. There were three fatalities in the control group compared to none in the patients receiving CP 15. Moreover 5 studies, all of which were either case series or case reports, found CPT to decrease symptoms, viral load, body temperature, increase the level of neutralizing antibody over time and resolve acute respiratory distress syndrome (ARDS) with no serious side effects 16. However, it is critical that plasma from newly recovered patients is collected as soon as possible because antibody titre begins to decrease from as early as four months after recovery 17.
Monoclonal antibody (Mab) therapy has certain advantages over CPT such as being highly reproducible and readily available. Therefore, Mab therapy is being explored as an alternative to CPT. During investigation Mabs like CR3022 and 47D11 were found to effectively neutralize SARS-CoV-2 although in vitro 18. Others such as Tocilizumab, Sarilumab, Siltuximab have an anti-inflammatory effect by blocking the IL-6 receptor a central player in the cytokine storm. A clinical trial reported positive outcomes upon administration of Tocilizumab to serious hospitalized COVID-19 patients; body temperature subsequently decreased to normal on the first day after treatment, oxygen requirement decreased by the fifth day for 75% and pulmonary lesions absolved in 90.5% of patients. Blood counts and CRP also returned to normal 19.
There is currently insufficient data available for the FDA to approve for or against these Convalescent Plasma Therapy and the use antibodies.
Type 1 Interferons are a set of cytokines that are further made up of two sub-types alpha and beta. They are part of the initial immune response and are able to recognize viruses through their pattern recognition receptors (PRR) and inhibit viral replication and spread. Previous studies against SARS-CoV-1 and MERS have established that interferon 1beta would be the best candidate against COVID-19.
Interferon 1beta has shown therapeutic potential when combined with Lopinavir, Ritonavir and Ribavirin 8. Interferon alpha 2b spray has also been successfully used to decrease COVID-19 infection rates and China has recommended 5 million units of its use by vapour inhalation in combination with ribavirin 20. However, their use has not been approved by the FDA outside the context of clinical trials due to their lack of efficacy against previous Corona Virus infections and their side effects.
Traditional Chinese Medicine (TCM) has been in use and has developed over 3500 years. In fact, according to reports 91.5% COVID-19 patients in China have received TCM as a part of their treatment (Huanget al. , 2020). The National Health Commission of the People’s Republic of China has included TCM in each of the 7 guidelines it has published so far for the treatment of COVID-19.
Some common ones are HuoxiangZhengqi, LianhuaQingwen (LHQ), ShufengJiedu, XueBijing injections and Qing Fei Pau Du Tang. The most prominent proposed antiviral effects of TCM are inhibition of viral entry into host cells and the reduction of pro-inflammatory cytokines such as IL-6 and TNF-alpha. According to the National Administration of Chinese Medicine, symptoms notably improved in 60% of the 214 patients treated with Qing Fei Pau Du Tang up to 5th February 202022. LHQ capsules are also currently under phase 2 clinical trials in the USA 23. Randomized, double-blind and placebo-controlled studies are needed to test the true therapeutic potential of traditional Chinese medicines.
Anticoagulant therapy: There are increased chances of thrombosis during SARS-CoV-2 infection. 24 has reported elevated levels of D-dimer, fibrinogen, and fibrinogen degradation products in critically ill COVID-19. The use of low molecular heparin and unfractionated heparin has significantly been able to lower mortality rates in patients with raised D-Dimer (six times the normal level) levels 25. However, there are certain challenges with anti-thrombotic drugs as they can interact with other therapies. For example, co-administration of Clopidogrel and Apixaban with antivirals such as Lopinavir and Ritonavir should be avoided. These antivirals influence the cytochrome P450 mediated metabolism of the anticoagulants which in turn deranges anticoagulant pharmacokinetic properties and increase the risk of side effects like hemorrhages26. There is still insufficient data to recommend for or against the prophylactic use of anti-coagulants outside the context of a clinical trial.
Antibiotics have also been used together with antivirals as a large proportion of viral respiratory infections can be associated with bacterial pneumonia and other co-infections. Patients that are receiving ventilatory support for prolonged periods of time are also at a higher risk of picking up nosocomial infections. Around 74.5% patients under critical care receive antibiotics as a part of their treatment. National Institute for Health and Care Excellence (NICE), UK has recommended the use of the broad-spectrum antibiotic Co-amoxiclav and a macrolide for the treatment of severe pneumonia 27. WHO has recommended the use of Ceftriaxone/Ampicillin plus a macrolide for the treatment of severe pneumonia in adults.
Tetracyclines have been proposed for use against COVID-19. These antibiotics chelate zinc to the metalloproteinases (MMPs) of target cells that bind to SARS-CoV-2. They also have anti-inflammatory actions28. Doxycycline has been able to inhibit pro-inflammatory cytokines such as IL-6 and IL-1 in vitro at doses as low as 20-40 mg/day 29. DYNAMIC (DoxycYcliNeAMbulatoIre COVID-19 NCT04371952), consisting of 330 patients, has been the only study proposed to compare a treatment with doxycycline in COVID-19 patients vs a placebo group.