Could Thalidomide, the largest man‐made medical disaster in history, helps us to cope with Covid 19 Pandemia?
Domenico LAZZARO MD PhD Clinical Pathologist Montpellier 34080 France [email protected]
Considering the title of a clinical study enrolled in the N.I.H Clinical trials list ClinicalTrials.gov Identifier: NCT04273529 (7) the answer to this question seems to be apparently yes : “The Efficacy and Safety of Thalidomide in the Adjuvant Treatment of Moderate New Coronavirus (COVID-19) Pneumonia”. This study is sponsored by the Hospital of Wenzhou Medical University .
At present there is no effective antiviral therapy, therefore prevention or treatment of lung injury caused by COVID-19 can be only symptomatic and/or palliative with the goal to alleviate the clinical situation and to resolve the life threatening ADRS (acute distress respiratory syndrome ) in the restricted number of patients which are affected by this potentially fatal respiratory . The causative mechanism of such respiratory failure was easily circumscribed in the hyperinflammatory immune response elicited by the virus and the consequent “Cytokine storm” was tentatively variously targeted.(6)
As a consequence different immunomodulatory and/or immunosuppressive approach have been undertaken. In this arena Thalidomide can possibly play an important role in consideration of its anti-inflammatory, anti-fibrotic, anti-angiogenesis, and immune regulatory effects. This study is the first Prospective, Multicenter, Randomized, Double-blind, Placebo, Parallel Controlled Clinical Study at home and abroad to use immunomodulators to treat patients with COVID-19 infection.
What is under our eyes since the beginning of the year 2020, that starts easily to be called “Annus Horribilis” in several publications and public documents, is the rampant rise of a new viral Pandemia originated at the end of 2019 in China in the city of Wuhan.
The virus Covid 19 is a new unknown pathogen that started to recently affect human patients inducing, in a limited number, a life threatening sometimes fatal ADRS (acute distress respiratory syndrome ).
Due to the high infectivity of the virus the number of patients that need hospitalization is amazingly high for countries that were not prepared for such a catastrophic event. The number of daily victims is in the range of thousands and are dramatically growing every day.
One of the most tantalizing feature of this pathogen is the variability in its capability to impact human organisms according to the age of the patients, the symptoms are spanning from the very mild range of a common winter cold mostly in younger patients (20 to 35 y.o.) to a life threatening and in some cases fatal ADRS (acute distress respiratory syndrome ) in patients largely over 60s y.o.. This virus apparently is exerting its deadly power mostly over patients in their 70s to 80s and older.
At the moment, the only therapeutic approach to face the infection seems to foster supportive, and prevention care with the goal to reduce transmission in the different community. Tight and very strict isolation measures in China produced a sensitive reduction in the incidence of the infection .
In Italy, similar initiatives had been undertaken by the central government with the hope to restrain the unprecedented Pandemic shock that was manifesting in restricted regions of the north, initially, and subsequently throughout the peninsula but at a much lesser extent compare to the scary situation observed in the north of the country.
Similar containment actions based on a lockdown strategy which is limiting people circulation in a drastic way have been also implemented in the rest of EU countries with various degrees of tightness.
The therapeutic challenge of this new Covid 19 pandemia is constituted by the SarsCov2 peculiar Pathophysiology and organ tropism.
Pathophysiology of Covid 19 is based on its special tropism for the host enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in the type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. As consequence The lungs are the organs most affected by COVID-19. The multi organ clinical spectrum observed in some cases is due to the ACE2 organ specific expression pattern, in the intestine , testes, kidney, endothelial cells. The intestine can be particularly affected as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.
Autopsies of people who died of COVID-19 have found diffuse alveolar damage (DAD), and lymphocyte-containing inflammatory infiltrates and Giant multinucleated cells within the lung. A common finding in fatal cases is an increase of the lung fibrotic component. A diffuse lung fibrotic lesion is a not uncommon relinquate observed in some patients who recovered from serious Covid-19 ADRS and this lesion seem s to permanently affect them .
The clear signs of a viral systemic immunopathology based hyperinflammation have been observed . Which are mainly summarized in Clinical laboratory values of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α). This list of data is clearly suggesting a viral induce cytokine release syndrome (CRS) or “Cytokine Storm “ . (6)
What seems the main life threatening aspect of Covid 19 Respiratory Syndrome are its Immunopathology traits, which are particularly exacerbated in the restricted pinnacle of patients who are affected by serious ADRS.
These ARDS patients have a collection of laboratory classical serum markers indicating a strenuous CRS or “Cytokine Storm “including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.
The clinical situation of each patients depends on the Systemic inflammation resulting in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration to be recruited into the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in COVID-19 patients.
In Particular the capability to the Virus to affect the deep bronchial tree and alveolar spaces induce a frank interstitial pneumonitis, that is characterized by inflammatory cells engulfment with giant cells and also later by a thickening of the fibrous component. All these factors are hindering the normal Oxygen respiratory exchange and constitute the main life treat.
Therapeutic Efforts were immediately focused in the facing the “Cytokine Storm “.(6)With different approach clinicians started to fight hyperinflammation symptoms.
Drug Repurposing: due to the fact that some inflammatory and autoimmune diseases, as well as some cancers, they have in common similar mechanisms with this virus-induced “Cytokine Storm” , some drugs initially developed for cancer (EUSA Pharma’s siltuximab) or conditions such as rheumatoid arthritis (Regeneron/Sanofi sarilumab and Roche’s tocilizumab) are being tested for COVID-19. Especially potent IL6 signal blockers (Roche's Actemra & Sanofi/Regeneron's Kevzara, both bind IL6Ra.
Thalidomide repurposing :despite the major drawbacks of thalidomide - teratogenicity and axonal neuropathy - the drug has acquired a unique, albeit limited, role in the treatment of severe, disabling conditions where standard anti-inflammatory or immunosuppressive therapies have failed. Best studied amongst these are leprosy, Beh?et's disease, graft-versus-host disease (GVHD) and some dermatoses. At this point it ws worth to mention Thalidomide use also in Oncology. (8)
Thalidomide is thought to exert anti-inflammatory and immunosuppressive effects by the selective inhibition of tumour necrosis factor-alpha (TNFalpha) production by monocytes and alterations in cellular surface integrins, among other mechanisms it is also a strong IL-6 inhibitor. (1-4)
A recent paper (5) is reporting the efficacy of Thalidomide in conjunction with low doses of Glucorticoid at low dosage for the treatment of Covid 19 Pneumonia.
At present there are 24 different clinical studies devoted to the screening of a variety of repurposed established drugs for Covid 19 Pneumonia treatment. In this effort of drug repurposing testing, possibly Thalidomide is showing a clear efficacy to regulate immunity, inhibiting the inflammatory cytokine surge, alleviating anxiety and to reduce oxygen consumption, relieving vomit and lung exudation as suggested by Chen C. eta all. (5)
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2. Powell RJ, Gardner-Medwin JMM. Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J 1994; 70: 901-4
3. Lary JM, Lyon Daniel K, Erickson JD, et al. The return of thalidomide: can birth defects be prevented? Drug Safety 1999; 21: 161-169
4. Tseng S, Pak G, Washenik K, et al. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996; 35: 969-79
5. Chen, C.; Qi, F.; Shi, K.; Li, Y.; Li, J.; Chen, Y.; Pan, J.; Zhou, T.; Lin, X.; Zhang, J.; Luo, Y.; Li, X.; Xia, J. Thalidomide Combined with Low-dose Glucocorticoid in the Treatment of COVID-19 Pneumonia. Preprints 2020,
6. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16.
7. https://clinicaltrials.gov/ct2/show/NCT04273529
8. Palumbo A1, Facon T, Sonneveld P, Bladè J, Offidani M, Gay F, Moreau P, Waage A, Spencer A, Ludwig H, Boccadoro M, Harousseau JL. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008 Apr 15;111(8):3968-77. doi: 10.1182/blood-2007-10-117457. Epub 2008 Feb 1.