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Covid-19: what treatments are being investigated?

BMJ 2020; 368 doi: (Published 26 March 2020) Cite this as: BMJ 2020;368:m1252

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Re: Covid-19: what treatments are being investigated? ; Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. Cromolyn Sodium May Attenuate Covid-19 SARS and Systemic Complications and May Be Useful ...

Dear Editor

Re: : 1) Mahase Elisabeth. Covid-19: what treatments are being investigated? BMJ 2020; 368 :m1252, 2) Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.

Dear Editor,
Cromolyn Sodium May Attenuate Covid-19 SARS and Systemic Complications and May Be Useful Prophylactically.
Fatalities due to SARS-COV2 (COVID 19) infection continue rising worldwide. The need exists for additional treatment options addressing antiviral replication, Severe acute respiratory syndrome (SARS) and the cytokine storm (1-4).
In the most recent article by Tao Chen et al (2), it is noted that interferon treatment has more recovered patients than deceased. Modulation of the host immune response may be an important strategy to improve patient survival. Interferon b 1a trial is underway in the U.K. (1).
Severe acute respiratory syndrome (SARS) and the cytokine storm account for a large part of the high mortality in intensive care units (2).
The NF-κB pathway is often targeted by viral pathogens to enhance viral replication, host cell survival and host immune evasion. Viruses may activate or suppress NF-kB. (5). There have many studies on SARS-COV since 2002-2003 SARS epidemic. SARS-COV2 (COVID-19) belongs to the same family of corona viruses and shares many similarities (3)
COVID 19 activates NF-kB pathway, like MERS and SARS-COV (3). SARS-COV virus has been studied in vitro and in mice and was shown to promote inflammatory mediators in vitro and in vivo through actions on NF-kB. Levels of NF-kB were higher in lungs of (recombinant SARS (rSARS)-infected mice. Inhibitors of NF-kB improved survival of BALB/c mice and reduced rSARS-COV-induced inflammation, without influencing viral titers (6) . NF-kB is specifically induced by SARS-COV S protein to produce inflammatory mediators that are associated with ARDS in SARS in vitro (7).
NF-kB pathway has complex interactions with interferons. Suppression of NF-kB may enhance IFN-mediated antiviral activity (8). Suppression of NF-kB needs to be carried out cautiously due to the central role this pathway plays in maintaining normal cellular functions (9).
In addition to many substances that have been described to inhibit NF-kB and hence may be candidates for attentuating inflammation responses in SARS-COV2 infection (10,11), Cromolyn may be proposed as an adjunct treatment. Cromolyn has been found to have broader anti-inflammatory and anti-tumor mechanisms than what has been described historically as an antiallergy and mast cell stabilizer (12). Cromolyn has been identified to inhibit of S100P activation of RAGE and inhibited elevated basal activity of NF-kB pathway in pancreatic cancer cells in vitro and in vivo in (13). S100P proteins as therapeutic targets has been reviewed elswhere (14). Cromolyn binds S100P in a stable complex (15 ). Cromolyn has been found to be effective in reducing inflammation pathways in several other diseases (16 - 22).
Another reported mechanism of Cromolyn sodium is that it acts as a chloride channel inhibitor (Reviewed in reference 12, 28). Viral infections and replication depend on host cell membrane chloride channels (29, 30, 31, 32, 33, 34), . Viruses posses ion channels called viroporins (30, 31). Cromolyn may also directly affect these channels. Furthermore, Cromolyn may attenuate innate immune responses that are influenced by chloride ion channels (35).
Some of deaths due to COVID 19 are due to cardiac involvement (2). Cromolyn may also act on NF-kB mediated remodeling in the inflamed heart in acute viral myocarditis (36).
Inhaled Cromolyn has a favorable safety profile and having been used for asthma treament for several decades since the sixties, including children and pregnant women, and with renewed interest in for repurposing in other diseases, has well-studied pharmacokinetics (37).
In summary, Cromolyn may be effective in decreasing inflammation, ARDS, and cytokine storm in COVID 19 patients. It may also reduce viral replication and systemic inflammation, in particular cardiac inflammation. It may be administerd in a variety of ways. It may be administered as a nebulized therapy, oral, nasal and IV. Nebulized therapy may achieve better penetration of the inflammed tissues of the lung of progressively worsening patients. Cromolyn sodium may be included as part of the treatment of COVID 19 patient at different stages in their infection, mild, moderate or severe. Cromolyn may work synergistically with interferon therapy. Exploration of using Cromolyn prophylactically intranasal, inhaled or oral cromolyn sodium may also be feasible.

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Competing interests: No competing interests

27 March 2020
Adli J Karadsheh
Physician (Internal Medicine, allergy/immunology)
Private Practice
Hillsborough Medical Associates, 7519 Paula Drive, Tampa, FL 33615