Mucormycosis in Covid: Can NaHCO3 be of use?
Incidence of mucormycosis and other fungal infections seem to be increasing in this covid pandemic times, where one of the treatments for covid involves high doses of steroids and immunosuppressants. Steroids are not only immunosuppressants but also cause upsurge in blood glucose levels. Patients who are given these steroids are already in cytokine storm with significant lung involvement, and therefore many of them are also put on very high antibiotics. To add to that in patients with diabetes glucose control goes haywire in presence of infection. High antibiotics are known to be associated with fungal infections, as they suppress bacterial infection but have no role against fungi. All these create suitable milieu for a fungal infection along the respiratory passage. And from there into the bloodstream. Diabetics are known to be susceptible to recurrent fungal infections.
Mucormycosis is a deadly disease. And requires very strong antifungal medications with some serious side effects. Therefore, a prevention would be better than a cure. In laboratory testing to detect fungus and examine it under a microscope we use KOH, a potassium hydroxide solution to fix it. The fungus is dead in the alkaline medium. In medical practice we have a similar alkaline product called NaHCO3 in injectable form of 4–8.4% solution. This 4–8.4% NaHCo3 is often given intravenously to compensate for metabolic acidosis, in hyperkalemia (high potassium levels) to stabilise the pH of blood, at times even as bolus in cases of cardiac arrest. Though it has no direct side effects, it may interfere with some medications in their absorption or enhance or reduce their effect. And in excess quantities it can cause severe alkalosis, pulmonary oedema, hypokalaemia.
So, should we explore the possible use of NaHCO3 against mucormycosis?
In 2013 Letscher-bru et al published their work in Mycopathologia[1]. Their findings, “In vitro antifungal activity of SB (Sodium Bicarbonate) on 70 fungal strains isolated from skin and nail infections: 40 dermatophytes, 18 yeasts and 12 molds. A concentration of 10 g/L SB inhibited the growth of 80% of all the fungal isolates tested on Sabouraud dextrose agar. The minimal inhibitory concentration 90 (MIC90) of SB measured on Sabouraud dextrose agar, Sabouraud dextrose broth and potato dextrose broth was 5 g/L for the yeasts, 20 g/L for the dermatophytes and 40 g/L for the molds. In a second step, we prospectively evaluated the ex vivo antifungal activity of SB on 24 infected (15 dermatophytes, 7 yeasts and 2 molds) clinical specimens (15 nails and 9 skin scrapings). The fungal growth was completely inhibited for 19 (79%) specimens and reduced for 4 (17%) specimens after 7 days of incubation on Sabouraud dextrose-chloramphenicol agar supplemented with 10 g/L of SB as compared to Sabouraud dextrose-chloramphenicol agar without SB. In conclusion, we documented the antifungal activity of SB on the most common agents of cutaneous fungal infection and onychomycosis, and we specified the effective concentrations for the different groups of pathogenic fungi.”[1]
There is another interesting article by Badrawy et al[2] in 2018 where they reported that bronchoalveolar lavage (BAL) with 50 ml of Sodium bicarbonate 8.4% is inhibitory for bacterial, fungal and mycobacterial growth in the specific cultures and disturbs staining of Mycobacteria by ZN stain… BAL with SB 8.4% is safe to the patients with no considerable side effects. It is known that infection and inflammation reduce the pH.[3]
Gabremariam et al[4] in 2016 published that correction of ketoacidosis in diabetic patients with Sodium Bi Carbonate alleviates mucormycosis. In an excellent detailed article, they explained how high glucose, serum iron and β-hydroxy butyrate–induced (BHB-induced) acidosis increases the invasion of mucormycosis. To quote, “Mucormycosis is a severe, frequently fatal fungal infection that has a unique predisposition to infect patients with diabetic ketoacidosis (DKA)
A hallmark of mucormycosis is the ability of the causative agent to invade blood vessels that results in rapidly progressive infection (1, 2) …Therefore, interactions of Mucorales with the endothelial cell lining of the blood vessels represent a critical step in the pathogenesis of mucormycosis. We have shown that Mucorales adhere to and invade endothelial cells (3) by expressing CotH proteins (4). CotH proteins bind to the heat shock host receptor glucose-regulated protein 78 (GRP78) (5), causing host cells to endocytose the organisms. We also found that elevated concentrations of glucose and iron, comparable to those seen during hyperglycemia and DKA, enhance GRP78 expression, leading to enhanced fungal invasion and damage of endothelial cells (5)… NaHCO3 protects endothelial cells from R. oryzae–enhanced injury due to BHB exposure and reverses mucormycosis pathogenesis in vivo. NaHCO3 is commonly used to correct severe acidosis of pH less than 6.9 (11, 12). Additionally, the lower pH in DKA hosts compromises the ability of transferrin to chelate iron (8), which induces the expression of GRP78 (5) and CotH (Figure 2) and thereby enhances invasion and subsequent damage of the endothelium. Therefore, we investigated whether NaHCO3 and the iron chelator phenanthroline could reverse the enhanced invasion and subsequent damage to endothelial cells caused by R. oryzae when incubated with BHB. GRP78 expression by endothelial cells that had been exposed to BHB or BHB + NaHCO3 was evaluated using anti-GRP78 antibody by flow cytometry. As expected, endothelial cells incubated with BHB expressed higher levels of GRP78 on their cell surface than cells that were not exposed to the ketone body. Importantly, NaHCO3 reversed this enhanced expression to the normal levels detected (Figure 8A).”
Further Chen et al[5] reported that NaHCO3 helps liquify mucus. “The results demonstrate that HCO3− enhances mucin swelling and hydration by reducing Ca2+ cross-linking in mucins, thereby decreasing its viscosity and likely increasing its transportability. In addition, HCO3− can function as a Ca2+ chelator like EGTA to disperse mucin aggregates. This study indicates that poor HCO3− availability in CF may explain why secreted mucus remains aggregated and more viscous in affected organs.”
Gomez et al[6] found that inhalation of 4.2% and 8.4% NaHCO3 is safe with no side effects and is beneficial to the patients with cystic fibrosis. To quote, “apparent benefits of inhaled NaHCO3 are due most likely to its effects on raising the pH of the ASL and on improving sputum rheology as a function of more fully expanded mucin and DNA macromolecules in the presence of higher concentrations of HCO3− in the ASL. These changes would enhance the respiratory immune defence and favour improved mucociliary clearance of the airways in maintaining improved airway hygiene.”
Isn’t it then worth exploring this simple, nontoxic molecule as a preventive agent by giving it in a nebulised or aerosol form through a mask to patients who are highly susceptible to mucormycosis, for ex: people with severe uncontrolled diabetes on high steroids, people on immunosuppressants? Just by changing the pH of bronchoalveolar space there is a possibility that we may be able to prevent the very growth of such fungal infection or reduce its impact.
Even when there is a mucormycosis, should we try spraying or covering the wound with a gauze soaked in 8.4% NaHCO3? Wouldn’t it be worth trying injecting 4.2% or even 8.4% NaHCO3 (of course not exceeding safe limits) in and around the lesion? Wouldn’t it be helpful in neutralising ketoacidosis and reduce the chances of fungal infection?
A task force may be assigned by ICMR to evaluate the effectiveness of NaHCO3 as a prophylactic and preventive agent against mucormycosis. If proven useful it may be a very simple, cost effective and safe remedy to prevent and treat a devastating disease.
We may find that NaHCO3 can be used as an adjuvant to reduce the need of local and systemic antifungal, thereby reducing the undesirable side effects as well as both morbidity and mortality.
© Dr. Kalpesh Gajiwala, Mumbai, India.
21.05.2021
References:
[1] Letscher-Bru V, Obszynski CM, Samsoen M, Sabou M, Waller J, Candolfi E. Antifungal activity of sodium bicarbonate against fungal agents causing superficial infections. Mycopathologia. 2013 Feb;175(1–2):153–8. doi: 10.1007/s11046–012–9583–2. Epub 2012 Sep 19. PMID: 22991095.
[3] Grinstein S, Swallow CJ, Rotstein OD. Regulation of cytoplasmic pH in phagocytic cell function and dysfunction. Clin Biochem. 1991 Jun;24(3):241–7. doi: 10.1016/0009–9120(91)80014-t. PMID: 1651820.
[4] Gebremariam T, Lin L, Liu M, Kontoyiannis DP, French S, Edwards JE Jr, Filler SG, Ibrahim AS. Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest. 2016 Jun 1;126(6):2280–94. doi: 10.1172/JCI82744. Epub 2016 May 9. PMID: 27159390; PMCID: PMC4887168.
[5] Chen EY, Yang N, Quinton PM, Chin WC. A new role for bicarbonate in mucus formation. Am J Physiol Lung Cell Mol Physiol. 2010;299(4):L542-L549. doi:10.1152/ajplung.00180.2010
