INTRODUCTION:

The rapid spread of COVID-19 has been declared a global health crisis by the World Health Organization (WHO), which led to major disruptions, national emergencies, and lockdowns, leaving only the essential services to continue.¹ The disease pattern shows a wide range of variations with life‑threatening pneumonia that may or may not be associated with coinfections.²Due to the associated comorbidities, patients who are affected by the virus are more prone to develop various opportunistic infections.^3,4 The severity of the disease is mainly attributed to a rise in the level of cytokines and chemokines in the systemic circulation which includes interleukin, tumor necrosis factor, C-reactive protein, ferritin, and D-dimers.^5,6 Among the elevated level, the IL-6 is majorly responsible for an increased mortality rate that is referred to as cytokine release syndrome.^7,8Whereas therapeutic option by targeting IL-6R by various chemical modulators will be the best cause of action to reduce the severity of the disease.⁹

Among treatments, corticosteroid is widely used in patients with the associated hyper-inflammatory syndrome.¹⁰ Whereas excessive use in COVID-19 indirectly suppress immunity, resulting in various secondary infections like majorly mucormycosis and other fungal infection.¹¹ This so-called mucormycosis is characterized by the hyphal invasion of sinus tissue that shows black eschar along with various mild to moderate symptoms.^12,13

Due to the severity and nature of the conditions of both coronavirus diseases and associated coinfection, it is important to have early diagnosis and therapeutic management, as there can be a rapid spread of the disease resulting in increased mortality as a result of intra-orbital and intracranial complications. This narrative review is focused to provide a detailed as well as a comprehensive summary of cytokine storm, immunomodulators, and mucormycosis in COVID-19.

Diagnostic Dilemmas In Covid-19 Patient:

The conclusive diagnosis of COVID-19 is predicated on a positive RT-PCR result from swabs (nasopharynx, oropharynx), sputum, and faeces, as well as a chest x-ray and also monitoring of inflammatory mediators.¹⁴The chance of getting a false negative from RT-PCR initial day of exposure is almost 100%, then drops to 38% after 4 days, and finally to 20% later.¹⁵ Factors like the accuracy of the sampling and the quantity of rhino-pharyngeal tissue present could influence the swab's outcome. Antibody testing, on the other hand, is useless in the case of an acute illness.

A qualitative lateral flow immunoassay (LFIA) test, as well as bronchoalveolar lavage fluid (BALF), can be used to assess the immunoglobulin (Ig) M and IgG antibodies level in the sample.¹⁶The reason for a false-negative LFIA test could be due to a variety of causes, such as low antibody concentrations or a variation in immunological response of each individual and also antibody titer. Due to the late emergence of the antibodies, a combination of antibody testing and RTPCR may be useful for diagnosing COVID19 in individuals with delayed symptoms when compared with the period of infection.¹⁷

CYTOKINE STORM:

The word “cytokine release syndrome” was initially used to describe a condition after the use of muromonab-CD3.¹⁸ Cytokine storm and cytokine release syndrome is life-threatening systemic inflammatory syndromes that involve increased levels of circulating cytokines and immune-cell. This can be triggered by various medication or treatments, pathogens, cancers, autoimmune conditions, and monogenic disorders.¹⁹

From a historical standpoint, a cytokine storm was referred to as an influenza-like syndrome that occurred after systemic infections such as sepsis and after immunotherapies. Other conditions also could be described as a reason for cytokine storm such as sepsis, primary and secondary hemophagocytic lymphohistiocytosis (HLH), autoinflammatory disorders, and coronavirus disease 2019.²⁰

In the case of COVID19 patients, major reasons for mortality and morbidity are due to multiple-organ failure followed as a sequela of complications from cytokine storm. This condition is a result of the apoptosis of epithelial cells of the lung.²¹ In cytokine storm, increase in severity of the disease is because of the rise levels of interleukins, and various other factors like C-X-C motif chemokine ligand 10, monocyte chemoattractant protein-1, CCL9 etc along with respiratory distress and other cardiac complications.²²

The initial symptoms start with fever, cough further leading to breathlessness, fatigue, and myalgia whereas, in severe conditions, dyspnea along with hyper inflammation, coagulopathy, and low platelet counts along with cytokine storms with spontaneous haemorrhage.^23,24 In some cases, renal failure, acute liver injury or cholestasis, and cardiomyopathy can be seen.²⁵ The combination of renal dysfunction, endothelial-cell death, and acute-phase hypoalbuminemia can lead to capillary leak syndrome and anasarca.²⁶ Neurologic toxicity associated with T-cell immunotherapy is referred to as cytokine release syndrome–associated encephalopathy.²⁷

In a study involving 214 covid cases, 36.4% of critical patients showed various neurological symptoms like seizure and ataxia that is mainly due to ACE receptor involvement in addition to increased levels of cytokines in serum that is associated with cytokine storm, that lead to neurological symptoms because to muscle damage.^28,29

Immunomodulators for Cytokine Storm:

Controversy remains regarding the management and guidelines regarding the treatment of cytokine storm. It is necessary to diagnose the condition as early as possible to reduce the burden of mortality associated with it. The initial therapy involves early use of various immunomodulators that could strengthen the therapeutic protocol in critically ill patients.^30,31

Immunomodulators in the management of cytokine storm belong to different groups, and some are currently being developed based on compassionate recommendations.³² Various treatment options include:(Figure 1)

Figure 1: Management of Cytokine Storm

Corticosteroids:

Various steroids like methylprednisolone and dexamethasone have been widely used as a life-saving drugs that significantly decreased mortality in severe cases with ARDS.³⁰ According to a study by Burrage DR et al., a single dose of methylprednisolone is very effective in reducing hyper-inflammation along with specific production of IgG. However, according to the study continuous therapeutic use of methylprednisolone significantly reduce viral clearance and suppressed the immune system.³²

According to a previous study, glucocorticosteroids have been used to treat lung inflammation during previous epidemics which resulted in various side effects like prolonged viral presence and induced diabetes.³³ The WHO advised that the risk and benefit analysis should be done for individual patients before administering corticosteroids.³⁴

Current evidence shows that SARS-CoV-2 induces an increase in cytokines that might lead to overuse to counteract a wide range of cytokines. Furthermore, SARS-CoV-2 result in serious lymphocytopenia and lymphocyte exhaustion.³⁵ Thus, the long-term use of corticosteroids is a double-edged sword, therefore the dose, duration, and timing of corticosteroid therapy need to be monitored regularly.

QTY Code-Designed Detergent-Free Chemokine Receptors is considered to be one of the effective methods to reduce the severity of cytokine storms in advanced stages of infection. This method works by inhibiting the release of excessive cytokines, thereby decreasing multi-organ complications and toxicity. Another mechanism involves the presence of Cytokine receptor–Fc fusion proteins, which would serve as a decoy to reduce the level of cytokine.³⁶

Tocilizumab (TCZ) is another option available to reduce the levels of cytokine in the systemic circulation. It is a recombinant humanized anti-human IL-6 receptor monoclonal antibody that will act by preventing IL-6 binding to its receptor which will exert the immunosuppression thereby reducing the hyperinflammatory response in the body.³⁷

Chloroquine is another option available in treatment. It works by inhibiting the production of inflammatory mediators. There is unresolved controversy about its efficacy in treating COVID-19 patients.Stem cell therapy helps in resisting the formation of fibrosis and in the repairing of damaged lung tissues. In the case of artificial liver technology, blood purification treatments such as plasma exchange and filtration could also decrease inflammation.²¹

Other therapy includes INF-λ, artificial liver technology. In the case of IFN-λ, it acts on epithelial cells and diminishes the activity of IFN-αβ. Also, it inhibits the recruitment of the early inflammatory cells to the sites of inflammation. Another treatment option by artificial liver technology that carries out blood purification therapies like plasma exchange and filtration which in turn can reduce inflammation.²¹ It is significantly more vital to vaccinate to avoid infection in communities than it is to impose measures to minimise the transmission of SARS-CoV-2. During the pandemic, clinical researchers made extraordinary efforts to discover innovative vaccines that activate the immune system and cause the formation of neutralising antibodies against SARS-CoV-2.³⁸

COVID‑19 AND MUCORMYCOSIS:

A complex interplay between multiple factors like diabetes mellitus, respiratory diseases, immunosuppressive treatment, and immune alterations of COVID-19 infection could lead to various opportunistic coinfection, that needed to be given almost important due to their severity and complications.^39,40As the treatment of covid-19 requires prolonged use of steroids, that may indirectly lead to conditions such as osteoporosis, myopathy, osteonecrosis. Along with various effects on endocrine, cardiovascular, dermatologic, ophthalmologic as well as neuropsychiatric effects.^41,42 Pathophysiologic of the disease can result in secondary fungal conditions, which can worsen preexisting pulmonary disease and the subsequent alveolar-interstitial pathology that could enhance the further invasive fungal diseases.^43,44

Mucormycosis has also known as phycomycosis, was first described by Paltauf in the year 1885 as an aggressive fungal disease that is associated with alteration of their immunological system.⁴⁵ The clinical picture varies in individuals although rhinocerebral presentation is considered to be one of the most common types.^46,47 The spores of the fungus are present everywhere and can spread through soil, air, food, and decaying organic structures.⁴⁸ Because of its low virulence potential, it can be seen in the healthy individual also. When the patient becomes immune-compromised, these germinate within the paranasal sinuses and later may affect intracranial as well as orbital structures in an aggressive manner.^49,50

According to a recent study, 8% of post-COVID patients had secondary opportunistic infections with the widespread use of broad-spectrum antibiotics as well as steroids. The possible reason for this is the association between immunomodulators and the immunosuppression is causing an exacerbation of pre-existing fungal conditions. The various recommendations are given about the use of steroids in COVID-19 patients who needs ventilator support or those who need additional oxygen support.⁵¹ Diagnosis of mucormycosis varies from clinical to radiographic to histopathologic examination. Histopathologically the organism appears as large, non-septate hyphae with branching at an obtuse angle. Round or ovoid sporangia are also seen frequently seen in the tissue section. (Figure 2). Even though various methods are used, the non-contrast computed tomographic technique is considered to be the first choice for investigation which shows focal bony erosion and spread. Gadolinium-enhanced magnetic resonance imaging is also an option in the case where orbital and cranial structures are involved.⁵¹

Management of mucormycosis is based on a multidisciplinary approach that involves the collective involvement of various branches of medicine and dentistry.^52,53,54 Initial treatment is focused on the prevention of the spread of infection utilizing therapeutic measures by the use of Amphotericin-B as a treatment of choice, with its liposomal preparations preferred because of decreased nephrotoxicity.⁵¹ Once there is large scale involvement of various structures craniofacial area, surgical or operative procedures should be considered to prevent further complications. Surgical option alone is not considered to be curative, but an aggressive surgical procedure has been shown to reduce mortality in critically ill patients.^49,55,56

Figure 2: Microscopic feature of Mucor species in culture. Lactophenol cotton blue staining shows a globose intact sporangium with sporangiospores and branched sporangiophores

CONCLUSION:

The cytokine storm is represented by various pathological conditions like hyper inflammation, coagulopathy, multiorgan dysfunctions etc which is highly correlated with the increase in IL-6 levels that plays a pivotal role in the disease augmentation. In this regard, various immunomodulators are used in the management of moderate to severe cases to reduce mortality. But due to excessive usages of various therapeutic drugs like steroids and others, patients are being prone to various opportunistic coinfection like invasive mucormycosis and aspergillosis etc. Due to the destructive nature of mucormycosis, early operative treatment or surgical procedure along with anti-fungal therapy must be used to minimize further complications. In the current scenario, it is very much necessary to judiciously use any therapeutic measures which may further complicate the post coronavirus situation.

Human and Animal Rights: The authors declare that the work has not involved any experimentation on animals/humans.

Informed Consent and Patient details: The authors declare that they have not highlighted or mentioned any patient details that could result in identification of patient(s) and/or personel.

Conflict of Interest: The authors have stated that there are no competing financial interests or personal relationships that could have influenced the work conducted and reported in this article.

Funding: The work has not received any financial incentives from any private or governmental organization. The study is self-funded.

REFERENCES:

1. Kondody RT, Sana S, Reddy R, Fatima A, Bangi SL. Coronavirus Disease 2019- Challenges Today and Tomorrow in Orthodontic Practice: A Review. Turk J Orthod 2021;34(1):61-7.

2. Mehta S, Pandey A. Rhino‑orbital mucormycosis associated with COVID‑19. Cureus 2020;12:10726.

3. Chowdhary A, Tarai B, Singh A, Sharma A. Multidrug‑resistant Candida auris infections in critically Ill coronavirus disease patients, India, April–July 2020. Emerg Infect Dis 2020;26:2694‑6.

4. Mekonnen ZK, Ashraf DC, Jankowski T, Grob SR, Vagefi MR, Kersten RC et al. Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respiratory Distress Syndrome. Ophthalmic Plast Reconstr Surg. 2021;37(2):40-80.

5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.

6. Kim JY, Ko JH, Kim Y, Kim YJ, Kim JM, Chung YS et al. Viral load kinetics of SARS-CoV-2 infection in first two patients in Korea. J Korean Med Sci. 2020;35(7):86.

7. Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020;111:102452.

8. Hirano T, Murakami M. COVID-19: A new virus, but a familiar receptor and cytokine release syndrome. Immunity. 2020;52(5):731–3.

9. Hojyo S, Uchida M, Tanaka K, Hasebe R, Tanaka Y, Murakami M et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen. 2020;40:37

10. Rello J, Storti E, Belliato M, Serrano R. Clinical phenotypes of SARS-CoV-2: implications for clinicians and researchers. Eur Respir J. 2020;55(5):2001028.

11. Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Ralph ZJ. Invasive fungal diseases during COVID-19: we should be prepared. J Mycol Med 2020;30:100971

12. Chakrabarti A, Denning DW, Ferguson BJ, Ponikau J, Buzina W, Kita H et al. Fungal rhinosinusitis: a categorization and definitional schema addressing current controversies. Laryngoscope 2009;119:1809–18

13. Scheckenbach K, Cornely O, Hoffmann TK, Engers R, Bier H, Chaker A et al. Emerging therapeutic options in fulminant invasive rhinocerebral mucormycosis. Auris Nasus Larynx 2010;37:322–8

14. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020;S1473–3099:30086–4

15. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction-Based SARS-CoV-2 Tests by Time Since Exposure. Ann Intern Med. 2020;173(4):262-267.

16. Winichakoon P, Chaiwarith R, Liwsrisakun C, Salee P, Goonna A, Limsukon A et al. Negative nasopharyngeal and oropharyngeal swabs do not rule out COVID-19. J Clin Microbiol 2020;58:e00297-20

17. Patel R, Babady E, Theel ES, Storch GA, Pinsky BA, St George K et al. Report from the American Society for Microbiology COVID-19 International Summit, 23 March 2020: Value of diagnostic testing for SARS–CoV-2/COVID-19. Am Soc Microbiol 2020;11:e00722-20.

18. Chatenoud L, Ferran C, Bach JF. The anti-CD3-induced syndrome: a consequence of massive in vivo cell activation. Curr Top Microbiol Immunol 1991;174:121-134.

19. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci 1893;105:487-511.

20. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med 2020; 383:2255-2273

21. Mustafa MI, Abdelmoneim AH, Mahmoud EM, Makhawi AM. Cytokine Storm in COVID-19 Patients, Its Impact on Organs and Potential Treatment by QTY Code Designed Detergent Free Chemokine Receptors.Mediators Inflamm 2020;2020:8198963

22. Zhang Y, Yu L, Tang L, Zhu M, Jin Y, Wang Z et al.,. A promising anti-cytokine storm targeted therapy for COVID-19: the artificial-liver blood-purification system. Engineering (Beijing) 2021;7(1):11-13.

23. Ouyang Y, Yin J, Wang W, Shi H, Shi Y, Xu B et al. Downregulated gene expression spectrum and immune responses changed during the disease progression in COVID-19 patients. Clin Infect Dis. 2020;71(16):2052–2060

24. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical Features of 69 Cases With Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71(15):769-777.

25. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M et al. Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929-938.

26. Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother 2001;24:287-293.

27. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625-638.

28. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA neurol. 2020;77(6):683–690.

29. Cabello-Verrugio C, Morales MG, Rivera JC, Cabrera D, Simon F. Renin-angiotensin system: an old player with novel functions in skeletal muscle. Med Res Rev. 2015;35(3):437–463.

30. Sahu KK, Kumar R. Preventive and treatment strategies of COVID-19: from community to clinical trials. J Family Med Prim Care. 2020;9(5):2149–2157.

31. Khokra SL, Parashar B, Dhamija HK, Bala M. Immunomodulators: Immune System Modifiers. Research J. Pharm. and Tech. 5(2): Feb. 2012;169-174.

32. Burrage DR, Koushesh S, Sofat N. Immunomodulatory Drugs in the Management of SARS-CoV-2. Front Immunol. 2020;11:1844

33. Liu J, Zheng X, Huang Y, Shan H, Huang J. Successful use of methylprednisolone for treating severe COVID-19. J Allergy Clin Immunol. 2020;146(2):325–327.

34. Kapugi M, Cunningham K. Corticosteroids. Orthop Nurs. 2019;38(5):336–339.

35. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085–2094.

36. Hao S., Jin D., Zhang S., Qing R. “QTY code-designed water-soluble Fc-fusion cytokine receptors bind to their respective ligands,” QRB Discovery 2020;1:1–18.

37. Zhang X, Song K, Tong F, Fei M, Guo H, Lu Z et al. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv/. 2020;4:1307–10.

38. Cascella M, Rajnik M, Aleem A, Dulebohn SC, Napoli RD. Features, Evaluation, and Treatment of Coronavirus (COVID-19) [Updated 2021 Jul 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/

39. Agarwal A, Rochwerg B, Lamontagne F, Siemieniuk RA, Agoritsas T, Askie L et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379.

40. Mankar SD, Poonam W, Jejurkar P. Review on Mucormycosis: It is a life Threatening infection. Asian Journal of Research in Pharmaceutical Sciences. 2021; 11(4):316-8

41. Nambiar M, Varma R.S, Damdoum M. Post-Covid alliance mucormycosis, a fatal sequel to the pandemic in India. Saudi J Biol Sci. 2021, 28(11); 6461-6464

42. Aniket D, Aishwarya P, Kajal D, Pratik K, Yogesh D, Murgude MM. A Review on Mucormycosis (Black Fungus) and its Recent Study. Asian Journal of Research in Chemistry. 2021; 14(5):393-4

43. Nambiar M, Varma R.S, Jaber M, Sreelatha S.V, Thomas B, Nair S.A. Mycotic Infections-mucormycosis and oral candidiasis associated with covid-19: a significant and challenging association. J oral Micro 2021; 13(1); 1967699

44. Gupta R, Saikhedkar R. Spontaneous Necrosis of the Maxilla in an Immunocompetent Patient: A Case Report. Res. J. Pharmacology and Pharmacodynamics. 2019; 11(3): 89-91

45. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–13

46. Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Zahar JR. Invasive fungal diseases during COVID-19: we should be prepared. J Mycol Med. 2020, 30:100971

47. Kolap MB, Dashwant AV. Mucormycosis. Research Journal of Pharmacology and Pharmacodynamics. 2021; 13(3):89-2

48. Rawson TM, Moore LS, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M et al. Bacterial and fungal coinfection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis 2020;71:2459–68

49. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell LC et al. Dexamethasone in hospitalized patients with Covid-19--preliminary report. N Engl J Med 2021;384:693–704.

50. Aniket D, Sudha J. Mucormycosis its Pathogenesis and Treatment. Research Journal of Science and Technology. 2021; 13(3):205-7

51. Sipsas NV, Gamaletsou MN, Anastasopoulou A, Kontoyiannis DP. Therapy of Mucormycosis. J Fungi (Basel). 2018;4(3):90.

52. Sholly. CK. An evaluation of Mucormycosis, Outburst. Asian Journal of Nursing Education and Research. 2021; 11(4):591-3

53. Sharma NA. Mucormycosis: Why Incidence Rate is more in Covid -19 patients. Asian Journal of Nursing Education and Research. 2021; 11(4):599-0

54. Biradar KV, Pawar A. Corticosteroids and way of inflammation. Research J. Pharmacology and Pharmacodynamics. 2012; 4(1): 45-54.

55. Gupta R, Saikhedkar R. Spontaneous Necrosis of the Maxilla in an Immunocompetent Patient: A Case Report. Res. J. Pharmacology and Pharmacodynamics. 2019; 11(3): 89-91

56. Rani EJ. Alcohol and Covid – 19. Int. J. of Advances in Nur. Management. 2020; 8(4):341-344

Received on 08.12.2021 Modified on 25.05.2022

Research J. Pharm. and Tech 2022; 15(11):4871-4875.

DOI: 10.52711/0974-360X.2022.00818