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Review Article

COVID-19 and Fungal Infection

Ji Hyun Lee,Hwa Jung Yook
10.17966/JMI.2020.25.3.47 Epub 2020 October 06

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Abstract



Keywords



Co-infection Corona virus COVID-19 Dermatologic department Fungus



INTRODUCTION

Coronavirus Disease-2019 (COVID-19) was announced on November 16, 2019 when the first patient was diagnosed. Subsequently, the World Health Organization declared COVID- 19 as a pandemic disease caused by SARS-CoV-21 on March 11, 2020. 

A total of 25,051,178 confirmed patients were reported worldwide with 843,586 COVID-19 related deaths by August 31, 2020. The COVID-19 pandemic has caused a serious health crisis worldwide. There were 19,947 confirmed cases and 324 deaths in South Korea, and the trend is increasing rapidly. Approximately 14% of COVID-19 patients have severe symptoms of breathing difficulties and low oxygen saturation, and 5% of patients have respiratory failure, septic shock, and fatal symptoms such as complex organ failure, resulting in death in 2.3% of patients2, even though they mostly improved with conservative treatment. The mortality of COVID-19 in- creases in patients with comorbidities. The fatality rate was 10.5% in patients with cardiovascular disease, 7.3% in people with diabetes, 6.3% in chronic respiratory disease, and 6.0% in hypertension. However, there are still insufficient data on the association between COVID-19 and fungal infection. Therefore, we would like to review fungal infection related to COVID-19.

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-CoV-2)

Coronavirus belongs to the family Coronaviridae which are enveloped and single-stranded RNA viruses. Coronaviruses are classified into 4 groups: α, β, γ, and δ-coronavirus. Severe acute respiratory syndrome (SARS)-CoV-2 belongs to the beta-coronaviruses and is similar to bat COV and SARS-CoV-13. SARS-CoV-2 has a specific spike glycoprotein that has a strong binding affinity to the angiotensinogen-converting enzyme 2 (ACE2) receptors, which is approximately 20 times higher than that of SARS-CoV-14,5. 

SARS-CoV-2 is a highly contagious disease transmitted through the respiratory droplets of infected patients, including asymptomatic carriers directly or indirectly6. Fever, cough, fatigue, anorexia, myalgia, and diarrhea are the most com- mon symptoms of COVID-197. Severe symptoms are dyspnea, hypoxemia, and rapid progression of respiratory failure8. The overall mortality rate is 2.3%2. CUTANEOUS MANIFESTATIONS

CUTANEOUS MANIFESTATIONS IN PATIENTS WITH COVID-19

A variety of cutaneous manifestations can accompany viral infection9,10. Previous reports showed COVID-19 patients with urticarial rash11-14. Since then, several related symptoms have been reported. Recalcati demonstrated that 20.4% of COVID-19 patients in Italy developed cutaneous manifesta- tions, and the patients had cutaneous manifestations such as erythematous rash, urticaria, and chickenpox-like vesicles15. Skin findings, including chilblain-like (40.2%), maculopapular (22.7%), urticarial (8.9%), vesicular (6.4%), livedoid and ne- crotic (2.8%), and other skin lesions (19.8%), were reviewed by Jia et al.10. Furthermore, patients may complain of pain, burning, or itching. On the other hand, cutaneous symptoms were subdivided into 6 patterns by Marzano et al., as fol- lows: urticarial rash, confluent erythematous-maculopapular-morbilliform rash, papulovesicular exanthem, chilblain-like acral pattern, livedo reticularis-livedo racemosa-like pattern, and purpuric "vasculitic" pattern9. As such, there have been few reports of additional fungal or bacterial infections in patients with COVID-19 who visited a dermatology clinic.

COVID-19 AND FUNGAL INFECTION

It has been suggested that COVID-19 might increase the risk of co-infection or superinfections. Zhu et al. reported SARS-CoV-2 co-infection with other pathogens in laboratory-confirmed COVID-19 patients16, where 94.2% of patients had co-infection with one or more pathogens, with bacterial co-infection being dominant. Furthermore, 31.5% of patients had viral co-infection, 91.8% had a bacterial co-infection such as Streptococcus pneumonia, Klebsiella pneumonia, or Haemophilus influenza, among others, and 23.3% had fungal co-infection. The co-infection fungal pathogens included Aspergillus (23.3%), Mucor (2.5%), Candida (0.8%), and Cryptococcus (0.4%). The rates of viral co-infection (35.3%), fungal co-infection (29.5%), and bacterial-fungal co-infection (29.5%) were the highest in severe COVID-19 patients16. Three cases of Candida albicans, 1 case of Candida glabrata, and 1 case of Aspergillus flavus co-infection among 99 COVID-19 patients were presented by Chen et al.17. Yang et al. found 3 cases including Aspergillus flavus, Aspergillus fumigatus, and Candida albicans among 52 COVID-19 patients18. Zhang et al. also found that co-infections in severe patients with COVID-19 were significantly higher than those in non-severe patients. They suggested that this is due to a decrease in host immune function and the presence of invasive catheters. This may lead to increased susceptibility to secondary infections by multidrug-resistant pathogens19. Therefore, clinicians should consider co-infection when diag- nosing COVID-19.

Co-infection with COVID-19 and invasive pulmonary asper- gillosis was found20. It has recently been reported that COVID-19-associated pulmonary aspergillosis (CAPA) causes serious pulmonary abnormalities that require therapy in intensive care unit (ICU) due to its high mortality21,22. CAPA was found in 33% of ICU patients admitted for COVID-19 in France, and 26% in Germany23,24. Severe COVID-19 is associated with impaired immune regulation, affecting both T-helper cell 2 (Th2) and Th1 responses, thus explaining the mechanism behind co-infection. CAPA due to Aspergillus fumigatus requires early diagnosis with the identification of a triazole-resistant isolate21. However, exposure to antifungal drugs may reduce sensitivity of the serum galactomannan test and delay the diagnosis.

Meanwhile, it has been reported that co-infection of bacteria or fungi is associated with the use of empirical anti- microbial agents in patients with coronavirus-related respira- tory infections25. Approximately 60% of the articles did not mention bacterial/fungal infections. Regarding COVID-19, 8% of patients had bacterial/fungal co-infection during hospitali- zation25. There were not many simultaneous bacterial/fungal infections, as expected, even though patients with coronavirus-related respiratory infections actually use a wide range of empirical antimicrobial agents. Hughes et al. also reported no evidence of risk of concomitant fungal infections in the early stages of COVID-19 in the UK26.

CONCLUSIONS

The skin provides a shield against external stimuli and is a major part of the immune system. Loss of the skin barrier increases the risk of multiple infections, despite the lack of reports of fungal co-infection in the dermatologic department. More attention should therefore be paid to the COVID-19 pandemic era.

Diagnosis of COVID-19 and fungal co-infection can be delayed, missed, or misdiagnosed. Afterwards, COVID-19 can cause impairment of cellular immune responses and lead to high mortality.



References


1. World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report – 51 [Internet]. 11 March. 2020. URL https://www.who.int/docs/default-source/ coronaviruse/situation-reports/20200311-sitrep-51-covid -19.pdf?sfvrsn=1ba62e57_10 (last accessed: 23 March 2020)

2. . Wu Z, McGoogan JM. Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Pre- vention. JAMA 2020;323:1239-1242
Google Scholar 

3. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579: 270-273
Google Scholar 

4. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-292 e6
Google Scholar 

5. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-1448
Google Scholar 

6. World Health Organization. Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations. URL https://www.who.int/news-room /commentaries/detail/modes-of-transmission-of-virus-causing-covid-19-implications-for-ipc-precaution-recom-mendations (last accessed: 7 April 2020)
Google Scholar 

7. Gandhi RT, Lynch JB, Del Rio C. Mild or moderate Covid-19. N Engl J Med 2020 Online ahead of print
Google Scholar 

8. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med 2020 Online ahead of print
Google Scholar 

9. Marzano AV, Cassano N, Genovese G, Moltrasio C, Vena GA. Cutaneous manifestations in patients with COVID-19: a preliminary review of an emerging issue. Br J Dermatol 2020;183:431-442
Google Scholar 

10. Jia JL, Kamceva M, Rao SA, Linos E. Cutaneous mani- festations of COVID-19: A preliminary review. J Am Acad Dermatol 2020;83:687-690
Google Scholar 

11. Henry D, Ackerman M, Sancelme E, Finon A, Esteve E. Urticarial eruption in COVID-19 infection. J Eur Acad Dermatol Venereol 2020;34:e244-e245
Google Scholar 

12. Fernandez-Nieto D, Ortega-Quijano D, Segurado-Miravalles G, Pindado-Ortega C, Prieto-Barrios M, Jimenez-Cauhe J. Comment on: Cutaneous manifestations in COVID-19: a first perspective. Safety concerns of clinical images and skin biopsies. J Eur Acad Dermatol Venereol 2020; 34:e252-e254
Google Scholar 

13. Quintana-Castanedo L, Feito-Rodriguez M, Valero-Lopez I, Chiloeches-Fernandez C, Sendagorta-Cudos E, Herranz-Pinto P. Urticarial exanthem as early diagnostic clue for COVID-19 infection. JAAD Case Rep 2020;6:498-499
Google Scholar 

14. van Damme C, Berlingin E, Saussez S, Accaputo O. Acute urticaria with pyrexia as the first manifestations of a COVID-19 infection. J Eur Acad Dermatol Venereol 2020; 34:e300-e301
Google Scholar 

15. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol 2020; 34:e212-e213
Google Scholar 

16. Zhu X, Ge Y, Wu T, Zhao K, Chen Y, Wu B, et al. Co-infection with respiratory pathogens among COVID-2019 cases. Virus Res 2020;285:198005
Google Scholar 

17. 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;395:507-513
Google Scholar 

18. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020;8:475-481
Google Scholar 

19. Zhang G, Hu C, Luo L, Fang F, Chen Y, Li J, et al. Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China. J Clin Virol 2020;127:104364
Google Scholar 

20. Verweij PE, Gangneux JP, Bassetti M, Brüggemann RJM, Cornely OA, Koehler P, et al. Diagnosing COVID-19-associated pulmonary aspergillosis. Lancet Microbe 2020; 1:e53-e55
Google Scholar 

21. Meijer EFJ, Dofferhoff ASM, Hoiting O, Buil JB, Meis JF. Azole-resistant COVID-19-associated pulmonary asper- gillosis in an immunocompetent host: A case report. J Fungi (Basel) 2020;6:79
Google Scholar 

22. van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-associated pulmonary aspergillosis. Am J Respir Crit Care Med 2020;202:132-135


23. Alanio A, Delliere S, Fodil S, Bretagne S, Megarbane B. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir Med 2020;8:e48-e49
Google Scholar 

24. Koehler P, Cornely OA, Böttiger BW, Dusse F, Eichenauer DA, Fuchs F, et al. COVID-19 associated pulmonary aspergillosis. Mycoses 2020;63:528-534
Google Scholar 

25. Rawson TM, Moore LSP, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, et al. Bacterial and fungal co-infection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis 2020:ciaa530
Google Scholar 

26. Hughes S, Troise O, Donaldson H, Mughal N, Moore LSP. Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting. Clin Microbiol Infect 2020; 26:1395-1399
Google Scholar 

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