Fungal positivity seen in tertiary care hospital during COVID-19 pandemic

  1. Ravinder Kaur
  2. Deepti Rawat
  3. Ashish William
  4. Pradeep Kumar Singh
  5. Neelam S.S Kandir
  6. Akanksha Sharma

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Abstract

Coronavirus disease 2019 (COVID-19) pandemic has been prevailing for more than a year associated with increased number of opportunistic invasive fungal infections in patients who have been critically ill or immunocompromised. In this retrospective study, details of various clinical specimens received from suspected patients of fungal infections were studied. The fungal cultures were seen to be positive in 64% (51/79) COVID-19 positive patients and 43% (163/381) COVID-19 negative patients during the year 2021 in the second wave of COVID-19. Among COVID-19 infected patients, the fungal isolations mostly observed were Candida spp. (63%) followed by Aspergillus spp. (15% ) and Mucor spp. (6%). The maximum samples (17% - COVID-19 positive and 83% - COVID-19 negative patients) which had shown positive results in COVID-19 infected patients were urine followed by serum (for aspergillus galactomannan). The candida isolation was seen in 27% (21/79) urine and 15%(12/79) respiratory samples (BAL, tracheal aspirate, sputum) in COVID-19 positive patients. Rhizopus arrhizus and Rhizopus homothallicus isolations were seen in nasal samples and tissue samples of 6% COVID-19 positive patients. There was an overall increase in fungal co-isolations  during the COVID-19 pandemic (64% in COVID-19 positive and 43% in COVID-19 negative patients) which is a matter of great concern. The correlation of clinical symptomatology and laboratory isolation is important for the diagnosis and effective management of these patients.

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  1. Version published to 10.1099/acmi.0.000640.v4 on Access Microbiology
  2. Access Microbiology

    Thank you very much for submitting your revised manuscript to Access Microbiology. We really appreciate your efforts in including the suggested corrections. However, as mentioned in the previous round of review, the statistical analyses statement needs further clarifications. This includes, how the fact that the groups were unmatched was taken into account, variance and normality tests applied or any corrections applied to the chi-square test. Please provide a revised version of the manuscript (with a tracked changes document) addressing these clarifications within one month.

  3. Version published to 10.1099/acmi.0.000640.v3 on Access Microbiology
  4. Access Microbiology

    Thank you very much for submitting your revised manuscript to Access Microbiology and addressing the reviewer suggestions. This revised version of the manuscript has been re-assessed by the same reviewers again, who have provided further comments. In general, they are still concerned about the clinical criteria that led to suspect a fungal infection in the patients and how this is explained in the manuscript. Please clarify the diagnosis criteria and the signs that suggested a fungal infection. I recommend that you add a statement saying the causative agent cannot be 100% attributed to the isolated fungus, but sample positivity together with symptoms were used in the study to denote a possible fungal infection (or along these lines). The reviewers also have concerns about the statistical significance of the results given the sample groups are unmatched. As the key conclusion of this study comes from the statistical analysis between these groups, and statistical analysis of unmatched groups has additional requirements, please include a more elaborated paragraph on the statistical methodology used in this analysis and the parameters that resulted in statistical significance. Please provide a revised version of the manuscript (along with a tracked-changes version) and a point-by-point response to these comments within two months.

  5. Access Microbiology

    Comments to Author

    Material and methods are still not clear regarding "defining illness" caused by these Fungal species. Candida was most common isolate, yet we do not know about urine complete exam of these patients. For aspergillus, Galactomannan positivity suggests invasive infection, but its negativity with positive culture, amke diagnosis doubtful. Same goes for your other fungi. You have worked hard to show co morbidities and immune status of the patients, table are clear, but there are insufficient evidence of "clinical infection" because just isolating the fungus does NOT mean infection. your groups are totally unmatched, hence comparison is not possible like this , which makes p value highly doubtful.

    Please rate the manuscript for methodological rigour

    Poor

    Please rate the quality of the presentation and structure of the manuscript

    Satisfactory

    To what extent are the conclusions supported by the data?

    Not at all

    Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?

    No

    Is there a potential financial or other conflict of interest between yourself and the author(s)?

    No

    If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?

    Yes

  6. Access Microbiology

    Comments to Author

    Authors have addressed all my previous comments adequately. While I still have some reservations on clinical definitions used throughout the manuscript, authors have referenced and accounted for same. Data is presented well and the methodology clear.

    Please rate the manuscript for methodological rigour

    Satisfactory

    Please rate the quality of the presentation and structure of the manuscript

    Good

    To what extent are the conclusions supported by the data?

    Partially support

    Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?

    No

    Is there a potential financial or other conflict of interest between yourself and the author(s)?

    No

    If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?

    Yes

  7. Version published to 10.1099/acmi.0.000640.v2 on Access Microbiology
  8. Access Microbiology

    Comments to Author

    1. Methodological rigour, reproducibility and availability of underlying data: There should be a demographic and baseline characteristics table of both comparator groups. We need to see how these two groups differ in terms of baseline characteristics, demographic, were these groups comparable or not. 2-Presentation of results: Results are presented in a clear manner with each table and diagram explained well. 3. How the style and organization of the paper communicates and represents key findings: I have a major reservation regarding overall key findings. You have mentioned that candidiasis was most common infection in Covid-19 patients, that too in urine samples. When we further explore results , we see it was more common in females as compared to the males. Was it really the infection? or just colonization? It is a tricky thing to consider candida UTI as infection, especially in females. We have to see whole clinical picture and its correlation with urine complete examination before labeling it UTI. If you further dwell in data collected , or give reader a clearer picture. Getting candida in urine and sputum samples does NOT depicts infection straightaway. So please provide a little more detail. It might affect your overall results and outcome. 4. Literature analysis or discussion: This section is comprehensive and well presented.

    Please rate the manuscript for methodological rigour

    Satisfactory

    Please rate the quality of the presentation and structure of the manuscript

    Good

    To what extent are the conclusions supported by the data?

    Partially support

    Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?

    No

    Is there a potential financial or other conflict of interest between yourself and the author(s)?

    No

    If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?

    Yes

  9. Access Microbiology

    Thank you very much for submitting your manuscript to Access Microbiology. It has now been reviewed by two experts in the field, whose comments and concerns are attached at the bottom of this email. In general, the reviewers express their reservations about the study design, and indicate lack of detail and structure in the text, repetition of information in tables/figures/text (grammar corrections are also needed). They also spot conclusion that are not supported by the presented results and data They both have a coincidental opinion in that the presence of Candida in urine may not mean an infection has been established, so this would need extensive clarifications. Additionally, one of them includes a suggestion to change the focus of the study, which you should consider in the context of their results and the reviewers' feedback.

  10. Access Microbiology

    Comments to Author

    Your Abstract can be greatly improved. Please review for grammatical errors, namely erroneous capitalisation. Line 27 - Remove the ")" after patients Line 27 - Try to stay consistent with your phrasing - COVID-19 vs Covid vs Covid-19, as well as the documentation of same - either use all capitals (COVID-19) or not (Covid-19). This should be maintained throughout your manuscript. Lines 29-30 - How many samples in comparison to the non-COVID-19 cohort? Lines 30-31 - What proportion of urinary and respiratory samples? What do you mean by maximum positivity of Candida species was seen? In comparison to what? Lines 32-33 - Again, how many patients were Rhizopus isolated from? Overall, statements are being made without any data from your study. What exactly did your study find? We need details. Introduction While you have aimed to preface your study, there are quite a few grammatical errors throughout which hampers the understanding of your statements. Please do a thorough re-read. Your Introduction may also benefit from further references of invasive fungal infections with statistical rigour - there are a multitude of studies to date, albeit some conflicting. The proposed pathophysiology between COVID-19 and fungal disease could also be clearer. Materials and Methods Line 72-23 - Perhaps state which clinical specimens were obtained and how they were processed, as well as explain what is meant by "standard protocol". Your standards may not be the standards used elsewhere so please clarify. It also is not clear at all which patients were included - I know you state "suspected patients of fungal infections" but it would be useful to know which clinical parameters were used in selecting those patients. Was it solely on respiratory status and the suspicion was principally an invasive pulmonary fungal infection prompting investigation? For the non-clinical reader this should be explained. Results The number of patients studied would be useful to note at the start. Abbreviations are being used which were not previously defined - BAL, CSF Line 111 - What do you mean by "maximum positivity"? This is not clear. I am presuming you mean isolation of fungi from urine and a significant galactomannan result but it needs to be reworded. Line 119 - Do you mean Table 1? Your Results are not the easiest to follow. They are long-winding and repetitive. I do not think Figures 1 and 2 are relevant as they are essentially repeated in Table 1, with really only Tables 2 and 3 of significant results contributing to your study. I would also think it important for you to define what criteria was used for fungal infection. Isolation of a Candida species in a urine sample without urinary symptoms or objective evidence of a fungal urinary infection - was this defined as a fungal infection, for can it not just be colonisation? I think it would be very imperative that you are clearer in what you mean, for isolation of a fungus does not automatically mean fungal infection, especially in the case of Candida and Aspergillosis. Phrasing is important. Lines 138-147 - Repeated from the table. Unnecessary. Maybe state 2-3 lines with the pertinent findings. Figure 3 - Concerns as stated above Figure 4 - Unnecessary Table 4 - Unnecessary Table 5-7 - Too much information. Perhaps include as an Appendix if you wish. A few lines SUMMARIZING the key findings, i.e., the high prevalence of immunocompromise in terms of diabetes and steroid use among patients would suffice. Figure 5 - Unnecessary Discussion Lines 191-192 - Incorrect. There have been many studies investigating the prevalence of fungal infection in COVID-19 infection. Perhaps you meant something else? Overall, the Discussion highlights important studies related to your own but your structure and grammar can be improved. The information is there but does not read cohesively. Thank you for your study but I do think there are quite a number of areas of improvement in your study. Your study design is not very clear, in particular your definition of fungal infection. Your Results are unstructured with all your data repeated. Multiple figures and tables are made which add nothing to the manuscript. I think you need to re-focus your vision and think about what you really want to highlight. Personally, a Case Series on the patients with mucormycosis would be neater and more contained.

    Please rate the manuscript for methodological rigour

    Poor

    Please rate the quality of the presentation and structure of the manuscript

    Very poor

    To what extent are the conclusions supported by the data?

    Partially support

    Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?

    No

    Is there a potential financial or other conflict of interest between yourself and the author(s)?

    No

    If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?

    Yes

  11. Version published to 10.1099/acmi.0.000640.v1 on Access Microbiology