Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders

David Quispe-Aranda; Gloria Cruz-Gonzales; Víctor Rojas-Zumaran; Arístides Hurtado-Concha; William Cruz-Gonzales; Jeel Moya-Salazar; Eder Walttuoni-Picón

doi:10.12688/f1000research.139438.1

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Research Article

Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders

[version 1; peer review: 1 approved with reservations]

David Quispe-Aranda¹, Gloria Cruz-Gonzales ^1,2, Víctor Rojas-Zumaran^1,3, [...] Arístides Hurtado-Concha¹, William Cruz-Gonzales⁴, Jeel Moya-Salazar^2,5, Eder Walttuoni-Picón ⁶

David Quispe-Aranda¹, Gloria Cruz-Gonzales ^1,2, [...] Víctor Rojas-Zumaran^1,3, Arístides Hurtado-Concha¹, William Cruz-Gonzales⁴, Jeel Moya-Salazar^2,5, Eder Walttuoni-Picón ⁶

PUBLISHED 18 Oct 2023

Author details Author details

¹ Research Group Public Health: Comprehensive health, Faculty of Medical Technology, Federico Villarreal National University, San Miguel, Lima Region, 15007, Peru
² Faculties of Health Science, Technological University of Peru, Lima District, Lima Region, 15046, Peru
³ Diagnostic Support Department, National Teaching Hospital Mother Child San Bartolome, Lima District, Lima Region, 15001, Peru
⁴ Faculty of Financial and Accounting Sciences, Federico Villarreal National University, San Miguel, Lima Region, 15001, Peru
⁵ South American Center for Research in Education and Public Health, Private University Norbert Wiener, Lima District, Lima Region, 15046, Peru
⁶ Postgraduate University School, Federico Villarreal National University, San Miguel, Lima Region, 15088, Peru

David Quispe-Aranda
Roles: Conceptualization, Data Curation, Investigation, Writing – Original Draft Preparation

Gloria Cruz-Gonzales
Roles: Conceptualization, Investigation, Project Administration, Resources, Supervision

Víctor Rojas-Zumaran
Roles: Formal Analysis, Investigation, Visualization, Writing – Original Draft Preparation

Arístides Hurtado-Concha
Roles: Conceptualization, Data Curation, Investigation, Supervision

William Cruz-Gonzales
Roles: Data Curation, Project Administration, Validation, Visualization

Jeel Moya-Salazar
Roles: Formal Analysis, Methodology, Visualization, Writing – Review & Editing

Eder Walttuoni-Picón
Roles: Formal Analysis, Investigation, Methodology, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: The COVID-19 pandemic caused by SARS-CoV-2 has affected millions of people around the world. Most cytochemical studies of cerebrospinal fluid (CSF) in patients infected with SARS-CoV-2 have shown abnormal results. The objective of the present investigation was to determine the physical, cytological, and chemical alterations of the CSF cytochemical examination of COVID-19 patients with neurological disorders in Peru. Methods: An observational and cross-sectional study was carried out at the Edgardo Rebagliati Martins Hospital. The study population consisted of 94 CSF samples obtained by lumbar puncture from inpatient patients. Likewise, the paired T-test and one-way ANOVA with the Bonferroni post-hoc test was used to determine the differences in the values of CSF biochemical markers. Results: The most frequent neurological disorders were encephalopathy (43%) and brain tumor (23%). The most relevant physical characteristics were cloudy and reddish fluids in the brain tumor and intracerebral hemorrhage; however, in encephalopathies, transparent-looking liquids were observed. CSF glucose from patients with encephalopathy (30%) and intracerebral hemorrhage (13%) had concentrations >70 mg/dL. Proteins >45mg/dl corresponded to 20% of patients with encephalopathy and 17% of patients with intracerebral hemorrhage and brain tumor. Likewise, no differences were found in glucose concentration between neurological disorders (p>0.05); however, differences in protein concentration were observed (p=0.001). Finally, among the cytological characteristics, it was found that patients with encephalopathy (33%) and brain tumor (20%) presented a leukocyte count <5 cells/ul. Conclusion: These findings suggest that the characteristics of CSF may differ depending on the type of neurological complication experienced by patients with COVID-19.

Keywords

COVID-19, cytology, neurological disorders, leukocytes, glucose, protein, SARS-CoV-2, Peru

Corresponding authors: Gloria Cruz-Gonzales, Eder Walttuoni-Picón

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2023 Quispe-Aranda D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Quispe-Aranda D, Cruz-Gonzales G, Rojas-Zumaran V et al. Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:1354 (https://doi.org/10.12688/f1000research.139438.1) First published: 18 Oct 2023, 12:1354 (https://doi.org/10.12688/f1000research.139438.1) Latest published: 18 Oct 2023, 12:1354 (https://doi.org/10.12688/f1000research.139438.1)

Introduction

The COVID-19 pandemic caused by SARS-CoV-2 has affected millions of people around the world, resulting in an unprecedented health and economic crisis.¹ The virus mainly affects the respiratory system; however, there is increasing evidence to suggest that it can also affect the nervous system, resulting in symptoms and neurological comprlications.² The interaction between SARS-CoV-2 and the nervous system is complex and not yet fully understood.³

Neurological symptoms associated with COVID-19 range from mild symptoms, such as headache and anosmia, to severe symptoms, such as encephalitis and stroke.⁴ Additionally, COVID-19 can exacerbate pre-existing neurological conditions, such as Parkinson’s disease and multiple sclerosis.⁵^,⁶ The mechanisms underlying the neurological effects of COVID-19 are thought to involve direct viral invasion of the nervous system, immune-mediated damage, and hypercoagulability. However, the precise mechanisms and long-term effects of COVID-19 on the nervous system remain unclear.⁷

Recognizing and managing neurological cases related to COVID-19 presents a significant challenge that requires a comprehensive understanding of the underlying pathophysiological mechanisms.⁴ COVID-19 has been associated with a wide range of neurological syndromes, including encephalopathies, cerebrovascular events, and neuropathies such as Guillain-Barré Syndrome, which affects the entire neuraxis, including the cerebral vasculature.⁸ In patients with neurological manifestations related to COVID-19, brain MRI abnormalities such as leptomeningeal enhancement and increased inflammatory markers in the cerebrospinal fluid are frequently observed. Furthermore, acute disseminated encephalomyelitis with hemorrhagic changes is highly prevalent in severe cases of COVID-19.⁹

Most cytochemical studies of cerebrospinal fluid (CSF) in patients infected with SARS-CoV-2 have shown abnormal results, including elevated leukocyte and protein counts.¹⁰ Given the importance of timely management of neurological complications in critically ill patients, it is crucial to assess the impact of cerebrospinal fluid analysis. Wu et al.¹¹ have emphasized that requesting a CSF analysis in a timely manner can significantly improve patient outcomes, but further studies are needed to fully characterize the range of neurological conditions associated with COVID-19 and to identify CSF profiles and biomarkers that may help in the diagnosis of this disease.¹⁰

The objective of this study was to determine the physical, cytological, and chemical alterations of the CSF cytochemical examination of COVID-19 patients with neurological symptoms in Peru.

Methods

Ethical considerations

This study has followed the guidelines of the Helsinki Guide¹² and has been approved by the Ethics Committee of the Edgardo Rebagliati Martins Hospital (N°881-GRPR-ESSALUD-2021). Based on a retrospective approach, the reference records were used to obtain only the data corresponding to the results, excluding any other information from the clinical record (for example, the names of the patients), to preserve effective confidentiality and protection of the participants involved.

Study design and settings

This cross-sectional observational study was conducted during the first outbreak of COVID-19. The study was developed in the Clinical Laboratory of the Emergency Center of Metropolitan Lima (CELIM) of the Edgardo Rebagliati Martins Hospital in Lima, Peru. This hospital belongs to the Social Security (EsSalud) and annually receives 350 thousand patients. During the pandemic, it has become a reference hospital for the care of patients with COVID-19 with isolation centers and 24-hour care. This study followed the guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guide.¹³

Population and inclusion criteria

The study population consisted of 94 CSF samples obtained by lumbar puncture from inpatient patients. The inclusion criteria were samples of patients with COVID-19 diagnosed by polymerase chain reaction (PCR) from patients of both sexes and over 18 years of age with neurological symptoms and who had a complete cytochemical analysis (physical, cytological, and chemical). Samples from pregnant patients, with cancer or HIV were excluded. Only 30 samples met the criteria, which is why they were included in the study (Figure 1).

Figure 1. Flowchart for the selection of study patients.

Variables and procedures

The age and sex of the participants were obtained by analyzing the medical records, the SAGER guidelines were considered to report information about sex and gender.¹⁴ The CSF cytochemical analysis variable included physical (color and appearance), cytological (cellular characteristics), and chemical (glucose and protein) characteristics. Taking into account the reference values in CSF, for glucose from 40 to 70 mg/dl and for proteins from 15 to 45 mg/dl. The other variable was neurological disorders defined according to clinical neurological guidelines and DSM-V.¹⁵^,¹⁶ CSF samples were sent to the laboratory for cytochemical examination following the recommendations of the Clinical and Laboratory Standards Institute (CLSI) H-56A and C49-A guidelines.¹⁷^,¹⁸ The clinical records were obtained from the digital database in MS-Access (Microsoft, Redmond, US) of the emergency laboratory – CELIM.

Analysis of data

The data analysis has been done in SPSS v24.0 (Armonk, USA). Data analysis was initially descriptive to estimate the frequencies of the continuous variables and the mean and the standard deviation of the categorical variables. We used paired T-test and ANOVA one-way with Bonferroni post-hoc test to determine the differences in the values of biochemical markers of CSF considering the p-value <0.05 and the confidence interval of 95% as the significant. The database containing the original data as it was collected, without having been processed or analyzed is available under Underlying data (Database.sav).¹⁹

Results

The age range of the 30 patients with COVID-19 was 22 to 77 years (mean 52.2±14.2 years) and 17 (57%) were male. The most frequent neurological disorders were encephalopathy and brain tumor in 13 (43%) and 7 (23%) patients, respectively. Table 1 describes the demographic and clinical characteristics of the patients with COVID-19, whose cerebrospinal fluid was analyzed.

Table 1. Baseline characteristics of patients with COVID-19 (n=30).

Baseline characteristics	Categories	f	%
Sex	Female	13	43.3
Sex	Male	17	56.7
Age range (years)	<50 years	10	33.3
	50-60 years	12	40
	>60 years	8	26.7
Neurological disorders	Encephalopathy	13	43.3
	Brain tumor	7	23.3
	Intracerebral hemorrhage	6	20
	Hydrocephalus	2	6.7
	Schizophrenia	2	6.7

Among the most outstanding physical characteristics, 14 (47%) liquids were colorless and 21 (70%) had a transparent appearance, corresponding to encephalopathies as the most frequent neurological complication in both cases (Table 2). Brain tumors and intracerebral hemorrhage were neurological complications that frequently presented a cloudy appearance and reddish color in the macroscopic evaluation.

Table 2. Characteristics of the cerebrospinal fluid of patients with COVID-19 (n=30).

CSF analysis		Encephalopathy n (%)	Brain tumor n (%)	Intracerebral hemorrhage n (%)	Schizophrenia n (%)	Hydrocephaly n (%)
Physical characteristics
Color	Colorless	9 (30)	2 (7)	1 (3	1 (3)	1 (3)
	Yellow	3 (10)	2 (7)	1 (3)	1 (3)	1 (3)
	Red	1 (3)	3 (10)	4 (13)	0 (0)	0 (0)
Aspect	Transparent	12 (40)	3 (10)	2 (7)	2 (7)	2 (7)
	Slightly turbid	0 (0)	2 (7)	2 (7)	0 (0)	0 (0)
	Cloudy	1 (3)	2 (7)	2 (7)	0 (0)	0 (0)
Biochemical characteristics
Glucose (mg/dl)	<40	1 (3)	2 (7)	1 (3)	0 (0)	1 (3)
	40-70	3 (10)	4 (13)	1 (3)	1 (1)	1 (3)
	>70	9 (30)	1 (3)	4 (13)	1 (1)	0 (0)
Protein (mg/dl)	<15	1 (3)	1 (3)	0 (0)	0 (0)	0 (0)
	15-45	6 (20)	2 (7)	1 (3)	1 (1)	0 (0)
	>45	6 (20)	4 (13)	5 (17)	1 (1)	2 (7)
Cytologic characteristics
White blood cell count (cells/mm³)	≤5	10 (33)	6 (20)	2 (7)	2 (7)	1 (3)
White blood cell count (cells/mm³)	>5	3 (10)	1 (3)	4 (13)	0 (0)	1 (3)

Glucose concentration in COVID-19 patients with encephalopathy, brain tumor, intracerebral hemorrhage, and others was 70.9±20 mg/dl (95%CI 60 to 81.8), 67.6±38.5 mg/dl (95%CI 39.1 to 96.1), 76.8±42.3 mg/dl (95%CI 43 to 110.7), and 56.5±26.0 mg/dl (95%CI 31 to 82), respectively. Among the biochemical parameters, we found that glucose in the CSF of 9 (30%) patients with encephalopathy had values greater than 70 mg/dl, 4 (13%) patients with brain tumors had glucose concentrations between 40 and 70 mg/d. Finally, only 4 (13%) patients with intracerebral hemorrhage had glucose >70 mg/dl.

Protein concentration in COVID-19 patients with encephalopathy, brain tumor, intracerebral hemorrhage, and others was 68.1±74.1 mg/dl (95%CI 27.8 to 108.3), 80.4±96.3 mg/dl (95%CI 9 to 151.7), 221.5±326.3 mg/dl (95%CI -39.6 to 482.6), and 273±271.6 mg/dl (95%CI 6.8 to 539.2), respectively. Proteins >45 mg/dl corresponded to 6 (20%) patients with encephalopathy and 5 (17%) patients with hemorrhage and brain tumor. No differences were found in glucose concentration between neurological disorders (Figure 2); however, differences were observed in protein concentration (p=0.001).

Figure 2. CSF and glucose concentrations, and leukocyte count in CSF of COVID-19 patients with neurological disorders.

*p>0.05, **p<0.001 and ***p<0.05 (significant).

Among the cytological characteristics, the leukocyte count <5 cells/ul was found in 10 (33%) patients with encephalopathy and in 6 (20%) patients with brain tumors. Patients with encephalopathy and Intracerebral Hemorrhage had a leukocyte count >5 cells/ul which was significant (p>0.05).

Discussion

This study demonstrated in a cohort of Peruvian patients with COVID-19 an increase in leukocyte count in patients with encephalopathy or intracerebral hemorrhage. In addition, the brain tumor and intracerebral hemorrhage had very marked cytochemical changes and the protein concentration varied significantly according to the neurological condition.

This is the first comprehensive Peruvian study describing the physical, cytological, and biochemical characteristics of CSF in COVID-19 patients with neurological complications. Our study addresses a critical gap in understanding the unique characteristics of CSF in this patient population and contributes to advancing the field of neurological health.²⁰ By characterizing the CSF in patients with COVID-19, we provide valuable information that can inform and improve care processes for neurological complications associated with COVID-19. Our study also offers significant implications for laboratory professionals, providing critical information on the biochemical and cytological features of these disorders. This knowledge is essential to recognize the key cellular and biochemical changes observed in the CSF of COVID-19 patients and ensure the quality of clinical laboratory results. By providing a detailed understanding of the biochemical and cytological profile of CSF, we hope to contribute to more effective diagnosis and management of neurological complications in patients with COVID-19.

The study found that the most frequent neurological disorders were encephalopathy (43%) and brain tumor (23%). Likewise, the age group with the highest frequency of patients was between the ages of 50 to 60 years (40%) with a mean ±SD of 52.2±14.2 years and 57% were male. Some investigations such as the studies by Neumann et al.,⁴ Poyiadji et al.,²¹ and Ghosh et al.,²² indicate an association between SARS-CoV-2 infection with encephalopathies as one of the neuropathological manifestations with greater relevance in this disease. A systematic review identified 430 patients with COVID-19 presenting with neurological symptoms, with the majority (56%) having encephalopathy.

In the present investigation, no statistically significant differences were found in glucose concentration between neurological disorders (p>0.05); however, differences in protein concentration were observed (p=0.001) and the highest levels were observed in patients with intracerebral hemorrhage and brain tumors. An investigation in patients with and without neurological disease found that elevated total protein concentrations were associated with the presence of neurological disease, mental disorders, and central nervous system infections.²³ On the other hand, Espindola et al.⁹ observed that patients with encephalopathy had a mean glucose concentration of 64.5 mg/dl in CSF and total protein of 35.5 mg/dl, finding an elevation of total protein in 29.2% of patients; however, the analysis of these analytes did not present significant differences with other neurological manifestations.

Espindola et al.⁹ and Keller et al.,²⁴ described a high incidence of acute disseminated encephalomyelitis with hemorrhagic changes in these patients, in this work, Intracerebral Hemorrhage was detected as one of the three main diagnoses, this limits the possibility that a patient without any risk factor could develop the formation and rupture of an aneurysm as described in their work Al Saiegh et al.²⁵

When comparing the results with what Jaijakul et al.,²⁶ in their work where they indicate that 25% of patients with central nervous system (CNS) viral infections are typically characterized by lymphocytic or neutrophilic pleocytosis of the cerebrospinal fluid (CSF), we could not determine this because, in most Of the study cases, the COVID-19 patients with neurological alterations did not have more than 5 cells/ul, so the cytomorphological differential study was not performed.

Miller et al.,¹⁰ in their work mentioned that the few cytochemical studies of the CSF in patients infected with SARS-CoV-2 are mostly abnormal, results with which this work is not related, because, unlike the present work This author found elevated leukocyte counts, in terms of proteins if we had similarity in the study, finding hyperproteinorrachia in both investigations.

The study has some limitations. First, because it is a cross-sectional study, it was not possible to establish a causality criterion between the independent variables and the dependent variable. Second, the small sample size is a limitation that may limit the generalizability of the findings; because 30 samples of cerebrospinal fluid were obtained using a non-probability sampling for convenience, rigorously classified according to the eligibility criteria, now although the sample may not be very representative, it must be taken into account that it was carried out in full swing of the COVID-19 pandemic, where studies were carried out day by day so that the scientific community began to detail a wealth of knowledge that is available to date about the virus. In addition, the study does not provide information on the long-term outcomes of the patients. Despite these limitations, the study provides important information on the neurological complications of COVID-19 and highlights the need for further research in this area of cytology applied to neurology.

Conclusions

These findings suggest that the characteristics of CSF may differ depending on the type of neurological complication experienced by patients with COVID-19. These differences may be helpful in diagnostic and treatment decisions for these patients. However, more research is needed to fully understand the relationship between CSF characteristics and neurological complications of COVID-19.

Early recognition, investigation, and treatment of neurological diseases related to COVID-19 are crucial to improve patient outcomes and reduce disease burden. A better understanding of the neurological effects of COVID-19 is essential to optimize patient care and develop effective preventive and therapeutic strategies.

Data availability

Underlying data

Figshare: Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders, DOI: https://doi.org/10.6084/m9.figshare.23620983.¹⁹

This project contains the following underlying data:

- Database.sav¹⁹

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC BY 4.0 Public domain dedication).

Reporting guidelines

Figshare: STROBE checklist for Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders: a cross-sectional study’, https://doi.org/10.6084/m9.figshare.23621217.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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Comments on this article Comments (0)

Version 1

VERSION 1 PUBLISHED 18 Oct 2023

Author details Author details

David Quispe-Aranda
Roles: Conceptualization, Data Curation, Investigation, Writing – Original Draft Preparation

Gloria Cruz-Gonzales
Roles: Conceptualization, Investigation, Project Administration, Resources, Supervision

Víctor Rojas-Zumaran
Roles: Formal Analysis, Investigation, Visualization, Writing – Original Draft Preparation

Arístides Hurtado-Concha
Roles: Conceptualization, Data Curation, Investigation, Supervision

William Cruz-Gonzales
Roles: Data Curation, Project Administration, Validation, Visualization

Jeel Moya-Salazar
Roles: Formal Analysis, Methodology, Visualization, Writing – Review & Editing

Eder Walttuoni-Picón
Roles: Formal Analysis, Investigation, Methodology, Visualization, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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Published: 18 Oct 2023, 12:1354

https://doi.org/10.12688/f1000research.139438.1

© 2023 Quispe-Aranda D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Quispe-Aranda D, Cruz-Gonzales G, Rojas-Zumaran V et al. Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:1354 (https://doi.org/10.12688/f1000research.139438.1)

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Reviewer Report 18 Jun 2024

Daniel van Wamelen, King's College London, London, England, UK

Approved with Reservations

https://doi.org/10.5256/f1000research.152713.r290326

The authors have determined changes occurring in the cerebrospinal fluid of patients with COVID-19. The study addresses an interesting topic, but I feel there are a few issues around study design and inclusion criteria that would need to be better clarified. In addition, I have several other comments and suggestions.

1. I feel the rationale for performing these analyses should be clarified better. A mere description of changes that occur in the CSF of patients with COVID-19 does not add much to the existing literature in my opinion. Related to this the authors state in the introduction ''...further studies are needed...to identify CSF profiles and biomarkers that may help in the diagnosis of this disease''. What would be the additional benefit of CSF analyses when patients have developed (sub)acute neurological symptoms and have also been diagnosed with COVID-19?
2. In the abstract, the authors suggest that they included 94 participants in whom CSF analyses were performed. However, in the results it becomes clear they only included 30 participants in their final analyses. This should be made explicit. In addition, I wonder why they excluded participants without a diagnosis of COVID-19; would this not make a good comparison group to determine the changes in CSF profile between patients with neurological conditions and COVID-19 and those with neurological conditions without COVID-19? Could the authors clarify the reason for not including a ''control'' group?
3. From figure 1 it becomes clear that the authors excluded patients without cytochemical analyses of the CSF. Could they provide an explanation why these analyses where not performed and what the reasons were for these patients to undergo lumbar puncture?
4. Do the authors feel that the participant cohort might represent only a selection of patients with neurological problems and COVID-19? I.e. could the selection criteria have introduced a bias and skewed the cohort towards those with e.g. uncertainty about neurological diagnosis or inflammatory presentations?
5. The methods are rather brief and would benefit from a more detailed description of procedures and whether analyses of CSF had been standardised. In relation to statistical analyses, I would suggest mentioned whether the data were normally distributed justifying the use of parametric statistical tests such as a t-test. If non-normally distributed, non-parametric tests would be more appropriate.
6. In the results (and abstracts) the authors mention ''brain tumor'' as a common neurological diagnosis. Could they specify what is meant by this and what type of brain tumors were included in this diagnostic category? Moreover, what was the evidence on which they based the conclusion that these tumors were related to COVID-19 to exclude the possibility that these tumors were mere coincidental findings?
7. In the results: ''Brain tumors and intracerebral hemorrhage were neurological complications that frequently presented a cloudy appearance and reddish color in the macroscopic evaluation''. What is the relevance in relation to COVID-19? Would this be any different in patients presenting with the same diagnoses but without COVID-19?
8. Table 1: ''Schizophrenia'' is mentioned as a neurological diagnosis in two cases. How was this diagnosed and what evidence is available to assume these diagnoses were related to COVID-19?
9. In the discussion, the authors mention that ''This study demonstrated in a cohort of Peruvian patients with COVID-19 an increase in leukocyte count in patients with encephalopathy or intracerebral hemorrhage''. However, from the results and figures the increase in leukocyte count in patients with encephalopathy is not present.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Movement disorders, particularly Huntington's and Parkinson's disease; COVID-19 related neurological disorders; Neuroimaging.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

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Author Response 05 Jul 2024

Eder Walttuoni Picón, Postgraduate University School, Federico Villarreal National University, San Miguel, 15088, Peru

05 Jul 2024

Author Response
Please go through the Authors' point by point response respectively to the Reviewer Comments:
1. In the current scientific literature, one mainly finds descriptions and case reports regarding the
... Continue reading
Please go through the Authors' point by point response respectively to the Reviewer Comments:

In the current scientific literature, one mainly finds descriptions and case reports regarding the study of cerebrospinal fluid (CSF) in COVID-19 patients. Within this context, the present study provides a detailed analysis of the physical, chemical, and cytological parameters of CSF in a specific group of patients.

At the outset of the research, there were 94 participants who had undergone a lumbar puncture for the corresponding cytological study requested by the attending physician. In the initial phase, 44 samples were excluded due to incomplete or inconsistent data in the physical, chemical, and cellular indicators of the cytological examination, presence of clots, therapeutic lumbar puncture (such as in cases of intrathecal chemotherapy), or studies for lymphoma or other hematologic neoplasms. Additionally, 20 more patients were excluded for lacking a confirmed molecular diagnosis (PCR-RT), resulting in a final cohort of 30 eligible patients for the study. A control group was not included because the research was conducted at a hospital exclusively serving patients diagnosed with COVID-19 based on clinical criteria or molecular tests, where cerebrospinal fluid samples were obtained.

Patients were excluded if they lacked complete cerebrospinal fluid (CSF) cytological analysis due to shortages of reagents and supplies in the laboratory. In Peru, as in many countries worldwide, most reagents and supplies used by automated equipment are imported by multinational healthcare companies. During the first wave of the pandemic, we faced shortages of these reagents, resulting in incomplete results in these and other tests. The reason these patients underwent lumbar puncture was due to the attending physician's suspicion of a pathology necessitating cytological examination as part of a rapid and precise evaluation for potential neurological disorders of the central nervous system.

Yes, we believe that the cohort of participants represents only a selection of patients with neurological issues and COVID-19. We do not believe there is selection bias.

The procedures for cerebrospinal fluid cytological analysis were adapted according to our laboratory's internal procedure manual, following recommendations from the Clinical and Laboratory Standards Institute (CLSI), as outlined in their guidelines CLSI C49A "Analysis of Body Fluids in Clinical Chemistry" and CLSI H56 "Body Fluid Analysis for Cellular Composition". Regarding statistical analysis, it was noted that the data did not follow a normal distribution.

Among the clinical characteristics of the patients included in the study, it was observed that 7 (23%) had a diagnosis of brain tumor, distributed as follows: malignant tumor of the temporal lobe (1), malignant brain tumor (3), malignant brain tumor unspecified (2), and unspecified brain tumor (1). We did not conclude that these tumors were related to COVID-19 but rather that these were patients diagnosed with COVID-19. This aligns with literature indicating that some cancer patients and those undergoing cancer treatment have a higher risk of developing severe forms of COVID-19.

Unfortunately, as mentioned earlier, a control group was not included in this study. This prevented comparisons and the assessment of the relevance of the findings in relation to patients who had similar diagnoses but without COVID-19.

The diagnoses were obtained from the ESSI system (EsSalud Intelligent Health Service), the information management system for medical records. Access to this system allowed us to view the patients' diagnoses, with the appropriate authorization from the institution's ethics and research committee.

Among the cytological characteristics of patients infected with COVID-19, it was observed that 10 (33%) of the patients with encephalopathy and 6 (20%) of the patients with brain tumors had a leukocyte count of less than 5 cells/µL.
Please go through the Authors' point by point response respectively to the Reviewer Comments:

In the current scientific literature, one mainly finds descriptions and case reports regarding the study of cerebrospinal fluid (CSF) in COVID-19 patients. Within this context, the present study provides a detailed analysis of the physical, chemical, and cytological parameters of CSF in a specific group of patients.

At the outset of the research, there were 94 participants who had undergone a lumbar puncture for the corresponding cytological study requested by the attending physician. In the initial phase, 44 samples were excluded due to incomplete or inconsistent data in the physical, chemical, and cellular indicators of the cytological examination, presence of clots, therapeutic lumbar puncture (such as in cases of intrathecal chemotherapy), or studies for lymphoma or other hematologic neoplasms. Additionally, 20 more patients were excluded for lacking a confirmed molecular diagnosis (PCR-RT), resulting in a final cohort of 30 eligible patients for the study. A control group was not included because the research was conducted at a hospital exclusively serving patients diagnosed with COVID-19 based on clinical criteria or molecular tests, where cerebrospinal fluid samples were obtained.

Patients were excluded if they lacked complete cerebrospinal fluid (CSF) cytological analysis due to shortages of reagents and supplies in the laboratory. In Peru, as in many countries worldwide, most reagents and supplies used by automated equipment are imported by multinational healthcare companies. During the first wave of the pandemic, we faced shortages of these reagents, resulting in incomplete results in these and other tests. The reason these patients underwent lumbar puncture was due to the attending physician's suspicion of a pathology necessitating cytological examination as part of a rapid and precise evaluation for potential neurological disorders of the central nervous system.

Yes, we believe that the cohort of participants represents only a selection of patients with neurological issues and COVID-19. We do not believe there is selection bias.

The procedures for cerebrospinal fluid cytological analysis were adapted according to our laboratory's internal procedure manual, following recommendations from the Clinical and Laboratory Standards Institute (CLSI), as outlined in their guidelines CLSI C49A "Analysis of Body Fluids in Clinical Chemistry" and CLSI H56 "Body Fluid Analysis for Cellular Composition". Regarding statistical analysis, it was noted that the data did not follow a normal distribution.

Among the clinical characteristics of the patients included in the study, it was observed that 7 (23%) had a diagnosis of brain tumor, distributed as follows: malignant tumor of the temporal lobe (1), malignant brain tumor (3), malignant brain tumor unspecified (2), and unspecified brain tumor (1). We did not conclude that these tumors were related to COVID-19 but rather that these were patients diagnosed with COVID-19. This aligns with literature indicating that some cancer patients and those undergoing cancer treatment have a higher risk of developing severe forms of COVID-19.

Unfortunately, as mentioned earlier, a control group was not included in this study. This prevented comparisons and the assessment of the relevance of the findings in relation to patients who had similar diagnoses but without COVID-19.

The diagnoses were obtained from the ESSI system (EsSalud Intelligent Health Service), the information management system for medical records. Access to this system allowed us to view the patients' diagnoses, with the appropriate authorization from the institution's ethics and research committee.

Among the cytological characteristics of patients infected with COVID-19, it was observed that 10 (33%) of the patients with encephalopathy and 6 (20%) of the patients with brain tumors had a leukocyte count of less than 5 cells/µL.
Competing Interests: No competing interests were disclosed. Close
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Author Response 05 Jul 2024

Eder Walttuoni Picón, Postgraduate University School, Federico Villarreal National University, San Miguel, 15088, Peru

05 Jul 2024

Author Response
Please go through the Authors' point by point response respectively to the Reviewer Comments:
1. In the current scientific literature, one mainly finds descriptions and case reports regarding the
... Continue reading
Please go through the Authors' point by point response respectively to the Reviewer Comments:

In the current scientific literature, one mainly finds descriptions and case reports regarding the study of cerebrospinal fluid (CSF) in COVID-19 patients. Within this context, the present study provides a detailed analysis of the physical, chemical, and cytological parameters of CSF in a specific group of patients.

At the outset of the research, there were 94 participants who had undergone a lumbar puncture for the corresponding cytological study requested by the attending physician. In the initial phase, 44 samples were excluded due to incomplete or inconsistent data in the physical, chemical, and cellular indicators of the cytological examination, presence of clots, therapeutic lumbar puncture (such as in cases of intrathecal chemotherapy), or studies for lymphoma or other hematologic neoplasms. Additionally, 20 more patients were excluded for lacking a confirmed molecular diagnosis (PCR-RT), resulting in a final cohort of 30 eligible patients for the study. A control group was not included because the research was conducted at a hospital exclusively serving patients diagnosed with COVID-19 based on clinical criteria or molecular tests, where cerebrospinal fluid samples were obtained.

Patients were excluded if they lacked complete cerebrospinal fluid (CSF) cytological analysis due to shortages of reagents and supplies in the laboratory. In Peru, as in many countries worldwide, most reagents and supplies used by automated equipment are imported by multinational healthcare companies. During the first wave of the pandemic, we faced shortages of these reagents, resulting in incomplete results in these and other tests. The reason these patients underwent lumbar puncture was due to the attending physician's suspicion of a pathology necessitating cytological examination as part of a rapid and precise evaluation for potential neurological disorders of the central nervous system.

Yes, we believe that the cohort of participants represents only a selection of patients with neurological issues and COVID-19. We do not believe there is selection bias.

The procedures for cerebrospinal fluid cytological analysis were adapted according to our laboratory's internal procedure manual, following recommendations from the Clinical and Laboratory Standards Institute (CLSI), as outlined in their guidelines CLSI C49A "Analysis of Body Fluids in Clinical Chemistry" and CLSI H56 "Body Fluid Analysis for Cellular Composition". Regarding statistical analysis, it was noted that the data did not follow a normal distribution.

Among the clinical characteristics of the patients included in the study, it was observed that 7 (23%) had a diagnosis of brain tumor, distributed as follows: malignant tumor of the temporal lobe (1), malignant brain tumor (3), malignant brain tumor unspecified (2), and unspecified brain tumor (1). We did not conclude that these tumors were related to COVID-19 but rather that these were patients diagnosed with COVID-19. This aligns with literature indicating that some cancer patients and those undergoing cancer treatment have a higher risk of developing severe forms of COVID-19.

Unfortunately, as mentioned earlier, a control group was not included in this study. This prevented comparisons and the assessment of the relevance of the findings in relation to patients who had similar diagnoses but without COVID-19.

The diagnoses were obtained from the ESSI system (EsSalud Intelligent Health Service), the information management system for medical records. Access to this system allowed us to view the patients' diagnoses, with the appropriate authorization from the institution's ethics and research committee.

Among the cytological characteristics of patients infected with COVID-19, it was observed that 10 (33%) of the patients with encephalopathy and 6 (20%) of the patients with brain tumors had a leukocyte count of less than 5 cells/µL.
Please go through the Authors' point by point response respectively to the Reviewer Comments:

In the current scientific literature, one mainly finds descriptions and case reports regarding the study of cerebrospinal fluid (CSF) in COVID-19 patients. Within this context, the present study provides a detailed analysis of the physical, chemical, and cytological parameters of CSF in a specific group of patients.

At the outset of the research, there were 94 participants who had undergone a lumbar puncture for the corresponding cytological study requested by the attending physician. In the initial phase, 44 samples were excluded due to incomplete or inconsistent data in the physical, chemical, and cellular indicators of the cytological examination, presence of clots, therapeutic lumbar puncture (such as in cases of intrathecal chemotherapy), or studies for lymphoma or other hematologic neoplasms. Additionally, 20 more patients were excluded for lacking a confirmed molecular diagnosis (PCR-RT), resulting in a final cohort of 30 eligible patients for the study. A control group was not included because the research was conducted at a hospital exclusively serving patients diagnosed with COVID-19 based on clinical criteria or molecular tests, where cerebrospinal fluid samples were obtained.

Patients were excluded if they lacked complete cerebrospinal fluid (CSF) cytological analysis due to shortages of reagents and supplies in the laboratory. In Peru, as in many countries worldwide, most reagents and supplies used by automated equipment are imported by multinational healthcare companies. During the first wave of the pandemic, we faced shortages of these reagents, resulting in incomplete results in these and other tests. The reason these patients underwent lumbar puncture was due to the attending physician's suspicion of a pathology necessitating cytological examination as part of a rapid and precise evaluation for potential neurological disorders of the central nervous system.

Yes, we believe that the cohort of participants represents only a selection of patients with neurological issues and COVID-19. We do not believe there is selection bias.

The procedures for cerebrospinal fluid cytological analysis were adapted according to our laboratory's internal procedure manual, following recommendations from the Clinical and Laboratory Standards Institute (CLSI), as outlined in their guidelines CLSI C49A "Analysis of Body Fluids in Clinical Chemistry" and CLSI H56 "Body Fluid Analysis for Cellular Composition". Regarding statistical analysis, it was noted that the data did not follow a normal distribution.

Among the clinical characteristics of the patients included in the study, it was observed that 7 (23%) had a diagnosis of brain tumor, distributed as follows: malignant tumor of the temporal lobe (1), malignant brain tumor (3), malignant brain tumor unspecified (2), and unspecified brain tumor (1). We did not conclude that these tumors were related to COVID-19 but rather that these were patients diagnosed with COVID-19. This aligns with literature indicating that some cancer patients and those undergoing cancer treatment have a higher risk of developing severe forms of COVID-19.

Unfortunately, as mentioned earlier, a control group was not included in this study. This prevented comparisons and the assessment of the relevance of the findings in relation to patients who had similar diagnoses but without COVID-19.

The diagnoses were obtained from the ESSI system (EsSalud Intelligent Health Service), the information management system for medical records. Access to this system allowed us to view the patients' diagnoses, with the appropriate authorization from the institution's ethics and research committee.

Among the cytological characteristics of patients infected with COVID-19, it was observed that 10 (33%) of the patients with encephalopathy and 6 (20%) of the patients with brain tumors had a leukocyte count of less than 5 cells/µL.
Competing Interests: No competing interests were disclosed. Close
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Daniel van Wamelen, King's College London, London, UK

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18 Jun 2024 | for Version 1

Daniel van Wamelen, King's College London, London, England, UK

13 Views Cite this report Responses(1)

Approved With Reservations

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Movement disorders, particularly Huntington's and Parkinson's disease; COVID-19 related neurological disorders; Neuroimaging.

Respond to this report

Responses (1)

Author Response

05 Jul 2024

Eder Walttuoni Picón, Postgraduate University School, Federico Villarreal National University, San Miguel, 15088, Peru

Please go through the Authors' point by point response respectively to the Reviewer Comments:

In the current scientific literature, one mainly finds descriptions and case reports regarding the study of cerebrospinal fluid (CSF) in COVID-19 patients. Within this context, the present study provides a detailed analysis of the physical, chemical, and cytological parameters of CSF in a specific group of patients.
At the outset of the research, there were 94 participants who had undergone a lumbar puncture for the corresponding cytological study requested by the attending physician. In the initial phase, 44 samples were excluded due to incomplete or inconsistent data in the physical, chemical, and cellular indicators of the cytological examination, presence of clots, therapeutic lumbar puncture (such as in cases of intrathecal chemotherapy), or studies for lymphoma or other hematologic neoplasms. Additionally, 20 more patients were excluded for lacking a confirmed molecular diagnosis (PCR-RT), resulting in a final cohort of 30 eligible patients for the study. A control group was not included because the research was conducted at a hospital exclusively serving patients diagnosed with COVID-19 based on clinical criteria or molecular tests, where cerebrospinal fluid samples were obtained.
Patients were excluded if they lacked complete cerebrospinal fluid (CSF) cytological analysis due to shortages of reagents and supplies in the laboratory. In Peru, as in many countries worldwide, most reagents and supplies used by automated equipment are imported by multinational healthcare companies. During the first wave of the pandemic, we faced shortages of these reagents, resulting in incomplete results in these and other tests. The reason these patients underwent lumbar puncture was due to the attending physician's suspicion of a pathology necessitating cytological examination as part of a rapid and precise evaluation for potential neurological disorders of the central nervous system.
Yes, we believe that the cohort of participants represents only a selection of patients with neurological issues and COVID-19. We do not believe there is selection bias.
The procedures for cerebrospinal fluid cytological analysis were adapted according to our laboratory's internal procedure manual, following recommendations from the Clinical and Laboratory Standards Institute (CLSI), as outlined in their guidelines CLSI C49A "Analysis of Body Fluids in Clinical Chemistry" and CLSI H56 "Body Fluid Analysis for Cellular Composition". Regarding statistical analysis, it was noted that the data did not follow a normal distribution.
Among the clinical characteristics of the patients included in the study, it was observed that 7 (23%) had a diagnosis of brain tumor, distributed as follows: malignant tumor of the temporal lobe (1), malignant brain tumor (3), malignant brain tumor unspecified (2), and unspecified brain tumor (1). We did not conclude that these tumors were related to COVID-19 but rather that these were patients diagnosed with COVID-19. This aligns with literature indicating that some cancer patients and those undergoing cancer treatment have a higher risk of developing severe forms of COVID-19.
Unfortunately, as mentioned earlier, a control group was not included in this study. This prevented comparisons and the assessment of the relevance of the findings in relation to patients who had similar diagnoses but without COVID-19.
The diagnoses were obtained from the ESSI system (EsSalud Intelligent Health Service), the information management system for medical records. Access to this system allowed us to view the patients' diagnoses, with the appropriate authorization from the institution's ethics and research committee.
Among the cytological characteristics of patients infected with COVID-19, it was observed that 10 (33%) of the patients with encephalopathy and 6 (20%) of the patients with brain tumors had a leukocyte count of less than 5 cells/µL.

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Cerebrospinal fluid cytochemical analysis from COVID-19 patients with neurological disorders

Abstract

Keywords

Introduction

Methods

Ethical considerations

Study design and settings

Population and inclusion criteria

Figure 1. Flowchart for the selection of study patients.

Variables and procedures

Analysis of data

Results

Table 1. Baseline characteristics of patients with COVID-19 (n=30).

Table 2. Characteristics of the cerebrospinal fluid of patients with COVID-19 (n=30).

Figure 2. CSF and glucose concentrations, and leukocyte count in CSF of COVID-19 patients with neurological disorders.

Discussion

Conclusions

Data availability

Underlying data

Reporting guidelines

References

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