Pyuria in hospitalized general medical patients without urinary tract infection

Praveenkumar Thyagaraju; Jharna Mandal; Hariswar Pari Thenmozhi; Surendran Deepanjali

doi:10.12688/f1000research.144853.1

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Brief Report

Pyuria in hospitalized general medical patients without urinary tract infection

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

Praveenkumar Thyagaraju¹, Jharna Mandal², Hariswar Pari Thenmozhi¹, Surendran Deepanjali ¹

PUBLISHED 18 Apr 2024

Author details Author details

¹ Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, Puducherry, 605006, India
² Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Reserach, Dhanvantri Nagar, Puducherry, 605006, India

Praveenkumar Thyagaraju
Roles: Data Curation, Investigation, Project Administration, Resources, Writing – Original Draft Preparation

Jharna Mandal
Roles: Conceptualization, Investigation, Methodology, Supervision, Validation

Hariswar Pari Thenmozhi
Roles: Data Curation, Formal Analysis, Visualization, Writing – Review & Editing

Surendran Deepanjali
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Urine microscopy for detecting pus cells is a common investigation ordered in hospitalized general medical patients as part of routine care. A few previous studies have shown that sterile pyuria is not uncommon in this population. We studied the prevalence of pyuria among patients hospitalized with non-urinary tract infection (UTI) diagnosis in the medical wards. We excluded patients with asymptomatic bacteriuria (ASB). Pyuria was quantified in uncentrifuged urine using the chamber counting method, and ≥ 10 pus cells per mm3 was considered significant. We also compared this method with the commonly used but less accurate method of counting pus cells/high power field using centrifuged urine (routine method). We studied 196 patients; 113 (57.7%) were males. Most (175[89.3%]) patients were hospitalized for an infection. We found that 18.4% of the study group had sterile pyuria, and it was strongly associated with the presence of concomitant microscopic hematuria (unadjusted odds ratio, 3.74 [1.65 to 8.50]; P=0.002). We found no association of pyuria with female gender, diabetes, acute kidney injury, or current antibiotic use. By routine method, 56 (28.6 %) patients had significant pyuria. In comparison to the chamber counting method, the routine method was 69.4(63—75.8) % sensitive and 80.6(75.1—86.2) % specific. The positive and negative predictive values were 44.6 (37.7— 51.6) % and 92.1 (88.4 — 95.9) %. We concluded that sterile pyuria and microscopic hematuria could be present in a proportion of hospitalized general medical patients without UTI or ASB. Clinical judgment is essential in interpreting the significance of abnormal urinalysis reports.

Keywords

microscopic pyuria, urinalysis, urinary tract infection, asymptomatic bacteriuria, general medical patients

Corresponding author: Surendran Deepanjali

Competing interests: No competing interests were disclosed.

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

Copyright: © 2024 Thyagaraju P 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: Thyagaraju P, Mandal J, Pari Thenmozhi H and Deepanjali S. Pyuria in hospitalized general medical patients without urinary tract infection [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 13:291 (https://doi.org/10.12688/f1000research.144853.1) First published: 18 Apr 2024, 13:291 (https://doi.org/10.12688/f1000research.144853.1) Latest published: 22 May 2024, 13:291 (https://doi.org/10.12688/f1000research.144853.2)

Introduction

Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission. In a retrospective cohort study using a national dataset of inpatient admissions from 263 hospitals in the United States from 2009 to 2014, Horstman et al. found that urinalysis was ordered in 47% of admissions.¹ They also found that the test is frequently repeated during hospital stay suggesting large-scale overuse. More recent studies show that urinalysis is often ordered without proper indication in the emergency department.²^,³

In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.⁴

In a previous study including hospitalized general medical patients done in our centre, almost 80% patients who had asymptomatic bacteriuria (ASB) also had pyuria.⁵ Even in the absence of a positive urine culture, a significant proportion of hospitalized patients could have pyuria, often referred to as ‘sterile pyuria.’ In a retrospective study done including 210 consecutive patients (both adults and children) with infections outside of the urinary tract and who were admitted under medical and surgical services of an academic medical center in Oklahoma, nearly one-third had >5 white blood cells (WBCs) per high-power field (hpf) of urine.⁶

Pyuria can occur in non-infectious conditions like interstitial nephritis, diabetic nephropathy, and malignant hypertension also.⁷ With this background, we studied the prevalence of significant microscopic pyuria among patients hospitalized with non-UTI diagnosis. We defined sterile pyuria as ≥ 10 WBCs per mm³ of uncentrifuged urine using the chamber counting method, which is a more accurate method of quantifying pyuria. We also compared this with the commonly practiced method of reporting the number of WBCs per high power field (hpf) in centrifuged urine sample (referred to as ‘routine method’ hereafter).

Methods

We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.

Once the patients were recruited in the study, one of the investigators (TP) collected the clinical details from the patients. Patients submitted a fresh mid-stream urine sample (about 50 mL) in a sterile vial. A portion of this sample was further divided between 2 more sterile vials. One was sent to microbiology lab for culture. The second one was to the medicine side lab, where a portion of the sample was subjected to dipstick analysis of proteinuria and glucosuria. The other portion was centrifuged at a rate of 1500 to 2000 rpm for 3 to 5 minutes, and then it was resuspended. From this re-suspended urine sample, a drop was placed in a clean glass slide using a micropipette and then covered by a coverslip. This slide preparation was then counted for a total number of pus cells under 40× magnification of a compound microscope by trained and experienced technicians (routine method). The presence of ≥5 WBCs/hpf was considered significant pyuria by this method. Microscopic hematuria was defined as presence of ≥3 red blood cell/hpf.

Using the third urine sample, TP performed a microscopic examination of uncentrifuged urine loaded in a Neubauer’s chamber under 40× magnification (chamber counting method). The number of WBCs per mm³ was calculated by multiplying the total number of WBCs in the four corner squares of the chamber by a factor of 2.5.⁸ Significant pyuria by this method was defined as ≥10 WBCs per mm³.⁹

Exclusion of patients with ASB

Among patients without a positive UTI symptom screening, we further excluded those in whom urine culture showed significant growth of organisms that could represent asymptomatic bacteriuria. We also excluded patients with contaminated urine cultures and those in whom the treating team administered any UTI-directed antibiotics.

Workup and treatment decisions were taken by the treating medical units. We followed the patients during their hospital stay and noted their discharge diagnosis.

Statistical analysis

The data were compiled using Microsoft Excel and analyzed using Stata/IC 12.1 for Windows (StataCorp. 2012. Stata Statistical Software: Release 12.1. College Station, TX). Categorical variables were expressed as percentages and frequencies, and continuous variables were reported as mean and standard deviation or median with the interquartile range as appropriate. The Shapiro-Wilk test was used to assess the normality of continuous variables. Categorical variables were compared using the Chi-square test. The strength of association was expressed as odds ratios with their 95% confidence intervals. A P-value less than 0.05 was considered statistically significant.

Results

During the study period, 256 patients with suspected non-UTI diagnosis were recruited. The STROBE diagram (Figure 1) shows the enrolment of patients in the study. Finally, 196 patients with an unambiguous diagnosis of a non-UTI condition were chosen as the study group. Of 196 patients, 113 (57.7%) were males. The median (IQR) age of the study population was 42 (29-55 years). Most (175[89.3%]) patients were hospitalized for an infection. The major co-morbidities in the study population were diabetes mellitus 48(24.5%), systemic hypertension 29(14.8%), chronic kidney disease 14(7.1%), coronary artery disease 10(5.1%), autoimmune diseases 10(5.1%), malignancy 8(4.1%), chronic liver disease 7(3.6%) and HIV infection 6(3.1%). The final diagnosis at discharge of these patients can be found at https://doi.org/10.6084/m9.figshare.24454228.v2.

Figure 1. STROBE diagram depicting flow of participants through the study.

Comparison of the two methods of detecting pyuria

By routine method, 56 (28.3%) patients had significant pyuria. Of them, 29 (52%) had 5-10 pus cells/hpf, 19 (34%) had 11-20 pus cells/hpf, and 8 (14%) had ‘plenty’ of us cells/hpf. By chamber counting method, 36 (18.2%) had significant pyuria. Considering the chamber counting method as the gold standard, the routine method was 69.4(63–75.8) % sensitive and 80.6(75.1–86.2) % specific. The positive and negative predictive values were 44.6 (37.7–51.6) % and 92.1 (88.4–95.9) %.

Associations of significant pyuria

We compared the distribution of previously known and clinically intuitive risk factors for significant pyuria among patients with and without it (Table 1). The microscopic hematuria was the only factor significantly associated with pyuria (Odds ratio 3.74[1.65–8.50]; P=0.002).

Table 1. Associations of significant pyuria.

Characteristic	Patients with pyuria^a (N=36)	Patients without pyuria (N=160)	Unadjusted OR (95% CI)	P-value
Age (years)	41(27.5–52)	42 (29.5–55)	0.99 (0.98–1.02)	0.814
Female sex	15	68	1.03 (0.49–2.1)	0.927
Diabetes mellitus	10	38	1.24 (0.55–2.79)	0.612
Hypertension	3	26	0.47 (0.13–1.64)	0.236
Chronic kidney disease	2	12	0.73 (0.16–3.39)	0.683
Presence of fever	33	149	0.81 (0.21–3.07)	0.759
Current antibiotic use	26	126	0.70 (0.31–1.60)	0.398
Total leucocyte count (cells/mm³)	10030 (8130–14200)	10455(6050–14462.5)	1.00 (0.99–1.00)	0.689
Serum creatinine (mg/dL)	1.15(0.75–2.2)	0.9(0.69–1.3)	1.03 (0.91–1.16)	0.644
Acute kidney injury	11	31	1.77 (0.79–3.99)	0.166
Dipstick glucosuria	8	23	1.70 (0.69–4.19)	0.244
Dipstick proteinuria	22	76	1.73(0.83–3.63)	0.140
Microscopic hematuria	13	21	3.74 (1.65–8.50)	0.002

a Significant pyuria by chamber counting method.

Discussion

In this prospective study including hospitalized general medical patients with a non-UTI diagnosis, we observed that about 1 out of 5 patients had significant pyuria. Further, microscopic hematuria was observed to be significantly associated with pyuria. We did not observe any association with pyuria and female sex, diabetes mellitus, hypertension, AKI, and infections.

In the study done by Hooker et al., including hospitalized patients with infections outside the urinary tract, nearly one-third of adults (43 of 144; 29.9%) patients had pyuria (≥5 WBCs/hpf).⁶ They found that pyuria was more common in women and patients with genital tract infections. In their study, urine culture was positive in 42% of adult patients, and 38% were reclassified as UTI. We excluded patients with symptoms and signs of UTI, those with a positive urine culture, and also those patients who received UTI-directed antibiotics. Hence, we did not reclassify anyone as UTI. Moreover, we have included patients with non-infectious diseases also. Using the routine method, we found 28% had significant pyuria of >5 cells/hpf. However, using the chamber counting method, the proportion was noted to be 18%.

Pyuria expressed as pus cells/mm³ using unspun urine is a more accurate and reproducible method than counting the number of pus cells per hpf in using centrifuged urine.¹⁰^,¹¹ We found that the diagnostic performance characteristics of the routine method is modest in comparison to chamber counting method with a sensitivity of 70% and specificity of 81%. As early as 1962, Stansfeld had reported that the co-efficient of variation of the chamber counting method is 8.8%, while it is 21% for the routine method.⁸ In the context of UTI diagnosis, studies have shown that more than 96% of symptomatic UTI with significant bacteriuria had ≥10 cells/mm³, while this finding was present in less than one percent of asymptomatic non-bacteriuric patients.¹²

It is important to note that 18% of hospitalized patients had significant pyuria in our study. The cause of pyuria in this population is neither UTI nor ASB. Microscopic hematuria was found to be strongly associated with pyuria, and thus, we can infer that microscopic urinary abnormalities are not uncommon in this population. In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.⁹ The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Most of these conditions were absent in our study population. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. Of note, previous studies have found that pyuria is more common with female sex and diabetes.⁶^,¹³ We did not find these associations in our study population, but this could possibly because the study was underpowered to a significant difference.

Finding pyuria might also trigger the ordering of urine cultures even when patients have no clinical features suggestive of UTI. A positive urine culture in such a setting most likely represents ASB, a condition that accounts for 20-45% of positive urine cultures in hospitalized patients.⁵^,¹⁴ Inappropriate use of antibiotics for ASB is quite common in hospital settings, and the presence of concomitant pyuria is an important driver for this.¹⁵^,¹⁶ Thus, un-indicated urinalysis should be avoided in hospitalized patients.

Our study has the merit that pyuria was ascertained using the chamber counting method. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. However, our study would have been more informative had we checked for persistent pyuria and other urinary casts.

In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.

Ethics and consent

The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021).

Written informed consent was obtained from all study participants.

Author contributions

Study design: Surendran Deepanjali, Jharna Mandal

Data acquisition: Praveenkumar Thyagaraju, Hariswar Pari Thenmozhi

Data analysis: Surendran Deepanjali, Hariswar Pari Thenmozhi

Drafting of manuscript: Surendran Deepanjali, Hariswar Pari Thenmozhi, Praveenkumar Thyagaraju

Critical revision of the manuscript: Jharna Mandal

Data availability

Underlying data

Figshare: Sterile pyuria in hospitalized general medical patients, DOI https://doi.org/10.6084/m9.figshare.24454228.v2.

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

Acknowledgments

We thank the medicine side lab technicians for helping in conduct of study.

References

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4. Johnson JR, Drekonja DM: Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS): Common, but Currently Nameless. Am. J. Med. 2017; 130(5): e201–e204. PubMed Abstract | Publisher Full Text
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7. Dieter RS: Sterile pyuria: a differential diagnosis. Compr. Ther. 2000; 26(3): 150–152. Publisher Full Text
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Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 18 Apr 2024

Author details Author details

Praveenkumar Thyagaraju
Roles: Data Curation, Investigation, Project Administration, Resources, Writing – Original Draft Preparation

Jharna Mandal
Roles: Conceptualization, Investigation, Methodology, Supervision, Validation

Hariswar Pari Thenmozhi
Roles: Data Curation, Formal Analysis, Visualization, Writing – Review & Editing

Surendran Deepanjali
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Resources, Supervision, 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.

Article Versions (2)

version 2

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Published: 22 May 2024, 13:291

https://doi.org/10.12688/f1000research.144853.2

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Published: 18 Apr 2024, 13:291

https://doi.org/10.12688/f1000research.144853.1

© 2024 Thyagaraju P 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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Thyagaraju P, Mandal J, Pari Thenmozhi H and Deepanjali S. Pyuria in hospitalized general medical patients without urinary tract infection [version 1; peer review: 1 approved, 1 approved with reservations] F1000Research 2024, 13:291 (https://doi.org/10.12688/f1000research.144853.1)

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Version 1

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Reviewer Report 13 May 2024

Kartikeya Cherabuddi, University of Florida, Gainesville, FL, USA

Approved

https://doi.org/10.5256/f1000research.158706.r273342

This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.

Some recommendation to further enhance the article:
1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.

2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?

3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.

4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.

5. Were patients with recent urinary catheterisation excluded? If so, please state it.

5. Minor typographical errors
a) had ‘plenty’ of us cells/hpf.
b) medicine side lab

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?

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

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

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

Partly
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Infectious diseases

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.

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Author Response 25 May 2024

Surendran Deepanjali, Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, 605006, India

25 May 2024

Author Response

Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in ... Continue reading Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.
Response
We are very grateful to the reviewer for his very kind words of appreciation.
Comment
1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.
Response
We did a repeat literature search whether any more recent studies comparing the two methods of pyuria have been published, but could not find any. However, we found a study more recent than reference 8 which describes that chamber counting method is more accurate and hence we will include this reference in the modified version of the manuscript. (Saito A, Kawada Y. Reliability of pyuria detection method. Infection. 1994;22 Suppl 1:S36-7.)
Comment
2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?
The reviewer is correct in postulating that a cut-off of ≥ 10 cells/hpf would be more comparable to the chamber counting method. Such a cut-off would be more specific and have a better positive predictive value. We could have done this analysis using our dataset; however, our lab reports the pus cells/hpf as 5-10 and 11-20 etc, hence it is not possible to find out how many had exactly 10 WBCs/hpf. We came across this comparison (between 5 versus 10 WBCs/hpf) in the study quoted in the previous response, where Saito et al observed a sensitivity of 52% and a specificity of 86% for ≥5 WBCs/hpf versus a sensitivity of 48% and 87% for ≥10 WBCs/hpf. Nevertheless, we would like to bring to the kind attention of the reviewer that presence of ≥5 WBCs/hpf in urine has been reiterated as an entry criterion for UTI in a very recently published consensus definition for UTI (Bilsen MP, Conroy SP, Schneeberger C, et al.; UTI Reference Standard Consensus Group. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect Dis. 2024 Mar 5:S1473-3099(23)00778-8.)
Comment
3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.
We will be happy to make this change in the Conclusion section.
Comment
4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.
Response
In the Discussion section of the manuscript (Paragraph 3) we plan to include the following statements: “However, detecting pyuria using the chamber counting method could be time -consuming and requires expertise. Moreover, operators should be cognizant of possible calibration and observer errors while using a hemocytometer.” (Gadeholt H. Counting of cells in urine. The variability of haemocytometer counts. Acta Med Scand. 1968 Jan-Feb;183(1-2):9-16.)
Comment
5. Were patients with recent urinary catheterisation excluded? If so, please state it.
Response
Yes, they were excluded. We will state it in exclusion criteria.
Comment
5. Minor typographical errors
a) had ‘plenty’ of us cells/hpf.
b) medicine side lab
Response
We thank the reviewer for pointing them out. The lab in our department is actually called a ‘side lab’, but we will change this to ‘medicine lab’ to avoid confusion.

We thank the reviewer again for his constructive comments.

Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.
Response
We are very grateful to the reviewer for his very kind words of appreciation.
Comment
1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.
Response
We did a repeat literature search whether any more recent studies comparing the two methods of pyuria have been published, but could not find any. However, we found a study more recent than reference 8 which describes that chamber counting method is more accurate and hence we will include this reference in the modified version of the manuscript. (Saito A, Kawada Y. Reliability of pyuria detection method. Infection. 1994;22 Suppl 1:S36-7.)
Comment
2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?
The reviewer is correct in postulating that a cut-off of ≥ 10 cells/hpf would be more comparable to the chamber counting method. Such a cut-off would be more specific and have a better positive predictive value. We could have done this analysis using our dataset; however, our lab reports the pus cells/hpf as 5-10 and 11-20 etc, hence it is not possible to find out how many had exactly 10 WBCs/hpf. We came across this comparison (between 5 versus 10 WBCs/hpf) in the study quoted in the previous response, where Saito et al observed a sensitivity of 52% and a specificity of 86% for ≥5 WBCs/hpf versus a sensitivity of 48% and 87% for ≥10 WBCs/hpf. Nevertheless, we would like to bring to the kind attention of the reviewer that presence of ≥5 WBCs/hpf in urine has been reiterated as an entry criterion for UTI in a very recently published consensus definition for UTI (Bilsen MP, Conroy SP, Schneeberger C, et al.; UTI Reference Standard Consensus Group. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect Dis. 2024 Mar 5:S1473-3099(23)00778-8.)
Comment
3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.
We will be happy to make this change in the Conclusion section.
Comment
4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.
Response
In the Discussion section of the manuscript (Paragraph 3) we plan to include the following statements: “However, detecting pyuria using the chamber counting method could be time -consuming and requires expertise. Moreover, operators should be cognizant of possible calibration and observer errors while using a hemocytometer.” (Gadeholt H. Counting of cells in urine. The variability of haemocytometer counts. Acta Med Scand. 1968 Jan-Feb;183(1-2):9-16.)
Comment
5. Were patients with recent urinary catheterisation excluded? If so, please state it.
Response
Yes, they were excluded. We will state it in exclusion criteria.
Comment
5. Minor typographical errors
a) had ‘plenty’ of us cells/hpf.
b) medicine side lab
Response
We thank the reviewer for pointing them out. The lab in our department is actually called a ‘side lab’, but we will change this to ‘medicine lab’ to avoid confusion.

We thank the reviewer again for his constructive comments.

Competing Interests: We declare no conflicts of interests Close
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Respond or Comment

COMMENTS ON THIS REPORT

Author Response 25 May 2024

Surendran Deepanjali, Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, 605006, India

25 May 2024

Author Response

Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in ... Continue reading Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.
Response
We are very grateful to the reviewer for his very kind words of appreciation.
Comment
1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.
Response
We did a repeat literature search whether any more recent studies comparing the two methods of pyuria have been published, but could not find any. However, we found a study more recent than reference 8 which describes that chamber counting method is more accurate and hence we will include this reference in the modified version of the manuscript. (Saito A, Kawada Y. Reliability of pyuria detection method. Infection. 1994;22 Suppl 1:S36-7.)
Comment
2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?
The reviewer is correct in postulating that a cut-off of ≥ 10 cells/hpf would be more comparable to the chamber counting method. Such a cut-off would be more specific and have a better positive predictive value. We could have done this analysis using our dataset; however, our lab reports the pus cells/hpf as 5-10 and 11-20 etc, hence it is not possible to find out how many had exactly 10 WBCs/hpf. We came across this comparison (between 5 versus 10 WBCs/hpf) in the study quoted in the previous response, where Saito et al observed a sensitivity of 52% and a specificity of 86% for ≥5 WBCs/hpf versus a sensitivity of 48% and 87% for ≥10 WBCs/hpf. Nevertheless, we would like to bring to the kind attention of the reviewer that presence of ≥5 WBCs/hpf in urine has been reiterated as an entry criterion for UTI in a very recently published consensus definition for UTI (Bilsen MP, Conroy SP, Schneeberger C, et al.; UTI Reference Standard Consensus Group. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect Dis. 2024 Mar 5:S1473-3099(23)00778-8.)
Comment
3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.
We will be happy to make this change in the Conclusion section.
Comment
4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.
Response
In the Discussion section of the manuscript (Paragraph 3) we plan to include the following statements: “However, detecting pyuria using the chamber counting method could be time -consuming and requires expertise. Moreover, operators should be cognizant of possible calibration and observer errors while using a hemocytometer.” (Gadeholt H. Counting of cells in urine. The variability of haemocytometer counts. Acta Med Scand. 1968 Jan-Feb;183(1-2):9-16.)
Comment
5. Were patients with recent urinary catheterisation excluded? If so, please state it.
Response
Yes, they were excluded. We will state it in exclusion criteria.
Comment
5. Minor typographical errors
a) had ‘plenty’ of us cells/hpf.
b) medicine side lab
Response
We thank the reviewer for pointing them out. The lab in our department is actually called a ‘side lab’, but we will change this to ‘medicine lab’ to avoid confusion.

We thank the reviewer again for his constructive comments.

Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.
Response
We are very grateful to the reviewer for his very kind words of appreciation.
Comment
1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.
Response
We did a repeat literature search whether any more recent studies comparing the two methods of pyuria have been published, but could not find any. However, we found a study more recent than reference 8 which describes that chamber counting method is more accurate and hence we will include this reference in the modified version of the manuscript. (Saito A, Kawada Y. Reliability of pyuria detection method. Infection. 1994;22 Suppl 1:S36-7.)
Comment
2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?
The reviewer is correct in postulating that a cut-off of ≥ 10 cells/hpf would be more comparable to the chamber counting method. Such a cut-off would be more specific and have a better positive predictive value. We could have done this analysis using our dataset; however, our lab reports the pus cells/hpf as 5-10 and 11-20 etc, hence it is not possible to find out how many had exactly 10 WBCs/hpf. We came across this comparison (between 5 versus 10 WBCs/hpf) in the study quoted in the previous response, where Saito et al observed a sensitivity of 52% and a specificity of 86% for ≥5 WBCs/hpf versus a sensitivity of 48% and 87% for ≥10 WBCs/hpf. Nevertheless, we would like to bring to the kind attention of the reviewer that presence of ≥5 WBCs/hpf in urine has been reiterated as an entry criterion for UTI in a very recently published consensus definition for UTI (Bilsen MP, Conroy SP, Schneeberger C, et al.; UTI Reference Standard Consensus Group. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect Dis. 2024 Mar 5:S1473-3099(23)00778-8.)
Comment
3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.
We will be happy to make this change in the Conclusion section.
Comment
4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.
Response
In the Discussion section of the manuscript (Paragraph 3) we plan to include the following statements: “However, detecting pyuria using the chamber counting method could be time -consuming and requires expertise. Moreover, operators should be cognizant of possible calibration and observer errors while using a hemocytometer.” (Gadeholt H. Counting of cells in urine. The variability of haemocytometer counts. Acta Med Scand. 1968 Jan-Feb;183(1-2):9-16.)
Comment
5. Were patients with recent urinary catheterisation excluded? If so, please state it.
Response
Yes, they were excluded. We will state it in exclusion criteria.
Comment
5. Minor typographical errors
a) had ‘plenty’ of us cells/hpf.
b) medicine side lab
Response
We thank the reviewer for pointing them out. The lab in our department is actually called a ‘side lab’, but we will change this to ‘medicine lab’ to avoid confusion.

We thank the reviewer again for his constructive comments.

Competing Interests: We declare no conflicts of interests Close
Report a concern

Views

Reviewer Report 10 May 2024

Rani Diana Sahni, Christian Medical College Vellore Association, Vellore, Tamil Nadu, India

Approved with Reservations

https://doi.org/10.5256/f1000research.158706.r273337

Dear authors,

Thank you for submitting your work for review.

In our daily work we come across protocols that are sometimes questionable but have not been revised due to a lack of sufficient evidence to change the norm. This topic is one such issue.

Please find below the comments / suggestions of this review.

1. Introduction:

"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department."

The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis.
However, urine microscopy to detect "pyuria" has its merits and is ordered as a cheaper and quicker method to "rule out" a urinary tract pathology rather than to "rule-in" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting.
Therefore, the introductory passage needs to be modified.

2. Methodology:

1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.

2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI).
Therefore, the reasons for hospitalization, need to be addressed. Please include the same.
It is relevant as they could contribute to the presence of inflammatory cells in urine.
To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis.
As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.

3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis.
Please explain if these were a part of the exclusion criteria.

Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria.
However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.

Best wishes.

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?

No
If applicable, is the statistical analysis and its interpretation appropriate?

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

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Genitourinary infection diagnostics, antimicrobial susceptibility

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

Report a concern

Author Response 25 May 2024

Surendran Deepanjali, Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, 605006, India

25 May 2024

Author Response
Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by ... Continue reading
Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by the reviewer as much as possible and make modifications in the revised version of our manuscript which will be uploaded after obtaining further comments from more reviewers (as advised by the editorial team). Please find the point-to-point responses for your comments below. Please note that the parts planned to be modified are italicized and bolded for ready reference.
Comment

1. Introduction:

"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department."

The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis.
However, urine microscopy to detect "pyuria" has its merits and is ordered as a cheaper and quicker method to "rule out" a urinary tract pathology rather than to "rule-in" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting.
Therefore, the introductory passage needs to be modified.
Response
We agree with the reviewer that urinalysis is a cheap and quick ‘rule-out’ test in the ED (except in those with obstructive uropathy or absolute neutropenia). To that effect, we will modify the Introduction as given below. We will also add a new reference to point this out.
The second paragraph of Introduction:

“In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. Also, it has been observed that urinalysis serves as a useful “rule-out” test for UTI (Advani SD, North R, Turner NA, Ahmadi S, Denniss J, Francis A, Johnson R, Hasan A, Mirza F, Pardue S, Rao M, Rosshandler Y, Tang H, Schmader KE, Anderson DJ. Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all? Clin Infect Dis. 2024 Apr 26:ciae230.) However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.⁴”
Comment
2. Methodology:

1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.

3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis.
Please explain if these were a part of the exclusion criteria.
Response
We thank the reviewer for pointing this out. All patients were recruited from the emergency department setting within 24 hours of presentation. We confirm that we have excluded patients on urinary catheter (already mentioned as an exclusion criterion) and those with urosepsis (excluded all patients with suspected/confirmed urosepsis). Further, we did exclude patients who have been hospitalized or treated with antibiotics in the previous 2 weeks of admission to our hospital. Please find the modifications effected below.
Methods
We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We also excluded who had a recent (past 2 weeks) hospitalization or exposure to antibiotics. Patients were recruited within 24 hours of hospitalization. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.
Comment
2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI).
Therefore, the reasons for hospitalization, need to be addressed. Please include the same.
It is relevant as they could contribute to the presence of inflammatory cells in urine.
To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis.
As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.
Response
The reviewer is correct in pointing out that pus cells in urine is not always indicative of UTI and that non-infective and inflammatory conditions can cause it. Our study shows that infections other than UTI also could also result in urine pus cells. We would like to bring to the kind attention of the reviewer that we do discuss regarding other possible causes of pyuria like urethritis and renal calculi in the Discussion section of the manuscript, which we are quoting here, “In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.⁹ The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Our study population did not include those with these diagnoses. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. “
The presenting complaints at admission and the discharge diagnosis of all the study participants are available in the open access dataset attached with the manuscript. It was not possible to tabulate all diagnoses to be included in the manuscript. However, we will include the major diagnostic categories for all 196 participants the Results section as follows: “Most (175[89.3%]) patients were hospitalized for an infection. The major diagnostic categories in the remainder (21 patients) were metabolic disorders like diabetic ketoacidosis in 5, connective tissue disorders in 4, cardiovascular diseases in 3, hepatic diseases in 2, malignancies in 2 and central nervous system, renal and gastrointestinal involvement in one patient each.”
Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria.
However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.
Response
The primary objective of the study was to see the frequency of pyuria in patients with a non-UTI diagnosis and the sample size may not have been adequate to test the diagnostic performance characteristics of the ‘routine’ method. We do discuss about the merits of chamber counting method for pyuria detection in Paragraph 3 of Discussion section. However, as the reviewer suggested we will include this point in Conclusion section. Further, we will give a suggestion regarding the utility of this test as a ‘rule-out’ rather than a ‘rule-in’ test for UTI. Please read the modified Conclusion here:
“In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Estimating the number of pus cells per high power field in centrifuged urine has only modest diagnostic performance compared to the chamber counting method. Urinalysis may be best used as a ‘rule-out’ test for UTI rather than a specific test for diagnosing UTI. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.
Comment

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?

No
Response
We believe we have explained the methods and analysis in detail; however, we will be happy to clarify them further if deemed necessary by the reviewer.
Thank you once again for reviewing our study and providing constructive comments!!
Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by the reviewer as much as possible and make modifications in the revised version of our manuscript which will be uploaded after obtaining further comments from more reviewers (as advised by the editorial team). Please find the point-to-point responses for your comments below. Please note that the parts planned to be modified are italicized and bolded for ready reference.
Comment

1. Introduction:

"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department."

The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis.
However, urine microscopy to detect "pyuria" has its merits and is ordered as a cheaper and quicker method to "rule out" a urinary tract pathology rather than to "rule-in" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting.
Therefore, the introductory passage needs to be modified.
Response
We agree with the reviewer that urinalysis is a cheap and quick ‘rule-out’ test in the ED (except in those with obstructive uropathy or absolute neutropenia). To that effect, we will modify the Introduction as given below. We will also add a new reference to point this out.
The second paragraph of Introduction:

“In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. Also, it has been observed that urinalysis serves as a useful “rule-out” test for UTI (Advani SD, North R, Turner NA, Ahmadi S, Denniss J, Francis A, Johnson R, Hasan A, Mirza F, Pardue S, Rao M, Rosshandler Y, Tang H, Schmader KE, Anderson DJ. Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all? Clin Infect Dis. 2024 Apr 26:ciae230.) However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.⁴”
Comment
2. Methodology:

1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.

3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis.
Please explain if these were a part of the exclusion criteria.
Response
We thank the reviewer for pointing this out. All patients were recruited from the emergency department setting within 24 hours of presentation. We confirm that we have excluded patients on urinary catheter (already mentioned as an exclusion criterion) and those with urosepsis (excluded all patients with suspected/confirmed urosepsis). Further, we did exclude patients who have been hospitalized or treated with antibiotics in the previous 2 weeks of admission to our hospital. Please find the modifications effected below.
Methods
We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We also excluded who had a recent (past 2 weeks) hospitalization or exposure to antibiotics. Patients were recruited within 24 hours of hospitalization. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.
Comment
2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI).
Therefore, the reasons for hospitalization, need to be addressed. Please include the same.
It is relevant as they could contribute to the presence of inflammatory cells in urine.
To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis.
As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.
Response
The reviewer is correct in pointing out that pus cells in urine is not always indicative of UTI and that non-infective and inflammatory conditions can cause it. Our study shows that infections other than UTI also could also result in urine pus cells. We would like to bring to the kind attention of the reviewer that we do discuss regarding other possible causes of pyuria like urethritis and renal calculi in the Discussion section of the manuscript, which we are quoting here, “In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.⁹ The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Our study population did not include those with these diagnoses. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. “
The presenting complaints at admission and the discharge diagnosis of all the study participants are available in the open access dataset attached with the manuscript. It was not possible to tabulate all diagnoses to be included in the manuscript. However, we will include the major diagnostic categories for all 196 participants the Results section as follows: “Most (175[89.3%]) patients were hospitalized for an infection. The major diagnostic categories in the remainder (21 patients) were metabolic disorders like diabetic ketoacidosis in 5, connective tissue disorders in 4, cardiovascular diseases in 3, hepatic diseases in 2, malignancies in 2 and central nervous system, renal and gastrointestinal involvement in one patient each.”
Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria.
However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.
Response
The primary objective of the study was to see the frequency of pyuria in patients with a non-UTI diagnosis and the sample size may not have been adequate to test the diagnostic performance characteristics of the ‘routine’ method. We do discuss about the merits of chamber counting method for pyuria detection in Paragraph 3 of Discussion section. However, as the reviewer suggested we will include this point in Conclusion section. Further, we will give a suggestion regarding the utility of this test as a ‘rule-out’ rather than a ‘rule-in’ test for UTI. Please read the modified Conclusion here:
“In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Estimating the number of pus cells per high power field in centrifuged urine has only modest diagnostic performance compared to the chamber counting method. Urinalysis may be best used as a ‘rule-out’ test for UTI rather than a specific test for diagnosing UTI. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.
Comment

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?

No
Response
We believe we have explained the methods and analysis in detail; however, we will be happy to clarify them further if deemed necessary by the reviewer.
Thank you once again for reviewing our study and providing constructive comments!!
Competing Interests: We declare no competing interests Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 25 May 2024

Surendran Deepanjali, Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, 605006, India

25 May 2024

Author Response
Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by ... Continue reading
Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by the reviewer as much as possible and make modifications in the revised version of our manuscript which will be uploaded after obtaining further comments from more reviewers (as advised by the editorial team). Please find the point-to-point responses for your comments below. Please note that the parts planned to be modified are italicized and bolded for ready reference.
Comment

1. Introduction:

"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department."

The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis.
However, urine microscopy to detect "pyuria" has its merits and is ordered as a cheaper and quicker method to "rule out" a urinary tract pathology rather than to "rule-in" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting.
Therefore, the introductory passage needs to be modified.
Response
We agree with the reviewer that urinalysis is a cheap and quick ‘rule-out’ test in the ED (except in those with obstructive uropathy or absolute neutropenia). To that effect, we will modify the Introduction as given below. We will also add a new reference to point this out.
The second paragraph of Introduction:

“In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. Also, it has been observed that urinalysis serves as a useful “rule-out” test for UTI (Advani SD, North R, Turner NA, Ahmadi S, Denniss J, Francis A, Johnson R, Hasan A, Mirza F, Pardue S, Rao M, Rosshandler Y, Tang H, Schmader KE, Anderson DJ. Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all? Clin Infect Dis. 2024 Apr 26:ciae230.) However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.⁴”
Comment
2. Methodology:

1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.

3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis.
Please explain if these were a part of the exclusion criteria.
Response
We thank the reviewer for pointing this out. All patients were recruited from the emergency department setting within 24 hours of presentation. We confirm that we have excluded patients on urinary catheter (already mentioned as an exclusion criterion) and those with urosepsis (excluded all patients with suspected/confirmed urosepsis). Further, we did exclude patients who have been hospitalized or treated with antibiotics in the previous 2 weeks of admission to our hospital. Please find the modifications effected below.
Methods
We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We also excluded who had a recent (past 2 weeks) hospitalization or exposure to antibiotics. Patients were recruited within 24 hours of hospitalization. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.
Comment
2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI).
Therefore, the reasons for hospitalization, need to be addressed. Please include the same.
It is relevant as they could contribute to the presence of inflammatory cells in urine.
To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis.
As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.
Response
The reviewer is correct in pointing out that pus cells in urine is not always indicative of UTI and that non-infective and inflammatory conditions can cause it. Our study shows that infections other than UTI also could also result in urine pus cells. We would like to bring to the kind attention of the reviewer that we do discuss regarding other possible causes of pyuria like urethritis and renal calculi in the Discussion section of the manuscript, which we are quoting here, “In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.⁹ The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Our study population did not include those with these diagnoses. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. “
The presenting complaints at admission and the discharge diagnosis of all the study participants are available in the open access dataset attached with the manuscript. It was not possible to tabulate all diagnoses to be included in the manuscript. However, we will include the major diagnostic categories for all 196 participants the Results section as follows: “Most (175[89.3%]) patients were hospitalized for an infection. The major diagnostic categories in the remainder (21 patients) were metabolic disorders like diabetic ketoacidosis in 5, connective tissue disorders in 4, cardiovascular diseases in 3, hepatic diseases in 2, malignancies in 2 and central nervous system, renal and gastrointestinal involvement in one patient each.”
Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria.
However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.
Response
The primary objective of the study was to see the frequency of pyuria in patients with a non-UTI diagnosis and the sample size may not have been adequate to test the diagnostic performance characteristics of the ‘routine’ method. We do discuss about the merits of chamber counting method for pyuria detection in Paragraph 3 of Discussion section. However, as the reviewer suggested we will include this point in Conclusion section. Further, we will give a suggestion regarding the utility of this test as a ‘rule-out’ rather than a ‘rule-in’ test for UTI. Please read the modified Conclusion here:
“In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Estimating the number of pus cells per high power field in centrifuged urine has only modest diagnostic performance compared to the chamber counting method. Urinalysis may be best used as a ‘rule-out’ test for UTI rather than a specific test for diagnosing UTI. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.
Comment

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?

No
Response
We believe we have explained the methods and analysis in detail; however, we will be happy to clarify them further if deemed necessary by the reviewer.
Thank you once again for reviewing our study and providing constructive comments!!
Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by the reviewer as much as possible and make modifications in the revised version of our manuscript which will be uploaded after obtaining further comments from more reviewers (as advised by the editorial team). Please find the point-to-point responses for your comments below. Please note that the parts planned to be modified are italicized and bolded for ready reference.
Comment

1. Introduction:

"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department."

The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis.
However, urine microscopy to detect "pyuria" has its merits and is ordered as a cheaper and quicker method to "rule out" a urinary tract pathology rather than to "rule-in" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting.
Therefore, the introductory passage needs to be modified.
Response
We agree with the reviewer that urinalysis is a cheap and quick ‘rule-out’ test in the ED (except in those with obstructive uropathy or absolute neutropenia). To that effect, we will modify the Introduction as given below. We will also add a new reference to point this out.
The second paragraph of Introduction:

“In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. Also, it has been observed that urinalysis serves as a useful “rule-out” test for UTI (Advani SD, North R, Turner NA, Ahmadi S, Denniss J, Francis A, Johnson R, Hasan A, Mirza F, Pardue S, Rao M, Rosshandler Y, Tang H, Schmader KE, Anderson DJ. Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all? Clin Infect Dis. 2024 Apr 26:ciae230.) However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.⁴”
Comment
2. Methodology:

1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.

3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis.
Please explain if these were a part of the exclusion criteria.
Response
We thank the reviewer for pointing this out. All patients were recruited from the emergency department setting within 24 hours of presentation. We confirm that we have excluded patients on urinary catheter (already mentioned as an exclusion criterion) and those with urosepsis (excluded all patients with suspected/confirmed urosepsis). Further, we did exclude patients who have been hospitalized or treated with antibiotics in the previous 2 weeks of admission to our hospital. Please find the modifications effected below.
Methods
We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We also excluded who had a recent (past 2 weeks) hospitalization or exposure to antibiotics. Patients were recruited within 24 hours of hospitalization. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.
Comment
2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI).
Therefore, the reasons for hospitalization, need to be addressed. Please include the same.
It is relevant as they could contribute to the presence of inflammatory cells in urine.
To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis.
As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.
Response
The reviewer is correct in pointing out that pus cells in urine is not always indicative of UTI and that non-infective and inflammatory conditions can cause it. Our study shows that infections other than UTI also could also result in urine pus cells. We would like to bring to the kind attention of the reviewer that we do discuss regarding other possible causes of pyuria like urethritis and renal calculi in the Discussion section of the manuscript, which we are quoting here, “In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.⁹ The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Our study population did not include those with these diagnoses. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. “
The presenting complaints at admission and the discharge diagnosis of all the study participants are available in the open access dataset attached with the manuscript. It was not possible to tabulate all diagnoses to be included in the manuscript. However, we will include the major diagnostic categories for all 196 participants the Results section as follows: “Most (175[89.3%]) patients were hospitalized for an infection. The major diagnostic categories in the remainder (21 patients) were metabolic disorders like diabetic ketoacidosis in 5, connective tissue disorders in 4, cardiovascular diseases in 3, hepatic diseases in 2, malignancies in 2 and central nervous system, renal and gastrointestinal involvement in one patient each.”
Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria.
However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.
Response
The primary objective of the study was to see the frequency of pyuria in patients with a non-UTI diagnosis and the sample size may not have been adequate to test the diagnostic performance characteristics of the ‘routine’ method. We do discuss about the merits of chamber counting method for pyuria detection in Paragraph 3 of Discussion section. However, as the reviewer suggested we will include this point in Conclusion section. Further, we will give a suggestion regarding the utility of this test as a ‘rule-out’ rather than a ‘rule-in’ test for UTI. Please read the modified Conclusion here:
“In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Estimating the number of pus cells per high power field in centrifuged urine has only modest diagnostic performance compared to the chamber counting method. Urinalysis may be best used as a ‘rule-out’ test for UTI rather than a specific test for diagnosing UTI. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.
Comment

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?

No
Response
We believe we have explained the methods and analysis in detail; however, we will be happy to clarify them further if deemed necessary by the reviewer.
Thank you once again for reviewing our study and providing constructive comments!!
Competing Interests: We declare no competing interests Close
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VERSION 2 PUBLISHED 18 Apr 2024

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Version 2 (revision) 22 May 24
Version 1 18 Apr 24	read	read

Rani Diana Sahni, Christian Medical College Vellore Association, Vellore, India
Kartikeya Cherabuddi, University of Florida, Gainesville, FL, USA

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Reviewer Report

10 Views

13 May 2024 | for Version 1

Kartikeya Cherabuddi, University of Florida, Gainesville, FL, USA

10 Views Cite this report Responses(1)

Approved

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?

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

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

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

Partly
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Infectious diseases

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.

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Responses (1)

Author Response

25 May 2024

Surendran Deepanjali, Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, 605006, India

Response to reviewer
Comment
This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.
Response
We are very grateful to the reviewer for his very kind words of appreciation.
Comment
1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.
Response
We did a repeat literature search whether any more recent studies comparing the two methods of pyuria have been published, but could not find any. However, we found a study more recent than reference 8 which describes that chamber counting method is more accurate and hence we will include this reference in the modified version of the manuscript. (Saito A, Kawada Y. Reliability of pyuria detection method. Infection. 1994;22 Suppl 1:S36-7.)
Comment
2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?
The reviewer is correct in postulating that a cut-off of ≥ 10 cells/hpf would be more comparable to the chamber counting method. Such a cut-off would be more specific and have a better positive predictive value. We could have done this analysis using our dataset; however, our lab reports the pus cells/hpf as 5-10 and 11-20 etc, hence it is not possible to find out how many had exactly 10 WBCs/hpf. We came across this comparison (between 5 versus 10 WBCs/hpf) in the study quoted in the previous response, where Saito et al observed a sensitivity of 52% and a specificity of 86% for ≥5 WBCs/hpf versus a sensitivity of 48% and 87% for ≥10 WBCs/hpf. Nevertheless, we would like to bring to the kind attention of the reviewer that presence of ≥5 WBCs/hpf in urine has been reiterated as an entry criterion for UTI in a very recently published consensus definition for UTI (Bilsen MP, Conroy SP, Schneeberger C, et al.; UTI Reference Standard Consensus Group. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect Dis. 2024 Mar 5:S1473-3099(23)00778-8.)
Comment
3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.
We will be happy to make this change in the Conclusion section.
Comment
4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.
Response
In the Discussion section of the manuscript (Paragraph 3) we plan to include the following statements: “However, detecting pyuria using the chamber counting method could be time -consuming and requires expertise. Moreover, operators should be cognizant of possible calibration and observer errors while using a hemocytometer.” (Gadeholt H. Counting of cells in urine. The variability of haemocytometer counts. Acta Med Scand. 1968 Jan-Feb;183(1-2):9-16.)
Comment
5. Were patients with recent urinary catheterisation excluded? If so, please state it.
Response
Yes, they were excluded. We will state it in exclusion criteria.
Comment
5. Minor typographical errors
a) had ‘plenty’ of us cells/hpf.
b) medicine side lab
Response
We thank the reviewer for pointing them out. The lab in our department is actually called a ‘side lab’, but we will change this to ‘medicine lab’ to avoid confusion.

We thank the reviewer again for his constructive comments.

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Competing Interests

We declare no conflicts of interests

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Reviewer Report

19 Views

10 May 2024 | for Version 1

Rani Diana Sahni, Christian Medical College Vellore Association, Vellore, Tamil Nadu, India

19 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?

No
If applicable, is the statistical analysis and its interpretation appropriate?

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

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Genitourinary infection diagnostics, antimicrobial susceptibility

Respond to this report

Responses (1)

Author Response

25 May 2024

Surendran Deepanjali, Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, 605006, India

Response to reviewer

We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by the reviewer as much as possible and make modifications in the revised version of our manuscript which will be uploaded after obtaining further comments from more reviewers (as advised by the editorial team). Please find the point-to-point responses for your comments below. Please note that the parts planned to be modified are italicized and bolded for ready reference.
Comment

1. Introduction:

"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department."

The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis.
However, urine microscopy to detect "pyuria" has its merits and is ordered as a cheaper and quicker method to "rule out" a urinary tract pathology rather than to "rule-in" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting.
Therefore, the introductory passage needs to be modified.
Response
We agree with the reviewer that urinalysis is a cheap and quick ‘rule-out’ test in the ED (except in those with obstructive uropathy or absolute neutropenia). To that effect, we will modify the Introduction as given below. We will also add a new reference to point this out.
The second paragraph of Introduction:

“In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. Also, it has been observed that urinalysis serves as a useful “rule-out” test for UTI (Advani SD, North R, Turner NA, Ahmadi S, Denniss J, Francis A, Johnson R, Hasan A, Mirza F, Pardue S, Rao M, Rosshandler Y, Tang H, Schmader KE, Anderson DJ. Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all? Clin Infect Dis. 2024 Apr 26:ciae230.) However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.⁴”
Comment
2. Methodology:

1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.

3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis.
Please explain if these were a part of the exclusion criteria.
Response
We thank the reviewer for pointing this out. All patients were recruited from the emergency department setting within 24 hours of presentation. We confirm that we have excluded patients on urinary catheter (already mentioned as an exclusion criterion) and those with urosepsis (excluded all patients with suspected/confirmed urosepsis). Further, we did exclude patients who have been hospitalized or treated with antibiotics in the previous 2 weeks of admission to our hospital. Please find the modifications effected below.
Methods
We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We also excluded who had a recent (past 2 weeks) hospitalization or exposure to antibiotics. Patients were recruited within 24 hours of hospitalization. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.
Comment
2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI).
Therefore, the reasons for hospitalization, need to be addressed. Please include the same.
It is relevant as they could contribute to the presence of inflammatory cells in urine.
To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis.
As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.
Response
The reviewer is correct in pointing out that pus cells in urine is not always indicative of UTI and that non-infective and inflammatory conditions can cause it. Our study shows that infections other than UTI also could also result in urine pus cells. We would like to bring to the kind attention of the reviewer that we do discuss regarding other possible causes of pyuria like urethritis and renal calculi in the Discussion section of the manuscript, which we are quoting here, “In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.⁹ The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Our study population did not include those with these diagnoses. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. “
The presenting complaints at admission and the discharge diagnosis of all the study participants are available in the open access dataset attached with the manuscript. It was not possible to tabulate all diagnoses to be included in the manuscript. However, we will include the major diagnostic categories for all 196 participants the Results section as follows: “Most (175[89.3%]) patients were hospitalized for an infection. The major diagnostic categories in the remainder (21 patients) were metabolic disorders like diabetic ketoacidosis in 5, connective tissue disorders in 4, cardiovascular diseases in 3, hepatic diseases in 2, malignancies in 2 and central nervous system, renal and gastrointestinal involvement in one patient each.”
Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria.
However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.
Response
The primary objective of the study was to see the frequency of pyuria in patients with a non-UTI diagnosis and the sample size may not have been adequate to test the diagnostic performance characteristics of the ‘routine’ method. We do discuss about the merits of chamber counting method for pyuria detection in Paragraph 3 of Discussion section. However, as the reviewer suggested we will include this point in Conclusion section. Further, we will give a suggestion regarding the utility of this test as a ‘rule-out’ rather than a ‘rule-in’ test for UTI. Please read the modified Conclusion here:
“In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Estimating the number of pus cells per high power field in centrifuged urine has only modest diagnostic performance compared to the chamber counting method. Urinalysis may be best used as a ‘rule-out’ test for UTI rather than a specific test for diagnosing UTI. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.
Comment

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?

No
Response
We believe we have explained the methods and analysis in detail; however, we will be happy to clarify them further if deemed necessary by the reviewer.
Thank you once again for reviewing our study and providing constructive comments!!

View more View less

Competing Interests

We declare no competing interests

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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Pyuria in hospitalized general medical patients without urinary tract infection

Abstract

Keywords

Introduction

Methods

Exclusion of patients with ASB

Statistical analysis

Results

Figure 1. STROBE diagram depicting flow of participants through the study.

Comparison of the two methods of detecting pyuria

Associations of significant pyuria

Table 1. Associations of significant pyuria.

Discussion

Ethics and consent

Author contributions

Data availability

Underlying data

Acknowledgments

References

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