Urinary Symptoms Are Unrelated to Leukocyte Esterase and Nitrite Among Indwelling Catheter Users

Abstract

Objectives

To explore the association between dipstick results and urinary symptoms.

Method

This was a prospective 12-month observational study of real-time self-administered urine dipstick results and symptoms in a community setting that included 52 spinal cord injury/disease (SCI/D) participants with neurogenic lower urinary tract dysfunction (NLUTD) who use an indwelling catheter. Symptoms were collected using the Urinary Symptom Questionnaire for Neurogenic Bladder–Indwelling Catheter (USQNB-IDC). The USQNB-IDC includes actionable (A), bladder (B1), urine quality (B2), and other (C) symptoms; analyses focused on A, B1, and B2 symptoms. Dipstick results include nitrite (NIT +/−), and leukocyte esterase (LE; negative, trace, small, moderate, or large). Dipstick outcomes were defined as strong positive (LE = moderate/large and NIT+), inflammation positive (LE = moderate/large and NIT−), negative (LE = negative/trace and NIT−), and indeterminate (all others).

Results

Nitrite positive dipsticks and moderate or large LE positive dipsticks were each observed in over 50% of the sample in every week. Strong positive dipstick results were observed in 35% to 60% of participants in every week. A, B1, or B2 symptoms co-occurred less than 50% of the time with strong positive dipsticks, but they also co-occurred with negative dipsticks. Participants were asymptomatic with a strong positive dipstick an average of 30.2% of the weeks. On average, 73% of the time a person had a negative dipstick, they also had no key symptoms (95% CI, .597-.865).

Conclusion

No association was observed between A, B1, and B2 symptoms and positive dipstick. A negative dipstick with the absence of key symptoms may better support clinical decision-making.

Introduction

Urinary tract infection (UTI) is the most common outpatient infection worldwide.¹ For people with neurogenic lower urinary tract dysfunction (NLUTD; also known as neurogenic bladder) due to spinal cord injury or disease (SCI/D), UTI is the most common infection, secondary condition, cause for emergency room visits, and infectious cause for hospitalization.^2–5

The diagnosis of a UTI requires a combination of urinary symptoms, bladder inflammation (white blood cell count on urinalysis), and bacterial growth (urine culture).⁶ Among people with NLUTD due to SCI/D, UTI diagnosis is complicated due to altered or absent perception of urinary symptoms and the presence of bladder inflammation and bacteriuria during the asymptomatic (healthy) state.^7–9 Further, there is a lack of clarity around which symptoms, when present, are more or less likely to be indicative of a UTI.^10–12

There is a need to better define diagnostic criteria (i.e., which symptoms or symptom complexes, level of inflammation, and amount of bacterial growth) for UTI in people with NLUTD. Although “UTI diagnosis” is an appealing outcome, it is not a uniform clinical construct and lacks a gold standard^10–13; therefore, it is not a suitable outcome for clinical or research purposes. Recent national samples of individuals with NLUTD who manage their bladders with varying methods^14–17 experience urinary symptoms that are not included in some UTI diagnostic criteria (see Table 1).¹⁴ Thus, to advance evidence supporting UTI diagnostic criteria for NLUTD, we developed and validated patient-centered, patient-reported tools based on bladder management (indwelling, intermittent, or void)—the Urinary Symptom Questionnaires for Neurogenic Bladder (USQNBs).^14–17 Validity and reliability of the USQNBs have been established,^14–17 and the next step is to determine whether the USQNB symptoms are associated with more objective measures such as inflammation.

Table 1.

Categorization of urinary symptoms on the Urinary Symptom Questionnaire for Neurogenic Bladder–Indwelling Catheter (USQNB-IDC)

Clinically actionable (A) symptoms (n = 9)
A1. Bladder spasms A2. Increased spasticity (not bladder spasms) A3. Sweating A4. Flushing of the chest, neck, or face A5. Autonomic dysreflexia	A6. Felt feverish/like you had a fever A7. Irritability, mental slowing/confusion A8. Bladder discomfort A9. Pain in suprapubic region
Bladder (B1) symptoms (n = 4)
B1.1. Blood in urine B1.2. Blood clots in urine	B1.3. Sensation of urinary urgency B1.4. Urine leakage that is not normal
Urine quality (B2) symptoms (n = 4)
B2.1. Bad-smelling, stronger or fouler urine B2.2. Dark urine	B2.3. Cloudy urine B2.4. Sediment/debris in urine/clogged catheter
Other (C) symptoms (n = 9)
C1. Diarrhea C2. Fatigue/lethargy C3. Back pain C4. Numbness, tingling in your extremities C5. Pain more than usual below the level of injury C6. Discharge, redness, or sensitivity around catheter site C7. Generalized abdominal discomfort or pain, bloating, pressure, or cramping C8. Sense of burning in the extremities or throughout the body C9. Increase or decrease from your usual blood pressure

Bladder inflammation is typically measured using white blood count (WBC) detected on urinalysis. As an alternative to urinalysis, urine dipstick offers a fast approach that individuals can use at home to generate an estimate of urine WBC (leukocyte esterase) and has been found accurate in testing for leukocyte esterase and nitrite.¹⁸ Given the numerous challenges that people with NLUTD (and conditions giving rise to it) often have when accessing health care (transportation, inaccessible buildings, etc.), self-assessment with a urinary dipstick is a potentially cost-effective way to monitor for potential UTIs. However, the dipstick literature is scarce for those with NLUTD.¹⁹ Pordanjani et al.²⁰ describe (“positive”) dipstick results as inconsistent in terms of validity, reliability, sensitivity, and specificity with respect to UTIs in the SCI/D population.^20,21 In addition, dipstick testing has contributed to overtreatment for UTI.²² By contrast, negative dipstick may be useful to rule out a UTI.^9,23 UTI is inconsistently defined over time and across studies in individuals with SCI/D and NLUTD, so further research is warranted.

The objective of the present study is to explore the association between dipstick-determined bladder inflammation, presence of nitrite, and valid and reliable urinary symptoms among people with NLUTD using indwelling catheterization. Symptoms and dipsticks were collected repeatedly over time, and our analyses focused on the pair of symptom and dipstick assessments at each visit.

Method

The study was reviewed and approved by the MedStar Health Research Institute Institutional Review Board (IRB# 2016-088). All study personnel were certified in, and the study protocol conformed to, the ethical guidelines of the 1975 Declaration of Helsinki.

Design

This was a prospective 12-month observational study in which a link to an online survey was sent every other week to participants via email. Participants with NLUTD due to SCI/D reported which of the 26 symptoms they were currently experiencing using the Urinary Symptom Questionnaire for Neurogenic Bladder–Indwelling Catheter version (USQNB-IDC).^16,17 Simultaneously, Siemens Uristix 4 urine dipsticks were used to measure leukocyte esterase (LE) and nitrite (NIT). Glucose and protein were not collected on this dipstick. This design follows STROBE cohort study guidelines.²⁴

Participants

Inclusion criteria were SCI/D longer than 1 year, use of an indwelling catheter (IDC), living in the community (i.e., not a long-term facility), diagnosed with at least three UTIs since SCI/D, and residence within the United States. We excluded participants with known genitourinary pathology beyond NLUTD, psychological or psychiatric conditions influencing the ability to follow instructions, participation in a confounding study, antibiotic use in the previous 2 weeks, UTI within the previous 2 weeks, instillation of any intravesical agent to prevent UTI (i.e., gentamicin), and color blindness (unless a caregiver could read the dipstick results for the subject). All inclusion and exclusion criteria were self-reported. A total of 133 individuals were screened, 52 were enrolled, and 46 completed the study (see Figure 1). All available data were used, leaving 49 to 52 observations in various analyses. Individuals received a unique identifier when screened; anonymized data were utilized in the statistical analysis.

Figure 1.

Disposition of study participation: screen fails, screen pass, consented, and dropouts.

Study procedures

After informed consent and eligibility were confirmed, demographics were collected. Then, a training manual and Siemens Uristix 4 reagent strips for urinalysis were sent to the participant for one-on-one training with a consumer expert on how to record urinary symptoms using the USQNB-IDC and how to record dipstick LE and NIT results. The symptom and dipstick data were captured using Research Electronic Data Capture (REDCAP) software.^25,26

USQNB-IDC assessment

The 26 items on the USQNB-IDC have been classified into mutually exclusive and exhaustive categories: clinically actionable (A), bladder (B1), urine quality (B2), and “other” symptoms (C) (as discussed in Tractenberg et al.¹⁴). The symptoms are shown in Table 1. Our a priori analyses focused on only B1 and B2 symptoms, as these are focused on bladder and urine, with post hoc analyses including A symptoms.

Statistical analysis

Outcomes definition

Data were exported as a .csv file to IBM SPSS v.25²⁷ and R for analysis. The analytic methods focused on obtaining a rate of the target symptoms (A, B1, B2) and the dipstick results for NIT and LE. Two analytical challenges were (1) to determine an appropriate summarization of symptom experience over 26 consecutive biweekly administrations of the instrument and (2) to determine how to define “positive dipstick” results.

Summarizing symptoms. One major challenge was determining the most appropriate summarization of symptoms over time. First, we describe participant symptom experience throughout the study by estimating their burden (burden calculation in Tractenberg et al., 2020¹⁴) for each symptom type (A, B1, B2). Burden is estimated as the total number of symptoms in a category that were experienced, multiplied by the number of times the survey was filled out, and divided by the total number of symptoms in that category that could have been experienced over surveys. Burden of each symptom type can range from 0% to 100%. We determined a priori that the B1 (bladder) and B2 (urine quality) symptoms (four in each category) were most likely to be associated with positive dipstick results. Post hoc, we determined the nine A (actionable) symptoms may have clinically relevant associations with the objective measure of inflammation (LE and NIT).

Defining a “positive dipstick.” The second challenge was defining a “positive dipstick.” In preliminary methodological discussions, a “positive dipstick” could have been based on a “positive LE” result (with multiple definitions), positive NIT (only one definition), or a combination of LE and NIT. NIT was always either positive (+) or negative (−), so NIT+ was intuitive. By contrast, defining a “positive” and “negative” LE result was more difficult given the five different possible LE outcomes: negative, trace, small, moderate, and large. Initially, we explored four (not mutually exclusive) definitions of a positive LE:

1. LE > negative

2. LE > trace

3. LE = moderate or large

4. LE = large

Preliminary exploratory analyses (data provided in Urinary Symptoms are Unrelated to Dipstick Findings in Indwelling Catheter Users: Supplemental Material: https://doi.org/10.6084/m9.figshare.13087166.v4) indicated no associations between individual symptoms and either NIT+ or LE+ by any definition. Explorations of combinations of NIT+ and LE+ also showed differences in conclusions depending on the definition of LE+ that we selected. Based on discussions with subject matter experts (physician scientists and research scientists who study urinary symptoms), we chose the combination of “NIT+ and LE moderate to large” as our definition of a “strong positive dipstick” and utilized the number of weeks a subject had a “strong positive dipstick” in our analysis. However, post hoc evaluations of results identified many dipsticks with LE moderate to large but NIT−; we subsequently defined these outcomes as “inflammation positive.”

Then, for a “negative dipstick,” we focused on NIT− and two possible LE results, “negative” and “negative or trace.” Our discussions with subject matter experts suggested that LE = small, whether or not NIT was positive, could not be included in either “positive dipstick” definition nor was it clearly negative; thus, any dipstick with LE = small was characterized as “indeterminate.” Finally, preliminary analyses identified that NIT+ co-occurred with LE negative and trace; these results were also not obviously negative and did not meet either definition of positive, so these were also classified as “indeterminate” (see Table 2). This outcome, “indeterminate dipstick,” will be further discussed in a subsequent article.

Table 2.

Dipstick outcome definitions

Dipstick outcome	Nitrite (NIT)	Leukocyte esterase (LE)
Negative	NIT−	LE = 0 or trace
Indeterminate	Irrespective of NIT+ or NIT−	LE = Small LE = 0 or trace
Strong positive	NIT+	LE = Moderate or large
Inflammation positive	NIT−	LE = Moderate or large

The identification of positive (strong and inflammation) and negative dipstick outcomes allowed us to estimate the associations with urinary symptoms more confidently. If an association could be found with conservative definitions like these, then extending our examination to the indeterminate dipstick outcomes would be supported; however, if no association could be found with the extremes of “strong positive” and “negative,” then further analysis of less clearly defined dipstick results would not be supported.

We next combined the dipstick results with the USQNB-IDC symptom summaries to estimate associations between each. We derived a rate of co-occurrence between the A, B1, and/or B2 symptom burden per week and dipstick results to describe each participant over their time in the study (missed visits were not included, and all available data were used).

Analysis of outcomes

Descriptive statistics were generated for demographic variables and for the symptom and dipstick results that we described previously. We used qualitative (plots) and quantitative (one-sample t tests against the test value 0.50) approaches to assess the strengths of associations between symptoms and dipstick results. If there was an association between a strong positive dipstick and the presence of any specific symptom(s), then we would expect their rates of co-occurrence to be greater than 50%. Because of the multitude of analyses in this exploratory study, we limited inference tests but used a Scheffe correction²⁸ to t tests against the .50 reference value to help summarize analytic results (which would also be reflected in the qualitative assessments).

Results

Fifty-two subjects were consented, and 46 subjects completed the 12-month study. All available data were used (no imputation) (see Table 3).

Table 3.

Study population

Demographic variable	n or %
Subjects	52
Age, years	55.0
Median (range)	(20–74)
Time living with injury, years	24.0
Median (range)	(1–47)
Women	37%
Level of injury
Cervical	75%
Thoracic	25%
Complete injury	44.2%
Incomplete injury	55.7%

Univariate summaries

Burden of A, B1, and B2 symptoms were estimated each week using the burden calculation¹⁴ as described (shown in https://doi.org/10.6084/m9.figshare.13087166.v4).

Dipsticks. Exploratory univariate analyses showed no association between any symptom and NIT+ or LE+ by any definition (see https://doi.org/10.6084/m9.figshare.13087166.v4). Figure 2A summarizes dipstick results for 49 subjects (five participants did not record any dipstick results). The figure shows what percent of subjects had which dipstick result (NIT+, LE negative, trace, small, moderate, and large). As Figure 2A shows, when considering NIT and LE results separately in any given week, at least 50% of our sample had dipstick results of NIT+, and approximately 50% had LE = moderate in any given week. Figure 2B shows the dipstick outcomes in each category by week.

Figure 2.

(A) Percent of dipstick with given results (leukocyte esterase [LE] values and nitrite [NIT] positivity) by week. NIT+ = % of dipsticks returned that week that were NIT+ (100%-NIT+ value = NIT−); all other lines reflect LE result for that same dipstick/week. LE Negative = LE result was negative; LE Trace = LE result was trace; LE Small = LE result was small; LE Moderate = LE result was moderate; LE Large = LE result was large. Dipsticks were classified from every week (1–26, x axis), and the percent of dipsticks with each outcome is plotted on the y axis (range, 0%–100%). (B) Percent of dipsticks meeting the mutually exclusive categories of combined NIT and LE results by week. Negative = NIT− and LE = 0 or trace; Strong Positive = NIT+ and LE > small; Inflammation Positive = NIT− and LE > small; Indeterminate = LE = small and NIT either + or - or LE = negative or trace and NIT+. Dipsticks were classified from every week (1–26, x axis), and the percent of dipsticks classified into each of these mutually exclusive and exhaustive categories is plotted on the y axis (range, 0%–100%).

The most common dipstick outcome was “strong positive,” describing dipsticks of 35% to 60% of participants in every study week. Of participants with at least one dipstick performed, 21 participants (43% of the sample) reported a strong positive dipstick for more than 50% of the dipsticks they recorded (57% of the sample had a strong positive in fewer than 50% of their dipsticks).

“Inflammation positive” was the next most common dipstick result over the first 13 assessments, but then “indeterminate” became roughly equally common over the remainder of the study; dipsticks were “inflammation positive” between 10% and 35% of the time and “indeterminate” between 5% and 30% of the time. The least common outcome was “negative,” which was observed between 4% and 23% of people in any given week.

Additionally, we computed the number of weeks individuals met our conservative definition of “strong positive dipstick” and had no symptoms at all on the USQNB-IDC. Overall, participants were asymptomatic and had a strong positive dipstick an average of 30.2% of the weeks (SD 0.299; range, 0%–96% of weeks).

Are individual symptoms associated with strong positive dipstick? Table 4 summarizes (mean ± SD and range) the percent of 26 weeks an individual had co-occurrence of B1 or B2 symptoms (in the presence of others or not) and a strong positive dipstick. Nearly all B1 (bladder) symptoms, and most B2 (urine quality) observations fall below the 50% reference line. This suggests no evidence of a relationship between a strong positive dipstick result and bladder or urine quality symptoms at the time of the dipstick.

Table 4.

The number of times a subject had each B1 (bladder) or B2 (urine quality) symptom and a “strong positive dipstick” (LE+ [moderate or large] and NIT+) or a “negative dipstick” (LE < moderate and NIT−)

Symptom present or absent and dipstick (strong positive or negative)	Symptom present and strong positive	Symptom present and negative	Symptom absent and strong positive	Symptom absent and negative
B1.1 Blood in urine	3.46 ± 6.76 (0–26.7)	0 ± 0 (0–0)	96.5 ± 6.77 (73–100)	100 ± 0 (100–100)
B1.2 Blood clots in urine	0 ± 0 (0–0)	0.56 ± 3.04 (0–16.7)	97.3 ± 8.41 (55.6–100)	99.4 ± 3.04 (83.3–100.0)
B1.3 Sensation of urinary urgency	6.01 ± 14.8 (0–78.9)	1.22 ± 4.67 (0–20.0)	93.9 ± 14.8 (21.4–100)	98.8 ± 4.67 (80.0–100)
B1.4 Urine leakage not normal	4.19 ± 10.7 (0–50.0)	1.94 ± 7.48 (0–33.3)	95.8 ± 10.7 (50.0–100)	98.1 ± 7.48 (66.7–100)
B2.1 Bad-smelling, stronger, or fouler urine	24.6 ± 27.6 (0–100)	6.61 ± 20.2 (0–100)	75.4 ± 27.6 (0–100)	93.4 ± 20.2 (0–100)
B2.2 Dark urine	16.9 ± 25.5 (0–100)	4.56 ± 14.2 (0–60.0)	83.1 ± 25.5 (0–100.0)	95.4 ± 14.2 (40.0–100)
B2.3 Cloudy urine	26.5 ± 27.9 (0–100)	7.83 ± 21.8 (0–100.0)	73.5 ± 27.9 (0–100)	92.2 ± 21.8 (0–100)
B2.4 Sediment/debris in urine/clogged catheter	21.0 ± 26.5 (0–100)	6.44 ± 26.5 (0–100)	79.0 ± 26.5 (0–100)	93.6 ± 21.5 (0–100)

Note: Values shown as average ± SD (range).

Collapsing over time and person, Table 4 shows that B1 and B2 symptoms co-occur with strong positive dipsticks and with negative dipsticks. B2 symptoms tended to co-occur more often with strong positive than they did with negative, whereas B1 symptoms, which were less frequently reported than B2 symptoms, tended to co-occur similarly with both strong positive and negative dipsticks. We also observed that both strong positive and negative dipsticks most often co-occurred with the absence of each symptom.

We explored the association between strong positive dipstick results and A type symptoms. We assessed the distributions of the percent of the time (of 26 weeks) an individual had co-occurrence of an A symptom (in the presence of others or not) and a strong positive dipstick. All co-occurrence of A symptoms with strong positive dipsticks was below 25%: we found no evidence of a relationship with clinically actionable symptoms (see Figure 3 in https://doi.org/10.6084/m9.figshare.13087166.v4).

Finally, Of the 52 participants, 30 had a negative dipstick at least once during the study. On average, 73% of the time a person had a negative dipstick, they also had no bladder (B1) or urine quality (B2) symptoms (95% CI, .597-.865).

Discussion

Our results show that among people with NLUTD due to SCI/D and who manage their bladders with IDC, none of the clinically actionable (A), bladder (B1), or urine quality (B2) symptoms are associated with the presence of NIT, LE levels, or combinations of these as determined by self-administered dipstick. This was true regardless of which definition of “positive dipstick” we utilized (further analyses shown in https://doi.org/10.6084/m9.figshare.13087166.v4). Moderate to large LE (strong positive + inflammation positive) levels were observed in 45% to 100% of the sample in each week. This high baseline prevalence of inflammation was consistent throughout the year of observation, irrespective of symptoms.

The frequency with which inflammation was observed is consistent with the known and progressive pathophysiology of NLUTD. Among people with suprasacral SCI/D, NLUTD is characterized by reduced bladder capacity, high intravesical pressure, and detrusor-sphincter dyssynergia that, if left untreated, may lead to upper urinary tract damage.^29,30 Over time, muscular and connective tissue anomalies in the neurogenic bladder are characterized by detrusor fibrosis^30,31 and inflammation.³² Local inflammation is a frequent finding, regardless of the duration of NLUTD, and is characterized by a rich cell infiltrate of lymphocytes and plasma cells, with edema, hyperemia, and eosinophil granulocytes, thereby thickening the lamina propria.³³ The origin of this inflammation is thought to be multifactorial and due to mechanical stimulation from catheterization and/or catheters, infection, and urologic procedures. Additionally, it is likely that neurogenic inflammation plays a role; increased expression of excitatory sensory receptors and activated Schwann cells observed in neurogenic bladders have led to the hypothesis that chronic and active neurogenic inflammation increases histological inflammation.³² The consistent inflammation signal in our sample supports this hypothesis.

We restricted our study to people with NLUTD due to SCI/D who manage their bladders with IDCs. This relatively homogeneous sample provided real-time evidence that inflammation, as determined by self-administered urine dipstick, does not co-occur with key urinary symptoms that would be expected to precede (if not indicate) a UTI. Our findings are in contrast with those of Duanngai et al.,²¹ who cross-sectionally applied the NIDRR UTI criteria in 56 participants with SCI in whom urinalysis, urine culture, and urine dipstick were performed. They found 90% sensitivity of NIT+ and 87% specificity of LE and NIT positive dipstick in a single timepoint. However, Duanngai et al. provided no cutoff point for their LE+ determination, whereas our analyses were explicitly focused on our definition of “strong positive.” Moreover, their participants were younger (mean age 45 years), with a shorter duration of injury (5 years), and with a mixture of condom, indwelling, and intermittent catheter users as compared to the cohort we describe. Duanngai et al.²¹ concluded that the urine dipstick test should be promoted for UTI screening in people with SCI. Our larger and IDC-only study suggests that the consistently high inflammation signal, together with inconsistent co-occurrence with bladder and urine quality symptoms in IDC-using participants, renders dipstick results less informative for UTI. However, although we collected both symptoms and dipstick results repeatedly over time, we did not follow-up with participants to determine whether symptoms or dipstick results were followed by worsening symptoms or a UTI diagnosis.

In a meta-analysis of different patient groups (pregnant women, elderly, family medicine patients, and urology patients), Deville et al.⁹ concluded that among these populations, urine dipstick could be useful to exclude the presence of infection if both NIT and LE are negative; however, the usefulness to rule in infection was considered doubtful.⁹ More recently, Lei et al.³⁴ reviewed urinalysis trends, reporting low levels of sensitivity, specificity, and reliability for dipstick results across many clinical applications. We observed each of the symptoms of bladder and urine quality to be absent between 92.2% (B2.3, cloudy urine) to 100% (B1.1, blood in urine) of the time that both NIT and LE were negative (Table 4), supporting Deville’s conclusions. However, bladder-specific symptoms were more likely to be absent—and with less variability in the sample—when the dipstick was negative, and urine quality symptoms were less likely to be absent with variation ranging from 0% to 100% co-occurrence for all but one (B2.2, darker urine range 40%–100%). This variability may explain why results in the literature have been inconsistent for decisions based on negative dipsticks. Although we observed between 0% and 100% co-occurrence of negative dipstick and no bladder or urine quality symptoms, consistent with other reports,⁹ our results suggest that for people with NLUTD, negative dipstick with the absence of bladder or urine quality symptoms may better support clinical decision-making.

Lastly, a substantial number of our participants were likely to meet current criteria for “asymptomatic bacteriuria” each week, given the prevalence of NIT+ urine dipstick results. It is important to note that while long-held dogma has been that healthy urine is sterile, we now understand that there are rich perineal, urethral, and bladder bacterial ecosystems that are present in the healthy (and disease) states (based on utilization of enhanced quantitative urine culture or sequencing techniques).^7,8 For this reason, we have not incorporated “asymptomatic bacteriuria” in our analyses; in fact, we agree with current science^7,8 and suggest jettisoning the term altogether. Not only is urine not sterile, but it is probable that “asymptomatic bacteriuria,” as determined by newer culture or sequencing techniques, is now recognized to be the normal state (i.e., not needing a special designation).^34,35 Our results suggest inflammation is also part of the normal state for those with SCI and IDCs.

Limitations

This is the first longitudinal study of both real-time symptoms and dipstick results in individuals with NLUTD who manage their bladders with IDC, but several limitations should be noted. Firstly, rather than focusing on UTI as an outcome (which lacks a gold standard^{10–13,21,23,34,36,37}), our study focused on 26 symptoms specific to IDC users.^16,17 While it would have been possible to choose one authoritative UTI diagnostic criterion and add urinalysis and urine culture to our data collection, UTI diagnosis for individuals with NLUTD is complex and lacks consistency.^{10–13,21,23,37},³⁸ Moreover, collecting urinalysis and urine culture from this prospective sample over 1 year (for UTI diagnosis with a single criterion) would have impeded our ability to collect as much data as we did over the yearlong study. A further limitation is that we asked participants to report their symptoms during the previous week, but the dipstick reflected the LE and NIT on that specific day. Therefore, we cannot tell if the dipstick results preceded additional symptoms or a UTI. Because we were unable to definitively obtain “UTI diagnosis” either before or after the dipstick results were recorded, our analyses and conclusions are limited to the specific co-occurrences of LE and NIT results with USQNB-IDC symptoms. Our analyses, while incorporating observations over a full year, emphasized the pairs of dipstick results with symptom reports. We therefore did not assess whether dipstick results preceded symptom worsening or a diagnosis of UTI. Finally, while this study replicates the real-world, at-home self-monitoring situation in which we intend the USQNB-IDC to be useful, it also limited our data to self-reporting of both symptoms and objective (dipstick) results. Future work can utilize the categories of LE/NIT outcomes to explore changes in symptoms and dipsticks over time.

Conclusion

Our longitudinal dipstick findings support the long-held clinical observations of bladder inflammation among individuals with NLUTD who use IDC to manage their bladders. Given the clear disassociation between the presence of a wide range of urinary symptoms and dipstick-determined inflammation (LE and NIT) in real time, we agree with the perspective that current clinical assessments to diagnose NLUTD-related UTI are likely inadequate, and consideration of other approaches is warranted.³⁴

Funding Statement

Financial Support This work was funded by Craig H. Neilsen Foundation, Senior Investigator Award grant #385077.