Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection

Abstract

After clinical evaluation, suspicion of urinary tract infection might be modified by different tests that have the ability to augment (or diminish) the probability of a positive urinary culture and a confirmed diagnosis. In this review, we evaluate the possible role of different non microbiological test for the diagnosis of an urinary tract infection. Some of them might be easily available in the office or a busy emergency room, while others require more sophisticated infrastructure. Due to the high frequency of urinary tract infections, the diversity of symptoms, the difficulty of the diagnosis in some group of patients (e.g., older patients, those with dementia, etc.), and the lack of a gold standard, those non-microbiological tests might contribute to a correct diagnosis and a proper use of antibiotics in difficult cases.

1. Introduction

Urinary tract infection (UTI) is an inflammation of the uroepithelial tissue, renal parenchyma or prostate resulting from pathological interaction with a microorganism. According to the anatomical location of the involvement, it might be divided into upper infection when it corresponds to pyelonephritis and lower, related to the renal pelvis or lower urinary tract, and refers almost exclusively to cystitis. Although this infectious disease is one of the most frequent reasons for consultation in all age groups, the most affected are women of reproductive age, with a peak between 14 and 24 years of age, due to the fact that sexual activity increases the probability of urovaginal colonization by Enterobacteriaceae present in the gastrointestinal tract. It is estimated that during their lifetime more than 60% of women may have at least one episode of urinary tract infection, and that it may recur 27% in the first 6 months, and more than once in 2.7% of patients [1].

The Enterobacterales group is the most frequent etiology of urinary tract infection, whose main pathogen is Echerichia coli in up to 90% of cases, followed by Klebsiella spp, Proteus spp, Enterobacter spp, and Citrobacter spp. Other microorganisms are Enterococcus spp, Pseudomonas spp, and Staphylococcus saprophyticus. UTI might be divided into complicated or uncomplicated, according to the presence of predisposing factors for failure of antimicrobial treatment such as anatomical or functional alterations of the urinary tract, pregnancy, and comorbidities such as diabetes mellitus [2]. The specific frequency of microorganisms for each group varies according to the clinical scenario, since in uncomplicated UTI, E. coli accounts for more than 90% of isolations, while in complicated UTI it is usually found in only 50 to 60% of patients.

In the diagnosis of UTI, the analysis of symptoms is fundamental; patients may present a variety of clinical manifestations, the finding of which is not specific. In general, it is important to consider differential diagnoses at the abdominal level, urological pathologies such as urolithiasis, genital pathology in women, and sexually transmitted diseases. The clinical presentation of the disease varies depending on the location; in the case of cystitis, the most important manifestations are the irritative symptoms of dysuria, tenesmus, hematuria, tenesmus, polyuria, and pollakiuria, in the absence of vaginal symptoms such as irritation or leucorrhea. Upper tract infection is characterized by systemic inflammatory signs such as fever (temperature greater than 38.3°C), tachycardia, tachypnea, nausea, and chills, which are accompanied by laboratory alterations such as leukocytosis or leukopenia; severe lumbar or abdominal pain may also occur. Approximately 30% of cases of high UTI are accompanied by irritative urinary symptoms [3]. Because of the broad clinical presentation and the nonspecificity of symptoms, the most important criterion for the diagnosis of UTI is the identification of bacteriuria, usually with elevated colony-forming unit counts (greater than 100, 1000 or 100,000 depending on the clinical scenario). However, although urine culture is fundamental for establishing the picture, the differential diagnosis is broad, and the frequency of bacteriuria without symptoms of cystitis is relatively frequent in patients with complicated infection. Therefore, to improve diagnostic certainty in the presence of bacteriuria and to support the rational use of antimicrobials, non-microbiological laboratory tools can be used to support the diagnosis. The aim of this chapter is precisely to describe the usefulness of several non-microbiological diagnostic tests that can help support the diagnosis of a urinary tract infection.

2. Limitations of bacteriuria identification

Given the need to establish bacteriuria as a fundamental element in the diagnosis of UTI, it is important to understand the limitations of its identification. Often, the presence of bacteriuria alone, in relation to unclear clinical pictures or patients at risk of poor progression (e.g., patients with Alzheimer’s disease) is used as an argument for the use of antibiotics. This brings problems such as diagnostic uncertainty, poor clinical results, risk of bacterial resistance, and adverse effects derived from their use. This is the reason why additional tests may be required, hopefully with rapid results, to clearly differentiate the sick patient from the colonized one. Here, we will briefly describe the problems of sample collection and bacteriuria.

2.1 Collection and processing of the urine sample

The proper collection of a urine sample is of vital importance in the study of a UTI, and the spontaneous midstream urine collection technique is preferable. Another strategy is the use of an urinary catheter. However, this may increase the risk of development an infectious process, and it has been found that the use of catheter for the collection of the sample, even used only once, may favor the development of an infection in up to 1% of cases [4]. It is preferable to obtain the sample from the middle of the urinary stream in order to clean the urethra, which may be colonized by microorganisms not responsible for the clinical manifestations, at the beginning of urination. This strategy also favors the reduction of sample contamination that may be suspected with the finding of low epithelial cells and mucus in the urinary sediment. Some cleaning methods prior to sample collection have been used, such as washing the skin or periurethral mucous membranes, without finding consistent benefits for recommending it routinely [5]. In some cases, spontaneous sampling is difficult, especially in elderly patients or those with comorbidities involving compromised mobility, in which case the alternative is the use of catheterization. Suprapubic puncture is the method that best guarantees the absence of contamination of the sample, but it is uncomfortable, invasive, and impractical, so it is only used in very specific scenarios.

All samples should be processed as soon as possible and refrigerated, as bacteria can grow rapidly and their presence would be overestimated. Increases in the number of colony forming units (CFU) per ml greater than 10⁵ CFU/mL have been documented 2–4 hours after collection, which increases the likelihood of false positives. The recommendation is to process the sample within 2 hours, otherwise refrigerate it or place it in a preservative. The processing of the sample for cultures corresponds to a microbiological test that is beyond the scope of this chapter. In general, it is considered the use of conventional media, semiquantitative methods, and an overnight incubation at 35–37°C in ambient air for a maximum of 48 hours or more in case of suspicion of fungal etiology [6, 7].

2.2 Bacteriuria, risk factors, and frequency

Traditionally it has been mentioned that urine is sterile in healthy individuals, without comorbidity. However, studies have identified bacteriuria in up to 5% of non-pregnant premenopausal women [8], and a complete microbiota related to urine has been recently identified [9]. Other classical risk factors for bacteriuria include urinary tract catheterization. Short-term use of bladder catheters may be associated with bacteriuria in relation to device care and duration of use. It is estimated that between 9 and 23% of patients may acquire bacteriuria as a result of device use [10]. Most patients resolve bacteriuria after device removal; however, a proportion may end up with a urinary tract infection that becomes clinically evident within 48 hours. Predictors of bacteriuria include ICU stay and a duration of the device for more than 10 days [11]. In fact, catheters of long duration, greater than 30 days, are considered to have a colonization frequency close to 100%, independent of other care measures. Intermittent catheterization in individuals who have spinal cord injury and require it for problems related to neurogenic bladder may have a frequency of bacteriuria ranging from 23 to 69%. Age, comorbidity, and site of care also have an effect on the frequency of bacteriuria: Postmenopausal women increase the frequency of bacteriuria in relation to decades of life and can reach 20% in those over 80 years of age. However, in the latter scenario, it is confounded by comorbidity and site of care [10]. Patients with diabetes may have a prevalence of bacteriuria that can reach 27%, while men or women residing in nursing homes or chronic care settings may have a frequency of up to 40 or 60%, respectively [10].

3. Non-microbiologic urine tests for the diagnosis of urinary tract infection

3.1 Urinalysis

Macroscopic and microscopic analysis of urine includes several parameters. Relevant information on each of them is presented below:

3.1.1 Color, odor, and pH

There are several initial characteristics to evaluate in a urine sample, such as color, odor, and pH. A change in odor does not suggest infection; finding it “strong” is usually due to a concentrated sample, although the presence of UTI may give a pungent odor. There are findings in urine color that may be nonspecifically related to infection, such as cloudy for pyuria, greenish or blue for Pseudomonas spp, purple for Proteus spp, Morganella spp, Providencia spp, and even E. coli (product of tryptophan metabolism to indoxyl sulfate) and red in relation to hematuria [12, 13, 14]. Normal urinary pH is slightly acidic between 4.5 and 5.5; alkalinization of urine may occur in the case of urolithiasis due to magnesium and ammonium phosphate crystals, due to infection related to microorganisms that interfere with urea metabolism, such as Proteus spp [12].

3.1.2 Pyuria by direct microscopy

Pyuria supports the diagnosis of urinary tract inflammation, although it is not a specific element of infection because other pathologies can cause it, such as non-infectious prostatitis, urolithiasis, postoperative abdominal or pelvic procedures, use of urinary devices, sexually transmitted diseases, trauma, or sepsis. The absence of pyuria in patients decreases the likelihood of an infectious process in light of the relevant clinical elements; but it cannot be considered alone for the analysis of absence of disease. For the search of pyuria in the microscopic study of urine, the sample must be rapidly processed, in less than two hours, because of the accelerated deterioration of leukocytes. It is possible to directly observe leukocytes and leukocyte casts that can be counted in a centrifuged sample or with Gram stain. In general, counts greater than 2 leukocytes/mm³ are suggestive of inflammation, which, as noted, does not necessarily refer to infection. The most accurate test for the detection of pyuria is the measurement of the urinary leukocyte excretion rate, with a cut-off point for infection greater than 400. 000 leukocytes/hour, but this is not routinely used because of the impracticality of its realization; for this reason, it has been opted for the counting of cells with hemocytometers, where the correlation with the cut-off point of the leukocyte excretion rate and with significant Gram bacteriuria ≥10⁵CFU/ml is ⩾10 leukocytes/mm3; counts of 8–10 cells/mm3 have been correlated with values below <10⁵CFU/ml in samples without contamination by suprapubic aspiration in patients with dysuria [15, 16].

3.1.3 Bacteriuria (without culture): direct microscopy and gram staining

The finding of bacteria in the examination of a urine specimen is the main aid in the diagnosis of UTI. Bacteria can be observed directly in the sediment of an uncentrifuged specimen or with Gram staining, the later being the most relevant method. Gram staining is simple and allows an early approach to the diagnosis of infection; it can even guide empirical antimicrobial treatment based on the characterization of infectious agents as Gram-positive or Gram-negative. The cut-off values of CFU/ml are not entirely standardized, and the main studies on their diagnostic performance are old. Significant bacteriuria without symptoms is defined as a repeated finding in women of ≥10⁵ CFU/ml in a midstream urine specimen; in pregnant women, of more than ≥10³ CFU/ml; and in men, of a specimen with ≥10⁵ CFU/ml. For patients with symptoms, bacteriuria is significant with a finding on midstream urine collection in women ≥10³ CFU/ml and in men ≥10² CFU/ml. For these cut-off points, different diagnostic yields have been reported with a sensitivity between 81 and 97% and specificity between 71 and 96%, [17, 18, 19, 20, 21].

3.2 Dipstick test

The dipstick allows the detection of enzyme activity in patients with suspected UTI such as nitrites from bacterial nitrate reductase activity, leukocyte elastase from leukocytes that are presumably active in the infected urinary tract, and the presence of red blood cells in relation to hematuria due to inflammation of the urinary tract. The dipstick has become a noninvasive, practical, and rapid tool that supports the diagnosis of an infection and can guide early decisions to initiate empirical antimicrobial treatment, but should always be interpreted in conjunction with the clinical picture of the patients.

3.2.1 Nitrite test

Urinary tract infection is often associated with the presence of nitrite in the urine as a result of bacterial nitrate reductase enzyme activity on nitrates [22]. The uropathogens that most cause UTI are nitrite producers; however, other microorganisms such as Enterococcus spp, Pseudomonas spp, Streptococcus saprophyticus, and other non-fermenting microorganisms do not produce it. One of the difficulties of this test is that it should ideally be performed after at least 4 hours without urination, because it requires the time necessary for the production of nitrites in the bladder by bacteria. The diagnostic performance of the nitrite test in correlation with significant bacteriuria in patients with UTI has been analyzed in several studies with variable findings, reaching sensitivity values of 70.5% and specificity of 58% [23]. However, sensitivity might be as low as 28.9% [24]. In a meta-analysis that included various population groups such as the elderly, children, pregnant women and the general population, a sensitivity of 40 to 60%, and a specificity of 85 to 98% were found, with the best performance in the elderly and the worst in pregnant women [25]. Therefore, its most important value is its positive predictive value.

3.2.2 Leukocyte esterase test

The leukocyte esterase test suggests pyuria in urine, its basis is the hydrolysis of ester substrates by the stereolytic activity of enzymes present in leukocytes that produce alcohols and acids, mainly in neutrophils, which have more than 10 proteins with this function. The positive result is evidenced by a change in the color of the test strip whose intensity is proportional to the amount of pyuria, due to the presence of resting or active leukocytes. The main false-positives of the test are the presence of bacteria in the vaginal discharge, parasites such as Trichomonas and eosinophils. The most frequent false-negatives are high levels of protein or glucose, use of boric acid preservatives or large amounts of ascorbic or oxalic acid [6]. The diagnostic yield of leukocyte esterase is good in patients with suspected UTI in correlation with bacteriuria, with sensitivity varying from 72% to 97.5% and specificity from 74.5% to 84.7% [26, 27]. In association with UTI, a sensitivity of 64% and specificity of 73% has been documented. This performance varies according to the sampling setting; in primary care the sensitivity is 76%, while in tertiary care units it is 62%. Due to the fact that the reading of the test is observer dependent, if the physician is the one who performs it, the sensitivity is 86%; in the case of the test performed by nursing group, the sensitivity lowers to 67%, while if it is done by laboratory personnel, the resulting sensitivity is 59%. Therefore, the professional involved in the interpretation of the test strip must be well trained [28].

3.2.3 Leukocyte esterase and nitrites

The positive result of leukocyte esterase and nitrite simultaneously could further support the diagnosis; this has been evaluated in several studies where it has been found that the combination of these positive tests increases the sensitivity from 68–88%, with a variable performance in specificity. These findings appear to be more accurate in urology patients. However, it is not clear that finding these two positive tests together helps to clarify the diagnosis of UTI or asymptomatic bacteriuria [28, 29, 30]. The finding of a negative result of both tests helps to rule out infection, due to their high negative predictive value; however, the interpretation must be made taking into account the clinical scenario and the suspicion of differential diagnoses [25].

4. Acute phase reactants serum tests

4.1 C-reactive protein

C-reactive protein (CRP) is a pentraxin that is released by the liver as part of the acute response to damage such as infection or inflammation, which has proven useful in the diagnosis of different infectious processes; in UTI it can support the anatomical location of the infection, the highest values have been correlated with acute pyelonephritis. Levels of 113.48 mg/L are associated with upper UTI versus 12.84 ± mg/L for those with lower tract infection. CRP has also been reported to be between 126.6 and 127.33 mg/L for upper UTI and between 4.7 and 14.5 mg/L for lower UTI. Attempts have been made to establish cut-off points for this biomarker in relation to upper UTI, finding that levels above 100 mg/L may be useful for this diagnosis [31, 32]. The performance of CRP with a cut-off point of 20 mg/L for acute pyelonephritis in adults has a sensitivity of 85.71% and specificity of 48%. However, in the search for the degree of renal damage related to the differentiation between tissue invasion by the microorganism vs. only cystitis, there is no clear usefulness of the role of this biomarker [33]. In children, a Cochrane meta-analysis found that a CRP value of 20 mg/L had a sensitivity of 94% and specificity of 39% for the diagnosis of acute pyelonephritis [34].

4.2 Procalcitonin

Procalcitonin (PCT) is a calcitonin precursor protein free of hormonal activity, used for the early diagnosis of bacterial infections and sepsis; it is also useful for the correlation with the severity of disease and therefore corresponds to a prognostic predictor [35]. PCT is generally elevated in systemic involvement and not in localized infection such as cystitis. This biomarker is increased in acute pyelonephritis with a variable sensitivity and specificity ranging between 70 and 100% and between 70 and 95%, respectively [36, 37]. In a study performed with children where PCT was compared for the early diagnosis of UTI with CRP, erythrocyte sedimentation rate (ESR) and leukocyte count, with a cut-off value greater than 0.85 μg/L, it had a better performance with a sensitivity of 89%, a specificity of 97% and positive and negative predictive values of 96% and 91%, respectively [38]. Another benefit of the use of PCT in adults in this context is the prediction of secondary bacteremia that occurs in up to 23% of patients; a level higher than 0,25 μg/L has a sensitivity of 95% and a specificity of 50% for this clinical presentation, so PCT values could be helpful for early identification of complications of acute pyelonephritis that lead to longer hospital stay, mortality, and health care costs. A PCT level ≤ 0,25 μg/L reduces the use of blood cultures by up to 40%, with a loss in the detection of bacteremia of 3% [39]. It is worth remembering that PCT elevates its value in patients with renal failure (acute or chronic) and is not interpretable in patients with creatinine levels above 1.5 mg/dl. Currently, the available information on PCT in adults with pyelonephritis could not be used to generate a clear recommendation.

4.3 Other biomarkers in urinary tract infection

Due to the low specificity and intermediate sensitivity of non-microbiological tests for the diagnosis of UTI such as leukocyte esterase, nitrites, pyuria, PCT, and CRP, which even lead to overtreatment in up to 43% of patients and undertreatment in 13% [40], with consequences such as high recurrence, prolonged hospital stays, increased bacterial resistance and renal damage, in recent years there has been increased interest in the search for diagnostic tests that are reliable and easily performed.

One of the biomarkers is neutrophil gelatinase-associated lipocalin (NGAL), which is also an acute phase protein like CRP; it rises after 12 hours from the onset of a UTI, and its maximum peak occurs at 72 hours; it can be measured in serum or urine, and in the later, it is even a predictor of the resolution of the infection and at the same time of its duration [41]. One of the advantages of the use of NGAL is that it is not influenced by the glomerular filtration rate unlike CRP and PCT, but apparently it does not allow to establish the localization of the infectious process [42].

Another group of promising biomarkers are the cytokines present in all infectious and inflammatory processes, which could have a good sensitivity for UTI with an intermediate specificity. The most studied are interleukin 1-beta (IL-1ß) in urine and serum, and in children a value in urine greater than 150 pg./mL for the diagnosis of acute pyelonephritis has a sensitivity of 79% and a specificity of 88% [43]. Interleukin 6 (IL-6) in urine in elderly adult patients with a cut-off level of 30 pg./mL allows differentiation of acute pyelonephritis from asymptomatic bacteriuria with a sensitivity of 80% and a specificity of 82%, while its usefulness in defining UTI vs. asymptomatic bacteriuria has a sensitivity of 48% [44, 45]. Regarding interleukin-8 (IL-8) in urine, a value higher than 200 pg./mL in children indicates a UTI, with a sensitivity of 93% and a specificity of 90% [46].

Other tests have been studied such as heparin-binding protein product of neutrophil activation, matrix metalloprotease-9 (MMP-9) whose increase occurs simultaneously with NGAL, lactoferrin, and heat shock protein-70 which appear to be promising [47].

5. Imaging tests

Although diagnostic imaging has traditionally been considered in the context of suspected complicated pyelonephritis as a strategy for the identification of comorbidities that may explain the presence of the infection, in some complex scenarios its use may be considered to reach the diagnosis.

5.1 Renal ultrasound

Some authors recommend early imaging as a strategy for the timely detection of complications or confirmation of the suspicion of acute pyelonephritis, but it is considered that new and significant abnormal findings will be found in only 16% of patients; therefore, it is necessary to perform new studies that evaluate cost–benefit [48]. One of the most readily available imaging tests is ultrasonography (US), which allows an initial approach, with findings such as hydronephrosis, obstructive uropathy, papillary necrosis, renal abscess, local nephritis, inflammation of the perirenal fat, and emphysematous pyelonephritis. One study found a sensitivity of ultrasonography of only 33% compared to tomography for the diagnosis of acute pyelonephritis [49]. Now the use of contrast has been added to US, finding that compared to scintigraphy marked with dimercaptosuccinic acid and technetium 99 m (Tc-DMSA and 99mTc), the sensitivity of this test is 86.8%, and the specificity is 71.4% [50].

5.2 Computerized axial tomography

Another imaging technique for the diagnosis of high UTI is computed tomography (CT). The most frequently described findings for the diagnostic support of the infectious disease are the presence of localized hypodense lesions, product of renal ischemia due to infiltration of immune system cells such as neutrophils and lymphocytes, parenchymal edema, and perirenal fat and/or gas (suggestive of emphysematous pyelonephritis or abscesses). In a study with 24 patients with acute pyelonephritis, a correlation between CT and scintigraphy marked with DMSA and 99mTc was found in 11 cases, but 11 of the remaining 13 had an abnormal CT with normal scintigraphy, concluding that tomography has greater precision compared to scintigraphy [51]. CT vs. US has a sensitivity of 81% vs. 33% for the diagnosis of acute pyelonephritis [49]. In children the diagnosis of this infection is even more difficult, so imaging strategies have greater importance, one of the most used is the DMSA scan, which has been compared with CT, finding that the latter has the advantage of differentiating and determining the local inflammatory changes of the renal parenchyma that in the scan may go unnoticed [52].

5.3 Nuclear magnetic resonance imaging (NMR)

Magnetic resonance imaging is an imaging test that has the advantage of not using radiation, but may not be readily available in all clinical settings. Alterations in patients with acute pyelonephritis include areas of hyperintensity or hypointensity, decrease or loss of normal corticomedullary differentiation, scarring, complications such as perirenal fluid, collections or abscesses and gas. This diagnostic tool can also differentiate acute lesions from scarring, which cannot be determined with conventional nuclear medicine techniques. The diagnostic performance of this test in patients with acute pyelonephritis has shown a sensitivity of 96% and a specificity of 86% [53]. Another study showed a sensitivity of 89,5% and specificity of 87,5% for NMR and a S of 86,8% and E of 87,5% for computed tomography [49].

5.4 Nuclear medicine: radioactive isotope scintigraphy

Scintigraphy labeled with radioactive isotopes such as DMSA and 99mTc is a test that has been used mainly in pediatric patients in order to identify renal involvement and to define prognosis. Its use in adults has been limited. This diagnostic tool is useful to determine the functional renal tubular mass, so its great advantage is to detect regional damage, specially cortical involvement. There is consensus on its use in the search for renal scarring, for example, after acute pyelonephritis, but its diagnostic capacity for acute events is controversial. Single photon emission computed tomography (SPECT) is another scintigraphy technique, which is also more popular in the pediatric setting. In animal models when comparing SPECT vs. CT vs. MRI for the diagnosis of acute pyelonephritis, SPECT has a sensitivity of 92.1% and a specificity of 93.8%, MR of 89,5% and 87,5%, CT of 88,2% and 93,5%, and US of 56,6% and 81,4%, respectively [54]. For the detection of acute pyelonephritis, in the comparison of the use of planar or standard DMSA vs. SPECT, the latter technique has a sensitivity of 97% and specificity of 66%, vs. 82% and 97%, respectively, for standard DMSA [55].

In Table 1, the diagnostic performance of the different non-microbiological tests for urinary tract infection is summarized. Cut-off points and specific test findings are given in the text.

Diagnostic test	Sensibility% (Range%)	Specificity% (Range %)	Clinical scenario	Reference
Pyuria (⩾10 leukocytes/mm3)	85 (75–96)	96 (94–98)	Patients with significant bacteriuria ≥105 CFU/ml as diagnostic criteria for UTI.	[16]
Bacteriuria in urine Gram (⩾105 CFU/mL)	89 (81–97)	93 (91–96)	Adults with a clinical diagnosis of UTI and a positive urine culture	[10, 17, 18, 20, 21]
Dipstick: nitrites	50 (40–60)	91 (85–98)	Children, adults, elderly, and pregnant women with UTI	[28]
Dipstick: esterase	85 (72–97,5)	84 (74,5-84,7)	Adults and elderly with significant bacteriuria ≥105 CFU/ml and symptoms of UTI	[27, 28]
Dipstick: nitrites and esterase	78 (68–88)	62 (55–87)	Adults with significant bacteriuria ≥105 CFU/ml and symptoms of UTI.	[28, 30]
C-reactive protein ⩾ 20 mg/L	94 (85–97)	39 (23–58)	Children	[34]
C-reactive protein ⩾ 6.5 mg/L	57,2 (48.9–65.4)	54,4 (51.8–57.0)	Adults aged ≥65 years	[56]
Procalcitonin ⩾ 0.5 μg/L	86 (72–93)	74 (55–87)	Children	[34]
Procalcitonin ⩾ 0.25 μg/L	95 (89–98)	50 (46–55)	Adults with bacteremia secondary to UTI	[39]
Interleukin 1-beta (IL-1B) ⩾ 150 pg./ml	79	88	Children with acute pyelonephritis	[43]
Interleukin 6 (IL-6) ⩾ 30 pg./ml	80	86	Elderly with acute pyelonephritis	[44]
Interleukin 8 (IL-8) ⩾ 200 pg./ml	93	90	Children	[46]
Ultrasonography with contrast	86,8	71,4	Children with acute pyelonephritis vs. Tc-DMSA and 99mTc	[50]
Computerized axial tomography	81	—	Adults with acute pyelonephritis vs. US and vs. DMSA	[49]
Nuclear magnetic resonance	96	86	Adults with acute pyelonephritis vs. CT scan	[53]

Table 1.

Diagnostic yield of non-microbiological tests for urinary tract infection.

6. Conclusions

Urinary tract infection is a common disease in all age ranges, which requires early diagnosis for timely treatment to reduce patient complications. There are several non-microbiological tests available that support the diagnosis of this infection and decision making for the start of empirical antimicrobial treatment; the most commonly used are direct microscopy of the urine sample, Gram stain and dipstick, all of which should always be interpreted with the clinical manifestations of the patients. The most important finding is the presence of bacteria in the urine sample. There are several biomarkers that can aid in UTI diagnosis, localization and prognosis of patients, such as CRP; promising new biomarkers that may contribute to diagnosis are being studied, such as NGAL, IL-1ß, IL-6, and IL-8. Imaging techniques are also tools for the diagnosis of UTI, with greater importance in the search for complications or associated structural or functional alterations, and limited information for their routine use in clinical settings.