Sterile pyuria: a forgotten entity

Abstract

Sterile pyuria is a common entity. Yet there are no guidelines to address this issue. We have conducted a systematic review over 20 years and reviewed the results. Guidelines for assessment, diagnosis and management are developed based on these results.

Introduction

Urine dipstick testing is an important screening tool [Jefferys et al. 2002]. Dipstick findings of urinary leucocytes or nitrite are suggestive of urinary tract infection (UTI). If sterile pyuria on dipstick is persistent but UTI is not confirmed by repeated midstream urine culture, further investigation is warranted [Jefferys et al. 2002].

When encountered in the community, based on the collective consensus opinion of general practitioners (GPs), most would retest urine. If it came back positive again, they would start treatment with antibiotics then refer on for further investigation. Patients who routinely have greater than 20 leukocytes per microlitre, but have abacterial urine, are said to have sterile pyuria [Matthews et al. 1990]. This has been linked to a number of causes including sexually transmitted diseases (STDs), tuberculosis (TB), interstitial cystitis, chlamydia, carcinoma in situ of the bladder and cystitis. Very often, this can be a neglected cohort, with the sterile pyuria often thought of as being not significant. This is not the case. We review the literature on sterile pyuria and then develop guidelines that should be followed as part of its management.

Search strategy

The search strategy aimed to identify all references related to sterile pyuria, AND diagnosis and management. The selection criteria specified that papers must be related to primary research only. All secondary research apart from systematic reviews and meta-analyses was excluded. Search terms used were as follows: (sterile pyuria) AND (diagnosis) OR (management). The following databases were screened from 1984 to October 2014: Cumulative Index to Nursing and Allied Health Literature (CINAHL) and MEDLINE (NHS Evidence), Cochrane, AMed, British Nursing Index (BNI), Excerpta Medica database (EMBASE), Health Business Elite, Health Management Information Consortium (HMIC) and PschINFO. In addition, searches using Medical Subject Headings (MeSH) and keywords were conducted using Cochrane databases.

Results

We now present the results of our systematic review.

Genitourinary tuberculosis

Sterile pyuria may also be associated with UTIs such as genitourinary tuberculosis (GU-TB) [Lin et al. 2008]. GU-TB is seen in approximately 30% of extrapulmonary TB cases and is usually the result of dissemination from pulmonary disease [Newby et al. 2014]. Sterile pyuria can be present in up to 46% of males with GU-TB [Garcia-Tello et al. 2010]. This has a higher prevalence in the setting of immunosuppression such as in human immunodeficiency virus (HIV) or organ transplant recipients [Newby et al. 2014]. GU-TB is difficult to recognize, as bacterial urine culture media are less favourable for mycobacterial growth [Newby et al. 2014]. The gold standard for diagnosis of GU-TB is acid-fast bacilli (AFB) urine culture, which has a 37–79% sensitivity rate. However, this test can take up to 8 weeks for a result. Newer polymerase chain reaction (PCR) techniques have variable sensitivity (25–93 %), with high specificity (95–100%) [Newby et al. 2014]. Overall however, PCR for GU-TB is a rapid, sensitive, specific diagnostic method and avoids a delay in treatment [Ahmad and Ullah, 2011].

Radiological findings may direct a diagnosis towards renal TB. The genitourinary site is the most common site of extrapulmonary TB [Lin et al. 2008]. Patients may present with dysuria, frequency, microscopic haematuria, flank pain and sterile pyuria [Lin et al. 2008]. Systemic symptoms tend to be less common [Lin et al. 2008]. Radiological evidence of this is present in <50% of patients with renal TB [Lin et al. 2008]. Computerized tomography (CT) is helpful in renal TB and is the most sensitive method for identifying renal calcification, which occurs in approximately 40–70% of renal TB cases [Lin et al. 2008]. Other CT features include various patterns of hydronephrosis, stricture or scarring. Ultrasonography (USS) is less sensitive than CT in the evaluation of urogenital TB [Lin et al. 2008]. The cost of these, at the time of writing, are as follows: CT intravenous urogram (CT IVU) £661 and USS urinary tract £263. The definitive diagnosis still rests on microbiological tests such as finding AFB in the urine, urine culture, tissue biopsy and PCR for Mycobacterium tuberculosis. The cost of an AFB test is £27. PCR for M. tuberculosis is a rapid, sensitive, and specific diagnostic method, and avoids a delay in treatment; however, the Cepheid gene expert molecular test costs £100 [Ahmed et al. 1999]. PCR is recommended for instant diagnosis and screening before further examination [Ahmed et al. 1999].

Patients are treated by antituberculous combination drugs, with or without percutaneous nephrostomy. If required, nephrectomy with poor response to isolated medical therapy occurs.

Sterile pyuria may also be the only sign of prostatic TB. Because the prostate is at the external sphincter, the classic clue of sterile pyuria is only helpful when collected properly using the ‘4 Glass Test’ [Schnack et al. 2014]. Prostate massage yields secretions which can be sent for AFB culture; however, only 36% of such cases are positive and thus PCR evaluation may be necessary [Schnack et al. 2014]. Utilizing a ‘provocation test’ may increase the diagnostic yield by 16% [Schnack et al. 2014]. Transrectal ultrasound can also be helpful in detection if irregular hyperechoic lesions are found at the periphery of the gland [Schnack et al. 2014].

STDs

One of the causes of sterile pyuria may be STDs. Young sexually active patients may undergo culture for organisms such as Chlamydia trachomatis. This can cause 10% of cases of sterile pyuria [Matthews et al. 1990]. The nucleic acid test (NAT) test is considered the gold standard for diagnosis of C. trachomatis [Matthews et al. 1990], but it has been shown to be only 70% effective at picking up this organism. An enzyme-linked immunosorbent assay (ELISA), however, tends to have 100% sensitivity. The cost of a NAT molecular test is £18.70. Additionally, UTIs may be further investigated by flexible cystoscopy, including those patients with sterile pyuria. This costs £515 per person. Normal urine culture alone costs £2.50.

However, the most likely cause of sterile pyuria is recent or incomplete antibiotic use [Newby et al. 2014]. Negative urine cultures can also been seen with atypical infections such as Chlamydia and Ureaplasma species [Newby et al. 2014]. C. trachomatis was detected in 10% of patients with sterile pyuria, Ureaplasma urealyticum in (5%), Mycoplasma hominis in (3%) and Mycoplasma genitalium in (1%) [Nassar et al. 2008]. PCR testing of sterile pyuria showed a significant number of C. trachomatis, Mycoplasma and Ureaplasma infections. Consequently, PCR is recommended for the detection of those microorganisms in urine samples [Nassar et al. 2008].

Rarer causes of sterile pyuria include antiretrovirals. Indinavir therapy is associated with a continuum of crystal-related syndromes including nephrolithiasis, renal colic, flank pain without recognizable stone formation, dysuria and asymptomatic crystalluria [Sarcletti et al. 2000]. The mean duration of indinavir treatment, until sterile pyuria occurred, was 22 weeks [Sarcletti et al. 2000]. Sterile pyuria in patients taking indinavir may help to identify patients being at risk for nephrotoxicity [Sarcletti et al. 2000].

Renal tract stones

In addition, UTIs need to be excluded when urinalysis and an imaging study show sterile pyuria and calcifications, hypercalcaemia, hypercalciuria, primary hyperparathyroidism, sarcoidosis and diuretics abuse [Hwang et al. 2013]. Sterile pyuria may also be a sign of staghorn calculi [Rowen et al. 1992].

Alkaline-encrusted pyelitis is a UTI characterized by encrustations in the wall of the urinary tract [Lieten et al. 2011]. It is caused by fastidious growing urea splitting microorganisms, mainly Corynebacterium group D2. The diagnosis should be evoked on the basis of sterile pyuria, alkaline urine pH and calcifications of the urinary excretion ways on the CT scan, and then confirmed by prolonged culture [Lieten et al. 2011].

Intra-abdominal infections

Additionally, sterile pyuria can be a sign of intra-abdominal infection unrelated to the urinary tract. In patients with abdominal pain, pyuria is often found and attributed to a UTI [Chan et al. 2014]. The sterile pyuria rate in acute appendicitis was found to be 87.5%, while the sterile pyuria rate in acute diverticulitis was 72.7% [Chan et al. 2014]. In both appendicitis and diverticulitis, pyuria was significantly more common in females (p < 0.001) [Chan et al. 2014]. In acute appendicitis, pyuria was also more likely in older patients (p = 0.003) [Chan et al. 2014]. Pyuria was more common in women (p < 0.001) and in patients with gynaecological (GYN) infections (p = 0.001) [Hooker et al. 2014]. Sterile pyuria can also be a sign of upper tract transitional cell carcinoma (TCC) [Di Capua et al. 2012].

Kawasaki’s disease and autoimmune diseases

Although Kawasaki’s disease (KD) is another disease which often presents with sterile pyuria, bacterial pyuria (UTI) occasionally occurs. Sterile pyuria in KD may originate from the urethra and/or from the kidney as a result of mild and subclinical renal injury possibly due to transcatheter urine [Watanabe et al. 2007]. Positive and negative predictive values of sterile pyuria as a predictor of a UTI were 19% and 93.9%, respectively [Wirojanan et al. 2004]. However, pyuria was not always sterile in patients with KD. UTI should be considered and evaluated in KD patients with pyuria, a positive nitrite test or a positive result of urine culture. If a UTI is definitively diagnosed, the patient should be treated for a UTI as well as for KD and complete post-UTI workup is recommended. Although sterile pyuria with fever is often found in KD, before definitive symptoms of KD are found or pyuria is proved sterile, consideration of UTI is essential. KD should be one of the differential diagnoses in patients who are suspected of having a UTI and do not respond to antibiotic therapy, or who have negative urine culture [Wirojanan et al. 2004].

Additionally sterile pyuria can be a manifestation of systemic lupus erythematosus (SLE); 23% of SLE patients had at least one episode of isolated sterile pyuria [Rahman et al. 2001].

A new pathway for guidance

Patients with sterile pyuria are increasingly common. Therefore we suggest the pathway shown in Figure 1 as guidance – none currently exists. This new guidance will hopefully act as an aid to any doctor who encounters sterile pyuria, either in the community or secondary care.

Figure 1.

New guidance for sterile pyuria.