Sterile Pyuria

Etiology

Sterile pyuria is not a diagnosis but rather a term that encompasses a wide array of conditions, each requiring distinct management approaches or recommendations.[4] Contrary to what the name implies, sterile pyuria is not always aseptic and can be caused by several infectious organisms, including Mycobacterium tuberculosis, viruses, fungi, and protozoan species, as well as atypical bacteria (such as Chlamydia trachomatis and Ureaplasma urealyticum), which do not grow on conventional culture media.[5]

Sexually transmitted infections (STIs) caused by C trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis are especially significant in adolescent patients presenting with sterile pyuria.[6][7] Infections outside the urinary tract, including pelvic inflammatory disease, appendicitis, diverticulitis, pneumonia, and sepsis, have also been associated with sterile pyuria, likely secondary to external genitourinary tract inflammation leading to leukocyte transluminal migration.[5][8]

Noninfectious causes of sterile pyuria include inflammatory conditions such as Kawasaki disease, systemic lupus erythematosus, and sarcoidosis, as well as conditions that compromise the immune system, including poorly controlled diabetes, chronic corticosteroid therapy, malignancy, AIDS, and renal transplant graft rejection. Other causes include drug-induced nephropathy and iatrogenic factors such as contrast dye, radiation cystitis, and indwelling urinary catheters.[5]

Eosinophiluria is a distinct form of pyuria and can be associated with conditions such as allergic interstitial nephritis, cystitis, urinary tract obstruction, immunoglobulin A (IgA) nephropathy, cholesterol emboli, and contrast-induced acute renal failure. Additionally, urine contamination during specimen collection can lead to false positive results for sterile pyuria, either by showing no bacteriuria or by revealing polymicrobial growth on urine culture.

Epidemiology

Sterile pyuria is not an uncommon laboratory finding, with up to 13.9% of females and 2.6% of males affected, based on population-based studies. Certain patient populations, including immunocompromised individuals and those hospitalized with infections unrelated to the urinary tract, have even higher prevalence rates. Notably, approximately 87.5% of patients with acute appendicitis and 72.7% of those with acute diverticulitis were found to have sterile pyuria.[8][9][10]

History and Physical

Clinical evaluation should include a detailed history and physical examination to identify factors contributing to sterile pyuria and potential underlying etiologies. The assessment should cover social, sexual, family, and travel history, as well as any recent infections, antibiotic use, surgeries, or other invasive procedures. The presence of localized urinary symptoms, such as dysuria or hematuria, may suggest a renal or genitourinary origin of sterile pyuria. In contrast, more generalized symptoms, including fatigue, edema, joint pain, or skin rash, could indicate an underlying systemic pathology.[11] 

The physical examination should involve a detailed abdominal and pelvic assessment to check for localized inflammation, such as suprapubic or costovertebral angle tenderness, and systemic signs like pallor, organomegaly, or lymphadenopathy. If an STI is suspected, genital cultures should be performed. 

Evaluation

Before proceeding with further investigation, clinicians should ensure that the urine specimen has been correctly obtained using the appropriate collection technique. Contamination from normal flora at the urethral meatus or leukocytes present in vaginal secretions can lead to a false finding of sterile pyuria.[11] Repeating the urinalysis is advisable, ensuring the urine is collected as a midstream clean-catch sample. Complete blood counts and chemistry panels should be routinely obtained as adjunctive tests, as they may offer early indications of underlying systemic disease processes.

Based on the patient's history and physical examination, further evaluation is necessary to exclude differential diagnoses, such as genitourinary tuberculosis (GU-TB) or STIs. In addition, it is recommended that genital cultures or urine specimens be collected to test for C trachomatis and N gonorrhoeae. For patients from high-prevalence TB regions or those with significant TB exposure, 3 consecutive midstream clean-catch urine samples should be provided for acid-fast bacillus (AFB) staining and polymerase chain reaction (PCR). Additionally, renal, bladder, and abdominal imaging should be considered for symptomatic patients.[12] 

Genitourinary Tuberculosis 

GU-TB is the most common form of extrapulmonary TB, accounting for approximately 30% of such cases, and typically arises from the systemic spread of primary pulmonary disease. GU-TB should be considered in individuals at increased risk, including those with a family history or epidemiological exposure to TB, immigrants, and immunocompromised patients (e.g., those with diabetes or HIV). GU-TB can affect various parts of the genitourinary tract, presenting with a diverse array of symptoms, such as dysuria, flank pain, lower urinary tract symptoms, and hematuria. Furthermore, GU-TB may be associated with constitutional symptoms, including fever, weight loss, anorexia, and night sweats. In some cases, infertility may occur due to TB involvement of the reproductive organs, leading to obstruction or scarring.[13] Sterile pyuria may be detected in up to 46% of males with GU-TB, with an increased prevalence observed in individuals experiencing immunosuppression, such as organ transplant recipients or those with HIV infection.

Recognizing GU-TB can be challenging, as conventional urine cultures are not conducive to mycobacterial growth. The gold standard for diagnosing GU-TB is the AFB urine culture or culture from a tissue biopsy sample. However, AFB urine culture alone has a sensitivity rate of only 37% to 79%. To improve diagnostic accuracy, collecting at least 3 consecutive first-void morning urine samples for AFB cultures is recommended, which increases sensitivity to 80% to 90% and ensures nearly 100% specificity. Although isolating a specific organism provides critical data on drug susceptibility, the culture results can take up to 8 weeks. Newer PCR techniques offer variable sensitivity, ranging from 25% to 93%, with high specificity of 95% to 100%. A nucleic acid amplification test (NAAT) in urine for GU-TB allows for early and rapid diagnosis while awaiting culture and susceptibility data.[10][14]

Radiological findings can significantly aid in the diagnosis of renal TB. Renal calcification is observed in approximately 40% to 70% of renal TB cases, with computerized tomography (CT) being the most sensitive method for detecting these calcifications. Additional CT findings may include various patterns of ureteral stricture, scarring, calyceal blunting, or hydronephrosis. Ultrasonography is less sensitive than CT for evaluating GU-TB.[15] Prostatic TB may also present with sterile pyuria, which can be the only clinical sign. Diagnosis of prostatic TB often occurs incidentally during transurethral prostatectomy or at autopsy. Prostate massage can obtain secretions for AFB culture, but this test is positive in only 36% of cases. PCR evaluation of prostatic secretions should also be considered for a more accurate diagnosis.[10]

Sexually Transmitted Infections 

STIs can lead to sterile pyuria because traditional culture methods often fail to detect the causative organisms. Clinicians frequently order urine studies as part of the initial diagnostic workup for STIs due to the considerable symptom overlap between UTIs and STIs. In a survey by Shipman et al, 1052 patients were diagnosed with either C trachomatis, N gonorrhoeae, or T vaginalis. Among these patients, 389 (37%) exhibited pyuria, of which 74% exhibited sterile pyuria. Despite only 101 out of the 1052 urine cultures returning positive results, antibiotics were prescribed to 295 patients for suspected UTIs, highlighting significant antibiotic overuse in these cases.[16] 

Current tests of the most common STIs are simple, accurate, and cost-effective. The preferred method for STI testing for women is a vaginal swab or first-catch urine sample, whereas a first-catch urine specimen sent for NAAT is the preferred method for men; however, urethral swabs may also be considered.[17] If STIs are suspected, it is essential to assess the patient and any sexual partners for HIV.

Viral Infections

Viral infections, including herpes simplex virus and HIV, may present with pyuria. Urethritis and cervicitis caused by herpes simplex virus 2 can lead to sterile pyuria; diagnosis is typically based on identifying vesicular lesions during physical examination and confirmed through cell culture or PCR assay. A study on untreated HIV found that 14 of 104 patients (13%) had pyuria.[18][12] Less frequently encountered viruses, such as cytomegalovirus, Epstein-Barr virus, BK virus (human polyomavirus 1), and adenovirus, are more common in immunocompromised patients. These viral infections are occasionally associated with pyuria, with hemorrhagic cystitis being the most common presentation.

Fungal Infections 

Risk factors for fungal infections, such as Candida, Aspergillus, and Cryptococcus, include immunosuppression, organ and bone marrow transplantation, diabetes, and prolonged courses of multiple antibiotics or glucocorticoids. Individuals living in regions where coccidioidomycosis, blastomycosis, and histoplasmosis are endemic, particularly in the Southwest and Midwest, are at a higher risk for these infections. Diagnosis typically involves microscopic examination of urine to identify budding yeast or hyphae, urine fungal cultures, and, in some cases, bladder and prostate biopsies. Radiological assessments can also be helpful, particularly for detecting filling defects such as fungal balls in the bladder and renal masses.[12] 

Parasitic Infections

Schistosomiasis affects the urogenital system in approximately 75% of infected individuals. Those who have lived in or traveled to Africa, particularly sub-Saharan and southern Africa, are at increased risk due to exposure to freshwater sources. Diagnosis is often made through microscopic examination of urine for Schistosoma haematobium eggs, biopsy of the bladder, and antischistosomal antibody testing. PCR is also being increasingly used for accurate diagnosis.[19] 

The most prevalent nonviral STI is T vaginalis. Traditionally, the preferred diagnostic test involved identifying the motile parasite through a wet-mount preparation of genital secretions in women and urethral discharge in men, which was less sensitive compared to culture. Currently, NAAT is the gold standard for diagnosing T vaginalis infections due to its high sensitivity and specificity. NAAT detects the genetic material of T vaginalis, allowing for accurate identification even in cases with low organism load. These tests can be performed using vaginal, endocervical, or urine specimens.[20]

Inflammation Outside the Urinary Tract

In 2014, Hooker et al reported that 31 out of 210 patients (15%) hospitalized for infections unrelated to the urinary tract exhibited sterile pyuria. These infections included bacterial septicemia, pneumonia, and intraabdominal infections. Conditions such as urinary stones, radiation cystitis, renal transplant rejection, ureteral stents, urinary fistulae, and intrinsic renal disease can also be associated with pyuria. Therefore, further evaluation based on clinical risk factors is essential to exclude these potential etiologies.[8]

Systemic Inflammatory Diseases 

Sterile pyuria, along with proteinuria and microscopic hematuria, is commonly seen in Kawasaki disease with renal involvement. In these cases, sterile pyuria may result from mild or subclinical renal injury affecting either the kidney or urethra. However, a UTI should be ruled out if urinalysis shows a positive nitrite test or if the urine culture is positive. Systemic lupus erythematosus can also present with sterile pyuria; isolated sterile pyuria has been reported in approximately 23% of patients with systemic lupus erythematosus.[21][12]

Malignancy 

Genitourinary malignancies, such as bladder, kidney, and prostate cancer, can be associated with sterile pyuria. In these cases, pyuria has been studied as a potential marker for tumor recurrence and treatment response.[22] However, the relationship between pyuria, urinary microbiome, and genitourinary malignancies requires further investigation.

Urinary Tract Stones

Sterile pyuria can also indicate the presence of staghorn calculi, as noted in a 1992 study by Rowen et al. Evaluation typically involves imaging to confirm the presence of these large kidney stones.

Treatment / Management

The management of sterile pyuria is primarily guided by the underlying etiology. Infectious causes are typically treated with antimicrobials, with specific regimens tailored to the identified infectious species (see Table. Antimicrobials for Infectious Etiologies of Sterile Pyuria).

Table. Antimicrobials for Infectious Etiologies of Sterile Pyuria

Differential Diagnosis

Differential diagnoses for sterile pyuria include a range of infectious and noninfectious etiologies, as mentioned below.

• Infectious causes include:
  • Recent treatment for UTIs
  • Urethritis caused by N gonorrhoeae, C trachomatis, or M genitalium
  • Genitourinary tuberculosis
  • Parasitic infections (eg, trichomoniasis or schistosomiasis)
  • Genitourinary tract infections due to viruses and fungi
  • Gynecologic infections
  • Balanitis
  • Prostatitis
  • Appendicitis 

• Noninfectious causes include:
  • Malignant hypertension (hematuria is usually associated with pyuria)
  • Systemic inflammatory diseases (eg, Kawasaki disease and sarcoidosis)
  • Glomerulopathy related to cyanotic congenital heart disease
  • Pregnancy
  • Indwelling urinary catheters
  • Recent urological procedures
  • Foreign objects, such as a retained stent or a surgical mesh in the urethra
  • Urinary tract pathology (eg, stones, neoplasm, fistula, and polycystic kidney disease)
  • Renal transplant rejection
  • Renal vein thrombosis
  • Interstitial cystitis or bladder pain syndrome
  • Papillary necrosis
  • Drug-related causes (eg, analgesic nephropathy or interstitial nephritis) [5][12]

Prognosis

Sterile pyuria typically resolves with accurate diagnosis and targeted management of the underlying pathology, especially when caused by infectious agents. However, resolution may not occur in chronic inflammatory conditions, immunosuppression, or malignancy, where ongoing disease processes lead to persistent leukocyte extrusion into the genitourinary tract. In many cases, the degree of pyuria correlates with disease burden, notably in patients with non-muscle invasive bladder cancer, where preoperative pyuria has been identified as a predictive factor for cancer recurrence following transurethral resection.[23]

Complications

Complications of sterile pyuria can arise from its misinterpretation as a UTI, resulting in inappropriate initiation of antibiotic therapy. Empiric antibiotics commonly prescribed for UTIs often offer limited or no coverage against bacteria-causing STIs (eg, C trachomatis or N gonorrhea) and may contribute to antibiotic resistance. Misdiagnosis can also delay the recognition and treatment of GU-TB, allowing the disease to progress. Untreated GU-TB can result in extensive strictures along the genitourinary tract, leading to obstructive symptoms and potential sequelae such as hydroureter, hydronephrosis, and renal failure.[24]