Sterile Pyuria

Sterile pyuria is the presence of white blood cells in urine (more than 10 cells/microL or more than 5 cells/HPF in a centrifuged specimen, or leucocyte esterase positive) with negative routine bacterial culture. It reflects inflammation of the urinary tract or kidney that is not caused by common culturable uropathogens, or infection that routine culture does not detect.

Causes by mechanism:

• Partially treated or prior antibiotic urinary tract infection
• Fastidious or non-culturable pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, Ureaplasma urealyticum, Mycoplasma genitalium, Mycobacterium tuberculosis (genitourinary tuberculosis, which is always considered), Schistosoma haematobium, anaerobes
• Tubulointerstitial inflammation: acute interstitial nephritis (antibiotics, NSAIDs, proton pump inhibitors), analgesic nephropathy, sarcoidosis, systemic lupus erythematosus
• Structural: calculi, papillary necrosis, polycystic kidney disease, tumours, indwelling catheters, foreign bodies
• Adjacent inflammation: appendicitis, diverticulitis, pelvic inflammatory disease, prostatitis, urethritis, vaginitis
• Systemic: Kawasaki disease in children, adenovirus cystitis

Genitourinary tuberculosis is the most important cause in endemic regions and presents with sterile pyuria in a high proportion of cases.

• Many patients are asymptomatic
• Dysuria, frequency, urgency, suprapubic or loin pain
• Urethral or vaginal discharge in sexually transmitted infection; genital ulcers; history of new sexual partner
• Genitourinary tuberculosis: chronic cystitis not responding to antibiotics, haematuria, night sweats, weight loss, epididymitis, contracted bladder; history of pulmonary tuberculosis or HIV
• Drug induced interstitial nephritis: fever, rash, eosinophilia, recent new drug, rising creatinine
• Kawasaki disease: fever for at least 5 days, conjunctivitis, rash, oral changes, cervical lymphadenopathy
• Schistosomiasis: terminal haematuria after fresh water exposure

Red flags: rising creatinine, haematuria, hydronephrosis, fever over 5 days in a child, genital ulceration, immunosuppression or HIV, failure of antibiotics, sterile pyuria that persists over 4 weeks.

• Confirm sterile pyuria on a midstream sample, with a repeat sample before further treatment
• Three consecutive early morning urine samples for acid fast bacilli microscopy, mycobacterial culture and rapid molecular test (Xpert MTB/RIF)
• Urine nucleic acid amplification test (first void) for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium; urethral or cervical swabs; HIV, syphilis, hepatitis B and C
• Urine for schistosome eggs in endemic exposure
• Creatinine, eGFR, eosinophils, ESR, CRP, urinary protein:creatinine ratio
• Ultrasound and CT urogram: hydronephrosis, calcification, papillary necrosis, renal scarring, ureteric strictures, contracted bladder
• Chest radiograph
• Biopsy if renal impairment with sterile pyuria and unexplained interstitial nephritis

Differentials: contamination (vaginal), urinary tract infection with prior antibiotics, chronic catheterisation, interstitial cystitis, tumour.

Treat the cause

• Chlamydia trachomatis: doxycycline 100 mg orally twice daily for 7 days; treat partners.
• Neisseria gonorrhoeae: ceftriaxone 1 g intramuscularly as a single dose; add doxycycline 100 mg twice daily for 7 days if chlamydia is not excluded.
• Mycoplasma genitalium: doxycycline 100 mg twice daily for 7 days followed by moxifloxacin 400 mg daily for 7 days where macrolide resistance is present.
• Genitourinary tuberculosis: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg and ethambutol 15 mg/kg daily for 2 months, then isoniazid and rifampicin daily for 4 months (total 6 months); pyridoxine 10 to 25 mg daily; monitor liver function at baseline and 2 weeks; stop for ALT above 3 times the upper limit with symptoms or above 5 times without.
• Schistosomiasis: praziquantel 40 mg/kg orally as a single dose.
• Interstitial nephritis: stop the causative drug; prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) for 2 to 4 weeks if no improvement within 7 days, then taper.
• Stones: manage by size and obstruction.
• Kawasaki disease: intravenous immunoglobulin 2 g/kg as a single infusion and aspirin 30 to 50 mg/kg daily until afebrile, then 3 to 5 mg/kg daily.

Specialist

• Urology for obstructing tuberculous strictures: ureteric stenting or nephrostomy; reconstructive surgery once 4 to 6 weeks of therapy is complete.
• Nephrology for impaired renal function with interstitial inflammation.

Special groups

• Pregnancy: avoid doxycycline; use azithromycin 1 g single dose for chlamydia; tuberculosis therapy with rifampicin, isoniazid, ethambutol and pyridoxine.
• Renal impairment: adjust ethambutol (15 mg/kg three times weekly for eGFR below 30) and pyrazinamide (25 to 35 mg/kg three times weekly).