Purple urine bag syndrome (PUBS) is an uncommon condition that occurs in urinary catheterized patients with urinary tract infection (UTI). It was first described in 1978, though a possible mechanism was not established until 1988 (1,2). With regard to the mechanism, tryptophan is metabolized by intestinal bacteria, after which the by-product indoxyl sulfate is expelled into the urine and digested into indoxyl by sulfatases/phosphatases produced by certain bacteria including Escherichia coli (E. coli), Proteus mirabilis, Morganella morganii (M. morganii), Klebsiella pneumoniae, Providencia stuartii, Providencia rettgeri and Pseudomonas aeruginosa (2,3). This indoxyl may convert into indigo and indirubin in the urine drainage bag and create purple discoloration (2).

A higher prevalence of PUBS has been reported in females and in patients with alkaline urine, an indwelling urinary catheter and constipation (3). The majority of patients with PUBS are catheterized due to significant disability, typically being chair-bound or bed-bound elderly patients (3). In previous years, PUBS has been considered to be a benign syndrome rather than a disease with lethal potential, and appropriate empirical oral antibiotics including ciprofloxacin remain to be suggested for its treatment (3). To the best of our knowledge, there have been no previous studies on the clinicopathological or epidemiological trends of PUBS; therefore, the current study retrospectively reviewed PUBS cases for characteristic analysis. A systematic review of PUBS cases reported between October 1980 and August 2016 was conducted, in which data regarding patient age and gender, comorbidities (diabetes mellitus, uremia, constipation and residence in long-term care facility), vital signs (presence or absence of fever), laboratory tests results [seral white blood cell (WBC) count, urine pH value] and mortality were evaluated. This aimed to identify trends in the epidemiology of PUBS. Through the systematic approach, the different clinicopathological aspects and general trends of PUBS were determined.

It is well established that urinary tract infection (UTI) may occur at variable ages, while PUBS is commonly observed in elderly compared with non-elderly patients (3), as in the present report (84.5 vs. 15.5%). As we know, PUBS can be observed in sepsis of asymptomatic bacteriuria (ABU) or CA-UTI.

The mechanism of PUBS originates from the dietary digestion and absorption of tryptophan in the bowel. Bacteria in the intestine metabolize the tryptophan to indole, and further hepatic enzymes form the conjugate indoxyl sulfate for secretion into urine by the kidneys. In the urinary tract, gram-negative bacteria phosphatases and sulfatases metabolize the indoxyl sulfate to indoxyl, and through oxidation, this may convert to indigo and indirubin (2). For patients with indwelling catheters, blue indigo deposited on the urine drainage bag surface and red indirubin dissolved in the urine mixes into a purple discoloration (2). A previous study demonstrated that not all bacterial organisms of the same species produce the phosphatase and sulfatase enzymes (2). Based on the above mechanism, bacteriuria should be present in all patients with PUBS, which should be diagnosed as ABU for those without clinical symptoms or signs including fever or shock. A case control study reported that bacterial counts in urine were significantly higher (by 1 to 2 logs) in patients with PUBS compared with those without the syndrome, thus suggesting that a higher bacterial load in the urine is an important factor leading to PUBS (75).

Regarding gender, females are generally more vulnerable to UTI and PUBS, and female gender has been previously considered a risk factor of catheter-associated (CA)-UTI among urinary catheterized patients (76,77). In the present study, the number of PUBS cases became equal between the genders within the most recent 5 years. A similar finding was observed in a recent prospective observational study performed between November 2011 and October 2013 (78). This study analyzed the incidence of healthcare-associated urinary tract infections in patients admitted to the urology ward of University Hospital 12 de Octubre in Spain with an indwelling urinary catheter. The incidence of CA-UTI in males vs. females was 8.22 vs. 8.46% without significant difference (78). The study also analyzed the four most frequently cultured bacteria species in CA-UTI (E. coli, Enterococcus, Klebsiella, Pseudomonas) and identified no significant difference between genders. The diversities in the results of these studies results may be affected by other unidentified factors, including urinary catheter management or personal hygiene influence.

In accordance with PUBS being associated with infectious pathology of the urinary tract, the mean WBC count of all reviewed cases was elevated to 12,242/µl. Furthermore, WBC count significantly increased with time between 2001–2010 and 2011–2016.

There were 11.8% of PUBS cases presenting with fever and 8.6% of cases presenting with hypotension without significant difference between the decades. A total of 58.3% of subjects lived in long-term care units, and 19.2% had a history of diabetes. Urine pH value was the most stationary variable in each decade, varying between 8.0 and 8.1, which is compatible with the recognized conclusion from studies on PUBS: That PUBS more readily occurs in alkaline over acidic urine (2–4).

A small cohort study of Taiwanese patients demonstrated chronic kidney disease (CKD) to be a risk factor for PUBS (79). The serum and urine levels of indoxyl sulfate are increased markedly in patients with chronic kidney disease or in those undergoing dialysis due to impaired renal clearance (80). In the present study, 18.8% of PUBS cases had a history of uremia. Previous studies have also indicated comorbid conditions including diabetes mellitus, dementia and iron deficiency anemia are independent risk factors for ABU and UTI (80,81).

It has previously been concluded there is an association of CA-UTI with increased mortality rate and prolonged length of stay in acute care facilities (82). Furthermore, for PUBS involving Fournier's gangrene in immunosuppressed patients, the morbidity and mortality rates were increased (30). Nevertheless, in uremic patients with PUBS, the elimination of indoxyl sulfate during dialysis is limited as it is bound to albumin, leading to exponential increase in serum indoxyl sulfate concentration. When treating patients with CKD and PUBS, clinicians should consider the elevated serum and urinary concentration of indoxyl sulfate due to its potential role in the progression of CKD, as well as its contribution to cardiovascular events (57).

Constipation is considered to be a predisposing factor in PUBS due to the increased time it elicits for bacterial deamination. In the present study, constipation rate significantly decreased after 2001, though this may have been an artifact based on the relatively small number of cases reported in the decade of 1991–2000.

Overall mortality rate was 6.8%, thus indicating that PUBS is not always a benign process. However, mortality rate declined with time over the three decades, concordant with the introduction of EGDT for severe sepsis in 2001 (83). Therefore, this progress may be attributed to the new recommendation of EGDT, which may achieve aggressive correction of septic shock when combined with early appropriate antibiotic administration. Nonetheless, the mortality rate of patients with severe sepsis declined following the implementation of EGDT (84–87). A recent meta-analysis study also concluded that important factors contributing to improved outcome are time-to-first antibiotic administration and appropriate antibiotic use (88).

In conclusion, the ratio of males: females with PUBS increased over recent decades. Therefore, the urine color in catheterized patients should be monitored not only in female but also male patients. PUBS may not always be a benign process, and emphasis is required on early examination and aggressive antibiotic administration. Although WBC count was elevated over the recent decades, the morality rate was lowest in the most recent five years and decreased by decade; the overall mortality rate was 6.8%, and lowered to 4.3% in the last five years.

This was a case-controlled study that searched relevant articles in the PubMed database. A limitation of this may have been the exclusion of cases based on inadequate information, leading to bias and introducing confounding factors. Furthermore, the relatively small number of PUBS studies in each decade may have limited the accuracy of statistical analyses. There may also be cases of PUBS unreported in the PubMed database which were unaccounted for.