Urinary Tract Infection Caused By Bacterial Pathogens of The Respiratory Tract In Children

doi:10.21203/rs.3.rs-1216166/v1

Urinary tract infection (UTI) caused by bacterial pathogens of the respiratory tract such as Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis is rare and little is known about their characteristics and potential host risk factors. We conducted a retrospective descriptive study on pediatric UTI due to S. pneumoniae, Haemophilus spp., or M. catarrhalis at a tertiary-care pediatric hospital. Pediatric patients with diagnosed UTI between 2002 and 2020 were included. Patient demographics, laboratory data, and microbiological findings were extracted from their electronic medical records and the infectious disease surveillance system. Among 46,332 urine samples, 76 bacteriuria (0.16%) and 22 UTI (0.05%) events due to the targeted species were identified (S. pneumoniae [n=7] and Haemophilus spp. [n=15]). Of the patients, 17 (85%) had underlying urinary tract abnormalities and 13 (60%) had vesicocutaneous fistula. All the UTI episodes caused by S. pneumoniae and Haemophilus spp. occurred after cystostomy. All the patients had satisfactory clinical outcomes.

Conclusion: Although S. pneumoniae and Haemophilus spp. are rare causes of UTI in children, they could be the true causative bacteria of UTI even when detected in urine specimens, particularly in the patients with urinary tract abnormalities and vesicocutaneous fistula.

Pediatrics

urinary tract infection

vesicocutaneous fistula

Streptococcus pneumoniae

Haemophilus influenzae

children

・Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are uncommon causes of UTI.

・Malformations of the urinary tract is risk factors of complex UTI.

What is new

・Although S. pneumoniae and Haemophilus spp. are rare causes of UTI in children, they could be the true causative bacteria of UTI

・Patients with vesicocutaneous fistula could be its risk factor.

Urinary tract infections (UTIs) are common bacterial infections in children. [1] An imbalance between bacterial virulence and host defense systems leads to UTIs. [1] The most common causative organisms are Escherichia coli that accounts for about 80%–90%, followed by Klebsiella spp. and Proteus spp. [1] In terms of host factors, malformations or dysfunction of the urinary tract are known to be risk factors of UTIs and low-virulent pathogens are often identified as true causative agents of UTI. Both delayed treatment of pediatric UTI and recurrent UTI are associated with renal scarring. [1] Thus, deep understanding the causative bacteria is important for appropriate prevention and treatment of UTIs.

Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are recognized as the three most common bacterial causes of respiratory tract infections in children. In contrast, these bacteria are uncommon causes of UTI. Although a few case reports have been published, little is known about the associated clinical characteristics, risk factors, and pathogenesis in UTI caused by these bacteria.

We aimed to clarify the characteristics of pediatric patients with UTI caused by bacterial pathogens of the respiratory tract and identify potential host risk factors.

We conducted a single-center retrospective review of all pediatric patients (≤18 years of age) with diagnosed upper UTI due to S. pneumoniae, Haemophilus spp., or M. catarrhalis between March 1, 2002 and December 31, 2020. The study was conducted at our tertiary care children’s hospital in Japan. Patient demographics, laboratory data, and microbiological findings were extracted from their electronic medical records and the infectious disease surveillance system.

Data were extracted for all urine cultures positive for the following targeted species: S. pneumoniae, Haemophilus spp. (H. influenzae, H. parainfluenzae, H. parahaemolyticus, and unidentified Haemophilus spp.), and M. catarrhalis. We defined UTI according to the following three criteria: (1) at least 2 symptoms consistent with UTI, including temperature greater than 38 °C, abdominal pain, new back pain, new or worsened incontinence, pain with catheterization, or malodorous or cloudy urine; (2) at least 10 urinary white blood cells per high-powered field (HPF) and (3) the presence of at least 10⁴ colony-forming units (CFUs) per mL of a pathogen cultured from urine obtained by catheterization, based on previous literature. [2-4] All the consecutive UTI events caused by the targeted species were included. Patients who had an alternative diagnosis other than upper UTI and asymptomatic bacteriuria, which was defined as a positive urine culture that did not meet criteria for UTI [5], were excluded. We also excluded the case with the presence of other known uropathogens greater than 10⁴ CFU/mL because it is hard to define the true pathogenic bacteria (Supplemental Figure 1). The final diagnosis of upper UTI was determined by two pediatricians according to the clinical criteria above.

During the study period, the national immunization program in Japan was changed as follows: pneumococcal conjugate vaccine 7 (PCV7) and H. influenzae type b (Hib) vaccine became available in December 2008 on a voluntary basis, became government funded for children since November 2010, and became part of the national immunization program in April 2013. PCV7 was replaced by PCV13 in November 2013. We classified patient vaccination status into the following three categories: 1) full, four doses of PCV7 or PCV13 and Hib vaccine; 2) partial, one to three doses of PCV7 or PCV13 and Hib vaccine; 3) none, never vaccinated with PCV7/13 or Hib vaccine.

This study was performed under the institutional opt-out passive consent policy and approved by the ethics committee and the Institutional Board of Privacy and Security at the institution (2020-369).

During the study period, 46,332 urine samples were cultured and bacteriuria due to the targeted species was found in 76 samples accordingly, that is, S. pneumoniae (n=22) and Haemophilus spp. (n=54) (Supplemental Figure 1). M. catarrhalis was not identified from any urine sample. Of these, 36 samples were excluded based on colony count of less than 10⁴CFU/mL, and 18 events were also excluded based on our criteria. Thus, 22 events (20 patients) were identified and included in our study (S. pneumoniae [n=7] and Haemophilus spp. [n=16]). All the patients had no complaint of respiratory symptoms.

Patient demographics are shown in Table 1. Of 20 patients (22 events), median age at the event was 3 years (range, 2.5–6 years), and 11 patients (55%) were male. Six patients (26%) were fully vaccinated at the time of UTI, six (30%) were partially vaccinated and ten (44%) were non-vaccinated. All but one patient had past medical history related either to chronic liver disease (n=4, 20%) or genitourinary disease (n=17, 85%). Common urological abnormalities were hydronephrosis (n=7), polycystic kidney disease (n=5), chronic kidney disease (n=4), and neurogenic bladder (n=3). Most of the events (n=18, 83%) were recurrent UTI. Importantly, two thirds of the patients (n=13, 60%) had vesicocutaneous fistula and eight (36%) were undergoing clean intermittent catheterization (CIC) at that point. Distribution of age, sex, and vaccination status seemed similar in both S. pneumoniae and Haemophilus spp. groups. More patients had underlying urinary tract abnormality in the Haemophilus spp. group (n=14, 93%) compared with the S. pneumoniae group (n=3, 60%). Patients with hydronephrosis or chronic kidney disease were only seen in the Haemophilus spp. group. The presence of vesicocutaneous fistula was observed in both groups. S. pneumoniae was the only pathogen isolated in five cases (71%), compared with seven (47%) in the Haemophilus spp. group. Among the cases with multiple pathogens, one grew significant number of uropathogen.

Because of the high rate of cases with vesicocutaneous fistula, we detailed 13 events in 10 patients with vesicocutaneous fistula in Supplemental Table 1. Indications for cystostomy were mainly recurrent UTI and/or severe hydronephrosis. All the UTI episodes caused by S. pneumoniae and Haemophilus spp. occurred after cystostomy. These bacteria had never cultured before the operation. Nine children were hospitalized and initially treated with intravenous antibiotics followed by oral antibiotics. Duration of treatments varied from 5−14 days (median 7 days). All the patients had satisfactory clinical outcomes with rapid response to antibiotics and without any recurrent episodes due to the same pathogens and serious sequelae.

There are few case reports in the literature on UTIs caused by Haemophilus spp., M. catarrhalis, and S. pneumoniae. [6,7] To the best of our knowledge, this may be the first report investigating UTI caused by all three major bacterial pathogens of the respiratory tract. Although UTI due to these bacteria were rare, up to 0.04% of urine cultures, they could be pathogenic. Most of the patients had at least one underlying urinary tract abnormality and experienced recurrent UTIs. Interestingly, a high rate of these cases had received cystostomy before the onset.

S. pneumoniae, Haemophilus spp., and M. catarrhalis are microorganisms that often cause infections in the respiratory tract. They may also cause skin and soft tissue infections, and invasive infections including bacteremia, meningitis, pyogenic arthritis, and osteomyelitis. However, they are an extremely rare cause of UTIs. There are several reports about UTIs from S. pneumoniae and Haemophilus spp. on a case-report basis. [6-8] A common feature of patients described in those reports in both adults and children was an underlying urinary tract abnormality, such as cystic-dysplastic kidney and chronic kidney disease. [6-8] Although we did not have UTIs due to M. catarrhalis, case reports were very limited as well. [9]

In our cases, 60% had received vesicostomy, which may be a remarkable feature. CIC is widely used in pediatric patients with neurogenic bladder and other urinary difficulties including vesicoureteral reflux, hydronephrosis, and recurrent UTI. CIC aims to prevent UTIs and preserve renal function. Recurrent UTI is also the most common complication in patients who undergo CIC. [10] The overall rate of frequent UTI among patients undergoing CIC is 25%. Gram-negative rods, such as E. coli and Klebsiella pneumoniae, are the common microorganisms in patients with CIC. [10] Staphylococci and streptococci can be resided in the urine microbiomes of children with neuropathic bladders. [5]^{13, 14} Vesicostomy is chosen when patients have difficulty in undergoing CIC from the urethra, deteriorated renal function, or recurrent UTI. [11] The frequency of febrile UTI may decrease after vesicostomy. However, little is known about the causative pathogens before and after the vesicostomy.

Neither S. pneumoniae nor Haemophilus spp. have properties to invade and colonize the urinary tract under normal conditions. [7] According to some reports, S. pneumoniae might not be uncommon colonizer of the skin and soft tissues or a pathogen than usually thought before. [12] We hypothesize that S. pneumoniae and Haemophilus spp. colonizing the respiratory tract or skin might accidentally invade the urinary tract of patients with vesicocutaneous fistula because of constant communication between the urinary tract and skin under vesicostomy, which increased their UTI risks.

There are several limitations to this study. First, this was a single-center-based retrospective study and thus the number of patients was limited. We collected detailed information as much as possible and described the patient demographics and characteristics in the current study. Although it is difficult to strictly distinguish “colonization” from “infection” for the rare pathogens of UTI investigated in this study, two pediatricians retrospectively evaluated the clinical criteria and determined to be upper UTI. Second, history of nasopharyngeal carriage of these respiratory pathogenic bacteria before the illness onset could not be evaluated. In conclusion, our results suggest that although S. pneumoniae and Haemophilus spp. are rare causes of UTIs in children, clinicians should not ignore these pathogens because they could be the true causative bacteria of UTI particularly in the patients with urinary tract abnormality and vesicocutaneous fistula.

CFU, colony-forming units; CIC, clean intermittent catheterization; Hib, H. influenzae type b; HPF, high-powered field; PCV, pneumococcal conjugate vaccine; UTI, urinary tract infections

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflicts of Interest/Competing Interests: The authors have no relevant financial or non-financial interests to disclose.

Availability of data and material: De-identified patient data will be available upon written request to the corresponding author after publication.

Code availability: Not applicable

Authors’ Contributions: YT conceptualized and designed the study, carried out the initial analyses, drafted the initial manuscript, and approved the final manuscript as submitted. TF contributed to study design, data collections, review and revision of the manuscript and approved the final manuscript as submitted. AI and IM coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Ethics approval: This study was performed in line with the principle of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the National Center for Child Health and Development (2020-369).

Consent to participate: Not applicable

Consent for publication: Not applicable

1. Tullus, K.; Shaikh, N. Urinary tract infections in children. Lancet 2020, 395, 1659-1668, doi:10.1016/S0140-6736(20)30676-0.

2. Madden-Fuentes, R.J.; McNamara, E.R.; Lloyd, J.C.; Wiener, J.S.; Routh, J.C.; Seed, P.C.; Ross, S.S. Variation in definitions of urinary tract infections in spina bifida patients: a systematic review. Pediatrics 2013, 132, 132-139, doi:10.1542/peds.2013-0557.

3. Subcommittee on Urinary Tract Infection, S.C.o.Q.I.; Management; Roberts, K.B. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011, 128, 595-610, doi:10.1542/peds.2011-1330.

4. Burckhardt, I.; Zimmermann, S. Streptococcus pneumoniae in urinary tracts of children with chronic kidney disease. Emerg Infect Dis 2011, 17, 120-122, doi:10.3201/eid1701.100895.

5. Forster, C.S.; Panchapakesan, K.; Stroud, C.; Banerjee, P.; Gordish-Dressman, H.; Hsieh, M.H. A cross-sectional analysis of the urine microbiome of children with neuropathic bladders. J Pediatr Urol 2020, 16, 593 e591-593 e598, doi:10.1016/j.jpurol.2020.02.005.

6. Burckhardt, I.; Panitz, J.; van der Linden, M.; Zimmermann, S. Streptococcus pneumoniae as an agent of urinary tract infections - a laboratory experience from 2010 to 2014 and further characterization of strains. Diagn Microbiol Infect Dis 2016, 86, 97-101, doi:10.1016/j.diagmicrobio.2016.06.009.

7. Hansson, S.; Svedhem, A.; Wennerstrom, M.; Jodal, U. Urinary tract infection caused by Haemophilus influenzae and Haemophilus parainfluenzae in children. Pediatr Nephrol 2007, 22, 1321-1325, doi:10.1007/s00467-007-0531-1.

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9. Elbashier, A.M.; Deshpande, H. Recurrent urinary tract infection with haematuria caused by Moraxella (Branhamella) catarrhalis. J Infect 1993, 27, 216-217, doi:10.1016/0163-4453(93)95160-k.

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11. Ting, C.S.; Chang, P.Y. Vesicocutaneous fistula: continent vesicostomy, an easier route for comfortable clean intermittent catheterization. J Pediatr Urol 2020, 16, 354 e351-354 e358, doi:10.1016/j.jpurol.2020.02.004.

12. Garcia-Lechuz, J.M.; Cuevas, O.; Castellares, C.; Perez-Fernandez, C.; Cercenado, E.; Bouza, E.; Spanish Pneumococcal Study Network. Streptococcus pneumoniae skin and soft tissue infections: characterization of causative strains and clinical illness. Eur J Clin Microbiol Infect Dis 2007, 26, 247-253, doi:10.1007/s10096-007-0283-7.

Table 1. Characteristics of the pediatric patients with UTI caused by Streptococcus pneumoniae and Haemophilus spp.

	All	*Streptococcus pneumoniae*	*Haemophilus* spp.
Patients (n)†	20	5	15
Events (n)	22	7	15
Age (year), median (IQR)	3 (2.5–6)	3 (2.5–6)	3.5 (2.5–6)
Male (n, %)†	11 (55%)	2 (40%)	9 (60%)
Vaccination (n, %)
Full	6 (26%)	2 (29%)	4 (25%)
Partial	6 (30%)	1 (14%)	5 (33%)
None	10 (44%)	4 (57%)	6 (38%)
Immunocompromised host†(n, %)	2 (10%)	1 (20%)	1 (6%)
Past medical history†
None	1 (5%)	0 (0%)	1 (6%)
Liver disease	4 (20%)	2 (40%)	2 (13%)
Genitourinary disease	17 (85%)	3 (60%)	14 (93%)
Hydronephrosis	7	0	7
Polycystic kidney disease	5	1	4
Chronic kidney disease	4	0	4
Neurogenic bladder	3	1	2
Vesicoureteral reflux	3	1	2
Pyeloureteral junction stenosis	3	1	2
Anovestibular fistula	2	0	2
Double urethra	2	0	2
Horseshoe kidney	2	1	1
Renal hypoplasia	2	0	2
Others¶	6	2	4
Past medical history of UTI
First UTI	4 (18%)	2 (29%)	2 (13%)
Recurrent UTI	18 (82%)	5 (71%)	13 (87%)
Medical devices
CIC	8 (36%)	3 (43%)	5 (33%)
Vesicocutaneous fistula	13 (60%)	5 (71%)	8 (54%)
Symptoms and signs
Fever	19 (86%)	7 (100%)	12 (80%)
Pyuria	22 (100%)	7 (100%)	15 (100%)
Nitrituria	12 (54%)	2 (29%)	10 (66%)
Urine culture
1×10⁴ CFU/mL	9 (41%)	3 (43%)	6 (40%)
1×10⁵CFU/mL	4 (18%)	1 (14%)	3 (20%)
1×10⁶CFU/mL	2 (9%)	1 (14%)	1 (6%)
1×10⁷ CFU/mL	7 (32%)	2 (29%)	5 (33%)
UTI cause by a single pathogen	12 (55%)	5 (71%)	7 (47%)
Positive blood culture (n, %)‡	1 (5%)	0 (0%)	1 (6%)
Blood culture taken (n, %)	17 (77%)	5 (71%)	12 (80%)

Parameters are †patients' numbers, ‡blood culture taken and others are total events.

Others include cloacal exstrophy (n=1), megaloureter (n=1), ureterocele (n=1), renal dysplasia (n=1), urethrorectal fistula (n=1), and urolithiasis (n=1).

Abbreviations: CIC, clean intermittent catheterization; IQR, interquartile range; UTI, urinary tract infection.

EJPFigure1final.jpg
Supplemental Figure 1: Patient’s selection flow in this study
20211229SupplementalTablefinal.pdf

Urinary Tract Infection Caused By Bacterial Pathogens of The Respiratory Tract In Children

Status:

Version 1

Abstract

What Is Known

Introduction

Methods

Results

Discussion

List Of Abbreviations

Statements & Declarations

References

Table

Supplementary Files

Status:

Version 1