Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Urinary HSP70 improves diagnostic accuracy for urinary tract infection in children: UTILISE study.

BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

The role of height and weight growth in spontaneous resolution of vesicoureteral reflux.

BACKGROUND: The aim of this study was to investigate the role of height and weight growth in the resolution of primary vesicoureteral reflux (VUR). METHODS: We retrospectively evaluated the data of 74 males and 135 females who were diagnosed with primary VUR. According to the vesicoureteral reflux resolution, patients were divided into two groups. Patients with complete or partial resolution of VUR were included in Group 1 and patients with no resolution of VUR were included in Group 2. Patients were evaluated for weight Z-score, height Z-score and body mass index at the diagnosis and in the follow-up. In addition, age, sex, grade of reflux and laterality were recorded. RESULTS: There were no significant differences between the two groups, according to height Z-score, weight Z-score and body mass index at the diagnosis, in the follow-up and also annual changes of these parameters. In addition, the same parameters did not significantly differ in Groups 1 and 2, between the initial and final evaluations. However, when we evaluate the patients older than 12 months old, weight Z-scores were significantly higher at the final evaluation than at the diagnosis, in Group 1. This significant difference was not detected in Group 2 at the same age. CONCLUSIONS: Although we could not detect the hectic pace of height growth as being important in the prediction of long-term outcomes of VUR, weight growth should be considered to predict the resolution of VUR.

IL-1ß blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: case-based review.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and familial Mediterranean fever (FMF) are considered as inflammasome disorders associated with uncontrolled interleukin (IL)-1ß production. Anti-IL1 agents are used in colchicine-resistant cases of FMF. Increase in pro-inflammatory mediators even between febrile attacks in PFAPA suggests that anti-IL1 treatment might be beneficial in these patients. We describe a child presenting with recurrent, self-limited febrile attacks at 1 year of age who was diagnosed as FMF being heterozygous for M694 V mutation. Her clinical findings were only controlled by the addition of canakinumab (2 mg/kg/8 week) to colchicine treatment. However, she developed typical PFAPA attacks during this treatment at 3 years of age. We conducted a literature search focusing on English articles with keywords including PFAPA, anakinra, canakinumab, and rilonacept. Five children and one adult patient with PFAPA were found and evaluated. Anakinra was reported to abort PFAPA attacks in children, while the adult patient first responded and then became resistant to anakinra. Canakinumab was effective in preventing febrile attacks in this patient. Failure of canakinumab to prevent PFAPA attacks in our case may arise from the differences in the pathophysiology of PFAPA and FMF. Thus, further experience with higher doses or shorter intervals of canakinumab is needed in children with PFAPA.

Clinical predictive value of the urine leukocyte esterase test positivity in childhood.

BACKGROUND: False negative or positive results may occur in the urine dipstick test for leukocyte esterase (LE), which is used to determine urinary tract infection (UTI). We aimed to investigate the clinical importance of the presence or absence of pyuria in urine sediment for diagnosing UTI in the presence of positive LE in dipstick analysis. METHODS: Patients admitted to the pediatric nephrology outpatient clinic with positive urine LE tests were divided into two groups: those without pyuria (Group 1) and those with pyuria (Group 2) in their urine sediment. Hospital files of the patients were evaluated retrospectively for demographic variables, lower or upper UTI symptoms, physical examination for phimosis and vulvovaginitis, urinalysis for LE and nitrite tests, urine sediment microscopy, urine culture, complete blood count and C-reactive protein. Both groups were compared for the significant growth of pathogenic bacteria in urine cultures along with clinical and laboratory parameters. RESULTS: Among 578 children giving samples for urinalysis, there were 287 cases with positive LE tests. Groups 1 and 2 included 123 and 164 cases, respectively. The proportion of girls was higher in Group 1 and vulvovaginitis rate was higher among the girls in Group 1. Girls with vulvovaginitis were mostly prepubertal. Upper UTI symptoms, significant pathogen growth rate, and elevated acute phase response were more common in Group 2. In addition, the phimosis rate was more common among the boys in Group 1 with false positive LE test. CONCLUSIONS: Children with positive LE tests without pyuria are mostly prepubertal girls and there is a high rate of vulvovaginitis in these girls. Unnecessary tests and treatments for UTI may be avoided with detailed history and physical examination in prepubertal girls who have a false positive LE test. We also found, for the first time, that a false positive LE test is significantly associated with phimosis in boys.

Assessments of left ventricular systolic and diastolic functions with tissue Doppler imaging and myocardial performance index in children with chronic kidney disease.

BACKGROUND: This study aimed to document early left ventricular (LV) dysfunction in chronic kidney disease (CKD) using methods such as tissue Doppler imaging and the myocardial performance index (MPI). METHODS: A total of 40 patients diagnosed with CKD (mean age, 10.1 ± 4.1 years) and 40 sex- and age-matched healthy controls (mean age, 9.6 ± 4.3 years) were examined. In the patient group, 20 patients had early stage (Stage 2-3) CKD and 20 patients had late-stage (stage 4-5) CKD, and 18 patients had hypertension. RESULTS: The pulmonary artery systolic pressure (PAPs) and LV mass index (LVMI) were significantly higher in the patient group (P < 0.05). The LV septal and lateral margins of the mitral annulus E'/A' ratio, E/E' ratio and MPI results were significantly different between the groups (P < 0.05). The MPI scores were higher in late-stage CKD than in early stage CKD (P < 0.05). The E'/A' ratio was lower and the MPI was higher in the hypertensive CKD group compared with the normotensive CKD group (P < 0.05). The E/E' ratio was correlated positively with the LVMI, and the PAPs, and negatively with glomerular filtration rate, S' value, E'/A' ratio. The MPI was correlated positively with blood pressure, LVMI, PAPs, and the S value, and negatively with the E'/A' ratio. CONCLUSIONS: The E'/A' ratio, the E/E' ratio, and the isovolumetric relaxation time measured by tissue Doppler imaging is highly accurate and easily applicable for detecting diastolic LV function, and the MPI is suitable for detecting both systolic and diastolic LV dysfunction. Their routine use may be useful in evaluating LV functions in children with CKD.

Evaluation of left ventricular systolic functions in two-dimensional speckle-tracking echocardiography in children with chronic renal failure.

BACKGROUND AND AIM: Chronic kidney disease may lead to left ventricular dysfunction. Early detection of cardiovascular disease in children with chronic kidney disease is essential to prevent cardiovascular morbidity and mortality in early adulthood. This study aimed to document the dysfunction using methods such as two-dimensional speckle-tracking echocardiography in the early stage. METHODS: A total of 34 patients diagnosed with chronic kidney disease (mean age ± standard deviation, 10.5 ± 4.1 years) and 37 sex- and age-matched (mean age 9.8 ± 4.2 years) healthy controls were studied. The results of the two groups were compared along with those of the published studies. RESULTS: The echocardiography measurements had no significant difference in the end-diastolic and end-systolic diameter values of left ventricular, ejection fraction, shortening fraction, mitral E value, mitral A value, and E/A ratio between the groups. Pulmonary artery systolic and diastolic pressure and left ventricular mass index were significantly higher in the patient group (p < 0.01). The longitudinal global strain values in the apical four-chamber, three-chamber, and two-chamber views and the total global strain values were significantly lower in the patients (p < 0.01). The circumferential global strain values in the apical, mid, basal, and total global strain were lower in the patient group, but this difference was statistically significant in the apical global and total global strain values (p < 0.05). CONCLUSIONS: Speckle-tracking echocardiography might help identify subclinical left ventricular dysfunction in patients with chronic kidney disease with unremarkable conventional echocardiography.

Obesity is associated with severe clinical course in children with Henoch-Schonlein purpura.

BACKGROUND: We aimed to evaluate the role of obesity on the clinical course and response to treatment in patients with Henoch-Schonlein purpura (HSP). METHODS: Data charts of children with HSP followed in a tertiary hospital between 2000 and 2018 were reviewed retrospectively. Persistent purpura was defined as skin involvement persisting for ≥ 30 days. Mild nephropathy was defined as the presence of microscopical hematuria and/or non-nephrotic proteinuria, while severe nephropathy as nephrotic proteinuria, nephritic syndrome, and/or kidney insufficiency. Obese and non-obese patients were compared for demographic, clinical, and laboratory parameters. RESULTS: There were 199 patients (M/F, 104/95; median (IQR) presenting age 7.1 (5.0-9.2) years; follow-up period 17.5 (6-50) months). Obese patients (n = 35 (17.6%)) had significantly higher rate of persistent purpura (46% vs 21%), severe renal involvement (58% vs 31%), high-grade renal histopathological lesions (83% vs 39%), hypertension (29% vs 9%), and increased erythrocyte sedimentation rate (79% vs 56%). Obese patients also showed delayed improvement of cutaneous (25 vs 14 days), articular (12.5 vs 10.0 days), and kidney (280 vs 57 days) symptoms. Obese children used steroids for significantly longer period of time (236 vs 40 days). Furthermore, need for immunosuppressive medications were higher in obese patients (40% vs 9%). CONCLUSIONS: Obese children with HSP had higher erythrocyte sedimentation rate, hypertension, and severe renal involvement; showed delayed improvement of skin, joint, and kidney findings; and need more immunosuppressive medications and a longer period of steroid treatment. These findings may be associated with the effect of adipose tissue on inflammation.

Contribution of Electron Microscopy to the Clinicopathologic Diagnosis in Childhood Glomerular Renal Diseases.

Background: Electron microscopy (EM) provides another diagnostic assessment of glomerular lesions in addition to light and fluorescent microscopy. Objectives: We evaluated the contribution of diagnostic EM in childhood glomerular diseases. Patients and methods: Forty-eight renal biopsies which were assessed by EM between 2000 and 2014 were evaluated. Results: There were 21 (44%) females and 27 (56%) males, ages ranged between 6 and 204 months. EM findings were compatible with light and immunofluorescence microscopy in 65%, made additional contributions to diagnosis in 31% (especially in focal segmental glomerulosclerosis, Alport disease, membranoproliferative glomerulonephritis, dense deposit disease, thin basement membrane disease, and nephronophthisis), and was non-contributory in 4%. Conclusion: Electron microscopic evaluation supports other histopathological diagnoses in most cases, contributes additional diagnostic information in pediatric glomerular disease, especially in FSGS, thin glomerular basement membrane nephropathy, Alport disease, MPGN, and dense deposit disease, and its utilization should clinically justify the increase in cost and testing time.

A Case of Familial Mediterranean Fever Having Intermittent Leukopenia.

Familial Mediterranean fever (FMF) is a genetically inherited autoinflammatory disorder characterized by inflammatory attacks and may result in amyloidosis as a severe complication. Elevation of acute phase reactants, including leukocytosis, is seen during attack periods. Here we describe a 13-year-old female patient with a very rare clinical presentation of FMF, who would experience FMF attacks when she did not regularly take her colchicine. During these attacks she had leukopenia and neutropenia instead of leukocytosis. The leukocyte count returned to normal when she continued the medication and avoided attacks. Ethnicity and clinical signs are important in leukopenic patientsand should be investigated for FMF to avoid unnecessary procedures and complications.

Cyclosporine causes no hearing defect in paediatric patients with nephrotic syndrome.

OBJECTIVE: We aimed to evaluate the ototoxicity of cyclosporine A (CsA) in children with nephrotic syndrome (NS). DESIGN: Data of paediatric patients with NS followed in paediatric nephrology department were evaluated retrospectively, and hearing functions were evaluated by pure tone audiometry (PTA) and transient evoked otoacoustic emissions (TEOAEs). Age, gender, type of NS, duration and cumulative doses of immunosuppressives were noted. STUDY SAMPLE: The patients who had received CsA (n: 16) and immunosuppressives other than CsA (n: 13) for at least 6 months formed two patient groups and healthy cases formed a control group (n: 20). Children with known previous hearing defect, inner ear trauma or surgery, recurrent otitis media and those using hearing aid were excluded. RESULTS: Gender, age at first clinical presentation, laboratory tests and number of relapses were similar between the groups. No hearing loss was defined in PTA at frequencies of 250, 500, 1000, 2000, 4000 and 8000 Hz. The results of TEOAEs were similar between the groups and compatible with normal hearing. CONCLUSIONS: CsA is not responsible for permanent sensorineural hearing loss in children with NS, and there is no sufficient evidence to consider routine hearing assessment in children with NS treated with CsA.

Body composition with bioelectrical impedance analysis and body growth in late-diagnosed vesicoureteral reflux.

BACKGROUND: This study aimed to evaluate together body composition and growth in children with vesicoureteral reflux (VUR). METHODS: The study was performed in children presenting with recurrent urinary tract infection. The patients were grouped as VUR(+) (Group 1) and VUR(-) (Group 2). A group of healthy cases formed the control group (Group 3). The patients and control cases were evaluated from respect to age, gender, body weight, height, Z-scores of weight (WZ) and height (HZ), and Weight-for-Height Index (WHI). In addition, Body Mass Index, lean body mass, body fat mass, fat-free mass, and body cell mass were measured with bioimpedance analyzer. The parameters compared among groups. RESULTS: There were 53 patients in Group 1, 27 patients in Group 2, and 20 subjects in Group 3. While age, sex, weight, and height were not different among groups, WZ and HZ score were lower in the Group 1 than Group 2 and 3 (P=0.002 and P=0.012 to WZ score, P=0.003 and P=0.016 to HZ score, respectively). WHI was lower Group 1 than Group 2 (P=0.036). Among body composition values, only body cell mass was lower in Group 1 than Group 2 and 3 (P=0.015 and P=0.009, respectively). However, there was no difference between the Group 2 and Group 3. CONCLUSIONS: Deficit of body cell mass with body growth evident in patients with VUR in compared with other groups. Therefore, early evolution and treatment in terms of VUR of children with recurrent urinary tract infections may be important.

Screening of celiac disease in children with Henoch-Schoenlein purpura.

Prevalence of celiac disease (CD) is 2.42 % in healthy Turkish children. The frequency of IgA-associated disorders is increased in CD. Henoch-Schoenlein purpura (HSP) is an IgA-associated vasculitis. Association of HSP with CD has not been evaluated. We aimed to evaluate whether CD prevalence is increased in children with HSP. Children with HSP were evaluated for demographic, anthropometric, clinical, and laboratory data including urinalysis, complete blood count, albumin, creatinine, and IgA levels. In addition, tTG-IgA, EMA-IgA, anti-DGP-IgA, and IgG antibody levels were measured. Seropositive patients were evaluated by endoscopic small bowel biopsy. The rate of CD seropositivity and confirmed CD in HSP patients was compared to the rate in healthy Turkish children. There were 42 children (25 male) with HSP. No patient had classical CD symptoms, but two patients had growth failure. None of them had IgA deficiency, anemia or hypoalbuminemia. Celiac serology was positive in five (12 %) children. Endoscopic evaluation was performed in four patients, and two (5 %) of them were confirmed to have CD. Prevalence of both CD seropositivity and histologically confirmed CD in children with HSP was significantly higher compared to healthy Turkish children (p < 0.001 and p = 0.019, respectively). CD seropositivity rate in children with HSP (12 %) is significantly higher than the rate in healthy children. Although the number of children with HSP is small in this preliminary study, this result suggests that celiac screening may be considered in children with HSP.

Antireflux surgery does not change ongoing renal functional deterioration.

AIM: Treatment modalities of vesicoureteral reflux (VUR) consist of antimicrobial prophylaxis and antireflux surgery. In this study, we aimed to determine if antireflux surgery changes the course of renal functional deterioration in children with VUR and urinary tract infections (UTI). METHODS: Medical files of patients with VUR diagnosed during evaluation for UTI were evaluated retrospectively for gender, age, follow-up period, and renal ultrasonography (US) and serial 99mTc-dimercaptosuccinic acid (99mTc-DMSA) scintigraphy findings. Estimated glomerular filtration rate and urinary protein levels were determined at the initial and last visits, and before the operation in children who had antireflux surgery. The patients were divided into two groups as solely medically treated (Group 1) and both medically and surgically treated (Group 2). Group 2 was further divided as those with stable renal function (Group 2a) and with progressive renal injury (Group 2b). RESULTS: There were 140 patients (77 female; mean age 51.6 ± 51.9 months). Group 1 and Group 2 included 82 and 58 patients, respectively. In Group 2, the number of patients with the abnormal US, DMSA scintigraphy, and renal function was higher than in Group 1. Recurrent UTI rate was similar, but progressive scarring was more prominent in the antireflux surgery group. In Group 2, 31 patients had a stable renal function (Group 2a) while 27 had progressive deterioration of renal functions (Group 2b). These subgroups were not different with respect to the rate of high-grade VUR, the presence of a renal scar in DMSA, and UTI recurrence. However, the bilateral renal scar was more common in Group 2b. CONCLUSION: Antireflux surgery does not change the course of ongoing renal injury and renal functional deterioration.

Development of a medication adherence scale for familial Mediterranean fever (MASIF) in a cohort of Turkish children.

OBJECTIVES: To develop and assess the validity and reliability of an adherence scale concerning medical treatment in paediatric FMF patients. METHODS: The Medication Adherence Scale in FMF Patients (MASIF) is a 18-item questionnaire that evaluates adherence to medication in four domains. Validation of the instrument was accomplished in paediatric FMF patients (aged 2-18 years) under medication at least for 6 months. The first step was to build up the scale through qualitative approach (with interviews using semi-structured questions). Validation analyses included assessment of feasibility, face and content validity; construct validity, internal consistency and test-retest reliability. RESULTS: One hundred and fifty patients with FMF were enrolled in the study. The mean age of the patients was 11.11±4.02 years and 48.7% of them were male. The MASIF was found to be feasible and valid for both face and content. It correlated with the Morisky Medication Adherence Scale as a gold standard thereby demonstrating good construct validity (r=0.515, p<0.001). Assessment of content validity identified four subscales. The internal consistency, Cronbach's alpha was 0.728. There was a positive and significant correlation between test and retest scores (r=0.843; p<0.001). Also, a significant correlation between parents' and children's reports (r=0.781, p<0.001). CONCLUSIONS: Based on these results, the use of this scale to assess and follow up the adherence to treatment in paediatric FMF patients under medical treatment is recommended.

Risk factors for subclinical inflammation in children with Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common autosomal recessive inherited inflammatory disease characterized by attacks of painful inflammation. Some patients with FMF have subclinical inflammation persisting between the attacks. We aimed to identify the demographic, clinical and genetic risk factors for subclinical inflammation in children with FMF. The medical records of the children with FMF were evaluated retrospectively for acute-phase response along with gender, age at the onset of symptoms and at the time of diagnosis, clinical signs and symptoms, the presence of amyloidosis and MEFV genotype. Patients with persistently elevated acute-phase response between the attacks were considered to have subclinical inflammation. Patients with or without subclinical inflammation (Group 1 and Group 2, respectively) were compared for the parameters defined above. Independent risk factors for subclinical inflammation were identified by multivariate logistic regression analysis. There were 105 children (male/female: 52/53) who were compliant on colchicine treatment. Subclinical inflammation was detected in 22 (20 %) patients. Group 1 had significantly higher rate of myalgia, arthritis/arthralgia, erysipelas like erythema, amyloidosis, protracted febrile myalgia and M694V mutation compared with Group 2. However, only the presence of myalgia and erysipelas like erythema were found to be independent risk factors for subclinical inflammation (OR 9.8 and 5.9, respectively). Children with FMF who have myalgia and erysipelas like erythema during the attacks are particularly at risk of ongoing inflammation and should be closely monitored for subclinical inflammation even during attack-free periods.