Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.

BACKGROUND: The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities. CASE PRESENTATION: We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options  provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome. CONCLUSIONS: This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.

Unusual localization and presentation of osteoid osteoma mimicking juvenile spondyloarthritis: a case report.

BACKGROUND: Osteoid osteoma is a painful benign skeletal tumour of unknown aetiology. Most often it occurs in the long bones of extremities and responds well to nonsteroidal anti-inflammatory medications. However, unusual localization and atypical presentation of this tumour might present a diagnostic challenge, especially if symptoms mimic that indicative of juvenile spondyloarthritis. CASE PRESENTATION: A misdiagnosed ten-and-a-half-year-old girl with osteoid osteoma involving the distal phalanx of a little finger is presented. Her initial symptoms were pain and swelling of the little finger resembling dactylitis, while various imaging modalities showed signs of tenosynovitis, indicating a possible development of juvenile spondyloarthritis. Several trials of different non-steroid anti-inflammatory drugs gave no satisfactory results and ultrasound guided triamcinolone-hexacetonide injection provided only a short relief. Finally, almost three years after initial presentation, persistent clinical symptoms warranted repeated imaging that raised suspicion of an osteoid osteoma. Directed treatment with surgical intervention led to almost immediate and complete resolution of her symptoms. CONCLUSIONS: Osteoid osteoma should be suspected in case of a tender swelling of a digit in children and adolescents, regardless of initial imaging findings and clinical presentation. Early diagnosis and treatment of this benign condition can have a substantial impact on quality of life of patients and their families and protect them from many unnecessary diagnostic procedures and treatment.

S100A12 and S100A8/9 proteins are biomarkers of articular disease activity in Blau syndrome.

OBJECTIVE: To identify biomarkers of articular and ocular disease activity in patients with Blau syndrome (BS). METHODS: Multiplex plasma protein arrays were performed in five BS patients and eight normal healthy volunteers (NHVs). Plasma S100A12 and S100A8/9 were subsequently measured by ELISA at baseline and 1-year follow-up in all patients from a prospective multicentre cohort study. CRP was measured using Meso Scale Discovery immunoassay. Active joint counts, standardization uveitis nomenclature for anterior uveitis cells and vitreous haze by Nussenblatt scale were the clinical parameters. RESULTS: Multiplex Luminex arrays identified S100A12 as the most significantly elevated protein in five selected BS vs eight NHVs and this was confirmed by ELISA on additional samples from the same five BS patients. In the patient cohort, S100A12 (n = 39) and S100A8/9 (n = 33) were significantly higher compared with NHVs (n = 44 for S100A12, n = 40 for S100A8/9) (P = 0.0000004 and P = 0.0003, respectively). Positive correlations between active joint counts and S100 levels were significant for S100A12 (P = 0.0008) and S100A8/9 (P = 0.015). CRP levels did not correlate with active joint count. Subgroup analysis showed significant association of S100 proteins with active arthritis (S100A12 P = 0.01, S100A8/9 P = 0.008). Active uveitis was not associated with increased S100 levels. CONCLUSION: S100 proteins are biomarkers of articular disease activity in BS and potential outcome measures in future clinical trials. As secreted neutrophil and macrophage products, S100 proteins may reflect the burden of granulomatous tissue in BS.

Intraarticular infliximab therapy in patients with juvenile idiopathic arthritis: the role of musculoskeletal ultrasound and disease activity scores in monitoring therapy response.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, with heterogeneous clinical features. Although therapeutic options are wide and in the majority of children symptoms improve with the combination of non-steroidal anti-inflammatory and disease-modifying drugs, there are a number of patients who do not respond to conventional therapy and who do not meet the criteria for systemic biologics, namely anti TNF-alpha. Those patients are potential candidates for intraarticular therapy with biologics and in this report we present the results of intra-articular infliximab treatment in a series of patients diagnosed with oligoarticular subtype of JIA. METHODS: Twenty patients (30 joints) were treated with intraarticular infliximab and monitored by power Doppler musculoskeletal ultrasound according to the OMERACT and Juvenile Arthritis Disease Activity Score (JADAS 10) before intraarticular application and during the follow-up period of 18 months (0, 1, 12, 18 months). RESULTS: The results showed statistically significant improvement in PD-MSUS measures and JADAS in both B mode and power Doppler mode scores (p<0.001, p<0.001, respectively) in patients treated with i.a. infliximab with persistent response in fifteen patients. The JADAS score, as well as the ultrasound scores, were significantly reduced during the follow-up period. CONCLUSIONS: This study showed promising results, good safety and potential for the clinical benefit of intraarticular infliximab treatment in a selected group of patients with oligoarticular subtype of JIA.

The Croatian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Croatian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability and construct validity (convergent and discriminant validity). A total of 100 JIA patients (7% systemic, 38% oligoarticular, 19% RF negative polyarthritis, 36% other categories) and 100 healthy children, were enrolled in the paediatric rheumatology centres of the Clinical Hospital Center Sestre Milosrdnice and Childen's Hospital Srebrnjak in Zagreb. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed satisfactory psychometric performances. In conclusion, the Croatian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

[JUVENILE SPONDYLOARTHRITIS].

Juvenile spondyloartrhritis is a group of multifactorial diseases in which a disturbed interplay occurs between the immune system and environmental factors on a predisposing genetic background, which leads to inflammation and structural damage of the target tissue. First symptoms of jSpA rarely involve the spine, while asymmetrical oligoarthritis of lower extremities, dactylitis, and peripheral enthesitis are much more common. There are many classification criteria for jSpA, but the majority of pediatric rheumatologists currently use the International League Against Rheumatism (ILAR) criteria according to which most patients with jSpA are classified into the enthesitis-related arthritis group of juvenile idiopathic arthritis. To meet these criteria, a patient should have arthritis and/or enthesitis, with two or more symptoms such as sacroiliac joint tenderness and/or inflammatory back pain, HLAB27 genotype, HLA B27 genotype-associated disease in a first- or second-degree relative, uveitis, and male sex with eight or more years of age. Therefore, diagnosis is most oft en made only based on clinical examination and medical history. Anti- nuclear antibodies (ANA), rheumatoid factor (RF), and HLA testing with B27, B7, and DR4 alleles are preferred. Since subclinical gut inflammation is present in many patients, it is recommended to check fecal calprotectin levels. In patients with signs of peripheral enthesitis it is warranted to perform power Doppler musculoskeletal ultrasound (PDUS), and in patients with signs of axial involvement radiographic and contrast-enhanced magnetic resonance imaging. Most patients are treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy, while in refractory cases with peripheral disease synthetic disease- modifying antirheumatic drugs (DMARDs), such as sulfasalazine, are used. In patients with axial involvement, biological DMARDs such as adalimumab, infliximab, and etanercept are obligatory. Although a number of studies gave us a good insight into the disease pathogenesis, the response to treatment and prognosis are still difficult to predict.

Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes.

OBJECTIVE: To report baseline articular, functional and ocular findings of the first international prospective cohort study of Blau syndrome (BS). METHODS: Three-year, multicentre, observational study on articular, functional (HAQ, Childhood HAQ and VAS global and pain), ophthalmological, therapeutic and radiological data in BS patients. RESULTS: Baseline data on the first 31 recruited patients (12 females and 19 males) from 18 centres in 11 countries are presented. Of the 31 patients, 11 carried the p.R334W NOD2 mutation, 9 the p.R334Q and 11 various other NOD2 missense mutations; 20 patients were sporadic and 11 from five BS pedigrees. Median disease duration was 12.8 years (1.1-57). Arthritis, documented in all but one patient, was oligoarticular in 7, polyarticular in 23. The median active joint count was 21. Functional capacity was normal in 41%, mildly impaired in 31% and moderate-severe in 28% of patients. The most frequently involved joints at presentation were wrists, ankles, knees and PIPs. On radiographs, a symmetrical non-erosive arthropathy was shown. Previously unknown dysplastic bony changes were found in two-thirds of patients. Ocular disease was documented in 25 of 31 patients, with vitreous inflammation in 64% and moderate-severe visual loss in 33%. Expanded manifestations (visceral, vascular) beyond the classic clinical triad were seen in 52%. CONCLUSION: BS is associated with severe ocular and articular morbidity. Visceral involvement is common and may be life-threatening. Bone dysplastic changes may show diagnostic value and suggest a previously unknown role of NOD2 in bone morphogenesis. BS is resistant to current drugs, suggesting the need for novel targeted therapies.

[MICROARRAY AND GENE EXPRESSION ANALYSIS]. / SITNOPOLJE I ANALIZA GENSKOG IZRAZAJA.

Microarray gene expression analysis is high-throughput method in which many different sized DNA molecules are attached to solid surface in designated spots. These molecules are used for the discovery of specific RNA molecules isolated from various biological samples of interest. Core principle of this method is hybridization of complementary nucleotides (A-T and G-C), which leads to creation of double stranded nucleic acids. Gene expression differences in two groups of samples are discovered and quantificated by comparison of signal intensity values in microarray spots. Systemic analysis of data gathered in microarray gene expression measurement is performed by various bioinformatic methods such as group analysis, annotation analysis as well as network and pathway analysis. Expression comparison of all genes in different cells of the same individual or same cells of different individuals provides an insight into the mechanism responsible for development of a certain condition or disease.

[PATHOGENESIS OF UNDIFFERENTIATED SPONDYLOARTHRITIS]. / PATOGENEZA NEDIFERENCIRANOG SPONDILOARTRITISA.

Spondyloarthritis or spondyloarthropathy (SpA) is a multifactorial disease in which a disturbed interplay occurs between the immune system and environmental factors on a predisposing genetic background, which leads to inflammation and structural damage of target tissue. Many recent researches on development of SpA showed important role of innate and adaptive immunity as well as of prominent bone tissue remodeling which leads to osteoproliferation and ankylosis. It is believed that possible sites of inflammation in SpA are entheses, sinovium and gut. Current knowledge on inflammation and tissue destruction leads to conclusion that SpA is disease characterized by disorders on different levels. Disorder on the first level is disturbed pathogen recognition and immune response activation, on second level disturbed inflammatory cells migration and on third level disturbed immune response regulation. As follows, disease progress depends on range of disturbances: disease course can be short, as in reactive arthritis, or long-lasting with substantial structural damage, as in ankylosing spondylitis. Unfortunately, there are still no confident markers of disease progression, so at the mere beginning disease is often described as undifferentiated.

[Genetic predisposition for various forms of spondyloarthritis]. / Genetska podloga razlicitih oblika spondiloartritisa.

In addition to the long-established association of HLA-B27 antigen and spondyloarthritis, several studies have shown a similar association with HLA-B7 antigen. But since the whole MHC region carries less than half of the risk for the development of the disease, the main goal of many recently performed researches, which implemented various high-throughput methods, was to discover the influence of genes outside the MHC region on disease development. The results showed that genes closely linked to spondyloarthritis participate in antigen processing and coding of various cytokines. This can lead to the conclusion that diseases from the spondyloarthritis group are polygenic, affected by both autoinflammatory and autoimmune mechanisms.

Non-traumatic Limping in the Child: A Pediatric Rheumatologist Perspective on Etiology, Clinical Evaluation, Laboratory Diagnosis, and Diagnostic Algorithms using Musculoskeletal Ultrasound (MSUS).

Limping refers to an asymmetrical gait that deviates from the typical gait pattern expected for a child of a certain age. In most children, limping is caused by a mild, self-limiting event, such as a contusion, strain, or sprain. However, a child's limping is always a pathological finding that poses a particular diagnostic challenge and necessitates a thorough assessment. The pediatrician must weigh a wide range of acute and chronic potential causes of a non-traumatic limp, including infection, neoplasia, and chronic inflammatory disorders. A thorough history and clinical examination will help us arrive at the correct diagnosis. Understanding the typical gait is essential to recognizing and correctly interpreting the disordered one. The examination of child limping involves using a variety of diagnostic methods. Efficient and cost-effective diagnosis and treatment of the underlying condition requires a systematic approach. This review provides the pediatric rheumatologist perspective and approach for evaluating non-traumatic limp in children, with a focus on the use of point-of-care (PoC) musculoskeletal ultrasound (MSUS) as a crucial tool in daily practice.

Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease.

BACKGROUND: Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations. OBJECTIVE: This study aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2-related BS and CD. METHODS: Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4(+)/CD8(+) T-cell ratio, and CD20(+) B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-ß expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent. CONCLUSION: Granulomas from patients with BS and granulomas from patients with NOD2-associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the T(H)17 axis might be involved in the pathogenesis of BS, whereas T(H)1 is important in both patients with BS and patients with CD.

[Hematopoietic stem cell transplantation in treatment of autoimmune diseases]. / Transplantacija krvotvornih maticnih stanica u lijecenju autoimunosnih bolesti.

Hematopoietic stem cell transplantation (HSCT) has become an effective therapeutic option for the treatment of severe cases of autoimmune diseases (AD). Hematopoietic stem cells (HSC) can be collected from the patient (autologous), identical twin (syngenic) or HLA identical donor (allogenous). In allogenous transplantation autoagressive immunological effector cells are substituted with non-autoagressive cells of the donor. Possible graft versus host reaction (GVHD) makes this type of transplantation less attractive. On the other hand, autologous transplantation can induce the >>resetting<< of immunological clock without any fear of GVHD, but it requires previous conditioning. As an alternative option, transplantation ofmesenchymal stem cells (MSS) was developed. MSS has a strong immunosuppressive effect, while it doesn't require previous conditioning, nor does it induce GVHD. Due to the treatment related mortality, these therapeutic option should remain reserved for the most severe cases of AD. Nevertheless, they present a great opportunity for these patients, and even a chance for full recovery.

[The most frequent childhood vasculitides]. / Najcesci vaskulitisi u djecjoj dobi.

Childhood vasculitis is a challenge for pediatric rheumatologists. It is multisystem in nature and often requires integrated care from multiple subspecialties, including rheumatology, dermatology, cardiology, nephrology, neurology, and gastroenterology. Vasculitis is defined as the presence of inflammation in the blood vessel wall. The site of vessel involvement, size of the affected vessels, extent of vascular injury, and underlying pathology determine the disease phenotype and severity. This article explores the classification and general features of pediatric vasculitides, with detailed analisys of the two most common vasculitides: Henoch-Schönlein purpura and Kawasaki disease.

[Guidelines on biologic drugs for the treatment of children with juvenile idiopathic arthritis (JIA)]. / Smjernice za primjenu bioloske terapije u djece s juvenilnim idiopatskim artritisom (JIA).

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, and one of the major causes of short-term or long-term disability, and impairment of quality of life in childhood. Without early and adequate treatment the disease will progress and result with irreparable joint damage. The choice of therapy depends on the JIA subtype, disease activity index, prognostic factors, and prooven efficacy and probable side-effects of the drugs. The goal of modern JIA therapy is the achievement of complete disease remission, and not only the improvement of symptoms and temporarily inflammation control. The implementation of biologics significantly altered therapeutic approach to children with resistant JIA. We present Croatian guidelines on biologic drugs for the treatment of patients with JIA.

Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease affecting children. Even if remission is successfully induced, about half of the patients experience a relapse after stopping anti-inflammatory therapy. The present study investigated whether patients with JIA at risk of relapse can be identified by biomarkers even if clinical signs of disease activity are absent. METHODS: Patients fulfilling the criteria of inactive disease on medication were included at the time when all medication was withdrawn. The phagocyte activation markers S100A12 and myeloid-related proteins 8/14 (MRP8/14) were compared as well as the acute phase reactant high-sensitivity C reactive protein (hsCRP) as predictive biomarkers for the risk of a flare within a time frame of 6 months. RESULTS: 35 of 188 enrolled patients experienced a flare within 6 months. Clinical or standard laboratory parameters could not differentiate between patients at risk of relapse and those not at risk. S100A12 and MRP8/14 levels were significantly higher in patients who subsequently developed flares than in patients with stable remission. The best single biomarker for the prediction of flare was S100A12 (HR 2.81). The predictive performance may be improved if a combination with hsCRP is used. CONCLUSIONS: Subclinical disease activity may result in unstable remission (ie, a status of clinical but not immunological remission). Biomarkers such as S100A12 and MRP8/14 inform about the activation status of innate immunity at the molecular level and thereby identify patients with unstable remission and an increased risk of relapse.

[Non-invasive imaging of chronic inflammatory myopathies]. / Neinvazivna slikovna dijagnostika kronicnih upalnih bolesti misica.

In patients with chronic inflammatory myositis noninvasive diagnostic modalities, such as magnetic resonance (MR) imaging, and ultrasonography (US), are able to demonstrate muscular edema, fluid collections, fatty infiltration, atrophy, fibrosis, and calcifications. Because MR imaging is sensitive to the presence of edema and offers better tissue differentiation, current MR imaging with fat suppressed T2-weighted techniques or STIR images appears to be more efficient than US in the diagnosis and management of inflammatory myopathies. MR imaging has also been proposed as a means to guide biopsy in an area of active disease, thereby reducing the problem of sampling error. These changes in signal intensity, however, are not specific for myositis. Although MR imaging is now the imaging modality of choice in this issue, reduced availability, patient discomfort, and exclusion of certain patients with indwelling metal objects, such as pacemakers, are disadvantages. The availability and ease of use of US makes it preferable to MR imaging. Real-time sonoelastography can be used for various musculoskeletal applications, but the clinical utility in diagnosis of myositis is yet to be established. On the other hand, the contrast-enhanced US is a feasible method for noninvasively demonstrating increased perfusion in the involved muscle groups, and most likely, will soon become preferable, noninvasive imaging method in patients with myositis.

[Juvenile dermatomyositis]. / Juvenilni dermatomiozitis.

Juvenile dermatomyositis is the most common idiopathic inflammatory myopathy in children, and presents a heterogeneous group of subacute, chronic and acute diseases of skeletal muscles. Its unique presentation is marked with characteristic skin rushes and progressive muscle weakness. JDM is clinically distinct from adult dermatomyositis, because it is a systemic vasculopathy not associated with malignancy and it often overlaps with other chronic childhood inflammatory diseases. Although immunopathology of JDM is complex, new studies are completing our knowledge of disease pathogenesis. Corticosteroids represent the first line therapy, afterwards combined with immunomodulatory drugs and biological agents. Better knowledge of the disease combined with modem treatment modalities resulted in reduced mortality rates and in much improved quality of life in patients with JDM.

Value of thymic stromal lymphopoietin as a biomarker in children with asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP), an epithelium-derived pro-inflammatory cytokine, activates distinct immune and non-immune cells. It has been shown to be a master regulator of type 2 immune responses. Limited information is available on TSLP in childhood asthma. The aim of the present study was to find out whether there is association between TSLP concentrations and asthma phenotypes or disease activity. METHODS: A total of 207 children with asthma and 100 healthy children aged 1-13 years were enrolled. This study examined serum TSLP concentrations using ELISA Kit in asthma patients and controls, analyzed its correlation with asthma phenotypes and pulmonary function. We also examined TSLP concentrations in 23 patients during stable asthma and in acute asthma exacerbation. RESULTS: The serum concentrations of TSLP were significantly elevated in asthma patients compared with healthy controls (p < 0.05), but there was no significant difference (p > 0.05) in TSLP concentrations between three different asthma phenotypes (allergic asthma, virus induced asthma and nonallergic asthma). There was no significant correlation between TSLP concentrations and FEV1pred% (r = 0.01, p > 0.05). In the acute asthma exacerbation TSLP concentrations were not significantly different than in stable phase of disease (p > 0.05). CONCLUSION: Children with asthma have higher serum TSLP concentrations when compared to healthy controls. TSLP does not seem to be a biomarker of disease exacerbation in children. Different asthma phenotypes have similar TSLP concentration profile in peripheral blood and TSLP does not seem to be useful biomarker in asthma phenotyping in children.

Serum Calprotectin Is a Valid Biomarker in Distinction of Bacterial Urinary Tract Infection From Viral Respiratory Illness in Children Under 3 Years of Age.

Background: Febrile illnesses in young children can be a major diagnostic challenge, despite the routine use of various laboratory markers. Recent advancements in the understanding of inflammatory processes have highlighted the role of calprotectin, a heterodimer consisting of S100A8 and S100A9 proteins, with many studies suggesting its clinical value as a biomarker of inflammation. This research aimed to evaluate the usefulness of serum calprotectin (sCal) as a biomarker of urinary tract infection (UTI), which was due to its high pooled prevalence and feasibility of urine culture as a diagnostic reference standard selected for a model of bacterial infection in children. Methods: Febrile children aged 0-36 months with suspected UTI based on positive urinalysis or viral respiratory tract infection were included. Children with significant bacteriuria in urine culture were labeled as cases (n = 58), while those with confirmed viral infection (n = 51), as well as those with suspected UTI but sterile urine culture who went on to develop symptoms consistent with viral respiratory infection (n = 7), were labeled as controls. sCal levels were determined by a commercial immunoassay. Conventional inflammation markers (C-reactive protein, procalcitonin, white blood cell count, absolute neutrophil count, and neutrophil percentage) were measured on the day of the clinical examination. Differences in measured inflammatory markers between cases and controls were analyzed with Mann-Whitney U-test. ROC analysis reported cut-off values with the best sensitivity and specificity to distinguish bacterial UTI from viral respiratory infection. Results: All analyzed inflammatory biomarkers, including sCal, were significantly higher in cases than in controls. Median concentration of sCal was 4.97 µg/mL (IQR 3.43-6.42) and 2.45 µg/mL (IQR 1.63-3.85) for cases and controls, respectively (p < 0.001). For identifying bacterial UTI, sensitivity and specificity of sCal were 77.6 and 69.0%, respectively, at an adjusted cut-off point of >3.24 µg/mL (AUC 80.2%). Conclusion: sCal could have substantial added value in the management of a child with fever and positive urinalysis and is a promising biomarker in distinction between bacterial UTI and viral respiratory causes of febrile illness in children under the age of 3 years.