[Guidelines for the diagnosis and treatment of hereditary angioedema]. / Smjernice za dijagnostiku i lijecenje hereditarnog angioedema.

Hereditary angioedema (HAE) is a rare but potentially fatal genetic disorder with nonpitting, nonerythematous, and not pruritic swelling which can affect the hands, feet, face, genitals and visceral mucosa. The type, frequency, and severity of the attacks vary between patients, and over the lifetime of an individual patient. Efforts in Croatian counties have identified approximately 100 patients (but there must be more undiagnosed patients). The first global guideline for the management of HAE was developed by the World Allergy Organization HAE International Alliance and published in 2012. Based on that document the Working group of Croatian experts was assigned to propose guideline for HAE management in Croatia. HAE is is most often related to decreased or dysfunctional C1 inh with autoactivation of C1 and bradykinin accumulation leading to localized dilatation and increased permeability of blood vessels resulting in tissue swelling. A diagnosis of HAE can be confirmed by measuring complement and C1 inh quantitative and functional levels.Three HAE types could be differentiated: HAE type 1 (C1 inh level is low), HAE type 2 (C1 inh level is normal but dysfunctional), and HAE type 3 (normal level and function of C1 inh). All patients suspected to have HAE-1/2 should be assessed for blood levels of C4, C1 inh protein, and C1 inh function. All attacks that result in debilitation/dysfunction and/or involve the face, the neck, or the abdomen should be considered for on-demand treatment. It is recommended that attacks are treated as early as possible. HAE attacks are treated with C1 inh, ecallantide, or icatibant.If these drugs are not available, attacks should be treated with solvent detergent-treated plasma (SDP). If SDP is not available, then attacks should be treated with frozen plasma.Intubation or tracheotomy should be considered early in progressive upper airway edema. Patients with attacks could receive adjuvant therapy when indicated (pain management, intravenous fluids). All patients should have on-demand treatment for two attacks and carry their on-demand treatment at all times. The administration of short-term prophylaxis should be considered before surgeries (dental/intraoral surgery, where endotracheal intubation is required), where upper airway or pharynx is manipulated, and before bronchoscopy or endoscopy. Long-term prophylaxis should be considered in all severely symptomatic HAE-1/2 patients. C1 inh concentrate or androgens can be used. Screening children for HAE-1/2 should be deferred until the age of 12 months, and all offspring of an affected parent should be tested.

Childhood-onset systemic lupus erythematosus in Croatia: demographic, clinical and laboratory features, and factors influencing time to diagnosis.

OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE) presents with diverse clinical features and often with non-classical symptoms that may delay diagnosis and increase risk of morbidity and mortality. This paper aims to analyse incidence, and clinical and laboratory features of cSLE in Croatia between 1991 and 2010, and to identify factors influencing time to diagnosis. RESULTS: Medical records at three university-based tertiary care centres were analysed retrospectively for 81 children with cSLE (68 girls). Mean age at onset was 13.4±2.8 yr (interquartile range 3), and annual incidence varied from 1-15 per million at risk. The most frequent clinical and laboratory features were musculoskeletal symptoms (80%) and increased erythrocyte sedimentation rate (96%). The most frequent immunological laboratory findings were the presence of antibodies against histones (86%), double-stranded DNA (73%), and Sm protein (64%), as well as low levels of C3 complement (69%). Haematuria was present in 58% of children, proteinuria in 56%, and biopsy-confirmed lupus nephritis in 43%. Median time from symptom onset to diagnosis was 2 months (range 0-96). Time to diagnosis was inversely associated with ECLAM score (p<0.001), but it showed no association with age, gender, clinical features or distance from the nearest paediatric centre. CONCLUSIONS: This is the first large-scale, in-depth study of clinical and laboratory features of cSLE in Croatia. Among all demographic, laboratory and clinical features examined, ECLAM score alone was inversely associated with time to diagnosis. This highlights the need to improve detection of children with fewer symptoms early in the course of the disease, therefore serious consequences for prognosis could be avoided.

Rising trends in the prevalence of asthma and allergic diseases among school children in the north-west coastal part of Croatia.

OBJECTIVE: To estimate time trends in prevalence of symptoms and reported diagnosis related to asthma, allergic rhinitis/conjunctivitis and eczema among school children in the north-west coastal part of Croatia. METHODS: Results of two identical cross-sectional surveys conducted on the same area 8 years apart (school years 2001/02 versus 2009/10) in complete adherence to the protocol of the International Study of Asthma and Allergies in Childhood were compared. Surveyed population comprised two age groups: 6-7 years (n = 1634 versus n = 1052) and 13-14 years (n = 2194 versus 1181). RESULTS: Significant (p < 0.001) increases in prevalence (%) of symptoms related to asthma (8.4 versus 14.0), allergic rhinitis (17.5 versus 25.6), allergic rhinoconjunctivitis (6.7 versus 15.3) and eczema (3.4 versus 5.9) were observed in the 13-14-year-olds. In the 6-7-year-olds there were observed significant (p < 0.001) increases in prevalence of symptoms of eczema (5.4 versus 8.7) and allergic rhinitis (16.9 versus 22.1) whereas prevalence of symptoms related to asthma (9.7 versus 9.4; p = 0.398) and allergic rhinoconjunctivitis (5.6 versus 6.8; p = 0.102) showed to be stable. Significant increases in prevalence of reported diagnosis were observed for asthma (5.2 versus 6.9; p = 0.02) and hay fever (10.5 versus 14.6; p < 0.001) in the older, and for eczema (10.6 versus 14.1; p < 0.001) in the younger age group. CONCLUSION: Prevalence of asthma and allergic diseases among the school children living on the surveyed area showed a rising trend.

Tibial stress fracture simulate osteomyelitic foci in the course of chronic recurrent multifocal osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an extremely rare and most severe form of chronic nonbacterial osteomyelitis of unknown etiology. Here we present the first case of a six-year-old girl in which was observed that the stress fracture mimic osteomyelitic foci in the course of CRMO.

Role of magnetic resonance imaging and scintigraphy in the diagnosis and follow-up of osteomyelitis in cat-scratch disease.

Cat-scratch disease (CSD) is a self-limiting infectious disease characterised with lymphadenopathy in a patient with a history of cat contact. Cases of bone involvement in patients with CSD are rare. We reported a case of 11-year-old boy with prolonged intermittent fever, inguinal lymphadenopathy and osteomyelitis. He had a history of exposure to kittens. The physical examination revealed a febrile boy without an apparent site of infection except an enlarged inguinal lymph node. Its histopathology demonstrated granulomatous lesion with no presence of acid-fast bacilli. Serum titers for Bartonella henselae were positive. Multiple bone lesions were detected by skeletal scintigraphy. Magnetic resonance imaging (MRI) confirmed and characterised osteolytic masses. The oral combination of azithromycin and rifampicin were given for 6 weeks with a good clinical response. At follow-up, the boy was without symptoms or signs of the disease. Successive MRI controls showed gradual regression of the bone lesions together with significant decrease of acute-phase reactants. In conclusion, CSD should be considered in the differential diagnosis of osteomyelitis. MRI is more reliable for the characterisation, evaluation of soft-tissue extension and follow-up of the bone lesions than scintigraphy. However, the later method permits an overview of the multiple osseous lesions. Therefore, standard MRI equipment may not exclude bone scintigraphy. Both methods are required until whole-body MRI units become routine.

Prevalence of asthma and allergic diseases in Croatian children is increasing: survey study.

AIM: To estimate the prevalence of asthma, allergic rhinitis, and atopic dermatitis among school children in the region of Primorsko-goranska County in Croatia, and compare the results with data from other countries. METHODS: The study was conducted during the 2001-2002 school year, in complete adherence to the Phase One protocol of the International Study of Asthma and Allergies in Childhood (ISAAC). The target population comprised two age groups (6-7 and 13-14 years) in the region of Primorsko-Goranska County in Croatia. Data were collected using standardized ISAAC written questionnaire and asthma video questionnaire. RESULTS: There were 1,634 participating children in the 6-7 age group (response rate 80.3%) and 2,194 participating children in the 13-14 age group (response rate 89.8%). Estimated 12-month prevalence rates of symptoms were: wheezing 9.7% and 8.4%, allergic rhinitis symptoms 16.9% and 17.5%, allergic rhinoconjunctivitis symptoms 5.6% and 6.7%, and atopic dermatitis symptoms 5.4% and 3.4%, for younger and older age group, respectively. CONCLUSION: Results suggest an increase in the prevalence of atopic disease symptoms in north-west part of Croatia over the last few decades when compared to prior studies. The results are suitable for international comparison, suggesting that this part of Croatia is a county with a moderate prevalence of atopic diseases in the pediatric population. The results represent a baseline for further epidemiological research of asthma and allergic diseases.

[Congenital diaphragmatic hernia in older children]. / Prirodena dijafragmalna hernija u vece djece.

The incidence of congenital diaphragmatic hernia (CDH) is about 4.8/10,000 live births. Its typical clinical presentation is respiratory distress occurring immediately after birth or in the first few hours or days of a child's life. It is characterized by a high mortality rate. Exceptionally, CDH can occur at an older age, its symptoms then frequently reflecting gastrointestinal obstruction or mild respiratory symptoms. In such cases CDH presents a far more complex diagnostic problem. The paper presents the cases of two girls without typical symptomatology, aged 5.5 and 10 years, in whom CDH was detected incidentally upon thorough physical examination and chest x-rays. Further radiographic evaluation, which included barium contrast study and spiral computed tomography, confirmed the suspicion of a left-sided posterolateral diaphragmatic hernia with associated intestinal malrotation. Surgical intervention conclusively confirmed a diaphragmatic defect at the site of Bochdalek's foramen in both cases. The vital capacity of the older girl, which was low before the surgery (VC 1.66 L; 69% of predicted), was significantly increased a month after the surgical treatment (VC 2.25 L; 92% of predicted). The generally expressed view that the clinical onset of CDH is rare after the neonatal period seems to be erroneous. Some papers report on the clinical presentation of CDH after the neonatal period in as many as 13%-14% of infants and young children suffering from CDH. Infants and young children with a delayed clinical occurrence of CDH can present with respiratory or gastrointestinal symptomatology. Children presenting with gastrointestinal symptoms have been shown to be significantly older than those presenting with respiratory symptoms. In older children and adolescents, the symptoms and signs of CDH, which include acute hernial incarceration, nausea, recurrent vomiting, diarrhea, obstipation, acute gastric dilatation, subcostal pain, failure to thrive and recurrent chest infections, habitually present a significant diagnostic problem. Diagnostic errors are mainly due to the fact that the possibility of CDH in that age is totally neglected. The most recurrent diagnostic misinterpretations in such cases are pneumonia or massive pleuropneumonia, empyema, pneumothorax, lung cysts and bullae, and gastric volvulus. Thus, whenever a child presents with uncommon respiratory or gastrointestinal symptoms and an anomalous chest x-ray, a differential diagnosis of CDH should be considered. Otherwise, an accurate diagnosis in both young and older children will most probably be only reached at autopsy. In conclusion, the presented cases corroborate the finding that CDH in older children may present with scarce symptoms, mostly gastrointestinal, or may be altogether asymptomatic and unrecognized until as late as adolescence. However, when a diagnosis of CDH has been established, albeit asymptomatic, it must be promptly treated surgically in order to prevent complications, such as strangulation or bowel perforation, and thus avert a potentially fatal outcome. The size itself of the herniac foramen is unlikely to be a determining factor at the time of clinical presentation of CDH. Surgical occlusion of CDH may in older children result in an improved vital capacity, as such cases are rarely associated with major pulmonary hypoplasia. Complications resulting from surgical treatment of CDH in older children are more likely to occur in the gastrointestinal system, as a consequence of the associated bowel malrotation and inadequate bowel fixation. Finally, these two cases corroborate the diagnostic value of accurate history taking and thorough physical examination.

Gastroesophageal reflux and sequelae of chronic tubotympanal disorders in children.

OBJECTIVE: To compare sequelae of chronic tubotympanal disorders in children with and without gastroesophageal reflux (GER). MATERIAL AND METHODS: In 32 patients with chronic tubotympanal disorders GER was studied by means of 24-h continuous esophageal pH monitoring. After a period of 2-6 years (mean 4 years) sequelae of the tubotympanal disorders were examined, together with the clinical status of the ears and hearing status. The criteria for classification into mild, moderate and severe sequelae were based on the clinical status of the ear. Hearing was determined using tonal audiograms. Conductive hearing loss was classified as either slight (< or = 35 dB hearing loss in speech frequencies) or severe (>35 dB hearing loss in speech frequencies). RESULTS: In the group of 16 patients (mean age 6.1 years) with GER, sequelae were observed in 29 ears (mild, n=11; moderate, n=5; severe, n=13). Hearing impairment was determined in 20 ears (mild, n=8; severe, n=12). In the group of 16 patients (mean age 7.1 years) without GER, sequelae were observed in 17 ears (mild, n=11; moderate, n=1; severe, n=5). Hearing impairment was determined in 10 ears (mild, n=6; severe, n=4). CONCLUSION: The total number of ears with sequelae and the total number of ears with conductive hearing impairment were significantly higher in patients with GER.

Drug-induced acute tubulointerstitial nephritis: a case with elevated urinary cadmium.

Acute tubulointerstitial nephritis (ATIN) has many different causes, but is most frequently caused by drugs. We report a 13-year-old vegetarian girl with drug-induced ATIN, confirmed by renal biopsy, and simultaneous occurrence of elevated urinary cadmium. Four weeks prior to admission she had been treated with antibiotics and acetaminophen for respiratory infection, and remaining febrile, was treated with different "home-made" herbal mixtures. She presented with acute non-oliguric renal failure, tubular dysfunction, and sterile pyuria, but without skin rash or edema. Laboratory data showed a raised erythrocyte sedimentation rate, normal white blood count with eosinophilia, and a serum creatinine of 245 micromol/l. Urinalysis was remarkable for glycosuria, tubular proteinuria, and elevated beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase excretion. Immunoserological tests characteristic of acute glomerulonephritis and systemic diseases were negative. She was treated with steroids and her renal function improved. Follow-up analyses disclosed normal urinary cadmium and enzyme excretion within 6 months. Heavy metal analysis of herbal preparations that she had taken confirmed the presence of cadmium, but within approved concentrations. In conclusion, elevated urinary cadmium in the case of drug-induced ATIN may be assumed to be an accidental finding. However, consumption of different herbs containing cadmium and cadmium-induced nephro-toxicity could be the reason for such serious renal damage.

Prolonged esophageal pH monitoring in the evaluation of gastroesophageal reflux in children with chronic tubotympanal disorders.

BACKGROUND: Children with ear, nose and throat disorders are believed to have a high incidence of pathologic gastroesophageal reflux (GER). This study was designed to establish the frequency and ratio of pathologic GER in the development of chronic tubotympanal disorders. METHODS: Twenty-seven children with chronic tubotympanal disorders (mean age, 2 to 13 years; average age, 6.8 years) underwent 24-hour continuous pH monitoring. Fourteen of the examined patients had secretory otitis, whereas 13 patients had recurrent otitis. From each 24-hour pH monitoring, 12-hour daytime and nighttime periods were selected. Eleven patients were tested using simultaneous dual pH monitoring (distal and proximal pH monitoring). RESULTS: Fifteen (55.6%) of 27 patients had pathologic GER. The authors did not find a relation between pathologic GER and different types of ear disorders. Daytime pH monitoring yielded significantly more episodes of reflux than did nighttime monitoring. The reflux index was substantially higher during the day. In the current study, distal pH monitoring showed that 6 of 11 patients had pathologic GER, whereas proximal pH monitoring showed that only only 3 of 11 patients had pathologic GER. CONCLUSIONS: The authors recommend that a pH study be performed in children with chronic tubotympanal disorders when standard treatment is ineffective. The method of choice for the diagnosis of pathologic GER in patients with chronic tubotympanal disorders should be pH monitoring of the esophagus and throat.

Manifold significance of serum eosinophil cationic protein in asthmatic children.

Asthma is the result of complex interaction between different cells, mediators and nervous system that leads to an inflammatory response accompanied by increased bronchial hyperactivity. Its clinical manifestations include recurrent cough, wheezing and difficult breathing. The purpose of this study was to establish the possibility of diagnosing inflammation in asthmatic patients based on the assessment of serum eosinophil cationic protein (ECP), and of following the efficacy of asthmatic treatment by the levels of inflammation mediators. In a prospective study, 134 children aged 1 to 18 (mean 8) years underwent serum ECP assessment. Experimental group included 87 patients with asthma, 56 boys and 31 girls, mean age 9.1 (range 2-17) years. Control group included patients with recurrent non-allergic disorders, 27 boys and 20 girls aged 1-16 (mean 6.1) years. Serum ECP was assessed using the Pharmacia CAP system ECP-FEIA method, i.e. fluoroimmunoassay test for quantitative assessment of serum ECP levels. Serum values of ECP were significantly higher in asthmatics than in controls (p = 0.001). Our results showed that increased levels of serum ECP to significantly correlate with increased eosinophil (p = 0.018) and immunoglobulin E (p = 0.003) levels. Increased ECP levels reflect the degree of inflammation and correlate with the clinical picture severity in asthmatic patients. Assessment of serum ECP levels can reveal eosinophilic activity, and indirectly detect immunologic inflammation in asthmatics. It is possible to follow the dynamics of immunologic inflammation during the course of treatment as well as treatment efficacy.