Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (€ per kg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448€ (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years.

Inhibitor development in previously untreated patients with severe haemophilia A: a nationwide multicentre study in Finland.

INTRODUCTION: Currently the most serious treatment complication of haemophilia is the inhibitor development (ID), i.e. neutralizing antibody development. AIM: This nationwide multicentre study in Finland evaluated the incidence and risk factors of ID in previously untreated patients (PUPs) with severe haemophilia A (FVIII:C < 0.01 IU mL(-1) ). METHODS: We enrolled all PUPs (N = 62) born between June 1994 and May 2013 with at least 75 exposure days (EDs) to screen ID during follow-up extending to September 2013. RESULTS: Thirteen ID (21% of 62) occurred; 10 (16% of 62) with high titre. Fifty-one patients (82%) were on primary prophylaxis (regular prophylaxis before the age of 2 and before the first joint bleed) from the median age of 11.4 months, 90% via a central venous access device. The initial product was rFVIII in 63% and pd-FVIII in 37%, moreover in 24% pd-FVIII was switched to rFVIII concentrate during the 75 EDs. Non-transient inhibitors developed in 9/51 (17.6%; 13.7% high titre) children with primary and in 4/11 (36.4%; 27.3% high titre) patients with secondary prophylaxis (P = 0.24). Overall, 74% had a high-risk genotype similarly distributed among the prophylaxis groups. The history of a major bleed enhanced ID (aHR, 4.0; 95% CI, 1.2-13.7), whereas FVIII treatment intensity or source and early implantation of ports did not increase ID risk. CONCLUSION: The cumulative incidence of ID was low notwithstanding prevalent high-risk mutations. Despite patient-related risk factors, our management involving early intensive primary prophylaxis via ports helps to prevent bleeds and lower the incidence of inhibitors.

Complications associated with central venous access device in children with haemophilia: a nationwide multicentre study in Finland.

Children with haemophilia require venous access for regular infusion of coagulation factors. A central venous access device (CVAD) ensures long-term access but associates with infectious and non-infectious complications with proposed risk factors of young age at initial CVAD implantation and presence of an inhibitor. Our aim was to evaluate the incidence and risk factors for complications associated with CVAD usage in a retrospective nationwide multicentre study in five Finnish Paediatric Haemophilia Treatment Centers. Our study investigated 106 CVADs in 58 patients with 137 971 CVAD days. The median access survival was 1159 CVAD days, and most often a malfunction led to CVAD removal after a long survival (median of 1640 CVAD days). We detected a very low bloodstream infection rate (0.12/1000 CVAD days). The presence of neutralizing inhibitor was a significant risk factor for infection. Heparin vs. saline flushing did not influence the CVAD outcome. We detected a lower infection rate than previously reported, although 90% of the patients were very young (<2 years) at first insertion (median age = 1.02 year). Port access was frequent after initial implantation: six patients (10%) used the port daily for immune tolerance induction therapy and 74% at least twice weekly for prophylaxis. Young age did not increase the risk of infections, as 59% of the CVAD-related infections were recorded in children over 6 years of age. Our national experience confirms the safety of prophylactic factor concentrate administration via ports even in very young children.

Cardiovascular morbidity in long-term survivors of early-onset cancer: a population-based study.

Improvements in cancer therapy have resulted in an expanding population of early-onset cancer survivors. In contrast to childhood and adolescent cancer survivors, there is still a lack of data concerning late morbidities among young adult (YA) cancer survivors. Thus, our aim was to investigate cardiac and vascular morbidity among early-onset cancer survivors with a special interest in YA cancer survivors. In a population-based setting, we explored the risk of cardiovascular disease in early-onset cancer survivors compared to healthy siblings. Patients diagnosed with cancer below 35 years of age since 1975 were identified from the Finnish Cancer Registry, and 5-year survivors were included in our study (N = 13,860). Information on cardiovascular morbidity was collected from the national hospital discharge registry. Compared to siblings, cancer survivors aged 0-19 and 20-34 at diagnosis had significantly elevated hazard ratios (HRs) for the studied outcomes: HR 13.5 (95% CI 8.9-20.4) and 3.6 (95% CI 2.8-4.6) for cardiomyopathy/cardiac insufficiency; HR 3.4 (95% CI 2.3-5.1) and 1.7 (95% CI 1.4-2.0) for atherosclerosis/brain vascular thrombosis; HR 3.3 (95% CI 1.7-6.5) and 1.8 (95% CI 1.5-2.1) for myocardial infarction/cardiac ischemia and HR 1.7 (95% CI 1.2-2.6) and 1.4 (95% CI 1.2-1.7) for cardiac arrhythmia. In both groups, depending on the outcome, the HR for adverse events was highest among lymphoma, brain tumor, leukemia and testicular malignancy survivors. Our results regarding late effects of childhood cancer survivors confirmed previous findings. Additionally, our study provides novel information concerning the YA cancer survivor population. Hence, our data may help in planning the risk-based long-term follow-up of early-onset cancer survivors.

Male reproductive health after childhood cancer.

AIM: Twenty-five male patients were investigated to elucidate the correlation of semen parameters and other related parameters in the assessment of spermatogenesis after childhood cancer treatment. METHODS: Evaluation of given cancer treatment, anthropometric and testicular size measurements, semen analysis, and measurement of gonadotrophins, testosterone, sex hormone-binding globulin (SHBG), and inhibin B were performed according to a protocol. RESULTS: Median (range) sperm concentration (SC) was 35.5 (0-273)x10(6)/mL, and percentage of motile sperm 56 (0-86)%. Testicular size (r=0.73, p<0.001) and the level of inhibin B (r=0.66, p<0.001) correlated strongly to SC. SC correlated negatively to FSH (r=0.46, p=0.03). Only testicular size predicted SC significantly (p=0.03). Inhibin B showed highest area under ROC curve (0.83, 95%CI 0.67-0.99) in showing SC<20x10(6)/mL. Body mass index (BMI) did not correlate with SC, but negative correlation between BMI and SHBG was found (r=-0.41, p=0.04). CONCLUSION: Although semen analysis is a useful instrument for fertility assessment in men, it is often difficult to get these samples from childhood cancer survivors. Thus, indirect methods are needed in prediction of possible sperm count impairment in postpubertal adolescents after cancer treatment. When combined with the data on testicular size and follicle-stimulating hormone (FSH) level, inhibin B gives valuable addition to the estimations of spermatogenesis.

A novel deletion in a Pearson syndrome infant with hypospadias and cleft lip and palate.

Pearson syndrome is a rare multiorgan mitochondrial disorder that causes substantial disability and usually leads to premature death. We describe an infant with Pearson syndrome who showed, in addition to the typical features of the syndrome, cleft lip and palate and hypospadias.

Causas de muerte y antecedentes en fallecidos, registrados de muerte no natural, desde 1982 a 1992 en la provincia de Guipúzcoa / Causes of death and previous deaths since 1982 till 1992 in Guipúzcoa registred of natural deaths

En la actualidad el número de fallecidos por causa de muerte no natural está en aumento.En este trabajo se analizan las causas de muerte y antecedentes en fallecidos, de cadáveres identificados en los departamentos de Policía Científica del Cuerpo Nacional de Policía, registrados de muerte no natural, desde el año 1982, en la provincia de Guipúzcoa.Se ha constatado que existe una relación entre las causas de muerte y la influencia de factores de salud, socio-económicos y familiares en estos fallecidos, y es por ello que se quiere hacer reflexionar sobre todos los aspectos que influyen en un individuo con el fin de mejorar su calidad de vida (AU)

CNS tumours in south-western Finland: high location, high incidence.

The Department of Paediatrics at the University Central Hospital of Turku, Finland has 130,000 children under 17 y of age within its catchment area. We collected all 103 cases of newly diagnosed CNS tumours from the 15-y period of 1981-95. The incidence was 5.3:100,000, a figure twofold those usually presented. During the period 1981-85 the incidence was lower (4) than during the subsequent 5-y periods (5.7 and 6.2). There were no statistical differences between the incidences of the supra- vs infratentorial brain tumours. Optic glioma was unusually common (17%, CI 13.9-20%).

Respiratory virus infections during anticancer treatment in children.

To evaluate the occurrence and clinical significance of respiratory virus infections in children during anticancer treatment, we studied 75 consecutive episodes of febrile infection in 32 children during 17 months. Viral antigen detection for 7 respiratory viruses, viral culture for rhinoviruses and enzyme immunoassay serology were used. Evidence for respiratory virus infection was found in 28 (37%) cases. Rhinovirus was the most common virus detected in 13 (17%) episodes. The other etiologic agents were respiratory syncytial virus (6 episodes), parainfluenza virus type 3 (5 episodes), adenovirus (4 episodes), influenza A virus (3 episodes), and influenza B virus (1 episode). Respiratory virus infections were diagnosed as often in leukopenic as in non-leukopenic patients (37% vs. 38%). In 4 cases bacteremic infection was diagnosed. We found no difference in serum C-reactive protein values when episodes positive for respiratory viruses were compared with virus-negative episodes. Our observations show that respiratory virus infections are common in febrile children receiving anticancer treatment. Diagnostic tests for respiratory viruses should be used more often in evaluation of fever in these patients.

Influenza vaccination in the prevention of acute otitis media in children.

We studied a new approach to the prevention of acute otitis media through the administration of influenza vaccine to 187 day-care center children aged 1 to 3 years before the influenza A epidemic of 1988-1989. The control group consisted of 187 unvaccinated children of similar age and background. During the 6-week study period, influenza A infection was diagnosed in five (3%) of 187 vaccinees and in 29 (16%) of 187 controls. Acute otitis media developed in three (60%) of five vaccinees with an influenza A infection compared with 18 (67%) of 27 controls (excluded were two children with a double viral infection). The incidence of acute otitis media associated with influenza A was reduced by 83% in the vaccinees. The total number of children with acute otitis media in the vaccine group was 35, compared with 55 in the control group, disclosing a 36% reduction among the vaccinees. We conclude that influenza vaccination decreases the incidence of acute otitis media in children during an influenza A epidemic, suggesting also that other vaccines against respiratory viruses may be an effective way to reduce the incidence of acute otitis media.

Pharmacokinetics and clinical response of hyoscine plus morphine premedication in connection with cardiopulmonary bypass surgery.

Plasma hyoscine and morphine levels and various pharmacodynamic responses have been examined in seven patients scheduled for a coronary-artery bypass graft. Hyoscine 0.006 mg kg-1 and morphine 0.20 mg kg-1 were administered intramuscularly as routine premedication. Surgery was performed using high-dose fentanyl anaesthesia (100 micrograms kg-1). The clinical responses followed were heart rate, blood pressure, subjective sedation and antisialogogue effect. The plasma hyoscine levels were determined by radioreceptor assay, and plasma morphine levels by liquid chromatography, both up to 24 h. The maximum levels of plasma hyoscine (6.6 micrograms l-1) and morphine (158 micrograms l-1) and the time they were reached (13.0 and 9.7 min, respectively) were comparable with the values obtained in earlier studies using young healthy subjects. After the start of cardiopulmonary bypass, significant decreases in plasma levels of both hyoscine and morphine were found. The elimination half-life of hyoscine in the plasma was 2.4 h, which is somewhat greater than obtained in earlier studies with young healthy patients under regional anaesthesia. Elimination of plasma morphine (t1/2el = 3.3 h) was not significantly altered by the procedure. The sedative and antisialogogue effects of the drugs appeared quickly and were significant, but no tachycardia or other side effects were observed. In conclusion, the kinetic properties of both hyoscine and morphine are suitable for routine use as premedicants before cardiac surgery.

Clinical role of respiratory virus infection in acute otitis media.

The clinical characteristics of acute otitis media in relation to coexisting respiratory virus infection were studied in a 1-year prospective study of 363 children with acute otitis media. Respiratory viruses were detected using virus isolation and virus antigen detection in nasopharyngeal specimens of 42% of the patients at the time of diagnosis. Rhinovirus (24%) and respiratory syncytial virus (13%) were the two most common viruses detected. Adenovirus, parainfluenza viruses, and coronavirus OC43 were found less frequently. The mean duration of preceding symptoms was 5.9 days before the diagnosis of acute otitis media. Ninety-four percent of the children had symptoms of upper respiratory tract infection. Fever was reported in 55% and earache in 47% of cases. Patients with respiratory syncytial virus infection had fever, cough, and vomiting significantly more often than patients with rhinovirus infection or virus-negative patients. No significant differences were found in the appearance of the tympanic membrane and outcome of illness between virus-negative and virus-positive patients with acute otitis. Most patients respond well to antimicrobial therapy despite the coexisting viral infection. If the symptoms of infection persist, they can be due to the underlying viral infection, and viral diagnostics preferably with rapid methods may be clinically useful in these patients.

Rhinovirus in otitis media with effusion.

We studied rhinovirus in the middle ear fluid of 61 children with subacute or chronic otitis media with effusion. Rhinovirus was recovered from the middle ear fluid of 5 children with subacute otitis media with effusion. The minimum duration of effusion was 32 to 60 days. Additionally, 1 patient had middle ear fluid that was positive for adenovirus. Bacterial pathogens were cultured from the middle ear fluid of 20 of 61 patients. Our finding that rhinovirus can be isolated from middle ear fluid after an asymptomatic period of several weeks suggests its possible role in the development of otitis media with effusion.

[Practical application in oral health of a health education program for students]. / Aplicación práctica en el área de la salud oral de un progrma de educación para la salud en escolares.

Oral health has been studied in a group of 680 students. E.F.H. program has been integred in the contents of the General teaching.

Respiratory virus infection as a cause of prolonged symptoms in acute otitis media.

We studied respiratory viruses in 22 children with acute otitis media who had failed to improve after at least 48 hours of antimicrobial therapy. The mean duration of preenrollment antimicrobial therapy was 4.8 days. For comparison we studied 66 children with newly diagnosed acute otitis media. Respiratory viruses were isolated from middle ear fluid or from the nasopharynx, or both, significantly more often in the patients unresponsive to initial antimicrobial therapy than in the comparison patients (68% vs 41%, p less than 0.05). Viruses were recovered from the middle ear fluid in 32% of the study patients and from 15% of the comparison group. Bacteria were isolated from the middle ear fluid of four (18%) children in the study group; one child had an isolate resistant to initial antimicrobial therapy. All four children with bacteria in the middle ear fluid had evidence of concomitant respiratory virus infection. Our results indicate that respiratory virus infection is often present in patients with acute otitis media unresponsive to initial antimicrobial therapy, and may explain the prolongation of symptoms of infection. Resistant bacteria seem to be a less common cause of failure of the initial treatment.