Steen Rosthøj

Childhood idiopathic thrombocytopenic purpura in the Nordic countries: Epidemiology and predictors of chronic disease

Aim: To describe the epidemiology of idiopathic thrombocytopenic purpura (ITP) in the Nordic countries, to define clinical subgroups and to investigate factors predicting chronic disease. Methods: A prospective registration was done from 1998 to 2000, including all children with newly diagnosed ITP aged 0–14 y and at least one platelet count <30×109/l. Results: 506 children were registered and 423 followed for 6 mo. The incidence was 4.8/105 per year. Most children were aged 0–7 y (78%), with a predominance of boys, while patients aged 8–14 y had equal representation of the two sexes. There were seasonal variations determined by variations in postinfectious cases with sudden onset. The platelet count was <10×109/l in 58%, but bleeding manifestations were mild or moderate in 97%. The insidious form (symptoms for more than 2 wk) was more frequent in older children and girls, showed little seasonal variation, had milder manifestations and ran a chronic course in more than half the cases. Intracranial haemorrhages did not occur in the first 6 mo after diagnosis. Chronic ITP developed in 25%. The strongest predictor of chronic disease was insidious onset of symptoms (OR 5.97).

Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: a prospective nordic study of an unselected cohort☆

OBJECTIVE To determine the duration of the risk period with platelet counts <20 x 10(9)/L and the frequency of bleeding episodes in unselected children with idiopathic thrombocytopenic purpura (ITP). STUDY DESIGN We established a registry for patients with newly diagnosed ITP in the five Nordic countries, enrolling children aged 0 to 14 years with platelet counts <30 x 10(9)/L. Treatment centers prospectively reported presenting features, management details, and disease-related events during the first six months after diagnosis. RESULTS At presentation (n=501), more than half of the children had a platelet count <10 x 10(9)/L, but only 15 (3.0%) had a hemorrhage requiring blood transfusion. During follow-up of 409 patients, thrombocytopenia resolved uneventfully in 277. A risk period was present in 376 cases. Among 283 with self-limiting ITP, 26 were at risk >1 month and 25 had 30 events. Among 93 patients with chronic ITP, 73 were at risk >1 month and 44 had 111 events. Events occurred with an average frequency of 0.39 per month at risk. Life-threatening hemorrhages did not occur in the first six months after diagnosis. CONCLUSION Most children with ITP are at risk for serious bleeding for less than one month. Continuing severe thrombocytopenia is associated with little morbidity, bleeding episodes being infrequent and very rarely serious.

Different NK cell–activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity

The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation.

Role of parvovirus B19 infection in childhood idiopathic thrombocytopenic purpura

Heegaard ED, Rosthøj S, Petersen BL, Nielsen S, Karup Pedersen F, Hornsleth A. Role of parvovirus B19 infection in childhood idiopathic thrombocytopenic purpura. Acta Pædiatr 1999; 88: 614‐7. Stockholm. ISSN 0803‐5253

A clinical score predicting a brief and uneventful course of newly diagnosed idiopathic trombocytopenic purpura in children

The Nordic idiopathic thrombocytopenic purpura study data showed that morbidity occurred mainly in children with thrombocytopenia lasting >3 months, whereas, the risk period with platelet counts <20 × 109/l was short and the number of bleeding events low in children with shorter disease duration. These brief, uneventful courses were predicted by developing a scoring system based on six clinical features: abrupt onset (weight 5), age <10 years (3), preceding infection (2), platelet count <5 × 109/l, wet purpura (1) and male gender (1). The score was derived and validated in two different cohorts of children. High scores (10–14) clearly identified low‐risk patients. The score provides valid prognostic information and may be useful in clinical decision‐making.

Duration and morbidity of chronic immune thrombocytopenic purpura in children: Five-year follow-up of a Nordic cohort

Aim:  To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP).

A population-based observational study of dental caries among survivors of childhood cancer

The few published studies on caries among childhood cancer survivors are small and their results are conflicting. The study aim was to examine the risk of dental caries among children who have survived cancer.

Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity

Aim: To explore whether early treatment of children with idiopathic thrombocytopenic purpura (ITP) with immunoglobulin and/or corticosteroids reduces subsequent morbidity. Methods: Centres participating in a Nordic ITP study were divided according to whether they had treated more than 2/3, from 1/3 to 2/3, or less than 1/3 children within 14 days of diagnosis. The course of disease from 15 days to 6 months after diagnosis was compared for children managed at the three centre categories. The comparison was restricted to children in whom at least one platelet count <20×109/l was measured, numbering 156, 143 and 84 in the three different categories, respectively. Results: The three groups of children were clinically similar but were managed with initial treatment rates of 89%, 57% and 14%, respectively. By day 15, the platelet count had stabilised to >20×109/l in 67%, 67% and 52% (p<0.05) and to >150×109/l in 38%, 29% and 29% (p<0.20). At 1 month after diagnosis there was no difference in recovery rates. Chronic ITP developed in 27%, 22% and 25% in the three groups. During follow-up, one or more disease-related events occurred in 23%, 22% and 19%, with no difference in the average numbers of episodes with mucosal bleeding. Treatment courses were administered to 19%, 13% and 11%, respectively. Conclusion: Active treatment policies accelerated platelet recovery in children with short-lasting ITP but did not avert the development of chronic ITP and did not cause a reduction in morbidity during follow-up.

Capnocytophaga (Capnocytophaga ochracea group) bacteremia in hematological patients with profound granulocytopenia.

The clinical and microbiological features of 7 cases of bacteremia due to Capnocytophaga (Capnocytophaga ochracea group) are reported. They were diagnosed during 1991-93 at three hospital clinics. Five patients were < 10 years old and all had hematological disorders, 4 acute lymphoblastic leukemia and 1 each had aplastic anemia, non-Hodgkin lymphoma, and myelodysplastic syndrome. All were profoundly granulocytopenic with an absolute granulocyte count < 0.13 x 10(9)/l, and all but 1 had oral lesions as a possible portal of entry. A favourable response to antibiotic therapy was recorded in all patients but one who, being profoundly granulocytopenic, rapidly succumbed to Pseudomonas aeruginosa septicemia. None of the isolates were beta-lactamase producers. In addition to penicillin the isolates were susceptible to broad-spectrum cephalosporins and ciprofloxacin, but resistant to aminoglycosides.

Arthritis as presenting manifestation of acute lymphoblastic leukaemia in children

Background At disease onset, children with acute lymphoblastic leukaemia (ALL) may present with arthralgia or even signs of arthritis. This might cause misdiagnosis and thereby lead to prolonged diagnostic delay. The present study aimed to identify children with ALL with joint involvement and to compare their characteristics and outcome with children with ALL without joint involvement. Methods Case records of 286 children diagnosed with ALL between 1992 and 2013 were reviewed and analysed in this retrospective, descriptive study. Results Fifty-three (18.5%) children with ALL presented with localised joint pain, and half of them had objective signs of arthritis. The mean number of joints involved was 2.5, most frequently presenting as asymmetric oligoarthritis. The suspected misdiagnosis were reactive arthritis (19/53), osteomyelitis (9/53) and juvenile idiopathic arthritis (8/53). Children with joint involvement had less objective signs of haematological disease. Cytopenia was absent in 24% in children with joint involvement (vs 8% without, p=0.001), 50% had only one cell line affected (vs 21%, p=0.0005) and 44% had no organomegaly (vs 29%, p=0.05). Median diagnostic delay was 4 vs 2 weeks. The 5-year event-free and overall survival was superior for children with joint involvement: 94% vs 87% (p=0.049), and 96% vs 83% (p=0.044). Conclusions ALL with joint involvement is a frequent finding (18.5%). The clinical signs of leukaemia are less prominent, but non-articular pain should alert the clinician of a possible diagnosis of leukaemia. The overall and event-free survivals were superior compared with the children without joint involvement.