In honour of Professor Rossi's 80th birthday we review the development of our understanding of the immune and auto-immune nature of the pathogenesis of immune thrombocytopenic purpura (ITP). The immune aspects have been documented by postviral alterations of the cellular and humoral immune system, by new methods of specific auto-antibody detection against platelet glycoproteins and by the therapeutic effect of administering immunoglobulin concentrate from healthy blood donors. The various possible mechanisms of action of immunoglobulin treatment have led to use of this treatment as an alternative for other immune-related disorders. The treatment of severe chronic ITP in children, however, remains unsatisfactory. With a new international clinical and laboratory study of children and adolescents with early chronic ITP we are continuing the investigation of the pathogenesis and treatment of ITP.

The Wiskott-Aldrich syndrome is an X-linked inherited immunodeficiency disorder characterized by thrombocytopenia, recurrent infections and eczema. Its best management option is HLA-identical bone marrow transplantation; when this is not feasible, splenectomy, followed by continuous prophylactic antibiotics, represents the alternative of choice. The present case report relates the excellent outcome of an adult with the Wiskott-Aldrich syndrome who suffered his first major complication of the disease at age 33 years, an intracerebral hemorrhage. Since an uneventfull splenectomy, thrombocytopenia has significantly improved, and he has remained free of infections for a follow-up period of 3 years while being treated with prophylactic antibiotics.

Aim: Development of allergy was studied in relation to nutritional allergen challenge and infectious diseases during the first 16 months of life. Methods: 240 infants were allocated either to breast-milk feeding during first 5 months, followed by a hypoallergenic diet (BM), or hypoallergenic whey formula feeding (Nidina HA, Nestlé: HA). Results: In a high risk group ol infants (positive family history and cord blood IgE > 0.5 kU/L) prevalence of atopic disease was similarly frequent in both nutritional groups (BM 12 %, HA 11 % at age 4 months; 32 %, 39 % at age 16 months resp.). While upper RTI equally frequent occurred in both nutritional groups, the HA group showed a significantly higher prevalence of lower RTI (BM 12 %; HA 36 %; p < 0.05), associated with a more frequent development of respiratory allergy (29 % with lower RTI: 2 % without lower RTI; p < 0.005) Other atopic diseases (skin and gastrointestinal symptoms) occurred in 19 % of infants with lower RTI and 22 % without lower RTI (n.s.). Prevalence of atopic disease was also signilicantly different in relation to gastrointestinal infections (41 % with vs. 25 % without), although gastrointestinal intolerance was similar in both groups (38 % vs. 40 %). Conclusion: While there was a similar allergy prevalence in Nidina HA fed and breast-milk fed infants at risk, a particular group of infants exposed to gastrointestinal or lower RT infections showed a higher allergy prevalence in association with Nidina HA feeding and should therefore favorably be nourished by breast-milk.

PURPOSE:The impact of megakaryocyte growth in vitro on clinical data, especially outcome, was studied in 25 consecutive children with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS:Twenty children with untreated de novo ITP and five children with pretreated ITP were evaluated. The number of megakaryocyte colonies (cloning efficiency), the mean cell number per colony (mitotic amplification) and the percentages of polyploid megakaryocytes after 7 and 12 days in culture (relative size of the endomitotic compartment) were determined in two separate clonal assays. The culture data were related to clinical findings and outcome of the thrombocytopenia. RESULTS:The mean cell number per megakaryocyte colony was significantly correlated with the observed increase in the platelet count 5 days after starting therapy (n = 23; r = 0.642), and a significant negative correlation was found between the relative size of the endomitotic compartment and the duration of thrombocytopenia after bone marrow culture analysis (n = 25; r = -0.503). If all 25 children with ITP (untreated de novo and pretreated ITP) were considered, a normal frequency of polyploid megakaryocytes was associated with a duration of ITP for < 6 months in 14 of 16 cases, whereas an impaired polyploidization predicted a persistence of ITP for > 6 months in 9 of 9 cases (p < 0.0005); if only children with untreated de novo ITP (n = 20) were considered, 13 of 15 children with a normal polyploidization had an acute course of their ITP and 5 of 5 children with an impaired polyploidization developed chronic ITP (p < 0.003). CONCLUSIONS:The results in this small group of patients suggest that the assessment of the relative size of the endomitotic compartment after 7 and 12 days in plasma clot culture actually appears to be the best method for predicting a chronic course in children with ITP.

Forty-two children (22 girls and 20 boys, ranging in age between 2 months and 13 years, median age 17 months) were admitted with acute hemolytic-uremic syndrome to the University Children's Hospital, Berne from 1973 to 1991. Seventeen patients developed hypertension and 30 renal failure. Three out of the 19 case's necessitating acute dialysis progressed to end stage renal failure. Four out of the 7 patients with signs of severe central nervous system involvement died. The initial clinical course was consistently more favourable in 35 patients with diarrheal prodrome. Increased protein excretion in association with high blood pressure was observed in 4 patients with initial favourable course who were examined one year after disease onset. This study indicates the generally favourable immediate prognosis of childhood hemolytic uremic syndrome and the possible persistence of high blood pressure and pathological proteinuria on follow-up.

In 1980, it was observed in a child with idiopathic thrombocytopenic purpura (ITP) that intravenous administration of pooled human immunoglobulin-G (IVIG) was followed by a rapid increase of the platelet count. Prompted by this finding, a pilot study and two prospective multicenter studies on children with ITP were organized. Efficacy of this new treatment for ITP was soon confirmed worldwide. In addition to the immediate effect, long-term observations following administration of IVIG suggested the occurrence of modulation of the immune response. Also, concomitant with studies on the mechanism of action of IVIG, the use of IVIG in the treatment of patients with other immune-related disorders was explored.

Acute megakaryoblastic leukemia (AMkL), defined by the presence of the platelet-associated glycoprotein IIb/IIIa complex on malignant cells, was diagnosed in 4 (4%) of 103 consecutive children with untreated acute leukemia or 4 (21%) of 19 children with acute nonlymphoblastic leukemia (ANLL). Particular features in the four children with AMkL were an age below 12 months at diagnosis (two patients), the absence of a significant hepatosplenomegaly (three patients), a leukocyte count below 20 x 10(9)/L with only a few blast cells in the peripheral blood (four patients), a technically difficult bone marrow aspiration (three patients), the presence of many megakaryocytes in marrow particles (two patients), and an inconclusive cytochemistry (four patients). The four children with AMkL were treated according to protocols for ANLL and a complete remission was obtained in all patients. One patient died from relapse after 3 months, one patient is a long-term survivor (38+ months), and two patients still on chemotherapy are disease-free for 11+ and 13+ months.

In children with acute lymphoblastic leukemia (ALL), megakaryocytopoiesis was investigated in vitro by the semisolid agar culture technique. In untreated ALL the median number of committed megakaryocyte progenitor cells (CFU-Mk) in the bone marrow was 2 (range less than 0.1-8) per 10(5) bone marrow cells instead of 30 (range 14-93) in controls, the impairment being dependent on the degree of leukemic bone marrow infiltration. However, if the number of CFU-Mk was related to residual nonleukemic bone marrow cells only, two-thirds of the children investigated had a frequency of CFU-Mk within the normal range. After 2 weeks of induction therapy the majority of the children had a low number of CFU-Mk in the bone marrow (median 6, range 0.5-40), a fact that could no longer be explained by a dilution of CFU-Mk by leukemic cells. After 4 weeks of chemotherapy (day 29) the frequency of CFU-Mk had risen to 18 (range 3-67) per 10(5) bone marrow cells, a value still significantly (p less than 0.01) below the normal range. In contrast to the changes in the number of CFU-Mk the median cell number per megakaryocyte colony remained constant during induction of remission. After cessation of long-term chemotherapy all children investigated had a normal number of CFU-Mk, suggesting that no permanent chemotherapy-related damage to committed megakaryocyte progenitor cells was induced.

In a prospective multicenter study 42 thrombocytopenic (<30×109 platelets/l) children with chronic idiopathic thrombocytopenic purpura (ITP) or with acute ITP, dependent on or refractory to corticosteroids, were given 0.4 g i.v. IgG/kg body weight/day on 5 consecutive days and thereafter once a week if the platelet count fell to <20×109/l or if the patient bled. After the initial 5 days of i.v. IgG the platelets rose within a mean of 7–8 days to >30×109/l in all and to >150×109/l in 33 of 42 patients (79%). After a mean observation time of 26.6 months 26 of 42 patients (62%) showed a satisfactory long-term effect, i.e. no need for treatment for at least 6 months without bleeding and with no platelet counts below 20×109/l. No difference in response rate was found between children with chronic and those with previously treated acute ITP. These results indicate that i.v. IgG could be used to control emergency situations, e.g. to stop bleeding or to prepare a patient for surgery. I.v. IgG also represents a good alternative to treatment modalities, such as splenectomy and/or the administration of cytostatic immunosuppressants with potentially serious side effects. In addition to the expected transient rise in serum IgG levels, i.v. IgG induced a more prolonged elevation of serum IgM. Platelet associated IgG, elevated before therapy, was correlated with the clinical long-term outcome.

Clinical and laboratory findings in 9 patients with transient erythroblastopenia of childhood (TEC) are presented and compared with the literature. TEC mainly affects infants presenting with normochromic, normocytic anemia and reticulocytopenia. Liver, spleen and lymph nodes are not enlarged. As a rule the white blood cell count is normal and the platelet count elevated. Bone marrow examination reveals absence of erythropoiesis. TEC is a self-limiting disorder which needs no therapeutic measures other than transfusion where necessary.

Clinical and laboratory findings in 9 patients with transient erythroblastopenia of childhood (TEC) are presented and compared with the literature. TEC mainly affects infants presenting with normochromic, normocytic anemia and reticulocytopenia. Liver, spleen and lymph nodes are not enlarged. As a rule the white blood cell count is normal and the platelet count elevated. Bone marrow examination reveals absence of erythropoiesis. TEC is a self-limiting disorder which needs no therapeutic measures other than transfusion where necessary.

Seven immunosuppressed children with varicella and two with herpes zoster were treated with large intravenous doses of polyvalent, intact immunoglobulin (IgG i.v.). In all patients the treatment was effective for controlling fever and skin lesions and for preventing progression and complications, even if this therapy was started late and/or if the patient was severely lymphopenic . More IgG was needed to control disseminated than less advanced varicella. No untoward effects of IgG therapy were observed. The preliminary results suggest that in future trials i.v. IgG should be used for comparison with antiviral agents.

In a prospective, nonrandomized trial clinical (initial WBC and chest film) and immunological (surface immunoglobulin and rosetting with pretreated sheep red blood cells) criteria were used to stratify 69 children with previously untreated acute lymphoid leukemia (ALL). Forty of 61 evaluable patients had low-risk ALL (initial WBC less than or equal to 20,000/mm3, no mediastinal mass) and were treated less intensively. Twenty-one of 61 patients had high-risk ALL (initial WBC greater than 20,000/mm3 and/or mediastinal mass) and were treated more intensively. Of the high-risk patients 15 had non-T non-B and 6 T ALL. Sixty of 61 patients went into complete remission. After a median observation period of 27 months, 32 of 40 low-risk, 7 of 14 high-risk non-T non-B, and none of 6 high-risk T ALL patients were in continuous first remission. Thirty-six of 40 low-risk, 9 of 15 high-risk non-T non-B, and none of 6 T ALL patients were alive. Despite more intensive treatment, the duration of remission and the survival were significantly shorter in the high-risk than in the low-risk patients. Among the high-risk ALL, non-T non-B ALL did better than T ALL.

Frequent transfusions improve the general well being in patients with beta-thalassemia major but carry the risk of iron intoxication including the development of diabetes mellitus. Of 22 patients with beta-thalassemia major (age 3-17 years) only 3 had a normal oral glucose tolerance. The remainder had either borderline or moderately pathological glucose curves. The mean glucose concentration was increased, and the mean insulin concentration and insulin/glucose ratio were diminished. In contrast to the oral test, the i.v. glucose tolerance test gave pathological results in only 2 of 16 patients tested. The i.v. glucose test thus may be less selective than the oral test. The mean insulin concentration was lower also after intravenous glucose, but the early insulin peak was preserved. Arginine infusion led to a normal insulin and growth hormone release. This moderate impairment of insulin release found in most of the patients leaves the hope that an efficient chelating therapy scheme might reverse beta-cell dysfunction.