Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM(197) among infants with sickle cell disease. Pneumococcal Conjugate Vaccine Study Group.

OBJECTIVES: To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM(197) (7-valent conjugate pneumococcal vaccine [7VPnC]) among infants with sickle cell disease (SCD) and a comparison group of infants without SCD (non-SCD). DESIGN: Two cohorts of infants were enrolled and received open-label doses of 7VPnC vaccine; infants enrolled before 2 months of age received 7VPnC vaccine at 2, 4, and 6 months of age followed by 23-valent pneumococcal polysaccharide vaccine (PS-23) at 24 months of age for those infants with SCD (schedule A), and infants enrolled between 2 and 12 months of age received 7VPnC at 12 months of age followed by PS-23 at 24 months of age for infants with SCD (schedule B). Safety data were collected for 3 days after each dose of vaccine. Antibody concentrations were measured to each of the 7VPnC serotypes by enzyme-linked immunosorbent assay before each vaccine dose and 1 month after the last 7VPnC dose and the PS-23 vaccine dose. RESULTS: Forty-five infants (34 SCD and 11 non-SCD) were vaccinated according to schedule A and 16 infants (13 SCD and 3 non-SCD) according to schedule B. The 7VPnC vaccine was highly immunogenic for all serotypes among infants with and without SCD who received 3 doses of vaccine according to schedule A: depending on serotype, 89% to 100% achieved antibody concentrations above.15 microg/mL and 56% to 100% achieved antibody concentrations above 1.0 microg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above.15 microg/mL in 53% to 92% by serotype and above 1.0 microg/mL in 31% to 71% by serotype. A single dose of PS-23 resulted in dramatic increases in the antibody concentrations to all serotypes regardless of 1- or 3-dose priming. There was no difference in the reactogenicity of the 7VPnC vaccine between those with and without SCD. There were no serious reactions to the 7VPnC or PS-23 vaccines, even among those with high antibody concentrations before immunization. CONCLUSIONS: Infants with SCD respond to 7VPnC vaccine with antibody concentrations that are at least as high as infants without SCD. Infants immunized with 7VPnC vaccine at 2, 4, and 6 months of age developed antibody concentrations in the same range as those achieved among infants without SCD enrolled in a large trial that demonstrated vaccine efficacy against invasive disease. Significant rises were seen in antibody concentrations to all 7VPnC serotypes after the PS-23 booster in children receiving schedule A or B.

Infection in major sickle hemoglobinopathies: should management strategies change?

Four children with major sickle hemoglobinopathies developed severe pneumococcal infection. Three had sickle cell hemoglobin C (Hb SC) disease and one had sickle cell anemia (Hb SS). In three instances, there was a fatal outcome. The authors' experience with these cases leads them to question whether any patient with a major sickle hemoglobinopathy should be excluded from receiving prophylactic penicillin or if outpatient management with long-acting cephalosporin treatment in the sickle cell patient with suspected sepsis is appropriate therapy.

Thalassemia screening in Baltimore.

An education and screening program for beta-thalassemia was offered to members of the Greek and Italian communities in the Baltimore area to allow for educated decisions regarding childbearing. Similar programs have been effective in decreasing the incidence of beta-thalassemia major in other countries.

Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia.

In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.

Inflammatory pseudotumor of the retroperitoneum.

A child presenting with the findings of inflammatory disease was found to have a pseudotumor of the retroperitoneum. Following surgical removal, all signs of the systemic inflammatory process resolved. These rare, benign tumors of unknown etiology must not only be differentiated from locally invasive malignant lesions, but may present with findings suggesting a chronic inflammatory disorder.

Intestinal Salmonella carriage in patients with major sickle cell hemoglobinopathies.

The increased incidence of Salmonella osteomyelitis in patients with sickle cell disease has never been entirely explained. Problems such as cholelithiasis, intestinal infarction, and frequent antibiotic use in this population could possibly result in prolonged or chronic intestinal carriage of Salmonella after acute gastroenteritis. If prolonged carriage were a factor in the pathogenesis of osteomyelitis, attempts to eliminate the Salmonella with antibiotics would be indicated. We did a stool culture survey of 71 patients attending our pediatric sickle cell clinic to determine the incidence of asymptomatic Salmonella carriage. At least two rectal swab cultures were obtained from each patient; 69% of patients also mailed in a stool sample for culture. No Salmonella was isolated. It therefore appears unlikely that prolonged intestinal Salmonella carriage is an important mechanism in the development of Salmonella osteomyelitis in patients with major sickle hemoglobinopathies.

Cat-scratch disease simulating malignant lymphoma.

A six-year-old girl with induration, swelling and discoloration of the lower eyelid, a temporal mass, preauricular adenopathy and enlarged parotid gland, underwent biopsy, She was initially diagnosed as having a malignant disorder of histiocytic origin. All lesions resolved without therapy. Further evaluation revealed that the child had oculoglandular cat-scratch disease. Cat-scratch disease should be added to the list of nonmalignant disorders which may simulate a malignant neoplasm in its clinical and histologic appearance. Recognition of this fact is important in order to avoid erroneous diagnosis, unnecessary procedures and hazardous therapy.

67Ga scintigraphy in granulocytic sarcoma.

Several granulocytic sarcomas (chloromas) developed in a patient with acute myelogenous leukemia while in hematologic remission. A positive diagnosis of the symptomatic lesion was made by means of open biopsy examination. The other lesions, which were unsuspected, were detected with a 67Ga-citrate scan. Subsequent 67Ga-citrate scans indicated a favorable response to treatment. The incidence and significance of silent granulocytic sarcomas in patients in hematologic remission is not known. Documentation of such lesions might prove valuable for diagnosing extramedullary relapse or for delivering intensive local therapy.

Elevation of pyrimidine enzyme activities in the RBC of patients with congenital hypoplastic anaemia and their parents.

The activities of orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (ODC) were significantly elevated (P less than 0.001) in erythrocytes (RBC) from five patients with prednisone-responsive congenital hypoplastic anaemia (CHA). (OPRT: patients - 10.1--64.2 nmol/h/10(9) RBC; controls - 2.8 +/- 0.3 (mean +/- SEM, n = 37); ODC: patients = 30--124 nmol/h/10(9) RBC; controls = 10.2 +/- 0.7 (mean SEM, n = 37).) Two patients had a less pronounced, but significant, increase of aspartate transcarbamylase activity and three patients had marginal increases of dihydroorotase activity. Dihydroorotate dehydrogenase activity was not detected in any CHA patient or control. In one patient prior to prednisone therapy, the OPRT and ODT activities were elevated 10-fold and remained elevated 3-fold after 16 months of therapy. An elevated enzyme pattern similar to that of RBC from CHA patients was observed in three parents of three CHA patients, but not in three parents of two other CHA patients. The activities of all five pyrimidine enzymes were normal for one patient with transient erythroblastopenia of childhood. In contrast, the activities of all the pyrimidine biosynthetic enzymes were elevated in blood from patients with a young RBC population: sickle cell anaemia, sickle-beta-thalassaemia, hereditary spherocytosis, and DiGuglielmo syndrome and from the newborn. It is postulated that factors which affect the activities of pyrimidine enzymes in CHA may also result in diminished erythropoiesis.

A fatal myeloproliferative syndrome in a family with thrombocytopenia and platelet dysfunction.

Three siblings with a lifelong history of a bleeding disorder and thrombocytopenia died from a myeloproliferative disease. In 2, the terminal event resembled juvenile chronic myelogenous leukemia, and in the third, the diagnosis was acute monocytic leukemia. A family study revealed that the mother and 5 other siblings had a variety of hematologic abnormalities. These included chronic thrombocytopenia, abnormal platelet function, elevated concentrations of HgbF or serum vitamin B12, and low leukocyte alkaline phosphatase (LAP) scores either singly or in combination. At the time of study, none had evidence of malignancy. Members of this family have a myeloproliferative disorder that has the potential for terminating in nonlymphocytic leukemia, a combination of events which appears not to have been reported previously.

Disseminated intravascular coagulation in childhood acute lymphocytic leukemia with poor prognostic features.

Three children with ALL having poor prognostic features developed clinical and laboratory evidence of disseminated intravascular coagulation (DIC). Two developed a bleeding diathesis associated temporally with a rapid drop in blast cell counts during induction therapy with L-asparaginase, prednisone, and vincristine. One of these children died of massive cerebral hemorrhage. The third patient developed episodes of superficial thrombophlebitis associated with relapses and rising blast cell counts which responded to chemotherapy and treatment with heparin. The unusual association of ALL with DIC and the fact that all 3 patients had multiple poor prognostic signs have led us to monitor carefully the coagulation system and withhold L-asparaginase in patients with massive disease until the white cell count and organomegaly have responded to prednisone and vincristine. The more common association of DIC with non-lymphocytic leukemia and recent reports of the presence of the Ph' chromosome in children with leukemia morphologically resembling ALL suggest that chromosomal evaluation be done in selected leukemic patients.

The effects of four commonly used drugs on platelet function.

A number of commonly used drugs have been reportd to inter

Heterozygous beta thalassaemia of unusual severity.

The proband of each of three families of Northern European or Italian extraction had an unusual form of heterozygous beta-thalassaemia, confirmed by haematological, genetic and peripheral blood globin synthesis studies. The unusual severity of this disorder was indicated by chronic haemolysis leading to splenectomy and cholecystectomy, by numerous nucleated red cells and reticulocytes in the peripheral blood, and by leg ulcers in one family. The diversity of clinical expression in many family members with heterozygous beta-thalassaemia was striking. Bone marrow examination in the probands showed numerous large inclusion bodies of the type usually found only in thalassaemia major. In addition, there was unbalanced globin synthesis in the bone marrow, in contrast to the more balanced synthesis found in asymptomatic beta-thalassaemia trait. The amount of newly synthesized alpha-chain found in the free alpha-chain pool was markedly elevated. The unbalanced globin synthesis and alpha-chain inclusions in the bone marrow cells suggest that the severity of the disorder in these patients may be due to the inability of their red cell precursors to fully compensate for the thalassaemic defect or to remove excess alpha-chains. The diversity of clinical expression suggests the influence of undefined acquired or genetic factors on the expression of beta-thalassaemia in these families.