Ruth E. Luddy

Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM197 Among Infants With Sickle Cell Disease

Objectives. To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM197 (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 μg/mL and 56% to 100% achieved antibody concentrations above 1.0 μg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above .15 μg/mL in 53% to 92% by serotype and above 1.0 μg/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.

Paraplegia following intrathecal methotrexate

A child with lymphosarcoma and acute leukemia developed permanent flaccid paralysis and sensory loss below the sixth thoracic cord level following an injection of intrathecal methotrexate. She did not have leukemic meningitis and had not recently received neurotoxic drugs. Eleven other cases of paraplegia following intrathecal methotrexate have been reported. These patients either had concomitant leukemic meningitis or metastatic tumor, or had received intrathecal methotrexate or other neurotoxic agents previously. The etiology of neurotoxicity after intrathecal methotrexate is unknown but may be related to high drug concentration in stagnant cerebrospinal fluid. Neurotoxicity has been reported after injections of other agents into the cerebrospinal fluid. The occurrence of significant neurotoxicity following intrathecal injections emphasizes the need for extreme caution with the instillation of any intrathecal medication and for search for less toxic forms of central nervous system therapy.

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

Summary. 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‐α 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‐α 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‐α produced a profound increase in JCML colonies when tested individually and anti‐GM‐CSF Ab reversed the TNF‐α effect. Expression studies of TNF‐α and TNF‐α receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF‐α 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‐α values. Recombinant interleukin‐1 alpha (IL‐1α) 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‐α or GM‐CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF‐α and that the endogenously‐produced TNF‐α and GM‐CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL‐1α also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM‐CSF, TNF‐α or both.

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.

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.

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 β‐thalassaemia, confirmed by haem‐atological, 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 β‐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 β‐thalassaemia trait. The amount of newly synthesized α‐chain found in the free δ‐chain pool was markedly elevated. The unbalanced globin synthesis and δ‐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 δ‐chains. The diversity of clinical expression suggests the influence of undefined acquired or genetic factors on the expression of β‐thalassaemia in these families.

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

Summary. The activities of orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (ODC) were significantly elevated (P<0.001) in erythrocytes (RBC) from five patients with prednisone‐responsive congenital hypoplastic anaemia (CHA). (OPRT: patients=10.1–64.2 nmol/h/109 RBC; controls=2.8·0.3 (mean×SEM, n=37); ODC: patients=30–124 nmol/h/109 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‐β‐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.

IMMUNOGENICITY OF A PNEUMOCOCCAL PROTEIN CONJUGATE VACCINE IN INFANTS WITH SICKLE CELL DISEASE. ▴ 946

Pneumococcal infections are an important cause of morbidity/mortality in children with sickle cell disease (SCD). Pneumococcal conjugate vaccines linked to protein carriers are immunogenic in healthy infants < 2 yrs of age, but have not been evaluated in children with SCD. Infants with SCD were immunized with a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (CRM; cross-reacting diphtheria mutant) at 2, 4, and 6 mos. Type specific antibodies were measured by ELISA after pre-absorption with C-polysaccharide. No side effects have been observed. This vaccine appears to be safe and immunogenic, and should provide protection against pneumococcal infections in infants with SCD. (Funded in part by Lederle-Praxis Biologicals.) Table

The effects of four commonly used drugs on platelet function

A number of commonly used drugs have been reportd to inter