Frances M. Gill

Bacteremia in sickle hemoglobinopathies

We analyzed 178 episodes of bacteremia that occurred during 13,771 patient-years of follow-up of 3451 patients with sickle hemoglobinopathies. Age-specific incidence rates of bacteremia were calculated for patients with sickle cell anemia (SS) and sickle cell-hemoglobin C (SC) disease. The incidence rate was highest among children with SS and SC younger than age 2 years. Children with SC showed an abrupt decrease after age 2 years, whereas children with SS had a gradual decline in rate from 2 to 6 years of age. The predominant pathogen in patients younger than 6 years was Streptococcus pneumoniae (66%); gram-negative organisms were responsible for 50% of bacteremias in patients 6 years and older. Urinary tract infection was present during 73% of Escherichia coli bacteremias, and 77% of Salmonella bacteremias were associated with osteomyelitis. In contrast, no focus of infection was present in 52% of pneumococcal bacteremias. The incidence of pneumococcal bacteremia in children with SS younger than age 3 years was 6.1 events/100 patient-years; the case fatality rate for pneumococcal sepsis in this age group was 24%. No hematologic or demographic variables were associated with occurrence of pneumococcal bacteremia in young children. Retrospective analysis of pneumococcal bacteremia suggests that the prophylactic use of penicillin may decrease the incidence in children younger than 3 years of age.

Acute chest syndrome in sickle cell disease: Etiology and clinical correlates

Acute chest syndrome (ACS) is a new pulmonic process in a clinically ill patient with sickle cell disease. We prospectively analyzed 102 episodes of ACS in patients in our hospital during a 2-year period to study cause and clinical correlates. In 12% of the episodes, ACS was judged to be secondary to bacterial pneumonia (including only 3% secondary to Streptococcus pneumoniae), 8% was associated with uncomplicated viral pneumonias, and 16% with mycoplasmal pneumonias. The clinical course and seasonal variations in these groups were compared with those in the remaining 64% of episodes. In comparison with episodes of ACS of undetermined origin (presumably secondary to pulmonary infarct, atelectasis, or missed infections), patients with bacterial pneumonia were sicker, as shown by fever and hospitalization of longer duration, the percent of those requiring red blood cell transfusion, and the presence of pleural effusions. The lower incidence of bacterial pneumonias among our patients compared with that previously reported may reflect our use of penicillin prophylaxis and pneumococcal immunization to prevent S. pneumoniae infections.

Indigent children who are denied care in the emergency department

We conducted a six-month prospective study of the diagnoses and outcomes of 588 children who were denied care in our emergency department under a new primary-care case management health system for 100,000 indigent patients. The mean patient age was 4.7 years (39% were less than 2 years old). The most common presenting complaints were colds, earaches, rash, vomiting, and diarrhea. Nine percent of children presented for trauma, and 10% had fever of more than 38.2 C. Follow-up was available from the primary care physician for 388 children (66%). Of the 60% of patients who kept their arranged appointment, 42% received antibiotics, 3% were referred for further evaluation, and two children were hospitalized. Follow-up was available from the parents for 125 children (21%). No follow-up information of any kind was available for 111 children (19%), and no follow-up regarding the health of the child was available for 265 children (45%). This last group included 10% with a chief complaint of trauma and 6% with temperature of more than 39 C. Forty-nine percent of patients in this group were less than 2 years old.

α-Thalassemia in Negro Infants

Extract: A total of 104 of 693 Negro infants (15.0%) had moderate or small amounts of hemoglobin Barts visible on starch gel electrophoresis. Moderate amounts were found in 21 infants (3.0%) and small amounts in 83 infants (12.0%). In 17 Negro infants judged to have moderate amounts of Hb Barts, the quantitation showed 2.0–9.3% with a mean of 5.4 ± 2.1 (1 SD). A significant decrease in mean cell volume and mean cell hemoglobin was found in the Negro neonate with more than 2% Hb Barts studied at 4 days of age. In 10 Negro infants with more than 2.0% Hb Barts studied at 4 days of age, the α α/(β + γ) ratio was 0.97 ± 0.06 (1 SD) (range 0.88–1.06). In nine infants aged 5—24 months who had more than 2.0% Hb Barts in the newborn period, including six infants studied in the first group, the mean α/β ratio was 0.74 ± 0.06, (range 0.65–0.83). Each of the nine infants with more than 2.0% Hb Barts at birth had marked microcytosis and hypochromia at 5—24 months despite adequate iron therapy. Two newborn infants with moderate levels of Hb Barts at birth (8.2% and 6.8%) and balanced total globin synthesis had no free radioactive α chain by gel filtration studies. Our studies indicate clearly that the presence of more than 2% Hb Barts in the newborn period denotes the presence of α-thalassemia trait.Speculation: In a group of Negro newborn infants, 3% had more than 2% Hb Barts. These infants had the genetic disorder, α-thalassemia trait. An additional 12% of the infants had elevated levels of Hb Barts between 1% and 2%. This group may also have an α-thalassemia disorder, as has been shown in other racial groups. The absence of hydrops fetalis due to α-thalassemia in Negro neonates suggests that the molecular defect of α-thalassemia detected in Negro neonates differs from that seen in Orientals in that it is not associated with a complete absence of α-chain synthesis.

Hemoglobin Lepore Trait: Globin Synthesis in Bone Marrow and Peripheral Blood

There was decreased synthesis of the β-globin chain in the peripheral blood, and equal synthesis of α- and non-α-chains in the bone marrow of three patients with hemoglobin Lepore trait, similar to the findings in patients with heterozygous β-thalassemia. There is a relative instability of the synthetic mechanism for normal β-chain in these patients.

Computerized tomography in the management of intracranial bleeding in hemophilia

Computerized tomography was used to evaluate the severity of six episodes of suspected intracranial bleeding in four patients with hemophilia. In all instances the CT scan rapidly provided information on the extent and location of the intracranial hemorrhage. Results of the initial scan provided a rational basis for therapy, and subsequent scans were a noninvasive means of evaluating the effects of treatment. If available, computerized tomography is a valuable aid in the management of the hemophiliac patient with intracranial bleeding.

Synthesis of Globin Chains in Sickle β-Thalassemia

In five patients with sickle beta-thalassemia there was balanced alpha- and beta-globin synthesis in the bone marrow and decreased total beta-chain synthesis relative to that of alpha-chain in the peripheral blood. These findings are similar to those in patients with simple beta-thalassemia trait. Despite a range of hemoglobin concentrations from 6.8 to 12.5 g/100 ml in the patients with sickle thalassemia, there was no evidence of a significant excess of alpha-chains in the red cells of the bone marrow which could contribute to the hemolysis and anemia. In patients heterozygous for beta-thalassemia the capacity to synthesize beta-chain decreases more rapidly than that for alpha-chain. In nonthalassemic subjects the rates of beta- and alpha-chain synthesis decrease equally as the red cell matures. The beta(S)- and beta(A)-chains serve as convenient markers for globin synthesis due to the nonthalassemic and thalassemic alleles in patients with sickle beta-thalassemia. The unbalanced globin synthesis in the peripheral blood of these patients is explained by the decrease in relative synthesis of beta(S)-chain, in comparison with that of alpha-chain. This instability is not present in sickle cell trait. The beta(A)-chain synthesis was only unstable in the two patients who had the most marked anemia. The major mechanism for achieving balanced globin production in the bone marrow in the presence of one thalassemic gene appears to be increased synthesis of beta-chain due to the nonthalassemic allele. In addition, there may be a decrease of total alpha-chain synthesis in some patients.

Free α-Globin Pool in Human Bone Marrow

: A pool of free alpha-globin chains was found in the bone marrow samples from three controls, two patients with beta-thalassemia trait, three with sickle beta-thalassemia, three with hemoglobin (Hb) Lepore trait, one with alphabeta-thalassemia, four with homozygous beta-thalassemia, and one doubly heterozygous for Hb Lepore and beta-thalassemia. The average percentage of newly synthesized alpha-chains found in the free alpha-globin pool was 6.2% in the controls and 33.0% in the patients heterozygous for thalassemia or Hb Lepore. These controls and patients had balanced beta- and alpha-globin synthesis in the bone marrow. In the homozygous patients and in the one patient doubly heterozygous for thalassemia and Hb Lepore, there was a marked deficit of beta-chain synthesis in the bone marrow and also a large pool of newly synthesized free alpha-chains. The function of this pool of free alpha-chains is not known, but it may be involved in the regulation of globin chain synthesis in normal patients and in the compensatory synthesis of beta-chains that occurs in the bone marrow of patients heterozygous for thalassemia or for Hb Lepore.

Normal fluidity of red cell membranes in hereditary spherocytosis.

The molecular defect responsible for the red cell abnormality in hereditary spherocytosis (HS) remains elusive. A number of workers have qucstiond whether the defect in HS results from an abnormality of either lipid composition or lipid organization in the membrane. However, direct measurements of the cholesterol/phospholipid mole ratio of HS membranes have been normal (Cooper 8( Jandl, 1969a). Although early measurements suggested that phospholipid composition was abnormal a number of laboratories have established that phospholipid composition is normal in HS (e.g. Reed & Swisher, 1966). Similarly, a suggestion that fatty acid composition is abnormal (Kuiper 8( Livne, 1972) has not been confirmed (Zail & Pickering, 1979). Three findings which appear to be established arc that HS red cells have less lipid per cell than normal both before and after splenectomy (Reed & Swisher, 1966; Cooper & Jandl, I%%), that they have less surface area per unit lipid (Cooper & Jandl, 1969a), and that lipid is lost from HS cell membranes a t a rate more rapid than normal under conditions of metabolic deprivation (Reed & Swisher, 1966; Cooper & Jandl, 1969b). Fluidity is a characteristic Lvhich reflects the organization of lipid in cell membranes (Cooper, 1977). It is influenced by factors such as the length and saturation of membrane fatty acids, the composition of phospholipids, the presence of lysophosphatides, and the relative amounts of cholesterol and phospholipid. Membrane proteins may also influence the fluidity of lipids in membranes. Aloni et a1 (1975) have reported that membrane fluidity is decreased in HS. Because studies in a number of laboratories have established that HS membrane lipid composition is normal, we undertook to reinvestigate the question of membrane fluidity in HS. This report represents a pooling of data obtained in two separate laboratories on two continents utilizing red cells from 13 patients with HS. It includes both children and adults, and it includes patients with and without spleens. Ghost membranes were prepared from freshly obtained red cells by the method of Ilodge et a1 (1963). The fluorescent probe, 1 ,&diphenyl1,3,5-hexatriene (IDPH) (Aldridge Chemical Company, Milwaukee, WI), was used to label ghosts. DPH was kept as a stock solution in tetrahydrofuran at a concentration of 2 x lop3 M. Immediately prior to use, it was diluted 132000 in 0.155 M NaCl with vigorous mixing. One volume of dilute DPH dispersion was added to one volume of red cell ghosts suspended in 0.155 M NaCl at a ghost concentration of 1 x 10X/ml and the mixture was incubated a t 37°C for 30 min. Measurements of fluorescence polarization in Philadelphia were performed at 37°C with an Elscint MV-1 microviscosimeter (Elscint Corporation, Hackensack, NJ), as described previously (Cooper et a l , 1978). Measurements of fluorescence polarization in Melbourne were performed at 25°C with a Hitachi-Perkin-Elmer MPM spectrofluorometer equipped with a thermostated cell block and polarization accessory (Thulborn &

Anemia in Early Infancy

Special circumstances unique to the newborn infant may increase the risk of anemia from blood loss, hemolysis, or decreased production of red cells. A summary of the normal state of erythropoiesis in this period precedes a discussion of the most common phenomena associated with early anemia.