Studies on the mechanism of penicillin-induced fever.

Rabbits immunized to benzylpenicillin G responded with fever when challenged with a penicillin-serum protein conjugate, but not with penicillin itself. After one or two challenges with conjugate, the rabbits became unresponsive (tolerant) to further injections. This form of hypersensitivity was transferable with plasma of immunized donors to normal rabbits. Blood leukocytes of immunized rabbits incubated with penicillin-protein conjugate and hypersensitive serum released endogenous pyrogen in vitro. Spleen cells from the same animals, on the other hand, were inactive when incubated with this antigen in vitro. These experiments appear to be the first to demonstrate in vitro a possible mechanism of drug-induced fever.

Experimental bacterial keratitis: a quantitative model of leukocyte migration following transfusion.

A model for the study of polymorphonuclear leukocyte (PMN) migration after transfusion employing induction of keratitis in guinea pigs was developed. Initial studies demonstrated that compared with other agents, intracorneal injection of Pseudomonas aeruginosa following in vivo labelling of PMN by administration of 3H-thymidine produced the greatest influx of radiolabelled PMN into corneas. In subsequent studies, donor peritoneal PMN were radio-labelled by injection of donors with 3H-thymidine. Neutropenia was induced in recipients by whole body irradiation, and they were infected intracorneally with Pseudomonas prior to transfusion. Corneal radioactivity was assayed 24 h after induction of keratitis and the number of donor PMN in corneas was calculated. Half-life of transfused PMN in non-neutropenic recipients was 1.9 h. Arrival of labelled PMN at infected corneas in recipient animals ranged between 0.1-1.0% of transfused cells. Exposure of donor PMN to sonication or to 45 degrees C for 20 min reduced the proportion of PMN arriving at infected corneas (P less than 0.001). Storage of PMN for 24 h at 4 degrees C led to a greater ingress of donor PMN compared with storage at 37 degrees C (P less than 0.01). This model allows quantitation of in vivo PMN function after transfusion and should allow assessment of the effects of most aspects of PMN transfusion technique upon such function.

The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature.

Several closely related disease entities make up the idiopathic hypereosinophilic syndrome (HES). The syndrome is manifest by persistent and prolonged eosinophilia with organ damage. A group of 14 patients had hematologic, cardiac, and neurologic abnormalities attributable to this disease. Patient survival and response to chemotherapy was significantly better in this group than in previously reported patients. The etiology of HES remains unknown, as does the mechanism of tissue damage.

Eosinophilic leukemia. Remission with vincristine and hydroxyurea.

A 40 year old man with eosinophilic leukemia was treated with a variety of chemotherapeutic agents. A long-term remission, unusual for eosinophilic leukemia, was maintained with chronic hydroxyurea therapy after induction with vincristine. Hydroxyurea and vincristine may offer an effective mode of therapy for this disease.

Cyclic neutropenia in identical twins.

Cyclic neutropenia developed in identical twin girls. The onset of neutropenia in these children occurred three years apart. Neutrophil cycling diminished, and symptoms decreased in the initially affected twin during a five-year follow-up. Some cases of cyclic neutropenia may be genetically determined; however, the onset and clinical manifestations may be modified by other internal and external factors. There may also be a prodromal period during which neutrophils cycle, but the patient is neither neutropenic nor symptomatic.

Correction of infantile agranulocytosis (Kostmann's syndrome) by allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation has been unsuccessful as therapy for genetically determined bone marrow disorders. In patients prepared for transplantation with drugs alone long-term hematopoietic engraftment is not achieved due to the overgrowth of the infused donor bone marrow cells by residual recipient hematopoietic stem cells. Utilizing a combination of total body irradiation and antihuman thymocyte serum, the successful eradication of the abnormal hematopoietic stem cells of patients with the Wiskott-Aldrich syndrome and now infantile agranulocytosis has been achieved. Following preparation with total body irradiation and antihuman thymocyte serum a 20 month old patient with infantile agranulocytosis has complete donor hematopoietic and lymphoid engraftment one year after a histocompatible allogeneic bone marrow transplant. Prior to transplantation, this patient had no circulating or bone marrow granulocytes; following transplantation he has normal numbers of circulating granulocytes with normal in vivo and in vitro function. This therapeutic result demonstrates that genetic disorders of myeloid function can be corrected by allogeneic bone marrow transplantation following preparation with total body irradiation and antihuman thymocyte serum, and suggests that infantile agranulocytosis is due to an intrinsic defect of the pluripotent hematopoietic stem cell and not to a micro-environmental defect.

Selective immunoglobulin M (IgM) deficiency in two immunodeficient adults with recurrent staphylococcal pyoderma.

Two adult men with recurrent pyoderma due to Staphylococcus aureus and a selective deficiency of immunoglobulin M (IgM) antibody synthesis are described. An analysis of each patient's polymorphonuclear leukocyte chemotaxis, phagocytosis and killing of Staph. aureus, serum opsonizaiton of Staph. aureus, and serum and lymphocyte-mediated responses to antigenic stimulation was performed. Family studies revealed a possible autosomal dominant inheritance pattern with heterogenetic expression of various dysgammaglobulinemic states in each patient's first degree relatives. In vivo studies of delayed hypersensitivity and in vitro studies of polymorphonuclear leukocyte and lymphocyte function were normal. A defect in IgM, but not in IgG (immunoglobulin G), antibody synthesis to a number of antigens, and a mild decrease in serum opsonic activity to Staph. aureus correctable by heat inactivated normal human serum were found in each patient. In these patients, the recurrent staphulococcal pyoderma prompted an investigation of host defense mechanisms and revealed low to absent IgM levels and a defect in IgM antibody synthesis.

Pyogenic hepatic abscess in infancy and childhood.

Five cases of childhood pyogenic hepatic abscess at Milwaukee Children's Hospital and 61 cases in the literature were reviewed. Hepatic abscess occurred most often in infants who had sepsis or umbilical infection. Cases in older children were associated with underlying host defense defects, particularly chronic granulomatous disease (CGD) and leukemia. Common clinical findings were fever, abdominal pain and hepatomegaly. Radionuclide scan was useful in diagnosis of lesions larger than 2 cm. Small or microscopic lesions were diagnosed at autopsy. Staphylococcus aureus was the most common etiologic agent. Mortality in all evaluable cases was 27% in patients with CGD and 42% in those without CGD. Open drainage and appropriate antibiotic therapy is the treatment of choice and should lower the mortality of this infection.

Survival of transfused normal granulocytes in a patient with chronic granulomatous disease.

A 5-year-old boy with chronic granulomatous disease (CGD) received four granulocyte transfusions from unrelated HLA-matched donors as part of therapy for a hepatic abscess. Survival studies of transfused granulocytes using the endotoxin-stimulated nitroblue tetrazolium (NBT) test on two occasions demonstrated 19.6% and 16.8% transfusion efficiency and a biphasic granulocyte disappearance curve. These curves were similar whether or not the patient had serum leukoagglutinins directed against donor granulocytes. Transfused granulocytes were present 24 hours after transfusion. Parallel studies demonstrated normal stimulated NBT activity of donor PMNs after overnight storage at 4 C. Kinetic studies of transfused granulocytes in the non-neutropenic recipient with CGD may be performed without radioactive labeling of granulocytes because of the distinctive metabolic abnormality of their cells compared with normal donor granulocytes.

An outbreak of Pneumocystis carinii pneumonia at a pediatric hospital.

Eleven cases of Pneumocystis carinii pneumonia were diagnosed during a 3 1/2-year period at a pediatric hospital where this infection had never been identified previously despite appropriate studies. The incidence of infection was 3.0, 7.4, and 4.2 cases per 1,000 patient months in children being treated for acute leukemia, neuroblastoma, and rhabdomyosarcoma, respectively. The outbreak coincided with increased intensity of chemotherapy for these malignancies. Ten of the patients had received four or more chemotherapeutic agents within three months of the onset of infection. Because no exogenous source of the epidemic was found, latent endogenous infection activated by immunosuppression was presumed to be the ultimate cause of the outbreak. Increased intensity of chemotherapy may result in P carinii outbreaks and may be an indication for anti-Pneumocystis prophylaxis with trimethoprim/sulfamethoxazole in patients at risk.

Fatal rhabdomyolysis following influenza infection in a girl with familial carnitine palmityl transferase deficiency.

Severe rhabdomyolysis following an influenza B infection developed in a previously well 13-year-old girl. There was no history of trauma. Her course was complicated by episodes of severe hyperkalemia, hypocalcemia, hyperphosphatemia, and myoglobinuria. Renal failure, hypertension, and life-threatening arrhythmias developed; she died. Muscle biopsy revealed that this girl had carnitine palmityl transferase deficiency. An asymptomatic sister was demonstrated to have the same disorder. Although carnitine palmityl transferase deficiency is usually associated with mild bouts of rhabdomyolysis that become apparent only in adulthood, severe forms of this disorder may be seen in children. Life-threatening rhabdomyolysis and myoglobinuria may follow any infection associated with decreased intake. If carnitine palmityl transferase deficiency is diagnosed in a proband, other siblings should be evaluated so that proper preventative measures can be undertaken to help prevent the development of symptoms in susceptible individuals who have not been recognized to have the disease.

Defective polymorphonuclear leukocyte chemotaxis and bactericidal capacity in a boy with recurrent pyogenic infections.

A 13-year-old boy with a history of recurrent pyogenic infections had abnormalities of polymorphonuclear leukocyte (PMN) function which probably accounted for his susceptibility to infection. PMN phagocytosis and nitroblue tetrazolium dye reduction were normal but glucose 14C oxidation was abnormally increased in resting cells. The patient's PMNs possessed decreased bactericidal activity against Staphylococcus aureus and Escherichia coli. Also documented were decreased PMN chemotactic activity and leukocyte accumulation in Rebuck skin windows. PMN random motility, PMN bone marrow reserve, PMN kinetics, lymphocyte blastogenesis, and delayed cutaneous hypersensitivity were normal. This patients represents another of the growing number of distinct granulocytopathies currently being recognized which may result in increased susceptibility to infection.

Measles severity and serum retinol (vitamin A) concentration among children in the United States.

BACKGROUND: Studies in developing countries have shown that children with measles have low serum retinol concentrations and that lower retinol levels are associated with measles-related mortality. Vitamin A therapy has been shown to reduce mortality among African children with acute measles. OBJECTIVES: To determine whether serum retinol concentration is low among children with measles in the United States and to determine whether retinol concentration is associated with illness severity. SETTING: Pediatric referral hospital and clinic in Milwaukee, WI, during the measles outbreak of 1989-1990. PATIENTS: One hundred fourteen patients < or = 5 years of age evaluated for serologically confirmed measles with serum obtained within 5 days following rash onset. METHODS: Serum retinol concentration was determined by high-performance liquid chromatography. Clinical data were collected by hospital record review. A modified Pediatric Risk of Mortality (PRISM) score was used to assess physiologic instability as a measure of illness severity. RESULTS: Retinol concentrations ranged from 0.25 to 1.18 mumol/L (median 0.58 mumol/L); 82 (72%) patients had low retinol concentration (< or = 0.70 mumol/L). Median retinol concentrations were lower among hospitalized patients (0.56 vs 0.70, P = .006) and patients with pneumonia (0.52 vs 0.64, P = .02) but higher among children with otitis media (0.63 vs 0.54, P = .01). Higher modified PRISM scores, reflecting greater physiologic instability, were associated with lower retinol concentration (beta coefficient -.0147, P = .025). In multivariate analysis, higher modified PRISM scores were associated with lower retinol concentration (beta coefficient -.0144, P = .025) even after controlling for hospitalization, presence of complications, race, age, receipt of Aid to Families With Dependent Children, gender, and interval from rash onset until serum was collected. CONCLUSIONS: Among these children with measles in an urban United States community, retinol concentrations were depressed, and the degree of depression was associated with illness severity. Vitamin A therapy should be considered for children with measles in the United States who require hospitalization.

The role of the polymorphonuclear leukocyte in the induction of corneal edema.

Corneal inflammation is frequently associated with the development of corneal edema. It has been suggested the development of corneal edema might in some way be related to the presence of polymorphonuclear leukocytes (PMNLs) within inflamed corneas. In the present studies, it was found that corneal thickness markedly increased after experimental infection with Pseudomonas aeruginosa, but in guinea pigs made neutropenic by whole body irradiation, significantly less of an increase in corneal thickness occurred. Furthermore, corneas from non-neutropenic animals experimentally infected with P. aeruginosa consistently showed a greater increase in water content than did infected corneas from neutropenic animals. Over the first 48 hr of infection, the increase in corneal water was directly proportional to the corneal ingress of radiolabelled PMNLs. Corneal inflammation induced by intracorneal injection of the PMNL chemotactic agents phorbol myristate acetate (PMA) or endotoxin was also associated with a significant increase in corneal water compared with neutropenic animals. These data strongly suggest that activated PMNLs in the cornea are responsible for the induction of corneal edema in infected corneas.

Epidemiologic markers of pediatric infections caused by coagulase-negative staphylococci.

Several epidemiologic markers (species, slime production and antimicrobial susceptibility) were examined for 256 isolates of coagulase-negative staphylococci (C-S) obtained from clinical specimens in a 1-year period. The medical records of the 169 pediatric patients from whom the C-S were obtained were reviewed and divided into infected (N = 11) and uninfected (N = 158) groups. The phenotypic traits of strains associated with infection included: (1) slime production (P = 0.014); (2) slime-positive Staphylococcus epidermidis (P = 0.002); and (3) resistance to penicillin (P = 0.03), oxacillin (P less than 0.001), clindamycin (P = 0.003), chloramphenicol (P less than 0.001) and trimethoprim/sulfamethoxazole (P less than 0.001). Infected patients were significantly older (P = 0.006) than uninfected patients. Simultaneous isolation of the same strain of C-S from the aerobic and anaerobic bottles of a single blood culture increased the probability of sepsis (P = 0.004). The combination of these patient and laboratory data may be useful in determining the clinical significance of C-S recovered from pediatric patients.

Structure of a primary care support system to coordinate comprehensive care for children and families infected/affected by human immunodeficiency virus in a managed care environment.

BACKGROUND: Children with HIV infection require coordinated primary and tertiary care. OBJECTIVES: To describe the structure of the Wisconsin HIV Primary Care Support Network, a decentralized program for care of children and families infected or affected by HIV infection. METHODS: Review of data concerning all children with HIV infection included in the Network's database. RESULTS: In this Network centralized HIV specialists work with primary care practitioners throughout Wisconsin to assure that children with HIV infection have access to care of uniform quality no matter where they live. Network staff care for children with HIV infection both directly and through the education and support of primary care providers. Care requirements are outlined in a state-published protocol supplied to practitioners. Audit of care is possible because of a centralized data collection system, and ongoing feedback and education occur via the activities of nursing care coordinators and both hospital- and community-based social workers. CONCLUSIONS: This system of care may serve as a model for care delivery to children with HIV infection in low prevalence areas and may be applicable to the care of children with other chronic diseases being cared for in a managed care environment.

Effectiveness of intensive nurse case management in decreasing vertical transmission of human immunodeficiency virus infection in Wisconsin.

BACKGROUND: During a clinical trial (ACTG Study 076), perinatal HIV transmission was reduced by two-thirds when pregnant women with HIV infection and their infants were treated with zidovudine (ZDV). A similar benefit has not been uniformly found in practice settings. OBJECTIVES: To measure the effectiveness of a nurse case management system in supporting prenatal ZDV use in women with HIV infection and their infants and in decreasing perinatal HIV transmission. METHODS: We performed a retrospective cohort study of all children with or at risk for HIV infection cared for in the Wisconsin HIV Primary Care Support Network. The Network uses intensive nurse case management to optimize the care of pregnant women with HIV infection and their children. For children born between January 1, 1992, and April 30, 1996, we measured the association of prenatal case management by a Network nurse with (1) ZDV use by pregnant women with HIV infection and (2) the rate of vertical HIV transmission. RESULTS: In the 26 months after March 1, 1994 (shortly after the release date of ACTG 076 results), 5 of 39 (13%) infants born to women with HIV infection and enrolled in the Network acquired HIV perinatally compared with 12 of 30 (40%) infants in the 26 months preceding March 1, 1994 (P = 0.01). Between March 1, 1994, and April 30, 1996, 25 of 25 (100%) women whose prenatal care included intensive case management by a Network nurse were treated with prenatal orally administered ZDV, compared with 3 of 14 (21%) women whose prenatal care did not include Network case management (P < 0.0001). There were 2 of 25 (8%) infants who acquired HIV infection in the former group, compared with 3 of 14 (21%) in the latter group (P = 0.2) CONCLUSIONS: Perinatal transmission of HIV was significantly decreased following implementation of national recommendations for ZDV treatment of pregnant women. Prenatal care that included case management by a specialized nurse was significantly more likely to result in appropriate ZDV therapy in women and showed a trend toward a lower rate of HIV infection in their infants, compared with prenatal care that did not include such personnel.

Polymorphonuclear leukocyte kinetics in experimentally induced keratitis.

The movement of polymorphonuclear leukocytes (PMNLs) into inflamed corneas was studied using a quantitative technique to measure PMNL chemotaxis in vivo. Our studies suggested that, in this model, most PMNLs enter the cornea through limbal vessels. A variety of bacterial agents, including viable bacteria, killed bacteria, culture filtrates, and endotoxin, were found to induce a significant corneal inflammatory response. Of the agents tested, viable Pseudomonas aeruginosa produced greatest inflammation. Host factors (serum, PMNLs) also induced movement of PMNLs into corneas, but only after preincubation with activating agents. Normal serum, resting PMNLs, and PMNL lysates derived from resting cells did not promote PMNL corneal ingress. These studies provide further insight into the movement of PMNLs into the inflamed cornea and information that may be of use in developing techniques to inhibit the corneal inflammatory response.

Quantitation of corneal inflammation by chemiluminescense.

Various inflammatory agents, including Pseudomonas aeruginosa, bacterial filtrates, endotoxin, and phorbol myristate acetate were found to induce significant increases in corneal chemiluminescense (CLM). Disruption of polymorphonuclear leukocytes within corneas by sonication, freeze-thawing or cryotherapy, or reduction of corneal infiltration by induction of neutropenia resulted in marked decreases of CLM. Increased corneal CLM was associated with significant increases in corneal thickness and water content. Oxygen-free radical scavengers significantly inhibited CLM of experimentally infected corneas in vitro, as did the anti-inflammatory agents prednisolone acetate, indomethacin, and salicylic acid. In vivo therapy of infected corneas with prednisolone resulted in significant reductions in corneal CLM, thickness, and water content compared with saline-treated eyes. The CLM assay is a simple technique that allows quantitation of corneal inflammation and evaluation of the effect of therapeutic agents on corneal inflammation.

Cerebral toxoplasmosis in an immunocompromised host. A precise and rapid diagnosis by electron microscopy.

In immunocompromised patients with cerebral toxoplasmosis, the tachyzoite forms rather than cystic and bradyzoite forms of the protozoon are commonly seen. These tachyzoites are minute, scattered among cellular debris, sometimes lodged inside macrophages and neutrophils, and difficult to visualize by light microscopy, even with special stains. Immunodiagnostic tests may be falsely negative due to inability of the host to produce appropriate antibodies. Isolation of the organism is dangerous because Toxoplasma gondii is highly infective. In this situation, transmission electron microscopy (EM) may be a diagnostic tool of choice. It demonstrates the fine definitive features of the protozoon and can be expedited to give results in five hours. Further evaluation of EM for diagnosing possible toxoplasmosis in immunocompromised patients is indicated.