Abstract
Concurrent Session
1:30 PM
Friday, January 29, 1999
A Randomized, Double-Blind, Placebo-Controlled Trial Of Granulocyte Colony Stimulating Factor (G-Csf) Administration To Treat Neonatal Neutropenia.
Term and preterm newborns frequently develop neutropenia due to sepsis or maternal preeclampsia (PIH). It is unclear whether administration of G-CSF to newborns with neutropenia due to maternal PIH increases neutrophil counts over placebo, or alters the course of disease in preterm infants with presumed sepsis. We randomized 30 neutropenic infants to 10 μg/kg/day of G-CSF or placebo for 3 days, and monitored neutrophil counts and illness severity. Infants in the PIH group (8) had similar absolute neutrophil counts (ANC) and severity scores (SNAP) at the start of the study (G-CSF: ANC=666±204/μL, SNAP=12±3; placebo: ANC: 664±193/μL, SNAP: 16±4). Infants in the sepsis group (22) were similarly neutropenic (G-CSF: ANC: 1,014±99/μL, SNAP: 12±3; placebo: ANC: 853±143, SNAP: 12±3). Changes in ANC and SNAP (mean±SEM) are shown in the table (
Neutrophil counts increased in both PIH and sepsis groups with G-CSF, although infants with presumed sepsis in the placebo group increased their ANCs by day 5. There were no differences in SNAP scores between treatment groups throughout the study. We conclude that G-CSF can increase neutrophil counts, but it is unclear what clinical benefit this affords preterm infants.
A Comparison Of Early Vs. Late Conversion From Intravenous To Oral Therapy In The Treatment Of Bacterial Arthritis.
Ambulatory Management Of Bacteremia And Fever In Bone Marrow Transplant Patients.
Historically, most bone marrow transplant (BMT) recipients at our center who presented with fever or bacteremia were admitted for observation and empiric treatment. With the advent of better outpatient monitoring and once-daily antibiotics, we feel a less restrictive policy should be considered. Treatment in the outpatient department is less expensive than inpatient management and patients prefer home care. To identify factors that are predictive of safe outpatient management, we retrospectively studied consecutive BMT recipients admitted from our ambulatory clinic for fever or bacteremia in the calendar year 1996. We coded which cases could have been handled safely and effectively in the ambulatory setting. Fifty percent (35 of 70) of the admissions for bacteremia and/or fever could have been managed safely in the outpatient department. Multivariable logistic regression models suggest that patients with bacteremia and/or fever who present with gastrointestinal symptoms, or are in the first thirty days after transplantation are significantly less likely to be handled safely as outpatients. Among febrile, pediatric patients, those who are greater than 30 days post-transplant are significantly more likely to be managed safely as outpatients than those who are less than 30 days post-transplant. We have implemented an ambulatory protocol for management of BMT recipients with fever and/or bacteremia that is flexible in its use of hospital admission, but is not a substitute for clinical judgement. This protocol gives criteria for ambulatory management based on a nontoxic appearance, hemodynamic stability, and willingness by the ambulatory physician to observe patients for the necessary duration. A future retrospective study will analyze the effects of this ambulatory-inclusive protocol on morbidity and mortality and will further clarify the indications for ambulatory management presented in this study.
Prospective Study Of A Protocol To Evaluate Infants Born To Group B Streptococcus Colonized Mothers Who Receive Intrapartum Antibiotic Prophylaxis.
Meningitis In Pediatric Patients With Cancer.
Meningitis is a serious life-threatening infection in patients with either normal or compromised immune function. The clinical features of bacterial meningitis in adult cancer patients and in healthy children have been described, however little data describe the clinical features of CNS infections in pediatric cancer patients. To characterize cases of meningitis in pediatric cancer patients, the medical records of all patients under 18 with a diagnoses of any malignancy and meningitis at a major pediatric medical center from January 1981 to June 1998 were reviewed. During the 18.5 year study period there were 40 cases of bacterial or fungal meningitis in 36 pediatric cancer patients. Neutropenic patients were diagnosed with 30% of the CNS infections in this study. In most cases (68%), patients were predisposed to infection due to neurosurgical manipulation, defined as recent neurosurgery, a CNS device, or CSF leak. Fever and altered mental status were the most consistent signs at presentation. While no other single sign or symptom was consistently present in all the patients, at least one of the following was present 77% of the time: headache, neck pain or rigidity, seizures, or photophobia. Neck pain or rigidity was seen less often in neutropenic patients than in neurosurgical patients, and most often in non-neutropenic patients without neurosurgical manipulation. Overall, S. aureus and S. pneumoniae were the most common CSF isolates. H. influenzae type b (HIb), S. pneumoniae, and Group B Strep are the most common organisms responsible for meningitis in normal children and were isolated in 6 of the 8 patients without neurosurgical manipulation or neutropenia. HIb was responsible for 3 out of 10 cases of meningitis during the first four years of this study, and became notably absent from this population since 1985. This decline reflects the nationwide decrease in HIb meningitis, coinciding with the introduction of the vaccine. This retrospective review represents the first large experience of meningitis in pediatric patients. Significant morbidity and mortality was associated with meningitis in pediatric cancer patients. Neutropenia and seizures within two days of presentation are consistent with poor outcomes. All five deaths observed in this series were in neutropenic patients. The absence of meningeal signs did not reliably exclude the diagnosis of meningitis. Therefore the diagnosis must rely heavily on CSF findings and culture. Pediatric cancer patients with meningitis have distinct clinical features and infectious etiology compared to adult cancer patients and normal children with meningitis. Recognizing the unique features of meningitis in this population may aid physicians in early diagnosis and treatment of this serious disease.
Impact Of Polymerase Chain Reaction On Management Of Enteroviral Meningitis In Infants.
Viral meningitis, most often caused by Enteroviruses (EVs), is often difficult to diagnose rapidly in young infants and may be confused with bacterial and/or herpetic CNS disease. In the past, results of viral cultures, the conventional method to diagnose enteroviral meningitis, have not been available in time to impact clinical decision-making. Polymerase Chain Reaction (PCR), a powerful technique recently implemented for the amplification and detection of EV RNA, has been shown to be more sensitive and rapid than viral culture. We assessed, by retrospective chart review, the impact of EV PCR on management of enteroviral meningitis in children less than 1 year of age. Data was gathered from 184 cases at two institutions in San Diego County in 1992 (when viral culture was the only diagnostic tool available) and 1995 (when EV PCR was first being routinely utilized along with viral culture). 128 cases were from 1992, and 56 cases were from 1995. Median age of patients was 45.0 days. PCR results were available in a median of 47.5 hours in 1995, while CSF viral culture results were available in a median of 6.0 days for positive results and generally 2 weeks for negative results. Median duration of hospital stay was 7.5 hours shorter in 1995 versus 1992, in part attributable to changing clinical practices emphasizing shorter hospital stays. While performing a EV PCR or getting back a positive PCR result did not shorten hospital stay or reduce the amount of ancillary tests and antibiotics administered in 1995, a trend toward shorter hospitalization time was evident when PCR result turnover time was less than 36 hours. In addition, a positive PCR reduced the total number of ancillary tests done by 64%, with the greatest impact in infants over 30 days of age. Although the impact of PCR was not dramatic for patients, it was greater than that made by viral culture. In order for EV PCR for have a greater impact on management of EV meningitis, results must be available in less than 48 hours.
Study Of Perinatal Hiv Transmission Rates In Nevada: Pre And Post Distribution Of 076 Protocol.
The purpose of studying perinatal HIV transmission rates in Nevada, and correlating them to the distribution of Aids Clinical Trials Group (ACTG) 076 protocol, is due to the lack of a thorough investigation of the protocol's impact on Nevada's pediatric HIV cases. In 1994, ACTG 076 demonstrated that the use of a 3-part Zidovudine (AZT) regimen for HIV positive pregnant woman and their infants significantly reduced perinatal HIV transmission. Several of Nevada's doctors have noted a reduction in perinatal HIV transmission since the distribution of ACTG 076 protocol, but this reduction has yet to be documented. In this study, two counties in Nevada (Washoe County and Clark County) were selected, based on population and number of pediatric HIV cases, to investigate the statistics of perinatal HIV transmission. The number of HIV-exposed infants (born to HIV positive mothers) during the period of 1992 to 1998 for Washoe County was 21, and for Clark County it was 100. The HIV statuses of the infants were evaluated from 1992 to March of 1994 (before the introduction of 076 protocol) and from March of 1994 to 1998 (after the distribution of the 076 protocol). Results of the statistical investigation showed a reduction of perinatally transmitted HIV cases in Washoe County from 40% (2 out of 5 infants born from 1/92 to 3/94) to 6.25% (1 out of 16 infants born from 3/94 to 6/98), and in Clark County from 24.3% (9 out of 39 infants born from 1/92 to 3/94) to 12.7% (8 out of 63 infants born from 3/94 to 3/98). Therefore, perinatal HIV transmission rates did decrease after the distribution of 076. 5.4% of the mothers were taking AZT prior to March of 1994 in Clark County, as compared to 32% of the mothers after the distribution of 076, and 20% of the mothers were taking AZT prior to 076 in Washoe County with an increase to 87.5% after the protocol's distribution. Other confounding factors, such as the number of repeat pregnancies (32% of cases in Clark County and 28.6% in Washoe County), the hospital of delivery, and the prenatal HIV screening habits of OB/GYN's were also studied with respect to the noted perinatal HIV decrease. In conclusion, perinatal transmission rates of HIV dramatically declined with the introduction of AZT prenatal therapy. Further studies may be necessary to practically analyze the efficacy of the ACTG 076 protocol use worldwide.
Sterol Biosynthesis Inhibitors With Potent Activity Against Trypanosoma Cruzi And Leishmania Mexicana
F.S. Buckner1, J.H. Griffin2, A.J. Wilson1, and W. C. Van Voorhis1. 1Department of Medicine, University of Washington, Seattle, WA. 2Department of Chemistry, Stanford University, Stanford, CA.
Trypanosoma cruzi and Leishmania spp. are closely related parasitic protozoa that cause Chagas' disease and leishmaniasis. Millions of persons are infected worldwide and current drug therapies are inadequate. In contrast to their mammalian hosts, these protozoa contain ergosterol in the cell membrane. In the biosynthesis of ergosterol, the enzyme oxidosqualene cyclase catalyzes the formation of lanosterol. A series of pyridinium ion based compounds were synthesized to mimic monocyclized species and inhibit the cyclase enzyme. Of 57 compounds synthesized, several had dramatic in vitro effects inhibiting parasite growth. The IC50 for seven compounds against mammalian stage T. cruzi was between 1-10 nM; high picomolar-range activity was observed for another 5 compounds. Similarly, growth inhibition activity against L. mexicana (insect stage) was determined to be below 10 nM for 10 of the compounds. Toxicity to mammalian cells was observed at concentrations 100 to >1000 times higher than the toxicity to parasites. Analysis of sterols from T. cruzi treated with a cyclase inhibitor revealed accumulation of oxidosqualene and the appearance of a new sterol species. This suggests the compounds are acting on the sterol biosynthesis. Studies are underway to further characterize the mechanism(s) of toxicity of these potent compounds and to determine the activity in animal models of Chagas' disease and leishmaniasis.
Long Term Effect Of Interleukin-15 On Activated Natural Killer Cytotoxicity And Cd16/56 Receptor Expression In Hiv-Infected Patients.
We investigated the ability of interleukin (IL)-15 to induce activated natural killer (ANK) activity and CD16/56 expression (NK cell markers) of peripheral blood mononuclear cells (MNC) from HIV-infected (HIV+) children and adults and normal adult controls. MNC were cultured with IL-15 for 1 to 4 weeks. ANK activity was assessed by 51Cr release assays using K562 cells. Flow cytometry assays were performed using antibodies to CD16 and CD56 receptors. The table illustrates percent lysis at an effector:target ratio of 25:1 ± standard error and mean percentage of cells ± standard error expressing both CD16 and CD56 cultured in IL-15 (10 ng/ml).
MNC from HIV patients were deficient compared to controls in ANK activity and in CD16/56 expression in the absence of IL-15 (week 1**). Both ANK activity and CD16/56 expression declined to <5% in patients and controls by 4 weeks without IL-15 (not shown). IL-15 enhanced ANK activity in patients and controls over 4 weeks, although there was some decline in patient response by weeks 3 and 4. IL-15 increased the percentage of NK cells (CD16+/56+) in patients and controls to comparable levels throughout the 4 week period. IL-15 also increased total CD56 expression 3-fold in patients, which may indicate expansion of a sub-population of CD16 NK cells. In other studies, we found that IL-15 increases T suppressor cytotoxic cells (CD3+/8+) cells in HIV patients (not shown). Thus, IL-15 restores impaired ANK activity in HIV patients and may be used for immunomodulative therapy in HIV infection.
Epidemiology Of Tuberculosis In Hiv-Infected Persons In Santiago, Chile.
Chile is a country early in the HIV epidemic with a low but increasing prevalence of HIV infection predominantly transmitted through sexual exposure (91.6%). The majority of HIV transmission has been in homosexual males, however the incidence in women is steadily increasing. TB infection, however, has maintained a low and stable prevalence due to a rigorous control program. As the HIV epidemic in Chile progresses, coinfection with TB and HIV can pose a further public health threat by increasing the incidence of drug-resistant TB, increasing the window of transmissibility for TB infection, and increasing the morbidity and mortality of patients with AIDS. In this three part study, we reviewed records and interviewed patients among a 430 patient cohort in the HIV-control program treated between January 1988 and June 1998 at the Hospital Sotero del Rio in the South-Eastern Metropolitan Region of Santiago, Chile. Risk factors were studied through an administered questionnaire and the effect of TB on HIV progression was examined through a detailed examination of a 30 patient cohort. Among the HIV cohort, prevalences of 7.14%, 6.9%, 5.1%, and 6.6% of TB cases confirmed either clinically or bacteriologically were found for years 1994 through 1997, respectively. Prevalences of bacteriological confirmation were 5.1%, 5.4%, 3.9%, and 3.7%, respectively. These levels are consistent with measures made prior to 1994 by the Ministry of Health and fail to demonstrate significant increase. 72.2% co-infected patients displayed pulmonary TB alone, while 22.2% displayed extrapulmonary TB, and 5.5% displayed both pulmonary and extrapulmonary infection. These results do not corroborate high levels of extrapulmonary TB found in many other cohorts of coinfected patients. 13.9% patients demonstrated relapse of TB, which is consistent with other reports. 21.1% co-infected patients died while still infectious for TB, 5.3% abandoned treatment, and 10.5% remain of unknown disposition. Rates of abandonment and death while infectious were significantly higher than rates in patients with TB alone suggesting higher vigilance in TB control of coinfected patients may be important to prevent spread of TB from this highly susceptible population.