Under-recognition and reporting of dengue in Cambodia: a capture-recapture analysis of the National Dengue Surveillance System.

Robust disease burden estimates are important for decision-making concerning introduction of new vaccines. Dengue is a major public health problem in the tropics but robust disease burden estimates are lacking. We conducted a two-sample, capture-recapture study in the largest province in Cambodia to determine disease under-recognition to the National Dengue Surveillance System (NDSS). During 2006-2008, community-based active surveillance for acute febrile illness was conducted in 0- to 19-year-olds in rural and urban areas combined with testing for dengue virus infection. Of 14 354 individuals under active surveillance (22 498 person-seasons), the annual incidence ranged from 13·4 to 57·8/1000 person-seasons. During the same period, NDSS incidence rates ranged from 1·1/1000 to 5·7/1000, which was 3·9- to 29·0-fold lower than found in the capture-recapture study. In hospitalized cases, the rate of under-recognition was 1·1- to 2·4-fold. This study shows the substantial degree of under-recognition/reporting of dengue and that reported hospitalized cases are not a good surrogate for estimating dengue disease burden.

The Larimer County Children's Clinic. A public-private partnership to provide medical care to indigent children.

OBJECTIVE: To describe a unique collaboration between private and public entities to provide comprehensive health care to medically indigent children in rural Larimer County, Colo. SETTING: The Children's Clinic, Fort Collins, Colo. STUDY PARTICIPANTS: Uninsured children and those eligible for Medicaid, living in families with incomes below 150% of the federal poverty level. SELECTION PROCEDURES: Eligible patients have been enrolled in the Children's Clinic on a first-come, first-served basis. INTERVENTIONS: A community collaboration involving an interactive system with the Children's Clinic staff, the Larimer County Department of Health and Environment, private primary care and subspecialty physicians, ancillary health providers, and the family practice residency program at Poudre Valley Hospital, Fort Collins. Funding for this endeavor has been composed of city and county funds, public and private grants, community business support, and local fund-raising efforts, as well as Medicaid reimbursements. MEASUREMENTS/MAIN RESULTS: Since 1989, comprehensive pediatric care has been provided to a growing number of eligible children. At present, 3619 children, aged birth to 18 years, from 2230 families are being served. From this population, there were 8945 office visits to the Children's Clinic, 1392 patient contacts by the clinic social workers, 1287 visits to the Larimer County Department of Health and Environment for well-child care, 543 referrals to subspecialists and other community health care providers, and 615 after-hours visits to the Poudre Valley Hospital emergency department between July 1, 1992, and June 30, 1993. The clinic's professional staff consists of 2 1/4 full-time pediatric care providers, one nurse, one medical social worker, one receptionist, and one administrator, with an expenditure of $356,471. CONCLUSIONS: The Children's Clinic collaboration has provided comprehensive pediatric health care to a population that previously received only fragmented care. The next step is to assess the impact of this program on the frequency of emergency department visits for these patients.

Congenital yellow fever virus infection after immunization in pregnancy.

To determine whether yellow fever (YF) vaccine administered in pregnancy causes fetal infection, women who were vaccinated during unrecognized pregnancy in a mass campaign in Trinidad were studied retrospectively. Maternal and cord or infant blood were tested for IgM and neutralizing antibodies to YF and dengue viruses. One of 41 infants had IgM and elevated neutralizing antibodies to YF virus, indicating congenital infection. The infant, the first reported case of YF virus infection after immunization in pregnancy, was delivered after an uncomplicated full-term pregnancy and appeared normal. Congenital dengue 1 infection may have occurred in another case. The frequency of fetal infection and adverse events after such exposure could not be estimated; however, the neurotropism of YF virus for the developing nervous system and the now documented possibility of transplacental infection underscores the admonition that YF vaccination in pregnancy should be avoided.

Eastern equine encephalitis (EEE): a description of the 1989 outbreak, recent epidemiologic trends, and the association of rainfall with EEE occurrence.

An Eastern equine encephalitis (EEE) outbreak in 1989 led to nine human and 196 equine cases, chiefly in coastal Atlantic and Gulf Coast counties. In the past two decades, EEE age-specific incidence and mortality rates have declined compared with earlier years. Analysis of rainfall patterns in areas where human EEE cases occurred between 1983 and 1989 revealed an association between occurrence of human cases and excess rainfall. The association was stronger with data from local weather stations than from statewide rainfall averages and the predictive models were best when applied to northern states. The sensitivity and specificity of these measures varied, depending on the model used, but the positive predictive value was no better than 50%, regardless of the rainfall model applied.

Congenital yellow fever virus infection after immunization in pregnancy

To determine whether yellow fever (YF) vaccine administered in pregnancy causes fetal infection, women who were vaccinated during unrecognized pregnancy in a mass campaign in Trinidad were studied retrospectively. Maternal and cord or infant blood were tested for IgM and neutralizing antibodies to YF virus, indicating congenital infection. The infant, the first repotred case of YF virus infection after immunization in prgnancy, was delivered after an uncomplicated full-term pregnancy and appeared normal. Congenital dengue 1 infection may have occurred in another case. The frequency of fetal infection and adverse events after such exposure could not be estimated; however, the neurotropism of YF virus for the developing nervous system and the now documented possibility of trans-placental infection underscores the admonition that YF vaccination in pregnancy should be avoided (AU)

Comparative immunogenicity of four Haemophilus influenzae type b conjugate vaccines in Alaska Native infants.

We compared the immunogenicity of the four available Haemophilus influenzae type b (Hib) conjugate vaccines in Alaska Native infants. Three of the vaccines, Hib oligosaccharide-CRM197 (HbOC), polyribosylribitol phosphate-diphtheria toxoid (PRP-D) and polyribosylribitol phosphate-tetanus toxoid (PRP-T), were given at 2, 4 and 6 months of age, and the PRP Neisseria meningitidis outer membrane protein (PRP-OMP) conjugate vaccine was given at 2 and 4 months of age. Enrollment was largely sequential by vaccine availability beginning with HbOC and ending with PRP-T. A total of 225 infants completed the full vaccination series. Groups of infants receiving the different vaccines did not differ significantly by sex, ethnicity, degree Alaska Native or age at vaccination. The only vaccine that induced a response with the first 2-month dose was PRP-OMP; 91% of infants had > or = 0.15 micrograms/ml and 57% had > or = 1.0 microgram/ml of anti-PRP antibody by 4 months of age. After two doses it also remained the most immunogenic. After the full three vaccine series, trials that requires cough of 21 days is excessively restrictive.

Prevention of Haemophilus influenzae type b infections in Apache and Navajo children.

Prospective surveillance of Haemophilus influenzae type b (Hib) disease has been done since 1981 in two high-risk populations, White Mountain Apaches and Navajos. The attack rate in children less than 5 years of age is 5-10 times higher than in the general US population. Three vaccines were evaluated. Unconjugated Hib capsular polysaccharide produced lower antibody responses in 18- and 24-month-old Apache infants than in white infants. HbOC (Hib oligosaccharide covalently linked to the nontoxic mutant diphtheria toxin CRM197) produced low antibody responses in Navajo infants after one or two doses but induced responses similar to those in whites after three doses. The responses of 18-month-old Navajos to HbOC were lower than those of whites, but most achieved protective levels. PRP-OMP (Hib capsular polysaccharide linked to the outer membrane protein complex of Neisseria meningitidis) produced good immune responses in 2-month-old Navajo and Apache infants after a single dose. This vaccine was greater than 90% efficacious in protecting Navajo infants from Hib disease when given at 2 and 4 months of age. Even a single dose achieved a high protective efficacy.

Severity and frequency of sequelae of bacterial meningitis in Alaska Native infants. Correlation with a scoring system for severity of sequelae.

OBJECTIVES: To (1) determine the frequency and severity of sequelae of Haemophilus influenzae type b and Streptococcus pneumoniae meningitis in Alaska Native children, (2) compare morbidity and mortality of H influenzae b and S pneumoniae meningitis, and (3) evaluate the applicability of the Herson-Todd prognostic score (HTPS) to both H influenzae b and S pneumoniae meningitis in this population. DESIGN: A retrospective study of all cases of H influenzae b and S pneumoniae meningitis in Alaska Native children younger than age 5 years. Data on meningitis sequelae, obtained from medical charts and records of the Infant Learning Program, were collected, and incidence of sequelae tabulated. Data obtained on admission to the hospital were used to calculate HTPS. SETTING: Indian Health Service facility for the Yukon-Kuskokwin Delta region of southwest Alaska. STUDY SUBJECTS: 51 of 63 Alaska Native children with H influenzae b meningitis and 13 of the same 63 Alaska Native children with S pneumoniae meningitis occurring between 1980 and 1988. One child was infected with both organisms, producing a total of 64 cases for study. SELECTION PROCEDURES: Cases were identified by surveillance for these diseases between January 1, 1980, and December 31, 1988, maintained by the Arctic Investigations Program, Centers for Disease Control. MEASUREMENTS AND RESULTS: Sequelae of bacterial meningitis caused by H influenzae b were equal to or exceeded rates of sequelae described in other children in the United States. After H influenzae b meningitis, motor abnormalities (29%) and hydrocephalus (7%) occurred two to four times more often in Alaska Native children than in children in other parts of the United States. Differences in severity of H influenzae b sequelae could not be accounted for by microbiologic markers of the H influenzae b strain, including ampicillin sensitivity, biotype, outer membrane protein type, or electropherotype. Numbers of cases of S pneumoniae meningitis were too small for statistically valid comparison, but sequelae of S pneumoniae meningitis occurred in roughly equal proportion as sequelae of H influenzae b meningitis. The HTPS was applied to Alaska Native children with H influenzae b meningitis and was found to be very accurate in predicting children with major sequelae. Analysis of the prognostic factors used in deriving the HTPS revealed a unique set of predictors for sequelae in Alaska Native children: seizures at admission, glucose levels in cerebrospinal fluid of less than 1.1 mmol/L; and male gender, with a significant predictive interaction between male gender and age less than 6 months at admission. CONCLUSIONS: Alaska Native children suffer greater neurologic morbidity as a result of H influenzae b meningitis than do their non-Native counterparts. The HTPS was a good predictor of major sequelae in Alaska Native children with H influenzae b or S pneumoniae meningitis and could be useful in determining which patients need referral to a tertiary care center.

DTP immunization and susceptibility to infectious diseases. Is there a relationship?

A two-part study was carried out in Alaskan Native children to evaluate the potential risk of invasive bacterial disease and the occurrence of minor illnesses after immunization with diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP). First, a case-control comparison was performed with 186 children who had invasive Haemophilus influenzae type b or Streptococcus pneumoniae disease (cases) and 186 healthy controls matched for sex, region of residence, birth date, and number of DTP immunizations. The proportion of cases and controls immunized in the 30-day period before onset of disease for cases or reference date for controls was identical, suggesting no association with DTP immunization. In a second analysis, the occurrence of any illness, particularly infectious diseases, in 104 study subjects was compared for the period 30 days before and after 377 DTP immunizations. The rate of illness before immunization was 53%, and after immunization, 43%, again suggesting no causative effects from DTP immunization. Despite the high rates of invasive bacterial disease and nearly compete DTP immunization status in this population, no consistent relationship could be demonstrated between DTP immunization and susceptibility to infectious diseases.

A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population.

A double-blind, randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of a rhesus rotavirus vaccine and RIT 4237, a bovine rotavirus vaccine, in a Navajo population. Infants aged 2-5 months were randomized to receive one dose of either 10(4) pfu of the rhesus rotavirus vaccine or 10(8) pfu of the RIT 4237 vaccine or placebo. Eleven (10.2%) of 108 infants in the rhesus vaccine group, 11 (10.4%) of 106 in the RIT 4237 group, and 9 (8.4%) of 107 in the placebo group experienced rotavirus diarrhea during the follow-up period of 17 months. Thus, in this population, neither vaccine was efficacious in preventing rotavirus diarrhea.

Limited efficacy of a Haemophilus influenzae type b conjugate vaccine in Alaska Native infants. The Alaska H. influenzae Vaccine Study Group.

BACKGROUND: The prevention of invasive Haemophilus influenzae type b disease requires a vaccine that is effective when administered during the first six months of life. The infants of Alaska Natives are at particularly high risk of invasive H. influenzae type b disease. METHODS: To evaluate the protective efficacy of a H. influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]), we enrolled 2102 Alaska Native infants in a randomized, double-blind, placebo-controlled trial in which either the vaccine or a saline placebo was administered at approximately two, four, and six months of age. RESULTS: After 3969 subject-years of follow-up and 32 episodes of H. influenzae type b disease, the overall incidence of invasive disease was not reduced significantly in the vaccinated subjects (6.0 cases per 1000 patient-years), as compared with the placebo controls (9.6) or with other Alaska Native infants (6.0). After one, two, or three doses there was no significant protective efficacy with the vaccine; after three doses the efficacy was only 35 percent (95 percent confidence interval, -57 to 73). The lack of efficacy was not related to the age at onset of disease, age at immunization, type of disease, degree of Alaska Native heritage, time after immunization, or year of the study. Levels of H. influenzae type b anticapsular antibody in recipients of the vaccine became significantly higher than levels in those who received placebo only after the second and third doses. Even after the third dose, only 48 percent of the vaccinated infants had antibody levels of more than 0.1 microgram per milliliter (geometric mean titer, 0.18). Antibody responses did not vary with the level of maternally acquired antibody, degree of Alaska Native ancestry, or age at time of the first or second immunizations, but they increased with increasing age at time of the third dose (P less than 0.001). CONCLUSIONS: We found no evidence that the PRP-D vaccine provides significant protection, at least for Alaska Native infants, against invasive diseases caused by H. influenzae type b. The ineffectiveness of the vaccine paralleled its limited immunogenicity.

Passive immunization for infection with Haemophilus influenzae type b.

Haemophilus influenzae type b is the leading cause of meningitis in children younger than 5 years of age in the United States. The incidence of infection with H influenzae type b in certain populations, such as Apache and Navajo Indians and Alaskan Eskimos, is 10 to 20 times higher than in the general US population. Another important feature of H influenzae type b infections in these populations is that more than 80% of the cases occur during the first year of life, with 35% to 45% occurring during the first 6 months. One of the currently licensed vaccines that contains the capsular polysaccharide of the H influenzae type b organism is not reliably immunogenic in infants younger than 18 months of age. A number of new H influenzae type b vaccines prepared by covalently coupling the H influenzae type b capsular polysaccharide with a protein carrier antigen are undergoing clinical evaluation. One of these conjugate vaccines was shown to be efficacious in preventing disease caused by H influenzae type b in Finnish infants when they were immunized at 3, 4, and 6 months of age. Unfortunately, in a recently concluded trial, the same vaccine was not found to be efficacious in preventing such disease in infants younger than 1 year of age among the Alaskan Eskimo population. We have evaluated an alternative approach for protecting high-risk infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of active and combined passive/active immunization of Navajo children against Haemophilus influenzae type b.

In a high risk Navajo population we compared the immunogenicity of a new Haemophilus influenzae type b mutant-diphtheria toxic conjugate vaccine (HbOC) with simultaneous active (HbOC) and passive immunization with bacterial polysaccharide immunoglobulin prepared from adults immunized with H. influenzae b, pneumococcal and meningococcal vaccines. Only 7 of 26 (27%) 2-month-olds had an increase in H. influenzae b capsular polysaccharide antibody after a single dose of HbOC, a proportion similar to that of saline controls (9 of 25, 36%). After a second HbOC dose at 4 months 88% had antibody concentrations of 0.15 microgram or more, and after a third dose at 6 months all had antibody levels greater than or equal to 0.15 microgram/ml. The group receiving both HbOC and bacterial polysaccharide immunoglobulin at 2 months uniformly had H. influenzae b CP antibody concentrations of greater than or equal to 0.15 microgram/ml at 4 months (P less than 0.001 relative to "HbOC alone" group) and subsequently responded similarly to second and third doses of HbOC vaccine as did also the "HbOC alone" group. We conclude that combined passive/active immunization with bacterial polysaccharide immunoglobulin and HbOC at 2 months maintains antibody at concentrations thought to be protective (greater than or equal to 0.15 microgram/ml) without interfering with the active antibody response to second and third doses of HbOC at 4 and 6 months of age.

Isolation of enterotoxigenic Bacteroides fragilis from humans with diarrhea.

Enterotoxigenic Bacteroides fragilis was isolated from stool specimens of 8 of 44 diarrheic individuals (ages, 4 months to 69 years). The individuals had watery diarrhea and intestinal cramping; and infants had hyperthermia, vomiting, and blood in the stools. No recognized enteric pathogens were detected in seven of the eight diarrheic individuals positive for enterotoxigenic B. fragilis. The bacterium produced an enterotoxin detectable in concentrated broth that supported bacterial growth. Fifteen adult rabbits with ligated ceca developed fatal enteric disease following intraileal injection with 5 x 10(9) CFU of enterotoxigenic B. fragilis. Conversely, eight control rabbits injected with nonenterotoxigenic B. fragilis remained clinically normal. As few as 5 x 10(3) CFU of enterotoxigenic B. fragilis caused fatal enteric disease in the rabbit model. Disease in rabbits was characterized by mucoid, often hemorrhagic, diarrhea. The bacterium colonized the caudal small intestine and the colon of the rabbits and caused moderate to severe necrotizing colitis. Enterotoxigenic B. fragilis is widespread in the intestinal tract of diarrheic humans and is enteropathogenic in adult rabbits with ligated ceca. Its possible role in the enteric disease complex merits further study.

Glycine-based oral rehydration solution: reassessment of safety and efficacy.

We evaluated the safety and efficacy of a glycine-based orally administered rehydration solution by comparing it with a standard oral rehydration solution (ORS) without glycine in a randomized double-blind trial in United States infants (age less than 15 months) given treatment for acute gastroenteritis as inpatients or outpatients. The response to therapy (stool volume and duration of illness) was similar in the two groups, except that in four (13%) of 31 hospitalized infants receiving glycine-ORS hypernatremia developed, (one had symptoms) compared with none of 35 receiving ORS (P less than 0.04). Among the 77 outpatients there were no differences between the groups. This study demonstrates that glycine-ORS did not provide any therapeutic advantage over standard ORS, and hypernatremia developed in some patients receiving glycine-ORS. We suggest that caution be used with this type of solution until further safety studies have been done.

Galactorrhea secondary to chest wall surgery in an adolescent.

Although nonpuerperal galactorrhea in youth may be a sign of pituitary prolactinoma, the etiology may be benign and extensive neurologic or endocrinologic evaluation and treatment may be unnecessary. An 18-year-old female with an unusual but benign form of transient galactorrhea due to chest wall surgery is reported. It is hypothesized that the sectioning of the intercostal nerves may result in reflex stimulation of hypothalamic centers controlling lactation through the same neural pathways involved in puerperal lactation. The patient experienced galactorrhea for two months and transient amenorrhea. She is asymptomatic without galactorrhea at nine months follow up.