Does oseltamivir work against influenza B?
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Aging↗
Biomedical subjects
Peter F Wright
Publications and source records attributed to Peter F Wright.
The histopathology of fatal untreated human respiratory syncytial virus infection.
The pathology of respiratory syncytial virus (RSV) infection was evaluated 1 day after an outpatient diagnosis of RSV in a child who died in a motor vehicle accident. We then identified 11 children with bronchiolitis from the Vanderbilt University autopsy log between 1925 and 1959 who met criteria for possible RSV infection in the preintensivist era. Their tissue was re-embedded and evaluated by routine hematoxylin and eosin and PAS staining and immunostaining with RSV-specific antibodies. Tissue from three cases was immunostain-positive for RSV antigen and was examined in detail. Small bronchiole epithelium was circumferentially infected, but basal cells were spared. Both type 1 and 2 alveolar pneumocytes were also infected. Although, not possible for archival cases, tissue from the index case was evaluated by immunostaining with antibodies to define the cellular components of the inflammatory response. Inflammatory infiltrates were centered on bronchial and pulmonary arterioles and consisted of primarily CD69+ monocytes, CD3+ double-negative T cells, CD8+ T cells, and neutrophils. The neutrophil distribution was predominantly between arterioles and airways, while the mononuclear cell distribution was in both airways and lung parenchyma. Most inflammatory cells were concentrated submuscular to the airway, but many cells traversed the smooth muscle into the airway epithelium and lumen. Airway obstruction was a prominent feature in all cases attributed to epithelial and inflammatory cell debris mixed with fibrin, mucus, and edema, and compounded by compression from hyperplastic lymphoid follicles. These findings inform our understanding of RSV pathogenesis and may facilitate the development of new approaches for prevention and treatment.
Antigens, Viral↗
Contribution of bacterial sepsis to morbidity in infants born to HIV-infected Haitian mothers.
BACKGROUND: Haiti is a country with a heavy burden of HIV infection in childbearing women. Previous studies have shown that early infant deaths are common in children of HIV-infected women. This study was designed to define the rates of and risk factors for systemic bacterial and mycobacterial infection in such children and to identify the causative agents. METHODS: A cohort of 120 children born to HIV-infected mothers between May 2001 and December 2003 were prospectively observed to 15 months of age. They received comprehensive pediatric care at the GHESKIO Centers. Children were assigned to being HIV-infected by serology, RNA detection, and/or defining clinical illnesses. Blood cultures were obtained before giving antibiotics in children who were febrile or chronically ill. Blood cultures also were obtained at selected visits on well children. RESULTS: The mortality rate in the first 15 months was high, 22 of 106 (207/1,000 live births) in these children. Sixteen (70%) deaths were within 6 months of birth. Fourty-eight blood cultures had clinically significant organisms of which 38 were Staphylococcus aureus. Blood cultures were more likely to be positive in symptomatic and in HIV-infected children. CONCLUSIONS: Despite perinatal HIV treatment, mortality in children born to HIV-infected mothers remained high. Bacteremia, particularly with Staphylococcus aureus, is a partial explanation for excess illness.
AIDS-Related Opportunistic Infections↗
Optimal bandaging of smallpox vaccination sites to decrease the potential for secondary vaccinia transmission without impairing lesion healing.
OBJECTIVE: To assess the optimal method for covering smallpox vaccination sites to prevent transmission of vaccinia. DESIGN: Randomized, nonblinded clinical trial. SETTING: Tertiary care medical center. PARTICIPANTS: Vaccinia-naive and vaccinia-experienced volunteers. INTERVENTIONS: After vaccination, study participants were randomized to receive 1 of 3 types of bandage: gauze, occlusive with gauze lining, or foam. Vaccination sites were assessed every 3 to 5 days until the lesion healed. During each visit, specimens were obtained from the vaccination site, the bandage surface before removal, and the index finger contralateral to the vaccination site and were cultured for vaccinia. Time to lesion healing was assessed. RESULTS: All 48 vaccinia-naive and 47 (87%) of 54 vaccinia-experienced participants developed a vesicle or pustule at the injection site 6-11 days after vaccination. Fourteen (14%) of 102 participants had bandage cultures positive for vaccinia. All but 1 of these vaccinia-positive cultures were of a bandage from participants randomized to the gauze bandage group, and all but 3 were of bandages from vaccinia-naive participants. No finger-specimen cultures were positive for vaccinia. One episode of neck autoinoculation occurred in a vaccinia-naive individual who had vaccinia recovered from his gauze bandage on multiple visits. The foam bandage was associated with more local adverse effects (skin irritation and induration). The time to healing did not differ among the bandage groups. CONCLUSIONS: The potential for transmission of vaccinia from a vaccination site is greater if the site is covered by gauze than if it is covered by occlusive or foam bandages. Use of an occlusive bandage with a gauze lining is the best choice for coverage of smallpox vaccination sites because of a reduced potential for vaccinia transmission and a lower reactogenicity rate. Bandage choice did not affect vaccination lesion healing.
Adult↗
The use of an educational video during informed consent in an HIV clinical trial in Haiti.
BACKGROUND: Research volunteers from developing countries who enroll in HIV clinical trials may be illiterate and unfamiliar with the conduct of medical research. Educating volunteers about the contents of the consent form is essential but can be difficult and time consuming. We evaluated the feasibility and effectiveness of an educational video during the informed consent process for an HIV clinical trial conducted in Port-au-Prince, Haiti. METHODS: HIV-seronegative volunteers were recruited into a longitudinal cohort to study rates of high-risk sexual behavior and incidence of HIV-1 infection. Before enrollment, all volunteers received information about the consent form during 2 educational sessions. In the first session, groups of 5 to 10 volunteers viewed an educational video on the essential elements of the consent form. In the second, the volunteers met one-on-one with a social worker. Volunteers' comprehension was then evaluated orally by 16 true-false questions and 4 open-ended questions. Volunteers who failed the first evaluation received additional education and had a second evaluation. RESULTS: Two hundred fifty volunteers received education, and 186 (74%) passed the first evaluation. Higher formal education was a significant predictor of passing the first evaluation (odds ratio, 1.60; 95% confidence interval, 1.05-2.44). Of the 64 who failed, 47 returned for a repeat one-on-one education session and a second evaluation. Among these 47, 39 (83%) passed, and 8 (7%) failed the second evaluation. In total, 225 (90%) of 250 individuals passed either the first or second evaluation and were eligible to enroll in the study. CONCLUSIONS: Informed consent using an educational video ensured good comprehension in most of the volunteers. Additional educational sessions may be necessary for some participants with lower educational level.
Adult↗
The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans.
BACKGROUND: Respiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the host's interferon- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics. METHODS: Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children. RESULTS: At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene. CONCLUSIONS: Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.
Adult↗
The use of inactivated influenza vaccine in children.
The impact of influenza in the very young appears to be comparable to that in the elderly. Influenza vaccine strategy is changing to reflect that impact. Currently, the broader recommendations include vaccination with trivalent inactivated influenza vaccines (TIVs) for children aged 6 to 59 months. This article reviews TIV safety, immunogenicity, and efficacy in children, current vaccine recommendations, and vaccine administration and dosage.
Adolescent↗
The role of human metapneumovirus in upper respiratory tract infections in children: a 20-year experience.
BACKGROUND: The role that human metapneumovirus (hMPV) plays in the etiology of upper respiratory tract infections (URIs) in children over a period of many years has not been evaluated previously. METHODS: By use of real-time reverse-transcriptase polymerase chain reaction, we retrospectively tested nasal wash (NW) specimens for hMPV that had been obtained from a cohort of 1532 infants and children with URIs who were prospectively followed for an average of 2.4 years during the period from 1982 to 2001. Virus genes were sequenced, and prospectively collected clinical data were analyzed. RESULTS: There were 2710 visits for URIs for which routine cultures did not reveal a viral etiology. Archival NW specimens from 2384 of these visits were available. hMPV RNA was detected in 118 (5%) of 2384 specimens. The mean age of the children with hMPV infection was 20 months, and 78% of illnesses occurred from December through May. Acute otitis media (AOM) was detected in 50% of these children. hMPV circulated each year, but the numbers of isolates detected varied by year. Reinfections with both homologous and heterologous strains occurred. Four distinct genetic lineages were present over the 20 years of surveillance, with several different lineages circulating during some seasons. CONCLUSIONS: hMPV was detected in a substantial number of children with URIs and concomitant AOM.
Child, Preschool↗
Transmissibility, infectivity and immunogenicity of a live human parainfluenza type 3 virus vaccine (HPIV3cp45) among susceptible infants and toddlers.
BACKGROUND: This study examined the transmissibility between young children of an intranasally administered live attenuated human parainfluenza virus type 3 (HPIV3)-cp45 vaccine candidate. METHODS: Eighty subjects were enrolled in playgroups among whom there was at least one infected vaccinee in close contact with a seronegative placebo recipient over 21 days without a confounding infection with wtHPIV3. Following vaccination viral cultures were obtained on nine occasions to detect shedding and transmission of HPIV3cp45. Serum antibody titers were measured before and 7 weeks after vaccination. RESULTS: No child fulfilled the criteria for transmission of HPIV3cp45 giving a risk of transmission of 0.04 (95% CI 0.01-0.19), hence establishing that HPIV3cp45 is less infectious than wtHPIV3 and risk of transmission is not a limitation to further clinical development of this vaccine candidate.
Antibodies, Viral↗
Antiretroviral therapy in a thousand patients with AIDS in Haiti.
BACKGROUND: The one-year survival rate of adults and children with the acquired immunodeficiency syndrome (AIDS), without antiretroviral therapy, has been about 30 percent in Haiti. Antiretroviral therapy has recently become available in Haiti and in other developing countries. Data on the efficacy of antiretroviral therapy in developing countries are limited. High rates of coinfection with tropical diseases and tuberculosis, along with malnutrition and limited laboratory monitoring of therapy, may decrease the efficacy of antiretroviral therapy in these countries. METHODS: We studied the efficacy of antiretroviral therapy in the first 1004 consecutive patients with AIDS and without previous antiretroviral therapy who were treated beginning in March 2003 in Port-au-Prince, Haiti. RESULTS: During a 14-month period, three-drug antiretroviral therapy was initiated in 1004 patients, including 94 children under 13 years of age. At enrollment, the median CD4 T-cell count in adults and adolescents was 131 per cubic millimeter (interquartile range, 55 to 211 per cubic millimeter); in children, a median of 13 percent of T cells were CD4-positive (interquartile range, 8 to 20 percent). According to a Kaplan-Meier survival analysis, 87 percent of adults and adolescents and 98 percent of children were alive one year after beginning treatment. In a subgroup of 100 adult and adolescent patients who were followed for 48 to 56 weeks, 76 patients had fewer than 400 copies of human immunodeficiency virus RNA per milliliter. In adults and adolescents, the median increase in the CD4 T-cell count from baseline to 12 months was 163 per cubic millimeter (interquartile range, 77 to 251 per cubic millimeter). In children, the median percentage of CD4 T cells rose from 13 percent at baseline to 26 percent (interquartile range, 22 to 36 percent) at 12 months. Treatment-limiting toxic effects occurred in 102 of the 910 adults and adolescents (11 percent) and 5 of the 94 children (5 percent). CONCLUSIONS: This report documents the feasibility of effective antiretroviral therapy in a large number of patients in an impoverished country. Overall, the outcomes are similar to those in the United States. These results provide evidence in support of international efforts to make antiretroviral therapy available to patients with AIDS in developing countries.
AIDS-Related Opportunistic Infections↗
Differential regulation of granzyme and perforin in effector and memory T cells following smallpox immunization.
Primary immunization of healthy adults with vaccinia virus induces a local vesicle or "take" in the majority of vaccinees that previously has been shown to correlate with protection against smallpox. However, the immunologic mechanisms underlying this protective response in humans are not well characterized. We have studied human CD8+ T cells for the expression patterns of phenotypic markers and cytolytic effector molecules before and after primary smallpox immunization using nine-color polychromatic flow cytometry. One month after immunization, vaccinees developed vaccinia virus-specific CD8+ T cells with an effector cell phenotype containing both granzyme A and granzyme B. One year after immunization, we found a significant decrease in granzyme B containing cells and an increased memory cell phenotype in virus-specific CD8+ T cells. Perforin was rarely expressed directly ex vivo, but was highly expressed after Ag-specific activation in vitro. Together, these data suggest an important role for effector CD8+ T cells in controlling poxvirus infection, and have implications for our understanding of human CD8+ T cell differentiation.
Adult↗
Prevalence of reovirus-specific antibodies in young children in Nashville, Tennessee.
Although reovirus infections are thought to be common in adults, there have been few assessments of the seroprevalence of reovirus in young children. We developed an indirect enzyme-linked immunosorbent assay to measure levels of total antireovirus immunoglobulin A, G, and M in serum specimens collected from otherwise healthy infants and children (1 month to 5 years of age) in Nashville, Tennessee. Of the 272 serum specimens evaluated, 64 (23.5%) tested positive for reovirus-specific antibodies. We observed an age-dependent increase in reovirus-specific antibodies in children 1 year of age and older, peaking at 50.0% in children 5-6 years of age. These findings suggest that reovirus infections are common during early childhood.
Age Distribution↗
Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants.
BACKGROUND: Recombination technology can be used to create live attenuated respiratory syncytial virus (RSV) vaccines that contain combinations of known attenuating mutations. METHODS: Two live attenuated, recombinantly derived RSV vaccine candidates, rA2cp248/404 Delta SH and rA2cp248/404/1030 Delta SH, were evaluated in 31 adults and in 95 children >/=6 months old. rA2cp248/404/1030 Delta SH was subsequently evaluated in 44 infants 1-2 months old. These vaccine candidates share 4 attenuating genetic elements and differ only in a missense mutation (1030) in the polymerase gene. RESULTS: Both vaccines were highly attenuated in adults and RSV-seropositive children and were well tolerated and immunogenic in RSV-seronegative children. Compared with that of rA2cp248/404 Delta SH, replication of rA2cp248/404/1030 Delta SH was restricted in RSV-seronegative children (mean peak titer, 10(4.3) vs. 10(2.5) plaque-forming units [pfu]/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/1030 Delta SH was well tolerated in infants, only 44% of infants who received two 10(5.3)-pfu doses of vaccine had detectable antibody responses. However, replication after administration of the second dose was highly restricted, indicating that protective immunity was induced. At least 4 of 5 attenuating genetic elements were retained in recovered vaccine viruses. CONCLUSIONS: rA2cp248/404/1030 Delta SH is the first RSV vaccine candidate to be sufficiently attenuated in young infants. Additional studies are needed to determine whether rA2cp248/404/1030 Delta SH can induce protective immunity against wild-type RSV.
Adult↗
Respiratory syncytial virus infection: denominator-based studies in Indonesia, Mozambique, Nigeria and South Africa.
OBJECTIVE: To assess the burden of respiratory syncytial virus (RSV)-associated lower respiratory infections (LRI) in children in four developing countries. METHODS: A WHO protocol for prospective population-based surveillance of acute respiratory infections in children aged less than 5 years was used at sites in Indonesia, Mozambique, Nigeria and South Africa. RSV antigen was identified by enzyme-linked immunosorbent assay performed on nasopharyngeal specimens from children meeting clinical case definitions. FINDINGS: Among children aged < 5 years, the incidence of RSV-associated LRI per 1000 child-years was 34 in Indonesia and 94 in Nigeria. The incidence of RSV-associated severe LRI per 1000 child-years was 5 in Mozambique, 10 in Indonesia, and 9 in South Africa. At all study sites, the majority of RSV cases occurred in infants. CONCLUSION: These studies demonstrate that RSV contributes to a substantial but quite variable burden of LRI in children aged < 5 years in four developing countries. The possible explanations for this variation include social factors, such as family size and patterns of seeking health care; the proportion of children infected by human immunodeficiency syndrome (HIV); and differences in clinical definitions used for obtaining samples. The age distribution of cases indicates the need for an RSV vaccine that can protect children early in life.
Age Distribution↗
Medical and economic impact of a respiratory syncytial virus outbreak in a neonatal intensive care unit.
BACKGROUND: Respiratory syncytial virus (RSV) causes frequent nosocomial outbreaks in general pediatric wards but is less commonly reported in neonatal intensive care units (NICUs). We investigated an outbreak of RSV infection in a NICU and its impact on health care delivery, outcomes and costs. METHODS: Retrospective chart review was performed after an RSV outbreak occurred in the NICU. A case was defined as an infant with a nasopharyngeal aspirate positive for RSV by viral culture. Nucleotide sequencing of the isolates was done to determine relatedness. Hospital bills for all RSV culture-positive infants were reviewed. RESULTS: Nine infants (mean age, 34 days; mean birth weight, 1757 g; and mean estimated gestational age 31 weeks and 5 days) were infected with RSV subgroup B during this outbreak. By nucleotide sequencing, the isolates were identical. Clinical manifestations included cough, congestion, increased oxygen requirement, apnea and respiratory failure. The 5 infants requiring intubation had a significantly lower mean birth weight (1301 g versus 2328 g, P = 0.027), mean estimated gestational age (28 weeks and 5 days versus 35 weeks and 2 days, P = 0.014) and mean weight at onset of symptoms (2093 g versus 2989 g, P = 0.049) than the 4 nonintubated infants. More than 1.15 million dollars in hospital charges were attributable to the outbreak. All infants survived. CONCLUSION: Infants in a NICU who develop cough, congestion or apnea should be tested for RSV and other common respiratory viruses during the winter respiratory season. Even in a closed NICU, nosocomial outbreaks of these viruses can occur and have a major effect on healthcare delivery, costs and outcomes.
Cross Infection↗
Growth of respiratory syncytial virus in primary epithelial cells from the human respiratory tract.
Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract disease in infants and children. To study RSV replication, we have developed an in vitro model of human nasopharyngeal mucosa, human airway epithelium (HAE). RSV grows to moderate titers in HAE, though they are significantly lower than those in a continuous epithelial cell line, HEp-2. In HAE, RSV spreads over time to form focal collections of infected cells causing minimal cytopathic effect. Unlike HEp-2 cells, in which wild-type and live-attenuated vaccine candidate viruses grow equally well, the vaccine candidates exhibit growth in HAE that parallels their level of attenuation in children.
Cells, Cultured↗
Evaluation of combined live, attenuated respiratory syncytial virus and parainfluenza 3 virus vaccines in infants and young children.
We evaluated a combination respiratory syncytial virus (RSV) and parainfluenza 3 virus (PIV3) live, attenuated intranasal vaccine for safety, viral replication, and immunogenicity in doubly seronegative children 6-18 months old. RSV cpts-248/404 and PIV3-cp45 vaccines were combined in a dose of 10(5) plaque-forming units of each per 0.5-mL dose and compared with monovalent vaccines or placebo. The virus shedding pattern of RSV was not different between monovalent RSV cpts-248/404 vaccine and combination vaccine. Modest reductions in the shedding of PIV3-cp45 vaccine virus were found after the administration of RSV cpts-248/404 and PIV3-cp45 vaccine, relative to monovalent PIV3 vaccine; 16 (76%) of 21 children given combination vaccine shed PIV3-cp45 versus 11 (92%) of 12 of those given monovalent PIV3 vaccine. Both vaccines were immunogenic, and antibody responses were similar between the monovalent groups and the combination group. Combined RSV/PV3 vaccine is feasible for simultaneous administration, and further studies are warranted.
Administration, Intranasal↗
How do influenza vaccines work?
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Adolescent↗