Gaston De Serres

Human Metapneumovirus Infections in Hospitalized Children

We evaluated the percentage of hospitalizations for acute respiratory tract infections in children <3 years of age attributable to human metapneumovirus (HMPV) and other respiratory viruses in a prospective study during winter and spring 2002. We used real-time polymerase chain assays and other conventional diagnostic methods to detect HMPV, human respiratory syncytial virus (HRSV), and influenza viruses in nasopharyngeal aspirates of children. HMPV was detected in 12 (6%) of the 208 children hospitalized for acute respiratory tract infections, HRSV in 118 (57%), and influenza A in 49 (24%). Bronchiolitis was diagnosed in 8 (68%) and pneumonitis in 2 (17%) of HMPV-infected children; of those with HRSV infection, pneumonitis was diagnosed in 99 (84%) and bronchiolitis in 30 (25%). None of the HMPV-infected children was admitted to an intensive-care unit, whereas 15% of those with HRSV or influenza A infections were admitted. HMPV is an important cause of illness in young children with a similar, although less severe, clinical presentation to that of HRSV.

Morbidity of Pertussis in Adolescents and Adults

The effect of age on the clinical presentation of pertussis was assessed in 664 adolescent and adult cases. Complications were more frequent in adults than in adolescents (28% vs. 16%). Pneumonia occurred in 2% of patients <30 years old but in 5%-9% of older patients. Urinary incontinence occurred in 34% of women >/=50 years old. Duration of cough, risk of sinusitis, and number of nights with disturbed sleep increased with smoking and asthma. The secondary attack rate in other household members >/=12 years was 11%. Pertussis in secondary case patients was less severe than in index case patients but presented with classic symptoms. The main source of infection in adolescents was schoolmates or friends; in adults it was workplace or their children. Teachers and health care workers had a greater risk of pertussis than did the general population. The burden of disease appears to increase with age, with smoking, and with asthma.

Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during Spring-Summer 2009: four observational studies from Canada.

BACKGROUND In late spring 2009, concern was raised in Canada that prior vaccination with the 2008-09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association. METHODS AND FINDINGS STUDIES INCLUDED (1) test-negative case-control design based on Canadas sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008-09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33-0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases. CONCLUSIONS Prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.

The Changing Age and Seasonal Profile of Pertussis in Canada

During the postvaccine era in Canada, most cases of pertussis have been reported in children <5 years of age, with the highest incidence, morbidity, and mortality in infants <1 year old. Population-based data, with very high laboratory confirmation rates and hospital separation and mortality statistics, chronicle the changing age and seasonal profile associated with pertussis over recent successive outbreaks in British Columbia, Canada. A large outbreak during 2000 highlights 2 important changes to the postvaccine profile. For the first time in Canada, the incidence of pertussis among preteens and teens surpassed that of all other age groups. At the same time, a decreasing incidence of pertussis among infants and preschool children highlights reduced susceptibility in the very young. Recent changes in the childhood immunization program (including introduction of an acellular pertussis vaccine), waning immunity, and changes in laboratory methods are considered in explaining these 2 simultaneous but divergent trends in the pertussis profile.

Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses

Background Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012–13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. Methods/Findings Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33–63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17–59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16–80%) against A(H1N1)pdm09, 67% (95%CI: 30–85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29–91%) against B/Victoria (non-vaccine-lineage) viruses. Conclusions These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

An outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility.

BACKGROUND Human metapneumovirus (hMPV) is a newly described paramyxovirus that is mainly associated with bronchiolitis in children. We sought to describe the epidemiological, virological, and histopathological findings associated with a large outbreak of hMPV infection in a long-term care facility. METHODS An investigation of the outbreak was performed by public health authorities, who used standardized questionnaires to collect relevant clinical information from all residents of the facility. Nasopharyngeal samples were obtained from a subset of patients who had influenza-like illnesses for testing by viral culture and reverse-transcriptase polymerase chain reaction. Lung tissue samples from a patient whose case was fatal were available for molecular, histopathological, and immunohistochemical testing. RESULTS A total of 96 (27%) of 364 residents of a long-term care facility presented with respiratory or constitutional symptoms between 1 January 2006 and 15 February 2006. The attack rate in the most affected ward was 72% (31 of 43 patients), which included 4 of the 6 polymerase chain reaction-confirmed cases of hMPV infection. In contrast, viral culture results were positive for hMPV in only 2 of the 5 polymerase chain reaction-positive samples tested. The most reported diagnosis was an upper respiratory tract infection or an influenza-like illness, although 21% of residents in 1 of the 3 wards that had confirmed cases of hMPV infection had lower respiratory tract infections. The fatality rate was 50% (3 of 6 patients) among confirmed cases and 9.4% (9 of 96 patients) among patients with possible cases. A patient with a fatal case had histopathological findings that confirmed the presence of hMPV RNA and proteins in the bronchiolar epithelium of affected lobes. Phylogenetic analysis revealed the presence of 2 distinct strains of hMPV circulating simultaneously on different wards. CONCLUSION hMPV can be associated with important outbreaks of acute respiratory tract infection in elderly institutionalized persons.

Multiplex Real-Time PCR Assay for Detection of Influenza and Human Respiratory Syncytial Viruses

ABSTRACT A multiplex real-time PCR assay was developed with a LightCycler instrument for detection of influenza viruses A and B and the human respiratory syncytial virus (HRSV). Detection of each viral product and of an internal control was based on determination of specific melting temperatures by the LightCycler software. The lower limit of detection in the multiplex PCR assay was found to be 50 copies for each viral target. In an evaluation of nasopharyngeal samples collected from hospitalized children (ages, 0 to 3 years) with acute respiratory tract infections during the winter of 2001 to 2002, a viral pathogen was detected by the multiplex PCR test in 139 (66.8%) of 208 cases, including 45 (21.6%) influenza A virus infections, no (0%) influenza B virus infections, 106 (51%) HRSV infections, and 12 (5.8%) coinfections. The multiplex PCR test was compared to rapid antigen detection assays for influenza viruses A and B (Directigen; Becton Dickinson, Sparks, Md.) and HRSV (RSV TestPack; Abbott Laboratories, Abbott Park, Ill.) in 172 and 204 samples, respectively. After resolution of discrepant test results by use of additional PCR assays targeting other viral genes, the sensitivity (Se) and specificity (Sp) of the multiplex PCR assay for influenza A virus were 100 and 97.7% compared to 43.6 and 98.5% for the antigenic test. Similarly, the Se and Sp of the multiplex PCR assay for HRSV were 94.5 and 98.9% compared to 81.6 and 94.7% for the antigenic test. In conclusion, our multiplex real-time PCR assay combines both rapidity and sensitivity for detecting the most important respiratory viral pathogens in children.

Human bocavirus infections in hospitalized children and adults.

The pathogenic role of this virus in infected children is unclear.

Component-Specific Effectiveness of Trivalent Influenza Vaccine as Monitored through a Sentinel Surveillance Network in Canada, 2006–2007

BACKGROUND Trivalent inactivated influenza vaccine (TIV) is reformulated annually to contain representative strains of 2 influenza A subtypes (H1N1 and H3N2) and 1 B lineage (Yamagata or Victoria). We describe a sentinel surveillance approach to link influenza variant detection with component-specific vaccine effectiveness (VE) estimation. METHODS The 2006-2007 TIV included A/NewCaledonia/20/1999(H1N1)-like, A/Wisconsin/67/2005(H3N2)-like, and B/Malaysia/2506/2004(Victoria)-like components. Included participants were individuals >or=9 years of age who presented within 1 week after influenza like illness onset to a sentinel physician between November 2006 and April 2007. Influenza was identified by real-time reverse-transcriptase polymerase chain reaction and/or culture. Isolates were characterized by hemagglutination inhibition assay (HI) and HA1 gene sequence. VE was estimated as 1-[odds ratio for influenza in vaccinated versus nonvaccinated persons]. RESULTS A total of 841 participants contributed: 69 (8%) were >or=65 years of age; 166 (20%) received the 2006-2007 TIV. Influenza was detected in 337 subjects (40%), distributed as follows: A/H3N2, 242 (72%); A/H1N1, 55 (16%); and B, 36 (11%). All but 1 of the A/H1N1 isolates were well matched, half of A/H3N2 isolates were strain mismatched, and all B isolates were lineage-level mismatched to vaccine. Age-adjusted estimated VE for A/H1N1, A/H3N2, and B components was 92% (95% CI, 40%-91%), 41% (95% CI, 6%-63%), and 19% (95% CI, -112% to 69%), respectively, with an overall VE estimate of 47% (95% CI, 18%-65%). Restriction of the analysis to include only working-age adults resulted in lower VE estimates with wide confidence intervals but similar component-specific trends. CONCLUSIONS Sentinel surveillance provides a broad platform to link new variant detection and the composite of circulating viruses to annual monitoring of component-specific VE.

Rapid Decline of Influenza Vaccine—Induced Antibody in the Elderly: Is It Real, or Is It Relevant?

Advisory committees have cautioned that influenza vaccine-induced antibody declines more rapidly in the elderly, falling below seroprotective levels within 4 months. We conducted a literature review to assess this assertion. The articles that were included in this review reported antibody levels > or =4 months after influenza immunization in persons > or =60 years old, interpretable in the context of annual influenza vaccine-approval criteria (seroprotection/seroconversion) specified by the Committee for Proprietary Medicinal Products (CPMP) for the elderly. The final review included 14 studies; 8 of which reported seroprotection rates. Seroprotection exceeding CPMP criteria was maintained > or =4 months after influenza immunization in all 8 of the studies reporting this for the H3N2 component and in 5 of the 7 studies reporting this for the H1N1 and B components. In determining whether CPMP criteria were met at seasons end, primary antibody response appeared to be more relevant than secondary antibody decline. Both studies reporting seroprotection rates that failed CPMP criteria > or =4 months after influenza immunization for each of the H1N1 and B components had also reported failed seroprotection at 1 month after immunization. If initially achieved after immunization, seroprotection rates of 70%-100% were maintained not just at 4 months (2 studies) but also at 5 months (2 studies) and even at >6 months (4 studies), for the H3N2 and H1N1 vaccine components. Seroprotection rates appeared less consistent for the B vaccine component, throughout the postimmunization period. Seroconversion appears to vary substantially and inversely with preimmunization titers but not with age. In 2 of 6 studies reporting seroconversion alone, CPMP criteria were still met at 4 months. In the other 4 studies, the main reason for failure at 4 months was primary failure at 1 month. A total of 6 studies compared antibody persistence by age, and no consistent differences were found on that basis. The historic concern that the influenza vaccine-induced antibody response in the elderly declines more rapidly and below seroprotective levels within 4 months of immunization should be reconsidered.