Marilda M. Siqueira

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

Global Distribution of Measles Genotypes and Measles Molecular Epidemiology

A critical component of laboratory surveillance for measles is the genetic characterization of circulating wild-type viruses. The World Health Organization (WHO) Measles and Rubella Laboratory Network (LabNet), provides for standardized testing in 183 countries and supports genetic characterization of currently circulating strains of measles viruses. The goal of this report is to describe the lessons learned from nearly 20 years of virologic surveillance for measles, to describe the global databases for measles sequences, and to provide regional updates about measles genotypes detected by recent surveillance activities. Virologic surveillance for measles is now well established in all of the WHO regions, and most countries have conducted at least some baseline surveillance. The WHO Global Genotype Database contains >7000 genotype reports, and the Measles Nucleotide Surveillance (MeaNS) contains >4000 entries. This sequence information has proven to be extremely useful for tracking global transmission patterns and for documenting the interruption of transmission in some countries. The future challenges will be to develop quality control programs for molecular methods and to continue to expand virologic surveillance activities in all regions.

Respiratory tract viral infections in bone marrow transplant patients.

Background. Community respiratory viruses such as respiratory syncytial virus (RSV), adenovirus, influenza A, influenza B, and the parainfluenza group are frequent causes of respiratory disease in bone marrow transplant (BMT) patients. Material and Methods. During the period from March 1993 to August 1999, 810 samples of respiratory secretions, nasopharyngeal aspirate (NPA) or bronchoalveolar lavage (BAL), from 722 patients with upper respiratory infections symptoms at the BMT unit of the Federal University in the state of Paraná, Brazil were evaluated for respiratory virus infection. Results. One hundred thirty‐six (17%) samples were reactive in 62 patients. RSV was found in 30 of 62 (48%), influenza A in 14 of 62 (23%), influenza B in 9 of 62 (15%), parainfluenza group in 7 of 62 (11%), and adenovirus in 2 of 62 (3%) infected patients. The most frequent clinical manifestations were cough and fever. Pneumonia occurred in 19 of 62 (31%) cases. The mortality rate was 23 of 62 (37%), being higher among patients infected with adenovirus and influenza A. Conclusions. Infections in BMT patients occurred during the outbreak period of these viruses in the community, highlighting the need to establish surveillance measures in units with immunocompromised patients in addition to the development of sensitive and rapid diagnostic tests for the detection of these viruses in patients with respiratory symptoms.

Infecções do trato respiratório inferior pelo vírus sincicial respiratório em crianças hospitalizadas menores de um ano de idade

For analysis of clinical features and outcome of hospitalized infants with respiratory syncytial virus lower respiratory tract infection, was carried out. Cross-sectional study with 89 infants, hospitalized in two public hospitals during the 1997 and 1998 RSV seasons, in Rio de Janeiro city. Nasopharyngeal secretions were obtained and specimens processed for viral antigens detection by indirect immunofluorescence assay with the use of anti RSV, anti-influenza A and B and anti parainfluenza type 3 monoclonal antibodies. Patients were allocated into three diagnostic groups: bronchiolitis or wheeze bronchitis (n = 44); Pneumonia (n = 26) and bronchiolitis or wheeze bronchitis and pneumonia (n = 19). Positivity for RSV was found in 42 (47.1%) patients. More days of hospitalization were seen in 1997 in comparison with the follow year (p >0.05). No clinical differences were found between RSV positive and negative children. The sensitivity and specificity for wheezing concerning the isolation of RSV were, respectively, 85% and 65%. RSV was the major cause of LRTI in hospitalized infants.

Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014–2015

The World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza (WHO CCs) tested 13,312 viruses collected by WHO recognized National Influenza Centres between May 2014 and May 2015 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Ninety-four per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.5% (n = 68) of viruses showed either highly reduced inhibition (HRI) or reduced inhibition (RI) (n = 56) against at least one of the four NAIs. Of the twelve viruses with HRI, six were A(H1N1)pdm09 viruses, three were A(H3N2) viruses and three were B/Yamagata-lineage viruses. The overall frequency of viruses with RI or HRI by the NAIs was lower than that observed in 2013–14 (1.9%), but similar to the 2012–13 period (0.6%). Based on the current analysis, the NAIs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.

Viral etiology of acute respiratory infections among children in Porto Alegre, RS, Brazil

Although acute respiratory infections (ARIs) are a major cause of child morbidity and mortality in Southern Brazil, little information is available on their seasonality and viral etiology. This study was conducted on children under 5 years of age with ARI to assess viral etiology in the State of Rio Grande do Sul, from 1990 to 1992. A total of 862 nasopharyngeal secretion (NPS) samples were tested using indirect immunofluorescence. The results showed that 316 (36.6%) NPS samples were positive: 26.2% for RSV, 6% for adenovirus, 1.7% for influenza viruses, 1.5% for parainfluenza viruses, and 1.2% for mixed infection. The mean viral prevalence rates in out-patient services, emergency wards, and in-patient hospital wards were 26.7%, 53% and 42.3%, respectively. Respiratory syncytial virus (RSV) and adenovirus accounted for 91.4 % of the viral diagnoses. RSV was more frequent in children under one year of age at the three levels of health care and was prevalent in infants under six months. Adenovirus was the most prevalent pathogen in hospitalized children, in 1992. Influenza A virus showed an increased prevalence with age among out-patient children. This study shows the annual occurrence of viral respiratory infections in the coldest months, with a significant annual variation in the frequency of RSV infection.

Longitudinal study of acute respiratory diseases in Rio de Janeiro: occurrence of respiratory viruses during four consecutive years

The occurrence of different viruses in nasopharyngeal secretions from children less than 5 years old with acute respiratory infections (ARI) was investigated over a period of 4 years (1982-1985) in Rio de Janeiro. Of the viruses known to be associated with ARI, all but influenza C and parainfluenza types 1, 2 and 4 were found. Viruses were found more frequently in children attending emergency or pediatric wards than in outpatients. This was clearly related to the high incidence of respiratory syncytial virus (RSV) in the more severe cases of ARI. RSV positive specimens appeared mainly during the fall, over four consecutive years, showing a clear seasonal occurrence of this virus. Emergency wards provide the best source of data for RSV surveillance, showing sharp increase in the number of positive cases coinciding with increased incidence of ARI cases. Adenovirus were the second most frequent viruses isolated and among these serotypes 1, 2 and 7 were predominant. Influenza virus and parainfluenza virus type 3 were next in frequency. Influenza A virus were isolated with equal frequency in outpatient departments, emergency and pediatric wards. Influenza B was more frequent among outpatients. Parainfluenza type 3 caused outbreaks in the shanty-town population annually during the late winter or spring and were isolated mainly from outpatients. Herpesvirus, enterovirus and rhinovirus were found less frequently. Other viruses than RSV and parainfluenza type 3 did not show a clear seasonal incidence.

Prevalence and clinical aspects of respiratory syncytial virus A and B groups in children seen at Hospital de Clínicas of Uberlândia, MG, Brazil

Respiratory syncytial virus (RSV) is well recognized as the most important pathogen causing acute respiratory disease in infants and young children, mainly in the form of bronchiolitis and pneumonia. Two major antigenic groups, A and B, have been identified; however, there is disagreement about the severity of the diseases caused by these two types. This study investigated a possible association between RSV groups and severity of disease. Reverse transcription-polymerase chain reaction was used to characterize 128 RSV nasopharyngeal specimens from children less than five years old experiencing acute respiratory disease. A total of 82 of 128 samples (64.1%) could be typed, and, of these, 78% were group A, and 22% were group B. Severity was measured by clinical evaluation associated with demographic factors: for RSV A-infected patients, 53.1% were hospitalized, whereas for RSV B patients, 27.8% were hospitalized (p = 0.07). Around 35.0% of the patients presented risk factors for severity (e.g., prematurity). For those without risk factors, the hospitalization occurred in 47.6% of patients infected with RSV A and in 18.2% infected with RSV B. There was a trend for RSV B infections to be milder than those of RSV A. Even though RSV A-infected patients, including cases without underlying condition and prematurity, were more likely to require hospitalization than those infected by RSV B, the disease severity could not to be attributed to the RSV groups.

Respiratory viruses in the pediatric intensive care unit: prevalence and clinical aspects.

A survey was conducted in two pediatric intensive care units in hospitals in Porto Alegre, Brazil, in order to monitor the main respiratory viruses present in bronchiolitis and/or pneumonia and their involvement in the severity of viral respiratory infections. Viral respiratory infection prevalence was 38.7%. In bronchiolitis, respiratory syncytial virus (RSV) was detected in 36% of the cases. In pneumonia, the prevalence rates were similar for adenovirus (10.3%) and RSV (7.7%). There was a difference among the viruses detected in terms of frequency of clinical findings indicating greater severity. Frequency of crackles in patients with RSV (47.3%) showed a borderline significance (p = 0.055, Fishers exact test) as compared to those with adenovirus (87.5%). The overall case fatality rate in this study was 2.7%, and adenovirus showed a significantly higher case fatality rate (25%) than RSV (2.8%) (p = 0.005). Injected antibiotics were used in 49% of the children with RSV and 60% of those with adenovirus. Adenovirus was not detected in any of the 33 children submitted to oxygen therapy.

Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14–16 June 2010

• For almost 60 years, the WHO Global Influenza Surveillance and Response System (GISRS) has been the key player in monitoring the evolution and spread of influenza viruses and recommending the strains to be used in human influenza vaccines. The GISRS has also worked to continually monitor and assess the risk posed by potential pandemic viruses and to guide appropriate public health responses. • The expanded and enhanced role of the GISRS following the adoption of the International Health Regulations (2005), recognition of the continuing threat posed by avian H5N1 and the aftermath of the 2009 H1N1 pandemic provide an opportune time to critically review the process by which influenza vaccine viruses are selected. In addition to identifying potential areas for improvement, such a review will also help to promote greater appreciation by the wider influenza and policy-making community of the complexity of influenza vaccine virus selection. • The selection process is highly coordinated and involves continual year-round integration of virological data and epidemiological information by National Influenza Centres (NICs), thorough antigenic and genetic characterization of viruses by WHO Collaborating Centres (WHOCCs) as part of selecting suitable candidate vaccine viruses, and the preparation of suitable reassortants and corresponding reagents for vaccine standardization by WHO Essential Regulatory Laboratories (ERLs). • Ensuring the optimal effectiveness of vaccines has been assisted in recent years by advances in molecular diagnosis and the availability of more extensive genetic sequence data. However, there remain a number of challenging constraints including variations in the assays used, the possibility of complications resulting from non-antigenic changes, the limited availability of suitable vaccine viruses and the requirement for recommendations to be made up to a year in advance of the peak of influenza season because of production constraints. • Effective collaboration and coordination between human and animal influenza networks is increasingly recognized as an essential requirement for the improved integration of data on animal and human viruses, the identification of unusual influenza A viruses infecting human, the evaluation of pandemic risk and the selection of candidate viruses for pandemic vaccines. • Training workshops, assessments and donations have led to significant increases in trained laboratory personnel and equipment with resulting expansion in both geographical surveillance coverage and in the capacities of NICs and other laboratories. This has resulted in a significant increase in the volume of information reported to WHO on the spread, intensity and impact of influenza. In addition, initiatives such as the WHO Shipment Fund Project have facilitated the timely sharing of clinical specimens and virus isolates and contributed to a more comprehensive understanding of the global distribution and temporal circulation of different viruses. It will be important to sustain and build upon the gains made in these and other areas. • Although the haemagglutination inhibition (HAI) assay is likely to remain the assay of choice for the antigenic characterization of viruses in the foreseeable future, alternative assays - for example based upon advanced recombinant DNA and protein technologies - may be more adaptable to automation. Other technologies such as microtitre neuraminidase inhibition assays may also have significant implications for both vaccine virus selection and vaccine development. • Microneutralization assays provide an important adjunct to the HAI assay in virus antigenic characterization. Improvements in the use and potential automation of such assays should facilitate large-scale serological studies, while other advanced techniques such as epitope mapping should allow for a more accurate assessment of the quality of a protective immune response and aid the development of additional criteria for measuring immunity. • Standardized seroepidemiological surveys to assess the impact of influenza in a population could help to establish well-characterized banks of age-stratified representative sera as a national, regional and global resource, while providing direct evidence of the specific benefits of vaccination. • Advances in high-throughput genetic sequencing coupled with advanced bioinformatics tools, together with more X-ray crystallographic data, should accelerate understanding of the genetic and phenotypic changes that underlie virus evolution and more specifically help to predict the influence of amino acid changes on virus antigenicity. • Complex mathematical modelling techniques are increasingly being used to gain insights into the evolution and epidemiology of influenza viruses. However, their value in predicting the timing and nature of future antigenic and genetic changes is likely to be limited at present. The application of simpler non-mechanistic statistical algorithms, such as those already used as the basis of antigenic cartography, and phylogenetic modelling are more likely to be useful in facilitating vaccine virus selection and in aiding assessment of the pandemic potential of avian and other animal influenza viruses. • The adoption of alternative vaccine technologies - such as live-attenuated, quadrivalent or non-HA-based vaccines - has significant implications for vaccine virus selection, as well as for vaccine regulatory and manufacturing processes. Recent collaboration between the GISRS and vaccine manufacturers has resulted in the increased availability of egg isolates and high-growth reassortants for vaccine production, the development of qualified cell cultures and the investigation of alternative methods of vaccine potency testing. WHO will continue to support these and other efforts to increase the reliability and timeliness of the global influenza vaccine supply. • The WHO GISRS and its partners are continually working to identify improvements, harness new technologies and strengthen and sustain collaboration. WHO will continue in its central role of coordinating worldwide expertise to meet the increasing public health need for influenza vaccines and will support efforts to improve the vaccine virus selection process, including through the convening of periodic international consultations.