We identified differences in the peripheral cellular immune response between mild and severe influenza. Our findings suggest that individuals with severe influenza may experience immune activation ...that, despite a slow start, is prolonged, compared with those with mild influenza.
Abstract
Background
The immunologic factors underlying severe influenza are poorly understood. To address this, we compared the immune responses of influenza-confirmed hospitalized individuals with severe acute respiratory illness (SARI) to those of nonhospitalized individuals with influenza-like illness (ILI).
Methods
Peripheral blood lymphocytes were collected from 27 patients with ILI and 27 with SARI, at time of enrollment and then 2 weeks later. Innate and adaptive cellular immune responses were assessed by flow cytometry, and serum cytokine levels were assessed by a bead-based assay.
Results
During the acute phase, SARI was associated with significantly reduced numbers of circulating myeloid dendritic cells, CD192+ monocytes, and influenza virus–specific CD8+ and CD4+ T cells as compared to ILI. By the convalescent phase, however, most SARI cases displayed continued immune activation characterized by increased numbers of CD16+ monocytes and proliferating, and influenza virus–specific, CD8+ T cells as compared to ILI cases. SARI was also associated with reduced amounts of cytokines that regulate T-cell responses (ie, interleukin 4, interleukin 13, interleukin 12, interleukin 10, and tumor necrosis factor β) and hematopoiesis (interleukin 3 and granulocyte-macrophage colony-stimulating factor) but increased amounts of a proinflammatory cytokine (tumor necrosis factor α), chemotactic cytokines (MDC, MCP-1, GRO, and fractalkine), and growth-promoting cytokines (PDGFBB/AA, VEGF, and EGF) as compared to ILI.
Conclusions
Severe influenza cases showed a delay in the peripheral immune activation that likely led prolonged inflammation, compared with mild influenza cases.
Cytokines and chemokines are key signaling molecules of the immune system. Recent technological advances enable measurement of multiplexed cytokine profiles in biological samples. These profiles can ...then be used to identify potential biomarkers of a variety of clinical phenotypes. However, testing for such associations for each cytokine separately ignores the highly context-dependent covariation in cytokine secretion and decreases statistical power to detect associations due to multiple hypothesis testing. Here we present CytoMod-a novel data-driven approach for analysis of cytokine profiles that uses unsupervised clustering and regression to identify putative functional modules of co-signaling cytokines. Each module represents a biosignature of co-signaling cytokines. We applied this approach to three independent clinical cohorts of subjects naturally infected with influenza in which cytokine profiles and clinical phenotypes were collected. We found that in two out of three cohorts, cytokine modules were significantly associated with clinical phenotypes, and in many cases these associations were stronger than the associations of the individual cytokines within them. By comparing cytokine modules across datasets, we identified cytokine "cores"-specific subsets of co-expressed cytokines that clustered together across the three cohorts. Cytokine cores were also associated with clinical phenotypes. Interestingly, most of these cores were also co-expressed in a cohort of healthy controls, suggesting that in part, patterns of cytokine co-signaling may be generalizable. CytoMod can be readily applied to any cytokine profile dataset regardless of measurement technology, increases the statistical power to detect associations with clinical phenotypes and may help shed light on the complex co-signaling networks of cytokines in both health and infection.
Recent experience with pandemic influenza A(H1N1)pdm09 highlighted the importance of global surveillance for severe respiratory disease to support pandemic preparedness and seasonal influenza ...control. Improved surveillance in the southern hemisphere is needed to provide critical data on influenza epidemiology, disease burden, circulating strains and effectiveness of influenza prevention and control measures. Hospital-based surveillance for severe acute respiratory infection (SARI) cases was established in New Zealand on 30 April 2012. The aims were to measure incidence, prevalence, risk factors, clinical spectrum and outcomes for SARI and associated influenza and other respiratory pathogen cases as well as to understand influenza contribution to patients not meeting SARI case definition.
All inpatients with suspected respiratory infections who were admitted overnight to the study hospitals were screened daily. If a patient met the World Health Organization's SARI case definition, a respiratory specimen was tested for influenza and other respiratory pathogens. A case report form captured demographics, history of presenting illness, co-morbidities, disease course and outcome and risk factors. These data were supplemented from electronic clinical records and other linked data sources.
Hospital-based SARI surveillance has been implemented and is fully functioning in New Zealand. Active, prospective, continuous, hospital-based SARI surveillance is useful in supporting pandemic preparedness for emerging influenza A(H7N9) virus infections and seasonal influenza prevention and control.
The failure to mount an antibody response following viral infection or seroconversion failure is a largely underappreciated and poorly understood phenomenon. Here, we identified immunologic markers ...associated with robust antibody responses after influenza virus infection in two independent human cohorts, SHIVERS and FLU09, based in Auckland, New Zealand and Memphis, Tennessee, USA, respectively. In the SHIVERS cohort, seroconversion significantly associates with (1) hospitalization, (2) greater numbers of proliferating, activated CD4+ T cells, but not CD8+ T cells, in the periphery during the acute phase of illness, and (3) fewer inflammatory monocytes (CD14hiCD16+) by convalescence. In the FLU09 cohort, fewer CD14hiCD16+ monocytes during early illness in the nasal mucosa were also associated with the generation of influenza-specific mucosal immunoglobulin A (IgA) and IgG antibodies. Our study demonstrates that seroconversion failure after infection is a definable immunological phenomenon, associated with quantifiable cellular markers that can be used to improve diagnostics, vaccine efficacy, and epidemiologic efforts.
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Post-infection seroconversion is associated with severity of influenza virus infectionSeroconverters have early proliferation and activation of CD4+ T cellsCD8+ T cells are unaffectedCD14hiCD16+ monocytes in the blood and nasal mucosa is associated with antibody response
Wong et al. show that antibody responsiveness after influenza virus infection is associated with CD4+ T cells and CD14hiCD16+ monocytes. CD14hiCD16+ monocytes are also important in the mucosal antibody response. This demonstrates that seroconversion failure after infection is a definable immunological phenomenon, an important consideration for diagnostics and epidemiological studies.
Pregnant women are prioritized for seasonal influenza vaccination, but the evidence on the risk of influenza during pregnancy that is used to inform these policies is limited.
Individual-level ...administrative data sets and active surveillance data were joined to estimate influenza-associated hospitalization and outpatient visit rates by pregnancy, postpartum, and trimester status.
During 2012-2015, 46 of 260 (17.7%) influenza-confirmed hospitalizations for acute respiratory infection and 13 of 294 (4.4%) influenza-confirmed outpatient visits were among pregnant and postpartum women. Pregnant and postpartum women experienced higher rates of influenza-associated hospitalization than nonpregnant women overall (rate ratio RR, 3.4; 95% confidence interval CI, 2.5-4.7) and by trimester (first, 2.5 95% CI, 1.2-5.4; second, 3.9 95% CI, 2.4-6.3; and third, 4.8 95% CI, 3.0-7.7); the RR for the postpartum period was 0.7 (95% CI, 3.0-7.7). Influenza A viruses were associated with an increased risk (RR for 2009 pandemic influenza AH1N1 virus, 5.3 95% CI, 3.2-8.7; RR for influenza A(H3N2) virus, 3.0 95% CI, 1.8-5.0), but influenza B virus was not (RR, 1.8; 95% CI, .7-4.6). Influenza-associated hospitalization rates in pregnancy were significantly higher for Māori women (RR, 3.2; 95% CI, 1.3-8.4), compared with women of European or other ethnicity. Similar risks for influenza-confirmed outpatient visits were not observed.
Seasonal influenza poses higher risks of hospitalization among pregnant women in all trimesters, compared with nonpregnant women. Hospitalization rates vary by influenza virus type and ethnicity among pregnant women.
Abstract
Background
Understanding the attack rate of influenza infection and the proportion who become ill by risk group is key to implementing prevention measures. While population-based studies of ...antihemagglutinin antibody responses have been described previously, studies examining both antihemagglutinin and antineuraminidase antibodies are lacking.
Methods
In 2015, we conducted a seroepidemiologic cohort study of individuals randomly selected from a population in New Zealand. We tested paired sera for hemagglutination inhibition (HAI) or neuraminidase inhibition (NAI) titers for seroconversion. We followed participants weekly and performed influenza polymerase chain reaction (PCR) for those reporting influenza-like illness (ILI).
Results
Influenza infection (either HAI or NAI seroconversion) was found in 321 (35% 95% confidence interval, 32%–38%) of 911 unvaccinated participants, of whom 100 (31%) seroconverted to NAI alone. Young children and Pacific peoples experienced the highest influenza infection attack rates, but overall only a quarter of all infected reported influenza PCR–confirmed ILI, and one-quarter of these sought medical attention. Seroconversion to NAI alone was higher among children aged <5 years vs those aged ≥5 years (14% vs 4%; P < .001) and among those with influenza B vs A(H3N2) virus infections (7% vs 0.3%; P < .001).
Conclusions
Measurement of antineuraminidase antibodies in addition to antihemagglutinin antibodies may be important in capturing the true influenza infection rates.
New Zealand’s seroepidemiological cohort study found that neuraminidase inhibition assay identified more influenza virus infections than hemagglutination inhibition assay. This result highlights the importance to measure serologically defined infections against not just hemagglutinin but also neuraminidase antigens in future seroepidemiologic cohort studies.
Despite evidence that antibodies targeting the influenza virus neuraminidase (NA) protein can be protective and are broadly cross-reactive, the immune response to NA during infection is poorly ...understood compared to the response to hemagglutinin (HA) protein. As such, we compared the antibody profile to HA and NA in two naturally infected human cohorts in Auckland, New Zealand: (i) a serosurvey cohort, consisting of pre- and post-influenza season sera from PCR-confirmed influenza cases (
= 50), and (ii) an immunology cohort, consisting of paired sera collected after PCR-confirmation of infection (
= 94). The induction of both HA and NA antibodies in these cohorts was influenced by age and subtype. Seroconversion to HA was more frequent in those <20 years old (yo) for influenza A (serosurvey,
= 0.01; immunology,
= 0.02) but not influenza B virus infection. Seroconversion to NA was not influenced by age or virus type. Adults ≥20 yo infected with influenza A viruses were more likely to show NA-only seroconversion compared to children (56% versus 14% 5 to 19 yo and 0% 0 to 4 yo, respectively). Conversely, children infected with influenza B viruses were more likely than adults to show NA-only seroconversion (88% 0 to 4 yo and 75% 5 to 19 yo versus 40% ≥20 yo). These data indicate a potential role for immunological memory in the dynamics of HA and NA antibody responses. A better mechanistic understanding of this phenomenon will be critical for any future vaccines aimed at eliciting NA immunity.
Data on the immunologic responses to neuraminidase (NA) is lacking compared to what is available on hemagglutinin (HA) responses, despite growing evidence that NA immunity can be protective and broadly cross-reactive. Understanding these NA responses during natural infection is key to exploiting these properties for improving influenza vaccines. Using two community-acquired influenza cohorts, we showed that the induction of both HA and NA antibodies after infection is influenced by age and subtypes. Such response dynamics suggest the influence of immunological memory, and understanding how this process is regulated will be critical to any vaccine effort targeting NA immunity.
Background
New Zealand's (NZ) complete absence of community transmission of influenza and respiratory syncytial virus (RSV) after May 2020, likely due to COVID‐19 elimination measures, provided a ...rare opportunity to assess the impact of border restrictions on common respiratory viral infections over the ensuing 2 years.
Methods
We collected the data from multiple surveillance systems, including hospital‐based severe acute respiratory infection surveillance, SHIVERS‐II, ‐III and ‐IV community cohorts for acute respiratory infection (ARI) surveillance, HealthStat sentinel general practice (GP) based influenza‐like illness surveillance and SHIVERS‐V sentinel GP‐based ARI surveillance, SHIVERS‐V traveller ARI surveillance and laboratory‐based surveillance. We described the data on influenza, RSV and other respiratory viral infections in NZ before, during and after various stages of the COVID related border restrictions.
Results
We observed that border closure to most people, and mandatory government‐managed isolation and quarantine on arrival for those allowed to enter, appeared to be effective in keeping influenza and RSV infections out of the NZ community. Border restrictions did not affect community transmission of other respiratory viruses such as rhinovirus and parainfluenza virus type‐1. Partial border relaxations through quarantine‐free travel with Australia and other countries were quickly followed by importation of RSV in 2021 and influenza in 2022.
Conclusion
Our findings inform future pandemic preparedness and strategies to model and manage the impact of influenza and other respiratory viral threats.
Highlights • This study adds to the limited research on VE to influenza from the southern hemisphere. • TIV vaccines show low to moderate protection against influenza positive hospitalisation in ...2012. • VE varied by influenza type and subtype. • Vaccination appeared to be less effective in patients aged 65 years and older. • Older people did not appear to be significantly protected against infection with influenza A (H3N2).
Abstract By early 2022, the highly transmissible Omicron variant of SARS-CoV-2 had spread across most of the world. For the first time since the pandemic began, New Zealand was experiencing high ...levels of community transmission of SARS-CoV-2. We enroled a cohort of households to better understand differences in transmission dynamics among subvariants of Omicron. We enroled 71 households, comprising 289 participants, and aimed to use viral genomes to gain a clearer understanding of variant-specific differences in epidemiological parameters affecting transmission dynamics. Approximately 80% of the households enroled experienced transmission of BA.2, while most of the remaining households had infections with BA.1 or BA.5. Using a logistic regression generalised linear mixed model, we found no difference in household secondary infection rate between Omicron subvariants BA.1, BA.2 and BA.5. Of the households recruited, the vast majority (92%) experienced a single chain of transmission with one inferred introduction. Further, we found that in 48% of the households studied, all household participants became infected following an index case. Most household participants tested positive within a week following an introduction, supporting the seven-day isolation requirement for household contacts that was in place in New Zealand at the time. By integrating genomic and epidemiological data, we show that viral transmission dynamics can be investigated with a higher level of granularity than with epidemiological data alone. Overall, households are a high risk setting for viral transmission in New Zealand.
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