Comparison of Risk Factors for Human Metapneumovirus and Respiratory Syncytial Virus Disease Severity in Young Children

Papenburg, Jesse; Hamelin, Marie‐Ève; Ouhoummane, Najwa; Carbonneau, Julie; Ouakki, Manale; Raymond, Frédéric; Robitaille, Lucie; Corbeil, Jacques; Caouette, Georges; Frenette, Lyne; Serres, Gaston De; Boivin, Guy

doi:10.1093/infdis/jis333

Cited by 136 publications

(165 citation statements)

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“…A cute respiratory infection (ARI) due to respiratory syncytial virus (RSV) is a leading cause of emergency department (ED) visits and hospitalizations in infants and children (1)(2)(3). RSV also produces substantial morbidity and mortality among the elderly and adults with underlying medical conditions (4,5).…”

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Diagnostic Accuracy of Rapid Antigen Detection Tests for Respiratory Syncytial Virus Infection: Systematic Review and Meta-analysis

et al. 2015

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eRespiratory syncytial virus (RSV) rapid antigen detection tests (RADT) are extensively used in clinical laboratories. We performed a systematic review and meta-analysis to evaluate the accuracy of RADTs for diagnosis of RSV infection and to determine factors associated with accuracy estimates. We searched EMBASE and PubMed for diagnostic-accuracy studies of commercialized RSV RADTs. Studies reporting sensitivity and specificity data compared to a reference standard (reverse transcriptase PCR [RT-PCR], immunofluorescence, or viral culture) were considered. Two reviewers independently extracted data on study characteristics, diagnostic-accuracy estimates, and study quality. Accuracy estimates were pooled using bivariate random-effects regression models. Heterogeneity was investigated with prespecified subgroup analyses. Seventy-one articles met inclusion criteria. Overall, RSV RADT pooled sensitivity and specificity were 80% (95% confidence interval [CI], 76% to 83%) and 97% (95% CI, 96% to 98%), respectively. Positive-and negative-likelihood ratios were 25.5 (95% CI, 18.3 to 35.5) and 0.21 (95% CI, 0.18 to 0.24), respectively. Sensitivity was higher in children (81% [95% CI, 78%, 84%]) than in adults (29% [95% CI, 11% to 48%]). Because of this disparity, further subgroup analyses were restricted to pediatric data (63 studies). Test sensitivity was poorest using RT-PCR as a reference standard and highest using immunofluorescence (74% versus 88%; P < 0.001). Industry-sponsored studies reported significantly higher sensitivity (87% versus 78%; P ‫؍‬ 0.01). Our results suggest that the poor sensitivity of RSV RADTs in adults may preclude their use in this population. Furthermore, industry-sponsored studies and those that did not use RT-PCR as a reference standard likely overestimated test sensitivity.A cute respiratory infection (ARI) due to respiratory syncytial virus (RSV) is a leading cause of emergency department (ED) visits and hospitalizations in infants and children (1-3). RSV also produces substantial morbidity and mortality among the elderly and adults with underlying medical conditions (4, 5).Accurate and prompt diagnosis of RSV ARI can have important benefits for patient care. Because concurrent serious bacterial infection with RSV is uncommon, especially in children (6), a timely diagnosis of RSV ARI should diminish unnecessary antibiotic use (7)(8)(9). It may also minimize ancillary testing (10), decrease hospital stay durations (11), and permit prompt implementation of cohort assignment for the purpose of limiting nosocomial transmission within hospitals and long-term-care facilities (13)(14)(15)(16)57). Laboratory testing of respiratory secretions is required for confirmation of RSV infection because its seasonality and nonspecific clinical manifestations may overlap those of other viral and bacterial causes of ARI (17,18).There are currently four RSV diagnostic modalities in clinical use. Viral culture was long considered the gold standard for RSV diagnosis, but it has a turnaround time of 3 to 7 day...

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Diagnostic Accuracy of Rapid Antigen Detection Tests for Respiratory Syncytial Virus Infection: Systematic Review and Meta-analysis

et al. 2015

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“…uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1)(2)(3)(4)(5)(6)(7)(8)(9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection.…”

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Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Hastings

Erickson

Schuster

et al. 2015

J Virol

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Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR ؊/؊ ) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8 ؉ T cell response. HMPV-infected IFNAR ؊/؊ mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR ؊/؊ mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8؉ T cells of IFNAR ؊/؊ mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8 ؉ T cells of IFNAR ؊/؊ mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1 low dendritic cells (DCs), but not PD-L1 high alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8 ؉ T cell impairment. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8 ؉ T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8؉ T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8 ؉ T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8 ؉ T cell impairment. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1-9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection. Nearly all individuals have been exposed to HMPV by the age of 5 years (10, 11). Infection with this virus results in a neutralizing antibody (n...

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“…uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract infection worldwide, with high prevalence in pediatric, elderly, and immunocompromised patients (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). There are no licensed vaccines against HMPV.…”

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Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Cox

Erickson

Hastings

et al. 2014

J Virol

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Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract infection worldwide, with high prevalence in pediatric, elderly, and immunocompromised patients (1-12). There are no licensed vaccines against HMPV. Several strategies to develop live-attenuated HMPV vaccines have been explored, including cold passage, gene deletion, and chimeric viruses (13-17). While live-virus vaccines elicit humoral and cellular responses, they also pose safety risks. Attenuated virus strains have the potential to revert to a wild-type phenotype and cause disease or be transmitted to nonimmune individuals. For these reasons, live attenuated vaccines are often contraindicated for immunocompromised patients, individuals who are at risk for severe HMPV infections. Moreover, it is often difficult to find the correct balance between attenuation and immunogenicity. Many years of research on respiratory syncytial virus (RSV) live attenuated vaccines attest to the challenges (18)(19)(20)(21)(22).GSubunit protein vaccines against HMPV targeting mainly the fusion (F) protein have been effective in rodent models by inducing B cell responses only (23,24). Experience with formalin-inactivated (FI) RSV and HMPV vaccines in humans and animals further raises concern about imbalanced immunity (25)(26)(27)(28)(29)(30). Studies demonstrate that the generation of antibodies to a denatured F protein or low-affinity nonneutralizing antibodies is associated with enhanced respiratory disease (31-36). Thus, a safe and effective vaccine should induce both potent neutralizing antibodies and cytotoxic T cell responses.A vaccination strategy combining elements of both live virus and subunit vaccines is virus-like particles (VLPs). VLPs are formed by the self-assembly of viral structural proteins but lack

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Comparison of Risk Factors for Human Metapneumovirus and Respiratory Syncytial Virus Disease Severity in Young Children

Abstract: hMPV and RSV severity risk factors may differ slightly. These findings will inform hMPV prevention strategies.

Cited by 136 publications

References 29 publications

Diagnostic Accuracy of Rapid Antigen Detection Tests for Respiratory Syncytial Virus Infection: Systematic Review and Meta-analysis

Diagnostic Accuracy of Rapid Antigen Detection Tests for Respiratory Syncytial Virus Infection: Systematic Review and Meta-analysis

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

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