Human Factors Contributing to Infection Prevention in Outpatient Hemodialysis Centers: A Mixed Methods Study.

RATIONALE & OBJECTIVE: Infection prevention efforts in dialysis centers can avert patient morbidity and mortality but are challenging to implement. The objective of this study was to better understand how the design of the work system might contribute to infection prevention in outpatient dialysis centers. STUDY DESIGN: Mixed methods, observational study. SETTING & PARTICIPANTS: Six dialysis facilities across the United States visited by a multidisciplinary team over 8 months. ANALYTICAL APPROACH: At each facility, structured macroergonomic observations were undertaken by a multidisciplinary team using the SEIPS 1.0 model. Ethnographic observations were collected about staff encounters with dialysis patients including the content of staff conversations. Selective and axial coding were used for qualitative analysis and quantitative data were reported using descriptive statistics. RESULTS: Organizational and sociotechnical barriers and facilitators to infection prevention in the outpatient dialysis setting were identified. Features related to human performance, (eg, alarms, interruptions, and task stacking), work system design (eg, physical space, scheduling, leadership, and culture), and extrinsic factors (eg, patient-related characteristics) were identified. LIMITATIONS: This was an exploratory evaluation with a small sample size. CONCLUSIONS: This study used a systematic macroergonomic approach in multiple outpatient dialysis facilities to identify infection prevention barriers and facilitators related to human performance. Several features common across facilities were identified that may influence infection prevention in outpatient care and warrant further exploration.

Differentiated cultures of an immortalized human neural progenitor cell line do not replicate prions despite PrPC overexpression.

Prions are misfolded proteins that accumulate within the brain in association with a rare group of fatal and infectious neurological disorders in humans and animals. A current challenge to research is a lack of in vitro model systems that are compatible with a wide range of prion strains, reproduce prion toxicity, and are amenable to genetic manipulations. In an attempt to address this need, here we produced stable cell lines that overexpress different versions of PrPC through lentiviral transduction of immortalized human neural progenitor cells (ReN VM). Differentiated cultures made from the neural progenitor cell lines overexpressed PrPC within 3D spheroid-like structures of TUBB3+ neurons and we observed evidence that PrPC modulates formation of these structures, consistent with PrPC's role in neurogenesis. However, through repeated measurements of amyloid seeding activity in 6-week time course experiments, we failed to observe any evidence of prion replication within the differentiated ReN cultures following challenge with four prion isolates (human sCJD subtypes MM1 and VV2, and rodent adapted scrapie strains RML and 263K). We attributed amyloid seeding activity detected within the cultures to residual inoculum and concluded that PrPC overexpression was insufficient to confer permissiveness of ReN cultures to prion infection. While our ReN cell prion infection model was unsuccessful, additional efforts to develop cellular models of human prion disease are highly warranted.

Development of an Automated Capillary Immunoassay to Detect Prion Glycotypes in Creutzfeldt-Jakob Disease.

Creutzfeldt-Jakob disease (CJD) comprises a group of transmissible neurodegenerative diseases with vast phenotypic diversity. Sporadic CJD heterogeneity is predominantly influenced by the genotype at codon 129 of the prion-encoding gene and the molecular weight of PrPSc fragments after protease digestion, resulting in a classification of 6 subtypes of CJD (MM1, MM2, MV1, MV2, VV1, and VV2). The majority of cases with CJD can be distinguished using this classification system. However, a number of reported CJD cases are phenotypically unique from others within their same subtype, such as variably protease-sensitive prionopathies, or exist as a mixture of subtypes within the same patient. Western blotting of brain tissue, along with the genotyping of codon 129 of the prion-encoding gene, is considered the "gold standard" for the biochemical characterization of CJD. Western blotting requires a significant amount of prion protein for detection, is labor-intensive, and is also associated with high interassay variability. In addition to these limitations, a growing body of research suggests that unique subtypes of CJD are often undetected or misdiagnosed using standard diagnostic western blotting protocols. Consequently, we successfully optimized and developed a capillary-based western assay using the JESS Simple Western (ProteinSimple) to detect and characterize prion proteins from patients with CJD. We found that this novel assay consistently differentiated CJD type 1 and type 2 cases with a limit of detection 10 to 100× higher than traditional western blotting. Cases with CJD in which type 1 and type 2 coexist within the same brain region can be detected using type 1-specific and type 2-specific antibodies, and we found that there was remarkable specificity for the detection of cases with variably protease-sensitive prionopathy. The assay presented displays outstanding sensitivity, allowing for the preservation of valuable samples and enhancing current detection methods.

Engineered AAV8 capsid acquires heparin and AVB sepharose binding capacity but has altered in vivo transduction efficiency.

Naturally occurring adeno-associated virus (AAV) serotypes that bind to ligands such as AVB sepharose or heparin can be purified by affinity chromatography, which is a more efficient and scalable method than gradient ultracentrifugation. Wild-type AAV8 does not bind effectively to either of these molecules, which constitutes a barrier to using this vector when a high throughput design is required. Previously, AAV8 was engineered to contain a SPAKFA amino acid sequence to facilitate purification using AVB sepharose resin; however, in vivo studies were not conducted to examine whether these capsid mutations altered the transduction profile. To address this gap in knowledge, a mutant AAV8 capsid was engineered to bind to AVB sepharose and heparan sulfate (AAV8-AVB-HS), which efficiently bound to both affinity columns, resulting in elution yields of >80% of the total vector loaded compared to <5% for wild-type AAV8. However, in vivo comparison by intramuscular, intravenous, and intraperitoneal vector administration demonstrated a significant decrease in AAV8-AVB-HS transduction efficiency without alteration of the transduction profile. Therefore, although it is possible to engineer AAV capsids to bind various affinity ligands, the consequences associated with mutating surface exposed residues have the potential to negatively impact other vector characteristics including in vivo potency and production yield. This study demonstrates the importance of evaluating all aspects of vector performance when engineering AAV capsids.

SARS-CoV-2 Infections among Vaccinated Patients on Maintenance Dialysis, January 1-August 31, 2021, United States.

Dialysis facilities voluntarily reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in vaccinated dialysis patients detected between January 1, 2021, and August 31, 2021, to the Centers for Disease Control and Prevention.Among 4087 patients reported, most were symptomatic, a third required hospitalization, and 9% died within 30 days of diagnosis.Monitoring SARS-CoV-2 infections and outcomes among vaccinated people on dialysis provides valuable insight into this population.

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease.

Prion diseases are neurodegenerative disorders with long asymptomatic incubation periods, followed by a rapid progression of cognitive and functional decline culminating in death. The complexity of intercellular interactions in the brain is challenging to unravel and the basis of disease pathobiology remains poorly understood. In this study, we employed single cell RNA sequencing (scRNAseq) to produce an atlas of 147,536 single cell transcriptomes from cortex and hippocampus of mice infected with prions and showing clinical signs. We identified transcriptionally distinct populations and sub-populations of all the major brain cell-types. Disease-related transcription was highly specific to not only overarching cell-types, but also to sub-populations of glia and neurons. Most striking was an apparent decrease in relative frequency of astrocytes expressing genes that are required for brain homeostasis such as lipid synthesis, glutamate clearance, synaptic modulation and regulation of blood flow. Additionally, we described a spectrum of microglial activation states that suggest delineation of phagocytic and neuroinflammatory functions in different cell subsets. Differential responses of immature and mature neuron populations were also observed, alongside abnormal hippocampal neurogenesis. Our scRNAseq library provides a new layer of knowledge on single cell gene expression in prion disease, and is a basis for a more detailed understanding of cellular interplay that leads to neurodegeneration.

Dialysis Water Supply Faucet as Reservoir for Carbapenemase-Producing Pseudomonas aeruginosa.

During June 2017-November 2019, a total 36 patients with carbapenem-resistant Pseudomonas aeruginosa harboring Verona-integron-encoded metallo-ß-lactamase were identified in a city in western Texas, USA. A faucet contaminated with the organism, identified through environmental sampling, in a specialty care room was the likely source for infection in a subset of patients.

AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge.

Filoviruses cause severe hemorrhagic fever with case fatality rates as high as 90%. Filovirus-specific monoclonal antibodies (mAbs) confer protection in nonhuman primates as late as 5 days after challenge, and FDA-approved mAbs REGN-EB3 and mAb114 have demonstrated efficacy against Ebola virus (EBOV) infection in humans. Vectorized antibody expression mediated by adeno-associated virus (AAV) can generate protective and sustained concentrations of therapeutic mAbs in animal models for a variety of infectious diseases, including EBOV. Here we demonstrate that AAV6.2FF-mediated expression of murine IgG2a EBOV mAbs, 2G4 and 5D2, protects from mouse-adapted (MA)-EBOV infection with none of the surviving mice developing anti-VP40 antibodies above background. Protective serum concentrations of AAV6.2FF-2G4/AAV6.2FF-5D2 did not alter endogenous antibody responses to heterologous virus infection. AAV-mediated expression of EBOV mAbs 100 and 114, and pan-ebolavirus mAbs, FVM04, ADI-15878, and CA45, as human IgG1 antibodies conferred protection against MA-EBOV at low serum concentrations, with minimum protective serum levels as low as 2 µg/mL. Vectorized expression of murine IgG2a or human IgG1 mAbs led to sustained expression in the serum of mice for >400 days or for the lifetime of the animal, respectively. AAV6.2FF-mediated mAb expression offers an alternative to recombinant antibody administration in scenarios where long-term protection is preferable to passive immunization.

Neurons and Astrocytes Elicit Brain Region Specific Transcriptional Responses to Prion Disease in the Murine CA1 and Thalamus.

Progressive dysfunction and loss of neurons ultimately culminates in the symptoms and eventual fatality of prion disease, yet the pathways and mechanisms that lead to neuronal degeneration remain elusive. Here, we used RNAseq to profile transcriptional changes in microdissected CA1 and thalamus brain tissues from prion infected mice. Numerous transcripts were altered during clinical disease, whereas very few transcripts were reliably altered at pre-clinical time points. Prion altered transcripts were assigned to broadly defined brain cell types and we noted a strong transcriptional signature that was affiliated with reactive microglia and astrocytes. While very few neuronal transcripts were common between the CA1 and thalamus, we described transcriptional changes in both regions that were related to synaptic dysfunction. Using transcriptional profiling to compare how different neuronal populations respond during prion disease may help decipher mechanisms that lead to neuronal demise and should be investigated with greater detail.

Non-Productive Infection of Glial Cells with SARS-CoV-2 in Hamster Organotypic Cerebellar Slice Cultures.

The numerous neurological syndromes associated with COVID-19 implicate an effect of viral pathogenesis on neuronal function, yet reports of direct SARS-CoV-2 infection in the brain are conflicting. We used a well-established organotypic brain slice culture to determine the permissivity of hamster brain tissues to SARS-CoV-2 infection. We found levels of live virus waned after inoculation and observed no evidence of cell-to-cell spread, indicating that SARS-CoV-2 infection was non-productive. Nonetheless, we identified a small number of infected cells with glial phenotypes; however, no evidence of viral infection or replication was observed in neurons. Our data corroborate several clinical studies that have assessed patients with COVID-19 and their association with neurological involvement.

Single Immunization with Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters against SARS-CoV-2-Caused Clinical Disease.

Increasing cases of SARS-CoV-2 breakthrough infections from immunization with current spike protein-based COVID-19 vaccines highlight the need to develop alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins based on a novel vaccinia virus (VACV) ACAM2000 platform (rACAM2000). In this platform, the vaccinia virus host range and immunoregulatory gene E3L was deleted to make the virus attenuated and to enhance innate immune responses, and another host range gene, K3L, was replaced with a poxvirus ortholog gene, taterapox virus 037 (TATV037), to make virus replication competent in both hamster and human cells. Following a single intramuscular immunization, the rACAM2000 coexpressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and shorter recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titer, and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate, and further studies will investigate if the rACAM2000 vaccine candidate can induce a long-lasting immunity against infection by SARS-CoV-2 variants of concern. IMPORTANCE Continuous emergence of SARS-CoV-2 variants which cause breakthrough infection from the immunity induced by current spike protein-based COVID-19 vaccines highlights the need for new generations of vaccines that will induce long-lasting immunity against a wide range of the variants. To this end, we investigated the protective efficacy of the recombinant COVID-19 vaccine candidates based on a novel VACV ACAM2000 platform, in which an immunoregulatory gene, E3L, was deleted and both the SARS-CoV-2 spike (S) and nucleocapsid (N) antigens were expressed. Thus, it is expected that the vaccine candidate we constructed should be more immunogenic and safer. In the initial study described in this work, we demonstrated that the vaccine candidate expressing both the S and N proteins is superior to the constructs expressing an individual protein (S or N) in protecting hamsters against SARS-CoV-2 challenge after a single-dose immunization, and further investigation against different SARS-CoV-2 variants will warrant future clinical evaluations.

Generation and Characterization of a SARS-CoV-2-Susceptible Mouse Model Using Adeno-Associated Virus (AAV6.2FF)-Mediated Respiratory Delivery of the Human ACE2 Gene.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) that has caused a pandemic with millions of human infections. There continues to be a pressing need to develop potential therapies and vaccines to inhibit SARS-CoV-2 infection to mitigate the ongoing pandemic. Epidemiological data from the current pandemic indicates that there may be sex-dependent differences in disease outcomes. To investigate these differences, we proposed to use common small animal species that are frequently used to model disease with viruses. However, common laboratory strains of mice are not readily infected by SARS-CoV-2 because of differences in the angiotensin-converting enzyme 2 (ACE2), the cellular receptor for the virus. To overcome this limitation, we transduced common laboratory accessible strains of mice of different sexes and age groups with a novel a triple AAV6 mutant, termed AAV6.2FF, encoding either human ACE2 or luciferase via intranasal administration to promote expression in the lung and nasal turbinates. Infection of AAV-hACE2-transduced mice with SARS-CoV-2 resulted in high viral titers in the lungs and nasal turbinates, establishment of an IgM and IgG antibody response, and modulation of lung and nasal turbinate cytokine profiles. There were insignificant differences in infection characteristics between age groups and sex-related differences; however, there were significant strain-related differences between BALB/c vs. C57BL/6 mice. We show that AAV-hACE2-transduced mice are a useful for determining immune responses and for potential evaluation of SARS-CoV-2 vaccines and antiviral therapies, and this study serves as a model for the utility of this approach to rapidly develop small-animal models for emerging viruses.

A multi-country investigation of influenza vaccine coverage in pregnant individuals, 2010-2016.

BACKGROUND: Many countries recommend influenza vaccination during pregnancy. Despite this recommendation, influenza vaccine among pregnant individuals remains under-utilized and uptake varies by country. Factors associated with influenza vaccine uptake during pregnancy may also vary across countries. METHODS: As members of the Pregnancy Influenza Vaccine Effectiveness Network (PREVENT), five sites from four countries (Australia, Canada, Israel, and the United States) retrospectively identified cohorts of individuals aged 18-50 years who were pregnant during pre-defined influenza seasons. Influenza vaccine coverage estimates were calculated for the 2010-11 through 2015-16 northern hemisphere and the 2012 through 2015 southern hemisphere influenza seasons, by site. Sites used electronic health records, administrative data, and immunization registries to collect information on pregnancy, health history, demographics, and vaccination status. Each season, vaccination coverage was calculated as the percentage of individuals who received influenza vaccine among the individuals in the cohort that season. Characteristics were compared between those vaccinated and unvaccinated, by site. RESULTS: More than two million pregnancies were identified over the study period. Influenza vaccination coverage ranged from 5% to 58% across sites and seasons. Coverage increased consistently over the study period at three of the five sites (Western Australia, Alberta, and Israel), and was highest in all seasons at the United States study site (39-58%). Associations with vaccination varied by country and across seasons; where available, parity >0, presence of a high-risk medical condition, and urban residence were consistently associated with increased likelihood of vaccination. CONCLUSIONS: Though increasing, uptake of influenza vaccine among pregnant individuals remains lower than recommended. Coverage varied substantially by country, suggesting an ongoing need for targeted strategies to improve influenza vaccine uptake in this population.

Intranasal vaccination with a Newcastle disease virus-vectored vaccine protects hamsters from SARS-CoV-2 infection and disease.

The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Worldwide efforts are being made to develop vaccines to mitigate this pandemic. We engineered two recombinant Newcastle disease virus (NDV) vectors expressing either the full-length SARS-CoV-2 spike protein (NDV-FLS) or a version with a 19 amino acid deletion at the carboxy terminus (NDV-Δ19S). Hamsters receiving two doses (prime-boost) of NDV-FLS developed a robust SARS-CoV-2-neutralizing antibody response, with elimination of infectious virus in the lungs and minimal lung pathology at five days post-challenge. Single-dose vaccination with NDV-FLS significantly reduced SARS-CoV-2 replication in the lungs but only mildly decreased lung inflammation. NDV-Δ19S-treated hamsters had a moderate decrease in SARS-CoV-2 titers in lungs and presented with severe microscopic lesions, suggesting that truncation of the spike protein was a less effective strategy. In summary, NDV-vectored vaccines represent a viable option for protection against COVID-19.

The impact of varicella vaccination on paediatric herpes zoster epidemiology: a Canadian population-based retrospective cohort study.

The impact of universal varicella vaccination on herpes zoster (HZ) risk in unvaccinated and vaccinated children, and its long-term influence on HZ epidemiology, remains unknown. We conducted a retrospective cohort study using population-based administrative health data for children born between 1993 and 2018 (n = 924,124). We calculated age-specific cumulative HZ incidence rates by vaccination status for cohorts born before (1993-1999) and after (2000-2018) programme implementation; results were used to calculate relative risk of HZ by age group, vaccination status and vaccine availability period. Annual HZ incidence rates were calculated for 1993-2018. HZ risk was higher among unvaccinated children compared to vaccinated children across age groups; 64% higher before universal vaccination (RR: 0.36, 95% CI: 0.33, 0.39), and 32% higher after universal vaccination (RR: 0.68, 95% CI: 0.64, 0.73). Among unvaccinated children, HZ risk was 60% lower after vaccine programme implementation (RR: 0.40, 95% CI: 0.38, 0.43). Two-dose receipt corresponded with a 41% lower risk of HZ compared to one-dose receipt (RR: 0.59, 95% CI: 0.53, 0.65). Crude annual HZ incidence rates declined 64% after programme implementation, with decreases observed across age groups. Universal varicella vaccination programme implementation corresponds to decreased paediatric HZ incidence across age groups, in both vaccinated and unvaccinated individuals. Results from this study can be used to help inform varicella vaccination programme decision-making in other countries.

Suggestions for the prevention of Clostridioides difficile spread within outpatient hemodialysis facilities.

Clostridioides difficile infections (CDIs) cause substantial morbidity and mortality. Patients on maintenance hemodialysis are 2 to 2.5 times more likely to develop CDI, with mortality rates 2-fold higher than the general population. Hospitalizations due to CDI among the maintenance hemodialysis population are high, and the frequency of antibiotic exposures and hospitalizations may contribute to CDI risk. In this report, a panel of experts in clinical nephrology, infectious diseases, and infection prevention provide guidance, based on expert opinion and published literature, aimed at preventing the spread of CDI in outpatient hemodialysis facilities.

Differential pathogenesis between Andes virus strains CHI-7913 and Chile-9717869in Syrian Hamsters.

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory disease caused by orthohantaviruses in the Americas with a fatality rate as high as 35%. In South America, Andes orthohantavirus (Hantaviridae, Orthohantavirus, ANDV) is a major cause of HCPS, particularly in Chile and Argentina, where thousands of cases have been reported since the virus was discovered. Two strains of ANDV that are classically used for experimental studies of the virus are Chile-9717869, isolated from the natural reservoir, the long-tailed pygmy rice rat, and CHI-7913, an isolate from a lethal human case of HCPS. An important animal model for studying pathogenesis of HCPS is the lethal Syrian golden hamster model of ANDV infection. In this model, ANDV strain Chile-9717869 is uniformly lethal and has been used extensively for pathogenesis, vaccination, and therapeutic studies. Here we show that the CHI-7913 strain, despite having high sequence similarity with Chile-9717869, does not cause lethal disease in Syrian hamsters. CHI-7913, while being able to infect hamsters and replicate to moderate levels, showed a reduced ability to replicate within the tissues compared with Chile-9717869. Hamsters infected with CHI-7913 had reduced expression of cytokines IL-4, IL-6, and IFN-γ compared with Chile-9717869 infected animals, suggesting potentially limited immune-mediated pathology. These results demonstrate that certain ANDV strains may not be lethal in the classical Syrian hamster model of infection, and further exploration into the differences between lethal and non-lethal strains provide important insights into molecular determinants of pathogenic hantavirus infection.Importance:Andes orthohantavirus (ANDV) is a New World hantavirus that is a major cause of hantavirus cardiopulmonary syndrome (HCPS, also referred to as hantavirus pulmonary syndrome) in South America, particularly in Chile and Argentina. ANDV is one of the few hantaviruses for which there is a reliable animal model, the Syrian hamster model, which recapitulates important aspects of human disease. Here we infected hamsters with a human isolate of ANDV, CHI-7913, to assess its pathogenicity compared with the classical lethal Chile-9717869 strain. CHI-7913 had 22 amino acid differences compared with Chile-9717869, did not cause lethal disease in hamsters, and showed reduced ability to replicate in vivo Our data indicate potentially important molecular signatures for pathogenesis of ANDV infection in hamsters and may lead to insights into what drives pathogenesis of certain hantaviruses in humans.

Exposure Risk of Chronic Wasting Disease in Humans.

The majority of human prion diseases are sporadic, but acquired disease can occur, as seen with variant Creutzfeldt-Jakob disease (vCJD) following consumption of bovine spongiform encephalopathy (BSE). With increasing rates of cervid chronic wasting disease (CWD), there is concern that a new form of human prion disease may arise. Currently, there is no evidence of transmission of CWD to humans, suggesting the presence of a strong species barrier; however, in vitro and in vivo studies on the zoonotic potential of CWD have yielded mixed results. The emergence of different CWD strains is also concerning, as different strains can have different abilities to cross species barriers. Given that venison consumption is common in areas where CWD rates are on the rise, increased rates of human exposure are inevitable. If CWD was to infect humans, it is unclear how it would present clinically; in vCJD, it was strain-typing of vCJD prions that proved the causal link to BSE. Therefore, the best way to screen for CWD in humans is to have thorough strain-typing of harvested cervids and human CJD cases so that we will be in a position to detect atypical strains or strain shifts within the human CJD population.

Characterization of a novel STAT 2 knock-out hamster model of Crimean-Congo hemorrhagic fever virus pathogenesis.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates.

An international cohort study of birth outcomes associated with hospitalized acute respiratory infection during pregnancy.

OBJECTIVES: Findings during the 2009 pandemic suggest severe maternal infection with pandemic influenza had adverse perinatal health consequences. Limited data exist evaluating the perinatal health effects of severe seasonal influenza and non-influenza infections during pregnancy. METHODS: A retrospective cohort of pregnant women from Australia, Canada, Israel, and the United States was established using birth records to identify pregnancies and birth outcomes and hospital and laboratory testing records to identify influenza and non-influenza associated acute respiratory or febrile illness (ARFI) hospitalizations. ARFI hospitalized women were matched to non-hospitalized women (1:4) by country and season of conception. Log-binomial regression was used to estimate the relative risk (aRR) of preterm birth (PTB), small-for-gestational-age (SGA), and low birthweight (LBW) birth, adjusting for pre-existing medical conditions, maternal age, and parity. RESULTS: 950 pregnant women hospitalized with an ARFI were matched with 3,800 non-hospitalized pregnant women. Compared to non-hospitalized women, risk of PTB was greater among women hospitalized with influenza-associated ARFI (aRR: 1.57; 95% CI: 1.15-2.15) and non-influenza ARFI (aRR: 2.78; 95% CI: 2.12-3.65). Similar results were observed for LBW; there were no associations with SGA birth. CONCLUSIONS: ARFI hospitalization during pregnancy was associated with increased risk of PTB and LBW.