Unraveling the Role of Viral Interference in Disrupting Biennial RSV Epidemics in Northern Stockholm.

Respiratory syncytial virus (RSV) primarily impacts infants and older adults, with seasonal winter outbreaks in temperate countries. Biennial cycles of RSV activity have also been identified in Northern Europe and some states in the United States. Delayed RSV activity was reported worldwide during the 2009 influenza pandemic, and a disrupted biennial pattern of RSV activity was observed in northern Stockholm following the pandemic. Biennial patterns shifted to early/large outbreaks in even-numbered years and late/small outbreaks in odd-numbered years. However, the mechanisms underpinning this change in pattern remain unknown. In this work, we constructed an age-stratified mechanistic model to explicitly test three factors that could lead to the change in RSV transmission dynamics: 1) birth rates, 2) temperatures, and 3) viral interference. By fitting the model to weekly RSV admission data over a 20-year period and comparing different models, we found that viral interference from influenza was the only mechanism that explained the shifted biennial pattern. Our work demonstrates the complex interplay between different respiratory viruses, providing evidence that supports the presence of interactions between the H1N1 pandemic influenza virus and RSV at the population level, with implications for future public health interventions.

Rates and risk factors of severe respiratory syncytial virus infection in 2008-2016 compared with 1986-1998.

AIM: Since the introduction in 1979 of rapid testing using immunofluorescence, we have collected information about children hospitalised for confirmed respiratory syncytial virus (RSV) infection in the northern Stockholm area. We here report hospitalisation rates, risk factors and complications in 2008-2016 compared with 1986-1998. METHODS: Microbiological laboratory reports and retrospective chart review. Comparison of the two periods was complicated by changing testing routines, with a more sensitive method and increased testing of older children in the late period. RESULTS: In infants, there was an 12.3% increase in the population-based rate of hospital admission for RSV infection from 12.2 to 13.7/1000. Including all children <5 years, there was a 48% increase from 2.7 to 4.0/1000. The median length of stay remained unchanged at 3 days. The need of intensive care decreased in healthy infants but remained high in older children with comorbidity. CONCLUSION: Considering the changed diagnosis routines, we believe that the rate of hospital admission of infants for RSV infection was unchanged throughout the observed years. The increased rates of older children with confirmed RSV likely resulted from increased testing of children with risk factors for a complicated course.

Urinary PGE2 metabolite levels in hospitalised infants with infections compared to age-matched controls.

AIM: To determine the urinary tetranor-prostaglandin E2 metabolite in healthy infants and in hospitalised infants with upper and lower respiratory tract as well as gastrointestinal infections. METHODS: A prospective cross-sectional study to determine baseline concentrations of urinary tetranor-prostaglandin E2 metabolite was conducted in 81 healthy infants aged one week to one year and in 142 hospitalised infants with infections. Prostaglandin metabolite levels were measured by liquid chromatography tandem mass spectrometry. RESULTS: In healthy infants, urinary prostaglandin E2 metabolite levels decreased with age and did not differ between girls and boys. Infections of the lower respiratory (n = 78) and gastrointestinal tract (n = 12) correlated with increased levels of the prostaglandin E2 metabolite. In contrast, infants hospitalised with upper respiratory tract infections (n = 23) exhibited similar levels as healthy, age-matched controls. Lower prostaglandin E2 levels were found after treatment with acetaminophen in hospitalised children. Prostaglandin E2 metabolite levels did not correlate with length of hospitalisation or need for respiratory support. CONCLUSION: This study first provides normal levels of urinary prostaglandin E2 metabolite in infants and secondly demonstrates elevated levels in hospitalised children with lower respiratory tract and gastrointestinal infections.

Influenza epidemiology among hospitalized children in Stockholm, Sweden 1998-2014.

BACKGROUND: Influenza remains a common reason for the hospitalization of children. There is a need for long term studies that are also population based. We describe the epidemiology of severe influenza in a defined population 1998-2014. METHOD: Retrospective study of annually collected data of virologically confirmed influenza in hospitalized children 0-17 years living in the catchment area (230,000 children). We gathered information about comorbidity and complications from case records, and compared Influenza A, B and A(H1N1)pdm09 with respect to these factors. RESULTS: A total of 922 children with influenza were hospitalized. The mean rate remained unchanged at 22.5-24.2 per 100,000 children per year. There were two major outbreaks: influenza A(H3N2) in 2003-2004 and the A(H1N1) pandemic in 2009-2010. The proportion of children with influenza B increased from 8% during the first half of the study period to 28% during the second half. The highest admission rate was found in children <3 months of age, 169 per 100,000. Children with influenza B were older than those with influenza A. Comorbidity was found in 34%, complications in 41%, and 11% needed intensive care management. The mortality rate was 0.17/100,000 children. CONCLUSION: Influenza remains an important reason for the hospitalization of children, especially during the first years of life. The increasing proportion of influenza B may have to be considered when recommending influenza vaccines.

Long term effectiveness of adjuvanted influenza A(H1N1)pdm09 vaccine in children.

BACKGROUND: Immunological studies have indicated that the effectiveness of AS03 adjuvanted monovalent influenza A(H1N1)pdm09 vaccine (Pandemrix) may be of longer duration than what is seen for non-adjuvanted seasonal influenza vaccines. Sixty-nine percent of children 6 months-18 years of age in Stockholm County received at least one dose of Pandemrix during the 2009 pandemic. We studied the effectiveness of the vaccine during the influenza seasons 2010-2011 and 2012-2013 in children hospitalized with virologically confirmed influenza. The season 2011-2012 was not included, since influenza A(H3N2) was the predominant circulating strain. METHODS: In a retrospective case-control study using a modified test-negative design we compared the percentage vaccinated with Pandemrix among children diagnosed with influenza A(H1N1)pdm09 (cases), with that of those diagnosed with influenza A(H3N2) or influenza B (controls) during the two seasons. We excluded children born after July 1, 2009, since only children who were 6 months of age or older received the pandemic vaccine in October-December 2009. RESULTS: During the 2010-2011 season, 3/16 (19%) of children diagnosed with influenza A(H1N1)pdm09, vs. 32/41 (78%) of those with influenza A(H3N2) or influenza B had been vaccinated with Pandemrix in 2009. The odds ratio, after adjustment for sex, age and underlying diseases, for becoming a case when vaccinated with Pandemrix was 0.083 (95%CI 0.014, 0.36), corresponding to a VE of 91.7%. During the season 2012-2013, there was no difference between the two groups; 59% of children diagnosed with influenza A(H3N2)/B and 60% of those with influenza A(H1N1)pdm09 had been vaccinated with Pandemrix in 2009. CONCLUSION: The AS03 adjuvanted monovalent influenza A(H1N1) pdm09 vaccine (Pandemrix) was effective in preventing hospital admission for influenza A(H1N1)pdm09 in children during at least two seasons.

Evaluation of urinary prostaglandin E2 metabolite as a biomarker in infants with fever due to viral infection.

We have investigated the clinical feasibility of the major urinary metabolite of prostaglandin (PG) E2, tetranor-PGEM, as a biomarker of inflammation in infants with fever. We tested two different and clinically relevant sampling methods, using self-adhesive urinary bags or gauze pads, with respect to stability of tetranor-PGEM and ease of sampling from infants. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was used to quantify tetranor-PGEM in urine, and different normalization parameters, i.e., urinary creatinine and body surface area, were investigated. To study inflammation, infants (1 month-1 year) that were hospitalized with fever of unknown origin at admittance (n=14) were compared to age-matched healthy controls (n=14). Levels of urinary tetranor-PGEM in infants with viral induced fever were increased compared to controls (102.4±56.2 vs. 37.0±21.6pmol/ml/m(2) body surface area, p<0.001). We conclude that urinary tetranor-PGEM is a potential non-invasive biomarker of inflammation in infants.

Respiratory viruses in hospitalized children with influenza-like illness during the h1n1 2009 pandemic in Sweden [corrected].

BACKGROUND: The swine-origin influenza A(H1N1)pdm09 pandemic of 2009 had a slower spread in Europe than expected. The human rhinovirus (HRV) has been suggested to have delayed the pandemic through viral interference. The importance of co-infections over time during the pandemic and in terms of severity of the disease needs to be assessed. OBJECTIVE: The aim of this study was to investigate respiratory viruses and specifically the presence of co-infections with influenza A(H1N1)pdm09 (H1N1) in hospitalized children during the H1N1 pandemic. A secondary aim was to investigate if co-infections were associated with severity of disease. METHODS: A retrospective study was performed on 502 children with influenza-like illness admitted to inpatient care at a pediatric hospital in Stockholm, Sweden during the 6 months spanning the H1N1 pandemic in 2009. Respiratory samples were analyzed for a panel of 16 viruses by real-time polymerase chain reaction. RESULTS: One or more viruses were detected in 61.6% of the samples. Of these, 85.4% were single infections and 14.6% co-infections (2-4 viruses). The number of co-infections increased throughout the study period. H1N1 was found in 83 (16.5%) children and of these 12 (14.5%) were co-infections. HRV and H1N1 circulated to a large extent at the same time and 6.0% of the H1N1-positive children were also positive for HRV. There was no correlation between co-infections and severity of disease in children with H1N1. CONCLUSIONS: Viral co-infections were relatively common in H1N1 infected hospitalized children and need to be considered when estimating morbidity attributed to H1N1. Population-based longitudinal studies with repeated sampling are needed to improve the understanding of the importance of co-infections and viral interference.

Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa.

Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensure mutual prevention against a selection and spread of drug-resistant parasites. We have studied if mutations in the pfcrt and pfmdr1 genes selected in recurrent infections after AQ monotherapy are also selected after AQ plus ART combination therapy. Samples for molecular analysis were derived from three clinical trials on children<5 years old with uncomplicated Plasmodium falciparum malaria; one AQ monotherapy study conducted in Kenya 2003 and two AQ plus ART combination therapy studies conducted in Zanzibar 2002-2003 and 2005, respectively. The PCR-adjusted treatment failure rates in the three studies were 19%, 8% and 9%, respectively. After monotherapy there was a significant selection of pfcrt 76T in re-infections (OR not calculable; p=0.048) and of pfmdr1 86Y in recrudescent infections (OR 8.0; p=0.048). No such selection was found after combination therapy. A selection of pfmdr1 1246Y and the pfmdr1 haplotype (a.a 86, 184, 1246) YYY was found in recrudescent infections both after monotherapy (OR 7.6; p=0.009 and OR 3.1; p=0.029) and combination therapy in 2005 (OR 3.6; p=0.017 and OR 5.4; p<0.001). Hence, pfmdr1 1246Y with synergistic or compensatory addition of pfmdr1 86Y and 184Y appears to be involved in AQ/DEAQ resistance and treatment failure. Our results suggest that ART may protect against a selection of these SNPs initially, but maybe not after continuous drug pressure in a population. However, treatment failure rate and spread of pfmdr1 SNPs may remain at a low level because of the suggested opposite selection by ART and the pharmacodynamic advantages with ACT.