Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12–13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.     

Deaths Associated with Respiratory Syncytial and Influenza Viruses among Persons ≥5 Years of Age in HIV-Prevalent Area,South Africa, 1998–20091

We estimated deaths attributable to influenza and respiratory syncytial virus (RSV) among persons >5 years of age in South Africa during 1998–2009 by applying regression models to monthly deaths and laboratory surveillance data. Rates were expressed per 100,000 person-years. The mean annual number of seasonal influenza–associated deaths was 9,093 (rate 21.6). Persons >65 years of age and HIV-positive persons accounted for 50% (n = 4,552) and 28% (n = 2,564) of overall seasonal influenza-associated deaths, respectively. In 2009, we estimated 4,113 (rate 9.2) influenza A(H1N1)pdm09–associated deaths. The mean of annual RSV-associated deaths during the study period was 511 (rate 1.2); no RSV-associated deaths were estimated in persons >45 years of age. Our findings support the recommendation for influenza vaccination of older persons and HIV-positive persons. Surveillance for RSV should be strengthened to clarify the public health implications and severity of illness associated with RSV infection in South Africa.     

Zoonotic Transmission of Avian Influenza Virus (H5N1), Egypt, 2006�C2009

During March 2006–March 2009, a total of 6,355 suspected cases of avian influenza (H5N1) were reported to the Ministry of Health in Egypt. Sixty-three (1%) patients had confirmed infections; 24 (38%) died. Risk factors for death included female sex, age >15 years, and receiving the first dose of oseltamivir >2 days after illness onset. All but 2 case-patients reported exposure to domestic poultry probably infected with avian influenza virus (H5N1). No cases of human-to-human transmission were found. Greatest risks for infection and death were reported among women >15 years of age, who accounted for 38% of infections and 83% of deaths. The lower case-fatality rate in Egypt could be caused by a less virulent virus clade. However, the lower mortality rate seems to be caused by the large number of infected children who were identified early, received prompt treatment, and had less severe clinical disease.     

Respiratory syncytial virus bronchiolitis in ex-preterm infants in the Scottish highlands: review of hospital admissions and an analysis of hospital cost

Ex-preterm infants are vulnerable to respiratory syncytial virus (RSV) bronchiolitis and their hospital admission is associated with increased morbidity. Palivizumab is currently available as prophylaxis against RSV infection but its use in ex-preterm infants is controversial. A retrospective case review study was, therefore, carried out to determine the rate of readmission with RSV bronchiolitis among ex-preterm infants in the Highland Region of Scotland and to estimate the hospital cost per admission. Between 1995 and 1999, a total of 3,046 children under 2 years of age were admitted to Raigmore Hospital, 1,691 of whom (60.4%) lived outwith Inverness. 507 children had acute bronchiolitis and ex preterm infants with RSV positive bronchiolitis accounted for 3.6% of total admissions with acute bronchiolitis. 72% of these children lived outwith Inverness. The median length of hospital stay for children born at less than 30 weeks and for children who had had bronchopulmonary dysplasia (BPD) was 6 and 10.5 days respectively. The average hospital costs per admission for children of less than 30 weeks and children of more than 30 weeks were 3,376 Pounds and 2,074 Pounds respectively. It was more expensive for children with BPD (4,431 Pounds per admission) when compared with those without BPD (1,959 Pounds per admission). This study has shown that most of the children admitted to hospital lived outwith Inverness, many at some considerable distance, and this, as much as severity of illness, may have contributed to hospital admission. Further studies are required to determine productivity losses associated with RSV infection and justification of use of Palivizumab in ex preterm infants of less than 30 weeks gestation and of BPD living in remote areas of Scottish Highlands.     

Emergency triage assessment for hypoxaemia in neonates and young children in a Kenyan hospital: an observational study

Objective

To describe the prevalence of hypoxaemia in children admitted to a hospital in Kenya for the purpose of identifying clinical signs of hypoxaemia for emergency triage assessment, and to test the hypothesis that such signs lead to correct identification of hypoxaemia in children, irrespective of their diagnosis.

Methods

From 2002 to 2005 we prospectively collected clinical data and pulse oximetry measurements for all paediatric admissions to Kilifi District Hospital, Kenya, irrespective of diagnosis, and assessed the prevalence of hypoxaemia in relation to the WHO clinical syndromes of “pneumonia” on admission and the final diagnoses made at discharge. We used the data collected over the first three years to derive signs predictive of hypoxaemia, and data from the fourth year to validate those signs.

Findings

Hypoxemia was found in 977 of 15 289 (6.4%) of all admissions (5% to 19% depending on age group) and was strongly associated with inpatient mortality (age-adjusted risk ratio: 4.5; 95% confidence interval, CI: 3.8–5.3). Although most hypoxaemic children aged ≥ 60 days met the WHO criteria for a syndrome of “pneumonia” on admission, only 215 of the 693 (31%) such children had a final diagnosis of lower respiratory tract infection (LRTI). The most predictive signs for hypoxaemia included shock, a heart rate < 80 beats per minute, irregular breathing, a respiratory rate > 60 breaths per minute and impaired consciousness. However, 5–15% of the children who had hypoxaemia on admission were missed, and 18% of the children were incorrectly identified as hypoxaemic.

Conclusion

The syndromes of pneumonia make it possible to identify most hypoxaemic children, including those without LRTI. Shock, bradycardia and irregular breathing are important predictive signs, and severe malaria with respiratory distress is a common cause of hypoxaemia. Overall, however, clinical signs are poor predictors of hypoxaemia, and using pulse oximetry in resource-poor health facilities to target oxygen therapy is likely to save costs.     

Age as Risk Factor for Death from Pandemic (H1N1) 2009, Chile

Pandemic (H1N1) 2009 affected Chile during the winter of 2009. The hospitalization rate was 0.56% overall and 3.47% for persons >60 years of age at risk for severe disease and death independent of concurrent conditions. Age >60 years was the major risk factor for death from pandemic (H1N1) 2009.     

Natural history and epidemiology of respiratory syncytial virus infection in the Middle East: Hospital surveillance for children under age two in Jordan

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children worldwide. In the Middle East and Arab countries, the burden of RSV-associated hospitalizations is not well characterized. We sought to determine the burden and clinical/epidemiological characteristics of RSV hospitalization in young children in Amman, Jordan. We investigated risk factors for severity including vitamin D levels.MethodsWe conducted viral surveillance with clinical and demographic data in children <2 years admitted with respiratory symptoms and/or fever at the Al-Bashir Government Hospital from March16, 2010 to March 31, 2013. Nasal/throat swabs were obtained and placed into lysis buffer, and frozen at −80 °C until testing by real-time RT-PCR for 11 respiratory viruses. Heel stick blood or sera samples for 25-hydroxyvitamin D [25(OH)D] levels were obtained and sent to a central laboratory for mass spectrometry.ResultsOf the 3168 children, >80% testing positive for one virus, with RSV the most common virus detected (44%). The RSV-associated hospitalization rate was highest in children <6 months with an annual range of 21.1–25.9 per 1000, compared to 6.0–8.0 in 6–11-month-olds and 1.6–2.5 in 12–23-month-olds. RSV-positive children compared with RSV-negative were more likely to be previously healthy without underlying medical conditions, less likely to be born prematurely, had a higher frequency of supplemental oxygen use, and had lower median vitamin D levels. Risk factors for oxygen use in RSV-positive children included underlying medical conditions, lack of breastfeeding, younger age, and higher viral load.ConclusionRSV is a major cause of illness in hospitalized Jordanian children and is associated with increased severity compared to other respiratory viruses. Children with RSV in the Middle East would benefit from future RSV vaccines and antiviral therapy.     

呼吸道感染患儿咽拭子病毒检测分析

目的了解某医院住院下呼吸道感染患儿咽拭子常见呼吸道病毒检出情况,为临床疾病诊治提供参考依据。方法采用直接免疫荧光法,对该院2013年5月—2014年4月8 425例下呼吸道感染住院患儿咽拭子进行检测,了解患儿合胞病毒(RSV)、腺病毒(ADV)、流感病毒(IV)-A、IV-B、副流感病毒(PIV)-1、PIV-2和PIV-3感染/携带情况。结果 8 425例住院患儿的咽拭子样本,1 879例患儿咽拭子检出病毒,总检出率为22.30%,其中以RSV检出率最高(11.31%),其次为PIV-3(4.37%)。不同性别患儿呼吸道病毒总检出率比较,差异无统计学意义(P=0.051)。婴、幼儿组RSV检出率最高,学龄前组各病毒检出比例相对接近,而小学组以ADV检出居多(37.50%)。春、冬季患儿以RSV感染为主,分别占62.82%和69.88%;夏季则以PIV-3为主,占41.71%,各病毒所占比例在秋季差异小。结论下呼吸道感染住院患儿咽拭子中7种病毒检出率与年龄、季节等变化有关;婴、幼儿组7种病毒检出率高,以RSV为主。     

Household Transmission of Pandemic (H1N1) 2009, San Antonio, Texas, USA, April�CMay 2009

To assess household transmission of pandemic (H1N1) 2009 in San Antonio, Texas, USA, during April 15–May 8, 2009, we investigated 77 households. The index case-patient was defined as the household member with the earliest onset date of symptoms of acute respiratory infection (ARI), influenza-like illness (ILI), or laboratory-confirmed pandemic (H1N1) 2009. Median interval between illness onset in index and secondary case-patients was 4 days (range 1–9 days); the index case-patient was likely to be <18 years of age (p = 0.034). The secondary attack rate was 4% for pandemic (H1N1) 2009, 9% for ILI, and 13% for ARI. The secondary attack rate was highest for children <5 years of age (8%–19%) and lowest for adults >50 years of age (4%–12%). Early in the outbreak, household transmission primarily occurred from children to other household members and was lower than the transmission rate for seasonal influenza.     

Epidemiology of respiratory syncytial virus bronchiolitis in hospitalized infants in Greece

New therapies have been introduced for the prophylaxis and treatment of respiratory syncytial virus (RSV) infection in recent years. The aim of the study was to determine the epidemiological and clinical characteristics of infants hospitalized with bronchiolitis in our area. All patients under 1 year of age admitted with acute bronchiolitis during four consecutive RSV seasons from February 1, 1997 to June 30, 2000 were enrolled in the study. The records of patients admitted during the first season were reviewed retrospectively while the rest were followed prospectively. A total of 636 infants with bronchiolitis were admitted and RSV infection was documented in 61% of those tested. Admission to intensive care unit (ICU) was required for 6.2% of them and was more common in premature infants (26%) (p < 0.001). Case fatality rate was 0.7% (overall 0.3%). RSV bronchiolitis accounted for about 12% of all infant admissions during the 5 months of the yearly outbreak. Patients with documented RSV infection had a more severe illness with a higher ICU admission rate (6 vs. 1%, p = 0.008) and longer duration of hospitalization (mean 6.3 vs. 5.3 days, p < 0.001) compared to those who tested negative. Although none of the patients had a positive blood culture on admission a considerable number of them (210/636, 33%) were treated with antibiotics. RSV infection has a significant impact on infant morbidity in our settings which is more serious among those born prematurely. Documentation of RSV infection may be a marker of more severe illness in infants hospitalized with bronchiolitis. Antibiotic use has to be restricted since the occurrence of a serious bacteraemic illness on admission is a very rare event.     

Hospitalizations for lower respiratory tract infections in children in relation to the sequential use of three pneumococcal vaccines in Quebec

ObjectivesIn Quebec, three pneumococcal conjugate vaccines (PCV) were used sequentially starting in December 2004. The objective of the study was to investigate the association between exposure to different PCV regimens and hospitalizations for lower respiratory tract infection (LRTI).MethodsRecords with a main diagnosis of LRTI in children born in 2000–2012 and observed up to their second birthday were extracted from the provincial hospital administrative database. Main vaccine regimen in different birth cohorts was derived from the Quebec City Immunization Registry. Hospital admission risk was analyzed by Poisson regression models adjusting for age, season of birth, ambient air temperature, circulation of respiratory viruses, and the weekly hospital admission rate for all other causes excluding LRTI to control for temporal changes in hospital admission practices.ResultsIn univariate analyses, hospitalizations for LRTI, pneumonia, and bronchiolitis were less frequent in cohorts exposed to PCVs than in unvaccinated cohorts with no difference between PCV regimens. For pneumonia, the difference in cumulative incidence was 16% (13%; 18%). In multivariate analyses, exposure to any PCV schedule was associated with a lower although statistically non-significant hospitalization risk for pneumonia as compared with unvaccinated cohorts. Again, differences between PCV regimens were minimal.ConclusionsInterpretation of results of this ecological study should be made with care as many factors could influence hospitalizations for respiratory infection in young children. Results are compatible with a modest effect of PCVs in reducing hospitalizations for pneumonia in children. No substantial differences between various PCV schedules were observed.Electronic supplementary materialThe online version of this article (10.17269/s41997-020-00329-y) contains supplementary material, which is available to authorized users.     

Risk Factors of Mortality in Severely-malnourished Children Hospitalized with Diarrhoea

This case-control study was conducted in the Dhaka Hospital of ICDDR,B to identify the risk factors of mortality in severely-malnourished children hospitalized with diarrhoea. One hundred and three severely-malnourished children (weight-for-age <60% of median of the National Center for Health Statistics standard) who died during hospitalization were compared with another 103 severely-malnourished children who survived. These children were aged less than three years and admitted to the hospital during 1997. On admission, characteristics of the fatal cases and non-fatal controls were comparable, except for age. The median age of the cases and controls were six and eight months respectively (p=0.05). Patients with low pulse rate or imperceptible pulse had three times the odds of death compared to the control group (p<0.01). The presence of clinical septicaemia and clinical severe anaemia had 11.7 and 4.2 times the odds of death respectively (p<0.01). Patients with leukocytosis (>15,000/cm³) had 2.5 times the odds of death (p<0.01). Using logistic regression, clinical septicaemia [adjusted odds ratio (AOR)=8.8, confidence interval (CI) 3.7-21.1, p=0.01], hypothermia (AOR=3.5, CI 1.3-9.4, p<0.01), and bronchopneumonia (AOR=3.0, CI 1.2-7.3, p<0.01) were identified as the significant risk factors of mortality. Severely-malnourished children (n=129) with leukocytosis, imperceptible pulse, pneumonia, septicaemia, and hypothermia had a high risk of mortality. The identified risk factors can be used as a prognostic guide for patients with diarrhoea and severe malnutrition.Key words: Bronchopneumonia, Case-control studies, Child nutritional disorders, Diarrhoea, Hypoglycaemia, Leukocytosis, Marasmic-kwashiorkor, Mortality, Risk factors, Bangladesh     

Healthcare-associated Viral Gastroenteritis among Children in a Large Pediatric Hospital, United Kingdom

Viruses are the major pathogens of community-acquired (CA) acute gastroenteritis (AGE) in children, but their role in healthcare-associated (HA) AGE is poorly understood. Children with AGE hospitalized at Alder Hey Children’s Hospital, Liverpool, UK, were enrolled over a 2-year period. AGE was classified as HA if diarrhea developed >48 hours after admission. Rotavirus, norovirus, adenovirus 40/41, astrovirus, and sapovirus were detected by PCR. A total of 225 children with HA-AGE and 351 with CA-AGE were enrolled in the study. HA viral gastroenteritis constituted one fifth of the diarrheal diseases among hospitalized children and commonly occurred in critical care areas. We detected >1 virus in 120 (53%) of HA-AGE cases; rotavirus (31%), norovirus (16%), and adenovirus 40/41 (15%) were the predominant viruses identified. Molecular evidence indicated rotaviruses and noroviruses were frequently introduced into the hospital from the community. Rotavirus vaccines could substantially reduce the incidence of HA-AGE in children.     

Burden of Influenza-Associated Respiratory Hospitalizations,Vietnam, 2014–2016

Influenza burden estimates are essential to informing prevention and control policies. To complement recent influenza vaccine production capacity in Vietnam, we used acute respiratory infection (ARI) hospitalization data, severe acute respiratory infection (SARI) surveillance data, and provincial population data from 4 provinces representing Vietnam’s major regions during 2014–2016 to calculate provincial and national influenza-associated ARI and SARI hospitalization rates. We determined the proportion of ARI admissions meeting the World Health Organization SARI case definition through medical record review. The mean influenza-associated hospitalization rates per 100,000 population were 218 (95% uncertainty interval [UI] 197–238) for ARI and 134 (95% UI 119–149) for SARI. Influenza-associated SARI hospitalization rates per 100,000 population were highest among children <5 years of age (1,123; 95% UI 946–1,301) and adults >65 years of age (207; 95% UI 186–227), underscoring the need for prevention and control measures, such as vaccination, in these at-risk populations.     

Comparison of Pandemic (H1N1) 2009 and Seasonal Influenza, Western Australia, 2009

We compared confirmed pandemic (H1N1) 2009 influenza and seasonal influenza diagnosed in Western Australia during the 2009 influenza season. From 3,178 eligible reports, 984 pandemic and 356 seasonal influenza patients were selected; 871 (88.5%) and 288 (80.9%) were interviewed, respectively. Patients in both groups reported a median of 6 of 11 symptoms; the difference between groups in the proportion reporting any given symptom was <10%. Fewer than half the patients in both groups had >1 underlying condition, and only diabetes was associated with pandemic (H1N1) 2009 influenza (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1–3.5). A total of 129 (14.8%) persons with pandemic (H1N1) 2009 and 36 (12.5%) persons with seasonal influenza were hospitalized (p = 0.22). After controlling for age, we found that patient hospitalization was associated with pandemic (H1N1) 2009 influenza (OR 1.5; 95% CI 1.1–2.1). Contemporaneous pandemic and seasonal influenza infections were substantially similar in terms of patients’ symptoms, risk factors, and proportion hospitalized.     

Respiratory syncytial virus activity--United States, 1999-2000 season

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness (LRTI) among infants and children worldwide (1) and is an important cause of LRTI among older children and adults (2). Despite the presence of maternal antibodies, most hospitalizations occur among infants aged <6 months, and nearly all children are infected by age 2 years (3). Although primary infection is usually most severe, reinfection throughout life is common (4). In temperate climates, RSV infections occur primarily during annual outbreaks, which peak during winter months (5). In the United States, RSV activity is monitored by the National Respiratory and Enteric Virus Surveillance System (NREVSS), a voluntary, laboratory-based system. This report summarizes trends in RSV activity reported to NREVSS from July 1999 through June 2000 and presents preliminary surveillance data from July 8 through November 21, 2000, which indicate that RSV community outbreaks are becoming widespread.     

Distant Relatives of Severe Acute Respiratory Syndrome Coronavirus and Close Relatives of Human Coronavirus 229E in Bats, Ghana

We tested 12 bat species in Ghana for coronavirus (CoV) RNA. The virus prevalence in insectivorous bats (n = 123) was 9.76%. CoV was not detected in 212 fecal samples from Eidolon helvum fruit bats. Leaf-nosed bats pertaining to Hipposideros ruber by morphology had group 1 and group 2 CoVs. Virus concentrations were <45,000 copies/100 mg of bat feces. The diversified group 1 CoV shared a common ancestor with the human common cold virus hCoV-229E but not with hCoV-NL63, disputing hypotheses of common human descent. The most recent common ancestor of hCoV-229E and GhanaBt-CoVGrp1 existed in ≈1686–1800 ad. The GhanaBt-CoVGrp2 shared an old ancestor (≈2,400 years) with the severe acute respiratory syndrome–like group of CoV.     

SARS-CoV-2 Antibody Prevalence and Population-Based Death Rates,Greater Omdurman,Sudan

In a cross-sectional survey in Omdurman, Sudan, during March–April 2021, we estimated that 54.6% of the population had detectable severe acute respiratory syndrome coronavirus 2 antibodies. Overall population death rates among those >50 years of age increased 74% over the first coronavirus disease pandemic year.