Respiratory syncytial virus – more chimera than chimpanzee?

“…the Chimera prowled with lungs of fire and lion’s breast and head and serpent’s tail.” Metamorphoses 9. 647 – Publius Ovidius Naso (Ovid – Roman poet; 43 BCE–17 CE)

Respiratory syncytial virus (RSV) is an old foe with outbreaks of pyrexial respiratory illnesses having been described for many centuries, with probably the first description of an outbreak of RSV reported in 1941¹. Adams described an outbreak of nosocomial chest infections in 32 infants in a neonatal unit that resulted in 9 deaths, with cytoplasmic inclusions identified in the lungs at autopsy. RSV was first identified in 1955 from a colony of chimpanzees with coryza and designated ‘chimpanzee coryzal agent’². Subsequently it was isolated from human children with lung disease in Baltimore, USA, a year later in 1956³. Owing to the characteristic cytopathologic finding in tissue culture where infected epithelial cells clump together forming syncytia (giant multinucleated cells), the virus was soon named respiratory syncytial virus (RSV)³. Since then this Paramyxovirus (Greek para for ‘beside’ + myxa for ‘mucus’) has been recognized as the single most important virus causing acute respiratory tract infections in infants and young children throughout the world^4–6. RSV-related pediatric hospitalizations account for around 60,000 admissions in the USA, 26,000 in Germany, 20,000 in the UK and 8000 in Spain every year^5,7–9. Annually more than 2,000,000 children in the USA alone are estimated to require medical attention for RSV-related illnesses⁵. The reported RSV bronchiolitis hospital admission rates for children under 1 year of age in the USA and Europe is generally around 25–30 per 1000 infants¹⁰. Incidence and hospitalization rates for RSV bronchiolitis in resource-limited areas are lacking due to the paucity of epidemiological studies along with cost-saving restrictions in laboratory confirmation of RSV infection⁶. It has been estimated that in infants alone nearly 50 deaths per year in the UK and over 120 deaths in the USA are attributable to RSV (‘chimpanzee coryzal agent’)^11,12. Globally RSV bronchiolitis was directly or indirectly accountable for up to 199,000 deaths in children less than 5 years of age in 2005⁶. Mortality is higher in those with comorbidity (especially underlying congenital heart disease, chronic lung disease, immunocompromise, neuromuscular disease), with nosocomial infection, and in developing/resource-limited nations^6,8,12–14. RSV is the most common viral respiratory cause of death in children below 5 years of age and especially in infants less than 1 year old⁶.

In this journal Sanchez-Luna and colleagues add to the expanding evidence against this far from innocuous multifaceted beast, RSV, with a large industry-sponsored national cohort study from Spain⁹. The objective of this study was to analyze national temporal trends in community-acquired RSV bronchiolitis hospitalizations, in-hospital mortality and readmissions for children under 1 year of age (i.e. infants), in pain between 2004 and 2012. They also scrutinized the influence of risk factors on outcome measures/‘health outcomes’ – “hospitalization, in-hospital mortality and hospital readmission” – in this study population of infants with community-acquired RSV bronchiolitis. Their chosen outcome measures ‘hospitalization’ and ‘in-hospital mortality’ measure the severity of the initial RSV bronchiolitis (need for hospitalization or resultant death), and ‘hospital readmission’ (readmission within 30 days for any cause, except if an elective admission) measures the postulate of subsequent clinical impact due to the recent RSV illness. Additionally they developed a risk-adjustment model for RSV bronchiolitis in-hospital mortality.

Utilizing the minimum basic data set (MBDS) which was/is a compulsory national hospital discharge register of the Spanish National Health Service, they retrospectively analyzed a cohort of infants (under 1 year of age) discharged with RSV bronchiolitis as a primary diagnosis or one of the principal diagnoses⁹. The study period, 2004–2012, presumably captured data from seven full RSV seasons and two half seasons – as the RSV season in Europe usually runs from around October into March, peaking typically between November and January^10,13,15. In their compulsory MBDS the diagnoses and procedures were coded according to the International Disease Classification, Clinical Modification (ICD-9-CM)⁹. During the study period there were 1,328,563 hospital discharges for infants (under 1 year old); 122,832 discharges (9% of all infant discharges) had ‘acute bronchiolitis’ as the principal diagnosis (ICD-9 diagnostic code 466.1x) and 63,990 (52% of the acute bronchiolitis) of them ‘RSV bronchiolitis’ (ICD-9 diagnostic code 466.11)⁹.

The criteria for ‘high-risk’ categorization are reasonable in that Sanchez-Luna et al. have defined their ‘high-risk’ group within their own Spanish context, supported by their national bodies (Spanish Societies of Neonatology and of Paediatric Cardiology)⁹. Only a cynic would conjecture whether the selection criteria were in any way influenced by their study sponsor. Of course there are additional established ‘high-risk’ groups – for example large airways abnormalities like tracheomalacia, nosocomial RSV infection, etc.^{8,13,14,16–18}. Additionally some sectors may challenge previous 33–36 week pretermers (‘late prematurity’) being a ‘high-risk’ group^19,20. However, Sanchez-Luna et al. have clearly defined their ‘high-risk’ group and stuck to their criteria throughout the study deeming “all other hospitalized children without any of these medical conditions” as the ‘non-high-risk’ group⁹. Approximately 2% (1054) of the 63,990 infants hospitalized for RSV bronchiolitis inhabited the ‘high-risk’ group and 98% (62,904) the ‘non-high-risk’ group.

Temporal trends over the 2004–2012 study period⁹ demonstrating an increase in RSV bronchiolitis incidence and decline in non-RSV incidence most probably reflects improved diagnostic accuracy with increasing utilization (and decreasing pricing/cost) of RSV antigen and multiplex PCR testing. There was a reported temporal decline in the annual in-hospital RSV bronchiolitis mortality rate from 120 deaths per 100,000 hospitalizations in 2004 to only 69 per 100,000 hospitalizations in 2012⁹. However, “this decrease was not statistically significant when adjusted by complexity”. It is a pity that Sanchez-Luna et al. have not elucidated the ‘complexities’ or the statistics used, as it curtails an understanding of this 43% reduction in the annual in-hospital RSV bronchiolitis mortality rate from start to end of the study period. There is incongruence when this statistical insignificance is offset against “we have not found any significant change during the analyzed period in the complexity mix of RSV bronchiolitis episodes”. A recent American study (also utilizing administrative ICD-9-CM data) similarly found a temporal decline in the RSV mortality rate in the USA over a parallel time period (2000–2011)¹². Likewise they ascribed the decline to improvement and advancement in both in-hospital and outpatient medical care¹². However, changing virulence cannot be discounted as potentially playing a role^21,22.

I warm to the hypothesis that recent RSV bronchiolitis will have an ongoing clinical impact and may be reflected in subsequent ‘hospital readmission’ (readmission within 30 days for any cause, except if an elective admission). Certainly our experience with nosocomial RSV infection would support this hypothesis¹⁷. However, risk factor analysis is dependent on solid comparison, as is the odds ratio. Apples should be compared to apples. Comparison should be between (sub)groups of RSV bronchiolitis (e.g. ‘high-risk’ versus ‘no-risk’), RSV bronchiolitis versus non-RSV bronchiolitis, or similar comorbidities with and without RSV bronchiolitis. Comparison between a homogenous ‘high-risk’ RSV group and a vastly heterogeneous ‘any cause other than RSV bronchiolitis’ patient group is potentially confounded by dissimilarity and dilutional effects. The reported higher readmission rate in the ‘high-risk’ group compared to the ‘non-high-risk’ group may be related to the former all uniformly having underlying chronic medical conditions/comorbidity, unlike the latter. To tease out whether the recent RSV bronchiolitis influenced the higher readmission rate would require comparison between groups of similar comorbidities with and without RSV bronchiolitis.

There should be caution that small subgroup numbers do not assert exaggerated influence in risk-adjustment exercises or modeling. I suspect that “premature children born between 33 and 36 weeks of gestation were associated with a 37 times higher risk of in-hospital mortality due to RSV bronchiolitis compared to non-high-risk children” may be an example. This is based on one death in the ‘33–36 weeks’ gestation/‘late prematurity’ subgroup out of a total of 10 deaths in the whole 1054 ‘high-risk’ group and RSV study population of 63,990. The odds ratio 95% confidence interval was 5–276⁹. Sanchez-Luna et al. are correct that they “are not able to conclude any recommendation due to the wide confidence intervals of the association between late prematurity and higher in-hospital mortality due to RSV bronchiolitis”⁹. Having said this, I am puzzled how they then deduce that “the high rate of RSV bronchiolitis in this group not receiving immunoprophylaxis suggests a careful reconsideration of the cost–benefit of policies aimed at withdrawing RSV bronchiolitis immunoprophylaxis for this group”. Hopefully this deduction was in no way influenced by their study sponsor. Additionally, no data at all were presented on receipt of any medication or types of treatment (perhaps a product of their ICD-9-CM database). Out of the 129,458 total hospital discharges in the ‘33–36 weeks’ gestation/‘late prematurity’ subgroup there were 43 infants with RSV bronchiolitis⁹ – i.e. an incidence of 3 per 1000 ‘late prematurity’ hospital discharges.

Sanchez-Luna et al. have convincingly demonstrated that the in-hospital mortality rate is much increased (19 times higher) in the ‘high-risk’ (comorbidity) group compared to the ‘non-high-risk’ (low or no risk) group for infants hospitalized in Spain with RSV bronchiolitis. Their logistic regression analysis also supports this finding of increased risk of death in the ‘high-risk’ (comorbidity) group⁹. This data reinforces the published medical literature on the topic^5,6,12,13,16.

Two key messages arise from this large national cohort study from Spain: 1. RSV infection continues to kill infants; 2. not all babies are born equal – those with comorbidity are at increased risk of severe RSV disease and death. Currently there still is no magical elixir, just good supportive clinical practice, though in time an effective RSV vaccine may yet provide a panacea for this chimera. I would warn that to be insightful of the risk factors for severe RSV bronchiolitis is prudent, and to dismiss its threat is foolhardy. “Before God we are all equally wise, and equally foolish” – Albert Einstein (1879–1955).

Transparency

Kentigern Thorburn
Alder Hey Children's Hospital, E Prescot Rd, Liverpool, L12 2AP, UK
[email protected]

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

K.T. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.