Respiratory Syncytial Virus (RSV) in the Pediatric Intensive Care Unit

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Intensive Care Unit

M.C.J. Kneyber and F.B. Plötz

Introduction

It is more than half a century ago that Robert Chanock and co-workers recovered a cytopathogenic agent from lung secretions of young infants with lower respiratory tract disease that was similar to an agent that had been identified in an outbreak of infection resembling the common cold in chimpanzees [1, 2]. Because of its charac- teristic cytopathologic findings in tissue culture where it forms syncytia in epithelial cells, the virus was named respiratory syncytial virus (RSV) [1]. From serological studies, it was observed that almost all children have been infected by RSV by the age of two years [3]. Epidemiological research carried out since its discovery has designated RSV as the most important causative agent of viral lower respiratory tract disease [4]. Approximately 100,000 infants are admitted annually with RSV- induced bronchiolitis in the United States, and the number of hospitalizations is increasing [5]. Because of this, RSV-associated disease imposes a major burden on health care resources [6]. More recently, RSV is increasingly being recognized as an important pathogen causing severe lower respiratory tract disease in elderly and immunocompromised patients [7].

Each winter, pediatric intensivists are challenged by infants with lower respiratory tract disease due to RSV. This chapter summarizes the current knowledge regarding the role of RSV in the pediatric intensive care unit (PICU) and its possible therapeutic options.

Epidemiologic Aspects

RSV is classified within the genus pneumoviridae which is a member of the family of paramyxoviridae. It is a single stranded enveloped RNA virus. The RSV genome codes for 10 major proteins [8]. Of these proteins, the F (fusion) and the G (attach- ment) glycoprotein are the major surface antigenic determinants. Two antigenic strains of RSV, group A and group B, can be identified. Both groups co-circulate together but also independently from each other during annual epidemics [9]. The clinical spectrum of RSV-associated disease extends from mild upper respiratory tract infection to severe lower respiratory tract infection including bronchiolitis and pneumonia [4]. Re-infections occur frequently, although they tend to be mild [10].

Severe RSV infection necessitating mechanical ventilation occurs in 2 – 16 % of previously healthy infants [11]. This percentage may increase among so-called ‘high- risk’ patients. Wang et al. enrolled 689 children younger than two years of age into the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC)

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prospective cohort study [12]. They observed a higher need for mechanical ventilation among infants with congenital heart disease (19.3 %), chronic lung disease (25.3 %), compromised immune function (14.3 %), prematurity (defined by a gesta- tional age less than 37 weeks) (18.2 %), and postnatal age below 6 weeks (16.8 %) compared to infants with no risk factor (3.2 %) [12]. The mean duration of mechanical ventilation may be as long as 10 days [13]. However, not unusually, alternative modes of ventilation, such as high-frequency oscillatory ventilation (HFOV) or extra-corporeal membrane oxygenation (ECMO), are required when severe impaired oxygenation or ventilation persists [11].

RSV is also a neurotrophic virus. We have observed that it causes apnea (defined by a cessation of respiration or a bradycardia with accompanying cyanosis for a period of 20 seconds or longer) in approximately one of every five patients with RSV [14]. Apnea may be the presenting symptom. The odds for mechanical ventilation are increased 6.5-fold in infants who present with RSV – associated apnea. The exact mechanism underlying RSV-associated apnea is unknown, although it is observed that the apnea is of central origin [15].

Usually mortality rates are less than 1 % for previously healthy infants, although these percentages may increase up to 10 % among high-risk infants [16].

Clinical Phenotype

Lower respiratory tract disease due to RSV is often referred to as ‘bronchiolitis’. In fact, an increase in total respiratory system resistance compatible with obstructive disease has been demonstrated [17 – 20]. However, it is increasingly appreciated that RSV-associated lower respiratory tract disease is a heterogeneous disease, implicat- ing that it is incorrect to label all RSV-associated lower respiratory tract disease as bronchiolitis [21]. It is being argued that RSV can present as an obstructive disease (defined by increased respiratory system resistance with subsequent decreased air- flow on expiration, responsible for the audible wheezing) or a restrictive disease [22]. This discrimination is supported by work performed by Hammer et al. in 37 mechanically ventilated infants [19]. These infants were categorized as having obstructive or restrictive disease based upon the findings from pulmonary function testing. Ten infants had decreased respiratory system compliance (Crs) compatible with restrictive disease in conjunction with four-quadrant alveolar consolidation on chest radiograph compared to healthy controls. The remaining 27 children had increased respiratory system resistance (Rrs), compatible with obstructive disease.

Infants with restrictive disease required prolonged ventilation compared to infants with obstructive disease. It should be noted, however, that infants with underlying diseases such as prematurity and/or chronic lung disease were also included for analysis. Among the infants with restrictive disease there were three infants with chronic lung disease; it cannot be excluded that these infants had pre-existing lung abnormalities that might have contributed to the altered respiratory system mechanics. For instance, prematurely born infants with chronic lung disease have higher Rrs that predispose them to symptomatic RSV-associated lower respiratory tract disease compared to controls [23].

In most PICUs however, pulmonary function testing is not done routinely. Yet, identification of the type of RSV-associated lower respiratory tract disease is clinically relevant because of the proposed differences in ventilatory strategies needed to treat obstructive or restrictive disease [22]. In addition, identification of the clinical

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phenotype aids in targeting a specific population of infants for a therapeutic modality. An alternative for pulmonary function testing could be the use of ventilatory indices that characterize gas exchange. These include the oxygenation index and the alveolar-arterial oxygen gradient (Aa-DO₂). These indices could serve as an easy bedside tool to characterize the patient’s pulmonary condition. Tasker and co-workers found an Aa-DO₂ 8 400 mmHg during the first 24 hours of mechanical ventilation and a mean airway pressure 8 10 cmH₂O associated with radiographic appear- ances suggestive of RSV restrictive disease [24]. All infants were previously healthy, and had four-quadrant alveolar consolidation on their chest radiograph on PICU admission. However, the definition of severe RSV-associated lower respiratory tract disease in this study was based upon a chest radiograph scoring system developed for prematurely born infants with infant respiratory distress syndrome (IRDS) and has not been validated for patients with RSV to our knowledge [25].

The findings of Hammer et al. [19] as well as those of Tasker et al. [24] are not conclusive. We have retrospectively studied parameters for gas exchange in 53 mechanically ventilated infants with RSV-associated lower respiratory tract disease admitted between 1995 and 2005, and were unable to detect significant differences in the oxygenation index or in the Aa-DO₂between infants with radiological classified restrictive disease and obstructive disease (unpublished data). We further observed a comparable duration of mechanical ventilation between infants with obstructive and restrictive disease. Our findings suggest that RSV-associated lower respiratory tract disease is a heterogeneous disease that cannot be strictly dichotomized into restrictive and obstructive forms.

Importantly, there are no data on the short-term and long-term airway morbidity in mechanically ventilated infants with RSV-associated lower respiratory tract disease. It is known that post-RSV wheezing (i.e., recurrent wheezing during early childhood) is seen frequently among infants who were hospitalized with mild to moderate RSV-associated lower respiratory tract disease [26]. The exact mechanisms underlying post-bronchiolitis wheezing are unknown. For mechanically ventilated infants it can be hypothesized that the virus causes structural damage to the airways that might be exaggerated by mechanical ventilation. This paucity of data requires further investigations.

Concurrent Bacterial Infection

The majority of infants who are admitted to the PICU with RSV-associated lower respiratory tract disease will have antibiotics prescribed. Clinicians often assume that concurrent bacterial pulmonary infection is probably (partially) accountable for the development of respiratory failure due to RSV. Randolph et al. retrospectively studied the number of positive cultures from blood, urine, cerebrospinal fluid (CSF), and endotracheal aspirates on PICU admission among 63 mechanically ventilated previously healthy infants [27]. All of these infants were treated with antibiotics.

They observed a low percentage (‹ 2 %) of concurrent bacterial blood stream infection. In addition, 24 of the children (38.1 %) had positive cultures from endotracheal aspirates that could be linked to either possible or probable bacterial pneumonia.

These observations were supported by the findings of Bloomfield et al. [28]. These authors observed bacteremia in 6 children out of 208 PICU admissions. Four infants were mechanically ventilated. All of them had been born prematurely or had congenital heart disease.

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We have also studied, retrospectively, the occurrence of concurrent bacterial infection in 65 mechanically ventilated infants during 1996 – 2001 [29]. In 38 of these infants microbiological investigations were performed. All had antibiotics on PICU admission. We found only one positive culture from blood, and 37.5 % positive cultures from endotracheal aspirates compatible with bacterial pneumonia. Infants with concurrent bacterial infection had similar C-reactive proteins (CRP) concentrations and white blood cell (WBC) counts compared to infants with negative cultures.

In addition, the presence of bacterial pulmonary infection upon PICU admission was undetectable by the oxygenation index as this was equal in infants with and without positive cultures. There were two additional remarkable findings from our study. First, concurrent bacterial infection occurred almost exclusively in previously healthy, term born infants. Second, infants with positive concurrent bacterial infection required prolonged ventilatory support (14.3 „ 2.4 versus 10.6 „ 1.0 days).

All these retrospective observations were confirmed by a study by Thorburn et al.

[30]. Their group prospectively collected endotracheal aspirates in 165 mechanically ventilated infants during three consecutive RSV seasons. They observed that 21.8 % of the children had concurrent bacterial pneumonia upon PICU admission. Strik- ingly, these infants also required prolonged ventilatory support compared to infants without bacterial pneumonia. Only 36 % of these infants were receiving antibiotics on PICU admission. The majority of bacterial pneumonias occurred in infants with pre-existing morbidity.

All of these results suggest that, at least in some of the children, bacterial pneumonia (partially) contributes to the development of respiratory failure (Fig. 1).

Whereas others report such findings among children with pre-existing morbidity, we were unable to confirm this. We advocate refraining from the routine use of antibiotics in children admitted to the PICU. Immediate investigation of the endotracheal aspirate may identify those children in whom antibiotics are justified, although this hypothesis calls for further study, such as a randomized, controlled trial.

Fig. 1. Percentage of patients with positive microbiologic investigations suggestive for bacterial pneumonia in mechanically ventilated infants with respiratory syncytial virus (RSV) lower respiratory tract disease

Pathophysiology and Disease Severity

The pathophysiological mechanisms underlying RSV-induced respiratory failure with subsequent need for mechanical ventilation are unknown. It seems rational to hypothesize that disease severity can at least in part be related to viral strain or viral

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load. Viral strain seems not to be an important factor. We observed that the need for PICU admission and mechanical ventilation is equally distributed among infants with RSV group A and B [31]. The effect of viral load on disease severity is less clear. Conflicting data have been reported on differences in viral load between ventilated and non-ventilated infants. DeVincenzo et al. were unable to find significant differences in viral load obtained from nasal washes between previously healthy ventilated (n = 22) and non-ventilated (n = 119) infants (5.185 versus 4.963 log pfu/ml) [32]. Others, however, observed significantly higher nasal viral load among ventilated (n = 15) versus non-ventilated (n = 24) previously healthy infants (5.06 „ 0.34 vs. 3.91 „ 0.35 log pfu/ml, p=0.022) [33]. There is one report on differences in viral load among ventilated infants. Van Woensel et al. found a higher viral load in tracheal aspirates of infants (n = 14) who met criteria for “severe RSV lower respiratory tract disease” (PaO₂/FiO₂ ratio e 200 mmHg and a mean airway pressure 8 10 cmH₂O (72.0 „ 28.0 RNA copies) compared to infants (n=8) with “mild” disease (21.1 „ 9.2 RNA copies, p=0.20) [34]. Unfortunately, there are no reports on differences in viral load among various categories of mechanically ventilated, high-risk infants.

Since viral strain and viral load are not fully accountable for disease severity, it can be argued that pre-existing structural abnormalities of the respiratory system predispose prematurely born children and children with chronic lung disease or congenital heart disease to a severe disease course. For instance, prematurely born but otherwise healthy infants have an underdeveloped respiratory system that is easily compromised by the direct toxic effects of an infectious agent, such as epithelial necrosis due to invading virus [35]. Young children with chronic lung disease have structurally abnormal airways that tend to collapse easily. In addition, there are structural abnormalities of the lung as a result of pulmonary immaturity at premature birth, that (partially) predisposes them to severe disease necessitating mechanical ventilation [35]. For infants with congenital heart disease with pulmonary hyper- tension it can be argued that the pre-existing hypoxia is further aggravated during the RSV-associated lower respiratory tract disease.

However, these pre-existing conditions do not fully account for the severity of RSV-associated lower respiratory tract disease since the majority of ventilated infants were previously healthy. Various groups have postulated that the immune response against RSV plays an important role in determining disease severity. This is probably especially valid for healthy term and pre-term infants since they have normal airways [36]. However, it is subject to debate whether or not the immune response against RSV is protective or disease-enhancing. Results from animal studies have led to the assumption that an overshoot of the T-cell response towards a T- helper 2 (Th2) profile may be responsible for severe disease [37]. However, there is much debate on the Th1/Th2 skewing in infants with RSV-associated lower respiratory tract disease. The observation of a Th2 skewed immunological response associated with severe disease in humans has not been universally confirmed [36].

In contrast to the hypothesis that the immune responses against RSV are disease- enhancing, there are strong arguments that both humoral and cellular immune responses against RSV actually protect against severe disease. Low titers of neutralizing antibodies were associated with severe RSV-associated lower respiratory tract disease, although there are no data on the relationship between the titer of neutralizing antibodies and the need for mechanical ventilation [38, 39]. It is well known that, in general, prematurely born infants lack sufficient titers of protective immu- noglobulin G neutralizing antibodies because placental transport of IgG occurs late

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in gestation, near the end of the third trimester. In addition, early post-natal life is also associated with a physiological immune deficiency defined by hyporesponsive- ness of mononuclear phagocytes to stimuli and a diminished T-cell response [40, 41]. This low level of immune response could render very young infants susceptible to severe disease.

The suggestion that cellular immunity protects against severe RSV-associated lower respiratory tract disease has originated from various human studies. Low numbers of T-cells are found in peripheral blood samples of ventilated infants compared to non-ventilated infants, although this may also suggest recruitment of acti- vated T-cells to the lungs [42]. More importantly, low levels of interferon (IFN)* (a Th1 cell cytokine) were found in nasopharyngeal aspirates of mechanically ventilated children compared to non-ventilated children [43]. In addition, monocyte- derived interleukin (IL)-12 was observed to be inversely related to the duration of mechanical ventilation. IL-12 promotes the differentiation of naive CD4 – positive T cells into Th1 cells [44]. Finally, mononuclear cells of ventilated infants exhibited diminished ex vivo lymphoproliferative responses and the capacity to produce IFN* and IL-4 compared to non-ventilated infants. It seems thus likely that severe RSV- associated lower respiratory tract disease in healthy term and pre-term born infants originates from an immature immune system so that they cannot neutralize the virus sufficiently. For children with pre-existing abnormalities of the respiratory system it is probably a combination of both. In addition, it cannot be ruled out that genetic polymorphisms also play an important role in the host susceptibility for severe RSV-associated lower respiratory tract disease.

Therapeutic Options

Four different therapeutic approaches have been the subject of investigation [45].

These include the virostatic drug, ribavirin, corticosteroids, the use of bronchodilators, and exogenous surfactant. Whereas ribavirin and corticosteroids could be curative, bronchodilators and exogenous surfactant remain supportive therapies.

Three reports on the efficacy of ribavirin, comprising 104 mechanically ventilated infants, were reviewed systematically in a Cochrane review [46]. The use of ribavirin was associated with a significant decrease in the duration of mechanical ventilation (mean difference 1.2 days [95 % confidence interval –0.2 to –3.4, p = 0.03]). Normal saline was used as placebo in two studies, whereas sterile water was used in the third study. Because of the serious potential side-effects of sterile water (i.e., induction of bronchospasm), this study was excluded in an additional analysis. Subsequently, the difference in duration of mechanical ventilation became insignificant. In addition, ribavirin is not easy to administer and is associated with teratogenic side-effects.

Ribavirin is, therefore, currently seldom used.

The efficacy of corticosteroids has been studied in three investigations [47 – 49].

These studies cannot be easily compared because of the different dosing and duration of treatment. Van Woensel et al. performed a post-hoc analysis of 14 mechanically ventilated infants in their original trial of prednisolone 1 mg/kg for seven days versus placebo in hospitalized children with RSV [48]. These authors observed a non-significant difference in mean duration of mechanical ventilation (4.7 „ 2.91 versus 6.3 „ 4.23 days). Based upon this post-hoc analysis, they designed a randomized clinical trial in mechanically ventilated infants [49]. Dexamethasone, 15 mg/kg/

day every 6 hours for 48 hours, was compared with placebo in 85 patients. Again, no

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significant difference in mean duration of mechanical ventilation was found between the two treatment arms. Similar results were obtained in a study including 41 mechanically ventilated infants [47]. Currently, Van Woensel et al. are performing a third randomized, controlled trial (the so-called Steroid Treatment in Artificially ventilated children with Respiratory syncytial virus infection [STAR] trial). A post- hoc analysis from their second randomized trial suggested that corticosteroids might be beneficial among ventilated infants who met criteria for mild disease as defined by Tasker et al. [24].

Depending on the results from the randomized controlled STAR trial, there is at present no rationale to use corticosteroids in mechanically ventilated infants with RSV-associated lower respiratory tract disease. Is it possible to explain why corticosteroids do not improve the disease course? One explanation would be that severe RSV disease does not result from a vigorous immune response (as discussed earlier in this chapter). On the other hand, if it is assumed that the pathophysiology of RSV bronchiolitis resembles that of childhood asthma, then (similar to asthma) corticosteroids would seem to be beneficial [50]. This suggests that correct identification of the clinical phenotype of RSV-assocated lower respiratory tract disease would identify those patients who might benefit from a certain therapeutic modality.

Three studies have evaluated the efficacy of bronchodilators for ventilated infants with RSV-associated lower respiratory tract disease [18, 20 – 51]. Mallory and co- workers observed a 30 % improvement in maximum expiratory flow at 25 % (MEF₂₅) of functional residual capacity (FRC) in 13 of 14 mechanically ventilated children with RSV-associated lower respiratory tract disease [20]. Pulmonary function was assessed by deflation flow-volume curve analysis. Hammer et al. performed a more elegant study by excluding infants with restrictive disease [18]. However, only 10 out of 20 infants with obstructive RSV-associated lower respiratory tract disease responded to nebulized albuterol (defined by a & 2-fold improvement of intra-indi- vidual coefficient of variation for MEF₂₅). Derish et al. included 25 infants and observed a significant increase in MEF at FRC and a decrease in Rrs in some patients [51]. Do these studies justify the use of bronchodilators in mechanically ventilated children with RSV-associated lower respiratory tract disease? All three studies incorporated infants with pre-existing morbidity, and none were designed to detect an effect on the duration of mechanical ventilation and/or PICU stay. The routine use of bronchodilators, therefore, seems unjustified.

The use of exogenous surfactant seems highly rational, as low levels of surfactant phospholipids and proteins as well as a diminished function of surfactant (lowering surface tension at the alveolar-capillary level) have been described and recently summarized by us [52]. Three randomized, controlled trials on the efficacy of exogenous surfactant have been published [53 – 55]. The group of Luchetti et al. performed two studies investigating porcine surfactant versus no placebo [53, 54]. In their first study, 20 children with bronchiolitis (only 20 % were RSV positive) were randomized to receive either 50 mg/kg porcine surfactant once, or nothing [53].

Methodologic flaws from their first study were corrected in a second study [54]. In this study, 40 children with RSV-associated lower respiratory tract disease were randomized. Oxygenation improved in both studies, and the mean duration of mechanical ventilation was also significantly different between the surfactant and the placebo group (4.4 „ .4 vs 8.9 „ 1.0 days in the first study and 4.6 „ .8 vs 5.8 „ .7 days in the second study). These findings were confirmed by a study by Tibby et al., ran- domizing 19 infants to receive either 100 mg/kg bovine surfactant twice or air placebo [55]. These investigators observed no further decrease in oxygenation (oxygen-

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ation index and Aa-DO₂) after administration of surfactant. In addition, a trend towards a reduced duration of mechanical ventilation was observed (126 hours vs 170 hours in the control group). Taken together, the findings of these three studies strongly call for a randomized, controlled trial of this strategy with duration of mechanical ventilation as primary endpoint.

Mechanical ventilation remains the mainstay of supportive therapy for infants with RSV – induced respiratory failure. Interestingly, there have been no randomized controlled trials on, for instance, various ventilatory strategies (volume controlled versus pressure controlled) or the level of positive end-expiratory pressure (PEEP) [11]. Mechanical ventilation with heliox has been scantily studied among infants with RSV-associated lower respiratory tract disease. From a pathophysiological point of view, mechanical ventilation with heliox seems rational. Heliox has a den- sity that is one-seventh that of air, resulting in a decreased resistance to gas flow [56]. There is one trial investigating the effect of mechanical ventilation with various concentrations of heliox in ten infants with RSV-associated lower respiratory tract disease [57]. No beneficial effect could be demonstrated. As the study has methodo- logical flaws, and no attempt was made to discriminate the clinical phenotype of the RSV-associated lower respiratory tract disease, the role of mechanical ventilation with heliox requires further study.

Until now, the mainstay of therapy for mechanically ventilated infants with RSV- associated lower respiratory tract disease has been symptomatic. Judging from the outcomes of the various randomized controlled trials, it is highly unlikely that this will change in the near future. The only promising therapeutic modality seems to be exogenous surfactant, although this has no direct curative effect.

Prevention

Vaccination against RSV will not readily be available, but passive immunization can be applied [58]. Passive immunization can be achieved through palivizumab, which is a monoclonal antibody directed against the F – glycoprotein. Presently, its use is advised for: (a) infants not older than 12 months without chronic lung disease born after a gestation of 28 weeks; (b) infants not older than six months without chronic lung disease born after a gestation of 29 to 32 weeks; and (c) infants born after a gestation of 32 to 35 weeks with at least two of the following risk factors: attending child care, with school-aged siblings, exposed to environmental air pollutants, with congenital abnormalities of the airways, or diagnosed with severe neuromuscular disease. Palivizumab is also advised for children younger than two years of age with chronic lung disease or a hemodynamically significant congenital heart disease [59].

Figure 2 summarizes the results of passive immunization with palivizumab and the effect on the number of PICU admissions and mechanical ventilation. Although in the first study on the efficacy of palivizumab (the Impact study), an overall reduction in hospitalizations of 55 % was reported in palivizumab recipients (n = 1002 vs 500 controls), this was not observed for the number of PICU admissions (1.3 % vs 3 %) or the number of mechanically ventilated children (0.2 % vs 0.7 %) [60]. Chil- dren with congenital heart disease were studied separately (639 palivizumab recipients vs 648 controls) [61]. Again, the overall reduction in hospitalizations of 45 % was not observed for the number of PICU admissions (2 % vs 3.7 %) or number of mechanically ventilated children (1.3 % vs 2.2 %).

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Fig. 2. Percentage of patients in whom mechanical ventilation (MV) and pediatric intensive care unit (PICU) admission was warranted before and after the introduction of the monoclonal antibody palivizumab.

There have been two post-licensure studies reported after the introduction of palivizumab. Pedraz and co-workers studied the efficacy of palivizumab in four consecutive RSV seasons (children without prophylaxis (n = 1583) admitted between 1998 – 2000, and children with prophylaxis (n = 1919) admitted between 2000 – 2002) in Spain [62]. Although they observed a 70 % decrease in overall hospitalizations, the numbers of children admitted to the PICU (13 % vs 20 %) or requiring mechanical ventilation (8 % vs 11 %) were comparable. Similar observations were made in a national survey performed in Israel during two consecutive RSV seasons (2000 – 2002), including 296 children [63]. After the first season (2000 – 2001), the Israel Ministry of Health issued guidelines stipulating the use of palivizumab in children ‹ 2 years with chronic lung disease and infants born at a gestation of 28 weeks or less. The number of children admitted to the PICU or mechanically ventilated was similar before and after the introduction of palivizumab. They also found that the majority of children admitted to their PICU did not meet the American Academy of Pediatrics criteria, concluding that monthly prophylaxis with palivizumab would be very unlikely to influence the number of PICU admissions.

It thus seems that monthly prophylaxis with palivizumab does not have an effect on the occurrence of severe RSV-associated lower respiratory tract disease necessitating PICU admission and/or mechanical ventilation. This suggests that not only virological and/or immunological factors are (partially) responsible for the development of severe RSV-associated lower respiratory tract disease.

Conclusion

RSV-associated lower respiratory tract disease remains an annual recurring chal- lenge for pediatric intensivists. Despite intensive research over the past decades, the mainstay of therapy for infants with RSV-associated lower respiratory tract disease is still symptomatic. But there are a number of scientific challenges that must be pursued. The role of exogenous surfactant requires further study, as also does mechanical ventilation with heliox. In addition, future studies should focus on the question of why an infant clinically deteriorates and needs mechanical ventilation.

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These studies should integrate not only epidemiological aspects, but also virological and immunological aspects, as well as characteristics of respiratory system mechanics. By doing so, it would be possible to identify those infants who might benefit the most from a specific therapeutic approach. Importantly, we also must know what happens to the infants once they are discharged from our ICUs. What is the effect of mechanical ventilation on short-term and long-term airway morbidity? Is there an association with clinical phenotype? As we continue to care for these infants, we eagerly await the results of such studies.

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