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Pulmonary hypertension: smaller kids, smaller stepsDespite tremendous advances in the understanding and treatment of pulmonary arterial hypertension, the prognosis of children with this disorder remains poor. For adults, several drugs for pulmonary arterial hypertension have been approved, evidence-based treatment algorithms have been developed, and outcomes have improved. By contrast, treatment and prognosis of children with pulmonary arterial hypertension seem to have benefi ted from these advances substantially less than have adults. For many years, robust data on disease characteristics, outcomes, and treatment of children with pulmonary arterial hypertension were missing, and the only available level of evidence was the invaluable expertise of professionals in the paediatric specialty.

Randomised effi cacy trials in paediatric pulmonary arterial hypertension are almost non-existent and unfortunately are unlikely to be done in the near future, because of several obstacles. First, adequate sample sizes are diffi cult to achieve because of the rarity and heterogeneity of the disease in infants and children. Second, no validated endpoints and treatment goals exist in paediatric pulmonary arterial hypertension. Third, pulmonary arterial hypertension targeted drugs, although not approved for children, are widely used and therefore deemed standard of care for children, which thus poses legal and ethical issues for paediatric study designs.

Finally, there are the general medical ethical issues that are associated with clinical research involving children.

During recent years, relevant data on paediatric pulmonary arterial hypertension have started to accumulate, mostly obtained from registries and national multicentre cohorts. Important insights into the epidemiology, presentation, diagnostics, and predictors of outcomes of pulmonary arterial hypertension in children have been gained through large multicentre registries, such as the global tracking-outcomes-and-practice-in-paediatric-pulmonary-hypertension (TOPP)-registry andthe subgroup of patients with childhood-onset pulmonary arterial hypertension from the US registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) registry. National cohorts have provided data on incidence and prevalence, as well as more targeted information on paediatric pulmonary arterial hypertension, including genetics and complex comorbidities .1–5

These sources showed that pulmonary arterial hypertension in childhood shares many similarities with pulmonary arterial hypertension in adulthood. However, they also confi rmed that unique features of paediatric pulmonary vascular disease preclude simple extrapolation from adult data to infants and children. Such features include types and distribution of associated

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ability to care for severely ill patients with infl uenza and reduce the risk of mortality further.

Alicia M FryInfl uenza Division, National Centers for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USAafry@cdc.gov

I declare that I have no competing interests.

1 Centers for Disease Control and Prevention. Antiviral agents for infl uenza: guidance on the use of infl uenza antiviral agents. http://www.cdc.gov/fl u/professionals/antivirals/summary-clinicians.htm (accessed March 5, 2014).

2 Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014; published online March 19. http://dx.doi.org/10.1016/S2213-2600(14)70041-4

3 Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefi t of infl uenza treatment. J Antimicrob Chemother 2003; 51: 123–29.

4 Nicholson KG, Aoki FY, Osterhaus ADME, et al, for the Neuraminidase Inhibitor Flu Treatment Investigator Group. Effi cacy and safety of oseltamivir in treatment of acute infl uenza: a randomised controlled trial. Lancet 2000; 355: 1845–50.

5 Heinonen S, Silmennoinen H, Lehtinen P, et al. Early oseltamivir treatment of infl uenza in children 1–3 years of age: a randomized controlled trial. Clin Infect Dis 2010; 51: 887–94.

6 Joff e MM, Rosenbaum PR. Invited commentary: propensity Scores. Am J Epidemiol 1999: 150: 327–33.

7 Louie JK, Yang S, Samuel MC, Uyeki TM, Schechter R. Neuraminidase inhibitors for critically ill children with infl uenza. Pediatrics 2013; 132: e1539–45.

8 Nair H, Brooks WA, Katz M, et al. Global burden of respiratory infections due to seasonal infl uenza in young children: a systematic review and meta-analysis. Lancet 2011; 378: 1917–30.

9 Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal infl uenza—United States, 1976–2007. MMWR Morb Mortal Wkly Rep 2010; 59: 1057–60.

10 Kostova D, Reed C, Finelli L, et al. Infl uenza illness and hospitalizations averted by infl uenza vaccination in the United States, 2005–2011. PLoS One 2013; 8: e66312.

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conditions and comorbidities, the frequent co-existence of genetic, developmental, or adaptive disorders, and the eff ects of growth during the disease (often already present in utero).6 Clearly, these aspects are not adequately addressed in the widely adopted clinical classifi cation of pulmonary hypertension proposed at the World Symposia on Pulmonary Hypertension (WSPH).7 Consequently, a debate has emerged as to whether a dedicated classifi cation covering the unique features of paediatric pulmonary vascular disease is needed.8 Disease characteristics, such as underdevelopment or maladaptation of the pulmonary vasculature, lung hypoplasia, complex cardiovascular anomalies, associated congenital malformations, or genetic disorders might substantially aff ect patho-physiology, prognosis, and treatment options in paediatric pulmonary vascular disease. Does this suggest that a new, customised paediatric classifi cation of pulmonary vascular disease is required? A dedicated paediatric classifi cation has been proposed recently, in which the structure of the WSPH classifi cation was abandoned and ten main classes and 109 subclasses of paediatric pulmonary vascular disease were suggested,8 illustrating the challenge to balance being all-inclusive with adequate simplicity. In this respect, one should keep in mind that characterisation and classifi cation of disease are not similar.

A key value of the current clinical WSPH classifi cation of pulmonary hypertension is that it has organised a complex, heterogeneous disease into fi ve main classes, sharing similarities in pathophysiology, histopathology, and clinical characteristics.7 Although inevitably associated with limitations, this classifi cation has proven to be invaluable in improving communication between physicians, conduct of trials in relatively homogeneous groups of patients, standardisation of diagnostics and treatment, and identifi cation of pathobiological mechanisms in populations with similar characteristics.

Also in adult pulmonary arterial hypertension, it is becoming clear that there is great heterogeneity in the disorder, with various comorbidities, including hypertension, diabetes, COPD, heart failure with preserved ejection fraction, obesity, and sleep apnoea, which confound outcomes and treatment strategies.9 These growing insights will lead to ongoing refi nements of the current classifi cation.

To profi t optimally from the achievements made in the fi eld of adult pulmonary arterial hypertension, this strategy should also be applied to paediatric patients with pulmonary vascular disease: incorporation of age-specifi c refi nements that address genetic, developmental, and intrauterine growth aspects into the basic structure of the existing classifi cation, and, probably, the addition of a specifi c chapter on perinatal developmental pulmonary vascular disease. This approach will provide a strong basis for diagnosis and management, will facilitate research in the specifi c paediatric phenotypes of the disease and fi nally, will support the transition of an increasing number of paediatric patients into adolescence and adulthood. The fi rst small steps in this respect have been made during the fi fth WSPH in Nice 2013, incorporating some developmental neonatal pulmonary vascular diseases in the WSPH classifi cation.6,7

In the absence of controlled trials in paediatric pulm-onary arterial hypertension, disease registries are powerful tools and an invaluable source of information. The design of a registry, however, dictates which questions can be answered from the collected data. In designing a registry, clearly predefi ned aims are necessary to defi ne the type of patients and data that should be included, but also to outline the scope of the registry in terms of size, setting, geographical coverage, and anticipated duration. Since the TOPP and REVEAL registries were designed, new questions in the fi eld of paediatric pulmonary vascular disease requiring new registry-designs have emerged.

One such question and an urgent, unmet need in children with pulmonary vascular disease is the identifi cation of clinical endpoints or treatment goals, applicable in paediatric age groups. Validated treatment goals will allow for adequate assessment of treatment responses, timing of therapy escalation, and thereby improvement of treatment strategies for these children. Validated endpoints will form pivotal support for the design of smart paediatric studies. To identify treatment goals (in which treatment-induced changes actually aff ect outcomes) from registries, a standardised collection of candidate variables during follow-up is imperative. This is challenging in observational registries that do not dictate frequency and mode of follow-up. New registries for paediatric pulmonary vascular disease should be designed to answer specifi c questions; addressing subtypes of perinatal and developmental pulmonary vascular disease, age-specifi c comorbidities, validation of recently

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Extracorporeal lung support for COPD reaches a crossroadThe natural course of chronic obstructive pulmonary disease usually evolves into a form of acute respiratory failure characterised by alveolar hypoventilation and severe respiratory acidosis. As the severity and frequency of hypercapnic respiratory failure increases, the negative evolution of the syndrome progresses. Non-invasive mechanical ventilation delays fatal evolution through restoration of suffi cient alveolar ventilation.1 Unfortunately, such ventilation can fail in up to 40% of the most severe cases and patients then have to undergo invasive ventilation to restore gas exchange.1 These patients have a risk of death 600-times greater than patients successfully treated with non-invasive mechanical ventilation,2 probably because of the well-known complications of mechanical ventilation.3

Respiratory acidosis could also be managed by removal of excessive carbon dioxide through extracorporeal circuits (ie, extracorporeal carbon dioxide removal [ECCO2R]). Blood fl ow, size of vascular access, and heparin use requirements with this technique are smaller than with conventional extracorporeal membrane oxygenation because

ECCO2R removes only carbon dioxide and does not aff ect oxygenation. ECCO2R was proposed to reduce ventilator assistance in patients with acute respiratory distress syndrome4 but occurrence of severe bleeding restricted its use.5 In the past 5 years, however, technological developments have reduced the iatrogenic complications of ECCO2R, allowing its use to enhance protective ventilation in patients with acute respiratory distress syndrome.6 Until 2012, few studies had assessed ECCO2R in patients with chronic obstructive pulmonary disease, but since then several devices have been approved and commercialised in Europe for such patients.7,8 This increase in interest is based on the potential eff ectiveness of ECCO2R to rescue the ability of non-invasive mechanical ventilation to increase alveolar ventilation (fi gure). However, the observational nature of available data leaves unanswered the question as to whether patients with respiratory acidosis that is refractory to non-invasive ventilation should be intubated and face the risks of invasive ventilation, or should be connected to ECCO2R to avoid intubation but risk severe bleeding. Moreover, widespread application of ECCO2R might

proposed and new treatment goals and clinical endpoints for children of various ages and, fi nally, the effi cacy of treatment strategies. Further expansion and cooperation of global networks in paediatric pulmonary arterial hypertension will be needed for these goals to be realised.

In summary, incorporating developmental and growth aspects of pulmonary vascular disease in the current clinical classifi cation of pulmonary arterial hypertension, running disease registries that are appropriately designed to target current clinical questions in paediatric pulmonary hypertension, and eventually designing smart effi cacy-trials are steps that will narrow the current gap between children and adults in the understanding and treatment of pulmonary vascular disease.

Rolf M F BergerCenter for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen 9713GZ, Netherlandsr.m.f.berger@umcg.nl

I have received fees for advisory board activities from Actelion, GlaxoSmithKline, Pfi zer, Lilly, and Novartis, outside of the submitted work.

1 Berger RM, Beghetti M, Humpl T, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet 2012; 379: 537–46.

2 Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Circulation 2012; 125: 113–22.

3 van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation 2011; 124: 1755–64.

4 Moledina S, Pandya B, Bartsota M, et al. Prognostic signifi cance of cardiac magnetic resonance imaging in children with pulmonary hypertension. Circ Cardiovasc Imaging 2013; 6: 407–14.

5 Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT, et al. TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension. J Med Genet 2013; 50: 500–06.

6 Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25 suppl): D117–26.

7 Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classifi cation of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25 suppl): D34–41.

8 del Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classifi cation of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ 2011; 1: 286–98.

9 Poms AD, Turner M, Farber HW, Meltzer LA, McGoon MD. Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. Chest 2013; 144: 169–76.