In medicine, there is hardly a “one size fits all” approach to any disease category. For example, treatment guidelines for most diseases have separate categories for adults, children, and pregnant women. Particular attention is given to children, since their rate of growth can determine, for example, the dosage of medication given, and the level of comprehension one can expect them to have regarding their condition.
It is often easier to talk about medicine by drawing attention to real-world parallels that remain fresh in our minds. During the COVID-19 pandemic, the record-breaking speed at which vaccines were developed and approved provided the world with a collective sigh of relief. At the time of writing, vaccines have achieved something truly remarkable: high daily figures of new cases do not automatically translate to a certain percentage of them being severely ill (as was the case before vaccines were available). In Malaysia, where I am from, new cases have risen astronomically in recent months but the number of severely ill remain roughly the same.
However, when COVID-19 vaccines became approved for use in children, parents were concerned about the effects vaccines might have on the young, since data on them are relatively scarce, compared to the adult population. The reluctance of some parents to vaccinate their children highlights an important point: the biology of children differs from adults, and the threshold for the approval of drugs for children is very high, and rightly so.
Differing Etiologies, Presentation, and Outcomes
Pulmonary arterial hypertension (PAH) is one example of a condition that health care providers must manage differently in pediatric patients than in adults.
“The distribution of etiologies in pediatric PH is quite different to that of adults, with children having a greater predominance of idiopathic pulmonary arterial hypertension (IPAH), pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) and developmental lung diseases,“ Rosenzweig and colleagues wrote in the World Symposium on Pulmonary Hypertension. “Differences in etiology, presentation and outcomes require a unique approach in children.”
Read more about PAH etiology
This is further complicated by a point highlighted earlier: evidence for therapeutics is always more abundant in adult populations than among children (with a few exceptions). This means physicians have no choice but to make treatment decisions based largely on studies carried out on adults. Physicians have to use their best judgment when evaluating how children differ from adults in terms of the effectiveness of treatments, formulation of medications, optimal dosing for children of different ages, and pharmacokinetics.
Before we go any further, let’s define PAH in pediatric patients. The 2018 World Symposium on Pulmonary Hypertension defined it as having a mean pulmonary arterial pressure (PAP) of more than 20 mm Hg at rest via heart catheterization. Another more traditional definition, provided by Rosenzweig and colleagues, was essentially the same as in adults: having a mean PAP of at least 25 mm Hg.
Questions on Treatment Approaches and Dosages Remain
Regardless of the subtle differences in the definition of pediatric PAH, progress has been made to develop a treatment protocol specific to these patients. In Annals of the American Thoracic Society, Steffes and Austin wrote about some treatment strategies and the success of pulmonary-specific vasodilator therapies in improving lung transplant-free survival in this population. These therapies work by targeting 3 distinct pathways: the nitric oxide pathway, endothelin pathway, and prostacyclin pathway.
Studies have shown that the upfront dual therapy regimen of ambrisentan and tadalafil, when compared to monotherapy, demonstrated decreased disease progression and hospitalization and improved clinical outcomes such as 6-minute walk test results. Hence, such a therapy for pediatric PAH patients may very well improve clinical outcomes and prognosis. Studies with adult participants likewise displayed similar benefits of aggressive upfront combination therapy.
Read more about PAH complications
As is often the case in pediatric patients, “current recommendations lack direction for goal prostanoid dosing and safe parameters for therapy de-escalation from parenteral to oral/inhaled prostanoid,” Steffes and Austin wrote. In other words, dosing remains an issue when it comes to pediatric patients, which may be a strong enough concern to cast doubt on the entire therapeutic approach in the first place.
However, medical researchers are not giving up. A clinical trial examining the efficacy and long-term safety of early, upfront combination therapy for patients with PAH is soon to begin in North America. Other therapeutic approaches for pediatric PAH are also currently being explored. As we piece together the findings from these various studies, we inevitably gain a deeper insight into how best to treat pediatric patients with PAH that secures them the disease-free future they deserve.
Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J. 2019;53(1):1801916. doi:10.1183/13993003.01916-2018
Frank BS, Ivy DD. Pediatric pulmonary arterial hypertension. Pediatr Clin North Am. 2020;67(5):903-921. doi:10.1016/j.pcl.2020.06.005
Steffes LC, Austin ED. Upfront combination therapy: growing the case to get ahead of pediatric pulmonary arterial hypertension. Ann Am Thorac Soc. 2022;19(2):163-165. doi:10.1513/AnnalsATS.202108-975ED
Clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed-dose combination therapy in subjects with pulmonary arterial hypertension (PAH) (A DUE). ClinicalTrials.gov. April 5, 2019. Accessed April 7, 2022.