A live conversation between
Paul Saenger New York, NY, USA
And, Cheri Deal, Montreal, Canada
With a comment by Ze’ev Hochberg
October 17, 2020
Cheri Deal: I’m going to introduce you, Paul Saenger. Although everyone knows you I’ll start by saying that you actually graduated from medical school in Munich and came to the US in 1969 where you worked at the Montefiore Medical Center. You did a fellowship with Maria new at Cornell and then for 30 years worked at the amount of your medical center and Albert Einstein College of Medicine. You cite having trained 50 fellows. And you mentioned also that you were president of LWPES (as PES was called once upon a time) in 2004 as well as President of the ninth joint meeting of LWPES, SLEP and ESPE welcoming 4000 delegates in 2009 in New York City. You were a visiting professor in both the Munich medical school and the Beijing Children’s Hospital. For the past 10 years you’ve been at the NYU Langone Health—Long Island in Mineola, New York.
Paul Saenger: Burden of treatment is defined as the impact of the work of being a patient or the parent of a patient on functioning and wellbeing. It is most often associated with chronic conditions. 45 % of people have a chronic condition. Burden of treatment is therefore very common.
In pediatric endocrinology burden of treatment is particularly common in:
- Type 1 and 2 Diabetes mellitus. Dexcom (Continuous Glucose Monitor) and closed loop systems diminish burden somewhat.
- Congenital adrenal hyperplasia: longer acting glucocorticoids may help
- Thyroid adherence to drug therapy is the major burden here and adherence diminishes in adolescence
- Novel drug therapy may help somewhat. Bypass surgery is helpful but carries an enormous burden of treatment after the procedure
- Hypogonadism, precocious Puberty: Longer acting GnRH inhibitors are helpful, new testosterone formulations allow self-injection.
- Growth disorders: Long acting growth hormone will be a new formulation touted to reduce treatment burden. Data to document that claim are not yet available. It will help to reduce treatment burden as growth hormone will only be injected once a week.
The idea that illness sometimes involves hard and heavy work is not a new one. Patients with a chronic illness exhibit illness trajectories and help-seeking behaviors that health care providers and policymakers perceive as costly and complex.
The emergence of the chronic patient has been seen in terms of symptom burdens, first conditions and then in the context of multi-morbid conditions. The burdens of treatment itself as they engage with services, insurance companies, drug companies, clinicians, administrators, social workers aim at conditions that unfortunately cannot be cured but must instead be managed. This division over time, between curative effort applied to episodes of acute illness and injury (in hospital) and the efforts devoted to the management of life time illness trajectories (mainly as outpatients has profoundly changed the nature of patient hood and health care providers). Endocrine care is not taking care of an appendicitis or an undescended testicle, it is chronic care. Parents and child have to do treatment work, this adding the burden of treatment to the burden of symptoms as parents and patients confront new and growing demands to organize and coordinate their own care, to comply with complex treatment and self-monitoring regimens and to meet a whole range of expectations of personal motivation, expertise and self -care.
As burdens accumulate and some groups of patients and parents are overwhelmed the consequences are likely to be poor healthcare outcomes increasing strain on care givers and rising demands and costs of health services. (Carl R May et al Rethinking the patient: using burden of treatment theory to understand the changing dynamics of illness BMC Health Services Research 2014 1428100).
Particularly important is treatment burden in adolescence where the treating physician will encounter major nonadherence to therapy and the keeping of appointments.
How can we address adherence to treatment a major aspect of treatment burden? (see Blaschke T and L Ostertag, NEJM 2005 353 :487-97).
Adherence is the preferred term because compliance suggests that the patient is passively following the doctors’ orders and that the treatment plan is not based on a therapeutic alliance or contract between patient and physician. Achieving full adherence in pediatric patients requires not only the child’s cooperation but also a devoted, persistent, and adherent care giver. Adolescent patients create even more challenges, given the ubique developmental, psychosocial, and lifestyle issues implicit of adolescence. An added dimension of the situation is the involvement of the patient’s families. Rates of adherence to medication regimens among children with chronic conditions are similar to those among adults, averaging about 50 % with decrements occurring over time.
To improve adherence several strategies have been developed. One is use of medications with long half-lives (e.g. for precocious puberty, depot or extended release medications such as long acting growth hormone, transdermal preparations such as an estrogen patch for transexual or Turner patients).
Adherence is very variable over time with a steady decline with years of treatment, age. Year 1 and 2 always report excellent adherence (see also M Brod et al Understanding treatment burden for children treated for GH deficiency Patient 2017 10 653-666.)
Growth hormone deficiency
GH deficiency has a frequency of about 1: 3 500. In 2003 the US FDA approved idiopathic short stature defined as a height of below -2.25 SD ( Below 1st percentile in height). The potential patient number jumped from 2100 suddenly to 1.2 % of US pediatric population that is 890000 potential patients who were meeting these criteria.
Idiopathic short stature was the first indication that emphasized height rather than underlying pathology as the qualifying criterion for treatment. This was blurring the boundary between disease and variation of normal- as an example of expansive biotechnology (Ada Grimberg et al, J of the Endocrine Society 2019;3(11):2023).
What is the burden of growth hormone deficiency?
Symptoms related:
Problems reaching things
Reduced performance in sports, physical aspects concerning also care givers
Reduced endurance
Reduced sleep
Poor appetite
Smallest among peers, concerning especially parents
Social /emotional wellbeing domain:
Worries about growing
Hurt feelings
Worries about being different
Bothered by size
Social unease, not fitting in
Teasing or being bullied
Mistaken for being younger
Parents worried about side effects
Administration burden of GH
Daily injections
Worrying when travelling
Worrying about storage and keeping supplies
According to F Haverkamp (Haverkamp F et al Clin Ther 2008 30 :307-16) the following factors might affect adherence:
Patient related actors: Forgetfulness, other priorities, underestimating the disease
Treatment related factors: Frequent dosing, daily injections associated with pain
Health Care related factors (affecting especially parents): Shipping of GH, Insurance denials, Co Pay
Physician related factors: Communication skills, medical competency, providing medical information.
Nonadherence with GH therapy is therefore common and is associated with reduced growth
Duration of GH therapy is negatively related to adherence. Other important factors are: age, convenience of an injection device, level of education, awareness of consequences of therapy.
Poor adherence has been studied and published for New Zealand, US and Spain showing that poor to moderate adherence leads to impaired growth velocity and lower IGF-1 levels. (De Pedro S et al Growth Hormone IGF Res. 2016 26:32-35, Cutfield WS et al, PLoS one 20;6e:16223 Bagnasco B et al, Endocrine Practice 2017;23:929-41)
US data show that only 20 % of pediatric patients initiated in 1997- 2001 remained on treatment after 4 years (Unpubl data, 2006. Genentech Rosenfeld R, Bakker B, Endocrine Practice 2008 vol 14,No 2). Adherence of treatment is an extremely important variable that is difficult to assess reliably.
Recently a drug Vosoritide, a biological analogue of C-type natriuretic peptide (Savairayan R et al, Lancet 396 Sep5, 2020), is being explored for this chronic, daily treatment a achondroplasia. In this disease entity, lack of interest in parents for using this chronic treatment in their children has been recognized. Particularly parents who are themselves achondroplastic ( about 20 % of all achondroplastic patients have parents with achondroplasia) are much less interested in treating their affected child because they feel the height improvement is minimal and the treatment lasts from infancy to adolescence with small improvements in final height (less than 1SD). Parents have “dwarf pride” and don’t want to subject their children to this treatment (NYT Sept 7, 2020 page A11).
A more forgiving treatment using long acting Vosoritide may be more acceptable to parents and patients in this condition as well.
In summary since most endocrine diseases are chronic treatment burden is high and it is measurable. One of the approaches utilized in Pediatric Endocrinology is less frequent dosing which reduces treatment burden. Whether it will improve adherence and/or outcomes such as height has not been shown to date. This will hopefully lead to clinical studies after approval of the novel therapy with long acting growth hormone.
Recognized parent treatment burdens are emotional wellbeing and interference. Treatment interfered with overnight sleepovers or other travel activities. We must recognize that daily injections are disruptive Long acting growth hormone may diminish these disruptions. Treatment burden severity may be modified by the duration of treatment and treatment effectiveness.
Ze’ev Hochberg: In various parts of the world, the main burden of pediatric endocrine diseases is financial. When you sit it in a clinic in Africa or India or in many other countries, you have to think of the costs of a blood test or a prescription. Do you need to test both LH and FSH or one is enough? In developed country there is also the issue of cost, but the cost is covered by the society.
Deal: Yeah, I think that’s very true. So, what do you think, Paul?
Saenger: We can see it in countries where heightism is more prevalent – Asian countries. This economic gap is even more magnified and just because you said about FSH and LH. I know lots of colleagues in New York who insist on measuring free T3 and the reverse T3 because they didn’t know look at their lab manuals. I mean, talking about throwing money out the window. That’s what it is for the growth problems, I think, unless you want to re-educate the population.