The second of three original observations

That inhaled corticosteroids (Becotide) could impair the growth of some children with asthma – contrary to establish teaching.          

Littlewood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. Lancet. 1988 Jan 16;1(8577):115-6. 2891952

As I noted in the introduction to the First Original Observation section of this website, there are advantages for a clinician personally seeing and treating many patients over a prolonged period. A prolonged period is necessary to observe the effects of any interventions. A wise observation of that great physician Sir William Osler is relevant to the following section –“ Medicine is to be learned by experience; and is not an inheritance; it cannot be revealed. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone can you become expert”. One could also add the value of continuity of care – sometimes sadly lacking in modern times.

Hence my enthusiasm for seeing as many patients as possible in clinics where one could improve knowledge of a condition and observe where improvements and changes in management were needed. Certainly in 1968, when I was first appointed as an NHS consultant paedaitrician, there was room for improvement in many areas.

All three original observations were the result of accumulating considerable experience derived from personally following, investigating or treating many children with a particular condition. The importance of significant patient numbers, careful follow-up and note-taking and particularly continuity of personal professional involvement are of great importance. Good care is a team effort. The care and dedication of the nurses and other professional staff in the paediatric clinics and wards and the skill, interest and collaboration of people in many other departments at St James’s in Leeds was of crucial importance in providing a effective professional service and bringing these observations to eventual publication.

As a general paediatric consultant appointed in the late Sixties it was to be expected there would be many children with asthma of varying degrees of severity refered to my outpatient clinic. As my experience increased and the numbers of children with asthma attending my outpatients mounted, on moving to St James’s in 1980 I devoted a regular outpatient session to children with asthma.

We published a number of papers on various aspects of asthma during the Eighties and I also was invited to give postgraduate talks on the subject around the country.

Littlewood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate.  Lancet. 1988 Jan 16;1(8577):115-6. 

Gillies DR, Littlewood JM, Sarsfield JK. Controlled trial of house dust mite avoidance in children with mild to moderate asthma.   Clin Allergy. 1987 Mar;17(2):105-11.

Conway SP, Littlewood JM. Admission to hospital with asthma.   Arch Dis Child. 1985 Jul;60(7):636-9.

Gillies DR, Conway SP, Littlewood JM. Chest X-rays and childhood asthma.   Lancet. 1983 Nov 12;2(8359):1149. No abstract 
Arch Dis Child.

Littlewood J M, Asthma in childhood. Internat Med Suppl No 6, 1983, 9-13.

There was a very efficient paediatric outpatient clinic at St James’s with one of my regular session devoted to children with asthma. The clinic was run by an efficient Sister and experienced Nurses who appreciated the importance of careful weighing and measuring each child in minimal clothing on every attendance; the height was measured very accurately with a Harpenden Stadiometer. The results were recorded on a standard outpatient asthma follow-up form. Simple respiratory function tests using a peak flow meter were carried out each attendance. When the child came in to see the doctor (always myself or my Registrar) the recorded height and weight were charted by the doctor on the child’s Tanner growth chart.

Chancellor Wing Outpatients at St James’s – windows above the sign

This routine became a permanent method of accurately documenting and recording the child’s progress. It was following the child heights recorded on these charts over a number of years that first drew my attention to the fall off in growth of some children who were receiving inhaled corticosteroids. We had been assured in publications by paediatric respiratory experts such as Simon Godfrey that inhaled steroids did not affect growth. Nonetheless, in some of our children, despite a marked improvement of their asthma, there was a slowing of height gain but normal or even accelerated weight gain – and many of these were children in mid-childhood and nowhere near puberty.

So I decided to look at our whole clinic to see if other children had changes in growth rate. The co-authors were Dr Andrew Johnson a scientist from the University Department of Medicine at St James’s, Dr Phoebe Edwards a general practitioner who worked with me for two days a week and Ann Littlewood SRN, a nurse who was responsible for the unit’s clinical computerised database.

We reviewed 346 children with asthma attending my outpatients, 81 of whom were receiving inhaled beclomethasone in doses ranging from 200 to 800 ug daily. Those receiving the inhaled corticosteroids had significantly lower height standard deviation scores than those not on steroids. The slowing of growth in some was obvious on the growth charts.

For example although Balfour-Lynn had noted a high prevalence of delated puberty he had not noted adverse growth effects with inhaled corticosteroids with doses up to 600 ug daily (Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986;61:1049-55).

It was noted that there was a difference in age between the two groups and it was suggested the difference could be related to the natural pattern of prepubertal growth declaration seen in older corticosteroid treated patients. There were quite strong objections to our findings from a number of colleagues.

Stephen Holgate

There was a comment from Professor Stephen Holgate who is the MRC Clinical Professor of Immunopharmacology and Hon. Consultant Physician within Medicine at the University of Southampton. However, although at the time of writing (2019) he had published over 1000 reviewed papers, he is not a paediatrician; but in 1988 nonetheless he was surprised at our findings as he “uses inhaled beclomethasone in young children and has not come across the problem”.

George Russell

Dr George Russell of Aberdeen, a respiratory paediatrician, was particularly and repeatedly critical of our findings (Russell G. Asthma and growth. Arch Dis Child 1993;69:695-98). Previously he had published, with Dr Titus Ninan (now a paediatrician in Birmingham), a much smaller study of 58 prepubertal children receiving budesonide or beclomethasone in doses ranging from 200-1600 ug daily where they had failed to detect a relation between height standard deviation score and corticosteroid use although there was a relation with asthma severity (Ninan T, Russell G. Asthma, inhaled corticosteroid treatment and growth. Arch Dis Child 1992; 67:703-705). Commenting on our publication they noted “many of their patients were of an age where pubertal changes would be expected to be influencing growth”. Russell and Ninan therefore concluded they had been “unable to demonstrate any adverse effect of inhaled ICT on growth”

Typical examples of obvious slowing of growth in two children after starting inhaled beclomethasone (BDP). Both were in mid-childhood – well before any delay in puberty could be implicatedpuberty

In 1994 Russell was again reviewing the side effects of inhaled corticosteroids in children in a Editorial for the Thorax. “Despite anxieties raised by the series of Littlewood et al which included older children in whom the effects of delayed puberty could not be excluded, studies on the effect of inhaled corticosteroid therapy on growth have generally continued to give reassuring results”. However, Russell continues “However the introduction of knemometry a technique for measuring the length of the ulna or lower leg with great accuracy has reopened the debate. Using knemometry Wolthers and Pedersen demonstrated a convincing a convincing dose-related suppression of short term lower leg growth in children receiving inhaled corticosteroid therapy. (Wolthers OD, Pedersen S. BMJ1991;303:163-5 and also Pediatrics 1992; 89:839-42); similar results were reported by MacKenzie CA, Wales JCH.(BMJ1991; 303:416).

So the tide was turning and the truth was becoming apparent! Two further studies confirmed the adverse effect of inhaled corticosteroids on childrens’ growth (Doull IJM et al, Am Rev Respir Dis 1993; 147:A265; Doull IJM et al Thorax 1994; 49:398-9P)

So George Russell, despite all the early criticism of our findings by him and other UK paediatric respiratory experts, in 1994, he was forced to conclude “Inhaled corticosteroid therapy therefore affects growth”.

The subsequent literature on the subject is vast and beyond the scope of this piece – suffice it to say the effect of inhaled steroids on some children’s growth is now an established fact but the emphasis must be on their value as one of the really important treatments for asthma – now well established. In the experience of this writer they are also a valuable treatment for a minority of children with cystic fibrosis.

This story does emphasise there still remains a place for careful clinical observation. The wise observation of that great physician Sir William Osler is relevant to the following section –“ Medicine is to be learned by experience; and is not an inheritance; it cannot be revealed. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone can you become expert”. One could also add the value of continuity of care, sometimes increasingly sadly lacking in modern times, is also of crucial importance. One doctor treating many patients in the clinic over a prolonged period may reveal more important information than a Systematic Review of the world literature.