A 60 year voyage in cystic fibrosis

Emeritus Professor R.B.Elliott writes about his personal 60 year voyage in cystic fibrosis.

I made my first diagnosis of cystic fibrosis in 1958. Rocco Barbaro, from an Italian immigrant family, was admitted to the Adelaide Children's Hospital during a summer heat wave of over 40°C with heat exhaustion – he was dehydrated and seriously ill.

He did not respond well to the usual measures of intravenous hydration and cooling and went on to develop serious pneumonia. In the light of this, I asked for the newly invented sweat test which came back positive. It should be remembered that cystic fibrosis had only been clearly separated out from other causes of failure to thrive in 1939.

The current treatment at that time was to use antibiotics (usually chloramphenicol as the predominant organism was the staphylococcus), pancreatin, reduction of fat intake to lessen fat malabsorption and “mist tents”. The latter involved placing the child in a plastic tent filled with cold water vapor in the hope it would hydrate sputum. This continued for many years until it was shown that very little of the vapour entered the lungs and the damp atmosphere bred many harmful bacteria.

Reduced fat intake was an attempt to compensate for the relative inefficiency of the enzyme supplements then available. Chest physiotherapy was much in vogue, involving postural drainage and percussion. Its benefits were not apparent.

In the 1960s, I set up a special clinic for children with CF in Adelaide but contributed little new to their management. I became obsessed with measurement of sweat electrolytes and developed a very elaborate modification, as I was convinced if we could solve the cause of the excessive salt content of sweat the cause of the disease would become apparent. It appeared that sweat was secreted with normal salt content in the first part of the sweat gland, but salt failed to be reabsorbed further along the sweat tubule.

In the early 1960s, I travelled by ship to the USA and noted that swimming in the onboard salt water pool for very long periods did not cause fingertip skin wrinkling unlike swimming in fresh water pools. I decided to try immersing the hands of CF children in fresh water and found their fingertips wrinkled much faster than normal children. On questioning, mothers of CF children all knew this! Though I claimed it was my discovery in a scientific paper – my first in CF.

In 1970, I took up my new job as head of the department of paediatrics in Auckland and was determined to set up the first NZ special CF clinic and undertake serious research. I chanced to see a scientific paper which showed that chickens deprived of essential fatty acids in their diet developed “mesobronchitis” which looked remarkably like CF lung. This set off a chain of thought.

Were we doing the right thing in restricting fat in the diet? Was there any other way to improve the absorption of fats – particularly those containing essential fatty acids ?

The first indication I might be on the right track came when we measured the levels of essential fatty acids in CF blood and found a consistently low level of linoleic acid, the commonest of the essential fatty acids. This in turn led to attempts to correct this deficiency using intravenous fat emulsions. In 1976 this culminated in a properly conducted clinical trial which showed clinical benefits

About the same time as this attempt at a novel treatment was underway, my attention turned to trying to diagnose CF in the newborn period. The rationale was quite simple. We knew the ducts draining the pancreatic juices into the intestine are blocked in CF, so where were all the enzymes going? Were the dammed up enzymes flowing back into the blood? The answer was YES, and this could be easily detected in the same dried blood spots collected for other diseases from all newborns in NZ. This test works really well and is now used all over the world. I think it has been responsible for much of the improved outcomes for CF we are seeing today, though impossible to prove as about that time new, much more effective enzyme supplements became available and more intensive use of antibiotics was fashionable. Physiotherapy had changed more to the “huffing” technique.

The next breakthrough came with the discovery of the nature of the genetic defect in CF. I happened to be working in the Toronto Children’s Hospital when the news broke of this discovery amidst much excitement. Within a year the defect had been corrected in a laboratory dish, but unfortunately this has not been accomplished in humans with disease – the nirvana of CF research. It has however led to the development of drugs which can potentiate the activity of the defective chloride pump in some varieties of the genetic disorder. They are not particularly useful in the commonest variety however and are prohibitively expensive.

Antibiotic treatment of CF has improved, but has seen the emergence of drug resistant new infections caused by such things as cepacia, atypical mycobacteria, Wuchereria etc. It seems new infections keep one step ahead of new antibiotics.

Longevity has improved from about 5–6 years at the start of my career to more than 40 years these days and there is more to come. Lung transplants are now possible as a last resort for some.

My predictions for the future include:

  • better and cheaper drugs to improve the function of the defective genes
  • renewed attempts to correct the gene defect in the patient using new gene editing techniques such as CRISPR
  • better means of reducing the adherence and stickiness of sputum using nebulised drugs.

I am involved with the first and third of these areas and hope to live long enough to see their success.

Many years ago, the then President of the NZ CF Association made the comment to me “Bob please keep doing research . It would be nice if it succeeds but even if it doesn’t it gives hope to those who live with CF”.