[  Site Map  ]

Intriguing Cases

The Importance of Timing

Intriguing case 6
Dr David L. J. Freed, MB, MD, MIBiol

Every stand-up comedian knows the importance of timing, but we allergists have been slow to appreciate it.

Back in the antedeluvian times when I was a young immunologist, clinicians used to use the Kveim test to help diagnose sarcoid. It was based on the tuberculin test for TB, but unlike TB the causative organism had not been isolated so we couldn’t use that. Instead the spleen was taken from a sarcoid patient (probably long deceased), homogenised and mixed with an antiseptic, and a small quantity of the resultant goop was injected intradermally in the hope that it contained enough of the unknown antigen to evoke a reaction if the patient were hypersensitive. After five weeks the area of the injection was biopsied and examined for evidence of inflammation. I believe it was quite a reliable test, although nowadays, in these hyper-regulated times, we’d never be permitted to use it. Note, we didn’t bother biopsying the injection site until five weeks after injection, it wasn’t worth it – a truly delayed hypersensitivity. Lesson so far – allergic reactions, at least in the human skin, can be very slow indeed.

Conventional allergists knew about food allergy in those far-off days, but the issue of speed of reaction was largely ignored. We knew about classic food reactions such as the one reported in 1921 by Küstner [1] – he was so exquisitely allergic to fish that even eating parsley that had been chopped on a board previously used for anchovies brought on rhinoconjunctivitis, asthma and urticaria within half-an-hour, followed a few hours later by vomiting. The entire reaction was finished and gone within 12 hours. Küstner and his colleague Prausnitz ascertained that injecting serum from the allergic patient into a non-allergic person’s skin transferred the food sensitivity, thus discovering IgE antibodies. Reactions that start hours later (‘late’ reactions at 6-8 hours, and ‘delayed’ reactions at 24-48 hr) were beginning to be recognised, but reactions starting only days or weeks later had not really been considered, although delayed skin test reactions were known, as we have seen.

I was taught, back then, that the way to diagnose food allergies was to start by withdrawing all food allergens, by a fortnight on either a “few-foods diet” or an elemental diet (supposedly free of antigens). After this, if food intolerance was involved, we expected the symptoms to have gone. If the symptoms did indeed recede, the patient would then gradually re-introduce foods, one-by-one, to see which caused reactions.

That approach is sometimes very effective, but it presupposes that reactions will be reasonably quick, unrelated to dose or frequency, and (crucially) that reactions will resolve reasonably quickly once the trigger factors have gone. Trouble is, these assumptions are all axiomatic, not tested. Food reactions that :
(a) start many days, (or weeks) later, or which
(b) last for months (or years?) once they have started, or
(c) require a gradual build-up of daily ingestions or
(d) some combination of foods, or
(e) only happen when other stress factors are simultaneously present (such as fear, exercise, menstruation) or
(f) make the sufferer feel transiently better, albeit worse in the longer term (“masked”), or finally
(g) any combination of these [2],
are very difficult to spot with this approach and in most cases impossible [3].

In these complex cases stepwise reintroduction of foods doesn’t work – the patient doesn’t get “reactions”, he just gradually relapses back into illness. Only Soothill’s and Hunter’s groups made any realistic attempt to tackle factors (a) and (c), by insisting on daily consumption in real-life quantities for a full week, for every food challenge [4,5] – but even they had to draw the line after that. (Their results, needless to say, have been resolutely ignored by the medical community – including our conventional allergy colleagues who persist in their criminal folly of dismissing patients as “not allergic” if they fail to satisfy the doctor’s simple-minded criteria).

It is only because of the existence of numerous clear-cut, well-studied and “fast” cases such as that of Küstner - cases that are amenable to confirmation by challenge studies and therefore acceptable to our conventional colleagues - that the phenomenon of food allergy/intolerance can be proven to exist at all. More complex cases such as the ones we are discussing are likely to be forever unprovable, providing fertile ground for controversy that will never be resolved.

But that does necessarily not preclude successful treatment.

A 31-year old female came to me as a tertiary referral from another allergist with a long history of anaphylactic attacks (brazil nuts plus unknown triggers), IBS, rhinoconjunctivitis, thrush and recurrent angioedema. She had been very well worked up by her doctors. Her total IgE was raised at 396 KU/l and her brazil-nut RAST was positive grade 2 on one occasion though negative on another. She had been managed with elimination dieting, nutritional supplements and antifungals and her chronic hyperventilation had been addressed with physiotherapy. In an attempt to track down specific food allergies she had been consuming an elemental diet. She was now dependent on that because, although she remained ill, she became far worse whenever she attempted to reintroduce foods - but without any clear-cut “reactions”. She was now painfully thin and the referring allergist wondered whether neutralisation might enable her at least to eat food again in safety.

Not all patients respond to modern low-dose desensitisation. One of the reasons I like neutralisation is that you can find out quickly and fairly cheaply whether or not it is going to work in any particular patient. I persuaded the patient to choose a dozen “stone-age” foods that she thought she could survive on (meats, fishes and leafy vegetables are usually easy to neutralise), and neutralised those. There were no classic weal-and-flare skin reactions. She then started eating those dozen foods (only), and although she got no better, at least she got no worse. Since she was now consuming real food again instead of elemental diet I took that as presumptive evidence that neutralisation would be useful, if only to improve her nutrition. Maybe clinical improvement would follow.

After lengthy discussion the patient opted to come for more neutralisation, expanding the cover to include 20 foodstuffs, 30 inhalants, C. albicans and various miscellaneous items. The range of foods was not as wide as I like but we were concerned to conserve money, and she felt that these 20 foods would be enough for the time being (and certainly an improvement on elemental diet). As is my usual practice, I checked the skin the day after testing for delayed reactions, but there were none. She went home to self-inject daily her four bottles of neutragen.

To my dismay she got no better, indeed after a couple of weeks she reported being a lot worse, and now had new symptoms also – hot inflamed “pimples” in various parts of the body. She lived too far away to come in person but she posted me photographs.

The spots on the right thigh clearly corresponded to where she had been self-injecting. The spots on her left shoulder, a neat row starting with a juicy red type IV reaction and getting progressively weaker, corresponded to the row of sunflower seed injections I had given her four weeks previously. The similar row on her upper back corresponded to the row of C albicans skin tests. No surprises there, and in neither case did these delayed reactions change the neutralising end-point.

The neat row of delayed reactions on her lower back corresponded to the spots where, four weeks previously, she had been tested for nystatin, and this one did change the end-point. On the day of testing she had neutralised on the second dilution, and, there having been no delayed reaction next day, that was the strength in her bottle, which she had been dutifully injecting into her right thigh (where the spots now were). It was now clear that the neutraliser was actually the fourth dilution, 25 times weaker.

I adjusted the dose of her treatment accordingly. Injecting this revised neutragen she now got rapidly better, reintroduced foods (ice-cream, cereals and other horrors) at a dizzying rate, and within three months was eating and drinking ad lib, gaining weight, and virtually symptom-free. She never actually needed the nystatin for which I had prepared her, and which nearly caused her undoing.

NB. The delayed reactions to her skin-tests made their first appearance ten days after the intradermal testing. Keith Eaton always insisted on monitoring all skin tests to extinction, but I don’t think even he would have waited that long for a positive.


1) Prausnitz C, Küstner H (1921) Studies on supersensitivity. Centrallblatt fur Bakteriologie, 1 Abt Origin 86: 160-9, translated and printed as appendix to Clinical Aspects of Immunology (eds Gell PGH, Coombs RRA) 2nd ed, Blackwell, Oxford 1968, pp 1298-1306.

2) Freed DLJ, Waickman FJ (2002). Laboratory diagnosis of food intolerance In Food Allergy and Intolerance 2nd edn (eds Brostoff J, Challacombe SJ) Elsevier, London, pp 837-856.

3) Freed DLJ (2002) False-negative food challenges. Lancet, 359: 980-1

4) Egger J, Carter CM (1983), Wilson J et al. Is migraine food allergy? Lancet, ii: 865-8

5) Jones VA, McLaughlan P, Shorthouse M et al (1982), Lancet ii: 115-7

# Back to top of page

Return to Medical Information Index

Return to the Home Page