DIAGNOSING COLIC TYPE IN AN ENFANT

Abstract: A method for diagnosing colic type in an infant exhibiting one or more symptoms characteristic of unspecified colic comprises the steps of optionally measuring in said infant at least one parameter indicative of unspecified colic; orally administering a liquid formulation of a beta -D-galactosidase enzyme separately, simultaneously with or sequentially to a lactose-containing feed; and determining at selected intervals of time any alteration in said infant of colic-type symptoms. An improvement in said symptoms of at least 50 % or greater is indicative of lactose-based intolerance. Where the enzyme formulation fails to alleviate the symptoms of unspecified colic, the infant is then placed on a diet of low allergen feed. An improvement in said symptoms of 50 % or more is indicative of allergen-based colic requiring maintenance on a low allergen-based diet. A failure to respond to such a low allergen-based diet is indicative of a need of further investigation, because the symptoms may be due to low-level infection or a metabolic error.

Description: Description DIAGNOSING COLIC TYPE IN AN ENFANT Technical Field This invention relates to a method of distinguishing between different types of colic in infants and as a result allowing for more effective management and therapy of colic in such infants. Background Art Infant colic affects between 10% and 30% of babies between 3 and 13 weeks (Weisbult, H. ( 1994) Current Pediatric Therapy ( 14 th ed) Philadelphia Saunders, pp 233-236), whether bre&st-or formula-fed. Although it is not generally considered to be a serious medical condition, colic can lead to failure to thrive and in extreme cases to dehydration and electrolyte imbalance. More commonly it may contribute to impaired parent-child bonding, and increase the risk of child abuse (Wolke, D. et al (1994) Pediatr. 94: 322-332). The aetiology of the condition is unclear, and this has led to a proliferation of treatment strategies, none of which is very successful. Indeed, one of the most commonly used remedies (dimethicone) was shown to be no better than placebo in two double-blind cross-over studies (Metcalfe T.J. et al (1994) Paediatr. 94: 29-34). One current theory suggests that colic may be caused by transient relative lactase deficiency, which may reflect an immature digestive system (Barr, R.G. et al (1984) J. Pediatr. 104: 527-533). The resulting failure to break down all the lactose in the feed allows significant amounts of lactose in breastmilk or formula to enter the large bowel. It then becomes a substrate for lactobacilli and bifidobacteria in the colon, which break it down in a fermentation reaction to produce various acids, including acetic, propionic and butyric acids and hydrogen. The subsequent increase in breath hydrogen is an accepted indirect biomarker for hypolactasia (Levitt '69), and has been reported in infants with colic (Moore D.J. et al (1988) J. Pediatr, Vol. 113, p979-984) The rapid production of hydrogen in the lower bowel distends the colon, causing pain. The osmotic pressures generated by the lactose and lactic acid in the colon cause an influx of water, leading to further distension and acidic diarrhoea. This model of colic implies that symptoms could be relieved by reducing the lactose content of the infant's feed. This hypothesis has been tested in a small double-blind study in which the feed of colicy babies was pre-incubated with lactase (Kearney P.J. et al (1998) J Hum Nut. Dietetics, 11: 281-285). The results were positive, but the trial size (n=13) precluded formal proof. Kearney et al found that all thirteen infants were responders which would appear to be statistically anomalous as in a representative population all of the infants presenting with symptoms of colic would not all be expected to be suffering from transient lactose intolerance. Accordingly, there is a need for a method of diagnosing colic type in infants, especially as failure to identify colic type at an early date can have serious consequences. In infants whose colic is caused by factors other than transient lactose intolerance, such as carry food allergies, low- level infection or metabolic errors, failure to diagnose such conditions can have serious and often irreversible effects. Disclosure of Invention The invention provides a method for diagnosing colic type in an infant exhibiting one or more symptoms characteristic of unspecified colic, which comprises the steps of: a) optionally measuring in said infant at least one parameter indicative of unspecified colic; b) orally administering a liquid formulation of a β-D- galactosidase enzyme separately, simultaneously with or sequentially to a lactose-containing feed; and c) determining at selected intervals of time any alteration in said infant of colic-type symptoms. In one aspect of the invention, an improvement in said symptoms of at least 50% or greater is indicative of lactose-based intolerance. Accordingly, where administration of lactase results in a positive result, the infant should remain on lactase therapy for a period of three months or until symptoms no longer present or as the attending clinician may prescribe. In an alternative aspect of the invention, when said enzyme formulation fails to alleviate the symptoms of unspecified colic, the infant is then placed on a diet of low allergen feed. In a further aspect of the invention, an improvement in said symptoms of 50% or more is indicative of allergen-based colic requiring maintenance on a low allergen-based diet. If food allergy, principally bovine serum albumin (BSA) allergy, is the cause of the colic, then the symptoms will be alleviated by a low allergen feed. Furthermore, if early BSA allergy is a significant cause of infant colic, as has been suggested, non-responders to lactase may include significant numbers of early atopy. As BSA allergy is increasingly regarded as the cause of Type 1 diabetes (Karjalainen, J. et al (1992) New Eng. J. Med. 327: 302-307) the use of lactase in accordance with the invention will help to identify those infants where BSA allergy is developing, and enable the clinician to initiate dietary shifts (dairy to soy) which could reduce the numbers of Type 1 diabetics. This would in turn lead to considerably reduced healthcare costs for this life-long disease. Accordingly, it will be appreciated that application of the invention would result in additional, longer-term health and medeconomic benefit. The benefits to both infants and their parents will be appreciated, because in the majority of infants presenting with unspecified colic, effective management and therapy can be implemented at a very early stage, namely at the onset of symptoms. The benefits to healthcare visitors and other healthcare professionals, including A & E departments and paediatricians, will result in fewer calls by concerned parents with the attendant advantages. In a still further aspect of the invention a failure to respond is indicative of a need for further investigation. In one embodiment of the invention when said infant is fed a man- made formula, said formula is pre-incubated with said enzyme. In an alternative embodiment of the invention, wherein when said infant is breast-fed, said enzyme is added to an aliquot of fore-milk and then administered to the infant at the end of a feed. Preferably, the parameter measured is selected from one or more of the following: breath hydrogen, stool pH, stool reducing substances; and bowel distension. In a preferred embodiment of the invention there is provided a method for diagnosing colic type in an infant exhibiting one or more symptoms characteristic of unspecified colic, which comprises the steps of: a) measuring breath hydrogen in said infant; b) orally administering a liquid formulation of a β-D- galactosidase enzyme separately, simultaneously with or sequentially to a lactose-containing feed; c) measuring breath hydrogen at intervals over a period of at least one hour; and d) determining the difference in breath hydrogen relative to said pre-feed measurement. In one embodiment of this aspect of the invention a reduction in said breath hydrogen of the order of 50% or more relative to said pre- feed measurement is indicative of lactose intolerance-based colic. In an alternative embodiment of this aspect of the invention a failure to respond to said enzyme formulation as measured by a breath hydrogen which is substantially unchanged relative to said pre-feed measurement is indicative of colic other than lactose intolerance-based colic. Preferably, the breath hydrogen is measured at time intervals of 30, 60, 190 and 120 min. post lactose-based feed. Further preferably, the breath hydrogen is measured by means of a portable hydrogen monitor. A suitable probable hydrogen monitor is a Micro H 2 (Micro Medical Ltd, Chatman, UK). This is a portable hydrogen monitor designed for the simple screening of lactose or sucrose malabsoφtion by automatic sensor drift detection (Peuhkuri K. et al (1998) Scand. J. Clin. Invest. 55: 217-224). Preferably, the enzyme is a β-galactosidase obtained from the controlled fermentation of Kluyveromyces lactis. A β-galactosidase (lactase) preparation is commercially available as a in over-the-counter preparation sold under the trade mark COLIEF. (COLIEF is a registered trade mark of Crosscare Limited, Dublin, Ireland). Further, preferably, the diagnosis is confirmed by an alteration in cry time. The invention will be further illustrated by the following Example. Mode for Carrying Out the Invention Example Double-blind randomised entry study with cross-over to investigate colic type in infants exhibiting one or more symptoms of unspecified colic. A double-blind study with randomised entry and cross-over was set up to investigate colic type in infants exhibiting one or more symptoms of unspecified colic. Infants who met the trial criteria were assessed in both limbs of the study for colic symptoms and breath hydrogen as hereinbelow described. Experimental Procedures Subjects Fifty three infants aged between 3 and 13 weeks were recruited. New mothers were given trial-related literature in the recovery rooms, and contacted by phone in the following 3 to 4 weeks to see if their newborn was presenting symptoms of colic. Follow-up was by a midwife who visited the parents in their homes, and determined acceptability according to the trial criteria. These included cry time per 24 hours, incidence of spasm, and diarrhoea, and are in line with Wessel's criteria (Wessel MA. et al (1954) Pediatr. 14: 421-424), except that a 3 week duration of symptoms was not required. Parental consent was obtained after full explanation of the puφose and nature of the trial, and the study was approved by the Guy's & St Thomas Ethics Committee. Materials The β-galactosidase (lactase) used was COLIEF (registered trade mark) as described above. COLIEF and a heat-inactivated placebo were obtained from the manufacturers. Breath hydrogen measurement Breath hydrogen was measured using a Micro H 2 as hereinabove described. Samples were taken using face-masks with one-way valves, before feeding, and at 10 minute intervals thereafter, up to a maximum of 120 minutes. Experimental design The trial design was double-blind. Subjects were randomly assigned to the verum or placebo arm for an initial period often days, and then switched after a 5 day wash-out phase to ten days in the alternate arm. The severity of symptoms of colic was assessed by the parents, who filled in a daily record denoting cry time, incidence of spasm, stool habit and feed details. Breath hydrogen testing was performed by a health visitor where possible during the last two days at the end of each arm. The preparations were given in bottles marked with the infant's entry code, and either 'A' or 'B', to maintain the double-blind. All bottles were retrieved at the end of the two courses in order to ascertain compliance. Lactase incubation In formula-fed babies, mothers were instructed to add 3 drops of COLIEF or placebo to each (cooled or body temperature) feed, shake gently, refrigerate for approximately 4 hours before re-warming and giving as normal. A similar procedure has been shown to be effective in reducing milk osmolality in vitro (Malone, A.J. et al (1995) Irish J. Med. Sci. 164: 22). In breast-fed babies, mothers were instructed to express the foremilk (which has a particularly high lactose content) into a tea-spoon, and add to this 3 drops of COLIEF. They then breast-fed as usual, and gave the treated fore-milk to the infant at the end of the feed. The relatively short incubation period in this case is compensated for by the higher concentration of lactase in the small volume of expressed fore-milk. Results Fifty three subjects entered the trial as indicated above . There were 6 drop-outs, 1 subject mislaid the case record form (CRF), and 1 subject who appeared on checking to be inelligible; leaving 45 subjects who were processed through the trial. Of these 45 subjects, 4 were judged to be non-compliant based on the bottle returns (i.e. the bottle was not used), and showed no reduction in crying time. In this group, breath hydrogen measurements were not carried out. It was considered that nothing useful was known about this group, and thus they were discarded from further consideration. This left 41 subjects who were considered to have validity. This is the figure used in subsequent calculations on % responders and non-responders. Of the 41 valid subjects, an additional 5 subjects were non- compliant, but when challenged with a COLIEF dose for breath testing, showed a nul result. This group were considered to be non-responders. Of the remaining 36 subjects who were compliant, another 11 were non-responders. Summing groups C and D gave a total of 16/41 non-responders, and left a residual number of 25/41 subjects who can be described as compliant, and variously responsive to COLIEF treatment. Of the 25 subjects, 8 reduced cry time and breath hydrogen by 50% or more. An additional 2 subjects reduced cry time and breath hydrogen by within 5% of the 50%) margin. Because cry time and breath hydrogen shifted significantly and in parallel, these subjects were considered to be responders. A further 2 subjects showed a 50% reduction in cry time, but were not breath tested. A further 7 subjects showed a 50% reduction in cry time, but did not show any significant breath hydrogen shifts. In responders on placebo, baseline scores were: 5.2 ppm, rising at 30, 60, 90 and 120 min. to 5.7, 7.3, 9, 7.5, 7.8 ppm. On verum, their baseline score was 1.8 ppm, and at 30, 60, 90 and 120 min. this shifted to 1.8, 1.5, 1.5, 1.5 ppm respectively. The above figures represent average readings, taken from the set of responders. It will be observed that the differences between verum and placebo are significant. In the subjects who showed a 50% reduction in cry time but did not show any significant breath hydrogen shifts, this may be due to different bacterial strains colonising the gut in those subjects. Different bacterial strains produce different amounts of gas as a result of fermentation. In such subjects it is possible that the colic symptoms are mediated by the acid produced. The final 4 subjects were non-compliant, as measured by bottle returns, and unsuφrisingly showed no change in cry time. However, when challenged with verum, they showed a 3 -fold or more reduction in breath hydrogen. This could be considered to be a positive response. However, it was decided to discard this group on the basis that they were inadequately characterised. If Group 1 are defined as responders, then it can be said that of the 41 subjects who were tested, 16 were non-responders (39%), and 25 were responders (61%). More conservatively, if Group I is discarded, the data reconfigures as 16/37 non-responders (43%), and 21/37 responders (57%). In the above study, only half of the subjects responded to lactase, but in the group that did respond the treatment was very effective, reducing cry time and/or breath hydrogen by half or more. The above results can be inteφreted as follows. The diagnostic entity of infant colic does not describe aetiology, but is merely a description of symptoms. In these situations, it is not unusual to find that new analytical techniques may reveal that the condition is heterogeneous, with different underlying pathophysiology and aetiology. The above trial can be inteφreted as showing that the difference between responders and non-responders is due to different aetiologies.

Claims: Claims: - 1. A method for diagnosing colic type in an infant exhibiting one or more symptoms characteristic of unspecified colic, which comprises the steps of: a) optionally measuring in said infant at least one parameter indicative of unspecified colic; b) orally administering a liquid formulation of a β-D- galactosidase enzyme separately, simultaneously with or sequentially to a lactose-containing feed; and c) determining at selected intervals of time any alteration in said infant of colic-type symptoms. 2. A method according to Claim 1, wherein an improvement in said symptoms of at least 50% or greater is indicative of lactose-based intolerance. 3. A method according to Claim 1, wherein when said enzyme formulation fails to alleviate the symptoms of unspecified colic, the infant is then placed on a diet of low allergen feed. 4. A method according to Claim 3, wherein an improvement in said symptoms of 50% or more is indicative of allergen-based colic requiring maintenance on a low allergen-based diet. 5. A method according to Claim 3, wherein a failure to respond is indicative of a need for further investigation. 6. A method according to any preceding claim, wherein when said infant is fed a man-made formula, said formula is pre-incubated with said enzyme. 7. A method according to any one of Claims 1-5, wherein when said infant is breast-fed, said enzyme is added to an aliquot of foremilk and then administered to the infant at the end of a feed. 8. A method according to any preceding claim, wherein the parameter measured is selected from one or more of the following: breath hydrogen, stool pH, stool reducing substances; and bowel distension. 9. A method for diagnosing colic type in an infant exhibiting one or more symptoms characteristic of unspecified colic, which comprises the steps of: a) measuring breath hydrogen in said infant; b) orally administering a liquid formulation of a β-D- galactosidase enzyme separately, simultaneously with or sequentially to a lactose-containing feed; c) measuring breath hydrogen at intervals over a period of at least one hour; and d) determining the difference in breath hydrogen relative to said pre-feed measurement. 10. A method according to Claim 9, wherein a reduction in said breath hydrogen of the order of 50% or more relative to said pre-feed measurement is indicative of lactose intolerance-based colic. 11. A method according to Claim 9, wherein a failure to respond to said enzyme formulation as measured by a breath hydrogen which is substantially unchanged relative to said pre-feed measurement is indicative of colic other than lactose intolerance-based colic. 12. A method according to any one of Claims 9-11, wherein the breath hydrogen is measured at time intervals of 30, 60, 90 and 120 min. post lactose-based feed. 13. A method according to any preceding claim, wherein the breath hydrogen is measured by means of a portable hydrogen monitor. 14. A method according to any preceding claim, wherein the enzyme is a lactase obtained from the controlled fermentation of Kluyveromyces lactis. 15. A method according to any preceding claim, wherein the diagnosis is confirmed by an alteration in cry time. 16. A method according to Claim 1, substantially as hereinbefore described and exemplified. 17. A method according to Claim 9, substantially as hereinbefore described and exemplified.

Inventors: BUCKLEY MARY MARGARET, CLAYTON PAUL RODNEY, TIERNEY JONATHAN JAMES, BUCKLEY, MARY, MARGARET, CLAYTON, PAUL, RODNEY, TIERNEY, JONATHAN, JAMES
Applicants: BUCKLEY MARY MARGARET, CLAYTON PAUL RODNEY, CROSSCARE RES & DEV LTD, TIERNEY JONATHAN JAMES, BUCKLEY, MARY, MARGARET, CLAYTON, PAUL, RODNEY, CROSSCARE RESEARCH & DEVELOPMENT LIMITED, TIERNEY, JONATHAN, JAMES
Application year: 2000
Main classification: A61K49
IPC codes: A61K49