- Email: [email protected]
Skin testing in systemic cutaneous drug reactions
COMMENTARY
Leukotriene synthesis
Arachidonic acid
5-LO FLAP
5HPETE LTA4
Glutathione
This picture contrasts with the absence of neurological abnormalities both in the 5-lipoxygenase knockout mice and in animal studies of 5-lipoxygenase inhibitors or cysLT1 receptor antagonists. Differences between species could be the explanation. Alternatively, the difference might be related to the site of the defect within the leukotriene pathway. Or perhaps the child had a second disorder that led to the neurological problems, especially since her parents were first cousins. It is, therefore, too soon to conclude that leukotrienes are essential for normal development, but the report highlights uncertainty about the role of leukotrienes in the brain.
LTA4 hydrolase
LTC4 synthase
LTB4
LTC4
*Andrew A M Morris, Ian W Rodger
LTD4
*Depar tment of Child Health, Royal Victoria Infirmar y, Newcastle upon Tyne NE1 4LP, UK; and Depar tment of Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada
LTE4 5-lipoxygenase (5-LO) is activated by transmembrane signals, such as rises in intracellular calcium concentration. This causes 5-LO translocation to the nuclear envelope, where it interacts with an activating protein (FLAP). 5-LO/FLAP catalyse a two-stage reaction converting arachidonic acid to LTA4. LTA4 can either be hydrolysed to LTB4 or conjugated with reduced glutathione to form LTC4. Both LTB4 and LTC4 are exported from cells. LTD4 and LTE4 are formed from LTC4 extracellularly by the consecutive removal of glutamic acid and glycine.
1
2
3
4
reproduced normally. They were resistant to induction of airway hyper-responsiveness. They also showed reduced inflammatory responses to some stimuli and a slightly reduced capacity to clear parasitic and bacterial infections.5,8 The mildness of these inflammatory abnormalities can partly be attributed to functional redundancy among the many mediators of inflammation. The lack of overt neurological or reproductive problems suggests that, under some circumstances, leukotrienes may also be functionally redundant in the brain: the existence of more than one second messenger for GnRH and somatostatin seems compatible with this finding. Experience with antileukotriene drugs is similar to that with 5-lipoxygenase knockout mice. No neurological effects were seen in animals exposed to cysLT1 receptor antagonists or 5-lipoxygenase inhibitors at doses far higher than would be clinically relevant. Moreover, no developmental or postnatal neurological abnormalities were seen in animals exposed in utero to the cysLT1 receptor antagonist, montelukast, even at doses that would lead to significant concentrations in the fetal brain. Glutathione-synthetase deficiency is the only previously reported human inborn error affecting leukotriene synthesis. Patients with this disorder have impaired production of cysteinyl leukotrienes,9 for which glutathione is required. The clinical features include progressive neurological abnormalities as well as metabolic acidosis, haemolytic anaemia, and neutropenia. It is, however, impossible to find out whether any of the problems are caused by the leukotriene defect rather than other effects of glutathione deficiency. The patient reported by Mayatepek and Flock seems to have had LTC4-synthase deficiency. She presented with microcephaly, hypotonia, and psychomotor retardation, failed to thrive, and died at 6 months of age. 1488
5
6
7
8
9
Lammers CH, Schweitzer P, Facchinetti P, et al. Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and its role in somatostatin signaling. J Neurochem 1996; 66: 147–52. Lindgren JÅ, Hökfelt T, Dahlén S-E, et al. Leukotrienes in the rat central nervous system. Proc Natl Acad Sci USA 1984; 81: 6212–16. Miyamoto T, Lindgren JÅ, Hökfelt T, Samuelsson B. Regional distribution of leukotriene and mono-hydroxyeicosanoic acid production in the rat brain. FEBS Lett 1987; 216: 123–27. Yokimozo T, Izumi T, Chang K, et al. A G-protein coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997; 387: 620–24. Goldhill J, Morris SC, Maliszewski C, et al. Interleukin-4 modulates cholinergic neural control of mouse small intestinal longitudinal smooth muscle. Am J Physiol 1997; 272: G1135–40. Kiesel L, Przylipiak AF, Habenicht AJR, et al. Production of leukotrienes in gonadotrophin-releasing hormone-stimulated pituitary cells: potential role in luteinizing hormone release. Proc Natl Acad Sci USA 1991; 88: 8801–05. Schweitzer P, Madamba S, Champagnat J, Siggins GR. Somatostatin inhibition of hippocampal CA1 pyramidal neurons: mediation by arachidonic acid and its metabolites. J Neurosci 1993; 13: 2033–49. Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice. Biochem Biophys Acta 1996; 1304: 65–84. Mayatepek E, Hoffmann GF, Carlsson B, et al. Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency. Pediatr Res 1994; 35: 307–10.
Skin testing in systemic cutaneous drug reactions Adverse reactions to pharmacological agents are common among inpatients and outpatients.1 The skin is affected in up to 30% of these reactions.2 Although cutaneous adverse drug reactions only rarely result in death or severe morbidity, they cause substantial discomfort. In addition, such reactions generally result in substitution of the suspected agent with an unrelated drug, which may increase cost of treatment and cause further morbidity, for reasons such as treatment failure due to use of a secondline agent, or the possibility that the replacement drug may be more toxic than the first.1 Inpatients receive an average of eight drugs so, to reduce cost and morbidity, the agent causing the adverse effect must be correctly identified. Adverse drug reactions may be due to the effects of overdosage, side-effects, indirect effects, and drug interactions, which occur in the general population, or to hypersensitivity reactions, which occur only in selected THE LANCET • Vol 352 • November 7, 1998
COMMENTARY
individuals. Hypersensitivity reactions are further classed by mechanism as intolerance, idiosyncrasy, and immunological reactions. Most adverse reactions affecting the skin represent hypersensitivity reactions, and although the mechanisms of many such reactions are poorly understood, most are believed to be immunological in nature. The diagnosis of drug allergy and the identification of the offending agent when the patient is on several drugs is almost entirely a clinical exercise. It is based on a careful history of the time of onset and the development of the eruption as related to the time of administration and doses of the drugs being taken, the clinical and histological appearances of the eruption, and knowledge of the pharmacoepidemiology of each suspected agent.1 Once the putative agent is identified, it is discontinued. Waning of the eruption then suggests that the agent is the cause of the reaction. Challenge with the suspected agent is risky and should be undertaken only when therapeutically necessary. Although these steps have served clinicians well, more definitive methods of identifying drugs as allergens would reduce morbidity and the cost of the management of patients with drug reactions. The development of such assays and their validation would be an important advance in this era of rapidly increasing numbers of new therapeutic agents and of polypharmacy. The work reported by A Barbaud and colleagues3 represents such an advance and illustrates the power of such assays as well as their limitations. The two major problems in the development of diagnostic tests for cutaneous drug reactions are related to lack of knowledge. The delineation of the immunological mechanism of each of the various types of skin-reaction patterns is incomplete, as is the identification of the chemical structure of the allergen that leads to the reactions. Most cutaneous drug reactions are thought to be mediated by either Gel and Coombs type I or type IV reactions. Urticaria and angio-oedema are the expression of type I reactions mediated by IgE. The immune mechanism and the immunochemistry of these reactions, especially to common offending agents such as penicillin and other -lactam antibiotics, have been extensively characterised, hence skin-testing procedures and standardisation of intradermal allergens for the confirmation of suspected IgE-mediated allergy to such agents have been validated and are in common use.4 The common maculopapular and morbiliform eruptions, the less common eczematous, fixed-drug and photodrug reactions, as well as the more severe and life-threatening exfoliative erythrodermas, erythema multiforme (including Stevens-Johnson reactions), and toxic epidermal necrolysis,5 are all thought to be T-cellmediated type IV reactions. (Vasculitis and serum sickness reactions are believed to be mediated by type III immune complexes.) Since the evidence for T-cell mediation of such reactions is primarily inferential, it is possible that many of these reactions represent intolerance or idiosyncratic types of hypersensitivity. Such uncertainty makes the development of diagnostic tests for cutaneous drug allergy of the delayed type conceptually difficult. This difficulty is further complicated in the practical sense, by the issue of allergen structure. For many agents the epitope that induced the immune response is potentially contained in a drug metabolite rather than the native agent. THE LANCET • Vol 352 • November 7, 1998
Despite this uncertainty, researchers are, increasingly, endeavouring to use skin testing, particularly patch testing, for the confirmation of sensitivity in patients with delayed-type reactions. The choice of the patch test seems reasonable, since it has been used extensively for almost a century for the diagnosis of contact allergy (also T-cell mediated) to hundreds of specific allergens, in hundreds of thousands of patients. Although extremely well validated, it remains a crude biological assay with significant variability.6 It is not surprising therefore that the patch test is an imperfect system for the diagnosis of systemic reactions to drugs. The clinical sensitisation and elicitation of such reactions, unlike that of contact dermatitis, is not mimicked by the test procedure. In Barbaud and colleagues’ prospective study, inpatients with adverse drug reactions were extensively investigated to confirm that a drug reaction did indeed occur. Next, stringent clinical criteria were applied to confirm that one drug was the cause of the reaction. The patients were then tested with patch tests to the putative allergenic drug. If negative, the patients underwent prick testing, and if that produced a negative reaction, they were tested intradermally. Reactions were assessed immediately and over a period of days for delayed reactivity. 72% of individuals investigated reacted positively to the putative aetiological agent, with the majority, 42%, reacting to a patch test. With patch testing for contact allergy, the most difficult assessment is whether the response is due to true allergy or irritation. Discrimination between the two can be difficult, even for experienced patch testers, and factors such as morphology and variation in reactivity over a period of days have to be taken into account. The discrimination has been made more consistent by the standardisation of allergens in terms of chemical structure, concentration, and vehicle, in large numbers of allergic and non-allergic people, to eliminate the likelihood of false-positive reactions while maintaining the sensitivity of the assay. The development of skin testing for systemic drug allergy necessitates the standardisation of allergens in a similar fashion, with validation in large numbers of allergic and non-allergic individuals. The experience with patch testing for contact allergy suggests that validation is best done in multicentre trials, to obtain the numbers of people required. The Barbaud study is an exciting beginning. However, the small number of controls tested and the criteria for their selection suggest that further study is indicated before epicutaneous testing can be thought to be a promising assay for systemic drug allergy. Reactions to only a few drugs were studied. Although they were common causes of adverse reactions, more drugs need to be evaluated to explore the agent specificity of the test system. Until such time as these issues can be settled, clinicians should be cautious and recognise that skin testing for systemic drug allergy is still experimental, and that such testing can induce relapse of the original reaction with serious consequences. Further, it must be emphasised that the sensitivity of this assay is low, so a negative skin test does not rule out causation by a particular agent.
Vincent A DeLeo Department of Dermatology, St Luke’s Roosevelt Hospital Center, New York, NY 10025, USA
1489
COMMENTARY 1
2 3
4 5 6
Adkinson NF, Jr. Drug allergy. In: Middleton E, Jr, Reed CE, Ellis EF, et al, eds. Allergy: principles and practice. St Louis: Mosby, 1989: 1212–24. Breathnach SM. Mechanisms of drug eruptions: part 1. Austral J Dermatol 1995; 36: 121–27. Barbaud A, Reichert-Penetrat S, Trechot F, et al. The use of skin testing in the investigation of cutaneous adverse drug reactions. Br J Dermatol 1998; 139: 49–58. Sullivan TJ, Wedner HJ, Shatz GS, et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol 1981; 68: 171–80. Rougeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331: 1272–85. Marks JG Jr, DeLeo VA. Contact and occupational dermatology, 2nd edn. St Louis: Mosby, 1997.
Heads or tails in a positive faecal occult blood test Now that screening of symptom-free average-risk individuals aged over 50 for colorectal cancer by guaiac-based faecal occult blood tests (FOBT) is widely endorsed, at least in the USA,1 the work-up of a positive test assumes substantial importance. Positive FOBT results are obtained not only from 2% of such people screened,2 but also from many patients being routinely investigated because of gastrointestinal symptoms. The FOBT field has been dominated by studies describing colonic neoplasms in symptom-free individuals who collect spontaneously passed stools while following dietary restrictions. Why all the focus on the colon? First, FOBT was originally introduced as a screening test for cancer of the colon. Second, the guaiac test should be more indicative of lower than of upper gastrointestinal bleeding because the pseudoperoxidase activity of haemoglobin necessary to generate a positive test is generally lost as haemoglobin from an upper gastrointestinal lesion becomes degraded or mixed with the stool. Thus, the conventional strategy, appropriately intended for assessment of the symptom-free patient with a positive FOBT, is to start with a colonic investigation, preferably by colonoscopy because of its diagnostic and therapeutic superiority over a sigmoidoscopy and barium enema, and to reserve upper gastrointestinal investigation for patients with negative colonoscopy who remain FOBT positive. The relative contribution of upper gastrointestinal lesions to the frequency of positive FOBTs is not well established because few studies have subjected individuals to bidirectional endoscopy. Actually, oesophagogastroduodenoscopy can reveal significant upper gastrointestinal abnormalities in 27–43% of patients with positive FOBT and negative colonoscopy;3–5 results differ according to whether patients with anaemia or symptoms are included, inpatient status, and definition of a significant lesion. The best study to date sheds new light on the stomach and duodenum. D C Rockey and colleagues6 prospectively did colonoscopy, followed immediately by oesophagogastroduodenoscopy, on 248 patients who had positive results at least once on an FOBT (Hemoccult). They carefully excluded individuals with anaemia. Predetermined criteria were established for judging a lesion to be the cause of a positive FOBT. Groups were separately analysed according to the presence or absence of upper or lower gastrointestinal symptoms, and by the method of stool sampling—by “screening” three separate stools on the customary dietary/ medication restrictions, or by digital rectal examination. 1490
The investigators’ main conclusion was that upper gastrointestinal abnormalities were detected more commonly than were colonic abnormalities (28·6% vs 21·8%). The increase in frequency of upper gstrointestinal abnormalities was apparent only when patients with upper gastrointestinal symptoms were included. In symptom-free patients, rates of upper and lower gastrointestinal pathology were identical, irrespective of the method of stool collection. Not surprisingly, symptoms were predictive of a bleeding site in the area to which the symptoms related. Curiously, abnormalities were most likely to be detected in patients with upper gastrointestinal symptoms who were FOBTpositive by digital rectal examination, which suggests high rates of blood loss from these upper gastrointestinal lesions, although the amount of faecal haemoglobin was not measured (eg, by the HemoQuant assay). The finding that more abnormalities were detected in both the upper and lower gastrointestinal tract when stools were collected by digital rectal examinations adds fuel to the controversy behind this method of stool collection. Should the approach to the FOBT-positive patient be changed? There is no reason to do so. In symptomatic patients, endoscopic investigations will obviously be directed by symptoms. In the symptom-free individual, a positive FOBT carries a positive predictive value for colonic neoplasia of 30–50% (over age 50), and almost all lesions found in the upper gastrointestinal tract are benign. Furthermore, in the absence of a control group (which might arguably be difficult to justify), the true frequency of upper gastrointestinal lesions in symptomfree FOBT-negative individuals is not known. Nonetheless, the study by Rockey and colleagues is a reminder not to ignore the upper gastrointestinal tract in FOBT-positive patients. Although the merits of FOBT by digital rectal examination and the efficacy of the more colon-specific immunochemical FOBT will continue to be assessed, it must be remembered that blood is not a specific tumour product. Stool tests for the detection of tumour-specific gene mutations are being developed7 and may help to distinguish patients with malignant gastrointestinal lesions from those with benign ones.
Steven H Itzkowitz Dr Henr y D Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY 10029, USA 1
2 3
4
5
6
7
Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594–642. Winawer WJ, Schottenfeld D, Flehinger BJ. Colorectal cancer screening. J Natl Cancer Inst 1991; 83: 243–53. Hsia PC, Al-Kawas FH.Yield of upper endoscopy in the evaluation of asymptomatic patients with Hemoccult-positive stool after a negative colonoscopy. Am J Gastroenterol 1992; 87: 1571–74. Zuckerman G, Benitez J. A prospective study of bidirectional endoscopy (colonoscopy and upper endoscopy) in the evaluation of patients with occult gastrointestinal bleeding. Am J Gastroenterol 1992; 87: 62–66. Chen YK, Gladden DR, Kestenbaum DJ, Collen MJ. Is there a role for upper gastrointestinal endoscopy in the evaluation of patients with occult-blood-positive stool and negative colonoscopy? Am J Gastroenterol 1993; 88: 2026–29. Rockey DC, Koch J, Cello JP, Sanders LL, McQuaid K. Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult-blood tests. N Engl J Med 1998; 339: 153–59. Skoletsky JE, Shuber AP. High frequency of detecting amplifiable DNA in stools of apparently normal individuals Gastroenterology 1998; 114: A681.
THE LANCET • Vol 352 • November 7, 1998
Leukotriene synthesis
Arachidonic acid
5-LO FLAP
5HPETE LTA4
Glutathione
This picture contrasts with the absence of neurological abnormalities both in the 5-lipoxygenase knockout mice and in animal studies of 5-lipoxygenase inhibitors or cysLT1 receptor antagonists. Differences between species could be the explanation. Alternatively, the difference might be related to the site of the defect within the leukotriene pathway. Or perhaps the child had a second disorder that led to the neurological problems, especially since her parents were first cousins. It is, therefore, too soon to conclude that leukotrienes are essential for normal development, but the report highlights uncertainty about the role of leukotrienes in the brain.
LTA4 hydrolase
LTC4 synthase
LTB4
LTC4
*Andrew A M Morris, Ian W Rodger
LTD4
*Depar tment of Child Health, Royal Victoria Infirmar y, Newcastle upon Tyne NE1 4LP, UK; and Depar tment of Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada
LTE4 5-lipoxygenase (5-LO) is activated by transmembrane signals, such as rises in intracellular calcium concentration. This causes 5-LO translocation to the nuclear envelope, where it interacts with an activating protein (FLAP). 5-LO/FLAP catalyse a two-stage reaction converting arachidonic acid to LTA4. LTA4 can either be hydrolysed to LTB4 or conjugated with reduced glutathione to form LTC4. Both LTB4 and LTC4 are exported from cells. LTD4 and LTE4 are formed from LTC4 extracellularly by the consecutive removal of glutamic acid and glycine.
1
2
3
4
reproduced normally. They were resistant to induction of airway hyper-responsiveness. They also showed reduced inflammatory responses to some stimuli and a slightly reduced capacity to clear parasitic and bacterial infections.5,8 The mildness of these inflammatory abnormalities can partly be attributed to functional redundancy among the many mediators of inflammation. The lack of overt neurological or reproductive problems suggests that, under some circumstances, leukotrienes may also be functionally redundant in the brain: the existence of more than one second messenger for GnRH and somatostatin seems compatible with this finding. Experience with antileukotriene drugs is similar to that with 5-lipoxygenase knockout mice. No neurological effects were seen in animals exposed to cysLT1 receptor antagonists or 5-lipoxygenase inhibitors at doses far higher than would be clinically relevant. Moreover, no developmental or postnatal neurological abnormalities were seen in animals exposed in utero to the cysLT1 receptor antagonist, montelukast, even at doses that would lead to significant concentrations in the fetal brain. Glutathione-synthetase deficiency is the only previously reported human inborn error affecting leukotriene synthesis. Patients with this disorder have impaired production of cysteinyl leukotrienes,9 for which glutathione is required. The clinical features include progressive neurological abnormalities as well as metabolic acidosis, haemolytic anaemia, and neutropenia. It is, however, impossible to find out whether any of the problems are caused by the leukotriene defect rather than other effects of glutathione deficiency. The patient reported by Mayatepek and Flock seems to have had LTC4-synthase deficiency. She presented with microcephaly, hypotonia, and psychomotor retardation, failed to thrive, and died at 6 months of age. 1488
5
6
7
8
9
Lammers CH, Schweitzer P, Facchinetti P, et al. Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and its role in somatostatin signaling. J Neurochem 1996; 66: 147–52. Lindgren JÅ, Hökfelt T, Dahlén S-E, et al. Leukotrienes in the rat central nervous system. Proc Natl Acad Sci USA 1984; 81: 6212–16. Miyamoto T, Lindgren JÅ, Hökfelt T, Samuelsson B. Regional distribution of leukotriene and mono-hydroxyeicosanoic acid production in the rat brain. FEBS Lett 1987; 216: 123–27. Yokimozo T, Izumi T, Chang K, et al. A G-protein coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997; 387: 620–24. Goldhill J, Morris SC, Maliszewski C, et al. Interleukin-4 modulates cholinergic neural control of mouse small intestinal longitudinal smooth muscle. Am J Physiol 1997; 272: G1135–40. Kiesel L, Przylipiak AF, Habenicht AJR, et al. Production of leukotrienes in gonadotrophin-releasing hormone-stimulated pituitary cells: potential role in luteinizing hormone release. Proc Natl Acad Sci USA 1991; 88: 8801–05. Schweitzer P, Madamba S, Champagnat J, Siggins GR. Somatostatin inhibition of hippocampal CA1 pyramidal neurons: mediation by arachidonic acid and its metabolites. J Neurosci 1993; 13: 2033–49. Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice. Biochem Biophys Acta 1996; 1304: 65–84. Mayatepek E, Hoffmann GF, Carlsson B, et al. Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency. Pediatr Res 1994; 35: 307–10.
Skin testing in systemic cutaneous drug reactions Adverse reactions to pharmacological agents are common among inpatients and outpatients.1 The skin is affected in up to 30% of these reactions.2 Although cutaneous adverse drug reactions only rarely result in death or severe morbidity, they cause substantial discomfort. In addition, such reactions generally result in substitution of the suspected agent with an unrelated drug, which may increase cost of treatment and cause further morbidity, for reasons such as treatment failure due to use of a secondline agent, or the possibility that the replacement drug may be more toxic than the first.1 Inpatients receive an average of eight drugs so, to reduce cost and morbidity, the agent causing the adverse effect must be correctly identified. Adverse drug reactions may be due to the effects of overdosage, side-effects, indirect effects, and drug interactions, which occur in the general population, or to hypersensitivity reactions, which occur only in selected THE LANCET • Vol 352 • November 7, 1998
COMMENTARY
individuals. Hypersensitivity reactions are further classed by mechanism as intolerance, idiosyncrasy, and immunological reactions. Most adverse reactions affecting the skin represent hypersensitivity reactions, and although the mechanisms of many such reactions are poorly understood, most are believed to be immunological in nature. The diagnosis of drug allergy and the identification of the offending agent when the patient is on several drugs is almost entirely a clinical exercise. It is based on a careful history of the time of onset and the development of the eruption as related to the time of administration and doses of the drugs being taken, the clinical and histological appearances of the eruption, and knowledge of the pharmacoepidemiology of each suspected agent.1 Once the putative agent is identified, it is discontinued. Waning of the eruption then suggests that the agent is the cause of the reaction. Challenge with the suspected agent is risky and should be undertaken only when therapeutically necessary. Although these steps have served clinicians well, more definitive methods of identifying drugs as allergens would reduce morbidity and the cost of the management of patients with drug reactions. The development of such assays and their validation would be an important advance in this era of rapidly increasing numbers of new therapeutic agents and of polypharmacy. The work reported by A Barbaud and colleagues3 represents such an advance and illustrates the power of such assays as well as their limitations. The two major problems in the development of diagnostic tests for cutaneous drug reactions are related to lack of knowledge. The delineation of the immunological mechanism of each of the various types of skin-reaction patterns is incomplete, as is the identification of the chemical structure of the allergen that leads to the reactions. Most cutaneous drug reactions are thought to be mediated by either Gel and Coombs type I or type IV reactions. Urticaria and angio-oedema are the expression of type I reactions mediated by IgE. The immune mechanism and the immunochemistry of these reactions, especially to common offending agents such as penicillin and other -lactam antibiotics, have been extensively characterised, hence skin-testing procedures and standardisation of intradermal allergens for the confirmation of suspected IgE-mediated allergy to such agents have been validated and are in common use.4 The common maculopapular and morbiliform eruptions, the less common eczematous, fixed-drug and photodrug reactions, as well as the more severe and life-threatening exfoliative erythrodermas, erythema multiforme (including Stevens-Johnson reactions), and toxic epidermal necrolysis,5 are all thought to be T-cellmediated type IV reactions. (Vasculitis and serum sickness reactions are believed to be mediated by type III immune complexes.) Since the evidence for T-cell mediation of such reactions is primarily inferential, it is possible that many of these reactions represent intolerance or idiosyncratic types of hypersensitivity. Such uncertainty makes the development of diagnostic tests for cutaneous drug allergy of the delayed type conceptually difficult. This difficulty is further complicated in the practical sense, by the issue of allergen structure. For many agents the epitope that induced the immune response is potentially contained in a drug metabolite rather than the native agent. THE LANCET • Vol 352 • November 7, 1998
Despite this uncertainty, researchers are, increasingly, endeavouring to use skin testing, particularly patch testing, for the confirmation of sensitivity in patients with delayed-type reactions. The choice of the patch test seems reasonable, since it has been used extensively for almost a century for the diagnosis of contact allergy (also T-cell mediated) to hundreds of specific allergens, in hundreds of thousands of patients. Although extremely well validated, it remains a crude biological assay with significant variability.6 It is not surprising therefore that the patch test is an imperfect system for the diagnosis of systemic reactions to drugs. The clinical sensitisation and elicitation of such reactions, unlike that of contact dermatitis, is not mimicked by the test procedure. In Barbaud and colleagues’ prospective study, inpatients with adverse drug reactions were extensively investigated to confirm that a drug reaction did indeed occur. Next, stringent clinical criteria were applied to confirm that one drug was the cause of the reaction. The patients were then tested with patch tests to the putative allergenic drug. If negative, the patients underwent prick testing, and if that produced a negative reaction, they were tested intradermally. Reactions were assessed immediately and over a period of days for delayed reactivity. 72% of individuals investigated reacted positively to the putative aetiological agent, with the majority, 42%, reacting to a patch test. With patch testing for contact allergy, the most difficult assessment is whether the response is due to true allergy or irritation. Discrimination between the two can be difficult, even for experienced patch testers, and factors such as morphology and variation in reactivity over a period of days have to be taken into account. The discrimination has been made more consistent by the standardisation of allergens in terms of chemical structure, concentration, and vehicle, in large numbers of allergic and non-allergic people, to eliminate the likelihood of false-positive reactions while maintaining the sensitivity of the assay. The development of skin testing for systemic drug allergy necessitates the standardisation of allergens in a similar fashion, with validation in large numbers of allergic and non-allergic individuals. The experience with patch testing for contact allergy suggests that validation is best done in multicentre trials, to obtain the numbers of people required. The Barbaud study is an exciting beginning. However, the small number of controls tested and the criteria for their selection suggest that further study is indicated before epicutaneous testing can be thought to be a promising assay for systemic drug allergy. Reactions to only a few drugs were studied. Although they were common causes of adverse reactions, more drugs need to be evaluated to explore the agent specificity of the test system. Until such time as these issues can be settled, clinicians should be cautious and recognise that skin testing for systemic drug allergy is still experimental, and that such testing can induce relapse of the original reaction with serious consequences. Further, it must be emphasised that the sensitivity of this assay is low, so a negative skin test does not rule out causation by a particular agent.
Vincent A DeLeo Department of Dermatology, St Luke’s Roosevelt Hospital Center, New York, NY 10025, USA
1489
COMMENTARY 1
2 3
4 5 6
Adkinson NF, Jr. Drug allergy. In: Middleton E, Jr, Reed CE, Ellis EF, et al, eds. Allergy: principles and practice. St Louis: Mosby, 1989: 1212–24. Breathnach SM. Mechanisms of drug eruptions: part 1. Austral J Dermatol 1995; 36: 121–27. Barbaud A, Reichert-Penetrat S, Trechot F, et al. The use of skin testing in the investigation of cutaneous adverse drug reactions. Br J Dermatol 1998; 139: 49–58. Sullivan TJ, Wedner HJ, Shatz GS, et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol 1981; 68: 171–80. Rougeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331: 1272–85. Marks JG Jr, DeLeo VA. Contact and occupational dermatology, 2nd edn. St Louis: Mosby, 1997.
Heads or tails in a positive faecal occult blood test Now that screening of symptom-free average-risk individuals aged over 50 for colorectal cancer by guaiac-based faecal occult blood tests (FOBT) is widely endorsed, at least in the USA,1 the work-up of a positive test assumes substantial importance. Positive FOBT results are obtained not only from 2% of such people screened,2 but also from many patients being routinely investigated because of gastrointestinal symptoms. The FOBT field has been dominated by studies describing colonic neoplasms in symptom-free individuals who collect spontaneously passed stools while following dietary restrictions. Why all the focus on the colon? First, FOBT was originally introduced as a screening test for cancer of the colon. Second, the guaiac test should be more indicative of lower than of upper gastrointestinal bleeding because the pseudoperoxidase activity of haemoglobin necessary to generate a positive test is generally lost as haemoglobin from an upper gastrointestinal lesion becomes degraded or mixed with the stool. Thus, the conventional strategy, appropriately intended for assessment of the symptom-free patient with a positive FOBT, is to start with a colonic investigation, preferably by colonoscopy because of its diagnostic and therapeutic superiority over a sigmoidoscopy and barium enema, and to reserve upper gastrointestinal investigation for patients with negative colonoscopy who remain FOBT positive. The relative contribution of upper gastrointestinal lesions to the frequency of positive FOBTs is not well established because few studies have subjected individuals to bidirectional endoscopy. Actually, oesophagogastroduodenoscopy can reveal significant upper gastrointestinal abnormalities in 27–43% of patients with positive FOBT and negative colonoscopy;3–5 results differ according to whether patients with anaemia or symptoms are included, inpatient status, and definition of a significant lesion. The best study to date sheds new light on the stomach and duodenum. D C Rockey and colleagues6 prospectively did colonoscopy, followed immediately by oesophagogastroduodenoscopy, on 248 patients who had positive results at least once on an FOBT (Hemoccult). They carefully excluded individuals with anaemia. Predetermined criteria were established for judging a lesion to be the cause of a positive FOBT. Groups were separately analysed according to the presence or absence of upper or lower gastrointestinal symptoms, and by the method of stool sampling—by “screening” three separate stools on the customary dietary/ medication restrictions, or by digital rectal examination. 1490
The investigators’ main conclusion was that upper gastrointestinal abnormalities were detected more commonly than were colonic abnormalities (28·6% vs 21·8%). The increase in frequency of upper gstrointestinal abnormalities was apparent only when patients with upper gastrointestinal symptoms were included. In symptom-free patients, rates of upper and lower gastrointestinal pathology were identical, irrespective of the method of stool collection. Not surprisingly, symptoms were predictive of a bleeding site in the area to which the symptoms related. Curiously, abnormalities were most likely to be detected in patients with upper gastrointestinal symptoms who were FOBTpositive by digital rectal examination, which suggests high rates of blood loss from these upper gastrointestinal lesions, although the amount of faecal haemoglobin was not measured (eg, by the HemoQuant assay). The finding that more abnormalities were detected in both the upper and lower gastrointestinal tract when stools were collected by digital rectal examinations adds fuel to the controversy behind this method of stool collection. Should the approach to the FOBT-positive patient be changed? There is no reason to do so. In symptomatic patients, endoscopic investigations will obviously be directed by symptoms. In the symptom-free individual, a positive FOBT carries a positive predictive value for colonic neoplasia of 30–50% (over age 50), and almost all lesions found in the upper gastrointestinal tract are benign. Furthermore, in the absence of a control group (which might arguably be difficult to justify), the true frequency of upper gastrointestinal lesions in symptomfree FOBT-negative individuals is not known. Nonetheless, the study by Rockey and colleagues is a reminder not to ignore the upper gastrointestinal tract in FOBT-positive patients. Although the merits of FOBT by digital rectal examination and the efficacy of the more colon-specific immunochemical FOBT will continue to be assessed, it must be remembered that blood is not a specific tumour product. Stool tests for the detection of tumour-specific gene mutations are being developed7 and may help to distinguish patients with malignant gastrointestinal lesions from those with benign ones.
Steven H Itzkowitz Dr Henr y D Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY 10029, USA 1
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Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594–642. Winawer WJ, Schottenfeld D, Flehinger BJ. Colorectal cancer screening. J Natl Cancer Inst 1991; 83: 243–53. Hsia PC, Al-Kawas FH.Yield of upper endoscopy in the evaluation of asymptomatic patients with Hemoccult-positive stool after a negative colonoscopy. Am J Gastroenterol 1992; 87: 1571–74. Zuckerman G, Benitez J. A prospective study of bidirectional endoscopy (colonoscopy and upper endoscopy) in the evaluation of patients with occult gastrointestinal bleeding. Am J Gastroenterol 1992; 87: 62–66. Chen YK, Gladden DR, Kestenbaum DJ, Collen MJ. Is there a role for upper gastrointestinal endoscopy in the evaluation of patients with occult-blood-positive stool and negative colonoscopy? Am J Gastroenterol 1993; 88: 2026–29. Rockey DC, Koch J, Cello JP, Sanders LL, McQuaid K. Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult-blood tests. N Engl J Med 1998; 339: 153–59. Skoletsky JE, Shuber AP. High frequency of detecting amplifiable DNA in stools of apparently normal individuals Gastroenterology 1998; 114: A681.
THE LANCET • Vol 352 • November 7, 1998