Vitamin D deficiency and tuberculosis

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error, these individuals should be excluded from the data analysis.

interpreted as providing support for the hypothesis.

Lars C Stene

Ian R Reid

Section of Epidemiology, National Institute of Public Health, PO Box 4404 Torshov, N-0403 Oslo, Norway

Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand (e-mail: [email protected])

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Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000; 355: 618–21. Kleinbaum DG, Kupper L, Morgenstern H. Interaction, effect modification, and syndergism. In: Kleinbaum DG, Kupper L, Morgenstern H, eds. Epidemiologic research: principles and quantitative methods. New York: Wiley & Sons, 1982: 403–18. Greenland S, Rothman KJ. Concepts of interaction. In: Rothman KJ, Greenland S, eds. Modern epidemiology, second edn. Philadelphia: Lippincott-Raven publishers, 1998: 329–42.

Sir—Robert Wilkinson and colleagues1 simply describe an association between serum concentrations of 25-hydroxyvitamin D in Gujarati patients with tuberculosis and they conclude that vitamin D deficiency “may account for a proportion of the acquired susceptibility of Gujarati immigrants to tuberculosis”. They conclude with the suggestion that vitamin D supplementation may have a role in tuberculosis prevention. This study is potentially confounded by the striking dependence of serum 25-hydroxyvitamin D levels on sunlight exposure and by the near certainty that individuals requiring admission to hospital with tuberculosis will have had less sunlight exposure in previous months than the noninfected control subjects studied. Several publications have documented hypovitaminosis D in patients with a variety of conditions requiring admission to hospital,2,3 and in individuals who are seldom outdoors because of frailty.4 It should also be noted that lower concentrations of serum 25-hydroxyvitamin D, are frequently found in individuals from the Indian subcontinent than in Europeans.5 On the basis of the evidence presented by Wilkinson and colleagues, there is no reason to conclude that tuberculosis is associated with any greater degree of vitamin D deficiency than other illnesses producing comparable debility. The laboratory data cited in their paper provide the basis for an interesting hypothesis, but since these changes in serum vitamin D concentrations would be predicted on the basis of the basic principles of vitamin D metabolism, they cannot be

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Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000; 355: 618–21. Thomas MK, Lloydjones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338: 777–83. Sato Y, Kikuyama M, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in Parkinsons-disease. Neurology 1997; 49: 1273–78. Gloth FM, Gundberg CM, Hollis BW, Haddad JG, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995; 274: 1683–86. Awumey EMK, Mitra DA, Hollis BW, Kumar R, Bell NH. Vitamin D metabolism is altered in Asian Indians in the southern United States—a clinical research center study. J Clin Endocrinol Metab 1998; 83: 169–73.

according to their genotype, and the odds ratio (OR) for the association between vitamin D deficiency and the risk of tuberculosis calculated separately for each genotype (ORnon-tt and ORtt). Evidence for interaction would require, at the very least, that these two odds ratios were significantly different from each other. Unfortunately, Wilkinson and colleagues did not present their data in a way that permits the appropriate calculations to be carried out. *Amy Berrington, Jane Green, Robert Newton ICRF Cancer Epidemiology Unit, Gibson Building, The Radcliffe Infirmary, Oxford OX2 6HE, UK (e-mail: [email protected]) 1

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Sir—According to Richard Bellamy in his commentary,1 Robert Wilkinson and colleagues2 showed an interaction between vitamin D deficiency and both of the vitamin D receptor polymorphisms under investigaton. Although in table 3 they showed a significantly increased risk of tuberculosis in several small subgroups (eg, in participants with the non-tt genotype and vitamin D deficiency, compared with all other participants) this itself is not a test for interaction. Evidence for an interaction between an environmental exposure (such as vitamin D deficiency) and a genotype would require that the association between the exposure of interest and disease risk in those with a certain genotype was significantly different from the exposure–disease association in those with another genotype.3 A simple method of presenting the data to look for evidence of a geneenvironment interaction in the study by Wilkinson and colleagues is shown in the table. The participants are split Genotype Non-tt

tt

Vitamin D Vitamin D Vitamin D Vitamin D deficient nondeficient nondeficient deficient Tuberculosis a patients Healthy c contacts

b

e

f

d

g

h

ORnon-tt=ad/bc

ORtt=eh/fg

Data presentation for investigation of gene-environment interaction in tuberculosis

Bellamy R. Evidence of gene-environment interaction in development of tuberculosis. Lancet 2000; 355: 588–89. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000; 355: 618–21. Greenland S, Rothman KJ. Concepts of interaction. In: Greenland S, Rothman KJ, eds. Modern epidemiology, 2nd edn. Philadelphia: Lippincott-Raven; 1998: 329–42.

Authors’ reply Sir—Undetectable 25-hydroxy vitamin D concentrations reflected the lower limit of sensitivity (5–7 nmol/L) of the assay in use and do not therefore constitute an error. Only one healthy contact had an undetectable concentration. Lars Stene makes the point that the analysis of complex traits often necessitates statistical modelling, and Amy Berrington and colleagues suggest a simpler alternative. We did not do this because the preliminary nature of the study meant that it was of insufficient power to confirm a moderate protective effect of the t allele. As stated in the text, there was also no independent association between 25-hydroxy vitamin D deficiency and severity. There was a non-significant trend linking the nontt genotype to severity (table 2). In table 3 the combination non-tt and deficient accounted for 52% of patients with severe disease by comparison with 24% healthy contacts (x2 for linear trend 0·0146), which indicated that these two factors do act synergistically. Alternatively, taking the genotype TT and 25-hydroxy vitamin D deficiency as predisposing factors for severe disease and carrying out the analysis suggested by Berrington and colleageas yields an ORtt of 4 and ORnon-tt of 2·8, again

THE LANCET • Vol 356 • July 1, 2000

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CORRESPONDENCE

indicative of synergy. However, a much larger study is required to resolve this issue with confidence. Our primary reason for seeking early publication was, the independent association of tuberculosis with 25-hydroxy vitamin D deficiency. We emphasised the likely importance of sunlight exposure in our discussion and Ian Reid re-emphasises this point. Many patients had localised disease, the median duration of symptoms before diagnosis was 31 days and more than 90% were ambulant at presentation. These observations do not suggest gross debility. In addition, we took care to sample healthy controls at the end of winter when their 25-hydroxy vitamin D concentrations were likely to be at their lowest, thus potentially biasing the analysis against association. Stene and Reid raise the issue of causality posed by any association study. We have shown a dose effect and that vitamin-D receptor geno-types associated with less receptor activity show the same trend. There is also considerable data from other laboratories that support our findings,1–3 so the interpretation that our findings are biologically plausible is well founded. Moreover there was wide experience, in the pre-chemotherapy era, of treating tuberculosis with vitamin D supplements, vitamin-D-rich diets, and by sun and arc-light bathing.4 As Richard Bellamy points out in his accompanying editorial,5 the best way to resolve whether vitamin D deficiency predisposes to tuberculosis is by a randomised study of vitamin D supplementation in people at risk of tuberculosis. *Robert J Wilkinson, Robert N Davidson Wellcome Centre for Clinical Tropical Medicine, Imperial College School of Medicine, Department of Infection and Tropical Medicine, Northwick Park Hospital, Harrow HA1 3UJ, UK (e-mail: [email protected]) 1

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Rockett KA, Brooks R, Udalova I, Vital V, Hill AV, Kwiatkowski D. 1,25Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998; 66: 5314–21. Rook GA, Steele J, Fraher L, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57: 159–63. Bellamy R, Ruwende C, Corrah T, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999; 179: 721–24. Evans CC. Historical perspective. In: Davies PDO, ed. Clinical tuberculosis. London: Chapman and Hall, 1994: 1–19. Bellamy R. Evidence of gene environment interaction in development of tuberculosis. Lancet 2000; 355: 588–89.

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Allergy to icodextrin Sir—David Goldsmith and colleagues (March 11, p 897)1 report their experience of icodextrin-induced adverse skin reactions in patients with renal failure. We have also found such reactions. Over 18 months (Feb, 1998–Aug 1998) we observed six skin reactions associated with icodextrin2,3 that were somewhat different from those described by Goldsmith and colleagues. The prevalence in our series was 9·3%. Four patients presented with severe generalised skin eruption: three were psoriasiform and exfoliative such as in Goldsmith’s report, and one was an acute generalised exanthematous pustulosis-like eruption with mucosal involvement. In the first patient, the imputability of icodextrin was confirmed by recurrence of skin lesions after rechallenge. Skin reactions did not develop exclusively in the 4 days (one patient) after first icodextrin administration, as Goldsmith reported, but were also observed at day 10–12 in three cases. These late cases were the most severe. Skin healing was observed 5 to 14 days after icodextrin withdrawal. No exit-site infection or peritonitis were observed, despite extensive cutaneous abdominal involvement. None of the patients had had psoriasis in the past. In contrast to Goldsmith’s series, two thirds of the patients with skin reactions had severe diffuse exanthema. Two other patients presented with limited cutaneous lesions of the palms and soles that healed without icodextrin withdrawal: they shared similar clinical findings to the seven cases initially reported by Wilkie and colleagues.4 Putative pathophysiological mechanism may cause sensitisation against icodextrin-related molecules, such as dextran, with cross-reactive antibodies or progressive sensitisation against icodextrin itself. We never observed fever, eosinophilia, or visceral involvement in our patients, so we did not consider Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome as a diagnosis. Skin tests with icodextrin including patch, prick, and intradermal tests, were done on two patients with severe icodextrin skin reaction. All tests were negative, even in the patient who developed the acute exanthematous generalised pustulosislike eruption. However, skin tests are known to be negative in an average of 50% of such drug-induced skin reaction. Finally, icodextrin skin reaction limited to palms and soles does not necessitate icodextrin withdrawal but careful medical attention is needed. However, we propose immediate

icodextrin withdrawal when diffuse rash develops. We agree with Goldsmith and colleagues in their recommendation to be particularly vigilant about when this new, effective, and useful glucose polymer, is being used. This vigilance should be maintained until the 14th day of exposure. *G Queffeulou, B Lebrun-Vignes, P Wheatley, R Montagnac, F Mignon *Department of Nephrology, Hôpital Bichat, 75877 Paris Cedex 18, France; Department of Dermatology, Hôpital Bichat, Paris; Department of Nephrology, Hôpital de Boulogne sur Mer, Boulogne; and Department of Nephrology, Hôpital de Troyes, Troyes 1

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Goldsmith D, Jayawardene S, Sabharwal N, Cooney K. Allergic reactions to the polymeric glucose-based peritoneal dialysis fluid icodextrin in patients with renal failure. Lancet 2000; 355: 897. Queffeulou G, Bernard M, Vrtovsnik F, et al. Severe cutaneous hypersensitivity requiring permanent icodextrin withdrawal in a CAPD patient. Clin Nephrol 1999; 51: 184–86. Queffeulou G, Vrtovsnik F, Wheatley P, et al. Five cases of toxidermia due to icodextrin. J Am Soc Nephrol 1999; 10: 320A. Wilkie ME, Brown CB. Polyglucose solutions in CAPD (suppl). Perit Dial Int 1997; 17 (2): 547–50. Bocquet H, Bagot M, Roujeau JC. Druginduced pseudolymphoma and drug hypersensitivity syndrome (Drug rash with eosinophilia and systemic symptoms— DRESS). Semin Cut Med Surg 1996; 15: 250–57.

QTc and psychotropic drugs Sir— J G Reilly and colleagues1 draw our attention to QT prolongation by non-cardiac drugs. QT prolongation is a surrogate marker of cardiotoxicity, used for regulatory purposes because of the rare occurrence of drug-induced Torsades de Pointes, which makes the routine use of the latter impractical. Notably, a similar study2 found significant QTc (rate corrected QT interval) increases in antipsychotic drug recipients without cardiac disease, but failed to detect increased occurrence of ventricular tachyarrhythmias. Several regulatory interventions into the use of non-cardiac drugs for QT-related effect have generated alarm, partly because of the low level of awareness of risk factors for the occurrence of Torsade de Pointes and partly because QT prolongation is sometimes viewed as an intrinsic effect of a whole therapeutic class (eg, antihistamines). However, QT prolongation is caused by class III antiarrhythmic properties, which are shown only by some compounds.3 The data given by Reilly and co-workers bring out different

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