Shingles and Statin Treatment: Confounding by Cholesterol or APOE4 Status?
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CID 2014:58 (1 April)
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Note Potential conflicts of interest. T. E. S. has had educational, consultative, and research roles with various companies marketing statins (now generic in Finland), and a small amount of stock of a listed company, Orion Pharma, which also markets generic statins. P. T. reports no conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Downloaded from http://cid.oxfordjournals.org/ at FU BerlinFB Humanmedizin on May 9, 2015
TO THE EDITOR— In a large cohort, Antoniou et al report a 13% increased risk of herpes zoster among statin users compared with nontreated individuals [1]. The relationship between herpes zoster and statin treatment is probably complex [2], and we would like to offer a further view to this conundrum. Identifying possible new adverse effects is important, but on the other hand, great care must be used when drawing conclusions from observational studies. The large numbers of statin users worldwide also make possible spurious associations without the existence of cause and effect. This seems to be the case in the recent association between statins and cataracts in a population cohort [3], where confounding by indication— longer cholesterol burden among statin users—may explain the epidemiological association, not confirmed in clinical trials [4]. Despite the careful propensity score matching and comparison with knee arthroplasty in the study by Antoniou et al, we believe there still is a possibility for confounding by indication or through the carriership of the apolipoprotein E epsilon 4 allele (APOE4). There was no matching for cholesterol levels nor APOE4 in the study by Antoniou et al. According to our counter-hypothesis, herpes zoster risk is increased among statin users because these individuals have higher than average serum cholesterol levels and higher than average frequency of APOE4. High serum cholesterol levels have been associated with herpes zoster in one study [5], and there are several reports on the connection of APOE4 with immunity against Herpesviridae [6, 7]. Intestinal cholesterol absorption is known to be increased in individuals
with APOE4, reflected in their higher serum cholesterol levels [8], but the connection between APOE4 and Herpesviridae is less well known. Sufferers of cold sores, skin presentations of herpes simplex 1 activation (herpes simplex labialis), are more often APOE4 carriers than noncarriers [6]. There are scarce and conflicting data from small studies about a connection between APOE4 carrier status and herpes zoster [9, 10], but a similar mechanism between cold sores and shingles (activation through peripheral nerves) makes the connection plausible. Higher cholesterol levels observed in patients with herpes zoster in one study support the link between APOE4 and herpes zoster [5]. Conversely, because there hardly is any association between serum cholesterol or APOE4 with probability of knee arthroplasty, it is no wonder that there was no association with statin treatment. Of the variables in Table 1 by Antoniou et al, overall cardiovascular disease burden seems to be higher among statin users; for example, myocardial infarction and angina were more common in statin users than controls (5.8% vs 4.5%, and 7.7% vs 6.3%, respectively) Although the absolute differences are small, the data indicate that the risk factors for vascular events are not equally distributed in the 2 groups (29% more myocardial infarctions and 22% more angina in the statin group). Thus, is there a causal link between statins and herpes zoster? Do the authors have any data on cholesterol levels or APOE4 in their cohort to confirm or refute our hypothesis?
Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Timo E. Strandberg1,2 and Pentti Tienari3 1
Department of Medicine, Geriatric Clinic, University of Helsinki and University Central Hospital; 2Institute of Health Sciences, University of Oulu; and 3Department of Neurology, University Central Hospital and Research Programs Unit, Molecular Neurology, University of Helsinki, Finland
References
Downloaded from http://cid.oxfordjournals.org/ at FU BerlinFB Humanmedizin on May 9, 2015
1. Antoniou T, Zheng H, Singh S, Juurlink DN, Mamdani MM, Gomes T. Statins and the risk of herpes zoster: a population-based cohort study. Clin Infect Dis 2014; 58:350–6. 2. Pirmohamed M. Statins, immunomodulation and infections: a complex and unresolved relationship. Clin Infect Dis 2014; 58:357–8. 3. Leuschen J, Mortensen EM, Frei CR, Mansi EA, Panday V, Mansi I. Association of statin use with cataracts: a propensity score– matched analysis. JAMA Ophthalmol 2013; 131:1427–34. 4. Strandberg TE, Tarkkanen A. Cataracts and statin usecause and effect not confirmed. JAMA Ophthalmol 2014. In press. 5. Del Pozo JL, van de Beek D, Mandrekar JN, et al. High serum cholesterol levels are associated with herpes zoster infection after heart transplantation. Clin Infect Dis 2010; 50:121–2. 6. Strandberg TE, Pitkälä K, Eerola J, Tilvis R, Tienari P. Interaction of Herpesviridae, APOE gene, and education in cognitive impairment. Neurobiol Aging 2005; 26:1001–4. 7. Itzhaki R, Wozniak M. Susceptibility to herpes simplex labialis conferred by the gene encoding apolipoprotein E. J Infect Dis 2008; 198:624–5. 8. Kesäniemi YA, Ehnholm C, Miettinen TA. Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype. J Clin Invest 1987; 80:578–81. 9. Pirttilä T, Haanpää M, Mehta PD, Lehtimäki T. Apolipoprotein E (APOE) phenotype and APOE concentrations in multiple sclerosis and acute herpes zoster. Acta Neurol Scand 2000; 102:94–8. 10. Wozniak MA, Shipley SJ, Dobson CB, et al. Does apolipoprotein E determine outcome of infection by varicella zoster virus and by Epstein Barr virus? Eur J Hum Genet 2007; 15:672–8. Correspondence: Timo Strandberg, MD, PhD, PO Box 22, FIN-00029 HUS, Finland (timo.strandberg@oulu.fi). Clinical Infectious Diseases 2014;58(7):1042–3 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/ciu030
CORRESPONDENCE
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CID 2014:58 (1 April)
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1042
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CID 2014:58 (1 April)
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CORRESPONDENCE
Note Potential conflicts of interest. T. E. S. has had educational, consultative, and research roles with various companies marketing statins (now generic in Finland), and a small amount of stock of a listed company, Orion Pharma, which also markets generic statins. P. T. reports no conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Downloaded from http://cid.oxfordjournals.org/ at FU BerlinFB Humanmedizin on May 9, 2015
TO THE EDITOR— In a large cohort, Antoniou et al report a 13% increased risk of herpes zoster among statin users compared with nontreated individuals [1]. The relationship between herpes zoster and statin treatment is probably complex [2], and we would like to offer a further view to this conundrum. Identifying possible new adverse effects is important, but on the other hand, great care must be used when drawing conclusions from observational studies. The large numbers of statin users worldwide also make possible spurious associations without the existence of cause and effect. This seems to be the case in the recent association between statins and cataracts in a population cohort [3], where confounding by indication— longer cholesterol burden among statin users—may explain the epidemiological association, not confirmed in clinical trials [4]. Despite the careful propensity score matching and comparison with knee arthroplasty in the study by Antoniou et al, we believe there still is a possibility for confounding by indication or through the carriership of the apolipoprotein E epsilon 4 allele (APOE4). There was no matching for cholesterol levels nor APOE4 in the study by Antoniou et al. According to our counter-hypothesis, herpes zoster risk is increased among statin users because these individuals have higher than average serum cholesterol levels and higher than average frequency of APOE4. High serum cholesterol levels have been associated with herpes zoster in one study [5], and there are several reports on the connection of APOE4 with immunity against Herpesviridae [6, 7]. Intestinal cholesterol absorption is known to be increased in individuals
with APOE4, reflected in their higher serum cholesterol levels [8], but the connection between APOE4 and Herpesviridae is less well known. Sufferers of cold sores, skin presentations of herpes simplex 1 activation (herpes simplex labialis), are more often APOE4 carriers than noncarriers [6]. There are scarce and conflicting data from small studies about a connection between APOE4 carrier status and herpes zoster [9, 10], but a similar mechanism between cold sores and shingles (activation through peripheral nerves) makes the connection plausible. Higher cholesterol levels observed in patients with herpes zoster in one study support the link between APOE4 and herpes zoster [5]. Conversely, because there hardly is any association between serum cholesterol or APOE4 with probability of knee arthroplasty, it is no wonder that there was no association with statin treatment. Of the variables in Table 1 by Antoniou et al, overall cardiovascular disease burden seems to be higher among statin users; for example, myocardial infarction and angina were more common in statin users than controls (5.8% vs 4.5%, and 7.7% vs 6.3%, respectively) Although the absolute differences are small, the data indicate that the risk factors for vascular events are not equally distributed in the 2 groups (29% more myocardial infarctions and 22% more angina in the statin group). Thus, is there a causal link between statins and herpes zoster? Do the authors have any data on cholesterol levels or APOE4 in their cohort to confirm or refute our hypothesis?
Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Timo E. Strandberg1,2 and Pentti Tienari3 1
Department of Medicine, Geriatric Clinic, University of Helsinki and University Central Hospital; 2Institute of Health Sciences, University of Oulu; and 3Department of Neurology, University Central Hospital and Research Programs Unit, Molecular Neurology, University of Helsinki, Finland
References
Downloaded from http://cid.oxfordjournals.org/ at FU BerlinFB Humanmedizin on May 9, 2015
1. Antoniou T, Zheng H, Singh S, Juurlink DN, Mamdani MM, Gomes T. Statins and the risk of herpes zoster: a population-based cohort study. Clin Infect Dis 2014; 58:350–6. 2. Pirmohamed M. Statins, immunomodulation and infections: a complex and unresolved relationship. Clin Infect Dis 2014; 58:357–8. 3. Leuschen J, Mortensen EM, Frei CR, Mansi EA, Panday V, Mansi I. Association of statin use with cataracts: a propensity score– matched analysis. JAMA Ophthalmol 2013; 131:1427–34. 4. Strandberg TE, Tarkkanen A. Cataracts and statin usecause and effect not confirmed. JAMA Ophthalmol 2014. In press. 5. Del Pozo JL, van de Beek D, Mandrekar JN, et al. High serum cholesterol levels are associated with herpes zoster infection after heart transplantation. Clin Infect Dis 2010; 50:121–2. 6. Strandberg TE, Pitkälä K, Eerola J, Tilvis R, Tienari P. Interaction of Herpesviridae, APOE gene, and education in cognitive impairment. Neurobiol Aging 2005; 26:1001–4. 7. Itzhaki R, Wozniak M. Susceptibility to herpes simplex labialis conferred by the gene encoding apolipoprotein E. J Infect Dis 2008; 198:624–5. 8. Kesäniemi YA, Ehnholm C, Miettinen TA. Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype. J Clin Invest 1987; 80:578–81. 9. Pirttilä T, Haanpää M, Mehta PD, Lehtimäki T. Apolipoprotein E (APOE) phenotype and APOE concentrations in multiple sclerosis and acute herpes zoster. Acta Neurol Scand 2000; 102:94–8. 10. Wozniak MA, Shipley SJ, Dobson CB, et al. Does apolipoprotein E determine outcome of infection by varicella zoster virus and by Epstein Barr virus? Eur J Hum Genet 2007; 15:672–8. Correspondence: Timo Strandberg, MD, PhD, PO Box 22, FIN-00029 HUS, Finland (timo.strandberg@oulu.fi). Clinical Infectious Diseases 2014;58(7):1042–3 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/ciu030
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CID 2014:58 (1 April)
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