- Email: [email protected]
Parental smoking increases the risk for eczema with sensitization in 4-year-old children
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6. Helgesson G, Lyno¨e N. Should physicians fake diagnoses to help their patients? J Med Ethics 2008;34:133-6. 7. Macauley R. The Hippocratic underground: civil disobedience and health care reform. Hast Ctr Rep 2005;35:38-45. 8. VanGeest J, Weiner S, Johnson T, Cummins D. Impact of managed care on physicians’ decisions to manipulate reimbursement rules: an explanatory model. J Health Ser Res Policy 2007;12:147-52. 9. Kaiser Family Foundation. Kaiser health tracking poll: many Americans still delaying care, struggling to pay medical bills. April 2009. Available at: http:// www.kff.org/kaiserpolls/upload/7891.pdf. Accessed December 14, 2009. 10. Casalino LP, Nicholson S, Gans DN, Hammons T, Morra D, Karrison T, et al. What does it cost physician practices to interact with health insurance plans? Health Affairs Web Exclusive. April 2009;28:w533-w543. Available at: http://content.health affairs.org/cgi/content/abstract/hlthaff.28.4.w533. Accessed December 14, 2009. 11. American Medical Association. Opinion 1.02: the relation of law and ethics: code of ethics. Updated June 1994. Available at: http://www.ama-assn.org/ama/pub/ physician-resources/medical-ethics/code-medical-ethics/opinion102.shtml. Accessed December 14, 2009. 12. Carter SL. Integrity. New York: Basic Books; 1996. Available online March 12, 2010. doi:10.1016/j.jaci.2009.12.988
Parental smoking increases the risk for eczema with sensitization in 4-year-old children To the Editor: Parental smoking is one of the proposed risk factors for eczema, but results from previous studies appear inconsistent,1-3 and to our knowledge, none of these have divided eczema into atopic and nonatopic forms. We used data from a Swedish prospective birth cohort (BAMSE) to investigate the association between fetal/early infancy exposure to tobacco smoke and eczema at 4 years of age divided into atopic eczema (AE) and non-AE. The BAMSE study includes 4,089 children born between 1994 and 1996 in Stockholm, Sweden. The children were consecutively recruited to the project at one of their first child health center visits in their first months of life. Access to a community population register ensured that all infants born in the area were included. The cohort has been described in detail elsewhere.4,5 At baseline, when the children were about 2 months old, the parents answered a questionnaire focusing on parental allergic disease and environmental factors, including parental smoking habits. At 1, 2, and 4 years of age, new questionnaires contained questions on symptoms and signs of eczema, as well as the child’s environmental exposures. Exposure to tobacco smoke was divided into maternal smoking during pregnancy, which was defined as the mother smoking at least 1 cigarette per day during any trimester, and parental smoking, which was defined as any parent smoking at least 1 cigarette per day when the child was about 2 months old. Eczema was defined as itchy rash for at least 2 weeks with typical distribution and dry skin, a doctor’s diagnosis of eczema, or both. This definition has proved to have high sensitivity (92%) and specificity (100%) compared with clinical diagnosis by a dermatologist.4 Serum IgE antibodies to inhalant and food allergens were analyzed with Phadiatop and fx5 mixes of relevant inhalant and food allergens, respectively (Pharmacia UniCAP System; Phadia AB, Uppsala, Sweden). Sensitization required a positive Phadiatop, fx5, or both result. Eczema was divided into AE (eczema according to the definition plus sensitization at 4 years of age) and non-AE (eczema according to the definition but no sensitization). Only children with answers to all 4 questionnaires and complete information on exposure to tobacco smoke and covariates, as well as an
available measure of serum IgE (n 5 2505) were included in these analyses. Statistical analyses were made with the Stata Statistical Software, Release 7.0 (StataCorp, College Station, Tex). Logistic regression models adjusting for established risk factors (parental allergic disease, breast-feeding, furred pets at home, sex, and parental education) were used. Because the analyses had 4 levels of outcome (ie, no eczema and no sensitization, sensitization without eczema, non-AE, and AE), a multinomial logistic regression model was used. The resulting odds ratios (ORs) were interpreted as the odds of being sensitized, having non-AE, and having AE, respectively, relative to the odds of having neither eczema nor sensitization. Proportions and ORs are shown with 95% CIs. A logistic regression model was used, with the categorical exposure variable as continuous, to test for a linear trend over categories. Maternal smoking during pregnancy was reported in 12% of families, and parental smoking during the child’s first months was reported in 20% of families. In 4% of families the mother had smoked during pregnancy without reported smoking during the child’s first months, whereas in 12% of families, only smoking during the child’s first months had occurred. Smoking both during pregnancy and during the child’s first months was reported in 8% of families. There were no differences in the prevalence of potential confounders between the study population and the 4,089 children who answered the baseline questionnaire (data not shown). Of the 2505 children included in the study, 529 (21%) reportedly had symptoms meeting the definition of eczema at 4 years of age. Of these, 8% had AE, and 13% had non-AE. Both maternal smoking during pregnancy and parental smoking during the child’s first months increased the risk for AE (OR, 1.82 [95% CI, 1.22-2.73] and OR, 1.62 [95% CI, 1.15-2.30], respectively) but not for non-AE (OR, 0.97 [95% CI, 0.65-1.44] and OR, 1.02 [95% CI, 0.75-1.40], respectively) or sensitization (OR, 0.89 [95% CI, 0.62-1.28] and OR, 1.10 [95% CI, 0.83-1.45], respectively) at 4 years of age. When separating prenatal and postnatal exposure, we observed a statically significant increased risk for AE only among children exposed to both maternal smoking during pregnancy and parental smoking during the child’s first months (Table I). As shown in Table II, a doseresponse effect was indicated for parental smoking during the child’s first months, as well as for maternal smoking during pregnancy, although it was more consistent for postnatal exposure. Both maternal and paternal smoking increased the risk for AE (OR, 2.01 [95% CI, 1.24-3.28] and OR, 1.46 [95% CI, 1.002.13], respectively). When separating these exposures from each other, only the effect of maternal smoking reached significance (Table III). The present study has several advantages. First, the prospective design, following children from birth with annual questionnaires, minimizes recall bias concerning eczema in the child. Second, the first questionnaire containing questions on parental smoking was in most cases completed very early in the child’s life and in 86% of cases by both parents. Thus the risk of the child’s disease status influencing the answers on the questions concerning parental smoking or recall bias from informant parents regarding smoking in the other parent is low. Third, a validated definition of eczema with high sensitivity and specificity was used.4 One limitation of our study is that all data on smoking were self-reported. However, a strong correlation between reported smoking and residential air nicotine concentrations has been
942 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL APRIL 2010
TABLE I. Risk for sensitization, non-AE, and AE at 4 years of age in relation to maternal smoking during pregnancy and parental smoking during the child’s first months Smoking exposure Pregnancy*
No Yes No Yes
Sensitization without eczema
Non-AE
AE
Child’s first months*
Total no.
No.
Percent
ORy
95% CI
No.
Percent
ORy
95% CI
No.
Percent
ORy
95% CI
No No Yes Yes
1902 98 303 202
303 14 54 30
15.9 14.3 17.8 14.9
1.00à 0.87 1.19 0.95
0.48-1.57 0.85-1.65 0.61-1.46
256 10 36 25
13.5 10.2 11.9 12.4
1.00à 0.77 0.97 1.08
0.39-1.52 0.66-1.42 0.67-1.72
137 11 27 27
7.2 11.2 8.9 13.4
1.00à 1.56 1.39 2.14
0.79-3.05 0.89-2.18 1.33-3.46
AE, Eczema plus sensitization at 4 years; Non-AE, eczema without sensitization at 4 years. *One or more cigarettes per day smoked by the mother during any trimester or by any parent during the child’s first months. Adjusted for sex, parental allergic disease, breast-feeding, pets at home, and parental education. àReference group: children without sensitization or eczema.
TABLE II. Risk for AE at 4 years of age in relation to quantity of maternal smoking during pregnancy and parental smoking during the child’s first months AE* Maternal smoking during pregnancy
No smoking Total of 1-10 cigarettes/d _11 cigarettes/d Total of > P for trend
Parental smoking during child’s first months
Total no.
No.
Percent
OR
95% CI
Total no.
No.
Percent
OR
95% CI
2205 212 88
164 26 12
7.4 12.3 13.6
1.00 1.85à 1.77à .007
1.16-2.94 0.91-3.46
2000 303 202
148 30 24
7.4 9.9 11.9
1.00 1.44à 1.95à .003
0.94-2.21 1.19-3.19
*Eczema plus sensitization at 4 years. Reference group: children without sensitization or eczema. àAdjusted for sex, parental allergic disease, breast-feeding, pets at home, and parental education.
TABLE III. Risk for AE at 4 years of age in relation to maternal and paternal smoking during child’s first months Smoking exposure Maternaly
No Yes No Yes
AE*
Paternaly
Total no.
No.
Percent
ORà
95% CI
No No Yes Yes
2000 94 317 94
148 13 29 12
7.4 13.8 9.2 12.8
1.00§ 2.03 1.37 2.24
1.06-3.87 0.89-2.11 1.14-4.40
*Eczema plus sensitization at 4 years. One or more cigarettes per day smoked by the mother or father, respectively, during the child’s first months. àAdjusted for sex, parental allergic disease, breast-feeding, pets at home, and parental education. §Reference group: children without sensitization or eczema.
reported,6 and maternal recall of smoking during pregnancy has been shown to be reproducible and accurate.7 Another limitation is that blood samples and complete information on exposure to tobacco smoke and covariates were available only from 61% of the children in the original cohort, leaving 2505 for the analyses of AE and non-AE. However, selection bias occurs only if the relation between environmental tobacco smoke and eczema is different among those who were included and those eligible for the study. The mechanism behind the increased risk for AE in children of smoking parents is not clear. There is evidence that maternal smoking could have in utero effects on immune development,8-10 and environmental tobacco smoke exposure might influence the immune system after birth. There are studies suggesting that both prenatal and postnatal tobacco smoke exposure increase the risk of allergic immune responses.11 In conclusion, our prospective study including 2505 Swedish boys and girls indicates that maternal smoking during pregnancy, parental smoking during the child’s first months, or both increase
the risk for AE, but not non-AE, in 4-year-old children. Decreased exposure to parental smoking might reduce the prevalence of AE in young children. Maria Bo¨hme, MD, PhDa Inger Kull, RN, PhDb,c Anna Bergstro¨m, PhDb Magnus Wickman, MD, PhDb,c,d Lennart Nordvall, MD, PhDe Go¨ran Pershagen, MD, PhDb Carl-Fredrik Wahlgren, MD, PhDa From athe Dermatology and Venereology Unit, Department of Medicine Solna, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden; bthe Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; cthe Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; dSachs’ Children’s Hospital, Sodersjukhuset, Stockholm, Sweden; and ethe Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden. E-mail: [email protected]. Supported by the Swedish Asthma and Allergy Association, the Va˚rdal Foundation, the Welander-Finsen Foundation, the Swedish Research Council, and the Gillbergska Foundation. Financial support was also provided through regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet.
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Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Hjern A, Hedberg A, Haglund B, Rose´n M. Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents. Clin Exp Allergy 2001;31:908-14. 2. Magnusson LL, Olesen AB, Wennborg H, Olsen J. Wheezing, asthma, hayfever, and atopic eczema in childhood following exposure to tobacco smoke in fetal life. Clin Exp Allergy 2005;35:1550-6. 3. Kramer U, Lemmen CH, Behrendt H, Link E, Schafer T, Gostomzyk J, et al. The effect of environmental tobacco smoke on eczema and allergic sensitization in children. Br J Dermatol 2004;150:111-8. 4. Bo¨hme M, Lannero¨ E, Wickman M, Nordvall SL, Wahlgren CF. Atopic dermatitis and concomitant disease patterns in children up to two years of age. Acta Derm Venereol 2002;82:98-103. 5. Wickman M, Kull I, Pershagen G, Nordvall SL. The BAMSE project: presentation of a prospective longitudinal birth cohort study. Pediatr Allergy Immunol 2002; 13(suppl 15):11-3. 6. Gehring U, Leaderer BP, Heinrich J, Oldenwening M, Giovannangelo ME, Nordling E, et al. Comparison of parental reports of smoking and residential air nicotine concentrations in children. Occup Environ Med 2006;63:766-72. 7. Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A. Tobacco smoke exposure, wheeze, and atopy. Pediatr Pulmonol 2004;37:492-8. 8. Magnusson CG. Maternal smoking influences cord serum IgE and IgD levels and increases the risk for subsequent infant allergy. J Allergy Clin Immunol 1986;78: 898-904. 9. Devereux G, Barker RN, Seaton A. Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy 2002;32:43-50. 10. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003;58:1053-8. 11. Kulig M, Luck W, Lau S, Niggemann B, Bergmann R, Klettke U, et al. Effect of pre- and postnatal tobacco smoke exposure on specific sensitization to food and inhalant allergens during the first 3 years of life. Multicenter Allergy Study Group, Germany. Allergy 1999;54:220-8. Available online March 15, 2010. doi:10.1016/j.jaci.2009.12.997
Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease To the Editor: Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system (1 in 200,000 to 1 in 250,000 live births per year; see also this article’s Online Repository at www.jacionline.org). A hallmark of the disease is uncontrolled inflammation often accompanied by granuloma formation both in the presence and absence of microorganisms. Such inflammation can affect various organ systems, including the gastrointestinal tract. Furthermore, patients with CGD are highly susceptible to distinct opportunistic bacteria and fungi, but the disorder does not always manifest itself through infections.1 Inflammatory bowel disease (IBD) is a well-known complication of CGD.1-4 However, in previous large cohort studies typical infections, such as pneumonia, and abscesses in lymph nodes or the liver facilitated the diagnosis of this rare disorder. CGD manifested as IBD in 7.8% of 154 cases (see this article’s Online Repository). Here we report 8 patients with p47-phox deficient (A478) CGD who primarily presented with symptoms typical for IBD, such as severe granulomatous colitis (5/8 patients), aphthous stomatitis (3/8 patients), bloody diarrhea (4/8 patients), and perianal abscesses, eczema, fissures, or fistula formation (5/8 patients), as summarized in Table I. In 7 patients the symptoms started very early in life, between 6
weeks and 5 years of age. Initially, Crohn disease was presumed in the majority of patients. However, ulcerative colitis and other diagnoses, such as juvenile idiopathic arthritis, Behc xet disease, and pyoderma gangrenosum, were also considered. Histopathological evaluation of biopsy samples can provide clues for CGD in patients with IBD (eg, pigmented macrophages, as seen in patient 2), but the diagnosis has to be confirmed biochemically.5 As typical for p47-phox deficiency, we found residual nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity (see this article’s Online Repository) in our patients, which likely prevented early infectious complications. In general, patients with CGD with such residual activity manifest symptoms later in life, experience longer symptom-free intervals, and have a better overall prognosis than patients with complete lack of NADPH oxidase activity. However, it is important to note that patients with residual NADPH oxidase activity can also acquire life-threatening CGD-typical infections. Therefore it is important to diagnose CGD as early as possible to provide CGD-specific care, such as surveillance and prophylactic antimicrobial treatment. It is possible that patients with Crohn-like disease and unrecognized CGD succumb to severe infections that are erroneously attributed to the effects of immunosuppressive drugs. In our patients p47-phox deficient CGD was diagnosed 2 to 10 years after the first manifestation (median, 6 years; patients 1–7 included; Table I), with c.75-76delGT in the neutrophil cytosolic factor 1 (NCF1) gene being the most common mutation.6 IBD was the prominent and first clinical CGD manifestation, but 5 patients (nos. 1, 3, 5, 6, and 8) also had other symptoms of dysregulated inflammation, such as granulomatous lymphadenopathy, arthritis, encephalitis, and pyoderma-like skin lesions. Infections typical for CGD, such as lymph node and organ abscesses or Aspergillus species–induced pneumonias, did not occur. Our patients with CGD either received prophylactic antibiotics (mostly co-trimoxazole) or the full standard CGD prophylactic treatment comprising cotrimoxazole and itraconazole. Before and after CGD had been detected, several therapeutic approaches were chosen to treat IBD, such as polymeric diet, mesalazine, steroids, thalidomide, azathioprine, methotrexate, anakinra, infliximab, and adalimumab. The improvements after such therapies varied considerably (see this article’s Online Repository). Steroids were most frequently applied in our and other studies and were helpful in several patients. In some patients all treatments failed. Symptoms in 2 patients (nos. 2 and 6; Table I) improved after a combination of polymeric diet, mesalazine, and azathioprine. However, patient 6 acquired Candida albicans–induced encephalitis. Reduced-intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT) was performed in this and 2 other patients (nos. 4 and 8; Tables I and II) because of intractable or steroid-dependent colitis, severe osteopenia, and failure to thrive. All patients are alive 8, 19 and 59 months after RIC-HSCT, respectively, with complete remission of intestinal and other CGDrelated symptoms in the absence of graft-versus-host disease. HSCT should be considered in any patients with CGD with a history of life-threatening infections or therapy-refractory inflammatory conditions that lead to organ dysfunction, chronic pain, or failure to thrive.7 HSCT might also be indicated if necessary therapy is hampered by unacceptable side effects, such as steroidassociated osteoporosis, hypertension, or diabetes, or in cases of complete intolerance or incompliance to standard and alternative CGD prophylaxis. Yet the pros and cons of HSCT must be
J ALLERGY CLIN IMMUNOL VOLUME 125, NUMBER 4
6. Helgesson G, Lyno¨e N. Should physicians fake diagnoses to help their patients? J Med Ethics 2008;34:133-6. 7. Macauley R. The Hippocratic underground: civil disobedience and health care reform. Hast Ctr Rep 2005;35:38-45. 8. VanGeest J, Weiner S, Johnson T, Cummins D. Impact of managed care on physicians’ decisions to manipulate reimbursement rules: an explanatory model. J Health Ser Res Policy 2007;12:147-52. 9. Kaiser Family Foundation. Kaiser health tracking poll: many Americans still delaying care, struggling to pay medical bills. April 2009. Available at: http:// www.kff.org/kaiserpolls/upload/7891.pdf. Accessed December 14, 2009. 10. Casalino LP, Nicholson S, Gans DN, Hammons T, Morra D, Karrison T, et al. What does it cost physician practices to interact with health insurance plans? Health Affairs Web Exclusive. April 2009;28:w533-w543. Available at: http://content.health affairs.org/cgi/content/abstract/hlthaff.28.4.w533. Accessed December 14, 2009. 11. American Medical Association. Opinion 1.02: the relation of law and ethics: code of ethics. Updated June 1994. Available at: http://www.ama-assn.org/ama/pub/ physician-resources/medical-ethics/code-medical-ethics/opinion102.shtml. Accessed December 14, 2009. 12. Carter SL. Integrity. New York: Basic Books; 1996. Available online March 12, 2010. doi:10.1016/j.jaci.2009.12.988
Parental smoking increases the risk for eczema with sensitization in 4-year-old children To the Editor: Parental smoking is one of the proposed risk factors for eczema, but results from previous studies appear inconsistent,1-3 and to our knowledge, none of these have divided eczema into atopic and nonatopic forms. We used data from a Swedish prospective birth cohort (BAMSE) to investigate the association between fetal/early infancy exposure to tobacco smoke and eczema at 4 years of age divided into atopic eczema (AE) and non-AE. The BAMSE study includes 4,089 children born between 1994 and 1996 in Stockholm, Sweden. The children were consecutively recruited to the project at one of their first child health center visits in their first months of life. Access to a community population register ensured that all infants born in the area were included. The cohort has been described in detail elsewhere.4,5 At baseline, when the children were about 2 months old, the parents answered a questionnaire focusing on parental allergic disease and environmental factors, including parental smoking habits. At 1, 2, and 4 years of age, new questionnaires contained questions on symptoms and signs of eczema, as well as the child’s environmental exposures. Exposure to tobacco smoke was divided into maternal smoking during pregnancy, which was defined as the mother smoking at least 1 cigarette per day during any trimester, and parental smoking, which was defined as any parent smoking at least 1 cigarette per day when the child was about 2 months old. Eczema was defined as itchy rash for at least 2 weeks with typical distribution and dry skin, a doctor’s diagnosis of eczema, or both. This definition has proved to have high sensitivity (92%) and specificity (100%) compared with clinical diagnosis by a dermatologist.4 Serum IgE antibodies to inhalant and food allergens were analyzed with Phadiatop and fx5 mixes of relevant inhalant and food allergens, respectively (Pharmacia UniCAP System; Phadia AB, Uppsala, Sweden). Sensitization required a positive Phadiatop, fx5, or both result. Eczema was divided into AE (eczema according to the definition plus sensitization at 4 years of age) and non-AE (eczema according to the definition but no sensitization). Only children with answers to all 4 questionnaires and complete information on exposure to tobacco smoke and covariates, as well as an
available measure of serum IgE (n 5 2505) were included in these analyses. Statistical analyses were made with the Stata Statistical Software, Release 7.0 (StataCorp, College Station, Tex). Logistic regression models adjusting for established risk factors (parental allergic disease, breast-feeding, furred pets at home, sex, and parental education) were used. Because the analyses had 4 levels of outcome (ie, no eczema and no sensitization, sensitization without eczema, non-AE, and AE), a multinomial logistic regression model was used. The resulting odds ratios (ORs) were interpreted as the odds of being sensitized, having non-AE, and having AE, respectively, relative to the odds of having neither eczema nor sensitization. Proportions and ORs are shown with 95% CIs. A logistic regression model was used, with the categorical exposure variable as continuous, to test for a linear trend over categories. Maternal smoking during pregnancy was reported in 12% of families, and parental smoking during the child’s first months was reported in 20% of families. In 4% of families the mother had smoked during pregnancy without reported smoking during the child’s first months, whereas in 12% of families, only smoking during the child’s first months had occurred. Smoking both during pregnancy and during the child’s first months was reported in 8% of families. There were no differences in the prevalence of potential confounders between the study population and the 4,089 children who answered the baseline questionnaire (data not shown). Of the 2505 children included in the study, 529 (21%) reportedly had symptoms meeting the definition of eczema at 4 years of age. Of these, 8% had AE, and 13% had non-AE. Both maternal smoking during pregnancy and parental smoking during the child’s first months increased the risk for AE (OR, 1.82 [95% CI, 1.22-2.73] and OR, 1.62 [95% CI, 1.15-2.30], respectively) but not for non-AE (OR, 0.97 [95% CI, 0.65-1.44] and OR, 1.02 [95% CI, 0.75-1.40], respectively) or sensitization (OR, 0.89 [95% CI, 0.62-1.28] and OR, 1.10 [95% CI, 0.83-1.45], respectively) at 4 years of age. When separating prenatal and postnatal exposure, we observed a statically significant increased risk for AE only among children exposed to both maternal smoking during pregnancy and parental smoking during the child’s first months (Table I). As shown in Table II, a doseresponse effect was indicated for parental smoking during the child’s first months, as well as for maternal smoking during pregnancy, although it was more consistent for postnatal exposure. Both maternal and paternal smoking increased the risk for AE (OR, 2.01 [95% CI, 1.24-3.28] and OR, 1.46 [95% CI, 1.002.13], respectively). When separating these exposures from each other, only the effect of maternal smoking reached significance (Table III). The present study has several advantages. First, the prospective design, following children from birth with annual questionnaires, minimizes recall bias concerning eczema in the child. Second, the first questionnaire containing questions on parental smoking was in most cases completed very early in the child’s life and in 86% of cases by both parents. Thus the risk of the child’s disease status influencing the answers on the questions concerning parental smoking or recall bias from informant parents regarding smoking in the other parent is low. Third, a validated definition of eczema with high sensitivity and specificity was used.4 One limitation of our study is that all data on smoking were self-reported. However, a strong correlation between reported smoking and residential air nicotine concentrations has been
942 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL APRIL 2010
TABLE I. Risk for sensitization, non-AE, and AE at 4 years of age in relation to maternal smoking during pregnancy and parental smoking during the child’s first months Smoking exposure Pregnancy*
No Yes No Yes
Sensitization without eczema
Non-AE
AE
Child’s first months*
Total no.
No.
Percent
ORy
95% CI
No.
Percent
ORy
95% CI
No.
Percent
ORy
95% CI
No No Yes Yes
1902 98 303 202
303 14 54 30
15.9 14.3 17.8 14.9
1.00à 0.87 1.19 0.95
0.48-1.57 0.85-1.65 0.61-1.46
256 10 36 25
13.5 10.2 11.9 12.4
1.00à 0.77 0.97 1.08
0.39-1.52 0.66-1.42 0.67-1.72
137 11 27 27
7.2 11.2 8.9 13.4
1.00à 1.56 1.39 2.14
0.79-3.05 0.89-2.18 1.33-3.46
AE, Eczema plus sensitization at 4 years; Non-AE, eczema without sensitization at 4 years. *One or more cigarettes per day smoked by the mother during any trimester or by any parent during the child’s first months. Adjusted for sex, parental allergic disease, breast-feeding, pets at home, and parental education. àReference group: children without sensitization or eczema.
TABLE II. Risk for AE at 4 years of age in relation to quantity of maternal smoking during pregnancy and parental smoking during the child’s first months AE* Maternal smoking during pregnancy
No smoking Total of 1-10 cigarettes/d _11 cigarettes/d Total of > P for trend
Parental smoking during child’s first months
Total no.
No.
Percent
OR
95% CI
Total no.
No.
Percent
OR
95% CI
2205 212 88
164 26 12
7.4 12.3 13.6
1.00 1.85à 1.77à .007
1.16-2.94 0.91-3.46
2000 303 202
148 30 24
7.4 9.9 11.9
1.00 1.44à 1.95à .003
0.94-2.21 1.19-3.19
*Eczema plus sensitization at 4 years. Reference group: children without sensitization or eczema. àAdjusted for sex, parental allergic disease, breast-feeding, pets at home, and parental education.
TABLE III. Risk for AE at 4 years of age in relation to maternal and paternal smoking during child’s first months Smoking exposure Maternaly
No Yes No Yes
AE*
Paternaly
Total no.
No.
Percent
ORà
95% CI
No No Yes Yes
2000 94 317 94
148 13 29 12
7.4 13.8 9.2 12.8
1.00§ 2.03 1.37 2.24
1.06-3.87 0.89-2.11 1.14-4.40
*Eczema plus sensitization at 4 years. One or more cigarettes per day smoked by the mother or father, respectively, during the child’s first months. àAdjusted for sex, parental allergic disease, breast-feeding, pets at home, and parental education. §Reference group: children without sensitization or eczema.
reported,6 and maternal recall of smoking during pregnancy has been shown to be reproducible and accurate.7 Another limitation is that blood samples and complete information on exposure to tobacco smoke and covariates were available only from 61% of the children in the original cohort, leaving 2505 for the analyses of AE and non-AE. However, selection bias occurs only if the relation between environmental tobacco smoke and eczema is different among those who were included and those eligible for the study. The mechanism behind the increased risk for AE in children of smoking parents is not clear. There is evidence that maternal smoking could have in utero effects on immune development,8-10 and environmental tobacco smoke exposure might influence the immune system after birth. There are studies suggesting that both prenatal and postnatal tobacco smoke exposure increase the risk of allergic immune responses.11 In conclusion, our prospective study including 2505 Swedish boys and girls indicates that maternal smoking during pregnancy, parental smoking during the child’s first months, or both increase
the risk for AE, but not non-AE, in 4-year-old children. Decreased exposure to parental smoking might reduce the prevalence of AE in young children. Maria Bo¨hme, MD, PhDa Inger Kull, RN, PhDb,c Anna Bergstro¨m, PhDb Magnus Wickman, MD, PhDb,c,d Lennart Nordvall, MD, PhDe Go¨ran Pershagen, MD, PhDb Carl-Fredrik Wahlgren, MD, PhDa From athe Dermatology and Venereology Unit, Department of Medicine Solna, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden; bthe Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; cthe Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; dSachs’ Children’s Hospital, Sodersjukhuset, Stockholm, Sweden; and ethe Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden. E-mail: [email protected]. Supported by the Swedish Asthma and Allergy Association, the Va˚rdal Foundation, the Welander-Finsen Foundation, the Swedish Research Council, and the Gillbergska Foundation. Financial support was also provided through regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet.
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Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Hjern A, Hedberg A, Haglund B, Rose´n M. Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents. Clin Exp Allergy 2001;31:908-14. 2. Magnusson LL, Olesen AB, Wennborg H, Olsen J. Wheezing, asthma, hayfever, and atopic eczema in childhood following exposure to tobacco smoke in fetal life. Clin Exp Allergy 2005;35:1550-6. 3. Kramer U, Lemmen CH, Behrendt H, Link E, Schafer T, Gostomzyk J, et al. The effect of environmental tobacco smoke on eczema and allergic sensitization in children. Br J Dermatol 2004;150:111-8. 4. Bo¨hme M, Lannero¨ E, Wickman M, Nordvall SL, Wahlgren CF. Atopic dermatitis and concomitant disease patterns in children up to two years of age. Acta Derm Venereol 2002;82:98-103. 5. Wickman M, Kull I, Pershagen G, Nordvall SL. The BAMSE project: presentation of a prospective longitudinal birth cohort study. Pediatr Allergy Immunol 2002; 13(suppl 15):11-3. 6. Gehring U, Leaderer BP, Heinrich J, Oldenwening M, Giovannangelo ME, Nordling E, et al. Comparison of parental reports of smoking and residential air nicotine concentrations in children. Occup Environ Med 2006;63:766-72. 7. Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A. Tobacco smoke exposure, wheeze, and atopy. Pediatr Pulmonol 2004;37:492-8. 8. Magnusson CG. Maternal smoking influences cord serum IgE and IgD levels and increases the risk for subsequent infant allergy. J Allergy Clin Immunol 1986;78: 898-904. 9. Devereux G, Barker RN, Seaton A. Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy 2002;32:43-50. 10. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003;58:1053-8. 11. Kulig M, Luck W, Lau S, Niggemann B, Bergmann R, Klettke U, et al. Effect of pre- and postnatal tobacco smoke exposure on specific sensitization to food and inhalant allergens during the first 3 years of life. Multicenter Allergy Study Group, Germany. Allergy 1999;54:220-8. Available online March 15, 2010. doi:10.1016/j.jaci.2009.12.997
Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease To the Editor: Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system (1 in 200,000 to 1 in 250,000 live births per year; see also this article’s Online Repository at www.jacionline.org). A hallmark of the disease is uncontrolled inflammation often accompanied by granuloma formation both in the presence and absence of microorganisms. Such inflammation can affect various organ systems, including the gastrointestinal tract. Furthermore, patients with CGD are highly susceptible to distinct opportunistic bacteria and fungi, but the disorder does not always manifest itself through infections.1 Inflammatory bowel disease (IBD) is a well-known complication of CGD.1-4 However, in previous large cohort studies typical infections, such as pneumonia, and abscesses in lymph nodes or the liver facilitated the diagnosis of this rare disorder. CGD manifested as IBD in 7.8% of 154 cases (see this article’s Online Repository). Here we report 8 patients with p47-phox deficient (A478) CGD who primarily presented with symptoms typical for IBD, such as severe granulomatous colitis (5/8 patients), aphthous stomatitis (3/8 patients), bloody diarrhea (4/8 patients), and perianal abscesses, eczema, fissures, or fistula formation (5/8 patients), as summarized in Table I. In 7 patients the symptoms started very early in life, between 6
weeks and 5 years of age. Initially, Crohn disease was presumed in the majority of patients. However, ulcerative colitis and other diagnoses, such as juvenile idiopathic arthritis, Behc xet disease, and pyoderma gangrenosum, were also considered. Histopathological evaluation of biopsy samples can provide clues for CGD in patients with IBD (eg, pigmented macrophages, as seen in patient 2), but the diagnosis has to be confirmed biochemically.5 As typical for p47-phox deficiency, we found residual nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity (see this article’s Online Repository) in our patients, which likely prevented early infectious complications. In general, patients with CGD with such residual activity manifest symptoms later in life, experience longer symptom-free intervals, and have a better overall prognosis than patients with complete lack of NADPH oxidase activity. However, it is important to note that patients with residual NADPH oxidase activity can also acquire life-threatening CGD-typical infections. Therefore it is important to diagnose CGD as early as possible to provide CGD-specific care, such as surveillance and prophylactic antimicrobial treatment. It is possible that patients with Crohn-like disease and unrecognized CGD succumb to severe infections that are erroneously attributed to the effects of immunosuppressive drugs. In our patients p47-phox deficient CGD was diagnosed 2 to 10 years after the first manifestation (median, 6 years; patients 1–7 included; Table I), with c.75-76delGT in the neutrophil cytosolic factor 1 (NCF1) gene being the most common mutation.6 IBD was the prominent and first clinical CGD manifestation, but 5 patients (nos. 1, 3, 5, 6, and 8) also had other symptoms of dysregulated inflammation, such as granulomatous lymphadenopathy, arthritis, encephalitis, and pyoderma-like skin lesions. Infections typical for CGD, such as lymph node and organ abscesses or Aspergillus species–induced pneumonias, did not occur. Our patients with CGD either received prophylactic antibiotics (mostly co-trimoxazole) or the full standard CGD prophylactic treatment comprising cotrimoxazole and itraconazole. Before and after CGD had been detected, several therapeutic approaches were chosen to treat IBD, such as polymeric diet, mesalazine, steroids, thalidomide, azathioprine, methotrexate, anakinra, infliximab, and adalimumab. The improvements after such therapies varied considerably (see this article’s Online Repository). Steroids were most frequently applied in our and other studies and were helpful in several patients. In some patients all treatments failed. Symptoms in 2 patients (nos. 2 and 6; Table I) improved after a combination of polymeric diet, mesalazine, and azathioprine. However, patient 6 acquired Candida albicans–induced encephalitis. Reduced-intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT) was performed in this and 2 other patients (nos. 4 and 8; Tables I and II) because of intractable or steroid-dependent colitis, severe osteopenia, and failure to thrive. All patients are alive 8, 19 and 59 months after RIC-HSCT, respectively, with complete remission of intestinal and other CGDrelated symptoms in the absence of graft-versus-host disease. HSCT should be considered in any patients with CGD with a history of life-threatening infections or therapy-refractory inflammatory conditions that lead to organ dysfunction, chronic pain, or failure to thrive.7 HSCT might also be indicated if necessary therapy is hampered by unacceptable side effects, such as steroidassociated osteoporosis, hypertension, or diabetes, or in cases of complete intolerance or incompliance to standard and alternative CGD prophylaxis. Yet the pros and cons of HSCT must be