correspondence
Aortic Dilatation with Bicuspid Aortic Valve To the Editor: In their review on thoracic aortic dilatation associated with bicuspid aortic valve, Verma and Siu (May 15 issue)1 do not mention the increased prevalence of bicuspid aortic valve and its strong association with aortic dilatation and dissection in women with Turner’s syndrome.2 This sex-chromosome disorder, which is caused by the loss of all or part of one X chromosome, affects approximately 1 in 2000 live-born females and approximately 80,000 women in the United States. The prevalence of bicuspid aortic valve in Turner’s syndrome (approximately 1 in 3) is much greater than that in the general population and is frequently accompanied by other cardiovascular complications, such as dilatation or coarctation of the thoracic aorta.3 Its presence also increases the risk of aortic dissection and occurs more frequently, at younger ages, and during pregnancy in patients with Turner’s syndrome.4,5 Investigation of bicuspid aortic valve in patients with Turner’s syndrome may provide generalizable insights into the contribution of X chromosome genes to bicuspid aortic valve in men, in whom increased susceptibility to bicuspid aortic valve may be due in part to a reduced dose of X
chromosome genes. The unique association among bicuspid aortic valve, aortic disease, and Turner’s syndrome is clearly important. Angela E. Lin, M.D. MassGeneral Hospital for Children Boston, MA
[email protected]
Siddharth Prakash, M.D., Ph.D. Dianna M. Milewicz, M.D., Ph.D. University of Texas Health Science Center at Houston Houston, TX No potential conflict of interest relevant to this letter was reported. 1. Verma S, Siu SC. Aortic dilatation in patients with bicuspid
aortic valve. N Engl J Med 2014;370:1920-9.
2. Bondy CA. Care of girls and women with Turner syndrome:
a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10-25. 3. Olivieri LJ, Baba RY, Arai AE, et al. Spectrum of aortic valve abnormalities associated with aortic dilation across age groups in Turner syndrome. Circ Cardiovasc Imaging 2013;6:1018-23. 4. Carlson M, Airhart N, Lopez L, Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the International Turner Syndrome Aortic Dissection Registry. Circulation 2012; 126:2220-6. 5. Hadnott TN, Bondy CA. Risks of pregnancy for women with Turner syndrome. Exp Rev Obstet Gynecol 2011;6:217-27. DOI: 10.1056/NEJMc1407391
Lyme Disease To the Editor: Given that 20 to 30% of patients with Lyme disease present without a rash,1 physicians must maintain a high level of suspicion when evaluating a patient presenting with nonspecific constitutional symptoms suggestive of infection who has spent time in a region where Lyme disease is endemic. This is particularly true during the spring and summer months. In his review of Lyme disease, Shapiro (May 1 issue)2 did not address the management of care for such patients. Early nonspecific infectious symptoms that can suggest Lyme disease include regional unilateral lymphadenopathy (typically inguinal), body aches, arthralgias, headache, fevers, and chills. I believe that when patients present in this manner without an erythema migrans rash and without symptoms that localize the infection to the gastrointestinal tract, respiratory tract, or genitourinary tract, it is prudent to consider empirical treatment with an antibiotic that is directed
toward Lyme disease, although I am not aware of any evidence-based protocols that have evaluated this practice. Thomas F. Castiglione, M.D. South Shore Medical Center Kingston, MA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Steere AC, Sikand VK. The presenting manifestations of
Lyme disease and the outcomes of treatment. N Engl J Med 2003; 348:2472-4. 2. Shapiro ED. Lyme disease. N Engl J Med 2014;370:1724-31. DOI: 10.1056/NEJMc1407264
To the Editor: I agree with Shapiro that congenital Lyme disease has never been clearly identified; however, there are case reports of fetal loss in mothers with untreated or inadequately treated Lyme disease during pregnancy.1-3 Are these case reports flawed?
n engl j med 371;7 nejm.org august 14, 2014
683
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF TENNESSEE - KNOXVILLE on September 15, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
A deer-tick bite during pregnancy, in my experience, causes high anxiety on the part of the pregnant woman and her physician. Shapiro and colleagues4 reported that 10 days of treatment with amoxicillin (at a dose of 250 mg three times per day) for prophylaxis against Lyme disease after deer-tick bites resulted in 0 cases of the disease among 192 participants who received the drug versus 2 cases among 173 participants who received placebo. This difference did not reach statistical significance. Nevertheless, is amoxicillin an option for prophylaxis during pregnancy? Shapiro stated that the Internet contains misinformation about “chronic” Lyme disease. The Internet is also riddled with warnings to mothers not to breast-feed during treatment for Lyme disease.5 Is there evidence that breast-feeding during Lyme disease involves risks? Henry M. Feder, Jr., M.D. University of Connecticut Health Center Farmington, CT [email protected] No potential conflict of interest relevant to this letter was reported. 1. Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman
MT. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985;103:67-8. 2. MacDonald AB, Benach JL, Burgdorfer W. Stillbirth following maternal Lyme disease. N Y State J Med 1987;87:615-6. 3. Weber K, Bratzke HJ, Neubert U, Wilske B, Duray PH. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 1988;7:286-9. 4. Shapiro ED, Gerber MA, Holabird NB, et al. A controlled trial of antimicrobial prophylaxis to prevent Lyme disease after deer-tick bites. N Engl J Med 1992;327:1769-73. 5. Cooper JD, Feder HM Jr. Inaccurate information about Lyme disease on the Internet. Pediatr Infect Dis J 2004;23:1105-8. DOI: 10.1056/NEJMc1407264
The author replies: Castiglione asks whether empirical antibiotic treatment is warranted for patients in endemic areas with only nonspecific symptoms in whom the suspicion of Lyme disease is high. The merit of this approach will depend on the proportion of patients in whom the nonspecific symptoms are actually due to Lyme disease, the extent to which the outcomes of the patients are improved by treatment with antibiotics, and the costs and adverse effects of antibiotic treatment. For the overwhelming majority of patients with only nonspecific symptoms, Lyme disease will not be the cause, even in hyperendemic areas. In the absence of specific signs of 684
of
m e dic i n e
Lyme disease, it is not clear that any characteristic would justify a heightened suspicion of Lyme disease (perhaps unusually extensive exposure to ticks might). The proportion of patients with only nonspecific symptoms who will go on to have late Lyme disease is extremely small, and those few patients could then be effectively treated. Late Lyme disease (arthritis) developed in only 1 of 30 patients with unrecognized seroconversion.1 Thus, I would not recommend this strategy in the absence of evidence that the benefits outweigh the risks and costs. There have been a small number of case reports in which spirochetes that resemble Borrelia burgdorferi were seen in tissues of miscarried fetuses. However, there was no associated inflammation in the affected tissues, and the causes of death were apparently unrelated to the presence of the spirochetes. Despite extensive surveillance of women with evidence of B. burgdorferi infection both for increased risk of abnormalities and for patterns of congenital malformations in fetuses and children, no such associations have been found.2,3 Given that Lyme disease and unrecognized infection with B. burgdorferi are common in endemic areas, I would expect that if congenital Lyme disease were a serious problem, well-documented cases would have been described by now. I would not recommend single-dose prophylaxis with amoxicillin, because the pharmacokinetics of amoxicillin are substantially different from those of doxycycline.4 The minimum duration of treatment with amoxicillin that would be effective prophylaxis for patients bitten by a deer tick is unknown. There is no evidence that B. burgdorferi can be transmitted by breast-feeding. Eugene D. Shapiro, M.D. Yale University New Haven, CT [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Steere AC, Dhar A, Hernandez J, et al. Systemic symptoms
without erythema migrans as the presenting picture of early Lyme disease. Am J Med 2003;114:58-62. 2. Lakos A, Solymosi N. Maternal Lyme borreliosis and pregnancy outcome. Int J Infect Dis 2010;14(6):e494-e498. 3. Strobino BA, Williams CL, Abid S, Chalson R, Spierling P. Lyme disease and pregnancy outcome: a prospective study of two thousand prenatal patients. Am J Obstet Gynecol 1993;169:367-74. 4. Lee J, Wormser GP. Pharmacodynamics of doxycycline for chemoprophylaxis of Lyme disease: preliminary findings and possible implications for other antimicrobials. Int J Antimicrob Agents 2008;31:235-9. DOI: 10.1056/NEJMc1407264
n engl j med 371;7 nejm.org august 14, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF TENNESSEE - KNOXVILLE on September 15, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Aortic Dilatation with Bicuspid Aortic Valve To the Editor: In their review on thoracic aortic dilatation associated with bicuspid aortic valve, Verma and Siu (May 15 issue)1 do not mention the increased prevalence of bicuspid aortic valve and its strong association with aortic dilatation and dissection in women with Turner’s syndrome.2 This sex-chromosome disorder, which is caused by the loss of all or part of one X chromosome, affects approximately 1 in 2000 live-born females and approximately 80,000 women in the United States. The prevalence of bicuspid aortic valve in Turner’s syndrome (approximately 1 in 3) is much greater than that in the general population and is frequently accompanied by other cardiovascular complications, such as dilatation or coarctation of the thoracic aorta.3 Its presence also increases the risk of aortic dissection and occurs more frequently, at younger ages, and during pregnancy in patients with Turner’s syndrome.4,5 Investigation of bicuspid aortic valve in patients with Turner’s syndrome may provide generalizable insights into the contribution of X chromosome genes to bicuspid aortic valve in men, in whom increased susceptibility to bicuspid aortic valve may be due in part to a reduced dose of X
chromosome genes. The unique association among bicuspid aortic valve, aortic disease, and Turner’s syndrome is clearly important. Angela E. Lin, M.D. MassGeneral Hospital for Children Boston, MA
[email protected]
Siddharth Prakash, M.D., Ph.D. Dianna M. Milewicz, M.D., Ph.D. University of Texas Health Science Center at Houston Houston, TX No potential conflict of interest relevant to this letter was reported. 1. Verma S, Siu SC. Aortic dilatation in patients with bicuspid
aortic valve. N Engl J Med 2014;370:1920-9.
2. Bondy CA. Care of girls and women with Turner syndrome:
a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10-25. 3. Olivieri LJ, Baba RY, Arai AE, et al. Spectrum of aortic valve abnormalities associated with aortic dilation across age groups in Turner syndrome. Circ Cardiovasc Imaging 2013;6:1018-23. 4. Carlson M, Airhart N, Lopez L, Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the International Turner Syndrome Aortic Dissection Registry. Circulation 2012; 126:2220-6. 5. Hadnott TN, Bondy CA. Risks of pregnancy for women with Turner syndrome. Exp Rev Obstet Gynecol 2011;6:217-27. DOI: 10.1056/NEJMc1407391
Lyme Disease To the Editor: Given that 20 to 30% of patients with Lyme disease present without a rash,1 physicians must maintain a high level of suspicion when evaluating a patient presenting with nonspecific constitutional symptoms suggestive of infection who has spent time in a region where Lyme disease is endemic. This is particularly true during the spring and summer months. In his review of Lyme disease, Shapiro (May 1 issue)2 did not address the management of care for such patients. Early nonspecific infectious symptoms that can suggest Lyme disease include regional unilateral lymphadenopathy (typically inguinal), body aches, arthralgias, headache, fevers, and chills. I believe that when patients present in this manner without an erythema migrans rash and without symptoms that localize the infection to the gastrointestinal tract, respiratory tract, or genitourinary tract, it is prudent to consider empirical treatment with an antibiotic that is directed
toward Lyme disease, although I am not aware of any evidence-based protocols that have evaluated this practice. Thomas F. Castiglione, M.D. South Shore Medical Center Kingston, MA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Steere AC, Sikand VK. The presenting manifestations of
Lyme disease and the outcomes of treatment. N Engl J Med 2003; 348:2472-4. 2. Shapiro ED. Lyme disease. N Engl J Med 2014;370:1724-31. DOI: 10.1056/NEJMc1407264
To the Editor: I agree with Shapiro that congenital Lyme disease has never been clearly identified; however, there are case reports of fetal loss in mothers with untreated or inadequately treated Lyme disease during pregnancy.1-3 Are these case reports flawed?
n engl j med 371;7 nejm.org august 14, 2014
683
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF TENNESSEE - KNOXVILLE on September 15, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
A deer-tick bite during pregnancy, in my experience, causes high anxiety on the part of the pregnant woman and her physician. Shapiro and colleagues4 reported that 10 days of treatment with amoxicillin (at a dose of 250 mg three times per day) for prophylaxis against Lyme disease after deer-tick bites resulted in 0 cases of the disease among 192 participants who received the drug versus 2 cases among 173 participants who received placebo. This difference did not reach statistical significance. Nevertheless, is amoxicillin an option for prophylaxis during pregnancy? Shapiro stated that the Internet contains misinformation about “chronic” Lyme disease. The Internet is also riddled with warnings to mothers not to breast-feed during treatment for Lyme disease.5 Is there evidence that breast-feeding during Lyme disease involves risks? Henry M. Feder, Jr., M.D. University of Connecticut Health Center Farmington, CT [email protected] No potential conflict of interest relevant to this letter was reported. 1. Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman
MT. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985;103:67-8. 2. MacDonald AB, Benach JL, Burgdorfer W. Stillbirth following maternal Lyme disease. N Y State J Med 1987;87:615-6. 3. Weber K, Bratzke HJ, Neubert U, Wilske B, Duray PH. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 1988;7:286-9. 4. Shapiro ED, Gerber MA, Holabird NB, et al. A controlled trial of antimicrobial prophylaxis to prevent Lyme disease after deer-tick bites. N Engl J Med 1992;327:1769-73. 5. Cooper JD, Feder HM Jr. Inaccurate information about Lyme disease on the Internet. Pediatr Infect Dis J 2004;23:1105-8. DOI: 10.1056/NEJMc1407264
The author replies: Castiglione asks whether empirical antibiotic treatment is warranted for patients in endemic areas with only nonspecific symptoms in whom the suspicion of Lyme disease is high. The merit of this approach will depend on the proportion of patients in whom the nonspecific symptoms are actually due to Lyme disease, the extent to which the outcomes of the patients are improved by treatment with antibiotics, and the costs and adverse effects of antibiotic treatment. For the overwhelming majority of patients with only nonspecific symptoms, Lyme disease will not be the cause, even in hyperendemic areas. In the absence of specific signs of 684
of
m e dic i n e
Lyme disease, it is not clear that any characteristic would justify a heightened suspicion of Lyme disease (perhaps unusually extensive exposure to ticks might). The proportion of patients with only nonspecific symptoms who will go on to have late Lyme disease is extremely small, and those few patients could then be effectively treated. Late Lyme disease (arthritis) developed in only 1 of 30 patients with unrecognized seroconversion.1 Thus, I would not recommend this strategy in the absence of evidence that the benefits outweigh the risks and costs. There have been a small number of case reports in which spirochetes that resemble Borrelia burgdorferi were seen in tissues of miscarried fetuses. However, there was no associated inflammation in the affected tissues, and the causes of death were apparently unrelated to the presence of the spirochetes. Despite extensive surveillance of women with evidence of B. burgdorferi infection both for increased risk of abnormalities and for patterns of congenital malformations in fetuses and children, no such associations have been found.2,3 Given that Lyme disease and unrecognized infection with B. burgdorferi are common in endemic areas, I would expect that if congenital Lyme disease were a serious problem, well-documented cases would have been described by now. I would not recommend single-dose prophylaxis with amoxicillin, because the pharmacokinetics of amoxicillin are substantially different from those of doxycycline.4 The minimum duration of treatment with amoxicillin that would be effective prophylaxis for patients bitten by a deer tick is unknown. There is no evidence that B. burgdorferi can be transmitted by breast-feeding. Eugene D. Shapiro, M.D. Yale University New Haven, CT [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Steere AC, Dhar A, Hernandez J, et al. Systemic symptoms
without erythema migrans as the presenting picture of early Lyme disease. Am J Med 2003;114:58-62. 2. Lakos A, Solymosi N. Maternal Lyme borreliosis and pregnancy outcome. Int J Infect Dis 2010;14(6):e494-e498. 3. Strobino BA, Williams CL, Abid S, Chalson R, Spierling P. Lyme disease and pregnancy outcome: a prospective study of two thousand prenatal patients. Am J Obstet Gynecol 1993;169:367-74. 4. Lee J, Wormser GP. Pharmacodynamics of doxycycline for chemoprophylaxis of Lyme disease: preliminary findings and possible implications for other antimicrobials. Int J Antimicrob Agents 2008;31:235-9. DOI: 10.1056/NEJMc1407264
n engl j med 371;7 nejm.org august 14, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF TENNESSEE - KNOXVILLE on September 15, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
