LETTERS COMMENTS AND RESPONSES
Annals of Internal Medicine 3. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Scott N, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005;41:1654-61. [PMID:
Factors Associated With Lack of Viral Suppression at Delivery TO THE EDITOR: Katz and colleagues (1) assessed the predic-
tors of detectable HIV viral load (VL) at delivery among treatment-naive women initiating highly active antiretroviral therapy (HAART) during pregnancy. One factor associated with lack of viral suppression at delivery was a high pretreatment VL, especially among women who initiated HAART in the third trimester (1). We compared these results— obtained in the Western hemisphere—with our experience in a resource-limited country (2) where even more treatment-naive women initiate HAART late during pregnancy, thus possibly accounting for high rates of detectable VL at delivery. From 2009 to 2012, we enrolled 802 HIV-positive pregnant women, of whom 471 (58.7%) initiated HAART for the first time during pregnancy. Among them, 187 (39.7%) started HAART in the third trimester. Viral load at HAART initiation was measured in 251 (53.3%) of these 471 treatment-naive women and was 10 000 copies/mL or greater in as many as 160 (63.7%). Up to 35.8% of these treatment-naive women (82 of 229 [data were missing for 242 women]) had a detectable VL at delivery. In a univariate analysis, we found that a pretreatment VL greater than 10 000 copies/mL (odds ratio, 4.3 [95% CI, 2.1 to 8.7]; P < 0.001) and HAART initiation in the third trimester of pregnancy (odds ratio, 2.4 [CI, 1.4 to 4.3]; P = 0.002) predicted a detectable VL at delivery. Although our analysis was not adjusted for confounders, such as type of HAART and adherence to treatment, these factors are unlikely to considerably reduce the number of women with a detectable VL at delivery when high rates of late HAART initiation and high pretreatment VL are considered. In addition, these impressive rates might also account for a high proportion of infants in resource-limited countries who are exposed to high VL for at least the first 6 months of pregnancy, thus increasing the risk for HIV during pregnancy and for death among HIV-exposed, uninfected children (3). We have to intervene earlier. Anna Calzi, MD Francesca Bisio, MD, PhD Daniele Roberto Giacobbe, MD Clinica Malattie Infettive, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Universita` di Genova Genova, Italy Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0178.
16267740]
IN RESPONSE: We agree with Dr. Calzi and colleagues that early delivery of HAART to pregnant women in low- and middle-income countries is an essential component in the prevention of mother-to-child transmission of HIV, which concurrently benefits maternal health. Sub-Saharan Africa in particular needs to remain the focus of this effort, given that 92% of pregnant women living with HIV reside in this region (1). The expansion of HAART in sub-Saharan Africa, as supported by such programs as the President's Emergency Fund for AIDS Relief in conjunction with partner nations, has achieved impressive gains in expanding treatment availability and preventing mother-to-child transmission (2). Nevertheless, countries with a high prevalence of HIV, such as South Africa, had 40 000 new HIV pediatric infections in 2010 (3). For HIV-infected women who do not present early during pregnancy, we support the incorporation of newer antiretroviral agents that rapidly decrease VL into HAART regimens. Research in low- and middle-income countries is essential, and we are pleased to read Dr. Calzi and colleagues' comments. Of note, the high rates of detectable VL shown in Dr. Bisio and colleagues' study (4) need to be interpreted with caution, because VL was not measured in approximately one half of the women in the study (it was measured in 47% at HAART initiation and 51% at delivery). If women perceived to be at higher risk were more likely to have VL measured, the estimated rates of detectable VL at HAART initiation and delivery may be higher than those in the whole study population. No analyses were presented to assess the effect of missing VL data on the conclusions. In contrast, in our article, the pre-HAART VL was missing in 29%, and, by design, all of the women included had a VL at delivery. We did multiple imputation analyses to assess the effect of missing pre-HAART VL data on our results. Ultimately, we hope that ongoing research in this area can inform future clinical and programmatic efforts to eliminate transmission of HIV to newborns and provide mothers with a healthy and safe pregnancy.
Ingrid T. Katz, MD, MHS Brigham and Women's Hospital, Massachusetts General Hospital Center for Global Health, and Harvard Medical School Boston, Massachusetts David E. Shapiro, PhD Harvard School of Public Health Boston, Massachusetts
References 1. Katz IT, Leister E, Kacanek D, Hughes MD, Bardeguez A, Livingston E, et al. Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study. Ann Intern Med. 2015;162:90-9. [PMID: 25599347] doi:10.7326/M13-2005 2. Bisio F, Masini G, Blasi Vacca E, Calzi A, Cardinale F, Bruzzone B, et al; Kento-Mwana group. Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo. J Antimicrob Chemother. 2013;68:1862-71. [PMID: 23587655] doi:10.1093/jac/dkt102
Ruth Tuomala, MD Brigham and Women's Hospital and Massachusetts General Hospital Center for Global Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M13-2005.
874 © 2015 American College of Physicians
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LETTERS References 1. UNAIDS. Regional fact sheet 2012: sub-Saharan Africa. 2012. Accessed at www.unaids.org/sites/default/files/en/media/unaids/contentassets /documents/epidemiology/2012/gr2012/2012_FS_regional_ssa_en.pdf on 23 March 2015. 2. Katz IT, Bassett IV, Wright AA. PEPFAR in transition—implications for HIV care in South Africa. N Engl J Med. 2013;369:1385-7. [PMID: 24106930] doi:10 .1056/NEJMp1310982 3. Black S, Zulliger R, Myer L, Marcus R, Jeneker S, Taliep R, et al. Safety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Afr Med J. 2013;103:557-62. [PMID: 23885739] doi:10.7196/samj.6565 4. Bisio F, Masini G, Blasi Vacca E, Calzi A, Cardinale F, Bruzzone B, et al; Kento-Mwana group. Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo. J Antimicrob Chemother. 2013;68:1862-71. [PMID: 23587655] doi:10.1093/jac/dkt102
Sedentary Time and Risk for Mortality TO THE EDITOR: Biswas and colleagues (1) did a metaanalysis of observational studies to examine the association between sedentary time and various health outcomes. Their analysis suggested that sedentary time was associated with an increased risk for all-cause mortality but was substantially heterogeneous (I2 = 94.96%). We wonder whether further sensitivity analyses are needed to elucidate the cause of this heterogeneity. First, sample sizes varied across studies, ranging from 217 to 240 819. A forest plot suggested that 5 of the 7 studies with fewer than 10 000 participants presented more exaggerated point estimates of hazard ratios than the remaining 8 studies. In clinical trials in medicine, large treatment effects are known to be derived from small trials (2). Likewise, smaller observational studies could be hypothesized to present larger hazard ratios than larger studies. An analysis examining the association between sample size and all-cause mortality might therefore be intriguing. Second, many studies included in the analysis of all-cause mortality were susceptible to attrition bias. Among the 13 studies, the completeness of 1 was unclear, and long-term completeness of 6 studies was less than 80%. A sensitivity analysis excluding studies at risk for attrition bias should be considered. Third, the selection criteria of participants included in the meta-analysis were somewhat unclear. For example, participants included from 1 study sat for 11 hours per day or greater (3), whereas those from another study sat for 9 hours per day or greater (4). Biswas and colleagues admitted that operational definitions and cutoffs were applied during the categorization of sedentary time. If so, analysis using different cutoffs of calculated energy expenditures or sedentary time might identify populations at higher risk for mortality. Finally, how the authors extracted the information from certain populations is unclear. All participants from a study seemed to be included in the analysis, whereas Biswas and colleagues quoted the number of deaths from the subgroup of sedentary time of 11 hours per day or greater from the same study (5). Clarification of this inconsistency is needed. The studies included in this systematic review were heterogeneous in terms of participant age. Every life stage has its www.annals.org
own societal role and lifestyle. Future research should define target generations or life stages to clarify who could benefit in the long run from not being sedentary. Seigo Urushidani, MD Akira Kuriyama, MD, MPH Kurashiki Central Hospital Kurashiki, Japan Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0180. References 1. Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med. 2015;162:123-32. [PMID: 25599350] doi:10.7326/M14-1651 2. Pereira TV, Horwitz RI, Ioannidis JP. Empirical evaluation of very large treatment effects of medical interventions. JAMA. 2012;308:1676-84. [PMID: 23093165] doi:10.1001/jama.2012.13444 3. Seguin R, Buchner DM, Liu J, Allison M, Manini T, Wang CY, et al. Sedentary behavior and mortality in older women: the Women's Health Initiative. Am J Prev Med. 2014;46:122-35. [PMID: 24439345] doi:10.1016/j.amepre.2013.10 .021 4. Matthews CE, George SM, Moore SC, Bowles HR, Blair A, Park Y, et al. Amount of time spent in sedentary behaviors and cause-specific mortality in US adults. Am J Clin Nutr. 2012;95:437-45. [PMID: 22218159] doi:10.3945/ ajcn.111.019620 5. van der Ploeg HP, Chey T, Korda RJ, Banks E, Bauman A. Sitting time and all-cause mortality risk in 222 497 Australian adults. Arch Intern Med. 2012; 172:494-500. [PMID: 22450936] doi:10.1001/archinternmed.2011.2174
IN RESPONSE: We acknowledge the concerns of Drs. Urushi-
dani and Kuriyama about our study's heterogeneity. Indeed, we focused much of our Discussion section to factors that may have contributed to heterogeneity. First, we agree that smaller sample sizes of 2 studies (1, 2) may exaggerate point estimates. Nonetheless, most studies based on large cohorts (all but 2 studies that we included were based on >500 participants) show a consistent positive association; as such, the precision of effect size should not change sufficiently to merit further examination. Second, excluding studies at risk for attrition bias may be helpful, but conclusions could be misleading because of the potential variability of follow-up times. This variation may unfairly penalize studies with lower completeness but longer follow-up over studies with higher completeness but shorter follow-up. Third, we agree about the need for a more standardized approach to quantifying sedentary times. We ensured that our findings were comparable by prioritizing the longest reported sitting time; if this was not reported directly, we selected the most comparable measure (such as the longest screen time). We resisted standardizing sedentary cutoffs, because the variability may result in misleading conclusions. For example, a question asking about the “time spent sitting while doing things, such as visiting friends . . . ” (2) may elicit a different response from one asking, “About how many hours in each 24-hour day do you usually spend sitting?” (3). Finally, we would like to address inconsistencies in extracting information from a study (3). Although we reported Annals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 875
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LETTERS deaths from all-cause mortality for sedentary time of 11 hours per day or greater, these findings were based on the combined total for men and women, that is, 649 deaths per 222 497 participants. Information was extracted from the total population of men and women across all studies, and we combined results when they were presented separately for men and women. Heterogeneity remains 1 of many important limitations. Additional analyses, although intriguing, will likely not address the many unanswered questions that remain. Instead, we hope that our meta-analysis serves as an impetus for future research. Aviroop Biswas, BSc Institute of Health Policy, Management and Evaluation, University of Toronto Toronto, Ontario, Canada
Increasingly more European guidelines consider acute sore throat a self-limiting disease (2). Antibiotics are prescribed immediately only when the patient has risk factors, decreased immunocompetence, or extreme illness (approximately 5% of cases). When the patient does not improve within 2 or 3 days, the physical examination must be repeated to exclude peritonsillar abscess and even the Lemierre syndrome. With this article, Centor and colleagues help clinicians consider the possibility of the feared Lemierre syndrome during scientific medical decision making. Jan Matthys, MD Marc De Meyere, MD An De Sutter, MD University Hospital Gent Gent, Belgium Disclosures: Authors have disclosed no conflicts of interest. Forms
David A. Alter, MD, PhD Institute for Clinical Evaluative Sciences Toronto, Ontario, Canada
can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0188.
Disclosures: Authors have disclosed no conflicts of interest. Forms
1. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med. 2015;162:241-7. [PMID: 25686164] doi:10.7326/M14-1305 2. Matthys J, De Meyere M, van Driel ML, De Sutter A. Differences among international pharyngitis guidelines: not just academic. Ann Fam Med. 2007; 5:436-43. [PMID: 17893386] 3. Linder JA. Sore throat: avoid overcomplicating the uncomplicated [Editorial]. Ann Intern Med. 2015;162:311-2. [PMID: 25686170] doi:10.7326/M14 -2899 4. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014;174:138-40. [PMID: 24091806] doi:10.1001/jamainternmed.2013.11673
References can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-1651. References 1. George ES, Rosenkranz RR, Kolt GS. Chronic disease and sitting time in middle-aged Australian males: findings from the 45 and Up Study. Int J Behav Nutr Phys Act. 2013;10:20. [PMID: 23394382] doi:10.1186/1479-5868-10-20 2. Pavey TG, Peeters GG, Brown WJ. Sitting-time and 9-year all-cause mortality in older women. Br J Sports Med. 2015;49:95-9. [PMID: 23243009] doi:10 .1136/bjsports-2012-091676 3. van der Ploeg HP, Chey T, Korda RJ, Banks E, Bauman A. Sitting time and all-cause mortality risk in 222 497 Australian adults. Arch Intern Med. 2012; 172:494-500. [PMID: 22450936] doi:10.1001/archinternmed.2011.2174
Fusobacterium-Positive and Streptococcal-Positive Pharyngitis TO THE EDITOR: We thank Centor and colleagues (1) for their interesting and important new data on causes of pharyngitis. As authors of the Belgian guideline on acute sore throat (2), we agree with Linder's editorial (3), which argues that these new findings on Fusobacterium necrophorum do not necessitate reconsideration in U.S. guidelines. Centor and colleagues' proposition implies more testing and more antibiotics but is not evidence-based. Even a positive culture for F. necrophorum is not definitive proof of infection, and arguments are lacking that treating infection with this organism with antibiotics decreases symptoms or prevents the Lemierre syndrome (3). We know that a positive culture for group A -hemolytic streptococcus is not definitive evidence of infection but may indicate carriership; this may also be true for a positive culture for F. necrophorum. We join Linder in noting the slow decrease in antibiotic prescribing for pharyngitis. However, more encouraging is the decrease in sore throat visits in the United States from 7.5% of primary care visits in 1997 to 4.3% in 2010 (4) without, to our knowledge, arise in (severe) complications.
TO THE EDITOR: We developed a real-time polymerase chain reaction (PCR) assay to detect F. necrophorum in throat swabs; assay evaluation yielded findings that support and expand those of Centor and colleagues (1). Between November 2010 and January 2011, a total of 239 swabs submitted for Streptococcus pyogenes PCR testing (2) was evaluated for F. necrophorum using culture and PCR targeting the phosphotransferase system I gene using fluorescence resonance energy transfer hybridization probes. For PCR, swabs were cut into 50 μL of 0.1-mm glass beads and 600 μL of Tris buffer solution and processed using an Eppendorf ThermoMixer (Eppendorf AG) for 6 minutes at 95 °C at 1400 revolutions per minute. For culture, 5 mL of fastidious anaerobe broth with 1 μg/mL of norfloxacin, 4 μg/mL of vancomycin, and 3 μg/mL of josamycin were added to swab pledgets, which were then incubated anaerobically at 37 °C for 2 days and subcultured to fastidious anaerobe agar plates with the same supplementation. Colonies consistent with F. necrophorum were identified by PCR and sequencing of a portion of the 16S ribosomal RNA gene. Nine (4%) and 84 (35%) swabs were PCR-positive for F. necrophorum and S. pyogenes, respectively. Culture confirmed 8 of 9 specimens with PCR-positive results for F. necrophorum. No culture-positive, PCR-negative results for F. necrophorum were observed. Patients with F. necrophorum
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LETTERS detected were aged 15 to 51 years (average age, 28 years), whereas those with S. pyogenes were aged 2 to 72 years, with 64% aged 2 to 15 years. One participant was positive for both. Among participants aged 0 to 14 years, 15 to 30 years, and 31 to 77 years, 0 of 123 (0%), 4 of 42 (10%), and 4 of 73 (5%), respectively, were positive for F. necrophorum. We tested throat swabs from 106 asymptomatic volunteers (Mayo Clinic employees) using F. necrophorum PCR and culture. Four (4%) were PCR-positive, of which 1 was culture-positive. Polymerase chain reaction testing can detect F. necrophorum in throat swabs faster than culture (1). As with S. pyogenes, asymptomatic persons may have positive results. Fusobacterium necrophorum was detected in a percentage of adolescents and young adults with presumed pharyngitis similar to that previously reported (3). We believe that a placebocontrolled evaluation of antibiotic treatment should be considered in adolescents and young adults with pharyngitis in whom F. necrophorum is detected to determine whether treatment affects duration and severity of symptoms, likelihood of progression to the Lemierre syndrome, or peritonsillar abscess and contagiousness. The antimicrobial agent that should be evaluated is debatable. Between November 2011 and December 2014, susceptibility testing on 30 F. necrophorum isolates showed that 74% were susceptible to penicillin (minimum inhibitory concentration ≤0.5 μg/mL), whereas all were susceptible to metronidazole and clindamycin (≤8 and ≤2 μg/mL, respectively). Our data, derived from a Minnesota population, add to the evidence suggesting that F. necrophorum may cause pharyngitis (4, 5). Seasonality, why this organism is primarily found in adolescents and young adults, and whether treatment is indicated are unknown. James R. Uhl, MS Daniel R. Gustafson, BS Stefanea L. Rucinski, MT (ASCP) Robin Patel, MD Mayo Clinic Rochester, Minnesota Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L15-0189.
References 1. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med. 2015;162:241-7. [PMID: 25686164] doi:10.7326/M14-1305 2. Uhl JR, Adamson SC, Vetter EA, Schleck CD, Harmsen WS, Iverson LK, et al. Comparison of LightCycler PCR, rapid antigen immunoassay, and culture for detection of group A streptococci from throat swabs. J Clin Microbiol. 2003; 41:242-9. [PMID: 12517855] 3. Eaton C, Swindells J. The significance and epidemiology of Fusobacterium necrophorum in sore throats [Letter]. J Infect. 2014;69:194-6. [PMID: 24642207] doi:10.1016/j.jinf.2014.03.005 4. Hedin K, Bieber L, Lindh M, Sundqvist M. The aetiology of pharyngotonsillitis in adolescents and adults—Fusobacterium necrophorum is commonly found. Clin Microbiol Infect. 2015;21:263.e1-7. [PMID: 25658556] doi:10.1016/j.cmi .2014.08.020 5. Jensen A, Hansen TM, Bank S, Kristensen LH, Prag J. Fusobacterium necrophorum tonsillitis: an important cause of tonsillitis in adolescents and www.annals.org
young adults. Clin Microbiol Infect. 2015;21:266.e1-3. [PMID: 25658551] doi:10.1016/j.cmi.2014.09.020
IN RESPONSE: We thank Dr. Matthys and colleagues for their comment. We do believe that F. necrophorum causes adolescent and young adult pharyngitis and deserves antibiotic treatment. Although the evidence is circumstantial, we believe that antibiotics would be prudent. The Lemierre syndrome is a devastating disease that has an estimated death rate of 5% with clinically significant short- and long-term morbidity (1). Chirinos and associates (2) reported that F. necrophorum causes approximately 80% of cases of the Lemierre syndrome. In most patients, it develops a few days after sore throat. We have strong evidence that F. necrophorum causes pharyngitis. Several European studies showed an association between this organism and pharyngitis. We reported a summary of 6 patients who had pharyngitis and F. necrophorum bacteremia but not internal jugular thrombophlebitis (3). Our article shows that, as the Centor score increased, so did the probability of a positive PCR result for F. necrophorum. Although we cannot prove that F. necrophorum pharyngitis precedes the Lemierre syndrome, the circumstantial evidence makes it seem very likely. Similarly, we cannot prove that treating F. necrophorum pharyngitis with appropriate antibiotics would decrease the probability of the Lemierre syndrome, but the biological plausibility seems high. Because we estimate that 1 in 400 cases of F. necrophorum pharyngitis result in the Lemierre syndrome (1), a randomized, controlled trial would require more than 10 000 patients to prove that we can prevent the Lemierre syndrome. In such a trial, approximately 12 or 13 patients would develop the Lemierre syndrome. We believe that one could legitimately question the ethics of this proposed trial. Does this circumstance mean that we would need to treat many patients with antibiotics? We reiterate that this bacterium rarely causes pharyngitis in preadolescents, and Mr. Uhl and coworkers' comment confirms this finding. We hope to have a rapid test in the future but in the meantime would favor empirical treatment of 50% of cases of adolescent and young adult pharyngitis, because we believe that the Lemierre syndrome deserves prevention. We agree with Mr. Uhl and coworkers that we should collect more epidemiologic data on F. necrophorum in adolescent and young adult patients with pharyngitis. We do not favor a randomized, controlled trial, because the Lemierre syndrome often presents with devastating metastatic infections.
Robert M. Centor, MD T. Prescott Atkinson, MD, PhD Ken B. Waites, MD University of Alabama at Birmingham Birmingham, Alabama Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-1305. References 1. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi:10 .7326/0003-4819-151-11-200912010-00011 Annals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 877
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LETTERS 2. Chirinos JA, Lichtstein DM, Garcia J, Tamariz LJ. The evolution of Lemierre syndrome: report of 2 cases and review of the literature. Medicine (Baltimore). 2002;81:458-65. [PMID: 12441902] 3. Centor RM, Geiger P, Waites KB. Fusobacterium necrophorum bacteremic tonsillitis: 2 cases and a review of the literature. Anaerobe. 2010;16:626-8. [PMID: 20813196] doi:10.1016/j.anaerobe.2010.08.005
Sore Throat: Avoid Overcomplicating the Uncomplicated TO THE EDITOR: Linder (1) discounts the possibility that Fusobacterium necrophorum causes pharyngitis and proposes that, even if it does, we should not assume that treating this condition would prevent suppurative complications (especially the Lemierre syndrome). He argues that we should stick to a simple strategy of using the Centor score to reassure some patients (those with scores of 0 or 1) and use a rapid streptococcus test for the remaining patients, treating only those with positive rapid test results. He asserts that we should not complicate the diagnosis and treatment decisions. We strongly disagree. Although preadolescent sore throat is relatively straightforward and the prevalence of F. necrophorum in these younger patients is clearly lower, the bacterial pathogenesis of adolescent and young adult pharyngitis is more complex. The highest-probability differential diagnosis in this age group includes group A -hemolytic streptococcus (Streptococcus pyogenes), group C or G -hemolytic streptococcus (Streptococcus dysgalactiae subsp equisimilis), infectious mononucleosis, acute HIV infection, and now F. necrophorum. Linder's recommendation is dangerous because it can lead to diagnostic errors through the anchoring bias. If our decision structure is binary (group A streptococcus or not), then we are at risk for missing a more serious infection. Our data suggest that the Centor criteria define a symptom complex for acute bacterial pharyngitis, with group A streptococcal infection being only 1 cause. The current empirical treatment algorithm based on the Centor criteria includes macrolides for patients with a history of penicillin allergy, and this class of antibiotics does not cover F. necrophorum. Treating Fusobacterium pharyngitis has a strong possibility of decreasing the likelihood of progression to the Lemierre syndrome. Although we cannot prove this assumption, its biological plausibility strongly supports this hypothesis. We have much evidence that F. necrophorum causes the pharyngitis. Several case reports have documented pharyngitis with Fusobacterium bacteremia (2). Our study (3) strongly supports the idea that F. necrophorum causes pharyngitis. As the Centor score increased, so did the probability of a positive polymerase chain reaction result for F. necrophorum. Although this finding does not absolutely prove that F. necrophorum causes pharyngitis, one has to develop a rather convoluted explanation to assert otherwise. Our concern about this topic relates to the devastation that the Lemierre syndrome causes. Having communicated with many survivors and the families of some patients who died of this condition, we feel passionately that the best approach to the Lemierre syndrome (like many other diseases) is prevention. As one of us pointed out several years ago, the incidence of the Lemierre syndrome developing after a sore
throat now exceeds that of rheumatic fever in the United States and Europe (4). The argument against treating patients with Fusobacterium pharyngitis centers on the lack of proof. The absence of a diagnostic test at present for F. necrophorum does not negate the need to adjust the recommendations for empirical, criteria-based therapy predicated on the latest epidemiologic evidence. In the absence of definitive proof, we favor treating patients with a substantial probability of F. necrophorum pharyngitis with targeted antibiotics in the hope that we may prevent some patients from developing this devastating complication. Robert M. Centor, MD T. Prescott Atkinson, MD Carlos Estrada, MD Ken B. Waites, MD University of Alabama at Birmingham Birmingham, Alabama Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0186.
References 1. Linder JA. Sore throat: avoid overcomplicating the uncomplicated [Editorial]. Ann Intern Med. 2015;162:311-2. [PMID: 25686170] doi:10.7326/M14 -2899 2. Centor RM, Geiger P, Waites KB. Fusobacterium necrophorum bacteremic tonsillitis: 2 cases and a review of the literature. Anaerobe. 2010;16:626-8. [PMID: 20813196] doi:10.1016/j.anaerobe.2010.08.005 3. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med. 2015;162:241-7. [PMID: 25686164] doi:10.7326/M14-1305 4. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi: 10.7326/0003-4819-151-11-200912010-00011
IN RESPONSE: I agree with Dr. Centor about quite a lot in the
management of patients with sore throat. In developed countries, rheumatic fever is a minor concern. Patients with Centor scores of 0 or 1 can be safely reassured. Those diagnosed with bacterial pharyngitis should be treated with penicillin. Physicians should not be overly anchored to guidelines if their patients are not doing well. The Lemierre syndrome can be devastating. However, we have legitimate disagreements. Dr. Centor's arguments recall other examples of injudicious antibiotic use. The use of empirical penicillin to prevent the Lemierre syndrome is reminiscent of the discredited practice of antibiotic prophylaxis for patients with heart murmurs to prevent infective endocarditis. Even if Fusobacterium pharyngitis were clearly linked to the Lemierre syndrome, only a tiny fraction of patients with Fusobacterium pharyngitis will develop the Lemierre syndrome. Dr. Centor has estimated it to be 1 in 400 (1), but the rate could be much, much lower (2). There is no evidence that antibiotics prevent the Lemierre syndrome. Pharyngeal detection of F. necrophorum is reminiscent of the detection and unnecessary treatment of group A streptococcus carriers. Point-of-care testing for group A streptococcus does not differentiate between true infection and car-
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LETTERS riage. Similarly, a “convoluted explanation” is not required to show that F. necrophorum does not necessarily cause pharyngitis; this organism is a normal part of the oropharyngeal flora (Dr. Centor and colleagues detected F. necrophorum in 9% of asymptomatic young adults). During viral infection, F. necrophorum overgrows and becomes more easily detected. Detection is not infection. Finally, “F. necrophorum fear” is reminiscent of antibiotic prescribing for “bacterial acute bronchitis.” There is no evidence that antibiotics substantively alter the course of acute bronchitis, but physicians prescribe these agents to 70% of adults with acute bronchitis (3). Similarly, raising the specter of F. necrophorum encourages antibiotic use at a time when physicians already prescribe antibiotics to approximately 60% of young adults with pharyngitis (4). These areas of disagreement can be addressed with new evidence. Studies can and should examine whether F. necrophorum causes a meaningful proportion of pharyngeal infections and whether antibiotic treatment of F. necrophorum–associated sore throat decreases symptoms and prevents complications. Present evidence points to widespread overprescribing of antibiotics. Jeffrey A. Linder, MD, MPH Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-2899. References 1. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi: 10.7326/0003-4819-151-11-200912010-00011 2. Petersen I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC. Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database. BMJ. 2007;335:982. [PMID: 17947744] 3. Barnett ML, Linder JA. Antibiotic prescribing for adults with acute bronchitis in the United States, 1996-2010. JAMA. 2014;311:2020-2. [PMID: 24846041] doi:10.1001/jama.2013.286141 4. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014;174:138-40. [PMID: 24091806] doi:10.1001/jamainternmed.2013.11673
OBSERVATION Hemorrhagic Stroke Probably Caused by Exercise Combined With a Sports Supplement Containing -Methylphenylethylamine (BMPEA): A Case Report Background: The U.S. Food and Drug Administration has warned consumers that an isomer of amphetamine, -methylphenylethylamine (BMPEA), is found in many sports supplements (1). The health effects of this chemical in humans are unknown (2, 3). Objective: To report a case of hemorrhagic stroke probably caused by exercise combined with BMPEA. Case Report: A 53-year-old woman presented with 1 day of numbness and clumsiness in her left hand. She reported www.annals.org
Figure. Computed tomography scan of the head.
Scan was obtained the day after onset of left arm numbness and clumsiness and shows a right parietal intracerebral hemorrhage.
the sudden onset of symptoms 45 minutes after beginning a vigorous exercise routine that she had repeated several times weekly for a few years. On examination, she was afebrile, blood pressure was 163/58 mm Hg, and heart rate was regular at 90 beats/min. She was alert with normal mental status. She had a subtle left pronator drift, but no definite weakness or dyscoordination in the limbs. She had hypesthesia involving the left upper arm, forearm, and hand. Reflexes were normal without a Babinski sign; gait was normal. The patient had no important medical history and did not receive any medications. However, she reported having consumed the recommended dose (13 g) of a sports supplement (Jacked Power, MM Sports) 30 minutes before beginning exercise. She had not consumed this or any similar sports supplement previously. She was physically active and had always been of normal weight with low blood pressure. She quit smoking 22 years ago, drank alcohol occasionally, and did not use illicit drugs. She had no family history of stroke or coagulation disorders. Laboratory results included levels of total cholesterol of 4.6 mmol/L (180 mg/dL), triglycerides of 1.0 mmol/L (89 mg/ dL), high-density lipoprotein cholesterol of 2.1 mmol/L (81 mg/dL), low-density lipoprotein cholesterol of 2.3 mmol/L (90 mg/dL), glucose of 5.3 mmol/L (95 mg/dL), and hemoglobin of 137 g/L; leukocyte count of 5.3 × 109 cells/L; platelet count of 250 × 109 cells/L; international normalized ratio of 1.2; and partial thromboplastin time of 31 s. An electrocardiogram was normal. Computed tomography of the head showed a 2-cm hemorrhage in the right parietal lobe (Figure). Magnetic resonance imaging of the brain revealed the hemorrhage with no underlying abnormalities. Cerebral angiography showed no evidence of vasculitis, aneurysm, or other vascular malforAnnals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 879
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LETTERS mation. Blood pressure normalized after admission and remained normal. She was discharged after 5 days with minor residual sensory symptoms. Neither BMPEA nor Acacia rigidula was listed on the supplement label. After the initial report was published in Swedish (4), we analyzed the patient's Jacked Power supplement at the Netherlands' National Institute for Public Health and the Environment (RIVM) using ultraperformance liquid chromatography– quadrupole/time-of-flight mass spectrometry (Acquity UltraPerformance LC SYNAPT G2 QTOF, Waters). We performed a general screening for pharmaceuticals and drugs. -Methylphenylethylamine was the only unlabeled pharmaceutical or drug found and was confirmed at 290 mg per dose using standard addition experiments with BMPEA (Sigma-Aldrich) and amphetamine (Merck) as reference standards. Discussion: Exercise combined with BMPEA, an isomer of amphetamine, probably caused this patient's stroke. Case reports are available of exercise-induced hemorrhagic stroke in otherwise healthy patients, and amphetamine has also been identified as a cause of hemorrhagic strokes in many case reports. However, the health effects of amphetamine's -isomer, BMPEA, are unknown. This isomer was first synthesized in the 1930s as a potential replacement for amphetamine (␣-methylphenethylamine) (3). In the 1930s and 1940s, researchers found that BMPEA increased blood pressure and heart rate in cats and dogs (3). However, to our knowledge, its physiologic effects in humans have not been studied (2, 3). We categorize causality as “probable/likely,” which the World Health Organization's Adverse Reaction Terminology defines as “A clinical event . . . with a reasonable time relation to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals and which follows a clinically reasonable response on withdrawal” (5). -Methylphenylethylamine is available in more than a dozen brands of supplements marketed to improve athletic performance and weight loss (1–3). To our knowledge, this is the first identified case of a hemorrhagic stroke probably caused by exercise combined with BMPEA. It was reported to the appropriate European authorities and on 4 April 2015 to the U.S. Food and Drug Administration. Physicians in the United States should report all suspected serious adverse events from dietary supplements to the U.S. Food and Drug Administration at www.safetyreporting.hhs.gov. In Europe, physicians should report these events to the appropriate national authority. Pieter A. Cohen, MD Harvard Medical School Boston, Massachusetts
Peter H.J. Keizers, PhD Bastiaan Venhuis, PhD National Institute for Public Health and the Environment (RIVM) Bilthoven, the Netherlands Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0106. This article was published online first at www.annals.org on 12 May 2015. References 1. U.S. Food and Drug Administration. BMPEA in dietary supplements. 24 April 2015. Accessed at www.fda.gov/food/dietarysupplements/qadietary supplements/ucm443790.htm on 28 April 2015. 2. Pawar RS, Grundel E, Fardin-Kia AR, Rader JI. Determination of selected biogenic amines in Acacia rigidula plant materials and dietary supplements using LC-MS/MS methods. J Pharm Biomed Anal. 2014;88:457-66. [PMID: 24176750] doi:10.1016/j.jpba.2013.09.012 3. Cohen PA, Bloszies C, Yee C, Gerona R. An amphetamine isomer whose efficacy and safety in humans has never been studied, -methylphenylethylamine (BMPEA), is found in multiple dietary supplements. Drug Test Anal. 2015. [PMID: 25847603] doi:10.1002/dta.1793 4. Zeijlon R, Andersson B. Hja¨rnblo¨dning efter intag av prestationsho¨jaren “Jacked Power.” Frisk kvinna insjuknade under tra¨ning efter en enda dos. La¨kartidningen. 2014;111:1782-4. [PMID: 25699325] 5. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356:1255-9. [PMID: 11072960]
CORRECTIONS Correction: Electronic Nicotine Delivery Systems The middle initial of an author of a recent policy paper (1) was incorrect. Dr. Lohr's middle initial is “H,” not “M.” This has been corrected in the online version. Reference 1. Crowley RA, for the Health Public Policy Committee of the American College of Physicians. Electronic nicotine delivery systems: executive summary of a policy position paper from the American College of Physicians. Ann Intern Med. 2015;162:583-4. [PMID: 25894027] doi:10.7326/M14-2481
Correction: Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma In Figure 2 of a recent article (1), the bottom of the right side of the forest plot is the true negative total, not the true positive total.
Rickard Zeijlon, MD Sahlgrenska University Hospital Gothenburg, Sweden
Reference
Rachel Nardin, MD Harvard Medical School Boston, Massachusetts
1. Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A, et al. Imaging techniques for the diagnosis of hepatocellular carcinoma. A systematic review and meta-analysis. Ann Intern Med. 2015;162:697-711. [PMID: 25984845] doi: 10.7326/M14-2509
This has been corrected in the online version.
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Annals of Internal Medicine 3. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Scott N, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005;41:1654-61. [PMID:
Factors Associated With Lack of Viral Suppression at Delivery TO THE EDITOR: Katz and colleagues (1) assessed the predic-
tors of detectable HIV viral load (VL) at delivery among treatment-naive women initiating highly active antiretroviral therapy (HAART) during pregnancy. One factor associated with lack of viral suppression at delivery was a high pretreatment VL, especially among women who initiated HAART in the third trimester (1). We compared these results— obtained in the Western hemisphere—with our experience in a resource-limited country (2) where even more treatment-naive women initiate HAART late during pregnancy, thus possibly accounting for high rates of detectable VL at delivery. From 2009 to 2012, we enrolled 802 HIV-positive pregnant women, of whom 471 (58.7%) initiated HAART for the first time during pregnancy. Among them, 187 (39.7%) started HAART in the third trimester. Viral load at HAART initiation was measured in 251 (53.3%) of these 471 treatment-naive women and was 10 000 copies/mL or greater in as many as 160 (63.7%). Up to 35.8% of these treatment-naive women (82 of 229 [data were missing for 242 women]) had a detectable VL at delivery. In a univariate analysis, we found that a pretreatment VL greater than 10 000 copies/mL (odds ratio, 4.3 [95% CI, 2.1 to 8.7]; P < 0.001) and HAART initiation in the third trimester of pregnancy (odds ratio, 2.4 [CI, 1.4 to 4.3]; P = 0.002) predicted a detectable VL at delivery. Although our analysis was not adjusted for confounders, such as type of HAART and adherence to treatment, these factors are unlikely to considerably reduce the number of women with a detectable VL at delivery when high rates of late HAART initiation and high pretreatment VL are considered. In addition, these impressive rates might also account for a high proportion of infants in resource-limited countries who are exposed to high VL for at least the first 6 months of pregnancy, thus increasing the risk for HIV during pregnancy and for death among HIV-exposed, uninfected children (3). We have to intervene earlier. Anna Calzi, MD Francesca Bisio, MD, PhD Daniele Roberto Giacobbe, MD Clinica Malattie Infettive, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Universita` di Genova Genova, Italy Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0178.
16267740]
IN RESPONSE: We agree with Dr. Calzi and colleagues that early delivery of HAART to pregnant women in low- and middle-income countries is an essential component in the prevention of mother-to-child transmission of HIV, which concurrently benefits maternal health. Sub-Saharan Africa in particular needs to remain the focus of this effort, given that 92% of pregnant women living with HIV reside in this region (1). The expansion of HAART in sub-Saharan Africa, as supported by such programs as the President's Emergency Fund for AIDS Relief in conjunction with partner nations, has achieved impressive gains in expanding treatment availability and preventing mother-to-child transmission (2). Nevertheless, countries with a high prevalence of HIV, such as South Africa, had 40 000 new HIV pediatric infections in 2010 (3). For HIV-infected women who do not present early during pregnancy, we support the incorporation of newer antiretroviral agents that rapidly decrease VL into HAART regimens. Research in low- and middle-income countries is essential, and we are pleased to read Dr. Calzi and colleagues' comments. Of note, the high rates of detectable VL shown in Dr. Bisio and colleagues' study (4) need to be interpreted with caution, because VL was not measured in approximately one half of the women in the study (it was measured in 47% at HAART initiation and 51% at delivery). If women perceived to be at higher risk were more likely to have VL measured, the estimated rates of detectable VL at HAART initiation and delivery may be higher than those in the whole study population. No analyses were presented to assess the effect of missing VL data on the conclusions. In contrast, in our article, the pre-HAART VL was missing in 29%, and, by design, all of the women included had a VL at delivery. We did multiple imputation analyses to assess the effect of missing pre-HAART VL data on our results. Ultimately, we hope that ongoing research in this area can inform future clinical and programmatic efforts to eliminate transmission of HIV to newborns and provide mothers with a healthy and safe pregnancy.
Ingrid T. Katz, MD, MHS Brigham and Women's Hospital, Massachusetts General Hospital Center for Global Health, and Harvard Medical School Boston, Massachusetts David E. Shapiro, PhD Harvard School of Public Health Boston, Massachusetts
References 1. Katz IT, Leister E, Kacanek D, Hughes MD, Bardeguez A, Livingston E, et al. Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study. Ann Intern Med. 2015;162:90-9. [PMID: 25599347] doi:10.7326/M13-2005 2. Bisio F, Masini G, Blasi Vacca E, Calzi A, Cardinale F, Bruzzone B, et al; Kento-Mwana group. Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo. J Antimicrob Chemother. 2013;68:1862-71. [PMID: 23587655] doi:10.1093/jac/dkt102
Ruth Tuomala, MD Brigham and Women's Hospital and Massachusetts General Hospital Center for Global Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M13-2005.
874 © 2015 American College of Physicians
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LETTERS References 1. UNAIDS. Regional fact sheet 2012: sub-Saharan Africa. 2012. Accessed at www.unaids.org/sites/default/files/en/media/unaids/contentassets /documents/epidemiology/2012/gr2012/2012_FS_regional_ssa_en.pdf on 23 March 2015. 2. Katz IT, Bassett IV, Wright AA. PEPFAR in transition—implications for HIV care in South Africa. N Engl J Med. 2013;369:1385-7. [PMID: 24106930] doi:10 .1056/NEJMp1310982 3. Black S, Zulliger R, Myer L, Marcus R, Jeneker S, Taliep R, et al. Safety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Afr Med J. 2013;103:557-62. [PMID: 23885739] doi:10.7196/samj.6565 4. Bisio F, Masini G, Blasi Vacca E, Calzi A, Cardinale F, Bruzzone B, et al; Kento-Mwana group. Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo. J Antimicrob Chemother. 2013;68:1862-71. [PMID: 23587655] doi:10.1093/jac/dkt102
Sedentary Time and Risk for Mortality TO THE EDITOR: Biswas and colleagues (1) did a metaanalysis of observational studies to examine the association between sedentary time and various health outcomes. Their analysis suggested that sedentary time was associated with an increased risk for all-cause mortality but was substantially heterogeneous (I2 = 94.96%). We wonder whether further sensitivity analyses are needed to elucidate the cause of this heterogeneity. First, sample sizes varied across studies, ranging from 217 to 240 819. A forest plot suggested that 5 of the 7 studies with fewer than 10 000 participants presented more exaggerated point estimates of hazard ratios than the remaining 8 studies. In clinical trials in medicine, large treatment effects are known to be derived from small trials (2). Likewise, smaller observational studies could be hypothesized to present larger hazard ratios than larger studies. An analysis examining the association between sample size and all-cause mortality might therefore be intriguing. Second, many studies included in the analysis of all-cause mortality were susceptible to attrition bias. Among the 13 studies, the completeness of 1 was unclear, and long-term completeness of 6 studies was less than 80%. A sensitivity analysis excluding studies at risk for attrition bias should be considered. Third, the selection criteria of participants included in the meta-analysis were somewhat unclear. For example, participants included from 1 study sat for 11 hours per day or greater (3), whereas those from another study sat for 9 hours per day or greater (4). Biswas and colleagues admitted that operational definitions and cutoffs were applied during the categorization of sedentary time. If so, analysis using different cutoffs of calculated energy expenditures or sedentary time might identify populations at higher risk for mortality. Finally, how the authors extracted the information from certain populations is unclear. All participants from a study seemed to be included in the analysis, whereas Biswas and colleagues quoted the number of deaths from the subgroup of sedentary time of 11 hours per day or greater from the same study (5). Clarification of this inconsistency is needed. The studies included in this systematic review were heterogeneous in terms of participant age. Every life stage has its www.annals.org
own societal role and lifestyle. Future research should define target generations or life stages to clarify who could benefit in the long run from not being sedentary. Seigo Urushidani, MD Akira Kuriyama, MD, MPH Kurashiki Central Hospital Kurashiki, Japan Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0180. References 1. Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med. 2015;162:123-32. [PMID: 25599350] doi:10.7326/M14-1651 2. Pereira TV, Horwitz RI, Ioannidis JP. Empirical evaluation of very large treatment effects of medical interventions. JAMA. 2012;308:1676-84. [PMID: 23093165] doi:10.1001/jama.2012.13444 3. Seguin R, Buchner DM, Liu J, Allison M, Manini T, Wang CY, et al. Sedentary behavior and mortality in older women: the Women's Health Initiative. Am J Prev Med. 2014;46:122-35. [PMID: 24439345] doi:10.1016/j.amepre.2013.10 .021 4. Matthews CE, George SM, Moore SC, Bowles HR, Blair A, Park Y, et al. Amount of time spent in sedentary behaviors and cause-specific mortality in US adults. Am J Clin Nutr. 2012;95:437-45. [PMID: 22218159] doi:10.3945/ ajcn.111.019620 5. van der Ploeg HP, Chey T, Korda RJ, Banks E, Bauman A. Sitting time and all-cause mortality risk in 222 497 Australian adults. Arch Intern Med. 2012; 172:494-500. [PMID: 22450936] doi:10.1001/archinternmed.2011.2174
IN RESPONSE: We acknowledge the concerns of Drs. Urushi-
dani and Kuriyama about our study's heterogeneity. Indeed, we focused much of our Discussion section to factors that may have contributed to heterogeneity. First, we agree that smaller sample sizes of 2 studies (1, 2) may exaggerate point estimates. Nonetheless, most studies based on large cohorts (all but 2 studies that we included were based on >500 participants) show a consistent positive association; as such, the precision of effect size should not change sufficiently to merit further examination. Second, excluding studies at risk for attrition bias may be helpful, but conclusions could be misleading because of the potential variability of follow-up times. This variation may unfairly penalize studies with lower completeness but longer follow-up over studies with higher completeness but shorter follow-up. Third, we agree about the need for a more standardized approach to quantifying sedentary times. We ensured that our findings were comparable by prioritizing the longest reported sitting time; if this was not reported directly, we selected the most comparable measure (such as the longest screen time). We resisted standardizing sedentary cutoffs, because the variability may result in misleading conclusions. For example, a question asking about the “time spent sitting while doing things, such as visiting friends . . . ” (2) may elicit a different response from one asking, “About how many hours in each 24-hour day do you usually spend sitting?” (3). Finally, we would like to address inconsistencies in extracting information from a study (3). Although we reported Annals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 875
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LETTERS deaths from all-cause mortality for sedentary time of 11 hours per day or greater, these findings were based on the combined total for men and women, that is, 649 deaths per 222 497 participants. Information was extracted from the total population of men and women across all studies, and we combined results when they were presented separately for men and women. Heterogeneity remains 1 of many important limitations. Additional analyses, although intriguing, will likely not address the many unanswered questions that remain. Instead, we hope that our meta-analysis serves as an impetus for future research. Aviroop Biswas, BSc Institute of Health Policy, Management and Evaluation, University of Toronto Toronto, Ontario, Canada
Increasingly more European guidelines consider acute sore throat a self-limiting disease (2). Antibiotics are prescribed immediately only when the patient has risk factors, decreased immunocompetence, or extreme illness (approximately 5% of cases). When the patient does not improve within 2 or 3 days, the physical examination must be repeated to exclude peritonsillar abscess and even the Lemierre syndrome. With this article, Centor and colleagues help clinicians consider the possibility of the feared Lemierre syndrome during scientific medical decision making. Jan Matthys, MD Marc De Meyere, MD An De Sutter, MD University Hospital Gent Gent, Belgium Disclosures: Authors have disclosed no conflicts of interest. Forms
David A. Alter, MD, PhD Institute for Clinical Evaluative Sciences Toronto, Ontario, Canada
can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0188.
Disclosures: Authors have disclosed no conflicts of interest. Forms
1. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med. 2015;162:241-7. [PMID: 25686164] doi:10.7326/M14-1305 2. Matthys J, De Meyere M, van Driel ML, De Sutter A. Differences among international pharyngitis guidelines: not just academic. Ann Fam Med. 2007; 5:436-43. [PMID: 17893386] 3. Linder JA. Sore throat: avoid overcomplicating the uncomplicated [Editorial]. Ann Intern Med. 2015;162:311-2. [PMID: 25686170] doi:10.7326/M14 -2899 4. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014;174:138-40. [PMID: 24091806] doi:10.1001/jamainternmed.2013.11673
References can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-1651. References 1. George ES, Rosenkranz RR, Kolt GS. Chronic disease and sitting time in middle-aged Australian males: findings from the 45 and Up Study. Int J Behav Nutr Phys Act. 2013;10:20. [PMID: 23394382] doi:10.1186/1479-5868-10-20 2. Pavey TG, Peeters GG, Brown WJ. Sitting-time and 9-year all-cause mortality in older women. Br J Sports Med. 2015;49:95-9. [PMID: 23243009] doi:10 .1136/bjsports-2012-091676 3. van der Ploeg HP, Chey T, Korda RJ, Banks E, Bauman A. Sitting time and all-cause mortality risk in 222 497 Australian adults. Arch Intern Med. 2012; 172:494-500. [PMID: 22450936] doi:10.1001/archinternmed.2011.2174
Fusobacterium-Positive and Streptococcal-Positive Pharyngitis TO THE EDITOR: We thank Centor and colleagues (1) for their interesting and important new data on causes of pharyngitis. As authors of the Belgian guideline on acute sore throat (2), we agree with Linder's editorial (3), which argues that these new findings on Fusobacterium necrophorum do not necessitate reconsideration in U.S. guidelines. Centor and colleagues' proposition implies more testing and more antibiotics but is not evidence-based. Even a positive culture for F. necrophorum is not definitive proof of infection, and arguments are lacking that treating infection with this organism with antibiotics decreases symptoms or prevents the Lemierre syndrome (3). We know that a positive culture for group A -hemolytic streptococcus is not definitive evidence of infection but may indicate carriership; this may also be true for a positive culture for F. necrophorum. We join Linder in noting the slow decrease in antibiotic prescribing for pharyngitis. However, more encouraging is the decrease in sore throat visits in the United States from 7.5% of primary care visits in 1997 to 4.3% in 2010 (4) without, to our knowledge, arise in (severe) complications.
TO THE EDITOR: We developed a real-time polymerase chain reaction (PCR) assay to detect F. necrophorum in throat swabs; assay evaluation yielded findings that support and expand those of Centor and colleagues (1). Between November 2010 and January 2011, a total of 239 swabs submitted for Streptococcus pyogenes PCR testing (2) was evaluated for F. necrophorum using culture and PCR targeting the phosphotransferase system I gene using fluorescence resonance energy transfer hybridization probes. For PCR, swabs were cut into 50 μL of 0.1-mm glass beads and 600 μL of Tris buffer solution and processed using an Eppendorf ThermoMixer (Eppendorf AG) for 6 minutes at 95 °C at 1400 revolutions per minute. For culture, 5 mL of fastidious anaerobe broth with 1 μg/mL of norfloxacin, 4 μg/mL of vancomycin, and 3 μg/mL of josamycin were added to swab pledgets, which were then incubated anaerobically at 37 °C for 2 days and subcultured to fastidious anaerobe agar plates with the same supplementation. Colonies consistent with F. necrophorum were identified by PCR and sequencing of a portion of the 16S ribosomal RNA gene. Nine (4%) and 84 (35%) swabs were PCR-positive for F. necrophorum and S. pyogenes, respectively. Culture confirmed 8 of 9 specimens with PCR-positive results for F. necrophorum. No culture-positive, PCR-negative results for F. necrophorum were observed. Patients with F. necrophorum
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LETTERS detected were aged 15 to 51 years (average age, 28 years), whereas those with S. pyogenes were aged 2 to 72 years, with 64% aged 2 to 15 years. One participant was positive for both. Among participants aged 0 to 14 years, 15 to 30 years, and 31 to 77 years, 0 of 123 (0%), 4 of 42 (10%), and 4 of 73 (5%), respectively, were positive for F. necrophorum. We tested throat swabs from 106 asymptomatic volunteers (Mayo Clinic employees) using F. necrophorum PCR and culture. Four (4%) were PCR-positive, of which 1 was culture-positive. Polymerase chain reaction testing can detect F. necrophorum in throat swabs faster than culture (1). As with S. pyogenes, asymptomatic persons may have positive results. Fusobacterium necrophorum was detected in a percentage of adolescents and young adults with presumed pharyngitis similar to that previously reported (3). We believe that a placebocontrolled evaluation of antibiotic treatment should be considered in adolescents and young adults with pharyngitis in whom F. necrophorum is detected to determine whether treatment affects duration and severity of symptoms, likelihood of progression to the Lemierre syndrome, or peritonsillar abscess and contagiousness. The antimicrobial agent that should be evaluated is debatable. Between November 2011 and December 2014, susceptibility testing on 30 F. necrophorum isolates showed that 74% were susceptible to penicillin (minimum inhibitory concentration ≤0.5 μg/mL), whereas all were susceptible to metronidazole and clindamycin (≤8 and ≤2 μg/mL, respectively). Our data, derived from a Minnesota population, add to the evidence suggesting that F. necrophorum may cause pharyngitis (4, 5). Seasonality, why this organism is primarily found in adolescents and young adults, and whether treatment is indicated are unknown. James R. Uhl, MS Daniel R. Gustafson, BS Stefanea L. Rucinski, MT (ASCP) Robin Patel, MD Mayo Clinic Rochester, Minnesota Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L15-0189.
References 1. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med. 2015;162:241-7. [PMID: 25686164] doi:10.7326/M14-1305 2. Uhl JR, Adamson SC, Vetter EA, Schleck CD, Harmsen WS, Iverson LK, et al. Comparison of LightCycler PCR, rapid antigen immunoassay, and culture for detection of group A streptococci from throat swabs. J Clin Microbiol. 2003; 41:242-9. [PMID: 12517855] 3. Eaton C, Swindells J. The significance and epidemiology of Fusobacterium necrophorum in sore throats [Letter]. J Infect. 2014;69:194-6. [PMID: 24642207] doi:10.1016/j.jinf.2014.03.005 4. Hedin K, Bieber L, Lindh M, Sundqvist M. The aetiology of pharyngotonsillitis in adolescents and adults—Fusobacterium necrophorum is commonly found. Clin Microbiol Infect. 2015;21:263.e1-7. [PMID: 25658556] doi:10.1016/j.cmi .2014.08.020 5. Jensen A, Hansen TM, Bank S, Kristensen LH, Prag J. Fusobacterium necrophorum tonsillitis: an important cause of tonsillitis in adolescents and www.annals.org
young adults. Clin Microbiol Infect. 2015;21:266.e1-3. [PMID: 25658551] doi:10.1016/j.cmi.2014.09.020
IN RESPONSE: We thank Dr. Matthys and colleagues for their comment. We do believe that F. necrophorum causes adolescent and young adult pharyngitis and deserves antibiotic treatment. Although the evidence is circumstantial, we believe that antibiotics would be prudent. The Lemierre syndrome is a devastating disease that has an estimated death rate of 5% with clinically significant short- and long-term morbidity (1). Chirinos and associates (2) reported that F. necrophorum causes approximately 80% of cases of the Lemierre syndrome. In most patients, it develops a few days after sore throat. We have strong evidence that F. necrophorum causes pharyngitis. Several European studies showed an association between this organism and pharyngitis. We reported a summary of 6 patients who had pharyngitis and F. necrophorum bacteremia but not internal jugular thrombophlebitis (3). Our article shows that, as the Centor score increased, so did the probability of a positive PCR result for F. necrophorum. Although we cannot prove that F. necrophorum pharyngitis precedes the Lemierre syndrome, the circumstantial evidence makes it seem very likely. Similarly, we cannot prove that treating F. necrophorum pharyngitis with appropriate antibiotics would decrease the probability of the Lemierre syndrome, but the biological plausibility seems high. Because we estimate that 1 in 400 cases of F. necrophorum pharyngitis result in the Lemierre syndrome (1), a randomized, controlled trial would require more than 10 000 patients to prove that we can prevent the Lemierre syndrome. In such a trial, approximately 12 or 13 patients would develop the Lemierre syndrome. We believe that one could legitimately question the ethics of this proposed trial. Does this circumstance mean that we would need to treat many patients with antibiotics? We reiterate that this bacterium rarely causes pharyngitis in preadolescents, and Mr. Uhl and coworkers' comment confirms this finding. We hope to have a rapid test in the future but in the meantime would favor empirical treatment of 50% of cases of adolescent and young adult pharyngitis, because we believe that the Lemierre syndrome deserves prevention. We agree with Mr. Uhl and coworkers that we should collect more epidemiologic data on F. necrophorum in adolescent and young adult patients with pharyngitis. We do not favor a randomized, controlled trial, because the Lemierre syndrome often presents with devastating metastatic infections.
Robert M. Centor, MD T. Prescott Atkinson, MD, PhD Ken B. Waites, MD University of Alabama at Birmingham Birmingham, Alabama Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-1305. References 1. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi:10 .7326/0003-4819-151-11-200912010-00011 Annals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 877
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LETTERS 2. Chirinos JA, Lichtstein DM, Garcia J, Tamariz LJ. The evolution of Lemierre syndrome: report of 2 cases and review of the literature. Medicine (Baltimore). 2002;81:458-65. [PMID: 12441902] 3. Centor RM, Geiger P, Waites KB. Fusobacterium necrophorum bacteremic tonsillitis: 2 cases and a review of the literature. Anaerobe. 2010;16:626-8. [PMID: 20813196] doi:10.1016/j.anaerobe.2010.08.005
Sore Throat: Avoid Overcomplicating the Uncomplicated TO THE EDITOR: Linder (1) discounts the possibility that Fusobacterium necrophorum causes pharyngitis and proposes that, even if it does, we should not assume that treating this condition would prevent suppurative complications (especially the Lemierre syndrome). He argues that we should stick to a simple strategy of using the Centor score to reassure some patients (those with scores of 0 or 1) and use a rapid streptococcus test for the remaining patients, treating only those with positive rapid test results. He asserts that we should not complicate the diagnosis and treatment decisions. We strongly disagree. Although preadolescent sore throat is relatively straightforward and the prevalence of F. necrophorum in these younger patients is clearly lower, the bacterial pathogenesis of adolescent and young adult pharyngitis is more complex. The highest-probability differential diagnosis in this age group includes group A -hemolytic streptococcus (Streptococcus pyogenes), group C or G -hemolytic streptococcus (Streptococcus dysgalactiae subsp equisimilis), infectious mononucleosis, acute HIV infection, and now F. necrophorum. Linder's recommendation is dangerous because it can lead to diagnostic errors through the anchoring bias. If our decision structure is binary (group A streptococcus or not), then we are at risk for missing a more serious infection. Our data suggest that the Centor criteria define a symptom complex for acute bacterial pharyngitis, with group A streptococcal infection being only 1 cause. The current empirical treatment algorithm based on the Centor criteria includes macrolides for patients with a history of penicillin allergy, and this class of antibiotics does not cover F. necrophorum. Treating Fusobacterium pharyngitis has a strong possibility of decreasing the likelihood of progression to the Lemierre syndrome. Although we cannot prove this assumption, its biological plausibility strongly supports this hypothesis. We have much evidence that F. necrophorum causes the pharyngitis. Several case reports have documented pharyngitis with Fusobacterium bacteremia (2). Our study (3) strongly supports the idea that F. necrophorum causes pharyngitis. As the Centor score increased, so did the probability of a positive polymerase chain reaction result for F. necrophorum. Although this finding does not absolutely prove that F. necrophorum causes pharyngitis, one has to develop a rather convoluted explanation to assert otherwise. Our concern about this topic relates to the devastation that the Lemierre syndrome causes. Having communicated with many survivors and the families of some patients who died of this condition, we feel passionately that the best approach to the Lemierre syndrome (like many other diseases) is prevention. As one of us pointed out several years ago, the incidence of the Lemierre syndrome developing after a sore
throat now exceeds that of rheumatic fever in the United States and Europe (4). The argument against treating patients with Fusobacterium pharyngitis centers on the lack of proof. The absence of a diagnostic test at present for F. necrophorum does not negate the need to adjust the recommendations for empirical, criteria-based therapy predicated on the latest epidemiologic evidence. In the absence of definitive proof, we favor treating patients with a substantial probability of F. necrophorum pharyngitis with targeted antibiotics in the hope that we may prevent some patients from developing this devastating complication. Robert M. Centor, MD T. Prescott Atkinson, MD Carlos Estrada, MD Ken B. Waites, MD University of Alabama at Birmingham Birmingham, Alabama Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0186.
References 1. Linder JA. Sore throat: avoid overcomplicating the uncomplicated [Editorial]. Ann Intern Med. 2015;162:311-2. [PMID: 25686170] doi:10.7326/M14 -2899 2. Centor RM, Geiger P, Waites KB. Fusobacterium necrophorum bacteremic tonsillitis: 2 cases and a review of the literature. Anaerobe. 2010;16:626-8. [PMID: 20813196] doi:10.1016/j.anaerobe.2010.08.005 3. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med. 2015;162:241-7. [PMID: 25686164] doi:10.7326/M14-1305 4. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi: 10.7326/0003-4819-151-11-200912010-00011
IN RESPONSE: I agree with Dr. Centor about quite a lot in the
management of patients with sore throat. In developed countries, rheumatic fever is a minor concern. Patients with Centor scores of 0 or 1 can be safely reassured. Those diagnosed with bacterial pharyngitis should be treated with penicillin. Physicians should not be overly anchored to guidelines if their patients are not doing well. The Lemierre syndrome can be devastating. However, we have legitimate disagreements. Dr. Centor's arguments recall other examples of injudicious antibiotic use. The use of empirical penicillin to prevent the Lemierre syndrome is reminiscent of the discredited practice of antibiotic prophylaxis for patients with heart murmurs to prevent infective endocarditis. Even if Fusobacterium pharyngitis were clearly linked to the Lemierre syndrome, only a tiny fraction of patients with Fusobacterium pharyngitis will develop the Lemierre syndrome. Dr. Centor has estimated it to be 1 in 400 (1), but the rate could be much, much lower (2). There is no evidence that antibiotics prevent the Lemierre syndrome. Pharyngeal detection of F. necrophorum is reminiscent of the detection and unnecessary treatment of group A streptococcus carriers. Point-of-care testing for group A streptococcus does not differentiate between true infection and car-
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LETTERS riage. Similarly, a “convoluted explanation” is not required to show that F. necrophorum does not necessarily cause pharyngitis; this organism is a normal part of the oropharyngeal flora (Dr. Centor and colleagues detected F. necrophorum in 9% of asymptomatic young adults). During viral infection, F. necrophorum overgrows and becomes more easily detected. Detection is not infection. Finally, “F. necrophorum fear” is reminiscent of antibiotic prescribing for “bacterial acute bronchitis.” There is no evidence that antibiotics substantively alter the course of acute bronchitis, but physicians prescribe these agents to 70% of adults with acute bronchitis (3). Similarly, raising the specter of F. necrophorum encourages antibiotic use at a time when physicians already prescribe antibiotics to approximately 60% of young adults with pharyngitis (4). These areas of disagreement can be addressed with new evidence. Studies can and should examine whether F. necrophorum causes a meaningful proportion of pharyngeal infections and whether antibiotic treatment of F. necrophorum–associated sore throat decreases symptoms and prevents complications. Present evidence points to widespread overprescribing of antibiotics. Jeffrey A. Linder, MD, MPH Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-2899. References 1. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi: 10.7326/0003-4819-151-11-200912010-00011 2. Petersen I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC. Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database. BMJ. 2007;335:982. [PMID: 17947744] 3. Barnett ML, Linder JA. Antibiotic prescribing for adults with acute bronchitis in the United States, 1996-2010. JAMA. 2014;311:2020-2. [PMID: 24846041] doi:10.1001/jama.2013.286141 4. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014;174:138-40. [PMID: 24091806] doi:10.1001/jamainternmed.2013.11673
OBSERVATION Hemorrhagic Stroke Probably Caused by Exercise Combined With a Sports Supplement Containing -Methylphenylethylamine (BMPEA): A Case Report Background: The U.S. Food and Drug Administration has warned consumers that an isomer of amphetamine, -methylphenylethylamine (BMPEA), is found in many sports supplements (1). The health effects of this chemical in humans are unknown (2, 3). Objective: To report a case of hemorrhagic stroke probably caused by exercise combined with BMPEA. Case Report: A 53-year-old woman presented with 1 day of numbness and clumsiness in her left hand. She reported www.annals.org
Figure. Computed tomography scan of the head.
Scan was obtained the day after onset of left arm numbness and clumsiness and shows a right parietal intracerebral hemorrhage.
the sudden onset of symptoms 45 minutes after beginning a vigorous exercise routine that she had repeated several times weekly for a few years. On examination, she was afebrile, blood pressure was 163/58 mm Hg, and heart rate was regular at 90 beats/min. She was alert with normal mental status. She had a subtle left pronator drift, but no definite weakness or dyscoordination in the limbs. She had hypesthesia involving the left upper arm, forearm, and hand. Reflexes were normal without a Babinski sign; gait was normal. The patient had no important medical history and did not receive any medications. However, she reported having consumed the recommended dose (13 g) of a sports supplement (Jacked Power, MM Sports) 30 minutes before beginning exercise. She had not consumed this or any similar sports supplement previously. She was physically active and had always been of normal weight with low blood pressure. She quit smoking 22 years ago, drank alcohol occasionally, and did not use illicit drugs. She had no family history of stroke or coagulation disorders. Laboratory results included levels of total cholesterol of 4.6 mmol/L (180 mg/dL), triglycerides of 1.0 mmol/L (89 mg/ dL), high-density lipoprotein cholesterol of 2.1 mmol/L (81 mg/dL), low-density lipoprotein cholesterol of 2.3 mmol/L (90 mg/dL), glucose of 5.3 mmol/L (95 mg/dL), and hemoglobin of 137 g/L; leukocyte count of 5.3 × 109 cells/L; platelet count of 250 × 109 cells/L; international normalized ratio of 1.2; and partial thromboplastin time of 31 s. An electrocardiogram was normal. Computed tomography of the head showed a 2-cm hemorrhage in the right parietal lobe (Figure). Magnetic resonance imaging of the brain revealed the hemorrhage with no underlying abnormalities. Cerebral angiography showed no evidence of vasculitis, aneurysm, or other vascular malforAnnals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 879
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LETTERS mation. Blood pressure normalized after admission and remained normal. She was discharged after 5 days with minor residual sensory symptoms. Neither BMPEA nor Acacia rigidula was listed on the supplement label. After the initial report was published in Swedish (4), we analyzed the patient's Jacked Power supplement at the Netherlands' National Institute for Public Health and the Environment (RIVM) using ultraperformance liquid chromatography– quadrupole/time-of-flight mass spectrometry (Acquity UltraPerformance LC SYNAPT G2 QTOF, Waters). We performed a general screening for pharmaceuticals and drugs. -Methylphenylethylamine was the only unlabeled pharmaceutical or drug found and was confirmed at 290 mg per dose using standard addition experiments with BMPEA (Sigma-Aldrich) and amphetamine (Merck) as reference standards. Discussion: Exercise combined with BMPEA, an isomer of amphetamine, probably caused this patient's stroke. Case reports are available of exercise-induced hemorrhagic stroke in otherwise healthy patients, and amphetamine has also been identified as a cause of hemorrhagic strokes in many case reports. However, the health effects of amphetamine's -isomer, BMPEA, are unknown. This isomer was first synthesized in the 1930s as a potential replacement for amphetamine (␣-methylphenethylamine) (3). In the 1930s and 1940s, researchers found that BMPEA increased blood pressure and heart rate in cats and dogs (3). However, to our knowledge, its physiologic effects in humans have not been studied (2, 3). We categorize causality as “probable/likely,” which the World Health Organization's Adverse Reaction Terminology defines as “A clinical event . . . with a reasonable time relation to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals and which follows a clinically reasonable response on withdrawal” (5). -Methylphenylethylamine is available in more than a dozen brands of supplements marketed to improve athletic performance and weight loss (1–3). To our knowledge, this is the first identified case of a hemorrhagic stroke probably caused by exercise combined with BMPEA. It was reported to the appropriate European authorities and on 4 April 2015 to the U.S. Food and Drug Administration. Physicians in the United States should report all suspected serious adverse events from dietary supplements to the U.S. Food and Drug Administration at www.safetyreporting.hhs.gov. In Europe, physicians should report these events to the appropriate national authority. Pieter A. Cohen, MD Harvard Medical School Boston, Massachusetts
Peter H.J. Keizers, PhD Bastiaan Venhuis, PhD National Institute for Public Health and the Environment (RIVM) Bilthoven, the Netherlands Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L15-0106. This article was published online first at www.annals.org on 12 May 2015. References 1. U.S. Food and Drug Administration. BMPEA in dietary supplements. 24 April 2015. Accessed at www.fda.gov/food/dietarysupplements/qadietary supplements/ucm443790.htm on 28 April 2015. 2. Pawar RS, Grundel E, Fardin-Kia AR, Rader JI. Determination of selected biogenic amines in Acacia rigidula plant materials and dietary supplements using LC-MS/MS methods. J Pharm Biomed Anal. 2014;88:457-66. [PMID: 24176750] doi:10.1016/j.jpba.2013.09.012 3. Cohen PA, Bloszies C, Yee C, Gerona R. An amphetamine isomer whose efficacy and safety in humans has never been studied, -methylphenylethylamine (BMPEA), is found in multiple dietary supplements. Drug Test Anal. 2015. [PMID: 25847603] doi:10.1002/dta.1793 4. Zeijlon R, Andersson B. Hja¨rnblo¨dning efter intag av prestationsho¨jaren “Jacked Power.” Frisk kvinna insjuknade under tra¨ning efter en enda dos. La¨kartidningen. 2014;111:1782-4. [PMID: 25699325] 5. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356:1255-9. [PMID: 11072960]
CORRECTIONS Correction: Electronic Nicotine Delivery Systems The middle initial of an author of a recent policy paper (1) was incorrect. Dr. Lohr's middle initial is “H,” not “M.” This has been corrected in the online version. Reference 1. Crowley RA, for the Health Public Policy Committee of the American College of Physicians. Electronic nicotine delivery systems: executive summary of a policy position paper from the American College of Physicians. Ann Intern Med. 2015;162:583-4. [PMID: 25894027] doi:10.7326/M14-2481
Correction: Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma In Figure 2 of a recent article (1), the bottom of the right side of the forest plot is the true negative total, not the true positive total.
Rickard Zeijlon, MD Sahlgrenska University Hospital Gothenburg, Sweden
Reference
Rachel Nardin, MD Harvard Medical School Boston, Massachusetts
1. Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A, et al. Imaging techniques for the diagnosis of hepatocellular carcinoma. A systematic review and meta-analysis. Ann Intern Med. 2015;162:697-711. [PMID: 25984845] doi: 10.7326/M14-2509
This has been corrected in the online version.
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