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5. Orte C, Polak JM, Haworth SG, Yacoub MH, Morrell NW. Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension. J Pathol 2000;192:379–384. 6. De Man FS, Handoko ML, Guignabert C, Bogaard HJ, Vonk-Noordegraaf A. Neurohormonal axis in patients with pulmonary arterial hypertension: friend or foe? Am J Respir Crit Care Med 2013;187:14–19. 7. De Man FS, Tu L, Handoko ML, Rain S, Ruiter G, Franc¸ois C, Schalij I, Dorfmüller P, Simonneau G, Fadel E, et al. Dysregulated reninangiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:780–789. 8. Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 2000;275:26765–26771. 9. Chen T-H, Wang J-F, Chan P, Lee H-M. Angiotensin II stimulates hypoxiainducible factor 1alpha accumulation in glomerular mesangial cells. Ann N Y Acad Sci 2005;1042:286–293. 10. Sánchez-López E, López AF, Esteban V, Yagüe S, Egido J, Ruiz-Ortega M, Alvarez-Arroyo MV. Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney. Antioxid Redox Signal 2005;7:1275–1284. 11. Pagé EL, Robitaille GA, Pouysségur J, Richard DE. Induction of hypoxiainducible factor-1alpha by transcriptional and translational mechanisms. J Biol Chem 2002;277:48403–48409. 12. Lauzier M-C, Pagé EL, Michaud MD, Richard DE. Differential regulation of hypoxia-inducible factor-1 through receptor tyrosine kinase transactivation in vascular smooth muscle cells. Endocrinology 2007;148:4023–4031. Copyright ª 2013 by the American Thoracic Society
Risk of Tuberculosis among QuantiFERON Converters and Nonconverters To the Editor:
A study in the Journal showed that the risk of tuberculosis (TB) disease was eightfold higher in adolescents with recent conversion to QuantiFERON Gold In-Tube (QFT) as compared with nonconverters in a high-burden setting (1). The effect persisted after controlling for age, gender, ethnic group, bacille CalmetteGuérin (BCG) scar, employment status, school attendance, or income. Apparently, exposure to tuberculosis in the household was ascertained, but the estimates were not shown nor assessed in the results. Exposed participants should have higher rates of disease and QFT conversion as compared with the unexposed. We wonder whether the difference in the risk of disease between QFT converters and nonconverters would persist after controlling for household exposure and whether the inclusion of exposure in the multivariable model would have an impact on the results. Similar rates of disease in QFT converters and nonconverters after controlling for exposure status would be indicative that serial QFT testing should be discouraged and confirm that two-step testing should be targeted. We also wonder whether physicians who made the TB diagnosis were blinded to QFT results. Knowing the QFT results beforehand may have biased physicians in establishing the diagnosis in non–mycobacteriologically confirmed clinical cases. The low positive predictive value found in QFT converters (2.8%) and its similarity with the positive predictive value of tuberculin skin test (TST) converters found in a previous study (2) suggests that the less expensive TST should be the first option when assessing for conversion, which is usually done in contacts after 8 to 12 weeks from a first negative TST. A previous study from the same authors showed no significant difference in the predictive ability of TST and QFT, concluding that QFT should not be used in preference to TST to predict the risk of TB disease in this study population (3). The QFT is unaffected by prior BCG vaccination, and therefore it is generally recommended in vaccinated people (4, 5). Regardless of the reluctance of some QFT advocates to show the analysis of the positive predictive value between TST and
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QFT in BCG-unvaccinated household contacts, a subanalysis showed that it was similar (6), indicating that the TST should have priority during screening of latent tuberculosis infection for this population as TST is less expensive. It is very unlikely that a positive TST found in BCG-unvaccinated close contacts would be secondary to other causes of TST positivity like nontuberculous mycobacterial infection particularly if the index case has smear-positive disease. In summary, this study determined the risk of TB in QFT converters and nonconverters for research purposes; however, in the real world, TB programs from high-burden, low-income settings cannot usually afford QFT testing for screening purposes and, in many instances, cannot even afford TST. Lowering the cost can make QFT more affordable, benefiting the BCG-vaccinated individuals who represent the majority in those settings. Author disclosures are available with the text of this letter at www.atsjournals.org.
Eduardo Hernández-Garduño, M.D. Gerardo Huitrón-Bravo, M.D. Universidad Autónoma del Estado de México Toluca, Mexico References 1. Machingaidze S, Verver S, Mulenga H, Abrahams DA, Hatherill M, Hanekom W, Hussey GD, Mahomed H. Predictive value of recent QuantiFERON conversion for tuberculosis disease in adolescents. Am J Respir Crit Care Med 2012;186:1051–1056. 2. Sutherland I. The evolution of clinical tuberculosis in adolescents. Tubercle 1966;47:308. 3. Mahomed H, Hawkridge T, Verver S, Abrahams D, Geiter L, Hatherill M, Ehrlich R, Hanekom WA, Hussey GD. The tuberculin skin test versus QuantiFERON TB Gold in predicting tuberculosis disease in an adolescent cohort study in South Africa. PLoS ONE 2011;6:e17984. [Published erratum appears in PLoS One 2011;6(6).] 4. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K; IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2010;59(RR-5):1–25. 5. Canadian Tuberculosis Committee. Recommendations on interferon gamma release assays for the diagnosis of latent tuberculosis infection: 2010 update. An Advisory Committee statement (ACS). Can Commun Dis Rep 2010;36:1–22. 6. Hernández-Gardun˜o E. An update: the predictive value of QuantiFERONTB-Gold In-Tube assay and the tuberculin skin test. Am J Respir Crit Care Med 2011;183:414, author reply 414–415. Copyright ª 2013 by the American Thoracic Society
Reply From the Authors:
We thank Drs. Hernandez-Gardun˜o and Huitrón-Bravo for their letter in response to our article (1). We would like to point out to Drs. Hernandez-Gardun˜o and Huitrón-Bravo that the predictive value of a tuberculin skin test (TST) conversion was not evaluated in our study and therefore no conclusions can be drawn with respect to the superiority or equivalence of the TST in relation to QuantiFERON TB Gold In Tube (QFT) (Cellestis, Victoria, Australia) based on our study alone. A recent World Health Organization report specifically discourages the use of interferon-g release assays (IGRAs) in high-TB-burden settings (2). However, the report also points to a lack of good-quality data to support the use of IGRAs in these settings. Our study contributes toward the evidence base of literature on IGRA use in high-burden settings, and our study should be seen in this light. In our study, only one household contact was reported out of the 15 TB cases among the QFT Converters and one out of the two
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cases among the QFT nonconverters during follow-up. Therefore, our data did not indicate that household exposure was a confounder/possible explanation for the difference in risk of TB between converters and nonconverters. Molecular epidemiology studies have shown that exposure often occurs outside of a household setting, and we accept that reported exposure may not be a reliable indicator of true exposure (3). We have previously shown that prior household contact is associated with a positive TST and QFT on multivariate analysis in this population (4). A conversion implies exposure, so it would not be surprising if TB exposure were associated with conversion. Thus, we believe that even if we had found an association between household exposure and disease, this would not invalidate the finding of the predictive value of a QFT conversion for TB disease. Specific measures to blind physicians diagnosing TB were not in place. However, most cases were diagnosed by public health services rather than study staff. Public sector personnel were unlikely to be aware of the QFT result given that latent TB infection in children over 5 years old is not treated in South Africa and no official notification was sent to the public health services when a positive test was found. We agree that lowering the cost would make QFT more accessible to countries with a high burden of TB. Author disclosures are available with the text of this letter at www.atsjournals.org.
Hassan Mahomed, M.Med. Stellenbosch University Cape Town, South Africa Shingai Machingaidze, M.P.H. Willem Albert Hanekom, M.B.Ch.B. Mark Hatherill, D.M. University of Cape Town Cape Town, South Africa Suzanne Verver, Ph.D. KNCV Tuberculosis Foundation The Hague, The Netherlands References
gamers are at risk for medical complications from excessive behaviors. Although complications from prolonged video gaming are reported in the lay press with educational websites now available (1), nothing is published in the medical literature. An otherwise healthy population is at risk for more serious medical complications due to extended periods of sitting. We describe pulmonary venous thromboembolism (VTE) in a 15-year-old male due to extreme video gaming that failed medical therapy and required pulmonary thromboendarterectomy. The patient presented with severe worsening of dyspnea. He reported noticing exertional dyspnea and foot swelling over the last 2 months. Prior to the onset of these symptoms, he had no previous medical or surgical history. His physical examination revealed obesity and moderate pedal edema with an accentuated pulmonary component of the second heart sound. Electrocardiography demonstrated sinus tachycardia and right axis deviation. A computed tomography scan of the chest (Figure 1) discovered multiple nonocclusive emboli in both lung distributions with moderate-to-large emboli in both main pulmonary arteries extending into several segmental and subsegmental branches. Thrombus in the left main pulmonary artery was partially calcified, indicating this to be a chronic process. Transthoracic echocardiography (Figure 2) demonstrated moderate to severe tricuspid regurgitation with dilated right atrium and depressed right ventricular function. Right ventricular pressure was estimated to be greater than 80 mm Hg or more than two-thirds of systemic pressure. He was treated with tissue plasminogen activator and heparin and then transitioned to warfarin. Extensive evaluation for hypercoagulable disorder on two separate occasions was negative. There was no history of trauma or recent travel, but he frequently played video games for an extended number of hours, with the family reporting 16–18 hours of straight video gaming. Due to refractory bilateral pulmonary emboli despite medical therapy and associated right heart strain, pulmonary thromboendarterectomy was performed. After surgical treatment, his course was complicated requiring extracorporeal membrane oxygenation temporarily. Furthermore, he needed tracheostomy and prolonged ventilatory support followed by inpatient rehabilitation. He has subsequently recovered fully
1. Machingaidze S, Verver S, Mulenga H, Abrahams DA, Hatherill M, Hanekom W, Hussey GD, Mahomed H. Predictive value of recent QuantiFERON conversion for tuberculosis disease in adolescents. Am J Respir Crit Care Med 2012;186:1051–1056. 2. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries. Geneva, Switzerland: World Health Organization; 2011. 3. Verver S, Warren RM, Munch Z, Richardson M, van der Spuy GD, Borgdorff MW, Behr MA, Beyers N, van Helden PD. Proportion of tuberculosis transmission that takes place in households in a highincidence area. Lancet 2004;363:212–214. 4. Mahomed H, Hawkridge T, Verver S, Geiter L, Hatherill M, Abrahams DA, Ehrlich R, Hanekom WA, Hussey GD; SATVI Adolescent Study Team. Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa. Int J Tuberc Lung Dis 2011;15:331–336. Copyright ª 2013 by the American Thoracic Society
Pulmonary Venous Thromboembolism Due to Extreme Video Gaming To the Editor:
There is a potential evolving public health concern in the United States. Media reports are now describing extreme video gamers who play 50 hours or more per week. Subsequently, these
Figure 1. Computed tomography scan of the chest demonstrating large and partially calcified embolism in the left pulmonary artery and smaller nonocclusive embolism in the right pulmonary artery. R = right; L = left.
