EDITORIALS 2. Loth DW, Artigas MS, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C, et al. Genome-wide association analysis identifies six new loci associated with forced vital capacity. Nat Genet 2014;46:669–677. 3. Melen ´ E, Pershagen G. Pathophysiology of asthma: lessons from genetic research with particular focus on severe asthma. J Intern Med 2012;272:108–120. 4. Bonner R, Lum S, Stocks J, Kirkby J, Wade A, Sonnappa S. Applicability of the global lung function spirometry equations in contemporary multiethnic children. Am J Respir Crit Care Med 2013;188: 515–516. 5. Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, Schulze TG, Cichon S, Rietschel M, Nothen ¨ MM, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 2008;13:197–207. 6. Narang I, Bush A. Early origins of chronic obstructive pulmonary disease. Semin Fetal Neonatal Med 2012;17:112–118. 7. Sharma S, Chhabra D, Kho AT, Hayden LP, Tantisira KG, Weiss ST. The genomic origins of asthma. Thorax 2014;69:481–487. 8. Panasevich S, Melen ´ E, Hallberg J, Bergstrom ¨ A, Svartengren M, Pershagen G, Nyberg F. Investigation of novel genes for lung function in children and their interaction with tobacco smoke exposure: a preliminary report. Acta Paediatr 2013;102: 498–503.

9. Kerkhof M, Boezen HM, Granell R, Wijga AH, Brunekreef B, Smit HA, de Jongste JC, Thijs C, Mommers M, Penders J, et al. Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes. J Allergy Clin Immunol 2014; 133:68–76. 10. Lodge CJ, Lowe AJ, Allen KJ, Zaloumis S, Gurrin LC, Matheson MC, Axelrad C, Welsh L, Bennett CM, Hopper J, et al. Childhood wheeze phenotypes show less than expected growth in FEV1 across adolescence. Am J Respir Crit Care Med 2014;189: 1351–1358. 11. Schultz ES, Gruzieva O, Bellander T, Bottai M, Hallberg J, Kull I, Svartengren M, Melen ´ E, Pershagen G. Traffic-related air pollution and lung function in children at 8 years of age: a birth cohort study. Am J Respir Crit Care Med 2012;186:1286–1291. 12. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088–1098. 13. Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, FitzGerald JM, Boedigheimer M, Davis BE, Dias C, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 2014;370:2102–2110.

Copyright © 2014 by the American Thoracic Society

HIV-related Chronic Obstructive Pulmonary Disease Are Lung CD4 T Cells Bothered? Antiretroviral therapy has enabled the care of HIV-infected individuals to move away from the treatment of opportunistic disease and toward the management of HIV as a chronic condition (1). This makes understanding the comorbidities associated with HIV more important. A growing body of evidence suggests that despite antiretroviral treatment, HIV infection is associated with increased rates of pulmonary disease and accelerated lung function decline that often resemble chronic obstructive pulmonary disease (COPD) (2). Evaluating the contribution made by HIV infection per se is complicated by high rates of smoking and other confounding factors in HIV-infected populations (3). However, most studies suggest that HIV is an independent risk factor for the development of obstructive lung disease (4, 5). Research, therefore, needs to address mechanistic questions about how HIV might lead to lung function decline. In this issue of the Journal, Popescu and colleagues (pp. 744– 755) take an important step in this direction (6). They show for the first time differences in CD41 T-cell number and function in the lungs (but not blood) of HIV-infected individuals with COPD compared with HIV-infected people without COPD and HIVnegative patients with COPD. This phenomenon has been reported before in the gastrointestinal tract, where HIV infection is characterized by an early profound depletion of mucosal CD41 T cells that may be only partially reconstituted by antiretroviral therapy (7). However, it is a first for lung mucosal immunology, where it was felt that little loss of lung CD4 cells in the chronic phase of HIV infection occurred (8) (of interest is that this concept is supported by the current report’s results in HIV-infected patients without COPD). Indeed, studies of HIV-related lung

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disease performed before the advent of antiretroviral therapy suggested that HIV infection was associated primarily with a CD81 alveolar lymphocytosis (9). So why does the new work find these differences? Have the researchers just done the wrong experiments? Their laboratory methodology is rigorous and robust; indeed, they show that the CD4 depletion is both qualitative and quantitative and is associated with HIV-specific T-cell impairments. They also demonstrate that the CD4 cell loss may occur as a result of immune exhaustion via a Fas-dependent activation-induced cell death mechanism (although they do not appear to have performed the same experiments using CD8 cells). Thus, they link the themes of HIV infection, chronic inflammation, and CD4 cell loss, which are central to current thinking regarding HIV-related disease pathogenesis. However, the populations under test are worthy of comment. They were recruited from either the AIDS Linked to the Intravenous Experience (ALIVE) study cohort or an HIV clinic in Baltimore, Maryland. As such, they all had a history of drug injection, quite apart from heavy cigarette smoking or use of other recreational drugs. Although the HIV-negative control patients with COPD are therefore well-matched, they are also young for the average patient with COPD (with a mean age of 51 yr). Even though the authors argue that they are showing HIV-specific effects that are independent of smoking, one needs to be cautious before extrapolating the results to other HIV-infected populations. Hence, this may be an ideal setting in which to study the development of obstructive lung disease, yet be less relevant to populations with different risk factors.

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EDITORIALS The study is also important as it reflects current clinical practice, with the majority of the HIV-infected group receiving antiretroviral therapy having undetectable viral loads and nearnormal blood CD4 counts. It is never easy to perform translational work such as this, where subjects undergo bronchoscopy and bronchoalveolar lavage (BAL) for the purposes of research and not symptoms (which in part explains the relatively small numbers studied; e.g., there were 14 patients with HIV and COPD). It also highlights the relevance of working both with blood and in the lung if one wishes to investigate pulmonary mucosal immunity and compartmentalized responses. The authors demonstrate a relationship between the BAL CD4: CD8 ratio, absolute CD4 count, and spirometry (FEV1). Taken together with the other data presented, this could suggest that HIVspecific abnormalities in immune function in certain individuals with HIV infection (who smoke) are associated with obstructive lung disease, and thus may result in COPD. Given the lack of longitudinal data available, this is inevitably at the level of conjecture, rather than fact, which is itself emphasized by previous work from the same researchers, who reported an increased rate of lung function decline in people with higher plasma HIV viral loads (10), whereas the current study indicates that reduced BAL CD4 counts do not appear to be associated with increased BAL HIV viral load. One possible explanation is that the majority of lung CD4 cells encountering HIV virus are resting T cells, and hence do not become productively infected (and so would not contribute to BAL viral load), although they still die by the process of pyroptosis (11). Unlike apoptosis, this results in a highly inflammatory local state. If this did occur in the lung, this could explain the apparent dissociation between low CD4 T cells and BAL viral load. The work of Popescu and colleagues offers the intriguing possibility that the pathogenesis of COPD in some HIV-infected individuals may be different than that in the HIV-uninfected patients. It should be noted that studies investigating the role of adaptive immunity in HIV-negative COPD have focused on CD8 T cells and B cells (12, 13) and, if anything, report an increase in airway CD4 cells. This study inevitably raises a number of scientific issues and questions. These include further defining the mechanism by which loss of lung CD4 cells could lead to airflow obstruction, as well as determining why some individuals with HIV infection develop lung CD4 cell depletion when others do not. Even then, does the loss of lung CD4 cells precede the development of airflow obstruction? And might antiretroviral treatment alter this process? Also, are those patients with HIV who do not smoke at risk of developing obstructive lung disease? And do respiratory infections drive lung function decline? Further work including prospective studies is required, although ongoing trials of the effect of antiretroviral therapy on lung function may provide some answers (14). What is the message for HIV-infected people and their healthcare providers? Certainly the high burden of obstructive lung disease argues forcefully for the introduction of programs that can reduce known risk factors such as smoking. In addition, the possibility of different pathogenic mechanisms for HIV-associated COPD means perhaps we should be cautious in assuming that treatments for COPD in the HIV-uninfected population can be employed routinely in those with HIV. This is backed up by Editorials

numerous reports of the hitherto unconsidered adverse events that can result when inhaled corticosteroids and antiretroviral therapy are used concurrently (15). The clinical bottom line is that patients with, or at risk of, HIV-related lung disease need combined pulmonary and HIV specialist management supported by research studies designed to define underlying mechanisms and, thus, prevent disease. n Author disclosures are available with the text of this article at www.atsjournals.org. Marc Lipman, M.D. James Brown, M.B. B.S. Department of Respiratory Medicine and Department of HIV Medicine Royal Free London National Health Service Foundation Trust London, United Kingdom and University College London London, United Kingdom

References 1. Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates and future implications. Curr Opin Infect Dis 2013; 26:17–25. 2. Drummond MB, Kirk GD. HIV-associated obstructive lung diseases: insights and implications for the clinician. Lancet Respir Med 2014;2: 583–592. 3. Smith CJ, Levy I, Sabin CA, Kaya E, Johnson MA, Lipman MC. Cardiovascular disease risk factors and antiretroviral therapy in an HIV-positive UK population. HIV Med 2004;5:88–92. 4. Attia EF, Akgun ¨ KM, Wongtrakool C, Goetz MB, Rodriguez-Barradas MC, Rimland D, Brown ST, Soo Hoo GW, Kim J, Lee PJ, et al. Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4. Chest (In press) 5. Morris A, Crothers K, Beck JM, Huang L; American Thoracic Society Committee on HIV Pulmonary Disease. An official ATS workshop report: emerging issues and current controversies in HIV-associated pulmonary diseases. Proc Am Thorac Soc 2011;8:17–26. 6. Popescu I, Drummond MB, Gama L, Coon T, Merlo CA, Wise RA, Clements JE, Kirk GD, McDyer JF. Activation-induced cell death drives profound lung CD41 T-cell depletion in HIV-associated chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014;190: 744–755. 7. Hayes TL, Asmuth DM, Critchfield JW, Knight TH, McLaughlin BE, Yotter T, McConnell DH, Garcia JC, Pollard RB, Shacklett BL. Impact of highly active antiretroviral therapy initiation on CD4(1) T-cell repopulation in duodenal and rectal mucosa. AIDS 2013;27:867–877. 8. Brenchley JM, Knox KS, Asher AI, Price DA, Kohli LM, Gostick E, Hill BJ, Hage CA, Brahmi Z, Khoruts A, et al. High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage. Mucosal Immunol 2008;1:49–58. 9. Agostini C, Poletti V, Zambello R, Trentin L, Siviero F, Spiga L, Gritti F, Semenzato G. Phenotypical and functional analysis of bronchoalveolar lavage lymphocytes in patients with HIV infection. Am Rev Respir Dis 1988;138:1609–1615. 10. Drummond MB, Merlo CA, Astemborski J, Kalmin MM, Kisalu A, Mcdyer JF, Mehta SH, Brown RH, Wise RA, Kirk GD. The effect of HIV infection on longitudinal lung function decline among IDUs: a prospective cohort. AIDS 2013;27:1303–1311. 11. Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 2014;505:509–514. 12. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The

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EDITORIALS nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653. 13. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009;360:2445–2454. 14. Kunisaki KM. Will expanded ART use reduce the burden of HIVassociated chronic lung disease? Curr Opin HIV AIDS 2014;9: 27–33.

15. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9: 389–396.

Copyright © 2014 by the American Thoracic Society

Former Preterm Infants, Caffeine Was Good for You, But Now Beware of Snoring! Extremely premature infants are surviving and reaching adulthood as a result of tremendous advancement in the field of medicine. This was unthinkable a few decades ago. However, they are not only surviving but also presenting with challenges and health-related issues, which are still not defined or characterized clearly. Recent data suggest that adults who were born at a premature gestational age may present with conditions similar to chronic obstructive pulmonary disease (1). We know very little about the effect of the therapies we use saving these premature infants during an extremely vulnerable time of growth, and even less is known about the long-term effects of the therapies. This becomes more relevant as the infants approach young adulthood. There is a critical need to assess the long-term effects of interventions applied to this vulnerable population as they grow older. One such intervention is the use of caffeine in premature infants. Caffeine, in different forms, is used throughout the human age spectrum for various reasons and has significant effects on neuronal circuitry and functions such as sleep. In this issue of the Journal, Marcus and colleagues (pp. 791– 799) report results of a cross-sectional study on the long-term effects of therapeutic caffeine on sleep characteristics in a subgroup of 201 infants who participated in the Caffeine for Apnea of Prematurity (CAP) study (2). This was a large, randomized controlled trial investigating the neurodevelopmental effects of caffeine citrate in 2,006 infants of less than 1,251 g birth weight. In the present followup study, patients underwent polysomnography and actigraphy at age 5–12 years to investigate the potential long-term effects of caffeine on sleep architecture and obstructive sleep apnea syndrome (OSAS). The authors report no significant differences in sleep quality or quantity or OSAS between the groups. Given that the incidence of OSAS in children born at term is around 1–4% (3, 4), the authors found a high prevalence of OSAS: 10% had polysomnographyconfirmed OSAS and 26% had either an elevated apnea/hypopnea index or a history of prior adenotonsillectomy. The authors also discovered an increased prevalence of periodic leg movements in both groups, irrespective of the use of caffeine. The strengths of this study include a high rate of successfully performed home polysomnographies (98%) and a large sample size. But what follows from its findings? Basically, there is good and bad news in these data. The bad news, as already shown with less sophisticated methodology or in much smaller patient samples (3, 5), is that infants born preterm have a 3–5 times higher risk of developing obstructive sleep apnea later in childhood. Is this plausible?

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OSAS is more likely to develop in patients with a narrow upper airway and/or reduced muscle tone. Traditionally, preterm infants often develop a narrow face and an arched palate, perhaps related to their being intubated or constantly lying in a prone position during their first postnatal weeks in the neonatal intensive care unit (6). They may also suffer from disturbed chemoreceptor functioning, at least if they also develop bronchopulmonary dysplasia (7). Thus, if the association between preterm birth and a high risk of obstructive sleep apnea were biologically plausible, what would be the consequences? Both preterm birth and OSAS are risk factors for developing metabolic syndrome. Recent data suggest that insulin levels of preterm infants are increased if they are measured in cord blood (8), making it unlikely that OSAS serves as an intervening variable for developing metabolic syndrome in former preterm infants, but suggesting instead that both are additive risk factors. Moreover, preterm birth and sleep-disordered breathing are both associated with poor academic achievements (9, 10), and although the contribution of the former is probably difficult to avoid, that of the latter should be preventable, but only if detected and treated early (11, 12). Identifying OSAS early after its occurrence is probably also important to prevent its recurrence when reaching adult age. Recent data show that children with OSAS have impaired twopoint discrimination in their tongue and hard palate, suggesting the permanent vibrations caused by their snoring may result in permanent nerve damage to their upper airway, potentially forming the basis for the recurrence of OSAS in adult life (13). Taken together, these data strongly suggest that sleepdisordered breathing in children, particularly those born preterm, should be identified, characterized, and treated (e.g., by antiinflammatory drugs or adenotomy) (14) to prevent long-term consequences extending into adulthood. The good news in the study by Marcus and colleagues (2) is that neonatal caffeine citrate treatment, recently shown to exert positive effects on motor development that extend into middle childhood (15), does not appear to come at the expense of poor sleep quality or quantity. This is particularly reassuring, given the fact that caffeine ranks third among drugs most commonly used in the neonatal intensive care unit (16). Thus, these new data provide further reassurance for a considerable proportion of children born preterm that neonatal caffeine administration is safe. Nonetheless, several open questions remain. For example, although it has recently been shown that caffeine

American Journal of Respiratory and Critical Care Medicine Volume 190 Number 7 | October 1 2014