TABLE 1

] Incidence of PCD, Thoracoabdominal Asymmetry Subgroups, and PCD-CHD Overlap

Population

Incidence

Situs Solitus

Situs Inversus

Situs Ambiguus Without Heterotaxic CHD

General



Majority

1 in 10,0001,2, a

Unknown

PCD

1 in 8,000 to 1 in 20,0006,7

47%

1,2

41%

1,2

Heterotaxy (Situs Ambiguus 1 CHD) 1 in 10,0003,5, b

9.5%

2.5% (1 in 40 patients with PCD)1,2

1,2

CHD 5 congenital heart disease; PCD 5 primary ciliary dyskinesia. Twenty-five percent or more may have PCD. b Unknown percentage associated with PCD. a

situs inversus, situs solitus, and situs ambiguus in litters with early loss of many situs ambiguus fetuses due to CHD. This raises the question of whether the lower incidence of human situs ambiguus in the study by Shapiro et al1 could be associated with in utero loss. This is also reflected by the fact that most patients with PCD with situs ambiguus do not have heterotaxic CHD but, rather, mild and isolated laterality defects.1,2 Further insight is required to answer why the majority of patients with PCD have situs solitus despite defective embryonic nodal ciliary function. The final question of how much human CHD could be attributed to defective ciliary function should be easier to address. By virtue of the severity of the defects in heterotaxic CHD, it is usually symptomatic and, thus, is identified either before or soon after birth.7 It is estimated that heterotaxic CHD comprises approximately 3% of congenital heart defects and has an estimated prevalence of one in 10,000 live births.5 Given that currently, approximately one in five genes identified as associated with heterotaxic CHD are ciliary genes4 and the number of genes identified as associated with PCD is growing exponentially and now includes genes expressed in the cytoplasm involved in preassembly of cilia,9 the initial study reporting ciliary dysfunction in . 40% patients with heterotaxic CHD may be an underestimation.3 With better genetic testing, it may be feasible and inexpensive to screen all patients with CHD for PCD-related genes, which may improve outcomes through early detection and treatment of respiratory disease associated with PCD.

References 1. Shapiro AJ, Davis SD, Ferkol T, et al; on behalf of the Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest. 2014;146(5): 1176-1186. 2. Kennedy MP, Omran H, Leigh MW, et al. Congenital heart dis ease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. 2007;115(22): 2814-2821. 3. Nakhleh N, Francis R, Giese RA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125(18):2232-2242.

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4. Brueckner M. Impact of genetic diagnosis on clinical management of patients with congenital heart disease: cilia point the way. Circulation. 2012;125(18):2178-2180. 5. Lin AE, Ticho BS, Houde K, Westgate MN, Holmes LB. Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med. 2000;2(3):157-172. 6. Torgersen J. Situs inversus, asymmetry, and twinning. Am J Hum Genet. 1950;2(4):361-370. 7. Katsuhara K, Kawamoto S, Wakabayashi T, Belsky JL. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest. 1972;61(1):56-61. 8. Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxias. Eur J Hum Genet. 2006;14(1):17-25. 9. Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013;188(8):913-922. 10. Strippoli MP, Frischer T, Barbato A, et al; ERS Task Force on Primary Ciliary Dyskinesia in Children. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J. 2012;39(6):1482-1491. 11. Barbato A, Frischer T, Kuehni CE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J. 2009;34(6):1264-1276. 12. Supp DM, Witte DP, Potter SS, Brueckner M. Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature. 1997;389(6654):963-966. 13. Ibañez-Tallon I, Gorokhova S, Heintz N. Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Hum Mol Genet. 2002;11(6):715-721. 14. Ibañez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet. 2004;13(18):2133-2141. 15. Tan SY, Rosenthal J, Zhao XQ, et al. Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia. J Clin Invest. 2007;117(12):3742-3752.

Atrial Fibrillation During Sepsis A Determinant of Long-term Outcomes? Yee C. Lau, MBChB Gregory Y. H. Lip, MD Birmingham, England

Despite the advancement of antimicrobial agents, sepsis remains a major global health issue and leading cause of death in low-income countries. In the United States,

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severe sepsis affects up to 750,000 Americans and is associated with a high mortality rate.1 In severe sepsis, atrial fibrillation (AF) also commonly occurs.2 Sepsis may precipitate AF per se, perhaps unmasking a propensity to develop the arrhythmia, or the association could reflect greater clinical vigilance or monitoring during treatment (or hospitalization) for severe sepsis. Nonetheless, the prognostic effects of sepsis-associated new-onset AF on the subsequent occurrence of AF and long-term outcomes remained uncertain until, in the present issue of CHEST, the article by Walkey et al3 (see page 1187) sheds some light on these questions. Using data extracted from Medicare claims between 1999 and 2010, Walkey et al3 report an observational study showing patients with sepsis and associated new-onset AF have a higher rate of AF occurrence following hospitalization compared with those without AF during sepsis (54.9% vs 15.5%). This finding is potentially of significant importance, as contemporary perception is that with the treatment of sepsis, sustained atrial arrhythmia will be eliminated. Nevertheless, a possible explanation for this finding may be that the more elderly population in the new-onset AF group possessed higher incidence of asymptomatic, chronic silent AF, which was brought to light by hospitalization secondary to acute sepsis, than the no-AF group (age 80.7 years vs 79.5 years). Sepsis and subsequent inflammatory response also may have unmasked those with higher propensity for development and maintenance of AF, as illustrated by the higher incidence of comorbidities classically associated with AF, among the new-onset AF group compared with the no-AF group, such as heart failure, ischemic heart disease, and valvular heart disease. AFFILIATIONS: From the University of Birmingham Centre for Cardiovascular Sciences, City Hospital. FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following conflicts of interest: Dr Lip has served as a consultant for Bayer AG, Astellas Pharma Inc, Merck & Co, Sanofi SA, Bristol-Myers Squibb Co/Pfizer Inc, Daiichi-Sankyo Co Ltd, Biotronik, Medtronic Inc, Portola Pharmaceuticals Inc, and Boehringer Ingelheim GmbH, and has been on the speakers bureau for Bayer AG, Bristol-Myers Squibb Co/Pfizer Inc, Boehringer Ingelheim GmbH, Daiichi-Sankyo Co Ltd, Medtronic Inc, and Sanofi Aventis US LLC. Dr Lau has reported no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. CORRESPONDENCE TO: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Rd, Birmingham, B18 7QH, England; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0986

journal.publications.chestnet.org

What are the clinical implications? This finding further emphasizes the need for clinicians to look harder and longer for AF among the at-risk population, for example, the sepsis survivor, through regular review of symptoms, opportunistic screening via pulse palpation, and/or ambulatory ECG monitoring.4 The need for diligent AF detection can be demonstrated by the high pick-up rate of previously undiagnosed AF by continuous monitoring, via implantable loop recorder, of patients with prior ischemic stroke or thromboembolism.5 Equally important, Walkey et al3 also uncovered that new-onset AF during sepsis leads to poorer long-term outcomes, with higher rate of hospitalization for heart failure, ischemic stroke, and death. This relationship remains, even after adjustment for several patient and sepsis factors. The article demonstrates a relatively low, cumulative, 5-year ischemic stroke event rate in newonset AF group (5.3%) vs no AF group (4.7%), but this perhaps reflects survivor bias, as the 5-year mortality rate in all patient groups far exceeded 70%. With the combination of increased AF occurrence and worse outcomes (hospitalization of heart failure, ischemic stroke, and death) among those sepsis survivors with new-onset AF, proactive vigilance for AF and its management, particularly stroke prevention, is important. An intimate relationship between sepsis and a propensity for thrombosis is evident, which may be ameliorated by antibiotics used to treat sepsis.6 In some patients, the use of oral anticoagulation therapy may not be recommended during the acute phase of severe sepsis, due to potential coagulopathy secondary to sepsis per se or corresponding sepsis-induced organ failure or difficulties achieving therapeutic anticoagulation with vitamin K antagonists (VKAs) (eg, warfarin) during an acute illness.7 The risk of bleeding is further increased by the need for frequent, invasive, therapeutic, or surgical procedures for resuscitation or resolution of the initial cause of sepsis. The availability of the non-VKA oral anticoagulants offer efficacy, safety, and convenience over the VKAs, and allows easier initiation of thromboprophylaxis and a potentially greater net clinical benefit.8 Current guidelines recommend use of the CHA2DS2-VASc (congestive heart failure, hypertension, age ⱖ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, and sex category) score to identify those with lowest risk for stroke or morbidity, following which effective stroke prevention with oral anticoagulation therapy can be

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offered to those with one or more risk factors. Prestroke risk assessment is simple and feasible, being supported by recent publications validating that the high prestroke CHA2DS2-VASc score predicts worse long-term outcome even in patients with sepsis but without AF.9,10 Finally, Walkey et al3 also highlight the potential of upstream therapy to tackle sepsis-associated new-onset AF. Sepsis triggers an inflammatory response, and this may directly increase the risk of AF via increased catecholamine release. Previous work has demonstrated the significant rise in C-reactive protein level prior to the onset of sepsis-induced AF.2 Thus, potential suppression of overwhelming inflammation may have a role in reducing the incidence of, or even preventing, subsequent arrhythmia. For example, the potential of perioperative use of corticosteroids in cardiac surgery to prevent AF has been promising.11 In sepsis, systemic steroids, however, may be counterproductive, so other options need to be found. Given the high prevalence of AF, the challenge is to accurately identify those patients who have an increased propensity for developing AF and those at particular risk of complications. Indeed, sepsis may simply be the catalyst to expose the vulnerability of developing this arrhythmia (and its complications). In conclusion, Walkey et al3 demonstrate a high incidence of occurrence of further AF in sepsis survivors who had previously experienced acute sepsis-associated AF. These patients also exhibited higher rates of mortality and stroke, and heart failure risk. As survival of sepsis improves, there is the need to diligently identify those at risk for AF recurrence and its complications.

References 1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 2. Meierhenrich R, Steinhilber E, Eggermann C, et al. Incidence and prognostic impact of new-onset atrial fibrillation in patients with septic shock: a prospective observational study. Crit Care. 2010; 14(3):R108. 3. Walkey AJ, Hammill BG, Curtis LH, Benjamin EJ. Long-term outcomes following development of new-onset atrial fibrillation during sepsis. Chest. 2014;146(5):1187-1195. 4. Lowres N, Neubeck L, Redfern J, Freedman SB. Screening to identify unknown atrial fibrillation. A systematic review. Thromb Haemost. 2013;110(2):213-222. 5. Cotter PE, Martin PJ, Ring L, Warburton EA, Belham M, Pugh PJ. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology. 2013;80(17):1546-1550. 6. Franks Z, Campbell RA, Vieira de Abreu A, et al. Methicillinresistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration. Thromb Haemost. 2013;109(4):684-695. 7. De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III).

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8.

9.

10.

11.

Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;110(6):1087-1107. Pisters R, Nieuwlaat R, Lane DA, Crijns HJ, Lip GY. Potential net clinical benefit of population-wide implementation of apixaban and dabigatran among European patients with atrial fibrillation. A modelling analysis from the Euro Heart Survey. Thromb Haemost. 2013;109(2):328-336. Ntaios G, Lip GY, Makaritsis K, et al. CHADS2, CHA2S2DS2-VASc, and long-term stroke outcome in patients without atrial fibrillation. Neurology. 2013;80(11):1009-1017. Tu HT, Campbell BC, Meretoja A, et al. Pre-stroke CHADS2 and CHA2DS2-VASc scores are useful in stratifying three-month outcomes in patients with and without atrial fibrillation. Cerebrovasc Dis. 2013;36(4):273-280. Dieleman JM, van Paassen J, van Dijk D, et al. Prophylactic corticosteroids for cardiopulmonary bypass in adults. Cochrane Database Syst Rev. 2011;(5):CD005566.

Fibroproliferative ARDS in the Era of Low-Tidal-Volume Ventilation Manu Jain, MD Chicago, IL

Though mortality in ARDS has been improving, in unselected populations, mortality may still be as high as 40%.1 Patients with ARDS infrequently die of refractory hypoxemia and more often die due to sepsis and multiorgan failure, both complications of prolonged mechanical ventilation (MV). Inability to discontinue MV likely reflects disordered lung repair which may in part be due to excessive fibroblast activation. Markers of fibroblast activation such as procollagen III2 and transforming growth factor-b are elevated early in ARDS3 and are associated with increased mortality. Factors that have contributed to better ARDS outcomes include less-injurious MV strategies, judicious fluid management, and generally improved supportive care.4,5 As more patients with ARDS are surviving their acute illness, long-term outcomes for these patients have garnered increased attention. It has been shown in multiple studies that survivors of ARDS continue to have reduced health-related quality of life (HRQoL) AFFILIATIONS:

From the Division of Pulmonary Critical Care, Department of Medicine, Northwestern University. FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. CORRESPONDENCE TO: Manu Jain, MD, Northwestern University, 240 E Huron Ave, McGaw M-332, Chicago, IL 60611; e-mail: m-jain@ northwestern.edu © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1210

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Atrial fibrillation during sepsis: a determinant of long-term outcomes?

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