Overview of the pulmonary complications of sickle cell disease
- Elizabeth S Klings, MD
Elizabeth S Klings, MD
- Associate Professor of Medicine
- Boston University School of Medicine
- Harrison W Farber, MD
Harrison W Farber, MD
- Professor of Medicine
- Boston University School of Medicine
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Jess Mandel, MD
Jess Mandel, MD
- Section Editor — Pulmonary Vascular Disease
- Professor of Medicine
- University of California, San Diego
Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by amino acid substitutions in the beta globin chain. The most frequently occurring form of SCD is caused by homozygous presence of hemoglobin S (HbSS). Hemoglobin S results from the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain. The resulting hemoglobin tetramer (alpha2/betaS2) is poorly soluble when deoxygenated. Other forms of SCD include HbSC disease, in which an individual is a compound heterozygote for the sickle mutation and hemoglobin C (created by substitution of lysine for glutamic acid as the sixth amino acid), and sickle hemoglobin-beta thalassemia0 or + in which one beta chain allele has the HbS mutation and the other has a beta thalassemia mutation with reduced or absent production of the beta chain.
Deoxygenated sickle hemoglobin polymerizes into sheets of elongated rope-like fibers, causing a marked decrease in red cell deformability and distortion of the cell into the classic crescent or sickle shape (picture 1), the primary pathophysiologic event responsible for vaso-occlusive complications (picture 1) . Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of SCD and result in recurrent painful episodes (previously called sickle cell crisis) and a variety of serious organ system complications that can lead to life-long disabilities and premature death. However, hemoglobin polymerization alone does not account for the full pathophysiology of SCD. Subsequent changes in red cell membrane structure and function, disordered cell volume control, and increased adherence to vascular endothelium also play an important role [1-3]. (See "Sickle hemoglobin polymer: Structure and functional properties" and "Mechanisms of vaso-occlusion in sickle cell disease".)
Chronic pulmonary complications are common in patients with SCD and contribute to morbidity and mortality [4-6]. These complications represent a broad group of disorders involving a spectrum of cell types and pathophysiologic processes and include:
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- Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337:762.
- Kaul DK, Fabry ME, Costantini F, et al. In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse. J Clin Invest 1995; 96:2845.
- Ergul S, Brunson CY, Hutchinson J, et al. Vasoactive factors in sickle cell disease: in vitro evidence for endothelin-1-mediated vasoconstriction. Am J Hematol 2004; 76:245.
- Minter KR, Gladwin MT. Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment, and research. Am J Respir Crit Care Med 2001; 164:2016.
- Siddiqui AK, Ahmed S. Pulmonary manifestations of sickle cell disease. Postgrad Med J 2003; 79:384.
- Machado RF, Gladwin MT. Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Br J Haematol 2005; 129:449.
- Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 2008; 359:2254.
- Klings ES, Anton Bland D, Rosenman D, et al. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. Am J Hematol 2008; 83:547.
- Klings ES, Machado RF, Barst RJ, et al. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med 2014; 189:727.
- Klings ES, Wyszynski DF, Nolan VG, Steinberg MH. Abnormal pulmonary function in adults with sickle cell anemia. Am J Respir Crit Care Med 2006; 173:1264.
- Knight-Madden JM, Forrester TS, Lewis NA, Greenough A. The impact of recurrent acute chest syndrome on the lung function of young adults with sickle cell disease. Lung 2010; 188:499.
- O Dosunmu A, A Akinola R, A Onakoya J, et al. Pattern of chronic lung lesions in adults with sickle cell disease in Lagos, Nigeria. Caspian J Intern Med 2013; 4:754.
- Anthi A, Machado RF, Jison ML, et al. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med 2007; 175:1272.
- Field JJ, Glassberg J, Gilmore A, et al. Longitudinal analysis of pulmonary function in adults with sickle cell disease. Am J Hematol 2008; 83:574.
- Mehari A, Klings ES. Chronic Pulmonary Complications of Sickle Cell Disease. Chest 2016; 149:1313.
- Arteta M, Campbell A, Nouraie M, et al. Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol 2014; 36:185.
- Koumbourlis AC. Lung function in sickle cell disease. Paediatr Respir Rev 2014; 15:33.
- Intzes S, Kalpatthi RV, Short R, Imran H. Pulmonary function abnormalities and asthma are prevalent in children with sickle cell disease and are associated with acute chest syndrome. Pediatr Hematol Oncol 2013; 30:726.
- Uong EC, Boyd JH, DeBaun MR. Daytime pulse oximeter measurements do not predict incidence of pain and acute chest syndrome episodes in sickle cell anemia. J Pediatr 2006; 149:707.
- Quinn CT, Ahmad N. Clinical correlates of steady-state oxyhaemoglobin desaturation in children who have sickle cell disease. Br J Haematol 2005; 131:129.
- Campbell A, Minniti CP, Nouraie M, et al. Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients. Br J Haematol 2009; 147:352.
- Rackoff WR, Kunkel N, Silber JH, et al. Pulse oximetry and factors associated with hemoglobin oxygen desaturation in children with sickle cell disease. Blood 1993; 81:3422.
- Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood 2006; 108:2923.
- Knight-Madden JM, Forrester TS, Lewis NA, Greenough A. Asthma in children with sickle cell disease and its association with acute chest syndrome. Thorax 2005; 60:206.
- Leong MA, Dampier C, Varlotta L, Allen JL. Airway hyperreactivity in children with sickle cell disease. J Pediatr 1997; 131:278.
- Koumbourlis AC, Zar HJ, Hurlet-Jensen A, Goldberg MR. Prevalence and reversibility of lower airway obstruction in children with sickle cell disease. J Pediatr 2001; 138:188.
- Glassberg JA, Strunk R, DeBaun MR. Wheezing in children with sickle cell disease. Curr Opin Pediatr 2014; 26:9.
- Field JJ, DeBaun MR. Asthma and sickle cell disease: two distinct diseases or part of the same process? Hematology Am Soc Hematol Educ Program 2009; :45.
- Ozbek OY, Malbora B, Sen N, et al. Airway hyperreactivity detected by methacholine challenge in children with sickle cell disease. Pediatr Pulmonol 2007; 42:1187.
- Sen N, Kozanoglu I, Karatasli M, et al. Pulmonary function and airway hyperresponsiveness in adults with sickle cell disease. Lung 2009; 187:195.
- Naik RP, Streiff MB, Lanzkron S. Sickle cell disease and venous thromboembolism: what the anticoagulation expert needs to know. J Thromb Thrombolysis 2013; 35:352.
- Haupt HM, Moore GW, Bauer TW, Hutchins GM. The lung in sickle cell disease. Chest 1982; 81:332.
- Oppenheimer EH, Esterly JR. Pulmonary changes in sickle cell disease. Am Rev Respir Dis 1971; 103:858.
- Haque AK, Gokhale S, Rampy BA, et al. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002; 33:1037.
- Graham JK, Mosunjac M, Hanzlick RL, Mosunjac M. Sickle cell lung disease and sudden death: a retrospective/prospective study of 21 autopsy cases and literature review. Am J Forensic Med Pathol 2007; 28:168.
- Mekontso Dessap A, Deux JF, Abidi N, et al. Pulmonary artery thrombosis during acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 2011; 184:1022.
- Naik RP, Streiff MB, Haywood C Jr, et al. Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication. Am J Med 2013; 126:443.
- Novelli EM, Huynh C, Gladwin MT, et al. Pulmonary embolism in sickle cell disease: a case-control study. J Thromb Haemost 2012; 10:760.
- Stein PD, Beemath A, Meyers FA, et al. Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease. Am J Med 2006; 119:897.e7.
- Kabrhel C, Mark Courtney D, Camargo CA Jr, et al. Factors associated with positive D-dimer results in patients evaluated for pulmonary embolism. Acad Emerg Med 2010; 17:589.
- Powars D, Weidman JA, Odom-Maryon T, et al. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine (Baltimore) 1988; 67:66.
- Vij R, Machado RF. Pulmonary complications of hemoglobinopathies. Chest 2010; 138:973.
- Kaleyias J, Mostofi N, Grant M, et al. Severity of obstructive sleep apnea in children with sickle cell disease. J Pediatr Hematol Oncol 2008; 30:659.
- Rogers VE, Lewin DS, Winnie GB, Geiger-Brown J. Polysomnographic characteristics of a referred sample of children with sickle cell disease. J Clin Sleep Med 2010; 6:374.
- Needleman JP, Franco ME, Varlotta L, et al. Mechanisms of nocturnal oxyhemoglobin desaturation in children and adolescents with sickle cell disease. Pediatr Pulmonol 1999; 28:418.
- Sharma S, Efird JT, Knupp C, et al. Sleep disorders in adult sickle cell patients. J Clin Sleep Med 2015; 11:219.
- Strauss T, Sin S, Marcus CL, et al. Upper airway lymphoid tissue size in children with sickle cell disease. Chest 2012; 142:94.
- Rosen CL, Debaun MR, Strunk RC, et al. Obstructive sleep apnea and sickle cell anemia. Pediatrics 2014; 134:273.
- Spivey JF, Uong EC, Strunk R, et al. Low daytime pulse oximetry reading is associated with nocturnal desaturation and obstructive sleep apnea in children with sickle cell anemia. Pediatr Blood Cancer 2008; 50:359.
- Hargrave DR, Wade A, Evans JP, et al. Nocturnal oxygen saturation and painful sickle cell crises in children. Blood 2003; 101:846.
- Kirkham FJ, Hewes DK, Prengler M, et al. Nocturnal hypoxaemia and central-nervous-system events in sickle-cell disease. Lancet 2001; 357:1656.
- Brooks LJ, Koziol SM, Chiarucci KM, Berman BW. Does sleep-disordered breathing contribute to the clinical severity of sickle cell anemia? J Pediatr Hematol Oncol 1996; 18:135.
- Roizenblatt M, Figueiredo MS, Cançado RD, et al. Priapism is associated with sleep hypoxemia in sickle cell disease. J Urol 2012; 188:1245.
- Narang I, Kadmon G, Lai D, et al. Higher nocturnal and awake oxygen saturations in children with sickle cell disease receiving hydroxyurea therapy. Ann Am Thorac Soc 2015; 12:1044.
- Ambrusko SJ, Gunawardena S, Sakara A, et al. Elevation of tricuspid regurgitant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease. Pediatr Blood Cancer 2006; 47:907.