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Overview of the pulmonary complications of sickle cell disease
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Overview of the pulmonary complications of sickle cell disease
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Apr 18, 2016.

INTRODUCTION — 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) [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 vasoocclusion 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:

Chronic dyspnea

Pulmonary function test abnormalities

Asthma or recurrent wheezing without a diagnosis of asthma

Pulmonary hypertension

Acute and chronic venous thromboembolic disease

Pulmonary fibrosis

Sleep-disordered breathing

Issues relating to the chronic pulmonary manifestations of SCD will be reviewed here [6,7]. Other aspects of SCD, such as diagnosis and management and acute pulmonary presentations, are discussed separately. (See "Overview of the clinical manifestations of sickle cell disease" and "Diagnosis of sickle cell disorders" and "Routine comprehensive care for children with sickle cell disease" and "The acute chest syndrome in children and adolescents with sickle cell disease" and "Acute chest syndrome in adults with sickle cell disease" and "Overview of the management and prognosis of sickle cell disease".)

ACUTE CHEST SYNDROME — Acute chest syndrome (ACS) is the most common form of acute pulmonary disease in patients with SCD, occurring in almost one-half of patients. ACS is defined as a new opacity on chest radiograph accompanied by fever and/or respiratory symptoms in a patient with SCD. Etiologies include pulmonary vasoocclusion and ischemia, pneumonia, fat embolization, and thromboembolism. Discussions of the acute chest syndrome in children, adolescents, and adults are presented separately. (See "The acute chest syndrome in children and adolescents with sickle cell disease" and "Acute chest syndrome in adults with sickle cell disease".)

CHRONIC DYSPNEA — Dyspnea is a common yet under-reported symptom in SCD, particularly in adults. Many SCD patients begin to experience subtle declines in their exercise capacity in early to late adolescence, and a careful history will often reveal self-limitations on previously performed sports and exertional activities. This subtle dyspnea becomes more overt as these patients reach adulthood. Screening questionnaires of 147 adults with HbSS and HbSC have helped to characterize this symptom more objectively. Approximately 50 percent of adults with HbSS and 40 percent of those with HbSC experience dyspnea with mild to moderate exertion [8].

The etiology of chronic dyspnea in SCD is likely multi-factorial. While anemia is an important contributor, other explanations for dyspnea often co-exist. A careful history (including specific questions about exercise limitations and level of conditioning), physical examination, comparison of hemoglobin level with baseline values, pulmonary function tests, and ambulatory oximetry are recommended to fully characterize dyspnea in this population (table 1) [9].  

Generally, this initial evaluation will provide clues as to the etiology of chronic dyspnea and direct further studies and management, as described in the following sections. Common causes of dyspnea in chronic SCD include anemia, deconditioning, asthma, pulmonary hypertension, venous thromboembolism, pulmonary fibrosis from recurrent acute chest events, and myocardial dysfunction. These conditions are discussed below and separately. (See "Pulmonary hypertension associated with sickle cell disease" and "Overview of the clinical manifestations of sickle cell disease", section on 'Cardiac complications' and "Overview of the clinical manifestations of sickle cell disease", section on 'Anemia'.)

PULMONARY FUNCTION TESTS — Pulmonary function tests (PFTs) are often abnormal in adult and pediatric patients with SCD. In these discussions, pediatric patients are defined by an age <18 years [4]. (See "Overview of pulmonary function testing in adults" and "Overview of pulmonary function testing in children".)

Adults — PFTs are generally obtained in adults with SCD in response to a report of dyspnea or to monitor known asthma. In a cross-sectional evaluation from the multi-center Cooperative Study of Sickle Cell Disease, pulmonary function was assessed in 310 adult African-American subjects with HbSS disease irrespective of symptoms [10]. Only 10 percent of these patients had completely normal PFTs. The following abnormal PFT patterns were found [10-12]:

Restrictive pattern – 74 percent

Isolated low diffusing capacity for carbon monoxide (DLCO) – 13 percent

Mixed obstructive/restrictive pattern – 2 percent

Obstructive pattern – 1 percent

These patterns were not significantly different between subjects with or without a prior history of acute chest syndrome. Similar findings were reported in another cohort of adult patients [13]. Even when corrected for anemia, the DLCO is often low, particularly in patients with a history of the acute chest syndrome (calculator 1 and calculator 2) [10].

Longitudinal studies of pulmonary function in adults with SCD demonstrate an average decline in forced expiratory volume in one second (FEV1) of 49 mL/year compared with 20 to 26 mL/year in the general population [14]. The decline is unrelated to smoking status.

Pulse oxygen saturation (SpO2) is reduced in adults with SCD, with steady-state baseline values below 96 percent in an appreciable portion of patients. Significant desaturations occur with exertion and with sleep. A widened alveolar-arterial oxygen gradient is observed both at rest and with exercise [15]. (See 'Sleep disordered breathing' below.)

Children — Children and adolescents with SCD commonly have abnormal PFTs, and asthma is common among children with SCD. Thus, we suggest performing spirometry in children with SCD every one to three years, using the more frequent intervals for those with dyspnea, a history of asthma or recurrent wheezing, or accentuated elevations in hemolytic markers [16].

While restrictive physiology, as observed in adults, can occur in the pediatric age group, a number of studies of non-referred cohorts report a predominance of obstructive disease [17,18].

A retrospective study of 127 children and adolescents with SCD found that obstructive airways disease was present in 35 percent while restrictive physiology occurred in 26 percent [18]. The remaining 39 percent had normal pulmonary function.

In a subsequent prospective study, 146 patients aged 7 to 20 years with HbSS or HbS-beta0 thalassemia were evaluated with PFTs [16]. In this study, 39 percent had abnormal PFTs with an obstructive pattern present in 19 percent, restrictive in 9 percent, and abnormal but not characterized in 11 percent. Increasing age, a family or patient history of asthma or wheezing, and an elevated lactate dehydrogenase (LDH) level reflective of hemolysis were all predictive of obstructive physiology.

Measurements of SpO2 are typically below normal in children with SCD. As examples:

In a prospective cohort study of 130 children from the Cooperative Study for Sickle Cell Disease (CSSCD), mean and median daytime SpO2 were 94 and 95 percent, respectively [19].

Similar results (95 to 96 percent) were seen in three other studies of mean daytime SpO2 [20-22].

In contrast to nocturnal hypoxemia, daytime SpO2 does not appear to independently predict subsequent pain or acute chest episodes [19]. In addition, there are currently no data correlating daytime SpO2 with nighttime SpO2, which generally is lower than daytime values [19]. Nevertheless, SpO2 values below baseline measurements for individual patients with SCD, either at rest or following exercise, are useful in detecting and monitoring for the presence of pulmonary complications.

ASTHMA — Asthma is common in patients with SCD, particularly among children and adolescents, and may affect the course of the disease [23]. As an example, in a case control study, asthma was more common among 80 children with SCD than among ethnically-matched controls (48 versus 22 percent) [24]. Similarly, small cohort studies suggest that children with SCD are at increased risk for developing airway hyperreactivity and airway obstruction [25,26].

The interrelationship of asthma and SCD is complex and not well-understood. Children with a history of acute chest syndrome (ACS) are more likely to develop asthma [24]. It is thought that severe airway narrowing due to asthma can lead to local hypoxia and promote sickling and systemic inflammation [27]. In addition, recurrent ACS may contribute to lung inflammation and increased bronchial hyperreactivity [28-30]. While some patients clearly have an atopic phenotype [24], others do not, suggesting that non-allergic mediated inflammation plays a role in the pathogenesis of asthma in patients with SCD [28]. The contribution of asthma to ACS is discussed separately. (See "The acute chest syndrome in children and adolescents with sickle cell disease", section on 'Asthma'.)

The diagnosis of asthma in SCD can be challenging because the symptoms and signs of asthma (eg, shortness of breath, cough, wheeze) overlap with other pulmonary complications of SCD. The presence of intermittent or chronic symptoms and wheezing on examination should lead to an evaluation for asthma. As in other settings, the diagnosis of asthma is based upon the demonstration of variable airflow limitation, preferably by spirometry before and after bronchodilator, and exclusion of alternate diagnoses. In addition to asthma, the differential diagnosis of wheezing in a patient with SCD includes processes such as viral infection, gastroesophageal reflux, congenital abnormalities (eg, vascular ring, congenital lobar emphysema), bronchiectasis, tuberculosis, and vocal cord dysfunction. (See "Asthma in children younger than 12 years: Initial evaluation and diagnosis" and "Wheezing illnesses other than asthma in children" and "Diagnosis of asthma in adolescents and adults" and "Evaluation of wheezing illnesses other than asthma in adults".)

Management of asthma in SCD should follow guidelines established for non-SCD patients with asthma. (See "An overview of asthma management" and "Asthma in children younger than 12 years: Initiating therapy and monitoring control".)

PULMONARY HYPERTENSION — Pulmonary hypertension (PH) is a relatively frequent and severe complication of SCD and an independent risk factor for mortality [7]. Exertional dyspnea is a clue to the presence of PH; initial evaluation typically includes Doppler echocardiography, measurement of N-terminal-pro-brain natriuretic peptide (NT-pro-BNP), and a six minute walk test. PH may be suspected on the basis of exertional dyspnea and noninvasive testing, but definitive diagnosis requires right heart catheterization (RHC) with demonstration of a resting mean pulmonary arterial pressure (PAP) ≥25 mmHg (algorithm 1). The prevalence, pathogenesis, screening and risk stratification, diagnosis, and treatment of PH in SCD are discussed in greater detail separately. (See "Pulmonary hypertension associated with sickle cell disease".)

VENOUS THROMBOEMBOLISM AND PULMONARY THROMBOSIS — SCD is a hypercoagulable state with reported abnormalities in coagulation and platelet function [31]. Autopsy examinations of the lungs from patients with SCD reveal fibrin thrombi in larger arteries with or without infarction, and extensive thrombosis in smaller arteries (in-situ thrombosis) [32-35]. As an example, in a series of 21 patients with SCD with sudden death, pulmonary thromboembolism and microvascular occlusive thrombi were noted in 38 and 28 percent, respectively [35].

Several studies suggest that the frequencies of venous thromboembolism (VTE) and pulmonary arterial thrombosis are increased among patients with SCD [36-39]:

In a cross-sectional study of 404 patients with sickle cell disease, a history of VTE was noted in 25 percent and non-catheter-related VTE in 19 percent [37].

Data from the National Hospital Discharge Survey revealed that a discharge diagnosis of pulmonary embolism (PE) was approximately three times higher among patients with SCD than without, although the risk of deep vein thrombosis (DVT) was not increased [39]. Compared with non-SCD patients with a PE, those with SCD and a PE were significantly older and had a longer length of stay, greater severity of illness, and higher mortality [38].

Among 125 patients with acute chest syndrome (ACS) who underwent multidetector computed tomography (MDCT) during 144 ACS episodes, twenty MDCTs (17 percent) showed pulmonary artery thrombosis [36]. Lower limb deep venous thrombosis was rarely found. Pulmonary artery thrombosis was more common in patients with higher platelet counts and lower bilirubin (suggesting lower hemolytic rate), although there was substantial overlap.

The evaluation of acute VTE is slightly different in patients with SCD than without. The D-dimer and the modified Geneva score, methods used to screen for VTE, have limited value in SCD [36,40]. D-dimer levels are increased in SCD relative to controls and fluctuate with vasoocclusive events [31]. The poor predictive value of scoring systems is likely due to the overlap between the signs used in the scoring systems for VTE and the characteristic features of ACS. Thus, we typically perform a computed tomography pulmonary angiogram (CTPA) when VTE is suspected due to factors such as acute onset or worsening of dyspnea, presence of lower extremity edema, lack of expected improvement in pulse oxygen saturation with treatment of ACS, or when the patient has other risk factors for VTE (eg, central venous catheter, recent surgery, pregnancy, or immobility) [15,31]. (See "Clinical presentation, evaluation, and diagnosis of the adult with suspected acute pulmonary embolism".)

The optimal treatment of confirmed acute VTE and pulmonary thrombosis in SCD is not known, so we follow the usual guidelines for VTE treatment. Due to the risks of anticoagulation in patients with anemia due to SCD, we delay full anticoagulation pending the results of the CTPA. (See "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)

The evaluation and management of chronic VTE in patients with pulmonary hypertension is described separately. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Long-term anticoagulation'.)

All adults with SCD admitted to the hospital with an acute medical illness, including pneumonia and pulmonary hypertension, should receive venous thromboembolism (VTE) prophylaxis. This is discussed in more detail separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis'.)

PULMONARY FIBROSIS — Pulmonary fibrosis (chronic scarring of the lung parenchyma) is occasionally seen in patients with recurrent episodes of acute chest syndrome (ACS) with pulmonary infarction. In the past, the term sickle cell chronic lung disease (SCCLD) was used to describe the association of pulmonary fibrosis and pulmonary hypertension in SCD, but now these processes are considered individually [7,41,42].

The clinical manifestations of pulmonary fibrosis in SCD include dyspnea and scattered areas of honeycombing on high resolution computed tomography (HRCT) of the chest. A restrictive pattern on pulmonary function tests is common in adults with SCD and might be expected to be present in SCD-associated pulmonary fibrosis, possibly in association with a reduction in diffusing capacity for carbon monoxide (DLCO). However, studies to correlate imaging and pulmonary function tests have not been done.

There is no specific therapy for pulmonary fibrosis in SCD, other than attention to measures to prevent future episodes of ACS. (See "Acute chest syndrome in adults with sickle cell disease", section on 'Prevention of ACS'.)

SLEEP DISORDERED BREATHING — Sleep disordered breathing (SDB), which is commonly due to obstructive sleep apnea (OSA), has been identified as an important comorbidity in SCD that may contribute to the frequency of acute pain episodes and possibly chronic cardiopulmonary disease. Nocturnal desaturations can occur with or without the coexistence of OSA; their etiology is not well defined. Sleep-disordered breathing is under-appreciated and consequently, often under-treated in SCD. A standardized approach for screening and treating these patients has not been developed.

Prevalence – Many patients with SCD and SDB do not report symptoms of SDB, and the exact prevalence of SDB in asymptomatic patients is not known. Some studies in children and adolescents have reported a prevalence of up to 79 percent, but most of these data emanate from relatively small retrospective cohorts of symptomatic patients [43,44]. In one of the few screening studies of SCD patients irrespective of SDB symptoms, 20 of 38 (53 percent) met criteria for nocturnal oxygen desaturation on overnight oximetry, defined as having an oxyhemoglobin saturation of less than 92 percent for >5 percent of total sleep time [45]. A prospective study of 32 consecutive HbSS adults found SDB in 44 percent with a mean apnea-hypopnea index of 17/hour (95% CI 10-24/hour) [46].

Etiology – The etiology of SDB is not well understood in sickle cell disease. Children and adolescents with SCD have reduced upper airway diameters and increased adenoid and tonsillar size (known risk factors for OSA) compared with normal volunteers [47]. It has been presumed that OSA is the primary cause of nocturnal hypoxemia in SCD, but this is not necessarily the case. In one study of 20 patients with nocturnal hypoxemia, 12 did not have obstructive events during a 16 channel polysomnogram (PSG) [45], which may explain why adenotonsillectomy fails to correct hypoxemia in some patients [44]. In a cohort of 243 children with sickle cell anemia who had not previously been evaluated for SDB, the only independent risk factors for moderate to severe OSA were habitual snoring and pulse oxygen saturation (SpO2) <96 percent while awake [48]. A model incorporating these two risk factors had a negative predictive value of 0.99, but a positive predictive value of only 0.32 for OSA documented by polysomnography. (See "Adenotonsillectomy for obstructive sleep apnea in children", section on 'High-risk populations'.)

Nocturnal hypoxemia and hypoventilation – Gas exchange abnormalities in SCD are not limited to hypoxemia. In a study of 19 children with SCD and a history concerning for SDB, 12 met criteria for OSA [43]. When these patients were compared to 10 age-, sex-, and racially-matched children with OSA without co-existent SCD, the children with SCD had a longer duration of oxygen desaturation, a lower oxygen saturation nadir, and a higher percentage of sleep time with end-tidal carbon dioxide levels >50 mmHg, suggesting greater impairments of both oxygenation and ventilation. Furthermore, oxygen desaturations with sleep are associated with daytime hypoxemia in SCD, suggesting that the pathologic impact on the endothelium is not limited to sleep-related events [49].

There is some evidence linking nocturnal hypoxemia with an increased rate of both vasoocclusive episodes [50] and cerebrovascular events [51], but these data are inconsistent [52]. As an example, an association has been noted between OSA, nocturnal hypoxemia, and priapism among men with SCD [53].

Treatment with hydroxyurea may reduce nocturnal hypoxemia. In a retrospective study, 37 children with SCD receiving hydroxyurea were compared with 104 who were not [54]. The hydroxyurea group had significantly higher nocturnal nadir in the median pulse oxygen saturation (SpO2) than the non-hydroxyurea group (91.4 and 85 percent saturation, respectively, p = 0.0002). The median sleep and awake SpO2 values were also greater in the hydroxyurea group. No difference was observed in the apnea-hypopnea index or the frequency of OSA. While promising, the observational nature of the study limits the conclusions that can be drawn in terms of the effect of hydroxyurea on clinical outcomes such as vasoocclusive crises and sleep quality. (See "Hydroxyurea and other disease-modifying therapies in sickle cell disease".)

Indications for polysomnography – Evaluation for OSA by polysomnography is usually performed in patients with complaints such as snoring, non-restorative sleep, nocturnal gasping, choking, observed apneas during sleep, or daytime hypersomnolence, although it is possible that screening should be considered more broadly for children and adolescents with snoring, unexplained hypoxemia, recurrent acute chest or vaso-occlusive episodes, or enuresis. Because of the known association of OSA with pulmonary hypertension (PH) in non-SCD populations, the clinical guidelines for diagnosis of PH in SCD recommend a formal sleep study for all SCD patients with PH or an elevated tricuspid regurgitation velocity (TRV) on echocardiography [9]. (See "Overview of obstructive sleep apnea in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Evaluation of suspected obstructive sleep apnea in children".)

Treatment – The treatment of OSA complicating SCD is essentially the same as that in children and adults with OSA in the absence of SCD. In a small case series, treatment of SCD children with OSA produced a reduction in TRV [55]. Although SDB may be exacerbated by adenoid and tonsillar hypertrophy, adenotonsillectomy is often not curative in SCD patients, and its impact on cardiopulmonary outcomes is unclear. All children and adolescents with SCD and OSA, however, should be evaluated for adenotonsillar hypertrophy, as adenotonsillectomy may be curative in some. (See "Management of obstructive sleep apnea in children" and "Management of obstructive sleep apnea in adults".)

SICKLE CELL TRAIT — Respiratory dysfunction is rare in patients with sickle cell trait. Minimal, if any, differences in exercise tolerance and pulmonary function have been observed either at sea level or at higher altitudes when comparing individuals with sickle cell trait and matched controls who have normal hemoglobin. However, pulmonary infarction, acute chest syndrome, and sudden death during intense military training have rarely been reported and are discussed separately. (See "Sickle cell trait", section on 'Rhabdomyolysis and sudden death during strenuous physical activity'.)

SUMMARY AND RECOMMENDATIONS

Chronic pulmonary complications contribute substantially to morbidity and mortality in sickle cell disease (SCD). (See 'Introduction' above.)

Acute chest syndrome (ACS; defined as a new opacity of chest radiograph with fever and/or respiratory symptoms) is the most common form of acute pulmonary disease in SCD, occurring in almost one-half of patients. ACS is discussed in detail separately. (See "The acute chest syndrome in children and adolescents with sickle cell disease" and "Acute chest syndrome in adults with sickle cell disease".)

Dyspnea is a common yet under-reported symptom in SCD, particularly in adults. Questions that may help elicit a history of dyspnea and alert clinicians to the need for further evaluation are provided in the table (table 1). (See 'Chronic dyspnea' above.)

Pulmonary function tests are often abnormal in SCD. A restrictive pattern is the most common pattern among adults with SCD, while an obstructive pattern is more common in the pediatric age groups. (See 'Pulmonary function tests' above.)

Asthma is an important disease modifier in SCD: children with a history of acute chest syndrome (ACS) are more likely to develop asthma, and those with asthma are more susceptible to ACS. Intermittent or chronic respiratory symptoms and wheezing should lead to an evaluation for asthma. (See 'Asthma' above.)

Pulmonary hypertension (PH) is a relatively frequent and severe complication of SCD and an independent risk factor for mortality. PH may be suspected on the basis of exertional dyspnea and noninvasive testing, but definitive diagnosis requires right heart catheterization with demonstration of a resting mean pulmonary arterial pressure (PAP) ≥25 mmHg (algorithm 1). (See 'Pulmonary hypertension' above and "Pulmonary hypertension associated with sickle cell disease".)

The risks of venous thromboembolism (VTE) and pulmonary artery thrombosis are increased in SCD. Screening tests such as the D-dimer and clinical scoring systems are not reliable in SCD, so we typically perform a computed tomography pulmonary angiogram (CTPA) when acute VTE is suspected. Due to the risks of anticoagulation in patients with anemia due to SCD, we delay full anticoagulation pending the results of the CTPA. (See 'Venous thromboembolism and pulmonary thrombosis' above.)

Pulmonary fibrosis (chronic scarring of the lung parenchyma) is another potential cause of dyspnea and is occasionally seen in patients with recurrent episodes of ACS with pulmonary infarction. There is no specific therapy other than attention to measures to prevent future episodes of ACS. (See 'Pulmonary fibrosis' above.)

Sleep disordered breathing (nocturnal hypoxemia and obstructive sleep apnea [OSA]) is common in children and adolescents with SCD. The prevalence in adults is not completely clear, but a high index of clinical suspicion is warranted. Tonsillectomy and adenoidectomy may be curative in some children with OSA. (See 'Sleep disordered breathing' above.)

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