Overview of the pulmonary complications of sickle cell disease

INTRODUCTION — Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by amino acid substitutions in the beta globin chain. Sickle cell anemia is caused by homozygous sickle mutation (Hb SS). The sickle mutation causes substitution of a valine for glutamic acid as the seventh amino acid of the beta globin chain. The resulting hemoglobin tetramer (alpha2/betaS2) is poorly soluble when deoxygenated. Other forms of SCD include Hb SC 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 seventh amino acid), and sickle-beta⁺-thalassemia or sickle beta⁰- thalassemia, in which one beta globin allele has the Hb S mutation and the other has a beta thalassemia variant with reduced or absent production of beta globin.

The chronic pulmonary manifestations of SCD will be reviewed here [1,2]. Other aspects of SCD care, including the 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 "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)" and "Overview of the management and prognosis of sickle cell disease".)

PATHOPHYSIOLOGY — Deoxygenated sickle hemoglobin (picture 1) is the primary pathophysiologic event responsible for vaso-occlusive complications of SCD [3]. Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of SCD and result in recurrent painful episodes referred to as vaso-occlusive events (VOEs; previously called sickle cell crisis) (see "Acute vaso-occlusive pain management in sickle cell disease", section on 'Terms and language we avoid'). Details of the pathophysiology of SCD are provided separately. (See "Pathophysiology 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 segmental opacity on chest radiograph accompanied by fever and/or respiratory symptoms in a patient with SCD. Etiologies include pulmonary vaso-occlusion and ischemia, pneumonia, fat embolization, and thrombosis (either intravascular or thromboembolic). Infection remains a significant cause of ACS, especially in children, and infectious etiologies are essential to investigate and treat [4]. Discussions of the ACS in children, adolescents, and adults are presented separately. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

CHRONIC DYSPNEA — Dyspnea is a common yet underreported 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 Hb SS and Hb SC have helped to characterize this symptom more objectively. Approximately 50 percent of adults with Hb SS and 40 percent of those with Hb SC experience dyspnea with mild to moderate exertion [5].

The etiology of chronic dyspnea in SCD is likely multifactorial. While anemia is an important contributor, other explanations for dyspnea often coexist. 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) [6].

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'.)

ASTHMA — Asthma is common in patients with SCD, particularly among children and adolescents [7,8]. 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) [9]. Similarly, small cohort studies suggest that children with SCD are at increased risk for developing airway hyperreactivity and airway obstruction [10,11].

The interrelationship of asthma and SCD is complex and not well understood. In three large cohort studies examining the interrelationship of asthma and SCD, children with a diagnosis of asthma have increased rates of both pain and acute chest syndrome (ACS) [12]. Additionally, children with a history of ACS are more likely to develop asthma [9]. It is thought that severe airway narrowing due to asthma can lead to local hypoxia and promote sickling and systemic inflammation [13]. In addition, recurrent ACS may contribute to lung inflammation and increased bronchial hyperreactivity [14-16]. While some patients clearly have an atopic phenotype [9], which has been associated with an increased risk for ACS in children [17] others do not, suggesting that nonallergic mediated inflammation also plays a role in the pathogenesis of asthma in patients with SCD [14]. The contribution of asthma to ACS is discussed separately. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Overview of pathogenesis'.)

The diagnosis of asthma in people with 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 decompensated heart failure, viral infection, gastroesophageal reflux, congenital abnormalities (eg, vascular ring, congenital lobar emphysema), bronchiectasis, tuberculosis, and vocal cord dysfunction. (See 'Pulmonary function test abnormalities' below and "Asthma in children younger than 12 years: Initial evaluation and diagnosis" and "Asthma in adolescents and adults: Evaluation and diagnosis" 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: Overview of initiating therapy and monitoring control".)

PULMONARY FUNCTION TEST ABNORMALITIES — 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 [18]. (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, but practice varies. While some experts obtain PFTs in response to a report of dyspnea or to monitor known asthma, others obtain them on a routine basis. In a cross-sectional evaluation from the multicenter Cooperative Study of Sickle Cell Disease, pulmonary function was assessed in 310 Black adults with Hb SS disease irrespective of symptoms [19]. Only 10 percent of these patients had completely normal PFTs. The following abnormal PFT patterns were found [19-21]:

●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 individuals with or without a prior history of acute chest syndrome (ACS). Similar findings were reported in another cohort of adult patients [22]. Even when corrected for anemia, the DLCO is often low, particularly in patients with a history of ACS (calculator 1 and calculator 2) [19].

One longitudinal study of pulmonary function in adults with SCD demonstrated 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 [23]. The decline was unrelated to smoking status. In a subsequent cohort of 193 adults with SCD who had at least two spirometry tests over up to 10 years of monitoring, FEV₁ declined by 23 mL/year (95% CI -28 to -18) [24]. In this cohort, the rate of decline was similar to that observed in adult patients with cystic fibrosis.

Reduced FEV₁ percent predicted is associated with an increased risk of death in patients with SCD, as evidenced by a cohort of 430 adults with SCD, mean age 32.6±9.5 (range 21.0-67.8) years, who were monitored for a median of 5.5 years, during which 63 deaths occurred [25]. In the final multivariable model, a lower FEV₁ percent predicted was associated with increased hazard ratio (HR) of death (HR 1.02, 95% CI 1.00-1.04; p = 0.037).

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 [26]. (See 'Sleep-disordered breathing' below.)

Children — Children and adolescents with SCD may 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 [27].

While restrictive physiology, as observed in adults, can occur in the pediatric age group, a number of studies of nonreferred cohorts report a predominance of obstructive disease in those with abnormal lung function [28,29].

●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 [29]. The remaining 39 percent had normal pulmonary function.

●In a subsequent prospective study, 146 patients aged 7 to 20 years with Hb SS or Hb S-beta⁰ thalassemia were evaluated with PFTs [27]. 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.

●A study of 149 nonreferred Hb SS or Hb S-beta⁰ thalassemia children and adolescents participating in the National Institutes of Health (NIH)-funded Sleep and Asthma Cohort Study found that percentages of normal, obstructive, restrictive, nonspecific, and mixed lung function patterns were 70, 16, 7, 6, and 1, respectively [30]. Lung function pattern was not predictive of future vaso-occlusive events or ACS nor reflective of prior history of ACS, thus calling into question the predictive role of PFTs in this population.

●In a prospective study involving 19 children and young adults (ages 2 to 21 years) who underwent haploidentical stem cell transplantation, pulmonary functions including FEV₁/forced vital capacity (FVC), total lung capacity (TLC), and DLCO were stable to improved two years posttransplant compared with baseline values [31]. Specific airway conductance was significantly improved at two years (p<0.004).

Longitudinal studies have shown variability in the magnitude of decline in FEV₁ percent predicted over time among children. In a single-institution prospective study of 92 children, a decline of 1.7 percent per year was noted in one cohort (47 children ages 3 to 13 years examined over two years) and 0.9 percent per year in a second (45 children ages 4 to 16 years examined over 10 years) [32]. Examination of 197 children ages 4 to 19 years from the Sleep and Asthma Cohort Study showed a small decline of 0.3 percent in FEV₁ percent predicted over time (approximately five years). Furthermore, none of the examined clinical covariates (sex, baseline laboratory values, rate of pain or ACS, asthma diagnosis, or treatment with hydroxyurea) were associated with this decline [33]. Therefore, both the degree of decline in lung function from the pediatric population to adulthood and the factors impacting this decline are variable and unclear.

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 [34].

●Similar results (95 to 96 percent) were seen in three other studies of mean daytime SpO₂ [35-37].

●A study of 39 SCD patients (median age of 10.8 years) found that 45 percent had post-exercise hypoxemia defined as an SpO₂ decrease ≥3 percent after a six-minute walk test [38].

Daytime SpO₂ does not appear to independently predict subsequent vaso-occlusive or acute chest episodes [34]. In addition, there are no data correlating daytime SpO₂ with nighttime SpO₂, which generally is lower than daytime values [34]. 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.

PULMONARY HYPERTENSION — Pulmonary hypertension (PH) is a relatively frequent (occurring in 6 to 11 percent of adults) and severe complication of SCD and an independent risk factor for mortality [2]. 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-proBNP) levels, 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 (mPAP) ≥25 mmHg (algorithm 1). Updated criteria for PH include an mPAP ≥20 mmHg, but this value has not been specifically studied in patients with SCD. The prevalence, pathogenesis, screening and risk stratification, diagnosis, and treatment of PH in SCD are discussed in 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 [39]. 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) [40-43]. 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 [43]. A separate autopsy study of 30 patients from Brazil revealed recent thrombosis in 80 percent and old thrombosis in 43 percent [44].

Frequency of venous and arterial thrombosis — Several studies suggest that the frequencies of venous thromboembolism (VTE) and pulmonary arterial thrombosis are increased among patients with SCD [45-48]:

●In a cross-sectional study of 404 patients with SCD, a history of VTE was noted in 25 percent and noncatheter-related VTE in 19 percent [46].

●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 [48]. 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 [47]. A separate study also reported higher rates of PE than DVT in patients with SCD [49].

●Data from the California Patient Discharge Database (CPDD) revealed that in 6237 patients with SCD, 696 (11 percent) had an incident VTE by age 40. Among those with severe disease (defined as three or more hospitalizations in the prior year), 17 percent had sustained a VTE, and the five-year recurrence rate in these patients was 37 percent [50].

●Among 877 SCD patients in the CPDD with an incident VTE, the cumulative incidence of recurrence at one year was 13.2 percent (95% CI 11.0-15.5 percent) and at five years was 24.1 percent (95% CI 21.2-27.1 percent). Risk factors for VTE recurrence included more severe SCD (HR 2.41, 95% CI 1.67-3.47), lower extremity DVT as the incident event (HR 1.64, 95% CI 1.17-2.30), and pneumonia/acute chest syndrome (ACS) (HR 1.68, 95% CI 1.15-2.45). The cumulative incidence of bleeding was 4.9 percent (95% CI 3.5-6.4 percent) at six months and 7.9 percent (95% CI 6.2-9.8 percent) at one year [51].

Evaluation — 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 [45,52]. D-dimer levels are increased in SCD relative to controls and fluctuate with vaso-occlusive events [39]. 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, or lack of expected improvement in pulse oxygen saturation (SpO₂) with treatment of ACS, or when the patient has other risk factors for VTE (eg, long-term central venous catheter, recent surgery [particularly hip replacement], pregnancy, prior surgical splenectomy, or immobility) [26,39]. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Treatment — The optimal treatment of confirmed acute VTE and pulmonary thrombosis in SCD is not known, but the ongoing thrombotic risk and high rate of recurrence has led to the practice of lifelong anticoagulation after a first-time VTE in SCD patients without a contraindication [53]. However, due to the risks of anticoagulation in patients with worsening anemia due to SCD, we typically delay full anticoagulation pending the results of the CTPA unless the clinical suspicion is high. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Venous thromboembolism: Initiation of anticoagulation".)

The management of chronic VTE in patients with pulmonary hypertension (PH) 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 PH, should receive 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 and the term "sickle cell chronic lung disease" is considered obsolete [2,54,55].

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 (PFTs) 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 PFTs 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 (ACS) in sickle cell disease (adults and children)", section on 'Prevention'.)

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 [56]. Nocturnal desaturations can occur with or without the coexistence of OSA; their etiology is not well defined. SDB is underappreciated and, consequently, often undertreated 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, yet the prevalence of SDB appears to be higher than in the general population. In the Sleep and Asthma Cohort Study, 243 children unselected for symptoms of OSA underwent full-channel, in-laboratory polysomnography [57]. Using various obstructive apnea hypopnea indices (OAHI), OSA was present in 100 (41 percent) or 25 (10 percent) children at cutpoints of ≥1 or ≥5, respectively.

One prospective study of 32 consecutive adults with Hb SS found SDB in 44 percent with a mean apnea-hypopnea index (AHI) of 17/hour (95% CI 10-24/hour) [58]. Another small prospective study of 20 adults between 21 and 30 years of age found that 10 had an AHI >5 consistent with OSA irrespective of symptoms; this was associated with reduced health-related quality of life and increased systolic blood pressures. Interestingly, OSA in these patients was not associated with either obesity or a history of snoring [59].

●Etiology – The etiology of SDB is not well understood in SCD. Children and adolescents with SCD have reduced upper airway diameters and increased adenoid and tonsillar size (known risk factors for OSA) compared with volunteers without SCD [60]. 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) [61], which may explain why adenotonsillectomy fails to correct hypoxemia in some patients [62]. In the Sleep and Asthma cohort, among 243 children with sickle cell anemia, the only independent risk factors for moderate to severe OSA were habitual snoring and pulse oxygen saturation (SpO₂) <96 percent while awake [57]. 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 [63]. When these patients were compared with 10 age-, sex-, and racially matched children with OSA without coexistent 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 [64].

A retrospective study in adults and children with SCD referred for a sleep study identified isolated nocturnal hypoxemia in both age groups, which was associated with reduced daytime oxygen saturations at rest, and markers of worsening anemia [65].

There is some evidence linking nocturnal hypoxemia with an increased rate of vaso-occlusive episodes [66], acute chest syndrome (ACS) [67], and cerebrovascular events [68,69], but these data are inconsistent [70]. Data from the Sleep and Asthma Cohort study did not find an association between low nocturnal SpO₂ or higher OAHI and vaso-occlusive pain or ACS episodes. Alternatively, higher mean nocturnal SpO₂ was associated with higher rates of severe acute pain episodes (incidence rate ratio 1.10, 95% CI 1.03-1.18) [71]. However, adult studies have shown an association between OSA, nocturnal hypoxemia, and priapism among men with SCD [72].

Treatment with hydroxyurea may reduce nocturnal hypoxemia. In a retrospective study, 37 children with SCD receiving hydroxyurea were compared with 104 who were not [73]. The hydroxyurea group had significantly higher nocturnal nadir in the median 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 AHI 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 vaso-occlusive crises and sleep quality. (See "Hydroxyurea use in sickle cell disease".)

●Indications for polysomnography – Evaluation for OSA by polysomnography is usually performed in patients with complaints such as snoring, nonrestorative 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 [6]. (See "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 [74].

While SDB may be exacerbated by adenoid and tonsillar hypertrophy, adenotonsillectomy is often not curative in patients with SCD, and the impact on cardiopulmonary outcomes is unclear. Nonetheless, children and adolescents with SCD and OSA should be evaluated for adenotonsillar hypertrophy, as adenotonsillectomy can be curative in some patients. (See "Management of obstructive sleep apnea in children" and "Obstructive sleep apnea: Overview of management in adults".)

TRANSFUSION-RELATED ACUTE LUNG INJURY — Since patients with SCD receive blood transfusions, they may develop transfusion-related acute lung injury (TRALI) [75]. A low threshold to suspect TRALI is important in this population. Details regarding diagnosis and management of TRALI are provided separately. (See "Transfusion-related acute lung injury (TRALI)" and "Approach to the patient with a suspected acute transfusion reaction".)

SICKLE CELL TRAIT — Respiratory dysfunction is rare in patients with sickle cell trait (SCT). 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 SCT and matched controls who have normal hemoglobin. One area of growing concern is the risk of venous thromboembolism (VTE) in patients with SCT. Several studies have demonstrated that SCT is a modest VTE risk factor, with an overall 1.5- to 2-fold increased risk of VTE comparing SCT carriers with noncarriers [76]. More specifically, a meta-analysis has shown that compared with controls, SCT is associated with a higher risk for pulmonary embolism (PE) (pooled odds ratio [OR] 2.1, 95% CI 1.2-3.8) but not of deep vein thrombosis (DVT) (pooled OR 1.2, 95% CI 0.9-1.7) [49]. 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'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

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

●Acute chest syndrome – 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 "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

●Chronic dyspnea – Dyspnea is a common yet underreported 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.)

●PFT abnormalities – Pulmonary function tests (PFTs) are often abnormal in SCD. A restrictive pattern is the most common pattern among adults, while an obstructive pattern is more common in children. (See 'Pulmonary function test abnormalities' above.)

●Asthma – Asthma is an important disease modifier in SCD: Children with a history of 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 – 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 (mPAP) ≥25 mmHg (algorithm 1). (See 'Pulmonary hypertension' above and "Pulmonary hypertension associated with sickle cell disease".)

●Thromboembolism – 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 typically delay full anticoagulation pending the results of the CTPA unless the clinical suspicion is high. (See 'Venous thromboembolism and pulmonary thrombosis' above.)

●Pulmonary fibrosis – 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 – 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.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges Harrison Farber, MD, who contributed to earlier versions of this topic review.