Objectives

1. Identify the pulmonary complications associated with sickle cell disease (SCD).
2. Understand the different mechanisms potentially involved in causing lung injury in SCD.
3. Assess the patient with pulmonary complications of SCD.
4. Follow the rational therapeutic approach to patients with pulmonary complications of SCD.

Key words

acute chest syndrome; hydroxyurea; nitric oxide; sickle cell disease; sickle chronic lung disease

Abbreviations

ACS = acute chest syndrome; EC = endothelial cell; FES = fat embolism syndrome; LTB4 = leukotriene B4; NO = nitric oxide; NOD = nocturnal oxygen desaturation; OLD = obstructive lung disease; PAF = platelet-activating factor; PH = pulmonary hypertension; PMN = polymorphonuclear cell; SCD = sickle cell disease; SCLD = sickle cell chronic lung disease; SRBC = sickle red blood cell; VCAM-1 = vascular cell adhesion molecule-1; VOC = vaso-occlusive crisis

Sickle cell disease (SCD) is a genetic disorder caused by a one-amino-acid substitution of valine for glutamic acid in the sixth position of the beta chain of the hemoglobin tetramer. In the United States, SCD is reported to affect ~70,000 African-Americans. In Africa and other parts of the world, millions of people are affected, making it one of the most common lethal hereditary diseases. The sickle cell gene mutation has been reported in India, Greece, Saudi Arabia, Sicily, Southern Italy, Israel, Turkey, Iran, Central America, Brazil, the United Kingdom, France, Belgium, Germany, and the Netherlands.¹ The estimated frequency of sickle cell anemia at birth among African-Americans in the United States is 1:625, with 8 to 12% of the African-American population being carriers of the sickle cell trait.

The Cooperative Study on Sickle Cell Disease recently reported an increase in life expectancy for individuals with SCD.² The median life expectancy for men and women with sickle cell anemia is 42 and 48 years, respectively. For hemoglobin SC disease, the median life expectancy is reported to be in the 60s for both sexes. This improvement in survival was primarily attributed to mandatory newborn screening, improved immunization standards, and parent education. While survival has improved, current evidence continues to support the finding that the most common cause of death in SCD after the age of 5 years is pulmonary complications.³ This makes it imperative that pulmonologists be knowledgeable about the acute and chronic lung complications of SCD.

Pathogenesis of Sickle Cell Lung Disease

Central to the pathogenesis of SCD is microvascular obstruction by sickle red blood cells (SRBCs). Regional hypoxemia, tissue hypoxia, and acidosis facilitate the unloading of oxygen by hemoglobin S.⁴ Deoxyhemoglobin S polymerizes, which results in sickling of the erythrocyte and microvascular occlusion. Obstruction of the microvasculature results in tissue hypoxia with parenchymal damage distal to the site of obstruction. Clinically, this is termed vaso-occlusive crisis (VOC).

Haynes et al,⁵ studying the isolated rat pulmonary circulation perfused with SRBCs, have demonstrated that hypoxemia causes an increase in total pulmonary vascular resistance greater than the resistance resulting from hypoxic pulmonary vasoconstriction alone. This observation suggests that part of the elevation in vascular resistance is secondary to obstruction. However, it has been clearly demonstrated that hemoglobin S polymerization does not occur immediately after deoxygenation, and that most SRBCs pass through the capillary before sickling. These observations suggest that factors capable of increasing capillary transit time are also operative and may initiate a VOC. Random precapillary obstruction by rigid, dense SRBCs and increased adhesion of SRBCs to vascular endothelial cells (ECs) are well described factors that prolong capillary transit time.⁶ Hebbel et al⁷ demonstrated that SRBCs, particularly reticulocytes, have an increased tendency to adhere to vascular ECs, and this adherence correlates with the clinical severity of VOC.

Receptors in the SRBC membrane (predominantly on stress reticulocytes) capable of adhering to ECs include the a₄ b₁ integrin known as very late activation antigen-4 (VLA-4) and the thrombospondin receptor, CD36. ECs express vascular cell adhesion molecule-1 (VCAM-1). Hypoxia up-regulates EC VCAM-1. This enhances the ability of stress reticulocytes to adhere to the vascular endothelium through VLA-4.⁸ In contrast, nitric oxide (NO) is a cytoprotective mediator that inhibits the up-regulation of VCAM-1. The progression of VOC to lung parenchymal damage may be determined by the ratio of expression of VCAM-1 to NO.⁸ Recently, NO has gained attention as a potential therapy for VOC and acute respiratory failure in SCD. In addition, nonreceptor markers also capable of EC adherence (eg, aggregated membrane band-3 and sulfated glycolipids) have been described.⁹

More recent reports have demonstrated that exposure of the anionic phospholipid, phosphotidylserine on the surface of SRBC results in increased adhesion to ECs in culture and to the endothelial matrix protein, thrombospondin.10 This observation suggests that disruption of the normal SRBC phospholipid asymmetry with phosphotidylserine surface exposure may facilitate the adhesion of reticulocytes and mature SRBCs as well.

There is a growing body of data that implicates inflammation in the initiation of vascular occlusion through mechanisms that involve SRBC-ECpolymorphonuclear cell (PMN) interactions. Clinical observations underline the potential role of PMNs in the pathogenesis of VOC. A leukocytosis of > 15,000 cells/mL has been associated with an increase in mortality and early death in patients with SCD.² An increase in the baseline number of PMNs has been associated with the onset of acute chest syndrome (ACS).¹¹ Furthermore, the finding of inflammatory cytokines (interleukin-6, interleukin-8) during the steady state of patients with SCD suggests that a chronic state of PMN activation is operative.¹²

Haynes and Obiako¹² have demonstrated that, in the isolated rat pulmonary circulation, the calculated retention of red blood cells after SRBCs are perfused is greater than the calculated retention of perfused normal red blood cells. The calculated retention was increased by adding activated PMNs or a supernatant of activated PMNs to the SRBC perfusate. A similar increase in calculated retention was observed when leukotriene B₄ (LTB₄) and platelet-activating factor (PAF) were added to the SRBC-containing perfusate. Both LTB₄ and PAF appear to be equally important because the inhibition of either PAF (by a PAF antagonist), or LTB₄ (by a 5-lipoxygenase inhibitor) caused a significant reduction in the calculated retention of SRBCs. Activated PMNs release arachidonic acid and lysoplatelet activity factor through the activation of phospholipase A₂. The resulting metabolism of arachidonic acid through 5-lipoxygenase produces LTB₄. The acetylation of lyso-platelet activity factor produces PAF. LTB₄ and PAF mediate inflammation, increase vascular permeability, promote PMN adhesion, and potentially promote SRBC adhesion to ECs.⁶ This inflammatory pathway recently has received a lot of attention as a potential target for new therapies in SCD.

Pulmonary Complications of Sickle Cell Lung Disease

ACS continues as the most common cause of death at > 5 years of age in SCD. It occurs in 15 to 20% of individuals and may complicate 50% of VOCs associated with a fatal outcome in patients without chronic organ failure. ACS is the second most common reason for hospitalization in SCD patients, and accounts for around 25% of premature deaths in this population. Patients older than 20 years tend to experience a more severe course of ACS.²

The definition of ACS is a new radiographic pulmonary infiltrate that is usually associated with a combination of fever, chest pain, hypoxemia, and leukocytosis in patients with SCD. The syndrome is a form of acute lung injury that may progress to ARDS. This is supported by autopsy data that demonstrate intraalveolar edema and hemorrhage and alveolar septa lined with hyaline membrane.³ This syndrome has been described with pulmonary vaso-occlusive episodes, pneumonia, bone infarcts, and fat embolism syndrome (FES).

High hemoglobin concentrations, high steady-state white blood cell counts, and low hemoglobin F concentration are risk factors that predispose a patient to the development of ACS.

Among the patients that develop ACS, one third to one half of the patients will develop the syndrome after having been admitted for other reasons, usually an episode of diffuse pain. A patient who develops ACS may present with nonproductive cough, pleuritic or nonpleuritic chest pain, and dyspnea. Dyspnea is most commonly seen in adult patients. Clinically, the patient may appear quite toxic, with a fever of up to 104°F, tachycardia, and tachypnea. At examination, wheezing (most commonly in pediatric patients), crackles, or decreased breath sounds may be present. The chest radiograph most commonly reveals lowerlobe infiltrates, frequently with some degree of atelectasis. The infiltrates are bilateral in about one third of the patients. Pleural effusions are predominantly exudative and ipsilateral to the infiltrate in 25 to 35% of patients.¹³ Laboratory abnormalities may include anemia, thrombocytopenia, leukocytosis, indirect hyperbilirubinemia, and an elevated lactate dehydrogenase level. A decrease in the hemoglobin concentration of ≥ 2 g/dL, thrombocytopenia, multilobar involvement, and a history of cardiac disease are predictors of individuals in whom acute respiratory failure is likely to develop. There are no laboratory abnormalities diagnostic of ACS, although interestingly, an increase in serum phospholipase A₂ has been suggested as an early marker of FES and the development of ACS during an episode of VOC.¹⁴

When considering the diagnosis of ACS, pneumonia deserves special consideration. Although an infectious pathogen is identified in slightly more than one third of ACS episodes, pneumonia may contribute to more than one half of the deaths from ACS.¹⁵ Several pathogens have been associated with the development of ACS. The more prevalent treatable microorganisms include Chlamydia and Mycoplasma.¹⁵ Among the viruses, the respiratory viruses are included. In addition, an association between parvovirus B19 and severe ACS with bone marrow necrosis has been described and should be suspected when concomitant thrombocytopenia is present without evidence of splenic sequestration.¹⁶

Autopsy studies of patients with SCD have described pulmonary infarcts in the absence of discernible vascular occlusion. These observations suggest that the infarct may result from a reversible microvasculature obstruction of the pulmonary circulation. Also described at autopsy are in situ thrombi of varying ages that involve small pulmonary arteries. Thrombocytosis during steady state, increased levels of beta-thromboglobulin, and increased levels of plasma thromboxane in SCD suggest that continuous platelet activation is operative and may contribute to the formation of in situ thrombus.¹⁷ Thomas et al¹⁸ reported “histological evidence of pulmonary embolism” in 13 of 60 patients dying from ACS. However, in one of the largest reported SCD autopsy series, the frequency of thromboemboli was not significantly greater than in matched controls.³ Based on the available information, it is not clear whether SCD causes a clinically significant hypercoagulable state. Our own experience suggests that the prevalence of this complication is low, but when the clinical index of suspicion is high, diagnostic procedures should be performed. When considering this diagnosis, it is important to emphasize that nonionic low osmolar contrast media should be used in angiographic studies to minimize the risk of precipitating a VOC. Ventilation-perfusion scans are usually not reliable and empiric anticoagulation is not recommended because of the increased risk of intracranial and renal bleeding complications.

Previously, FES was considered to be rare in SCD because the normal bone marrow fat was replaced by erythroid tissue. More recently, the incidence of FES has been reported to range from 13 to 75%.¹⁴ This range may depend on how this syndrome is diagnosed. Evidence of bone marrow embolism has been described in 9% of autopsies in patients with SCD.¹⁷ Bronchoalveolar lavage performed during ACS episodes has identified alveolar macrophages containing fat droplets in 77% of the cases.¹¹ The identification of fat in samples from the pulmonary artery, sputum, or urine also suggests FES.³ The clinical manifestations of FES result from the release of free fatty acids from embolic fat, metabolized by tissue lipases. At presentation, is associated with severe pain, lipemia retinalis, petechial lesions, or neurologic complications. When neurologic findings complicate FES, MRI of the brain may demonstrate hypointensities on T1-weighted images in the cortical white matter and brainstem. These lesions are reversible and thought to be related to blood-brain barrier breakdown.¹⁹

The blood supply to bony structures may be compromised by a VOC. An infarct of the ribs, sternum, or thoracic vertebrae can cause severe chest pain. If not adequately treated, the pain can impair respiratory function by causing splinting during inspiration and subsequent hypoventilation. Atelectasis may result with subsequent worsening of the ventilation/perfusion mismatch and hypoxemia. The management of pain is a priority. Nonetheless, it is important to consider that the use of narcotics can cause excessive sedation with subsequent hypoventilation.

Pulmonary edema has also been described with ACS; it is a common finding at autopsy in SCD patients and has been described in several case reports.¹³ Based on the available evidence, pulmonary edema is likely caused by an increase in capillary permeability, but may be aggravated by an increase in hydrostatic pressure. When pulmonary edema is due to increased hydrostatic pressure in SCD, it most often results from aggressive hydration with or without concomitant renal insufficiency. Massive hemolysis with subsequent severe anemia (hemoglobin < 5g/dL) may result in a “high output” state leading to heart failure and pulmonary edema.

With repetitive insults to the lung, the patient develops a form of progressive pulmonary dysfunction called sickle cell chronic lung disease (SCLD). The pathogenesis of this condition is not clear but includes the development of a vasculopathy of the pulmonary circulation in the form of endothelial hyperplasia and thrombosis in situ. Besides the damage to the pulmonary circulation with increased vascular resistance, pulmonary function testing reveals varying degrees of restrictive and obstructive physiology.

Since Powars et al²⁰ originally described 28 patients with SCLD in 1988, little has been published about SCLD. In that study, patients were staged according to disease severity based on clinical, physiologic, and radiographic criteria. Four stages were identified, with increasing severity in chest pain and associated symptoms of cough and dyspnea, hypoxemia, radiographic evidence of pulmonary fibrosis, pulmonary function testing abnormalities, and hemodynamic evidence of pulmonary hypertension (ECG, echocardiography, and pulmonary artery pressure). In this study, the average age at diagnosis of SCLD was 24.9 years (range, 6 to 43 years) and the mean time from diagnosis to death was 5.2 years. The patients progressed from one stage to another in an average of 2 to 3 years. The most significant risk factors associated with SCLD were the number of ACS episodes and the presence of avascular necrosis after 20 years of age. The number of ACS episodes has also been positively correlated with interstitial lung disease (described by thin-section CT) and obstructive lung disease (OLD).^21,22 Less clear is the association of asymptomatic pulmonary vascular obstruction secondary to thrombosis in situ and nondeformable SRBCs with the development of pulmonary hypertension (PH).

The development of PH in SCD is an independent predictor of mortality. Cor pulmonale with subsequent myocardial ischemia can be a cause of sudden death in patients with SCD. The appearance of unexplained chest pain and/or dyspnea out of proportion to the pulmonary function test results in a patient with SCD should alert the clinician to the possibility of underlying PH. Initially, the signs of right heart failure may be present only during an acute pulmonary complication, but later become persistent.^23,24

In our experience, airflow obstruction in an adult with SCD is most commonly irreversible. The pediatric literature suggests that a significant component of OLD in children with SCD is caused by airway hyperresponsiveness. This has been demonstrated by cold air challenges and also by a response to bronchodilators in the presence of evidence for airflow obstruction.²⁵ In a group of 63 children and adolescents with SCD, the prevalence of OLD was 35% and that of restrictive lung disease was 8%, with more than 50% of the latter group having concomitant evidence of OLD.²⁶

The prevalence of nocturnal oxygen desaturation (NOD) has been reported to be 40% in children and adolescents with SCD. For the most part, NOD is not associated with upper airway obstruction, but there appears to be a strong correlation with awake hemoglobin oxygen saturation.²⁷ Among the clinical implications of NOD, nocturnal VOC episodes may be triggered. More importantly, there is an apparent association between NOD and CNS events including strokes, transient ischemic attacks, and seizures.²⁸

Therapy

Overall, the therapy of SCD is supportive and symptomatic. Antibiotics should always be considered. Therapy for community-acquired pneumonia is reasonable, but emphasis on coverage for Chlamydia and Mycoplasma is important. Therefore, a quinolone or a combination of a macrolide and a betalactam should be used.

In the presence of hypoxemia, supplemental oxygen therapy must be implemented to keep PaO₂ at 70 to 80 mm Hg or oxygen saturation at 92 to 95%. When using supplemental oxygen, it is important to remember that a supraphysiologic PaO₂ may suppress erythropoiesis. In our experience, moderate cases of hypoxemia that are not responsive to supplemental oxygen may respond to noninvasive positive pressure ventilation. To maintain adequate oxygenation in severe cases of ACS, mechanical ventilation with endotracheal intubation and positive end-expiratory pressure may be needed.

In every SCD patient with ACS or chest pain, the use of incentive spirometry should be encouraged to prevent atelectasis from splinting. Patients hospitalized for pain control, even in the absence of chest pain, may also benefit from incentive spirometry.

Deep venous thrombosis prophylaxis should be considered in hospitalized, nonambulatory patients.

Pain control is primordial to prevent hypoventilation, but excessive sedation should be avoided. We recommend the administration of narcotics around the clock with periodic assessment of the respiratory pattern. In our experience, the use of patient-controlled analgesia has been of benefit, but it should not be a substitute for the frequent monitoring of respiration. The goal of hydration with hypotonic fluids should be achieving a euvolemic state.

In moderate to severe cases, therapy with exchange transfusion is directed to reduce hemoglobin S to 20 to 30% without exceeding a hematocrit of 30%. A higher hematocrit may increase the viscosity of the blood and precipitate sickling. The use of leukodepleted red blood cells with a complete antigenic phenotype match is mandatory. Lately, there has been a trend towards early exchange transfusion for the therapy of ACS.

In milder cases of worsening anemia and hypoxemia, a simple transfusion may suffice. Anemia can worsen the ventilation/perfusion mismatch by impairing hypoxic pulmonary vasoconstriction. Oxygen is the rate-limiting substrate for NO synthesis. After the regional production of NO is halted, the subsequent pulmonary vasoconstriction is dependent of the rate of NO scavenging by hemoglobin. By restoring this property of hemoglobin, an improvement in PaO₂ occurs. Furthermore, NO produced in the lung binds to oxyhemoglobin (Snitrosohemoglobin) and is carried to the microvasculature, causing arterial vasodilation and improving oxygen delivery. NO also inhibits the steps required for leukocyte recruitment.^29,30 The level of the precursor of NO, L-arginine, has been found to be lower in children during a VOC than during steady state, and the lowest L-arginine values have been seen during ACS, correlating with a decrease in NO levels.³¹ The same group has described an increase in NO production after oral L-arginine administration during VOC.³² The described benefits of NO make the administration of L-arginine potentially an attractive therapy for VOC and ACS, but more studies are needed.

There have been anecdotal reports that NO therapy reverses hypoxemia in severe cases of ACS. This observation may be clouded by the fact that the described patients received standard therapy for ACS aimed at reversing hypoxemia. It is known that inhaled NO is distributed to well-ventilated alveoli, inducing vasodilation locally. By causing vasodilation, NO improves the blood flow to normal lung, in theory sparing affected alveoli. By reducing pulmonary artery resistance, NO may be more beneficial when ACS occurs in a patient with baseline PH.

The therapy of SCLD should be directed at reversible causes. Because the risk of development of SCLD depends on the severity and number of ACS episodes, it makes sense to consider therapies aimed at the reduction of sickling propensity or triggers of VOC. It has been shown that hydroxyurea reduces the number of ACS episodes by 50% in two-thirds of patients.³³ In a recently published observational study by Steinberg et al,³⁴ the overall mortality in adult patients taking hydroxyurea was reduced by 40%. Interestingly, the reduced mortality was observed in patients with a clinical response to therapy defined by a reduction in ACS episodes, reduction in VOC, and an elevation in hemoglobin F.³⁴ By elevating the erythrocyte content of hemoglobin F, hydroxyurea decreases the propensity of the SRBC to sickle. Its beneficial effects may also be related to its ability to decrease the number of PMNs and to serve as a donor of NO. The NO donor properties of hydroxyurea may explain the reduction in VCAM-1 expression seen with its use.³⁰ Hydroxyurea is indicated as a preventive treatment for frequent pain episodes, history of ACS, other severe VOC, or severe symptomatic anemia. The treatment end points of hydroxyurea are less pain and an increase in fetal hemoglobin to 15 to 20%. During therapy, blood cell counts and contraception should be monitored.

Screening for NOD is controversial but should be considered in the presence of abnormal pulmonary function tests, repetitive VOCs, or abnormal awake hemoglobin oxygen saturation. Supplemental oxygen and bronchodilators should be administered if needed.

Patients with secondary PH associated with SCLD may benefit from therapeutic agents used in primary PH, such as prostacyclin analogs and endothelin receptor antagonists. Clinical studies are needed in this area.

Finally, similar to other forms of chronic lung disease, the use of influenza and pneumoccocal immunization is recommended.

References

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