Pulmonary Manifestations of Sickle Cell Disease

Marisa Magaña and Jess Mandel

INTRODUCTION

Sickle cell disease (SCD) is a hemoglobinopathy that has multisystem deleterious effects. It is one of the most common autosomal recessive genetic disorders worldwide. It occurs as a result of a single base pair substitution in the β-subunit of hemoglobin, which results in the production of hemoglobin-S. In response to various stressors such as hypoxemia, oxidative stress, and cellular dehydration, sickle hemoglobin (HbS) polymerizes, resulting in structural abnormalities of the red blood cell, including characteristic sickle forms. This structural abnormality of the red blood cell results in the two main pathophysiologic processes of SCD: (1) occlusion of vascular beds with resulting ischemia–reperfusion injury and (2) hemolytic anemia.

Pulmonary complications of SCD commonly result in significant morbidity and mortality. An estimated 25% to 85% of deaths in SCD are related to pulmonary complications. Acute chest syndrome (ACS) is the most common cause of mortality in these patients and is a frequent cause of hospital admissions. Pulmonary hypertension is an increasingly recognized complication of SCD and is also associated with mortality. In addition, patients often have significant reactive airway disease and may develop chronic lung disease as a sequela of SCD.

ACUTE CHEST SYNDROME

ACS is characterized by a new pulmonary infiltrate, fever, chest pain, dyspnea, and wheezing or cough in a patient with SCD. This complication is the second most common cause (behind painful vaso-occlusive crises) for SCD patients to be admitted to the hospital and is the number one cause of admission to the ICU and death in patients with SCD. A key 2000 study evaluated 671 episodes of ACS in 538 patients and demonstrated that more than one-half of the patients were admitted for other reasons such as pain crises and before developing clinical signs of ACS an average of 2 to 3 days after admission. On the basis of this observation, there is speculation that vaso-occlusive crises are likely to be a prodrome of ACS. Patients who developed ACS had an average hospital length of stay of 10.5 days; 22% developed neurologic complications, 13% developed respiratory failure requiring mechanical ventilation, and there was a mortality rate of 9% in patients above 20 years of age. Interestingly, 81% of the patients who developed respiratory failure requiring mechanical ventilation recovered. Older patients (age >20 years) were more likely to develop complications and die in this study.

Several causes of ACS have been proposed. It is likely they all play a role in certain clinical situations; however, in almost half of cases no clear cause for ACS can be found. Known causes of ACS include infection with respiratory pathogens, fat embolism related to bone marrow infarction, sequestration of sickled cells in the pulmonary vasculature, and bronchospasm. Once one of these processes develops, it initiates a cycle of steps: further endothelial damage, worsened ventilation/perfusion matching, additional local hypoxemia, and further sickling of red blood cells and propagation of the cycle. Despite an aggressive diagnostic algorithm, a definite etiology is found in a minority of ACS episodes. In addition, investigators have noted that a high complication rate (up to 13% in the study referenced above) occurred during diagnostic bronchoscopy, with eight patients requiring intubation. They concluded that aggressive diagnostic modalities should be reserved for patients who are not responding to standard therapy.

The diagnosis of fat embolism can be made from bronchoscopy with bronchioloaleolar lavage or from induced sputum with oil red O-staining of macrophages, although these findings are more specific than sensitive. Some studies suggest that patients with evidence of fat embolism as the etiology of ACS have a slightly worse clinical course, with more pain and neurologic complications. However, because treatment of ACS does not differ when fat embolism is a primary cause, the importance of its diagnosis is uncertain at this time.

Treatment for ACS is predominantly supportive. Chlamydia pneumoniae (11%), Mycoplasma pneumoniae (8%), respiratory syncytial virus (4%), and Streptococcus pneumoniae (2%) are common respiratory pathogens isolated. Early empiric treatment of potential respiratory pathogens with antibiotics is recommended, usually with a third generation cephalosporin and either a macrolide or respiratory fluoroquinolone. In addition to antibiotic therapy, hydration, oxygen, red cell or exchange transfusion, aggressive pain control, and incentive spirometry are all important parts of the treatment of ACS. A component of reactive airway disease is frequently present and should be treated aggressively with bronchodilators.

PULMONARY ARTERIAL HYPERTENSION

In recent years pulmonary hypertension (PH) has been increasingly recognized as a complication of the hemolytic anemias and as a risk factor for death in patients with SCD. Pulmonary hypertension is defined as a mean pulmonary artery pressure (PAP) greater than or equal to 25 mmHg at rest. Various studies have suggested that from 20% to 30% of patients with SCD have PH. The presence of PH is associated with increased mortality; in one study, the 22-month mortality rate was as high as 40%. However, most of these studies used an echocardiographic diagnosis of PH, which is not as accurate as cardiac catheterization. In a group of 192 patients with SCD evaluated by echocardiogram, 32% had evidence of PH as defined by a tricuspid regurgitant (TR) jet velocity of greater than 2.5 m/second. Right heart catheterization was performed in 18 of the 195 patients and there was a correlation with the echocardiographic diagnosis of PH and hemodynamics by right heart catheterization, with a mean PAP in the cohort of 34 ± 2.7 mmHg. These data are similar to published retrospective reviews, which estimate the echocardiographic prevalence of PH in SCD between 20% and 40%. There is evidence to suggest that when a TR jet velocity of greater than 2.5 m/second was present, it was associated with an increased risk of death (rate ratio 10.1) when compared to patients with a TR velocity of less than 2.5 m/second.

The etiology of PH in SCD is likely multifactorial. It appears to be associated with the severity of the hemolytic anemia and some studies have suggested that left heart disease may play a role in its development. In the study by Gladwin et al., when echocardiographic variables associated with diastolic dysfunction were analyzed in a logistic regression model, they were not associated with a risk of death; therefore the authors concluded that because PH was associated with an increased risk of death, PH was likely independent of diastolic dysfunction. Interestingly, in the Gladwin et al. study, the mean pulmonary artery wedge pressure was 17.2 ± 1.2 mmHg, suggesting that perhaps left heart disease may have been contributing in some of the cases that underwent right heart catheterization.

There is substantial data that demonstrate the presence of increased mortality when PH exists. Therefore, patients with SCD should be screened for PH with echocardiogram. However, to confirm the presence of PH and determine the etiology, right heart catheterization should be performed prior to the initiation of any treatment for PH. Hypoxemia, thrombosis, and volume status may all influence TR velocity. Therefore, it is important that screening for PH be done in the steady state.

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