Abstract
Pulmonary problems in children with sickle cell disease (SCD) cause significant morbidity and mortality. Acute chest syndrome (ACS) is the leading cause of death, and recurrent ACS episodes are the major risk factor for sickle chronic lung disease, for which only supportive treatment is available. Whereas adults with SCD tend to have restrictive lung function abnormalities, children more frequently have obstructive abnormalities. Children with SCD, as a consequence of their chronic anemia, have an elevated pulmonary capillary blood volume that significantly correlates with their increased airways obstruction. Whether more aggressive treatment of anemia would improve lung function and long-term outcomes merits testing. Children with SCD experience a decline in lung function that is most rapid in younger children in whom ACS episodes are most common, highlighting the importance of identifying effective strategies to prevent and optimally treat ACS. A physician’s diagnosis of asthma has been significantly related to an increased rate of ACS, but whether antiasthma therapy reduces ACS episodes has not been definitively evaluated. Furthermore, wheezing in SCD may be due to a number of causes, and affected children should be appropriately assessed before a diagnosis of asthma is assumed.
Keywords
sickle cell disease, pulmonary hypertension, acute chest syndrome, vaso-occlusive crisis, sickle chronic lung disease, asthma
Epidemiology
Sickle cell disease (SCD) is the most common inherited disorder affecting African and Caribbean populations. There are more than 200 million carriers of the sickle cell trait, and approximately 250,000 children are born each year with SCD. The sickle cell mutation arose on at least four separate occasions in Africa and as a fifth independent mutation in Saudi Arabia or central India. SCD occurs most commonly in tropical Africa where it affects approximately 1% of all infants, and the sickle cell trait is found in approximately 8% of African Americans and also occurs in the Middle East, Greece, and India. There is a high prevalence of the HbS gene in areas where malaria is common, suggesting that sickle cell trait gives an advantage against severe malaria syndromes. Indeed, although children with sickle cell trait are infected by Plasmodium falciparum, the parasite count is low. Individuals with SCD suffer increased respiratory related mortality and morbidity, as discussed in this chapter.
Etiology
Homozygous inheritance of the gene for HbS results in sickle cell anemia (HbSS), the most severe form of SCD. Other clinically important forms of SCD include sickle hemoglobin C disease (HbSC), sickle β 0 , and β + -thalassemia (HbSβthal). The sickle gene results in the substitution of valine for glutamic acid at the sixth position of the amino acid sequence in the beta-globin chain, forming HbS. HbC is produced when the glutamic acid is substituted by lysine at the same position. The β thalassemias have normal structured, but inadequate quantities of hemoglobin A. Coinheritance of various polymorphisms associated with these pathways may explain some of the variation in clinical presentation that occurs in those with identical sickle cell genotypes.
When deoxygenated, partially or fully, HbS undergoes conformational changes, a hydrophobic region surrounding the valine site in the β subunit is left exposed. Polymerization with other hemoglobin tetramers then occurs resulting in the formation of aggregates (crystals) that distort the red blood cell membrane. Neither fully oxygenated HbS nor fetal hemoglobin (HbF) polymerizes. When a “sickle” cell is exposed to a relatively hypoxic/acidic environment, the K + Cl − cotransport is activated with loss of potassium from the cell. Deoxygenation also increases intracellular free calcium, and calcium dependent dehydration occurs. HbS molecules form a viscous solution within the erythrocyte. The changes in the membrane stiffen the red blood cell and change it from a biconcave to a sickle shaped cell that is less deformable and subject to hemolysis. In addition, the rigid cells can obstruct small blood vessels, and over time, cells that have sickled repeatedly become irreversibly sickled. Deoxygenation is maximal in the venous circulation, and the sickled cells may cause extensive and progressive damage to the pulmonary vascular bed. The sickle cells occlude vessels especially to organs with sluggish circulation, such as atelectatic areas of the lung.
Pathogenesis
The systemic effects of ongoing hemolysis, the altered adhesion of cellular elements in blood to each other and the endothelium and the elevated activity of inflammatory pathways all interact to cause the morbidity of SCD involving all organ systems, but particularly the lungs.
Intact sickle erythrocytes are deficient in antioxidants (superoxide dismutase, catalase, and glutathione peroxidase) and are excessive producers of oxidant species. This may reflect the greater auto-oxidation of HbS compared to HbA red blood cells, which means that superoxide and hydrogen peroxide are removed less efficiently. Intravascular hemolysis in SCD produces high levels of cell free Hb and extracellular heme, which is a potent proinflammatory agent and oxidant and now classified as a damage-associated molecular pattern molecule (DAMP). Heme and other oxidant species promote the release from activated neutrophils of neutrophil extracellular traps (NET) that are decondensed chromatin decorated by granular enzymes. NET plasma levels increase during painful crises and are particularly elevated during ACS episodes. The scavenging capacity of plasma proteins, particularly haptoglobin and hemopexin, is overwhelmed, leaving them depleted. Hypoxia inhibits nitric oxide (NO) production by decreasing protein levels of constitutive NO synthase in the endothelium, and there is inactivation of NO by free radical species liberated from activated macrophages and leucocytes. Furthermore, extracellular heme scavenges NO resulting in increased cellular adhesion and diminished vasodilation, as NO inhibits endothelin vascular cell adhesion molecule (VCAM-1) upregulation and inhibits endothelin-1 production. The products of hemolysis have been linked to acute lung injury in a murine model of SCD. Toll-like receptor 4 (TLR4) was critical to that model, as TLR4-null mice remained asymptomatic when challenged with hemin, and the TLR4 antagonist TAK-242 was protective in exposed mice.
Enhanced adhesion of sickle erythrocytes to each other and the endothelium is an important part of the pathophysiology of SCD. In addition, neutrophils may adhere both to the endothelium and to the sickled erythrocyte. In murine SCD models, circulating erythrocytes were shown to attach to adherent neutrophils in the postcapillary venules initiating a vaso-occlusive crisis (VOC). Other leukocytes, including monocytes and T-lymphocytes, are involved in this adhesion cascade ; and the monocytes are activated by the nuclear factor κB (NF-κB) pathway. Platelet activation, as indicated by circulating platelet-monocyte and platelet-neutrophil aggregates, occurs in VOC, and human platelet alloantigens (HPA) 3 polymorphisms are related to VOC risk.
Monocytes from patients with SCD have elevated tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β production. Invariant natural killer T cells (iNKT) cells rapidly produce high levels of cytokines after stimulation by specific antigens, and NF-κB activation in CD4 + iNKT cells may be integral to reperfusion injury after VOC. Platelet activation is elevated at steady state in SCD and further enhanced during VOC. In addition, at least in part through NETs, it may be implicated in the development of pulmonary hypertension (PH) in SCD. Mast cell activation, resulting in the release of bioactive substances such as substance P, has been implicated in the pathophysiology of murine models of SCD and has been found in a proportion of patients who had frequent VOC. Other inflammatory mediators are elevated at SCD steady state or during acute episodes including chemokines, moieties within the coagulation cascade, and high-mobility group box 1 (HMGB1), a chromatin-binding protein that maintains DNA structure. Leukotrienes produced by the 5-lipoxygenase pathway are arachidonic acid derived mediators of inflammation, and leukotriene B 4 (LTB4) promotes neutrophil activation and chemotaxis. LTB 4 has been shown to be elevated during steady state and VOC.
Clinical Features
SCD is a hemolytic anemia. Newborns, however, are asymptomatic, as they have a high level of HbF in their erythrocytes, but as the levels of HbF decline, the manifestations of SCD become apparent, this may be as early as 10–12 weeks of age. SCD patients have periods of relative stability punctuated with acute episodes such as painful crises or VOCs. They may suffer severe pain, have cerebrovascular accidents, acute splenic sequestration, and acute chest syndrome (ACS). The ongoing inflammatory process leads to chronic end-organ injury.
Acute Chest Syndrome
The overall incidence of ACS is 10.5 per 100 patient years. ACS episodes occur more commonly in children than adults, and 50% of SCD children will have an ACS episode prior to the age of 10 years. The highest incidence of ACS occurs in children aged between 2 and 4 years of age, and recurrence is common. In addition, the majority of very young children who had an ACS episode were rehospitalized for ACS or severe pain within 1 year. Furthermore, recurrent ACS is the most important risk factor for the development of sickle cell chronic lung disease (SCLD) and increases morbidity.
Risk Factors
There are a number of genetic risk factors for ACS, and the incidence of ACS is most common in those with HbSS and less in those with HbSC. Similarly, the hemoglobin genotype influences the severity of ACS, being more severe in those with HbSS that in those with HbSC. The ACS incidence also varies according to the beta–globin gene cluster haplotype, as indicated by the prevalence and recurrence of ACS episodes being lower in Saudi Arabia than in Africa. This may reflect an interaction between SCD and the “Asian” haplotype, which is associated with a higher HbF level. The risk for ACS is also increased by certain endothelin NO synthase gene polymorphisms. Genetic polymorphisms of heme oxygenase-1(HO-1), an essential enzyme in heme catabolism, have been associated with ACS risk, and a polymorphism enhancing its expression was associated with lower ACS rates. ACS has been associated with rs6141803, a single nucleotide polymorphism (SNP) located 8.2 kilobases upstream of COMMD7, a gene highly expressed in the lung that interacts with NF-κB signaling.
Steady-state hematological profiles impact ACS risk, and the incidence of ACS is inversely proportional to the HbF level and directly proportional to the steady state white blood count. High HbF levels inhibit HbS polymerization, which protects against ACS. An elevated leucocyte count increases the risk as leukocytes release free radicals, elastase, proinflammatory mediators, and cytokines. Children presenting with fever have an increased risk of developing an ACS episode if they have an absolute neutrophil count greater than 9 × 10 9 /L, a hemoglobin level less than 8.6 g/dL, had a previous ACS episode, upper respiratory tract infection symptoms, or noncompliance to penicillin.
Infection is implicated in at least 30% of ACS episodes. In a multicenter study, although 27 different pathogens were identified, Chlamydia pneumoniae was the most frequent pathogen, followed by Mycoplasma pneumoniae and respiratory syncytial virus. Parvovirus B10 has been associated with marrow necrosis and a particularly severe form of ACS. The causative pathogen in any one area, however, reflects which pathogen is most common locally; and the seasonal variation in ACS episodes in young children reflects the increase in viral infections during the winter months.
In approximately 10% of patients, an ACS is precipitated by a pulmonary fat embolism. Infarction of the bone marrow with embolization of the fatty bone marrow to the lungs results in activation of pulmonary secretory phospholipase A2 (SPLA2). SPLA2 cleaves phospholipids and liberates free fatty acids, which cause acute pulmonary toxicity. Arachidonic acid results in vasoconstriction and oleic acid increases the upregulation of VCAM-1. Infarction of the bony thorax or pain following abdominal surgery may cause splinting, hypoventilation, and atelectasis, leading to hypoxia and intrapulmonary sickling. In addition, opioids prescribed for the pain may suppress respiratory drive compounding the hypoventilation.
Asthma has been reported to be more common in those with ACS and specifically in those who have had recurrent ACS episodes. In the cooperative study for SCD in which children were recruited before 6 months of age and followed beyond 5 years of age, asthma was associated with more frequent ACS episodes. Asthma may, however, have been overdiagnosed in previous studies that used a physician’s diagnosis rather than more objective tests such as determination of bronchial responsiveness. It is now apparent that wheezing, without a diagnosis of asthma, is associated with an increase in SCD complications. In a retrospective study, asthma and wheezing were independent risk factors for increased painful episodes, but only wheezing was associated with more ACS episodes. In an observational cohort study, adults who reported recurrent, severe episodes of wheezing, regardless of a diagnosis of asthma, had twice the rates of ACS, decreased lung function, and increased risk of death compared with adults without recurrent wheezing. Furthermore, in a cohort of 159 children followed from birth to a median of 14.7 years, an ACS episode prior to 4 years, female gender, wheezing with shortness of breath, and two or more positive skin prick tests were associated with future ACS episodes, but airways obstruction and a bronchodilator response were not.
Clinical Features
ACS episodes are characterized by chest pain, productive cough, and dyspnea; affected individuals are febrile and tachypneic and on auscultation there are crackles and wheezes. Fever and cough are more common in very young children, whereas chest pain, shortness of breath, and hemoptysis are more prominent with advancing age. Essential to the diagnosis of an ACS is a new pulmonary infiltrate on the chest radiograph ( Fig. 62.1 ), and the lower and middle lobes are more frequently affected than the upper lobes. Ten to 15% of patients develop severe respiratory failure, necessitating mechanical ventilation and may progress to multiorgan system failure.
If the ACS is precipitated by a fat embolism, the pulmonary signs and symptoms are preceded by bone pain. Affected patients have lower mean oxygen saturation at presentation and have a more severe clinical course. There may be systemic signs of a fat embolism, including changes in their mental state, thrombocytopenia, and petechiae. In addition, they have significant decreases in the hemoglobin and platelet counts and lipid-laden macrophages are found in fluid obtained by bronchoalveolar lavage.
Sickle Chronic Lung Disease
SCLD is a progressive disease with hypoxemia, restrictive lung disease, cor pulmonale, and evidence of diffuse interstitial fibrosis on chest radiography. Recurrent ACS episodes result in damage to the lung parenchyma resulting in restrictive lung disease.
Pulmonary Hypertension
PH in SCD is characterized by progressive obliteration of the pulmonary vasculature. Possible causes include chronic hypoxic stress causing irreversible remodeling of the pulmonary vasculature, recurrent pulmonary thromboembolism, sickle cell related vasculopathy, and pulmonary scarring from recurrent ACS episodes. Sudden death in SCLD patients with PH is common due to pulmonary thromboembolism and cardiac arrhythmia. Adult SCD patients therefore should be screened for PH with echocardiography as, although initially the patients may be asymptomatic, their condition progresses and they suffer worsening hypoxia and chest pain with impaired exercise tolerance.
Sleep-Disordered Breathing
Children with SCD may be at an elevated risk of sleep-disordered breathing (SDB) including chronic (>6 months) insomnia, restless leg syndrome, habitual snoring, daytime sleepiness evidenced by needing naps, waking up not feeling refreshed, short-term insomnia, and sleep onset latency. The prevalence of obstructive sleep apnea syndrome (OSAS) in children and adolescents with SCD varies from 10.6% to 94% in SCD children who had not undergone adenotonsillectomy. In children investigated for OSAS, although similar sleep architecture was noted, children with SCD had lower median and minimal oxygen saturations than those without SCD. Indeed, children with SCD and OSAS, compared to children with uncomplicated OSAS, had a fourfold risk of a nocturnal oxygen saturation level below 85%.
Risk factors for sleep-related disorders include acute pain and chronic pain syndromes. Functional asplenia leading to compensatory adenotonsillar hypertrophy in younger children and extramedullary hematopoiesis causing alterations in facial bone structure in older children may result in OSAS. An association has been reported between enuresis and SDB in children with SCD. SDB, particularly with nighttime desaturation, has been demonstrated to be associated with increased SCD complications including executive dysfunction, priapism in adults, and possibly painful crisis.
Lung Function Abnormalities
Obstructive lung abnormalities were reported, in a cross-sectional study, in young children with restrictive abnormalities becoming more prominent with advancing age. Those results have also been demonstrated in two longitudinal studies but not in a third. In a cohort of 45 children aged between 5 and 18 measured at baseline and approximately 4 years later, a predominately obstructive pattern was reported with increased prevalence over time. The occurrence of restrictive abnormalities also increased, but to a lesser extent. In contrast, retrospective analysis of data from 413 SCD children aged between 8 and 18 years demonstrated that the prevalence of restrictive abnormalities increased with increasing age. In two cohorts of SCD children, one of which was followed for 2 years and the other for 10 years, lung function deteriorated in the SCD children compared to contemporaneously studied ethnic and age matched controls. In the cohort followed for 10 years, restrictive abnormalities became more common. The rate of deterioration in lung function was greater in the younger children in whom ACS episodes were more common.
At all ages, obstructive, restrictive, and mixed lung function abnormalities have been documented, as well as normal lung function. Airways hyperresponsiveness (AHR) to methacholine has been reported to be more common in SCD children, but AHR to methacholine has not been related to signs or symptoms of allergy. Overall, the responses to bronchial challenges such as cold air, exercise, or methacholine have been variable, ranging from a positive response rate of 0% to 78%.
Etiology of the Lung Function Abnormalities
The obstructive lung function abnormalities seen in SCD children could be due to asthma. Exhaled NO is elevated in asthma, as there is enhanced expression of inducible NO synthase in inflamed airways. Yet, in a prospective study, the exhaled NO levels were similar in 50 SCD children and 50 controls and airway obstruction in SCD children was not associated with increased methacholine sensitivity or eosinophilic inflammation. An alternative explanation for the airways obstruction in SCD is the hyperdynamic pulmonary circulation due to a raised cardiac output secondary to chronic anemia. SCD children have an increased pulmonary capillary blood volume resulting from their chronic anemia, which has been shown to correlate with the degree of airways obstruction. In a study of 18 SCD children compared to 18 ethnic and age-matched controls, the SCD children had a significantly higher respiratory system resistance, alveolar NO production, and pulmonary blood flow, but not airway NO flux. In addition, there was a significant correlation between the alveolar NO production and pulmonary blood flow, but not between airway NO flux and respiratory system resistance. Furthermore, transfusion in SCD children acutely increased airways obstruction and this was significantly related to an increase in pulmonary capillary blood volume. Those results suggest that the airway obstruction seen, at least in some SCD children, relates to their increased pulmonary capillary blood volume. The clinical implication of those results is that whether a child with SCD and airways obstruction would benefit from bronchodilators should be assessed by comparing lung function assessment results pre and post bronchodilator.
Exercise Capacity
There have been few studies investigating the cardio-respiratory responses to exercise in children with SCD. They have been reported to have more adipose tissue with reduced fitness and exercise performance. Exercise capacity has been reported to be related to the baseline degree of anemia and significantly lower in subjects with a history of recurrent ACS. The metabolic changes imposed by exercise may initiate sickling and vaso-occlusive episodes. Therefore exercise should be started slowly and increased progressively, hydration should be maintained, and sudden changes in temperature should be avoided.
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