Asthma and chronic sickle cell lung disease a dynamic relationship

from each parent, is the underlying cause of sickle cell disease. The muta- . occlusive crises indicate an association with high concentrations . acute pulmonary hypertension, severe lung in- f lammation . asthma among children with sickle cell disease .. dynamically significant pulmonary hypertension. Children with sickle cell disease (SCD) and a comorbid condition of asthma have Asthma and chronic sickle cell lung disease: a dynamic relationship. Children with homozygous SS sickle cell disease (SCD) frequently suffer acute in the sickle lung from oxidant injury, and the underlying chronic subclinical.

Glassberg and colleagues found that a past history of asthma was associated with an increased risk of emergency department utilization for both pain and ACS in children with SCD [ 25 ]. They found that children with lower airway obstruction had twice the risk for a pain crisis or ACS compared to children with normal lung function [ 23 ]. Consistent with this observation, Nouraie and colleagues recently reported a hazards ratio of death of 5.

Case reports of asthma-related deaths have also been described [ 28 ]. Strong evidence is accumulating from multiple investigators and centers that asthma is an independent risk factor for early mortality in both adults and children with SCD [ 1518222729 ], yet no randomized controlled trials of asthma therapies in SCD have been published to date [ 30 ].

Since asthma is a modifiable risk factor, effective asthma management may ultimately impact morbidity and mortality in SCD.

Unique and Overlapping Pathophysiology in Asthma and SCD A number of inflammatory pathways contribute to asthma [ 31 — 34 ], many of which are outside the scope of this review.

Interestingly, several well-documented mechanisms of asthma are known to contribute to the pathophysiology of SCD. These specific pathways provide a framework to guide additional investigation into the commonly found asthma-like condition in children with SCD.

One potential underlying connection between SCD and asthma is the inflammation seen with each disease process. Vascular adhesion molecule-1 is also known to be elevated in SCD [ 36 ]. During VOEs, these inflammatory molecules have been seen to rise even higher [ 3536 ]. This inflammation could in turn result in a propensity towards clinical asthma. Supporting this hypothesis is the documentation of increased mortality and an enhanced inflammatory response to allergens in mice with SCD and experimentally induced asthma [ 37 ].

Leukotrienes are a particularly intriguing commonality between asthma and SCD. They are key signaling molecules involved in both inflammation and bronchoconstriction. There is also data to suggest a role for elevated sPLA2 in asthma in general [ 43 ], which is of interest given the difficulty in clinically differentiating ACS from asthma in a patient with SCD.

Thus, these molecules have a theoretical link from SCD to asthma. Although controlled clinical trials have not yet been done, montelukast, an inhibitor of leukotriene activity, is an intriguing candidate for the treatment of asthma in patients with SCD [ 44 ]. Dysregulated arginine metabolism and excess arginase activity has also been implicated in the pathophysiology of both asthma [ 2945 — 51 ] and SCD [ 72952 — 56 ].

Elevated plasma levels of the arginine analog asymmetric dimethyl arginine ADMA also contribute to arginine dysregulation in both asthma [ 5758 ] and SCD [ 59 — 61 ]. L-Arginine is the obligate substrate for both the arginases and nitric oxide synthetases NOS.

NO is a potent vasodilator that plays a role in maintaining bronchodilatory tone. NO in exhaled breath eNO is also an established marker of chronic inflammation in asthmatics [ 62 ].

However, a more recent study demonstrated elevated eNO levels in nonatopic children with SCD compared to normal controls [ 65 ], again illustrating a variance in NO metabolism in SCD versus control subjects. A plausible explanation may be found by considering potential mechanisms that contribute to the clinical phenotype that differed in each study. Metabolic profiling has revealed an arginine deficiency among subgroups of patients with SCD that is associated with clinical phenotypes and a mortality risk that varies from steady-state to acute events [ 46475253 ].

An increased prevalence of asthma in patients with SCD has also been documented as have increased morbidity and mortality amongst patients with coincident SCD and asthma.

The pathophysiology underlying the relationship between asthma and SCD has become a topic of interest, although little is known. Further insight will hopefully lead to targeted interventions that can help minimize the complications associated with coincident asthma and SCD.

For now, asthma management based on the guidelines published by the National Institutes of Health NIH should be implemented to minimize morbidity and mortality for patients with SCD and asthma. Concerns regarding the use of typical treatments for asthma in patients with SCD have arisen, but the benefits of optimal asthma treatment outweigh the risks of possible side effects.

One out of African-American births and 1 out of 36, Hispanic-American births are estimated to result in patients affected with SCD [ 1 ]. Meanwhile, the Center for Disease Control has published survey data documenting increased rates of asthma diagnoses in compared to Importantly, the greatest rise in asthma rates over the same time period was in African-American children. This is consistent with other studies of lower airway obstruction and airway hyperreactivity AHR in children with sickle cell disease.

Together, these studies document that SCD patients have a much higher prevalence of AHR than would otherwise be expected.

Asthma Management in Sickle Cell Disease

A recent study by Knight-Madden et al. Increased rates of acute chest syndrome ACSstroke, and vaso-occlusive episodes VOE have all been documented in patients with asthma and SCD [ 3141618 — 26 ]. Glassberg and colleagues found that a past history of asthma was associated with an increased risk of emergency department utilization for both pain and ACS in children with SCD [ 25 ].

They found that children with lower airway obstruction had twice the risk for a pain crisis or ACS compared to children with normal lung function [ 23 ]. Consistent with this observation, Nouraie and colleagues recently reported a hazards ratio of death of 5.

Demystifying Medicine 2015 - Sickle Cell Anemia: a Vicious Viscid Sickle Cycle

Case reports of asthma-related deaths have also been described [ 28 ]. Strong evidence is accumulating from multiple investigators and centers that asthma is an independent risk factor for early mortality in both adults and children with SCD [ 1518222729 ], yet no randomized controlled trials of asthma therapies in SCD have been published to date [ 30 ].

Since asthma is a modifiable risk factor, effective asthma management may ultimately impact morbidity and mortality in SCD. Unique and Overlapping Pathophysiology in Asthma and SCD A number of inflammatory pathways contribute to asthma [ 31 — 34 ], many of which are outside the scope of this review. Interestingly, several well-documented mechanisms of asthma are known to contribute to the pathophysiology of SCD.

These specific pathways provide a framework to guide additional investigation into the commonly found asthma-like condition in children with SCD. One potential underlying connection between SCD and asthma is the inflammation seen with each disease process.

SCD is a proinflammatory state with baseline elevations of cytokines such as interferon-tumor necrosis factor-and others [ 35 ]. Vascular adhesion molecule-1 is also known to be elevated in SCD [ 36 ].

During VOEs, these inflammatory molecules have been seen to rise even higher [ 3536 ]. This inflammation could in turn result in a propensity towards clinical asthma. Supporting this hypothesis is the documentation of increased mortality and an enhanced inflammatory response to allergens in mice with SCD and experimentally induced asthma [ 37 ]. Leukotrienes are a particularly intriguing commonality between asthma and SCD.

They are key signaling molecules involved in both inflammation and bronchoconstriction. There is also data to suggest a role for elevated sPLA2 in asthma in general [ 43 ], which is of interest given the difficulty in clinically differentiating ACS from asthma in a patient with SCD. Thus, these molecules have a theoretical link from SCD to asthma. Although controlled clinical trials have not yet been done, montelukast, an inhibitor of leukotriene activity, is an intriguing candidate for the treatment of asthma in patients with SCD [ 44 ].

Dysregulated arginine metabolism and excess arginase activity has also been implicated in the pathophysiology of both asthma [ 2945 — 51 ] and SCD [ 72952 — 56 ]. Elevated plasma levels of the arginine analog asymmetric dimethyl arginine ADMA also contribute to arginine dysregulation in both asthma [ 5758 ] and SCD [ 59 — 61 ].

L-Arginine is the obligate substrate for both the arginases and nitric oxide synthetases NOS. NO is a potent vasodilator that plays a role in maintaining bronchodilatory tone. NO in exhaled breath eNO is also an established marker of chronic inflammation in asthmatics [ 62 ]. However, a more recent study demonstrated elevated eNO levels in nonatopic children with SCD compared to normal controls [ 65 ], again illustrating a variance in NO metabolism in SCD versus control subjects.

A plausible explanation may be found by considering potential mechanisms that contribute to the clinical phenotype that differed in each study. Metabolic profiling has revealed an arginine deficiency among subgroups of patients with SCD that is associated with clinical phenotypes and a mortality risk that varies from steady-state to acute events [ 46475253 ].

Simultaneous plasma arginine and eNO levels were not measured in any of these studies, a variable that may impact eNO concentration [ 66 ].

Arginase metabolism of L-arginine decreases its bioavailability to NOS, effectively limiting NO production [ 46 ] and contributes to AHR in asthma [ 48496768 ].

In addition, downstream byproducts of arginase activity proline and polyamines are associated with collagen deposition, airway remodeling, smooth muscle proliferation, and fibrosis [ 6970 ], potentially contributing to both obstructive and restrictive lung disease Figure 1 [ 295671 ]. Although this is only one of many mechanisms contributing to AHR in asthma, this is an intriguing mechanism worthy of further study given the abnormal arginine metabolome in SCD [ 525356 ].

Altered arginine metabolism in sickle cell disease SCD. Dietary glutamine and glutamate serve as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Arginine is synthesized endogenously from citrulline primarily via the intestinal-renal axis [ 80 ]. Arginase and nitric oxide synthase NOS compete for arginine, their common substrate.

In SCD, bioavailability of arginine and nitric oxide NO is decreased by several mechanisms linked to hemolysis [ 53548182 ]. The release of erythrocyte arginase during hemolysis increases plasma arginase levels and shifts arginine metabolism towards ornithine production, limiting the amount of substrate available for NO production [ 53 ]. The bioavailability of arginine is further diminished by increased ornithine levels because ornithine and arginine compete for the same transporter system for cellular uptake cationic amino acid transporter—CAT [ 8384 ].

Despite an increase in NOS, NO bioavailability is low due to low substrate availability [ 53 ], NO scavenging by cell-free hemoglobin released during hemolysis [ 85 ], and through reactions with free radicals such as superoxide and other reactive NO species [ 86 — 88 ]. Superoxide will react with NO to form reactive nitric oxide species RNOS including peroxynitrite [ 93 ], which can contribute further to cell damage and cell death.

Endothelial dysfunction resulting from NO depletion and increased levels of the downstream products of ornithine metabolism polyamines and proline likely contributes to the pathogenesis of lung injury, pulmonary hypertension, and asthma in SCD. This model has implications for all hemolytic processes. This new disease paradigm is now recognized as an important mechanism in the pathophysiology of SCD.

Adults with SCD are arginine deficient, [ 5372 ] while children tend to have normal levels at steady-state compared to control subjects [ 52 ]. However both adults and children experience an acute decrease in plasma arginine concentrations during VOEs and episodes of ACS [ 5273 ]. Of interest, parenteral arginine significantly decreased total opioid use and improved pain scores in children with SCD hospitalized for VOE compared to placebo in a recently published randomized, placebo-controlled trial [ 74 ].

Plasma arginase activity is elevated in SCD as a consequence of inflammation, liver dysfunction, and, most significantly, by the release of erythrocyte arginase during intravascular hemolysis [ 53 ], which has been demonstrated by the strong correlation between plasma arginase levels and cell-free hemoglobin levels [ 53 ] and other markers of increased hemolytic rate including LDH [ 5375 ].

In a recent prospective cohort study, Field et al. However, AHR was noted to be related to increased LDH levels supporting hemolysis as a potential mechanism [ 75 ] contributing to airway hyper-reactivity and asthma in SCD [ 29 ]. In contrast, Pritchard et al.

Given that murine erythrocytes contain minimal arginase, this model is unfortunately limited to evaluate the impact of hemolysis-driven increases in arginase levels as a mechanism of AHR.

However, this study did find that SCD alone in the mouse model induces a baseline lung pathology that increases large and small airway resistance and primes the lungs for increased inflammation and AHR after allergic sensitization [ 76 ].

Hagar and colleagues [ 14 ] found an association of asthma in children with SCD who had an elevated tricuspid regurgitant jet velocity on Doppler echocardiography, a measure that is strongly associated with hemolytic rate [ 77 ]. Of interest, this association of asthma and pulmonary hypertension risk was not found in adults with SCD [ 14 ].

Future studies are needed to validate this hypothesis that includes asthma [ 729 ] in the hemolytic sub-phenotype of SCD [ 78 ], particularly in lieu of the controversy surrounding the hyperhemolysis pathway [ 79 ].

In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.

These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma [ 94 ]. Meanwhile, ACS is defined by the finding of a new infiltrate on CXR with at least one of the symptoms of fever, cough, sputum production, and dyspnea [ 95 ].

Although the recurrent nature of asthma symptoms associated with a trigger may help distinguish these two entities, ACS can also be recurrent and may present with wheezing, tachypnea, and rhinorrhea [ 9596 ]. Symptoms may also improve with beta-agonists [ 95 ], a common asthma therapy. These common characteristics may make it difficult to definitively distinguish between the two entities, and the safest management for some cases may be treatment for both possibilities.

Asthma is a clinical diagnosis.

Asthma Management in Sickle Cell Disease

However, at this time, it is not clear if clinical features of asthma are similar in patients with SCD compared to the general population. Field and colleagues found a sibling history of asthma as a risk factor for pain crisis in children with SCD, suggesting disease-modifying effects of asthma due to familial factors commonly seen in typical asthma [ 98 ].

Since parental history of asthma was not associated with significantly increased risk of pain or ACS episodes in this study, it is not clear if the association seen with sibling history was purely genetic, due to environmental influences or both.

Interestingly, a more recent study by Field et al. Regardless, patient history should be reviewed for symptoms suggestive of recurrent AHR or airflow obstruction to help establish a diagnosis of asthma, especially given the high prevalence of atopic asthma in African Americans.

Typical symptoms include wheezing, coughing, difficulty breathing, or chest tightness. It is also important to review the patient history for possible triggers and for the timing of symptoms. Classic triggers include exercise, respiratory infections, and inhaled allergens. Asthmatic symptoms are typically worse at night or upon awakening. The patient should also be questioned about risk factors for asthma such as a personal or family history of allergic rhinitis, asthma, and eczema.

Asthma symptoms are frequently missed by clinicians unless the information is specifically elicited in careful questioning about the presence of such symptoms like nighttime cough and poor exercise capacity [ 7 ], as families often will not spontaneously offer this information without prompting.

A history of snoring, daytime somnolence, presence of tonsillar, and adenoidal hypertrophy should prompt clinician to obtain an overnight polysomnogram to assess for nocturnal hypoxemia and sleep disordered breathing.