Sickle Chronic Lung Disease Research Articles

Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease.

Sickle cell disease is a genetic haemoglobin disorder, which can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Sickle cell disease is one of the most common severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. The two most common chronic chest complications due to sickle cell disease are pulmonary hypertension and chronic sickle lung disease. These complications can lead to morbidity (such as reduced exercise tolerance) and increased mortality. This is an update of a Cochrane Review first published in 2011 and updated in 2014 and 2016. We wanted to determine whether trials involving people with sickle cell disease that compare regular long-term blood transfusion regimens with standard care, hydroxycarbamide (hydroxyurea) any other drug treatment show differences in the following: mortality associated with chronic chest complications; severity of established chronic chest complications; development and progression of chronic chest complications; serious adverse events. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. Date of the last search: 19 September 2019. We also searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 10, 14 November 2018), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 14 November 2018. We included randomised controlled trials of people of any age with one of four common sickle cell disease genotypes, i.e. Hb SS, Sβº, SC, or Sβ+ that compared regular red blood cell transfusion regimens (either simple or exchange transfusions) to hydroxycarbamide, any other drug treatment, or to standard care that were aimed at reducing the development or progression of chronic chest complications (chronic sickle lung and pulmonary hypertension). We used the standard methodological procedures expected by Cochrane. No studies matching the selection criteria were found. There is a need for randomised controlled trials looking at the role of long-term transfusion therapy in pulmonary hypertension and chronic sickle lung disease. Due to the chronic nature of the conditions, such trials should aim to use a combination of objective and subjective measures to assess participants repeatedly before and after the intervention.

Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease.

Sickle cell disease is a genetic haemoglobin disorder, which can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Sickle cell disease is one of the most common severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. The two most common chronic chest complications due to sickle cell disease are pulmonary hypertension and chronic sickle lung disease. These complications can lead to morbidity (such as reduced exercise tolerance) and increased mortality.This is an update of a Cochrane review first published in 2011 and updated in 2014. We wanted to determine whether trials involving people with sickle cell disease that compare regular long-term blood transfusion regimens with standard care, hydroxycarbamide (hydroxyurea) any other drug treatment show differences in the following: mortality associated with chronic chest complications; severity of established chronic chest complications; development and progression of chronic chest complications; serious adverse events. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. Date of the last search: 25 April 2016.We also searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 26 January 2016), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 26 January 2016. We included randomised controlled trials of people of any age with one of four common sickle cell disease genotypes, i.e. Hb SS, Sß(0), SC, or Sß(+) that compared regular red blood cell transfusion regimens (either simple or exchange transfusions) to hydroxycarbamide, any other drug treatment, or to standard care that were aimed at reducing the development or progression of chronic chest complications (chronic sickle lung and pulmonary hypertension). We used the standard methodological procedures expected by Cochrane. No studies matching the selection criteria were found. There is a need for randomised controlled trials looking at the role of long-term transfusion therapy in pulmonary hypertension and chronic sickle lung disease. Due to the chronic nature of the conditions, such trials should aim to use a combination of objective and subjective measures to assess participants repeatedly before and after the intervention.

The effect of Duffy antigen receptor for chemokines on severity in sickle cell disease

The effect of Duffy antigen receptor for chemokines on severity in sickle cell disease

Elevated Tricuspid Regurgitation Jet Velocity on Echocardiogram In Patients with Sickle Cell Disease Is Associated with Worse Steady State Functional Class, Poor Lung Function and Low Haemoglobin but Not Other Markers of Haemolysis or Endothelin-1.

AbstractAbstract 1638 Introduction and Objectives:Pulmonary hypertension (PH) in Sickle cell disease (SCD) is defined as a tricuspid regurgitation jet velocity ≥2.5 metres/second on trans thoracic echocardiogram. World health organisation functional class (WHO FC), a measure of physical limitation due to symptoms of PH (class 1–4, class 1 describing no symptoms with ordinary activity and class 4 describing symptoms with any physical activity) and diffusion capacity (DLCOc, KCO) are important tools in the management of non SCD patients with PH.We have examined the association of WHO FC, lung function data, haemolytic and inflammatory markers in haemoglobin SS (HbSS) adults with PH (TRV≥ 2.5 m/s) and without PH (TRV < 2.5 m/s). Cytokines studied included interleukin 8 (IL-8), which may have a role in promoting adhesion of sickle red cells to vascular endothelium, stem cell factor (SCF), which acts on erythroid progenitor cells and endothelin-1, a potent pulmonary vasoconstrictor. Methods:32 adult HbSS patients (median 37 years, range 20–59) were recruited at steady state defined as at least two weeks or more following an acute crisis. Serum levels of haemolytic and inflammatory markers, asymmetric dimethylarginine (ADMA a naturally occurring nitric oxide synthase inhibitor), ferritin, SCF and IL 8 were measured. Results:Results are given in table and expressed as mean ± standard deviation.Of patients with PH 36% (5/14) were WHO FC ≥3 compared to 6% (1/18) without PH. There was a significant difference in functional class in patients with and without PH on echocardiogram (p< 0.05). There was a significant correlation between TRV and WHO functional class (p=0.002, r= 0.54). The correlation between TRV and functional class remained significant after correction for Hb.Neither PH nor WHO FC was associated with parenchymal abnormalities or chronic sickle lung disease visible on CT and/or chest radiograph.PH was also associated with a lower diffusion capacity (DLCOc mmol/min/kPa: 3.60 ± 0.79 vs. 7.60 ± 2.66, p=0.034) and a lower diffusion capacity corrected for alveolar volume (KCOc mmol/min/kPa/l: 1.04 ± 0.31 vs. 1.96 ± 0.3, p=0.034). TRV was significantly correlated with DLCOc only (p=0.036 r= -0.79).Conclusion: PH in SCD is associated with lower haemoglobin and elevated ADMA but not other markers of haemolysis. Patients with elevated TRV also had a significantly higher WCC, IL 8 and SCF which would support the possible role of inflammatory mediated endothelial dysfunction in the pathogenesis of PH associated with SCD.The elevated ferritin associated with patients with TRV ≥ 2.5 m/s may reflect cardiac dysfunction from iron overload as a cause of right heart dysfunction.Although patients with SCD may have a number of reasons to account for their breathlessness, echo, WHO functional class and measurements of gas transfer may be useful markers in screening patients for pulmonary hypertension regardless of low steady state anaemia. This may allow early detection, treatment and reduction in mortality. Disclosures:No relevant conflicts of interest to declare.

Cytoprotective Mechanisms of the Lung in Sickle Cell Disease.

Abstract 1538Poster Board I-561Circulating plasma hemoglobin contributes to major vasculopathies including pulmonary hypertension in patients who have sickle cell disease (SCD). There is an emerging concept that such vasculopathies are relatively mild because of activation of several cytoprotective pathways in SCD. The biochemical profile of plasma and the transcriptome of peripheral blood cells in patients who have SCD offer indirect support for this concept. Indeed, heme oxygenase-1 (HO-1), an acute phase enzyme that degrades heme into intermediates and byproducts with vasculoprotective properties is markedly elevated in mononuclear leukocytes of patients who have SCD. Nonetheless, the scope of the cytoprotective mechanisms of the lung and other organs impacted directly by sickle vasculopathies remain poorly appreciated. We previously identified an array of cytoprotective enzymes in lung endothelial cells chronically exposed to non-toxic concentrations of hemin in vitro. In this study, we examined the expression of NAD(P)H oxidase and candidate cytoprotective enzymes in two models of transgenic mice with SCD, and examined HO-1 expression in sickle chronic lung disease. Although NAD(P)H oxidase catalyzes reactive oxygen species generation by heme and is responsible for increased adhesion of leukocytes to the endothelium in SCD mice, there was no elevation of any of its subunits (gp91Phox and p22Phox, p47Phox, p67Phox and p40 Phox) in sickle mice lungs compared to hemizygote control mice lungs. Quantitative RT-PCR analysis revealed unexpectedly no difference in HO-1 mRNA level in sickle and non-sickle control lungs. On the contrary, analysis of the same tissues showed significantly higher NAD(P)H quinone oxidoreductase-1 (NQO1) mRNA level in both Berkeley and Townes knock-in sickle mice compared to controls (p<0.001). Enhanced expression of NQO1 but not HO-1 in sickle mice lungs was confirmed at the protein level by western blot analysis and by immunohistochemistry. Finally, we studied cases of sickle chronic lung disease (n=17) and discovered that NQO1 is expressed in the pulmonary endothelium at significantly higher levels than in normal lung tissues (p<0.002). In agreement with the data in mice, we found no difference in HO-1 staining in sickle human lung and normal lung tissues. Our findings indicate that despite its established role in acute elimination of excess heme, HO-1 is not elevated in sickle lungs. This study highlights the importance of dissecting the cytoprotective phenotype of individual organs impacted by SCD towards a rationale approach to developing efficacious antioxidant therapy for this disorder. DisclosuresNo relevant conflicts of interest to declare.

Molecular Phenotype of Sickle Chronic Lung Disease Revealed by Global Gene Expression Profiling

Emerging evidence indicate the concentration of circulating heme in patients who have sickle cell disease (SCD) is sufficient to contribute to vasculopathies such as pulmonary hypertension. Despite this significance, the identity of specific molecules and pathways responsible for heme-induced pulmonary complications in SCD remains poorly understood. This study was conceived with the idea that whole-genome expression profiling offered a rigorous approach to identify specific molecules involved in both pathological and vasculoprotective mechanisms of sickle chronic lung disease. Human pulmonary artery endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMVECs) were exposed to a concentration (0–25 mM) range of hemin for seven days and total RNA isolated and interrogated with Affymetrix U133 plus 2.0 Genechips. Microarray data from 24 independent experiments was analyzed using the Bioconductor in the R framework and GeneSpring to generate two unique lists of genes regulated by hemin in PAECs and PMVECs. Multiple genes widely known to be influenced by heme including heme oxygenase-1 (HO-1), ferritin, transferrin receptor, and delta-aminolevulinate synthase were altered as expected thus validating the experimental, statistical and bio-informatics approaches used in this study. The microarray expression data was validated for 26 transcripts in PAECs and 14 transcripts in PMVECs using low-density array multiplex quantitative RT-PCR. Our findings indicate that the cytoprotective response to hemin is markedly more enhanced in PMVECs than in PAECs as determined by the number and the magnitude of differential expression of genes in the oxidative stress response and glutathione metabolism pathways. This finding is supported by a higher basal expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in PMVECs than in PAECs. Heterogeneity of these anti-oxidant phenotypes was confirmed at the protein level in a concentration-dependent manner for multiple enzymes regulated by Nrf2 including NAD(P)H:quinone oxidoreductase 1 (NQO1), which is critical for preventing participation of quinones in redox cycling and generation of reactive oxygen species. Moreover, while NQO1 expression increased 3-fold in PMVECs exposed to hemin for seven days no significant increase in NQO1 expression occurred following shorter periods of hemin treatment. The clinicopathological and pathophysiological relevance of these findings were investigated in post-mortem lung tissues of cases of sickle chronic lung disease and in transgenic mice with SCD. Compared to normal human lung tissues, NQO1 expression increased 3-to 5-fold in the endothelium of small caliber size vessels as well as in both large and small airway epithelium in severe cases of sickle chronic lung disease with extensive pulmonary vascular remodeling. On the contrary, no significant difference in NQO1 expression was detected in the lungs of wild-type mice and transgenic hemizygous or homozygous SCD mice lacking pulmonary vascular remodeling. We conclude that different pulmonary segments and specific anti-oxidant molecules respond uniquely to heme. Unraveling this complex heterogeneity is critical to improving understanding of the pathogenesis and treatment of lung complications in SCD. Induction of NQO1 or its upstream regulator Nrf2 offers a potentially attractive strategy to augment the anti-oxidant phenotype of PAECs to slow the progression of pulmonary vasculopathies in SCD.

Pulmonary complications of sickle cell disease in children

Sickle cell disease is one of the most prevalent genetic diseases, affecting 1 in 600 African-Americans. The lung is one of the major organs affected in sickle cell disease and the pulmonary complications of sickle cell disease result in significant morbidity and mortality in children. Recent literature has provided evidence supporting the strong association between asthma and airway hyperreactivity and sickle cell disease, as well as a link with acute chest syndrome and vaso-occlusive crisis. Additionally, children with sickle cell disease who have acute chest syndrome episodes have worse pulmonary function than those who have not experienced acute chest syndrome episodes. An increasing amount of literature highlights the link between pulmonary hypertension and sickle cell disease, and multiple mechanisms have been invoked to explain why patients with sickle cell disease are prone to the development of pulmonary hypertension. Previous and current studies have also highlighted the manifestations of sleep disordered breathing in children with sickle cell disease. The pulmonary complications of sickle cell disease include airway hyperreactivity, acute chest syndrome, chronic sickle lung disease, pulmonary hypertension, and sleep disordered breathing. Further understanding of the interrelationships between these disorders will lead to improved therapies.

Lung Function and High Resolution Computed Tomography in Sickle Cell Disease.

Adults with sickle cell disease (SCD) may develop sickle chronic lung disease which appears to be a complication of chronic hemolysis and repeated episodes of pulmonary vaso-occlusion. Pulmonary function tests have usually been used to document the severity of lung disease in SCD, but some patients cannot successfully undertake such examinations. Recently, high resolution computed tomography (HRCT) has been shown to be of value in the evaluation of patients with diffuse lung diseases. Assessment of lung disease in SCD by HRCT, however, has not been fully explored. The study sets out to investigate the relationship of any pulmonary function abnormalities in adults with SCD to a non-invasive measure of hemolysis and findings on HRCT. The study population consisted of 33 Hb SS subjects (12 males) with a median age of 36 (range 17–67) years, median height of 167 (range 53–188) cm, and median weight of 69 (range 52–92) kg.Pulmonary function was assessed by measurements of lung volumes, spirometry, gas transfer and oxygen saturation, and hemolysis by measurement of end-tidal carbon monoxide (ETCO). The degree of a lobar volume loss and ground glass opacification and prominence of central vessels on HRCT were quantitatively assessed.There was a wide variation in the lung function of the cohort. Nine patients had a restrictive lung function abnormality, five an obstructive abnormality and four a mixed restrictive/obstructive abnormality. Twenty-seven of the patients completed assessment of ETCO levels. ETCO levels correlated positively with bilirubin levels (rs=0.66, p=0.0002) and the absolute reticulocyte count (rs=0.70, p=0.0002), and negatively with hemoglobin (rs=−0.51, p=0.008). ETCO levels negatively correlated with FEV1 (p=0.006), VCpleth (p=0.006), sGaw (p=0.04) and SpO2 (p=0.007). A reticular pattern, lobar volume loss and prominent central vessels were the three most common abnormalities on HRCT. FEV1 (p<0.05), FVC (p<0.005) and TLC (p=0.008) correlated with HRCT findings, particularly lobar volume loss. Lobar volume loss, prominent central vessels and a reticular pattern/ground glass opacification were all present on HRCT in 12 of 18 subjects with a restrictive, obstructive or mixed defect.Our results suggest that non-invasive assessment of hemolysis and/or HRCT examination might facilitate identification of SCD patients with respiratory function impairment. More of the patients had abnormalities on HRCT than on lung function testing, which suggests that HRCT is a more sensitive detector of respiratory abnormalities than lung function testing. This hypothesis merits testing by serially assessing SCD patients to determine if those with only HRCT abnormalities subsequently develop lung function abnormalities.

Outcome of Sickle Cell Anemia

Based on a prospective cohort study of 1056 patients with sickle cell anemia (Hb SS) initiated in 1959, we investigated the influence of calendar era, age, sex, and prior medical conditions on the subsequent development of irreversible organ damage and survival using the Cox regression model with time-dependent covariates adjusting for all prior occurrences. We studied 30 acute clinical events, and focused on 8 prototypic forms of irreversible organ damage. Childhood survival to age 20 years has improved from 79% for those born before 1975 to 89% for children born in or after 1975. Bone infarction was a significant risk factor for avascular necrosis (p = 0.01), and infantile dactylitis was a significant risk factor for stroke (p = 0.01). Prior hospitalized vaso-occlusive sickle crisis in adults was significantly associated with the increased rate of avascular necrosis (p < 0.001), leg ulcers (p < 0.001), sickle chronic lung disease (p < 0.001), renal failure (p < 0.005), and early death (p < 0.001). The diagnosis of clearly evident clinical conditions such as leg ulcer, osteonecrosis, and retinopathy predicted an increased likelihood of developing a more lethal form of organ damage and earlier death: 77% of patients with chronic lung disease, 75% of those with renal insufficiency, and 51% of those with stroke had a prior chronic condition. Of the 232 patients who died, 73% had 1 or more clinically recognized forms of irreversible organ damage. By the fifth decade, nearly one-half of the surviving patients (48%) had documented irreversible organ damage. End-stage renal disease (glomerulosclerosis), chronic pulmonary disease with pulmonary hypertension, retinopathy, and cerebral microinfarctions are manifestations of arterial and capillary microcirculation obstructive vasculopathy. The current study underscores the need for preventive therapy to ameliorate the progression of the sickle vasculopathy.

Clinicopathological Correlations in Chronic Sickle Cell Lung Disease.

Chronic lung injury is a major cause of morbidity and mortality in sickle cell disease. Although this pulmonary injury appears to be progressive and the etiology is multifactorial, the pathogenesis is incompletely understood. Study of the histopathologic changes can be useful as evidence of the underlying pathophysiology, especially if correlated with the clinical stage of the disease.HYPOTHESIS: The histopathology of the lung in sickle cell disease varies with the clinical stage of chronic lung disease.METHODS: Medical records and autopsy reports from 324 archived autopsies of homozygous sickle cell disease were reviewed and each case was assigned a clinical severity score that ranged from 0 (no pulmonary dysfunction) to 3 (severe pulmonary dysfunction). Histologic sections from these cases were then studied in a masked manner and findings were subjectively graded on a scale of 0 (absent) to 4+ (severe). The histopathologic findings were then correlated with the clinical stage of the lung disease, using Pearson's correlation coefficients and coefficient of determinations.RESULTS: The frequency of some histopathologic findings showed a positive correlation with the increasing severity of the clinical stage of the disease, including age (r = 0.92; R2 = 0.85), vascular intimal hyperplasia (r = 0.74; R2 = 0.55), vascular medial hyperplasia (r = 0.87; R2 = 0.76), dilation of capillary plexi (r = 0.98; R2 = 0.96) and interstitial fibrosis (r = 0.78; R2 = 0.61). Scoring of the severity of the histopathologic findings suggested a pattern of progression of the morphologic injury. The earliest evidence of injury seen during infancy consisted of focal disruption of alveolar septae with hemorrhages and interstitial fibrosis (1+). These findings were more pronounced during childhood (2+) when asymptomatic restrictive defects were reported, but capillary diffusion capacity remained normal. During adolescence, these findings were well defined (3+) along with increased tortuosity of capillaries, dilation of capillary plexi and intimal hyperplasia of medium-size vessels. In adulthood, these findings were most pronounced (4+) and were accompanied by episodic dyspnea. Obliterative vasculopathy was seen almost exclusively in cases with clinical pulmonary hypertension. At end stage there appeared to be less intra-alveolar hemorrhage and edema.DISCUSSION: These findings strongly suggest that the earliest evidence of chronic sickle lung disease is injury to capillaries and to pre- and post-capillary vessels. This early injury appears to be followed by increased tortuosity of capillaries, dilation of collateral vessels and then changes in larger arterial vessels. Interstitial fibrosis was seen in cases with restrictive defects. Increased capillary surface area secondary to tortuosity of capillaries probably accounts for the clinical evidence of normal diffusion capacity. These findings support the clinical evidence that sickle cell chronic lung disease is progressive. Furthermoore, this study strongly suggests that sickle chronic lung disease follows a pattern of injury and remains asymptomatic until the pulmonary architecture has undergone considerable remodeling. These findings help explain the stealthy way in which sickle cell disease steals the pulmonary reserve.

Levels in the follow-up of a long-term clinical process.

I developed a 5-stage, 7-compartment prognostic model for the long-term follow-up of 28 patients with sickle chronic lung disease. Estimated hazard functions for transition varied with Stage 1, 2, 3, or 4 sickle chronic lung disease as well as with stage at diagnosis and duration of observation with hematologic disease before the recognition of sickle chronic lung disease. Individualized hazard matrices produced 28 prognostic probability functions of time that had heterogeneous levels and shapes. The probability of death from the time of diagnosis to the end of each patient's period of follow-up determined that patient's prognostic integrated hazard. Such integrated hazard values, developed from a prognostic model, provide a superior context for carrying out standard formal tests and inferences regarding the effects of alternative treatments in randomized clinical trials.

Sickle Cell Anemia and Major Organ Failure

Major organ failure in sickle cell anemia is the direct consequence of the sickle cell evoked vasculopathy. Major organ failure is first clinically apparent as autosplenectomy, then during childhood presents as cerebral infarction and atrophy, and finally culminates in young adulthood as end stage renal failure (glomerulosclerosis), sickle chronic lung disease, intracranial hemorrhage, retinopathy, disabling leg ulcers, and generalized osteonecrosis. The vascular damage begins years before the overt clinical symptoms are apparent with no pain to act as a signal. Organ damage is progressive and irreversible. The rate of progression is genetically controlled from birth. Except for the management of life-threatening infections that are associated with the non-functioning spleen, disease expression has not been altered by therapy. The focus of future clinical investigations must be the prevention of the vasculopathy and tissue damage which is induced by the sickle red cell.