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Systemic Corticosteroids in Acute Chest Syndrome: Friend or Foe?
Paediatric Respiratory Reviews 15 (2014) 24–27
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-Symposium: Controversies in the Evaluation and Treatment of Sickle Cell Disease
Systemic Corticosteroids in Acute Chest Syndrome: Friend or Foe? Folasade Ogunlesi 1, Matthew M. Heeney 2, Anastassios C. Koumbourlis 1,* 1 2
Division of Pulmonary & Sleep Medicine, Children’s National Medical Center/George Washington University, Washington DC Division of Hematology/Oncology, Boston Children’s Hospital /Harvard Medical School, Boston MA
EDUCATIONAL AIMS THE READER WILL: Learn the the pathophysiology of the Acute Chest Syndrome (ACS) and its various triggers Review the inflammatory responses elicited by the various triggers of the ACS Be able to evaluate the evidence on the benefit of systemic steroids in the treatment of Acute Chest Syndrome (ACS) and of the potential side effects
A R T I C L E I N F O
S U M M A R Y
Keywords: Acute Chest Syndrome Sickle Cell Corticosteroids
Acute chest syndrome(ACS) is the most common pulmonary complication of sickle cell disease (SCD), the second most common cause of hospitalization and the primary cause of death in patients with sickle cell disease. Its highest prevalence is in early childhood. The pathogenesis of ACS is unknown but many predisposing conditions and mechanisms have been implicated including infections, pulmonary fat embolism, asthma and ischemic reperfusion injury. These conditions are associated with inflammation and therefore, the use of corticosteroids has been advocated because of their anti-inflammatory properties. Although, significant benefits from their use have been shown, there is great reluctance in using them because of reports of serious adverse effects, such as readmission to the hospital due rebound pain crisis, stroke, renal infarction, coma and even death. The current article reviews the evidence in favor and against the use of corticosteroids in ACS. Emphasis is given on the potential benefits vs. risks among the different types of corticosteroids, the importance of the dosing regimen and the role of underlying comorbidities. ß 2013 Elsevier Ltd. All rights reserved.
INTRODUCTION Acute chest syndrome (ACS) is the most common form of acute pulmonary disease among patients with sickle cell disease (SCD), occurring in as many as 50% of patients [1]. It is the second most common cause for admission to the hospital (after vaso-oclusive crises) and the leading cause of death accounting for up to 25% of SCD-related deaths [2]. ACS occurs in all ages but it is more common in children with the highest prevalence occurring between the ages of 2 and 5 years [3]. Several conditions and mechanisms are known to predispose, exacerbate or complicate the pathogenesis of ACS but the exact cause remains unknown [4].
* Corresponding author. Children’s National Medical Center, 111 Michigan Ave NW, Washington DC 20010. Tel.: +1 203 476 2642; fax: +1 202 476 5864. E-mail address: [email protected] (A.C. Koumbourlis). 1526-0542/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2013.10.004
As a result there is no specific therapy for ACS. Instead its management has focused on the treatment of presumed bacterial infection with broad spectrum antibiotics, judicious administration of intravenous fluids, and pain medications in order to alleviate the patient’s discomfort and to prevent atelectasis caused by the patients’ hypoventilation secondary to splinting. Simple or exchange blood transfusions decrease the percentage of sickled red blood cells, improve oxygenation and often stop the progression of ACS. Given the increasing evidence that inflammation is an important factor in the presentation of ACS [5,6], treatment with immunomodulatory agents such as systemic corticosteroids has been advocated [7]. However, reports of serious side effects has made many clinicians reluctant to use corticosteroids. The current article reviews the available evidence in favor and against the use of systemic corticosteroids in SCD.
F. Ogunlesi et al. / Paediatric Respiratory Reviews 15 (2014) 24–27
ACS & Inflammation The pathogenesis of ACS has been attributed to many diverse mechanisms in which the presence or development of inflammation feature prominently [4–6]. These conditions are briefly summarized below. Infection Patients with SCD develop functional asplenia due to infarction of the organ ‘in situ’ that predisposes them to infections especially by encapsulated organisms [eg pneumococcus]. Other mechanisms that may affect the immunity of patients with SCD have been also proposed including evidence from transgenic sickle mice that altered baseline immunity may be secondary to morphologic abnormalities of the splenic tissue [8]. Finally, there is clinical evidence of abnormal function of the complement system although the results have been contradictory [9]. Infants and young children are at higher risk for infections because of their naturally immature immune system. ACS is a syndrome defined on the basis of a combined clinical and radiographic characteristics (development of a new pulmonary infiltrate involving at least one complete lung segment; fever; and any other constellation of pulmonary symptoms including hypoxemia, dyspnea, tachypnea, wheezing, chest pain, or cough) that is often difficult to distinguish from a typical bacterial pneumonia in a patient without SCD [2]. Although inflammation is characteristic of both entities, patients with SCD and ACS seem to develop a much more rapidly progressive and severe presentation suggesting a propensity to develop a more significant inflammatory response than non-SCD individuals. Indeed, studies in transgenic sickle mice have shown that those with SCD tend to mount a much more violent inflammatory response, and they seem to be much more susceptible to injury from the inflammatory mediators that are being released than compared with the non-SCD mice [10–13]. In other words, it is possible that patients with SCD may suffer not only by the increased susceptibility to infections but also by their own exaggerated inflammatory response that may then become the main trigger for the ACS.
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damage secondary to the ACS and not the underlying pathogenic mechanism of ACS. Asthma Several epidemiologic studies have reported an unusually high prevalence of airway hyperresponsiveness and asthma among children and adults with SCD compared with the general population (even after adjusting for race, socioeconomic conditions etc) [18,19]. Patients with SCD and asthma seem to have a much higher (as high as 6-fold) risk of recurrent ACS compared with those without history of asthma [19–22]. Most importantly patients with SCD who are admitted to the hospital for pain crises are more likely to develop ACS if they have asthma, and they seem to improve after treatment with bronchodilators [19–22]. Asthma is a classic inflammatory disease and its association with ACS suggests a possible synergistic effect by the presence of inflammation. Animal data in transgenic sickle mice have shown that experimentally induced asthma is associated with greater mortality due to increased allergic lung inflammation (elevations in eosinophils, eosinophil peroxidase, and IgE levels) compared with control mice without asthma. Eosinophils (a major source of leukotrienes in asthma) and elevations of LTB4 and LTC4 in blood and LTE4 in urine also occur in patients with sickle cell disease [5]. Ischemia/reperfusion injury SCD has traditionally been considered a disorder of microvascular vaso-occlusion secondary to mechanical obstruction by of deformed RBCs and subsequent tissue hypoxia [23] However, more recently a modified paradigm has emerged suggesting that the wide spectrum of clinical manifestations of SCA results from recurrent episodes of ischemia-reperfusion injury [5]. Ischemiareperfusion triggers a multifactorial cascade including inflammatory response characterized by increased leukocyte and sickle erythrocyte adhesion to vascular endothelium and activation of coagulation, platelets and neutrophils. The data suggest that acute lung vaso-occlusive injury causes an inflammatory response that triggers chemotaxis of leukocytes and secondary injury [24–27]. SYSTEMIC CORTICOSTEROIDS AND ACS
Pulmonary fat embolism Pulmonary fat embolism (PFE) is currently recognized as one of the major mechanisms associated with ACS [14]. Fatty bone marrow may be released into the blood as a result of bone marrow necrosis caused by a vaso-occlusive bony crisis. Embolic fat activates secretory phospholipase A2 (sPLA2), an enzyme that cleaves phospholipids and liberates free fatty acids and generates arachidonic acid that in turn produces inflammatory leukotrienes and prostaglandins. These fatty acids injure the pulmonary endothelium, increase the expression of VCAM-1 and promote the adhesion of erythrocytes to endothelium in vitro providing evidence for pathologic adhesive interactions in PFE. The concentration of sPLA2 in peripheral blood has been proposed as a laboratory marker of ACS, because it correlates with the course and severity of ACS. Specifically, the sPLA2 increases before ACS becomes clinically apparent, it peaks at the onset, and declines during resolution [15]. The basis for the PFE as a mechanism for the development of ACS has been based on the presence of lipid-laden macrophages (LLM) in bronchoalveolar lavage fluid in patients with ACS [16]. However, increased numbers of LLMs are not pathognomonic of fatty bone marrow embolization. Increased numbers of LLMs can also be found in cases of aspiration of fat containing food products, and most importantly they can be released from injured cells (e.g. in severe pneumonia or ARDS) [17]. Thus, it is possible that the presence of increased LLMs in the BAL may be due to cellular
Corticosteroids are powerful anti-inflammatory medications with pleiotropic beneficial effects in a variety of diverse clinical conditions including cancer (pain control and mood-elevation), in trauma (decrease the risk of fat-embolism) and complications/ mortality from ARDS. [28–30] ACS shares many of the manifestations and pathology with these conditions (e.g. pain, fat embolism, hypoxemia and acute lung injury). Thus, there has been great interest in the role of systemic corticosteroids as the means of inhibiting the inflammatory response that accompanies tissue ischemia/infarction. Several clinical studies using different preparations and doses of corticosteroids have held promising results. Griffin et al. [31] used high dose methylprednisolone in vasoocclusive crisis and reported significant reduction in the duration of analgesic therapy and hospitalization. Bernini et al. [32] investigated the efficacy of a lower dose of a longer acting glucocorticoid, dexamethasone in 43 children with mild to moderately severe ACS in a randomized, double-blind, placebo-controlled trial. They showed reduction in the length of hospitalization by about 40%, in the need for transfusion due to worsening anemia, in the duration of fever, and in need of oxygen requirement and pain treatment. Unfortunately, the successes associated with the use of corticosteroids in the setting of SCD have been accompanied by reports of complications ranging from recurrence of pain requiring readmission to the hospital, to episodes of severe vaso-occlusive
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F. Ogunlesi et al. / Paediatric Respiratory Reviews 15 (2014) 24–27
crises, ACS, stroke, renal infarction and even coma and death [33– 36]. In the study by Griffin et al. [31] 15% of the patients who were treated with corticosteroids had ‘‘rebound’’ pain crisis that required readmission within 6 days after discharge. Similar results were reported by Bernini et al. [32], although in their study the difference between those treated with corticosteroids was not statistically significant (27% vs 5%; P = .095). In a retrospective study, Strouse et al. [33] reported that the odds ratio of readmission within 14 days following treatment with corticosteroids was 20 fold higher among those treated with corticosteroids. In contrast, Isakoff et al. [37], also in a retrospective study, reported no rebound pain episodes or other serious complications treated with dexamethasone although these patients also received transfusion. Preliminary data from a prospective, multicenter, randomized trial for dexamethasone by the Comprehensive Sickle Cell Centers (CSCC) network [38] showed that Dexamethasone shortened the duration of hospitalization by almost a day (20 hours) and resulted in the decrease of the leucocyte activation marker sL-selectin. Rebound pain occurred in both groups with more episodes occurring in the dexamethasone group. The sL-selectin also decreased with dexamethasone and increased in patients who had rebound pain. It should be noted that these results were derived from only 12 patients (the study was discontinued due to slow recruitment) and therefore generalization may not be appropriate. To some extent the discrepancies between the various studies regarding the frequency and severity of the side effects may be related to the type and/or the dose of the steroid preparation used. As Strouse et al. showed, patients with asthma and SCD treated with dexamethasone and those treated with high doses of prednisolone (>2mg/kg/day) were more likely to be readmitted compared with those treated with low dose prednisolone [33]. It is possible that the results of the prospective study might have been better had the investigators used oral prednisone instead of dexamethasone. It should also be noted that some of the more serious complications were reported in patients who had other co-morbidities such as autoimmune and/or systemic diseases receiving treatments other than corticosteroids that have the potential of causing serious complications on their own [34]. Similarly, the one corticosteroidassociated fatality occurred in a patient who had also received granulocyte colony stimulating factor [35]. Understandably, the possibility of serious side effects has created serious concerns and has led many physicians to avoid the use of systemic corticosteroids in patients with SCD. Using data from the Pediatric Health Information System (PHIS) database from 41freestanding children’s hospitals, Sobota et al. [39] analyzed the variation between hospitals regarding the use of corticosteroids for ACS. They found that systemic corticosteroid were used in only 17% of admission for ACS and determined that the likelihood of using corticosteroids varied widely among hospitals, ranging from as low as 10% to as high as 86%. Corticosteroids were used more often in patients with comorbid asthma and in ‘‘severe’’ patients (defined as Hb-SS genotype, comorbid asthma, requiring ventilator support and ICU care). In contrast to earlier studies, length of stay was found to be longer in the steroid group but the readmission rate within 72 hours was higher in the non-steroid group compared with the steroid group (4.4% vs. 1.9%). In a subsequent study the same investigators found that the 30-day readmission rate after sickle cell crisis was 17% [40]. The factors associated with readmission were older age, admission only for pain and inpatient use of steroids; simple transfusion had a protective effect for readmission [40]. The etiology of the ‘‘rebound’’ pain phenomenon after corticosteroid treatment is not clear. It is possible that a brief course of corticosteroids may temporarily suppress but not completely treat the underlying inflammation that is expected
to continue until vaso-occlusion is relieved and reperfusion injury resolves. In such case, it is likely that there will be a ‘‘flare-up’’ of the inflammation/pain shortly after the steroids are discontinued. By this mechanism the observed ‘‘rebound’’ effect may be due to the early discontinuation of the corticosteroids and not a side effect of their use. Special consideration should be given to the combination of blood transfusion with corticosteroids. Blood transfusions have been shown to decrease many inflammatory markers that are increased during episodes of ACS although this effect is not sustained [41]. It is not known whether the blood transfusion has any direct effect on the action of corticosteroids and it is more likely that they act synergistically. Systemic corticosteroids are relatively slow acting. Thus, by decreasing the amount of circulating inflammatory mediators, blood transfusion provides immediate anti-inflammatory action until the steroids start working (usually 12-24 hours after their administration), and it may also allow the use of a lower dose. Support to this theory is provided by the study by Isakoff et al. [37] who reported no side effects in their patients with ACS who were treated with steroids and blood transfusions. Sobota et al. [40] also reported that blood transfusion had a protective effect against readmission. Unfortunately, their analysis did not assess specifically the outcome in patients who received steroids plus transfusion. CONCLUSION It is clear that the role of corticosteroid therapy in SCD and its complications is anything but settled. That there is wide variability in their use clearly shows the need for further study. We believe that the legitimate concerns about possible complications should not obscure the evidence for potential positive therapeutic effect in the right setting and that the concern for protecting the patient from iatrogenic injury should not lead to the under-treatment of appropriate patients. This is particularly important for SCD patients with comorbid asthma that together are major risk factors for ACS. As Sobota et al. showed, less than 40% of the SCD patients with asthma received corticosteroids during their hospitalization for ACS, which may explain why those patients with co-morbid asthma had a greater relative risk of readmission [39,40]. We strongly recommend the evaluation of all patients with SCD for asthma (especially those who have had a prior episode of ACS) and their comprehensive treatment according to the guidelines for treatment of asthma. Based on the currently available evidence we believe that corticosteroids should be considered for patients with conditions such as asthma that are known to respond to corticosteroids. However, when used, it would be prudent to treat with relatively low dose (<2mg/kg/day; max: 60 mg/day) of oral prednisone and avoid the abrupt discontinuation of the medication but continue with a relatively prolonged tapering course [42]. Whether there is an ‘‘optimal’’ corticosteroid agent, dose and duration of treatment requires further investigation. FUTURE RESEARCH DIRECTIONS Low dose steroid treatment for asthma exacerbation and ACS The role of inhaled corticosteroid in patients with SCD and comorbid asthma
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F. Ogunlesi et al. / Paediatric Respiratory Reviews 15 (2014) 24–27 [3] Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995;86:776–83. [4] Vishinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000;342:1855–65. [5] Platt OS. Sickle cell anemia as an inflammatory disease. J Clin Invest 2000;106:337–8. [6] Wallace KL, Marshall MA, Ramos SI, et al. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-g and CXCR3 chemokines. Blood 2009;114:667–76. [7] Field JJ, Lin G, Okam MM, et al. Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood 2013;121:3329–34. [8] Szczepanek SM, McNamara JT, Secor Jr ER, et al. Splenic morphological changes are accompanied by altered baseline immunity in a mouse model of sickle-cell disease. Am J Pathol 2012;181:1725–34. [9] Test ST, Woolworth VS. Defective regulation of complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation. Blood 1994;83:842–52. [10] Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest 2000;106:411–20. [11] Holtzclaw JD, Jack D, Aguayo SM, et al. Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice. Am J Respir Crit Care Med 2004;169:687–95. [12] Belcher JD, Mahaseth H, Welch TE, et al. Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. Am J Physiol Heart Circ Physiol 2005;288:H2715–2. [13] Sabaa N, de Franceschi L, Bonnin P, et al. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J Clin Invest 2008;118:1924–33. [14] Vichinsky E, Williams R, Das M, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood 1994;83:3107–12. [15] Ballas SK, Files B, Luchtman-Jones L, et al. Secretory phospholipase A2 levels in patients with sickle cell disease and acute chest syndrome. Hemoglobin 2006;30:165–70. [16] Godeau B, Schaeffer A, Bachir D, et al. Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism. Am J Respir Crit Care Med 1996;153:1691–6. [17] Koumbourlis AC, Santiago MT, Mustafa U, et al. Lipid Laden Macrophages in bronchoalveolar lavage fluid: Aspiration or Infection? Proc Am Thorac Soc 2006;3:A166. [18] Newaskar M, Hardy KA, Morris CR. Asthma in sickle cell disease. Scientific World Journal 2011;11:1138–52. [19] Knight-Madden JM, Forrester TS, Lewis NA, Greenough A. Asthma in children with sickle cell disease and its association with acute chest syndrome. Thorax 2005;60:206–10. [20] Boyd JH, Macklin EA, Strunk RC, et al. Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood 2006;108:2923– 7. [21] Nordness ME, Lynn J, Zacharisen MC, et al. Asthma is a risk factor for acute chest syndrome and cerebral vascular accidents in children with sickle cell disease. Clin Mol Allergy 2005;3:2. [22] Sylvester KP, Patey RA, Broughton S, et al. Temporal relationship of asthma to acute chest syndrome in sickle cell disease. Pediatr Pulmonol 2007;42: 103–6.
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[23] Hebbel RP, Moldow CF, Steinberg MH. Modulation of erythrocyte-endothelial interactions and the vasocclusive severity of sickling disorders. Blood 1981;58:947–52. [24] Turhan A, Weiss LA, Mohandas N, et al. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. PNAS 2002;99:3047–51. [25] Francis Jr RB. Platelets, coagulation, and fibrinolysis in sickle cell disease: their possible role in vascular occlusion. Blood Coagul Fibrinolysis 1991;2:341–53. [26] Setty BN, Stuart MJ. Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 1996;88:2311–20. [27] Pujols L, Mullol J, Picado C. Importance of glucocorticoid receptors in upper and lower airways. Front Biosci 2010;15:789–800. [28] Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep 1985;69:751–4. [29] Bederman SS, Bhandari M, McKee MD, et al. Do corticosteroids reduce the risk of fat embolism syndrome in patients with long-bone fractures?. A metaanalysis. Can J Surg 2009;52:386–93. [30] Tang BM, Craig JC, Eslick GD, et al. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and metaanalysis. Crit Care Med 2009;37:1594–603. [31] Griffin TC, McIntire D, Buchanan GR. High-dose intravenous methylprednisolone therapy for pain in children and adolescents with sickle cell disease. N Engl J Med 1994;330:733–7. [32] Bernini JC, Rogers ZR, Sandler ES, et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood 1998;92:3082–9. [33] Strouse JJ, Takemoto CM, Keefer JR, et al. Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood Cancer 2007;50:1006–12. [34] Couillard S, Benkerrou M, Girot R, et al. Steroid treatment in children with sickle-cell disease. Haematologica 2007;92:425–6. [35] Darbari DS, Castro O, Taylor VI JG, et al. Severe vaso-occlusive episodes associated with use of systemic corticosteroids in patients with sickle cell disease. J Natl Med Assoc 2008;100:948–51. [36] Adler BK, Salzman DE, Carabasi MH, et al. Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood 2001;97:3313–4. [37] Isakoff MS, Lillo JA, Hagstrom JN. A single-institution experience with treatment of severe acute chest syndrome: lack of rebound pain with dexamethasone plus transfusion therapy. J Pediatr Hematol Oncol 2008;30:322–5. [38] Quinn CT, Stuart MJ, Kesler K, et al. Investigators of the Comprehensive Sickle Cell Centers. Tapered oral dexamethasone for the acute chest syndrome of sickle cell disease. Br J Haematol 2011;155:263–7. [39] Sobota A, Graham DA, Heeney MM, et al. Corticosteroids for acute chest syndrome in children with sickle cell disease: Variation in use and association with length of stay and readmission. Am J Hematol 2010;85:24–8. [40] Sobota A, Graham DA, Neufeld EJ, Heeney MM. Thirty-day readmission rates following hospitalization for pediatric sickle cell crisis at freestanding children’s hospitals: risk factors and hospital variation. Pediatr Blood Cancer 2012;58:61–5. [41] Liem RI, O’Gorman MR, Brown DL. Effect of red cell exchange transfusion on plasma levels of inflammatory mediators in sickle cell patients with acute chest syndrome. Am J Hematol 2004;76:19–25. [42] Hsu LL, Gee BE. Sickle Cell Pain After Abrupt Withdrawal of Glucocorticoids for Asthma. 2010: A6207, 10.1164/ajrccm-conference.2010.181.1 Meeting Abstracts. A6207.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-Symposium: Controversies in the Evaluation and Treatment of Sickle Cell Disease
Systemic Corticosteroids in Acute Chest Syndrome: Friend or Foe? Folasade Ogunlesi 1, Matthew M. Heeney 2, Anastassios C. Koumbourlis 1,* 1 2
Division of Pulmonary & Sleep Medicine, Children’s National Medical Center/George Washington University, Washington DC Division of Hematology/Oncology, Boston Children’s Hospital /Harvard Medical School, Boston MA
EDUCATIONAL AIMS THE READER WILL: Learn the the pathophysiology of the Acute Chest Syndrome (ACS) and its various triggers Review the inflammatory responses elicited by the various triggers of the ACS Be able to evaluate the evidence on the benefit of systemic steroids in the treatment of Acute Chest Syndrome (ACS) and of the potential side effects
A R T I C L E I N F O
S U M M A R Y
Keywords: Acute Chest Syndrome Sickle Cell Corticosteroids
Acute chest syndrome(ACS) is the most common pulmonary complication of sickle cell disease (SCD), the second most common cause of hospitalization and the primary cause of death in patients with sickle cell disease. Its highest prevalence is in early childhood. The pathogenesis of ACS is unknown but many predisposing conditions and mechanisms have been implicated including infections, pulmonary fat embolism, asthma and ischemic reperfusion injury. These conditions are associated with inflammation and therefore, the use of corticosteroids has been advocated because of their anti-inflammatory properties. Although, significant benefits from their use have been shown, there is great reluctance in using them because of reports of serious adverse effects, such as readmission to the hospital due rebound pain crisis, stroke, renal infarction, coma and even death. The current article reviews the evidence in favor and against the use of corticosteroids in ACS. Emphasis is given on the potential benefits vs. risks among the different types of corticosteroids, the importance of the dosing regimen and the role of underlying comorbidities. ß 2013 Elsevier Ltd. All rights reserved.
INTRODUCTION Acute chest syndrome (ACS) is the most common form of acute pulmonary disease among patients with sickle cell disease (SCD), occurring in as many as 50% of patients [1]. It is the second most common cause for admission to the hospital (after vaso-oclusive crises) and the leading cause of death accounting for up to 25% of SCD-related deaths [2]. ACS occurs in all ages but it is more common in children with the highest prevalence occurring between the ages of 2 and 5 years [3]. Several conditions and mechanisms are known to predispose, exacerbate or complicate the pathogenesis of ACS but the exact cause remains unknown [4].
* Corresponding author. Children’s National Medical Center, 111 Michigan Ave NW, Washington DC 20010. Tel.: +1 203 476 2642; fax: +1 202 476 5864. E-mail address: [email protected] (A.C. Koumbourlis). 1526-0542/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2013.10.004
As a result there is no specific therapy for ACS. Instead its management has focused on the treatment of presumed bacterial infection with broad spectrum antibiotics, judicious administration of intravenous fluids, and pain medications in order to alleviate the patient’s discomfort and to prevent atelectasis caused by the patients’ hypoventilation secondary to splinting. Simple or exchange blood transfusions decrease the percentage of sickled red blood cells, improve oxygenation and often stop the progression of ACS. Given the increasing evidence that inflammation is an important factor in the presentation of ACS [5,6], treatment with immunomodulatory agents such as systemic corticosteroids has been advocated [7]. However, reports of serious side effects has made many clinicians reluctant to use corticosteroids. The current article reviews the available evidence in favor and against the use of systemic corticosteroids in SCD.
F. Ogunlesi et al. / Paediatric Respiratory Reviews 15 (2014) 24–27
ACS & Inflammation The pathogenesis of ACS has been attributed to many diverse mechanisms in which the presence or development of inflammation feature prominently [4–6]. These conditions are briefly summarized below. Infection Patients with SCD develop functional asplenia due to infarction of the organ ‘in situ’ that predisposes them to infections especially by encapsulated organisms [eg pneumococcus]. Other mechanisms that may affect the immunity of patients with SCD have been also proposed including evidence from transgenic sickle mice that altered baseline immunity may be secondary to morphologic abnormalities of the splenic tissue [8]. Finally, there is clinical evidence of abnormal function of the complement system although the results have been contradictory [9]. Infants and young children are at higher risk for infections because of their naturally immature immune system. ACS is a syndrome defined on the basis of a combined clinical and radiographic characteristics (development of a new pulmonary infiltrate involving at least one complete lung segment; fever; and any other constellation of pulmonary symptoms including hypoxemia, dyspnea, tachypnea, wheezing, chest pain, or cough) that is often difficult to distinguish from a typical bacterial pneumonia in a patient without SCD [2]. Although inflammation is characteristic of both entities, patients with SCD and ACS seem to develop a much more rapidly progressive and severe presentation suggesting a propensity to develop a more significant inflammatory response than non-SCD individuals. Indeed, studies in transgenic sickle mice have shown that those with SCD tend to mount a much more violent inflammatory response, and they seem to be much more susceptible to injury from the inflammatory mediators that are being released than compared with the non-SCD mice [10–13]. In other words, it is possible that patients with SCD may suffer not only by the increased susceptibility to infections but also by their own exaggerated inflammatory response that may then become the main trigger for the ACS.
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damage secondary to the ACS and not the underlying pathogenic mechanism of ACS. Asthma Several epidemiologic studies have reported an unusually high prevalence of airway hyperresponsiveness and asthma among children and adults with SCD compared with the general population (even after adjusting for race, socioeconomic conditions etc) [18,19]. Patients with SCD and asthma seem to have a much higher (as high as 6-fold) risk of recurrent ACS compared with those without history of asthma [19–22]. Most importantly patients with SCD who are admitted to the hospital for pain crises are more likely to develop ACS if they have asthma, and they seem to improve after treatment with bronchodilators [19–22]. Asthma is a classic inflammatory disease and its association with ACS suggests a possible synergistic effect by the presence of inflammation. Animal data in transgenic sickle mice have shown that experimentally induced asthma is associated with greater mortality due to increased allergic lung inflammation (elevations in eosinophils, eosinophil peroxidase, and IgE levels) compared with control mice without asthma. Eosinophils (a major source of leukotrienes in asthma) and elevations of LTB4 and LTC4 in blood and LTE4 in urine also occur in patients with sickle cell disease [5]. Ischemia/reperfusion injury SCD has traditionally been considered a disorder of microvascular vaso-occlusion secondary to mechanical obstruction by of deformed RBCs and subsequent tissue hypoxia [23] However, more recently a modified paradigm has emerged suggesting that the wide spectrum of clinical manifestations of SCA results from recurrent episodes of ischemia-reperfusion injury [5]. Ischemiareperfusion triggers a multifactorial cascade including inflammatory response characterized by increased leukocyte and sickle erythrocyte adhesion to vascular endothelium and activation of coagulation, platelets and neutrophils. The data suggest that acute lung vaso-occlusive injury causes an inflammatory response that triggers chemotaxis of leukocytes and secondary injury [24–27]. SYSTEMIC CORTICOSTEROIDS AND ACS
Pulmonary fat embolism Pulmonary fat embolism (PFE) is currently recognized as one of the major mechanisms associated with ACS [14]. Fatty bone marrow may be released into the blood as a result of bone marrow necrosis caused by a vaso-occlusive bony crisis. Embolic fat activates secretory phospholipase A2 (sPLA2), an enzyme that cleaves phospholipids and liberates free fatty acids and generates arachidonic acid that in turn produces inflammatory leukotrienes and prostaglandins. These fatty acids injure the pulmonary endothelium, increase the expression of VCAM-1 and promote the adhesion of erythrocytes to endothelium in vitro providing evidence for pathologic adhesive interactions in PFE. The concentration of sPLA2 in peripheral blood has been proposed as a laboratory marker of ACS, because it correlates with the course and severity of ACS. Specifically, the sPLA2 increases before ACS becomes clinically apparent, it peaks at the onset, and declines during resolution [15]. The basis for the PFE as a mechanism for the development of ACS has been based on the presence of lipid-laden macrophages (LLM) in bronchoalveolar lavage fluid in patients with ACS [16]. However, increased numbers of LLMs are not pathognomonic of fatty bone marrow embolization. Increased numbers of LLMs can also be found in cases of aspiration of fat containing food products, and most importantly they can be released from injured cells (e.g. in severe pneumonia or ARDS) [17]. Thus, it is possible that the presence of increased LLMs in the BAL may be due to cellular
Corticosteroids are powerful anti-inflammatory medications with pleiotropic beneficial effects in a variety of diverse clinical conditions including cancer (pain control and mood-elevation), in trauma (decrease the risk of fat-embolism) and complications/ mortality from ARDS. [28–30] ACS shares many of the manifestations and pathology with these conditions (e.g. pain, fat embolism, hypoxemia and acute lung injury). Thus, there has been great interest in the role of systemic corticosteroids as the means of inhibiting the inflammatory response that accompanies tissue ischemia/infarction. Several clinical studies using different preparations and doses of corticosteroids have held promising results. Griffin et al. [31] used high dose methylprednisolone in vasoocclusive crisis and reported significant reduction in the duration of analgesic therapy and hospitalization. Bernini et al. [32] investigated the efficacy of a lower dose of a longer acting glucocorticoid, dexamethasone in 43 children with mild to moderately severe ACS in a randomized, double-blind, placebo-controlled trial. They showed reduction in the length of hospitalization by about 40%, in the need for transfusion due to worsening anemia, in the duration of fever, and in need of oxygen requirement and pain treatment. Unfortunately, the successes associated with the use of corticosteroids in the setting of SCD have been accompanied by reports of complications ranging from recurrence of pain requiring readmission to the hospital, to episodes of severe vaso-occlusive
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crises, ACS, stroke, renal infarction and even coma and death [33– 36]. In the study by Griffin et al. [31] 15% of the patients who were treated with corticosteroids had ‘‘rebound’’ pain crisis that required readmission within 6 days after discharge. Similar results were reported by Bernini et al. [32], although in their study the difference between those treated with corticosteroids was not statistically significant (27% vs 5%; P = .095). In a retrospective study, Strouse et al. [33] reported that the odds ratio of readmission within 14 days following treatment with corticosteroids was 20 fold higher among those treated with corticosteroids. In contrast, Isakoff et al. [37], also in a retrospective study, reported no rebound pain episodes or other serious complications treated with dexamethasone although these patients also received transfusion. Preliminary data from a prospective, multicenter, randomized trial for dexamethasone by the Comprehensive Sickle Cell Centers (CSCC) network [38] showed that Dexamethasone shortened the duration of hospitalization by almost a day (20 hours) and resulted in the decrease of the leucocyte activation marker sL-selectin. Rebound pain occurred in both groups with more episodes occurring in the dexamethasone group. The sL-selectin also decreased with dexamethasone and increased in patients who had rebound pain. It should be noted that these results were derived from only 12 patients (the study was discontinued due to slow recruitment) and therefore generalization may not be appropriate. To some extent the discrepancies between the various studies regarding the frequency and severity of the side effects may be related to the type and/or the dose of the steroid preparation used. As Strouse et al. showed, patients with asthma and SCD treated with dexamethasone and those treated with high doses of prednisolone (>2mg/kg/day) were more likely to be readmitted compared with those treated with low dose prednisolone [33]. It is possible that the results of the prospective study might have been better had the investigators used oral prednisone instead of dexamethasone. It should also be noted that some of the more serious complications were reported in patients who had other co-morbidities such as autoimmune and/or systemic diseases receiving treatments other than corticosteroids that have the potential of causing serious complications on their own [34]. Similarly, the one corticosteroidassociated fatality occurred in a patient who had also received granulocyte colony stimulating factor [35]. Understandably, the possibility of serious side effects has created serious concerns and has led many physicians to avoid the use of systemic corticosteroids in patients with SCD. Using data from the Pediatric Health Information System (PHIS) database from 41freestanding children’s hospitals, Sobota et al. [39] analyzed the variation between hospitals regarding the use of corticosteroids for ACS. They found that systemic corticosteroid were used in only 17% of admission for ACS and determined that the likelihood of using corticosteroids varied widely among hospitals, ranging from as low as 10% to as high as 86%. Corticosteroids were used more often in patients with comorbid asthma and in ‘‘severe’’ patients (defined as Hb-SS genotype, comorbid asthma, requiring ventilator support and ICU care). In contrast to earlier studies, length of stay was found to be longer in the steroid group but the readmission rate within 72 hours was higher in the non-steroid group compared with the steroid group (4.4% vs. 1.9%). In a subsequent study the same investigators found that the 30-day readmission rate after sickle cell crisis was 17% [40]. The factors associated with readmission were older age, admission only for pain and inpatient use of steroids; simple transfusion had a protective effect for readmission [40]. The etiology of the ‘‘rebound’’ pain phenomenon after corticosteroid treatment is not clear. It is possible that a brief course of corticosteroids may temporarily suppress but not completely treat the underlying inflammation that is expected
to continue until vaso-occlusion is relieved and reperfusion injury resolves. In such case, it is likely that there will be a ‘‘flare-up’’ of the inflammation/pain shortly after the steroids are discontinued. By this mechanism the observed ‘‘rebound’’ effect may be due to the early discontinuation of the corticosteroids and not a side effect of their use. Special consideration should be given to the combination of blood transfusion with corticosteroids. Blood transfusions have been shown to decrease many inflammatory markers that are increased during episodes of ACS although this effect is not sustained [41]. It is not known whether the blood transfusion has any direct effect on the action of corticosteroids and it is more likely that they act synergistically. Systemic corticosteroids are relatively slow acting. Thus, by decreasing the amount of circulating inflammatory mediators, blood transfusion provides immediate anti-inflammatory action until the steroids start working (usually 12-24 hours after their administration), and it may also allow the use of a lower dose. Support to this theory is provided by the study by Isakoff et al. [37] who reported no side effects in their patients with ACS who were treated with steroids and blood transfusions. Sobota et al. [40] also reported that blood transfusion had a protective effect against readmission. Unfortunately, their analysis did not assess specifically the outcome in patients who received steroids plus transfusion. CONCLUSION It is clear that the role of corticosteroid therapy in SCD and its complications is anything but settled. That there is wide variability in their use clearly shows the need for further study. We believe that the legitimate concerns about possible complications should not obscure the evidence for potential positive therapeutic effect in the right setting and that the concern for protecting the patient from iatrogenic injury should not lead to the under-treatment of appropriate patients. This is particularly important for SCD patients with comorbid asthma that together are major risk factors for ACS. As Sobota et al. showed, less than 40% of the SCD patients with asthma received corticosteroids during their hospitalization for ACS, which may explain why those patients with co-morbid asthma had a greater relative risk of readmission [39,40]. We strongly recommend the evaluation of all patients with SCD for asthma (especially those who have had a prior episode of ACS) and their comprehensive treatment according to the guidelines for treatment of asthma. Based on the currently available evidence we believe that corticosteroids should be considered for patients with conditions such as asthma that are known to respond to corticosteroids. However, when used, it would be prudent to treat with relatively low dose (<2mg/kg/day; max: 60 mg/day) of oral prednisone and avoid the abrupt discontinuation of the medication but continue with a relatively prolonged tapering course [42]. Whether there is an ‘‘optimal’’ corticosteroid agent, dose and duration of treatment requires further investigation. FUTURE RESEARCH DIRECTIONS Low dose steroid treatment for asthma exacerbation and ACS The role of inhaled corticosteroid in patients with SCD and comorbid asthma
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