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The acute chest syndrome of sickle cell disease
M EDICAL P ROGRESS
T
The acute chest syndrome of sickle cell disease Charles T. Quinn, MD, and George R. Buchanan, MD
The acute chest syndrome is a descriptive term for an acute pulmonary illness in a patient with sickle cell disease. ACS is defined as a new pulmonary infiltrate and some combination of fever, chest pain, and signs and symptoms of pulmonary disease such as tachypnea, cough, and dyspnea. This definition is vague because there are many causes of ACS, and its pathogenesis is not thoroughly understood. ACS is a frequent cause of hospitalization for patients with SCD, second only to painful crisis, and recurrent episodes may cause debilitating chronic pulmonary disease.1 Moreover, ACS causes approximately 25% of deaths in patients with SCD.2-4 Despite this, the treatment of ACS is often inadequate, and it is not possible to predict which patients will have severe disease. Recent studies have contributed new data and insight. Herein we review the clinical features, pathogenesis, treatment,
From the Division of Hematology-Oncology, Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
Supported in part by T32 training grant CA09640 from the National Institutes of Health. Submitted for publication Sept 25, 1998; revisions received Mar 9, 1999, and May 6, 1999; accepted June 4, 1999. Reprint requests: Charles T. Quinn, MD, Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235. J Pediatr 1999;135:416-22. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/19/101459
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and prevention of ACS with special reference to the unique characteristics of this disorder in children.
CLINICAL CHARACTERISTICS History and Physical Examination The clinical features of ACS have been extensively reviewed.5-8 Recently, the Cooperative Study for Sickle Cell Disease characterized 1722 episodes of ACS in 3751 children and adults.9 The most frequent presenting symptoms were fever, cough, chest pain, shortness of breath, chills, wheezing, and hemoptysis. The presenting symptoms differed by age. Fever and cough were most frequent in young children (aged 2 to 4 years). Chest pain, shortness of breath, chills, productive cough, and hemoptysis increased in frequency with advancing age. Wheezing occurred independent of age. The most frequent findings on physical examination were rales and dullness to percussion; however, normal pulmonary examination was the second most frequent finding.
Radiographic Findings A new pulmonary infiltrate is required for the diagnosis of ACS, although signs and symptoms may occur before the radiographic evidence. Lower and middle lobes are affected more frequently than upper lobes.5,6,8,10 However, children are
more likely than adults to have isolated upper lobe disease.9 Bilateral infiltrates or involvement of multiple lobes may predict a poorer prognosis.8,10 Pleural effusions also occur commonly but do not denote an infectious etiology of ACS in most patients.6,7 Martin and Buonomo11 reported that pulmonary infiltrates resolve quickly and dramatically in children with ACS not associated with infection, whereas children with infection have a prolonged radiographic course. ACS Acute chest syndrome SCD Sickle cell disease sPLA2 Secretory phospholipase A2
Laboratory Studies Approximately 70% of patients with ACS are hypoxemic (oxygen saturation as measured by pulse oximetry <90% or PO2 <80 mm Hg).5,12 Blood counts, compared with the steady state, typically show a decrease in the hemoglobin by about 1 to 2 g/dL, usually accompanied by an increased reticulocyte count.5,7-9,13 The white blood cell count may be increased up to 2-fold,5,9,13 and the platelet count may be relatively decreased in some patients at the onset of ACS, but thrombocytosis is common during convalescence.5,7,13
Hospital Course ACS will not be apparent in 30% to 60% of patients at the time of admission to the hospital.6,8,10 Typically, such patients have undergone surgery or have fever or a painful crisis but no
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 4 respiratory symptoms or pulmonary infiltrates. ACS then develops 2 to 3 days later. The symptoms of ACS may be preceded by an acute decrease in the hemoglobin concentration and the platelet count and an increase in the nucleated red blood cell count. Mean length of hospitalization for all patients with ACS is about 7 days6,7,9; however, children tend to be hospitalized approximately 3 days fewer than adults.9 A minority of children with ACS have a severe clinical course.6,9 Respiratory insufficiency and the acute respiratory distress syndrome may develop and necessitate mechanical ventilation.14,15 A concomitant encephalopathy, perhaps falsely attributed to opioid analgesia, occurs in some patients and may portend multi-organ system failure.16-18 Therefore it is important for clinicians to be vigilant of impending clinical deterioration, and likewise, to be aware that ACS can develop in children hospitalized for treatment of other conditions, such as a painful crisis, or after surgery.
Incidence and Risk Factors ACS occurs frequently, and some patients have multiple episodes. The Cooperative Study for Sickle Cell Disease prospectively followed up 3751 patients with SCD for at least 2 years.19 The group identified 2100 events of ACS in 1085 of these patients. ACS occurred most often in patients with homozygous sickle cell anemia and sickle cell–β0-thalassemia and less frequently in patients with sickle cell–hemoglobin C disease and sickle cell–β+-thalassemia. Risk factors for the development of ACS in patients with homozygous sickle cell anemia were younger age, lower concentration of hemoglobin F, higher steady-state hemoglobin concentration, and higher steady-state white blood cell count.
Sequelae ACS may be severe and cause death. The risk of death differs by age. The death rate is 1.8% in children and 4.3%
in adults.9 Thus although children are more likely to develop ACS, they are less likely to die from it. Recurrent episodes of ACS may cause pulmonary injury and in some patients a debilitating, progressive, and sometimes fatal pulmonary disease characterized by chest pain, dyspnea, chronic pulmonary infiltrates, abnormalities in pulmonary function, and hypoxemia.1,20 Pathophysiologically, there can be intimal hyperplasia, pulmonary fibrosis, pulmonary hypertension, and cor pulmonale.1,21,22
PATHOGENESIS ACS is a common clinical manifestation of many pathologic processes (Table I), which may be clinically indistinguishable, if not concurrent, in a patient with SCD.
Infection An infectious etiology of ACS was emphasized by early studies.23,24 Bacterial pneumonia was the presumed cause in most cases, especially in children, and pneumococcus was believed to be the most frequent pathogen. Indeed, young children are more likely than adults to present with fever and cough, and they are more likely to have concomitant pneumococcal bacteremia. In addition, there is a seasonal predilection for ACS in this group; that is, it is more likely to occur in winter.9 Unfortunately, the routine use of prophylactic penicillin in young children has not reduced the frequency of ACS. More recent studies have implicated infection less frequently, reporting an association of ACS with bacterial pneumonia in 2% to 40% of cases.6-10 The infectious agents are varied, including pneumococcus, Staphylococcus aureus, Hemophilus influenzae, Klebsiella pneumoniae, viruses, and mixed agents. Others have shown that infection with Mycoplasma pneumoniae and Chlamydia pneumoniae occurs commonly in patients with ACS and that these patients may have an unusually severe course when compared with patients without SCD.25,26 Howev-
Table I. Known and proposed causes of ACS Infection Bacterial pneumonia Atypical bacterial pneumonia Mycoplasma Chlamydia Viral pneumonia Parvovirus B19 Pulmonary vascular occlusion In situ pulmonary thrombosis Fat embolism Peripheral thromboembolism Hypoventilation/atelectasis Thoracic bony infarction Abdominal pain Opioids Pulmonary edema Intravenous fluids Opioids Pulmonary vascular injury Other Bronchospasm
er, all the aforementioned studies have significant limitations. The diagnoses of pneumonia were based on results of blood cultures, sputum cultures, serologic studies, and studies of urine and stool; potential pathogens such as viruses were often not investigated; and many of the series were retrospective. Because these biases affect the frequency of identification of pathogens, better diagnostic methods are needed. Bronchoscopy allows collection of specimens directly from the lower airway for quantitative cultures, which correlate with pneumonia. Two studies in which bronchoscopy was used during the course of ACS documented bacterial pneumonia infrequently. Kirkpatrick et al27 reviewed the histories of 19 adults with ACS who had undergone bronchoscopy and found pneumonia in 4 episodes. Godeau et al28 recovered bacteria from the lower airway in 2 of 20 consecutively evaluated adults with ACS. Both of these studies are limited by small sample size, lack of inclusion of children, and incomplete microbiologic methods. 417
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A
B Fig 1. A, Serum concentration of sPLA2 is markedly increased in patients with ACS when com-
pared with other patients with SCD and without SCD (VOC, vaso-occlusive crisis). B, Concentration of sPLA2 is directly proportional to severity of ACS as indicated by arterial partial pressure of oxygen (PaO2), alveolar-arterial oxygen gradient [(A-a)O2], and need for transfusion (TXN). Reprinted with permission from Blood.46 Copyright 1996,W.B. Saunders Company.
Pulmonary Vascular Occlusion Several lines of evidence indicate a causative role for pulmonary vascular occlusion in ACS. Post-mortem studies of patients who died of SCD show in situ pulmonary thrombosis, pulmonary infarction, and alveolar wall necrosis.22,29,30 Thin-section computed tomographic images obtained during ACS demonstrate pulmonary microvascular occlusion,31 and angiographic and nuclear studies document transient perfusion defects.32,33 Also, studies in animals show that regional alveolar hypoxia and pulmonary vasoconstriction promote retention of sickled erythrocytes in the pulmonary circulation.34 Possibly because of reversal of intrapulmonary sickling, patients with ACS may improve rapidly with transfusion.16,35-39 Likewise, patients may improve with nitric oxide therapy, possibly because of reversal of hypoxic pulmonary vasoconstriction.40 418
Primary in situ thrombosis may cause ACS. However, pulmonary vascular occlusion and infarction will likely accompany any significant pulmonary infection or injury, because sickling is promoted by hypoxia and vasoconstriction. Likewise, the clinical differentiation between infection and infarction is difficult.32,41,42 Therefore pulmonary vascular occlusion may be the final common pathway in the pathogenesis of ACS.
Pulmonary Fat Embolism Fat embolism is a unique type of pulmonary vascular occlusion, which may cause ACS. Pulmonary emboli containing fatty, necrotic bone marrow were noted in early post-mortem studies of patients with SCD, but their significance was not known.22,30 Evidence of a causal role in ACS includes the similar clinical features of the fat embolism syndrome caused by trau-
ma,43-45 identification of pulmonary fat embolism in patients with ACS by bronchoscopy,17,28 and measurement of the enzyme secretory phospholipase A2 in patients with ACS.46 Pulmonary fat embolism can be identified by quantification of fat droplets in alveolar macrophages obtained by bronchoscopy.47 Two groups have published their experience with this technique in patients with ACS. Vichinsky et al17 demonstrated fat embolism in 12 of 27 of children with ACS. Godeau et al28 demonstrated fat embolism in 12 of 20 adults with ACS. Secretory PLA2 is an enzyme that cleaves phospholipids and liberates free fatty acids. Free fatty acids cause acute pulmonary toxicity.17,43,48,49 If sPLA2 also releases arachidonic acid, then inflammatory leukotrienes and prostaglandins may be generated. The serum concentration of sPLA2 is markedly increased in patients with ACS, and its concentration is directly correlated with the severity of disease (Fig 1).46 Moreover, the concentration of sPLA2 increases before the development of ACS, peaks at its onset, and declines during resolution.46 The hypothesized sequence of events begins with infarction of the bone marrow, followed by embolization of fatty bone marrow to the lungs. There is activation of pulmonary sPLA2 and release of free fatty acids and inflammatory mediators, which cause pulmonary injury and ACS. The elevation of sPLA2 in other pulmonary conditions, although less pronounced, indicates that there may be factors other than embolic fatty material that activate sPLA2.
Hypoventilation/Atelectasis Infarction of the bony thorax may cause ACS. The proposed sequence begins with thoracic pain, which causes splinting and hypoventilation and hence atelectasis. Atelectasis then causes intrapulmonary sickling and ACS. Up to 40% of patients with SCD and thoracic pain have bony infarction demonstrated by bone scan.50 Addi-
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 4 tionally, there is a strong association between infarction of the bony thorax and the occurrence of ACS.51-53 To compound the issue, opioids are often prescribed for vaso-occlusive pain. Although opioids may control the pain, they can also suppress the cough reflex and respiratory drive, promoting further hypoventilation and atelectasis. Indeed, an association between the use of opioids and ACS has been reported.6,54 Therefore for patients with SCD and thoracic pain, the paradox is that either adequate or inadequate treatment of pain may promote ACS. If the pain persists, there may be splinting and hypoventilation; if the pain is well controlled, there may be suppression of respiratory reflexes.
Fig 2. Unified view of pathogenesis of ACS. Pulmonary vascular injury and occlusion of pulmonary vessels by intrapulmonary sickling, embolization of bone marrow, or both is a likely final common pathway in the development of ACS.
Other Factors Pulmonary edema caused by aggressive intravenous hydration, opioid analgesia, or both—therapies that are often prescribed for a painful crisis— may cause ACS.6,55 Recently, parvovirus B19 has also been implicated, causing increased adherence of erythrocytes and widespread necrosis of the bone marrow with consequent fat embolism.56,57 Peripheral thromboembolism and reactive airway disease may also be causal. Pulmonary vaso-occlusion may be a final common pathway in the development of ACS, whether by intrapulmonary sickling, embolization of fat or thrombus, or both (Fig 2). Diffuse pulmonary endothelial injury by toxic compounds, such as free fatty acids in the case of fat embolism, and consequent pulmonary edema may also be central in the pathogenesis of ACS.
TREATMENT Treatment of ACS is supportive and often inadequate, although early detection and attentive treatment may limit its severity and prevent death. Therapy includes continuous pulse oximetry and delivery of supplemental oxygen to patients with hypoxemia, empiric antimi-
crobial therapy, monitoring of the hemoglobin concentration, transfusion, adequate analgesia, and maintenance of good hydration (Table II).14,15 Care must be taken to avoid overhydration and excessive opioid analgesia because these may worsen ACS.6,54,55 Mechanical ventilation may be needed for patients with severe disease and acute respiratory distress syndrome. ACS may be caused by infection. However, it is difficult to prove an infectious etiology with routine clinical studies. Therefore antimicrobial agents should be administered empirically. A cephalosporin, such as cefuroxime or cefotaxime, is given to treat pathogens such as the pneumococcus. A macrolide, such as erythromycin, should also be administered to treat Mycoplasma or Chlamydia infection. The hemoglobin concentration often decreases during ACS, so transfusion may be needed. Transfusion of packed red blood cells has a number of potential benefits. It increases oxygen carrying capacity, decreases the fraction of hemoglobin S–containing cells, and decreases blood viscosity (especially in the case of exchange transfusion), and thereby potentially reduces or reverses intrapulmonary sickling.58 Several studies have shown improvement in in-
Table II. Treatment of ACS Administration of supplemental oxygen (for patients with hypoxemia) Empiric antimicrobial therapy Cefuroxime or cefotaxime Erythromycin or azithromycin Monitor hemoglobin concentration Transfusion Simple: decrease in hemoglobin concentration Exchange: severe disease Analgesia* Hydration* Mechanical ventilation if needed Steroids (investigational) *May exacerbate ACS if given excessively.
dices of oxygenation and rapid clinical improvement in select patients after transfusion.16,18,35-39 Simple transfusions should be given for a marked decrease in hemoglobin, and they may also be indicated for clinical deterioration. However, increasing the hemoglobin above 11 g/dL should be avoided to prevent increasing blood viscosity and exacerbating ACS or causing a stroke.58 Exchange transfusion should probably be reserved for rapid clinical deterioration, widespread pulmonary involvement, hypoxemia not corrected 419
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Table III. Prevention of ACS Avoid over-hydration Avoid excessive opioid analgesia Incentive spirometry Hydroxyurea Long-term transfusion Stem-cell transplantation
by delivery of supplemental oxygen, and multi-organ failure.58 Although patients with ACS are frequently transfused, transfusion has not been investigated thoroughly. There have been no randomized clinical trials to test this intervention in patients with ACS, so its role is poorly defined. Effective and specific therapy for ACS is clearly needed. Glucocorticoids may fill this role for several reasons. Specifically, steroids impair the production of inflammatory cytokines released during ischemia,59 alter arachidonic acid metabolism and inhibit phospholipase A2,60-62 prevent and possibly treat the fat embolism syndrome caused by trauma,63-65 and ameliorate the painful crises of SCD.66,67 We have evaluated the efficacy of dexamethasone for children with mild or moderately severe ACS in a prospective, randomized, doubleblind, placebo-controlled clinical trial.12 Dexamethasone given intravenously, 0.3 mg/kg every 12 hours, for 4 doses was compared with placebo in patients with mild to moderately severe ACS. Dexamethasone reduced the length of hospitalization by 33 hours, a 40% reduction, which was statistically and clinically significant. Moreover, there were significant decreases in the duration of supplemental oxygen administration, duration of opioid analgesia, need for transfusion, occurrence of clinical deterioration, and persistence of fever. No adverse effects were attributable to steroids. However, in the 72 hours after discharge, 6 patients from the dexamethasone group were readmitted to the hospital, compared with one from the 420
THE JOURNAL OF PEDIATRICS OCTOBER 1999 placebo group. Although the difference in number of readmissions was not statistically significant, one could infer a “rebound” effect after discontinuation of steroids. Dexamethasone is the first treatment shown to benefit patients with ACS in a randomized, placebo-controlled trial. No other trials of steroids for ACS have been reported, and further study of this treatment is needed.
PREVENTION Strategies to prevent ACS are outlined in Table III. Pain and infarction of the bony thorax may cause ACS. If the hypoventilation and splinting caused by chest pain could be minimized, perhaps ACS could be prevented. Bellet et al50 tested an aggressive regimen of incentive spirometry in a randomized clinical trial for patients with SCD and chest pain. Patients who received spirometry took 10 maximal inspirations every 2 hours between 8:00 AM and 10:00 PM and while awake at night until the chest pain subsided. Pulmonary complications developed during only 1 of 19 episodes in the spirometry group compared with 8 of 19 episodes in the control group (P = .019). Among patients who also had infarctions of the bony thorax, no pulmonary complications occurred in the 7 episodes assigned to the spirometry group, compared with 5 of 8 episodes in the control group (P = .025). Because it is simple, inexpensive, and likely beneficial, incentive spirometry is recommended for all patients with SCD and chest pain, and many centers, including ours, recommend its use for all patients receiving opioids for severe pain. Patients with SCD have an increased risk of postoperative complications after general anesthesia.68-70 This has been attributed to subtle perioperative alterations in pH, PO2, blood flow, blood volume, and temperature, which may promote sickling. Postoperative respiratory splinting and atelectasis
may also be causal. Pulmonary complications are common, and ACS may occur in 10% of patients after surgery.71 Risk factors for postoperative ACS include a higher-risk surgical procedure and a history of pulmonary disease.71 Principles of perioperative management for patients with SCD include intraoperative prevention of hypoxemia, acidemia, hypotension, hypovolemia, and hypothermia, as well as postoperative delivery of supplemental oxygen, aggressive management of pain, and incentive spirometry.69,70,72 Transfusion is generally also recommended before general anesthesia for major surgery in patients with sickle cell anemia or sickle cell–β0-thalassemia to prevent postoperative complications.68-70,73-75 Simple transfusion appears to be as effective as exchange transfusion,71 and lower-risk procedures, such as myringotomy, herniorrhaphy, or circumcision, may not require transfusion.76,77 Treatments that decrease the concentration of hemoglobin S can theoretically prevent all the complications of SCD, including ACS. Three presently available therapies are long-term red blood cell transfusion,78 hydroxyurea,79 and stem-cell transplantation.80 Each can be effective, and the latter curative, but all have limitations. Longterm transfusion is complicated in the long term by the morbidity of iron overload, hydroxyurea by the potential of unknown long-term consequences, and transplantation by the limited availability of donors.
CONCLUSION ACS is an acute pulmonary illness in patients with SCD, which occurs frequently and may be severe. It has a high mortality rate, and recurrent episodes may cause chronic pulmonary disease. ACS has many causes, although pulmonary vascular occlusion or injury appears to be a final common pathway. Treatment is primarily supportive, but clinical vigilance and at-
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 4 tentive care may mitigate the severity of ACS and prevent death and chronic pulmonary sequelae. Further investigation of the pathogenesis and a search for new treatments and preventive strategies are needed.
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REFERENCES 1. Powars D, Weidman JA, OdomMaryon T, Niland JC, Johnson C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine 1988;67:66-76. 2. Gray A, Anionwu EN, Davies SC, Brozovic M. Patterns of mortality in sickle cell disease in the United Kingdom. J Clin Pathol 1991;44:459-463. 3. Serjeant GR. Sickle cell disease. Oxford (UK): Oxford; 1986. 4. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 1994;330: 1639-44. 5. van Agtmael MA, Cheng JD, Nossent HC. Acute chest syndrome in adult Afro-Caribbean patients with sickle cell disease. Arch Intern Med 1994; 154:557-61. 6. Sprinkle RH, Cole T, Smith S, Buchanan GR. Acute chest syndrome in children with sickle cell disease. Am J Pediatr Hematol Oncol 1986;8:105-10. 7. Poncz M, Kane E, Gill FM. Acute chest syndrome in sickle cell disease: etiology and clinical correlates. J Pediatr 1985;107:861-6. 8. Davies SC, Luce PJ, Win AA, Riordan JF. Acute chest syndrome in sickle-cell disease. Lancet 1984;1:36-8. 9. Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson B. Acute chest syndrome in sickle cell disease: clinical presentation and course. Blood 1997;89:1787-92. 10. Charache S, Scott JC, Charache P. Acute chest syndrome in adults with sickle cell anemia: microbiology, treatment, and prevention. Arch Intern Med 1979;139:67-9. 11. Martin L, Buonomo C. Acute chest syndrome of sickle cell disease: radiographic and clinical analysis of 70 cases. Pediatr Radiol 1997;27:637-41. 12. Bernini JC, Rogers ZR, Sandler ES, Reisch JS, Quinn CT, Buchanan GR. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syn-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
drome complicating sickle cell disease. Blood 1998;92:3082-9. Poncz M, Greenberg J, Gill FM, Cohen A. Hematologic changes during acute chest syndrome in sickle cell anemia. Am J Pediatr Hematol Oncol 1985;7:96-9. Haynes J Jr, Michael BK. The acute chest syndrome of sickle cell disease. Am J Med Sci 1993;305:326-30. Dreyer ZE. Chest infections and syndromes in sickle cell disease of childhood. Semin Respir Infect 1996;11: 163-72. Hassell KL, Eckman JR, Lane PA. Acute multi-organ failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994;96:155-62. Vichinsky E, Williams R, Das M, Earles AN, Lewis N, Adler A, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood 1994;83:3107-12. Van de Pette JEW, Pearson TC, Slater NGP. Exchange transfusion in lifethreatening sickling crises. J R Soc Med 1982;75:777-80. Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gillette P, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. Blood 1994;84:643-9. Bowen EF, Crowston JG, De Cuelaer K, Serjeant GR. Peak expiratory flow rate and the acute chest syndrome in homozygous sickle cell disease. Arch Dis Child 1991;66:330-2. Yater WM, Hansmann GH. Sickle cell anemia: a new cause of cor pulmonale. Am J Med Sci 1936;191:474-84. Oppenheimer EH, Esterly JR. Pulmonary changes in sickle cell disease. Am Rev Respir Dis 1971;103:858-9. Barrett-Connor E. Acute pulmonary disease in sickle cell anemia. Am Rev Respir Dis 1971;104:159-65. Barrett-Connor E. Pneumonia and pulmonary infarction in sickle cell anemia. JAMA 1973;224:997-1000. Schulman ST, Bartlett J, Clyde WA Jr, Ayoub EM. The unusual severity of mycoplasmal pneumonia in children with sickle-cell disease. N Engl J Med 1972;287:164-7. Miller ST, Hammerschlag MR, Chirgwin K, Rao SP, Roblin P, Gelling M, et al. Role of Chlamydia pneumoniae in acute chest syndrome of sickle cell disease. J Pediatr 1991;118:30-3. Kirkpatrick MB, Haynes J Jr, Bass JB Jr. Results of bronchoscopically obtained lower airway cultures from
28.
29. 30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
adult sickle cell disease patients with the acute chest syndrome. Am J Med 1991;90:206-10. Godeau B, Schaeffer A, Bachir D, Fleury-Feith J, Galacteros F, Verra F, 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. Steinberg B. Sickle cell anemia. Arch Pathol 1930;9:876-97. Haupt HM, Moore W, Bauer TW, Hutchins GM. The lung in sickle cell disease. Chest 1982;81:332-7. Bhalla M, Abboud MR, McCloud TC, Shepard J-AO, Munden MM, Jackson SM, et al. Acute chest syndrome in sickle cell disease: CT evidence of microvascular occlusion. Radiology 1993; 187:45-9. Walker BK, Ballas SK, Burka ER. The diagnosis of pulmonary thromboembolism in sickle cell disease. Am J Hematol 1979;7:219-32. Babiker MA, Obeid HA, Ashong EF. Acute reversible pulmonary ischemia: a cause of the acute chest syndrome in sickle cell disease. Clin Pediatr 1985; 24:716-8. Aldrich TK, Dhuper SK, Patwa NS, Makolo E, Suzuka SM, Najeebi SA, et al. Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia. J Appl Physiol 1996;80:531-9. Emre U, Miller ST, Gutierez M, Steiner P, Rao SP, Rao M. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr 1995;127:901-4. Mallouh AA, Asha M. Beneficial effect of blood transfusion in children with sickle cell chest syndrome. Am J Dis Child 1988;142:178-82. Warrier RP, Ducos R, Yu LC. Acute chest syndrome in sickle cell disease [letter]. J Pediatr 1986;109:731. Lanzkowsky P, Shende A, Karayalcin G, Kim Y-J, Aballi AJ. Partial exchange transfusion in sickle cell anemia: use in children with serious complications. Am J Dis Child 1978;132: 1206-8. Bodó I, Khoury H, Blinder M. Rapid resolution of the acute chest syndrome of sickle cell disease after automated red cell exchange [abstract]. Blood 1997;90(suppl 1):23b. Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology 1997; 87:988-90. Moser KM, Shea JG. The relationship between pulmonary infarction, cor 421
QUINN AND BUCHANAN
42.
43. 44.
45. 46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
422
pulmonale and the sickle states. Am J Med 1957;22:561-79. Diggs LW, Barreras L. Pulmonary emboli vs. pneumonia in patients with sickle cell anemia. Memphis MidSouth Med J 1967;42:375-80. Levy D. The fat embolism syndrome: a review. Clin Orthop 1990;261:281-6. Bulger EM, Smith DG, Maier RV, Jurkovich GJ. Fat embolism syndrome: a 10-year review. Arch Surg 1997;132:435-9. Hulman G. The pathogenesis of fat embolism. J Pathol 1995;176:3-9. Styles LA, Schalkwijk CG, Aarsman AJ, Vichinsky EP, Lubin BH, Kuypers FA. Phospholipase A2 levels in acute chest syndrome of sickle cell disease. Blood 1996;87:2573-8. Chastre J, Fagon JY, Soler P, Fichelle A, Dombret MC, Huten D, et al. Bronchoalveolar lavage for rapid diagnosis of the fat embolism syndrome in trauma patients. Ann Intern Med 1990;113:583-8. Moylan JA, Birnbaum M, Katz A, Everson MA. Fat emboli syndrome. J Trauma 1976;16:341-7. Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 1994;149:245-60. Bellet PS, Kalinyak KA, Shukla R, Gelfand MJ, Rucknagel DL. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med 1995;333:699-703. Gelfand MJ, Daya SA, Rucknagel DL, Kalinyak KA, Paltiel HJ. Simultaneous occurrence of rib infarction and pulmonary infiltrates in sickle cell disease patients with acute chest syndrome. J Nucl Med 1993;34:614-18. Rucknagel DL, Kalinyak KA, Gelfand MJ. Rib infarcts and acute chest syndrome in sickle cell diseases. Lancet 1991;337:831-3. Ballas SK, Park CH. Severe hypoxemia secondary to acute sternal infarction in sickle cell anemia. J Nucl Med 1991;32:1617-8. Palmer J, Broderick KA, Naiman JL. Acute lung syndrome during painful sickle cell crisis: relation to site of pain and narcotic requirement [abstract]. Blood 1983;62:59a. Haynes J Jr, Allison RC. Pulmonary edema: complication in the manage-
THE JOURNAL OF PEDIATRICS OCTOBER 1999
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
ment of sickle cell pain crisis. Am J Med 1986;80:833-40. Lowenthal EA, Wells A, Emanuel PD, Player R, Prchal JT. Sickle cell acute chest syndrome associated with parvovirus B19 infection: case series and review. Am J Hematol 1996;51:207-13. Kolquist KA, Vnencak-Jones CL, Swift L, Page DL, Johnson JE. Fatal fat embolism syndrome in a child with undiagnosed hemoglobin S/β+ thalassemia: a complication of acute parvovirus B19 infection. Pediatr Pathol Lab Med 1996;16:71-82. Wayne AS, Kevy SV, Nathan DG. Transfusion management of sickle cell disease. Blood 1993;81:1109-23. Schwiebert LM, Beck LA, Stellato C, Bickel CA, Bochner BS, Schleimer RP, et al. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions. J Allergy Clin Immunol 1996;97:143-52. van den Bosch H, Schalkwijk C, Pfeilschifter J, Marki F. The induction of cellular group II phospholipase A2 by cytokines and its prevention by dexamethasone. Adv Exp Med Biol 1992;318:1-10. Vadas P, Stefanski E, Pruzanski W. Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock. Agents Actions 1986;19:194-202. Tocker JE, Durham SK, Welton AF, Selig WM. Phospholipase A2-induced pulmonary injury and hemodynamic responses in the guinea pig: effect of enzyme inhibitors and mediators antagonists. Am Rev Respir Dis 1990; 142:1193-9. Peltier LF. The diagnosis and treatment of fat embolism. J Trauma 1971; 11:661-7. Schonfeld SA, Ploysongsang Y, DiLisio R, Crissman JD, Miller E, Hammerschmidt DE. Fat embolism prophylaxis with corticosteroids: a prospective study in high-risk patients. Ann Intern Med 1983;99:438-43. Alho A. Fat embolism syndrome: etiology, pathogenesis, and treatment. Acta Chir Scand Suppl 1980;499:75-85. 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. Isaacs WA, Effiong CE, Ayeni O.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
Steroid treatment in the prevention of painful episodes in sickle-cell disease. Lancet 1972;1:570-1. Janik J, Seeler RA. Perioperative management of children with sickle hemoglobinopathy. J Pediatr Surg 1980; 15:117-20. Holzmann L, Finn H, Lichtman HC, Harmel MH. Anesthesia in patients with sickle cell disease. Anesth Analg 1969;48:566-72. Spigelman A, Warden MJ. Surgery in patients with sickle cell disease. Arch Surg 1972;104:761-4. Vichinsky EP, Haberkern CM, Neumayr L, Earles AN, Black D, Koshy M, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med 1995; 333:206-13. Banerjee AK, Layton DM, Rennie JA, Bellingham AJ. Safe surgery in sickle cell disease. Br J Surg 1991;78:516-7. Fullerton MW, Philippart AI, Sarnaik S, Lusher JM. Preoperative exchange transfusion in sickle cell anemia. J Pediatr Surg 1981;16:297-300. Morrison JC, Whybrew WD, Bucovaz ET. Use of partial exchange transfusion preoperatively in patients with sickle cell hemoglobinopathies. Am J Obstet Gynecol 1978;132:59-63. Koshy M, Weiner SJ, Miller ST, Sleeper LA, Vichinsky E, Brown AK, et al. Surgery and anesthesia in sickle cell disease. Blood 1995;86:3676-84. Griffin TC, Buchanan GR. Elective surgery in children with sickle cell disease without preoperative blood transfusion. J Pediatr Surg 1993;28:681-5. Neumayr L, Koshy M, Haberkern C, Earles AN, Bellevue R, Hassell K, et al. Surgery in patients with hemoglobin SC disease. Am J Hematol 1998;57:101-8. Serjeant GR. Chronic transfusion programmes in sickle cell disease: Problem or panacea? Br J Hematol 1997; 97:253-5. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-22. Vermylen C, Cornu G. Hematopoietic stem cell transplantation for sickle cell anemia. Curr Opin Hematol 1997;4: 377-80.
T
The acute chest syndrome of sickle cell disease Charles T. Quinn, MD, and George R. Buchanan, MD
The acute chest syndrome is a descriptive term for an acute pulmonary illness in a patient with sickle cell disease. ACS is defined as a new pulmonary infiltrate and some combination of fever, chest pain, and signs and symptoms of pulmonary disease such as tachypnea, cough, and dyspnea. This definition is vague because there are many causes of ACS, and its pathogenesis is not thoroughly understood. ACS is a frequent cause of hospitalization for patients with SCD, second only to painful crisis, and recurrent episodes may cause debilitating chronic pulmonary disease.1 Moreover, ACS causes approximately 25% of deaths in patients with SCD.2-4 Despite this, the treatment of ACS is often inadequate, and it is not possible to predict which patients will have severe disease. Recent studies have contributed new data and insight. Herein we review the clinical features, pathogenesis, treatment,
From the Division of Hematology-Oncology, Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
Supported in part by T32 training grant CA09640 from the National Institutes of Health. Submitted for publication Sept 25, 1998; revisions received Mar 9, 1999, and May 6, 1999; accepted June 4, 1999. Reprint requests: Charles T. Quinn, MD, Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235. J Pediatr 1999;135:416-22. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/19/101459
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and prevention of ACS with special reference to the unique characteristics of this disorder in children.
CLINICAL CHARACTERISTICS History and Physical Examination The clinical features of ACS have been extensively reviewed.5-8 Recently, the Cooperative Study for Sickle Cell Disease characterized 1722 episodes of ACS in 3751 children and adults.9 The most frequent presenting symptoms were fever, cough, chest pain, shortness of breath, chills, wheezing, and hemoptysis. The presenting symptoms differed by age. Fever and cough were most frequent in young children (aged 2 to 4 years). Chest pain, shortness of breath, chills, productive cough, and hemoptysis increased in frequency with advancing age. Wheezing occurred independent of age. The most frequent findings on physical examination were rales and dullness to percussion; however, normal pulmonary examination was the second most frequent finding.
Radiographic Findings A new pulmonary infiltrate is required for the diagnosis of ACS, although signs and symptoms may occur before the radiographic evidence. Lower and middle lobes are affected more frequently than upper lobes.5,6,8,10 However, children are
more likely than adults to have isolated upper lobe disease.9 Bilateral infiltrates or involvement of multiple lobes may predict a poorer prognosis.8,10 Pleural effusions also occur commonly but do not denote an infectious etiology of ACS in most patients.6,7 Martin and Buonomo11 reported that pulmonary infiltrates resolve quickly and dramatically in children with ACS not associated with infection, whereas children with infection have a prolonged radiographic course. ACS Acute chest syndrome SCD Sickle cell disease sPLA2 Secretory phospholipase A2
Laboratory Studies Approximately 70% of patients with ACS are hypoxemic (oxygen saturation as measured by pulse oximetry <90% or PO2 <80 mm Hg).5,12 Blood counts, compared with the steady state, typically show a decrease in the hemoglobin by about 1 to 2 g/dL, usually accompanied by an increased reticulocyte count.5,7-9,13 The white blood cell count may be increased up to 2-fold,5,9,13 and the platelet count may be relatively decreased in some patients at the onset of ACS, but thrombocytosis is common during convalescence.5,7,13
Hospital Course ACS will not be apparent in 30% to 60% of patients at the time of admission to the hospital.6,8,10 Typically, such patients have undergone surgery or have fever or a painful crisis but no
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 4 respiratory symptoms or pulmonary infiltrates. ACS then develops 2 to 3 days later. The symptoms of ACS may be preceded by an acute decrease in the hemoglobin concentration and the platelet count and an increase in the nucleated red blood cell count. Mean length of hospitalization for all patients with ACS is about 7 days6,7,9; however, children tend to be hospitalized approximately 3 days fewer than adults.9 A minority of children with ACS have a severe clinical course.6,9 Respiratory insufficiency and the acute respiratory distress syndrome may develop and necessitate mechanical ventilation.14,15 A concomitant encephalopathy, perhaps falsely attributed to opioid analgesia, occurs in some patients and may portend multi-organ system failure.16-18 Therefore it is important for clinicians to be vigilant of impending clinical deterioration, and likewise, to be aware that ACS can develop in children hospitalized for treatment of other conditions, such as a painful crisis, or after surgery.
Incidence and Risk Factors ACS occurs frequently, and some patients have multiple episodes. The Cooperative Study for Sickle Cell Disease prospectively followed up 3751 patients with SCD for at least 2 years.19 The group identified 2100 events of ACS in 1085 of these patients. ACS occurred most often in patients with homozygous sickle cell anemia and sickle cell–β0-thalassemia and less frequently in patients with sickle cell–hemoglobin C disease and sickle cell–β+-thalassemia. Risk factors for the development of ACS in patients with homozygous sickle cell anemia were younger age, lower concentration of hemoglobin F, higher steady-state hemoglobin concentration, and higher steady-state white blood cell count.
Sequelae ACS may be severe and cause death. The risk of death differs by age. The death rate is 1.8% in children and 4.3%
in adults.9 Thus although children are more likely to develop ACS, they are less likely to die from it. Recurrent episodes of ACS may cause pulmonary injury and in some patients a debilitating, progressive, and sometimes fatal pulmonary disease characterized by chest pain, dyspnea, chronic pulmonary infiltrates, abnormalities in pulmonary function, and hypoxemia.1,20 Pathophysiologically, there can be intimal hyperplasia, pulmonary fibrosis, pulmonary hypertension, and cor pulmonale.1,21,22
PATHOGENESIS ACS is a common clinical manifestation of many pathologic processes (Table I), which may be clinically indistinguishable, if not concurrent, in a patient with SCD.
Infection An infectious etiology of ACS was emphasized by early studies.23,24 Bacterial pneumonia was the presumed cause in most cases, especially in children, and pneumococcus was believed to be the most frequent pathogen. Indeed, young children are more likely than adults to present with fever and cough, and they are more likely to have concomitant pneumococcal bacteremia. In addition, there is a seasonal predilection for ACS in this group; that is, it is more likely to occur in winter.9 Unfortunately, the routine use of prophylactic penicillin in young children has not reduced the frequency of ACS. More recent studies have implicated infection less frequently, reporting an association of ACS with bacterial pneumonia in 2% to 40% of cases.6-10 The infectious agents are varied, including pneumococcus, Staphylococcus aureus, Hemophilus influenzae, Klebsiella pneumoniae, viruses, and mixed agents. Others have shown that infection with Mycoplasma pneumoniae and Chlamydia pneumoniae occurs commonly in patients with ACS and that these patients may have an unusually severe course when compared with patients without SCD.25,26 Howev-
Table I. Known and proposed causes of ACS Infection Bacterial pneumonia Atypical bacterial pneumonia Mycoplasma Chlamydia Viral pneumonia Parvovirus B19 Pulmonary vascular occlusion In situ pulmonary thrombosis Fat embolism Peripheral thromboembolism Hypoventilation/atelectasis Thoracic bony infarction Abdominal pain Opioids Pulmonary edema Intravenous fluids Opioids Pulmonary vascular injury Other Bronchospasm
er, all the aforementioned studies have significant limitations. The diagnoses of pneumonia were based on results of blood cultures, sputum cultures, serologic studies, and studies of urine and stool; potential pathogens such as viruses were often not investigated; and many of the series were retrospective. Because these biases affect the frequency of identification of pathogens, better diagnostic methods are needed. Bronchoscopy allows collection of specimens directly from the lower airway for quantitative cultures, which correlate with pneumonia. Two studies in which bronchoscopy was used during the course of ACS documented bacterial pneumonia infrequently. Kirkpatrick et al27 reviewed the histories of 19 adults with ACS who had undergone bronchoscopy and found pneumonia in 4 episodes. Godeau et al28 recovered bacteria from the lower airway in 2 of 20 consecutively evaluated adults with ACS. Both of these studies are limited by small sample size, lack of inclusion of children, and incomplete microbiologic methods. 417
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A
B Fig 1. A, Serum concentration of sPLA2 is markedly increased in patients with ACS when com-
pared with other patients with SCD and without SCD (VOC, vaso-occlusive crisis). B, Concentration of sPLA2 is directly proportional to severity of ACS as indicated by arterial partial pressure of oxygen (PaO2), alveolar-arterial oxygen gradient [(A-a)O2], and need for transfusion (TXN). Reprinted with permission from Blood.46 Copyright 1996,W.B. Saunders Company.
Pulmonary Vascular Occlusion Several lines of evidence indicate a causative role for pulmonary vascular occlusion in ACS. Post-mortem studies of patients who died of SCD show in situ pulmonary thrombosis, pulmonary infarction, and alveolar wall necrosis.22,29,30 Thin-section computed tomographic images obtained during ACS demonstrate pulmonary microvascular occlusion,31 and angiographic and nuclear studies document transient perfusion defects.32,33 Also, studies in animals show that regional alveolar hypoxia and pulmonary vasoconstriction promote retention of sickled erythrocytes in the pulmonary circulation.34 Possibly because of reversal of intrapulmonary sickling, patients with ACS may improve rapidly with transfusion.16,35-39 Likewise, patients may improve with nitric oxide therapy, possibly because of reversal of hypoxic pulmonary vasoconstriction.40 418
Primary in situ thrombosis may cause ACS. However, pulmonary vascular occlusion and infarction will likely accompany any significant pulmonary infection or injury, because sickling is promoted by hypoxia and vasoconstriction. Likewise, the clinical differentiation between infection and infarction is difficult.32,41,42 Therefore pulmonary vascular occlusion may be the final common pathway in the pathogenesis of ACS.
Pulmonary Fat Embolism Fat embolism is a unique type of pulmonary vascular occlusion, which may cause ACS. Pulmonary emboli containing fatty, necrotic bone marrow were noted in early post-mortem studies of patients with SCD, but their significance was not known.22,30 Evidence of a causal role in ACS includes the similar clinical features of the fat embolism syndrome caused by trau-
ma,43-45 identification of pulmonary fat embolism in patients with ACS by bronchoscopy,17,28 and measurement of the enzyme secretory phospholipase A2 in patients with ACS.46 Pulmonary fat embolism can be identified by quantification of fat droplets in alveolar macrophages obtained by bronchoscopy.47 Two groups have published their experience with this technique in patients with ACS. Vichinsky et al17 demonstrated fat embolism in 12 of 27 of children with ACS. Godeau et al28 demonstrated fat embolism in 12 of 20 adults with ACS. Secretory PLA2 is an enzyme that cleaves phospholipids and liberates free fatty acids. Free fatty acids cause acute pulmonary toxicity.17,43,48,49 If sPLA2 also releases arachidonic acid, then inflammatory leukotrienes and prostaglandins may be generated. The serum concentration of sPLA2 is markedly increased in patients with ACS, and its concentration is directly correlated with the severity of disease (Fig 1).46 Moreover, the concentration of sPLA2 increases before the development of ACS, peaks at its onset, and declines during resolution.46 The hypothesized sequence of events begins with infarction of the bone marrow, followed by embolization of fatty bone marrow to the lungs. There is activation of pulmonary sPLA2 and release of free fatty acids and inflammatory mediators, which cause pulmonary injury and ACS. The elevation of sPLA2 in other pulmonary conditions, although less pronounced, indicates that there may be factors other than embolic fatty material that activate sPLA2.
Hypoventilation/Atelectasis Infarction of the bony thorax may cause ACS. The proposed sequence begins with thoracic pain, which causes splinting and hypoventilation and hence atelectasis. Atelectasis then causes intrapulmonary sickling and ACS. Up to 40% of patients with SCD and thoracic pain have bony infarction demonstrated by bone scan.50 Addi-
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 4 tionally, there is a strong association between infarction of the bony thorax and the occurrence of ACS.51-53 To compound the issue, opioids are often prescribed for vaso-occlusive pain. Although opioids may control the pain, they can also suppress the cough reflex and respiratory drive, promoting further hypoventilation and atelectasis. Indeed, an association between the use of opioids and ACS has been reported.6,54 Therefore for patients with SCD and thoracic pain, the paradox is that either adequate or inadequate treatment of pain may promote ACS. If the pain persists, there may be splinting and hypoventilation; if the pain is well controlled, there may be suppression of respiratory reflexes.
Fig 2. Unified view of pathogenesis of ACS. Pulmonary vascular injury and occlusion of pulmonary vessels by intrapulmonary sickling, embolization of bone marrow, or both is a likely final common pathway in the development of ACS.
Other Factors Pulmonary edema caused by aggressive intravenous hydration, opioid analgesia, or both—therapies that are often prescribed for a painful crisis— may cause ACS.6,55 Recently, parvovirus B19 has also been implicated, causing increased adherence of erythrocytes and widespread necrosis of the bone marrow with consequent fat embolism.56,57 Peripheral thromboembolism and reactive airway disease may also be causal. Pulmonary vaso-occlusion may be a final common pathway in the development of ACS, whether by intrapulmonary sickling, embolization of fat or thrombus, or both (Fig 2). Diffuse pulmonary endothelial injury by toxic compounds, such as free fatty acids in the case of fat embolism, and consequent pulmonary edema may also be central in the pathogenesis of ACS.
TREATMENT Treatment of ACS is supportive and often inadequate, although early detection and attentive treatment may limit its severity and prevent death. Therapy includes continuous pulse oximetry and delivery of supplemental oxygen to patients with hypoxemia, empiric antimi-
crobial therapy, monitoring of the hemoglobin concentration, transfusion, adequate analgesia, and maintenance of good hydration (Table II).14,15 Care must be taken to avoid overhydration and excessive opioid analgesia because these may worsen ACS.6,54,55 Mechanical ventilation may be needed for patients with severe disease and acute respiratory distress syndrome. ACS may be caused by infection. However, it is difficult to prove an infectious etiology with routine clinical studies. Therefore antimicrobial agents should be administered empirically. A cephalosporin, such as cefuroxime or cefotaxime, is given to treat pathogens such as the pneumococcus. A macrolide, such as erythromycin, should also be administered to treat Mycoplasma or Chlamydia infection. The hemoglobin concentration often decreases during ACS, so transfusion may be needed. Transfusion of packed red blood cells has a number of potential benefits. It increases oxygen carrying capacity, decreases the fraction of hemoglobin S–containing cells, and decreases blood viscosity (especially in the case of exchange transfusion), and thereby potentially reduces or reverses intrapulmonary sickling.58 Several studies have shown improvement in in-
Table II. Treatment of ACS Administration of supplemental oxygen (for patients with hypoxemia) Empiric antimicrobial therapy Cefuroxime or cefotaxime Erythromycin or azithromycin Monitor hemoglobin concentration Transfusion Simple: decrease in hemoglobin concentration Exchange: severe disease Analgesia* Hydration* Mechanical ventilation if needed Steroids (investigational) *May exacerbate ACS if given excessively.
dices of oxygenation and rapid clinical improvement in select patients after transfusion.16,18,35-39 Simple transfusions should be given for a marked decrease in hemoglobin, and they may also be indicated for clinical deterioration. However, increasing the hemoglobin above 11 g/dL should be avoided to prevent increasing blood viscosity and exacerbating ACS or causing a stroke.58 Exchange transfusion should probably be reserved for rapid clinical deterioration, widespread pulmonary involvement, hypoxemia not corrected 419
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Table III. Prevention of ACS Avoid over-hydration Avoid excessive opioid analgesia Incentive spirometry Hydroxyurea Long-term transfusion Stem-cell transplantation
by delivery of supplemental oxygen, and multi-organ failure.58 Although patients with ACS are frequently transfused, transfusion has not been investigated thoroughly. There have been no randomized clinical trials to test this intervention in patients with ACS, so its role is poorly defined. Effective and specific therapy for ACS is clearly needed. Glucocorticoids may fill this role for several reasons. Specifically, steroids impair the production of inflammatory cytokines released during ischemia,59 alter arachidonic acid metabolism and inhibit phospholipase A2,60-62 prevent and possibly treat the fat embolism syndrome caused by trauma,63-65 and ameliorate the painful crises of SCD.66,67 We have evaluated the efficacy of dexamethasone for children with mild or moderately severe ACS in a prospective, randomized, doubleblind, placebo-controlled clinical trial.12 Dexamethasone given intravenously, 0.3 mg/kg every 12 hours, for 4 doses was compared with placebo in patients with mild to moderately severe ACS. Dexamethasone reduced the length of hospitalization by 33 hours, a 40% reduction, which was statistically and clinically significant. Moreover, there were significant decreases in the duration of supplemental oxygen administration, duration of opioid analgesia, need for transfusion, occurrence of clinical deterioration, and persistence of fever. No adverse effects were attributable to steroids. However, in the 72 hours after discharge, 6 patients from the dexamethasone group were readmitted to the hospital, compared with one from the 420
THE JOURNAL OF PEDIATRICS OCTOBER 1999 placebo group. Although the difference in number of readmissions was not statistically significant, one could infer a “rebound” effect after discontinuation of steroids. Dexamethasone is the first treatment shown to benefit patients with ACS in a randomized, placebo-controlled trial. No other trials of steroids for ACS have been reported, and further study of this treatment is needed.
PREVENTION Strategies to prevent ACS are outlined in Table III. Pain and infarction of the bony thorax may cause ACS. If the hypoventilation and splinting caused by chest pain could be minimized, perhaps ACS could be prevented. Bellet et al50 tested an aggressive regimen of incentive spirometry in a randomized clinical trial for patients with SCD and chest pain. Patients who received spirometry took 10 maximal inspirations every 2 hours between 8:00 AM and 10:00 PM and while awake at night until the chest pain subsided. Pulmonary complications developed during only 1 of 19 episodes in the spirometry group compared with 8 of 19 episodes in the control group (P = .019). Among patients who also had infarctions of the bony thorax, no pulmonary complications occurred in the 7 episodes assigned to the spirometry group, compared with 5 of 8 episodes in the control group (P = .025). Because it is simple, inexpensive, and likely beneficial, incentive spirometry is recommended for all patients with SCD and chest pain, and many centers, including ours, recommend its use for all patients receiving opioids for severe pain. Patients with SCD have an increased risk of postoperative complications after general anesthesia.68-70 This has been attributed to subtle perioperative alterations in pH, PO2, blood flow, blood volume, and temperature, which may promote sickling. Postoperative respiratory splinting and atelectasis
may also be causal. Pulmonary complications are common, and ACS may occur in 10% of patients after surgery.71 Risk factors for postoperative ACS include a higher-risk surgical procedure and a history of pulmonary disease.71 Principles of perioperative management for patients with SCD include intraoperative prevention of hypoxemia, acidemia, hypotension, hypovolemia, and hypothermia, as well as postoperative delivery of supplemental oxygen, aggressive management of pain, and incentive spirometry.69,70,72 Transfusion is generally also recommended before general anesthesia for major surgery in patients with sickle cell anemia or sickle cell–β0-thalassemia to prevent postoperative complications.68-70,73-75 Simple transfusion appears to be as effective as exchange transfusion,71 and lower-risk procedures, such as myringotomy, herniorrhaphy, or circumcision, may not require transfusion.76,77 Treatments that decrease the concentration of hemoglobin S can theoretically prevent all the complications of SCD, including ACS. Three presently available therapies are long-term red blood cell transfusion,78 hydroxyurea,79 and stem-cell transplantation.80 Each can be effective, and the latter curative, but all have limitations. Longterm transfusion is complicated in the long term by the morbidity of iron overload, hydroxyurea by the potential of unknown long-term consequences, and transplantation by the limited availability of donors.
CONCLUSION ACS is an acute pulmonary illness in patients with SCD, which occurs frequently and may be severe. It has a high mortality rate, and recurrent episodes may cause chronic pulmonary disease. ACS has many causes, although pulmonary vascular occlusion or injury appears to be a final common pathway. Treatment is primarily supportive, but clinical vigilance and at-
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 4 tentive care may mitigate the severity of ACS and prevent death and chronic pulmonary sequelae. Further investigation of the pathogenesis and a search for new treatments and preventive strategies are needed.
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14.
REFERENCES 1. Powars D, Weidman JA, OdomMaryon T, Niland JC, Johnson C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine 1988;67:66-76. 2. Gray A, Anionwu EN, Davies SC, Brozovic M. Patterns of mortality in sickle cell disease in the United Kingdom. J Clin Pathol 1991;44:459-463. 3. Serjeant GR. Sickle cell disease. Oxford (UK): Oxford; 1986. 4. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 1994;330: 1639-44. 5. van Agtmael MA, Cheng JD, Nossent HC. Acute chest syndrome in adult Afro-Caribbean patients with sickle cell disease. Arch Intern Med 1994; 154:557-61. 6. Sprinkle RH, Cole T, Smith S, Buchanan GR. Acute chest syndrome in children with sickle cell disease. Am J Pediatr Hematol Oncol 1986;8:105-10. 7. Poncz M, Kane E, Gill FM. Acute chest syndrome in sickle cell disease: etiology and clinical correlates. J Pediatr 1985;107:861-6. 8. Davies SC, Luce PJ, Win AA, Riordan JF. Acute chest syndrome in sickle-cell disease. Lancet 1984;1:36-8. 9. Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson B. Acute chest syndrome in sickle cell disease: clinical presentation and course. Blood 1997;89:1787-92. 10. Charache S, Scott JC, Charache P. Acute chest syndrome in adults with sickle cell anemia: microbiology, treatment, and prevention. Arch Intern Med 1979;139:67-9. 11. Martin L, Buonomo C. Acute chest syndrome of sickle cell disease: radiographic and clinical analysis of 70 cases. Pediatr Radiol 1997;27:637-41. 12. Bernini JC, Rogers ZR, Sandler ES, Reisch JS, Quinn CT, Buchanan GR. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syn-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
drome complicating sickle cell disease. Blood 1998;92:3082-9. Poncz M, Greenberg J, Gill FM, Cohen A. Hematologic changes during acute chest syndrome in sickle cell anemia. Am J Pediatr Hematol Oncol 1985;7:96-9. Haynes J Jr, Michael BK. The acute chest syndrome of sickle cell disease. Am J Med Sci 1993;305:326-30. Dreyer ZE. Chest infections and syndromes in sickle cell disease of childhood. Semin Respir Infect 1996;11: 163-72. Hassell KL, Eckman JR, Lane PA. Acute multi-organ failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994;96:155-62. Vichinsky E, Williams R, Das M, Earles AN, Lewis N, Adler A, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood 1994;83:3107-12. Van de Pette JEW, Pearson TC, Slater NGP. Exchange transfusion in lifethreatening sickling crises. J R Soc Med 1982;75:777-80. Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gillette P, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. Blood 1994;84:643-9. Bowen EF, Crowston JG, De Cuelaer K, Serjeant GR. Peak expiratory flow rate and the acute chest syndrome in homozygous sickle cell disease. Arch Dis Child 1991;66:330-2. Yater WM, Hansmann GH. Sickle cell anemia: a new cause of cor pulmonale. Am J Med Sci 1936;191:474-84. Oppenheimer EH, Esterly JR. Pulmonary changes in sickle cell disease. Am Rev Respir Dis 1971;103:858-9. Barrett-Connor E. Acute pulmonary disease in sickle cell anemia. Am Rev Respir Dis 1971;104:159-65. Barrett-Connor E. Pneumonia and pulmonary infarction in sickle cell anemia. JAMA 1973;224:997-1000. Schulman ST, Bartlett J, Clyde WA Jr, Ayoub EM. The unusual severity of mycoplasmal pneumonia in children with sickle-cell disease. N Engl J Med 1972;287:164-7. Miller ST, Hammerschlag MR, Chirgwin K, Rao SP, Roblin P, Gelling M, et al. Role of Chlamydia pneumoniae in acute chest syndrome of sickle cell disease. J Pediatr 1991;118:30-3. Kirkpatrick MB, Haynes J Jr, Bass JB Jr. Results of bronchoscopically obtained lower airway cultures from
28.
29. 30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
adult sickle cell disease patients with the acute chest syndrome. Am J Med 1991;90:206-10. Godeau B, Schaeffer A, Bachir D, Fleury-Feith J, Galacteros F, Verra F, 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. Steinberg B. Sickle cell anemia. Arch Pathol 1930;9:876-97. Haupt HM, Moore W, Bauer TW, Hutchins GM. The lung in sickle cell disease. Chest 1982;81:332-7. Bhalla M, Abboud MR, McCloud TC, Shepard J-AO, Munden MM, Jackson SM, et al. Acute chest syndrome in sickle cell disease: CT evidence of microvascular occlusion. Radiology 1993; 187:45-9. Walker BK, Ballas SK, Burka ER. The diagnosis of pulmonary thromboembolism in sickle cell disease. Am J Hematol 1979;7:219-32. Babiker MA, Obeid HA, Ashong EF. Acute reversible pulmonary ischemia: a cause of the acute chest syndrome in sickle cell disease. Clin Pediatr 1985; 24:716-8. Aldrich TK, Dhuper SK, Patwa NS, Makolo E, Suzuka SM, Najeebi SA, et al. Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia. J Appl Physiol 1996;80:531-9. Emre U, Miller ST, Gutierez M, Steiner P, Rao SP, Rao M. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr 1995;127:901-4. Mallouh AA, Asha M. Beneficial effect of blood transfusion in children with sickle cell chest syndrome. Am J Dis Child 1988;142:178-82. Warrier RP, Ducos R, Yu LC. Acute chest syndrome in sickle cell disease [letter]. J Pediatr 1986;109:731. Lanzkowsky P, Shende A, Karayalcin G, Kim Y-J, Aballi AJ. Partial exchange transfusion in sickle cell anemia: use in children with serious complications. Am J Dis Child 1978;132: 1206-8. Bodó I, Khoury H, Blinder M. Rapid resolution of the acute chest syndrome of sickle cell disease after automated red cell exchange [abstract]. Blood 1997;90(suppl 1):23b. Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology 1997; 87:988-90. Moser KM, Shea JG. The relationship between pulmonary infarction, cor 421
QUINN AND BUCHANAN
42.
43. 44.
45. 46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
422
pulmonale and the sickle states. Am J Med 1957;22:561-79. Diggs LW, Barreras L. Pulmonary emboli vs. pneumonia in patients with sickle cell anemia. Memphis MidSouth Med J 1967;42:375-80. Levy D. The fat embolism syndrome: a review. Clin Orthop 1990;261:281-6. Bulger EM, Smith DG, Maier RV, Jurkovich GJ. Fat embolism syndrome: a 10-year review. Arch Surg 1997;132:435-9. Hulman G. The pathogenesis of fat embolism. J Pathol 1995;176:3-9. Styles LA, Schalkwijk CG, Aarsman AJ, Vichinsky EP, Lubin BH, Kuypers FA. Phospholipase A2 levels in acute chest syndrome of sickle cell disease. Blood 1996;87:2573-8. Chastre J, Fagon JY, Soler P, Fichelle A, Dombret MC, Huten D, et al. Bronchoalveolar lavage for rapid diagnosis of the fat embolism syndrome in trauma patients. Ann Intern Med 1990;113:583-8. Moylan JA, Birnbaum M, Katz A, Everson MA. Fat emboli syndrome. J Trauma 1976;16:341-7. Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 1994;149:245-60. Bellet PS, Kalinyak KA, Shukla R, Gelfand MJ, Rucknagel DL. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med 1995;333:699-703. Gelfand MJ, Daya SA, Rucknagel DL, Kalinyak KA, Paltiel HJ. Simultaneous occurrence of rib infarction and pulmonary infiltrates in sickle cell disease patients with acute chest syndrome. J Nucl Med 1993;34:614-18. Rucknagel DL, Kalinyak KA, Gelfand MJ. Rib infarcts and acute chest syndrome in sickle cell diseases. Lancet 1991;337:831-3. Ballas SK, Park CH. Severe hypoxemia secondary to acute sternal infarction in sickle cell anemia. J Nucl Med 1991;32:1617-8. Palmer J, Broderick KA, Naiman JL. Acute lung syndrome during painful sickle cell crisis: relation to site of pain and narcotic requirement [abstract]. Blood 1983;62:59a. Haynes J Jr, Allison RC. Pulmonary edema: complication in the manage-
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56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
ment of sickle cell pain crisis. Am J Med 1986;80:833-40. Lowenthal EA, Wells A, Emanuel PD, Player R, Prchal JT. Sickle cell acute chest syndrome associated with parvovirus B19 infection: case series and review. Am J Hematol 1996;51:207-13. Kolquist KA, Vnencak-Jones CL, Swift L, Page DL, Johnson JE. Fatal fat embolism syndrome in a child with undiagnosed hemoglobin S/β+ thalassemia: a complication of acute parvovirus B19 infection. Pediatr Pathol Lab Med 1996;16:71-82. Wayne AS, Kevy SV, Nathan DG. Transfusion management of sickle cell disease. Blood 1993;81:1109-23. Schwiebert LM, Beck LA, Stellato C, Bickel CA, Bochner BS, Schleimer RP, et al. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions. J Allergy Clin Immunol 1996;97:143-52. van den Bosch H, Schalkwijk C, Pfeilschifter J, Marki F. The induction of cellular group II phospholipase A2 by cytokines and its prevention by dexamethasone. Adv Exp Med Biol 1992;318:1-10. Vadas P, Stefanski E, Pruzanski W. Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock. Agents Actions 1986;19:194-202. Tocker JE, Durham SK, Welton AF, Selig WM. Phospholipase A2-induced pulmonary injury and hemodynamic responses in the guinea pig: effect of enzyme inhibitors and mediators antagonists. Am Rev Respir Dis 1990; 142:1193-9. Peltier LF. The diagnosis and treatment of fat embolism. J Trauma 1971; 11:661-7. Schonfeld SA, Ploysongsang Y, DiLisio R, Crissman JD, Miller E, Hammerschmidt DE. Fat embolism prophylaxis with corticosteroids: a prospective study in high-risk patients. Ann Intern Med 1983;99:438-43. Alho A. Fat embolism syndrome: etiology, pathogenesis, and treatment. Acta Chir Scand Suppl 1980;499:75-85. 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. Isaacs WA, Effiong CE, Ayeni O.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
Steroid treatment in the prevention of painful episodes in sickle-cell disease. Lancet 1972;1:570-1. Janik J, Seeler RA. Perioperative management of children with sickle hemoglobinopathy. J Pediatr Surg 1980; 15:117-20. Holzmann L, Finn H, Lichtman HC, Harmel MH. Anesthesia in patients with sickle cell disease. Anesth Analg 1969;48:566-72. Spigelman A, Warden MJ. Surgery in patients with sickle cell disease. Arch Surg 1972;104:761-4. Vichinsky EP, Haberkern CM, Neumayr L, Earles AN, Black D, Koshy M, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med 1995; 333:206-13. Banerjee AK, Layton DM, Rennie JA, Bellingham AJ. Safe surgery in sickle cell disease. Br J Surg 1991;78:516-7. Fullerton MW, Philippart AI, Sarnaik S, Lusher JM. Preoperative exchange transfusion in sickle cell anemia. J Pediatr Surg 1981;16:297-300. Morrison JC, Whybrew WD, Bucovaz ET. Use of partial exchange transfusion preoperatively in patients with sickle cell hemoglobinopathies. Am J Obstet Gynecol 1978;132:59-63. Koshy M, Weiner SJ, Miller ST, Sleeper LA, Vichinsky E, Brown AK, et al. Surgery and anesthesia in sickle cell disease. Blood 1995;86:3676-84. Griffin TC, Buchanan GR. Elective surgery in children with sickle cell disease without preoperative blood transfusion. J Pediatr Surg 1993;28:681-5. Neumayr L, Koshy M, Haberkern C, Earles AN, Bellevue R, Hassell K, et al. Surgery in patients with hemoglobin SC disease. Am J Hematol 1998;57:101-8. Serjeant GR. Chronic transfusion programmes in sickle cell disease: Problem or panacea? Br J Hematol 1997; 97:253-5. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-22. Vermylen C, Cornu G. Hematopoietic stem cell transplantation for sickle cell anemia. Curr Opin Hematol 1997;4: 377-80.