Pediatrics

Acute chest syndrome in sickle cell disease

OVERVIEW: What every practitioner needs to know

Are you sure your patient has acute chest syndrome? What are the typical findings for this disease?

Acute chest syndrome (ACS) is a form of acute lung injury in patients with sickle cell anemia and presents with the symptoms listed below and a "new" pulmonary infiltrate on chest radiography. The most common symptoms are:

Fever (especially in infants and young children)

Cough (especially in children)

Chest pain (rare in infants; common in teenagers and young adults)

Associated respiratory signs and symptoms: rales (especially in older patients), wheezing, hypoxemia

What other disease/condition shares some of these symptoms?

Pneumonia (it is often indistinguishable from ACS)

Atelectasis secondary to mucus plugging (especially in patients who are splinting because of chest pain and/or those with concurrent asthma)

Pulmonary embolism

What caused this disease to develop at this time?

ACS is the second most common cause of hospitalization and the leading cause of admission to the intensive care unit and premature death in patients with sickle cell disease (SCD).

It is more common in children between the ages of 2 and 5 years.

It is more common in patients with the HbSS genotype followed, in descending order, by HbS-ßo, HbSC, and HbS-ß+.

The most common cause is:

Pulmonary infections:

Bacterial infections include Mycoplasma pneumoniae and Chlamydia pneumoniae. The incidence of pneumococcus and Hemophilus influenzae infections are less common in developed countries because of current immunization protocols; they remain the most common cause of bacterial infections in countries in which immunizations are not the standard of care.

Viral infectious causes are especially common in infants and include rhinovirus, respiratory syncitial virus (RSV), human metapneumovirus, adenovirus, influenza, parainfluenza, and parvovirus B19. The latter is often associated with aplastic or sequestration crisis.

Other causative factors include:

  • Previously diagnosed asthma/reactive airway disease

  • Fat embolism

  • Elevated white blood cell count

  • Elevated steady-state hemoglobin level

  • Hypoventilation secondary to vasoocclusive infarction of ribs, sternum, and thoracic vertebrae

  • Dehydration

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The following tests support the diagnosis of ACS.

Complete blood count with differential

Elevated white blood cell count (>20,000/mm3) with a left shift is suggestive of a bacterial infection that is often the precipitating or accompanying event.

Leukopenia is suggestive of parvovirus infection, but it can also be a sign of severe sepsis.

A decrease in hemoglobin (by at least 0.78 g/dL from the baseline) is seen at the onset of ACS.

Thrombocytopenia is suggestive of aplastic crisis.

Reticulocyte count

An abnormally low reticulocyte count is suggestive of aplastic crisis.

Secretory phospholipase A2 (sPLA2sPLA2(an enzyme that cleaves fatty acids from triglycerides) is a marker of the course of ACS. Its serum concentration rises before the appearance of the full clinical manifestations of ACS, peaks at the onset of the symptoms, and declines during the recovery period. Thus the sPLA2 level has to be tested serially.

Blood and sputum culture and viral polymerase chain reaction

Because pneumonia can be the precipitating event or a concurrent event with ACS, a positive result in any of the these tests is very suggestive of the precipitating organism. A negative sputum culture does not rule out the possibility of pneumonia.

Bronchoalveolar Lavage (BAL)

Culture, viral polymerase chain reaction, and cytopathologic analysis of the BAL fluid are important in identifying organisms that are difficult to isolate from other sources. The presence of large numbers of lipid-laden macrophages in the context of the clinical picture of ACS is suggestive of fat embolism.

Would imaging studies be helpful? If so, which ones?

Chest radiography should be performed in patients with respiratory symptoms to determine whether there is a new infiltrate that would be highly suggestive of ACS. To this effect it is advisable for patients to have a baseline chest radiograph when they are well to serve as a comparison.

Computed tomography of the chest is important for assessing the severity of the condition and/or identifying a pathologic condition that is difficult to determine from a simple radiograph (e.g., necrotizing pneumonia, abcess, nodules).

Computed tomography/angiography is important when pulmonary embolism has to be ruled out.

If you are able to confirm that the patient has acute chest syndrome, what treatment should be initiated?

Treatment should be started immediately after the diagnosis is made to prevent the progression and shorten the course of the disease. There is no single therapy for ACS. The treatment aims to prevent the sickling of red blood cells while maintaining adequate oxygen delivery to meet the increased metabolic demands. The therapeutic measures include the following:

Hydration

Maintaining normal hydration is essential to prevent and/or reverse the dehydration of the red cells that increases the concentration of hemoglobin S and leads to more sickling. After deficits are corrected, the patient should receive maintainance fluids. Overhydration may lead to pulmonary edema. A hypotonic solution with dextrose is usually used for maintainance. Isotonic solutions may be necessary for patients with volume contraction and low blood pressure.

Analgesics

Pain control is imperative for the patient's comfort but also to prevent atelectasis as a result of splinting.

Nonsteroidal antiinflammatory drugs (NSAIDs) are preferred over narcotics to avoid excessive sedation.

Common starting medications include:

Acetaminophen: 15 mg/kg every 4 hours as needed to a maximum of 75 mg/kg/day
Ibuprofen: 10 mg/kg every 6-8 hours as needed
Morphine: 0.05-0.15 mg/kg (intravenously [UV] every 2 hours (high doses associated with increased risk of ACS)
Ketorolac: 0.5mg/kg IV, maximum dose 30 mg followed by 0.5 mg/kg IV every 6 hours, maximum dose 15 mg, for up 3 to 5 days

If the pain cannot be controlled with the above medications, the pain service should be consulted for the administration of a continuous infusion of narcotics or for institution of patient-controlled anesthesia.

Continuous infusion of narcotics should be given under continuous cardiorespiratory monitoring.

Antibiotics

Empirical antibiotics should be started for the first 72 hours pending blood culture results and treatment response.

Combination therapy with a third-generation cephalosporin and a macrolide is recommended. Common combinations include cefriaxone: 75 mg/kg/day divided every 8 hours—maximum, 2 g/day; azithromycin: 10 mg/kg on day 1 (maximum, 500 mg/dose), then 5 mg/kg daily for 4 more days (maximum, 250 mg/dose). Erythromycin can be used instead of azithromycin.

Clindamycin, 10 mg/kg/day—maximum, 900 mg, can be used for patients allergic to cephalosporins.

Vancomycin (10-15 mg/kg/day divided every 8 hours—maximum, 1 g every 8 hours) should be added in patients with severe disease.

Red blood cell transfusion

Transfusion of red blood cells stabilizes the acute lung injury by lowering the percentage of sickled red blood cells and by increasing oxygen-carrying capacity.

Simple transfusion should be considered if the hemoglobin drops more than 1g/dL below baseline.

Exchange transfusion should be considered if the patient experiences signs and symptoms of adult respiratory distress syndrome (ARDS).

Oxygen

Supplemental oxygen is necassary to improve the oxygen content of the blood, which is severely decreased in the presence of severe anemia, and to prevent further sickling from hypoxemia.

Oxygen therapy should be administered to maintain O2 saturation greater than 94%. Oxygen should be administered by nasal cannula or face mask for mild to moderate hypoxemia.

Alveolar recruitment techniques

Incentive spirometry: at least 10 breaths every 1-2 hours

Oscillatory positive expiratory pressure: these are devices (e.g., flutter and acapella devices) that promote the mobilization of mucus plugs and the overall clearance of airway secretions.

Noninvasive positive pressure ventilation

Positive pressure ventilation should be considered for pain-induced hypoventilation and respiratory insufficiency as well as for progressive hypoxemia.

Mechanical ventilation

Intubation and mechanical ventilation are necessary in cases of progressive hypoxemia and/or hypercapnia that are refractory to nonivasive positive pressure ventilation. In such cases the ventilatory management is essentially that used for ARDS.

Corticosteroids

The efficacy of corticosteroids in the management of ACS is controversial.

Corticosteroids (1-2 mg/kg/day—maximum, 40-60 mg/day) should be considered in severe ACS, especially in patients with a history and/or symptoms of underlying or concurrent asthma.

Slow weaning (over 2 weeks or longer) may minimize the "rebound" complications that have been described in some patients who received high doses of corticosteroids and/or short courses.

Long-term therapy

Hydroxyurea: This has been shown to decrease the frequency of ACS in predisposed individuals. Hydroxyurea increases the hemoglobin F in red blood cells, thereby decreasing the level of hemoglobin S and the rate of sickling. It also decreases the white blood cell count and platelet count. Close monitoring by a hematologist is essential because of reported complications of bone marrow suppression.

Chronic blood transfusion: Chronic transfusions have been used for prevention of stroke in patients with sickle cell anemia. In the group receiving chronic transfusions, the incidence of ACS decreased significantly.

Inhaled corticosteroids: Their efficacy in ACS is not proved, but they should be considered in patients with a history of asthma.

What are the adverse effects associated with each treatment option?

Complications of Therapy

Red blood cell transfusion: The risks include transfusion incompatibility, infection, and alloimmunization. With improved screening techniques and extended crossmatching, these risks have decreased. Matching for minor antigens C, E, Kell, Duffy, and JKB can reduce alloimunization.

Hydration: Excessive hydration may lead to fluid overload and pulmonary edema.

Nonsteroidal antiinflammatory drugs: Large doses and prolonged use of nonsteroidal antiinflammatory drugs may cause renal toxicity and gastrointestinal bleeding.

Narcotics: Excessive doses cause respiratory depression that leads to hypoventilation and atelectasis. They also decrease gastrointestinal motility.

Oxygen:It may suppress erythropoetin and the production of red blood cells. High concentrations for prolonged periods may cause oxygen toxicity and pulmonary fibrosis.

Mechanical ventilation: Barotrauma can result from mechanical ventilation.

What are the possible outcomes of acute chest syndrome?

About one third of patients with SCD experience so-called sickle chronic lung disease (SCLD) characterized primarily by the development of pulmonary hypertension (PHT). The pathogenesis of PHT is unknown.

Changes in lung function (initially with obstructive lung disease and later in life with a restrictive or mixed pattern) are part of SCLD but do not correlate directly with the presence of PHT. Airway hyperreactivity and/or typical asthma are common among patients with SCLD and it appears to predispose to the development and/or excerbation of ACS. Chronic hemolysis that impairs the synthesis and function of nitric oxide may be the most important, although not the only, factor for the pathogenesis of PHT.

Because of the uncertainties as to the exact causes of SCLD, there is no single therapy that would be recommended for its prevention. At present, the best approach seems to be to identify and treat the individual components of the disease, which may differ from patient to patient..

Medications like hydroxyurea may help control the hematologic component of the disease; hydroxyurea is tolerated well by most patients but it does require close monitoring for the detection of possible complications.

Detection and early treatment of asthma with medications such as bronchodilators and inhaled steroids, which have very few adverse effects, may prevent or minimize the severity of episodes of ACS.

Chronic transfusion therapy would in theory be the "ideal" treatment for controlling the disease and its complications. However, chronic transfusion has a very high profile of possible adverse effects (e.g., infection, iron load) and thus it cannot be recommended routinely for all patients.

What causes this disease and how frequent is it?

ACS is the main pulmonary complication of SCD. It is the second most common cause of hospitalization in patients with SCD after vasoocclusive crisis. It is considered to be a form of acute lung injury that warrants admission to the intensive care unit and is the leading cause of premature mortality in SCD.

ACS lacks a precise definition and it is usually defined on the basis of its clinical and radiographic characteristics, namely the development of a new infiltrate involving at least one lung segment that is associated with fever, tachypnea, dyspnea, cough, or wheezing.

ACS is most prevalent in patients with SCD and the HbSS genotype followed, in decreasing frequency, by HbS-ßo thalassemia, HbSC, and HbS-ß+ thalassemia.

ACS is more common in children between the ages of 2 and 5 years. It does not have a specific seasonal variation. However, because it is often triggered by an infection, it may be more common during periods of high prevalence of respiratory viruses.

Risk Factors

A high steady-state hemoglobin level is considered a major risk factor and the actual onset is heralded by an acute drop in hemoglobin (by at least 0.78 g/dL) from the patient's baseline. A drop in the platelet count to less than 200,000/mm3has also been associated with severe pulmonary and neurologic complications.

Causes include a variety of heterogenous factors, including the following:

Pulmonary infection is the most common condition associated with ACS. Patients with SCD have a functional abnormality of their complement system and functional asplenia, which predisposes them to infections, especially by encapsulated organisms. Common organisms depend on age and geographic location. Infants are most susceptible to the typical respiratory viruses (rhinovirus, RSV, human metapneumovirus, adenovirus, rhinovirus, influenza, and parainfluenza .

Encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae used to be the most common bacterial pathogens before the introduction of the pneumococcal and H. influenzae vaccines. They remain prevalent in countries where these vaccines are not routinely given. In older children and adults, community-acquired organisms and atypical bacteria, especially Mycoplasma, are the major pathogens.

Fat embolism is the second major cause of ACS and occurs in approximately 16% of cases. It results from vasooclusion leading to infarction and edema of the bone marrow and the release of necrotic fat contents into the circulation, which leads to systemic fat emboli syndrome. The vasoocclusion often involves multiple bones, especially the pelvis and femur.

Asthma: A high proportion of patients with SCD have airway reactivity in response to cold air challenge (40%) and to metacholine challenge (73%-77%). Patients with SCD who have physician-diagnosed asthma reportedly have a four- to sixfold higher risk of recurrent ACS and twice the rate of ACS compared with individuals without asthma. Patients who are admitted for pain crises are more likely to experience ACS if they have asthma.

Ischemia/reperfusion injury: Vasoocclusion of the microvasculature causes organ ischemia/reperfusion injury, which is often associated with the release of inflammatory mediators that may contribute to the development of ACS.

What complications might you expect from the disease or treatment of the disease?

Respiratory failure is reportedly common and carries a mortality of up to 30%, probably because of exacerbated sickling from prolonged hypoxemia. The mortality is reduced (19%) in patients who are intubated and mechanically ventilated.

Bronchial casts (plastic bronchitis)can develop in the course of a severe episode of ACS associated with ARDS. The pathogenic mechanism is unknown, but it is potentially life threatening because it can occlude segments or entire lobes of the lung.

SCLD is characterized by the development of pulmonary hypertension that may progress to cor pulmonale and death. It is often associated with the development of a restrictive or obstructive pattern of lung function with significant decrease in diffusing capacity.

How can acute chest syndrome be prevented?

There are no specific interventions that could prevent ACS. However, controlling the various risk factors and possible causes of ACS may prevent some of the episodes and/or minimize their severity.

Specifically the following measures can be taken:

Adequate pain control in patients with vasoocclusive crisis to avoid hypoventilation and atelectasis either due to splinting oversedation

Airway recruitment techniques to prevent alveolar collapse and recruit collapsed alveoli

Institution of noninvasive ventilatory support with the first signs of progressive atelectasis or respiratory fatigue

Antibiotics for the treatment of confirmed or suspected infections

Transfusion of red blood cells when there is a sudden drop in the hemoglobin concentration

Treatment of asthma symptoms

Prevention and correction of hypoxemia

What is the evidence?

The following articles discuss the causes, risk factors, and incidence of ACS.

Castro, O, Brambilla, DJ, Thorington, B. "The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease". Blood. vol. 84. 1994. pp. 643-9.

(This study is a prospective multicenter study that investigated and showed the risk factors and incidence of ACS in 3000+ participants—children and adults.)

Vichinsky, EP, Neumayr, LD, Earles, AN. "Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group". N Engl J Med. vol. 342. 2000. pp. 1855-65.

(This is another multicenter study that analyzed 671 episodes of acute chest syndrome in 538 patients with SCD to determine the cause, outcome, and response to therapy.)

Gladwin, MT, Vichinsky, E. "Pulmonary complications of sickle cell disease". N Engl J Med. vol. 359. 2008. pp. 2254-65.

(Excellent review of of the pathophysiology of ACS and other pulmonary complications of SCD.)

Vinchinsky, E, Williams, R, Das, M. "Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia". Blood. vol. 83. 1994. pp. 3107-12.

Castro, O. "Systematic fat embolism and pulmonary hypertension in sickle cell disease". Hematol Oncol Clin North Am. vol. 10. 1996. pp. 1289-303.

The following articles discuss asthma, pulmonary function, and ACS in SCD.

Ozbek, OY, Malbora, B, Sen, N. "Airway hyperreactivity detected by metacholine challenge in children with SCD". Pediatr Pulmonol. vol. 42. 2007. pp. 1187-92.

(This was the first study that showed airway hyperreactivity in pediatric patients with SCD to metacholine challenge, whether they experienced ACS or not.)

Sylvester, KP, Patey, RA, Rafferty, GF. "Airway hyperresponsiveness and acute chest syndrome in children with sickle cell anemia". Pediatr Pulmonol. vol. 42. 2007. pp. 272-6.

(This study showed airway hyperresponsiveness to cold air challenge in patients with SCD .)

Leong, MA, Dampier, C, Varlotta, L. "Airway hyperreactivity in children with sickle cell disease". J Pediatr. vol. 131. 1997. pp. 278-83.

Koumbourlis, AC, Zar, HJ, Hurlet-Jensen, A. "Prevalence and reversibility of lower airway obstruction in children with sickle cell disease". J Pediatr. vol. 138. 2001. pp. 188-92.

Knight-Madden, JM, Forrester, TS, Lewis, NA. "Asthma in children with sickle cell disease and its association with acute chest syndrome". Thorax. vol. 60. 2005. pp. 206-10.

Boyd, JH, Moinuddin, A, Strunk, RC. "Asthma and acute chest in sickle cell disease". Pediatr Pulmonol. vol. 38. 2004. pp. 229-32.

Boyd, JH, Macklin, EA, Strunk, RC. "Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia". Blood. vol. 108. 2006. pp. 2923-29.

Blake, K, Lima, J. "Asthma in sickle cell disease: implications for treatment". Anemia. 2011 Mar 3. pp. 74023.

Newaskar, M, Hardy, KA, Morris, CR. "Asthma in sickle cell disease". Scientific World J. vol. 1. 2011. pp. 1138-52.

(These last 2 references are excellent review articles on the association of asthma with the complications of SCD.)

The following article discusses diagnosis and management of ACS.

Crabtree, EA, MAriscalco, MM, Hesselgrave, J. "Improving care for children with sickle cell disease/acute chest syndrome". Pediatrics. vol. 127. 2011. pp. e480-8.

(This is a well-designed quality improvement study that evaluated and validated clinical guidelines that were developed for the management of ACS. It has a valuable flow chart that can be considered for the management of ACS.)

The following articles discuss blood transfusion.

Ohene-Frempong, K. "Indications for red cell transfusion in sickle cell disease". Semin Hematol. vol. 38. 2001. pp. 5.

Claster, S, Vinchinsky, EP. "Managing sickle cell disease". BMJ. vol. 327. 2003. pp. 1151-55.

The following articles discuss hydroxyurea.

Wang, WC, Ware, RE, Miller, ST. "Hydroxycarbamide in very young children with sickle cell anemia: a multicenter, randomized control trial (BABY HUG)". Lancet. vol. 377. 2011. pp. 1663-72.

Kinney, TR, Helms, RW, O'Branski, EE. "Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase 1/2 trial". Blood. vol. 94. 1999. pp. 1550-4.

Singh, SA, Koumbourlis, AC, Aygun, B. "Resolution of chronic hypoxemia in pediatric sickle cell patients after treatment with hydroxyurea". Pediatr Blood Cancer. vol. 50. 2008. pp. 1258-60.

The following articles discuss systemic steroids and SCD.

Bernini, JC, Rogers, ZR, Sandler, ES. "Beneficial effect of intravenous dexamethasone in children with mild to mederately severe acute chest syndrome complicating sickle cell disease". Blood. vol. 92. 1998. pp. 3082.

Strouse, JJ, Takemoto, CM, Keefer, JR. "Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease". Pediatr Blood Cancer. vol. 50. 2008. pp. 1006.

Sobota, A, Graham, DA, Heeney, MM. "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. vol. 85. 2010. pp. 24.

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. vol. 30. 2008. pp. 322-5.

Ogunlesi, F, Koumbourlis, A. "Sickle cell disease and the lung; many questions still remain unanswered". Clin Pulm Med. vol. 18. 2011. pp. 119-28.

(Comprehensive review of various controversies regarding the pathogenesis, diagnosis, and management of ACS.)

Caboot, JB, Allen, JL. "Pulmonary complications of sickle cell disease in children". Curr Opin Pediatr. vol. 20. 2008. pp. 279-87.

(Comprehensive review of issues related to oxygenation in SCD.)

Ongoing controversies regarding etiology, diagnosis, treatment

Controversies regarding the pathogenesis and evaluation of ACS

Is ACS the expression of vasooclussive crisis in the lung or a distinctly different entity?

Is ACS an entity triggered by an infection or a complication of pneumonia specific to patients with SCD?

Is fat embolism a distinct mechanism causing ACS or are the increased number of fat molecules in the BAL fluid the result of cellular damage?

Is asthma a predisposing factor for the development of ACS or does ACS predispose to asthma?

Should the calculated oxygen content be used for the assessment of the severity of ACS instead of the oxyhemoglobin saturation or the partial pressure of oxygen in the arterial blood?

Do systemic steroids actually increase the risk of readmission or of neurologic complications?

Controversies regarding the treatment of ACS

Should all patients receive bronchodilators during an episode of ACS or only those with documented asthma symptoms? (The majority of patients with SCD, even those with a normal or restrictive pattern of lung function and no history of asthma, do show response to bronchodilators.)

Is a lower dose and/or a prolonged weaning of systemic steroids less likely to cause the "rebound" side effects that have been reported with short bursts of high-dose steroids? A study by Hsu et al showed that a prolonged taper of prednisone may provide the necessary therapeutic effect while minimizing the possibility of adverse effects.

Should supplemental oxygen be used until the discharge of the patient from the hospital or only until their condition stabilizes?

Should supplemental oxygen be used for chronic hypoxemia in otherwise asymptomatic patients?

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