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Acute chest syndrome (ACS) in sickle cell disease (adults and children)

Acute chest syndrome (ACS) in sickle cell disease (adults and children)
Literature review current through: Jan 2024.
This topic last updated: Apr 03, 2023.

INTRODUCTION — Acute chest syndrome (ACS) is defined as a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms. It is an acute complication of sickle cell disease (SCD) that is potentially fatal and requires immediate intervention regardless of the patient's age.

This topic discusses ACS in adults and children with SCD, including causes, evaluation, management, and prevention.

Other pulmonary complications of SCD and general management recommendations are presented separately:

Pulmonary complications – (See "Overview of the pulmonary complications of sickle cell disease".)

Pulmonary hypertension – (See "Pulmonary hypertension associated with sickle cell disease".)

Management, specialist – (See "Overview of the management and prognosis of sickle cell disease".)

Management, general pediatrician – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

DEFINITIONS AND PEDIATRIC-ADULT DIFFERENCES

Definition – The definition of ACS is the same in children and adults: a new radiodensity on chest radiograph together with fever and/or respiratory symptoms. (See 'Diagnostic criteria' below.)

ACS is clinically indistinguishable from pneumonia in individuals with SCD, and with rare exceptions, the distinction largely does not affect management. (See 'Management' below.)

The broad definition of ACS captures a nonspecific clinical endpoint that includes different underlying pathogenic processes. It does not differentiate between a presentation with fever, increased respiratory effort, and a new radiodensity due to bronchiolitis requiring a brief inpatient admission (a more common scenario in children) from intrapulmonary vaso-occlusion and respiratory failure due to fat embolism requiring management in the intensive care unit (a more common scenario in adults).

Children versus adults – In addition to differences in triggering events (see 'Common triggers' below), adults generally have greater disease severity and higher mortality rates, largely due to a higher incidence of bone marrow and fat emboli [1,2]. This and other differences are summarized in the table (table 1).

Although the management of ACS episodes is largely the same in adults and children, the greater likelihood of severe ACS in adults highlights the importance of certain interventions such as transfusions. (See 'Acute interventions' below.)

OVERVIEW OF PATHOGENESIS

Risk factors

Genotype – The more severe SCD genotypes (hemoglobin S [Hb S] and Hb S-beta0-thalassemia) confer a greater risk for ACS than the less severe genotypes (Hb SC disease [Hb SC] and Hb S-beta+ thalassemia), similar to other vaso-occlusive complications. However, genotype cannot be used to confirm or exclude an ACS diagnosis. (See "Overview of compound sickle cell syndromes".)

Hb F percentage – Higher levels of fetal hemoglobin (Hb F) are protective against SCD complications, but individuals with higher Hb F can still develop ACS [3].

Comorbidities

Acute pain (especially vaso-occlusive) can increase ACS risk by causing splinting and decreased inspiration.

Asthma and reactive airways dysfunction can cause ventilation perfusion mismatch and inflammatory changes [4-17].

Recent surgery (especially abdominal) can cause atelectasis and increased risk for venous thromboembolism [18-21].

Chronic hypoxemia can reduce perfusion, especially during sleep [22,23].

Avascular necrosis and bone (or bone marrow) infarction can cause pulmonary fat embolism.

Sedation or opioid analgesics can cause hypoventilation.

Environmental factors

ACS is more common in winter months due to cold temperature and more frequent upper respiratory infections.

Smoking or second-hand smoke exposure is associated with increased risk of ACS and more severe ACS [4,24,25].

Exposure to aeroallergens in sensitized individuals may contribute [10].

Prevention requires diligent care during hospitalization or postoperatively to minimize atelectasis and infection. (See 'Prevention' below.)

Attention to risk factor reduction is an important component of care once the acute ACS episode has subsided. (See 'Discharge planning and outpatient monitoring' below and 'Risk of ACS recurrence' below.)

Common triggers — A proximate trigger for an ACS episode can be identified in approximately one-half of individuals [2,26]. Triggers are not mutually exclusive and may coexist in the same individual.

In a prospective report from the National Acute Chest Syndrome Study Group (NACSSG) that evaluated 671 episodes of ACS in 538 patients, a definite cause was established in 38 percent of episodes after an extensive evaluation that included bronchial or sputum cultures, blood cultures, and serologic testing (Mycoplasma pneumoniae, parvovirus B19, Epstein-Barr virus) [2]:

Cause not identified – 46 percent overall; 30 percent in individuals with complete data

Infection – 29 percent

Chlamydia pneumoniae – 7 percent

M. pneumoniae – 7 percent

Viral (respiratory syncytial virus, parvovirus, rhinovirus) – 6 percent

Mixed – 4 percent

Other – 1 percent

Pulmonary infarction – 16 percent

Fat embolism – 9 percent

Infection and asthma are more common causes of ACS in children and a less-common cause in adults [2,26-28]. Vaso-occlusive pain is a more common cause in adults, but pain can also trigger ACS in children. Pulmonary embolism (PE) or pulmonary infarction is documented more often in adults than in children [29,30]. ACS etiologies other than vaso-occlusive pain may also be associated with bone marrow necrosis and fat emboli, such as parvovirus B19 infection [31]. Listing of the most likely causes by age group are discussed in the table (table 1) and below. (See 'Children' below and 'Adults' below.)

Coronavirus disease 2019 (COVID-19) has been reported as a cause of ACS. (See "COVID-19: Management in children" and "COVID-19: Management in hospitalized adults" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

Children — ACS in children is often triggered by infection. Other common causes include asthma, allergies, infarction, fat embolism, and vaso-occlusive pain. Multiple triggers may be present. In many cases, a proximate cause is not identified.

Infection – Infections are more common as a trigger of ACS in children than in adults and in younger children than older children. The relative frequency of causes was illustrated in the prospective NACSSG study discussed above (see 'Common triggers' above) [2].

Age ≤9 years – Of 329 episodes of ACS, 35 percent were due to infections, especially viral (11 percent), mycoplasma (9 percent), chlamydia (9 percent), and bacterial (4 percent).

Age 10 to 19 years – Of 188 episodes of ACS, 22 percent were due to infections, including chlamydia (8 percent), mycoplasma (4 percent), viral (3 percent), and bacterial (3 percent).

In a different study involving 141 children with SCD who had positive blood cultures, Streptococcus pneumoniae was the most common pathogen (42 percent of total); one-fourth of individuals with positive cultures for S. pneumoniae had ACS [32].

Asthma – Asthma is common in children with SCD; the prevalence seems to be similar to that in children without SCD. Asthma is associated with a statistically significant and clinically relevant increase in ACS and acute vaso-occlusive pain requiring hospitalization. In a pooled analysis of three studies including 1685 participants with a mean follow-up of 6.1 years (10,216 patient-years), the prevalence of asthma was 23.1 percent (390 of 1685 participants) [33]. After adjustment for age, hemoglobin, and white blood cell count, asthma was associated with higher rates of pain (incidence rate ratio [IRR] 1.34, 95% CI 1.16–1.55, p <0.001) and ACS (IRR 1.89, 95% CI 1.61–2.22, p <0.001).

Allergen sensitization – Data from a multicenter cohort study demonstrated additive effects of having positive skin prick allergy tests to respiratory allergens on future rates of ACS (IRR 1.23, 95% CI 1.11-1.36, p <0.001) [10]. Even a single positive allergy skin test was associated with an increased risk for ACS; more positive skin tests were associated with greater increases in the rates of future ACS events.

Vaso-occlusive pain – In the NACSSG study, almost half of all patients who developed ACS were initially admitted for other reasons, frequently vaso-occlusive pain [2]. In a different prospective observational study involving 176 children admitted for vaso-occlusive event, 35 developed ACS [34]. Multivariate analysis identified independent risk factors for ACS including high pain score (≥9/10); pain localization to abdomen, spine, or >2 limbs; high reticulocyte count (>260,000/microL); and high neutrophil count (>10,000/microL) at admission. There should be a low threshold for obtaining subsequent chest radiographs in these settings.

Adults — ACS in adults is often triggered by an acute vaso-occlusive pain episode and/or fat embolism. Infection and asthma are less-common causes. More than one trigger may be present.

Vaso-occlusive pain and fat embolism – In a series of 107 ACS events in 77 adults with SCD, 78 percent were associated with vaso-occlusive pain [35]. A common scenario is development of ACS within 2 to 3 days of the admission for pain.

Fat embolism may occur as a consequence of vaso-occlusive pain, and other studies have documented fat embolism as a cause for 44 to 77 percent of ACS episodes in adults [1,36-45]. (See 'Pathophysiology' below.)

Despite the challenging diagnosis of fat emboli as the initiating cause of ACS, significant evidence including bronchioalveolar lavage (BAL; showing fat in alveolar macrophages), post-mortem evaluation, imaging of the bone marrow, and bone marrow aspirate/biopsy (showing bone marrow necrosis) support this diagnosis [36,38-40,42,43,45]. However, since testing for fat emboli requires bronchoscopy and is not performed routinely, the true incidence of fat emboli in patients with ACS is not known. Individuals with hemoglobin SC disease (Hb SC) have been reported to have the highest frequency of fat emboli, especially during pregnancy.

The correlation between bone marrow infarction and fat embolism is strong. In a study of 20 adults with ACS, 92 percent of the cases demonstrating fat-containing alveolar macrophages by BAL showed some evidence of bone marrow infarction on magnetic resonance imaging (MRI) or radioisotopic bone imaging [36]. (See 'Pathophysiology' below.)

There is a distinct syndrome in some patients with fat embolism that has multisystem involvement and is often not diagnosed until organ failure occurs. (See 'Pathophysiology' below and 'Rapidly progressive ACS and multiorgan failure' below.)

Infection – In the prospective NACSSG study (see 'Common triggers' above), 26 percent of ACS episodes in adults were due to infection [2]. Numbers were small overall (153 episodes of ACS in 128 adults >20 years old). Common organisms included chlamydia (9 percent), bacteria (7 percent), mycoplasma (5 percent), and viruses (1 percent). Other organisms included respiratory syncytial virus (RSV) and Mycoplasma hominis. C. pneumoniae was more common in adolescents and young adults (median age 18 years) [2].

Asthma – Data from the Cooperative Study of Sickle Cell Disease reported wheezing as a presenting finding in a small proportion of adults (13 percent symptomatic and 8 percent detected on examination) [27].

Pathophysiology — Vaso-occlusion within the pulmonary microvasculature is the basis for ACS pathophysiology. A variety of inciting events (infection, asthma, hypoventilation due to pain, infarction due to fat embolism or venous thromboembolism) can trigger deoxygenation of Hb S leading to polymerization and sickling, leading to vaso-occlusion, ischemia, and endothelial injury [18,46,47]. (See 'Common triggers' above.)

Once vaso-occlusion is initiated in the pulmonary vasculature, it is propagated by hypoxia, inflammation, and acidosis, creating a cycle of ongoing vaso-occlusion. (See "Pathophysiology of sickle cell disease", section on 'Vaso-occlusion'.)

Hypoxia – Regional alveolar hypoxia from atelectasis, pulmonary edema, bronchospasm, pneumonia and/or vaso-occlusive pain involving the rib, spine, or abdomen will result in local ventilation-perfusion (V/Q) mismatch and hypoxemia. Focal hypoxia can further increase local sickling. Sedation from opioids can contribute to hypoventilation. In 102 children with SCD who underwent pulmonary function testing, patients with obstructive lung disease had twice the rate of hospitalizations for pain or ACS compared with those with restrictive disease (2.5 versus 1.2 hospitalizations) [48].

Inflammation – Infection may trigger release of cytokines and inflammatory mediators. Inflammation associated with fat emboli is likely due to proinflammatory free fatty acids [1,49]. Other contributing factors include endothelial dysfunction, increased expression of vascular adhesion molecules, increased platelet and coagulation factor activation, and disordered nitric oxide metabolism leading to thromboembolism and/or hemolysis [50,51].

Vasoconstriction – Elevated plasma arginase activity, decreased nitric oxide (NO), and NO synthase gene polymorphisms in patients with SCD may provide a possible biological link between SCD, asthma, and ACS [52-56]. (See "Overview of the pulmonary complications of sickle cell disease" and "Pulmonary hypertension associated with sickle cell disease", section on 'Pathogenesis'.)

Embolism/infarction – PE or pulmonary infarction can also cause regional hypoxemia. Pulmonary infarction (and/or in-situ thrombosis) can also occur as a manifestation of local intrapulmonary sickling or vaso-occlusive disease alone (without PE). In one study that used multidetector computed tomography in 144 episodes of ACS in 125 individuals, 17 percent showed evidence of pulmonary thrombosis [30]. Pulmonary thrombi have also been reported in autopsy studies of adults with ACS [57-61]. Findings of sickled RBCs within the thrombi suggest in situ thrombosis related to vaso-occlusion rather than emboli originating from deep veins [62,63]. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Venous thromboembolism and pulmonary thrombosis'.)

Fat embolism appears to be a contributing factor in a large number of cases. A study that performed BAL in 20 adults with SCD identified fat-laden macrophages in 12 (60 percent), consistent with fat embolism [36]. A BAL study in 27 children with SCD demonstrated evidence of fat in macrophages in 12 (44 percent); among 43 controls, none had evidence of fat in pulmonary macrophages [43]. Among the 12 children with pulmonary fat embolism, 11 (92 percent) presented with vaso-occlusive pain, whereas only 6 of 15 (40 percent) without pulmonary fat embolism had pain.

Multiorgan failure – There is a distinct syndrome in some patients with fat embolism, with multifocal involvement; fat embolism often is not diagnosed until organ failure occurs. Focal neurologic findings or altered level of consciousness may be caused by small cerebral fat emboli [64]. The pain is often described as the worst pain ever felt, or atypical pain compared with usual vaso-occlusive pain. This is due to massive bone marrow necrosis, often accompanied by a leukoerythroblastic picture on the peripheral blood smear with high nucleated RBC counts. Reports have sporadically identified parvovirus B19 infection [65]. Early diagnosis can reduce mortality but is challenging. Immediate exchange transfusion can be lifesaving [65,66]. (See 'Transfusion' below.)

Bone marrow necrosis with bone marrow and fat emboli is also thought to contribute to the etiology of acute multiorgan failure syndrome [42,67]. (See 'Rapidly progressive ACS and multiorgan failure' below.)

Recurrent episodes of ACS may lead to repeated lung infarctions and parenchymal fibrosis. (See 'Long-term complications' below.)

General mechanisms of vaso-occlusion, hypoxia, and infarction are presented separately. (See "Pathophysiology of sickle cell disease".)

EPIDEMIOLOGY — Data from the Cooperative Study of Sickle Cell Disease (CSSCD), the largest natural history study of SCD that includes both adults and children, suggest that approximately 50 percent of individuals with SCD will have an episode of ACS [3].

The peak incidence in children is between two to four years [3]. Incidence is higher during the winter months.

Data from the CSSCD suggest the following incidence rates [3]:

Hb SS (children) – 25.3 per 100 patient-years

Hb SS (adults) – 8.78 per 100 patient-years

Hb SC (children and adults) – 1.95 per 100 patient-years

Hb S-beta+-thalassemia (children and adults) – 3.27 per 100 patient-years

CLINICAL FEATURES

Typical presentation — Presentation and severity are quite variable [68]. Some individuals may present with severe disease, and in others, severe disease may evolve in the two to three days following a pain episode, consistent with fat emboli. Respiratory failure requiring mechanical ventilation occurs in approximately 10 percent [2]. (See 'Respiratory support' below.)

When the initial presentation is mild, there may be chest pain with minimal or no hypoxia/hypoxemia (<4 liters/minute of oxygen via nasal cannula required to maintain oxygen saturation ≥95 percent); there may be no infiltrate on chest imaging or a small infiltrate involving one lobe.

Two large cohort studies, the National Acute Chest Syndrome Study Group (NACSSG) and the Cooperative Study of Sickle Cell Disease (CSSCD), have best defined the clinical presentation [2,3,27]. Children accounted for the majority of individuals in both cohorts.

Both the NACSSG and CSSCD found chest pain to be a common presenting finding; the CSSCD found fever to predominate.

NACSSG – The NACSSG examined a cohort of 538 adults and children with SCD who had 671 episodes of ACS and reported the following [2]:

Children

-Chest pain – 41 percent

-Pain in arms and legs – 30 percent

-Rib and sternal pain – 18 percent

-Shortness of breath – 36 percent

-Neurologic findings – 8 percent

Adults

-Chest pain – 55 percent

-Pain in arms and legs – 59 percent

-Rib and sternal pain – 30 percent

-Shortness of breath – 58 percent

-Neurologic findings – 22 percent

CSSCD – The CSSCD examined a cohort of 939 patients with SCD who had 1722 episodes of ACS and reported the following [27]:

Children

-Fever – 85 percent

-Chest pain – 41 percent

-Shortness of breath – 20 percent

-Multilobe infiltrates – 24 percent

-Pain preceding the ACS episode – 11 percent

Adults

-Fever – 64 percent

-Chest pain – 84 percent

-Shortness of breath – 47 percent

-Multilobe infiltrates – 36 percent

-Pain preceding the ACS episode – 50 percent

Clinical course was more severe in adults; adults were more likely to require mechanical ventilation and to die. These differences must be considered when making treatment decisions. (See 'Management' below.)

Rapidly progressive ACS and multiorgan failure — Up to one-fifth of adults with a history of ACS can develop a distinct ACS phenotype characterized by rapid progression of respiratory compromise, with respiratory failure within 24 hours [69]. Multiorgan failure often occurs.

Acute multiorgan failure syndrome is characterized by acute dysfunction of at least two of three organs (lung, liver, and/or kidney) during a vaso-occlusive pain episode [67]. Fever, confusion, decreased hemoglobin, and decreased platelet count are often present [67]. Many patients who present with multiorgan failure have ACS that may not be identified initially. Some of these individuals (especially adults) may have massive fat embolism. (See 'Adults' above.)

In a retrospective cohort, rapidly progressive ACS occurred in 16 of 76 adults (21 percent) and 2 of 97 children (2 percent) [69]. Adults with rapidly progressive ACS had much higher complication rates than adults with ACS that was not rapidly progressive:

Acute kidney injury (69 versus 3 percent)

Hepatic dysfunction (75 versus 15 percent)

Altered mental status (44 versus 12 percent)

Multiorgan failure (94 versus 10 percent)

The only predictor of developing rapidly progressive ACS was a decline in platelet count at presentation (odds ratio [OR] 4.8, 95% CI 1.2-19.4) [69]. Mortality was 6 percent in the individuals with rapidly progressive ACS, compared with 0 percent in those without.

Since episodes of ACS with fat emboli are often characterized by infiltrates, hypoxia, confusion, and thrombocytopenia during a painful vaso-occlusive episode, these ACS events are likely due to the same underlying etiology of multiorgan failure (bone marrow and fat emboli), with the predominant organ affected being the lung. (See 'Pathophysiology' above.)

Neurologic events may complicate ACS, particularly when patients have severe pulmonary disease and/or respiratory failure [2]. In two small studies, reversible posterior leukoencephalopathy syndrome, silent cerebral infarcts, and acute necrotizing encephalitis were reported in children with severe ACS who developed neurologic complications [70,71]. These observations suggest that patients recovering from respiratory failure should be assessed with neurocognitive studies and brain MRI for the presence of silent infarcts [72]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

COVID-19 — Data are limited on the effects of coronavirus disease 2019 (COVID-19) in patients with SCD. However, since SARS-CoV-2 is a respiratory virus that causes pneumonia, we anticipate that infection could lead to ACS and a high risk of death. In a cohort study that included >5000 individuals with SCD compared with >12 million controls, the risk of testing positive for SARS-CoV-2 infection was only mildly increased with SCD (5.7 percent, versus 4.4 percent of controls), but the risk of hospitalization was dramatically higher (0.8 versus 0.2 percent; hazard ratio [HR] 4.1, 95% CI 3.0–5.7) [73]. Consideration of COVID-19, with rapid diagnosis and intervention, can result in excellent recovery [74,75].

Any patient with COVID-19 who develops respiratory symptoms should have a type and crossmatch and should be monitored closely for respiratory compromise. If there is a drop in hemoglobin, decrease in hemoglobin oxygen saturation, or both, we would consider initial simple transfusion therapy, with preparation for automated exchange. (See 'Transfusion' below.)

If there is evidence of respiratory compromise, early exchange transfusion to decrease the hemoglobin S to <30 percent of total hemoglobin, in addition to the usual supportive measures and COVID-19 therapies may be lifesaving. If the facility does not have the ability to perform automated exchange transfusion, consideration should be given to transfer the patient to a facility that does have the capacity. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

DIAGNOSTIC EVALUATION

High level of vigilance — Delays in diagnosis can adversely impact outcomes. A high level of vigilance for ACS should be maintained in any individual with SCD who has:

Fever

Respiratory symptoms

Chest or back pain

Vaso-occlusive pain in any location

Suspicion for ACS should also be maintained in individuals with SCD admitted to the hospital for any reason, including those with pain or respiratory symptoms in whom the initial chest radiograph is normal. Individuals with SCD are at increased risk for ACS during hospitalization due to a variety of causes including increased sedation with hypoventilation, splinting with atelectasis, increased inflammation, and others. (See 'Overview of pathogenesis' above.)

Implementation of a standardized clinical protocol or pathway for inpatient monitoring and treatment of early ACS has been demonstrated to improve outcomes [76,77]. Important elements of one protocol included [76]:

Use of a broad definition for ACS, consisting of lower respiratory symptoms including hypoxemia or a new lung infiltrate

Close monitoring and quantification of respiratory status using a clinical respiratory score

Staged escalation of treatment based on the respiratory score

Examination — Vaso-occlusive pain often accompanies ACS and can be intense, severe, and incapacitating. The gold standard for assessment of pain is the individual's (or family/caretaker's) report; no combination of clinical and laboratory findings can determine (or confirm) whether an individual with SCD is in pain. Appropriate pain medication should not be withheld while evaluating for ACS. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Management in the ED and hospital'.)

The examination should focus on:

Vital signs and oxygen saturation by pulse oximetry

Sites of pain, especially bone pain in the back and chest

Cardiac and respiratory status

Leg edema and possible deep vein thrombosis (DVT)

Presence of an indwelling catheter and signs of catheter site infection

Pulse oximetry is performed but has two important limitations. First, it tends to overestimate the presence and frequency of hypoxemia, and may not be accurate as the sole monitor for the respiratory course of patients with severe or progressive ACS [78,79]. Second, it can easily underestimate the extent of areas of alveolar hypoxia, which lead to sickling, possible infarction, and hypoxic vasoconstriction. (See "Pulse oximetry".)

Lipemia retinalis and petechiae are consistent with fat emboli but not commonly seen; their absence does not exclude fat embolism [18,80].

Laboratory testing — The following are obtained:

CBC – Complete blood count (CBC) with white blood cell (WBC) differential, platelet count, and reticulocyte count, on presentation and repeated daily until clinical improvement. A leukoerythroblastic picture may indicate infection or bone marrow necrosis with massive fat embolism, which can be fatal. (See 'Adults' above and 'Pathophysiology' above and 'Rapidly progressive ACS and multiorgan failure' above.)

Blood bank – Type and crossmatch for red blood cell (RBC) transfusions if needed. If at all possible, requested blood should be negative for Hb S, matched for C, E, and Kell, and leukoreduced (leukoreduction is routine at most centers in the United States). The type and crossmatch should remain active throughout the hospitalization based upon the local blood bank requirements. (See 'Transfusion' below and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching'.)

Percent Hb S – If exchange transfusions are used, the percent Hb S is monitored before and after each procedure.

Metabolic panel – Used to assess and monitor kidney and liver function. Many individuals with SCD have hyperfiltration (especially when younger) or impaired kidney function (when older). Markers for massive bone marrow necrosis such as serum ferritin and lactate dehydrogenase (LDH) may be helpful in selected cases [64-66].

Cultures – Cultures (blood, sputum) and other appropriate infectious disease testing if fever is present. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Diagnostic testing'.)

COVID-19 – During the coronavirus disease 2019 (COVID-19) pandemic, testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is appropriate for all individuals with SCD who present with fever, chest pain, decreased oxygen saturation, or respiratory symptoms, regardless of whether they have already had COVID-19 or have received a COVID-19 vaccine.

Limited role for ABG – We generally do not obtain arterial blood gasses (ABGs) unless there is significant respiratory distress or signs of impending respiratory collapse and need for intubation. Blood gas may be useful if there is significant respiratory distress, impending respiratory failure, inconsistency between the pulmonary clinical status and recordings from pulse oximetry, or to provide additional data to determine the need for simple or exchange transfusion (eg, PaO2 <60 mm Hg). (See "Arterial puncture and cannulation in children" and "Arterial blood gases".)

If respiratory failure is present, it is important to distinguish pure hypoxemic respiratory failure from mixed hypercapnic-hypoxemic respiratory failure. (See 'Respiratory support' below.)

Laboratory markers are not available to predict which patients with vaso-occlusive pain are at risk for ACS, although some markers such as secretory phospholipase A2 (sPLA2) and C-reactive protein (CRP) are under investigation. Both sPLA2 and CRP increase hours before the development of ACS [52,81,82]. In one small unblinded randomized trial of patients with SCD-associated pain and an elevated sPLA2, the addition of single transfusion to standard therapy appeared to reduce the risk of developing ACS [83]. Further study is needed to determine the usefulness of these markers.

Imaging

Imaging for new lung density – Chest imaging (typically, anteroposterior [AP] and lateral chest radiographs) should be obtained for all individuals with SCD who have fever, chest pain, decreased oxygen saturation, or respiratory symptoms. Often the radiologist cannot distinguish between an infiltrate or atelectasis; we prefer to refer to the new lung finding as new radiodensity rather than an infiltrate.

In one study of febrile patients with SCD, 61 percent were not clinically suspected by evaluating clinicians prior to the diagnosis by chest radiograph [84].

Chest radiograph – A chest radiograph should be obtained for all patients admitted with severe vaso-occlusive pain, particularly with chest or rib pain. Patients who demonstrate restrictive respiratory efforts and/or hypoxemia at rest should have repeat chest radiographs within 24 to 48 hours after admission, because ACS frequently develops after admission for a pain episode [2].

Ultrasound – Bedside chest ultrasound is not standard but may be performed by some experts. It may allow rapid diagnosis and allow patients to avoid radiation from chest radiographs [85,86].

A new radiodensity with one of the other findings listed below is sufficient to diagnose ACS [2,3,27,87-89]. (See 'Diagnostic criteria' below.)

Imaging for pulmonary embolism (PE) – PE should be considered in individuals with ACS and progressive respiratory difficulty where the cause remains obscure, especially when there is rapid clinical deterioration with worsening hypoxemia and/or cardiac dysfunction [90]. Observational studies suggest that PE is not rare in individuals with ACS (17 percent in one series) [91]. Many patients with PE will not have a demonstrable DVT on leg imaging [30]. If PE is diagnosed, anticoagulation is appropriate. Diagnosis and management are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Additional testing in selected individuals — Additional testing may be indicated on a case-by-case basis depending on clinical suspicion and prior history:

Computed tomography pulmonary angiography (CT-PA) of the chest to evaluate for PE. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Electrocardiogram (ECG) and serial serum troponin levels to evaluate for myocardial damage. If myocardial damage is identified, it may indicate acute multiorgan failure syndrome, and transfusion may be required if not already administered [42,67]. (See 'Rapidly progressive ACS and multiorgan failure' above and 'Transfusion' below.)

Bronchoscopy with bronchoalveolar lavage (BAL) is invasive and not standard care. It is typically reserved for refractory disease or atypical presentations in which BAL would provide important information that would change management. (See "Basic principles and technique of bronchoalveolar lavage".)

Diagnostic criteria — ACS is defined by a new pulmonary density on chest imaging involving at least one complete lung segment and at least one of the following [68]:

Temperature ≥38.5°C

>3 percent decrease in SpO2 (oxygen saturation) from a documented steady-state value on room air

Tachypnea (per age-adjusted normal)

Intercostal retractions, nasal flaring, or use of accessory muscles of respiration

Chest pain

Cough

Wheezing

Rales

Pneumonia can formally be considered as meeting the criteria for ACS (the two cannot be reliably distinguished).

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes other pulmonary complications of SCD and other conditions that cause chest pain, respiratory distress, or densities on chest radiography. Pneumonia cannot be reliably distinguished from ACS on clinical grounds, nor does it need to be, as management is similar.

SCD complications

Vaso-occlusive pain – Vaso-occlusive pain often precedes ACS and can accompany or exacerbate ACS, especially in adults; the presence of vaso-occlusive pain does not eliminate the possibility of ACS. Isolated vaso-occlusive pain does not cause an infiltrate on chest imaging. However, chest wall pain in the ribs and sternum can occur during a pain episode and can cause splinting, which could lead to ACS.

Severe anemia or splenic/hepatic sequestration – Severe anemia or splenic/hepatic sequestration can accompany or complicate ACS; the presence of these findings does not eliminate the possibility of ACS. Like ACS, severe anemia or splenic or hepatic sequestration can cause dyspnea and in some cases chest pain. Unlike ACS, these complications do not cause an infiltrate on chest imaging.

Multiorgan failure syndrome – Multiorgan failure can accompany or complicate ACS; the presence of multiorgan failure does not eliminate the possibility of ACS. Exchange transfusions and respiratory support treat multiorgan failure and severe ACS.

Other causes of chest pain or respiratory distress

Rib fracture – Like ACS, rib fracture can cause acute chest pain. Unlike ACS, rib fracture is usually obvious on chest imaging.

Asthma – Asthma can accompany or exacerbate ACS, especially in children; its presence does not eliminate the possibility of ACS. Unlike ACS, asthma does not cause an infiltrate on chest imaging.

PE – Pulmonary embolism (PE) can accompany or exacerbate ACS, especially in adults; its presence does not eliminate the possibility of ACS. A history of recent surgery or immobility, or evidence of deep vein thrombosis (DVT) on leg ultrasound, supports the diagnosis of PE but does not eliminate ACS. Identifying a PE is important because anticoagulation is required, and anticoagulation is not a routine component of ACS management.

Pulmonary hypertension – Pulmonary hypertension is a chronic complication of SCD that can cause dyspnea and other findings, typically in adults. (See "Pulmonary hypertension associated with sickle cell disease".)

Heart failure/pulmonary edema – Like ACS, heart failure or pulmonary edema can cause dyspnea and infiltrates on chest imaging. Unlike ACS, heart failure and pulmonary edema do not typically cause chest pain, and the infiltrates respond to diuresis.

Myocardial ischemia/infarction – Cardiac ischemia can accompany, exacerbate, or complicate ACS, especially in older adolescents and adults; the presence of cardiac ischemia does not eliminate the possibility of ACS, and the presence of ACS does not eliminate the possibility of cardiac ischemia.

Presenting findings in acute myocardial infarction may differ in individuals with SCD. In a series of over 2 million admissions for acute myocardial infarction, in which SCD was reported in 501 (0.02 percent), the individuals with SCD were less likely to have risk factors for coronary artery disease and more likely to have comorbidities including pneumonia, respiratory failure or need for mechanical ventilation, and acute kidney injury or need for dialysis [92].

MANAGEMENT — Vigilance for ACS is important so that early and escalated interventions can be started without delay. (See 'High level of vigilance' above.)

Acute interventions — Prompt intervention for ACS is essential to prevent clinical deterioration and death [68]. Moderate to severe ACS is typically managed in the intensive care unit (ICU).

Pain control — Pain control should be immediate and analgesic dosing adequate to control pain, which can be severe. Assessment of pain control should be based on the patient's report (or family members/caregivers if needed). (See 'Examination' above.)

In addition to reducing pain, adequate analgesia can help reduce hypoventilation and atelectasis.

Details of pain management are presented in detail separately and summarized briefly here (see "Acute vaso-occlusive pain management in sickle cell disease"):

Pain control with parenteral opioids, typically delivered by patient-controlled analgesia (PCA), is generally required to treat ACS episodes in adults. Opioids are also appropriate for children with severe pain. Careful attention to dosing is required to avoid oversedation, hypoventilation, and atelectasis. PCA may minimize oversedation and hypoventilation while providing adequate pain control. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Continuous opioids/patient-controlled analgesia (PCA)'.)

Ketorolac is sometimes used briefly in children as a nonsedating analgesic in the acute setting but is often avoided in adults due to potential toxicities, including acute kidney injury. An example pediatric dose is 0.5 mg/kg intravenously (maximum dose 30 mg), followed by 0.5 mg/kg intravenously (maximum dose 15 mg) every six hours for up to three or five days, with close monitoring of kidney function. Other nonsteroidal antiinflammatory drugs (NSAIDs) should not be used concurrently. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Therapies we do not use'.)

Patients should be ambulated as soon as possible once adequate pain control is achieved.

Respiratory support — Respiratory support may include supplemental oxygen, non-invasive ventilation, or intubation and mechanical ventilation.

Monitoring – Careful monitoring of respiratory status in patients with ACS is essential to determine the best approach and react to changes in the patient's clinical status. The monitoring protocol should include scheduled semiquantitative assessments of the following:

Respiratory rate

Auscultation (air movement, wheezing, rales)

Use of accessory muscles of respiration

Mental status

Color and perfusion

Oxygen saturation by pulse oximetry (SpO2) and associated tissue hypoxemia, which may be more severe than indicated by SpO2

These assessments should be performed on a regular schedule (eg, every four hours), and an algorithm should be designed that alerts the treating team to a need for advanced level of care, advanced respiratory support to avoid need for mechanical ventilation, and to guide timing of transfusion therapy.

Vasoconstriction, hypotension, and hypothermia can also affect SpO2 values because the basis for these measurements is light absorbed from fingertip blood flow and the equation is derived from a hemoglobin dissociation curve based on hemoglobin A and not hemoglobin S [93]. Co-oximetry measures different types of hemoglobin and provides the most accurate measure of oxygen saturation in patients with SCD. Most arterial blood gas (ABG) analyzers in the United States use co-oximetry to measure oxygen saturation. We rarely obtain ABGs, unless there are comorbidities and extenuating clinical situations; ABGs may be appropriate in selected cases with clinical deterioration, significant respiratory distress, or signs of impending respiratory collapse. (See 'Laboratory testing' above.)

Oxygen – Supplemental oxygen should be provided to individuals with dyspnea and respiratory distress, and to maintain arterial oxygen saturation ≥95 percent or at the level of the patient's baseline SpO2. The value of ≥95 percent is based on clinical experience; 2014 guidelines on management of SCD recommend a value of >95 percent, based on low quality evidence [94].

It is important to use a higher target for SpO2 than is used for other patient populations, due to the SCD disease physiology and risk of other complications. An SpO2 <96 percent is associated with increased risk of stroke and vaso-occlusive pain. If the patient is known to have a steady state SpO2 <95 percent, a comparison to the baseline value is helpful. Typically an absolute change of more than 3 percentage points is considered clinically significant [95].

While SpO2 can be used as a guide, it does not always reflect true tissue oxygenation. ABG may be helpful in some cases, although it should not be used indiscriminately.

Calculated oxygen saturation is based on a normal oxyhemoglobin dissociation curve, while patients with SCD have a right-shifted curve due to the presence of hemoglobin S [95]. Local sickling can reduce tissue oxygenation significantly, and SpO2-derived measurements of hemoglobin oxygen saturation typically underestimate oxygen pressure [93,96]. Consequently, it may be appropriate to provide additional oxygen if there are signs of tissue hypoxia. Hypoxia promotes sickling, and local tissue hypoxia can worsen sickling in tissues with reduced perfusion.

If adequate oxygenation cannot be achieved with a face mask, noninvasive or invasive ventilation may be required, along with other interventions including exchange transfusion. (See 'Transfusion' below.)

Incentive spirometry – Incentive spirometry with 10 maximal inspirations, preferably supervised, should be encouraged at least every two hours while awake to prevent ACS in those admitted to the hospital with acute vaso-occlusive pain [97-99].

Noninvasive ventilation – For patients with rising oxygen requirements or decreasing respiratory effort, noninvasive ventilation may be useful, such as nasal mask continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) [47,100,101]. (See "Acute severe asthma exacerbations in children younger than 12 years: Intensive care unit management", section on 'Noninvasive positive pressure ventilation'.)

Intubation – Intubation is used for standard indications. In the National Acute Chest Syndrome Study Group (NACSSG) study, 13 percent of patients required mechanical ventilation for respiratory failure [2]. (See "Initiating mechanical ventilation in children" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit".)

For patients with respiratory failure and acute respiratory distress syndrome (ARDS), conventional or high-frequency oscillatory mechanical ventilation can be used. In intubated patients with persistent hypoxemia, bronchoscopy with suction and removal of bronchial casts has been reported to improve patient ventilation [102,103]. It is important to distinguish pure hypoxemic respiratory failure from a mixed hypercapnic-hypoxemic respiratory failure. (See "Acute respiratory distress in children: Emergency evaluation and initial stabilization" and "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)

ECMO – If mechanical ventilation is insufficient, extra corporeal membrane oxygenation (ECMO) may be used. Efficacy of ECMO in ACS has been described in case reports [104,105]. (See "Pediatric advanced life support (PALS)" and "Extracorporeal life support in adults in the intensive care unit: Overview".)

Bronchodilators — Bronchodilators are commonly used in ACS, especially for children, despite the lack of high-quality supporting evidence and absence of randomized trials [18,106]. Bronchodilators are used less frequently in adults, for whom wheezing is a less-common presentation. (See 'Typical presentation' above.)

Potential uses of a bronchodilator during an ACS episode include:

Wheezing, regardless of asthma history.

History of reactive airways disease or asthma, regardless of whether wheezing is currently present.

Progressive respiratory distress during an ACS episode.

In the NACSSG, bronchodilators were administered to 61 percent of participants during an episode of ACS; clinical improvement (defined as >15 percent increase in FEV1) was reported in 20 percent [2].

A review of bronchodilators in ACS among large pediatric hospitals in North America between 2005 and 2011 identified wide variation in bronchodilator use (0 to 97 percent) [107]. Overall, bronchodilator use was associated with a 13 percent increase in length of stay, however for the subgroup with asthma, bronchodilator use was associated with an 18 percent decrease in length of stay.

Antibiotics — All patients with ACS require broad spectrum antibiotics. Infection is one of the most common causes of ACS in children and affects a significant proportion of adults with ACS, and individuals with SCD are immunocompromised due to absent splenic function, placing them at risk of life-threatening sepsis, especially with encapsulated organisms.

Antibiotics should be administered immediately due to the risk of life-threatening infection [99]. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Risk of life-threatening infection'.)

Antibiotic selection depends on clinical severity and findings that suggest a specific organism:

Empiric antibiotic therapy for community-acquired pneumonia includes coverage for atypical bacteria, typically with a macrolide and a third generation cephalosporin [26,28]. A fourth-generation fluoroquinolone is another option [2]. These antibiotics cover typical organisms seen in ACS, including atypical bacteria (Chlamydia and Mycoplasma) along with S. pneumonia and Haemophilus influenzae. (See 'Common triggers' above and "Mycoplasma pneumoniae infection in adults" and "Pneumococcal pneumonia in patients requiring hospitalization".)

Example regimens for adults include:

Cefotaxime 1 to 2 grams intravenously every eight hours plus azithromycin 500 mg orally or intravenously once daily for seven days

or-

Moxifloxacin 400 mg orally or intravenously for seven days

Additional antibiotic options, considerations for individuals with fever and penicillin allergy (use of clindamycin), and concerns about ceftriaxone-induced hyperhemolysis are discussed separately. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Antibiotic selection'.)

For a severely ill individual with large or progressive pulmonary infiltrates, addition of vancomycin may be appropriate to cover bacteria that are resistant to cephalosporins, such as methicillin resistant Staphylococcus aureus (MRSA).

In the absence of severe or life-threatening pneumonia (S. aureus pneumonia), we generally treat for a total of 7 to 10 days. For patients treated with azithromycin, the duration is five days.

Acetaminophen should be prescribed at appropriate doses for fever.

Transfusion — Transfusion is considered the mainstay of therapy for ACS, despite an absence of high quality randomized trials demonstrating efficacy [108]. Transfusion therapy is used because it improves oxygenation [2,109,110].

In the NACSSG study, 72 percent of patients received transfusions (two-thirds of these were simple transfusions), and the partial pressure of oxygen while breathing room air increased from 63 mmHg before transfusion to 71 mmHg after transfusion [2]. Oxygen saturation increased from 91 to 94 percent. Simple and exchange transfusions resulted in similar improvements of oxygenation.

Decisions – The main decisions are:

When to use transfusion

Whether to use simple transfusion or red blood cell (RBC) exchange

What hemoglobin and percent Hb S to target

Indications – Transfusion is generally indicated for any individual hospitalized with ACS. The consequences of not transfusing can be disastrous. The most important risk factor for death is the rapidity of respiratory deterioration, regardless of the number of lobes involved. In our experience, prompt transfusion has decreased the progression from mild to moderate or severe ACS in many cases [77]. Exceptions in which transfusion may be deferred include patients who are stable without severe hypoxia or other indicators of clinical deterioration. If transfusion is deferred, close monitoring is needed so that any changes in clinical status are rapidly appreciated and acted upon.

Simple versus exchange transfusion – A reasonable approach to determining the type of transfusion is to evaluate and monitor clinical respiratory effort, hemoglobin oxygen saturation, and hemoglobin level [18,68].

Simple transfusion – Simple transfusion can be administered rapidly without the need for blood bank personnel or specialized equipment. The goal of simple transfusion is to increase the hematocrit to 30 percent or the hemoglobin to 10 g/dL, as a means of reducing sickling and improving oxygenation [111,112]. Caution should be used not to increase the hemoglobin above 11 g/dL due to the risk of hyperviscosity. Simple transfusion is appropriate for:

-Oxygen saturation <95 percent on room air.

-Hemoglobin <5 g/dL.

-Hematocrit or hemoglobin 10 to 20 percent below the patient's baseline.

-Decreasing hemoglobin or hematocrit during hospitalization.

-Clinical or radiological progression of disease without impending respiratory failure.

-As a temporizing measure while awaiting/preparing for exchange transfusion.

Exchange transfusion – Exchange transfusion allows transfusion of a large blood volume (6 to 8 units of RBCs in an adult) that can dramatically lower the percentage of Hb S and decrease vaso-occlusion without risking hyperviscosity. The goal of exchange transfusion should be to decrease the Hb S to <30 percent of the total hemoglobin concentration [111-113]. Exchange transfusion can be safely performed in individuals with ACS; one series described use of exchange transfusion in 53 ACS episodes (44 patients) without any complications [114].

Exchange transfusion is appropriate for individuals with:

-Previous history of severe ACS or cardiopulmonary disease.

-Multilobar disease (>1 lobe affected) on chest imaging.

-Rapidly progressive ACS or multiorgan failure syndrome.

-Progression of ACS despite simple transfusion.

-Severe hypoxemia (SaO2 ≤85 percent or PaO2 ≤55 mm Hg).

-Declining SpO2 readings despite increasing oxygen delivery, particularly if the declining oxygen saturation occurs over a brief period of several hours. In practice, we rarely obtain an ABG unless the patient is in the ICU and has an arterial line placed.

The capability to perform exchange transfusion varies by institution. If the patient is at a facility that does not have the ability to perform automated exchange transfusion, we highly recommend that consideration be given to transfer the patient to a facility that does have the capacity for automated exchange transfusion.

Additional comparisons between simple transfusion and exchange transfusion are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

Additional transfusion considerations (phenotypic and extended crossmatching, avoidance of donors with sickle cell trait) are also presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Transfusion techniques'.)

Fluid management — Hypervolemia in SCD is associated with prolonged hospitalization compared with euvolemia [115].

Fluids should be administered to prevent hypovolemia, as would be the case for any hospitalized patient. The typical regimen is 1.5 times maintenance fluids of D5 in one-half normal saline for the first 24 to 48 hours. Thereafter, the rate can be decreased as the patient begins to drink fluids. Euvolemia should be maintained using hypotonic oral and intravenous fluids with the rate of fluid administration adjusted to the clinical status and needs of the patient (more fluids needed if fever is present). (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Hydration'.)

Fluid balance should be monitored frequently to avoid fluid overload. Overhydration or rapid hydration should be avoided because they may result in pulmonary edema or heart failure. Furosemide may be helpful if fluid overload is suspected. Weights should be monitored daily along with intake/output for assessment of the fluid status and management of the patient.

Calculators are available to help estimate the daily fluid requirement (calculator 1) or the hourly requirement (calculator 2) in children. (See "Maintenance intravenous fluid therapy in children".)

VTE prophylaxis — ACS is an acute medical illness that predisposes patients to venous thromboembolism (VTE). All adults with ACS should receive VTE prophylaxis. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis' and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

We do not use routine thromboprophylaxis for VTE in hospitalized children <18 years of age with SCD unless there are predisposing risk factors. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis' and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

Glucocorticoids — The role of glucocorticoids for ACS remains unclear. We generally do not use glucocorticoids in children or adults with SCD, and glucocorticoids are not considered part of standard practice. An exception may be an individual with evidence of reactive airways disease or asthma exacerbation, or those with rapidly progressive ACS. If a glucocorticoid is used, it should be tapered to reduce the risk of rebound vaso-occlusion. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Asthma' and 'Rapidly progressive ACS and multiorgan failure' above.)

Clinical trials have reported mixed results regarding efficacy, and several have suggested possible increased risk of rebound vaso-occlusive complications:

A randomized trial that assigned 38 children hospitalized with a total of 43 episodes of mild to moderately severe ACS to receive intravenous dexamethasone or placebo [116]. The dexamethasone group had better outcomes, including a shorter median length of hospital stay (47 versus 80 hours), less clinical deterioration, less use of opioids, and less need for blood transfusion.

A retrospective study involving 5247 hospitalizations for ACS in children from 32 hospitals in the Pediatric Health information System database in the United States, glucocorticoid use was associated with a significantly longer length of hospital stay (25 percent, 95% CI 14-38 percent) and a higher three-day readmission rate (odds ratio [OR] 2.3, 95% CI 1.6-3.4) [117]. Children who received glucocorticoids were more likely to have asthma.

In a retrospective study involving 129 episodes of ACS in 65 individuals <22 years of age, use of glucocorticoids was associated with increased risk of readmission (OR 20, P <0.005) and longer hospitalization [118]. Readmission also correlated with other risk factors such as use of an inhaler or nebulizer at home. Another retrospective study in individuals treated with glucocorticoids for vaso-occlusive pain also reported an increased risk of rebound pain following treatment with a glucocorticoid [119].

Inhaled nitric oxide — Case studies have reported inhaled nitric oxide (iNO), a selective pulmonary vasodilator, improved ventilation/perfusion mismatch, and decreased pulmonary hypertension [120,121]. iNO also increases the oxygen affinity of Hb S, thus potentially decreasing sickling of RBCs [122]. However, a randomized trial from 2015 found no benefit from iNO in ACS, and we do not use this strategy [123].

Discharge planning and outpatient monitoring — Thoughtful discharge planning is essential to minimize the risk of ACS recurrence, which is high, as well as other chronic complications that may be less common but carry high risks of morbidity and even mortality. (See 'Risk of ACS recurrence' below and 'Long-term complications' below.)

A comprehensive, multidisciplinary approach between a hematologist and pulmonologist is ideal, especially if the individual has other lung disease besides ACS [33]. A baseline assessment may include evaluation for the following:

Sleep apnea

Asthma, especially in children

Other risk factors for pulmonary disease (smoking or second-hand smoke exposure)

Clinicians should be alert for evidence of airway hyperreactivity in patients with SCD and should pursue further testing of children with allergic symptoms and/or recurrent ACS [5].

All episodes of bronchospasm should be recognized early and treated promptly with bronchodilator therapy [7,9,11,124,125]. Appropriate controller therapy with inhaled glucocorticoids is also an important component of care. (See "An overview of asthma management" and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control" and "Trigger control to enhance asthma management" and "Asthma education and self-management" and "Acute asthma exacerbations in children younger than 12 years: Emergency department management".)

Monitoring of pulmonary status is also important, with periodic assessment of resting oxygen concentration by SpO2 and pulmonary function tests to assess for asthma. One approach is to obtain pulmonary function testing starting at age 6 years and repeated at five-year intervals (individuals without asthma or additional ACS episodes) or two to three-year intervals (individuals with a history of asthma or recurrent ACS) [5]. (See "Overview of the pulmonary complications of sickle cell disease".)

PREVENTION

Risk of ACS recurrence — Individuals who have had an episode of ACS have an increased risk for future episodes.

In a study involving 125 children ages 1 to 4 years with Hb SS or Hb S-beta0-thalassemia who were admitted to the hospital with ACS, 112 (90 percent) had at least one additional episode of vaso-occlusive pain or ACS [126]. Of these, 27 percent had a recurrence within 6 months, 63 percent within 1 year, and 79 percent within 2 years. The proportion taking hydroxyurea was not stated.

A retrospective study involving 264 children with Hb SS or Hb S-beta0-thalassemia in the Dallas Newborn Cohort demonstrated that ACS in the first three years of life significantly increased the odds of more frequent episodes of ACS during childhood (odds ratio 2.5; 95% CI 1.7-3.9) [127].

Incentive spirometry during hospitalization — Incentive spirometry has been examined as a measure to prevent ACS episodes in children with sickle cell disease (SCD) who were admitted to the hospital for a vaso-occlusive pain episode. Performing incentive spirometry using 10 maximal breaths every two hours while awake was associated with a significantly reduced rate of developing ACS versus no incentive spirometry (5 versus 42 percent) [98]. There have been no studies to determine the efficacy of incentive spirometry to prevent worsening of ACS. However, standard practice includes ongoing use of incentive spirometry when a patient is admitted to the hospital and develops ACS. (See 'Respiratory support' above.)

Outpatient interventions for prevention — Interventions to reduce the risk of further ACS episodes are a critical component of management. The key interventions are:

Prepare for therapy – For children at risk for ACS, practice use of a nasal mask when well (during a routine clinic visit) to make use of a nasal mask during treatment of acute ACS more familiar and less frightening.

Prevent infections

Provide prophylactic penicillin to children up to at least five years of age. (See "Overview of the management and prognosis of sickle cell disease", section on 'Prophylactic penicillin'.)

Administer age-appropriate vaccines in all age groups. (See "Overview of the management and prognosis of sickle cell disease", section on 'Immunizations'.)

Optimize lung health – Children and adults with multiple episodes of ACS are typically evaluated for asthma symptoms and atopy, and, if present, environmental preventive strategies and asthma therapies are instituted. (See "An overview of asthma management".)

Asthma treatment involves establishing care with a pulmonologist. (See 'Discharge planning and outpatient monitoring' above.)

For adults with recurrent wheezing and repetitive ACS, there is no evidence-based strategy. Adults with SCD rarely have asthma, and there is not strong evidence that inhaled glucocorticoids affect outcomes.

Although baseline daytime pulse oximetry (SpO2) does not predict vaso-occlusive pain or ACS, children with suspected nocturnal hypoxemia (oxygen saturation <93 percent by SpO2) and/or prior history of ACS should be considered for polysomnography studies [22,47,128].

Reduce vaso-occlusion

Hydroxyurea is indicated for all individuals with Hb SS or Hb S-beta0-thalassemia and individuals with other SCD syndromes who have vaso-occlusive complications. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

Consider chronic transfusions if response to hydroxyurea is inadequate. In patients who are recovering from a life-threatening ACS, a six-month transfusion regimen with transition to hydroxyurea therapy is often used. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Acute chest syndrome treatment and prevention'.)

Consider other disease-modifying therapies (crizanlizumab, L-glutamine) if the response to hydroxyurea is inadequate. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Options if hydroxyurea is not tolerated or ineffective in individuals with Hb SS or Hb S-Beta(0)-thalassemia'.)

Perioperative period – Careful perioperative management, including appropriate presurgical transfusion support and postoperative pulmonary care can minimize risk; details and supporting evidence are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.)

Supporting evidence for prevention

Hydroxyurea – Multiple randomized trials have demonstrated that hydroxyurea markedly decreases the frequency of ACS in children and adults [129-134]. Despite this, hydroxyurea is under-used [135]. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

Hydroxyurea should be administered by experienced clinicians who can provide informed counseling about the risks and benefits, appropriate dose-titration, and close monitoring for potential toxicities. (See "Hydroxyurea use in sickle cell disease", section on 'Administration and dosing' and "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'.)

Transfusion – Transfusion therapy is an effective intervention for the prevention of recurrent ACS, especially if hydroxyurea is insufficiently effective [136,137]. Therapy can be short-term (<6 months) or long-term (>6 months). Short-term transfusion therapy can be used during high risk periods for ACS (winter months with increased frequency of respiratory illnesses) or during the transition to hydroxyurea therapy.

For individuals who have had two or more episodes of moderate to very severe ACS in the past 24 months despite maximal hydroxyurea therapy, we may consider chronic exchange transfusions (manual or via erythrocytapheresis). This strategy is rarely used in pediatrics. In one of the contributors' (MDB) center with 300 children and adolescents, there was no case requiring regular blood transfusion to prevent ACS in the last decade, and in 250 adults, only one individual required regular transfusions.

For transfusion therapy to attenuate ACS episodes, it should be done every four to six weeks to maintain a hemoglobin S (Hb S) percentage <50 percent and continued for one to two years. The upper limit for Hb S of <50 percent is less stringent than that used to treat acute ACS events or for primary or second stroke prevention. Decision-making, supporting evidence, technical considerations, and risks (infection, iron overload, allosensitization, transfusion reactions) are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques" and "Transfusion in sickle cell disease: Management of complications including iron overload".)

Other pharmacologic therapies – L-glutamine was approved by the US Food and Drug Administration in 2017. A randomized trial demonstrated that in patients five years of age and older, L-glutamine decreased the incidence of ACS, especially in children [138]. Two-thirds of study participants were also taking hydroxyurea. Although L-glutamine and crizanlizumab do not have sufficient evidence to determine efficacy for preventing ACS, we will consider using them in some cases, as they are effective in reducing pain episodes, and vaso-occlusive pain precedes a significant number of ACS episodes. Voxelotor also did not have enough evidence to evaluate efficacy in preventing ACS, but voxelotor did not reduce pain in a randomized trial and thus would be less optimal as a preventive therapy for ACS. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Options if hydroxyurea is not tolerated or ineffective in individuals with Hb SS or Hb S-Beta(0)-thalassemia'.)

Hematopoietic stem cell transplantation – For patients who have experienced multiple life-threating ACS events and who have an HLA-matched sibling donor, hematopoietic stem cell transplantation is an alternative. While potentially curative, it is not standard practice due to the high toxicity associated with myeloablative regimens. Decision-making, choice of transplant techniques, and supporting evidence is presented separately. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

LONG-TERM COMPLICATIONS

Pulmonary hypertension (PH) — Limited evidence suggests that repeated ACS episodes are associated with the development of restrictive lung disease (previously referred to as chronic sickle cell lung disease). (See "Overview of the pulmonary complications of sickle cell disease".)

The contribution of ACS to the development of PH, if any, is more difficult to discern, especially when different definitions for PH have been used across studies [139-142]. In a study of 195 adults with SCD, elevated tricuspid jet velocity (≥2.5 meters/second), a surrogate for an elevated pulmonary artery pressure, was not associated with repeated ACS episodes [143]. (See "Pulmonary hypertension associated with sickle cell disease".)

All individuals with SCD should have baseline pulmonary function tests (PFTs) and periodic spirometry to monitor for restrictive and obstructive pulmonary disease. In a study of 40 children with SCD in which half had ACS episodes and half did not, those who had an episode of ACS were more likely to have abnormal PFTs (increase in mean airway resistance, total lung capacity, and residual volume) [13]. Additional testing including polysomnography or overnight pulse oximetry may also be useful in selected individuals. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

Risk of death — In older studies, prior to established clinical guidelines for ACS management and use of hydroxyurea, conjugated pneumococcal vaccines, penicillin prophylaxis, and transfusion therapy for acute treatment, ACS was a leading cause of death in SCD, accounting for one-fourth of deaths in some series [144,145]. In the National Acute Chest Syndrome Study Group study, 3 percent of the patients died; all had received mechanical ventilation for respiratory failure [2]. The most common causes of death included pulmonary emboli and infectious bronchopneumonia. In a report from the Cooperative Study of Sickle Cell Disease, the death rate in patients with ACS is 1.1 percent in children and 4.3 percent in adults [27].

In the modern era, ACS is a rare cause of death in children and less common cause of death in adults. In a retrospective cohort study of children and adults with SCD from two medical centers, there were no deaths in children; death occurred only in adults with rapidly progressive ACS (in 6.3 percent) [69]. Prospective studies have demonstrated that death in children is very unlikely but the risk has not been eliminated [146]. Rapidly progressive ACS in adults remains a risk factor for death and requires timely clinical intervention with automated exchange transfusion, respiratory support, and monitoring for other organ injury with appropriate interventions. (See 'Management' above.)

Routine use of hydroxyurea may decrease the rates of ACS and ACS mortality. (See "Hydroxyurea use in sickle cell disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias" and "Society guideline links: COVID-19 – Index of guideline topics".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

Definition and triggers – Acute chest syndrome (ACS) is defined as a new radiodensity on chest imaging with fever and/or respiratory symptoms in an individual with sickle cell disease (SCD). Infection is a common trigger in children; in adults, hospitalization for vaso-occlusive pain is common. The table summarizes these and other differences (table 1). Other triggers include pulmonary infarction, fat embolism, and asthma. (See 'Definitions and pediatric-adult differences' above and 'Common triggers' above.)

Incidence – Approximately 50 percent of individuals with SCD will have an ACS episode, children more commonly than adults. The peak incidence in children is two to four years. (See 'Epidemiology' above.)

Clinical – Severity is variable. Common findings include fever, pain (chest, extremities, ribs), dyspnea, and neurologic symptoms. Adults tend to have severe disease and can develop respiratory compromise, respiratory failure, and multiorgan failure. (See 'Clinical features' above.)

Evaluation – Vigilance is required, especially in individuals with SCD hospitalized for any reason. Standardized assessment protocols improve outcomes. Pulse oximetry is important but may underestimate tissue hypoxia. Laboratory testing and chest imaging should be done promptly. Evaluation for pulmonary embolism (PE) and cardiac ischemia may be appropriate. (See 'Diagnostic evaluation' above.)

Diagnosis – A new radiodensity on chest radiography plus fever or respiratory symptoms is confirmatory. The differential diagnosis includes vaso-occlusive pain, severe anemia, multiorgan failure, rib fracture, asthma, PE, pulmonary hypertension, heart failure, and cardiac ischemia. These conditions can accompany or trigger ACS. (See 'Diagnostic criteria' above and 'Differential diagnosis' above.)

Immediate management – ACS can be fatal. All patients require urgent attention to:

Pain control – Opioids are typically required, especially for adults. (See 'Pain control' above and "Acute vaso-occlusive pain management in sickle cell disease".)

Oxygenation – We suggest maintaining a target oxygen saturation ≥95 percent (Grade 2C). Some individuals may require noninvasive or invasive ventilation. (See 'Respiratory support' above.)

Antibiotics – Antibiotics are used regardless of whether fever is present. We suggest empiric therapy for community-acquired pneumonia (a macrolide plus a third generation cephalosporin) (Grade 2C). Vancomycin may be added for severe disease, and other antibiotics may be reasonable if fever is absent. (See 'Antibiotics' above.)

Transfusions – Most individuals with ACS, especially adults, should receive transfusions. We recommend urgent exchange transfusion for individuals with clinical deterioration and multiorgan failure (Grade 1C). We also suggest transfusion (simple or exchange) for stable patients not requiring significant respiratory support (Grade 2C). The type of transfusion (simple versus exchange) and target hemoglobin and hemoglobin S percentages are discussed above and separately. (See 'Transfusion' above and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Supportive care – As needed supportive care includes fluids and venous thromboembolism (VTE) prophylaxis. Incentive spirometry should be used while awake. (See 'Fluid management' above and 'Bronchodilators' above and 'VTE prophylaxis' above.)

Prevention – Recurrence risk is high; thoughtful discharge planning helps minimize risk. Preventive interventions include vaccinations, penicillin for young children, asthma medications, and SCD controlling therapies (hydroxyurea, perioperative transfusion, chronic transfusion for some individuals). (See 'Discharge planning and outpatient monitoring' above and 'Prevention' above and 'Long-term complications' above.)

ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of the pediatric sections of this topic review.

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Topic 16353 Version 44.0

References

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