OAKLAND, CALIF--Until recently, surprisingly little has been known about the causes--or the optimal management--of acute chest syndrome in patients with sickle cell disease. A new study now provides a significant advance in our understanding of acute chest syndrome. For the first time, researchers have definitively documented the causes in a large number of these cases. This has enabled investigators to identify the most effective treatments for the syndrome.

These advances are the result of a seven-year, 30-center study of 671 acute chest syndrome episodes in 538 children and adults with sickle cell disease.[1]

Fat embolism and infection, especially community-acquired pneumonia, most often precipitated acute chest syndrome in these patients. However, their oxygenation status often significantly improved after they were given a standardized treatment protocol, which incorporated bronchodilators and blood transfusions (Table 1). Moreover, most of those who were ventilator-dependent due to respiratory failure recovered with aggressive application of these interventions.

Acute chest syndrome is the primary cause of death in sickle cell disease, said lead study author Elliott P. Vichinsky, MD, Chief of Hematology-Oncology at Children's Hospital in Oakland, Calif.[2-4] Application of the study findings could therefore dramatically improve survival in sickle cell patients, he told PULMONARY REVIEWS.

Patients included in the study had to have a hemoglobin SS, SC, or SS-ß-thalassemia phenotype. They also had to have chest pain, a temperature above 38.5°C, tachypnea, wheezing, or cough. In addition, a chest film had to show a new pulmonary infiltrate involving at least one complete lung segment (this was used to establish the presence of the acute chest syndrome). The pulmonary infiltrate had to be consistent with alveolar consolidation but not atelectasis.

Once admitted into the study, all patients had blood samples taken for culture (before treatment, if possible); these samples were collected during the acute phase of illness and again during convalescence, with a median interval of 48 days between samples. Patients also underwent bronchoscopy, tracheal aspiration, or aerosolized saline inhalation to permit collection of specimens for aerobic and anaerobic cultures and for a fat embolism assay.

Bronchial and nasopharyngeal samples were used for viral and mycoplasma cultures. For a subgroup of patients, pairs of serologic specimens and bronchoscopic or sputum samples were sent to a laboratory to be cultured for chlamydia and tested for chlamydia antibodies.

FINDING THE CAUSE

About half the patients, noted Dr. Vichinsky, were admitted not for acute chest syndrome, but for a sickle pain crisis. In these patients, the acute chest syndrome usually developed a couple of days postadmission. "Pain crisis," he explained, "was a prodrome for acute chest syndrome; in patients with fat embolism, for example, the embolism first injured the bone, causing necrosis, and then went to the lung."

In fact, fat embolism was the most common cause of acute chest syndrome among study subjects, accounting for nearly 9% of the episodes. Other leading causes were chlamydia (7.2%), mycoplasma (6.6%), viral (6.4%), other bacterial (4.5%), and mixed (3.7%) infections. Some patients had multiple infectious pathogens or a fat embolism in combination with an infection.

Of the 27 pathogens isolated, Chlamydia pneumoniae was the most common; it appeared in 71 acute chest syndrome episodes. The next most common were Mycoplasma pneumoniae (51 episodes), respiratory syncytial virus (26 episodes), and coagulase-positive Staphylococcus aureus (12 episodes). Smaller numbers of episodes involved various other pathogens, such as Streptococcus pneumoniae, M hominis, parvovirus, rhinovirus, parainfluenza virus, and Haemophilus influenzae.

Overall, a cause was identified in 256 (38%) of the acute chest syndrome episodes. However, "after the exclusion of episodes with incomplete data, a specific cause was identified in 70% of episodes," the authors indicated.

HIGHLY SUCCESSFUL TREATMENTS

The mean length of hospitalization was 10.5 days. The clinical course was often characterized by multilobar (especially lower lobe) involvement and effusion. All patients were given antibiotics and, on average, became afebrile after two days of hospitalization.

Transfusion, either simple or with phenotypically matched red cells, was required in 72% of patients (mean number of transfusions, 1.6; mean units, 3.2). It significantly improved oxygenation, increasing the mean arterial oxygen tension on room air from 63 mm Hg before transfusion to 71 mm Hg after.

The mean oxygen saturation also rose with transfusion, from 91% to 94%. This improvement was even greater--from 86% to 93%--in a separate analysis limited to patients with hypoxia (defined as an oxygen saturation below 91%). "We proved for the first time that transfusion has an immense impact on acute chest syndrome in sickle cell disease," Dr. Vichinsky emphasized.

Sixty-one percent of the patients received bronchodilators, which produced improvement in 20% of recipients. Improvement was defined as a 15% increase in forced expiratory volume in one second.

Thirteen percent of the subjects required mechanical ventilation (mean duration, 4.6 days) for respiratory failure, which was typically accompanied by multiorgan failure. "With aggressive treatment, meaning very aggressive transfusion and bronchodilator therapy, about 80% of these ventilator-dependent patients survived," said Dr. Vichinsky. That survival rate is much higher than usual in such cases, and it supports the concept that physicians "should be very aggressive with these patients and not give up," he asserted.

The frequency of complications correlated with age. Patients age 20 years and older were most likely to have complications, whereas children under the age of 10 were least likely. Complications most often included vaso-occlusive events, abdominal pain, pulmonary events (including respiratory failure), and neurologic events (eg, mental status changes).

The incidence of respiratory failure was particularly high (46%) in patients with neurologic complications. "The mechanism most likely involves sudden decreases in oxygenation in the vascular bed of the central nervous system," the study authors explained.

Eighteen patients died. In six patients, the primary cause of death was fat, bone marrow, or thrombotic pulmonary emboli; bronchopneumonia was responsible in another six cases. In the remaining subjects, the primary causes of death were pulmonary hemorrhage, cor pulmonale, hypovolemic shock caused by splenic sequestration, sepsis, intracranial hemorrhage, and seizure. Infection contributed to 10 of the deaths.

RECOMMENDATIONS

To minimize acute chest syndrome-related lung injury in sickle cell patients, the authors recommend prophylactic vaccination against influenza, pneumococci, and possibly respiratory syncytial virus. Broad-spectrum antibiotics, including a macrolide, should be given immediately if a diagnosis of acute chest syndrome is made, because chlamydia and mycoplasma infections are so often present. Because airway hyperreactivity should be assumed in acute chest syndrome, bronchodilators are usually required even if the patient is not wheezing.

"Transfusion therapy should be used aggressively and early," added Dr. Vichinsky. This may even save ventilator-dependent patients, he pointed out, and prevent acute chest syndrome from progressing in high-risk patients, such as the elderly.

--Timothy Begany

References
1. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342:1855-1865.
2. Vichinsky EP. Comprehensive care in sickle cell disease: its impact on morbidity and mortality. Semin Hematol. 1991;28:220-226.
3. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 1994;84:643-649.
4. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330: 1639-1644.

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