The symptom complex may be varied, and not all symptoms are present in every episode; however, some combination of these symptoms is required for this "diagnosis." The ACS is a common complication of the sickling disorders (Hb SS, Hb SC, Hb S ß+-thalassemia, Hb S ß0-thalassemia, etc.) and is responsible for considerable morbidity and mortality in these patients(1,2).
Recent data from the Clinical Course of Sickle Cell Disease Cooperative Study indicate that this complication occurs with an incidence of 10,500/100,000 patients/year(2). ACS occurs most often as a single episode, but certain patients have multiple episodes. A past history of an ACS is associated with early mortality compared to those who have never had an episode. The disorder is most common in the 2 to 4 year age group and gradually declines in incidence with age. It is believed that Hb F exerts a protective effect on those less than 2 years of age. Furthermore, the decline observed in older age groups is partially related to at least two other factors: (a) excess mortality in the group which had an ACS, and (b) fewer viral episodes in adults due to acquired immunity.
The incidence of ACS is related to genotype, where Hb SS = Hb S ß0-thalassemia > Hb SC = Hb S ß+-thalassemia. Additional data showed that a lower hematocrit or a higher Hb F was associated with a reduced incidence, whereas a high WBC was associated with a higher incidence. Other data indicate that recurrent episodes of ACS can lead to chronic lung disease; the resulting hypoxia is associated with the onset of osteonecrosis in multiple sites and with sudden death due to myocardial infarction(3).
The causes of the ACS are multiple; thus, the terminology "ACS" does not indicate a definite diagnosis but reflects the clinical difficulty of defining a distinct etiology in the majority of such episodes. The causes of the ACS include those disorders directly or indirectly related to the sickling process, as well as causes distinct from sickling.
| Direct consequences of Hb S | Indirect consequences of Hb S | ~|
| pulmonary infarction - in situ sickling fat embolism syndrome hypoventilation secondary to rib/sternal bone infarction hypoventilation secondary to narcotic administration pulmonary edema induced by narcotics or fluid overload |
Infections: bacterial viral fungal protozoan |
fibrin thromboembolism foreign body/intrinsic bronchial obstruction opportunistic infection related to HIV-1 infection acute sarcoidosis other common pulmonary diseases (e.g., aspiration, trauma, asthma, etc.) |
Recent studies in SCD show similar findings. Poncz et al. (7) studied 102 episodes of ACS in 70 patients, using careful culture techniques, and found that they could document bacterial infection in only 12 episodes. The single most common cause was mycoplasma (16%), and viral disease at 8% was almost as frequent as the common bacterial agents. In 66% of the episodes, no etiology was established. Nearly identical findings were seen by Sprinkle et al. (8). The report of fulminant mycoplasma pneumonia in the normal population(9) is worrisome for those with sickle cell disease(10). On the other hand, in Curacao(11), 43% of sputum cultures were positive in 81 episodes seen in 53 patients. The most common bacterium was H. Influenza. Both S. aureus and Klebsiella pneumoniae were more common than S. pneumoniae. Other reports have stressed the evolving importance of Chlamydiae pneumoniae and legionella; even tuberculosis, cryptococcus and cytomegalovirus have been reported in SCD. Viral agents causing ACS include influenza, respiratory syncytial virus, CMV, parvovirus, adenovirus, and para influenza. Prophylactic penicillin, Pneumovax and HiB vaccination may contributed to the changing epidemiology for SCD.
However, all studies stress the fact that the majority of ACS episodes cannot be proved to be of infectious origin, and non-infectious causes must be sought very carefully. Vichinsky et al. (12) recently published a study in which 12 of 27 episodes of ACS had evidence for fat embolism as the cause. This is the first documentation of a high frequency for fat embolism in the ACS. The preliminary result from the Multi-Institutional Study of Hydroxyurea in SCD, indicating a significant reduction in ACS in those on hydroxyurea, suggests that a substantial number of ACS episodes are secondary to vascular obstruction(13). Thus our focus on infection as the pre-eminent problem may have been misplaced. Currently, a cooperative study is attempting to establish the relationships among all of the causes of ACS listed in Table 1.
Serial chest x-rays are needed to assess the extent and course of the pulmonary changes. However, serial arterial blood gas determinations on an FiO2 of 0.21 provide a clearer picture of ongoing pulmonary function as the chest x-ray often lags physiologic events. Arterial blood gas measurements can be replaced by pulse oximetry, especially if there have been simultaneous determinations in the patient so as to establish the correlation between the two. Oxygen saturation and/or the alveolar-arterial oxygen gradient, rather than oxygen tension, provide more relevant information(19). Careful attention to clinical parameters (vital signs, respiratory effort, overall status) is a key ingredient in assessment.
The mainstay of successful treatment is high quality supportive care. Consultation with pulmonary, infectious disease and intensive care specialists is a necessary part of management. Fluid management, oxygenation, chest physiotherapy, bronchodilators, and intermittent incentive spirometry are essential elements of management in the absence of a specific therapy that consistently ameliorates clinical course.
On the other hand, exchange transfusion should be given promptly whenever there is evidence of clinical deterioration. Exchange transfusion has the obvious benefit of replacing sickle cells with normal cells and preventing further sickling induced damage to the lungs or other organs, while providing better oxygen carrying capacity. The indications for exchange transfusion in the ACS have not been fully defined but include poor pulmonary function as evidenced by:
In addition to these indications, exchange transfusion may have a specific therapeutic action in the FES where normal red cells may bind the free fatty acids, preventing further pulmonary damage. Finally, exchange should be considered whenever there is general clinical evidence of a declining course. The objective of transfusion in these situations is life-saving, since progressive worsening of clinical status is associated with high mortality. Exchange transfusion should be done early in the course so that it has prophylactic benefit rather than late when the patient is clearly moribund.
Transfusion carries three risks that are particularly relevant to the sickle cell patient: transmission of viral disease, allo-immunization and acute hyperviscosity. Evidence for hepatitis B infection has been found in 20% of these patients(20), while the data for hepatitis C indicate that the prevalence may be as high as 60%. Cirrhosis due to chronic active hepatitis B or C may be combined with hemosiderosis in these patients. Allo-immunization data from the pre-operative transfusion study indicate a 10% rate of new allo-antibody formation from a transfusion intervention (Vichinsky E, personal communication, 1995). Subsequent transfusion therapy has an increased risk of delayed hemolytic transfusion reaction; such reactions are extremely difficult to treat since further transfusion is usually ineffective in maintaining the hematocrit. An extended phenotype match can reduce the incidence of allo-immunization(21). The hyperviscosity syndrome may occur with mixtures of A and S cells at near normal hematocrits(22). The syndrome is characterized by hypertension and altered mental status and/or seizure activity. Screening donor units for sickle cell trait and maintaining the post transfusion hematocrit at levels less than 35% may prevent this syndrome.
It is widely believed that a post transfusion level of hemoglobin S less than 10% is therapeutically superior to one of 20% or 30%. While data in support of this contention is lacking, the hypothesis is intuitively attractive. The simplest method of monitoring the post transfusion hemoglobin S level is by determining the percentage of sickled cells in a meta-bisulfite preparation. Alternatively, hemoglobin S can be measured by one of the common column chromatography methods.
