How is Sickle Cell Diagnosed and Treated?

The acute chest syndrome (ACS) is an acute pulmonary illness that occurs in patients with sickle cell disease. ACS is currently defined as a new infiltrate on chest radiograph in conjunction with one other new symptom or sign: chest pain, cough, wheezing, tachypnea, and/or fever (Platt, 2000). The term acute chest syndrome was first suggested in 1979 by Charache et al (1979) and was developed to reflect the unique nature of acute pulmonary illness in patients with sickle cell disease. ACS can be caused by a variety of mechanisms, both infectious and noninfectious. Diagnostic considerations and treatment modalities are not typical of any other specific pulmonary illness experienced by the general population. Additionally, the typical course, possible complications, and outcomes are unique. For these reasons, the terminology persists and remains useful for both research purposes and effective clinical communication. As a leading cause of hospitalization and death in adults with sickle cell disease, the importance of ACS in sickle cell patients cannot be overstated (Hassel et al., 1994). Emergency physicians, family practitioners, pediatricians, internists, and hematologists who encounter these patients on a regular basis have the potential to prevent significant morbidity and mortality through early recognition and aggressive treatment of ACS.

Epidemiology

The incidence of ACS in patients with homozygous sickle cell disease is 12.8 episodes per 100 patient years (Castro et al., 1994). Incidence is inversely related to age, with children aged 2 through 4 years having the highest incidence (25.3 episodes/100 patient-years). ACS is associated with all genotypes but occurs most frequently in patients homozygous for the disease. Hematologic risk factors for the development of ACS include a high steadystate leukocyte count, low steady-state hemoglobin F concentration, and a high steady-state hemoglobin level (Castro et al., 1994). The risk for developing an ACS episode appears to be increased following surgery, with an average time for development of ACS of 3 days postsurgery (Vichinsky et al., 1995). Children often have a febrile episode preceding the event and are more likely to have an episode in the winter. Finally, both children and adults frequently have a painful event preceding the development of ACS (Vichinsky et al., 1997).

Infection has long been recognized as a cause of ACS. Initially Streptococcus pneumoniae was considered the most common infectious agent (Barrett-Connor 1971, 1973) but subsequent research has consistently reported lower rates of pneumococcal disease (Hassel et al., 1994; Sprinkle et al., 1986;  Kirkpatrick et al., 1991).  Chlamydia pneumoniae and Mycoplasma pneumoniae are now the most common documented infectious causes of ACS (Vichinsky et al, 2000). Other viral and bacterial organisms that have been linked to ACS include Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoniae, adenovirus, influenza viruses, parainfluenza viruses, respiratory syncytial virus, parvovirus B19, and cytomegalovirus (Vichinsky et al., 2000).

Pulmonary vascular occlusion has long been suspected as a cause of ACS, but its exact role remains unclear. It was first considered as a cause of ACS after alveolar wall necrosis, pulmonary arterial thrombosis, and pulmonary infarction were found on postmortem evaluations (Haupt et al., 1982; Thomas et al., 1982). Further supporting evidence was provided by perfusion defects identified during ACS by computed tomography, angiography, and nuclear ventilation and perfusion scans (Bhalla et al., 1993; Lisbona et al., 1997). Although pulmonary vascular occlusion by in situ thrombosis and thromboembolism might account for some of these perfusion defects, current evidence suggests that many of these defects are due to fat emboli (Hassell et al., 1994; Vichinsky et al., 2000; Naprawa et al., 2005) that originate from bone marrow that becomes infarcted during vaso-occlusive crises. Reduced blood flow to bone marrow during these crises can cause painful ischemia and necrosis of the marrow, and necrotic pieces of marrow that break loose can become emboli. Postmortem studies have found fatty necrotic bone marrow in the pulmonary vasculature (Haupt et al, 1982). Additionally, some studies have noted clinical similarities between the fat emboli syndrome of trauma patients and ACS and have used this as supportive evidence (Levy, 1990). More recent investigation has identified fat droplets within cells recovered by bronchoscopy with bronchoalveolar lavage, confirming an association between fat embolism and ACS (Vichinsky et al., 1994, 2000). Finally, increased serum levels of free fatty acids and the enzyme secretory phospholipase A2 that occur during the syndrome are similar to the levels seen in the fat emboli syndrome (Naprawa et al., 2005).

Another likely cause of ACS is infarction of the ribs and other bones of the thorax. Infarction has been documented during sickle cell vaso-occlusive crisis and ACS by nuclear medicine techniques, and these infarctions are often in proximity to infiltrates on chest radiograph (Bellet et al, 1995). It is proposed that bone infarction during vaso-occlusive crisis leads to localized splinting, atelectasis, radiographic infiltrates, and ACS.

The clinical presentation of ACS varies, with the most common symptoms in all age groups being fever, cough, and chest pain (Vichinsky et al., 2000). Other less common presenting symptoms have been documented, including shortness of breath, productive cough, wheezing, and hemoptysis. The symptoms appear to be age-related, with fever and cough occurring most commonly in children and becoming less common with increasing age. Chest pain, shortness of breath, and chills, on the other hand, are less common in childhood and become more common with increasing age. Tachycardia, tachypnea, and hypoxia are variably seen on presentation. The most common physical examination finding is rales, but notably, the second most common finding is a normal physical examination. Furthermore, no clinical finding is predictive of the degree of hypoxia. The presenting symptoms in a patient’s first event are predictive of symptoms during subsequent events. Notably, up to 50% of patients diagnosed with ACS are initially admitted to the hospital for other reasons and subsequently develop the disease. The reason for admission in these cases is most often vaso-occlusive crisis. The average time to development of ACS after hospitalization is 2.5 days (Vichinsky et al., 2000).

Explore Treatments

Other terms for Avascular Necrosis (AVN): osteonecrosis, bone infarction, aseptic necrosis, ischemic bone necrosis

A disease where there is a lack of blood supplied to bone tissue, resulting in cell death and bone collapse. It can also affect joints, with destruction of the articular cartilage surfaces causing arthritis. AVN primarily affects the shoulder, knee and hip joints.

As many as 50% of people with SCD may be chronically affected by AVN, especially in the hip or shoulder. Eight out of ten people with SCD and AVN have it in both the hip and shoulder. The jaw and spine can also be affected in people with SCD. AVN in the hip is more common in SCD patients from Kuwait, Africa, the Mediterranean and the USA (Marti-Carvajal et al., 2010).

Diagnosis

Pulmonary hypertension can be caused by:

The formation of gall stones is one complication of sickle cell disease. Historically, the standard treatment was to remove the gall stones to avoid bile duct occlusion. In Jamaica, Dr. Graham Serjeant conducted a pioneering study to determine whether leaving otherwise asymptomatic gall stones would yield better clinical outcomes. The study showed that patients who had not undergone invasive surgery to remove the gall stones had less mortality and morbidity than their counterparts who had their gall stones removed. Currently, the treatment for gall stones in Jamaica and across the world is to leave gall stones unless they become symptomatic.

Malaria

The parasites within the hepatocytes transform into a new entities called “schizonts”. The nuclear genetic material in the schizonts replicates to the point that the hepatocytes are totally filled with new forms called “merozoites”. A single schizont can produce thousands of merozoites. Erumpent hepatocytes release the merozoites into the bloodstream where they invade circulating red cells. After penetrating the red cells, the merozoites assume a ring form called trophozoites. These organisms consume the hemoglobin in the red cells and enlarge until they fill the cell completely. During their growth, the trophozoites metamorph into schizonts and produce new merozoites inside the red cells. The red cells subsequently lyse and release merozoites that can penetrate new red cells and restart the pernicious process.

Some of the trophozoites in the red cells take a different developmental pathway and form gametocytes. Gametocytes are the sexual form of the parasite and do no lyse the red cells. A mosquito taking a blood meal from a person whose red cells contain gametocytes acquires the malarial parasite. The sexual reproduction cycle then begins in the mosquito. The mosquito subsequently transmits the parasite when it attacks another human host.

Host immunity is crucial to survival of people infected with the malaria parasite. This is particularly true with respect to the nocuous falciparum parasite. The immune system works best when it has been primed against the invader. Children who suffer their first or second bout of malaria have not developed the immune response needed to provide adequate defense against the parasite. This explains in part the high mortality seen in children infected with P. falciparum. Vaccines are a common way of achieving host immunity prior to pathogen exposure. Polio immunization is a well-known example. Unfortunately, the malarial parasite constantly changes its immune makeup, making it difficult to produce an effective vaccine.

The sickle trait (heterozygous) provides a survival advantage over people with normal hemoglobin in regions where malaria is endemic, however, the trait provides neither absolute protection nor invulnerability to the disease. Rather, people (and particularly children) infected with P. falciparum are more likely to survive the acute illness if they have sickle cell trait. When people with sickle cell trait procreate, both the gene for normal hemoglobin and that for sickle hemoglobin are transmitted to the next generation.

The genetic selective scenario in which a heterozygote for two alleles of a gene has an advantage over either of the homozyous states is called “balanced polymorphism”. A key concept to keep in mind is that the selection is for sickle cell trait. A common misstatement is that malaria selects for sickle cell disease. This is not true. A person with sickle cell disease is at an extreme survival disadvantage because of the ravages of the disease process. This means that a negative selection exists for sickle cell disease. Having the sickle cell trait is the genetic condition selected for in regions of endemic malaria. Sickle cell disease is a necessary consequence of the existence of the trait condition because of the genetics of reproduction. The precise mechanism by which the sickle cell trait imparts resistance to malaria is unknown. A number of factors likely are involved and contribute in varying degrees to the defense against malaria.

Red cells from people with the sickle trait do not sickle to any significant degree at normal venous oxygen tension. Very low oxygen tensions will cause the cells to sickle, however. For example, extreme exercise at high altitude increases the number of sickled erythrocytes in venous blood samples from people with the sickle cell trait (Martin, et al., 1989). Sickle trait red cells infected with the P. falciparum parasite deform, presumably because the parasite reduces the oxygen tension within the erythrocytes to very low levels as it carries out its metabolism. Deformation of sickle trait erythrocytes would mark these cells as abnormal and target them for destruction by phagocytes (Luzzatto, et al., 1970).

Experiments carried out in vitro with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle much more readily than do uninfected cells (Roth Jr., et al., 1978). Since sickle cells are removed from the circulation and destroyed in the reticuloendothelial system, selective sickling of infected sickle trait red cells would reduce the parasite burden in people with the sickle trait. These people would be more likely to survive acute malarial infections.

Other investigations suggest that malaria parasites could be damaged or killed directly in sickle trait red cells. P. falciparum parasites cultured in sickle trait red cells died when the cells were incubated at low oxygen tension (Friedman, 1978). In contrast, parasite health and growth were unimpeded in cells maintained at normal atmospheric oxygen tensions. The sickling process that occurs at low oxygen tensions was presumed to harm the parasite in some fashion. Studies showed extensive vacuole formation in P. falciparum parasites inhabiting sickle trait red cells that were incubated at low oxygen tension, suggesting metabolic damage to the parasites (Friedman, 1979). Prolonged states of hypoxia are not physiological, raising questions about degree to which these data can be extrapolated to human beings. However, they do suggest mechanisms by which sickle hemoglobin at the concentrations seen with sickle cell trait red cells could impair parasite proliferation.

The thalassemias also reached levels of expression in human populations by protecting against malaria. The imbalance in hemoglobin chain production characteristic of thalassemia produces membrane oxidation by hemichromes and other molecules that generate reactive oxygen species (Grinberg, et al., 1995; Sorensen, et al., 1990). Reactive oxygen species also injure and kill malaria parasites (Clark, et al., 1989). In vitro malaria toxicity of thalassemic red cells is most easily seen in cells containing hemoglobin H (ß-globin tetramers) (Ifediba, et al., 1985; Yathavong, et al., 1988). Hemoglobin H occurs most often in people with three-gene deletion alpha-thalassemia (Zhu, et al., 1993). The compound heterozygous condition of two-gene deletion alpha thalassemia and hemoglobin Constant Spring also produces erythrocytes that contain hemoglobin H (Derry, et al., 1988). Alpha thalassemia may protect against malaria in part by altering the immune response to parasitized red cells (Luzzi, et al., 1991) In any event, epidemiological studies show clear evidence of protection provided by two-gene deletion alpha thalassemia (Flint, et al., 1986; Modiano, et al., 1991).