Asplenia

Etiology

Asplenia can be acquired, functionally reduced despite its anatomic presence, or in those who congenitally lack a spleen at birth. Most commonly, acquired asplenia is due to surgical removal or trauma. According to a survey by the National Hospital Discharge Survey in the United States done in 2005, approximately 22,000 splenectomies were performed.[7] The most common indication for splenectomy was due to preceding trauma. According to a retrospective study that reviewed the historic clinical indications for splenectomy, traumatic injury accounted for more than 41.5%; hematologic malignancy accounted for 15.4%, and cytopenias accounted for 15.4% of all splenectomies performed.[8]

A variety of benign and malignant hematologic disorders can result in the potential need for splenectomy. Some examples include hereditary spherocytosis, sickle cell disease, thalassemia major or intermedia, refractory immune thrombocytopenia (ITP), myeloproliferative disorders (eg, severe or symptomatic splenomegaly in myelofibrosis), certain types of autoimmune hemolytic anemias, lymphoproliferative disorders, and rarely in thrombotic thrombocytopenic purpura (TTP).[3] Congenital asplenia may be isolated or as a clinical sequela of broader (albeit rare) clinical syndromes such as Ivemark syndrome. This syndrome is classified under heterotaxy syndrome. It is associated with asplenia or hypoplasia of the spleen, malformation of the heart, and abnormal arrangements of organs of the chest and abdomen.[9]

In addition to the more common causes of asplenia, many other etiologies have been described in the literature affecting various body systems as listed below.

1. Gastrointestinal (GI) disorders such as Celiac disease, Whipple disease, and inflammatory bowel diseases (IBD) can be associated with hypofunction of the spleen.[10]
2. Infectious disease states and acquired immune deficiency syndromes, including HIV.[10]
3. Hepatic disorders such as alcoholic liver disease, cirrhosis, portal hypertension, and hepatorenal syndrome.[10]
4. Rheumatologic conditions such as systemic lupus erythematosus (SLE) have been associated with reduced spleen function.[3]

Epidemiology

The epidemiology of asplenia differs depending on its etiology. Nearly 100% of sickle cell anemia patients (ie, those with hemoglobin SS disease) will develop asplenia, and they are prone to overwhelming post-splenectomy infection.[10] Many other patients with similar hemoglobinopathies are at risk of splenomegaly and a possible need for splenectomy or may develop functional asplenia with the course of their disease (eg, hemoglobin SC disease). Other diseases associated with reduced function of the spleen include celiac disease, with an estimated prevalence of 33% to 76%, Whipple disease (47%), and alcoholic liver disease (37% to 100%).[10] Remark syndrome is seen in 1 in 10,000 to 40,000 cases.[5]

Pathophysiology

The pathophysiology of asplenia also varies depending on the underlying etiology and comorbid conditions. In many benign hematologic disorders, for example, functional asplenia is caused by persistent and recurrent hyper-sequestration of red blood cells (RBCs), leading to RBC entrapment. This entrapment leads to splenic enlargement and then later atrophy. Profound atrophy of the spleen is also known as autosplenectomy. Autosplenectomy is usually seen in sickle cell anemia patients, especially those with HgbSS disease.[10] In hematologic malignancies, by contrast, asplenia may result from direct infiltration of the malignant cells into the parenchyma of the spleen. 

Many GI disorders can lead to functional asplenia. For example, in cases of hepatic dysfunction or failure, asplenia can develop due to the disruption of the normal hepatic circulation, such as in portal hypertension. Alcohol consumption has been known to cause a direct toxic effect on splenic tissue. [10] In other disorders like Celiac disease, asplenia is caused by excessive loss of lymphocytes through inflamed enteric mucosa, leading to reticuloendothelial atrophy.[10]

Histopathology

Histologically, atrophy of the spleen is evident by degeneration of white pulp (ie, decreased periarteriolar lymphatic sheaths, or PALS, decreased follicles, germinal centers, and marginal zones). Decreased amounts of hematopoietic components characterize red pulp atrophy. Cytologically, the presence of Howell-Jolly bodies and pitted red blood cells visible upon review of a peripheral blood smear may suggest asplenia or reduced function of the spleen. Other non-specific cytologic findings include absolute monocytosis, lymphocytosis, and/or thrombocytosis.[11]

History and Physical

Patients with asplenia can be asymptomatic, while some can present with malaise, fatigue, fever, or encephalopathy. On physical examination, a normal spleen is not palpable.  When enlarged, it can typically be palpated below the costophrenic border on deep inspiration. In patients with various degrees of functional asplenia (autosplenectomy), the spleen will usually not be palpable due to chronic atrophy. Patients may also present with signs or symptoms indicative of underlying infection. Severe infection due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitides are the most common bacterial infections recognized in these patients. As such, it is important to assess for nuchal rigidity in these patients if they present with fever. In particular, pneumococcal meningitis can be up to four times more fatal in asplenic patients compared to other forms of bacterial meningitis and over 6 times more likely to result in poor health outcomes.[6]

Evaluation

As noted, analysis of the peripheral blood smear may demonstrate the presence of Howell-Jolly bodies, providing the clinician with a clue of underlying splenic dysfunction (e.g., congenital or functional asplenia). To confirm physical exam findings and establish the anatomic presence (or absence) and measurement of the spleen, various imaging modalities can be utilized, including abdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), or spleen scintigraphy.[5] Using ultrasonography, CT, or MRI of the abdomen may also help in better characterization of possible congenital or vascular abnormalities. Spleen scintigraphy is a specialized imaging modality using a 99-Tc labeled radio colloid that is specific for splenic tissue;  a lack of uptake signifies asplenia.

Treatment / Management

As noted, patients with asplenia are at a significantly increased risk of severe bacterial infection, especially from encapsulated microorganisms. As a result, efforts have been made over the last decade to improve the prevention, early detection, and management of infections encountered in asplenic patients. The most common bacterial pathogen leading to infection in patients with asplenia is Streptococcus pneumoniae. According to one study by Waghorn et al, up to 87% of asplenic patients were found to have been infected with Strep. pneumoniae.[12] To avoid morbidity, regardless of the cause of their asplenia, all patients should be counseled to receive vaccinations against these encapsulated bacteria. Vaccinations are recommended before splenectomy and after the surgical removal. Individuals with functional asplenia (or autosplenectomy) are also advised to continue aggressive vaccination schedules. Before planned surgery for splenectomy, it is recommended that patients receive the pneumococcal conjugate vaccine (PCV-13) 8 weeks in advance, as well as the pneumococcal polysaccharide vaccine (PPSV-23), Haemophilus influenzae type B vaccine (Hib), and the quadrivalent meningococcal conjugate vaccine 14 days before surgery.[6] 

Vaccination must continue in the postoperative period, and 5 years after the surgery, it is recommended that patients receive the PPSV-23 and then again at age 65. The meningococcal conjugate vaccine should be repeated every 5 years.[13] For those with acquired immunodeficiency, it may be advisable to check for titers to determine immune status. Apart from all these vaccines, patients should be encouraged to receive annual vaccination against the common strains of influenza. It has been recommended that prophylactic penicillin be considered in children with asplenia (eg, patients with sickle cell disease) until the age of 5,[14] although this prophylaxis is not recommended in adults. Asplenic adults, however, should have antibiotics readily available via their healthcare provider if they develop signs of infection, as any delay in antibiotic access may be detrimental.[6]

Overwhelming post-splenectomy infection is common, especially in children younger than 16 years old, due to their immune immaturity.[10] Patients with asplenia who present with signs of infection should be immediately started on broad-spectrum antibiotics until further testing can isolate the causative microorganism. According to the Surviving Sepsis Campaign guidelines, patients suspected of sepsis should be started on antibiotics within 1 hour to avoid poor outcomes.[14] Aggressive intravenous (IV) hydration should also be promptly initiated as per standard sepsis guidelines and as part of supportive care. Since asplenic patients are prone to developing septic shock, they may also require vasopressors to maintain their blood pressure. In certain circumstances, mechanical ventilation may be necessary if patients develop respiratory failure.

Differential Diagnosis

The differential diagnosis of asplenia includes hyposplenia. Hyposplenia shares many of the clinical features as asplenia and may precede further functional decline or autosplenectomy. Unlike asplenia, hyposplenia may be reversible if the underlying condition is treated. For instance, in patients with Celiac disease who develop hyposplenia, the spleen can return to normal function if the celiac disease is better controlled.

Prognosis

The prognosis of asplenia is poor if left unrecognized, as patients will be at higher risk of infection without proper vaccination. Antibiotic prophylaxis and vaccinations are the recommended management modalities in many patients who are asplenic and those with acquired immunodeficiency and asplenia.[10] As noted, patients who do not receive immunizations are at high risk of severe bacterial infection, sepsis, septic shock, and death. One case report by Huebner and colleagues provides evidence of the poor prognosis in asplenic patients who succumb to infection despite receiving standard medical care. This case described a 45-year-old man with a history of splenectomy during childhood who presented with high fevers. He was found to have pneumococcal meningitis and was appropriately started on antibiotics and fluid resuscitation, though unfortunately, his clinical status deteriorated quickly, and he was pronounced dead from sepsis.[6] Many such illustrative cases and case series are reported in the medical literature.

Complications

The most common medical complication in asplenic patients is an overwhelming post-splenectomy infection (OPSI). As noted, asplenic patients are at higher risk of infection with encapsulated microorganisms (e.g., streptococcal pneumonia). According to Kirkineska and colleagues, OPSI results in massive bacteremia caused by encapsulated microorganisms. The primary source of infection is not commonly identified; there is a short prodromal phase and septic shock occasionally associated with disseminated intravascular coagulopathy (DIC) can occur.  Up to 60% to 70% mortality rate has been observed in patients with OPSI if not appropriately managed.[10]

In a normal functioning spleen, the red pulp filters blood and removes old red blood cells; it causes phagocytosis of infected erythrocytes, which helps to form a defense against intraerythrocytic parasites.[15] Parasitic infections such as babesiosis and malaria are common in patients with asplenia due to loss of phagocytosis. The white pulp of the spleen has both T-cell and B-cell compartments, which help with adaptive immunity and antibody production. The spleen provides the largest B cells, which help in the humoral immune response.[15] The lack of memory B cells in the asplenic patient causes severe illness compared to the general population. Because the spleen functions as a reservoir for non-circulation and undifferentiated monocytes, splenectomy causes a lack of this reserve. According to Swirski et al, these undifferentiated monocytes stored in clusters in the red pulp, respond to myocardial injury and help in wound healing.[16]

Apart from its role in immunity, the spleen also has a role in vascular and thrombotic complications. Vascular complications were also observed, mostly in patients with hematologic diseases like beta-thalassemia. In a survey done by Taher et al, they found that in patients with asplenia due to beta-thalassemia, the prevalence of thrombotic events was 1.65%.[17] There have also been increased incidences of stroke, myocardial infarction, and CAD in these patients.[18] These vascular complications could be due to chronic inflammation and dysfunction of the endothelium. The destruction of the endothelial lining could lead to platelet activation and thrombosis.[15]

Due to the risk of thrombosis in patients with asplenia, another complication reported is pulmonary hypertension. According to Hoeper et al., the incidence of pulmonary hypertension in patients with asplenia is 8% to 11.5%, and numbers are even higher in patients with hemoglobinopathies.[15] In patients with sickle cell or beta-thalassemia, the incidence could be as high as 30%.[19] Patients also can develop adrenal hemorrhage, also known as Waterhouse-Friedrichsen syndrome, and purpura fulminans.[20] These two conditions require a high index of suspicion by the treating clinician. Early recognition and management are critical to avoid morbidity and mortality.