Special Feature
Prevention of Overwhelming Post-Splenectomy Infections
By Saadia R. Akhtar, MD, MSc, Idaho Pulmonary Associates, Boise, is Associate Editor for Critical Care Alert.
Dr. Akhtar reports no financial relationship to this field of study.
Case Presentation
A 53-year-old woman with a history of splenectomy 15 years ago for idiopathic thrombocytopenic purpura and no chronic medical problems awoke with headache, myalgias, and fever. She was seen at her local urgent care that evening where she had a temperature of 102°F with mild tachycardia but otherwise normal vital signs. Exam was unremarkable. Basic laboratory studies revealed leukocytosis with a leftward shift (13K WBC with 10% bands) and no other abnormalities. Chest X-ray and urinalysis were normal. Blood cultures were collected and she was sent home with the diagnosis of probable viral syndrome.
Six hours later the laboratory called the urgent care with positive blood cultures growing Gram-positive diplococci. The patient was called at home. She noted over the phone that she was feeling a bit weaker and was still febrile. She was instructed to come back to the hospital. Her husband drove her in and upon arrival to the urgent care, about 30 minutes after the phone conversation, she was somnolent and mottled-appearing with a systolic blood pressure of 60. She received aggressive resuscitation with intravenous fluids, vasopressors, antibiotics and mechanical ventilatory support. Laboratory studies now revealed acute renal failure, shock liver and disseminated intravascular coagulation. Bilateral alveolar infiltrates were noted on chest X-ray. Blood cultures ultimately revealed Streptococcus pneumoniae.
After a 3-week ICU stay with aggressive support (including ongoing mechanical ventilation, activated protein C and continuous renal replacement therapy) the patient ultimately recovered and was able to be discharged to a rehabilitation unit. In reviewing her history, this woman had not had pneumococcal vaccine since just after splenectomy and did not recall ever having had vaccination against meningococcus or Haemophilus. She and her family were not aware that she was at any particular risk for severe infection.
Introduction
Overwhelming post-splenectomy infection (OPSI), also termed post-splenectomy sepsis, is a fulminant form of sepsis (frequently due to or accompanied by pneumonia and/or meningitis) occurring in asplenic patients. The term OPSI is used loosely and applied to persons who have post-surgical as well as functional asplenia. The usual pathogen is Streptococcus pneumoniae, although patients have increased susceptibility to infection by a variety of other organisms. Mortality is high.
OPSI first came to widespread attention in 1952 after King and Shumacker’s report of sepsis and death in infants who had undergone splenectomy for hereditary spherocytosis.1 It was initially thought that adults were at little or no risk for OPSI but it quickly became clear that this was not the case. Today, although we have a better understanding of risk, presentation, treatment and prevention of OPSI, more work needs to be done to disseminate this information and incorporate it into practice.
Splenic Function and Causes of Asplenia
The spleen is the largest lymphoid organ in the body and serves multiple immune functions. It is responsible for antibody response to a variety of antigens including capsular polysaccharides (some of this response may be via production of 2 opsonins, tuftsin which may initiate phagocytosis and properdin which is important in the alternative complement activation pathway). Filtering of blood through splenic sinusoids and the action of splenic macrophages eliminate abnormal (non-deformable or antibody-coated) erythrocytes from the circulation, including those infected with parasites. The spleen may also play a role in removing endotoxin from the circulation. Thus splenectomy reduces clearance of circulating pathogens, particularly encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type B and Neisseria meningitidis, parasites such as Babesia or Plasmodium species, and Gram-negative bacteria such as Escherichia Coli, Pseudomonas species and Salmonella species (Salmonella infection is usually only seen in children with sickle cell anemia). Interestingly, Capnocytophaga canimorsus infection (typically acquired from animal bites) occurs almost exclusively in asplenic patients.2-4
Asplenia may be congenital, functional, or surgical. Congenital asplenia is usually associated with other major malformations and 95% of those affected die within the first year of life. Functional asplenia occurs in a wide variety of conditions including hemoglobinopathies (sickle cell anemia, thalassemia, hereditary spherocytosis), lymphoproliferative disorders, post-bone marrow transplantation, chronic liver disease, gastrointestinal diseases (celiac sprue, inflammatory bowel disease), some autoimmune diseases (systemic lupus erythematosus), infiltrative diseases (amyloidosis, sarcoidosis) and following splenic irradiation. Surgical splenectomy is performed for management of traumatic or iatrogenic splenic injury, idiopathic thrombocytopenic purpura (ITP), hemolytic anemia, some malignancies, and for other causes of hypersplenism.3
Epidemiology
There are no robust population-based epidemiological studies of post-splenectomy infection. The available information is further complicated by the fact that studies employ different definitions of serious infection, include different patient populations (surgical splenectomy vs asplenia of any cause) and may precede introduction of the current pneumococcal vaccine. Taking these factors into account, lifetime risk of OPSI is suggested to be about 0.5-5%.3-6
Risk is related to age, indication for and time after splenectomy, presence of immunosuppression for another reason and prior history of OPSI. OPSI rates are lower in adults than in children (risk may be up to 10% in children younger than age 5). Splenectomy for trauma appears to impart the lowest risk for OPSI along with splenectomy for ITP: the highest rates are in patients with thalassemia major, hereditary spherocytosis or malignancy.3-5
OPSI risk is greatest in the first 2-5 years after splenectomy but there are reports of OPSI occurring over 20 years after splenectomy: mean time interval between splenectomy and infection was 22.7 months in one large review of the literature.5 Asplenic patients who are also immunosuppressed for another reason are at higher risk for OPSI (for instance, up to 25-33% in patients who underwent splenectomy for Hodgkin’s disease followed by chemotherapy).4 Finally, patients appear to be at higher risk for infection after a first episode. Kyaw et al reviewed clinical course of a cohort of 1648 patients who underwent splenectomy in Scotland and found overall risk of first serious infection (requiring hospitalization but not necessarily with septicemia or meningitis) to be 7 in 100 person-years but that of second infection to be 44.9 in 100 person-years. The majority of first infections (84%) occurred within the first 3 years after splenectomy: the majority of second episodes occurred within 6 months of the first episode.7
S. pneumoniae accounts for 50-90% of the cases of OPSI and H. influenzae for about 8%. Mortality with OPSI is highest when the causative agent is S. pneumoniae but overall is estimated to be 38-69%.5,6
Clinical Presentation of OPSI4,6
Patients initially develop nonspecific mild symptoms of illness such as headache, myalgias, sore throat, cough, or gastrointestinal upset. Associated fever or rigors are key findings that should prompt patients to seek medical attention immediately and should alert medical personnel to be seriously concerned. These patients quickly become toxic-appearing: the hallmark of OPSI is rapid progression, often within a few hours (and no more than 1-2 days) to fulminant sepsis and shock with tachycardia, tachypnea, hypotension, altered mental status, oliguria or anuria and evidence of disseminated intravascular coagulopathy with petechiae and purpura. Laboratory studies are those usual for sepsis and septic shock (abnormal leukocyte counts with left shifts, metabolic acidosis, evidence of end-organ injury with abnormal creatinine, elevated liver function studies, coagulopathy, etc). It is relatively common, due to the high-grade bacteremia these patients experience, for blood cultures to become positive within hours of inoculation: altogether, positive blood cultures are found in about 95% of cases of OPSI. Pneumonia or meningitis are common in children with OPSI but a specific focus of infection may not be found in adult patients.
Treatment
Asplenic patients presenting with acute febrile illnesses should have blood cultures drawn and antibiotics administered immediately (including at a physician’s office prior to transfer to the emergency department).6 Strong consideration should be given to prolonged observation in the emergency department or overnight in the hospital for all febrile asplenic patients regardless of clinical appearance.
The initial empiric antibiotic regimen should treat penicillin-resistant, beta-lactamase producing encapsulated bacteria and also provide some Gram-negative coverage: intravenous ceftriaxone at meningitis-treatment doses (2 g IV q12 hours) is recommended. Strong consideration should be given to adding vancomycin (1 g IV q12 hours) for possible high-level penicillin-resistant pneumococci. For patients with a b-lactam allergy, fluoroquinolones (such as levofloxacin) are the suggested alternative.3 Dexamethasone should also be considered until meningitis is ruled out.8
Due to the relative deficiency of opsonizing antibody in asplenia, it has been suggested that administration of intravenous immune globulin (IVIG) may be beneficial. However, there are only very limited data in the form of animal studies and case reports suggesting possible benefit of IVIG in OPSI (3 days of IVIG at 0.4mg/kg/day). Granulocyte-macrophage colony stimulating factor (GM-CSF) has also been investigated and appears to increase macrophage bactericidal activity and improve outcomes in asplenic mice but clinical trials have not been undertaken.4,6 At this time, neither of these interventions can be routinely recommended in the management of OPSI.
Prevention
Randomized, controlled trials of the efficacy of these preventive strategies are currently lacking. The recommendations are based primarily on theoretical benefit, extrapolation from other clinical settings and expert opinion. The British Committee for Standards in Hematology has published guidelines for prevention and treatment of infection in asplenic patients (initially in 1996, revised in 2002).9 The Centers for Disease Control and Prevention (CDC) also provides recommendations for immunization of asplenic patients.10
Avoid Splenectomy9,11
As the medical community has become more aware of the risk of OPSI, surgical approaches have changed. Trauma care has shifted over time to focus on splenic preservation rather than immediate splenectomy for blunt injuries, particularly for low-to-mid-grade splenic injuries. After defining the splenic injury by CT scan, hemodynamically stable patients without other significant intra-abdominal injuries and with limited transfusion requirements related to the splenic injury can be monitored clinically for spontaneous healing: 40-65% of blunt splenic trauma may be successfully managed in this way. Another alternative to complete splenectomy (particularly for some non-trauma indications) is partial splenectomy, with the goal of leaving 30-50% of residual tissue with an identifiable blood supply (splenic artery or short gastric vessels): this appears to preserve enough splenic function to avoid OPSI. Limited data suggest that autotransplantation of a small amount of splenic tissue (usually into the greater omentum or, less commonly, the retroperitoneum) may be another option but the efficacy of this remains unclear. A recent large survey of North American trauma surgeons revealed that only about 4% of responders were re-implanting splenic tissue during splenectomy for trauma.12
Immunize9,10,13
The CDC and most authors recommend that all asplenic patients receive polyvalent pneumococcal vaccine (PPV-23) (containing purified capsular polysaccharides from 23 serotypes of pneumococcus, accounting for about 73% of strains that have been reported to cause OPSI), Haemophilus influenzae type B conjugate vaccine, and quadrivalent meningococcal A, C, Y and W135 vaccine. It is recommended that patients undergoing elective splenectomy receive these vaccines at least 2 weeks prior to the surgery. If this is not possible then initial vaccination should be given at discharge (no less than 2 weeks post-procedure as functional antibody titers are significantly higher with vaccination at that time compared to vaccination in the immediate post-operative period).14 For those patients with asplenia who have never previously been vaccinated, these vaccines may be given at any time. For patients receiving chemo- or radiotherapy, vaccination should be delayed for 6 months after completion of these treatments. (Antibiotic prophylaxis should be provided during this time, as detailed below.) Revaccination at least once after 5 years is crucial for PPV-23 and some authors recommend ongoing revaccination every 5 years. Finally, influenza vaccine is indicated yearly for asplenic individuals.
It is worth noting a few other issues and opinions regarding these immunizations. In Europe, based on prevalence of meningococcal C serotype, only the meningococcal C conjugate vaccine is recommended with suggestion that the quadrivalent vaccine be administered upon travel to other areas. Similarly, in North America, some experts suggest administration of meningococcal vaccine may not be necessary as the most prevalent serotype is B and that perhaps the vaccine should only be given prior to travel to other areas. The role of the new 7-valent conjugate pneumococcal vaccine for patients with asplenia is not clear. It has been used in patients who have failed to generate IgG to pneumococcus after receiving PPV-23 (discovered after an episode of OPSI prompted measurement of anti-pneumococcal antibodies).15 Due to concerns about such failures of immunization, some authors also suggest routine measurement of these antibodies after vaccination of asplenic patients but there is no clear consensus about this topic.
Despite the availability of consensus guidelines and recommendations, actual immunization rates vary greatly. Several studies report immunization rates post-splenectomy at 11-75%.16-18 Other aspects of immunization practice also vary, as demonstrated by Schatz’s survey of 557 trauma surgeons in the United States and Canada (members of the American Association for the Surgery of Trauma). Response rate was about 50%. Although Schatz found an excellent rate of vaccine administration at 99.2%, he found that the timing varied considerably: One-third of surgeons vaccinated in the operating room or immediate post-operative period and one-third at hospital discharge. One-third of responding surgeons felt revaccination was unnecessary. Of the 39% that did report revaccinating, the intervals ranges from < 1 year to 10 years.12
Provide antibiotics6,9
Daily penicillin or amoxicillin prophylaxis is recommended for children with asplenia. This is based primarily on evidence for protection again pneumococcal infection in children with sickle cell anemia.19 Some authors suggest continuing this up to age 16-21 years. It is also suggested that daily antibiotic prophylaxis be provided for up to 5 years post-splenectomy in adults. (Usual adult dose would be penicillin or amoxicillin 500 mg daily or twice a day.) As noted above, daily antibiotic prophylaxis is also recommended for patients who must begin chemo- or radiotherapy immediately post-splenectomy: in this case, prophylactic antibiotics must be continued at least until appropriate vaccinations can be given. For penicillin-allergic patients, co-trimoxazole or a newer-generation fluoroquinolone are reasonable alternatives.
These recommendations must be tailored based on regional antibiotic susceptibility patterns: due to increasing prevalence of penicillin-resistant Streptococci, some authors suggest using amoxicillin/clavulanate or cefuroxime routinely instead of penicillin or amoxicillin. Long-term development of antibiotic resistance is clearly a concern if these recommendations are followed: this issue has not been studied or specifically addressed in the literature for this clinical scenario.
Strong consideration should also be given to providing patients with a 5-day home supply of therapeutic doses of antibiotics to be initiated at the first sign of any febrile illness or in the event of an animal bite (along with instructions to then seek immediate medical care).
Finally, it is important to be aware of the infectious risks asplenic patients may face with travel. Some authors recommend resuming daily penicillin or amoxicillin prophylaxis with travel abroad as it may be more difficult in that setting for patients to get immediate medical attention if they become ill. Malaria prophylaxis is essential for asplenic patients traveling to high risk areas. As discussed above, if immunization for meningococcus has not been given previously, it should also be considered with travel to high-risk areas.20
Educate Patients and Ourselves
Multiple studies have shown that, like the patient in our case presentation, up to 50% of asplenic patients are not aware that they are at increased risk of sepsis and are not familiar with the need for routine immunizations or the need to seek medical attention and start antibiotics immediately for signs of infection.16,17,21 Repeated education of patients about their risk of life-threatening infection, recommendations for immunizations, what to do in the event of a febrile illness and travel-related infectious concerns is essential. It is also recommended that splenic patients wear a medical bracelet: per one study, < 30% of patients wear them.22
Similar surveys of physicians suggest deficient knowledge of risk of infection for asplenic patients.16, 22,23 For instance, Bridgen et al’s survey of 122 Canadian practitioners revealed a good understanding of the risk of pneumococcal infection after surgical splenectomy (94% recognized this) but poor knowledge of the risks of infection with functional asplenia or risks of infection with pathogens other than pneumococcus. Twenty-five percent (25%) of physicians felt revaccination for pneumococcus was not indicated and 35-40% were unaware of the recommendations for vaccines against H. influenzae and N. meningitides. Prophylactic antibiotics (either daily or for use in the event of febrile illness) were provided by < 30%.
Summary
Considerable work must be done to improve our understanding of the mechanisms, epidemiology, management, and prevention of OPSI. Until that time, greater awareness by physicians and patients of the known risks and clinical features of OPSI, knowledge and compliance with immunization guidelines, lower thresholds for use of antibiotics and early medical attention and admission for asplenic patients with febrile illnesses may improve outcomes for some of these patients.
References
- King H, Shumacker HB Jr. Splenic studies. I. Susceptibility to infection after splenectomy performed in infancy. Ann Surg. 1952;136:239-242.
- Altamura M, et al. Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance. Immunopharmacol Immunotoxicol. 2001;23:153-161.
- Brigden ML, Pattullo AL. Prevention and management of overwhelming postsplenectomy infection—an update. Crit Care Med. 1999;27:836-842.
- Sumaraju V, et al. Infectious complications in asplenic hosts. Infect Dis Clin North Am. 2001;15:551-565.
- Bisharat N, et al. Risk of infection and death among post-splenectomy patients. J Infect. 2001;43:182-186.
- Davidson RN, Wall RA. Prevention and management of infections in patients without a spleen. Clin Microbiol Infect. 2001;7:657-660.
- Kyaw MH, et al. Evaluation of severe infection and survival after splenectomy. Am J Med. 2006;119:276.
- de Gans J, et al. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347;1549-1556.
- Davies JM, et al. Update of guidelines for the prevention and treatment of infection is patients with an absent or dysfunctional spleen. Clin Med. 2002;2:440-443.
- www.cdc.gov/nip/recs/adult-schedule.htm
- Pachter HL, Grau J. The current status of splenic preservation. Adv Surg. 2000;34:137-174.
- Shatz DV. Vaccination practices among North American surgeons in splenectomy for trauma. J Trauma. 2002;53:950-956.
- Taylor MD, et al. Overwhelming postsplenectomy sepsis and trauma: time to consider revaccination? J Trauma. 2005;59:1482-1485.
- Shatz DV, et al. Immune responses of splenectomized trauma patients to the 23-valent pneumococcal polysaccharide vaccine at 1 versus 7 versus 14 days after splenectomy. J Trauma. 1998;44:760-765.
- Musher DM, et al. Administration of protein-conjugate pneumococcal vaccine to patients who have invasive disease after splenectomy despite their having received 23-valent pneumococcal polysaccharide vaccine. J Infect Dis. 2005;191:1063-1067.
- Hasse B, et al. Anti-infectious prophylaxis after splenectomy: current practice in an eastern region of Switzerland. Swiss Med Wkly. 2005;135:291-296.
- Rutherford EJ, et al. Efficacy and safety of pneumococcal revaccination after splenectomy for trauma. J Trauma. 1995;39:448-452.
- Waghorn DJ. Overwhelming infection in asplenic patients: current best practice preventive measures are not being followed. J Clin Pathol. 2001;54:214-218.
- Gaston MH, et al. Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. N Engl J Med. 1986;314:1593-1599.
- Watson DA. Pretravel health advice for asplenic individuals. J Travel Med. 2003;10:117-121.
- Hegarty PK, et al. Prevention of postsplenectomy sepsis: how much do patients know? Hematol J. 2000;1:357-359.
- Brigden ML, et al. Practicing physician’s knowledge and patterns of practice regarding the asplenic state: the need for improved education and a practical checklist. Can J Surg. 2001;44:210-216.
- de Montalembert M, Lenoir G. Antibiotic prevention of pneumococcal infections in asplenic hosts: admission of insufficiency. Ann Hematol. 2004;83:18-21.
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