Acute Splenic Infarction at an Academic General Hospital Over 10 Years

Few case series provide a current, comprehensive, and detailed description of splenic infarction (SI), an uncommon condition. Retrospective chart review complemented by imaging evaluation and patient follow-up. All adult patients with a confirmed diagnosis of acute SI discharged over 10 years from a single academic center were studied. A systematic literature review was done to compile a complete list of SI etiologies. SI was found in 32 patients, 0.016% of admissions. Ages ranged from 18 to 86 (median 64) years. Cardiogenic emboli were the predominant etiology (20/32, 62.5%) and atrial fibrillation was frequent. Other patients had autoimmune disease (12.5%), associated infection (12.5%), or hematological malignancy (6%). Nine of the patients (28%) had been previously healthy or with no recognized morbidity predisposing to SI. In 5 of 9 hitherto silent antiphospholipid syndrome or mitral valve disease had been identified. Two remained cryptogenic. Most patients presented with abdominal pain (84%), often felt in the left upper quadrant or epigastrium. Associated symptoms, leukocytosis or increased serum lactate dehydrogenase occurred inconsistently ( 25% each). Chest X-ray showed suggestive Lt. supra-diaphragmatic findings in 22%. Thus, the typical predisposing factors and/or clinical presentation should suggest SI to the clinician and be followed by early imaging by computed tomography (CT), highly useful also in atypical presentations. Complications were rare and patients were discharged after 6.5 days (median) on anticoagulant treatment. The systematic literature review revealed an extensive list of conditions underlying SI. In some, SI may be the first and presenting manifestation. SI is a rare event but should be considered in predisposed patients or those with any combination of suggestive clinical features, especially abdominal pain CT evaluation is diagnostic and the outcome is good. er Ella, MD, and Klepfish Abraham, MD CHADS2 = Risk score of arterial thromboembolism in AF, IE = infective endocarditis, LAC = lupus anticoagulant, LDH = lactate dehydrogenase, Lt = left, LUQ = left upper quadrant, RLQ = right lower quadrant, RUQ = right upper quadrant, SI = splenic infarction, SLE = systemic lupus erythematosus, TEE = trans-esophageal echocardiography, VZV = varicella zoster virus, WBC = white blood cells. INTRODUCTION S plenic infarction (SI) occurs when the splenic artery or 1 or more of its branches become occluded, either by an embolus or by in situ thrombosis. The spleen has a rich vascular supply and receives 5% of the cardiac output making it susceptible to emboli (cardiogenic, aortic, paradoxical). Furthermore, it is not infrequently affected by malignant hematological disorders which increase the risk of thrombosis. Only a few series of SI patients have been reported, and some of them are too old or too selective to be really useful. In addition, the current widespread availability and escalating early use of computed tomography (CT) scanning may have changed its etiologic distribution and presenting features. The ongoing publication of single case studies of SI in peer reviewed journals emphasizes the continued interest in the diagnostic challenge that SI often poses, and in its myriad etiologies which can be highly unusual. We have conducted a retrospective case series study of all patients diagnosed with SI at a single academic medical center to the diagnosis and including a comprehensive review of the literature listing all reported causes of SI. PATIENTS AND METHODS Kaplan Medical Center is an academic general hospital in central Israel caring for a mixed urban and rural population of 400,000 people. Following Institutional Review Board approval, the charts and imaging studies of all adult patients (ages 18 years and over) discharged from our 4 departments of medicine with an ICD-9 coded diagnosis of infarction of spleen were separately examined by 2 experienced clinicians and a radiologist. All patients whose SI diagnosis was confirmed were included in the study. Confirmation required unequivocal CT findings. In cases of disagreement, inclusion was dependent on a unanimous agreement following discussion. Demographic, past medical history, clinical, laboratory, and imaging details of each patient were obtained, as well as results of echocardiography, Holter monitoring and work up for an underlying disease. All imaging studies (chest X-ray, ultrasound, CT) were evaluated by 2 of the authors (AM, SA) to determine /3 of the spleen; moderate; or extensive ated supra-diaphragmatic findings (Lt. ower lobe linear atelectasis, or none). www.md-journal.com | 1 TABLE 1. Etiologic Classification of All Patients Diagnosed With Splenic Infarction (SI) at an Academic Medical Center Over 10 Years (n1⁄432) I. Cardiogenic Emboli (n1⁄4 20) a. In the context of hypertensive heart disease and/or coronary artery disease 11 Associated atrial fibrillation 8 (No. 4, 6, 9, 10, 11, 12 , 25, 26) Atrial fibrillation not demonstrated 2 (No. 20, 30) Acute anterior wall myocardial infarction 1 (No. 13) b. Associated with cardiac procedures (‘‘iatrogenic’’) 3 After catheter ablationy 1 (No. 3) After electrical cardioversiony 1 (No. 5) Medicine Volume 94, Number 36, September 2015 Patients who died from SI were included. Follow-up was obtained by examining hospital charts for any admissions or ambulatory visits occurring after the index admission as well as by contacting the patient’s primary care physician for an update on the patient’s condition and recommending repeated testing as needed. Statistical analysis was performed by using Chisquared test. In addition, all related PubMed-indexed articles (spleen AND infarction or infarct; English language; since inception; adult 19þ years) were screened (n1⁄4 533). Relevant manuscripts were retrieved and read to confirm validity of the diagnoses and their references examined to compile a comprehensive list of all reported etiologic associations of SI. Ami et al RESULTS During the 10 years of the study (January 2004 to December 31, 2013), there were 196,625 admissions to our division of After coronary angiography 1 (No. 14) c. Infective endocarditis-associated 2 (No. 15, 24) d. Valvular disease-associated 4 Rheumatic mitral valve disease (No. 16, 29) Myxomatous degeneration of the mitral valve (No. 28) Aortic valve replacement (No. 17) II. Autoimmune disease (n1⁄4 4) Antiphospholipid syndrome 2 (No. 1, 7—both lupus anticoagulant positive and No. 18) Systemic lupus erythematosus (APS not found) 1 (No. 22) III. Infection-associated (n1⁄4 4) Peripancreatic abscess (No. 19) Varicella zoster virus (VZV) infection (No. 21) Septicemia, in patients with extensive atherosclerosis (No. 23, 27) IV. Hematological disease (n1⁄4 2) Myeloproliferative disorder (No. 8) Myelodysplastic syndrome (No. 2) V. Cryptogenic (n1⁄4 2) (No. 31, 32)z For full individual patient data see Appendix, http://links.lww.com/ MD/A395. APS 1⁄4 antiphospholipid syndrome. This patient’s presentation with PAF and SI led to the diagnosis of pericarditis with effusion. y Trans-esophageal echocardiography before the procedure did not reveal any cardiac thrombi. z Extensive investigations after the event proved negative and prolonged course (6–9 years) was uneventful without extended anticoagulant treatment. One patient (No. 18) formerly considered cryptogenic SI received a diagnosis of APS based on persistently FIGURE 1. Coronal (A) and axial (B) contrast enhanced abdominal computed tomography of one of the patients showing multiple splenic infarcts (black arrows), and an associated small left pleural effusion with passive partial atelectasis of the left lower lobe (white arrows). 2 | www.md-journal.com medicine. Only 32 confirmed cases of SI have been found, 0.016% of admissions. Their essential background, presentation, pertinent laboratory data, imaging analysis, and outcome are reported in detail in Appendix, http://links.lww.com/MD/ A395. Figure 1 demonstrates typical imaging findings. Patients’ ages ranged from 18 to 86 years (median 64 years) and 50% were male (n1⁄4 16). Their final etiologic classification is summarized in Table 1. Cardiogenic emboli were by far the major etiologic mechanism (20/32, 62.5%), followed by autoimmune disease and infection-associated SI (4/32, 12.5% each). Two patients had a predisposing hematological disease with marked splenomegaly and 2 remain cryptogenic despite follow up and repeated investigations. The existence of a morbidity associated with SI was known in 23 of 32 patients (72%): 20 had structural heart disease begetting atrial fibrillation (AF) and cardiogenic emboli and the positive anti-cardiolipin and anti-b2 glycoprotein antibodies discovered 9 years after the event. remainder had hematological cancer or systemic lupus erythematosus. Notably, AF was not always documented (5/20, 3 had infective endocarditis [IE] or aortic valve replacement) and SI Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. TABLE 2. Previously Unsuspected Diagnoses Discovered in Patients Presenting With Splenic Infarction (n1⁄48) Antiphospholipid syndrome (n1⁄4 3) Mitral stenosis (associated flutter—fibrillation) Mitral regurgitation, severe Infective endocarditis (multiple emboli) Pericarditis/pericardial effusion (associated atrial fibrillation) Splenic vein thrombosis (following cured abdominal abscess) VZV infection? (see text) Medicine Volume 94, Number 36, September 2015 sometimes followed planned cardiac procedures (3/20) (Table 1). Nine of the patients (28%) had been previously healthy or with no disease predisposing to SI. A new diagnosis underlying the SI was discovered in 6 (66.6%) including 3 antiphospholipid syndrome (APS), 2 unsuspected mitral valve disease, and 1 splenic vein thrombosis associated with a peri-pancreatic abscess (Table 2). One APS patient was considered cryptogenic on discharge and diagnosed when retested during our study In 2 patients, the SI remained ‘‘cryptogenic.’’ The patients’ predominant symptom was abdominal pain (27/32, 84.4%). The pain was acute (duration 2 days) in 16 of 27 (59%); intense and severe in only 5; and showing a crescendo pattern in just 4. Pain location was most often in the left upper quadrant (LUQ)/left abdomen in 16 patients (13 had LUQ pain) or epigastrium in 6. One patient had pain in both locations (unspecified in 4). Thus, epigastric or left abdominal pain characterized 85% (23/27) of the patients who had pain. Importantly, 5 of 32 (16%) had no abdominal pain (Appendix, http://links.lww.com/MD/A395). Objective abdominal examination was generally nonrewarding (abdominal tenderness found in some of the patients) and associated symptoms (such as fever, vomiting) were infrequent (4 to 6/32). Only 8 of 32 (25%) had serum lactate dehydrogenase (LDH) levels greater than twice the upper limit of normal ( 920 IU/L) and white blood cells (WBC) 14 109 per L was also noted in just 8 of 32 (see Discussion section). Five patients had both LDH and WBC elevations, all had multiple SI. However, all ‘‘painless’’ SI patients had normal LDH and WBC values and no Lt. supra-diaphragmatic findings on the admission chest X-ray (see below). CT was the predominant diagnostic study and all patients who had a suspicious ultrasound had undergone a CT scan. Small SI was most frequent (15/32, 47%). The remaining patients had either moderate SI (9 patients) or extensive infarctions (8 patients). Sixteen patients (50%) had multiple SIs which were often associated with cardiogenic emboli (11/16, 69%) but 5 were nonembolic (Pts. 1, 2, 19, 27, and 31). Emboli in other organs than the spleen were identified in 7 of 32 cases, and these were all due to cardiogenic embolism (Appendix, http://links.lww.com/MD/A395). No features were unique to this subgroup (in 5/16 a combined significant WBC/LDH increase was found). Slightly more than half of the patients (18/32, 56%) had suggestive Lt. supra-diaphragmatic findings. In 12 of 32 (37.5%), the admission chest X-ray clearly demonstrated mild left pleural effusion and/or flat atelectasis. All patients were given anticoagulant treatment and all made full recovery except one (an 84-year-old patient who had cardiogenic emboli to multiple sites including the gut). Length of hospital stay ranged from 1 to 48 days (median 6.5 days). The full diagnostic spectrum of SI that Patients who were previously healthy or had no known disease predisposing to splenic infarction. was derived from the systematic literature search was not previously reported to our knowledge and is presented in Table 3 under 3 etiologic categories. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. DISCUSSION The survey of the literature clearly demonstrates the great diversity of mechanisms and etiological association reported for SI, which cannot be fully captured by any patient series (Table 3). Varied mechanisms of arterial embolization and hypercoagulability may mediate SI and SI can even be their first presenting manifestation (Table 3). The spleen may also become susceptible to infarction by anatomic abnormalities facilitating torsion, or by iatrogenic damage following diverse abdominal procedures. Nevertheless, SI is a rare event. In our retrospective series, only 32 patients with an ICD-9 coded diagnosis of SI (confirmed by a review of the actual imaging) were found over 10 years in a single academic hospital— 0.016% of admissions. Although the proportion of admissions was not previously reported, this observation is in agreement with previous studies. For example, a surgery-based group from Cleveland identified 75 patients over 10 years (1974–1984) and an emergency department-based study reported 48 patients over a similar period (1996–2007). We believe that the low incidence, the varied nonspecific clinical presentation, and the possible occurrence of SI as the first manifestation of an unsuspected disease add considerably to the diagnostic challenge and may contribute to underdiagnosis of SI. Our study adds to the existing literature since not many series of SI have been published, and of those, quite a few are too old (80s), too selective (surgical-based; autopsy-based; exclusively embolic) or too laconic (providing only basic patient information). One study reports on 75 patients but only 15 of 75 had a CT scan; understanding of hypercoagulability was at its infancy; and 39 of 75 patients were asymptomatic and diagnosed at autopsy. Later series were limited to SI diagnosed at autopsy, on splenectomy, or included only patients who had SI after splenic emboli. Thus, they are informative but obviously highly selective and different from ‘‘real world’’ patients. Only 2 studies were more generalizable, but provide little individual patient detail; use nonspecific cutoff points of WBC counts and LDH levels; and suffer from partial workup. Our study captures all patients with SI diagnosed over a decade in a single academic center and reports them in detail. Data derived are likely generalizable to other countries as well. Additional strengths of our study are the actual review of all imaging and extended follow-up by contacting the patients’ primary physicians and initiating repeated studies (eg, for APS) for patients whose SI had no clear etiology. We found that roughly 2 of 3 of the patients had an obvious condition predisposing to SI. The majority had a known cardiovascular disease associated with cardiogenic splenic emboli (17/32, 53%; 3 other embolic SI patients had no known predisposing disease). Documented atrial fibrillation (AF) was often etc. and high likelihood of paroxysmal atrial fibrillation (PAF) that was etc. Three patients had SI in the setting of cardiac procedures despite a preceding normal trans-esophageal echocardiography. In previous series emboli also constitute the predominant pathogenetic mechanism of SI, ranging from 17% to 66.6% (median 38%), as compared to 62.5% in our series (Table 1, I). These data highlight a high potential of preventability of SI that is only partially exploited. More intensive monitoring techniques of patients at risk can detect hitherto unsuspected silent episodic AF and timely treatment can be Splenic Infarction initiated. Emboli originating from extensive aortic atherosclerotic plaques constitute an important subset according to the literature (Table 3) and a potential cause of SI. Between 19% www.md-journal.com | 3 TABLE 3. Diagnostic Spectrum of Splenic Infarction A. Disease-associated SI Cardiogenic embolism Atrial fibrillation (of any cause); marantic endocarditis (NBTE); myocardial infarction; cardiomyopathy; cardiac tumor (Lt. atrial myxoma, other) Aortic embolism Thoracic aorta atherosclerosis aneurysm or mobile thrombus of ascending aorta/aortic arch; abdominal aortic aneurysm Vascular Cholesterol embolization syndrome, spontaneous; calcific emboli in end-stage renal disease; thrombangiitis obliterans (Buerger’s disease); vascular Ehlers–Danlos syndrome (type IV); splenic artery aneurysm arteriovenous fistula; splenic cavernous hemangioma; splenic vein thrombosis, idiopathic; celiac artery dissection; mesenteric ischemia, nonocclusive; neurofibromatosis vasculopathy; paradoxical embolism Anatomical Wandering spleen and pedicle torsion (‘‘autoinfarction,’’ rare) Infective Infective endocarditis (due to any cause), embolic; sepsis; M. tuberculosis, abdominal (LN compressing splenic hilum); herpesvirus infections, systemic; AIDS and disseminated infection (TB, Aspergillus, etc.); AIDS and immune reconstitution inflammatory syndrome; typhoid fever; rickettsial infection (endemic ‘‘murine’’ typhus); malaria; Trichosporon beigelii, disseminated; Mycoplasma pneumonia; C. canimorsus Autoimmune APS and catastrophic APS; vasculitides —Polyarteritis nodosa; Behcet’s disease; Wegener’s granulomatosis; Kawasaki disease, adult Inflammatory Pancreatitis; pancreatic pseudocyst Hematological, malignant Myeloproliferative disorders (Polycythemia vera; myelofibrosis; CML); malignant lymphoma; acute myelogenous leukemia; amyloidosis, primary systemic; mastocytosis, systemic Hematological, other Sickle cell disease, homozygous (rarely, trait); paroxysmal nocturnal heminoglobinuria ; spherocytosis; S–C hemoglobinopathy; autoimmune hemolytic anemia Oncological Adenocarcinoma (pancreas, bile ducts, lung, colon, renal, ovary ), often metastatic (þcarcinoma of unknown primary) Drug abuse Cocaine Varia Gaucher’s disease; sarcoidosis ; liver cirrhosis (rare); Menetrier’s disease (rare); Hirschprung’s disease B. Iatrogenic and traumatic SI Blunt trauma (rare) S/P abdominal surgery (eg, gastrectomy, Nissen fundoplication; adrenalectomy; liver transplantation) S/P abdominal endovascular procedures (eg, splenic arterial embolization for blunt trauma, variceal bleeding or aneurysm; transcatheter hepatic arterial chemoembolization or ethanol ablation of liver tumors) S/P cardiac catheterization, coronary artery bypass grafting or aortic aneurysm repair (atheroembolic SI) S/P varied abdominal procedures (injection of hypertonic saline/epinephrine for bleeding gastric ulcer, ligation of gastroduodenal artery aneurysm, continuous ambulatory peritoneal dialysis) Drug-induced (rare: heparin-induced thrombocytopenia, sumatriptan, clofazimine, glucantim) C. Cryptogenic (idiopathic) SI (diagnosed by exclusion) Derived from a systematic literature search (see Patients and Methods section). Many of the associations are quite rare. APS1⁄4 antiphospholipid syndrome; CML1⁄4 chronic myeloid leukaemia; LN1⁄4Lymph nodes; NBTE1⁄4 non-bacterial thrombotic endocarditis; SI1⁄4 splenic infarction. Conditions that may present as SI. Ami et al Medicine Volume 94, Number 36, September 2015 to 26.6% of embolic SI may originate in the aorta. Many of these patients with extensive atherosclerosis are also at an increased risk of AF and once detected, embolic risk can be likely reduced by anticoagulant treatment. Even in the presence of an obvious cause of SI, an open mind for a new diagnosis should be kept. Two such patients (6.25%) had a new diagnosis underlying SI (IE and pericarditis) (Table 2). Among patients with a known susceptibility the minority had a hematological malignancy associated with splenomegaly (Table 1, IV). In former reports, a median of 26% hematological malignancy 4 | www.md-journal.com patients had been reported (range 8% to 51%), differences that can be related to ethnic factors. When SI occurred in the absence of any known risk factors (9/32 patients, 28%) a new diagnosis was very likely (Table 2). Since unsuspected mitral valve disease and APS were prominent newly discovered etiologies, echocardiography and lupus anticoagulant testing are key investigations in this group. Four of 32 (12.5%) had infection-associated SI (other than IE). While associated sepsis/septic emboli had been previously reported, the occurrence of splenic vein thrombosis and SI in the wake of Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. predisposing factors or attention to suggestive presenting feaperi-pancreatic abscess is unusual and possibly related to septic thrombophlebitis, not unlike Lemierre syndrome. Another patient developed SI during an acute varicella zoster virus (VZV) infection as reported in other herpesvirus infections (Epstein–Barr virus and cytomegalovirus), not VZV. In 2 patients, SI remained cryptogenic (6%). Our review of the literature in search of the full spectrum of diagnoses that were reported to be associated with SI was extensive, systematic, and reproducible. Table 3 summarizes all etiologic entities found to be associated with SI. We are not aware of any similar effort in the existing literature to date. The classification of etiologies into 3 categories (disease-associated; iatrogenic or traumatic; and cryptogenic SI) is useful in exposing the large variety of pathological entities that may be associated with SI as well as its rarity—many have been described in isolated case reports. Intriguingly, SI may be the presenting symptom of several important conditions (Table 3), as our study also demonstrates. While recognizing a known predisposing condition in a patient with unexplained abdominal pain may help clinicians in risk stratification and in considering SI, we found that at least 1 in 4 SI patients may have no known risk factors. Clinical features remain therefore crucial in raising the index of suspicion and suggesting the diagnosis. However, in our series, abdominal pain was the only reliable symptom or sign, and even that most consistent symptom may sometimes be absent (16% in our patients and 16% to 20% painless presentation in other recent series). Nevertheless, most patients presented with significant abdominal pain, often felt at the left upper abdomen (17/32, 53%) or epigastrium (6/32, 19%). Only few had associated vomiting or fever and the latter was usually related to IE or sepsis, not the infarction. Physical examination was noncontributory showing no more than mild diffuse abdominal tenderness. Previous studies discuss leukocytosis and LDH as helpful in diagnosis. However, mild elevations of the WBC are common and nonspecific and many blood samples show small factitious LDH elevation due to in vitro hemolysis. Using more stringent cut-off points, we found that significant leukocytosis or LDH increases occur in 25%, each, without inter-correlation, limiting their diagnostic utility. Furthermore, in patients who presented was without abdominal pain, neither were increased. The chest X-ray may demonstrate changes in the left hemithorax which are secondary to the subdiaphragmatic SI. Their detection on admission may offer an important clue; however, their sensitivity was low (22%). Thus, early imaging by CT remains crucial for SI diagnosis. A recent study examined imaging strategies for detection of urgent conditions in patients with acute abdominal pain. Although no patients with SI were captured (supporting the rarity of this diagnosis), prospective data collection among >1000 patients demonstrated that the initial strategy of choice for patients without right upper quadrant or right lower quadrant tenderness was early CT. Among patients with SI, despite data indicating frequent complications requiring surgery in 20.5% to 34%, our group fared generally well with a median hospital stay of 6.5 days and full recovery on supportive and anticoagulant treatment (in all but 1 case). This observation held true even for patients with extensive SI or associated infarctions. Our study had several limitations including generalizability; the relatively small number of patients identified; the Medicine Volume 94, Number 36, September 2015 possibility that additional SI patients were admitted directly to surgical wards against hospital policy; the reliance on CT diagnosis; and the distinct possibility that additional patients Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. with SI may have been missed. However, we believe that our results accurately describe all patients admitted with a confirmed diagnosis of SI and that they are generalizable to other populations. A review of admissions to surgery failed to discover additional SI patients. Nevertheless, the possibility that some patients with SI have not been admitted due to atypical presentation, low index of suspicion and failure to obtain imaging are realistic and supported by our data. In conclusion, we presented a detailed analysis of a consecutive series of patients with SI, a rare diagnosis, diagnosed and treated over a decade at a single academic center. Myriad conditions can lead to SI (Table 3) and the patient population can be very heterogenic in its clinical presentation. A ‘‘full’’ or ‘‘typical’’ picture is often not found and diagnostic suspicion must depend on either the recognition of established Splenic Infarction tures (or both) leading to an early use of a CT scan whenever SI is suspected.