Still Consider the Source
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《新英格兰医药杂志》
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.
A 50-year-old man presented to the clinic with fever, chills, and generalized weakness that he had had for three weeks. He also noticed pain and swelling in his right hand and left elbow, a weight loss of about 4.5 kg, and occasional pressure in the upper abdominal area. He said that he had not had nausea, vomiting, diarrhea, dyspnea, or dysuria.
Fever is a manifestation of many infectious, collagen vascular, and malignant diseases. The weight loss and generalized weakness probably indicate a systemic disorder; his joint discomfort suggests an inflammatory arthritis. Arthritis can be a sign of either a rheumatic disorder (such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, vasculitis, or crystal-induced arthritides) or a nonrheumatic systemic disease (such as infective endocarditis). Fever and arthritis can also be symptoms of inflammatory bowel disease.
The patient's medical history was notable for adult-onset Still's disease (diagnosed more than 20 years earlier), autoimmune hepatitis, and corticosteroid-induced diabetes mellitus. His medications included methotrexate (25 mg orally per week), prednisone (15 mg orally per day), glipizide, naproxen, folic acid, calcium, and vitamin D. He was allergic to penicillin. He worked as an engineer and lived in Michigan. He said he did not smoke cigarettes and did not use alcohol or illicit drugs. He was an avid gardener and had not recently traveled outside the United States.
The patient's history suggests that he may be having a flare of adult-onset Still's disease, which typically involves arthritis (polyarticular or pauciarticular), fever, an evanescent rash, splenomegaly, and leukocytosis. Many patients have frequent recurrences of fever and arthritis; commonly involved joints include the knees, wrists, elbows, and the metacarpal and proximal interphalangeal joints of the hands.
Long-term use of methotrexate and prednisone may induce immune suppression; therefore, infection is a serious concern. The patient's gardening raises the possibility of an infection derived from plant or soil exposure, especially sporotrichosis. This infection is usually associated with cutaneous and regional lymph-node disease but may cause septic arthritis; however, fever would be an uncommon symptom of sporotrichosis.
Although the patient is a nonsmoker, his age and weight loss raise the question of an underlying malignant condition. Rheumatic symptoms may accompany cancer, and fever may be observed with hepatoma, renal-cell carcinoma, and lymphoma (especially Hodgkin's disease).
On physical examination, the patient appeared pale and jaundiced, but in no distress. His temperature was 36.5°C, blood pressure 78/46 mm Hg, heart rate 100 beats per minute, and respiratory rate 20 breaths per minute. He had no rash, oropharyngeal lesions, or lymphadenopathy. The results of auscultation of the lungs and heart were normal. An abdominal examination revealed a liver span of 12 cm in the right midclavicular line; the spleen was palpable 3 cm below the costal margin. A musculoskeletal examination revealed swelling, warmth, and tenderness over the metacarpophalangeal joints of the patient's right hand, his right wrist, and his left elbow. The remainder of the examination was normal.
The joint findings and splenomegaly are consistent with adult-onset Still's disease. Whereas fulminant forms of adult-onset Still's disease may result in a severe systemic inflammatory response syndrome or cardiac tamponade leading to hypotension, I remain very concerned about possible sepsis, especially given the patient's use of immunosuppressant medications. In addition, his long-term use of prednisone may be associated with adrenal insufficiency, contributing to hypotension.
The level of hemoglobin was 6.6 g per deciliter, with a mean corpuscular volume of 75.5 μm3, a hematocrit of 19 percent, a white-cell count of 4600 per cubic millimeter, and a platelet count of 54,000 per cubic millimeter. A complete blood count that had been done six weeks earlier revealed a hemoglobin level of 11.9 g per deciliter, a hematocrit of 33 percent, a white-cell count of 8400 per cubic millimeter, and a platelet count of 190,000 per cubic millimeter. Serum chemistry analysis revealed the following values: albumin, 3.1 g per deciliter; alkaline phosphatase, 298 U per liter (normal range, 30 to 130); alanine aminotransferase, 106 U per liter (normal range, 0 to 45); aspartate aminotransferase, 102 U per liter (normal range, 2 to 35); and total bilirubin, 4.5 mg per deciliter (77.0 μmol per liter; normal range, 0.1 to 1.1 mg per deciliter ). The serum level of sodium was 129 mmol per liter; potassium, 4.6 mmol per liter; glucose, 363 mg per deciliter (20.2 mmol per liter); bicarbonate, 23 mmol per liter; urea nitrogen, 45 mg per deciliter (16.1 mmol per liter); and serum creatinine, 0.9 mg per deciliter (79.6 μmol per liter). The reticulocyte count was 7.4 percent; the level of haptoglobin was 1 mg per deciliter (normal range, 22 to 239), and the level of lactate dehydrogenase 891 U per liter (normal range, 6 to 200). The direct antiglobulin test (Coombs' test) was positive. The prothrombin time was 14.0 seconds (international normalized ratio, 1.3); the C-reactive protein level was 19 mg per deciliter (normal range, 0 to 0.6), and the serum ferritin level 4240 ng per milliliter (normal range, 18 to 320). Analysis of a peripheral-blood smear revealed burr cells and ovalocytes; the platelet count was low, with no evidence of platelet clumping. No spherocytes were seen. The results of hemoglobin electrophoresis and chest radiography were normal.
Several of the laboratory abnormalities — the elevated levels of C-reactive protein, hepatic aminotransferases, and serum ferritin — are consistent with a flare of adult-onset Still's disease. The low-to-normal leukocyte count, however, argues against this diagnosis. The hemoglobin and hematocrit levels indicate severe anemia. The elevated reticulocyte count, along with the elevated level of serum lactate dehydrogenase and low level of serum haptoglobin, suggests hemolysis. However, the reticulocyte production index (percentage of reticu-locytes x x 0.5) is low at approximately 1.6 (a value of 2.0 or greater represents an adequate marrow response), suggesting that the anemia may be multifactorial or that the bone marrow has not completely responded. The positive result of the direct antiglobulin test indicates that autoimmune hemolytic anemia is probably present; this condition may be associated with adult-onset Still's disease, infection, or even cancer (such as Hodgkin's disease or leukemia). Curiously, the peripheral-blood smear did not reveal spherocytes, which are usually present in patients with autoimmune hemolytic anemia; false positive Coombs' tests have been reported. Although the findings are still consistent with a flare of adult-onset Still's disease, an infection of some type remains a serious concern and should be ruled out.
The patient was admitted to the hospital and received a blood transfusion. Stress doses of corticosteroids were administered, with a substantial improvement in his symptoms of polyarthritis. Serum glucose levels were controlled with insulin. Blood cultures were positive for Salmonella enterica serotype typhimurium (hereafter referred to as S. typhimurium). Treatment with levofloxacin and aztreonam was initiated.
The positive blood cultures for S. typhimurium explain the hypotension and perhaps the arthritis, but also raise some questions. The source of the bacteremia is still unclear. Bacteremia develops in a small percentage of patients with gastrointestinal salmonellosis. The patient reported no diarrhea or abdominal pain. Bacteremia without gastrointestinal disease may suggest endocarditis or an arterial infection, especially in patients with aortic atherosclerosis. Thus, in the absence of gastroenteritis, patients with salmonella bacteremia should always be evaluated for endovascular infection.
It is also unclear whether the symptoms in the patient's joints are due to septic arthritis or a reactive arthropathy. Reactive arthritis is a well-described complication of enteric infection with salmonella, shigella, campylobacter, or yersinia. Wrists, ankles, and knees are commonly involved. This patient's infection may have triggered an inflammatory response that exacerbated his chronic arthritis due to adult-onset Still's disease. However, synovial-fluid analysis and culture are necessary to rule out septic arthritis.
Bacteremia may activate the coagulation system, resulting in either isolated thrombocytopenia or disseminated intravascular coagulation. The absence of schistocytes on the peripheral-blood smear argues against a diagnosis of disseminated intravascular coagulation in this case. Autoimmune hemolytic anemia may also occur with infection, but salmonellosis is not among the commonly associated infections.
A transthoracic echocardiogram revealed that the systolic function and chamber sizes were normal; there was no valvular dysfunction, evidence of vegetations, or pericardial effusion. The patient's condition improved with antibiotic therapy, and his fever resolved. However, he continued to have episodes of sinus tachycardia. Synovial-fluid analysis was not performed, since the polyarthritis was considered to be consistent with a flare of adult-onset Still's disease, and the arthritis had responded to stress doses of corticosteroids.
Persistent tachycardia could suggest the presence of pericarditis or myocarditis as a complication of adult-onset Still's disease or myocardial dysfunction due to sepsis — but the echocardiogram did not suggest any of these conditions. A careful examination for peripheral stigmata of infectious endocarditis should be conducted, and a transesophageal echocardiographic study should be considered. It would also be important to reevaluate the patient's anemia and volume status, since these factors may contribute to tachycardia. I still wonder about the underlying source of the salmonella bacteremia; this avenue clearly needs to be further explored with repeated physical examination and more imaging studies.
Computed tomographic (CT) scanning of the chest, abdomen, and pelvis was performed to look for a source of the bacteremia. This procedure revealed multiple left periaortic lymph nodes, the largest of which was 10 mm in diameter. Located caudal to these nodes was a focal saccular aneurysm, 1.9 cm by 1.6 cm, along the left posterior aortic margin. In the adjacent left psoas muscle was a rim-enhancing fluid collection, 2.2 cm by 1.2 cm, which was in part contiguous with periaortic and adventitial tissue (Figure 1). The presence of moderate splenomegaly was also reported. There were signs of atherosclerotic plaques in both common and internal iliac arteries, but there was no evidence of atherosclerosis in the aortic wall.
Figure 1. An Abdominal CT Scan Obtained after the Administration of Oral and Intravenous Contrast Material.
A focal saccular aneurysm is present along the left posterior aortic margin (black arrow). Adjacent to this aneurysm is a rim-enhancing fluid collection in the proximal left psoas muscle, suggesting an abscess (white arrow).
The clinical and radiographic features are suggestive of salmonella-related infectious aortitis with reactive lymphadenopathy and the extension of an inflammatory pseudoaneurysm. Alternatively, these features could represent a psoas abscess with contiguous spread to the abdominal aorta. Either scenario would explain the patient's sepsis and tachycardia. S. typhimurium is frequently isolated from patients with infectious aortitis, especially those with atherosclerosis. The gastrointestinal tract is probably the source of infection; bacteremia is most likely to occur in patients with inadequate host defenses. Salmonellae may adhere to damaged arterial walls. CT scans usually suggest the diagnosis of infectious aortitis; however, aortography or magnetic resonance angiography should be performed to delineate the extent of the aneurysm and to plan for surgical resection.
Aortography showed an infrarenal abdominal aortic saccular aneurysm that was located 1 cm from the inferior mesenteric artery (Figure 2). The patient was taken to the operating room, and examination of the opened aorta revealed an aneurysm. At the posterolateral aspect, an area of the aorta had completely degenerated, and a false aneurysm had formed. The aneurysm was resected, and the iliopsoas abscess drained. Culture of the resected aortic wall grew S. typhimurium. There was no evidence of atherosclerosis in the aortic wall. The patient's symptoms resolved after surgery. Treatment with levofloxacin was continued for six weeks. Five months after admission, the patient felt well and returned to full-time employment.
Figure 2. Abdominal Aortogram.
A saccular aneurysm is present in the distal infrarenal abdominal aorta (arrow). The irregularities in the bilateral common iliac arteries and internal iliac arteries are consistent with atherosclerotic involvement.
Commentary
Salmonellae are gram-negative, facultative anaerobic bacteria that are widely distributed in nature. S. typhi and S. paratyphi cause typhoid fever, whereas organisms in the larger group of nontyphoidal salmonella serotypes typically cause gastrointestinal illness. Among the nontyphoidal salmonellae isolated from infected patients in the United States, S. typhimurium is the most common.1 Human infection with nontyphoidal salmonellae is typically acquired by ingestion of contaminated food. Despite improvements in food processing and in sanitation, the incidence of salmonellosis remains high; in the United States, it is estimated that there are about 2 million cases each year.2
Whereas most nontyphoidal salmonella infections result in short-lived gastroenteritis, bacteremia develops in approximately 5 percent of infected patients.3 In some cases, the initial gastrointestinal infection may be subclinical. Bacteremia is most likely to occur in immunocompromised hosts such as those who are at either extreme of the age spectrum or those who have diabetes or cancer, who are infected with the human immunodeficiency virus, or who use immunosuppressive medications.3 When bacteremia occurs, extraintestinal signs and symptoms may include osteomyelitis, abscess formation, and meningitis.3 In additional, salmonellae may adhere to endothelial surfaces, resulting in cardiovascular infections, such as infectious endocarditis and endarteritis. Although atherosclerotic blood vessels are more susceptible to bacterial adhesion,4 infection of normal endothelial surfaces can also occur. The organisms may infect preexisting aneurysms or atherosclerotic plaques, leading to arterial-wall necrosis and rapid aneurysm formation. The most frequently involved site is the infrarenal abdominal aorta.5 Risk factors for infective endarteritis, in addition to atherosclerosis, include diabetes mellitus and immunosuppression.5
Cardiovascular infections — with a slight predominance of cases of endarteritis — develop in approximately 25 percent of patients with salmonella bacteremia.5,6 In a review of 140 cases, the mean age of patients in whom salmonella aortitis developed was 61 years.7 Most patients initially have an indolent condition; fever, abdominal pain, back pain, and leukocytosis are common manifestations.5,7 A diagnosis of salmonella aortitis should be considered in any adult with salmonella bacteremia, particularly in the absence of associated gastrointestinal symptoms. CT performed with contrast material is considered to be the imaging method of choice.5 Features that might suggest this diagnosis include a saccular aneurysm, gas in the aneurysmal sac, and periaortic soft-tissue fluid.5 Infective endarteritis usually has a poor prognosis, which is the result of the high rate of failure of medical therapy alone. Treatment usually requires surgical resection and a prolonged course of antibiotics.
This patient's case was challenging in that several features were absent that might have suggested the correct diagnosis, such as abdominal pain, back pain, and leukocytosis. The patient's history of adult-onset Still's disease further complicated the picture. His fever, the pattern of polyarthritis, the presence of splenomegaly, and the high serum levels of ferritin were all typical symptoms of a flare of adult-onset Still's disease, leading the team caring for him to believe that he did indeed have a recurrence of the disease along with the infection. We have anecdotal evidence of a few patients who had flares of adult-onset Still's disease that appeared to be triggered by systemic infection. An association between disease flares and infection — especially in the upper respiratory tract — has been reported in children with Still's disease.8 Furthermore, the polyarthritis in this patient responded quickly to stress doses of corticosteroids before antibiotic treatment was initiated. Nevertheless, as the discussant noted, synovial-fluid analysis would have been appropriate to rule out septic arthritis.
The patient's hematologic findings, such as anemia, were probably multifactorial. In addition to hemolysis, other probable causes were leakage from the aortic aneurysm, anemia of chronic disease, and sepsis. The history of adult-onset Still's disease and autoimmune hepatitis increases the patient's risk for other autoimmune conditions, including autoimmune hemolytic anemia.9 In a review of 62 patients with adult-onset Still's disease, the majority of patients had a normochromic, normocytic anemia with a hemoglobin level that was no more than 10 g per deciliter, a white-cell count greater than 15,000 per cubic millimeter, and a platelet count between 120,000 and 1,118,000 per cubic millimeter.10 Thrombocytopenia and leukopenia in this patient could have been related to sepsis, although immune-mediated consumption of platelets and white cells is a possible explanation.
This case highlights the importance of diligently searching for infection in patients with rheumatic conditions before attributing systemic illness to a flare of the underlying rheumatic disease. Indeed, infection is one of the leading causes of death in a number of systemic autoimmune diseases, including adult-onset Still's disease.10 In the majority of cases, definitive treatment for the flare of rheumatic or autoimmune disease should be delayed until infection has been ruled out. This is especially important because active autoimmune diseases are usually treated with immunosuppressant medications. Once bacteremia is identified, the discussant's approach also underscores the need to routinely consider the source, a truism especially valid for salmonella species.
Supported by a Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs and a Patient Safety Developmental Center Grant (P20-HS11540) from the Agency for Healthcare Research and Quality (both to Dr. Saint).
We are indebted to Dr. Kyung J. Cho from the Department of Radiology at the University of Michigan for his help.
Source Information
From the Department of Internal Medicine, University of Michigan (A.H.S., S.S., R.W.I.); the Ann Arbor Veterans Affairs Health Services Research and Development Center of Excellence (S.S.); and the Patient Safety Enhancement Program, Ann Arbor Veterans Affairs Medical Center and the University of Michigan Health System (S.S.) — all in Ann Arbor; and the Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.S.B.).
Address reprint requests to Dr. Sawalha at the Division of Rheumatology, University of Michigan, 3918 Taubman Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, or at amr-sawalha@omrf.ouhsc.edu.
References
Bender JB, Hedberg CW, Boxrud DJ, et al. Use of molecular subtyping in surveillance for Salmonella enterica serotype typhimurium. N Engl J Med 2001;344:189-195.
Altekruse SF, Cohen ML, Swerdlow DL. Emerging foodborne diseases. Emerg Infect Dis 1997;3:285-293.
Hohmann EL. Nontyphoidal salmonellosis. Clin Infect Dis 2001;32:263-269.
Oskoui R, Davis WA, Gomes MN. Salmonella aortitis: a report of a successfully treated case with a comprehensive review of the literature. Arch Intern Med 1993;153:517-525.
Fernandez Guerrero ML, Aguado JM, Arribas A, Lumbreras C, de Gorgolas M. The spectrum of cardiovascular infections due to Salmonella enterica: a review of clinical features and factors determining outcome. Medicine (Baltimore) 2004;83:123-138.
Cohen PS, O'Brien TF, Schoenbaum SC, Medeiros AA. The risk of endothelial infection in adults with salmonella bacteremia. Ann Intern Med 1978;89:931-932.
Soravia-Dunand VA, Loo VG, Salit IE. Aortitis due to Salmonella: report of 10 cases and comprehensive review of the literature. Clin Infect Dis 1999;29:862-868.
de Vere-Tyndall A, Bacon T, Parry R, Tyrrell DA, Denman AM, Ansell BM. Infection and interferon production in systemic juvenile chronic arthritis: a prospective study. Ann Rheum Dis 1984;43:1-7.
Narigasawa Y, Ono Y, Kuriya S. Autoimmune hemolytic anemia associated with adult-onset Still's disease. Rinsho Ketsueki 2000;41:729-732.
Pouchot J, Sampalis JS, Beaudet F, et al. Adult Still's disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore) 1991;70:118-136.(Amr H. Sawalha, M.D., San)
A 50-year-old man presented to the clinic with fever, chills, and generalized weakness that he had had for three weeks. He also noticed pain and swelling in his right hand and left elbow, a weight loss of about 4.5 kg, and occasional pressure in the upper abdominal area. He said that he had not had nausea, vomiting, diarrhea, dyspnea, or dysuria.
Fever is a manifestation of many infectious, collagen vascular, and malignant diseases. The weight loss and generalized weakness probably indicate a systemic disorder; his joint discomfort suggests an inflammatory arthritis. Arthritis can be a sign of either a rheumatic disorder (such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, vasculitis, or crystal-induced arthritides) or a nonrheumatic systemic disease (such as infective endocarditis). Fever and arthritis can also be symptoms of inflammatory bowel disease.
The patient's medical history was notable for adult-onset Still's disease (diagnosed more than 20 years earlier), autoimmune hepatitis, and corticosteroid-induced diabetes mellitus. His medications included methotrexate (25 mg orally per week), prednisone (15 mg orally per day), glipizide, naproxen, folic acid, calcium, and vitamin D. He was allergic to penicillin. He worked as an engineer and lived in Michigan. He said he did not smoke cigarettes and did not use alcohol or illicit drugs. He was an avid gardener and had not recently traveled outside the United States.
The patient's history suggests that he may be having a flare of adult-onset Still's disease, which typically involves arthritis (polyarticular or pauciarticular), fever, an evanescent rash, splenomegaly, and leukocytosis. Many patients have frequent recurrences of fever and arthritis; commonly involved joints include the knees, wrists, elbows, and the metacarpal and proximal interphalangeal joints of the hands.
Long-term use of methotrexate and prednisone may induce immune suppression; therefore, infection is a serious concern. The patient's gardening raises the possibility of an infection derived from plant or soil exposure, especially sporotrichosis. This infection is usually associated with cutaneous and regional lymph-node disease but may cause septic arthritis; however, fever would be an uncommon symptom of sporotrichosis.
Although the patient is a nonsmoker, his age and weight loss raise the question of an underlying malignant condition. Rheumatic symptoms may accompany cancer, and fever may be observed with hepatoma, renal-cell carcinoma, and lymphoma (especially Hodgkin's disease).
On physical examination, the patient appeared pale and jaundiced, but in no distress. His temperature was 36.5°C, blood pressure 78/46 mm Hg, heart rate 100 beats per minute, and respiratory rate 20 breaths per minute. He had no rash, oropharyngeal lesions, or lymphadenopathy. The results of auscultation of the lungs and heart were normal. An abdominal examination revealed a liver span of 12 cm in the right midclavicular line; the spleen was palpable 3 cm below the costal margin. A musculoskeletal examination revealed swelling, warmth, and tenderness over the metacarpophalangeal joints of the patient's right hand, his right wrist, and his left elbow. The remainder of the examination was normal.
The joint findings and splenomegaly are consistent with adult-onset Still's disease. Whereas fulminant forms of adult-onset Still's disease may result in a severe systemic inflammatory response syndrome or cardiac tamponade leading to hypotension, I remain very concerned about possible sepsis, especially given the patient's use of immunosuppressant medications. In addition, his long-term use of prednisone may be associated with adrenal insufficiency, contributing to hypotension.
The level of hemoglobin was 6.6 g per deciliter, with a mean corpuscular volume of 75.5 μm3, a hematocrit of 19 percent, a white-cell count of 4600 per cubic millimeter, and a platelet count of 54,000 per cubic millimeter. A complete blood count that had been done six weeks earlier revealed a hemoglobin level of 11.9 g per deciliter, a hematocrit of 33 percent, a white-cell count of 8400 per cubic millimeter, and a platelet count of 190,000 per cubic millimeter. Serum chemistry analysis revealed the following values: albumin, 3.1 g per deciliter; alkaline phosphatase, 298 U per liter (normal range, 30 to 130); alanine aminotransferase, 106 U per liter (normal range, 0 to 45); aspartate aminotransferase, 102 U per liter (normal range, 2 to 35); and total bilirubin, 4.5 mg per deciliter (77.0 μmol per liter; normal range, 0.1 to 1.1 mg per deciliter ). The serum level of sodium was 129 mmol per liter; potassium, 4.6 mmol per liter; glucose, 363 mg per deciliter (20.2 mmol per liter); bicarbonate, 23 mmol per liter; urea nitrogen, 45 mg per deciliter (16.1 mmol per liter); and serum creatinine, 0.9 mg per deciliter (79.6 μmol per liter). The reticulocyte count was 7.4 percent; the level of haptoglobin was 1 mg per deciliter (normal range, 22 to 239), and the level of lactate dehydrogenase 891 U per liter (normal range, 6 to 200). The direct antiglobulin test (Coombs' test) was positive. The prothrombin time was 14.0 seconds (international normalized ratio, 1.3); the C-reactive protein level was 19 mg per deciliter (normal range, 0 to 0.6), and the serum ferritin level 4240 ng per milliliter (normal range, 18 to 320). Analysis of a peripheral-blood smear revealed burr cells and ovalocytes; the platelet count was low, with no evidence of platelet clumping. No spherocytes were seen. The results of hemoglobin electrophoresis and chest radiography were normal.
Several of the laboratory abnormalities — the elevated levels of C-reactive protein, hepatic aminotransferases, and serum ferritin — are consistent with a flare of adult-onset Still's disease. The low-to-normal leukocyte count, however, argues against this diagnosis. The hemoglobin and hematocrit levels indicate severe anemia. The elevated reticulocyte count, along with the elevated level of serum lactate dehydrogenase and low level of serum haptoglobin, suggests hemolysis. However, the reticulocyte production index (percentage of reticu-locytes x x 0.5) is low at approximately 1.6 (a value of 2.0 or greater represents an adequate marrow response), suggesting that the anemia may be multifactorial or that the bone marrow has not completely responded. The positive result of the direct antiglobulin test indicates that autoimmune hemolytic anemia is probably present; this condition may be associated with adult-onset Still's disease, infection, or even cancer (such as Hodgkin's disease or leukemia). Curiously, the peripheral-blood smear did not reveal spherocytes, which are usually present in patients with autoimmune hemolytic anemia; false positive Coombs' tests have been reported. Although the findings are still consistent with a flare of adult-onset Still's disease, an infection of some type remains a serious concern and should be ruled out.
The patient was admitted to the hospital and received a blood transfusion. Stress doses of corticosteroids were administered, with a substantial improvement in his symptoms of polyarthritis. Serum glucose levels were controlled with insulin. Blood cultures were positive for Salmonella enterica serotype typhimurium (hereafter referred to as S. typhimurium). Treatment with levofloxacin and aztreonam was initiated.
The positive blood cultures for S. typhimurium explain the hypotension and perhaps the arthritis, but also raise some questions. The source of the bacteremia is still unclear. Bacteremia develops in a small percentage of patients with gastrointestinal salmonellosis. The patient reported no diarrhea or abdominal pain. Bacteremia without gastrointestinal disease may suggest endocarditis or an arterial infection, especially in patients with aortic atherosclerosis. Thus, in the absence of gastroenteritis, patients with salmonella bacteremia should always be evaluated for endovascular infection.
It is also unclear whether the symptoms in the patient's joints are due to septic arthritis or a reactive arthropathy. Reactive arthritis is a well-described complication of enteric infection with salmonella, shigella, campylobacter, or yersinia. Wrists, ankles, and knees are commonly involved. This patient's infection may have triggered an inflammatory response that exacerbated his chronic arthritis due to adult-onset Still's disease. However, synovial-fluid analysis and culture are necessary to rule out septic arthritis.
Bacteremia may activate the coagulation system, resulting in either isolated thrombocytopenia or disseminated intravascular coagulation. The absence of schistocytes on the peripheral-blood smear argues against a diagnosis of disseminated intravascular coagulation in this case. Autoimmune hemolytic anemia may also occur with infection, but salmonellosis is not among the commonly associated infections.
A transthoracic echocardiogram revealed that the systolic function and chamber sizes were normal; there was no valvular dysfunction, evidence of vegetations, or pericardial effusion. The patient's condition improved with antibiotic therapy, and his fever resolved. However, he continued to have episodes of sinus tachycardia. Synovial-fluid analysis was not performed, since the polyarthritis was considered to be consistent with a flare of adult-onset Still's disease, and the arthritis had responded to stress doses of corticosteroids.
Persistent tachycardia could suggest the presence of pericarditis or myocarditis as a complication of adult-onset Still's disease or myocardial dysfunction due to sepsis — but the echocardiogram did not suggest any of these conditions. A careful examination for peripheral stigmata of infectious endocarditis should be conducted, and a transesophageal echocardiographic study should be considered. It would also be important to reevaluate the patient's anemia and volume status, since these factors may contribute to tachycardia. I still wonder about the underlying source of the salmonella bacteremia; this avenue clearly needs to be further explored with repeated physical examination and more imaging studies.
Computed tomographic (CT) scanning of the chest, abdomen, and pelvis was performed to look for a source of the bacteremia. This procedure revealed multiple left periaortic lymph nodes, the largest of which was 10 mm in diameter. Located caudal to these nodes was a focal saccular aneurysm, 1.9 cm by 1.6 cm, along the left posterior aortic margin. In the adjacent left psoas muscle was a rim-enhancing fluid collection, 2.2 cm by 1.2 cm, which was in part contiguous with periaortic and adventitial tissue (Figure 1). The presence of moderate splenomegaly was also reported. There were signs of atherosclerotic plaques in both common and internal iliac arteries, but there was no evidence of atherosclerosis in the aortic wall.
Figure 1. An Abdominal CT Scan Obtained after the Administration of Oral and Intravenous Contrast Material.
A focal saccular aneurysm is present along the left posterior aortic margin (black arrow). Adjacent to this aneurysm is a rim-enhancing fluid collection in the proximal left psoas muscle, suggesting an abscess (white arrow).
The clinical and radiographic features are suggestive of salmonella-related infectious aortitis with reactive lymphadenopathy and the extension of an inflammatory pseudoaneurysm. Alternatively, these features could represent a psoas abscess with contiguous spread to the abdominal aorta. Either scenario would explain the patient's sepsis and tachycardia. S. typhimurium is frequently isolated from patients with infectious aortitis, especially those with atherosclerosis. The gastrointestinal tract is probably the source of infection; bacteremia is most likely to occur in patients with inadequate host defenses. Salmonellae may adhere to damaged arterial walls. CT scans usually suggest the diagnosis of infectious aortitis; however, aortography or magnetic resonance angiography should be performed to delineate the extent of the aneurysm and to plan for surgical resection.
Aortography showed an infrarenal abdominal aortic saccular aneurysm that was located 1 cm from the inferior mesenteric artery (Figure 2). The patient was taken to the operating room, and examination of the opened aorta revealed an aneurysm. At the posterolateral aspect, an area of the aorta had completely degenerated, and a false aneurysm had formed. The aneurysm was resected, and the iliopsoas abscess drained. Culture of the resected aortic wall grew S. typhimurium. There was no evidence of atherosclerosis in the aortic wall. The patient's symptoms resolved after surgery. Treatment with levofloxacin was continued for six weeks. Five months after admission, the patient felt well and returned to full-time employment.
Figure 2. Abdominal Aortogram.
A saccular aneurysm is present in the distal infrarenal abdominal aorta (arrow). The irregularities in the bilateral common iliac arteries and internal iliac arteries are consistent with atherosclerotic involvement.
Commentary
Salmonellae are gram-negative, facultative anaerobic bacteria that are widely distributed in nature. S. typhi and S. paratyphi cause typhoid fever, whereas organisms in the larger group of nontyphoidal salmonella serotypes typically cause gastrointestinal illness. Among the nontyphoidal salmonellae isolated from infected patients in the United States, S. typhimurium is the most common.1 Human infection with nontyphoidal salmonellae is typically acquired by ingestion of contaminated food. Despite improvements in food processing and in sanitation, the incidence of salmonellosis remains high; in the United States, it is estimated that there are about 2 million cases each year.2
Whereas most nontyphoidal salmonella infections result in short-lived gastroenteritis, bacteremia develops in approximately 5 percent of infected patients.3 In some cases, the initial gastrointestinal infection may be subclinical. Bacteremia is most likely to occur in immunocompromised hosts such as those who are at either extreme of the age spectrum or those who have diabetes or cancer, who are infected with the human immunodeficiency virus, or who use immunosuppressive medications.3 When bacteremia occurs, extraintestinal signs and symptoms may include osteomyelitis, abscess formation, and meningitis.3 In additional, salmonellae may adhere to endothelial surfaces, resulting in cardiovascular infections, such as infectious endocarditis and endarteritis. Although atherosclerotic blood vessels are more susceptible to bacterial adhesion,4 infection of normal endothelial surfaces can also occur. The organisms may infect preexisting aneurysms or atherosclerotic plaques, leading to arterial-wall necrosis and rapid aneurysm formation. The most frequently involved site is the infrarenal abdominal aorta.5 Risk factors for infective endarteritis, in addition to atherosclerosis, include diabetes mellitus and immunosuppression.5
Cardiovascular infections — with a slight predominance of cases of endarteritis — develop in approximately 25 percent of patients with salmonella bacteremia.5,6 In a review of 140 cases, the mean age of patients in whom salmonella aortitis developed was 61 years.7 Most patients initially have an indolent condition; fever, abdominal pain, back pain, and leukocytosis are common manifestations.5,7 A diagnosis of salmonella aortitis should be considered in any adult with salmonella bacteremia, particularly in the absence of associated gastrointestinal symptoms. CT performed with contrast material is considered to be the imaging method of choice.5 Features that might suggest this diagnosis include a saccular aneurysm, gas in the aneurysmal sac, and periaortic soft-tissue fluid.5 Infective endarteritis usually has a poor prognosis, which is the result of the high rate of failure of medical therapy alone. Treatment usually requires surgical resection and a prolonged course of antibiotics.
This patient's case was challenging in that several features were absent that might have suggested the correct diagnosis, such as abdominal pain, back pain, and leukocytosis. The patient's history of adult-onset Still's disease further complicated the picture. His fever, the pattern of polyarthritis, the presence of splenomegaly, and the high serum levels of ferritin were all typical symptoms of a flare of adult-onset Still's disease, leading the team caring for him to believe that he did indeed have a recurrence of the disease along with the infection. We have anecdotal evidence of a few patients who had flares of adult-onset Still's disease that appeared to be triggered by systemic infection. An association between disease flares and infection — especially in the upper respiratory tract — has been reported in children with Still's disease.8 Furthermore, the polyarthritis in this patient responded quickly to stress doses of corticosteroids before antibiotic treatment was initiated. Nevertheless, as the discussant noted, synovial-fluid analysis would have been appropriate to rule out septic arthritis.
The patient's hematologic findings, such as anemia, were probably multifactorial. In addition to hemolysis, other probable causes were leakage from the aortic aneurysm, anemia of chronic disease, and sepsis. The history of adult-onset Still's disease and autoimmune hepatitis increases the patient's risk for other autoimmune conditions, including autoimmune hemolytic anemia.9 In a review of 62 patients with adult-onset Still's disease, the majority of patients had a normochromic, normocytic anemia with a hemoglobin level that was no more than 10 g per deciliter, a white-cell count greater than 15,000 per cubic millimeter, and a platelet count between 120,000 and 1,118,000 per cubic millimeter.10 Thrombocytopenia and leukopenia in this patient could have been related to sepsis, although immune-mediated consumption of platelets and white cells is a possible explanation.
This case highlights the importance of diligently searching for infection in patients with rheumatic conditions before attributing systemic illness to a flare of the underlying rheumatic disease. Indeed, infection is one of the leading causes of death in a number of systemic autoimmune diseases, including adult-onset Still's disease.10 In the majority of cases, definitive treatment for the flare of rheumatic or autoimmune disease should be delayed until infection has been ruled out. This is especially important because active autoimmune diseases are usually treated with immunosuppressant medications. Once bacteremia is identified, the discussant's approach also underscores the need to routinely consider the source, a truism especially valid for salmonella species.
Supported by a Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs and a Patient Safety Developmental Center Grant (P20-HS11540) from the Agency for Healthcare Research and Quality (both to Dr. Saint).
We are indebted to Dr. Kyung J. Cho from the Department of Radiology at the University of Michigan for his help.
Source Information
From the Department of Internal Medicine, University of Michigan (A.H.S., S.S., R.W.I.); the Ann Arbor Veterans Affairs Health Services Research and Development Center of Excellence (S.S.); and the Patient Safety Enhancement Program, Ann Arbor Veterans Affairs Medical Center and the University of Michigan Health System (S.S.) — all in Ann Arbor; and the Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.S.B.).
Address reprint requests to Dr. Sawalha at the Division of Rheumatology, University of Michigan, 3918 Taubman Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, or at amr-sawalha@omrf.ouhsc.edu.
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