Yersiniosis

Case Management Study

Walter Reed Army Medical Center

Introduction

A 39-year-old active duty Caucasian Lieutenant Colonel stationed in Saudi Arabia was seen at Walter Reed Army Medical Center for evaluation of back pain and arthritis. He initially noted the back pain after exercising in a gymnasium 3 1/2 weeks prior to evaluation. He sought medical attention, was diagnosed with low back strain, and was treated with ibuprofen and cyclobenzaprine. Although initially he noted improvement, the back pain persisted. Five days before evaluation, he developed pain and swelling in his right knee, bilateral ankles, and left elbow with associated fever, malaise, dyspnea, headache, and nonproductive cough. He denied shortness of breath, weakness, parasthesias, and the use of any other medications.

1. Regarding acute inflammatory arthritis in U.S. military personnel, which of the following is CORRECT.

a. Viral arthritis commonly presents as an acute polyarthritis.

b. Acute gout in military-aged males would be unusual.

c. Staphylococcus aureus commonly causes polyarticular disease in healthy active duty personnel.

d. Lyme disease is endemic to the Saudi Arabian peninsula.

e. Outbreaks of acute rheumatic fever in military recruits have not been reported since the early 1970s.

The differential diagnosis of inflammatory arthritis in military-aged individuals is extensive and broadly includes both infectious and inflammatory etiologies. Among infectious etiologies, viral illnesses commonly may present with an acute arthritis, especially polyarthritis (more than five joints). Common viruses causing acute polyarthritis include parvovirus, hepatitis B and C viruses, rubella, mumps, enterovirus, herpesvirus, adenovirus, and human immunodeficiency virus infection. Gout is a common cause of inflammatory etiology in males after they reach adolescence, that generally presenting as a monoarticular process. Females are typically not at risk for gout until they reach menopause, except in rare instances of purine metabolism enzymatic deficiencies or defects in the renal handling of uric acid. Lyme disease may present with acute polyarthritis (or monarthritis), but the causative organism has not been isolated from the Saudi Arabian peninsula. Neonates and the elderly, not otherwise healthy young or middle-aged adults are at the highest risk for staphylococcal joint infections. Although the incidence of acute rheumatic fever had been declining for decades, except for sporadic outbreaks in American school children, there have been recent reports of outbreaks of acute rheumatic fever in military recruits in California and Missouri.1

On examination, the patient had a blood pressure of 136/90 mm Hg, a heart rate of 140 bpm, and a temperature of 102 deg F. His respiratory rate was 22 breaths per minute. He was well developed and well nourished, but appeared to be ill. His examination was remarkable for dry mucous membranes, but no ulcers or adenopathy. Cardiac examination was remarkable only for tachycardia. His lungs were clear to auscultation and percussion. His neurological examination was normal; specifically, there were no meningeal signs. His most notable abnormalities were in his skin and joint examinations. He had marked synovitis and periarticular swelling in both ankles and tenderness in his left elbow. An erythematous, warm, tender, and confluent papulonodular rash extended from his ankles proximally to his lower leg (Fig. 1).

2. A broad differential diagnosis of papulonodular lesions associated with arthritis would include both inflamnatory and infectious etiologies. All of the following should be considered in this soldier EXCEPT:

a. Systemic lupus erythematosus

b. Inflammatory bowel disease

c. Sarcoidosis

d. Mycobacterial infections

e. Lyme disease

The diagnosis of rheumatic diseases is often based on pattern recognition. This soldier presents with a syndrome of arthritis, rash, and fever. Often the skin is the most accessible tissue to biopsy and ultimately may help to determine the diagnosis, or at least narrow the possibilities. Papulonodular lesions associated with arthritis occur in primary immune-mediated syndromes (systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, Behcet's syndrome, and numerous forms of vasculitis); infections (neisserial, rheumatic fever, syphilis, fungal, mycobacterial, numerous viruses, and subacute bacterial endocarditis); and miscellaneous conditions (diabetes mellitus, hyperlipidemia, gout, and thyroid disease). Lyme disease is frequently associated with a rash that may include macules, papules, erythema, urticaria, an evanescent rash, or a malar rash. Erythema migrans is the classic rash occurring with early localized Lyme disease, occurring within days to 1 month after the tick bite. The lesion may be uniformly red or have a more complex "bull's-eye" appearance due to central clearing. Nodular lesions would be very atypical for Lyme disease.

He was volume resuscitated and a work-up was started. Initial laboratory evaluation was as follows (normal values in parentheses): 11,100/mm3 white blood cell count, 76% polymorphonuclear neutrophils, 14% lymphocytes, 9% mononuclear cells (4,800-10,800/mm3), 14.6 g/ldL hemoglobin (14-18 g/dL), 309,000/mm3 platelets (130,000-400,OOO/MM3), 45 mm/ hour erythrocyte sedimentation rate (0-15 mm/hour), 17.29 mg/dL C-reactive protein (0.02-5.00 mg/dL). Initial radiographs of his ankles showed only soft tissue swelling and his chest radiograph was normal. During his inpatient stay, he continued to have daily fevers and headaches. His major complaint was constant pain associated with the erythematous lesions on his lower legs and ankles. His back pain resolved without any specific therapy. Dermatology was consulted and performed a biopsy of the erythematous lesions on his lower legs. Biopsy results revealed a septal panniculitis, consistent with erythema nodosum.

3. Erythema nodosum has been associated with all the following EXCEPT.

a. Blastomycosis

b. Streptococcal infection

c. Behcet's disease

d. Vitamin B12 deficiency

e. Sarcoidosis

Erythema nodosum is characterized by painful erythematous nodules on the anterior surface of both legs.

They frequently are numerous and may become confluent, leading to diagnostic confusion as it did in this patient. The nodules may evolve into bruise-like lesions. Regardless of its appearance, erythema nodosum typically resolves over a 2- to 8-week period without scarring or ulceration. Current hypotheses on the etiology of erythema nodosum suggest that the lesions represent a delayed hypersensitivity reaction to antigens associated with various infectious agents, drugs, and other diseases. The most common causes of erythema nodosum include idiopathic, infections, drugs, sarcoidosis, and other conditions (Fig. 2).2 Of the infectious etiologies, non-streptococcal upper respiratory infections, group A Streptococcus, tuberculosis, Escherichia coli, and Brucella are the most common. Several fungi, including blastomycosis, have also been associated with erythema nodosum. Antibiotics such as ampicillin, erythromycin, and other agents may also be associated with this condition. Other recognized syndromes associated with erythema nodosum include Sweet's syndrome, Behget's syndrome, malignancy, and inflammatory bowel disease. B 12 deficiency has not been associated with erythema nodosum.

By day 7 of the patient's hospitalization, his ankle pain and swelling improved markedly but the erythema nodosum lesions continued to migrate proximally on his legs. A highresolution computed tomographic scan of his lungs revealed right hilar adenopathy with the largest lymph node measuring 1.1 cm. A transbronchial biopsy was nondiagnostic. The pulmonary diffusing capacity for carbon monoxide (DLCO) was moderately reduced (69% of predicted).

Because the patient continued to have constitutional symptoms and because of the concern of the providers for possible malignancy, a repeat high-resolution computed tomographic scan of his lungs was performed. This revealed interval enlargement of his right hilar adenopathy with the largest lymph node now measuring 1.4 cm. To reduce any diagnostic uncertainty, a mediastinoscopy was performed and multiple lymph node biopsies were taken.

4. Conditions causing hilar adenopathy and erythema nodosum include all of the following EXCEPT.

a. Sarcoidosis

b. Cat scratch disease

c. Histoplasmosis

d. Hodgkin's disease

e. Tuberculosis

The differential diagnosis of hilar adenopathy associated with erythema nodosum is quite limited and includes sarcoidosis, tuberculosis, coccidioidomycosis, histoplasmosis, Hodgkin's disease, blastomycosis, chlamydial infection, and yersiniosis. Although cat scratch disease, caused by Bartonella henselae, is frequently associated with lymphadenopathy, the location of the adenopathy depends on the site of inoculation. Hilar adenopathy would therefore be rare. Cat scratch disease has not been associated with erythema nodosum.

Additional laboratory studies were obtained. The following tests were either normal or negative: complement levels, antinuclear antibody, Brucella titers, stool cultures, stool guaiacs, blood cultures, human immunodeficiency virus, parvovirus titers, and angiotensin-converting enzyme levels. Tuberculin and fungal skin testing were negative. Lymph node biopsies revealed confluent, well-formed noncaseating granulomas consistent with sarcoidosis.

5. The most appropriate initial treatment for this patient would be:

a. Prednisone, 60 mg orally every day

b. Hydroxychloroquine, 200 mg orally twice a day

c. Indomethacin, 50 mg orally three times a day

d. Methotrexate, 10 mg orally every week

e. Azathioprine, 100 mg orally every day

Sarcoidosis is a systemic granulomatous disorder that frequently affects young adults. Although all organ systems may be involved in sarcoidosis, the most common sites of involvement are the lungs, reticuloendothelial system, skin, eyes, myocardium, and musculoskeletal systems.

It is useful to divide the types of arthritis associated with sarcoidosis into acute and chronic presentations. Common acute presentations include inflammatory arthritis of peripheral joints, especially the ankles, knees, elbows, wrists, and hands. The acute arthritis frequently occurs with onset of the disease, remits over a short period of time, and is not associated with joint destruction. Conversely, chronic forms may occur at any time during the illness and is associated with granulomatous osseous involvement, joint destruction, and disability.

Therefore, initial therapy for this patient should include either observation or non-steroidal anti-inflammatory agents (NSAIDs). Any NSAID, including indomethacin, would be appropriate. In patients without systemic symptoms, it may be appropriate to simply observe the patient. Prednisone may be useful as second-line therapy if NSAIDs do not effectively control the patient's symptoms. Typical prednisone doses are in the range of 10 to 25 mg/day. Higher doses would be reserved for more chronic manifestations of sarcoidosis, especially progressive or refractory major organ involvement (i.e., central nervous system, muscle, pulmonary, or hepatic disease). In acute sarcoid arthritis, there is no role for immunosuppressive agents such as hydroxychloroquine, methotrexate, or azathioprine. However immunosuppressive medications may be necessary to treat more chronic, persistent forms of arthritis associated with sarcoidosis. Interestingly, another treatment for erythema nodosum that was originally used by the turn of the century dermatologists and was then recently "rediscovered" is potassium iodide, 300 to 900 mg orally every day.

After 1 week of treatment with indomethacin, 50 mg orally three times a day, the patient's fever and arthritis resolved. Within I month of his initial presentation, the patient's erythema nodosum had completely resolved and he had no further constitutional or musculoskeletal symptoms.

Discussion

Lofgren's syndrome is an acute clinical presentation of sarcoidosis manifested by erythema nodosum, hilar adenopathy, and arthritis. It is named after Sven Lofgren (1910-1978), a Swedish physician who studied sarcoidosis.3 As in this patient, the skin lesions and articular manifestations are often intensely painful. The erythema nodosum disappears in 1 to 2 months and the joint symptoms within 2 years. In fact, the presence of erythema nodosum has been noted as the best predictor of a good prognosis in patients with sarcoidosis.4 Lofgren's syndrome may be accompanied by fevers, arthralgias or arthritis, anterior uveitis, and pulmonary involvement. Several authors have noted that periarticular ankle inflammation with or without true arthritis is typical of Lofgren's syndrome.5 In a typical case of Lofgren's syndrome, biopsy confirmation of the diagnosis is not necessary. However, if clinical, laboratory, and radiologic findings are atypical then a biopsy may be necessary to rule out tuberculosis, lymphoma, or other malignancy.

Lofgren's syndrome is generally self-limited and has an excellent prognosis. A recent prospective study at a university hospital in Barcelona, Spain sought to evaluate the clinical features and outcomes of 186 patients with Lofgren's syndrome who were diagnosed from 1974 to 1996, They found that the mean age at presentation was 37 t 11 years and 85% were women. At the time of diagnosis, 87% had no respiratory symptoms. A decreased vital capacity was noted in 5% and a decreased carbon monoxide diffusing capacity in 15%. In the 133 patient patients who were followed up for at least 5 years, only 8% continued to have active disease.6

Because sarcoidosis commonly presents in military-aged individuals, it is clearly relevant to military caregivers. A recent epidemiologic study of military and veteran populations found that African Americans were at a three- to four-fold greater risk than Caucasians to be diagnosed with sarcoidosis,7 and have more severe disease manifestations with a seven-fold increased odds of hospitalization.8 Therefore, sarcoidosis is common in military-aged men and women, especially among African Americans, who currently represent 20.4% of the U.S. military.9 Military physicians need to be familiar with the more common chronic presentations of sarcoidosis, but also with the less common acute presentations such as Lofgren's syndrome.

Answers to questions:

1. a

2. e

3. d

4. b

5. c

References

1. Bisno A: The resurgence of acute rheumatic fever in the United States. Annu Rev Med 1990: 41: 319-29.

2. Garcia-Porrua C, GonzAlez-Gay MA, Vazquez-Caruncho M, et al: Erythema nodosum: etiologic and predictive factors in a defined population. Arthritis Rheum 2000: 43: 584-92.

3. Lofgren S: Primary pulmonary sarcoidosis. Acta Med Stand 1953; 145: 424-31. 4. Mafia J, et al: Clinical factors predicting persistence of activity in sarcoidosis: a multivariate analysis of 193 cases. J Rheumatol 1996; 23: 874-7.

5. Mafia J, Salazar A, Manresa F: Clinical factors predicting persistence of activity in sarcoidosis: a multivariate analysis of 193 cases. Respiration 1994; 61: 219-25.

6. Mafia J, Gomez-Vaquero C, Abelardo M, et at: L6ofgren's syndrome revisited: a study of 186 patients. Am J Med 1999; 107: 240-5.

7. Rybicki B, Maliarik M, Major M, et al: Epidemiology, demographics, and genetics of sarcoidosis. Semin Respir Infect 1998; 13: 166-73.

8. McDonough C, Gray GC: Risk factors for sarcoldosis hospitalization among U.S. Navy and Marine Corps personnel, 1981 to 1995. Milit Med 2000; 165: 630-2. 9. Department of Defense Almanac 2000: Minorities in uniform. Available at: http://www.defenselink.mil/pubs/almanac/.

Guarantor: LTC William R. Gilliland, MC

Contributors: MAJ Michael A. Malloy, MC; LTC William R Gilliland, MC

Rheumatology Service, Walter Reed Army Medical Center, Washington, DC.

The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

Reprints: LTC William R. Gilliland, Rheumatology Program Director, Walter Reed Army Medical Center Building 2, Ward 77, Washington, DC 20307-5001; email: wgillland@usuhs.mil.

This manuscript was received for review in October 2001. The revised manuscript was accepted for publication in October 2001.

Reprint & Copyright (c) by Association of Military Surgeons of U.S., 2002.

Copyright Association of Military Surgeons of the United States Jan 2002
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