Disseminated actinomycosis: multisystem mimicry in primary care. (Case Report).

Actinomycosis is an invasive, destructive infectious syndrome caused by Gram-positive, branching, filamentous bacteria in the order Actinomycetales. The principal agent of human infections is Actinomyces israelii. Actinomycosis typically involves four anatomic sites, resulting in cervico-facial, thoracic, abdominal, or pelvic infection. Occasionally, however, dissemination of organisms, coupled with desmoplastic tissue reactions, produces protean clinical manifestations easily mistaken for other indolent infections or metastatic malignancies. (1) We report the case of a patient with disseminated actinomycosis with predominant orthopedic, dermatologic, and radiologic features mimicking several other illnesses. We also compare our findings with published cases in the literature.

Discussion

Our patient's findings are consistent with other published reports in which organisms invade tissues, produce a granular discharge, extend to contiguous structures across anatomic boundaries, and form indurated lesions with burrowing sinus tracts and fistulas. Several members of the order Actinomycetales can cause infection, most commonly Actinomyces israelii, a Gram-positive rod colonizing the mouth, gastrointestinal tract, and vagina in healthy individuals. Other agents causing identical disease include A. odontolyticus, A. naeslundii, A. meyeri, A. viscosus, Rothia dentocariosa, and Propionibacterium propionicus (formerly Arachnia propionica). (2) Although A. israelii can be isolated from the oral cavity, gastrointestinal tract, female genital tract, and occasionally the bronchi of healthy persons, it has never been cultured from nonhuman sources, and no instance of direct person-to-person spread has been proven. Although infection may occur in individuals of any age, actinomycosis is more common in middle decades of life and in men by a 3:1 ratio. Traumatic disruption of oral, pulmonary, enteral, or genital mucosa enables penetration of organisms into deeper tissues following surgical procedures or destructive conditions, such as infection or trauma (eg, fish bones, intrauterine devices). Solitary or multiple abscesses develop, with slowly progressive induration, fluctuation, central suppuration, and a fibrotic "wooden" texture easily mistaken for carcinoma. (2) Fistula formation across normal tissue planes accompanies chronic draining lesions, and may lead to invasion of viscera, joints, or the central nervous system (CNS). Recurrent or persistent draining abscesses of the mouth and neck are the most frequently reported manifestations of actinomycosis. Pulmonary involvement, with parenchymal masses, pleural thickening, and cavitation or empyema, can be mistaken for malignancy or tuberculosis, although extension across fissures or into mediastinum or bone should lead to consideration of actinomycosis. Abdomin al, pelvic, CNS, and musculoskeletal manifestations are myriad due to indolent progression of disease and multifocal involvement through hematogenous or fistulous invasion. Disseminated infection is, therefore, a clinician's challenge, for the panorama of findings often eludes noninvasive diagnosis and may lead to unnecessary surgical intervention.

At times, the diagnosis of actinomycosis is first established, not by the attending physician, but by the pathologist, after biopsy or resection for suspected malignancy. Demonstration of grains (granules) in purulent discharge or biopsy specimens has been emphasized as the crucial diagnostic maneuver in early recognition of actinomycotic infection. (2)

Gram's and modified acid-fast stains, culture, and histologic examination differentiate actinomycosis from similar infections, such as nocardiosis and botryomycosis. (3) Prolonged antibiotic therapy for 6 to 12 months, usually with penicillin or amoxicillin, is required due to poor drug penetration into fibrotic lesions, rather than organism resistance.

Our patient is unique because certain features of his illness have received only scarce attention in the literature. Fifty years ago, Weed and Baggenstross (4) analyzed 21 cases of actinomycosis with fatal outcomes and autopsy evidence of lung, liver, kidney, ovarian, CNS, and bone involvement with suppuration, sinus formation, and scarring. None of their patients, however, had the degree of multisystem involvement evident in our case. Browns reviewed the records of 181 patients with actinomycosis on file at the Armed Forces Institute of Pathology, 41 of whom were autopsied, and documented disease of orofacial and neck structures, lungs, pelvis, intestine, and kidney in 33, 27, 9, 8, and 6% of patients, respectively. Of the 18 instances of disseminated disease, 10 involved liver and lung only, in contrast to the dermal, pulmonary, mediastinal, renal, nodal, and musculoskeletal invasion in our patient. Weese and Smith (6) reviewed 57 cases from the University of Iowa, documenting cervicofacial, thoracic, and a bdominal infection in 50, 18, and 23% of the patients, respectively. Interestingly, hip involvement occurred in 4 cases (3%), and mediastinal spread was evident in 3 (2%), consistent with what we observed. Only 1 of 57 cases (0.5%) was described as having disseminated disease, and that patient already had metastatie renal carcinoma. The authors emphasized the difficulty of early diagnosis, in that only 4 (3%) of 57 cases were correctly diagnosed at hospital admission, while carcinoma, cellulitis, osteomyelitis, and tuberculosis were more commonly suspected, as was the situation in our patient. Six of their severely infected patients died, however, in contrast to the favorable outcome in our patient.

Bennhoff (7) compiled an extensive review of the historical aspects of actinomycotic infection in animals and people, and analyzed 32 human cases in Cleveland. The range of presumptive diagnoses was diverse: 11 malignancies, 7 dental abscesses or masses, 4 tuberculosis, 4 pneumonia, and 1 each of stroke, endometritis, pilonidal cyst, pulmonary embolus, classical" appendicitis, and, in a 12-year-old girl, lung cancer. Frequent confusion with pulmonary infection or malignancy was further illustrated in 5 cases reviewed by Ariel et al. (8) Each patient had experienced more than 6 weeks of persistent pulmonary symptoms, infiltrates or masses on chest x-rays, and poor or no response to antibiotic therapy. Bronchoscopy was required for definitive diagnosis. Mimicry of metastatic endometrial carcinoma has been reported in a 41-year-old woman in Chicago. with an IUD, weight loss, pulmonary and hepatic nodules, uterine enlargement, a large salpingo-ovarian abscess, recurrent abdominal wall masses, and a stormy surgica l course. (9) Confusion with metastatic renal cell carcinoma has been documented in a cachectic 62-year-old man in Toronto with weight loss, weakness, and a 15-cm left renal mass infiltrating the psoas musculature. (10) After percutaneous biopsy revealed granules of A. israelii instead of carcinoma, he underwent 1 year of penicillin therapy and had a dramatic clinical and radiologic recovery. A similar response occurred in our patient. Nephrectomy was avoided in the Canadian patient, as was thoracotomy in our patient.

Manifestations of A. israelii dissemination can mimic metastatic lung carcinoma in convincing fashion, as in the case of a 41-year-old man in San Diego with cough, cachexia, fever, nodular pulmonary lesions, anemia, ESR of 143 mm/h, and hypodense hepatic lesions highly suggestive of metastases. (11) Fine-needle aspiration of the liver revealed yellowish granules and filamentous, branching, Gram positive bacteria, with morphology similar to organisms noted in our patient. Two patients (12) in an Illinois Veterans Affairs Hospital were thought to have colon carcinoma based on persistent abdominal pain and radiologic evidence of abdominal masses measuring 12 to 15 cm. At laparotomy, each patient was found to have "sulfur granules" and filamentous organisms on histologic examination, documenting colonic actinomycosis and not malignancy, similar to the diagnostic sequence in our patient. Younger patients thought to have hepatic malignancies warrant consideration of actinomycosis, as was the case in a 35-year-old m an with weight loss, anemia, pleural rub, pulmonary nodules, mediastinal adenopathy, and a necrotic liver mass invading the right kidney. (13) Aspiration of the liver mass yielded sulfur granules and A. meyeri on culture. Marked improvement followed penicillin therapy, and no surgical intervention was required. In similar fashion, dissemination of A. meyeri in a 34-year-old man from Switzerland (14) with a pulmonary infiltrate, 10-cm paravertebral mass, thigh abscess, and ESR of 118 mm/h was attributed to invasive portals from poor oral hygiene, gingivitis, and carious teeth, as were observed in our patient. Another Swiss patient, a 47-year-old man, presented with osteomyelitis of the left knee, firm abscesses of the trunk with fistulization, an infiltrative mass in the right middle lobe of the lung, and severe anemia. (15) A. meyeri was documented by Gram stain and culture of a dermal abscess aspirate, as was performed in our patient, and clinical and radiologic resolution accompanied prolonged penicillin th erapy, also as in our case.

Neurologic manifestations, while less common, may accompany actinomycotic infection, as demonstrated in a 53-year-old college professor with headaches, status epilepticus, and an enhancing 2-cm parieto-occipital brain mass suggestive of lymphoma or glioma. (16) At craniotomy, Gram positive, filamentous, branching bacteria were demonstrated, with culture confirming A. odontolyticus infection, presumably invasive from a tooth capped 3 months previously. An apical tooth abscess Was detected, drained, and found to contain A. odontolyticus as well. Penicillin provided complete cure of oral and CNS disease. Finally, diagnostic delay despite longstanding purulent drainage is illustrated in the case of a 40-year-old woman in Nashville (17) with 13 years of milky drainage from the gingiva, 12 months of numerous, oozing flank nodules repeatedly incised and drained by surgeons, lung infiltrates refractory to antibiotics, and a large paraspinous mass extending from the diaphragm to the iliac crest, invading thoracic vert ebrae and the left kidney. An observant physician expressed pustular material from a dermal lesion and noted yellow flecks, again similar to our patient's case. Cultures yielded A. israelii. Complete resolution of the 3 typical forms of actinomycotic illness-recurring cervicofacial, thoracic, and abdominal infection-accompanied prolonged penicillin therapy, and further surgery was unnecessary. Several features of this case are reminiscent of the protracted illness, definitive diagnostic evaluation, and response to therapy described in our patient.

Conclusions

Since the publication of Israel's initial treatise (18) 125 years ago, actinomycosis has remained an illness that has frequently eluded diagnosis because of prolonged, multisystem manifestations and clinical mimicry. Clinicians would be wise to consider a diagnosis of actinomycosis in patients with chronic draining abscesses of the jaw, neck, or skin, especially if these lesions have indurated or burrowing margins. Actinomycotic infection should also enter the differential diagnosis of destructive masses of bony structures or thoracic, abdominal, or pelvic organs if such processes display fistulization, sinus tracts, or extension across usual anatomic tissue planes. Surgical intervention for suspected carcinoma is often avoidable in hindsight, and a gratifying response can follow prolonged antibiotic therapy. Our patient's case illustrates many of the diagnostic pitfalls of this chronic disorder, and the impressive resolution of widely invasive infection with appropriate recognition and focused treatment. As Russo (2) aptly stated, "An awareness of the full spectrum of disease manifestations will expedite diagnosis and treatment and minimize the unnecessary surgical interventions and morbidity and mortality that all too often occur with actinomycosis." In our view, Perlow et al (9) best summarized this syndrome: "In the patient with actinomycosis, awareness of the problem by the physician is the initial key to a successful treatment plan."

Acknowledgments

We thank Dr. Francis W. Chandler, Department of Pathology, and Dr. John F. Fisher, Department of Infectious Disease, Medical College of Georgia, for their clinical insights and manuscript review.

Accepted December 13, 2001.

References

(1.) Hinnie J, Jaqucs BC, Bell E, Hansell DT, Milroy R. Actinomycosis presenting as carcinoma. Postgrad Med J 1995;71:749-750.

(2.) Russo TA. Agents of actinomycosis, in Mandell GL, Bennett JE, Dolin R (eds): Mandell. Douglas, and Bennett's Principles and Practice of Infectious Diseases. Philadelphia, Churchill Livingstone, 2000, vol 2, ed 5, pp 2645-2653.

(3.) Chandler FW, Connor DH: Actinomycosis, in Connor DH, Chandler FW (cds): Pathology of Infectious Diseases. Stamford, CT, Appleton & Lange, 1997, vol 1, pp 391-396.

(4.) Weed LA, Baggenstross AH. Actinomycosis: A pathologic and bacteriologic study of twenty-one fatal cases. Am J Clin Pathol 1949;19:201-216.

(5.) Brown JR. Human actinomycosis: A study of 181 subjects. Hum Pathol 1973;4:319-330.

(6.) Weese WC, Smith IM. A study of 57 cases of actinomycosis over a 36-year period: A diagnostic "failure" with good prognosis after treatment. Arch Intern Med 1975;135:1562-1568.

(7.) Bennhoff DF. Actinomycosis: Diagnostic and therapeutic considerations and a review of 32 cases. Laryngoscope 1984;94:1198-1217.

(8.) Ariel I, Breuer R, Kamal NS, Ben-Day 1, Mogel P, Rosenmann E. Endobronehial actinomycosis simulating bronchogenic carcinoma: Diagnosis by bronchial biopsy. Chest 1991;99:493-495.

(9.) Perlow JH Wigton T, Yordan EL, Graham J, wool N, Wilbanks GD. Disseminated pelvic actinomycosis presenting as metastatic carcinoma: Association with the Progestasert intrauterine device. Rev Infect Dis 1991;13:1115-l119.

(10.) Khalaff H, Srigley JR, Klotz L.H. Recognition of renal actinomycosis: Nephrectomy can be avoided--report of a case. Can J Surg 1995;38:77-79.

(11.) Hennrikus EF, Pederson L. Disseminated actinomycosis. West J Med 1987;147:201-204.

(12.) Cintron JR, Del Pino A, Duarte B, Wood D. Abdominal actinomycosis. Dis Colon Rectum 1996;39:105-108.

(13.) Marty HU, Wust J. Disseminated actinomycosis caused by Actinomyces meyeri. Infection 1989; 17:154-155.

(14.) Liaudet L, Erard P, Kaeser P. Cutaneous and muscular abscesses secondary to Actinomyces meyeri pneumonia. Clin Infect Dis 1996;22:185-186.

(15.) Apotheloz C, Regamey C. Disseminated infection due to Actinamyces meyeri: Case report and review. Clin Infect Dis 1996;22:621-625.

(16.) Pauker SG, Kopelman RI. Clinical problem-solving: A rewarding pursuit of certainty. N Engl J Med 1993;329:1103-1107.

(17.) Sehlech WF III, Gelfand M. Alper B, Kaiser AB. Medical management of visceral actinomycosis. South Med J 1983;76:921-922.

(18.) Israel J. Neue Beobachtungen auf dem Bebiete der Mykosen des Menschen. Virchows Arch Pathol Anat 1878;74:15-53.

RELATED ARTICLE: Case Report

A 39-year-old black man presented with a 2-month history of right hip pain and swelling, with worsening limp. He had been evaluated 2 weeks previously in the emergency department, where a diagnosis of osteoarthritis was made. He was treated with anti-inflammatory medication without benefit. He further reported several months of left shoulder pain and nonhealing, painful, cutaneous ulcers located on the left arm, in the left axilla, and in the lumbosacral region. Fatigue and a 40-pound weight loss accompanied the skin lesions. He had been treated elsewhere for a variety of dermatologic conditions, including impetigo, folliculitis, scabies, pediculosis, and herpes simplex infection, without improvement. He denied hip trauma, fever, chills, sweats, pruritus, cough, hemoptysis, dysphagia, diarrhea, other joint pain, risk factors for human immunodeficiency virus (HIV) infection, and ingestion of sharp objects. His wife and three children were in good health.

Physical examination revealed a thin male in no acute distress. His temperature was 38.9[degrees]C. Severe periodontal disease was present, along with multiple upper and lower dental caries (Fig. 1). There was no cervical adenopathy. Cardiopulmonary and abdominal examinations were unremarkable. Perineal and rectal examinations revealed bilateral inguinal adenopathy and normal testicular contours. Stool sample was negative for occult blood. Neurologic examination revealed no deficits. A fluctuant, erythematous, warm, tender, 8-cm mass with indurated borders was noted over the right greater trochanter (Fig; 2). Multiple contiguous fresh and fibrotic ulcers were located over the lumbosacral region and buttocks, consistent with recent and chronic fistula formation (Fig. 3). A 3-cm fluctuant, tender mass was detected over the anterior left shoulder. A tender, 1-cm ulcer with surrounding erythema was located in the left axilla (Fig. 4). Multiple tender, indurated, shallow ulcers measuring 1 to 2 cm with erythematou s bases were noted over the left forearm (Fig. 5).

A complete blood cell count revealed a hemoglobin level of 6.7 g/dl, with mean cell volume (MCV) of 70 fL. Platelet count was elevated at 631,000/[mm.sup.3]. The white blood cell count was 13,000/[mm.sup.3], with 84% neutrophils, 10% lymphocytes, 5% monocytes, and 1% eosinophils. The erythrocyte sedimentation rate (ESR) was elevated (>150 mm/h). C-reactive protein level was 23.8 mg/dl (normal, 0-1). Blood chemistry test revealed a low albumin level of 2.2 g/dl and evidence of iron deficiency. Serum protein electrophoresis revealed decreased albumin level, with increased [alpha]-2- and [gamma]-globulin levels. Total serum immunoglobulin levels were normal, rapid plasmin reagin test was negative for syphilis, and the patient was HIV-negative. A tuberculin skin test and blood cultures were negative for microorganisms.

X-rays of the right hip revealed soft tissue swelling and fluid accumulation corresponding to the fluctuant area noted on physical examination. There was no bone destruction. Computerized tomography (CT) scans revealed abnormally enhancing fluid collections and soft tissue masses throughout the musculature of the right hip, right gluteus maximus, and proximal right thigh, all suggestive of abscess or neoplasm. Similar findings involved the contralateral iliopsoas muscle, extending into the extraperitoneal soft tissues of the left pelvis, paraspinous musculature, and presacral space. These findings were consistent with myositis, cellulitis, fasciitis, and small sinus tracts. Soft tissue effusion over the right hip was documented (Fig. 6), with focal fluid collections in the right buttock suggestive of abscess or hematoma. A large soft tissue density (Fig. 7) encircled the midportion of the esophagus with tracking to the right hemidiaphragm, suspicious for tumor or an infectious process. Numerous small pulmonar y densities were scattered throughout the right upper, lower, and middle lobes. A 1.5-cm lesion was noted in the right kidney, representing an abscess or complex cystic lesion. Prominent bilateral axillary and inguinal adenopathy and soft tissue stranding were consistent with an infectious process or malignancy.

Initial diagnostic considerations for the dermatologic findings included cellulitis, actinomycosis, nocardiosis, or fungal infections, such as blastomycosis, coccidioidomycosis, histoplasmosis, or cryptococcosis. The orthopedic manifestations were thought to represent osteomyelitis, septic arthritis, or tuberculosis. Esophageal, pulmonary, and myofascial findings with adenopathy were suggestive of lymphoma, meta-static carcinoma, endocarditis, mycobacterial infection, HIV infection, or some other form of immunodeficiency.

Bloody material aspirated from the left shoulder abscess contained many discrete, lemon yellow sulfur granules (Fig. 8). Microscopic examination of a crushed granule demonstrated branching, beaded, Gram positive, filamentous rods in tangled clusters (Fig. 9).

Orthopedic consultants felt that osteomyelitis was unlikely, based on the radiographic findings of normal bone. Aspiration of the right hip mass produced 3 ml of serosanguinous fluid, subsequently found to be negative for microorganisms with Gram stain and culture. Infectious disease consultants suggested that disseminated actinomycosis was highly likely. A periodontal portal of entry was postulated, followed by widespread visceral involvement. Subsequent culture of aspirated shoulder discharge yielded Actinomyces species that could not be further characterized by laboratories at the Medical College of Georgia or by the Centers for Disease Control and Prevention in Atlanta. Cultures for acid-fast bacteria and Nocardia species were negative.

Therapeutic recommendations included 6 weeks of parenteral treatment with ceftriaxone (2 g/d), followed by 1 year of oral amoxicillin therapy (1,500 mg/d). On hospital Day 5, a percutaneous catheter was inserted into the superior vena cava for home administration of IV antibiotics, and the patient was discharged home. Follow-up revealed that the hip pain had resolved and all cutaneous ulcers had healed within 2 weeks. Within 4 weeks, the anemia had resolved and the ESR had normalized. Follow-up chest CT 2 months after discharge showed complete resolution of the paraesophageal mass. The patient reported increased vigor and appetite, a 45-pound weight gain, and full return to work as a cook.

Key Points

* Actinomycosis typically involves cervicofacial, thoracic, and abdominal structures, with abscess formation and tissue destruction.

* The invasive nature of Actinomyces organisms results in indurated lesions crossing the usual tissue planes; this is often misdiagnosed as metastatic malignancy.

* Purulent discharge material from actinomycotic abscesses yields yellow sulfur granules and clusters of gram-positive, branching, filamentous rods, confirming the infectious etiology of this multisystem syndrome and predicting a good response to long-term antibiotic therapy.

From the Department of Family Medicine, Medical College of Georgia, Augusta, GA.

Reprint requests to Michael W. Felz, MD, Department of Family Medicine, Medical College of Georgia, HB 4032, Augusta, GA 30912.

Copyright [C] 2003 by The Southern Medical Association

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