Nocardiosis

* The identification of Nocardia transvalensis, an unusual and probably underrecognized cause of nocardial infection, is clinically significant because of this species' resistance to aminoglycosides, a standard antinocardial therapy. Diagnosis requires analytic methods available predominately in reference laboratories. We report a case of disseminated infection with N transvalensis with primary pulmonary involvement and subsequent development of brain abscesses, and review the literature to date. Familiarity with the epidemiology, pathologic findings, and clinical significance of this and other unusual Nocardia species may increase early identification and antibiotic susceptibility testing in cases of nocardial infection.

(Arch Patrol Lab Med. 2003;127:224-226)

Nocardia is an uncommon cause of intracranial abscess, comprising 1% to 2% of cerebral abscesses. We report a case of disseminated nocardiosis with primary pulmonary involvement and secondary development of brain abscesses. The organism isolated was identified as Nocardia transvalensis, an unusual species resistant to some standard antinocardial therapies. Personnel involved in the diagnosis and treatment of Nocardia infections should be aware of the existence of several species with potentially clinically significant interspecies differences. Identification of some species requires analytic methods available predominantly in reference laboratories.

REPORT OF A CASE

Several months prior to admission, a 46-year-old man was diagnosed with lung cancer in Mexico and treated with radiation therapy. After moving to the United States, he was admitted with postobstructive pneumonia and headaches. Magnetic resonance imaging revealed multiple enhancing intracranial lesions, initially treated with dexamethasone for presumptive metastatic disease (Figure 1). In preparation for further treatment, the original biopsy slides were obtained from Mexico and were found to show only chronic inflammation. Attempted needle biopsy of the lung lesion yielded indeterminate results.

A right parietal craniotomy was performed with resection of intracranial masses. Frozen section evaluation showed a granulomatous/inflammatory process, and tissue was sent for culture. The culture isolate was tentatively identified as Nocardia asteroides. Treatment with trimethoprim-sulfamethoxazole, amikacin, and cefotaxime was initiated. The abscesses continued to enlarge, resulting in ventricular obstruction and hydrocephalus. The patient underwent 2 subsequent craniotomies for resection of a left caudate and multiple posterior fossa and occipital abscesses.

Isolates sent to the Mycobacterial/Nocardia Research Laboratory at the University of Texas Health Center (Tyler, Tex) for polymerase chain reaction and drug susceptibility testing were identified as N transvalensis, sensitive to trimethoprim-sulfamethoxazole and quinolones, and resistant to aminoglycosides. Amikacin (an aminoglycoside) was discontinued; levofloxacin (a quinolone) was initiated. The patients hospital course was further complicated by development of Corynebacterium jeikeium ventriculitis, which was treated with systemic and intrathecal vancomycin. The patients neurologic status continued to deteriorate, and he died approximately 2 months after admission. An autopsy was performed.

PATHOLOGIC FINDINGS

The initial cerebral abscess surgical resection yielded 2 ovoid, encapsulated, tan-yellow to white portions of tissue measuring 2 cm and 1.5 cm in maximum dimension. On cut section, the larger specimen contained abundant green, purulent material, while the smaller had a dull, light tan, homogenous cut surface. Microscopic evaluation demonstrated multiple confluent microabscesses with necrotic centers rimmed by a mixed inflammatory infiltrate, consisting primarily of lymphocytes and neutrophils. The surrounding brain parenchyma showed gliosis.

An acid-fast stain for mycobacterium was negative. A Gomori methenamine silver stain showed abundant delicate filamentous bacteria with frequent right-angle branching (Figure 5, a). A tissue Gram stain displayed the beaded character of these organisms (Figure 5, b).

At autopsy, significant findings included dense pleural fibrosis of the upper two thirds of the left lung, with adhesions to the adjacent parietal pleura. On cut surface, the left lung had multiple, confluent, cavitating abscesses in the left upper lobe and upper portion of the left lower lobe. The largest abscess measured 5 x 3 x 2.5 cm and was in the lower lobe (Figure 3). Abscesses had fibrous rims ranging in width from

The brain showed extensive postsurgical changes, including a small occipital subdural hematoma, sutures within the dura, and a ventriculostomy tract in each frontal lobe. There was cerebral edema with slight uncal and cerebellar tonsillar prominence without frank herniation. The right temporal-parietal region and right cerebellar hemisphere had areas of softening. Coronal sections of the cerebral hemispheres showed several abscesses in the right thalamus (Figure 2), right and left caudate nuclei, right pulvinar, right corpus callosum, and bilateral occipital horns. The left caudate lesion appeared to have ruptured into the lateral ventricle, causing obstruction of the foramen of Monroe and dilation of the left ventricle.

Microscopic sections of both lung and brain showed abscesses with a mixed inflammatory infiltrate composed of neutrophils, lymphocytes, and extensive granulomatous inflammation, including multinucleated giant cells (Figure 4). Numerous organisms as previously described were clearly demonstrated with the Gomori methenamine silver stain.

Cultures of blood, cerebrospinal fluid, and lung tissue taken at autopsy were negative for Nocardia and other organisms.

COMMENT

This case raises a variety of issues. The differential diagnosis of a pulmonary mass with associated brain masses includes both infectious and neoplastic processes. The case vividly illustrates how historical information (eg, a prior diagnosis of cancer), while often helpful to the pathologist, can be misleading and must be considered in the context of the pathologic findings. Although an uncommon agent, Nocardia can cause pulmonary infection in immunocompetent as well as immunocompromised patients, and must be considered along with more common fungal and mycobacterial agents. The following discussion reviews the findings in disseminated nocardial infection, with particular attention to N transvalensis, the species isolated in this case.

Nocardia species are aerobic, gram-positive, partially acid-fast, slender (about 1 (mu)m wide), filamentous bacteria with frequent right angle branching. Despite resemblance to fungi in colonial and microscopic morphology, as well as clinical infections, Nocardia are true bacteria, in the order Actinomycetales. Most infections begin in the lung following inhalation of these ubiquitous soil organisms, or in the skin after local traumatic inoculation. Infections may be self-limited or progressive. Hematogenous dissemination, usually from a primary pulmonary focus, most commonly involves the central nervous system and skin, although any organ may be affected.

Clinical and autopsy studies demonstrate that 15% to 44% of patients with systemic nocardial infections have cerebral abscesses, which may be single (54%) or multiple (32%).1 Less commonly, meningitis with or without associated abscess is seen. Nocardia is more common in immunocompromised patients. Thirty percent of patients with brain abscesses and as many as 50% of patients with nocardiosis in any location are reported to have impaired immune function; however, many patients have no reported immune dysfunction.2 When present, the predominant underlying conditions are chronic steroid use and prior organ transplant. Nocardial disease of the central nervous system is surprisingly uncommon in patients with human immunodeficiency virus infection, who comprised only 5% of cases of nocardial brain abscess in one study.1 Overall, the mortality rate for nocardial abscesses (31%) is high compared with other bacterial brain abscesses (

Histologically, nocardial brain abscesses show purulent exudate surrounded by variable amounts of fibrosis. They can be multiloculated. A granulomatous reaction is rare, and giant cells are very rare. The organisms (1 (mu)m in diameter branching bacteria) can be seen in routine hematoxylin-eosin preparations and are clearly seen with methenamine silver stain.

While most nocardial infections are due to N asteroides, other pathogenic species have been isolated, most commonly Nocardia brasiliensis and Nocardia otitidiscaviarum (formerly Nocardia caviae). Intrinsic interspecies differences include predisposing conditions, virulence, and antibiotic resistance.3 Infections with N transvalensis, the pathogen in this case, produce clinical manifestations similar to those caused by N asteroides. However, N transvulensis is frequently resistant to aminoglycosides, including amikacin, an important second-line or adjunctive parenteral antimicrobial for patients with nocardial infections of the central nervous system.

The frequency of reports of N transvalensis in the literature may be deceptively low. Only 25 cases of N transvalensis have been reported in the literature to date, with clinical manifestations including local colonization without disease, localized superficial infection (mycetoma), localized ocular infection, mild chronic respiratory infection, and fatal disseminated disease, including spread to the central nervous system.3-9 However, reference centers that routinely test for N transvalensis found it in 3% (45/1482) of clinical nocardial isolates submitted to 2 Texas laboratories during a 20-year period and in 4.2% (15/359) of the clinical isolates identified in a Queensland, Australia, laboratory during an 11-year period.10 This discrepancy appears to be largely due to the unavailability in community hospitals of the tests required for identification of these infrequent clinical isolates, and to the low level of suspicion for unusual or resistant Nocardia species. Nocardia farcinica is another rare Nocardia species that can produce localized or disseminated infection, particularly in immunocompromised individuals.11 It is resistant to a variety of antibiotics used to treat N asteroides; it is also indistinguishable from N asteroides by routine laboratory methods.12 Antibiotic susceptibility testing is essential for selection of appropriate therapy.11-13 Therefore, accurate identification and in vitro antibiotic susceptibility testing are essential in any nocardial infection and should improve clinical outcome, with lower morbidity and mortality.

Accepted for publication April 24, 2002.

References

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2. McNeil MM, Brown JM, Georghiou PR, Allworth AM, Blacklock ZM. Infections due to Nocardia transvatensis: clinical spectrum and antimicrobial therapy. Clin Infect Dis. 1992;15:453-463.

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6. Schiff TA, Goldman R, Sanchez M, et al. Primary lymphocutaneous nocardiosis caused by an unusual species of Nocardia: Nocardia transvalensis. J Am Acad Dermatol. 1993;28:336-340.

7. Mirza SH, Campbell C. Mycetoma caused by Nocardia transvalensis. I Clin Pathol. 1994;47:85-86.

8. Weinberger M, Eid A, Schreiber L, et al. Disseminated Nocardia transvalensis infection resembling pulmonary infarction in a liver transplant recipient. Eur Clin Microbiol Infect Dis. 1995;14:337-340.

9. Dyer JR, Ketheesan N, Norton RE, Ashhurst-Smith Clj, Keary P, La Brooy JT. Disseminated infection due to Nocardia transvalensis coincident with Cryptococcus neoformans variety gattii meningitis. Eur J Clin Microbiol Infect Dis. 1999; 18:587-590.

10. Wilson RW, Steingrube VA, Brown BA, et al. Recognition of a Nocardia transvalensis complex by resistance to aminoglycosides, including amikacin, and PCR-restriction fragment length polymorphism analysis. J Clin Microbiol. 1997; 35:2235-2242.

11. Torres OH, Domingo P, Pericas R, et al. Infection caused by Nocardia farcinica: case report and review. Eur J Clin Microbiol Infect Dis. 2000;19:205212.

12. Miralles GD. Disseminated Nocardia farcinica infection in an AIDS patient. Eur J Clin Microbiol Infect Dis. 1994; 13:497-500.

13. Peters BR, Saubolle MA, Costantino JM. Disseminated and cerebral infection due to Nocardia farcinica: diagnosis by blood culture and cure with antibiotics alone. Clin Infect Dis. 1996;23:1165-1167.

Rebecca F Yorke, MD; Emilie Rouah, MD

From the Department of Pathology, Baylor College of Medicine, Houston, Tex.

Reprints: Rebecca Yorke, MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

Copyright College of American Pathologists Feb 2003
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