49‐YEAR‐OLD TRANSPLANT RECIPIENT WITH FEVER AND ALTERED MENTAL STATUS

Clinical History and Imaging

A 49‐year‐old man presented with fever and altered mental status. He had a complex prior medical history notable for type I diabetes mellitus with end‐stage renal disease and peripheral vascular disease. Eight years prior to admission he underwent pancreatic and renal transplantation secondary to diabetes. The renal transplantation procedure was initially complicated by intra‐operative myocardial infarction, and subsequently by acute and chronic allograft rejection. Consequently, the patient had been on long‐term immunosuppressive therapy. He also suffered from chronic atrial fibrillation requiring warfarin and had undergone cardiac valve replacement one year earlier.

Upon admission for new onset of low‐grade fever, chills and disorientation, the patient was noted to have positive CMV IgG titers. His screening tests were negative for toxoplasmosis, HIV and HSV. Lumbar puncture revealed elevated leukocyte count (>600 with 89% neutrophils; 1% lymphocytes; 10% monocytes). Concurrently, a chest CT showed pulmonary edema with a right pleural effusion. Brain MRI and cultures were negative. The patient was empirically treated for meningitis and possible pneumonia with multiple broad‐spectrum antibiotics. However, pulmonary edema and dyspnea progressed over the course of his hospitalization, requiring increasing oxygen support.

Over the next few weeks, the patient exhibited worsening lethargy and developed a diffuse pustular rash on his extremities. Doxycycline was added to his regimen for concerns of possible rickettsial disease. Subsequent brain MRI with and without gadolinium revealed multiple small foci of abnormal enhancement scattered in the bilateral cerebral hemispheres, cerebellum and brainstem. These increased in number on serial studies (Figure 1a, 1b) despite persistently negative blood, cerebrospinal fluid (CSF), and sputum cultures.

Figure 1.

 

Ultimately, a large abscess developed on the patient's left calf; surgical drainage and culture recovered Gram‐positive rods. Full body CT scan also revealed a pancreatic cyst which yielded Enterococcus species, coagulase negative Staphylococcus, and Candida glabrata on evacuation. Continued intensive antibiotic therapy (including trimethoprim‐sulfamethoxazole and third‐generation cephalosporins) and ventilator assistance were administered, but the patient's respiratory failure did not remit. Approximately two months after initial presentation, his pupils were found to be pinpoint in size and non‐reactive to light, raising concern for a cerebrovascular accident. Given the patient's prognosis following these events, the family elected to withdraw life support and the patient died.

General Post‐Mortem Examination

At autopsy, the lungs were heavy and diffusely firm with prominent consolidation of the right lower and right middle lobes. Bilateral pleural effusions were noted; microscopic studies showed diffuse alveolar damage although there was no evidence of an infectious process within the heart or lungs. Hemorrhagic pancreatitis, cardiomegaly, and hepatosplenomegaly were identified. Diffusely scattered purulent micronodules were present on cut sections of hepatic parenchyma. Multiple cutaneous ulcers (0.3–3.0 cm in diameter) with tan‐yellow purulent exudate were also identified on the lower extremities.

Cranial Examination

Examination of the brain showed symmetrical gyral pattern with leptomeningeal opacities overlying the bilateral frontoparietal areas (Figure 2a). The basal vasculature showed no abnormalities. There was no evidence of uncal or cerebellar tonsillar herniation. Coronal sections of the fixed cerebral hemispheres displayed sharply demarcated cortical‐white matter junction. Scattered tan‐yellow micronodules were seen diffusely on gross examination of the cerebral and cerebellar hemispheres, basal ganglia and brainstem (Figures 2b, 2c).

Figure 2.

 

On microscopic examination the disseminated nodules corresponded to granulomata composed predominantly of lymphocytes and foamy macrophages (Figures 2d and 3a). Special studies with Gram, Periodic acid‐Schiff, Acid‐Fast, and Fite stains were all negative. However, Grocott's Methenamine Silver (GMS) stain highlighted aggregates of beaded, filamentous organisms (∼1 μm in diameter) with 90‐degree branching pattern (Figures 3b and 4). Sulphur granules were not appreciated.

Figure 3.

 

Figure 4.

 

What is the diagnosis?

Diagnosis

Disseminated Nocardiosis

Discussion

Nocardia species are ubiquitous, aerobic Actinomycetes that dwell predominantly in soil and water. Infection in humans usually occurs as opportunistic disease following respiratory inhalation of Nocardia asteroides 1, 4. Primary pulmonary infection may manifest as subclinical, transient, or progressive chronic disease. Introduction through the skin occurs less frequently after trauma or intravenous drug abuse and may spread via lymphocutaneous routes.

Hematogenous dispersal of Nocardia species occasionally develops after primary inoculation and involvement by two or more organs qualifies as dissemination of disease. The occurrence of disseminated nocardiosis has increased during recent years, concurrent with survival rates of immunodepressed populations (particularly transplant recipients, AIDS and cancer patients, and those with chronic diseases necessitating long‐term corticosteroid/cytotoxic therapies). Disease may also afflict immunocompetent persons 8. Although hematogenous spread of infection to the central nervous system (CNS) is still rare, preferential migration to this site has been well‐documented 4. Less common sites of dissemination include the skin, bone, and joints 4. Endogenous retinitis and endophthalmitis also occurs secondary to hematogenous dispersal, while ocular surface lesions (e.g. keratitis) generally result from penetrating injury or airborne spread 3, 6. Primary lesions may resolve spontaneously, however, making diagnosis of disseminated nocardiosis challenging 1, 2, 4, 5.

Symptomatology in CNS disease is variable and may include meningeal symptoms, focal neurological deficit(s), seizures, and/or altered mental status with or without febrile episodes. CNS nocardiosis may be asymptomatic. MRIs may show a localized mass with loculation, ring‐enhancement, and perilesional edema, or they may show dispersed micronodules. This raises a broad differential including high‐grade primary astrocytoma, stroke, lymphoma, vasculitis, septic emboli, mycotic infection, miliary Tuberculosis, or metastatic disease 5. However, Nocardia brasiliensis was ultimately cultured from the patient's lower extremity wound and appropriate therapy was instituted.

A high degree of clinical suspicion is necessary for timely diagnosis and treatment of CNS nocardiosis as steroid therapy may exacerbate infection. In cases without known primary lesions, stereotactic aspiration with culture and antimicrobial sensitivity studies are desirable, if possible, to document disease. Tissue biopsy may also help rule out malignancy or co‐infection by other microorganisms. Histopathologic changes on biopsy are variable but most frequently include focal meningitis, disseminated granulomata, or large pyogenic abscesses with or without fibroinflammatory encapsulation. GMS stain highlights beaded, branched, filamentous organisms. Typically, Gram stain yields positive rods while results of Acid‐Fast and Fite stains are variable. For proper culture, the microbiology laboratory should be informed of suspected nocardiosis as prolonged incubation is required for in vitro growth.

Therapy for CNS nocardiosis depends on the extent of disease and patient immune status. Medical management includes prolonged antibiotic regimen (often >1 year), as recurrent and/or resistant infection may develop. Sulfonamides are the preferred oral agent 7. Surgical excision is performed for large, abscesses. Early detection and management of CNS nocardiosis can yield favorable outcomes in immunocompetent patients. Nevertheless, prognosis of CNS nocardiosis remains guarded in immunodepressed individuals due to insidious onset, impaired host responses and usual delay in diagnosis.

Abstract

A 49‐year‐old man presented with fever, chills and altered mental status. He had undergone pancreatic and renal transplantation several years ago with several episodes of allograft rejection necessitating long‐term immunosuppressive therapy. Upon admission he was noted to have positive CMV IgG titers. CSF showed elevated leukocyte count (>600 with 89% neutrophils). There was pulmonary edema with a right pleural effusion although initial brain imaging studies and pan‐cultures were negative. The patient was empirically treated for meningitis and possible pneumonia with multiple broad‐spectrum antibiotics but subsequently developed worsening lethargy, respiratory insufficiency, and a diffuse pustular rash on his extremities. Later MRI revealed numerous, widespread foci of abnormal enhancement in the brain parenchyma. Later a calf abscess yielded Nocardia brasiliensis by culture. He died two months after presentation and autopsy showed disseminated nocardiosis. Sections of the brain also revealed scattered granulomata; and GMS stains demonstrated branched, filamentous organisms consistent with Nocardia species.