Rheumatology Advance Access originally published online on April 1, 2008
Rheumatology 2008 47(5):739-740; doi:10.1093/rheumatology/ken088
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Central nervous system Aspergillus fumigatus presenting as cranial nerve palsy in a patient with ankylosing spondylitis on anti-TNF therapy
1University of Miami/Jackson Memorial Medical Center, 2University of Miami Miller School of Medicine, 3Miami Veterans Affairs Medical Center, Miami, FL, USA.
Correspondence to: C. J. Lozada, 1120 N.W. 14th Street, Suite 973, Miami, FL 33136, USA. E-mail: clozada{at}med.miami.edu
SIR, A 52-yr-old black male with a 4-yr history of AS and mild apical pulmonary fibrosis previously responsive only to oral corticosteroids was started on etanercept 25 mg subcutaneously twice a week with excellent clinical response.
At 18 months of treatment with etanercept, the patient developed fevers, weight loss and night sweats. Etanercept therapy was immediately discontinued and work-up initiated for possible infectious aetiology. Prednisolone 12.5 mg/day and NSAIDs were continued.
The patient then developed right-sided facial pain and a sensation of inner-ear pressure with impaired audition. Decreased vision in the right eye was noted as well as right-sided paralysis of cranial nerves II, III, IV, V, VI and VIII. Purified protein derivative test (PPD), lumbar puncture and CT were unrevealing but MRI of the brain demonstrated an infiltrating right orbital apex mass contiguous with the superior orbital fissure extending into the middle cranial fossa (Fig. 1)
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Parietal craniotomy was performed to obtain biopsies of the mass. Purulent drainage was observed upon incision of the dura and extensive granulation tissue noted enveloping the right optic nerve, extending into the superior orbital fissure. Biopsy showed an acute inflammatory process with extensive necrosis, granulation tissue and presence of fungal organisms. Cultures grew Aspergillus fumigatus.
Treatment was initiated with intravenous voriconazole. Surgical intervention included debridement of the right optic nerve and orbital apical contents and decompression of cavernous sinus. There was complete resolution of symptoms and voriconazole was discontinued after one year.
TNF blockers have proven to be quite effective at relieving the symptoms of AS [1]. However, TNF-
is critical for granuloma formation and maintenance. Granulomas have a role in containing the systemic spread of intracellular pathogens. The first line of defence against granulomatous infections, such as Aspergillus, is the innate immune system. Bronchoalveolar macrophages secrete TNF- in response to Aspergillus conidia, the infectious spores of the fungus [2]. Mehrad et al. [3] demonstrated that challenging mice intrathecally with Aspergillus conidia resulted in a time-dependent increase in lung TNF- levels, and monoclonal antibody neutralization of TNF- resulted in a decrease in lung neutrophil recruitment, increase in fungal burden and increase in mortality.
Aspergillus fumigatus is a ubiquitous organism [4]. Its ecological niche is soil, surviving on decomposing organic material. It produces thousands of conidia that are dispersed in the air giving the fungus its omnipresent nature and predominant route of human infection. Aspergillus fumigatus accounts for 
90% of these [4].
The spectrum of disease caused by aspergillus is dependent on the health of the immune system. The range of illnesses individuals acquire (from usually less severe illness in an immunocompetent individual to more severe illness in the immunocompromised) are allergic bronchopulmonary aspergillosis, aspergilloma, chronic necrotizing aspergillosis and invasive aspergillosis. Invasive aspergillosis is generally seen in severely immunocompromised individuals and carries a high mortality rate. Risk factors for invasive aspergillosis include neutropenia, immunosuppressive therapy, high-dose systemic corticosteroids, AIDS, solid organ transplant and haematopoietic stem cell transplant [5]. Invasive aspergillosis can disseminate to any organ, but most frequently involves the respiratory system. However, CNS involvement in invasive aspergillosis is not uncommon. In an autopsy series of 71 patients with invasive aspergillosis, 42 had CNS aspergillosis [6]. Also, it appeared that once aspergillus disseminated beyond the lungs, most of the patients had CNS involvement at the time of their death. Treatment for invasive aspergillosis is a combination of anti-fungal antibiotics and surgical debridement [4]. Voriconazole has become the first-line anti-fungal agent for invasive aspergillosis [5].
This is the first reported case of CNS aspergillosis in the setting of anti-TNF- therapy. There have been six previous reports of invasive aspergillosis while on anti-TNF- therapy [7–9]. In five of these six cases, patients were on at least one other immunosuppressant in addition to anti-TNF- therapy. One review examined the incidence of granulomatous infections while on anti-TNF- therapy from January 1998 to September 2002 using data collected from the Adverse Event Reporting System database from the FDA and determined that there were 39 reports of infections with aspergillus [29 in those on infliximab and 10 in etanercept (reports from adalimumab were excluded)] [10]. Concomitant corticosteroids were reported in 41% using infliximab and 66% in etanercept. Information regarding other DMARD therapies, type and severity of the Aspergillus infection and outcomes was lacking.
It is unknown as to how much low-dose prednisolone contributes to the risk of developing invasive aspergillosis in cases such as this. The patient's lung involvement from AS likely contributed to his infection by serving as the nidus for haematogenous spread to the CNS.
Aspergillus infection of the CNS carries an almost universal mortality rate [5]. This case highlights the difficulties in making diagnoses of indolent infections in patients on immunosuppressive therapy. It is imperative for the treating physician to recognize risk factors unique to each patient prior to and during treatment with these powerful biologic therapies.
Disclosure statement: C.J.L. is a member of the speakers’ bureau for Abbott Pharmaceuticals and Wyeth. All other authors have declared no conflicts of interest.
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