Print version ISSN 0036-4665
Rev. Inst. Med. trop. S. Paulo vol.47 no.3 São Paulo May/June 2005
Abscessos cerebrais múltiplos causados por infecção por Penicillium spp
Danilo Teixeira NoritomiI; Guilherme Linhares BubI; Idal BeerI; Aloísio Souza Felipe da SilvaII; Roberto de ClevaI; Joaquim José Gama-RodriguesI
IGastroenterology Department, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, SP, Brasil
IIDepartment of Pathology, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, SP, Brasil
We present a case of central nervous system (CNS) infection by a member of the Penicillium genera in a HIV-negative man in Brazil. The patient was admitted complaining of loss of visual fields and speech disturbances. CT scan revealed multiple brain abscesses. Stereothacic biopsies revealed fungal infection and amphotericin B treatment begun with initial improvement. The patient died few days later as a consequence of massive gastrointestinal bleeding due to ruptured esophageal varices. The necropsy and final microbiologic analyses disclosed infection by Penicillium sp. There are thousands of fungal species of the Penicillium genera. Systemic penicilliosis is caused by the P. marneffei and was formerly a rare disease, but now is one of the most common opportunistic infection of AIDS patients in Southeast Asia. The clinical presentation usually involves the respiratory system and the skin, besides general symptoms like fever and weight loss. Penicillium spp infection caused by species other than P. marneffei normally cause only superficial or allergic disease but rare cases of invasive disease do occur. We report the fourth case of Penicillium spp CNS infection.
KEYWORDS: Penicilliosis; Penicillium spp; CNS infection; Fungal infection.
Apresentamos um caso de infecção do sistema nervoso central (SNC) por Penicillium spp em paciente do sexo masculino, HIV-negativo no Brasil. O paciente apresentou-se ao Serviço de Urgência do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo queixando-se de alteração visual e dificuldade na fala. Exames de neuroimagem mostraram lesões múltiplas, compatíveis com abscessos. A biópsia esterotáxica revelou infecção fúngica, iniciando-se o tratamento com anfotericina B com sucesso inicial. O paciente morreu poucos dias depois, vítima de uma hemorragia digestiva maciça devido a varizes de esôfago. A necropsia e a análise microbiológica final da biópsia cerebral revelaram infecção por Penicillium spp. Exixtem centenas de espécies de fungos do gênero Penicillium. A peniciliose sistêmica é causada pelo P. marneffei e costumava ser uma doença rara, mas atualmente é uma das infecções oportunistas mais comuns em associação com AIDS no Sudeste Asiático. Infecção pelo Penicillium spp de espécie diferente do P. marneffei normalmente causa apenas doenças superficiais ou alérgicas mas doenças invasivas também ocorrem raramente. Nós relatamos o quarto caso de infecção do SNC por Penicillium spp.
In recent years, invasive fungal infections have become increasingly common. Concomitantly, there has been a gradual rise in the number of rare fungal infections in immunocompromised and normal patients. Penicillium genera aggregates thousands of fungal species, being the P. marneffei infection the far most important one, mainly associated with AIDS in the Southern Asia2,3,5,22. However a number of infections caused by species other than P. marneffei have been reported13.
In this study, we report a non-HIV patient from Brazil who had central nervous system involvement by Penicillium spp documented by biopsy. To our knowledge, this is the first report of central nervous system involvement by Penicillium spp and also the first report of invasive penicilliosis in Brazil.
A 41 year-old man, with chronic liver disease caused by long term HBV infection (Child-Pugh C), has presented to the Emergency Department complaining of bilateral loss of visual fields and dysphasia for three days.
On physical examination he was conscious (Glasgow Coma Scale 15), pale, dehydrated, with axilar temperature of 37 ºC, heart rate of 88 bpm, blood pressure of 126 x 80 mmHg. The abdomen was tense, with signs of high volume ascites without focal tenderness. The neurological exam revealed complete right hemiparesia and expression aphasia. Pupils and retinal examination were normal.
Biochemical blood exams revealed a moderate degree of anemia and coagulopathy without any other important alterations. The liquor exam was normal and an HIV-serology was negative. A brain CT scan and MRI showed multiple lesions compatible with abscesses mainly in the subcortical regions of the brain (Fig. 1 and 2).
The patient was admitted to the hospital and empirical antibiotic treatment was initiated with ceftriaxone, metronidazole and vancomycin in adequate doses for central nervous system (CNS) infection. On the 2nd day the neurological signs were worse, evolving to complete right hemiplegia. A brain stereothactic biopsy was then indicated and revealed fungal infection, suggestive of Aspergillus or Mucor species. The specimen was sent to microbiological analyses. Amphotericin B was initiated with gradual initial improvement.
However, on the 15th hospital day the patient presented an important episode of hematemesis and deterioration of the consciousness level, requiring endotracheal intubation and transfer to the Surgical ICU.
Endoscopy revealed abundant bleeding from esophageal varices. An endoscopic elastic band ligation was unsuccessful and the patient died from refractory hemorrhagic shock few hours later.
Growth was observed after incubating biopsy material at 30 ºC on Sabouraud and Sabhi agar. Thereafter, it could be seen positivity on tube and plate with potato agar and the micromorphologic differentiation through microcultive revealed Penicillium spp. No other microbiologic technique resulted positive.
Approximately 225 species of Penicillium have already been described13. Substantial numbers of Penicillium spores are present in the normal fungal flora of the air. Penicillia are ascomycetes closely related to Aspergillus but without the same invasive capabilities, with the notable exception of P. marneffei. We will present a brief discussion on this two clinical entities: systemic penicilliosis due to P. marneffei and infection due to other species of Penicillium (Penicillium spp).
Systemic penicilliosis caused by P. marneffei: Systemic penicilliosis is a fungal infection caused by the dimorphic fungi Penicillium marneffei, a pathogenic species of the Penicillium genera17. SEGRETAIN initially isolated this specie in captive bamboo rats (Rhysomys sinesis) at the Pasteur Institute in 19561,18. The same author, through accidental inoculation of laboratorial fungi specimens also made the first description of human pathogenicity. Since then, few cases have been described until the emergence of AIDS epidemic widespread in that region.
In 1988, a great number of cases of systemic penicilliosis were diagnosed in patients who had lived or traveled to Southeast Asia. Between 1991 and 1997, the University Hospital of Chiang Mai reported the occurrence of 1173 cases of systemic penicilliosis, most of them related to AIDS20. Nowadays, systemic penicilliosis remains one of the most common opportunistic infections on late HIV-infected patients in endemic areas, such as China, Hong Kong, Taiwan and Malasia10,11,15,20,25.
Penicillium marneffei, like other endemic fungal species, lives in the soil. According to the actual evidences, it directly infects both of host species, bamboo rats and humans. Therefore, there seems to be no role for the rats on the natural occurring human disease. Like other pathogenic fungi, the conidia are inhaled and internalized by alveolar macrophages and transported to the reticuloendothelial system. The microorganism can then proliferate as soon as a host immune deficiency takes place, leading to systemic infection6,7,16. Vertical transmission has also been described in more than 20 children born to HIV-positive mothers21.
Systemic penicilliosis is an extremely rare disease in the non- immunocompromised host. Most of the patients have any form of immunodeficiency, acquired or iatrogenic. On the HIV-infected patients it is predominantly a late occurrence, with CD4 count normally around 50 cells/mm3,23.
Fever and weight loss are the most common first clinical manifestations, present in up to 95% of cases. Sometimes, prolonged fever is the only presenting symptom. Generalized lymphadenopathy and hepatomegaly were present in more than 60 to 80% of cases20. In both HIV-positive and HIV-negative patients the respiratory system is the most common organ affected at presentation5,19. Several clinical-radiological patterns have been described, the most common being the alveolar or interstitial infiltrates and the pleural effusions24. Cutaneous manifestations are frequent (up to 75% of cases) and are very important clues to the clinical diagnosis of penicilliosis. The majority of lesions are umbilicated papules (molluscum contagiosum-like). The lesions are mainly distributed on face and upper trunk.
Penicillium marneffei can be isolated from various clinical specimens by direct mycological examination or cultures. Specimens stained with Wright, Giemsa or Periodic Acid Schiff's show intracellular and extracellular basophilic, spherical, oval to elliptical, yeast-like organisms (3 ± 8 mm in diameter), with clear transverse section characteristic of P. marneffei yeast phase. Culture specimens from bone marrow aspiration and lymph nodes are the most sensitive (100%), followed by skin tissue (90%) and blood (76%), respectively20. In HIV-positive patients the fungemia seems to be more common than on HIV-negative patients especially in the context of AIDS patients of the Southeast Asia. The knowledge of this entity is far from complete: from its forms of infection to its best treatment, much has to be learned.
Penicillium spp infection other than P. marneffei: Penicillium spp infection other than P. marneffei can cause a spectrum of clinical entities, being the superficial and allergic diseases far more common13.
Sensitization to Penicillium as well as other fungi is relatively common among asthmatics. Various sero-epidemiological studies conducted in several countries imply Penicillium as an environmental allergen of variable significance among asthmatic and atopic individuals13.
Superficial infections due to Penicillium spp include skin infections such as onychomycosis and dermatitis, eye infections such as fungal keratitis and conjunctivitis and otomycosis.
Invasive disease due to Penicillium sp other than P. marneffei is rare but does exist. Over the last 50 years, according to a recent review, a total of 34 cases of invasive infection have been described in the literature, most of them associated with non-immunocompromised hosts. Until now there have been descriptions of lung infection, endocarditis, peritonitis in CAPD, urinary tract, endophthalmitis, oesophagitis and intracranial infection13.
Regarding CNS infection, only three cases had already been reported, two of them in non-immunocompromised patients9,13,14. In the first case intracranial infection was the result of local spread from primary orbital-sinus infection causing a mycotic cerebral aneurysm and eosinophilic CSF pleocytosis. In the second case intracranial Penicillium infection followed primary lung involvement in a patient with acute leukemia. The third case has recently been reported and was the first to be the result of haematogenous dissemination in a non-immunocompromised patient. Treatment with amphotericin B and surgery failed to prevent death in the last two cases.
To our knowledge, this is the fourth documented case of CNS infection by a member of the Penicillium genera and the first one in Brazil.
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Roberto de Cleva
Rua Coronel Arthur Godoy 125, Apto 152, Vila Mariana
04018-050 São Paulo, SP, Brazil
Phone: 55.11.3082-8000, Fax: 55.11.3082-8000
Received: 13 October 2004
Accepted: 17 January 2005