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netherlands journal of critical care Copyright ©2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received and accepted: oktober 2006 c a s e r e p o r t Fatal Invasive Aspergillosis in an Apparently Immunocompetent Host W.M. Dijkman 1 , B.H. Postma 2 1 dept. intensive care medicine, Máxima Medisch Centrum. 2 Laboratory for Medical Microbiology, Veldhoven. Abstract. A 51-year-old woman was admitted to the ICU because of perforation of the stomach. In spite of initial recovery following abdominal surgery, she succumbed from an invasive pulmonary infection with Aspergillus fumigatus. There were no signs or symptoms of an underlying immunodeficiency. Although rare, Aspergillus spp. is able to overcome seemingly normal pulmonary defences giving rise to a devastating and lethal infection. Introduction Aspergillus spp, a genus of mitosporic fungi commonly present in the environment, can cause a variety of conditions, ranging from superficial colonisation and allergic reactions to deep penetration of tissues like invasive pneumonia. These invasive infections are a major cause of morbidity and mortality in immunosuppressed patients. Although unusual, Aspergillus spp can cause pneumonia in the absence of an apparent predisposing immunodeficiency. In spite of advances made with azole therapy the outcome of invasive aspergillosis remains poor [1]. We describe a case to exemplify that critically ill patients without a known history of abnormal immune function can develop this severe opportunistic infection. Case history A 51-year-old woman with no medical history presented at the emergency ward after several days of abdominal pain. On examination she was hypotensive and barely responsive. The abdomen was tender and an ultrasound examination showed intra-abdominal free fluid. On laparotomy there was perforation of the stomach with extensive spill of contents. After apparently successful closure of the defect several re-laparotomies were needed to control persistent leakage. Initially she suffered from severe septic shock with multiple organ failure, and as the abdominal outflow decreased her situation improved slowly. Cultures of sputum, blood, peritoneal fluid and indwelling catheters yielded Enterobacter cloacae, Enterococcus faecium and Candida albicans. Antibiotic treatment consisted of cefuroxim, ciprofloxacin, metronidazole and fluconazole, either alone or in various combinations. After two weeks, respiratory support had to be increased because of rapidly diminishing compliance. Chest X-ray and computed tomography (Figure 1) showed progressive infiltrative abnormalities and pleural effusion. No cavities were observed. Bronchoscopy revealed extensive bumpy irregularities with a tattered surface extending through all visible parts of the bronchial tree (Figure 2). Bronchial alveolar lavage (BAL) fluid yielded Aspergillus fumigatus. A diagnosis of invasive aspergillosis was confirmed by pathological analysis of bronchus biopsies. No Aspergillus was found in specimens taken previously during abdominal surgery. In spite of treatment with voriconazole, itraconazole and caspofungin her condition progressively deteriorated and she died 48 days after admission. Autopsy was not permitted. Correspondence: W.M. Dijkman E-mail: w.dijkman@mmc.nl Discussion Our patient died of invasive pulmonary aspergillosis after a prolonged stay in the intensive care unit, during which she sustained a period of severe abdominal sepsis and multiple organ failure. In the course of her illness Aspergillus fumigatus was cultured several times from various clinical samples (Table 1). The first two positive cultures were considered to be due to contamination, but because of the combination of clinical findings and the abnormalities found at bronchoscopy antifungal treatment was started anyway and continued until she died. At the time of her admission renovation works were being carried out both at her home and in the hospital. Two circumstances may have triggered the development of invasive pulmonary aspergillosis in our patient. First, a period of severe abdominal sepsis and multiple organ failure, leading to a temporary state of acquired immunodeficiency, and second, inhalation of spores of Aspergillus. No Aspergillus spp. was found in multiple air samples taken during the construction period in the hospital. No samples were taken in the patient’s home. Although there is no evidence for inhalation of a heavy inoculum, the first option has only been postulated [2] and therefore cannot be proven. An explanation for this rare infection remains uncertain. The diagnosis ‘invasive pulmonary aspergillosis’ is usually based on a combination of clinical, microbiological, radiographical and histopathological findings, with clinical suspicion being of paramount importance. Two laboratory methods are of value to help establishing a diagnosis: direct microscopic examination of bronchoalveolar lavage BAL fluid for the presence of branched hyphae [3] and monitoring serum samples for Aspergillus galactomannan (GM), a specific cell wall component circulating during infection [4]. Previously described series of patients are small and mention a mortality of up to 100% [5]. In one study [6] the latex agglutination test for Aspergillus antigen yielded positive results only in advanced stages of infection in most patients suspected of having invasive aspergillosis and consequently did not contribute to early diagnosis. When Aspergillus was found for the first time in BAL fluid, our patient was not neutropenic and there were no other known risk factors for an invasive opportunistic infection. Therefore, she was not considered to be immunosuppressed or at risk for invasive aspergillosis and so here was no reason to monitor GM levels. Considering the increasing incidence of invasive aspergillosis in intensive care units and a mortality of over 90% in patients without a malignancy [7] our current concept of immune competence might be inadequate. The anti-inflammatory response in sepsis may be seen as 536 neth j crit care • volume 10 • no 5 • october 2006
netherlands journal of critical care Table 1. results of microscopy and culture for A. fumigatus Day in ICU Sample Method / Result 14 BAL Microscopy: hyphae Culture: A. fumigatus 15 Sputum Microscopy: hyphae Culture: A. fumigatus 20 Sputum Microscopy: no hyphae Culture: A. fumigatus 23 BAL Biopsy Microscopy: no hyphae Culture: A. fumigatus Microscopy: hyphae Culture: A. fumigatus 44 Sputum Microscopy: no hyphae Culture: A. fumigatus BAL = bronchoalveolar lavage fluid. a temporary acquired immunodeficiency, facilitating opportunistic infections to develop in apparently immunocompetent patients [2]. Conditions like, chronic lung disease, non-haematological malignancy, HIV infection, diabetes mellitus, liver failure, chronic alcohol abuse, malnutrition and extensive burns have been reported in association with invasive aspergillosis [8] and the interpretation of finding ubiquitous, branched hyphae in a culture taken from a nonsterile site remains difficult. In the absence of large epidemiological studies there are no known risk factors, single or in combination, for the acquisition of an invasive Aspergillus infection. Polymerase chain reaction (PCR) allows detection of the equivalent of 10-100 colonyforming units (CFU) of Aspergillus fumigatus per sample in serum or plasma. The combined use of PCR for A. fumigatus DNA and ELISA for galactomannan should provide a definitive diagnosis of invasive aspergillosis, even in the absence of obvious clinical signs [9]. As long as these methods are not generally available, direct microscopic examination of BAL fluid remains the first and most important clue to a potentially lethal mycosis. Retrospectively, there were no known predisposing factors for invasive aspergillosis or indications of reduced pulmonary host defences in our patient other than sepsis. For immunocompromised patients with cancer and hematopoietic stem cell transplants definitions of invasive fungal infections and the best methods for establishing the diagnosis are published as an international consensus [10]. However regarding immune competent hosts there remains much uncertainty. A diagnostic algorithm for patients without a malignancy as proposed by van de Woude et al. [8] should trigger physicians not to take a culture containing Aspergillus spp. too easily for contamination. Figure 1, CT scan of the thorax showing infiltrative abnormalities, mainly in the right upper lobe, and pleural effusion. No cavities were found. Figure 2, Bronchoscopic view of the carina showing extensive irregularities with a ragged surface. Biopsies confirmed the diagnosis of invasive aspergillosis. References 1. Hope WW, Denning DW: Invasive aspergillosis: current and future challenges in diagnosis and therapy. Clin Microbiol Infect 2004, 10(1):2-4. 2. Hartemink KJ, Paul MA, Spijkstra JJ, Girbes AR, Polderman KH: Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003, 29(11):2068- 2071. 3. Richardson MD WD: Fungal Infection. Diagnosis and treatment, 3 edn: Blackwell 2003. 4. Verweij PE, Dompeling EC, Donnelly JP, Schattenberg AV, Meis JF: Serial monitoring of Aspergillus antigen in the early diagnosis of invasive aspergillosis. Preliminary investigations with two examples. Infection 1997, 25(2):86-89. 5. Clancy CJ, Nguyen MH: Acute community-acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease. Chest 1998, 114(2):629-634. 6. Verweij PE, Rijs AJ, De Pauw BE, Horrevorts AM, Hoogkamp-Korstanje JA, Meis JF: Clinical evaluation and reproducibility of the Pastorex Aspergillus antigen latex agglutination test for diagnosing invasive aspergillosis. J Clin Pathol 1995, 48(5):474-476. 7. Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van Wijngaerden E: Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004, 170(6):621-625. 8. Vandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, Vogelaers D: Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care 2006, 10(1):R31. 9. Richardson MD K, M: Aspergillus. Philadelphia: Churchill Livingstone; 2003 10. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z et al: Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002, 34(1):7-14. neth j crit care • volume 10 • no 5 • october 2006 537
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