Cavling Arendrup, Maiken

Denning, David W.

Petersen, Eskild

Ronan O'Driscoll, B.

English

We describe 2 cases of immunocompetent males with acute community-acquired invasive pulmonary aspergillosis developing shortly after spreading bark chippings. One patient with a fatal outcome was initially diagnosed as allergic alveolitis rather than infection and received steroid treatment illustrating the obvious challenges in the differential diagnosis between these disease entities

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logous for HSV types 1 and 2. J Clin Microbiol 2005;/43:/205864.[8] Kaji M, Kusuhara T, Ayabe M, Hino H, Shoji H, Nagao T.Survey of herpes simplex virus infections of the centralnervous system, including acute disseminated encephalo-myelitis, in the Kyushu and Okinawa regions of Japan. MultScler 1996;/2:/837.[9] Martin JR, Stoner GL, Webster HD. Lethal encephalitis andnon-lethal multifocal central nervous system demyelinationin herpes simplex virus type 2 infections in mice. Br J ExpPathol 1982;/63:/65166.[10] Kristensson K, Svennerholm B, Vahlne A, Nilheden E,Persson L, Lycke E. Virus-induced demyelination in her-pes simplex virus-infected mice. J Neurol Sci 1982;/53:/20516.[11] Azumagawa K, Suzuki S, Tanabe T, Wakamiya E, Kawa-mura N, Tamai H. Neopterin, biopterin, and nitric oxideconcentrations in the cerebrospinal fluid of children withcentral nervous system infections. Brain Dev 2003;/25:/2002.[12] Studahl M, Hagberg L, Rekabdar E, Bergstrom T. Herpesvirus DNA detection in cerebral spinal fluid: differences inclinical presentation between alpha-, beta-, and gamma-herpes viruses. Scand J Infect Dis 2000;/32:/23748.[13] Gobbi C, Tosi C, Stadler C, Merenda C, Bernasconi E.Recurrent myelitis associated with herpes simplex virus type2. Eur Neurol 2001;/46:/2158.Acute pulmonary aspergillosis in immunocompetent subjects afterexposure to bark chippingsMAIKEN CAVLING ARENDRUP 1, B. RONAN O’DRISCOLL2, ESKILD PETERSEN3 &DAVID W. DENNING4From the 1Unit of Mycology and Parasitology, Statens Serum Institute, Copenhagen, Denmark, 2Hope Hospital, Salford,University of Manchester, UK, 3Department of Infectious Diseases, Aarhus University Hospital-Skejby, Aarhus, Denmark,and 4The University of Manchester and Wythenshawe Hospital, Southmoor Road, Manchester, UKAbstractWe describe 2 cases of immunocompetent males with acute community-acquired invasive pulmonary aspergillosisdeveloping shortly after spreading bark chippings. One patient with a fatal outcome was initially diagnosed as allergicalveolitis rather than infection and received steroid treatment illustrating the obvious challenges in the differential diagnosisbetween these disease entities.IntroductionCommunity-acquired pneumonia is usually causedby bacteria, occasionally viruses and, in the AIDSera, the fungus Pneumocystis jiroveci (formerlycarinii). While invasive pulmonary aspergillosis(IPA) commonly complicates neutropenia,transplantation and medical intensive care patients[13], it is rare among patients without underlyingimmune suppression. However, a few cases ofpulmonary aspergillosis in healthy subjects afterexposure to vegetal dust or mouldy hay have beendescribed [4,5]. Like Mycobacterium tuberculosisand Coccidioides immitis, Aspergillus fumigatus isnotable for causing pulmonary cavitation, eitherrapidly in resolving neutropenia [6] or more slowlyin those with chronic cavitary pulmonary aspergillo-sis [7]. Unlike most other microorganisms, A.fumigatus is also a major allergen causing allergicbronchopulmonary aspergillosis (ABPA) whichcomplicates asthma or cystic fibrosis and is treatedwith corticosteroids [8,9].Bilateral interstitial infiltrates and cavitation areuncommon radiographic features of community-acquired pneumonia. We here present 2 cases ofinvasive aspergillosis in immunocompentent patientsillustrating the difficult discrimination between in-vasive infection and allergic alveolitis and the unu-sual presentation with acute-onset cavitatingpneumonia. The cases were probably caused by amassive inhalation of Aspergillus conidia in barkchippings.Correspondence: M. Cavling Arendrup, Unit of Mycology and Parasitology, Statens Serum Institute Building 43/214C, Artillerivej 5, DK-2300 CopenhagenS, Denmark. Tel: /45 22 63 27 85. Fax: /45 32 68 81 80. E-mail: mad@ssi.dkCase Reports 945(Received 13 January 2005; accepted 17 January 2006)ISSN 0036-5548 print/ISSN 1651-1980 online # 2006 Taylor & FrancisDOI: 10.1080/00365540600606580Case 1A 33-y-old male was admitted to hospital on 6January 2004 with dry cough, shortness of breathand fever. His only previous illness had beenimplantation of a mechanical heart valve requiringlong-term warfarin since 2000. One month beforeadmission the patient had received a truck-load ofbark chippings at home. A week later he distributedsome of the bark chippings and that evening felt illand stayed in bed with fever for a few d. A week laterhe distributed the remaining bark chippings  whichwere wet and slightly steaming and showedmould-spots on the bark. During the work he feltirritation in the airways and later the same d he ran afever of 408C and cough. Penicillin for 7 d wasprescribed on 7 December followed by a 3-d courseof azithromycin initiated on 22 December 2003.At the time of admission, the patient presentedwith dry cough, dyspnoea, tachypnoea and fever(398C). Physical examination revealed slight basalcrackles. Chest radiograph and high resolutioncomputerized tomography scan of the thorax showedbilateral interstitial infiltrates (Figure 1a). Labora-tory findings included a C-reactive protein of 780(normal range B/75) nmol/l, negative blood culturesand Legionella urine antigen, PCR for Chlamydiapneumoniae and psittaci, Mycoplasma pneumoniae,Mycobacteria and Legionella, and negative micro-scopy and culture for Mycobacteria from sputumand BAL. Aspergillus antibody titre in serum taken 2d after admission was 16 (normal range B/1) and inBAL fluid on 15 January, lymphocytes were pre-dominantly detected. Tentative diagnoses were aty-pical pneumonia and allergic alveolitis;clarithromycin and prednisolone 5075 mg dailywere initiated and he was discharged on 28 January.On 19 February the patient was re-admitted dueto high fever (up to 408C), tachypnoea and cough.Chest radiograph showed bilateral infiltrates (Figure1b). Laboratory findings were 10/109/l leukocytes,C-reactive protein of 3300 nmol/l. A bronchialbiopsy and culture was performed the next d andhistological examination demonstrated hyphae andinflammation. Culture yielded Aspergillus fumiga-tus. Ambisome 150 mg/d was given but the patientdied on 28 February; autopsy revealed bilateralAspergillus pneumonia (Figure 2) with involvementof the mediastinal lymph nodes and retroperitonealbleeding. Subsequent testing of a serum sampledated 9 January showed an Aspergillus galactoman-nan antigen index of 5.1 (ref.B/1.0).Case 2A 63-y-old gardener who smoked 20 cigarettes per dwas admitted to hospital on 5 December 2003 withcavitating pneumonia of the right upper lobe (Figure3a), associated with a 3-week history of dry cough,pleuritic pain and excessive sweating. His symptomshad not responded to a course of amoxicillin fromhis general practitioner. He had lost 3 kg in weight.Figure 1. Chest radiograph a) at the time of admission(6 January) showing bilateral interstitial infiltrates, and b) dated24 February showing severe progression of the bilateral infiltrates(Case 1).Figure 2. Histopathology of post mortem lung sections showinginflammation and microabcesses with dichotomously branching,septate hyphae (Case 1). (PAS staining, magnification/200).946 Case ReportsHe had spread a large quantity of damp wood-barkchippings on the d before he developed his chestsymptoms. Prior medical problems included aBarrett’s oesophagus, mild airflow limitation(FEV1 7083% predicted), and early Dupuytrenscontracture. On examination, his pulse was 96 andrespiratory rate 14 and his temperature did notexceed 37.58C at any time. Oxygen saturation was92% breathing air and he had some soft cracklesconfined to the right upper lobe. CRP was extremelyhigh at 378 units (normal below 10 units) and hisESR was elevated at 110 mm/h. His white cell countwas elevated at 19.3/109/l (16.2 neutrophils).Renal and liver function tests were normal apartfrom slightly elevated alkaline phosphatase at 152units/l (normalB/130 units/l). Bronchoscopy wasentirely normal and bronchial washings for cultureand TB were negative but some ‘yeasts’ were seen onmicroscopy. Cytology showed mixed inflammatorycells and alveolar macrophages. He was treated withintravenous ceftriaxone and clarithromycin followedby oral levofloxacin and flucloxacillin and he wasdischarged on 12 December 2003.He was seen in the outpatient clinic on 9 February2004 and he continued to have excessive sweatingand was coughing up about 30 ml of white sputumwithout haemoptysis. He reported breathlessness atabout 50 m. On examination, his trachea haddeviated to the right and the movement andthe percussion note was diminished over the rightupper lobe with increased breath sounds but noadded sounds. His peak flow was 92% predicted at450 l/min and spirometry was mildly obstructed. Hischest radiograph at the clinic showed shadowing andmarked volume loss in the right upper lobe (Figure3b). His ESR remained elevated at 47 mm/h. A CTscan of his thorax showed considerable right upperlobe volume loss with fibrosis and cavitation. Thelargest cavity measured approximately 1.8 cm indiameter but no intracavitary mass was identified tosuggest the presence of an aspergilloma. The ex-tensive shadowing extended to the pleural spacewhere there was associated pleural thickening. Back-ground changes of small emphysematous bullae werenoted. There was also mild right paratracheal noduleenlargement without a detectable bronchial tumour.His Aspergillus precipitin test was strongly positive(2 arcs) and anti-nuclear factor was positive(1/1000). He was started on itraconazole 600 mgdaily for 4 d, then itraconazole 400 mg daily.Two weeks after starting itraconazole therapy, thepatient had improved substantially. His spirometrywas stable at 2.3/3.7 and he remained breathless onwalking about 50 m. His general condition andspirometry gradually improved over the following 6months. Spirometry was 2.6/3.7 in July 2004 and2.6/4.7 in November 2004. His weight was alsobetter, inflammatory markers had improved (CRPand ESR fell to normal values and remained normalover 12 months) but his Aspergillus precipitin testremained positive at 2 arcs in July 2004, falling to 1arc in January 2005. A control chest X-ray inSeptember 2005 is shown in Figure 3c showingfurther resolution.DiscussionIn the cases described here, a massive A. fumigatusinoculum from damp tree-bark chippings was prob-Figure 3. Chest radiographs a) at admission in December 2003showing cavitating pneumonia of the right upper lobe, b) atfollow-up in February 2004 showing shadowing and markedvolume loss in the right upper lobe, and c) at follow-up 1.75 ylater in September 2005 showing further resolution (Case 2).Case Reports 947ably responsible for the infections  a relationshipthat to our knowledge has only once previously beendescribed in a patient with chronic granulomatousdisease [10]. It is known that A. fumigatus is releasedinto the air in large quantities when bark is strippedfrom trees [11]. This could be of considerableimportance in the horticulture industry and thetimber industry where this material is in widespreaduse. It is likely that workers with immunodeficiencyor with ABPA would be at especially high risk butour patients had neither of these risk factors. Therisk is probably magnified by dampness and subse-quent mould growth.The other feature of note in case 2 was thepresence of an acute cavitating pneumonia. Thedifferential diagnosis in community-acquired pneu-monia would include staphylococcal, Klebsiella orLegionella infection or, with a subacute presenta-tion, tuberculosis or coccidioidomycosis (if ahistory of travel to or residence in an endemicarea). Both cases showed a failure to resolvepromptly to antibiotic therapy, and this causedthe clinicians to consider an Aspergillus-relatedproblem. In the case with cavitation, the cliniciansdiagnosed Aspergillus infection and the patientsimproved on itraconazole therapy. However, only 2of 12 cases of community-acquired invasive asper-gillosis reviewed recently developed cavitatingpneumonia; thus, cavitation appears to be aninfrequent sign of this infrequent infection [12].Case 1 had non-cavitating bilateral interstitialshadows with poor response to antibiotics, with apositive Aspergillus antibody test, which lead tothe working clinical diagnosis of allergic alveolitisrather than infection. Meeker et al. described thedevelopment of hypersensitivity lung disease andinvasive aspergillosis, respectively, in 2 siblingsexposed to mouldy hay and an overlap betweenthese 2 disease entities is possible [4].Serological testing is used in the diagnosis ofABPA as well as invasive infection. Precipitatingantibodies are typically present in ABPA and chroniccavitary pulmonary aspergillosis but not necessarilyso during invasive infection of the immunosup-pressed host [13]. On the other hand Aspergillusgalactomannan antigen, a major component of thecell wall of Aspergillus, is detectable in the majorityof cases of invasive pulmonary aspergillosis in thosewith underlying haematological disease and intensivecare [14], and notably was also found in case 1 inhigh titre in a serum sample taken at the time ofadmission, consistent with (perhaps diagnostic of)invasive infection at this early time point. Thissuggests that the initial massive inhalation of sporeslead directly to infection and not initially to anallergitic alveolitis which later progressed to invasiveinfection. The presence of antibody and antigentogether is seen in some cases of invasive infection[15].In the cases here described, the patients did nothave any recognized underlying immune incompe-tence. Defects in mannose binding protein have beendescribed in chronic cavitary pulmonary aspergillosis[16], and we cannot rule out that this or other subtleunrecognized immune defects were present in thesepatients.While corticosteroids are the mainstay of treat-ment for ABPA and allergic alveolitis they increasethe susceptibility to infection by Aspergillus fumiga-tus in 2 ways: 1) directly by decreasing oxidativekilling by the macrophages; and 2) indirectly byenhancing the growth of the Aspergillus fungus itself[1719]. Corticosteroids are a major risk factor forinvasive aspergillosis [20,21], and thus it is likely thatthe immunosuppression caused by the high-dosesteroids and the late onset of antifungal treatmentcontributed to the fatal outcome in case 1.The cases here described illustrate the multi-faceted nature of Aspergillus disease, and that thepossibility of invasive infection should always beborne in mind also in non-neutropenic patientsexposed to Aspergillus. The use of Aspergillusprecipitating antibody and antigen testing early incommunity-acquired pneumonia could provide suf-ficient evidence for A. fumigatus infection to initiatetreatment. A clinical history of excess mould orAspergillus exposure (bark, vegetal dust, renovationsetc.) may be a useful clinical clue, as may theradiographic appearance of cavitation and a lack ofresponse to antibiotics.Finally, it is advised that the manufacturers,distributors and end-users of tree-bark productsneed to be made aware of this potential hazard.People with known immuno-deficiency should beadvised to avoid spreading tree-bark products andhealthy people should be advised not to spread theproduct when it is wet and mouldy. We will notifythe Health and Safety agencies in each of ourcountries of this hazard with a recommendationthat the labelling of tree-bark products should bealtered to alert consumers to the above hazards.AcknowledgementsThe authors wish to thank Sten Langfeldt, Depart-ment of Radiology and Steve Hamilton, Departmentof Pathology, Aarhus University Hospital, whokindly provided the digital images of the chest X-rays and the digital image of the lung section,respectively, from patient no. 1.948 Case ReportsReferences[1] Marr KA, Patterson T, Denning D. Aspergillosis. Pathogen-esis, clinical manifestations, and therapy. Infect Dis ClinNorth Am 2002;/6:/87594.[2] Patterson TF, Kirkpatrick WR, White M, Hiemenz JW,Wingard JR, Dupont B, et al. Invasive aspergillosis. Diseasespectrum, treatment practices, and outcomes. I3 AspergillusStudy Group. Medicine (Baltimore) 2000;/79:/25060.[3] Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E,Peetermans WE, Van WE. Invasive aspergillosis in criticallyill patients without malignancy. Am J Respir Crit Care Med2004;/170:/6215.[4] Meeker DP, Gephardt GN, Cordasco EM Jr, WiedemannHP. Hypersensitivity pneumonitis versus invasive pulmonaryaspergillosis: 2 cases with unusual pathological findings andreview of the literature. Am Rev Respir Dis 1991;/143:/4316.[5] Batard E, Renaudin K, Morin O, Desjars P, Germaud P.Fatal acute granulomatous pulmonary aspergillosis in ahealthy subject after inhalation of vegetal dust. Eur J ClinMicrobiol Infect Dis 2003;/22:/3579.[6] Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;/26:/781803.[7] Denning DW, Riniotis K, Dobrashian R, Sambatakou H.Chronic cavitary and fibrosing pulmonary and pleuralaspergillosis: case series, proposed nomenclature change,and review. Clin Infect Dis 2003;/37 (Suppl 3):/S26580.[8] Stevens DA, Moss RB, Kurup VP, Knutsen AP, GreenbergerP, Judson MA, et al. Allergic bronchopulmonary aspergillosisin cystic fibrosis: state of the art. 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Autopsy-controlled prospectiveevaluation of serial screening for circulating galactomannanby a sandwich enzyme-linked immunosorbent assay forhaematological patients at risk for invasive aspergillosis. JClin Microbiol 1999;/37:/32238.[15] Herbrecht R, Letscher-Bru V, Oprea C, Lioure B, Waller J,Campos F, et al. Aspergillus galactomannan detection in thediagnosis of invasive aspergillosis in cancer patients. J ClinOncol 2002;/20:/1898906.[16] Crosdale DJ, Poulton KV, Ollier WE, Thomson W, DenningDW. Mannose-binding lectin gene polymorphisms as asusceptibility factor for chronic necrotizing pulmonaryaspergillosis. J Infect Dis 2001;/184:/6536.[17] Kan VL, Bennett JE. Lectin-like attachment sites on murinepulmonary alveolar macrophages bind Aspergillus fumigatusconidia. J Infect Dis 1988;/158:/40714.[18] Schaffner A. Therapeutic concentrations of glucocorticoidssuppress the antimicrobial activity of human macrophageswithout impairing their responsiveness to gamma interferon.J Clin Invest 1985;/76:/175564.[19] Ng TT, Robson GD, Denning DW. Hydrocortisone-enhanced growth of Aspergillus spp.: implications forpathogenesis. Microbiology 1994;/140:/24759.[20] Balloy V, Huerre M, Latge JP, Chignard M. Differences inpatterns of infection and inflammation for corticosteroidtreatment and chemotherapy in experimental invasive pul-monary aspergillosis. Infect Immun 2005;/73:/494503.[21] Cornet M, Mallat H, Somme D, Guerot E, Kac G, MainardiJL, et al. Fulminant invasive pulmonary aspergillosis inimmunocompetent patients: a 2-case report. Clin MicrobiolInfect 2003;/9:/12247.Case Reports 949

Acute pulmonary aspergillosis in immunocompetent subjects after exposure to bark chippings

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Acute pulmonary aspergillosis in immunocompetent subjects after exposure to bark chippings

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