Presentation on theme: "The extraordinary spectrum of diseases caused by Aspergillus"— Presentation transcript:
1The extraordinary spectrum of diseases caused by Aspergillus David W. DenningWythenshawe HospitalUniversity of Manchester
2The genus Aspergillus - importance to humanity on the negative side:cause invasive and allergic diseasein humans and other animals:A. fumigatuscause plant and food spoilage andproduce mycotoxins:A. flavus and A. parasiticusSeveral species of Aspergillus can cause disease in humans and animals particularly when the host is immunosuppressed, eg in cancer patients, transplant patients and AIDS patients. Aspergillus spores are airborne and occur naturally in the environment, but are often more abundant around building sites. Near compost or where damp conditions prevail. Invasive disease usually only occurs in immunosuppressed patients with inhalation being the primary route of infection. Allergic aspergillosis occurs in patients with asthma, atopy or cystic fibrosis.In many underdeveloped countries contamination of crops such as maize, groundnuts etc has lead to loss of crops and severe illness in both humans and farm stock where contaminated food is ingested (due to mycotoxins which harm the body).
3The genus Aspergillus - importance to humanity on the positive side:compostingwell-established model organism in cell biology and genetics:A. nidulansfood production:enzymes and organic acids: A. nigerEast Asian foods: A. oryzae and A. sojae1) Fungi play an essential role in both the Nitrogen and Carbon cycle by breaking down dead organic material.2) The detailed genetic study of A.nidulans has lead to some important discoveries, such as the parasexual cycle in fungi, and the genetic defect causing alkaptonuria3) Most of us use fungi every day without knowing it. We eat mushrooms and Quorn™ (a vegetarian fungal protein made from Fusarium graminarium), but we also prepare many other foods using fungi. The yeast Saccharomyces cerevisiae is used to ferment sugar to alcohol and carbon dioxide – the process used to make beer and wine and also to make bread rise. All citric acid is produced by Apergillus niger. The fungi Aspergillus oryzae and Aspergillus sojae are used in the production of the oriental foods soy sauce and miso. We also use fungi to produce flavourings, vitamins and enzymes and to mature many cheeses. 4) Apart from penicillin, the most important antibiotics from fungi are the cephalosporins (beta-lactams with similar mode of action to penicillin, but with less allergenicity) and griseofulvin (from Penicillium griseofulvum and related species) which is used to treat athlete's foot and related fungal infections of the skin. The echinocandins anidulafungin and aminocandin (HMR 327) are semi-synthetic antifungals originally derived from fermentation of A. nidulans var restrictus and A. sydowi respectively.Lovastatin a cholesterol lowering drug is produced by Aspergillus terreus. And the group of antifungal drugs called echinocandins have been produced using A nidulans and A sydowi.Fumagillin is a secondary metabolite that inhibits angiogenesis and antibiotic properties, especially against protozoa such as Entamoeba histolytica. LD50 in mice 800 mg/kg body-weight subcutaneously although as much as 2 mg/kg body-weight could be tolerated orally. Fumigillin or analogue TNP-470 have been used in the treatment of microsporidiosis, usually caused by the microscopic fungus Enterocytozoon bieneusi (Fumagillin treatment of intestinal microsporidiosis. New Engl J Med 2002;346: ).pharmaceuticals:echinocandins: A. nidulans and A. sydowilovastatin: A. terreusfumagillin: A. fumigatus
4Aspergillus Life-cycle GerminationSpores inhaledHyphal elongation and branchingMass of hyphae (plateau phase)Short movie clips showing germination of spores and growth of hyphae can be viewed on this website at the following link:
5The genus Aspergillus – ~180 species, 38 have caused disease (able to grow at 37C)Common in the environmentAspergillus fumigatus conidial headA. terreus – resistant to AmBA. nidulans – may be amphotericin B resistantA. nigerA. flavus -sometimes amphotericin B resistantA. fumigatus low frequency of azole resistanceThe relative frequency of species associated with acute invasive aspergillosis is 85-90% A. fumigatus, 5-10% A. flavus, 3-7% A. niger and 1% A. nidulans. There are approximately other species of Aspergillus which have caused disease in humans.. ( see view the species section within the image bank). The few species which cause disease in man and animals are also known to have some resistance to antifungal drugs.
6CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosisAcute (<1 month course)Subacute/chronic necrotising (1-3 months)Airways/nasal exposure to airborne AspergillusChronic aspergillosis (>3 months)Chronic cavitary pulmonaryAspergilloma of lungChronic fibrosing pulmonaryChronic invasive sinusitisMaxillary (sinus) aspergillomaPersistence without disease - colonisation of the airways or nose/sinusesAllergicAllergic bronchopulmonary (ABPA)Extrinsic allergic (broncho)alveolitis (EAA)Asthma with fungal sensitisationAllergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see slide 8), with probably a component of the inoculum size contributing to invasive disease.Acute and subacute disease is usually associated with immunocompromised patients eg AIDS, chemotherapy, transplant etc. and these will be discussed first.
7Immunosuppression and infection Inhalation of aspergillus spores is a common daily occurrence. A healthy immune system would normally remove the spores and no symptoms or infection would occur.In individuals whose immune system may be suppressed either because of illness eg AIDS, cancer patients or drugs, spores may germinate and resulting tissue or systemic aspergillus invasion can result.Individuals with allergies such as asthma, can also be vulnerable to aspergillus disease.
8Normal immune function Interaction of Aspergillus with the host A unique microbial-host interactionAcute IAABPAAllergic sinusitisSubacute IAFrequency of aspergillosisFrequency of aspergillosisTracheobronchitisAspergillomaChronic cavitaryChronic fibrosingObjective: The risk of developing invasive aspergillosis increases with increasing levels of immune deficiency. In contrast the risk of allergic aspergillosis is enhanced in individuals whose immune system is hyper-reactive (atopic).Immune dysfunctionNormal immune functionImmune hyperactivity.
9Changing incidence of fatal invasive mycoses in non-HIV patients in USA Rate per 100,000 populationCandidiasisAspergillosisThis slide contrasts the reduction in mortality related to candidaemia and invasive candidiasis with invasive aspergillosis in the US. Other figures from Europe indicate 4% of patients dying in teaching hospitals have invasive aspergillosis, including medical intensive care in patients not normally considered susceptible.McNeil et al, Clin Infect Dis 2001;33:641
10Invasive pulmonary aspergillosis IPANormal lungIPA occurs in ~7% of acute leukaemia patients, 10-15% allogeneic BMT patientsChest X ray showing large lesion due to invasive pulmonary aspergillosis.Chest radiograph with ‘classical’ appearance of a pulmonary infarction – a wedge-shaped lesion peripherally set against the pleura. This patient was receiving chemotherapy including corticosteroids, who had had a splenectomy previously presented with fever and right-sided pleuritic chest pain. Blood cultures grew Aspergillus fumigatus and he responded to amphotericin B and flucytosine. (Case published in Denning DW, Williams A H. Invasive pulmonary aspergillosis diagnosed by blood culture and successfully treated. Br J Dis Chest 1987, 81: 300. See also case 38 in the case history section
11Unequivocal ‘Halo sign’ surrounding a nodule CT scan showing characteristic halo sign - in a cavity with fungus ball there is a crescent shaped semi-translucent space along the upper portion, of a density giving the appearance of a halo.Angioinvasion is the pathological hallmark of acute IPA in the neutropenic setting. Two patterns of pathology are discernable: invasion of major proximal pulmonary arteries with resultant thrombosis and distal tissue infarction and a well circumscribed spherical nodule with a vessel in the centre of the lesion invaded by hyphae. Such nodules have a pale centre of coagulative necrosis with extensive permeation of tissue by hyphal elements but few inflammatory cells or haemorrhage. Surrounding this necrotic centre is haemorrhagic parenchyma. In the former, the radiological appearance is one of a wedge shaped lesion with the base abutting the visceral pleura. [Fraser]. The latter lesion is seen on CT as a nodule with or without an associated halo sign [Fraser, Meziane]. If the lesion cavitates, the area of central necrosis (sequestrum) contracts with replacement by an air-cap, and an air-crescent sign may be visible.Fraser RS. Pulmonary aspergillosis: pathologic and pathogenetic features. Pathol Annu 1993; 28 Pt 1:Meziane MA, Hruban RH, Zerhouni EA, et al. High resolution CT of the lung parenchyma with pathological correlation. Radiographics 1988; 8:Halo signHerbrecht, Denning et al, NEJM 2002;347:
12Recent examples of the frequency of invasive aspergillosis Underlying conditionIncidenceReference/yearAcute myeloid leukaemia8%Cornet, 2002Acute lymphatic leukaemia6.3%Allogeneic HSCT11-15%Grow, 2002;Marr, 2002Lung transplantation%Minari, 2002; Singh,2003Heart-lung transplantation11%Duchini, 2002Small bowel tranplantationAIDS2.9%Libanore, 2002Recent examples of the incidence of IA in different at risk groups. Actual numbers are unit dependant and diagnostic criteria dependent.
13Bleeding as an aspect of disseminated invasive aspergillosis Fumagillin is anti-angiogenicA haemolysin described from Aspergillus fumigatusOther factors that contribute to thrombosis or a coagulopathy?Fumagillin - a product of Aspergillus fumigatus is an inhibitor of endothelial cell proliferation and angiogenesis. Yet angiogenesis is a hallmark for invasive aspergillosis. (see previous slide). Certain proteases are probably important in contributing to a coagulation disorder.Gillies & Campbell,
14Interaction of conidia and endothelial cell projections How does Aspergillus fumigatus cause thrombosis (clotting of vessels) and also bleeding?Interaction of conidia and endothelial cell projectionsInternalisation of conidia (and hyphae) by endothelial cells with injury apparent at 4 hoursThese images show the interaction of swollen Aspergillus fumigatus conidia interacting with endothelial cells (the innermost layer of cells in blood vessels). The images direct interaction of conidia with the cells, phagocytosis by the endothelial cell, and then cellular damage, all in a 4 hour time-frame. The precise mechanisms are not clear.Filler et al, Blood 2004;103:2134; Paris et al, Infect Immun 1997;65:1510.
15Cerebral aspergillosis (abscess) in chronic lymphocytic leukaemia Dissemination via the blood stream to the brain occurs in ~5% of cases of invasive aspergillosis, and in ~40% of allogeneic bone marrow (HSCT) recipientsPatient diagnosed with Stage C Chronic Lymphocytic Leukaemia, treated in the MRC CLL4 study, with prednisolone for 4 weeks followed by oral chlorambucil for 7 days. Patient developed severe pneumonia due to pseudomonas and staphylococcus. Following treatment with broad spectrum antibiotics and 1 week of Abelcet, patient was readmitted with headache, disorientation and fever. CT brain scans showed 3 ring enhancing lesions, aspirated material showed neutrophils but grew aspergillus. Patient now improved on Abelcet (4 mg/kg) and oral itrconazole suspension 200mg b.d.
16Early diagnosis of invasive aspergillosis is important Treatment started <10d >11dMortality % 90%Von Eiff et al, Respiration 1995;62:241-7.
17Sputum Cultures for Fungus Bacteriological media inferior to fungal media – 32% higher yield on fungal mediaA four day A. fumigatus culture on malt extract agar (above). Light microscopy pictures are taken at 1000x, stained with lacto-phenol cotton blue.At least 3 sputum specimens should be submitted for fungal culture whenever fungal infection is suspected. On a survey of routine bacterial culture versus fungal culture, many positive cultures for Aspergillus were found on the routine cultures, but 32% of instances of Aspergillus were only seen in the fungal culture medium. Horvath & Dummer, Am J Med 1996;100:171-8.
18Aspergillus Antigen Test Diagnosis or surveillance?Only blood, or BAL, CSF etcBest OD cut-off - 0.7False positives in kids / antibioticsFalse negative with antifungalprophylaxisNot as useful for non-hematologyNot useful if pre-existing antibodyThere are substantial data on aspergillus antigen (galactomannan) using the commercial ELISA format published. Essentially, it can be detected in blood in most patients with acute invasive aspergillosis. False positives arise because of intestinal absorption of galactomannan which is found in many foods (see (oldest article), and contamination of some antibiotics batches with antigen. Most Aspergillus species are detected, as all the common pathogenic species produce galactomannan. False negatives do arise, probably partly because of complexing by antibody. If the absolute incidence of IA is high (ie >6%) the balance of argument is to use a screening approach, if less frequent than this, a diagnostic approach. However, anti-aspergillus prophylaxis (such as itraconazole solution) probably reduces the test’s utility. Once positive, rising titres on treatment predict failure, and usually death. CSF antigen is useful for diagnosing cerebral aspergillosis, and BAL antigen is probably useful for pulmonary aspergillosis, but the assay cut-off and performance is not yet clear.Herbrecht et al, J Clin Microbiol 2002;20: ; and others
19Outcome from invasive aspergillosis – amphotericin B therapy Note 60% death rate in 30 days from acute invasive pulmonary aspergillosis treated with amphotericin B.Lin et al, Clin Infect Dis 2001;32:358
20Sub-acute invasive aspergillosis in AIDS This patient, thought initially to have pulmonary tuberculosis in AIDS, has bilateral upper-lobe cavities, more marked on the left. He presented with fever, non-productive cough and dyspnoea. Bronchoscopy yielded Aspergillus fumigatus. He refused therapy and died with progressive disease. He is reported as patient 8 in (Denning DW, Follansbee S, Scolaro M, Norris S, Edelstein D, Stevens DA. Pulmonary aspergillosis in AIDS. N Engl J Med 1991; 324: )
21Sub-acute invasive aspergillosis Less immunocompromised patientsSlower progression of disease (> 1 month)Cavitary or nodular pulmonary disease typicalVascular invasion less commonDissemination less commonAntigen testing less usefulAntibody testing may be helpful in diagnosis
22Chronic necrotizing aspergillosis (CNPA) Chronic necrotizing pulmonary aspergillosis (CNPA) is a subacute process usually found in patients with some degree of immunosuppression.Usually it is associated with underlying lung disease, alcoholism, or chronic corticosteroid therapy. Because it is uncommon, CNPA often remains unrecognized for weeks or months and causes a progressive cavitary pulmonary infiltrate.
23Chronic necrotising pulmonary aspergillosis Right upper lobe showing circular shadow partly filled by a mass. PT MS 1996Right lobe shows huge cavity containing some debris, with +ve aspergillus precipitins.Pt MS 1999Same lobe shows expansion of the shadow, still partially filled with a mass. Pt MS 1998Right upper lobe. Patient has diabetes and pulmonary mycobacterium avium- shows small cavitary lesion PT MS 1995.This man was an insulin dependent diabetic, otherwise well. The first panel (chest X-ray) shows the original infection with mycobacterial infection (M. avium intracellulare (atypical)). The second shows a much larger cavity, with a fungal mass in it. An isolated film would allow a diagnosis of aspergilloma, but later X-rays show progression. The third chest X-ray shows an expanding cavity, with a larger fungal ball in it. The final X-ray shows a very large thin-walled cavity containing fluid. Aspiration of the fluid grew Staphylococcus aureus.Denning, Clin Microbiol Infect 2001;7(Suppl 2):25-31.
24CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosisAcute (<1 month course)Subacute/chronic necrotising (1-3 months)Airways/nasal exposure to airborne AspergillusChronic aspergillosis (>3 months)Chronic cavitary pulmonaryAspergilloma of lungChronic fibrosing pulmonaryChronic invasive sinusitisMaxillary (sinus) aspergillomaPersistence without disease - colonisation of the airways or nose/sinusesAllergicAllergic bronchopulmonary (ABPA)Extrinsic allergic (broncho)alveolitis (EAA)Asthma with fungal sensitisationAllergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease.However chronic disease if usually seen in patients with apparently normal immune systems.
25Aspergillus and airways Types of aspergillosis of the airwaysColonisation (no disease – could be at risk)Obstructing Aspergillus tracheobronchitis /Mucus impaction (non-invasive)Aspergillus bronchitis/tracheobronchitis (superficially invasive only)Ulcerative Aspergillus tracheobroncitis (locally invasive) (lung transplants – at anastomosis)Pseudomembranous Aspergillus tracheobronchitis (Extensive disease, locally invasive, associated with IPA and may disseminate)Langley, ATS 2004The categories of invasive aspergillosis of the the airways and whether the disease is likely to be invasive or not, is described.
26Aspergillus tracheobronchitis Autopsy drawing of a‘normal’ 3 year oldwho died over 10 daysThis drawing shows the appearance of the tracheobronchial tree at autopsy. It shows white plaques of fungal growth on the trachea and main bronchi. This is the first case of Aspergillus tracheobronchitis reported, and emphasises that some cases are in ‘normal’ patients, ie no immunosuppression.Wheaton, Path Trans 1890; 41:34-37
27Aspergillus tracheobronchitis Review of 58 patients in literature for normal and immuno compromised patients - risk factors%None (ie normal) 25Heart / Lung transplant 18Solid tumour 15BMTLeukaemia 13HIV/AIDS 8OtherKemper et al, Clin Infect Dis 1993; 17: 344
28Aspergilloma Patient RT December 2002 Fungus ball Pulmonary aspergilloma is a mass caused by a fungal infection that usually grows in pre-existing lung cavities. An aspergilloma can also form in the maxillary sinus, often related to dental work on the upper teeth. In the lung, it must be distinguished from chronic cavitary pulmonary aspergillosis (complex aspergilloma), characterised by multicavity disease. Aspergillomas are single, and always have substantial pleural thickening over them, and these patients have positive serum aspergillus precipitins.Patient RTDecember 2002
29Chronic pulmonary aspergillosis – pre-existing disease All 18 patients had prior pulmonary disease9 TB, 5 with atypical mycobacteria13 smokers or ex-smokersAll 18 non-immunocompromised3 excess alcoholStudied symptoms in 18 patients .Chronic cavitary pulmonary aspergillosis (complex aspergilloma),is characterised by multicavity disease.Denning DW et al, Clin Infect Dis 2003; 37:S265
31Chronic pulmonary aspergillosis - serology All 18 patients had positive Aspergillus precipitins ( )All 18 patients had elevated inflammatory markers, CRP, PV and / or ESR14 of 18 (78%) had elevated total IgE (>20), 13 >200 and 7 >4009 of 14 (67%) had Aspergillus specific IgE (RAST)Denning DW et al, Clin Infect Dis 2003; 37:S265
32Chronic cavitary pulmonary aspergillosis (CCPA) Close up view of right upper-lobe of the lung in a 45 year old man who smoked cigarettes showing an ill-defined shadow behind the clavicle and additional abnormalities inferior to this in the right upper-lobe. The lesions were considered to be possibly malignant and surgically resected. The specimen revealed a 2cm cavity with necrotic contents associated with local bronchiectasis and thickening of the parietal pleura. The lung specimen showed severe emphysema with fibrosis. Microscopically, the cavity was in an area of cystic bronchiectasis with erosion of the mucosa. The cavity contents were purulent and contained a fungus ball without apparent invasion or tissue eosinophilia. A fibrosing (necrotising) granuloma was seen superior to the cavity. Stains for acid fast organisms and cultures for TB were negative and fungal cultures were not done.. B. June 1992 Recurrence of disease. Chest radiograph demonstrating cavitary invasive aspergillosis. Despite resection of part of the right upper-lobe, invasive aspergillosis recurred six months later. Sputum cultures grew A. fumigatus and Aspergillus antibodies were detected in serum. He responded to itraconazole but subsequently progressed. Patient RWSeptember 1992Relapse in normal lungPatient RWDecember 1991Pre surgical resection
33Chronic cavitary pulmonary aspergillosis This CT scan of the thorax illustrates the formation of multiple cavities, without any fungal ball formation (aspergilloma) developing in ‘normal’ (emphysematous) lung a non immunocompromised patient. The appearances are reminiscent of tuberculosis and coccidioidomycosis. Pleural involvement is seen as well.Patient RWJuly 1993
34Chronic Cavitary Pulmonary Aspergillosis Young 33 year-old female smoker (no other risk factors) spontaneously developed these bilateral pulmonary shadows that then cavitated, and the cavities expanded in size of the next 3 years.Patient JAJan 2001
38Chronic cavitary pulmonary aspergillosis Case 004 (also published) in case histories section.Patient JPJune 1999Denning DW et al, Clin Infect Dis 2003; 37:S265
39Chronic Cavitary Pulmonary Aspergillosis, with aspergilloma Case 004 (also published) in case histories section.Patient JPJuly 2001Denning DW et al, Clin Infect Dis 2003; 37:S265
40Chronic Fibrosing Pulmonary Aspergillosis Case 004 (also published) in case histories section.Patient JPApril 2002Denning DW et al, Clin Infect Dis 2003; 37:S265
41Mannose Binding Lectin (MBL)- a key part of the innate immune system Mannose-binding lectin (MBL) is a serum protein of hepatic origin belonging to a family of Ca2+-dependent collagenous lectins, most of which are components of the innate immune system). MBL is able to bind through multiple sites to various carbohydrate structures and, on binding to its ligands, is able to activate complement in an antibody- and C1q-independent manner using MBL-associated serine protease 1 (MASP-1) and MASP-2).In humans, low levels of MBL are caused by one of three structural mutations found within exon 1 of the MBL gene. One - M54 - effects 16% of caucasians.Crosdale et al J Infect Dis 2001;184:653
42Mannose Binding Protein Mutations5 mutations described2 in promoter region (less important)3 in open reading frame (M52, M54, M57)Codon 54 mutation present in 16% of Caucasian homozygous in 2%Defects associated with bacterial infections in children and hepatitis B carriageEisen & Minchinton Clin Infect Dis 2003;37:1496
43CCPA and human gene defects 8 of 11 (72%) had low MBL genotypes p=<0.05(compared to normal controls)8 of 17 (47%) had low MBL genotypes p=0.000232% and 21.5% frequency of 2 SPA2 mutations, compared with normals (18% and 11%) (p=0.021 and p=0.044)not related to coeliac disease (<1 in 30)Mannose binding protein genetic defects are common in CCPA patients (47-72%). Less common are defects in superfactant A2 protein, one of the 5 main surfactants found in the lung. Cytokine defects are also likely.Crosdale et al J Infect Dis 2001;184:653; Vaid et al, unpublished.
44CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosisAcute (<1 month course)Subacute/chronic necrotising (1-3 months)Airways/nasal exposure to airborne AspergillusChronic aspergillosis (>3 months)Chronic cavitary pulmonaryAspergilloma of lungChronic fibrosing pulmonaryChronic invasive sinusitisMaxillary (sinus) aspergillomaPersistence without disease - colonisation of the airways or nose/sinusesAllergicAllergic bronchopulmonary (ABPA)Extrinsic allergic (broncho)alveolitis (EAA)Asthma with fungal sensitisationAllergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease.
45ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS – Key diagnostic criteria ABPA possibleABPA probableABPA almost certainAsthmaBlood eosinophilia (>1,000 / cu mm)History of pulmonary infiltratesCentral bronchiectasisPrecipitins against A. fumigatus positiveAspergillus IgE antibody >2x asthma controlAspergillus IgG antibody >2x asthma controlTotal serum IgE concentration, >1000 iu/mLIf 3 tests +ve, then ABPA very likely,If all 4 +ve the diagnosis establishedKey criteria for the diagnosis of ABPARickett et al. Arch Intern Med 1983; 143: 1553; Patterson, Chest 2000;118:7
46ABPA After bronchoscopy Before bronchoscopy www.aspergillus.org.uk Remarkably oedematous bronchial mucosa, as seen in ABPA. Before and after image shows remarkable obstruction by a mucus plug, subsequently removed by bronchoscopy.
47ABPA mucous plugging www.aspergillus.org.uk There was a long mucous plug in the anterior segment of the RUL. Half of this was aspirated and sent for microscopy and culture. The second half "fell into" the bronchus intermedius (which feeds the right middle lobe) and was only partially aspirated.
48ABPA - CT showing central bronchiectasis Central bronchiectasis is very characteristic of ABPA. It is also seen in cystic fibrosis. It is one of the diagnostic criteria for the disease.
49ABPA and surfactantStructures of 2 important surfactants.5 surfactant proteins in man, SPA1, SPA2, SPB, SPC and SPD – all ‘collectin’ familyMason et al, Am J Physiol 1998;275:L1-13.
50ABPA – surfactant defects 2 exonic polymorphisms, and 2 intronic polymorphisms in SP- A2 associated with ABPAA1660G = OR of 4.78; or if combined with G1649C = OR 10.4Also associated with higher peripheral eosinophiliaExamples of polymorphisms conferring susceptibility to ABPA in India.Saxena et al, J Allergy Clin Immunol 2003;111:
51Eosinophilic fungal rhinosinusitis or allergic fungal sinusitis Patient with chronic symptomsof nasal obstruction, loss of smell and nasal polypsPonikau et al, Mayo Clinic Proc 1999;74:877 &
52Eosinophilic fungal rhinosinusitis (link with airborne fungi - ?which most importantThese panels are the same/adjacent sections stained with H&E (left) and an immunofluorescent antibody to MBP. It shows the sinus cavity full of mucus which contains substantial amount of MBP.= Myelin basic protein, highly toxic to local epitheliumPonikau et al, Mayo Clinic Proc 1999;74:877
54Fungal-associated asthma – evidence Severe asthma linked with fungal sensitisationFrequency of fungal sensitisationFungal-associated asthmaABPAHigh spore counts and asthmatic attacksTreatment of ABPAand pilot data
55Spore counts and asthma attacks and admission to hospital All circumstantial evidenceThunderstorm asthma – linked to AlternariaAsthma deaths (Chicago) linked to high ambient spores counts and season (summer autumn) when spore counts highestAsthma hospital admission linked to high ambient spore counts (Derby, New Orleans, OttawaAsthma hospital attendance linked to high spore counts , but not pollen counts (Canada)Asthma symptoms increased on days of high spore counts (California, Pennsylvania)O'Hollaren, N Engl J Med 1991; 324: 359; Newson, Occup Environ Med 2000; 57:
56Fungus at home Environmental data Mouldy housing associated with worse asthma, with a correlation between asthma severity and degree of dampness in the home and separately with visible mould growthIn Germany bronchial reactivity in children was associated with damp housingMouldy and damp school associated with asthma symptoms and emergency room visitsHighest concentration of Aspergillus fumigatus is at homeWilliamson, Thorax 1997;52:229. Taskinen, Acta Paediatr 1999; 88:1373.
57Severe asthma and moulds Mild asthma – 564 (50%)Moderate asthma – 333 (29%)Severe asthma – 235 (21%) – linked with fungus skin test positivitySevere asthma and mouldsZureik et al, Br Med J 2002;325:411
58Asthma severity, house dust mites, cats and moulds AllergenNo asthman= 111Mild asthma FEV1 >75% <90%n= 67Moderate asthma FEV1 >60% <75%n= 42Severe asthma FEV1 >60%House dust mite61%71%45%77%Cats*49%51%38%35%Moulds#17%19%36%31%* P = 0.05# p = 0.01Langley, ATS 2004This study shows a high frequency of house dust allergy irrespective of the severity of asthma, a decreasing frequency of cat allergy with worsening asthma (perhaps these people stop keeping cats at home), and a higher frequency of mould (Cladosporium, Aspergillus, Alternaria and Penicillium) allergy as asthma gets measurably worse. Asthma is assessed based on FEV1 (forced expiratory volume in 1 second) a measure how open the airways are.