Aspergillosis and the lungs By Adetunji T.A.

1. Pulmonary Aspergillosis: Aspergilloma In Focus Adetunji T.A. Respiratory Unit Dept of Medicine OAUTHC Ile-Ife

2. Outline Introduction The organism/Ecology Epidemiology Disease Entities Pathophysiology Clinical features Differential Diagnosis Investigation Treatment Prognosis References

3. Introduction Aspergillosis refers to illness due to allergy, airway or lung invasion, cutaneous infection, or extrapulmonary dissemination caused by pathogenic species of Aspergillus Aspergillus species are ubiquitous molds found in organic matter/decaying vegetation Tissue invasion is uncommon and occurs most frequently in the setting of immunosuppression

4. The causative organism More than 100 species have been identified, majority of human illness is caused by - A. fumigatus - A. niger and, less frequently, by - A. flavus -A. clavatus and -A. nidulans . - A. terreus Transmission is via inhalation of fugal spores

5. The Organisms and Ecology Hyaline (non-pigmented),narrow, septate , branching mold P roduces vast numbers of conidia (spores) on stalks above the surface of mycelial growth. Hyphae are histologically distinct from other fungi in that the hyphae have frequent septae , which branch at 45° angles. The hyphae are best visualized in tissue with silver stains.

6. The organism

7. Epidemiology Invasive Aspergillosis now uncommon in US with the advent HAART - US National base reveals incidence 3.5 cases/1000 persons - incidence 0.02-013% per annum in HIV patients and 0.43% in transplant recipient in France Surveys & ABPA registry, - 0.25-0.8% of people with asthma - 7% of patients with Cystic fibrosis Higher incidence in steroid-dependent asthma 7-10% and bronchiectasis

8. Epidemiology Study of 77 patients in UMTH a 20-30yrs F>M; 30-40yrs M>F CNPA is rare found at autopsy a- Journal of Medicine and Medical Sciences Vol. 4(6) pp. 237-240, June, 2013

9. Epidemiology Frequency of invasive aspergillosis parallells disease states and treatments: neutropenia and immunosuppression . Occurs in 5-13% of recipients of bone marrow transplants 5-25% of patients with heart or lung transplants 10-20% of patients receiving intensive chemotherapy for leukemia. chronic cavitary lung disease- not rare In one survey of patients with chronic CLD due to tuberculosis, 17% developed aspergilloma

10. Risk factors Immunocompromised states - Coticosteroid use - Advanced HIV infection - Neutropenia - Bone marrow /solid organ transplant Chronic granulomatous disease: TB, Sarcoidosis Cystic Fibrosis

11. Pulmonary aspergillosis Primarily affects the lungs, causing the following main syndromes: Allergic bronchopulmonary aspergillosis (ABPA) Invasive aspergillosis Chronic necrotizing Aspergillus pneumonia (or chronic necrotizing pulmonary aspergillosis [CNPA]) Aspergilloma

12. In patients who are severely immunocompromised , Aspergillus may hematogenously disseminate beyond the lung, potentially causing ; E ndophthalmitis , E ndocarditis , and A bscesses in the myocardium, kidney, liver, spleen, soft tissue, and bone

13. Transmission Via inhalation and daily exposure abound Daily exposures vary from a few to many millions of conidia; High numbers of conidia are encountered in hay barns and other very dusty environment R equired size of the infecting inoculum is uncertain I ntense exposures (e.g., during construction work) are required to cause disease in healthy individuals.

14. Transmission2 The incubation period of invasive aspergillosis after exposure is highly variable 2 to 90 days. Outbreaks usually are directly related to a contaminated air source in the hospital

15. Pathophysiology A. fumigatus is the most common cause of infection in humans. Possess ability to grow at normal human body temperature Most other sp cannot

16. Pathophysiology Human host defense against the inhaled spores begins with the mucous layer and the ciliary action in the respiratory tract. Macrophages and neutrophils encompass, engulf, and eradicate the fungus. However, many species of Aspergillus produce toxic metabolites that inhibit macrophage and neutrophil phagocytosis . Corticosteroids also impair macrophage and neutrophil function.

17. Pathophysiology Underlying immunosuppression contributes directly to neutrophil dysfunction or decreased numbers of neutrophils . Vascular invasion is common in immunosuppressed states May result in infarction, hemorrhage , and necrosis of lung tissue. G ranuloma formation and alveolar consolidation may occur in CNPA

18. Pathophysiology Colonization of previously formed cavities in the lung Inhaled Aspergillus spores may also colonize the mucus within the bronchi, As obtained in moderately severe asthma with thick and tenacious mucus Aspergillus spores may invade adjacent lung tissues and produce a gradually progressive and destructive process in lung containing centrilobular emphysema

19. invasive Semi-invasive ABPA TRACHOEBRONCHITIS RISK FACTORS

20. CLINICAL FEASTURES Asymptomatic fever cough (sometimes productive), chest discomfort, trivial hemoptysis , shortness of breath. Cough Fever Wheeze Dyspnea Brownish sputun Poor response to ICS COMPLCATIONS Disemmination Upper lobe Fibosis , Brochiectasis

21. Disseminated Infections The most lethal form of aspergillosis is disseminated or pyemic aspergillosis . the fungi will grow within the alveoli and invade adjacent vascular structures, leading to occlusion of these vessels. Necrosis follows occlusion of the vessels, leading to wedge-shaped areas of infarction. Metastatic abscesses in brain, lung, liver, heart, and other organs are common. Skin involvement gives rise to a characteristic lesion: an area of central necrosis and a black eschar ( ecthyma gangrenosum ) Occasionally, Aspergillus endocarditis may follow pyemic spread or surgery

22. Aspergilloma Aspergilloma (fungal ball) occurs in up to 20% of residual chest cavities 2cm in diameter. Some fungal balls remain stable in a single cavity for many years, and 10% resolve spontaneously. They are often a feature of chronic pulmonary aspergillosis with its associated features

23. Aspergilloma2 Vast majority of fungal balls are caused by A. fumigatus A. niger implicated in diabetic patients; aspergillomas due to A. niger can lead to oxalosis with renal dysfunction

24. Classification Pulmonary aspergilloma is classified as - simple - complex pulmonary aspergilloma (CPA), based on the radiological aspect, which reveals the nature and extent of the pulmonary impairment caused by the pre-existing disease. SPA : Well-localized lesion, thin-walled cavities, and little or no change in the adjacent lung tissue. CPA : disseminated lesions, thick walls, parenchymal sequelae resulting from the previous lung disease-in most cases TB

25. Clinical Features May manifest as an asymptomatic Radiographic abnormality in a patient with pre-existing cavitary lung disease due to sarcoidosis , TB, necrotizing pulmonary processes, CF, emphsematous bullae May occur in cystic areas resulting from prior Pneumocystis jiroveci pneumonia in patients with HIV disease

26. Clinical Features Hemoptysis is the major feature 40-60% (rarely, occasional exsanguinating hemorrhage ) Less commonly, cough and fever. wheezing, and mild fatigue

27. Clinical Features Aspergillomata can form in other body cavities. abscesses in the brain, usually in people who are immunocompromised . They can also form within the different sinuses in the face, within the kidneys and urinary system, the ear canal, and on the heart valves

28. Diseases Featutes Bronchogenic ca Short duration Wt loss, hoarseness of voice Hx of risk factors ct bronchiectasis Mitral stenosis Acute lvf Paragonomiasia

29. Allergic Bronchopulmonary Aspergillosis (ABPA) characterised by an exaggerated response of the immune system (a hypersensitivity response) to the fungus Aspergillus (most commonly A. fumigatus). O ccurs most often in patients with asthma or cystic fibrosis 1 about 1% and 15% resp Occasional cases are reported in patients without either of these diseases

30. ABPA Patients develop a hypersensitivity response, both a type I response (atopic, with formation of IgE ) and a type III hypersensitivity response (with formation of IgG). The reaction of IgE with Aspergillus antigens results in mast cell degranulation with bronchoconstriction and increased capillary permeability. Immune complexes (a type III reaction) and inflammatory cells deposited within the mucous membranes leading to necrosis and an eosinophilic infiltrate. Type 2 T helper cells secreting interleukin 4 and interleukin 5, and attraction of neutrophils by interleukin 8 are also involved

31. ABPA In spite of this pronounced immune reaction, the fungus is not cleared from the airways. Proteolytic enzymes are released by the immune cells, and toxins are released by the fungi. Together these result in bronchiectasis , most pronounced in the central parts of the airways. Repeated acute episodes left untreated can result in progressive pulmonary fibrosis that is often seen in the upper zones and can give rise to a similar radiological appearance to that produced by TB.

32. ABPA The otherwise-severe course of underlying asthma is punctuated by episodes of worsening, when thick mucus plugs become inspissated in bronchi, causing an inflammatory process distal to the obstruction. This propensity to cause bronchial obstruction gives rise to the characteristic radiographic pattern of the disease, the so-called finger -in-glove appearance, in which multiple adjacent bronchi are distended with the mucus plug

33. Clinical Features Episodes of bronchial obstruction with mucous plugs leading to coughing fits, breathlessness and production of thick sputum casts, usually brown or clear Fever, unresponsive to antibacterial therapy

34. Clinical Features Hemoptysis . Wheezing People with asthma who have ABPA may have poorly controlled disease and difficulty tapering off oral corticosteroids. ABPA may occur in conjunction with allergic fungal sinusitis Development of chronic fibrous changes, the restrictive lung function pattern is overlaid on top of the reactive airways disease

35. ABPA Sequallae ABPA may be progressive, and the following 5 stages have been described Acute disease Remission Exacerbation or recurrence Corticosteroid-dependent asthma End-stage fibrosis

36. Invasive Aspergillosis Invasive aspergillosis is divided into Acute (<1mnth) Subacute forms (1-3mnths) >80% of cases of invasive aspergillosis involve the lungs. The keys to early diagnosis in at-risk patients are high index of suspicion, screening for circulating antigen, and urgent CT of the thorax.

37. Features Frequency and progression increase with greater degrees of immunocompromise Neutropenia and corticosteroid therapy are major risk factors increasingly observed in patients with COPD on long-term corticosteroid therapy Dissemination to other organs, particularly the central nervous system, may occur.

38. Clinical Features Asymptomatic commonly fever cough (sometimes productive), nondescript chest discomfort, trivial hemoptysis , shortness of breath. Although the fever often responds to glucocorticoids , the disease invariably progresses

39. Chronic Pulmonary Aspergillosis (CPA) A.k.a semi-invasive aspergillosis , Can be divided into chronic cavitary pulmonary aspergillosis chronic necrotizing aspergillosis ,

40. Features subacute pneumonia unresponsive to antibiotic therapy progresses and cavitates over weeks, months or years with expanding cavities have underlying disease, such as steroid-dependent COPD or alcoholism And others - TB, atypical mycobacterial infection, sarcoidosis and other granulomatous lung disease, ankylosing spondylitis , rheumatoid lung disease, pneumothorax , bullae , ILD or prior lung surgery

41. Clinical features Usually >3mnths Fever, cough, night sweats, and weight loss Hemoptysis If untreated, typically progresses (sometimes relatively rapidly) to unilateral or upper-lobe fibrosis. This end-stage entity is termed chronic fibrosing pulmonary aspergillosis .

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