7/21/09

1

ASPERGILLOSIS

Gina Milick Jennifer Hornick Andraele Reed Tiffany Shugart

HISTORY OF ASPERGILLOSIS

 1729 – Fungus Aspergillus first identified and catalogued by Italian biologist/priest Micheli

 Noticed under microscope the fungi looked like an aspergillum which is used to sprinkle holy water and named the genus after it.

 1815 – Aspergillus first observed in birds by Mayer

 1842 – British physician John Hughes Bennett discovered first case of pulmonary aspergillosis in humans.

 Called aspergilloma which means “fungus ball” in the lungs

HISTORY OF ASPERGILLOSIS

 Many early cases of aspergillosis were found in patients with tuberculosis or high risk occupations such as pigeon-crammers and wig combers   Some were invasive but most were

aspergillomas  1953 – Rankin described the ability of

Aspergillus to cause opportunistic infection in immunocompromised patients

 1970 – Histopathology and clinical features of disease described in 98 patients

TAXONOMY

 Kingdom: Fungi  Phylum: Ascomycota  Order: Eurotiales  Family: Trichocomaceae  Genus: Aspergillus

ETIOLOGY

 Genus Aspergillus includes over 185 species   ~20 species reported to cause infections   7 are facultatively pathogenic

 Aspergillus fumigatus most commonly isolated species   Found in 90% of infections   Widespread in nature   Commonly found in soil and compost heaps   Can also be found indoors   Thermophilic species (Growth at 40° C and above)   Angioinvasive

ASPERGILLUS FUMIGATUS

http://www.mycology.adelaide.edu.au/gallery/photos/aspergillus11.gif

Conidiospores are short ,smooth-walled with conical shaped terminal vesicles

7/21/09

2

ASPERGILLUS FUMIGATUS

http://www.mycology.adelaide.edu.au/images/fumigatus1.gif

• Grown on Czapek dox agar • Culture has a blue-green surface pigmentation with a suede-like surface consisting of a dense felt of conidiophores

ETIOLOGY

 Next most commonly isolated species include:   A. flavus   A. niger   A. clavatus   A. glaucus   A. nidulans   A. oryzae,   A. terreus   A. ustus   A. versicolor

EPIDEMIOLOGY

 Aspergillosis affects people with the following:   Weakened immune system   Low white blood cell levels   Lung cavities   Long-term corticosteroid therapy   A hospital stay   Asthma and cystic fibrosis

EPIDEMIOLOGY CONT.

 Invasive aspergillosis affects people who are immunosuppressed such as:   People who have had bone marrow

transplants or solid organ transplants   People who are taking high doses of

corticosteroids   People who undergo chemotherapy for

cancer   People who have chronic granulomateous

disease   People with advanced AIDS   Leukemia patients   Tuberculosis patients

EPIDEMIOLOGY CONT.

 Aspergillosis is common in the environment and is found world-wide   Most people breathe in aspergillus

spores everyday   It is impossible to completely avoid

breathing in aspergillus spores because they are ubiquitous

  People with compromised immune systems who breathe in the spores acquire infections

EPIDEMIOLOGY CONT.

 Aspergillosis occurs:   Soil   Air, spores are inhaled   Food-spices and ground pepper   Compost and decaying vegetation   Grains and crops   Fire proofing materials   Bedding, pillows, carpeting   Ventilation and air conditioning systems   Dust

7/21/09

3

MANIFESTATIONS

 Respiratory  Cranial  Pathologic  Clinical  Thoracic Initial CT

DISEASE SPECTRUM

  Forms of the disease involve:   Sinuses   Lungs   Pre-existing lung cavity   Pulmonary aspergillosis   CNS aspergillosis   Sinonasal aspergillosis   Osteomyelitis   Endophthalmitis   Endocarditis   Renal Abscesses   Cutaneous (Burns, post surgical wounds, IV insertion sites)   Otomycosis   Exogenous endophthalmitis   Allergic fungal sinusitis   Urinary tract fungus balls

HISTOPATHOLOGY

 Tissue reaction in aspergillosis is acute suppurative inflammation with areas of ischemic necrosis

 The fungus proliferates as septate hyphae 2.5-4.5 µm in diameter

 Hyphae can be characterized as branching dichotomously (Approx 45° angle)

 Blood vessel invasion, thrombosis, infarction, and dissemination are common

 The mortality rate for invasive aspergillosis is 50-100% and diagnosis by culutre may take as long as 4 weeks.

HISTOPATHOLOGY

Grocott’s methenamine silver (GMS) stained tissue sections showing Aspergillus fumigatus in lung tissue, Note : conidial heads forming in an alveolus.

Taken from: http://www.mycology.adelaide.edu.au/gallery/photos/aspergillus08.gif

PATHOGENESIS

  Virulence factors:   A. fumigatus has about 4 virulence factors alone:

 Gliotoxin-inhibits mucociliary system  Fumagillin  Fumagatin  Helvolic acid

  Since Aspergillus can be found almost everywhere world-wide, it is primary acquired through the respiratory tract.   However, there have been cases of disseminated

disease after skin or gastrointestinal infections.

PATHOGENESIS

 Host response in normal host (non-immunosuppressed)   Normal immune system response:

 Mucosal barriers – Traps  Macrophages – Phagocytosis  Neutrophils

 Kills conidiae and inhibits germination of hyphae

7/21/09

4

PATHOGENESIS

  Normal host response can be impaired by a number of factors:   Granulocytopenia   Impaired macrophages/neutropenia   Underlying disease impairing immune system   Lung destruction   Large numbers/prolonged exposure to organism   Hypersensitivity/allergic response

  In the immunocompromised:   Conidia spores colonize lesions or cavities   Hyphae begins to form and grow throughout

body

PATHOGENESIS

 There are three major ways Aspergillus involves the lungs:   Mycetoma (non-invasive)   IPA

 Invasive Pumonary Aspergillosis   Allergic

DIAGNOSIS

 Clinical Presentations:   Fever   Cough   Dyspnea

 Difficulty breathing   Hemoptysis

 Coughing up blood   Chest Pain

LABORATORY DIAGNOSIS

 Radiographic picture  Classical  CT Scan  Serological testing  Sputum culture  Transthoracic needle aspiration

DIAGNOSIS

http://www.isradiology.org/tropical_deseases/tmcr/chapter6/clinical23.htm; Courtesy of the Radiology Library, University of Cape  Town, South Africa

DIAGNOSIS

 The most extreme diagnosis is surgical procedures   Tissue examination   Transbronchial biopsy (TBB)   Open lung biopsy   CT guided percutaneous lung biopsy

7/21/09

5

DISEASE MANAGEMENT

 Allergic BronchopulmonaryAspergillosis (ABPA)   Caused by an allergy to the spores of the

Aspergillus moulds.   Commonly effects people with asthma and

cystic fibrosis patients.   Steroids by aerosol or mouth

 Prednisolone   Itraconazole

 An oral antifungal drug

DISEASE MANAGEMENT

 Aspergilloma and Chronic Pulmonary Aspergillosis   Fungus caused by the Aspergillous mould   Grows in the lung cavity   Treatment depends on the symptoms

present  Itraconazole  Voriconazole  Surgery  Amphotercin B

DISEASE MANAGEMENT

 Aspergillus Sinusitis   Disease occurs in the sinuses   May be associated with long standing

symptoms of runny blocked nose   May lead to nasal polyps   Surgical drainage, removal of polyps   Local steroids   Oral Steroids   Antifungals

DISEASE MANAGEMENT

  Invasive Aspergillosis   Effects people with poor immune systems   Fungus can transfer from the lung through the

blood to the brain and other organs   Antifungal Drugs

 Voriconazole  Caspefungin  Itraconazole  Amphotericin B

DISEASE PREVENTION

 This disease commonly effects people with a weak immune system   Avoid medications that may further weaken

the immune system.   Avoid forests, grain stores, rotting vegetation,

and piles of dead leaves.   Hospitals should have good ventilation

 Dust control  Adequate air flow rate

CASE STUDY – “SUDDEN DEATH DUE TO PULMONARY ASPERGILLOSIS”

 35 yr old  Moderately built and malnourished  TB patient for a year  Hemoptysis while traveling in a train.  Was declared dead upon arrival to the

hospital.  Same day autopsy was performed.

7/21/09

6

CASE STUDY - SYMPTOMS

External examination Internal examination

 Blood stains were present over the oral and nasal orifices

 Clubbing of fingers and toes

 No external injuries

 Trachea and bronchi contained blood clots.

 Right sided pleural internal scarring was present.

 Surface of lungs was grayish black with necrotic material.

 Enlarged lymph nodes.  Pale gastrointestinal

organs filled with blood.

CASE STUDY

CLUBBING OF FINGERS AND TOES.  Source: Courtesy of Journal of

Forensic and Legal Medicine

CASE STUDY - DIAGNOSIS

 Microscopy   Grocott’s methanamine silver stain

(GMS)  Biopsy of the lungs  Autopsy Findings of the lungs

  Dilated bronchioles   Alveolar septae showed congested

vessels.   Edema and hemorrhage

CASE STUDY - CONCLUSION

 It was diagnosed to be a case of old fibrocavitatory tuberculosis with Aspergillus colonization.

 No active TB was present.  Cause of death was as hemorrhage

secondary to pulmonary aspergillosis.

CASE STUDY

Fig. 1. Cut section of the lung showing grayish black areas and cavity containing yellowish black necrotic material.

Fig. 2. Microscopy of the lung with Grocott’s methanamine silver stain showing a cavity lined by fibrocollaginous tissue and colonized byAspergillus.

Source: Courtesy of Journal of Forensic and Legal Medicine

REFERENCES "The Aspergillus Website, Fungal Research Trust". July 18, 2009 <http://

www.aspergillus.org.uk/languages/english.php>.

Bhagavath, Prashantha, et al. "Sudden death due to pulmonary aspergillosis." Journal of Forensic and Legal Medicine 16.1 (2009), 27-30.

“Comparison of multiple typing methods for Aspergillus fumigatus.CrossRef DOI Query." Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases [No Volume/Issue] (2009) [No Pagination].

"Doctor Fungus". July 18, 2009 <http://www.doctorfungus.org/mycoses/human/aspergillus/aspergillosis.htm>.

Harmen, E (2008, March 7). eMedicine Specialties. Retrieved July 17,  2009, from Aspergillosis Web site:  http://emedicine.medscape.com/article/296052-overview

7/21/09

7

REFERENCES 6K.Marr, T.Patterson, D.Denning. Aspergillosis Pathogenesis, clinic

al  manifestations, and therapy Infectious Disease Clinics of North  America, Volume 16, Issue 4, Pages 875-894

"Knowledge Storage". July 18, 2009 <http://knowledge-storage.com/medicine/37-medicine/84-aspergillosis>.

Mayo Clinic Staff, (2009, May 2). Mayo Clinic. Retrieved July 17, 2009,  from Aspergillosis Web site:  http://www.mayoclinic.com/health/aspergillosis/ds00950

REFERENCES Nguyen MH. (2007). Use of bronchoalveolar lavage to detect 

galactomannan for diagnosis of pulmonary aspergillosis among  nonimmunocompromised hosts. Journal Of Clinical Microbiology, 45(9),  2787.

Unknown, (2008, March 27). Centers for Disease Control and Prevention.  Retrieved July 17, 2009, from Aspergillosis (Aspergillus) Web site: http://www.cdc.gov/nczved/dfbmd/disease_listing/aspergillosis_gi.html

Zmeili, O.S. and A.O. Soubani. "Pulmonary aspergillosis: a clinical update." Journal of the Association of Physicians 100.6 (2007), 317-334.

QUESTIONS

1. What species of Aspergillus most commonly causes infections?

A)  A. fumigatus B)  A. niger C)  A. versicolor D)  A. flavus

2. Aspergillus most commonly affects the: A)  Heart B)  Skin C)  Lungs D)  GI tract

QUESTIONS

3. In a normal host, which immune defense mechanism usually inhibits hyphae germination?

A) Mucosal barriers B) Thrombocytes C) Neutrophils D) All of the Above

4. What type of medications should people affected by Aspergillus avoid?

A)  Amphotericin B B)  Any that weaken the immune system C)  Anti-depressants D)  All above

QUESTIONS

5) What is a virulence factor for Aspergillus fumigatus?

A)  Fumagillin B)  Fumagatin C)  Gliotoxin D)  All of the above