1. Invasive Aspergillosis
34-year-old woman
Presents with 2-day history of weakness, dizziness, left calf pain, and black tarry stools.
Denies chest pain, cough, or shortness of breath
Medical history:
Diabetes leading to renal failure and renal transplant
3 weeks before presentation, acute graft rejection developed
Began an immunosuppressive regimen
Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007

2. Invasive Aspergillosis
On admission
Tachycardic, hypotensive and febrile
Initial chest x-ray was normal
Lab results:
Anemia
WBC = 4800/µl, 80% neutrophils
Blood cultures were positive for E. coli
Antibiotic therapy initiated
Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007

3. Invasive Aspergillosis
Day 6:
Vesicular rash developed on buttocks and left calf
Cultures positive for HSV, antiviral therapy initiated
Day 8:
Renal function continued to decline
Intermittent hemodialysis started
Day 12:
Decreased responsiveness
Intubated for respiratory distress
Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007

4. Invasive Aspergillosis
Chest x-ray:
Diffuse bilateral lung nodules
Culture of BAL:
Positive for Aspergillus spp.
Immunesuppression decreased
Liposomal Amphotericin B started
Condition deteriorates:
Acute MI, comatose
Mulitple acute infarcts in frontal lobe and cerebellum by MRI
Multiple skin nodules form on arms and trunk
Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007

5. Invasive Aspergillosis
Culture of skin nodule biopsy:
Aspergillus spp.
Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007

6. Aspergillosis Epidemiology: Most common fungus worldwide – Ubiquitous
Hospital acquired infection - Major problem
Virulence factors and pathogenesis:
Thermo-tolerant to 50C
Elastase, phospholipase, protease and catalase
Conidia bind to fibrinogen and laminin
Invasive disease is dependent on impaired neutrophil function
Unable to generate the oxidative burst to kill
AT RISK: Severe neutropenia, leukemia and lymphoma.

7. Aspergillosis - Clinical Aspects
Clinical Manifestations:
Route of infection: Inhalation
Incubation: days to weeks
Forms of infections:
Allergic aspergillosis
Cavitary colonization - aspergilloma
Primary pulmonary aspergillosis
Invasive aspergillosis

8. Types of Aspergilloses

9. ABPA – Allergic broncopulmonary aspergillosis (ABPA)
Asthma
Pulmonary infiltrates
Peripheral eosinophelia
Elevated serum IgE
Hypersensitivity to Aspergillus antigen
Skin test

10. Aspergilloma Colonization of paranasal sinuses and the lower airways
Obstructive bronchial aspergillosis
Occurs in pre-formed cavitary lesions
Cystic fibrosis
Chonic bronchitis TB
No tissue damage, asymptomatic

11. Disseminated invasive aspergillosis

12. Aspergillosis – Laboratory Diagnosis
Monomorphic true mould
Difficult because of the universality of the fungus
REPEAT ISOLATIONS ARE ESSENTIAL FOR DEFINITIVE DX
Serum: galactomannan Ag +  invasive aspergillosis
Histopathology:
Septate hyphae
dichotomous branching at ACUTE angles
May see full conidial structures (i.e. fruiting bodies)
In culture:
A. fumigatus – “rapid grower”
Septate, hyaline hyphae
conidiophores with phialides
pointing upwards, bearing chains of conidia

13. Aspergillosis Direct prep from tissue specimen
Acute, dichotomous branching

14. Conidiophore “fruiting body”
Aspergillosis
Septate hyphae
Aspergilloma
Conidiophore “fruiting body”

15. Aspergillosis

16. Aspergillosis
A. fumigatus

17. Aspergillosis - Treatment
Invasive disease is difficult to treat
Amphotericin B, caspofungin (echinocandins), voriconazole
Decrease immunosuppression or reconstitute immune defenses
Surgical debridement, if possible
Prevention in high-risk patients:
Neutropenic: Filtered air to minimize exposure!

18. Invasive Aspergillosis
Our patient:
Expired on hospital day 23
At autopsy, A. flavus was detected in multiple organs:
Heart, lungs, adrenal galnd, thyroid, kidney, and liver
Extreme example of disseminated aspergillosis in an immunocompromised host
Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007

19. Opportunistic hyalohyphomycoses
Diverse agents
Many are ubiquitous – inhaled conidia
Many are resistant to antifungal agents
In tissue, they appear indistinguishable from Aspergillus!
(i.e. branching, septate hyphae)
Repeated isolation from multiple sites/multiple times
is best criteria to determine clinical significance.
BOTTOM LINE: CULTURE IS CRITICAL FOR DX & TREATMENT

20. Opportunistic hyalohyphomycoses
Disseminated infection is increasing in incidence
Some examples:
Fusarium (R to ampB), immune reconst. + new triazoles
Scedosporium (R to ampB) – surgical resection
Acremonium (S unestablished)
Paecilomyces – voriconazole
…and many, many more.
Fus Sce Acr Pae

21. Phaeohyphomycoses Many are neurotropic:
present as brain abscesses, sinusitis CNS
BOTTOM LINE:
Response to therapy is unpredictable between genera
Culture is critical for diagnosis and therapy

22. Phaeohyphomycoses In tissue: Disseminated infection is increasing:
Pigmented hyphae w/ or w/o yeast are present
Disseminated infection is increasing:
Alternaria, Curvularia, Bipolaris, Cladosporium…and others
Alt Cur Bip Cla

23. Pneumocystosis Etiology: Pneumocystis jirovecii
Most common opportunistic infection among individuals with AIDS
Incidence has decreased significantly with HAART
Reservoir in nature unknown
Pneumonia is clearly the most common presentation
Interstitial pneumonitis, mononuclear infiltrate
Onset insidious
Diagnosis based on microscopic examination of BAL