Aspergillosis Aspergillus fumigatus The most common mould-type disease (among many other Aspergillus species)

Invasive Aspergillosis34-year-old womanPresents with 2-day history of weakness, dizziness, left calf pain, and black tarry stools.Denies chest pain, cough, or shortness of breathMedical history:Diabetes leading to renal failure and renal transplant3 weeks before presentation, acute graft rejection developedBegan an immunosuppressive regimenGuha, et al. Infect Med 24 (Suppl 8): 8-11, 2007Invasive AspergillosisOn admissionTachycardic, hypotensive and febrileInitial chest x-ray was normalLab results:AnemiaWBC = 4800/l, 80% neutrophilsBlood cultures were positive for E. coliAntibiotic therapy initiated

Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007Invasive AspergillosisDay 6:Vesicular rash developed on buttocks and left calfCultures positive for HSV, antiviral therapy initiatedDay 8:Renal function continued to declineIntermittent hemodialysis startedDay 12:Decreased responsivenessIntubated for respiratory distressGuha, et al. Infect Med 24 (Suppl 8): 8-11, 2007Invasive AspergillosisChest x-ray:Diffuse bilateral lung nodulesCulture of BAL:Positive for Aspergillus spp.Immunesuppression decreasedLiposomal Amphotericin B startedCondition deteriorates:Acute MI, comatoseMulitple acute infarcts in frontal lobe and cerebellum by MRIMultiple skin nodules form on arms and trunkGuha, et al. Infect Med 24 (Suppl 8): 8-11, 2007Invasive AspergillosisCulture of skin nodule biopsy:Aspergillus spp.

Guha, et al. Infect Med 24 (Suppl 8): 8-11, 2007AspergillosisEpidemiology: Most common fungus worldwide UbiquitousHospital acquired infection - Major problem

Virulence factors and pathogenesis:Thermo-tolerant to 50CElastase, phospholipase, protease and catalaseConidia bind to fibrinogen and lamininInvasive disease is dependent on impaired neutrophil functionUnable to generate the oxidative burst to kill

AT RISK: Severe neutropenia, leukemia and lymphoma.Aspergillosis - Clinical AspectsClinical Manifestations: Route of infection: InhalationIncubation: days to weeksForms of infections: Allergic aspergillosisCavitary colonization - aspergilloma Primary pulmonary aspergillosisInvasive aspergillosis

Types of AspergillosesABPA Allergic broncopulmonary aspergillosis (ABPA)AsthmaPulmonary infiltratesPeripheral eosinopheliaElevated serum IgEHypersensitivity to Aspergillus antigenSkin test

AspergillomaColonization of paranasal sinuses and the lower airwaysObstructive bronchial aspergillosisOccurs in pre-formed cavitary lesionsCystic fibrosisChonic bronchitisTB

No tissue damage, asymptomatic

Disseminated invasive aspergillosisLaboratory Diagnosis: Monomorphic true mouldDifficult because of the universality of the fungusREPEAT ISOLATIONS ARE ESSENTIAL FOR DEFINITIVE DXSerum: galactomannan Ag + invasive aspergillosis

Histopathology: Septate hyphaedichotomous branching at ACUTE anglesMay see full conidial structures (i.e. fruiting bodies)

In culture: A. fumigatus rapid grower Septate, hyaline hyphaeconidiophores with phialidespointing upwards, bearing chains of conidiaAspergillosis Laboratory Diagnosis

Direct prep from tissue specimenAcute, dichotomous branching

Aspergillosis

Septate hyphaeAspergillomaConidiophore fruiting bodyAspergillosis

Aspergillosis

AspergillosisA. fumigatusAspergillosis - TreatmentTreatment: Invasive disease is difficult to treatAmphotericin B, caspofungin (echinocandins), voriconazoleDecrease immunosuppression or reconstitute immune defensesSurgical debridement, if possible

Prevention in high-risk patients:Neutropenic: Filtered air to minimize exposure!Invasive AspergillosisOur patient:Expired on hospital day 23At autopsy, A. flavus was detected in multiple organs:Heart, lungs, adrenal galnd, thyroid, kidney, and liver

Extreme example of disseminated aspergillosis in an immunocompromised hostGuha, et al. Infect Med 24 (Suppl 8): 8-11, 2007Opportunistic hyalohyphomycosesDiverse agentsMany are ubiquitous inhaled conidiaMany are resistant to antifungal agentsIn 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 & TREATMENTDisseminated infection is increasing in incidence Some examples:Fusarium (R to ampB), immune reconst. + new triazolesScedosporium (R to ampB) surgical resectionAcremonium (S unestablished)Paecilomyces voriconazoleand many, many more.

Fus Sce Acr Pae Opportunistic hyalohyphomycosesPhaeohyphomycosesMany are neurotropic: present as brain abscesses, sinusitis CNS

BOTTOM LINE:Response to therapy is unpredictable between generaCulture is critical for diagnosis and therapy

In tissue:Pigmented hyphae w/ or w/o yeast are present

Disseminated infection is increasing:Alternaria, Curvularia, Bipolaris, Cladosporiumand others

Alt Cur Bip Cla PhaeohyphomycosesPneumocystosisEtiology: Pneumocystis jiroveciiMost common opportunistic infection among individuals with AIDSIncidence has decreased significantly with HAARTReservoir in nature unknownPneumonia is clearly the most common presentationInterstitial pneumonitis, mononuclear infiltrateOnset insidiousDiagnosis based on microscopic examination of BAL