Invasive Aspergillosis caused by Aspergillus fumigatus

1
Invasive Aspergillosis caused by Aspergillus
fumigatus

• Presented by
• Heidi Quackenbush

2
Hematopoietic Stem Cells

• Abbreviated HSC
• Arise in bone marrow
• Self-renewing
• Follow either myeloid or lymphoid lineage
• Differentiate into other cells
• Dendritic cells, Platelets, NK cells and more

3
HSC lineages

• Hematopoiesis follows many lineages
• Myeloid
• Lymphoid

4
HSC Transplantation

• Indications for HSC transplantation
• Leukemias
• Lymphomas
• Plasma cell disorders
• Solid tumors
• Acquired bone marrow disorders
• Congenital disorders
• Auto-immune diseases

5
Invasive Aspergillosis

• 357 increase in death rates in United States
  from 1980 to 1997
• Pulmonary fungal infection
• Common etiological agents
• A. fumigatus
• A. flavus
• A. fumigatus is found in
• Compost vegetation, wood chip piles, moldy hay,
  and soil
• Grows best between 20 and 50C

6
Aspergilli spp.

• Fungi
• Thick, polysaccharide walls
• Aiding in resistance to available penicillin
• Live in aerobic environments
• single- or multi-cellular
• Respiratory pathogens
• Conidia (fungal spores)
• Indoor and outdoor air
• Transmission
• Airborne spores, nosocomial and cutaneous
  infections

7
Pathogenicity of A. fumigatus

• Disturbs balance in Th1/Th2
• Th1 cell-med, intracellular
• Th2 Ab-med, but fungi are euks, like host cells
• Induces Th2, causing invasive aspergillosis
• Manifestations
• Immunocompromised host
• Fever, cough and chest pain
• Invasive pulmonary infection, spread to other
  organs
• Immunocompetent host
• Similar symptoms, but localized pulmonary
  infection, no spreading

8
Invasive Aspergillosis associated with HSC
transplant

• Risk factors following HSC transplant
• Individuals with underlying disease are
  susceptible to IA
• Aplastic anemia, multiple myeloma
• Another factor, age at time of transplant
• Increased risk in older patients,
  immunosuppressed?
• T-cell depletion or CD34 selection
• Protective Th1, IFN-gamma, IL-12
• Progression IL-4, IL-10, CD4 Th2

9
Categories of Infection

• Three categories
• Allergic bronchopulmonary hypersensitivity
• A. fumigatus present in the lung tissue
• Disseminated disease
• Also associated with presence of pathogen in the
  lungs
• Aspergilloma
• Mass of entangled hyphae
• Pre-existing lung cavities
• Can spread from lungs to blood vessels
• Thrombosis and possible infarction

10
Host Defenses

• Dendritic cells
• Transport conidia and hyphae from airways to
  draining lymph nodes
• Initiates Th responses to the fungus
• Macrophages
• Resting alveolar macrophages
• Phagocytosis and killing of conidia
• Non-oxidative mechanisms
• Induction of IL-12 production, Th1 cells
• T-cells, possibility, mentioned previously

11
Host Defenses (cont.)

• Neutrophils
• Attack developing hyphae
• Oxygen-dependent mechanisms
• Induces production of
• IL-4 T/B cell proliferation and Macrophage
  activation
• IL-10 inhibition of Th1 cytokine production
• NK cells
• Chemokine-mediated recruitment
• MCP-1 monocyte chemotactic protein-1
• CCL-2 CC chemokine ligand-2
• Neutralization caused reduced NK recruitment to
  lungs
• Defects in NK cells, predisposition to IA
• Antibody-mediated depletion of NK cells
• Impaired defense against the infection

12
Diagnosis and Treatment

• Techniques for diagnosis
• Microscopic observation
• Cultured specimens
• Skin tests
• Still many cases undetected and untreated
• Treatment suggestions
• Increased number of NK cells
• Antifungal drugs
• Amphotericin B, Fluconazole
• Collateral damage, fungi are also eukaryotic, low
  in selective toxicity

13
Treatment-new option

• Pentraxin 3 (PTX3)
• Alone or with other antifungals
• Activates complement, classical pathway, binds
  C1q
• Promotes phagocytosis
• Unidentified cell receptor
• New developments extremely important
• Limited use of amphotericin B, nephrotoxicity
• Inevitable resistance, antibiotics in general

14
Prevention Strategies

• HSCT patients
• Ventilation, hospital construction, equipment,
  plants, play areas and toys, skin and oral care
• Nosocomial Aspergillus infection
• Associated with dissemination of spores, hospital
  visitors and hand hygiene
• Isolation Protective (single room) and Source
  (separate building)
• Also use with HEPA filters and controlled
  air-flow.

15
Conclusion and Questions

• Many benefits to transplants and preventative
  surgeries
• Opportunistic eukaryotic pathogens
• Importance of cleanliness and awareness of
  surrounding environment
• Questions??

16
References

• Bozza, Silvia, et al. Dendritic cells transport
  conidia and hyphae of Aspergillus funmigatus
  from the airways to the draining lymph nodes and
  initiate disparate Th responses to the fungus.
  The Journal of Immunnology 168 (2002) 1362-71.
• Dykewicz, Clare A. Hospital Infection Control in
  Hematopoietic Stem Cell Transplant Recipients.
  Emerging Infectious Diseases 7 (2001) 263-267.
• Gaziano, Roberta et al. Anti-Aspergillus
  fumigatus Efficacy of Pentraxin 3 Alone and in
  Combination with Antifungals. Antimicrobial
  Agents and Chemotherapy 48 (2004) 4414-21.
• Goldsby, Richard, et al. Immunology Fifth
  Edition. New York W.H. Freeman and Company,
  2003.
• Jansen, Jan et al. Transplantation of
  hematopoietic stem cells from the peripheral
  blood. J. Cell. Mol. Med. 9 (2005) 37-50.
• Maier, Raina M., Ian L. Pepper and Charles P.
  Gerba. Environmental Microbiology. San Diego
  Elsevier, 2000.
• Marr, Kieren A., et al. Invasive aspergillosis
  in allogenic stem cell transplant recipients
  changes in epidemiology and risk factors. Blood
  100 (2002) 4358-66.
• McCance, Kathryn L. and Sue E. Huether.
  Pathophysiology The Biologic Basis For Disease
  in Adults Children. St. Louis Mosby, Inc.,
  2002.
• Mims, Cedric, et al. Medical Microbiology Third
  Edition. Spain Mosby-Year Book Europe Ltd.,
  2004.
• Morrison, Brad E. et al. Chemokine-mediated
  recruitment of NK cells is a critical host
  defense mechanism in invasive aspergillosis. The
  Journal of Clinical Investigation 112 (2003)
  1862-70.
• Panackal, Anil A., et al. Aspergillus ustus
  Infections among Transplant Recipients. Emerging
  Infectious Diseases 12 (2006) 403-8.