Invasive Pulmonary Aspergillosis

Epidemiology

  • Aspergillosis is the 3rd most common fungal disease diagnosed in hospitals (due to increase in Acute Invasive Aspergillosis)
  • Occurs almost exclusively in immunosuppressed (especially myelosuppressed), rarely reported in immunocompetent patients
  • Incidence is decreasing in organ transplants (possibly due to CSA steroid-sparing effect)
  • In a multicenter, retrospective cohort study of 310 Aspergillus cases in patients with hematologic malignancies, 69% were in patients with AML [The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075]
    – Among the various types of hematologic malignancies, AML had the highest incidence of invasive fungal infection (7.9% molds, 4.4% yeasts) [The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075]
    – The attributable mortality rate for aspergillosis in patients with AML reaches up to 38% [The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075]
  • In a multicenter, retrospective cohort study of 310 Aspergillus cases in patients with hematologic malignancies, 14% were in patients with ALL [The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075]
    – The attributable mortality rate for aspergillosis in patients with ALL reaches up to 43 [The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075]

Risk Factors

  • Anti-TNF Therapy (see Anti-TNF Therapy, [[Anti-TNF Therapy]])
    • Relative Risk: infliximab > etanercept > adlimumab
    • All patients were bone marrow transplants being treated with anti-TNFα medications for Graft vs Host Disease (see Graft vs Host Disease, [[Graft vs Host Disease]])
    • Most cases were invasive Aspergillosis
      [Tsiodras S, Samonis G, Boumpas DT, et al. Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194]
      [Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004; 104:649-654]
  • Hairy Cell Leukemia (see Hairy Cell Leukemia, [[Hairy Cell Leukemia]]): due to decreased monocyte count
  • Bone Marrow Transplant/Stem Cell Transplant (see Bone Marrow Transplant, [[Bone Marrow Transplant]]): period of risk extends for months beyond the time of transplant and the return of neutrophil counts towards normal (Marr, 2002, Clin Infect Dis; 34: 909-917)
    • Highest risk in those with chronic GVHD treated with high-dose steroids
  • Neutropenia
  • Steroids +/- Broad-Spectrum Antibiotics:

Physiology

  • Aspergillus infection and invasion (due to impaired phagocytosis)
  • Hemorrhagic pulmonary infarction, necrosis, and cavitation (cavitation often ocurs when PMN count returns to normal)
  • PMN Dysfunction: impaired defense against nycelial form
  • Macrophage Dysfunction: impaired defense against conidial form

Pathology

  • Organism: acute angle branching

Diagnosis

Serum Galactomannan

  • False-Positive
    • Cross-reactivity with other fungi
    • Gut translocation of galactomannan present in milk and cereals
    • Gut translocation of galactomannan with GVHD occurring after bone marrow transplant
    • Use of piperacillin/tazobactam (Zosyn) or amoxicillin/clavulanate (Augmentin)
  • False-Negative
    • Presence of anti-aspergillus antibodies
    • Localized or encapsulated infections
    • Use of antifungal therapy

CXR/HRCT Patterns

(mimics bacterial pneumonia)
(HRCT has an increasing role in diagnosing invasive Aspergillus in high-risk patients)

  • Bronchopneumonia (most common pattern): infiltrates may be multiple, peripheral/ may cavitate
    -“Halo sign”: low attenuation rim of hemorrhagic infarction seen on CT surrounding the higher attenuation nodular center (also seen in Pseudoallescheria, Mucormycosis, Fusarium)
    -“Air crescent sign”: rim of air between affected and normal lung, appears days-weeks after halo sign (also seen in Echinococcus/ Aspergilloma/ traumatic pulmonary hematoma/ cavitary mailgnancies/ lung abcess/ septic and non-septic PE/ TB)

    • Appearance of air crescent sign in cases of invasive Aspergillosis corresponds to recovery from neutropenia and resolution of infection
  • Lobar or Segmental Infiltrate (less common):
  • Pleural Effusion: usually occurs only in the setting of previous artificial PTX for TB treatment or post-resection with persistent BPF
    • Pleural thickening, pleural mycetoma, or air-fluid level (suggests BPF) may be seen
    • Head CT/MRI: recommended to r/o CNS spread, which occurs commonly

Sputum

  • Sputum GS/Cult+Sens: may be positive due to airway colonization
  • Sputum or BAL culture positive for Aspergillus: most often reflects contamination or colonization (Perfect, 2001; Clin Infect Dis; 33: 1824-1833)
  • Sputum or BAL culture positive for Aspergillus in a neutropenic/highly immunosuppressed patient: highly associated with invasive disease and merits therapy

FOB

  • FOB:
  • BAL: see sputum above
  • BAL Galactomannan: may be positive
  • TBB (high yield): thick septate acute-angle branching hyphae in tissue by Silver stain

OLB

  • May be procedure of choice

Pleural Fluid

  • Culture positive for Aspergillus

Aspergillus Precipitins

  • Usually positive in pleural Aspergillosis (but not useful in other situations)

Nasal Swabs

  • Positive cultures in neutropenic patients suggest invasive Aspergillosis

Clinical Presentations

  • Pneumonia (see Pneumonia, [[Pneumonia]])
    • Dry Cough
    • Dyspnea
    • Fever: may be high
  • Necrotizing Pneumonia (see Necrotizing Pneumonia, [[Necrotizing Pneumonia]])
  • Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])
    • Pleural Rub: may occur
  • Respiratory Failure: may lead to death

Treatment

  • As compared to Ampho IV, Voriconazole IV demonstrated improved first-line efficacy and survival
    [Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415]

Invasive Pulmonary and Non-Pulmonary Aspergillosis

  • Voriconazole 8 mg/kg/day until resolved
  • Recent study cites improved efficacy of Voriconazole, as compared to Ampho, in treatment of invasive Aspergillosis
    [Herbrecht, 2002, NEJM; 347: 408-415]

    • Vori is available both PO (5% bioavailable) and IV (solubilized with a different cyclodextrin than IV Itraconazole, avoiding nephrotoxicity)
    • Vori SE: hepatotoxicity, rash, photosensitivity, transient visual effects (30% of cases)
  • Alternative: Ampho 1-1.5 mg/kg/day until resolved (usually liposomal Ampho)
    • Lipid Ampho preparations (liposomal Ampho, Ampho colloidal dispersion, and Ampho lipid complex) are all less nephrotoxic than standard Ampho
    • Liposomal Ampho and Ampho lipid complex have fewer infusion-related SE
    • Lipid Ampho preparations are more costly, but are preferred in specific cases: stem cell or organ transplants, patients with pre-existing CRI, patients with invasive filamentous fungal infections (where higher doses are desired)
    • Limited studies demonstrate improved efficacy of lipid ampho preparations: improved survival in AIDS with severe Histoplasmosis treated with liposomal Ampho/fewer invasive fungal infections in febrile neutropenic patients treated with liposomal Ampho
  • Alternative: Itraconazole 400 mg/day
  • Refractory Cases: Caspofungin 50 mg/day (probably cidal for Aspergillus)

Future Prophylaxis

  • Patients with treated Aspergillus infections may require prophylactic anti-Aspergillus treatment during future immunosuppression

Resolution of Neutropenia

  • Aids clinical response to anti-fungal agent

Surgery

  • May resect residual nodular or cavitary lesions
  • Especially useful if further immunosuppression will be required

Treatment of Pleural Aspergillosis

  • Early resection of involved pleura and lung with pre and post-op Ampho (IV and intra-pleural)
  • Flap may be used in cases where resection would not be tolerated

Prognosis

  • Worst prognosis (80-90% mortality rates) in allogenic BMT’s (with chronic GVHD) and those with CNS Aspergillus

References

  • Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075
  • Herbrecht R, Denning DW, Patterson TF, et al; for the Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415
  • Tsiodras S, Samonis G, Boumpas DT, et al. Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194
  • False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation. Journal of Antimicrobial Chemotherapy (2008) 61, 411–416
  • False-positive results of Aspergillus enzyme-linked immunosorbent assays for a patient with gastrointestinal graft-versus-host disease taking a nutrient containing soybean protein. Clin Infect Dis 2005; 40: 333 – 4.
  • False-positive results of Aspergillus enzyme-linked immunosorbent assay in a patient with chronic graft-versus-host disease after allogeneic bone marrow trans- plantation. Bone Marrow Transplant 2001; 28: 633–4
  • False-Positive Aspergillus Galactomannan Enzyme-Linked Immunosorbent Assay Results In Vivo during Amoxicillin-Clavulanic Acid Treatment. J Clin Microbiol, Nov. 2004, p. 5362–5363
  • Occurrence and Kinetics of False-Positive Aspergillus Galactomannan Test Results following Treatment with Beta-Lactam Antibiotics in Patients with Hematological Disorders. JOURNAL OF CLINICAL MICROBIOLOGY, Feb. 2006, p. 389–394
  • False positive galactomannan results in adult hematological patients treated with piperacillin-tazobactam. Rev Iberoam Micol 2007; 24: 106-112