Invasive Aspergillosis

Epidemiology

Risk Factors

Anti-Tumor Necrosis Factor-α (TNFα) Therapy (see Anti-Tumor Necrosis Factor-α Therapy, Anti-Tumor Necrosis Factor-α Therapy)

  • Relative Risk: infliximab > etanercept > adlimumab
  • Clinical Data
    • Case Reports of Invasive Aspergillosis Associated with Anti-TNFα Therapy (NEJM, 2001) [MEDLINE]
    • Review of Granulomatous Infections Associated with Anti-TNFα Therapy (Clin Infect Dis, 2004) [MEDLINE]
    • Review of Invasive Fungal Infections in Association with Anti-TNFα Therapy (Mayo Clin Proc, 2008) [MEDLINE]
      • Use of at Least One Other Immunosuppressive (Usually Systemic Corticosteroids) was Reported in 98% of Cases
      • Distribution by Agent: Infliximab (80% of cases), Etanercept (16% of cases), Adalimumab (4% of cases)
      • Invasive Fungal Infections Included: Aspergillosis, Candidiasis, and Histoplasmosis
      • Lung was the Most Commonly-Affected Organ
      • Fatality Rate: 32%

Chronic Granulomatous Disease (CGD) (see Chronic Granulomatous Disease, Chronic Granulomatous Disease)

  • Epidemiology
    • Cases Have Been Reported

Corticosteroids (see Corticosteroids, Corticosteroids)

  • Epidemiology
    • Typically Associated with High-Dose Corticosteroids

Extracorporeal Membrane Oxygenation (ECMO) (see Venoarterial Extracorporeal Membrane Oxygenation, Venoarterial Extracorporeal Membrane Oxygenation and Venovenous Extracorporeal Membrane Oxygenation, Venovenous Extracorporeal Membrane Oxygenation)

  • Epidemiology
    • Cases Have Been Reported (Med Mycol Case Rep, 2014 [MEDLINE]

Hematopoietic Stem Cell Transplant (Bone Marrow Transplant) (see Hematopoietic Stem Cell Transplant, Hematopoietic Stem Cell Transplant)

Impaired Cell-Mediated Immunity (see Immune Defects, Immune Defects)

Influenza Virus Infection (see Influenza Virus, Influenza Virus)

  • Epidemiology
    • Cases Have Been Reported with H1N1 Virus (Intensive Care Med, 2012) [MEDLINE]
      • In this Case Series of 40 H1N1 Patients, Invasive Pulmonary Aspergillosis was Diagnosed in 23% of Cases (Occurring 3 Days After ICU Admission)
      • There Appeared to Be a Significant Association with Corticosteroid Use within 7 Days Prior to ICU Admission

Neutropenia (see Neutropenia, Neutropenia)

  • Epidemiology
    • Typically Severe and Prolonged Neutropenia

Other


Microbiology

Aspergillus (see Aspergillus, Aspergillus)

  • Aspergillus Fumigatus: accounts for 67% of invasive Aspergillosis cases (Clin Infect Dis, 2002) [MEDLINE]
  • Aspergillus Flavus: accounts for 13% of invasive Aspergillosis cases (Clin Infect Dis, 2002) [MEDLINE]
  • Aspergillus Niger: accounts for 9% of invasive Aspergillosis cases (Clin Infect Dis, 2002) [MEDLINE]
  • Aspergillus Terreus: accounts for 7% of invasive Aspergillosis cases (Clin Infect Dis, 2002) [MEDLINE]

Physiology

Inhalation of Aspergillus Conidia into the Airways is Common

  • In Normal Patients, Conidial Clearance Prevents the Occurrence of Aspergillus-Related Disease
    • For This Reason, Culture of Aspergillus from the Airway of Normal Patients Does Not Indicate the Presence of Disease

Diagnosis

Serum Galactomannan (see Serum Galactomannan, Serum Galactomannan)

Technique

  • False-Positive Serum Galactomannan
    • 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

Recommendations (Infectious Diseases Society of America 2016 Practice Guidelines) (Clin Infect Dis, 2016) [MEDLINE]

  • Serum Galactomannan is Recommended as an Accurate Marker for the Diagnosis of Invasive Aspergillosis in Adult and Pediatric Patients in Specific Populations (Hematologic Malignancy, Hematopoietic Stem Cell Transplant) (Strong Recommendation, High-Quality Evidence)
  • Serum Galactomannan is Not Recommended for Routine Blood Screening in Patients Receiving Mold-Active Antifungal Therapy or Prophylaxis, But Can Be Applied to Bronchoscopy Specimens from Those Patients (Strong Recommendation, High-Quality Evidence)
  • Serum Galactomannan is Not Recommended for Screening in Solid Organ Transplants or Patients with Chronic Granulomatous Disease (Strong Recommendation, High-Quality Evidence)

Serum (1,3)-β-D-Glucan (see Serum (1–3)-β-D-Glucan, Serum (1-3)-β-D-Glucan)

Recommendations(Infectious Diseases Society of America 2016 Practice Guidelines) (Clin Infect Dis, 2016) [MEDLINE]

  • Serum (1–3)-β-D-Glucan is Recommended for Diagnosing Invasive Aspergillus in High-Risk Patients (Hematologic Malignancy, Hematopoietic Stem Cell Transplant), But is Notably Not Specific for Aspergillus (Strong Recommendation, Moderate-Quality Evidence)

Culture

  • Aspergillus Grows Rapidly in the Laboratory: cultures are frequently visibly positive within 1-3 days
    • However, Identification of the Species Requires Sporulation, Allowing Examination of the Spore-Bearing Structures
    • Notably, Some Slow Sporulating Species (Such as Aspergillus Lentulus, Neosartorya Udagawae) Have Been Implicated in Invasive Infections
    • Hematopoietic Stem Cell Transplants with Invasive Aspergillosis (as Documented by Positive Galactomannan Results) May Have Negative Aspergillus Cultures in as Many as 25-50% of Cases (Clin Infect Dis, 2009) [MEDLINE] (Clin Infect Dis, 2010) [MEDLINE]

Pathology


Clinical Manifestations

Cardiovascular Manifestations

Endocarditis (see Endocarditis, Endocarditis)

Myocarditis (see Myocarditis, Myocarditis)

  • xx

Pericarditis (see Acute Pericarditis, Acute Pericarditis)

  • xxxx

Dermatologic Manifestations

Cutaneous Aspergillosis

  • Epidemiology
  • Diagnosis
  • Physiology
    • Direct Trauma with Inoculation
    • Contiguous Spread
    • Hematogenous Spread
  • Clinical
    • xxxx

Gastrointestinal Manifestations

General Comments

Abdominal Pain (see Abdominal Pain, Abdominal Pain)

  • Epidemiology
    • XXXX
  • Physiology
    • Direct Inoculation

Appendicitis (see Appendicitis, Appendicitis)

  • Epidemiology
    • XXXX
  • Physiology
    • Direct Inoculation

Colonic Ulcers (see Colonic Ulcer, Colonic Ulcer)

  • Epidemiology
    • XXXX
  • Physiology
    • Direct Inoculation

Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, Gastrointestinal Hemorrhage)

  • Epidemiology
    • XXXX
  • Physiology
    • Direct Inoculation

Typhlitis (Neutropenic Enterocolitis) (see Typhlitis, Typhlitis)

  • Epidemiology
    • XXXX
  • Physiology
    • Direct Inoculation

Peritonitis (see Peritonitis, Peritonitis)

  • Epidemiology
  • Treatment (IDSA 2016 Diagnosis and Management of Aspergillosis Guidelines) (Clin Infect Dis, 2016) [MEDLINE]
    • General Comments
      • Removal of Peritoneal Dialysis Catheter is Essential (If Present)
    • Primary: primary combination therapy is not routinely recommended
      • Voriconazole (Vfend) (see Voriconazole, Voriconazole)
        • IV: 6 mg/kg q12hrs x 1 day, then 4 mg/kg q12hrs
        • PO: 200-300 mg q12hrs (or weight-based mg/kg dosing)
    • Alternatives
    • Salvage

Neurologic/Ophthalmologic Manifestations

General Comments

  • Central Nervous System Disease May Occur as a Result of Hematogenous Dissemination or from Contiguous Extension from the Paranasal Sinuses

Brain Abscess (see Brain Abscess, Brain Abscess)

Endophthalmitis (see Endophthalmitis, Endophthalmitis)

  • Epidemiology
    • XXXX
  • Diagnostic
    • XXXX
  • Physiology
    • May Occur Secondary to Disseminated Aspergillosis, Corneal Infection, or Direct Trauma to the Eye
  • Clinical

Aspergillus-Related Ischemic Cerebrovascular Accident (CVA) with/without Hemorrhage (see Ischemic Cerebrovascular Accident, Ischemic Cerebrovascular Accident and Intracerebral Hemorrhage, Intracerebral Hemorrhage)

  • Epidemiology
    • XXXX

Contiguous Aspergillus Invasion of Central Nervous System From Paranasal Sinuses

Mycotic Aneurysm (Mycotic Aneurysm, Mycotic Aneurysm)

Otolaryngologic Manifestations

Aspergillus Rhinosinusitis

Pulmonary Manifestations

General Comments

  • Lungs the Most Common Site of Involvement in Invasive Aspergillosis

Aspergillus Tracheobronchitis

Invasive Pulmonary Aspergillosis

  • Epidemiology
    • Invasive Aspergillosis Most Commonly Involves the Lungs
  • Diagnosis
    • General Comments
      • Positive Culture for Aspergillus in Combination with the Histopathologic Demonstration of Tissue Invasion by Hyphae is Definitive Evidence of Invasive Apergillosis (Clin Infect Dis, 2016) [MEDLINE]: however, biopsy is often not possible due to risks (bleeding due to thrombocytopenia, etc)
    • Chest X-Ray (see Chest X-Ray, Chest X-Ray): poor sensitivity for invasive Aspergillosis
    • Chest CT (see Chest Computed Tomography, Chest Computed Tomography)

      Rheumatologic Manifestations

      Osteomyelitis (see Osteomyelitis, Osteomyelitis)

      • xxx

      Septic Arthritis (see Septic Arthritis, Septic Arthritis)

      • xx

      Disseminated Aspergillosis

      • Physiology
        • Hematogenous Spread from Angioinvasive Disease
      • Clinical
        • Brain Involvement
        • Hepatic Involvement
        • Ocular Involvement
        • Renal Involvement
        • Skin Involvement
      • Prognosis: poor

      Treatment

      Azole Antifungal Agents (see Azole Antifungals, Azole Antifungals)


      Prognosis

      Poor Prognostic Factors

      • Central Nervous System Disease
      • Disseminated Aspergillosis

      References

      General

      • Nonresolving pneumonia in steroid-treated patients with obstructive lung disease. Am J Med. 1992 Jul;93(1):29-34 [MEDLINE]
      • Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med. 2001;344(14):1099 [MEDLINE]

      • 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 [MEDLINE]

      • Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415 [MEDLINE]

      • Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002 Apr 1;34(7):909-17 [MEDLINE]

      • Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100(13):4358 [MEDLINE]

      • False-Positive Aspergillus Galactomannan Enzyme-Linked Immunosorbent Assay Results In Vivo during Amoxicillin-Clavulanic Acid Treatment. J Clin Microbiol, Nov. 2004, p. 5362–5363

      • Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38(9):1261 [MEDLINE]

      • Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004; 104:649-654 [MEDLINE]

      • 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 [MEDLINE]

      • Initial CT manifestations of invasive pulmonary aspergillosis in 45 non-HIV immunocompromised patients: association with patient outcome? Eur J Radiol. 2005;55(3):437 [MEDLINE]

      • The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075 [MEDLINE]

      • Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey. Clin Infect Dis. 2006;43(5):577 [MEDLINE]

      • 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 [MEDLINE]

      • False positive galactomannan results in adult hematological patients treated with piperacillin-tazobactam. Rev Iberoam Micol 2007; 24: 106-112 [MEDLINE]

      • Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194 [MEDLINE]

      • Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194 [MEDLINE]

      • False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation. Journal of Antimicrobial Chemotherapy (2008) 61, 411–416 [MEDLINE]

      • Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48(3):265 [MEDLINE]

      • Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50(8):1091 [MEDLINE]

      • Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD008794. doi: 10.1002/14651858.CD008794.pub2 [MEDLINE]

      • Invasive pulmonary aspergillosis post extracorporeal membrane oxygenation support and literature review. Med Mycol Case Rep 2014;4:12–15 [MEDLINE]
- Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med 2012;38:1761–8 [MEDLINE]
      • The clinical spectrum of pulmonary aspergillosis. Thorax. 2015 Mar;70(3):270-7. doi: 10.1136/thoraxjnl-2014-206291. Epub 2014 Oct 29 [MEDLINE]

      Diagnosis

      • The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med. 1996;100(2):171 [MEDLINE]
      • Computed tomographic pulmonary angiography for diagnosis of invasive mold diseases in patients with hematological malignancies. Clin Infect Dis. 2012;54(5):610 [MEDLINE]
      • High resolution computed tomography angiography improves the radiographic diagnosis of invasive mold disease in patients with hematological malignancies. Clin Infect Dis. 2015 Jun;60(11):1603-10 [MEDLINE]

      Treatment

      • Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63(4):e1-e60. doi: 10.1093/cid/ciw326. Epub 2016 Jun 29 [MEDLINE]