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)

• Factors Which Increase the Risk of Invasive Aspergillosis After Engraftment (Blood, 2002) [MEDLINE]
  • Corticosteroids (see Corticosteroids, Corticosteroids)
  • Cytomegalovirus (CMV) Disease (see Cytomegalovirus, Cytomegalovirus)
  • Graft vs Host Disease (GVHD) (see Graft vs Host Disease, Graft vs Host Disease)
  • Lymphopenia
  • Neutropenia (see Neutropenia, Neutropenia)
  • Respiratory Virus Infection
  • T-Cell-Depleted or CD34-Selected Stem Cell Products
• Factors Associated with Increased Risk of Invasive Aspergillosis Occurring >6 mo Post-HSCT (Blood, 2002) [MEDLINE]
  • Chronic Graft vs Host Disease (GVHD) (see Graft vs Host Disease, Graft vs Host Disease)
  • Cytomegalovirus (CMV) Disease (see Cytomegalovirus, Cytomegalovirus)

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

• Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) (see Human Immunodeficiency Virus, Human Immunodeficiency Virus)
• Solid Organ Transplant
  • Heart-Lung Transplant (see Heart-Lung Transplant, Heart-Lung Transplant)
  • Liver Transplant (see Liver Transplant, Liver Transplant)
    • Risk Factors
      • Cytomegalovirus (CMV) Infection (see Cytomegalovirus, Cytomegalovirus)
      • Hemodialysis (see Hemodialysis, Hemodialysis)
      • Immunosupression
  • Lung Transplant (see Lung Transplant, Lung Transplant)
  • Renal Transplant (se Renal Transplant, Renal Transplant)
    • Risk Factors in ≤3 mo Post-Renal Transplant
      • Leukopenia (see Leukopenia, Leukopenia)
      • Longer Duration of Hemodialysis (see Hemodialysis, Hemodialysis)
    • Risk Factors >3 mo Post-Renal Transplant
      • Donor CMV Seropositivity

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

• Hairy Cell Leukemia (see Hairy Cell Leukemia, Hairy Cell Leukemia)): due to decreased monocyte count

---

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

• All Hyaline Molds Appear Similar by Microscopic Examination with Sepated, Nonpigmented Hyphae and 45 Degree Acute Angle Branching
  • Hyaline Molds
    • Acremonium (see Acremonium, Acremonium)
    • Aspergillus
      • Size: 3-6 μm wide
      • Staining: seen using Gomori methenamine silver or periodic acid-Schiff stains
    • Fusarium (see Fusarium, Fusarium)
    • Lomentospora (see Lomentospora Prolificans, Lomentospora Prolificans)
    • Paecilomyces (see Paecilomyces, Paecilomyces)
    • Scedosporium (see Scedosporiosis, Scedosporiosis)
  • Culture is Required to Distinguish the Species

---

Clinical Manifestations

Cardiovascular Manifestations

Endocarditis (see Endocarditis, Endocarditis)

• Epidemiology
  • Aspergillus Endocarditis is the Second Most Common Fungal Etiology of Endocarditis, After Candida
  • Risk Groups
    • Prosthetic Heart Valve Replacements: most common risk factor
    • Long-Term Central Venous Catheter (CVC) (see Central Venous Catheter, Central Venous Catheter)
    • Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, Intravenous Drug Abuse)
• Diagnosis
  • Blood Culture (see Blood Culture, Blood Culture): rarely positive (even with use of a fungal isolator tube)
• Clinical
  • Embolic Phenomena
  • Fever (see Fever, Fever)

Myocarditis (see Myocarditis, Myocarditis)

• xx

Pericarditis (see Acute Pericarditis, Acute Pericarditis)

• xxxx

Dermatologic Manifestations

Cutaneous Aspergillosis

• Epidemiology
  • Risk Groups
    • Burns (see Burns, Burns): usually via direct inoculation
    • Hematologic Malignancy: usually via hematogenous spread
    • Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant, Hematopoietic Stem Cell Transplant): usually via hematogenous spread
    • Neonates: usually via direct inoculation
    • Solid Organ Transplant: usually via direct inoculation
• Diagnosis
  • Skin Biopsy (see Skin Biopsy, Skin Biopsy)
• Physiology
  • Direct Trauma with Inoculation
  • Contiguous Spread
  • Hematogenous Spread
• Clinical
  • xxxx

Gastrointestinal Manifestations

General Comments

• Risk Factors for Gastrointestinal Involvement
  • Corticosteroids (see Corticosteroids, Corticosteroids)
  • Mucositis (see Mucositis, Mucositis)
  • Neutropenia (see Neutropenia, Neutropenia)

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
  • May Occur in Patient with Peritoneal Dialysis Catheter (see Peritoneal Dialysis, Peritoneal Dialysis)
• 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
    • Liposomal Amphotericin B (see Amphotericin, Amphotericin): 3-5 mg/kg/day IV
    • Isavuconazole (Cresemba) (see Isavuconazole, Isavuconazole: 200 mg q8hrs x 6 doses PO, then 200 mg qday PO
  • Salvage
    • Amphotericin B Lipid Complex (see Amphotericin, Amphotericin): 5 mg/kg/day IV
    • Caspofungin (Cancidas) (see Caspofungin, Caspofungin): 70 mg/kg qday IV x 1 day, then 50 mg/kg qday IV
    • Micafungin (Mycamine) (see Micafungin, Micafungin): 100-150 mg/day IV
    • Posaconazole (Noxafil, Posanol) (see Posaconazole, Posaconazole)
      • Oral Suspension: 200 mg TID PO
      • Tablet: 300 mg BID PO x 1 day, then 300 mg qday PO
      • IV: 300 mg BID IV x 1 day, then 300 mg qday IV
    • Itraconazole (Sporanox) (see nItraconazole, Itraconazole))
      • Oral Suspension: 200 mg BID PO

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)

• Epidemiology
  • XXXX
• Diagnostic
  • Brain MRI (see Brain Magnetic Resonance Imaging, Brain Magnetic Resonance Imaging)
• Clinical
  • Focal Neurologic Signs
  • Seizures (see Seizures, Seizures)

Endophthalmitis (see Endophthalmitis, Endophthalmitis)

• Epidemiology
  • XXXX
• Diagnostic
  • XXXX
• Physiology
  • May Occur Secondary to Disseminated Aspergillosis, Corneal Infection, or Direct Trauma to the Eye
• Clinical
  • Eye Pain (see Eye Pain, Eye Pain)
  • Visual Changes

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

• Epidemiology
  • XXXX
• Diagnostic
  • Brain MRI (see Brain Magnetic Resonance Imaging, Brain Magnetic Resonance Imaging)

Mycotic Aneurysm (Mycotic Aneurysm, Mycotic Aneurysm)

• Epidemiology
  • XXXX
• Diagnostic
  • Brain MRI (see Brain Magnetic Resonance Imaging, Brain Magnetic Resonance Imaging)
• Clinical Complications
  • Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage, Subarachnoid Hemorrhage,
  • Intracerebral Hemorrhage (see Intracerebral Hemorrhage, Intracerebral Hemorrhage)
  • Empyema (see xxxx, xxxx)

Otolaryngologic Manifestations

Aspergillus Rhinosinusitis

• Epidemiology
  • Most Commonly Occurs in the Setting of Neutropenia
    • In Contrast, Mucormycosis Occurs Most Commonly in the Setting of Either Diabetes Mellitus or Hematologic Malignancy (see Mucormycosis, Mucormycosis))
• Diagnosis
  • Sinus CT (see Sinus Computed Tomography, Sinus Computed Tomography)
• Clinical
  • Mimics Presentation of Mucormycosis (see Mucormycosis, Mucormycosis)
  • Fever (see Fever, Fever)
  • Nasal Congestion
  • Facial/Sinus/Periorbital Pain (see xxxx, xxxx, Sinus Pain, Sinus Pain, and Eye Pain, Eye Pain)
• Treatment (IDSA 2016 Diagnosis and Management of Aspergillosis Guidelines) (Clin Infect Dis, 2016) [MEDLINE]
  • General Comments
    • Surgical Debridement is Required In Addition to Pharmacologic Therapy
  • 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
    • Liposomal Amphotericin B (see Amphotericin, Amphotericin): 3-5 mg/kg/day IV
    • Isavuconazole (Cresemba) (see Isavuconazole, Isavuconazole): 200 mg q8hrs x 6 doses PO, then 200 mg qday PO
  • Salvage
    • Amphotericin B Lipid Complex (see Amphotericin, Amphotericin): 5 mg/kg/day IV
    • Caspofungin (Cancidas) (see Caspofungin, Caspofungin): 70 mg/kg qday IV x 1 day, then 50 mg/kg qday IV
    • Micafungin (Mycamine) (see Micafungin, Micafungin): 100-150 mg/day IV
    • Posaconazole (Noxafil, Posanol) (Posaconazole, Posaconazole)
      • Oral Suspension: 200 mg TID PO
      • Tablet: 300 mg BID PO x 1 day, then 300 mg qday PO
      • IV: 300 mg BID IV x 1 day, then 300 mg qday IV
    • Itraconazole (Sporanox) (see Itraconazole, Itraconazole)
      • Oral Suspension: 200 mg BID PO

Pulmonary Manifestations

General Comments

• Lungs the Most Common Site of Involvement in Invasive Aspergillosis

Aspergillus Tracheobronchitis

• Risk Groups
  • Chronic Obstructive Pulmonary Disease (COPD) (see Chronic Obstructive Pulmonary Disease, Chronic Obstructive Pulmonary Disease)
  • Hematologic Malignancy
  • Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant, Hematopoietic Stem Cell Transplant)
  • Human Immunodeficiency Virus (HIV) (Human Immunodeficiency Virus, Human Immunodeficiency Virus)
  • Lung Transplant (see Lung Transplant, Lung Transplant): most commonly reported group
  • Solid Organ Transplant
• Diagnosis
  • Chest CT (see Chest Computed Tomography, Chest Computed Tomography)
  • Bronchoscopy (see Bronchoscopy, Bronchoscopy)
    • Aspergillosis of the Bronchial Stump: may occur in lung transplant patients
    • Obstructive Bronchial Aspergillosis
    • Pseudomembranous Tracheobronchitis
    • Ulcerative Tracheobronchitis
• Clinical
  • Cough (see Cough, Cough)
  • Dyspnea (see Dyspnea, Dyspnea)
  • Expectoration of Mucus Plugs
• Treatment (IDSA 2016 Diagnosis and Management of Aspergillosis Guidelines) (Clin Infect Dis, 2016) [MEDLINE]
  • 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)
  • Adjunct
    • Inhaled Amphotericin B May Be Useful (see Amphotericin, Amphotericin)
  • Alternatives
    • Liposomal Amphotericin B (see Amphotericin, Amphotericin): 3-5 mg/kg/day IV
    • Isavuconazole (Cresemba) (see Isavuconazole, Isavuconazole): 200 mg q8hrs x 6 doses PO, then 200 mg qday PO
  • Salvage
    • Amphotericin B Lipid Complex (see Amphotericin, Amphotericin): 5 mg/kg/day IV
    • Caspofungin (Cancidas) (see Caspofungin, Caspofungin): 70 mg/kg qday IV x 1 day, then 50 mg/kg qday IV
    • Micafungin (Mycamine) (see Micafungin, Micafungin): 100-150 mg/day IV
    • Posaconazole (Noxafil, Posanol) (see Posaconazole, Posaconazole)
      • Oral Suspension: 200 mg TID PO
      • Tablet: 300 mg BID PO x 1 day, then 300 mg qday PO
      • IV: 300 mg BID IV x 1 day, then 300 mg qday IV
    • Itraconazole (Sporanox) (see Itraconazole, Itraconazole)
      • Oral Suspension: 200 mg BID PO

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)
    • Findings
      • Patchy/Segmental Consolidation (see Pneumonia, Pneumonia)
      • Peribronchial Infiltrates with/without Tree-in-Bud Pattern (see Pneumonia, Pneumonia and Chest Computed Tomography-Tree-in-Bud Sign, Chest Computed Tomography-Tree-in-Bud Sign)
      • Single/Multiple Lung Nodules with/without Cavitation (see Lung Nodule or Mass, Lung Nodule or Mass)
    • Distribution of Types of Infiltrates in a Large Series of Patients with Invasive Pulmonary Aspergillosis (Eur J Radiol, 2005) [MEDLINE]
      • Small (>1 cm) Nodules (see Lung Nodule or Mass, Lung Nodule or Mass): occur in 43% of cases
      • Large Nodules (see Lung Nodule or Mass, Lung Nodule or Mass): occur in 21% of cases
      • Patchy/Segmental Consolidation (see Pneumonia, Pneumonia): occurs in 26% of cases
      • Peribronchial Infiltrates with/without Tree-in-Bud Pattern (see Pneumonia, Pneumonia and Chest Computed Tomography-Tree-in-Bud Sign, Chest Computed Tomography-Tree-in-Bud Sign): occurs in 9% of cases
      • Approximately 24% of Cases Had Combined Patterns
      • Halo Sign (Nodule with Surrounding Hypoattenuation) (see Chest Computed Tomography-Halo Sign, Chest Computed Tomography-Halo Sign): occurs in 82% of cases
      • Air-Crescent Sign with Cavitation (see Computed Tomography Pulmonary Artery Angiogram)
        • While CT Pulmonary Artery Angiogram Has Been Studied to Determine its Sensitivity in Detecting Angioinvasion, its Role is Currently Unclear in the Diagnosis of Invasive Pulmonary Aspergillosis (Clin Infect Dis, 2012) [MEDLINE] (Clin Infect Dis, 2015)[MEDLINE]
      • Sputum Culture (see Sputum Culture, Sputum Culture)
      • Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, Bronchoscopy)
        • 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]
        • Positive Predictive Value of Aspergillus Cultures Obtained Via BAL is 72% in Cases Following HSCT, 58% in Cases on Corticosteroids and Following Solid Organ Transplant, and 14% in Cases with HIV (Am J Med, 1996) [MEDLINE]
        • Recommendations (Infectious Diseases Society of America 2016 Practice Guidelines) (Clin Infect Dis, 2016) [MEDLINE]
          • Bronchoscopy with Bronchoalveolar Lavage (BAL) is Recommended in Patients with a Suspicion of Invasive Pulmonary Aspergillosis (Strong Recommendation, Moderate-Quality Evidence)
            • The Diagnostic Yield of BAL is Low for Peripheral Nodular Lung Lesions: in these cases, transthoracic needle aspiration should be considered
            • Bronchoalveolar Lavage Should Be Sent for Routine Culture, Cytology, and BAL Galactomannan (Strong Recommendation, Moderate-Quality Evidence)
      • Bronchoscopy with Transbronchial Biopsy (TBB) (see Bronchoscopy, Bronchoscopy)
      • Video-Assisted Thoracoscopic (VATS) Lung Biopsy (see Open Lung Biopsy, Open Lung Biopsy)
    • Clinical
      • Chest Pain (see Chest Pain, Chest Pain)
      • Cough (see Cough, Cough)
      • Dyspnea (see Dyspnea, Dyspnea)
      • Fever (see Fever, Fever)
      • Hemoptysis (see Hemoptysis, Hemoptysis)
    • Treatment (IDSA 2016 Diagnosis and Management of Aspergillosis Guidelines) (Clin Infect Dis, 2016) [MEDLINE]
      • 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
        • Liposomal Amphotericin B (see Amphotericin, Amphotericin): 3-5 mg/kg/day IV
        • Isavuconazole (Cresemba) (see Isavuconazole, Isavuconazole): 200 mg q8hrs x 6 doses PO, then 200 mg qday PO
      • Salvage
        • Amphotericin B Lipid Complex (see Amphotericin, Amphotericin): 5 mg/kg/day IV
        • Caspofungin (Cancidas) (see Caspofungin, Caspofungin): 70 mg/kg qday IV x 1 day, then 50 mg/kg qday IV
        • Micafungin (Mycamine) (see Micafungin, Micafungin): 100-150 mg/day IV
        • Posaconazole (Noxafil, Posanol) (see Posaconazole, Posaconazole)
          • Oral Suspension: 200 mg TID PO
          • Tablet: 300 mg BID PO x 1 day, then 300 mg qday PO
          • IV: 300 mg BID IV x 1 day, then 300 mg qday IV
        • Itraconazole (Sporanox) (see Itraconazole, Itraconazole)
          • Oral Suspension: 200 mg BID PO

    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)

    • Voriconazole (Vfend) (see Voriconazole, Voriconazole)
    • Posaconazole (Noxafil, Posanol) (see Posaconazole, Posaconazole)
    • Isavuconazole (Cresemba) (see Isavuconazole, Isavuconazole)

    ---

    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]