aspergillosis
ASPERGILLOSIS
Treatment Guideline Chart
Aspergillosis encompasses a variety of clinical syndromes depending on host immunity factors.
It is caused by Aspergillus, an ubiquitous, soil-dwelling, filamentous fungus that grows on soil, food, dead leaves, household dust, etc. It grows best at 37ºC and the small spores are easily inhaled and deposited deep in the lungs.
The most common pathogens are Aspergillus fumigatus, A. flavus, A. niger and A. terreus.
Aspergilloma is a conglomeration of intertwined Aspergillus hyphae, fibrin, mucus and cellular debris within a pulmonary cavity or an ectatic bronchus.

Aspergillosis Signs and Symptoms

Introduction

  • Encompasses a variety of clinical syndromes depending on the host immunity factor

Definition

Invasive Aspergillosis (IA)

  • A rapidly progressive and frequently fatal disease that occurs in highly immunocompromised individuals
  • Most common cause of infectious pneumonic mortality in patients undergoing hematopoietic stem cell transplantation (HSCT) and is an important cause of opportunistic respiratory and disseminated infection in other immunocompromised patients
    • Coronavirus disease-19 (COVID-19) has been shown to predispose patients to secondary pulmonary aspergillosis known as COVID-19-associated pulmonary aspergillosis (CAPA)
      • Please refer to COVID-19-associated pulmonary aspergillosis (CAPA) section 
  • Inhalation of etiologic agent is extremely common but disease is rare
  • Any organ may be involved in the immunocompromised host, but sinopulmonary disease is the most frequent

Allergic Bronchopulmonary Aspergillosis (ABPA)

  • A hypersensitivity reaction to Aspergillus antigens often due to A fumigatus and typically occurs in patients with long-standing asthma or cystic fibrosis
  • It is believed that the pathogenesis involves Aspergillus-specific, IgE-mediated type I hypersensitivity reaction and specific IgG-mediated type III hypersensitivity reactions

Allergic Aspergillus Sinusitis (AAS)

  • A hypersensitivity response to the presence of Aspergillus within the paranasal sinuses and is characterized by mucoid impaction similar to that of ABPA

Aspergilloma

  • Conglomeration of intertwined Aspergillus hyphae, fibrin, mucus and cellular debris within a pulmonary cavity or an ectatic bronchus
  • Most common pulmonary involvement due to Aspergillus
  • Pre-existing lung cavity formed secondary to tuberculosis, sarcoidosis, bronchiectasis, bronchial cysts and bullae, ankylosing spondylitis, neoplasm or pulmonary infarction is the most common predisposing factor

Chronic Pulmonary Aspergillosis (CPA)

  • Subtypes include chronic cavitary pulmonary aspergillosis (CCPA), chronic fibrosing pulmonary aspergillosis (CFPA), Aspergillus nodule, single (simple) aspergilloma, and subacute invasive pulmonary aspergillosis (previously known as chronic necrotizing pulmonary aspergillosis)
    • CCPA is the most common manifestation of CPA, which may progress to CFPA when left untreated
  • A pulmonary aspergillosis that commonly causes a slowly progressive inflammatory destruction of lung tissue in patients with underlying lung diseases and low-grade immunosuppression usually due to invasion by A fumigatus
  • No vascular involvement or dissemination to other organs

Cutaneous Aspergillosis

  • Primary cutaneous aspergillosis is usually resulting from a skin disruption site (eg intravenous devices, adhesive dressing, surgical wound, burn) creating access for the infection, or traumatic inoculation
  • Secondary cutaneous aspergillosis results from hematogenous seeding from a primary source in immunocompromised patients

Otic Aspergillosis

  • Otomycosis: A condition of superficial colonization typically due to A niger and A fumigatus
  • Usually occurs in patients with hypogammaglobulinemia, diabetes mellitus (DM), chronic eczema or human immunodeficiency virus (HIV) infection and those taking corticosteroids

COVID-19-Associated Pulmonary Aspergillosis (CAPA)

  • A secondary form of invasive pulmonary aspergillosis in temporal proximity to a prior SARS-CoV-2 infection
    • Associated with high mortality rate
  • Leading fungal disease in COVID-19 patients with acute respiratory distress syndrome (ARDS)

Proposed Definitions for CAPA

  • Proven CAPA: Tracheobronchitis or other pulmonary form of infection in patients with COVID-19 needing intensive care with ≥1 of the following:
    • Direct microscopic or histopathological detection or both of fungal hyphae that are morphologically consistent with Aspergillus spp, showing invasive growth with associated tissue damage or
    • Aspergillus recovered by culture, microscopy, histology or PCR obtained by a sterile aspiration or biopsy from a pulmonary site, showing an infectious disease process
  • Probable CAPA
    • Tracheobronchitis indicated by tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar, alone or in combination, seen on bronchoscopic analysis in patients with COVID-19 needing intensive care with ≥1 of the following:
      • Microscopic detection of fungal elements in bronchoalveolar lavage, indicating a mold or
      • Positive bronchoalveolar lavage or culture or PCR or
      • 1 serum galactomannan index >0.5 or serum lateral flow assay (LFA) index >0.5 or
      • Bronchoalveolar lavage galactomannan index ≥1.0 or bronchoalveolar lavage LFA index ≥1.0
    • Other pulmonary forms of infection are indicated by pulmonary infiltrate preferably documented by chest CT or cavitating infiltrate not attributed to another cause in patients with COVID-19 needing intensive care with ≥1 of the following:
      • Microscopic detection of fungal elements in bronchoalveolar lavage, indicating a mold or
      • Positive bronchoalveolar lavage culture or
      • Serum galactomannan index >0.5 or serum LFA index >0.5 or
      • Bronchoalveolar lavage galactomannan index ≥1.0 or bronchoalveolar lavage LFA index ≥1.0 or
      • ≥2 positive Aspergillus PCR in serum, plasma or whole blood or
      • A positive Aspergillus PCR in bronchoalveolar lavage fluid (<36 cycles) or
      • A positive Aspergillus PCR in serum, plasma, or whole blood and a positive Aspergillus PCR in bronchoalveolar lavage fluid (any threshold cycle)
  • Possible CAPA: Other pulmonary forms of infection indicated by pulmonary infiltrate preferably documented by chest CT or cavitating infiltrate not attributed to another cause in patients with COVID-19 with ≥1 of the following:
    • Microscopic detection of fungal elements in non-bronchoscopic lavage indicating a mold or
    • Positive non-bronchoscopic lavage culture or
    • A non-bronchoscopic lavage galactomannan index >4.5 or
    • Non-bronchoscopic lavage galactomannan index >1.2 and another positive non-bronchoscopic lavage mycology test (PCR or LFA)

Etiology

  • Caused by Aspergillus, an ubiquitous, soil-dwelling, filamentous fungus that grows on soil, food, dead leaves, household dust, etc
    • Grows best at 37°C, and the small spores are easily inhaled and deposited deep in the lungs
  • The most common pathogens are Aspergillus fumigatus, A flavus, A niger and A terreus
  • Other species can also cause disease, including A nidulans and A clavatus
  • In immunocompetent persons, aspergillosis can occur in previously damaged tissue or induce allergic responses

Signs and Symptoms

Invasive Aspergillosis (IA)

  • Patient may present with:
    • Fever refractory to empirical broad-spectrum antibacterials
    • Cough
    • Pleural pain
    • Paranasal sinus findings
    • Hemoptysis

Allergic Bronchopulmonary Aspergillosis (ABPA)

  • Patient usually presents with expectoration of brown mucus plugs, wheezing, fever and pleuritic chest pain

Allergic Aspergillus Sinusitis (AAS)

  • Patient usually presents with nasal obstruction, rhinorrhea, headache and epistaxis
  • May occasionally manifest as proptosis due to extension of fungal sinusitis into the orbit

Aspergilloma

  • Aspergilloma may exist for many years without causing symptoms
  • Hemoptysis that can be severe and life-threatening
  • Chronic cough and dyspnea that are more likely due to underlying disease
  • Rarely fever

Chronic Pulmonary Aspergillosis (CPA) 

  • Chronic pulmonary symptoms (fever, cough with or without hemoptysis, dyspnea, fatigue, chest pain, sputum production, weight loss) of at least 3 months’ duration

Cutaneous Aspergillosis

  • Erythematous indurated papules that progresses into ulcerative necrotic lesions

Otic Aspergillosis

  • Patient may usually present with ear pain, pruritus, hypoacusis and otic discharge

COVID-19-Associated Pulmonary Aspergillosis (CAPA)

  • COVID-19 patients with refractory respiratory failure for >5-14 days despite receiving recommended therapy should be suspected of CAPA
  • Onset of signs and symptoms is variable
  • May present any of the following signs and symptoms:
    • Refractory fever >3 days or new fever after a period of defervescence >48 hours during optimal antibiotic treatment not attributed to other causes
    • Worsening respiratory function (eg tachypnea, increasing oxygen requirements)
    • Hemoptysis
    • Pleural friction rub or chest pain

Risk Factors

Invasive Aspergillosis (IA) 

  • Major risk factors include:
    • Prolonged neutropenia (neutrophil count <100/microL for >10 days)
    • Intensive cytotoxic chemotherapy
    • Hematopoietic stem cell transplantation (HSCT) or solid-organ transplantation
    • Acquired immune deficiency syndrome (AIDS)
    • Chronic granulomatous disease (CGD)
    • Critical illness without documented immunodeficiency
    • Hematologic malignancies
    • Severe aplastic anemia
    • Primary immunodeficiencies
    • Prolonged corticosteroid use
    • Cytomegalovirus disease

COVID-19-Associated Pulmonary Aspergillosis (CAPA)

  • Severe lung damage during COVID-19 disease
  • Use of corticosteroids for ARDS
  • Use of broad-spectrum antibiotics
  • Underlying medical conditions in particular presence of structural pulmonary defects
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