Pulmonary

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• Pulmonary
• Manifestations of
• Aspergillosis
• Mutaz Labib, MD
• MHRI
• January 18, 2006

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ASPERGILLOSIS

• Aspergilloma. (Fungus ball)
• ABPA. (Hypersensitivity)
• Aspergillus necrotizing bronchitis.
• endo-bronchial mass, obstructive pneumonitis,
  collapse, hilar mass.
• Invasive Pulmonary Aspergillosis.
• Angioinvasive/ hemorrhagic infarcts.
• Airway invasive-obstructing.

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Saprophytic Aspergillosis
(Aspergilloma )

• Most common cause A. fumigatus 80-90 , then
  A.flavus, A.terreus, A.niger.
• Microscopic features of A fumigatus.
• High-power photomicrograph can show the
  conidiophores with the characteristic head
  appearance and minute spores.
• Medium-power photomicrograph shows septate hyphae
  branching and angulations.

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  Saprophytic Aspergillosis
(Aspergilloma )

• Review of 60.000 CXR indentified 0.01
  prevelance.
• Infection without tissue invasion.
• Solid rounded mass, some times mobile.
• Fungal hyphae mixed with mucus and cellular
  debris within a preexistent pulmonary cavity or
  ectatic bronchus .
• If peripheral, Pleural thickening is
  characteristic.
• Mass is usually seperated from the cavity wall.

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Saprophytic Aspergillosis
(Aspergilloma )

• Clinical findings could be non-specific.
• Some patients may remain asymptomatic.
• Most frequent symptom is HEMOPTYSIS 75.
• Less commonly chest pain, dyspnea , malaise.
• Wheezing and fever (could also be secondary to
  underlying disease, or bacterial super infection
  of the cavity or aspergilloma itself).

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Aspergilloma

• The most common predisposing factors are
  tuberculosis and sarcoidosis.
• Other conditions that occasionally may be
  associated with aspergilloma include bronchogenic
  cyst, pulmonary sequestration, and pneumatoceles
  secondary to Pneumocystis carinii pneumonia in
  patients with (AIDS) .
• Bronchiectasis, ankylosing spondylitis, neoplasm.

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Aspergilloma

• Tuberculosis is the most frequently associated
  condition.
• Aspergilloma with history of tuberculosis. May
  show multiple irregular fungus balls virtually
  filling the pulmonary cavity

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Aspergilloma

• Radiography
• Presence of a solid, round or oval mass with
  soft-tissue opacity within a lung cavity.
• Mass is separated from the wall of the cavity by
  an airspace of variable size and shape "air
  crescent" sign seen in thin section CT
  (mediastinal window).
• Other causes of the air crescent sign include
  angioinvasive aspergillosis, echinococcal cyst,
  and, rarely, tuberculosis, lung abscess,
  bronchogenic carcinoma, hematoma, and P carinii
  pneumonia.

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Aspergilloma

• Aspergillomas are often associated with
  thickening of the cavity wall and adjacent
  pleura.
• Pleural thickening may be the earliest
  radiographic sign before any visible changes are
  seen within the cavity.
• Associated scarring in lung lobes.
• Aspergillomas are usually single, they may also
  be present bilaterally.
• Change in position.

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Aspergilloma

• Mobile aspergilloma
• The aspergilloma usually moves when the patient
  changes position .
• Chest CT scans obtained with the patient supine
  and prone show a change in the position of the
  aspergilloma within a pulmonary cystic cavity.

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• Mobile aspergilloma within a pulmonary cystic
  cavity in a 43-year-old man. Chest CT scans
  obtained with the patient supine (a) and prone
  (b) show a change in the position of the
  aspergilloma. A fumigatus was discovered at
  bronchoscopy. (Courtesy of Josep M. Mata, MD,
  Unidad Diagnóstica de Alta Tecnología, Sabadell,
  Spain.)

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Aspergilloma

• Approximately 10 of mycetomas resolve
  spontaneously.
• Reversibility of the pleural thickening upon
  resolution of intracavitary fungal material
  suggests that the thickening of the cavity wall
  and pleura is due to a hypersensitivity reaction.

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Aspergilloma

• Treatment
• In asymptomatic patients, No therapy needed.
• Medical therapy with bed rest, humidified oxygen,
  cough suppressant, and postural drainage is
  helpful in cases of mild hemoptisis.
• Surgical resection is indicated for patients with
  severe life-threatening hemoptysis.
• Selective bronchial artery embolization can be
  performed in those with poor lung function.

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Aspergilloma

• Antifungal therapy
• Patient is not a candidate for surgery
• Concomitant tissue invasion
• Itraconazole with some help
• Ampho B for invasive component.
• Newer Azoles, Voriconazole , Posaconazole , and
  Ravuconazole.Their role is not clear.
• Antibiotics for bacterial superinfection.

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Hypersensitivity Reaction (Allergic
Bronchopulmonary Aspergillosis)

• ABPA is seen most commonly in patients with
  long-standing bronchial asthma (7-14) or CF (6)
  .
• Characterized by the presence of plugs of mucus
  containing Aspergillus organisms and eosinophils.
  
• This results in bronchial dilatation typically
  involving the segmental and sub segmental
  bronchi.

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Allergic Bronchopulmonary Aspergillosis

• ABPA is caused by a complex hypersensitivity
  reaction to Aspergillus organisms.
• The fungi proliferate in the airway lumen ,
  producing a constant supply of antigen.
• A type I hypersensitivity reaction with IgE and
  IgG release occurs.
• Immune complexes and inflammatory cells are then
  deposited in the bronchial mucosa.
• Production of necrosis and eosinophilic
  infiltrates (type III reaction) with bronchial
  wall damage and bronchiectasis.
  
  

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Allergic Bronchopulmonary Aspergillosis

• Excessive mucus production and abnormal ciliary
  function lead to mucoid impaction.
• Many patients cough up thick mucous plugs in
  which hyphal fragments can be demonstrated at
  culture or histologic analysis.
• Acute clinical symptoms include recurrent
  wheezing, malaise with low-grade fever, cough,
  sputum production, and pleuritic chest pain.
• Patients with chronic ABPA may also have a
  history of recurrent pneumonia.

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Allergic Bronchopulmonary Aspergillosis

• Radiologic manifestations
• Homogeneous, tubular, finger-in-glove areas of
  increased opacity in a bronchial distribution,
  usually predominantly involving the upper lobes.
• Band like opacities related to plugging of
  airways by hyphal masses with distal mucoid
  impaction and can migrate from one region to
  another.
• Occasionally, isolated lobar or segmental
  atelectasis may occur.

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Allergic Bronchopulmonary Aspergillosis

• In later stages central bronchiectasis and
  pulmonary fibrosis develop.
• CT findings in ABPA consist primarily of mucoid
  impaction and bronchiectasis involving
  predominantly the segmental and sub segmental
  bronchi of the upper lobes .
• In approximately 30 of patients, the impacted
  mucus has high attenuation or demonstrates frank
  calcification at CT.

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Allergic Bronchopulmonary Aspergillosis

• Diagnostic criteria
• Asthma.
• Immediate skin reactivity to Aspergillus.
• Serum precipitins to A fumigatus.
• Total serum IgE gt1.000 ng/ml
• Current or previous pulmonary infiltrates.
• Central Bronchiectasis.
• Peripheral Eosinophilia.

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Allergic Bronchopulmonary Aspergillosis

• Stages /Patterson et all
• Stage 1 ( Acute stage)
• Stage 2 ( Remission stage)
• Stage 3 ( Exacerbation stage)
• Stage 4 ( Steroid dependent stage)
• Stage 5 ( Fibrotic stage)

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Allergic Bronchopulmonary Aspergillosis

• Treatment
• Oral corticostroids, relief of bronchospasm,
  clearing of pulmonary infiltrates and decrease
  IgE levels( 0.5 mg/kg/d for 2 wks then taper).
• Most patients require prolonged low dose therapy.
• Itraconazole low dose(200 mg bid for 16 weeks)
  can Help in 50 reduction of corticosteroid dose.
  With no significant toxicity.

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Allergic Bronchopulmonary Aspergillosis

• Syndromes Related to ABPA
• Mucoid Impaction
• Without asthma, mucus plug lead to
  atelectasis. Usually presents with cough.
• Bronchocentric Granulomatosis.
• Necrotizing granulomas, obstruct and destroy
  bronchiols . Eosinophilic inflamatory infiltrate
  and fibrosis with no tissue or vascular invasion
  by aspergillus, almost always asthmatics with
  persistent cough and high IgE levels. good
  response to corticosteroids.

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Allergic Bronchopulmonary Aspergillosis

• Eosinphilic pneumonitis
• Rarely caused by aspergillus, cough dyspnea
  and fever with peripheral pulmonary infiltrate,
  diagnosis made by biopsy, good response to
  corticosteroids.
• Hypersesitivity pneumonitis
• Extrinsic allergic alveolitis, intense
  repeated inhalation of thermophilic bacteria,
  fungi, bird excreta, and chemical agents causes
  hypersensitivity granulomatous inflamation of
  distal airway disease.

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• Fungus is intermediate.
• No vascular invasion.
• Tissue necrosis and destruction.
• Granulomatous inflammation similar to that seen
  in reactivation tuberculosis.
• Usually no previous cavity, vs presence of cavity
  in non-invasive form.
• May occur with mild immunosuppression.

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• Predisposing factors
• Chronic debilitating illness, Advanced age.
• Alcoholism, Malnutrition.
• DM, CF, COPD.
• Prolonged steroid therapy, Radiation therapy.
• Inactive TB.
• Pneumoconiosis.
• Sarcoidosis.

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• Symptoms
• Often insidious and include chronic cough, sputum
  production, fever, and constitutional symptoms.
• Hemoptysis has been reported in 15 of affected
  patients .
• May manifest with chronic bronchitis and
  recurrent episodes of mild hemoptysis.

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• In patients with COPD, may manifest with
  non-specific clinical symptoms such as cough,
  sputum production, and fever lasting more than 6
  months.

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• Radiologic manifestations
• Thin-section CT scan (lung window) shows
  unilateral or bilateral rounded segmental areas
  of consolidation with or without cavitation or
  adjacent pleural thickening,
• Multiple nodular areas of increased opacity .
• The findings progress slowly over months or
  years.

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• Diagnosis Criteria
• Clinical and Radiologic features
• Isolation of Aspergillus species by culture from
  sputum, bronchoscopic or percutaneous samples.
• Exclusion of other conditions

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Semi-invasive (Chronic Necrotizing) Aspergillosis

• Treatment
• Antifungals should be initiated once the
  diagnosis is made. IV Ampho B, Itraconazole is
  also effective.
• Surgical resection for healthy individuals with
  good lung reserves, not tolerating antifungals or
  where antifungals are ineffective in setting of
  active disease.

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Invasive Pulmonary Aspergillosis (IPA)

• Major risk factors.
• Prolonged neutropenia gt3 wks or neutrophil
  dysfunction.
• Corticosteroid therapy (prolonged, high dose).
• Transplantation (Lung and BM )
• Hematologic malignancy( leukemia)
• Cytotoxic therapy.
• AIDS.

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Airway-invasive Aspergillosis

• The presence of Aspergillus organisms deep to the
  airway basement membrane.
• It occurs most commonly in immunocompromised
  neutropenic patients and in patients with AIDS.
• Clinical manifestations include acute
  tracheobronchitis, bronchiolitis, and
  bronchopneumonia.

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Airway-invasive Aspergillosis

• Patients with acute tracheobronchitis usually
  have normal radiologic findings.
• Occasionally, tracheal or bronchial wall
  thickening may be seen.
• Bronchiolitis is characterized at HRCT by the
  presence of centrilobular nodules and branching
  linear or nodular areas of increased attenuation
  having a "tree-in-bud appearance.

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Airway-invasive Aspergillosis

• The centrilobular nodules have a patchy
  distribution in the lung.
• Aspergillus bronchopneumonia results in
  predominantly peribronchial areas of
  consolidation.
• Rarely, the consolidation may have a lobar
  distribution.

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Airway-invasive Aspergillosis

• Centrilobular nodular areas of increased opacity
  similar to those seen in Aspergillus
  bronchiolitis have been described in a number of
  conditions, including endobronchial spread of
  pulmonary tuberculosis, Mycobacterium
  avium-intracellulare, and viral and mycoplasma
  pneumonia.
• The radiologic manifestations of Aspergillus
  bronchopneumonia are indistinguishable from those
  of bronchopneumonias caused by other
  micro-organisms.

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Airway-invasive Aspergillosis

• Obstructing bronchopulmonary aspergillosis
• noninvasive form of aspergillosis.
• Characterized by the massive intraluminal
  overgrowth of Aspergillus species.
• Usually A fumigatus, in patients with AIDS .
• Affected patients exhibit cough, fever, and new
  onset of asthma.
• Patients may cough up fungal casts of the bronchi
  and present with severe hypoxemia.

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Airway-invasive Aspergillosis

• CT findings in obstructing bronchopulmonary
  aspergillosis
• Mimic those in allergic bronchopulmonary
  aspergillosis.
• Bilateral bronchial and bronchiolar dilatation.
• large mucoid impactions (mainly lower lobes).
• Diffuse lower lobe consolidation caused by
  postobstructive atelectasis.

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Angioinvasive Aspergillosis

• Angioinvasive aspergillosis occurs almost
  exclusively in immunocompromised patients with
  severe neutropenia.
• For many reasons, however, there has been a
  substantial increase in the number of patients at
  risk for developing invasive aspergillosis.

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Angioinvasive Aspergillosis

• These reasons includes
• Development of new intensive chemotherapy
  regimens for solid tumors.
• Difficult-to-treat lymphoma, myeloma, and
  resistant leukemia.
• Increase in the number of solid organ
  transplantations.
• Increased use of immunosuppressive regimens for
  other autoimmune diseases.

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Angioinvasive Aspergillosis

• Despite having a normal neutrophil count,
  affected patients have functional neutropenia
  because the function of the neutrophils is
  inhibited by the use of high-dose steroids.
• Invasion and occlusion of small to medium-sized
  pulmonary arteries by fungal hyphae.
• This leads to the formation of necrotic
  hemorrhagic nodules or pleura-based, wedge-shaped
  hemorrhagic infarcts.

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Angioinvasive Aspergillosis

• Characteristic CT findings
• Nodules surrounded by a halo of ground-glass
  attenuation "halo sign or pleura-based,
  wedge-shaped areas of consolidation.
• These findings correspond to hemorrhagic
  infarcts.
• In severely neutropenic patients, the halo sign
  is highly suggestive of angioinvasive
  aspergillosis.

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Angioinvasive Aspergillosis

• However, a similar appearance has been described
  in a number of other conditions.
• Infection by Mucorales and Candida.
• Herpes simplex and cytomegalovirus.
• Wegener granulomatosis, Kaposi sarcoma , and
  hemorrhagic metastases .

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Angioinvasive Aspergillosis

• Separation of fragments of necrotic lung from
  adjacent paren-chyma results in air crescents
  similar to those seen in mycetomas.
• The air crescent sign in angioinvasive
  aspergillosis is usually seen during
  convalescence (ie, 23 weeks after initiation of
  treatment and concomitant with resolution of the
  neutropenia).

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Angioinvasive Aspergillosis

• Diagnosis
• The clinical diagnosis is difficult, and the
  mortality rate is high.
• Positive culture Methanamine silver, PAS
• BAL 97 specific. But less sensitive.
• Chest CT findings, Halo sign, Cresent sign.
• Open or thoracoscopic lung biopsy is the gold
  standard.

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Invasive Pulmonary Aspergillosis (IPA)

• Galactomannan Antigen
• Polysaccharide cell wall component.
• ELISA test.
• Approved for detection of IPA in pts who receive
  chemotherapy or Transplant.
• In these group of pts it has 67-100 sensitivity
  and 86-98.8 specificity.
• Can precede the clinical diagnosis by 6-14 day.

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Invasive Pulmonary Aspergillosis (IPA)

• Treatment
• Start empiric therapy ASAP, when diagnosis
  suspected.
• Most commonly used medicine Ampho B 0.6 1.2
  mg/kg/d , in severly immunocomromized 1 -1.5
  mg/kg/d.
• Duration depends on the period of
  immunosuppression. response 20-83.

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Invasive Pulmonary Aspergillosis (IPA)

• Other treatment options
• Itraconazol 200-400 mg/d , 39 response.
• Could be used in less immunocompromised.
• Late stage therapy after initial control of Ampho
  B.
• Combination therapy , no great efficacy.
• Caspofungin ,recently approved medicine.
• Voriconazole, Posaconazole.

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Invasive Pulmonary Aspergillosis (IPA)

• Voriconazole vs Ampho B, (391 pt randomized ).
• Succesfull response rate
  
• 49.7 for Vorico arm, 27.8 for Ampho B.
• 
  Herbrecht et al, NEM 347 408 (2002).
• Caspofungin, 70 favorable response in pulm.
  disease for salvage therapy, daily dose.
• Ampho B Caspo ,
• Vori Caspo, combination better out come.
• 
  marr et al, clin inf . Dis 2003.

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Invasive Pulmonary Aspergillosis (IPA)

• Surgical resection
• Massive hemoptysis.
• Localized lesion.
• Continuing immunosuppression.
• Further immunosuppressive therapy.
• Outcome is poor in BMT, Pt on mechanical
  ventilation and those who have multiple foci of
  infection.

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Invasive Pulmonary Aspergillosis (IPA)

• Outcome of therapy
• Early diagnosis.
• Recovery of underlying host defense defect.
• Resolution of neutropenia,
• Taper of immunosupressive therapy.
• Disease limited to the lung.

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Summary

• Aspergillosis is a serious complication that is
  frequently seen in immunocompromised patients.
• The radiologist plays a major role in the
  diagnosis of pulmonary Aspergillus infection.
• When radiographic findings are subtle or
  equivocal, CT frequently allows identification of
  the disease process.

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Summary

• In the appropriate clinical setting, familiarity
  with the thin-section CT findings may suggest and
  even help establish the specific diagnosis in
  various types of pulmonary aspergillosis .