Opportunistic Mycoses• Most important fungal pathogens: Candida Aspergillus Cryptococcus Pneumocystis Rhizopus Mucor Absidia 2
Infections by Candida: Candidiasis• Candida albicans• Widespread yeast• Infections can be short-lived, superficial skin irritations to overwhelming, fatal systemic diseases.• Budding cells of varying size that may form both elongate pseudohyphae and true hyphae• Forms off-white, pasty colony with a yeasty odor 3
Candida albicans• Normal flora of oral cavity, genitalia, large intestine or skin of 20% of humans• Account for 80% of nosocomial fungal infections• Account for 30% of deaths from nosocomial infections• Thrush – occurs as a thick, white, adherent growth on the mucous membranes of mouth and throat• Vulvovaginal yeast infection – painful inflammatory condition of the female genital region that causes ulceration and whitish discharge• Cutaneous candidiasis – occurs in chronically moist areas of skin and in burn patients 4
Clinical manifestations of pulmonary candidiasis• Cough productive of purulent sputum, dyspnea, and fever• The entirely nonspecific manifestations of pulmonary involvement help to explain why it is often not diagnosed until autopsy• A typical case would be a patient with faradvanced cancer developing a terminal mixed pneumonia with bacteria and Candida
Chest roentgenograms of pulmonary candidiasispatchy or lobar infiltrates
Diagnosis and Treatment• Presumptive diagnosis made if budding yeast cells and pseudohyphae are found; germ tube• Growth on selective, differential media differentiates Candida species• Topical antifungals for superficial infections, amphotericin B and fluconazole for systemics 7
Cryptococcosis and Cryptococcus neoformans• Cryptococcus neoformans causes cryptococcosis.• A widespread encapsulated yeast that inhabits soil around pigeon roosts• Common infection of AIDS, cancer or diabetes patients• Infection of lungs leads to cough, fever, and lung nodules• Dissemination to meninges and brain can cause severe neurological disturbance and death. 8
Diagnosis and Treatment• Negative stain demonstrating encapsulated budding yeast• Biochemical tests, serological testing• Systemic infection requires amphotericin B and fluconazole. 9
Pneumocystis (carinii) jiroveci and Pneumocystis Pneumonia• A small, unicellular fungus that causes pneumonia (PCP), the most prominent opportunistic infection in AIDS patients• This pneumonia forms secretions in the lungs that block breathing and can be rapidly fatal if not controlled with medication.• Pentamidine and cotrimoxazole 10
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.
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).
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.
Aspergilloma• Tuberculosis is the most frequently associated condition.• Aspergilloma with history of tuberculosis. May show multiple irregular fungus balls virtually filling the pulmonary cavity
AspergillomaRadiography• 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.
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.
AspergillomaMobile 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.
• 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.)
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.
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.
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.
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.
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.
Allergic Bronchopulmonary AspergillosisRadiologic 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.
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.
Allergic Bronchopulmonary Aspergillosis Diagnostic criteria• Asthma.• Immediate skin reactivity to Aspergillus.• Serum precipitins to A fumigatus.• Total serum IgE >1.000 ng/ml• Current or previous pulmonary infiltrates.• Central Bronchiectasis.• Peripheral Eosinophilia.
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.
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.
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.
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.
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.
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.
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
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.
Invasive Pulmonary Aspergillosis (IPA) Major risk factors.• Prolonged neutropenia >3 wks or neutrophil dysfunction.• Corticosteroid therapy (prolonged, high dose).• Transplantation (Lung and BM )• Hematologic malignancy( leukemia)• Cytotoxic therapy.• AIDS.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 .
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, 2–3 weeks after initiation of treatment and concomitant with resolution of the neutropenia).
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.
Invasive Pulmonary Aspergillosis (IPA) Treatment• Start empiric therapy, 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%.
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.
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.
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.
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.