Fungal Infections Flashcards
what is the Grand Mycological Challenge?
1.5 billion fungal infections of humans
> 3 million life threatening infections/year
Mortality rates typically > 50%
>400,000 cases of blindness per year
Allergens and asthma (>20 million)
we are going to focus on hat 3 fungal pathogens?
Aspergillus species - Aspergillus fumigatus
Candida species - Candida albicans
Cryptococcus species - Cryptococcus neoformans
Fungal pathogens are opportunistic in nature affecting what kind of patients?
Affecting patients with an impaired immune system:
- Patients with primary immunodeficiencies
- Patients with HIV/AIDS
- Patients with malignancies (neutropenia) & transplants
- Premature neonates (immature immune system)
Affecting patients with chronic lung diseases (pulmonary aspergillosis and other moulds):
- Asthma
- Cystic Fibrosis
- Chronic obstructive lung disorders
Affecting patients in ICU settings
Candida and Candidiasis
What is mucocutaneous candidiasis?
Chronic mucocutaneous candidiasis is an immune disorder of T cells, it is characterized by chronic infections with Candida that are limited to mucosal surfaces, skin, and nails
Who, when and where does Mucocutaneous Candidiasis occur in?
Antibiotic use
Moist areas
Inhalation steroids
Neonates < 3 months
Mucocutaneous Candidiasis - Presenting symptom of primary immunodeficiency disorders characterised by what?
Neutropenia
Low CD4+ T-cells
impaired IL-17 immunity:
AD-Hyper IgE syndrome - deficit of IL-17 producing cells
Dectin-1 deficiency - reduced levels of IL-17
CARD9 deficiency - low proportion of circulating IL-17 T-cells
APECED syndrome - high titers of neutralizing Ab against IL-17A, IL-17F and/or IL-22
Invasive Candidiasis cause infection where?
Gut commensal
Infections mostly endogenous of origin
4th most common bloodstream infection (BSI) in adults: 30/100.000 admissions
Premature neonates (< 1000 g): 150/100.000 admissions
What are the effects and risk factors of Invasive Candidiasis?
Clinical presentation as bacterial BSI
Mortality up to 40%
Additional risk-factors:
- Broad-spectrum antibiotics
- Intravascular catheters
- Total parenteral nutrition
- Abdominal surgery
What is the diagnosis of Invasive Candidiasis?
Blood culture or culture from normally sterile site
β-d-glucan high NPV and performs very well to exclude invasive candidiasis
Recent developments in PCR assays very promising
In infants and children performance lower due to sampling issues
Aspergillus and Aspergillosis
how is Aspergillus transmitted?
- sporulation
- hydrophobic conidia (a spore produced asexually by various fungi at the tip of a specialized hypha)
- diameter 2-3 µm
- airborne / inhalation
what are the different classification of pulmonary Aspergillus disease?
Acute invasive pulmonary aspergillosis
- Neutropenic patients (incidence 1-10%)
- Post transplants: stem cell > solid organ (incidence up to 8%)
- Patients with defects in phagocytes
Chronic pulmonary aspergillosis (> 3 months) - Patients with underlying chronic lung conditions
Allergic aspergillosis:
- Allergic bronchopulmonary aspergillosis in CF and asthma (incidence 10-15%)
- Asthma or CF with fungal sensitisation (incidence 5-15%)
what are the effects of Acute Invasive Pulmonary Aspergillosis in a neutropenic host (acute leukaemia, haematopoietic stem cell transplant)?
- Rapid and extensive hyphal growth (fungus growth)
- Thrombosis and hemorrhage
- Angio-invasive and dissemination
- Absent or non-specific clinical signs and symptoms
- Persistent febrile neutropenia despite broad-spectrum antibiotics
- Mortality rates around 50% (but depending on immune recovery)
what ar ethe effects of (Sub) Acute Invasive Pulmonary Aspergillosis in a non-neutropenic host (graft-versus-host disease, neutrophil disorders)?
Non-angioinvasive
Limited fungal growth
Pyogranulomatous infiltrates
Tissue necrosis
Excessive inflammation
Non-specific clinical signs and symptoms
Mild to moderate systemic illness
Mortality 20-50%
WHat are the effects of Chronic Pulmonary Aspergillosis in patients with asthma, cystic fibrosis, chronic obstructive lung disorders?
Pulmonary exacerbations (not responding to antibiotics)
Lung function decline
Increased respiratory symptoms as cough, decreased exercise tolerance and dyspnea
Positive sputum cultures for Aspergillus - 50% of CF patients are infected
High morbidity but causative mortality rates less clear
Allergic Bronchopulmonary Aspergillosis:
immunological responses to a variety of A. fumigatus antigens in the CF-host (10-15%) result in:
Acute/subacute deterioration of lung function and respiratory symptoms
New abnormalities chest imaging
Elevated immunoglobulin E (IgE) level
Increased Aspergillus specific IgE or positive skin-test
Positive Aspergillus specific IgG
what is a Pulmonary Aspergilloma?
Pulmonary aspergilloma is a mass caused by a fungal infection. It usually grows in lung cavities
a Pulmonary Aspergilloma may be seen in who?
Tuberculosis - In 22% if residual cavities
Sarcoidosis
Bronchiectasis
Bronchial cysts and bullae
After pulmonary infections
Diagnosis of Pulmonary Aspergillosis in non-neutropenic patients
- Cultures of sputum and/or bronchoalveolar lavage, and/or biopsy
- Aspergillus specific IgG and IgE in chronic and allergic pulmonary aspergillosis
Diagnosis of Pulmonary Aspergillosis in neutropenic patients
- High resolution CT-chest - ‘halo-sign’ and ‘air-crescent sign’
- Molecular markers in blood: galactomannan and PCR-Aspergillus (high NPV and are suited for screening purposes)
- BAL and biopsies if clinical condition allows (Bronchoalveolar lavage is a diagnostic method of the lower respiratory system in which a bronchoscope is passed through the mouth or nose into an appropriate airway in the lungs, with a measured amount of fluid introduced and then collected for examination)
Cryptococcus and Cryptococcosis
how is Cryptococcus transmitted?
Transmission by inhalation
can be found on the bark of a variety of trees, bird faeces and organic matter
what does Cryptococcus caue?
Pulmonary infection from asymptomatic to pneumonia
Dissemination to brain: meningoencephalitis in HIV/AIDS patients (CD4 < 100 cells/ul)
what is the clinical presentation of Cryptococcus?
headache, confusion, altered behaviour, visual disturbances, coma (due to raised intracranial pressure in 60-80%)
How is the diagnosis of cryptococcal disease made?
Cerebrospinal fluid: Indian Ink preparation (80% sensitivity), culture, high protein and low glucose, Cryptococcus antigen (lateral flow assay)
Blood: culture, Cryptococcus antigen
what is the outcome of cryptococcal meningitis?
Africa: 3-month mortality 70%
US: 3-months mortality 25%
what are some factors associated with mortality in cryptococcal meningitis?
Delay in presentation and diagnosis
Lack of access to antifungals
Inadequate induction therapy
Delays in starting antiretroviral therapy
Immune reconstitution syndrome
what are some antifungal agents to treat invasive fungal infections?
- Amphotericin B formulations (iv) - Acting on ergosterol > lysis
- Azoles (iv, oral) - Inhibiting ergosterol synthesis
- Echinocandins (iv) - Inhibiting glucan synthesis
- Flucytosine (iv, oral) - Inhibiting fungal DNA synthesis
Grand Mycological Challenge - we urgently need better what and what are the current problems?
