How do you identify and manage fungal infections?

Identification and Management of Fungal Infections

The highest level of evidence for invasive fungal disease should be obtained through histological and/or cultural evidence from tissue biopsies or positive cultures from normally sterile body fluids before initiating systemic antifungal therapy, though treatment decisions in immunocompromised hosts often must be based on clinical criteria combined with imaging and non-culture diagnostic methods. 1

Identification of Fungal Infections

Clinical Recognition

Most signs and symptoms of invasive fungal disease are non-specific and require further diagnostic procedures. 1 Key clinical presentations include:

• Unexplained fever despite broad-spectrum antibiotics or recurring febrile episodes after initial defervescence during antibiotic treatment 1
• Pulmonary manifestations: cough, pleural pain, hemoptysis, or pulmonary infiltrates developing during antibiotic therapy 1
• Sinusitis with local necrotic lesions during prolonged granulocytopenia suggests mould infection 1
• Esophageal symptoms: dysphagia and retrosternal burning (though these cannot distinguish fungal from viral or chemotherapy-related causes) 1
• Hepatosplenic manifestations: persistent fever, hepatosplenomegaly, increased alkaline phosphatase typically developing after neutrophil recovery 1
• Skin infiltrations during pancytopenia that may be misinterpreted as thrombocytopenic purpura 1

Diagnostic Procedures

Microscopy and Histopathology

Tissue samples from patients with suspected invasive fungal disease should be examined by both microscopy and mycological culture. 1 Specific staining techniques are critical:

• Bronchoscopic material or tissue biopsies should be examined with periodic acid-Schiff, Grocott's methenamine silver, or optical brighteners (e.g., calcofluor white) 1
• Gram or hematoxylin-eosin stains are inadequate as fungal elements may be misinterpreted as artifacts 1
• For Cryptococcus neoformans in CSF, use India ink preparation or mucicarmine stain in addition to antigen testing 1

Tissue and fluid specimens should be submitted in adequate quantities for simultaneous histopathologic/cytologic and culture examination. 1 This is essential because histopathology alone has suboptimal diagnostic accuracy, yet culture yield is often low. 1

Culture Methods

A definite diagnosis of proven invasive fungal disease requires histological and/or cultural evidence from tissue biopsies or resection material or positive cultures from normally sterile body fluids. 1 Important considerations:

• Blood cultures should be obtained before initiating antifungal therapy 1
• Diagnosis of invasive fungal GI infections should be confirmed through appropriate cultures of infected fluid from the peritoneal cavity or affected GI tissues 2
• Direct visualization through endoscopy with biopsy for histopathology and culture is essential for definitive diagnosis of GI fungal infections 2
• Cultures should be incubated for at least 5 days (up to 3 weeks for some pathogens) 1

Non-Culture Diagnostic Methods

Antigen Detection:

• Cryptococcal antigen detection in blood and/or CSF is highly indicative (>95%) of cryptococcal meningitis 1
• Galactomannan ELISA (Platelia® Aspergillus) testing should be performed at least twice weekly in high-risk granulocytopenic patients 1
• Candida mannan antigen testing (Platelia® Candida) may be more sensitive than latex agglutination but requires validation in granulocytopenic patients 1
• 1,3-β-D-glucan testing can support diagnosis but is not specific for individual fungal species 1

Molecular Methods:

• Molecular diagnostic tools display high sensitivity and specificity but are neither standardized nor widely available, so they are not yet mandatory in recommendations 1
• Molecular assays targeting ribosomal DNA sequences can be used for detection in tissues, though not FDA-cleared for clinical use 1
• PCR should be used in combination with other non-cultural tests such as antigen detection 1

Vaginal Candidiasis Specific:

• Direct microscopy of vaginal secretions to visualize yeast cells and pseudohyphae, plus culture on fungal selective media for species identification 3
• Commercial biochemical tests for yeast identification 3
• Species identification and susceptibility testing in recurrent/complicated cases 3

Imaging Procedures

High-Resolution CT and MRI:

• In patients with granulocytopenia, HRCT should be preferred to chest X-rays for primary diagnosis in high-risk patients 1
• The "halo sign" is highly suggestive (though not specific) as an early sign for invasive pulmonary mould infection in granulocytopenic patients 1
• Fungal infections in liver, spleen, and gastrointestinal tract are best visualized by CT and particularly by MRI scanning 1
• MRI should be preferred over CT for imaging studies in fungal diseases of CNS, sinuses, and eyes 1

Endoscopic Methods

• Bronchoscopy with BAL may be useful for work-up of pulmonary infiltrates 1
• Esophagogastroduodenoscopy (preferably with biopsy) should be carried out in patients with signs and symptoms of esophagitis not responding to preemptive antifungal therapy 1

Biopsy

If clinically feasible, biopsy specimens should be taken from suspected areas (skin, organ lesions). 1 This provides the highest level of diagnostic certainty.

Diagnostic Algorithm for High-Risk Patients

Baseline Screening (Before Granulocytopenia):

• Screening abdominal ultrasound and chest X-ray 1
• Physical examination to check for pre-existing fungal manifestations 1

During Granulocytopenia:

• Daily physical examination 1
• Aspergillus galactomannan antigen testing and/or PCR at least twice weekly 1
• If persistent fever beyond 48-72 hours despite antibiotics: repeat blood cultures, weekly abdominal ultrasound, chest X-ray or CT if pulmonary symptoms 1
• Bronchoscopy with BAL in patients with pulmonary signs and symptoms 1

After Granulocytopenia:

• Repeat diagnostic procedures if fever recurs 1

Management of Fungal Infections

Invasive Aspergillosis

Voriconazole is indicated for treatment of invasive aspergillosis in adults and pediatric patients (aged 12-14 years weighing ≥50 kg and those aged ≥15 years). 4 Dosing regimen:

• Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours 4
• Maintenance dose: 4 mg/kg IV every 12 hours 4
• Oral maintenance: 200 mg every 12 hours (similar to 3 mg/kg IV); may increase to 300 mg every 12 hours if response inadequate 4
• Administer oral voriconazole at least one hour before or after a meal 4
• Therapy must be initiated with IV loading dose on Day 1, followed by maintenance regimen 4
• IV treatment should continue for at least 7 days before switching to oral formulation 4

Candidemia and Deep Tissue Candida Infections

Echinocandins are the preferred initial treatment for intra-abdominal candidiasis, particularly in critically ill patients (Caspofungin, Micafungin, Anidulafungin). 2

Voriconazole dosing for candidemia in non-neutropenic patients:

• Loading dose: 6 mg/kg IV every 12 hours for first 24 hours 4
• Maintenance: 3-4 mg/kg IV every 12 hours (dose based on severity) 4
• Oral: 200 mg every 12 hours 4
• Patients should be treated for at least 14 days following resolution of symptoms or last positive culture, whichever is longer 4

Alternative options:

• Fluconazole 400 mg (6 mg/kg) daily may be used if patient has no recent azole exposure and is not colonized with azole-resistant Candida species 2
• Lipid formulation of Amphotericin B (3-5 mg/kg daily) can be considered if intolerance to other antifungal agents, though carries higher toxicity risk 2

Step-down therapy:

• After clinical improvement and culture results showing susceptible Candida species, consider step-down to oral fluconazole 400-800 mg daily 2
• This transition should only occur after significant clinical improvement and hemodynamic stability 2

Esophageal Candidiasis

Voriconazole dosing:

• Oral: 200 mg every 12 hours 4
• Patients should be treated for minimum of 14 days and for at least 7 days following resolution of symptoms 4

Scedosporiosis and Fusariosis

Voriconazole is indicated for serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. in patients intolerant of or refractory to other therapy. 4

• Loading dose: 6 mg/kg IV every 12 hours for first 24 hours 4
• Maintenance: 4 mg/kg IV every 12 hours 4
• Oral: 200 mg every 12 hours 4

Source Control and Surgical Management

Source control with appropriate drainage and/or debridement is essential for successful treatment. 2 Key principles:

• Inadequate source control is associated with treatment failure regardless of appropriate antifungal therapy 2
• Surgical intervention may be necessary for necrotic tissue removal or drainage of abscesses 2
• Fungal peritonitis requires drainage of infected fluid along with systemic antifungal therapy 2

Special Considerations

Septic Shock:

• Requires immediate echinocandin therapy along with aggressive fluid resuscitation and vasopressor support 2

Treatment Duration:

• Treatment should continue for at least 2-3 weeks after resolution of symptoms and clearance of infection 2
• Follow-up cultures should be obtained to ensure clearance 2

Nutritional Support:

• Patients with fungal GI infections often require nutritional support due to malabsorption and metabolic derangements 2
• Parenteral nutrition may be necessary if GI tract cannot be used 2

Critical Pitfalls to Avoid

• Delaying antifungal therapy in suspected invasive fungal infections significantly increases mortality 2
• Using fluconazole empirically in critically ill patients without knowing Candida species susceptibility can lead to treatment failure 2
• Premature discontinuation of therapy before complete resolution of infection 2
• Failure to consider fungal infection in patients with persistent symptoms despite antibacterial therapy 2
• Relying solely on clinical symptoms for diagnosis without obtaining appropriate cultures and histopathology 1
• Misinterpreting fungal elements as artifacts when using inadequate staining methods 1
• Not obtaining adequate specimen quantities for both histopathology and culture 1