01Approach to the Critical Patient/attcp54

Immediate priorities

›Airway and breathing threats

›Respiratory failure from pulmonary aspergillosis

›SpO2 < 90% on supplemental oxygen

›Rapidly escalating oxygen requirement

›Massive hemoptysis risk

›Angioinvasion causing vessel erosion

›Airway protection priority

›If hemoptysis with airway compromise, immediate intubation and IR consult

›Lateral decubitus positioning with bleeding lung down

›Bronchial artery embolization consideration

›Circulation threats

›Septic shock from disseminated disease

›MAP < 65 mmHg

›Lactate >= 2 mmol/l

›Pericardial tamponade from direct extension

›Muffled heart sounds, JVD, pulsus paradoxus

›Electrical alternans on ECG

›If septic shock, broad spectrum antifungal within 1 hour of recognition

›Do not await culture or biomarker confirmation

›Class I recommendation level

Monitoring and targets

›Monitoring bundle

›Continuous pulse oximetry

›SpO2 target 92 to 96%

›Trend for progressive decline

›Cardiac monitor

›QTc baseline before azole initiation

02History/hx62

Presentation pattern

›Classic symptoms

›Persistent fever refractory to broad spectrum antibiotics

›Duration > 96 hours in neutropenic patient

›Absence of response as key diagnostic clue

›Cough

›Dry or minimally productive

›Hemoptysis suggests angioinvasion

›Dyspnea

›Exertional limitation early

›Resting dyspnea with advancing disease

›Pleuritic chest pain

›Indicates pulmonary infarction from vascular invasion

›Effusion association

›Sinus and CNS symptoms

›Facial pain or swelling

›Nasal congestion and epistaxis

›Cacosmia suggests necrosis

›Neurologic symptoms

›Headache

›Seizures or focal deficits indicate CNS dissemination

Risk factors

›Classical high-risk host factors

›Prolonged neutropenia

›ANC < 500 for > 10 days

›Post-chemotherapy nadir

›Allogeneic HSCT

›Especially with active GVHD requiring immunosuppression

03Physical Exam/exam56

Vitals and general

›Stability snapshot

›Fever

›May be absent in profoundly immunosuppressed patients

›Hypothermia as severe sepsis marker

›Respiratory rate and SpO2

›Tachypnea and hypoxia indicate pulmonary involvement

›Trending deterioration rate

›Blood pressure

›Hypotension suggests sepsis or pericardial tamponade

›Pulsus paradoxus for pericardial assessment

›General appearance

›Work of breathing

›Accessory muscle use

›Inability to speak full sentences

›Mental status

›Agitation or somnolence from hypoxemia

›Focal deficits from CNS involvement

Focused organ examination

›Pulmonary exam

›Crackles and decreased breath sounds

›Focal or diffuse distribution

›Pleural rub suggests infarction

›Upper airway inspection

›Nasal mucosal pallor or necrosis

›Septal perforation

›Palatal ischemia or eschar

›Skin exam

04Differential Diagnosis/ddx48

Life-threatening differentials

›Other invasive mold infections

›Mucormycosis

›ICD-10 B46

›Sinus with black eschar, palatal necrosis

›Voriconazole NOT active — critical distinction requiring liposomal amphotericin B

›Fusarium or Scedosporium

›May have positive blood cultures unlike Aspergillus

›Require different antifungal coverage

›Bacterial pneumonia and sepsis

›Community-acquired pneumonia

›ICD-10 J18.9

›Responds to antibiotics within 48 to 72 hours

›Gram-negative bacteremia in neutropenic host

›ICD-10 A41.5

›Blood cultures typically positive

›Pneumocystis jirovecii pneumonia

›ICD-10 B59

›Bilateral ground-glass opacities on CT

›BDG positive, galactomannan negative

›Typical in HIV-AIDS or prolonged corticosteroid use

›CD4 count typically < 200

Pulmonary mimics

›Pulmonary embolism with infarction

›ICD-10 I26.9

›Pleuritic pain and hemoptysis

›CT pulmonary angiography distinguishes

›Hampton hump on imaging

05Laboratory Tests/lt69

Biomarkers for invasive fungal infection

›Serum galactomannan

›Sensitivity approximately 82%, specificity approximately 81% in hematologic malignancy and HSCT populations

›Less sensitive in SOT and non-neutropenic patients

›Optical density index >= 0.5 is positive

›False positives

›Piperacillin-tazobactam administration

›Cross-reactivity with other molds

›Serial testing twice weekly recommended in high-risk patients

›Rising titers indicate treatment failure or dissemination

›Declining titers suggest treatment response

›BAL galactomannan

›Higher sensitivity approximately 85.5% versus serum GM

›Preferred diagnostic modality when bronchoscopy performed

›Threshold OD >= 1.0 sometimes used for non-neutropenic patients

›Combined with BAL culture, PCR, and cytology for maximum yield

›BAL culture sensitivity 30 to 60%

›GMS stain and calcofluor white for morphology

›Beta-D-glucan

›Pan-fungal biomarker

›Positive in aspergillosis, candidiasis, PJP

›Not specific to Aspergillus

›Threshold >= 80 pg/mL considered positive

›False positives from cellulose-containing filters, albumin, IVIG

›Negative result useful to reduce probability of invasive fungal infection

›Aspergillus-specific PCR

›Blood or BAL sample

›Sensitivity 84%, specificity 76% for blood samples per Cochrane review

06Diagnostic Tests/dt92

Scoring Systems

›EORTC/MSG diagnostic criteria

›Classification of proven, probable, and possible IA

›Proven: histopathologic evidence of hyphal invasion

›Probable: host factors + clinical features + mycological evidence

›Possible: host factors + clinical features without mycological confirmation

›Clinical utility

›Guides intensity of diagnostic workup

›Informs treatment initiation threshold

›Used for research and clinical trials

›AspICU algorithm for ICU patients

›Designed for critically ill non-neutropenic patients

›Classifies colonization versus putative invasive pulmonary aspergillosis

›Does not require EORTC host factor criteria

›Criteria include

›Positive culture or GM from respiratory sample

›Chest imaging consistent with aspergillosis

›At least one host factor or clinical deterioration

›Global Comparative Aspergillosis study prognostic factors

›Independent mortality predictors

›CNS involvement

›Disseminated disease to >= 2 organs

›Failure to reduce immunosuppression

›Overall 1-year mortality approximately 32%

›HSCT attributable mortality up to 72%

›ICU patients mortality approximately 55%

MRI

›MRI brain for CNS aspergillosis

›Indications

›New neurologic symptoms in any IA patient

›Headache, seizures, or focal deficits

›Findings

›Ring-enhancing abscesses with restricted diffusion

›Hemorrhagic infarction from vessel invasion

›Meningeal enhancement with meningitis pattern

›Superiority over CT for early CNS lesions

›Higher sensitivity for small lesions

›Better characterization of lesion borders

›MRI sinus and orbit

›Extent of sinonasal disease

›Orbital invasion assessment

›Intracranial extension evaluation

›Soft tissue detail superior to CT

›Perineural spread identification

›Cavernous sinus involvement

CT

›CT chest for pulmonary aspergillosis

›Indications

›First-line imaging for suspected pulmonary IA in high-risk host

›Sensitivity superior to plain radiograph for early detection

›Classic CT findings

›Halo sign

›Ground-glass opacity surrounding a nodule

›Represents hemorrhagic infarction

›Early finding, seen in angioinvasive disease

›Air crescent sign

›Crescent of air within a cavitating nodule

›Later finding with neutrophil recovery

›Nodules, wedge consolidation, and cavitation

›Less specific findings

›Tree-in-bud pattern in airway-invasive disease

›Miliary nodules in disseminated disease

›Limitations

›Halo sign not specific to aspergillosis

›Early disease may appear normal

›Lesions may paradoxically enlarge with immune reconstitution

›Serial CT at 2 to 4 weeks to assess treatment response

›Radiographic improvement lags clinical improvement

›IDSA 2016 guideline recommendation

›CT sinuses

›Indications

›Facial pain, swelling, or nasal symptoms

›Mucosal thickening and opacification

›Findings suggestive of invasive disease

›Bone erosion or destruction

›Extension to orbit or intracranially

›Fat stranding in periorbital region

Ultrasound

›POCUS cardiac assessment

›Pericardial effusion identification

›Tamponade physiology

›Right ventricular diastolic collapse

›Endocarditis vegetation detection

›Aspergillus endocarditis requires formal echocardiography

›Transoesophageal echocardiography preferred for valve detail

›Lung ultrasound

›Pleural effusion identification

›Complex or septated fluid suggests empyema

›Ultrasound-guided thoracentesis planning

›Consolidation pattern

›Tissue-like echotexture with air bronchograms

›Limited utility for nodules compared to CT

›Abdominal ultrasound

›Hepatic and splenic involvement in disseminated disease

›Hypoechoic lesions suggesting fungal abscesses

›Follow-up imaging to assess response

07Disposition/dispo33

Admission indications

›Virtually all suspected or confirmed cases require inpatient admission

›Immunocompromised host with probable IA

›Expedited workup including bronchoscopy

›IV antifungal therapy initiation

›Confirmed IA at any site

›Minimum ward admission with ID consultation

›Oral step-down only after clinical stabilization

›ICU indications

›Respiratory failure

›Mechanical ventilation requirement

›HFNC with escalating FiO2

›Hemodynamic instability

›Vasopressor requirement

›Septic shock physiology

›Life-threatening complications

›Massive hemoptysis

›CNS involvement with deteriorating GCS

›Pericardial tamponade

Transfer and specialist criteria

›Transfer indications

›Lack of appropriate antifungal expertise or ID consultation

›Transfer to tertiary centre with transplant or hematology program

›Telemedicine ID consultation as alternative

›Surgical intervention required

›Sinus debridement

›CNS lesion resection

›Cardiac surgery for endocarditis

08Treatment/t103

Antifungal therapy — first-line

›Voriconazole

›Preferred first-line based on IDSA 2016 and ATS 2024 guidelines

›Class I recommendation

›Superior survival versus amphotericin B in landmark trial

›Dosing

›Loading dose 6 mg/kg IV every 12 hours for 2 doses on Day 1

›Maintenance 4 mg/kg IV every 12 hours

›Oral step-down 200 mg every 12 hours for weight >= 40 kg

›Therapeutic drug monitoring

›Trough at Day 5 to 7, then with dose changes

›Target trough 1 to 5.5 mcg/mL

›Adjust dose based on level and hepatic function

›Key adverse effects

›QTc prolongation

›Visual disturbances including photopsia (usually transient)

›Photosensitivity and long-term risk of cutaneous squamous cell carcinoma

›Hepatotoxicity requiring LFT monitoring

›Isavuconazole

›Noninferior to voriconazole with fewer adverse effects

›ATS 2024 and IDSA 2016 list as alternative first-line

›No QTc prolongation — causes QTc shortening instead

›Dosing

›Loading 200 mg IV or PO every 8 hours for 6 doses

›Maintenance 200 mg IV or PO daily

›Advantages over voriconazole

›No photosensitivity

›No visual disturbances

›Less drug interaction burden

›TDM not routinely required

Antifungal therapy — alternatives

›Liposomal amphotericin B

›Indicated when azole-resistant Aspergillus suspected or confirmed

›Or when azoles contraindicated

›Or when prior azole failure

›Dosing

›3 to 5 mg/kg IV daily

›Pre-hydration with normal saline to reduce nephrotoxicity

›Monitoring

›Daily creatinine, electrolytes

›Potassium and magnesium replacement

›Amphotericin B deoxycholate avoided due to severe nephrotoxicity

›Posaconazole

›Noninferior to voriconazole in phase 3 trial

›ATS 2024 conditionally recommends as alternative first-line

›Preferred tablet or IV formulation over oral suspension

›Dosing

›300 mg IV or PO twice daily on Day 1

›Then 300 mg daily

›Oral suspension requires administration with full meal or acidic beverage

›Trough target > 1 mcg/mL for treatment

Combination antifungal therapy

›Voriconazole plus echinocandin

›ATS 2024 conditionally suggests combination over monotherapy for primary treatment

›Evidence remains low certainty

›Consider in severe or critically ill patients

›Anidulafungin or caspofungin added to voriconazole

›Anidulafungin 200 mg IV loading then 100 mg daily

›Caspofungin 70 mg IV loading then 50 mg daily

›Echinocandins must NOT be used as monotherapy for IA

›Active as adjunct or salvage only

›Combination rationale

›Synergistic activity on fungal cell wall and membrane

›Beta-glucan synthase inhibition by echinocandin

›CYP51 inhibition by azole

›Particularly considered when

›Severe disease at presentation

›Disseminated disease

›Failure to reduce immunosuppression

Salvage therapy

›Options for refractory or intolerant disease

›Amphotericin B lipid complex

›5 mg/kg IV daily

›Alternative lipid formulation when liposomal not available

›Caspofungin monotherapy as salvage only

›70 mg IV loading dose then 50 mg IV daily

›Not first-line

›Micafungin as salvage

›100 to 150 mg IV daily

›Itraconazole

›Older agent, variable bioavailability

›Inferior to voriconazole for primary therapy

Treatment duration and adjuncts

›Duration of therapy

›Minimum 6 to 12 weeks for pulmonary disease

›Guided by clinical and radiographic response

›Longer courses often needed in persistently immunosuppressed patients

›Continue until resolution of immunosuppression and radiographic improvement

›Secondary prophylaxis if re-immunosuppression anticipated

›Immunosuppression reduction

›Single most important adjunctive measure

›Decrease corticosteroid dose when feasible

›Hold immunosuppressive agents if clinically permissible

›Growth factor support

›G-CSF or GM-CSF to shorten neutropenia duration

›Granulocyte transfusions in refractory cases with limited evidence

›Surgical intervention

›Sinus aspergillosis

›Surgical debridement when tissue necrosis present

›Otolaryngology consultation

›CNS aspergillosis

›Resection of accessible abscesses

›Drainage for obstructive hydrocephalus

›Endocarditis

›Valve replacement typically required

›High surgical mortality in immunocompromised patients

›Localized pulmonary lesion threatening vital structures

›Resection consideration in stable patient

09Special Populations/sp48

Pregnancy

›Pregnancy-specific considerations

›IA is rare in pregnancy

›Corticosteroid use, immunosuppressive therapy, and hematologic malignancy are predisposing factors

›Profound immunosuppression required for IA to develop

›Antifungal safety

›Voriconazole and posaconazole are teratogenic — avoid in pregnancy

›Liposomal amphotericin B is the preferred antifungal in pregnancy

›Echinocandins: limited human data, use only if alternatives not appropriate

›Imaging considerations

›CT chest with abdominal shielding when benefit outweighs risk

›MRI preferred for CNS evaluation without ionizing radiation

›Maternal oxygenation targets

›SpO2 >= 95% to optimise fetal oxygenation

›Fetal monitoring when viable gestation with maternal instability

Geriatric

›Older adult features

›Presentation differences

›Atypical or blunted fever response

›Delirium as primary presenting symptom

›Greater baseline organ impairment

›Drug metabolism changes

›Reduced hepatic and renal clearance

›Voriconazole levels higher and more variable in older adults

›Closer TDM required

›Drug toxicity risk

›QTc prolongation risk greater with polypharmacy

›Isavuconazole preferred in patients with QTc concerns

10Background/b84

Epidemiology

›Incidence and burden

›A. fumigatus is the causative species in approximately 70 to 80% of cases

›A. flavus, A. niger, A. terreus account for remainder

›A. terreus intrinsically resistant to amphotericin B

›Estimated 300,000 cases of IA globally per year

›Overall 1-year all-cause mortality approximately 32%

›Attributable mortality in hematologic malignancy approximately 42%

›Attributable mortality in HSCT recipients up to 72%

›Untreated patients: median survival only 20 days versus 130 days with voriconazole or posaconazole

›90-day all-cause mortality in contemporary cohorts approximately 46%

›Population distribution

›Hematologic malignancy and HSCT remain highest-risk groups

›AML and MDS predominate

›Allogeneic HSCT with GVHD treatment highest risk

›Emerging non-neutropenic populations

›COVID-19-associated pulmonary aspergillosis

›Influenza-associated pulmonary aspergillosis

›ICU patients with ARDS and prolonged mechanical ventilation

›Azole resistance trends

›Rising environmental azole resistance globally

›TR34/L98H cyp51A mutation most common

›Agricultural fungicide exposure driving resistance in environment

›Prevalence varies by region

›Netherlands and parts of Europe: up to 20% of clinical isolates resistant

›North America: lower but rising prevalence

Pathophysiology

›Infection mechanism

›Aspergillus spores (conidia) inhaled from environment

›Ubiquitous in soil, decaying vegetation, hospital construction sites

›Immunocompetent host clears conidia via mucociliary clearance and phagocytosis

›In immunosuppressed host

›Impaired neutrophil and macrophage function allows germination

›Hyphae invade pulmonary tissue and blood vessels

›Angioinvasion causes thrombosis and infarction

›Forms of invasive disease

›Angioinvasive pulmonary aspergillosis

›Halo sign on CT from hemorrhagic infarction

›Hemoptysis from vessel erosion

›Hematogenous dissemination risk

›Airway-invasive aspergillosis

›Tracheobronchitis and bronchopneumonia pattern

›Tree-in-bud pattern on CT

›More common in lung transplant recipients

›Chronic necrotising aspergillosis

›Indolent destructive infection in mildly immunocompromised hosts

›Cavitation predominates

›Dissemination pathways

›CNS involvement from hematogenous seeding

›Abscesses and hemorrhagic infarction

›Highest mortality among all IA presentations

›Sinus to orbit and intracranial extension

›Contiguous spread from sinonasal disease

›Cavernous sinus thrombosis

Therapeutic Considerations

›Antifungal mechanism principles

›Azoles target ergosterol synthesis via CYP51

›Fungistatic against Aspergillus

›Voriconazole and isavuconazole are mold-active triazoles

›Polyenes bind ergosterol and disrupt cell membrane

›Amphotericin B is fungicidal

›Lipid formulations reduce nephrotoxicity versus deoxycholate

›Echinocandins inhibit beta-1,3-glucan synthase

›Active against cell wall

›Not active as monotherapy but useful in combination

›Drug interaction principles

›All mold-active azoles are potent CYP3A4 inhibitors

›Cyclosporine, tacrolimus, sirolimus levels increase markedly

›Tyrosine kinase inhibitor levels increase

›Anticonvulsants and rifampin reduce azole levels significantly

›Review and adjust all concurrent medications

›ID pharmacy consultation for complex regimens

›Drug level monitoring for immunosuppressants

›Resistance and treatment failure

›Suspected when clinical deterioration on appropriate azole therapy

›Antifungal susceptibility testing indicated

›Switch to liposomal amphotericin B as empiric salvage

›Breakthrough IA definition

›IA developing while on azole prophylaxis or treatment

›Approximately 44% of breakthrough cases have resistant organisms in some series

›Prevention and prophylaxis

›Primary prophylaxis in highest-risk patients

›Posaconazole for AML or MDS with chemotherapy

›Voriconazole or posaconazole for allogeneic HSCT

›Secondary prophylaxis when re-immunosuppression anticipated

›Continue antifungal throughout period of immunosuppression

›Monitor for breakthrough despite prophylaxis

11Patient Discharge Instructions/pdi36

copy discharge instructions

›Invasive aspergillosis home care

›Antifungal medication must be taken exactly as prescribed

›Do not skip doses — subtherapeutic levels cause treatment failure

›Voriconazole or isavuconazole to be taken at same time each day

›Posaconazole oral suspension taken with a full meal or acidic drink

›Tablet or IV formulation preferred if available

›Blood tests are required regularly to check medication levels and liver function

›Do not miss scheduled bloodwork appointments

›Medication side effects to monitor

›Voriconazole: visual changes including seeing flashes of light

›Usually transient and improve over days to weeks

›Avoid driving at night initially

›Voriconazole: skin sensitivity to sunlight

›Use sunscreen and protective clothing outdoors

›Long-term risk of skin cancer with prolonged use — report any new skin lesions

›Any medication: nausea, abdominal pain, or yellowing of eyes or skin

›May indicate liver irritation — contact care team immediately

›Activity and diet

›Avoid construction sites, heavy gardening, and dusty environments

›Airborne fungal spores can worsen or cause new infection

›Avoid grapefruit and other foods that interfere with medication metabolism

›Ask pharmacist or doctor about specific interactions

›Maintain adequate hydration especially if on amphotericin B therapy

›Warning signs to return to the emergency department

›New or worsening coughing up blood

›Severe shortness of breath at rest

›New headache, vision changes, seizures, or confusion

12References/r20

Guidelines and key sources

›Primary clinical guidelines

›Patterson TF et al. IDSA Practice Guidelines for the Diagnosis and Management of Aspergillosis 2016 Update. Clinical Infectious Diseases 2016

›Epelbaum O et al. ATS Clinical Practice Guideline Treatment of Invasive Pulmonary Aspergillosis 2024. American Journal of Respiratory and Critical Care Medicine 2024

›Hage CA et al. ATS Clinical Practice Guideline Microbiological Laboratory Testing for Fungal Infections 2019. American Journal of Respiratory and Critical Care Medicine 2019

›Landmark studies and reviews

›Herbrecht R et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. NEJM 2002

›Segal BH. Aspergillosis review. New England Journal of Medicine 2009

›Thompson GR and Young JH. Aspergillus Infections review. New England Journal of Medicine 2021

›Heylen J et al. Acute Invasive Pulmonary Aspergillosis Clinical Presentation and Treatment. Seminars in Respiratory and Critical Care Medicine 2024

›Systematic reviews and meta-analyses

›de Heer K et al. Galactomannan Detection in BAL for Invasive Aspergillosis. Cochrane Database of Systematic Reviews 2019

›Cruciani M et al. PCR Blood Tests for the Diagnosis of Invasive Aspergillosis. Cochrane Database of Systematic Reviews 2019

›Society guidelines for specific populations

›Dadwal SS et al. ASTCT Management and Prevention of Aspergillosis in HCT Recipients 2021

›Husain S and Camargo JF. AST Invasive Aspergillosis in Solid-Organ Transplant Recipients 2019

›Koehler P et al. ECMM/ISHAM Consensus Criteria COVID-19-associated Pulmonary Aspergillosis 2021

›Coding reference

›ICD-10 B44.1 Other pulmonary aspergillosis

›ICD-10 B44.7 Disseminated aspergillosis

›ICD-10 B44.0 Invasive pulmonary aspergillosis

Evidence & Review