COVID-19 associated pulmonary aspergillosis (CAPA) is associated with excess mortality and requires bronchoscopy and BAL to diagnose. Antifungal therapy is recommended in CAPA, while discontinuation or tapering of concomitant corticosteroid therapy could be considered in patients who do not respond. |
Introduction
1. What is the case definition of COVID-19 associated pulmonary aspergillosis? |
2. What is the optimal approach towards diagnosing or refuting CAPA in patients with COVID-19? |
3. What is the reported prevalence of Aspergillus pneumonia in patients with COVID-19? |
4. What are the host-/risk factors that are associated with COVID-19 associated pulmonary aspergillosis (CAPA)? |
5. Is antifungal therapy indicated in patients suspected of CAPA? |
6. How should invasive Aspergillus tracheobronchitis be managed in CAPA patients? |
7. What is the role of immunomodulating agents in the management of CAPA in ICU patients? |
Methods
Key questions
What is the case definition of COVID-19 associated pulmonary aspergillosis?
Evidence summary
What is the optimal approach towards diagnosing or refuting CAPA in patients with COVID-19?
Recommendations | Strength of recommendation | Quality of evidence |
---|---|---|
A CAPA diagnostic work-up is recommended in mechanically ventilated COVID-19 patients with unexplained respiratory deterioration or a positive Aspergillus culture from the respiratory tract | Strong | Low |
Standard CT imaging is not recommended to refute or diagnose CAPA | Weak | Very low |
Screening of critically ill COVID-19 patients for serum GM or BDG is not recommended | Strong | Low |
Detection of Aspergillus in sputum and tracheal aspirate is considered insufficient evidence to support CAPA diagnosis, but warrants further diagnostics through bronchoscopy and BAL | Strong | Low |
We recommend maximum efforts to perform a bronchoscopy for inspection of the airways and bronchoalveolar lavage (BAL) to diagnose CAPA in patients with proven or high likelihood of COVID-19 in the ICU | Strong | Low |
There is no recommendation against or in favor of using lateral flow devices-based assays for diagnosing CAPA | Weak | Very low |
Evidence summary
Country | # of CAPA cases | BAL (#positive/#performed) | Aspergillus species | TA/BA (#positive/#performed) | Serum (#positive/#performed) | References |
---|---|---|---|---|---|---|
France | 9 | Culture 5/7 GM 2/7 PCR 3/7 | A. fumigatus (7) | Culture 2/2 GM – PCR 2/ 2 | GM 1/9 BDG 4/8 | [15] |
Germany | 5 | Culture 1/3 GM 3/3 PCR 3/3 | A. fumigatus (4) | Culture 2/3 GM ND PCR 1/2 | GM 2/5 BDG – | [16] |
Netherlands | 6 | Culture 2/3 GM 3/3 PCR – | A. fumigatus (5) | Culture 3/3 GM– PCR – | GM 0/3 BDG – | [17] |
Belgium | 6 | Culture 5/6 GM 5/6 PCR – | A. fumigatus (5), A. flavus (1) | Culture – GM– PCR – | GM 1/5 BDG – | [18] |
Italy | 30 | Culture 19/30 GM 30/30 PCR 20 /30 | A. fumigatus (16), A. niger (3), A. flavus (1) | Culture – GM—PCR – | GM 1/30 BDG – | [19] |
UK | 19 | Only NBL performed; Denominator not reported | A. fumigatus (9), A. versicolor (1) | Denominator not reported | Denominator not reported | [20] |
Belgium | 4 | Culture 4/4a GM 4/4 PCR 2/2 | Not specified | GM – BDG - | [21] | |
Switzerland | 3 | Culture – GM– PCR – | A. fumigatus (3) | Culture 3/3 GM – PCR 1/? | GM 1/? BDG 1/? | [22] |
France | 19 | Culture 7/9 GM 7/9 PCR – | A. fumigatus (14), A. calidoustus (1), A. niger (1) | Culture 9/10 GM– PCR – | GM 1/12 BDG – | [23] |
Pakistan | 5 | Not specified | A. fumigatus (1), A. flavus (4), A. niger (1) | Not specified | GM 0/5 BDG 1/5 | [24] |
USA | 4 | Not specified | A. fumigatus (4) | Not specified | GM 1/3 BDG – | [25] |
France | 7 | Culture not specified/5 GM 3/5 PCR 2/5 | A. fumigatus (5) | Not specified | GM 1/7 BDG 2/7 | [26] |
Netherlands | 8 | Culture 7/7 GM 2/6 PCR 4/5 | A. fumigatus (7) | Culture 1/1 GM 1/1 PCR 1/1 | GM 0/1 | [27] |
Netherlands | 11 | Culture 5/40 GM 11/37 PCR 11/40 | A. fumigatus (3) | Culture 3/47 GM not performed PCR 23/30 | GM 0/11 | [28] |
USA | 20 | Culture 2/20 GM 2/20 PCR not specified | Not specified | Not specified | GM 8/20 BDG 6/20 | [29] |
What is the reported prevalence of Aspergillus pneumonia in patients with COVID-19?
Evidence summary
Country | Case definition | CAPA prevalence | Time to first Asp. positive sample after ICU admission in days (range)a | Ventilated | Proven/probable/putative | References |
---|---|---|---|---|---|---|
France | 9/27 (33%) | Not specified | 27/27 | 0/1/8 | [15] | |
Franceb | Modified IAPA [3] and EORTC/MSGERC [7] | 21/366 (5.7%) | 6 (1 -15) | 246/366 | 0/21/0 | [33] |
Germany | 5/19 (26%) | Not specified | 5/5 | 0/–/5 | [16] | |
Netherlands | Modified IAPA [3] | 6/31 (19%) | 10 (3 – 28) | 6/6 | 0/3/3 | [17] |
Belgium | AspICU [8] | 6/34 (21%) | 8 (2 – 16) | 6/6 | 4/–/2 | [18] |
Italy | Modified IAPA [3] | 30/108 (28%) | 4 (2 – 8) daysc (study used screening protocol) | 30/30 | 0/30/– | [19] |
AspICU [8] | 19/108 (18%) | 8 (0 – 35)d | 19/19 | 0/–/19 | ||
UK | AspICU [8] | 8/135 (6%) | 7/8 | 0/–/8 | [20] | |
IAPA [5] | 20/135 (15%) | 15/20 | 0/–/20 | |||
Own definition | 19/135 (14%) | 14/19 | 0/–/19 | |||
Belgium | 4/131 (3%) | 4 | 4/4 | 0/–/4 | [21] | |
Switzerland | Modified IAPA [3] | 3/80 (4%)¥ | 6 (3–8) | 3/3 | 0/1/2 | [22] |
France | 19/106 (18%) | 11 (2–23) | 18/19 | 0/–/19 | [23] | |
France | 7/145 (5%) | 10 (median) | 27/27 | 0/0/7 | [24] | |
Ireland | Not stated | 0/55 | – | Not stated | 0/0/0 | [36] |
Netherlands | 2020 ECMM/ISHAM consensus definitions [10] | 7/33 (21%) | Not specified | Not specified | 0/7/– | [27] |
Netherlands | 2020 ECMM/ISHAM consensus definitions [10] | 11/63 (17%) | 21 (13–27) | 10/11 | 0/11/– | [28] |
USA | 2020 ECMM/ISHAM consensus definitions [10] | 20/396 (5%) | 13 (8.5–28) | 20/20 | 0/20/19e | [29] |
What are the host-/risk factors that are associated with COVID-19 associated pulmonary aspergillosis (CAPA)?
Evidence summary
Is antifungal therapy indicated in patients suspected of CAPA?
Recommendations | Strength of recommendation | Quality of evidence |
---|---|---|
Antifungal therapy is indicated in patients with CAPA | Strong | Low |
We recommend to follow national or international guidelines on antifungal therapy of invasive aspergillosis | Strong | Low |
We recommend to consider empirical therapy for CAPA in patients in who(m) a BAL has been performed and BAL GM/PCR results are pending | Weak | Very low |
In patients with a negative BAL GM, discontinuation of empirical antifungal therapy is recommended | Weak | Very low |
Therapeutic drug monitoring (TDM) is recommended in critically ill CAPA patients receiving triazole therapy | Strong | Low |
Evidence summary
Country | Case definition | # of CAPA patients | Mortality in CAPA | Mortality in controls | References |
---|---|---|---|---|---|
France | 9 | 44% | 39% (p = 0.99) | [15] | |
Francea | 21 | 71.4% | 36.8% (p < 0.01) | [35] | |
Italy | IAPA [5] | 30 | 44% (day 30) | 19% (day 30) (p = 0.002)b | [19] |
AspICU [8] | 19 | 74% | 26% ( p < 0.001) | ||
United Kingdom | 19 | 58% (day 77?) | 38% | [20] | |
Netherlands | 2020 ECMM/ISHAM [10] | 19 | 63.6% | 23.1% ( p = 0.013) | [28] |
USA | 2020 ECMM/ISHAM [10] | 20 | 50% | 41.5% | [29] |
Pharmacokinetic | Clinical manifestation | Recommendations | References |
---|---|---|---|
Critical illness (sepsis, altered fluid balance, altered protein binding/hypo-albuminemia, inflammation) | Voriconazole exposures unpredictable in critically ill patients; both low exposures with poor clinical outcomes and elevated exposures increased CNS toxicity are reported especially in the setting of systemic inflammation (0.015 mg/L increase in voriconazole Cmin for every 1 mg/L increase in C-reactive protein) | TDM to confirm adequate voriconazole drug exposuresa Fewer data in critically ill for isavuconazole but TDM could still be considered | |
Obesity | Increased Vd and CL of posaconazole, decreased serum drug exposures | Voriconazole dose based on adjusted body weight; no adjustment of fixed isavuconazole dose recommended. Posaconazole exposures reduced in obese patients | |
Renal replacement therapy | No effect on voriconazole or isavuconazole pharmacokinetics, sulfobutylether-β-cyclodextrin in IV voriconazole formulation is removed by CRRT at rate similar to ultrafiltration rate | TDM of voriconazole recommended even though voriconazole is not cleared by RRT | |
ECMO | Initial voriconazole doses are extracted into ECMO circuit; once circuit is saturated “redosing” of patient can occur; limited data with isavuconazole suggested exposures may be reduced by 50% | Patients at risk of voriconazole and isavuconazole underdosing at initiation of ECMO, overdosing of voriconazole at discontinuation. Limited data for isavuconazole Routine TDM-guided dosing essential for voriconazole and may be indicated for isavuconazole | |
Drug-interactions | Dexamethasone, methylprednisolone | Limited evidence that corticosteroids reduce voriconazole exposure, TDM-adjusted dosing indicated | [59] |
How should invasive Aspergillus tracheobronchitis be managed in CAPA patients?
Recommendation | Strength of recommendation | Quality of evidence |
---|---|---|
Patients with visible plaques in trachea and bronchi should undergo mucosal biopsy or brush to diagnose IATB | Strong | Low |
Evidence summary
What is the role of immunomodulating agents in the management of CAPA in ICU patients?
Recommendations | Strength of recommendation | Quality of evidence |
---|---|---|
We recommend not to stop concomitant dexamethasone or corticosteroid therapy in CAPA patients | Weak | Very low |
Evidence summary
Pathophysiology of CAPA
Discussion
Epidemiology | Determine the true epidemiology of CAPA Frequency of IATB in CAPA Identification of host/risk factors |
Diagnosis | Markers that discriminate between Aspergillus respiratory tract colonization and tissue invasion Validation of Aspergillus biomarkers in NBL and BA/TA Determine the immune status of the host (e.g. FACS) |
Strategy | Role for antifungal prophylaxis Management of COVID-19 patients with positive upper respiratory tract culture |
Antifungal agents | Benefit of nebulized antifungals in IATB Role of liposomal amphotericin B in the ICU-setting Effect of sequestration and drug interactions of antifungals on exposure (i.e. ECMO; CRRT) |
Therapy | Implications of antiviral and host-directed therapy for CAPA risk and outcome Host directed therapy: dampening or boosting immune response or both, dependent on host immune status |