COVID-19 associated invasive aspergillosis (CAPA)

Diagnostic challenges in

COVID-19 associated invasive aspergillosis

(CAPA)

Mohammad T. Hedayati Professor of medical mycology

Invasive Fungi Research Center/ Department of Medical Mycology,

Mazandaran University of Medical Sciences, Sari, Iran

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Invasive aspergillosis

Beautiful wicked

Low risk Intermediate risk High risk

Autologous HSCT Acute lymphoblastic leukaemia Acute myeloid leukaemia

Hodgkin’s lymphoma Chronic lymphocytic leukaemia Allogeneic HSCT

Chronic myeloproliferative disorders (CML, Ph- diseases)

Non-Hodgkin's lymphoma Heart, lung, liver transplantation

Solid cancer COPD CGD

Myeloma AIDS Severe influenza Kidney transplantation Myelodysplastic syndromes COVID-19 Chronic immunological disease

Systemic lupus erythematosus

Classification of risk for IFD

Similar to those identified for influenza-

IPA superinfections

The most important risk factors include

Severe lung damage during the course of

COVID-19

Using corticosteroids in those with ARDS

Risk factors predisposing for CAPA

Widespread use of broad-spectrum antibiotics in

ICU

Presence of comorbidities such as structural lung

defects

Underlying medical conditions - hypertension diabetes

- obesity COPD

- heart diseases asthma

Cont. (Risk factors predisposing for CAPA)

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Diagnostic approaches

Diagnostic algorithms

Lack of a consensus on a diagnostic algorithms in

COVID-19

Revised (EORTC/MSG-2020)

AspICU algorithm (Blot et al)

Recently proposed diagnostic algorithms for

CAPA (Koehler et al)

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-Host factors

and

-Clinical criteria

-Host factors and

-Clinical criteria

and

-Mycological criteria

-Histopathology, Cytology or

-Culture on normal sterile areas

and

-clinical and radiological

The Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and

Research Consortium (EORTC/MSG-2020)- IFI

Diagnosis Outcome

Possible

Probable Proven

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Criteria for

Probable IFI

Criteria for

Probable IFI

CSF: ≥1.0

Early diagnosis

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Lancet Infect Dis 2021;21: e149–62

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A single positive aspergillus PCR in plasma, serum, or whole

blood, and a single positive in BAL fluid (any threshold cycle

permitted)

Mycological evidences

At least one of the following

Microscopic detection of fungal

elements in BAL, indicating a mold Positive BAL culture

Serum GM index >0・5 or

serum LFA index >0・5

BAL GM index ≥1・0 or

BAL LFA index ≥1・0

Two or more positive aspergillus

PCR tests in plasma, serum, or

whole blood

A single positive

aspergillus PCR in BAL

fluid (<36 cycles)

Probable IA

Or

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Criteria for

Possible CAPA

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Non-bronchoscopic lavage GM index >1・2 plus

another non-bronchoscopic lavage mycology test

positive (non-bronchoscopic lavage PCR or LFA)

Microscopic detection of fungal

elements in non-bronchoscopic

lavage indicating a mold

Positive non-

bronchoscopic lavage

culture

Single non-bronchoscopic

lavage GM index >4・5 Non-bronchoscopic lavage GM

index >1・2 twice or more

Possible IA

Or

Mycological evidences

At least one of the following

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Microscopic Culture GM

detection

non-

bronchoscopic

lavage

BAL or

Blood

Probable CAPA Possible CAPA

Biopsied

materials

Histopat

hology Culture PCR

GM

detec

tion

Cultu

re

Micro

scopi

c

PCR

Proven CAPA

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In case of patients with COPD or chronic

respiratory disease, the PCR or culture results

should be confirmed by galactomannan testing

to rule out colonization or chronic aspergillosis.

Classification of possible CAPA will most

likely be sufficient to initiate antifungal

therapy in the clinic

BAL and non-bronchoscopic lavage are

currently not considered equal for diagnosing

CAPA.

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Lateral-flow Device Test

An immunochromatographic assay The JF5 Ag and monoclonal Ab (JF5) (extracellular glycoprotein antigen from Aspergillus spp., only secreted during active growth) Highly specific for Aspergillus species No cross-reactivity (Only cross-reactions with Penicillium spp.)

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(1,3)-β-D- Glucan assay (BDG) Cell wall polysaccharide in the of most pathogenic fungi, such as Aspergillus, Candida, Fusarium, Acremonium, Penicillium, Paecilomyces, and Pneumocystis jirovecii, - - Important exception of Mucorales and Cryptococcus spp?!. was not considered to provide mycological evidence for IA Facilitation of early diagnosis Useful for patients receiving antifungal prophylaxis Approved for use in serum only

For Candidiasis and Pneumocystosis: (Fungitell) ≥80 ng/L

(pg/mL) detected in at least 2 consecutive serum samples provided

that other etiologies have been excluded

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a water-soluble cell-wall polysaccharide

released by the growing hyphae

detectable in body fluids

detectable a median of 5 to 8 days (range 1 to 27 days) before clinical signs

positive results 10±4 days before culture methodologies

correlate with fungal tissue burden

Various assays, Platelia™Aspergillus EIA (Bio- Rad, France)

surrogate marker to follow the efficacy of treatment

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Mehmet Ergün et al. Aspergillus test profiles and mortality in critically-ill COVID-19 patients. J Clin Microbiol. 2021 Sep 8;JCM0122921.

•.

Methods A multinational case-control study, in which Aspergillus test results, use of antifungal therapy and

mortality were collected from critically-ill COVID-19 patients. Patients were classified using the 2020

ECMM/ISHAM consensus case definitions. Results 219 critically-ill COVID-19 cases were analyzed,

including one proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus colonized patients, seven

patients only positive for serum (1, 3)-ß-D-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality

was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (p=0.001). Positive serum

galactomannan (GM) and BDG were associated with increased mortality compared

to serum biomarker negative CAPA patients (87.5% versus 41.7%, p=0.046; 90.0% versus

42.1%, p=0.029, respectively). For each point increase in GM or ten-point BDG serum concentration, the

odds of death increased (GM, OR 10.208, 95%CI 1.621-64.291, p=0.013; BDG, OR 1.247, 95%CI 1.029-

1.511, p=0.024). Conclusions CAPA is a complex disease, probably involving a continuum of respiratory

colonization, tissue-invasion and angioinvasion. Serum biomarkers are useful for staging CAPA disease

progression and, if positive, indicate angioinvasion and a high probability of mortality.

There is need for a biomarker that distinguishes between respiratory tract colonization and tissue invasive

CAPA disease.

Take Home Message

None of the currently available diagnostic tests provides sufficient sensitivity and specificity alone

The hallmark of IFI diagnosis: - a combination of various testing

strategies

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