Invasive Pulmonary Aspergillosis in Coronavirus Disease 2019 Patients Lights and Shadows in the Current Landscape
Abstract
:Highlights
- A definite diagnosis of invasive pulmonary aspergillosis is elusive in patients with severe COVID-19.
- Experimental and clinical data indicate that delayed initiation of antifungal therapy could be detrimental to IA.
- The persistence of a respiratory co-infection in SARS-CoV-2 patients despite the administration of broad-spectrum antibiotics should lead to the pursuit of the confirmation or exclusion of IPA, especially in those patients who present risk factors for invasive pulmonary aspergillosis.
- Early treatment should be initiated, even in the absence of a definite diagnosis, when clinical suspicion is high.
Abstract
1. Introduction
2. Incidence, Risk Factors and Outcome of IPA in Patients with SARS-CoV-2 Infection
2.1. Incidence
- IPA frequently manifests with nonspecific symptoms and is not routinely suspected;
- Respiratory deterioration is considered to be caused by bacterial co-infection rather than fungal infection;
- Diagnosis of IA, frequently, requires invasive tissue specimens collection;
- Histopathologic identification is challenging;
- Cross-reaction of fungal antibody tests may exist;
- Lack of routine surveillance for IA is common.
2.2. Impact of IPA on Mortality in Patients with SARS-CoV-2 Infection
2.3. Risk Factors for IPA in Patients with SARS-CoV-2 Infection
3. Diagnosis of IPA in Patients with SARS-CoV-2 Infection
3.1. Diagnostic Criteria
3.2. The Role of Diagnostic Radiology
3.3. Diagnostic Challenges, Summary
- In light of the current difficulties and uncertainties relating to the diagnosis and the risks associated with IA in COVID-19 patients, clinicians should maintain a high level of suspicion for this infection, especially in ICU patients;
- The persistence of a respiratory co-infection in SARS-CoV-2 patients despite the administration of broad-spectrum antibiotics should lead to the pursuit of the confirmation or exclusion of IPA with culture- and non-culture-based methods, especially in those patients who present risk factors for IPA;
- Bronchoscopy has a limited role in these patients and should only be considered when diagnosis confirmation would significantly change clinical management;
- Conventional microscopic examination and qualitative culture of respiratory tract samples have quite low sensitivity and specificity;
- Confirmation test with blood biomarkers (serum GM or beta-D-glucan), blood PCR, or BAL GM or PCR, if possible, could be performed in cases of high clinical suspicion;
- The use of CT scans for diagnostic purposes is controversial due to practical concerns and the complex character of lesions presented in SARS-CoV-2 patients;
- Implementation of immuno-chromatographic LFD for the POC diagnosis of IPA could be helpful.
4. Challenges in the Treatment of IPA in Patients with SARS-CoV-2 Infection
Treatment Challenges, Summary
- Key objective is to improve survival, by avoiding misdiagnosis and by initiating early, targeted, and specific antifungal treatment. Any patient at risk should be considered by the responsible clinician as having IA and should receive antifungal therapy;
- There are possible drug–drug interactions between antifungal agents and agents used for specific treatment of coronavirus infection (tocilizumab-IL-6 receptor blocker-anakinra);
- The antifungal drug arsenal is very limited with high toxicity and severe side effects;
- Prolonged exposure to novel echinocandins (e.g., anidulafungin, micafungin), or triazoles (e.g., voriconazole, isavuconazole, and posaconazole) may result in the development of new resistance patterns leading to treatment failures;
- Lack of necessary equipment for microbiological examination, failure of early detection of fungal growth in infected tissue, incorrect technique of specimen sampling and clinicians’ failure to identify the precise fungi lead to high mortality rates;
- The optimal duration of antifungal therapy for CAPA is still under debate;
- Over-suppression of the immune system caused by the disease or the use of specific trial treatment (anakinra-recombinant IL-1Ra- or Janus kinase (JAK) inhibitors), might favor the rise of potential opportunistic fungal infections.
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Abbreviation | Expansion |
---|---|
ARDS AspICU | Acute Respiratory Distress Syndrome Clinical Algorithm to Diagnose Invasive Pulmonary Aspergillosis in Critically Ill Patients (by Blot et.al., ref. [53]) |
BAL | Bronchoalveolar Lavage |
BDG | b-D-glucan |
bmGT | bis(methylthio)gliotoxin |
CAPA | COVID-19-Associated Pulmonary Aspergillosis |
CDC | Centers for Disease Control and Prevention |
COP | Cryptogenic organizing pneumonitis |
COPD | Chronic Obstructive Pulmonary Disease |
COVID-19 | Coronavirus Disease 2019 |
CSF | Cerebrospinal Fluid |
CT | Computed Tomography |
CYP | Cytochrome P |
ECMM | European Confederation of Medical Mycology |
ELISA | Enzyme-Linked Immunosorbent Assay |
EORTC | European Organization for Research and Treatment of Cancer |
ERS | European Respiratory Society |
ESCMID | European Society for Clinical Microbiology and Infectious Diseases |
GAFFI | Global Action Fund for Fungal Infections |
GM | Galactomannan |
GM-EIA | Galactomannan Enzyme Immunoassay |
GT | Gliotoxin |
HIV | Human Immunodeficiency Virus |
IA | Invasive Aspergillosis |
IAPA | Influenza-Associated Pulmonary Aspergillosis |
IDSA | Infectious Diseases Society of America |
IFIs | Invasive Fungal Infections |
IPA | Invasive Pulmonary Aspergillosis |
JAK | Janus Kinase |
LFD | Lateral Flow Device |
Mab | Monoclonal Antibody |
MSGERC | Mycoses Study Group Education and Research Consortium |
OR | Odds Ratio |
PCR | Polymerase Chain Reaction |
POC | Point-Of-Care |
SARS-CoV-2 | Severe Acute Respiratory Syndrome Coronavirus 2 |
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Tests | Features | Diagnostic Value | Turnaround | Pitfalls |
---|---|---|---|---|
Conventional microscopic examination [36,49,50,51,69,70] | Availability. Simplicity. Low cost. | Suboptimal, low to moderate sensitivity and predictive value. | Rapid. | Challenging to differentiate between infection and colonization. May reflect airway colonization. |
Respiratory sample cultures [49,50,51,56,70] | Simplicity. Low cost. Identification of species. Antifungal susceptibility testing. | Suboptimal, low to moderate sensitivity and predictive value. | Prolonged. | Challenging to differentiate between infection and colonization. |
Galactomannan (GM) in biologic fluids [36,49,51,55,69,71,72,73,74,75] | Serum: Low or moderate sensitivity depending on the index cut-off used. Moderate specificity. Better performance in neutropenic than in non-neutropenic patients. BAL: Moderate or high sensitivity and high specificity of 81–96.6% depending on the optical density index cut-off used, sensitivity exceeds 70% in most studies. Raising the cutoff improves test specificity without compromising sensitivity. High NPV, moderate or high PPV. | Variable. | Variable performance. BAL: Optimal threshold has not been determined; sensitivity may be reduced in the presence of antifungals. | |
Serum 1-3-b-D-glucan (BDG) assay [36,49,51,66,76] | Low or moderate sensitivity (49.6–80%), good specificity (82–98.9%), acceptable PPV (83.5%), high NPV (89–94.6%) (useful to exclude diagnosis rather than confirm it). | Variable. | False-positive results (b-lactam antibiotics, human blood products, immunoglobulin, albumin plasma, cellulose hemodialysis membranes, bacterial bloodstream infections, e.g., Pseudomonas aeruginosa) | |
PCR-based methods [36,49,51,70,77,78,79,80,81,82] | High cost. Not affected by the immune status of the patients. Evaluation of phenotypes of strains. | Heterogeneity of results. High NPV. Two positive consecutive results have high specificity and high positive likelihood ratio, single negative PCR result has high NPV. High sensitivity in combination with other fungal biomarkers in serum (either GM or BDG) or in BAL and along with GM and/or LFD test. | Rapid. | Requires further clinical standardization. Potential for contamination due to the environmental ubiquity of fungal nucleic acids. |
Aspergillus-specific immuno-chromatographic lateral flow device (LFD) test [36,49,51,63,66,74,83] | Acceptable sensitivity, specificity, moderate PPV, high NPV (especially in combination with BAL GM) [66,84]. | Rapid. | Requires further clinical evaluation. Sensitivity of the BAL LFD assay may be reduced in the presence of antifungal treatment. | |
Novel assays: volatile organic compounds (VOC) assays, Gliotoxin (GT), bis(methylthio)gliotoxin (bmGT) assays [67,68,85,86,87] | High sensitivity and specificity. bmGT presents higher sensitivity and PPV than GM and similar specificity and NPV. Importantly, the combination of GM and bmGT increased the PPV (100%) and NPV (97.5%) of the individual biomarkers. | Rapid. | Requires further clinical evaluation. |
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Tsotsolis, S.; Kotoulas, S.-C.; Lavrentieva, A. Invasive Pulmonary Aspergillosis in Coronavirus Disease 2019 Patients Lights and Shadows in the Current Landscape. Adv. Respir. Med. 2023, 91, 185-202. https://doi.org/10.3390/arm91030016
Tsotsolis S, Kotoulas S-C, Lavrentieva A. Invasive Pulmonary Aspergillosis in Coronavirus Disease 2019 Patients Lights and Shadows in the Current Landscape. Advances in Respiratory Medicine. 2023; 91(3):185-202. https://doi.org/10.3390/arm91030016
Chicago/Turabian StyleTsotsolis, Stavros, Serafeim-Chrysovalantis Kotoulas, and Athina Lavrentieva. 2023. "Invasive Pulmonary Aspergillosis in Coronavirus Disease 2019 Patients Lights and Shadows in the Current Landscape" Advances in Respiratory Medicine 91, no. 3: 185-202. https://doi.org/10.3390/arm91030016