Fungal superinfections and COVID-19 in the ICU

The COVID-19 pandemic has caused a worldwide healthcare crisis. In addition to the morbidity caused by the initial infection, severely ill patients are also at increased risk of secondary infections. During the 26th Congress of the European Hematology Association (EHA), Martin Hoenigl presented a talk that examined fungal superinfection in patients with severe COVID-19 infection in intensive care units (ICUs).¹

Patients with COVID-19 acute respiratory distress syndrome (ARDS) are predisposed to superinfections by fungi. This predisposition is due to both clinical and immunological risk factors.

Clinical risk factors:

• steroid use
• anti-interleukin (IL)-6 treatment
• mechanical ventilation
• lung injury
• prolonged ICU stay
• use of broad-spectrum antibiotics
• extracorporeal membrane oxygenation
• central venous catheter use

Immunological mechanisms:

• danger-associated molecular patterns (DAMPs)
• antiviral recognition pathways that can facilitate mold growth in the lungs

Yeast infections

Secondary infection with yeast species has been recognized as a complication of severe COVID-19. However, this is thought to be due to clinical risk factors alone, such as prolonged ICU stays and central venous catheter use. No immunological defects specifically associated with SARS-CoV-2 infection have been shown to increase susceptibility to yeast infection.

Recent reports have demonstrated a possible increase in the risk of bloodstream infections in patients who were ventilated as a result of SARS-CoV-2 infection. This was thought to be from increased translocation of Saccharomyces cerevisiae from the gut 4−6 days after patients (n = 2) had received probiotic supplements of the same strain. The previous 320 patients who had been given this probiotic supplement did not develop any bloodstream infection.

The theory that COVID-19 patients may have a more permeable gut may also explain why some patients show increased levels of serum (1,3)-beta-D-glucan in COVID-19-associated pulmonary aspergillosis (CAPA). This has been previously interpreted as angio-invasive aspergillosis but may be a result of fungal translocation across the gut wall instead.

Mucormycosis Infection with mucormycetes in patients with COVID-19 has been reported in ICUs globally. Factors that result in a predisposition to mucormycosis include hyperglycemia and increased free iron. While hyperglycemia is more often associated with uncontrolled diabetes, the use of dexamethasone can also cause this and lead to an ongoing inflammatory state. This may predispose patients to a secondary infection with mucormycetes.

Patients with COVID-19 have been observed to have increased free iron levels. Mucorales species require free iron for their biological processes so have a growth advantage in patients with COVID-19. The level of free iron can also be increased in patients with COVID-19 if they develop ketoacidosis as this frees more iron from binding proteins.

In 80 cases of COVID-19-associated mucormycosis recorded recently, mortality was high at 49%, predominantly as a result of pulmonary or disseminated mucormycosis and patients with cerebral involvement. Of the patients that survived, 46% lost their sight.

Aspergillosis

DAMP release during ARDS in patients with severe COVID-19 infection causes lung injury and inflammation. In patients undergoing a stem cell transplant, the increased release of DAMPs has been previously associated with invasive aspergillosis. Activation of the pathways that are necessary to recognize viral infection seem to create an inflammatory environment that allows fungal infection. Notably, the IL-1 pathway is hyperactivated following SARS-CoV-2 infection and treatment with an anti-IL-1 agent has been found to be protective against Aspergillus colonization and infection.

Aspergillus infection causes a spectrum of disease ranging from allergic conditions, such as extrinsic asthma and allergic fungal sinusitis, to more invasive conditions depending on the degree of immunosuppression in the host.

In particular, the syndrome seen is dependent on whether the host is neutropenic or not.

In the neutropenic host, Aspergillus infections are

• primarily angio-invasive;
• diagnosed from blood or bronchoalveolar lavage (BAL); and
• show ‘typical’ radiographic signs (well circumscribed lesion(s) with or without a halo sign on computed tomography +/− air crescent sign).

In non-neutropenic hosts, Aspergillus infections are

• primarily airway invasive;
• diagnosed from BAL; and
• display unspecific radiological findings.

While there were initially problems with classification of CAPA, in 2020, The European Confederation for Medical Mycology (ECMM) and The International Society for Human and Animal Mycology consensus criteria have overcome these issues and provided a guideline for diagnosis and treatment of CAPA.² This guideline includes the use of a BAL lateral flow assay, which has been shown to be sensitive for detecting CAPA.

The incidence of CAPA varies between countries, with the median incidence being 3.1% (0.7–7.7%) in patients with COVID-19 (median taken across Pakistan, China, Italy, the Netherlands, and Spain). In patients in the ICU, this rises to 8.9% (2.5−39.1%), and in those patients receiving mechanical ventilation, the median incidence is 20.1% (3.2−38%). Analyses from various international studies and case series indicate that the mortality of patients with CAPA in the ICU is high at approximately 52%. CAPA is significantly associated with mortality in ventilated patients with COVID-19; however, treatment with systemic antifungals can significantly reduce this.

To investigate risk factors associated with CAPA in ICU patients, 108 cases were assessed in a study by ECMM. Multivariate analysis of this study showed that only age and mechanical ventilation were significantly associated with increased risk of CAPA.

The main choices for treatment are voriconazole and isavuconazole. There are some issues with the use of voriconazole in the ICU given its narrow therapeutic window and drug–drug interactions that can occur. Isavuconazole has a more favorable pharmokinetics and toxicity profile than voriconazole, with fewer drug–drug interactions.

An alternative treatment is liposomal amphotericin B which, although effective, may not be suitable for patients with renal insufficiency. As SARS-CoV-2 is linked with kidney injury, the use of amphotericin B must be considered carefully.

In the ECMM study, voriconazole or isavuconazole monotherapy was associated with significantly improved survival at ICU discharge and Day 84 compared with amphotericin B or echinocandins.

Future treatments

As there are limitations associated with the main current antifungal drugs available for the treatment of CAPA, new agents are needed. Fosmanogepix and olorofim are two possible antifungal agents under development, which do not have the same narrow therapeutic window or issue with drug interactions. Rezafungin and ibrexafungerp may have a role in antifungal combination therapy. For airway invasive fungi, there might be a role for inhalant antifungals such as opelconazole. There are several phase II/III trials currently ongoing for these agents.

Conclusion

Fungal superinfections are a serious problem for patients in the ICU with severe infections. Certain immunological features of infection with SARS-CoV-2 can make patients more susceptible to mucormycosis and aspergillosis. The mortality rate for these fungal superinfections can be >50% in ICU patients, and those who survive may experience life changing morbidity such as loss of sight. While mortality is significantly higher in patients who do not receive treatment with antifungals, there is still a need for additional options as the currently available treatments are associated with toxicities and drug–drug interactions that can limit their use in the ICU setting. Novel agents are currently being tested and show promise for the treatment of CAPA and other fungal superinfections.