INVASIVE FUNGAL INFECTIONS: WHY ARE THEY AN OVERLOOKED THREAT?

Changing Epidemiology of Fungal Infections

Invasive fungal infections (IFIs) cause considerable morbidity and mortality in critically ill patients.^[1] Within intensive care units (ICUs), invasive candidiasis and invasive aspergillosis are the most common IFIs in non-neutropenic patients; however, many other fungal pathogens also contribute to the burden of IFIs in neutropenic patients, including Cryptococcus, Trichosporon, Rhodotorula, Fusarium, Scedosporium, Pneumocystis, zygomycetes, and dematiaceous fungi.^[2,3] There has been a steady rise in IFIs in recent decades, associated with the rising number of patients who are ageing or immunocompromised, and the increasing use of immunosuppressant drugs and invasive medical devices.^[2] Approximately 50% of all cases of candidemia, the most common form of invasive candidiasis, occur within the ICU setting, with Candida albicans being the most common causative pathogen, associated with up to 70% of cases.^[4,5] In developed countries, Candida species rank among the top 3 or 4 pathogens causing bloodstream infections, together with Staphylococcus aureus and Enterococcus species.^[4]

The Burden of IFIs

Approximately 80% of IFIs are caused by Candida species and 0.3% to 19% by Aspergillus species.^[1] The most common IFIs found in non-neutropenic patients in ICU include invasive candidiasis, candidemia, and invasive aspergillosis which cause a significant burden to both patients and healthcare services. Candidemia alone has been reported in an estimated 1% to 2% of all medical and surgical ICU admissions, although the number of incidences varies depending on the geography and factors such as age.^[4] The overall mortality rate for invasive candidiasis is estimated to be between 10% and 47%, although the risk increases with increased age, higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, existing comorbidities, use of immunosuppressants, and the species of infecting pathogen.^[4] Although invasive aspergillosis is relatively uncommon in nonimmunocompromised patients, the incidence rate has been increasing, particularly in patients with serious COVID-19 or influenza who are admitted to the ICU.^[6,7] It has been associated with high mortality rates in high-risk patients, with a 42-day mortality rate of up to 27.5% and an 1-year survival rate of 25.4% to 59%.^[8-10]

In addition to individual patient morbidity and mortality, IFIs can place a significant strain on healthcare services, with estimated costs approximately between 48,000 USD and 157,00 USD per patient for inpatient care for invasive candidiasis^[11] and approximately at 37,000 USD to 59,000 USD for invasive aspergillosis.^[12]

Low Detection Rate and the Complexity of Diagnosis Contribute to Mortality

IFIs lack specific clinical signs or symptoms, which makes them difficult to diagnose. In addition, given that they mostly occur in critically ill patients, delays in diagnosis significantly increase the risk of mortality.^[4] In a review of published literature of autopsy reports, an estimated 50% of patients who had IFIs identified postmortem had not been diagnosed with an IFI while alive.^[13] Therefore, there is a considerable unmet need for the early diagnosis of IFIs, together with appropriate management, to reduce the disease burden and associated healthcare costs.

A number of tools are available for the diagnosis of IFIs. Direct detection method involves collecting samples of blood or tissue from normally sterile sites and culturing them to determine the presence of fungal infection. Indirect detection methods include polymerase chain reaction (PCR) assays and detection of fungal biomarkers (eg, β-D-glucan) in blood samples.^[14] As none of the diagnostic tests for IFIs have 100% sensitivity or specificity, and turnaround times for different tests vary, a combination of early and late assessments may be needed to make a robust diagnosis.^[5] An algorithm for the diagnosis of invasive candidiasis/candidemia in critically ill non-neutropenic nontransplanted ICU patients has been proposed by the European Society of Intensive Care Medicine/European Society of Clinical Microbiology and Infectious Diseases (ESICM/ESCMID) task force and includes combinations of clinical signs, blood cultures, PCR testing, biomarker evaluation, and risk stratification (Figure 1).^[15]

Figure 1. Algorithm for the Evaluation of Sepsis in Non-Neutropenic Nontransplanted ICU Patients at Risk of Invasive Candidiasis or Candidemia^[15]

BDG, 1,3-β-D-glucan; CAGTA, Candida species germ tube antibody; Col index, colonization index; CS, Candida score; m-MRBT, miniaturized magnetic resonance-based technology; Mn-A, anti-mannan antibody; Mn-Ag, mannan antigen.

Abdominal sepsis refers to anastomosis leak, postoperative abscess, and repeated surgery for recurrent abdominal sepsis or infected pancreatitis.

Reprinted by permission from Springer-Verlag GmbH Germany: Springer Nature, Intensive Care Medicine. Martin-Loeches, I., Antonelli, M., Cuenca-Estrella, M. et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med 45, 789–805 (2019), Copyright © 2019.

Because of their low sensitivity in detecting invasive candidiasis/candidemia and a slow turnaround time (up to 48-72 hours), blood cultures are not useful in deciding whether or not to treat a patient with antifungals; however, they are still a major tool in a comprehensive diagnosis of IFIs.^[5,15] Blood cultures allow identification of the species of pathogen and susceptibility testing and, therefore, are key in a directed therapy approach. Biomarker tests, such as β-D-glucan, mannan antigen, and Candida species germ tube antibody, have a more rapid turnaround time than blood cultures, but all have low or variable specificity. However, β-D-glucan has a high negative predictive value and, therefore, is beneficial in identifying patients for watchful waiting or early stopping of antifungal treatments.^[5] PCR-based testing allows a rapid detection of Candida species, and while a lack of standardization across tests is a major limitation for this method, considerable progress has been made toward validation of a standardized technique.^[3] Miniaturized magnetic resonance-based technology, which combines PCR testing with nanoparticle-based hybridization, has demonstrated very high sensitivity and specificity and allows identification of the five major Candida species within 5 hours. However, these technologies are considerably more expensive than biomarker tests or blood cultures, and the validity of the tests still requires assessment in large patient populations.^[15]

Similar to invasive candidiasis and candidemia, early diagnosis of invasive pulmonary aspergillosis on the basis of clinical signs and symptoms alone is challenging. Comprehensive diagnosis involves a combination of clinical signs, radiology, and microbiological data. Computed tomography, bronchoalveolar lavage, microscopy and culture are recommended for confirming suspected diagnoses.^[16,17] Galactomannan testing is recommended in certain subgroups [hematopoietic stem cell transplantation (HSCT) recipients and patients with hematologic malignancies] but is not universally recommended for routine screening, as sensitivity is lower in non-neutropenic patients.^[16,17]

Risk Factors for IFIs

A number of risk factors have been associated with the development of IFIs, which can be used to identify patients who would benefit from prophylaxis or preemptive therapy (Table 1). In a matched case-control study of hospitalized patients in France and Switzerland, the independent risk factors for candidemia were total parenteral nutrition, acute kidney injury, heart disease, prior septic shock, and exposure to aminoglycoside antibiotics in ICU patients. In non-ICU patients, additional risk factors included central venous catheter and exposure to glycopeptides and nitroimidazoles.^[18] In a meta-analysis of risk factors for invasive Candida infections, comorbid conditions (eg, HIV), Candida colonization, use of broad-spectrum antibiotics, central venous catheter, and total parenteral nutrition were identified as the most significant risk factors.^[19] Additional risk factors include critical illness, abdominal surgery, solid tumors, hematological malignancy, solid-organ transplant, and age (< 1 month or ≥ 65 years).^[14]

Table 1. Risk Factors for Invasive Candidiasis^[14]

Similar to invasive candidiasis and candidemia, the risk factors for invasive pulmonary aspergillosis include hematological malignancies, HSCT, immunosuppression, chronic respiratory diseases (eg, chronic obstructive pulmonary disease), solid cancers, prolonged ICU stay, solid-organ transplants, and prolonged steroid treatments.^[1] While some of these factors put patients at a high risk of invasive pulmonary aspergillosis, others are of lower risk but still associated with an increased likelihood of infection (Table 2).

Table 2. Risk Factors for Invasive Pulmonary Aspergillosis^[1]

A/H1N1, influenza A virus subtype H1N1; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid.

Patients at high risk of IFIs may be eligible for prophylactic or preemptive therapy. In general, immunocompromised patients should be offered prophylaxis because of the high risk of IFIs (including those from opportunistic pathogens other than Candida and Aspergillus species), whereas prophylaxis is often not required for other patients. Prophylaxis can be beneficial in preventing mortality in critically ill patients who are deemed to be at high risk, although current evidence recommends against routine administration of antifungals to critically ill patients without evidence of infection or predisposing risk factors.^[15] Similarly, preemptive therapy, given based on the presence of fungal biomarkers, is not currently recommended for critically ill patients because of a lack of evidence of efficacy combined with concerns about the development of antifungal resistance.^[15] Risk prediction models can be used to identify patients at the highest risk of IFIs for further microbiological assessment and can be a useful tool in antifungal stewardship for the identification of patients who have a low likelihood of IFIs and, therefore, do not require prophylaxis or empirical therapy.^[15]

Summary

IFIs represent a significant morbidity and mortality burden in critically ill patients in ICU. In non-neutropenic patients, invasive candidiasis, candidemia, and invasive aspergillus are the 3 most common IFIs seen in the ICU setting, with approximately 80% of infections caused by Candida species. Difficulty in establishing a robust diagnosis significantly contributes to mortality, with up to 50% of cases currently being identified postmortem. Tools to aid in diagnosis include blood culture, biomarker assessment, and PCR-based methods, but each have limitations, and a comprehensive diagnosis requires a combination of multiple methods. A risk-based approach can be used to identify patients who would most benefit from prophylaxis within antifungal stewardship programs to reduce the unnecessary use of antifungals. In general, immunocompromised patients are at high risk of IFIs and should be considered for prophylaxis or preemptive treatments, whereas most nonimmunocompromised or non-neutropenic patients can be treated with empirical or directed therapy, based on local susceptibility profiles or pathogen-specific susceptibility testing.