Fungal species are widely distributed in the environment and can cause opportunistic infections in immunocompromised hosts such as those with hematologic diseases. They can be classified according to their histologic forms: yeast (
Recently, the incidence of invasive fungal infections (IFIs) has risen substantially and became a major problem in hospitals because of increased immunosuppressive therapy, organ and hematopoietic stem cell transplantation (HSCT), cytotoxic chemotherapy, invasive procedures and indwelling catheter [3, 4]. Patients with hematologic malignancies are at high risk of developing IFIs, which have high mortality and morbidity. Moreover, these group of patients are more exposed to antifungal agents which has contributed to diverse epidemiology and antifungal resistance [5-7].
Definitions for IFIs have been proposed (proven, probable, possible) to have a standard, shared definition, which may aid in communication between researchers, and ultimately improve diagnosis and management in clinical practice. Proven IFI is defined by the detection of fungus by histology or sterile tissue culture. Probable or possible IFI is defined depending on the setting or population, with respect to three elements: host factors, clinical features, and mycologic evidence .
IFIs caused by rare fungi are also increasing [9-11]. However, this article focused on IFIs, specifically invasive candidiasis, aspergillosis, and mucormycosis in patients with hematologic diseases. Furthermore, we also aimed to discuss the recent epidemiology, diagnosis, treatment, prophylaxis, and quality control in IFIs.
In patients with hematologic diseases, candidemia is the most common form of invasive candidiasis and is associated with high mortality rates up to 40% . Neutropenia (neutrophil count <500 cells/mL) is a common risk factor and is usually related to cytotoxic chemotherapy or HSCT, use of broad-spectrum antibiotics gastrointestinal mucosal dysfunction, and indwelling vascular catheters . Acute disseminated candidiasis or hepatosplenic candidiasis might also be seen in patients with prolonged neutropenia. Evidence of defining neutropenia as neutrophil count of less than 500 cells/mL followed previous study result .
At least 15 distinct
In a single tertiary-care hospital in Korea where all data were collected from adult patients with hematologic diseases, the trend of decreasing
Classic diagnostic methods for candidiasis are microscopy, histopathology and culture . Tissue samples and body fluids from sterile sites must be collected aseptically and transported to the laboratory promptly. If it is candidemia, the preferred diagnostic would be blood culture . Yeast isolation from normally sterile tissues or fluids is usually indicative of deep-seated infection; however, negative results do not exclude candidiasis. Identification of the isolate to species level is mandatory. Microscopy should make use of special stains such as Grocott-Gomori methenamine silver (GMS) and Periodic Acid Schiff (PAS). β-D-glucan (BDG) is a cell wall component of most fungi and is not specific to detect
For patients with hematologic diseases, the possibility of obtaining samples of deep tissues is not warranted due to the patient’s condition . Therefore, many clinicians also rely on empirical evidence with prior exposure to antibacterial agents, existence of a central venous catheter (CVC), and recent abdominal surgery to establish diagnosis . As the number of fungal infections has increased and as hosts have become more vulnerable, newer diagnostic tests are needed to identify the pathogens more quickly .
Breakthrough invasive candidiasis is also a problem in patients with hematologic diseases. Breakthrough infection is defined as an infection occurring in a patient receiving antifungal agents. Azole-resistant
Chronic disseminated (hepatosplenic) candidiasis (CDC) is a unique clinical manifestation and almost seen in patients with hematologic diseases. CDC usually occur during recovery from neutropenia. Fever, right upper quadrant discomfort, nausea, elevate liver enzymes following recovery from neutropenia implicate CDC . CT, MRI, or ultrasound imaging is helpful and small, peripheral, target-like abscesses are seen in the liver or spleen [31, 38].
The mortality rate is closely correlated with delayed initiation of appropriate antifungal treatment. Therefore, prompt treatment is needed to improve prognostic outcomes in patients . In candidemia, echinocandin antifungals are recommended as initial therapy. Transition from an echinocandin to fluconazole, usually within 5–7 days, is suggested in non-neutropenic patients who are clinically stable, have isolates that are susceptible to fluconazole, and have negative repeat blood cultures following treatment . Fluconazole (intravenous or oral) is an acceptable alternative first line therapy if the patient is not critically ill and is unlikely to have a fluconazole-resistant
Follow-up blood cultures should be performed every day or every other day to check when candidemia has been cleared. Recommended duration of therapy for candidemia without obvious metastatic complications is at least 2 weeks after the documented clearance of
With CDC, therapy should be continued until lesions resolve on repeated imaging. The usual duration is several months and premature discontinuation of antifungal therapy can lead to relapse. If chemotherapy or HSCT is required, it may not be delayed because of the presence of chronic disseminated candidiasis .
For oropharyngeal candidiasis in patients with neutropenia, fluconazole 7–14 days is recommended. Chronic suppressive therapy is usually unnecessary. Esophageal candidiasis always requires systemic antifungal therapy. Diagnostic trial of antifungal therapy is available before endoscopic examination and intravenous therapy is recommended if the patient cannot tolerate oral therapy .
Echinocandin, a treatment of choice, has so-called sanctuary sites in the body such as eye, kidney, and meninges; therefore, it might be unsuitable for infection in those sites . In addition, there is an increase in the resistance of
Aspergillosis is the collective term used to describe all disease entities caused by any one of up to 50 pathogenic and allergenic species of
In patients with hematologic diseases,
Diagnosis of IA remains difficult in many reasons. Both microscopy and culture should be attempted and tissue invasion by hyphae would provide a definitive diagnosis of IA. However, examinations such as tissue sampling may be difficult in hematology patients because of neutropenia and thrombocytopenia and yield of culture is frequently suboptimal . Therefore, non-invasive diagnostic tests including non-culture-based tests have gained interest for improving diagnostic accuracy.
A high level of suspicion with meticulous physical examination is important since an immunocompromised patient may be relatively asymptomatic, interrupting early diagnosis . The most prevalent but unspecific sign of IPA reported in approximately 100% of patients is persistent fever despite treatment with broad-spectrum antibiotics . Imaging is a critical component in the diagnosis, and CT scan is recommended whenever there is clinical suspicion or when the patients present with 72–96 hours of persistent neutropenic fever to find IPA or sinusitis regardless of simple chest radiograph results . Routine contrast imaging is not recommended but could be considered if vessel involvement is suspected. Typical findings of IPA include consolidation with surrounding ground-glass opacity (halo sign) or cavitation . Lung ultrasound (US) imaging has been considered as an alternative modality to diagnose invasive fungal pneumonia, including US-guided transthoracic needle aspiration. Considering it is a rapid, bedside, non-invasive technique, lung US could have a significant role but more study is required for expected accuracy [56-58].
Bronchoscopy with bronchoalveolar lavage (BAL) is recommended in patients in the suspicion of IPA. It seems to be a valuable diagnostic tool with high yield and low complication rate even in neutropenic patients with hematologic diseases. Therefore, regarding the diagnostic delay and impact on mortality, bronchoscopy with BAL should be considered if possible [59-61]. Routine fungal culture, cytology, and non-culture-based methods should be performed. Galactomannan (GM) detection is more sensitive than culture in the diagnosis of IA. Additionally, BAL fluid GM is more sensitive compared to serum GM in terms of diagnostic performance . Serum assays for BDG with comparison to GM suggest higher sensitivity but are not a specific marker for
For suspected IA, current guideline recommends voriconazole or isavuconazole as the treatment of choice. Isavuconazole is a mold-active triazole antifungal agent and is also susceptible to other molds including mucormycosis. Therefore, isavuconazole could be considered when coinfection of IA with other molds cannot be excluded . If contraindicated or not tolerated, liposomal amphotericin B may be considered as an alternative. Amphotericin B deoxycholate is no longer a primary option but can be used in limited settings when no other antifungal agents are available . Itraconazole should not be used as first line therapy although it is a potential option due to drug-drug interactions. Echinocandin also is not recommended because outcomes were not favorable with monotherapy . Treatment should be continued for a minimum of 6–12 weeks, largely dependent on the degree and duration of immunosuppression, sites of infection, and evidence of disease improvement. Higher GM level is known as a risk factor related to mortality and follow up can be used to monitor disease progression or therapeutic response .
When persistent fever exists but no infiltrate seen in chest imaging, possible focus other than the lung should be considered. If there are no suspected focus and biologic markers such as GM, and PCR is negative, no empirical treatment would be required. However, in patients under mold-active prophylaxis, therapeutic drug monitoring (TDM) for prophylactic azoles such as posaconazole and voriconazole should be done and breakthrough IA should be considered . Triazole is not recommended for empiric therapy of breakthrough infection during triazole prophylaxis and a different class of mold-active antifungal agent is required. When fever of unknown origin persists in patients without mold-active prophylaxis, empiric antifungal therapy with triazole might be considered [14, 70].
Reducing the dose or cessation of immunosuppressive agents could be a component of aspergillosis treatment. Colony-stimulating factors in neutropenic patients may also be considered. Granulocyte transfusion can be considered if the patient is unlikely to respond to standard therapy and if the anticipated duration of neutropenia is more than one week . Surgery should be considered in localized disease [ex. invasive fungal sinusitis, endocarditis, osteomyelitis, focal invasion of central nervous system (CNS)]. IA is not an absolute contraindication to additional chemotherapy or stem cell transplantation. Decision must consider the risk of progressive aspergillosis during anti-neoplastic therapy versus the risk of clinical deterioration due to the aggravation of underlying hematologic diseases during delayed treatment [72, 73].
Voriconazole undergoes extensive hepatic metabolism and share metabolic pathways with many drugs. Therefore, TDM and drug interaction (ex. cyclosporin, tacrolimus, sirolimus and other CYP3A4 substrates) must be monitored for optimized therapeutic efficacy and to avoid potential toxicities. Genetic polymorphisms in CYP2C19 also contribute to serum drug levels. Common side effects include photopsia, photosensitivity, CNS disturbance, and prolonged QT interval. Amphotericin B deoxycholate, which is no longer used as primary IA treatment has many side effects including infusion-related toxicity and renal toxicity. However, some centers in Korea still use amphotericin B deoxycholate as the first line of treatment due to insurance and economic issues [73, 74].
Mucormycosis represents a group of life-threatening infections caused by fungi of the order
Six different syndromes are grouped according to the anatomic predilection: sinusitis (rhino-orbital or rhinocerebral), pulmonary, cutaneous, gastrointestinal, disseminated, and other. Disseminated mucormycosis, usually as pulmonary mucormycosis typically develops in hematology patients with profound neutropenia [76, 77] and graft-versus-host diseases after allogeneic HSCT [78, 79]. Similar to IA, persistent fever without suspected symptoms is seen in most patients . Rhino-orbito-cerebral mucormycosis typically develops in patients with diabetes mellitus, but can also be seen in patients with hematologic diseases .
In the mid-20th century, diabetes mellitus used to be a major risk factor for mucormycosis. However, in recent years, underlying malignancy emerged as another important risk factor due to the increasing number of patients undergoing chemotherapy, immunotherapy, or HSCT [81, 82]. The most frequently reported pathogens are
The diagnosis of mucormycosis depends on the availability of imaging techniques, trained personnel, and mycological and histological investigations. In patients with hematologic diseases and suspected pulmonary mucormycosis, chest CT scan is recommended. Typical finding includes ground glass opacity surrounded by a ring of consolidation (reversed halo sign).
If mucormycosis is a potential diagnosis, biopsy is strongly recommended. It is usually suspected based on the results of direct microscopy. However, diagnosis with histomorphological basis is challenging because misidentification of
Suspected and confirmed mucormycosis are medical and surgical emergencies and require rapid management. Breakthrough mucormycosis during mold-active prophylaxis is also possible [87, 88] and must be considered. Early complete surgical debridement with clean margins is strongly recommended for disease control, histopathology, and microbiologic diagnosis [89, 90]. In neutropenic patients, immediate surgery may be required; however, some still prefer surgical resection after the resolution of neutropenia and thrombocytopenia in IA .
For first line antifungal therapy, liposomal amphotericin B with dose of 5–10 mg/kg/day is recommended. When CNS involvement is suspected, dose of 10 mg/kg/day is needed . Increased dose tends to have an increased response rate, but doses higher than 10 mg/kg/day did not result in higher blood concentrations and instead increased the creatinine level [93, 94]. Amphotericin B deoxycholate has been the drug of choice for decades but its use is limited due to toxicity. It is only recommended when there is no other option. Isavuconazole has similar efficacy with liposomal amphotericin B and could be used as first line treatment for mucormycosis . Posaconazole is recommended as an alternative therapy if first line medication has side effect or is ineffective . Two oral forms (tablet and syrup) are available. Posaconazole syrup is influenced by food and concomitant use of other drugs such as proton pump inhibitors. Therefore, TDM must be monitored for optimal blood trough levels [96, 97].
The duration of therapy in mucormycosis is unknown. In general, weeks to months of therapy are usually given. If the underlying immune defect (ex. neutropenia or use of immunosuppressants) is resolved, therapy can be continued until there is resolution of signs and symptoms or radiographic improvement. There is moderate support for intravenous treatment until stable disease is achieved. The decision to switch to oral monotherapy with isavuconazole or posaconazole depends on the patient’s response to therapy and severity of the illness [75, 98].
Despite improvements in diagnosis and treatment, IFI-associated mortality remains high and thus, antifungal prophylaxis represents an important strategy in patients at high risk for IFI .
Patients with neutropenia lasting less than 7 days are at low risk and do not require antifungal prophylaxis. Antifungal prophylaxis is strongly recommended in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are in remission or undergoing induction chemotherapy as they are expected to have neutropenia for more than 7 days. Allogeneic HSCT recipients with risk factors such as GVHD are also recommended to have antifungal prophylaxis depending on the local incidence and epidemiology. Fluconazole was often used , but protection against non-albicans
Voriconazole is only used as secondary prophylaxis during HSCT in patients with a previous history of IA in Korea. Aerosolized liposomal amphotericin B inhalation was found to be effective in reducing IPA and may be considered as an option in the future, considering the increasing azole resistance . New chemotherapy drugs (ex. venetoclax) with drug interaction to triazoles are continuously developed, and strategies might be delicately managed considering the risk factors . An example of antifungal prophylaxis strategy in our hospital regarding guidelines mentioned above is shown in Table 2.
In addition to medical prophylaxis, environmental protection should be supervised. High risk patients should be placed in a protected environment to reduce mold exposure. High-efficiency particulate air (HEPA) filtration and maintenance of positive pressure room are examples. If protected environment is not available, a private room could be alternative. Reasonable precautions include avoidance of gardening, and not allowing plants or cut flowers to patient’s room . Health care workers can also play a key role in transmission . Therefore, regular surveillance of IFI cases and education of workers are needed .
There are guidelines recommended for the ideal managements of IFIs but following these guidelines may be challenging. To highlight the strongest recommendations and measure guideline adherence, the ECMM QUALity of Clinical management score (EQUAL score) was designed. Factors include diagnostic and follow-up procedures, and treatment parameters with different scores. Total score is measured by summing each item. Simplified figure cards for each disease showing items and weights are released for free so anyone can use. Physicians might get important recommendations concisely without reading complicated guidelines entirely. Whether a high score correlates with an outcome remains to be explored; however, these efforts might facilitate antifungal stewardship [109-111]. Previous studies reported that greater guideline adherence with a higher EQUAL
IFIs are related to high mortality and morbidity in patients with hematologic diseases and HSCT recipients. Diagnosis and treatment are complicated due to different epidemiology, risk factors, and immune status of the patients. There is a need to analyze the epidemiology regularly and be aware of risk factors to efficiently apply prophylactic antifungal agents. Various tests are mandatory to diagnose and treat IFIs as accurately as possible and further studies are required to improve the prognosis of IFIs in the future.
No potential conflicts of interest relevant to this article were reported.