Novel targeted cancer therapy
New drug classes for haematological and oncologic diseases such as tyrosine kinase inhibitors (TKI) and other immunomodulatory drugs put a broader spectrum of patients at risk for IFI [
84].
Among TKI, in particular inhibitors of bruton tyrosine kinase (BTK) [
77,
84], mammalian target of rapamycin (mTOR) [
31,
72,
88], janus kinase (JAK) [
41,
70,
113] and phosphatidylinositol 3 kinase (PI3K) delta [
58] showed attributable increase of risk of IFI. Targeting critical components of the immune system, they impair diverse features of immune cells (e.g. dendritic cells, T cells) [
42,
91,
114]. However, underlying haematological disease, recent treatment, as well as neutropenia put these patients at an increased baseline risk for IFI. Currently, it remains unclear, if antifungal prophylaxis is indicated in these cases.
Inhibition of immune checkpoints, e.g. programmed cell death protein 1 (PD1) or cytotoxic T lymphocyte-associated protein 4 (CTLA4), shows wide-ranging, mostly immune-related adverse events [
7,
59,
98]. Subsequent immunosuppression, primarily including corticosteroids, may result in opportunistic infections including fungi [
32,
57,
110]. Prospective clinical trials may help optimizing management of immune-related adverse events.
Hypomethylating agents such as azacitidine put patients with AML or MDS at risk of IFI (probable/proven IFI 1.6%,
n = 121, to 8.3%,
n = 64) [
30,
82]. Further, independent risk factors are low neutrophil and platelet counts [
68], as well as prior intensive chemotherapy [
30,
68]. Evaluation of risk factors should precede prescription of hypomethylating agents and antifungal prophylaxis could be considered accordingly.
Targeting CD20 leads to prolonged B cell depletion and in rare cases to late-onset neutropenia [
29,
106,
109]. One retrospective case-control study reported that a significantly higher IFI rate was reported in patients treated with rituximab regimens compared to chemotherapy alone (41.7 vs. 17.1% among all infections,
n = 69) [
61]. Large randomised trials evaluating efficacy and safety of adding rituximab to standard chemotherapy did not find increased IFI rates [
13,
38]. Antifungal prophylaxis should only be considered in case of additional risk factors.
Further antibodies target CD19, CD33 or interleukin-2 (IL-2). Low evidence on risk of IFI makes it difficult to give specific recommendations and guidelines on empiric or pre-emptive therapy should be followed [
43,
74]. In rare occasions where CD52 antibody is part of the antineoplastic strategy, mould directed prophylaxis should be considered [
51,
71]. Bispecific antibodies frequently cause neutropenic fever and infections, but direct causal relationship with these drugs is difficult to attribute being used in patients with advanced lymphoma at high risk for infection anyhow [
85]. An increased risk for IFI has not been reported to date.
Given the high attributable mortality of IFI, the individual risk of patients treated with the drug classes above should be evaluated, and antifungal prophylaxis prescribed on case by case basis. Guidance that is more precise needs prospective trials focussed on infections.
Infection control for prevention of IFI
Infection-control measures in the haematological and oncologic setting are heterogeneous and contentious, particularly about transmission of fungi. The
Robert Koch-Institute in Germany published recommendations on hygiene requirements for the medical care of immunocompromised patients [
3]. However, most recommendations are based on expert opinion rather than actual published evidence. We reviewed recent trials on infection-control measures intending to prevent or reduce the rate of IFI.
Most studies focusing on the role of protective isolation are non-randomised and biased by renovation and reconstruction [
67]. Available studies suggested clinical benefit of air filters and positive pressure environments, but mainly evaluated fungal conidia air concentration instead of patient outcome [
55,
76]. None was randomised. One meta-analysis confirmed the low level of available evidence. No data showing a reduction of mould infections are available [
90].
Surgical masks are used for protection of immunocompromised high-risk patients, but a clinical benefit has not been demonstrated [
64]. One RCT compared 80 adult patients treated for acute leukaemia or HSCT regarding standard hospital hygiene procedures with or without wearing masks. A reduction of IFI was not seen (proven/probable IFI in 19.5 and 20.5%) [
66]. In contrast, one study compared neutropenic patients wearing surgical masks during hospital construction with a historical control and found a reduction in
Aspergillus spp. infections [
83]. Specific settings may justify the use of well-fitting face masks; routine use seems inappropriate.
The value of germ-reduced diet including so-called “neutropenic diet” is unproven. No RCT proved a benefit for prevention of infection and related outcomes. All studies had limitations regarding confounding interventions, outcome definitions, intervention and control diets [
25,
33,
69,
105,
107].
Further clinical implications include appropriate hand hygiene. This aspect has recently been pointed out within the context of
Candida auris transmission considering that hands can be key vectors in the transmission of yeasts [
89]. Housing of patients as well as limitation of environmental exposure to air-borne conidia are matters of infection control and may outweigh impact of chemoprophylaxis. Because of difficulties in randomisation evidence remains low.
Due to lack of evidence, we do not provide recommendations for clinical practice.