Factor	Comments
Immunodeficiency related to status and type of underlying cancer	Certain cancers (eg, B-cell CLL) induce a broad spectrum of immune defects that worsen during progression of the underlying disease [63]; anecdotal observations suggest that disease remission has a positive effect on the infectious complications associated with treatment with SMKIs, whereas clinical studies of frontline ibrutinib-based therapy have not revealed any associations between remission and major infectious complications [64]
Patient-specific environmental exposure	Complex epidemiological factors that are associated with climatic variables, travel, occupation, nosocomial exposures, and previous lung colonization with molds (eg, Aspergillus) or other fungi (eg, PJP) have an effect on the fungal inoculum’s effect on individual patients [1, 3]
Broad inhibitory effects of SMKIs on the immune system	In contrast to patients with primary immunodeficiency, who may have cell-specific residual activity of the affected gene [47], pharmacological inhibition of the corresponding signaling pathway typically affects a broader range of immune cells that could result in a more severe immunosuppressive phenotype
Acute-onset effects of SMKIs on the immune system	Immune restoration mechanisms with a protective role against infectious insults are less likely to operate in the acute setting of pharmacologically induced immunodeficiency than in the long-term course of congenital immunodeficiency
Potential off-target effects of SMKIs	The off-target effects of kinase inhibitors depend on the structure, dosage, type of action (covalent binding vs noncompetitive inhibition of the target), and possibly other host-related factors that are difficult to assess (eg, PK/PD properties, metabolism, drug-drug interactions, and synergistic effects with other immunosuppressive medications) and could result in broad immunosuppressive effects
Genetic predisposition to IFI	Certain polymorphisms in innate immunity genes are associated with an increased risk for the development of IFI in hematopoietic stem cell transplant recipients and patients with hematological cancer and severe underlying immunodeficiency [44, 45]
Immune defects related to previous infectious episodes	IFIs are increasingly observed in patients recovering from sepsis or following infections with certain immunosuppressive viruses (eg, influenza and CMV) [1–3]; the complex underlying mechanisms of sepsis-induced immunodeficiency in these patients are incompletely understood [65]
Immunosuppressive effects of other drugs	Corticosteroids and other immunosuppressive medications (eg, purine analogues) markedly increase the risk for the development of IFIs [1–3]; previous, concomitant, or sequential receipt of immunosuppressive therapies makes it challenging to assess the relative risk of IFI in patients treated with SMKIs
Pharmacogenomics and drug-drug interactions on compound metabolism	The clinical efficacy, development of resistance, and toxicity associated with SMKI treatment largely depend on the PK/PD parameters of these compounds [60]; genetic variation in drug-metabolizing enzymes or transporters involved in the absorption, metabolism, and elimination of these SMKIs are influenced by a constellation of genetic and nongenetic factors (eg, disease, drugs, comorbid conditions, and exposures) [66, 67]
Net state of immunodeficiency related to aging and underlying comorbid conditions	Aging, structural lung disease, iron overload, diabetes mellitus or other metabolic abnormalities, chronic inflammatory disease, and comorbid conditions affect systemic and local antifungal host defense mechanisms; collectively, all these factors profoundly affect the net state of immunodeficiency of individual patients and increase the colonization risk for certain fungi (eg, Aspergillus, and PJP) [3]
Uncharacterized pathogen-associated risk factors	Dissecting the complex pathogenetic mechanisms of IFIs in immunocompromised patients will require understanding the molecular interactions among fungal virulence attributes and (1) the microbiome, (2) other copathogens, (3) local and systemic host defense pathways, and (4) immunosuppression related to underlying diseases, medications, and incompletely characterized environmental factors

Abbreviations: CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; IFI, invasive fungal infection; PJP, Pneumocystis jirovecii pneumonia; PK/PD, pharmacokinetic/pharmacodynamic; SMKIs, small molecule kinase inhibitors.