What are the risk factors for developing fungal infections, particularly in individuals with weakened immune systems, such as those with Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS), diabetes, or those taking immunosuppressive medications like prednisone?

Risk Factors for Fungal Infections

The primary risk factors for fungal infections are immunosuppression (particularly neutropenia, T-cell deficiency, and corticosteroid use), anatomical barrier disruption, and specific high-risk medical conditions including hematologic malignancies, transplantation, HIV/AIDS, diabetes, and critical illness. 1, 2

Immunosuppression-Related Risk Factors

Neutropenia

• Prolonged and profound neutropenia (<500 neutrophils/mm³ for >10 days) is the single most important risk factor for invasive fungal infections, particularly invasive aspergillosis 1
• Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy have invasive aspergillosis incidence rates of 10-24% 1
• Neutropenia combined with lymphopenia substantially increases risk, especially for late-onset infections 1

Corticosteroid Therapy

• High-dose corticosteroids (≥20 mg prednisolone daily for ≥2 weeks) significantly increase fungal infection risk, with Candida species being the most common pathogen 3, 2
• The FDA label for prednisone explicitly warns that corticosteroids "suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens" and can "reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, and increase the risk of reactivation or exacerbation of latent infections" 2
• Corticosteroids may exacerbate systemic fungal infections and should be avoided in the presence of such infections unless needed to control drug reactions 2

T-Cell and Cellular Immune Deficiency

• Patients with HIV/AIDS (particularly CD4 counts <200 cells/μL) face elevated risk of Pneumocystis pneumonia, cryptococcosis, and candidiasis 1, 4
• Chronic granulomatous disease carries an estimated incidence of 0.1 fungal infections per patient per year, with invasive aspergillosis being the main cause of death 1
• Graft-versus-host disease (GVHD) and its treatment with immunosuppressants increase post-transplant fungal infection risk 1

Combination Immunosuppression

• Triple immunosuppressive therapy (steroids, methotrexate, thiopurines, or biologics) carries substantially increased fungal infection risk 1, 3
• Calcineurin inhibitors combined with other immunosuppressants markedly elevate risk 1
• JAK inhibitors, especially when combined with high-dose corticosteroids or in patients with low lymphocyte counts, increase susceptibility 1

Transplantation-Related Risk Factors

Hematopoietic Stem Cell Transplantation (HSCT)

• Allogeneic HSCT recipients have invasive aspergillosis incidence of 5-8% with haploidentical donors and 10-25% with non-related donors 1
• Umbilical cord transplants and non-related donor transplants increase post-transplant infection rates 1
• Total body irradiation (TBI) causes gastrointestinal damage and is identified as a risk factor for higher rates of invasive fungal disease 1

Solid Organ Transplantation

• Invasive aspergillosis presents during the first year post-transplantation, with highest incidence in lung, heart, intestinal, and liver transplant recipients 1
• Recipients of solid organ transplants are at increased risk due to prolonged immunosuppression required to prevent rejection 1

Anatomical and Barrier Disruption Risk Factors

• Central venous catheters provide direct access for fungal pathogens, particularly Candida species 5
• Recent abdominal surgery increases invasive candidiasis risk 5
• Mucosal Candida colonization (particularly heavy colonization at multiple anatomic sites, especially rectal and respiratory) is almost a prerequisite for invasive candidiasis 1
• Breakdown of skin and mucosal barriers is a major risk factor for fungal infections 6

Disease-Specific Risk Factors

Hematologic Malignancies

• Acute lymphocytic leukemia (ALL) in pediatric patients has low risk except for Pneumocystis pneumonia 1
• Chronic lymphocytic leukemia (CLL) patients are at increased risk 1
• Fludarabine causes prolonged immunosuppression (months) affecting lymphopoiesis and medium-term (3-5 weeks) myelosuppression 1

Diabetes Mellitus

• Diabetic patients, particularly those with hyperglycemia and ketoacidosis, are at significantly increased risk for mucormycosis and candidal infections 1, 7
• Rhinocerebral mucormycosis is the most common form in diabetic patients 1

Chronic Obstructive Pulmonary Disease (COPD)

• COPD patients, especially those receiving chronic corticosteroid treatment, have documented increasing incidence of invasive fungal infections 1

Critical Illness

• Prolonged intensive care unit (ICU) stay increases invasive candidiasis risk 5
• Critically ill patients have documented increasing incidence of invasive fungal infections 1
• Age extremes (<1 month or >65 years) increase risk 5

Additional Risk Factors

Prior Infections and Antimicrobial Use

• Prior bacteremia and broad-spectrum antibacterial use are associated with increased invasive fungal disease risk due to sepsis-induced immunosuppression and alteration of gastrointestinal flora leading to fungal colonization 1
• Prior colonization with Candida species (particularly Candida tropicalis versus Candida albicans) is predictive of subsequent invasive infection 1

Nutritional and Metabolic Factors

• Total parenteral nutrition increases invasive candidiasis risk 5
• Renal failure is an additional risk factor for invasive candidiasis 5
• Cirrhosis increases susceptibility to invasive fungal infections 1

Environmental and Occupational Exposures

• Professions with repeated exposure to fungal spores (farmers, masons, carpenters/construction workers, outdoor workers) increase risk 1
• Ongoing construction at home, in the community, or in hospital wards/buildings with inadequate air filtration 1
• Lack of HEPA-filtered air during HSCT 1
• Contaminated food or spices (particularly pepper and unpasteurized products) have been traced to fungal outbreaks 1
• Current tobacco or marijuana use 1

Geographic Considerations

• Residence in or travel to endemic areas for specific fungi (Coccidioides, Histoplasma, Blastomyces, Penicillium marneffei) increases risk 1, 8
• Environmental spore counts vary geographically and temporally; counts above 25 CFU/m³ are considered very high 1

Important Clinical Caveats

• The risk of fungal infection increases with the cumulative number of risk factors present, not just individual factors in isolation 1, 5
• Very low birth weight infants (≤1500 g) constitute a distinct high-risk population 8
• Hyposplenism (more frequent in ulcerative colitis than Crohn's disease) may be associated with increased risk, though systematic screening is not currently recommended 1
• Cytomegalovirus (CMV) infection is a risk factor for late presentation of invasive aspergillosis 1
• The rate of infectious complications increases with increasing corticosteroid dosages 2