Infectious Diseases in Critical Care Medicine

developing invasive fungal infections such as histoplasmosis, coccidioidomycosis, blastomy-
cosis, aspergillosis, candidiasis, and other opportunistic infections” (34). The FDA has alerted
the medical community that infection dueHistoplasmainfection in patients on anti-TNF
therapy is inconsistently recognized by physicians causing increased mortality due to delayed
investigation and treatment (34). Effective investigation consists of travel and residential
history with subsequent serology or urine testing. Chest radiograph for patients with possible
exposure may offer insight to previous exposure (Table 2). If active disease is suspected,
biologic therapy should be stopped and appropriate anti-fungal treatment administered. In
severely and acutely ill patients with positive geographic history, empiric therapy should
include coverage for these entities until mycotic infection is excluded.

Endemic Mycoses
Along with inciting early apoptosis of infected macrophages thus foiling human adaptive
immunity’s ability to protect against life-threatening disseminated disease, TNF inhibition
creates a similar dilemma in endemic mycotic infection as in TB infection: derangement of
granuloma formation resulting in invasive fungal infection. Again, as with TB, most
declarations of infection occurred within three to six months of starting therapy indicating
likelihood of reactivation versus new infection and the importance of effective screening.
Infliximab was significantly more likely to be the associative anti-TNF therapy in these
granulomatous infections (14,20). TNF-a potentiates antifungicidal capability of human
monocytes (35). As with TB, in mycotic infection, TNF inhibition interferes with granuloma
formation and apoptosis of infected macrophages occurs, which undermines the host’s ability
to protect against disseminated infection.
The most important pathogens are Coccidioides sp. and Histoplasma capsulatum.
Coccidioidomycosis may have a greater than sixfold increased risk in patients receiving
anti-TNF agents (14,36). Proper investigation includes residential, travel, and recreational
history, prior history of CNS infection, and serology testing. Histoplasmosis, one of the most
prevalent mycoses in the United States, need be considered in patients on biologic therapy
presenting with fever, malaise, cough, pneumonitis, pulmonary nodules, or hematological

Table 2 Overview of Mycoses

Organism Region Transmission Investigation

Presentation in

Active Disease

Coccidioidessp. US southwest
desert and
Mexico

Disruption of soil or

dust with bat/bird

droppings

Inhalation of mold

spores

History:

l Travel

l Residential

l Hobbies

l Prior CNS infections

l Coccidioidesprior

infection

Serology

Chest X Ray

Cough

Fever

Headache

Rash

Mucosal ulcers

Myalgias

Neurological

Histoplasma
capsulatum

Ohio, Mississippi,

St Lawrence,

Rio Grande,

river valleys

As above History:

l Travel

l Residential

l Hobbies

Urine histoplasmin

Fever

Arthritis

Pulmonary

Rash

Gastrointestinal

Hematological

Neurological

Cryptococcussp. Ubiquitous As above History:
l Hobbies
l Work environment
Cryptococcusinfection

Pulmonary

Neurological

Abbreviation:CNS, central nervous system.

Infections Related to Steroids and Biologics in Critical Care 381