Immunotherapy for Infectious Diseases

316 Casadevall
CONCLUSION AND FUTURE PROSPECTS
The development of various types of immunotherapy is potentially the most important
advance in the therapy of human fungal infections since the introduction of amphotericin
B in the late 1950s. The impetus for developing immunotherapy comes from the
fact that fungal infections carry very high mortality and morbidity in patients with
impaired immunity despite aggressive antifungal chemotherapy. Many fungal infections
cannot be cured in severely immunocompromised patients with existing antifungal
therapy. The limitations of antimicrobial chemotherapy in patients with impaired
immune function combined with major advances in the field of clinical immunology
provide a fertile environment for the development of immune therapies against fungal
infections.
There is clear evidence that CSFs can shorten the period of myelosuppression and
neutropenia associated with vulnerability to many fungal infections. There are also
many encouraging reports of the use of granulocyte transfusions, CSFs, and IFN-� in
combination with antifungal agents for the treatment of fungal infections. The anecdotal
reports of cures in infections due to mucor, Fusarium, and other rare fungal
pathogens in patients with neutropenia are noteworthy, given the dismal historical
experience in the treatment of these infections. However, most clinical information
regarding the use of immunotherapy in severe fungal infections is anecdotal, fragmentary,
and not controlled for variables that can affect the outcome. Since we do not know
the number of patients treated with immunotherapy unsuccessfully, the literature may
be biased toward case reports of successful outcomes. Until prospective controlled
studies are completed, the efficacy of such measures must be considered uncertain.
Although there is a clear need for controlled trials of immunotherapy against fungal
infections, such trials are likely to be very difficult because of several factors. First,
many fungal infections are relatively rare, and only multicenter studies can accumulate
enough patients for meaningful studies. Second, the increasing number of reports of
successful outcomes after immune therapy raises difficult ethical questions of whether
such studies should be done given that conventional antifungal therapy has such a poor
historical record. Third, large sample sizes may be needed since biologic differences
in the patients and in the type of fungal infection could result in significant patient-topatient
variability in response and outcome. For example, the risk of fungal infection
in patients with neutropenia depends on many variables, including underlying illness,
antibiotic use, type of chemotherapy, and so on (reviewed in ref. 79). In addition, there
is uncertainty in the classification of some fungal pathogens. Fungal infections categorized
as Mucormycosis or Fusarium are caused by any of many species of fungi,
which may exhibit biologic differences in pathogenesis and response to therapy. Even
the most common type of fungal infection, candidiasis, can be caused by any of several
Candida species. Hence, the successful development of immune therapies may be
critically dependent on parallel advances in mycologic taxonomy, human genetics,
diagnostic techniques, and immunology.
The dawn of immune therapy for fungal infections is now, and one can anticipate that
some types of immunotherapies will become routine in the future. The initial experience
with the use of immunotherapy provides encouragement for the study, development, and
use of immune modulators as adjuncts of standard antifungal therapy. Several promising
agents are already available, and the major challenge is to learn how to use those