Page 555 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 37 Infections in the Immunocompromised Host 533

Fusariosis, mucormycosis, and dematiaceous and other mold such adenovirus and smallpox virus. Letermovir is a new, highly
infections are increasingly recognized as significant pathogens potent anti-CMV agent with a novel mechanism of action target-
in transplant recipients. Clinical disease can be similar to the ing the viral terminase subunit pUL56, a component of the
infection caused by Aspergillus spp., with largely sinopulmonary terminase complex involved in viral DNA cleavage and packaging.
disease. Fusarium spp. frequently disseminate hematogenously Initial trials have shown that letermovir is effective in reducing
and can be isolated in blood cultures. Many of these infections the incidence of CMV infection in allo-HSCT and has been used
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are resistant to most antifungal drugs and remain an important successfully in MDR infections. Phase III clinical trials are
cause of transplantation-related mortality. 51 currently underway. There are other antivirals in the pipeline,
but they are at much earlier stages of development. Because of
Invasive Candidiasis the scarcity of effective, nontoxic antivirals and because uncon-
Before routine use of antifungal prophylaxis, invasive candidiasis trolled viral infections correlate with a lack of cellular immunity
was the most common invasive fungal infection in transplant against viruses, several groups are working on the development
recipients. In SOT, most Candida infections occur during the of adoptive immunotherapy, which is the artificial reconstitution
first month after transplantation, usually related to the surgical of virus-specific T cells with in vitro expanded T cells.
procedure. Recipients of liver, pancreas, and small bowel are A number of small studies have now shown that virus-specific
at high risk for invasive candidiasis; lung transplant recipients T cells are effective in controlling CMV, EBV, and adenovirus
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can develop bronchial anastomotic infections. In HSCT, most infections in transplant recipients. The translation of adoptive
Candida infections occur in the preengraftment period and are immunotherapy into the clinic has been limited by technical
associated with mucosal injury, which results from the condition- difficulties associated with the generation of viral-specific cells
ing regimen and with the widespread use of antibiotics for the that are not alloreactive, that can be produced from naïve T cells,
treatment of fever and neutropenia. Fluconazole-resistant Candida and that can be developed rapidly and in a cost-effective way.
spp. are now increasingly isolated, and echinocandins (caspo- Cells obtained from the original donor can yield long-lasting
fungin, micafungin, and anidulafungin) are now considered the immunity, but the process of generating these cells can be
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drugs of choice in invasive candidiasis. Antifungal prophylaxis cumbersome and often not available in a timely manner. Some
reduces the incidence of invasive fungal infections after HSCT, groups have explored adoptive transfer of HLA partially matched
as well as infection-related and overall mortality. In SOT, anti- virus-specific T cells derived from third-party donors, that is,
fungal prophylaxis is recommended for high-risk liver transplant healthy individuals other than the donor of the patient’s trans-
recipients and in small bowel and lung transplant recipients. plant. Such cells yield high number of virus-specific T-cells, but
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these cells tend to be short lived. Currently, a few international
TRANSLATIONAL RESEARCH centers have established cryopreserved banks with virus-specific
T-cell lines from normal donors, but these are still mostly for
investigational use. Significant advances continue to be seen in
oN tHE HorIZoN the field of cellular therapy, and these could become part of the
armamentarium against viruses in the next decade.
• Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus
infections remain problematic infections in both hematopoietic-stem-cell
and solid-organ transplant recipients, and medications currently available CONCLUSIONS
to treat these infections have significant associated toxicities or lack
efficacy. Immunocompromised hosts are surviving longer as antimicrobials
• Adoptive immunotherapy, in which virus specific donor-derived T cells improve and as immunosuppressant agents become less toxic.
are expanded and infused into the transplant recipient, will likely become Both monogenetic primary immunodeficiencies and the increas-
more widespread in treating these infections.
ingly specific immunosuppressant agents allow insight into host
control of specific microbes. With this knowledge, new types of
Viral reactivation and disease are still a major cause of morbidity immunodeficiencies are being recognized, such as the autoan-
and mortality among transplant recipients. CMV, EBV, and tibody cytokine disorders described above. In addition, the
adenovirus are particularly problematic once disease develops. knowledge of specific host immunity will help in developing
Preemptive strategies have substantially decreased the incidence therapies to boost host responses in the increasing challenges
of invasive CMV disease; nevertheless, a significant number of of treatment-resistant microbes.
patients still go on to develop invasive disease. Preemptive therapy Please check your eBook at https://expertconsult.inkling.com/
and treatment are limited by the toxicity associated with the for self-assessment questions. See inside cover for registration
available antivirals and their lack of efficacy against EBV and details.
adenovirus. In addition, development of resistance can complicate
therapy. Development of new effective antivirals has been slow. REFERENCES
Brincidofovir (CMX001) is an ether lipid ester analogue of
cidofovir that has been reported to be 1000-fold more potent 1. Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol
than cidofovir against DNA viruses, such as CMV and adenovirus. 2010;38:3–10.
It is available in an oral formulation, but it lacks the nephrotoxic 2. Rosenzweig SD, Holland SM. Phagocyte immunodeficiencies and their
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effects of cidofovir. However, a recent trial in high-risk recipients infections. J Allergy Clin Immunol 2004;113:620–6.
in HSCT, in which brincidofovir was used to prevent CMV 3. Greenberg DE, Ding L, Zelazny AM, et al. A novel bacterium associated
with lymphadenitis in a patient with chronic granulomatous disease.
infection, did not achieve its primary endpoint for the prevention PLoS Pathog 2006;2:e28.
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of clinically significant CMV infection after transplantation. 4. Siddiqui S, Anderson VL, Hilligoss DM, et al. Fulminant mulch
There are ongoing clinical trials to determine the efficacy and pneumonitis: an emergency presentation of chronic granulomatous
safety of brincidofovir for the treatment of other DNA viruses, disease. Clin Infect Dis 2007;45:673–81.