Page 873 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

604 PART 5: Infectious Disorders

T-Lymphocyte Function: Indications from in vitro testing of lymphoid administration and opportunistic CMV infection. Pyrexia and TNFα
cell responsiveness to mitogen-induced blastogenesis suggest that release after the administration of ATG stimulates cellular nuclear factor
T-cell function may be moderately depressed in patients with acute κB (NFκB) binding to the promoter region of the immediate early anti-
leukemia. Among patients undergoing remission-induction therapy gen gene of CMV. 77,78 CMV infection after ATG administration depends
for acute leukemia, decreased cell-mediated immune responsiveness on the ATG product used, the dose administered, the pretransplant
can be detected for up to 6 months following chemotherapy-induced donor and recipient serologic status, and use of CMV prophylaxis.
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remission. 66,67 In some patients, immune function decline may herald The incidence of cancers, particularly posttransplant Epstein-Barr virus
a relapse. 67 transformed lymphoreticular disorders (PTLD), is increased in associa-
Patients who have received purine analogue therapy for chronic lym- tion with ATG administration and with coinfection by CMV. The highest
phocytic leukemia, specifically fludarabine, have prolonged qualitative risk for PTLD is among EBV seronegative organ transplant recipients
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and quantitative T-lymphocyte defects, and, in addition, B lymphocy- receiving a transplant from an EBV seropositive donor. Similarly,
topenia and monocytopenia. As result, there are enhanced suscepti- there is an increased dose-dependent risk for BK polyomavirus viremia,
bilities to pyogenic bacteria (Streptococcus pneumoniae, Haemophilus viruria, and nephropathy with ATG therapy. 80,81 These processes may
influenzae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas confound the assessment and management of critically ill transplant
aeruginosa), opportunistic bacteria (including Listeria monocytogenes, recipients unresponsive to broad-spectrum antibacterial therapies and
Nocardia spp, and Mycobacterium spp), invasive fungal pathogens (such should be considered in this context.
as Candida spp, Aspergillus spp, Pneumocystis jirovecii, and Cryptococcus The monoclonal IL-2α-chain receptor (CD25) antagonists, basilix-
spp), and DNA virus infections (such as herpes group viruses including imab and daclizumab, inhibit lymphocyte activation, differentiation,
varicella-zoster virus, herpes simplex, and cytomegalovirus). 68 and proliferation. Treatment results in a complete saturation of the
The clinical consequences of T-cell dysfunction vary with the under- receptor for 6 to 12 weeks. While little effect of these agents on bacte-
lying disease and the cytotoxic regimen. For example, Pneumocystis rial, EBV, or fungal infection has been recognized, CMV shedding does
jirovecii infection is an uncommon phenomenon among adult patients appear to be somewhat increased in solid organ transplant recipients. 79,82
undergoing remission induction for AML but relatively common among Increased infection-related mortality has been observed among dacli-
children undergoing consolidation and maintenance-phase chemother- zumab recipients for steroid-refractory GvHD in allogeneic stem trans-
apy for acute lymphoblastic leukemia (ALL). 69-71 An intermediate degree plantation.
of risk for pneumocystosis appears to be present in those undergoing Alemtuzumab, a humanized monoclonal antibody preparation, tar-
bone marrow allografting or autografting. The immunosuppressive gets cell surface CD52 present on the surface of normal and malignant
potential of the conditioning regimens for HSCT appears to be greater T and B lymphocytes, monocytes, and NK lymphocytes. The product
than that associated with AML induction regimens. Accordingly, most has been used in chronic lymphocytic leukemia and T-cell depletion of
centers managing these patients recommend administering primary allogeneic stem cell products, resulting in a sustained reduction in both
prophylaxis for P jirovecii in HSCT recipients or patients with ALL. CD4 and CD8 T lymphocytes within 4 weeks of administration that may
These infections rarely occur during the primary period of myelosup- last as long as 9 months. The infectious complications described in
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pressive therapy–induced neutropenia. association with the use of alemtuzumab include reactivation of herpes-
Monoclonal Antibodies There have been a number of anti-T-lymphocyte virus infections (human cytomegalovirus, varicella-zoster virus, herpes
monoclonal antibody products that have been licensed by the Federal simplex virus), new respiratory virus infections, and invasive fungal
Drug Association (FDA) for the treatment of lymphoma, AML, breast infections (including pulmonary pneumocystosis, invasive candidiasis,
68,82,84
cancer, colorectal cancers, rheumatoid arthritis, and Crohn disease. and invasive aspergillosis). Also, invasive zygomycoses, tuberculous
82
Treatment with some of these products has been associated with a and nontuberculous mycobacterial infections have been observed. In a
higher risk for opportunistic infections due to CMV, Epstein-Barr virus, retrospective analysis of post-engraftment infections in allogeneic stem
BK polyoma virus, and invasive fungal infections. cell transplant recipients conditioned with alemtuzumab or antithymo-
Tumor necrosis factor-α (TNFα) is a mediator that stimulates the cyte globulin, the incidence of non-CMV infections was significantly
85
release of pro-inflammatory cytokines (such as interleukin [IL]-1β, higher among alemtuzumab recipients. Moreover, the proportion of
IL-6, and IL-8), monocyte chemoattractant protein-1, adhesion mol- patients developing CMV disease or BK virus associated hemorrhagic
ecules, and phagocyte and T-lymphocyte activators. TNFα blockers cystitis were markedly higher among alemtuzumab recipients. 85
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such as infliximab, etanercept, and adalimumab have been used in the B-Lymphocyte Function: Modern cytotoxic therapy for acute leukemia
management of severe autoimmune disorders, chronic inflammatory appears to have a more profound effect on humoral immune com-
bowel disease, steroid-refractory graft-versus-host disease, and solid petence than on T-lymphocyte function. Serum immunoglobulin
organ transplant graft rejection. These products have been associated concentrations and the efficiency of new antigen-induced immuno-
with a two-to-threefold increase in serious infectious complications, globulin synthesis have been observed to decline following institution
particularly in patients with rheumatoid arthritis. Infectious complica- of remission-induction therapy, reaching a nadir at approximately
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tions have included mycobacterial diseases, due to both Mycobacterium 5 weeks. It has been difficult to separate the effects of the underlying
tuberculosis and nontuberculous mycobacteria. The median time malignant disease from the effects of the cytotoxic therapy. There
75
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of onset of clinical infection from the initiation of treatment has been does not appear to be a prognostically useful parameter of T- or
12 weeks. Such infections have tended to be fulminant and involve B-cell function that predicts infection risk in neutropenic patients
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extrapulmonary sites. Invasive fungal infections such as histoplasmosis, analogous to the predictive value of the ANC for pyogenic bacterial
invasive candidiasis, invasive aspergillosis, coccidiodomycosis, and or fungal infection. However, presence of hypogammaglobulinemia
cryptococcosis have also been associated with TNFα blocking agents. 76 may help identify increased risk of infection by encapsulated bacteria.
Immune modifiers of T-lymphocyte function are often deployed in Rituximab, a chimeric murine-human monoclonal IgG1 anti-
hematologic and solid organ transplantation to treat or prevent graft- body preparation administered for treatment of B-cell non-Hodgkin
versus-host disease or graft rejection, respectively. These products lymphoma, targets CD20 on the surface of normal and malignant B
include antithymocyte globulin (ATG) prepared from rabbits (rATG) lymphocytes, leading to a predictable depletion of these cells over a 6- to
or horses (hATG), the non-T lymphocyte depleting anti-interleukin-2α 9-month period. This agent does not affect CD3, CD4, CD8, or natural
receptor preparations (daclizumab and basiliximab), and alemtuzumab. killer T-lymphocyte populations. Based on a systematic review of five
All ATGs produce a dose-dependent depletion of T lymphocytes. randomized controlled trials on the treatment of non-HIV patients with
Treatment may result in significant lymphopenia for up to a year. For non-Hodgkin lymphoma, no incremental risk for infections has been
example, there is a direct dose-dependent relationship between ATG observed. This notwithstanding, two recently published systematic
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