Page 551 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 37 Infections in the Immunocompromised Host 529

and PTLD. Other infections that have occurred are overwhelming
Rituximab bacteremia, bacterial meningitis, toxoplasmosis, PML, dissemi-
Rituximab is a chimeric murine–human mAb that targets CD20 nated amoebiasis, parvovirus infection, and nocardiosis. All
on mature B lymphocytes. It results in rapid and profound patients receiving alemtuzumab should receive PJP and herpes-
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depletion of B cells that can last up to several months. In virus prophylaxis for a minimum of 2 months after therapy or
most adults, serum Ig levels remain largely stable, since plasma until CD4 counts are ≥200 cells/µL (Campath package insert).
cells do not express CD20. Initial trials suggested that rituximab Given the high incidence of CMV reactivation and disease,
had minimal effect on the occurrence of infections; however, prophylaxis or preemptive therapy is warranted.
more recent meta-analyses have reported a higher risk of infec-
tions, especially with repeated administration and in patients Daclizumab and Basiliximab
with underlying immune defects or concomitant significant Daclizumab and basiliximab are humanized and chimeric mAbs,
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immunosuppression. HBV reactivation occurs, and there have respectively, that target CD25, the α chain of the IL-2 receptor
been reports of fulminant hepatitis and death after rituximab complex expressed on activated alloantigen-reactive T lympho-
treatment, particularly when used in combination therapy (e.g., cytes. They competitively inhibit IL-2 binding and prevent IL-2
rituximab with cyclophosphamide, doxorubicin, vincristine, mediated activation of lymphocytes and cytokine release. They
and prednisone [R-CHOP]). Also a reverse seroconversion are mainly used in transplantation to prevent rejection or steroid-
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phenomenon has been described, with loss of protective HBV refractory GvHD. When used as prophylaxis for rejection in
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surface antibodies and reactivation. Assessment of HBV status SOT, their use does not seem to be associated with an increased
before starting rituximab is recommended. To reduce the risk of risk in infections. In allo-HSCT, high rates of mortality and of
reactivation, HBV suppression with antiviral medication should be OIs (95%) have been reported in patients receiving daclizumab
considered. for steroid-refractory GvHD; however, given the high risk of OIs
Since the initial approval of rituximab, there have been over in this population in general, the actual role of daclizumab is
280 cases of PML associated with its use. Most cases have been unclear. Infections described in this setting are common bacterial,
reported in patients with hematological malignancies; however, viral (CMV, BK virus, adenovirus, HSV, RSV, influenza virus),
some have been reported in patients with autoimmune or EBV-associated PTLD, invasive fungal infections (mold and
inflammatory diseases, who take other immunosuppressants yeasts), as well as Legionella and Nocardia and NTM infections,
as well. Rituximab now carries a black box warning about the TB, and toxoplasmosis. 38
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risk of PML and death. There have been many reports of
PJP following use of rituximab, although most patients also Natalizumab
received other immunosuppressive therapies. The need for PJP Natalizumab is a humanized IgG4 that targets the α 4 subunit of
prophylaxis with its use remains to be determined. The great- α 4 β 1 and α 4 β 7 integrins, found in lymphocytes; it inhibits their
est risk of infection appears to be related to viral reactivation, binding to cellular adhesion molecules (vascular cell adhesion
particularly in children; as usual, this is confounded by prior molecule-1[VCAM-1] and mucosal addressin-cell adhesion
or concomitant immunosuppressive medications. In children molecule-1 [MAdCAM-1]) in the central nervous system (CNS)
with immune-mediated neurological diseases, infections after and the GI tract, thereby attenuating inflammation in these
rituximab use are common; even lethal CMV disease has been tissues. 38,43 It is associated with a profound decrease in CD4,
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reported. Other rare infections that have been described are CD8, and CD19 lymphocytes in cerebrospinal fluid (CSF), and it
enteroviral meningoencephalitis, CMV disease, disseminated is used in the treatment of multiple sclerosis and Crohn’s disease.
VZV infection, refractory babesiosis, parvovirus B19 infection, Natalizumab was temporarily withdrawn from the market in
and nocardiosis. 37 2005 after three cases of PML were reported in patients with
prolonged exposure. It has now been reintroduced with a black
Alemtuzumab box warning about the risk of PML. Based on retrospective global
Alemtuzumab is a humanized IgG1 that targets CD52 on B and surveillance data, the overall incidence of PML in natalizumab
T lymphocytes, monocytes, macrophages, and NK cells. It lyses treated patients is 1.01 cases/1000 patient-years. However, the risk
these cell populations and results in profound and sustained of PML is significantly increased in patients who have detectable
deficits in cellular and humoral immunity that lasts for several anti-JC virus antibodies before the initiation of therapy, had
months; CD4 and CD8 cell count reach their nadir approximately prolonged exposure to natalizumab (>24 months), and had
4 weeks after treatment, but median counts remain at <25% prior use of immunosuppressants (11.1 cases/1000 patients [95%
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of baseline for approximately 9 months. Opportunistic and confidence interval (CI) 8.3–14.5]). The incidence in patients
nonopportunistic infections have been associated with its use, with no detectable anti-JC virus antibodies is calculated at 0.09
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particularly reactivation of herpes virus (e.g., Epstein-Barr virus cases/1000 patients (95% CI 0–0.48). Increases in bacterial
[EBV], CMV, disseminated VZV) and fungal infections (e.g., and viral infections and OIs have been reported as well, but
PJP, invasive molds, and dimorphic fungi). Moreover, several most patients with these infections were receiving concurrent
cases of TB and NTM infection have been reported. The incidence immunosuppression.
of these OIs varies with the administered dose and whether it
is used as a single agent or in combination with other immunosup- Bortezomib
pressants (e.g., induction therapy [4.5%] versus treatment for Bortezomib is a dipeptide boronate proteasome inhibitor that
rejection [21%] in SOT). 37,38 When used for T-cell depletion in causes G2–M cell cycle arrest and apoptosis, which ultimately
allogeneic HSCT (allo-HSCT) it has been associated with a very impacts T-cell immunity. It is now approved for the treatment
high risk of CMV reactivation (50–85%) and disease, severe of multiple myeloma and mantle cell non-Hodgkin lymphoma.
adenovirus infection, human herpesvirus-6 (HHV-6) encephalitis, An increased incidence of herpes virus infections, in particular
respiratory viral infections that frequently progress to pneumonia, VZV infection, has been reported. The incidence in patients