Adverse Consequences of
Prolonged Immunosuppression
Bone marrow suppression is the most common
toxicity with cytotoxic drugs, such as methotrexate, azathioprine,
6-mercaptopurine, and mycophenolate mofetil.
The degree of bone marrow suppression observed
with cytotoxic drugs is usually dose-related and can be modulated by dose
changes, although in rare cases the bone mar-row failure may become
irreversible. Usually if a patient’s white blood count (WBC) falls below 3000
cells/mm3, any of these drugs should be stopped until the WBC
increases to 3000 cells/mm3 and reinstituted at a lower dose.
When neutropenia develops, severe infections
are likely to develop; these infections are extremely difficult to treat, often
being the cause of death. For this reason, neutropenia is considered as the
most serious side effect of immunosuppression, and continuous moni-toring of
white cell count is essential in patients treated with these drugs. The
availability of recombinant G-CSF and GM-CSF provides the means to considerably
shorten the pe-riod of neutropenia .
Infections are another common adverse effect in
patients treated with all types of cy-totoxic or immunosuppressive drugs. This
is a consequence of global immunosuppression, as reflected by the patient’s
frequent inability to mount a primary immune response after adequate immunization.
Two main features characterize the infections of immunosup-pressed patients:
1.
They
usually involve low-grade pathogens or opportunistic microorganisms not usually
associated with clinical disease.
2.
The
extent and distribution of the infection are unusual, differing from those
commonly observed in noncompromised hosts.
Because the depression of cellular immunity is
the goal pursued when these drugs are used, the patients become more vulnerable
to viral infections, such as herpes simplex and varicella, which may
disseminate with a fatal outcome. The incidence of herpes zoster (shingles) is
increased, but the course of the disease is similar to that seen in oth-erwise
normal individuals. The impairment of cell-mediated immunity is also probably responsible
for the frequency and severity of opportunistic infections with mycobacteria,
viral (e.g., cytomegalovirus, herpes simplex, varicella-zoster), parasitic
(e.g., Pneumo-cystis carinii,
toxoplasmosis), and fungal infections (e.g.,
Candida sp. and Aspergillus sp.).
Those infections are much more likely to disseminate during immunosuppressive
treatment. Systemic candidiasis, measles encephalitis, measles retinitis,
progressive mul-tifocal leukoencephalopathy, and cerebral toxoplasmosis are
just a few examples of atyp-ical infections almost exclusively seen in
immunocompromised patients.
An increased incidence of neoplasms is a major
concern in patients chronically im-munosuppressed. Although the precise role of
the immune system in eliminating neoplas-tic clones in a normal individual is
not clear, the incidence of malignancies is clearly ele-vated in patients
receiving immunosuppressive drugs. The most frequently seen malignancies in
immunosuppressed patients after solid organ transplantation include basal cell
carcinoma, Kaposi’s sarcoma, carcinoma of the vulva and perineum, non-Hodgkin’s
lymphoma, squamous cell carcinoma, and hepatobiliary carcinoma. Also, the
location and pattern of spread of those malignancies is unusual. For example,
primary central nervous system lymphoma is associated with congenital,
acquired, or iatrogenic immunodeficiency states (e.g., immunosuppression after
a solid organ transplant). The highest incidence of central nervous system
lymphoma occurs in patients with AIDS (1.9–6% of the cases in dif-ferent
series). Azathioprine-based immunosuppressant regimens administered post–solid
organ transplantation are associated with the highest incidence of cutaneous
malignancies. In contrast, posttransplant high-intensity immunosuppressive
regimens, especially those including antilymphocyte antibody preparations
(e.g., OKT3, ATGAM), are associated with non-Hodgkin’s lymphoma. Reactivated
Epstein-Barr virus (EBV) infections are be-lieved to cause non-Hodgkin’s
lymphoma in immunocompromised patients because trans-forming proteins encoded
by integrated EBV genomes are expressed in the malignant cells. Interestingly,
the incidence of the most common cancers (e.g., breast, lung, prostate, and
colon) is not increased in immunosuppressed patients.
Other side effects are secondary to the
toxicity of these drugs (particularly those with cytotoxic properties) over
rapidly dividing cells and include hair loss or alopecia, loss of gonadal
function, bloody diarrhea, as well as constitutional symptoms (e.g., nausea,
vom-iting, anorexia, malaise, etc.), chromosomal changes, and teratogenic
effects.
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