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.