Clinical Description and Epidemiology
In the bone marrow/stem cell transplant recipient, various defects in cell-mediated and humoral immunity contribute to the increased risk for infection. Despite advances in prophylactic and supportive care, infections remain a major cause of morbidity and mortality in this population. Early in the post-transplant period, prolonged neutropenia occurs secondary to the myelosuppression from the preparative regimen. Integumentary defects, such as those from mucositis and the presence of intravascular catheters represent portals of entry for colonizing organisms. Total body irradiation, when utilized results in additional cellular immune deficiency, including defects in the mononu-clear-phagocyte cell system. These defects in T-lymphocyte function, in addition to B-lymphocyte dysfunction, are especially pronounced in the allogeneic transplant recipient. Graft-versus-host disease (GVHD) results in increased immunosuppression, including subnormal immunoglobulin production and a hyposplenic state (with chronic GVHD). Therapy for this complication only adds further to the immunosuppression. Lastly, the use of T-cell-depleted marrow results in pronounced and prolonged deficiencies in CD3, CD4, and CD8 T lymphocytes (36,37). The use of peripheral blood stem cell products and the ancillary use of hematopoietic colony-stimulating factors such as GM-CSF have been found to result in a shorter time to engraftment, and thus a briefer period of neutropenia and a lesser risk for infectious complications (38).
Bone marrow transplantation is associated with a characteristic spectrum of post-transplant infectious complications that occur in relation to the time interval following transplantation (39). Although this was initially described in allogeneic transplant recipients, a similar pattern of infection, although with a decreased frequency, is found in autologous transplant recipients. The first three to four weeks after transplantation are characterized by marrow aplasia with marked neutropenia. Bacterial infections caused by common Gram-positive isolates such as S. aureus, coagulase-negative staphylococci, and a-hemolytic streptococci, and less commonly Gram-negative enteric organisms predominate in this period (40). With the administration of broad-spectrum antimicrobial agents, the normal colonizing flora, including anaerobes is ablated, and replaced by potentially more resistant bacterial isolates and fungi, especially Candida species, with subsequent infections caused by these organisms (41). In patients who are seropositive for HSV, a high rate of reactivation HSV infections may occur during this period. In addition, HSV may cause pneumonia, hepatitis, and esophagitis. Respiratory syncitial virus infections may also occur in a seasonal pattern. The duration of neutropenia has been shortened by the use of hematopoietic CSFs such as G-CSF and GM-CSF in the immediate post-transplant period. Furthermore, stem cell transplant recipients may have a lower risk of infection (42).
The spectrum of infection is different in the period 1 to 3 mo post-transplant. Marrow engraftment with resolution of neutropenia has generally occurred by this time. However, acute GVHD has its onset in allogeneic recipients. Major pathogens observed during this time include CMV, Aspergillus species, other non-Candida fungi, and Pneumocystis carinii (43-45).
After 100 d following transplantation, chronic GVHD may complicate the course of allogeneic transplant recipients (46). The incidence of pneumococcal bacteremia rises dramatically, owing to the functional asplenic state induced by the chronic GVHD. Bacterial sinopulmonary infections, especially with encapsulated organisms, also become more common. The incidence of VZV infections, mostly dermatomal but occasionally disseminated, also increases. Infections with CMV continue to occur through this period. Other infections such as acute hepatitis C infection may also manifest. Catheter-related infections may occur throughout the entire post-transplant period (47,48).
Owing to the significant impact of infections on the prognosis for bone marrow transplant recipients, prophylactic antimicrobial use in this population has been extensively studied (49). Both trimethoprim-sulfamethoxazole and quinolone derivatives such as ciprofloxacin have been used for selective gut decontamination, and both are effective in reducing the frequency of bacteremia in the neutropenic period. Trimetho-prim-sulfamethoxazole is cheaper, but is associated with a higher incidence of Clostridium difficile colitis and Gram-negative infections. However, ciprofloxacin use is complicated by a greater incidence of a-hemolytic streptococcal infections. Because of the occurrence of Gram-positive infections early in the post-transplant period, van-comycin use had been advocated for 1-2 d prior to marrow/stem cell infusion (50). However this practice has been abandoned at many centers, owing to the concern for the development of vancomycin-resistant isolates, especially vancomycin-resistant enterococci and coagulase negative staphylococci.
Antifungal prophylaxis with fluconazole has also been utilized. In a large multicenter prospective randomized trial, the use of fluconazole (vs placebo) was found to result in a significantly decreased incidence of systemic fungal infection (51). Although there were fewer infections caused by Candida albicans and Candida tropicalis, there was no difference in the occurrence of Candida krusei infections, and no major impact on the occurrence of Aspergillus infections. However in other trials, the use of fluconazole was associated with higher rates of infection with Candida krusei and Torulopsis glabrata (15). Because of the limited ability of prophylactic fluconazole to prevent Aspergillus infections, other prophylactic antifungal regimens have been employed, including low-dose amphotericin B, aerosolized amphotericin B, and liposomal amphotericin B (52,53). However, late-onset infections with Aspergillus spp. remain a problem despite these prophylactic antifungal approaches.
Antiviral prophylactic measures in this population have been directed against several members of the herpesvirus family. CMV is a major cause of morbidity and mortality in allogeneic, and less so in autologous transplant recipients. Patients who are seropositive for CMV prior to transplantation are at greatest risk, especially if the donor is CMV seronegative. The use of either CMV-negative blood products or filtered blood products has been advocated (54). Prophylactic ganciclovir has been utilized, as has preemptive ganciclovir therapy. In the latter approach, patients identified as being at high risk for CMV disease by CMV antigen detection or polymerase chain reaction (PCR) testing receive ganciclovir prophylaxis (55-57). It is recommended that all CMV-seropositive allogeneic transplant recipients either receive prophylactic ganci-clovir for at least 100 d after the transplant, or that CMV screening be performed to identify those patients at risk. In contrast to CMV which most commonly occurs from 1 to 3 mo post-transplant, HSV infections typically have an onset within the first week or two following transplant. The use of acyclovir prophylaxis has markedly reduced the frequency of these infections. Occasional infections with acyclovir-resistant isolates have been reported, but are not common. In contrast to HSV and CMV, the majority of
VZV infections occur at a median of 5 mo post-transplant. Long-term prophylactic acyclovir therapy has not been shown to have a significant impact on the occurrence of these infections, and is not presently recommended.
Either twice weekly trimethoprim-sulfamethoxazole, aerosolized pentamidine, or dapsone may be utilized for Pneumocystis prophylaxis in these patients. The treatment is generally given for 6 mo after transplantation in allogeneic recipients, or for a longer period in patients with active GVHD for whom treatment with agents such as corticosteroids is required. Trimethoprim-sulfamethoxazole is also effective in preventing tox-oplasmosis following marrow transplantation.
The approach to therapy of established infection is similar to that in other highly immunocompromised hosts. Recovery of neutropenia is an important factor affecting infection outcome in the setting of infections caused by pathogens such as Candida and Aspergillus species. Immunosuppression, especially that resulting from GVHD and the subsequent treatment administered for this complication also impedes the resolution of these infectious complications.
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