Page 1154 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 82 Immune Reconstitution Therapy for Immunodeficiency 1119

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Whenever a conditioning regimen is used in the transplantation HLA-mismatched transplantation for SCID. In spite of this,
protocol, pharmacological prophylaxis of GvHD must also be infections remain the major cause of death. Challenging
included, even in the case of HSCT from a related HLA-identical viruses in infants with SCID include adenovirus, cytomegalovirus
donor. (CMV), parainfluenza type III virus, and Epstein-Barr virus
Long-standing approaches to prevention of GvHD include (EBV). In particular, CMV infection after HSCT can cause
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cyclosporine daily for 6 months or methotrexate (15 mg/m on interstitial pneumonia, enteritis, hepatitis, and encephalitis.
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the first day after HSCT, and then 10 mg/m at days +3, +6, and EBV can also cause lymphoproliferative disease. Filtering of
+11 after transplantation), or a combination of the two. Newer blood derivatives removes leukocytes and thus reduces the
regimens substitute another calcineurin inhibitor, tacrolimus, risk of transfusion-associated infections. Several antiviral
for cyclosporine. Serotherapy with ATG or alemtuzumab is often drugs (acyclovir, ganciclovir, foscarnet, cidofovir) are now available
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included in the preparatory regimen, with the aim of reducing and have good results, especially against CMV, and preemptive
the risk of GvHD. The timing of administration of alemtuzumab administration of anti-CD20 mAb is efficacious in the preven-
as part of the preparatory regimen has opposed effects on the tion of EBV-driven lymphoproliferative disease. Furthermore,
prevention of aGvHD and the speed of T-cell reconstitution. In transfusion of virus-specific cytotoxic T lymphocytes (CTLs)
particular, use of alemtuzumab in the days that immediately represents another important resource to fight severe viral
precede transplantation has more potent effects on aGvHD infections. 14
prevention but is associated with delayed T-cell reconstitution, Pneumocystis jiroveci is a common cause of pneumonia in
whereas the opposite is observed when the drug is administered severely immunocompromised patients. Treatment is based on
a few weeks before HSCT. Finally, mycophenolate mofetil and intravenous cotrimoxazole (20 mg/kg/day).
methotrexate can also be used to prevent GvHD. Aspergillus infection is a severe complication in patients with
Attempts to prevent cGvHD have been less satisfactory. In chronic granulomatous disease (CGD) and in patients with
particular, use of a prolonged immune suppression after transplant profound neutropenia. Voriconazole offers some advantage
does not decrease the incidence of cGvHD. compared with liposomal amphotericin B for treatment of invasive
aspergillosis, whereas prophylactic itraconazole reduces the
Treatment of GvHD incidence of fungal infections in patients with CGD before
Once GvHD has developed, treatment is mainly based upon the transplantation.
use of immunosuppressive drugs. Corticosteroids remain the Bacterial infections are usually amenable to successful treat-
first-line therapy and are usually effective, especially for mild ment, if the pathogen is identified, and appropriate and aggressive
and moderate forms of aGvHD. Second-line therapy includes use of antibiotics is initiated. Prophylactic administration of
ATG, mycophenolate mofetil, cyclosporine, or tacrolimus. mAbs, immunoglobulins (Igs) following HSCT also reduces the frequency
such as anti-CD25 (daclizumab), are also used. However, the and severity of infections. Administration of Bacille Calmette-
efficacy of second-line agents in severe or steroid unresponsive Guérin (BCG) vaccine at birth to prevent tuberculosis is still
aGvHD is limited. practiced in many countries worldwide. In severely immuno-
Treatment of cGvHD is also based on immunosuppression, compromised infants who undergo HSCT, this live vaccine may
but with limited efficacy. 11,12 Topical steroids and calcineurin cause disease, which often manifests at the time of engraftment
inhibitors may alleviate mucosal and skin symptoms. Systemic with local and systemic immune reconstitution inflammatory
steroids have been shown to improve survival, but at the risk of syndrome (IRIS).
significant adverse effects. Ursodeoxycholic acid may be useful
in cGvHD with significant liver involvement. Extracorporeal Toxicity Related to Conditioning Regimen
photopheresis can be used with the goal to induce tolerance; Chemotherapeutic agents that are used in the conditioning
typically, its benefits, if present, are delayed until 2–3 months regimen of HSCT often cause significant short-term and long-
after initiation of treatment. Use of hydroxychloroquine, myco- term toxicity. Chemotherapeutic drugs that damage the liver
phenolate mofetil, anti-TNF-α mAb, etanercept (a recombinant vascular endothelium, particularly busulfan and cyclophospha-
form of soluble tumor necrosis factor [TNF]-receptor), and mide, can cause veno-occlusive disease (VOD), which is clinically
anti-CD20 antibody (rituximab) remains investigational. marked by painful hepatomegaly, jaundice, ascites, fluid retention,
and weight gain and can ultimately result in fatal multiorgan
Infections failure (MOF). Defibrotide is the most effective agent studied
Infections represent one of the major complications following to date in the treatment of VOD. Busulfan can also cause seizures
HSCT. Patients with severe PID are intrinsically highly susceptible and lung damage. Cyclophosphamide can cause hemorrhagic
to infections. In infants with SCID and with other forms of cystitis, a syndrome of inappropriate antidiuretic hormone
combined immune deficiency, viral and opportunistic infections secretion, or more rarely, cardiac disturbances.
can develop before transplantation and are one of the factors Long-term hormonal complications are more common
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that adversely affect the outcome of HSCT itself. Regardless of when total body irradiation (TBI) is used. However, the busulfan
the type of underlying PID, T cell–depleted HSCT carries a high and cyclophosphamide regimen can cause delayed puberty or
risk of infections because of the longer time required to achieve sterility, and thyroid dysfunction is frequently observed, even in
immune reconstitution. Furthermore, use of a pretransplant patients who have not received TBI. Delayed or incomplete tooth
conditioning regimen with myeloablative and immunosuppressive eruption is also a possible consequence of conditioning regimens.
drugs, and GvHD prophylaxis, contribute to the increased Effects on final height and growth, as well as long-term neuro-
susceptibility to infections after HSCT. cognitive effects, are emerging as more children are treated
Strict isolation of the patients during and after HSCT, and followed up. Patients with defects of DNA repair (e.g.,
and prophylactic administration of antibiotics, have been some forms of SCID) are particularly at risk for drug-related
associated with a better survival rate, particularly after related toxicities.