Infectious Complications of HSCT

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Chapter 132 Infectious Complications of HSCT

Andrea Velardi, Franco Locatelli

Hematopoietic stem cell transplantation (HSCT) recipients experience a transient but profound state of immune deficiency. Immediately after transplantation, patients are particularly susceptible to bacterial and fungal infections, because neutrophils are absent. Consequently, most centers start prophylactic antibiotic or antifungal treatment during the conditioning regimen. Despite these prophylactic measures, most patients will develop fever and signs of infection in the early post-transplant period. The common pathogens include enteric bacteria and fungi such as Candida and Aspergillus. An indwelling central venous line is a significant risk factor for bacterial and fungal infections with staphylococcal species and Candida being the most frequent pathogens in catheter-related infections (Chapter 172).

HSCT recipients remain at increased risk of developing severe infections even after the neutrophil count has normalized, because T-cell number and function remain below normal for months after transplantation. Unrelated donor transplant recipients are at increased risk of developing graft versus host disease (GVHD), which is an additional risk factor for fungal and viral opportunistic infections. After cord blood transplantation, infections are the consequence of the slow neutrophil engraftment and donor T-cell naïveté. In haploidentical transplantation, the increased risk of infection observed in the 1st 4-6 mo after the allograft is the consequence of T-cell depletion of the graft.

Among HSCT recipients, invasive aspergillosis, cytomegalovirus (CMV) infection and Epstein-Barr virus (EBV)–related lymphoproliferative disorders represent life-threatening complications that significantly affect patient’s outcome.

Invasive aspergillosis remains a significant cause of infectious morbidity and mortality in HSCT recipients. Despite prompt and aggressive administration of potent antifungal agents, proven cases of aspergillosis remain difficult to treat, with case fatality rates of 80-90%. The annual incidence of invasive aspergillosis has risen with use of stem cells from alternative sources. The incidence has been reported to be 7.3% in recipients of a human leukocyte antigen (HLA)-matched related donor transplant and 10.5% in patients given the allograft from either an HLA-mismatched family donor or an unrelated donor volunteer. Most cases of aspergillosis are diagnosed from 40 to 180 days after HSCT, with 30% diagnosed <40 days and 17% >6 mo after transplantation. The risk of developing aspergillosis is mainly influenced by the duration of neutropenia, GVHD occurrence, use of corticosteroid therapy, post-transplant CMV infection, viral respiratory tract infections, older age, and T-cell depletion of the graft. Patients with a previous history of invasive aspergillosis are at particular risk.

Aspergillus infection often originates from the upper airway mucosa. Early lesions in the nose should be sought in patients with neutropenia who have fever and minimal epistaxis. Rapid extension into the adjacent paranasal sinuses, orbit, or face is usual, with or without the appearance of lung lesions. In the lung, invasive aspergillosis generally presents as an acute, rapidly progressive, densely consolidated pulmonary infiltrate. Infection progresses by direct extension across tissue and by hematogenous dissemination to brain and other organs. One or more small pulmonary nodules are the earliest finding on CT scan. As a nodule enlarges, the dense central core of infarcted tissue becomes surrounded by edema or hemorrhage, forming a hazy rim, the halo sign. This rim disappears in a few days as the dense core enlarges. In neutropenic patients, when bone marrow function recovers, the infarcted central core cavitates, creating the crescent sign. Antifungal prophylaxis includes isolation of the patient in a laminar air flow or positive pressure room. Liposomal amphotericin B, azole compounds (itraconazole, voriconazole), and echinocandins (caspofungin, micafungin, anidulafungin) are useful for both preventing and treating the fungal infection. Voriconazole represents the treatment of choice for patients with invasive apsergillosis. However, often aspergillosis does not respond satisfactorily to antifungal agents alone, and patients remain at risk until T-cell counts and function recover. This observation provides the rationale for developing strategies to accelerate the recovery of pathogen-specific immune responses.

Cytomegalovirus (CMV) infection remains the most common and potentially severe viral complication in patients given allogeneic HSCT. Seropositivity for CMV is an independent risk factor for mortality, even in recipients of matched sibling or unrelated donor transplants. CMV is itself immunosuppressive, as it impairs dendritic cell and T-lymphocyte function. Moreover, ganciclovir, the most frequently used anti-CMV agent, may cause leukopenia and T-cell immune suppression.

The period of maximal risk for CMV infection is 1-4 mo after transplantation. Until CMV-specific T-cell responses develop several months after transplant, CMV infection may result in a variety of syndromes, including fever, leukopenia, thrombocytopenia, hepatitis, pneumonitis, esophagitis, gastritis, and colitis. CMV pneumonia is the most life-threatening complication related to viral infection and has been reported to occur in up to 15-20% of bone marrow transplant recipients, with a case fatality rate of 85%. The risk is greatest between 5 and 13 wk after transplantation. Risk factors include T-cell depletion of the graft, donor seronegative status, recipient seropositive status, acute GVHD, and patient older age.

Tachypnea, hypoxia, and unproductive cough signals respiratory involvement. Chest x-ray often reveals bilateral interstitial or reticulonodular infiltrates, which begin in the periphery of the lower lobes and spread centrally and superiorly. The differential diagnosis includes infection with Pneumocystis jiroveci or other fungal, viral, or bacterial pathogens; pulmonary hemorrhage; and injury secondary to irradiation or to treatment with cytotoxic drugs. Gastrointestinal CMV involvement may lead to ulcers of the esophagus, stomach, small intestine, and colon that may result in bleeding or perforation.

Fatal CMV infections are often associated with persistent viremia and multiorgan involvement. CMV disease has largely been prevented through prophylaxis and a preemptive approach. Prophylaxis is based on administration of antiviral drugs to all transplanted patients for a median duration of 3 mo after transplantation. Preemptive (presymptomatic) therapy aims at treating only patients who experience CMV reactivation and, thus, are at risk of developing overt disease; it starts only upon detection of CMV in blood by any assay. The most widely used assays detect CMV antigenemia (pp65) or CMV DNA in blood and have been used to decide inception of treatment when they either become positive or reach a predetermined threshold. While in the past treatment usually started after one of these assays became positive, nowadays therapy is usually initiated when a certain viral load is reached. Moreover, quantification of CMV DNA in blood provides a more reliable approach for deciding interruption of treatment. The major drawback of this strategy is the need for serial monitoring that is required for the period in which patients are at risk of developing CMV disease. In this regard, approaches able to reliably prove the restoration of virus-specific immunity have been developed recently. Ganciclovir or sometimes foscarnet is usually used for prophylaxis and preemptive treatment of CMV infection.

Epstein-Barr virus (EBV)–related lymphoproliferative disease (EBV-LPD) is a major complication in HSCT and solid organ transplantation. In patients receiving HSCT, selective procedures of T-cell depletion sparing B lymphocytes and use of HLA partially matched family and unrelated donors are risk factors for the development of EBV-LPD. These disorders usually present in the 1st 4-6 mo after transplantation as high-grade diffuse large cell B-cell lymphomas, which are oligoclonal or monoclonal, express the full array of EBV antigens, and are of donor origin. High levels of EBV-DNA in blood and in vitro spontaneous growth of EBV-lymphoblastoid cell lines predict development of EBV-LPD.

In immunocompromised hosts, EBV-LPD originates from a deficiency of virus-specific cytotoxic T lymphocytes (CTL), which control outgrowth of EBV-infected B cells. This finding provided the original rationale for developing strategies of adoptive cell therapy to restore EBV-specific immune competence. Unselected donor leukocyte infusion (DLI), the first attempt at EBV-directed adoptive immunotherapy in humans, can induce EBV-LPD remission but exposes patients to a high risk of developing clinically relevant GVHD and is not suitable for patients transplanted from an HLA-mismatched donor. A safer approach is infusion of in vitro generated EBV-specific CTL lines of donor origin containing both CD8+ and CD4+ T lymphocytes. These CTL lines prevent lymphoproliferative disorders in patients considered at high risk, such as patients given T-cell depleted HSCT from HLA-disparate donors, and cure clinically overt LPD. In recent years, use of monoclonal antibodies directed against CD20, a molecule expressed on B cells, has significantly contributed to reduce the incidence and severity of EBV-related LPD, although it can be associated with the emergence of neoplasms in which cells are CD19+ but CD20 negative, thus rendering patients no longer susceptible to the treatment with the monoclonal antibody.

Feuchtinger T, Matthes-Martin S, Richard C, et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol. 2006;134:64-76.

Lilleri D, Gerna G, Fornara C, et al. Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplantation. Blood. 2006;108:1406-1412.

Lilleri D, Gerna G, Furione M, et al. Use of a DNAemia cut-off for monitoring human cytomegalovirus infection reduces the number of pre-emptively treated children and young adults receiving haematopoietic stem cell transplantation as compared to qualitative pp65-antigenemia. Blood. 2007;110:2757-2760.

Perruccio K, Tosti A, Burchielli E, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood. 2005;106:4397-4406.

Safdar A, Rodriguez GH, De Lima MJ, et al. Infections in 100 cord blood transplantations. Medicine (Baltimore). 2007;86:324-333.

Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18:348-357.

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