Infections In Hematopoietic Stem Cell Transplantation Research Articles

Multiple-Factor Analysis of Human Herpes Virus 6 Infection in Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood

Background: Hematopoietic stem cell transplantation (HSCT) can ultimately cure various hematological disorders. Building upon the basis of post-transplant cyclophosphamide (PT-cy) haploidentical HSCT, we innovatively employed a combination of haploidentical related donors and unrelated cord blood donors for complementary transplantation to treat pediatric leukemia and severe thalassemia. This approach has been successful, and complementary transplantation has become an important option in haploidentical HSCT. However, with the development of haploidentical HSCT and the long-term use of immunosuppressive agents, viral infections have gained increasing attention, and human herpesvirus 6 (HHV-6) is one of the concerning viruses. HHV-6 exists in two variants, HHV-6A and HHV-6B, with HHV-6B being the common infection in HSCT. HHV-6B is characterized by a preference for lymphocytes and neurons and can easily reactivate in patients with compromised immune systems after HSCT, leading to severe and irreversible brain and nerve damage, and in severe cases, death. In this study, we aim to identify the susceptible factors for HHV-6B infection in cases of complementary transplantation, with the goal of improving the safety of complementary transplantation in HSCT. Objective: Through a retrospective analysis, we aim to identify the factors associated with HHV-6 infection after complementary transplantation in HSCT, providing clinical evidence for prevention, diagnosis, and treatment. Methods: We selected cases of HSCT using complementary transplantation from December 2018 to May 2022. Factors such as the primary disease of the patients, gender, age, donor-recipient blood type, haploidentical donor engraftment, different HLA-matched cord blood engraftment, neutrophil and platelet engraftment times, use of ATG and glucocorticoids, fever condition, timing of HHV-6 infection, and the time to seronegativity after treatment were analyzed to identify the characteristics and related risk factors of HHV-6B infection. Results: Among 142 cases (73 with thalassemia, 19 with AML, 37 with JMML, 2 with Fanconi anemia, 8 with SAA, and 8 with ALL) using complementary transplantation, 91 cases were infected with HHV-6, resulting in an infection rate of 64%. In the infection group, 8 patients were under the age of 2 years (8.8%), while 83 patients were 2 years or older (91.2%). In the uninfected group, 17 patients were under 2 years of age (33.3%), and 34 patients were 2 years or older (66.7%). (p<0.001). Regarding the type of graft, 79 patients in the infection group received cord blood transplantation (86.8%), and 12 patients received peripheral blood transplantation (13.2%). In the uninfected group, 19 patients received cord blood transplantation (37.3%), and 32 patients received peripheral blood transplantation (62.7%). (p<0.05). Regarding ATG use, 61 patients in the infection group received ATG (67%), and 12 patients did not (33%). In the uninfected group, 25 patients received ATG (49%), and 26 patients did not (51%). (p=0.035). In terms of glucocorticoid use, 82 patients in the infection group received glucocorticoids (90.1%), and 9 patients did not (9.9%). In the uninfected group, 13 patients did not receive glucocorticoids (25.5%), and 38 patients did (74.5%). (p<0.05). Regarding neutrophil engraftment time, it was 36 days in the infection group and 23 days in the uninfected group. Regarding platelet engraftment time, it was 43.5 days in the infection group and 18.5 days in the uninfected group. In terms of CMV and EB virus infection, only one patient in the infection group had concurrent CMV infection, and there were no cases of concurrent EB virus infection. Conclusion: In complementary transplantation, cord blood transplantation, glucocorticoid use, ATG use, and recipient age are high-risk factors for HHV-6 infection/reactivation. There were no significant differences in HHV-6 infection between different diseases treated with complementary transplantation. Furthermore, HHV-6 infection significantly delays the engraftment of neutrophils and platelets. Keywords: Hematopoietic stem cell transplantation, haploidentical, cord blood, human herpesvirus 6 (HHV-6)

The Relationship between Conditioning Regimen with Viral and Fungal Infections in Allogeneic Hematopoietic Stem Cell Transplantation

Background: Infections are one of the most important factors that adversely affect the transplantation process at hematopoietic stem cell transplantation (HSCT). Quality of life and even the loss of patients due to infection may result in the failure of the HSCT. While the studies in the literature were mostly related to bacterial infections in HSCT, the viral and fungal infections were evaluated. The relationship between viral and fungal infections and the types of conditioning regimens used in HSCT was investigated.
 Methods: Three hundred fifthy one (351) patients who had allogeneic HSCT were performed. The viral and / or fungal infections and conditioning regimens were determined from the medical records. The conditioning regimens were evaluated in two groups as myeloablative and non-myeloablative. We aimed to determine the statistical relationship between viral and fungal infections and type of conditioning regimen.
 Results: Of the 351 patients, 104 had CMV infection, 4 had parvovirus infection, and 87 had fungal infection. Myeloablative regimen was used in 226 of 351 patients and non-myeloablative regimen was used in 125 patients. There was no significant relationship between the type of conditioning regimen and CMV, parvovirus and fungal infections.
 Conclusion: The lack of a significant relationship between the type of conditioning regimen and the viral and fungal infections during HSCT provides the clinician with the choice of the conditioning regimen. However; we need to do more studies with larger case series and also relationship between the type of conditioning regimen and viral and fungal infections should be more clearly demonstrated.

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications.

In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.

Retrospective Analysis of Opportunistic Brain Abscesses in Patients With Hematologic Malignancies

Background Patients with hematologic malignancies have a high rate of opportunistic infections (OIs) with pathogens that could lead to the formation of brain abscesses. Nocardia, toxoplasmosis, Aspergillus, zygomycetes and Fusarium are a few of these organisms, which may be increasing in prevalence. Several immunologic defects such as severe neutropenia (absolute neutrophil count < 500), impaired B-cell immunity, hypogammaglobulinemia, and defective T-cell immunity are related with increased risk of OIs. Recipients of hematopoietic stem cell transplantation (HSCT) are similarly at an increased risk of these OIs due to prolonged neutropenia and defective T-cell–mediated immunity. Design and Methods A retrospective case series analysis at Moffitt Cancer Center, a tertiary cancer hospital, screened for patients with hematologic malignancies and microbiological proven diagnosis of opportunistic brain abscess (OBA) from January 1998 to January 2010. The OBAs were diagnosed via positive cultures from cerebrospinal fluid, brain tissue, or bronchoalveolar lavage for one of the following microorganisms: Nocardia species, Toxoplasmosa species, Aspergillus species, zygomycetes, or Fusarium species; 5 of the 13 cases involved recipients after allogeneic HSCT. A literature review of the most common pathogens related to OBAs in hematologic patients from PubMed between 1998 and 2011 is also included. Results The OBAs documented by culture included Nocardia (5/13, 38%), zygomycetes (3/13, 23%), toxoplasmosis (2/13, 15%), Aspergillus (2/13, 15%), and a single case of disseminated Fusarium (1/13, 8%). The underlying hematologic malignancies were as follows: lymphoma (4/13, 2 cases involved Hodgkin lymphoma and 2 cases involved non-Hodgkin lymphoma), chronic myeloid leukemia (3/13), acute lymphoblastic leukemia (ALL) (3/13), acute myelogenous leukemia (AML) (1/13), multiple myeloma (1/13), and myelodysplastic syndrome (1/13). The age range at diagnosis was 26 to 76 years, with a median age of 51 years at the time of diagnosis with OBA. The male-to-female ratio was 3.3:1 (10 males, 3 females). The most common predisposing factors were severe neutropenia for 7 to 15 days within the month before the diagnosis (6/13, 46%), chronic graft-versus-host disease (GVHD) after allogeneic HSCT (5/13, 38%), lymphoma (4/13, 30%), chronic lymphocytic leukemia, and ALL (3/13, 23%). Of the 13 patients, 7 (54%) had severe neutropenia (absolute neutrophil count < 500 cell/µL) within the month before OBA diagnosis, but only 1 had a prolonged neutropenia for more than 6 months. None of the patients with Nocardia brain abscesses were neutropenic during the year before the diagnosis. The most common presenting symptoms were focal neurologic deficits (7/13, 54%), headaches (5/13, 38%), and altered mental status (5/13, 38%). Conclusions An OBA should be highly suspected in patients with lymphoma, chronic lymphocytic leukemia, ALL, or chronic GVHD presenting with headache and focal neurologic deficits. The most important risk factor for OBA in allogeneic transplant after engraftment is the development of chronic GVHD and effects of its subsequent immunosuppressive treatment. Chronic GVHD is associated with persistently depressed T-cell and humoral immunity. Perhaps Trimethoprim- and sulfamethoxazole-based prophylaxis should be considered for the prevention of OBA infections in HSCT with chronic GVHD complications. Early OBA diagnosis, surgical intervention if indicated, and culture-directed treatment is vital for decreased morbidity and mortality.

Comparison of Posaconazole Versus Weekly Amphotericin B Lipid Complex for the Prevention of Invasive Fungal Infections in Hematopoietic Stem-Cell Transplantation

Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT. We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug-related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater. A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug. High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity.

Managing Invasive Fungal Infection in Hematopoietic Stem-Cell Transplantation

Reduced intensity conditioning regimens and a wider range of donor sources, including cord blood, mean that more patients can be offered potentially curative allogeneic hematopoietic stem cell transplantation than ever before. Although these modalities aim to reduce procedure-related morbidity and mortality, their potential benefit may be overshadowed by a changing spectrum of problems related to the immunocompromised status of affected patients. Acute or chronic extensive graft-versus-host disease, which occasionally emerges in the late post-transplant period, and prolonged neutropenia due to delayed engraftment still carry a substantial risk of invasive fungal and other infections. As a result, advances in antifungal prophylaxis and pre-emptive treatment were widely reported at the 36th Annual Meeting of the European Group for Blood and Marrow Transplantation attended this year by approximately 3800 delegates.

Novel H1N1 Influenza in Hematopoietic Stem Cell Transplantation Recipients: Two Centers’ Experiences

Respiratory virus infections, such as influenza A, cause significant morbidity in hematopoietic stem cell transplantation (HSCT) recipients. The clinical characteristics and impact of infection with the novel H1N1 virus in this patient population is not yet well defined, however. HSCT recipients diagnosed with proven or probable H1N1 during the 2009 pandemic were identified and charts were retrospectively reviewed with analysis of clinical descriptions, risk factors, diagnosis, treatments, and outcomes. Twenty-seven patients from two medical centers were identified. Fever and cough were the most common presenting symptoms. The incidence of influenza lower respiratory tract infection (LRTI) was 52% (14/27). Compared with patients with LRTI, those with influenza upper respiratory tract infection (URTI) were more likely to have a classic influenza-like syndrome. Compared to patients with URTI, those with LRTI were started on antiviral therapy significantly later after symptom onset (3.0 days vs 6.58 days after onset of symptoms; P = .03; 95% confidence interval [CI], 0.29-6.8). Overall influenza-related 30-day mortality was 22% (6/27), and that in patients with LRTI was 43% (6/14). Chronic steroid use (≥20 mg/day of prednisone equivalent) at the time of presentation was associated with LRTI (P = .006) and mortality (P = .003) on univariate analysis. Five cases were hospital-acquired. In this first season of the novel H1N1 pandemic, infection in HSCT often presented as an atypical severe illness with a high incidence of LRTI and high mortality.

Respiratory Syncytial Virus Infection in Recipients of Allogeneic Stem-Cell Transplantation: A Retrospective Study of the Incidence, Clinical Features, and Outcome

Respiratory syncytial virus (RSV) is a common cause of serious respiratory infections in hematopoietic stem-cell transplant (HSCT) recipients. We aimed to determine the frequency, risk factors, and outcome of RSV infection in allo-HSCT recipients. Data were collected from 275 allo-HSCT recipients and identified 32 patients (11.6%, 26 adults and 6 children) RSV infection. A control group was selected matched for age, conditioning intensity and regimens, year of transplant. Eighteen patients had upper and 14 had lower respiratory tract infection (LRTI). The duration of viral shedding was long (20 days; 7-84). Twenty-eight patients received ribavirin (6 received intravenously, 11 orally, 9 both, 1 oral +aerosolized, and 1 received all three forms). The median duration of therapy was 22.5 days (7-54 days). Three (1.1% of entire cohort, 9.4% of infected patients; 21.4% of patients with LRTI) patients died from the RSV (attributable mortality), whereas two patients died from other subsequent infections 38 days to 5 months after diagnosis of RSV. Seven patients died from progression of underlying disease. Long-term respiratory function was assessed in 14 patients. Two patients died from respiratory failure. Three of 14 patients developed marked respiratory dysfunction after SCT. Three of 16 patients in the RSV group had normal respiratory function compared with 18 of 26 in the control group (P<0.01). RSV infection results in a low overall attributable mortality after allo-HSCT, but progression of the infection to LRTI is associated with increased risk for death. Late respiratory dysfunction is more common among patients, experienced RSV infection compared with controls.

Association of Mannose Binding Lectin (MBL-2) Deficiency with Pulmonary Infection after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Background: Low MBL2 concentration and MBL2 genotype variants have been associated with an increased risk of infection in various clinical settings. Pulmonary infection is a major complication of HSCT. We examined the relationship of MBL genotypes with post-engraftment bacterial (B-PNA) and fungal (F-PNA) pneumoniaMethods: Retrospective review of 236 non-consecutive, non-selected patients who underwent HSCT at MSKCC from 1/1/2000–4/30/2007. Microbiologically confirmed infections and pneumonias were recorded. Antifungal prophylaxis consisted of fluconazole 400 mg daily. Patients at high risk for mold infection received mold-active prophylaxis. After 1/1/2006 voriconazole was the first line anti-mold prophylaxis. Genotype was determined by PR-Melting Curve Analysis on blood or buccal swab specimens. MBL genotype was classified as wild-type: A/A (MBL-sufficient, MBL-S) or variant-type: A/O, O/O (MBL deficient, MBL-D). Patients were followed for up to 2 years. Statistical analysis: Fisher's Exact test was used to compare the incidence rate between MBL-S and MBL-D patients. Multivariate logistical regression models were used to investigate the relationship between bacterial or fungal pneumonia and MBL genotype, matched related donor (MRD), myeloablative conditioning (MC) peripheral blood as stem cell source (PBSC), acute GVHD grade 2–4 (aGVHD). The results from Maximum Likelihood Estimates were summarized.Results: Transplant characteristics: 80% MC, 76% PBSC, 48.6% MRD. Incidence of aGVHD: 22.4%. MBL genotypes: One-hundred and forty-two (60%) patients were homozygous for wild-type MBL2 (AA), 85(36%) were heterozygous (A/0) and 9 (3.8%) were homozygous for variant genotypes (OO). Transplant characteristics, rates of GVHD, relapse-free and overall survival were similar between MBL-D and MBL-S. There was higher incidence of overall bacterial infections in MBL-D compared to MBL-S pts (47.87% vs 36.62%, p=0.1049). MBL-D had a higher incidence of B-PNA (12.7% vs 4.9%, p=0.048). In multivariate logistic regression analysis, MBL-D(p=0.04) and aGVHD(p=0.06) were likely associated with B-PNA. Rates of overall fungal infections and F-PNA were similar [among MBL-D and MBL-S pts (12.77% vs 9.86%, p=0.5277) and (8.51% vs 7.75%, p=0.1049) respectively]. In multivariate logistic regression analysis only aGVHD was statistically significantly associated with F-PNA p=0.0002.Conclusions: 1) MBL-D genotype was likely associated with increased risk of bacterial pneumonia. 2) MBL-D and aGVHD were risk factors for B-PNA. 3) Further analyses are in progress to evaluate the effect of MBL-D on fungal pneumonia in patients who received mold prophylaxis versus patients who did not receive mold prophylaxis. 4) Prospective studies are needed to assess the relative contribution of MBL-D genotype on the risk of pulmonary infection in HSCT.