key: cord-1039376-vowfvsr0
authors: Slade, Michael; Goldsmith, Scott; Romee, Rizwan; DiPersio, John F.; Dubberke, Erik R.; Westervelt, Peter; Uy, Geoffrey L.; Lawrence, Steven J.
title: Epidemiology of infections following haploidentical peripheral blood hematopoietic cell transplantation
date: 2016-12-28
journal: Transpl Infect Dis
DOI: 10.1111/tid.12629
sha: ab75cb3685b8732439b252ecd470dfbdb4b5f3cd
doc_id: 1039376
cord_uid: vowfvsr0

BACKGROUND: The use of T‐cell replete haploidentical hematopoietic cell transplant (haplo‐HCT) has increased substantially since the introduction of post‐transplant cyclophosphamide (PTCy) regimens. Limited data exist concerning infectious complications of haplo‐HCT utilizing mobilized peripheral blood (PB) hematopoietic cells. METHODS: This retrospective cohort study included all adult patients at our institution undergoing PB haplo‐HCT with PTCy between June 2009 and June 2015. Infections were microbiologically confirmed. Invasive fungal infections (IFI) classified as “proven” or “probable” by standard definitions were included. RESULTS: In total, 104 patients were identified. Median follow‐up was 218 days (range: 6–1576). A total of 322 episodes of infection were recorded. Eighty‐nine percent of patients experienced at least one infection. Median time to first infection was 22 days. Patients experiencing at least one bacterial, viral, and IFI were 62%, 72%, and 6%, respectively. The majority (69%) of bacterial infections were caused by enteric organisms. Seven cases of Staphylococcus aureus infection were recorded, with one bacteremia case. Cytomegalovirus (CMV) viremia occurred in 54/71 (76%) at‐risk patients at a median time of 24 days. Sixteen (15%) patients developed CMV disease. Nineteen percent (20/104) of patients developed BK polyomavirus‐associated cystitis. Six (6%) patients experienced a total of seven IFI. Infection was the primary cause of death for 12% (6/51) of patients and was a secondary cause for 41%. CONCLUSION: In PB haplo‐HCT patients, a high incidence of CMV viremia and disease was observed. Infections with enteric bacteria were common. Fungal and staphylococcal infections were uncommon. Further studies are needed to compare infectious complications in haplo‐HCT with other transplant modalities.

an alternative graft source that yield higher CD34 + cell counts and obviate the need for donor anesthesia during hematopoietic cell collection. 5 The use of PBSC grafts, which contain up to 10-fold more CD3 + T cells than BM grafts, has been limited by concerns about increased GVHD, although no difference in GVHD has been found in haplo-HCT. 6, 7 The epidemiology and incidence of infectious disease complications associated with haplo-HCT is incompletely understood. The largest study to date consists of 70 patients undergoing BM haplo-HCT with PTCy. 8 They reported a moderate incidence of cytomegalovirus (CMV) reactivation, peaking in the early post-engraftment period. Bacterial infections were highest during the pre-engraftment period and over half of patients had at least one bacterial infection.

In matched-related donor (MRD) allogeneic transplants, PBSC grafts have been associated with increased early CMV reactivation 9 and decreased rates of bacterial and fungal infection 10 compared to BM grafts. Meanwhile, in matched-unrelated donor allogeneic transplants, PBSC grafts have been associated with significantly fewer infectious complications. 11 Limited information is available concerning PBSC haplo-HCT. 5, 12, 13 In this study, we describe the epidemiology of infectious complications associated with haplo-HCT using PTCy and PBSC grafts. All patients received peripherally mobilized hematopoietic cell grafts. Donors were selected by HLA typing, with match grade ranging from 5/10 to 9/10. Optimal donor was determined by, in order, lack of donor-specific antibodies in recipient, CMV serostatus match, and donor health status. Donors were mobilized with granulocyte colonystimulating factor (G-CSF). Graft cell counts were characterized using flow cytometry. Target CD34 + dose was 5.0 × 10 6 cells/kg. No T-cell depletion was used.

All patients received 50 mg/kg PTCy on days +3 and +4, 4 mycophenolate mofetil, and either tacrolimus or sirolimus starting on day +5. Unless contraindicated, all patients received herpesvirus, Pneumocystis, and fungal prophylaxis. Standard herpesvirus prophylaxis was 400 mg acyclovir three times a day (TID) or 500 mg valacyclovir once daily (QD) until day +180 or cessation of immunosuppression. Patients discharged on ganciclovir (GCV) for CMV treatment were transitioned to standard herpesvirus prophylaxis following completion of treatment. Primary fungal prophylaxis was 400 mg fluconazole QD until day +100. Patients with a history of invasive fungal infections (IFI) or discharged on antifungal treatment received secondary prophylaxis, which was continued until cessation of immunosuppression. Pneumocystis prophylaxis was given from day +28 to +180 and consisted of trimethoprim-sulfamethoxazole, dapsone, or atovaquone.

At our institution, patients are actively screened for vancomycinresistant Enterococcus (VRE) colonization. Whole blood CMV polymerase chain reaction (PCR) testing was performed twice weekly during transplant hospitalization and then weekly until day +100. Subsequent monitoring was determined by each patient's physician.

Patients received antiviral treatment for CMV disease, consecutive doubling of blood DNA levels on PCR, and for significant viremia defined as >40 000 IU/mL, or an approximate equivalent level when alternative PCR assays were used. 

Standard descriptive statistics were used to characterize the study population and evaluate distribution of variables. None of the variables of interest was normally distributed, so median and range were used for central tendency and dispersion of continuous variables. The chi-square test and Fisher's exact test, as appropriate, were used to evaluate distribution of categorical variables. The Mann-Whitney U-test was used to compare distribution of continuous variables.

Survival analysis was conducted with the log-rank test.

We identified 104 patients for inclusion in the study. As shown in Table 1 , our cohort contained a large number of high-risk patients.

Acute myeloid leukemia was the most common diagnosis (67%).

Twenty-seven percent of patients had received a previous HCT and 33% had active disease at transplantation. The majority (93%) underwent one of three previously described conditioning regimens. [22] [23] [24] (Figure 2A and B). 14 Disease associated with each pathogen class is summarized in Sixteen patients (15%) experienced CMV-associated end-organ disease, affecting the gut in 7 cases, the lungs in 6 cases, and both in 2 cases. One case involved the retina, meninges, and lungs. 

Seven fungal infections were diagnosed in the follow-up period. Six were classified as "proven" according to EORTC/MSG criteria 20 via blood culture (n=3), biopsy (n=2), and autopsy (n=1). The positive blood cultures were for Candida (n=2) and Zygomycetes (n=1) species. Disseminated mucormycosis was found in kidneys and lungs of one patient who died following a stroke. Both patients who developed a fungal infection during their transplant hospitalization died before discharge. One infection was classified as "probable" by galactomannan assay and cavitary nodules on chest computed tomography. No

Pneumocystis infections were observed. Nineteen patients (18%) were discharged from their initial hospitalization while receiving either secondary prophylaxis with voriconazole (n=15) or therapeutic antifungal treatment (n=4). Only one of these patients later developed a fungal infection.

During the follow-up period, 51 patients (49%) died. Per published criteria, 17 the most common primary COD was relapse (54%), followed by GVHD (17%). Primary and contributing COD in periods of infectious risk are summarized in Table 3 . Infection was the primary COD in 12% (6/52). Infection was a contributing COD in an additional 41%. 

In this analysis, we describe infectious complications in 104 patients receiving PB haplo-HCT with PTCy. Overall, infections were a primary or contributing COD in more than half of the patients who died patient-days. 8 We observed a slightly higher rate of early bacterial infection and a markedly higher rate of early viral infections (Figure 2A ).

Of note, patients reported by Crocchiolo et al. 8 received routine bacterial prophylaxis with levofloxacin, whereas ours did not. Our median time to neutrophil engraftment was shorter (17 vs 20 days).

This difference may have skewed the attribution of infections into the "pre-engraftment" period, despite neutrophil recovery. In particular, a large number of viral infections occurred after neutrophil engraftment but before day 30 (Figure 2A vs B) . Our observed rate of IFI and increased early CMV reactivation is consistent with previous literature comparing PBSC and BM grafts. 9, 10 We also observed a high incidence of early neutropenic fever in our cohort. The association of PB haplo-HCT with post-infusion fever is increasingly recognized in the literature. [25] [26] [27] The high incidence of enterococcal infections in this population was notable. Our finding that colonization with VRE is associated with later infections is consistent with previously published work, as is the association between enterococcal infection and early mortality. 28 In contrast, we observed few S. aureus infections, similar to previous reports in allogeneic HCT. 29 The observed rate of CDI was comparable to the previously reported rates of 9%-25%, as was our rate of recurrent infection. [30] [31] [32] The high proportion of early-onset CDI has been reported in the literature. 30 An association between CDI and gastrointestinal GVHD has also been noted, which was not observed in our population. 31 CDI had no discernible impact on survival.

The role of graft source on CMV infection is still a matter of debate. In the MRD setting, Young et al. 11 found no difference in CMV infection within a large retrospective cohort of patients undergoing HCT with either BM or PBSC. However, early CMV reactivation and higher rates of reactivation and disease in patients receiving PBSC grafts were reported by Guerrero et al. 9 , who analyzed a cohort of MRD patients randomized to PBSC or BM grafts. They found altered prevalence and proliferation of CMV-specific CD4 + cells following G-CSF mobilization. Compared to previously published data in BM haplo-HCT, the rate of CMV viremia associated with previous donor and/or recipient CMV seropositivity and CMV disease were considerably higher (76% vs 54%, 12% vs 4%). 8 The rate of CMV viremia among seropositive recipients was similar to another cohort of PBSC haplo-HCT patients (90% vs 79%), although the incidence of CMV disease was considerably higher (12% vs 0%). 12 The association of early viremia and recipient CMV pre-transplant seropositivity with CMV disease is consistent with altered CMV immunity in this setting and may indicate the need for an alternative approach to treatment of CMV viremia in this population. We also observed a relatively high rate of HSV prophylaxis failure, especially among patients seropositive for HSV-2.

We observed a low rate of incident IFI in our cohort, similar to previously reported rates in haplo-HCT with BM grafts. 8 This low rate may reflect the efficacy of receiving extended primary antifungal prophylaxis until day +100, or the relatively large proportion (18%) of patients receiving secondary fungal prophylaxis. 5, 12 Our inclusion of only "probable" and "proven" fungal infections is consistent with the literature, but likely results in underestimating the true incidence of fungal infection in our population. Follow-up time in our cohort is also limited and may also contribute to an underestimation of fungal infections, which often occur later in patients with cGVHD.

Our study has several limitations. First, by excluding suspected infections that were not microbiologically confirmed, we underestimate the true incidence of infection in our population. Febrile episodes with no identified organism are a common occurrence in this population. 33 Furthermore, many patients with suspected pneumonia cannot undergo bronchoscopy owing to thrombocytopenia. However, by employing strict criteria, our results are more specific than relying on retrospective clinical judgment. Second, our study did not include a comparison group. This makes contextualizing the reported rates of infection more difficult, especially given regional variations in some pathogens. However, it also allows us to provide an extremely broad and comprehensive description of the infectious experience within this novel cohort. Pathogen-specific comparative studies are a direction of future research and may help illuminate differences in immune reconstitution following haplo-HCT when compared to more traditional donors. Third, we were limited to collecting data from our own medical records system. Generally, patients receive all transplantrelated care at our institution. In the case of acute illness, some patients likely received treatment closer to home and these episodes would not be captured in this study. However, these patients are usually transferred to our institution when hospitalized and most data should be captured. Overall, our data represent a conservative estimate of the infectious experience of this population.

To our knowledge, our cohort represents the largest analysis of 

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