BackgroundNeutropenia is a common complication in lung transplant recipients (LTRs). Filgrastim may be used to treat neutropenia in LTRs, but its consequences on acute cellular rejection (ACR) remain controversial. Objective: The purpose was to examine the association between filgrastim and incidence of ACR 6 months after filgrastim administration in LTRs. Secondary outcomes included burden of ACR, infections, chronic lung allograft dysfunction (CLAD), and survival. Methods: This was a matched cohort study of patients transplanted between January 2010 and October 2019. LTRs who received filgrastim for neutropenia were compared to a cohort who did not. LTRs were matched on transplant indication, sex, age, and time post-transplant and multivariable logistic regression models were used to evaluate the likelihood of ACR. Results: 212 patients were included in the analysis (106 in each group). 50 patients (47.2%) in the filgrastim group experienced ACR compared to 37 patients (34.9%) in the no filgrastim group (P = .070). In multivariable analysis, filgrastim use was not associated with ACR at 6 months (OR 1.409, 95% CI 0.772-2.571). Time to first ACR was shorter (P = .049) and 6-month ACR score was higher in the filgrastim group (.49 vs .33, P = .047). LTRs in the filgrastim group had higher incidence of bacterial pneumonia and 1-year mortality. Conclusions: Although not associated with increased likelihood of ACR at 6 months, our study found that filgrastim is associated with increased ACR burden and decreased time to ACR. This study can help inform clinicians of ACR risk after filgrastim use in LTRs.

Appropriate use of antimicrobials for hematologic malignancy, hematopoietic stem cell transplant recipients, and other cellular therapies is vital, with infection causing significant morbidity and mortality in this unique population of immunocompromised hosts. However, often in this population the choice and management of antimicrobial therapy is complex. When selecting an antimicrobial agent, key considerations include the need for dose adjustments due to renal or hepatic impairment, managing drug interactions, the potential for additive drug toxicity among those receiving polypharmacy and therapeutic drug monitoring. Other factors include leveraging pharmacodynamic principles to enable optimization of directed therapy against challenging pathogens, as well as judicious use of antimicrobials to limit drug resistance and adverse drug reactions.

This review summarizes the clinical considerations for commonly used antimicrobials in this setting, including antibacterial, antiviral, and antifungal agents.

Neutropenia is generally defined as an absolute neutrophil count in the circulation of less than 1500/mm³ and occurs in up to 25%-30% of pediatric solid organ transplant recipients (SOT) within the first year after transplantation. In the SOT population, neutropenia is most often a result of drug-induced bone marrow suppression but can also be secondary to viral infection, nutritional deficiencies, lymphoproliferative infiltrate, and inherited causes. Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Management of neutropenia should begin by addressing the underlying cause, including reducing or removing medications when appropriate, treating infections, and addressing nutrient deficiencies; however, consultation with an experienced pediatric hematologist and use of granulocyte colony-stimulating factor (G-CSF) may be helpful in some cases. Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with infections or severe neutropenia.

Neutropenia post-kidney transplantation is associated with adverse graft and patient outcomes. We aimed to analyze the effect of granulocyte colony-stimulating factor (G-CSF) use with and without immunosuppression reduction on graft outcomes in neutropenic recipients. In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first-year post-transplant. Of these, 45.0% underwent no intervention, 17.5% had immunosuppression reduced, 18.3% were only given G-CSF, and 19.2% had both interventions. Overall, 61 patients experienced the composite outcome of de-novo DSA, biopsy-proven acute rejection, and all-cause graft failure and the cumulative incidence of this outcome did not vary by any of the four interventions (p = 0.93). When stratifying the cohort by G-CSF use alone, those who received G-CSF were more likely to have had severe neutropenia (<500/mm³ :51.1%vs.12.0%, p<0.001), and immunosuppression reduction (51.1%vs.28.0%, p = 0.003). However, the composite outcome was not different in the G-CSF and no G-CSF cohort (53.3%vs.49.3%, p = 0.67), and in a multivariate model, G-CSF use was not associated with this outcome (aHR = 1.18, 95%CI:0.61-2.30). However, a trend towards higher DSA production was noted in the G-CSF cohort (87.5%vs.62.2%) and this observation warrants prospective evaluation. Overall, we conclude that G-CSF use with or without immunosuppression reduction was not associated with graft outcomes. This article is protected by copyright. All rights reserved.

Neutropenia is common in the first year after pediatric kidney transplant and is associated with an increased risk of infection, allograft loss, and death. Granulocyte colony-stimulating factor (G-CSF) increases neutrophil production, but its use in pediatric solid organ transplant recipients remains largely undescribed.

We performed a multicenter retrospective cohort study of children with neutropenia within the first 180 days after kidney transplant. Multivariable linear regression and Poisson regression were used to assess duration of neutropenia and incidence of hospitalization, infection, and rejection.

Of 341 neutropenic patients, 83 received G-CSF during their first episode of neutropenia. Median dose of G-CSF was 5 mcg/kg for 3 (IQR 2-7) doses. G-CSF use was associated with transplant center, induction immunosuppression, steroid-free maintenance immunosuppression, hospitalization, and decreases in mycophenolate mofetil, valganciclovir, and trimethoprim-sulfamethoxazole dosing. Absolute neutrophil count nadir was also significantly lower among those treated with G-CSF. G-CSF use was not associated with a shorter duration of neutropenia (p = .313) and was associated with a higher rate of neutropenia relapse (p = .002) in adjusted analysis. G-CSF use was associated with a decreased risk of hospitalization (aIRR 0.25 (95%CI 0.12-0.53) p < .001) but there was no association with incidence of bacterial infection or rejection within 90 days of neutropenic episode.

G-CSF use for neutropenia in pediatric kidney transplant recipients did not shorten the overall duration of neutropenia but was associated with lower risk of hospitalization. Prospective studies are needed to determine which patients may benefit from G-CSF treatment.

Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps.

For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened.

The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window.

Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transpl. Infect. Dis. Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A new approach was employed with the goal of better serving clinical providers by publishing each standalone topic in the infectious diseases series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious diseases and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The fourth topic in the series focuses on the management and treatment of cytomegalovirus (CMV) resistant and refractory infections. The diagnosis, definitions of resistant and refractory CMV, risk factors, virological genotypes and treatment algorithms are reviewed.

Neutropenia is common after kidney transplant. There are few data on febrile neutropenia episodes (FNE) after kidney transplant. We studied FNE in a single-center retrospective cohort of 1682 kidney transplant recipients. Neutropenia (absolute neutrophil count [ANC] <1000) occurred in 32% and FNE in 3%. There were 56 FNE. Median time to FNE was 143 days, and median time from onset of neutropenia to onset of FNE was 5.5 days. The most common sources of infection were urine, blood, and lungs, and in 20% of FNE no source was identified. No infectious organism was identified in 46% of FNE, and opportunistic infections were uncommon. Patient survival was similar among those with and without FNE, but FNE was associated with increased death-censored graft failure (DCGF). Following FNE, acute rejection occurred in 31% and DCGF in 15%, often in the setting of persistent reduced immunosuppression. In conclusion, FNE are common after kidney transplant and are associated with inferior long-term outcomes.

The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance.

To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population.

An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for.

Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline.

This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid organ transplant (SOT). Severe acute respiratory coronavirus 2 (SARS-CoV-2), which causes the novel betacoronavirus 2019 disease (COVID-19), has become the first global pandemic in 100 years. The world's attention has turned to address this unanticipated development; however, the viral infection that has long plagued outcomes after solid organ transplantation still requires vigilance. With physical distancing as the key intervention to reduce the healthcare burden, and the unease related to healthcare contact within the transplant population given the associated morbidity and mortality of COVID-19 in transplant recipients, providers have struggled to evaluate and streamline essential in-person healthcare contact, including laboratory visits. Owing to this, the COVID-19 pandemic has placed a significant strain on the delivery of CMV prophylaxis and treatment after solid organ transplantation. In this piece, we will describe issues our CMV antiviral stewardship service has encountered in the care of the transplant recipient with CMV during the this unprecedented time and share our expert opinion to approaches to providing optimal, evidenced based care during a pandemic associated with a seemingly unrelated viral infection.

Leukopenia occurs frequently following kidney transplantation and is associated with adverse clinical outcomes including increased infectious risk. In this study we sought to characterize the causes and complications of leukopenia following kidney transplantation.

In a cohort of adult patients (≥18 years) who underwent kidney transplant from Jan 2006-Dec 2017, we used univariable Cox proportional Hazards models to identify predictors of post-transplant leukopenia (WBC < 3500 mm³). Factors associated with post-transplant leukopenia were then included in a multivariable backwards stepwise selection process to create a prediction model for the outcome of interest. Cox regression analyses were subsequently used to determine if post-transplant leukopenia was associated with complications.

Of 388 recipients, 152 (39%) developed posttransplant leukopenia. Factors associated with leukopenia included antithymocyte globulin as induction therapy (HR 3.32, 95% CI 2.25-4.91), valganciclovir (HR 1.84, 95% CI 1.25-2.70), tacrolimus (HR 3.05, 95% CI 1.08-8.55), prior blood transfusion (HR 1.17 per unit, 95% CI 1.09- 1.25), and donor age (HR 1.02 per year, 95% CI 1.00-1.03). Cytomegalovirus infection occurred in 26 patients with leukopenia (17.1%). Other than cytomegalovirus, leukopenia was not associated with posttransplant complications.

Leukopenia commonly occurred posttransplant and was associated with modifiable and non-modifiable pretransplant factors.

Incidence and impact of CMV infection in pancreas-transplant recipients (PTRs) in the valganciclovir prophylaxis era has not been completely elucidated.

Adult D+/R- PTRs were divided into a current era (1/1/2011-12/31/17; 6-month PPX) and a historic era (1/1/2003-12/31/09; 3-month PPX).

effect of prophylaxis extension on the incidence of CMV infection.

impact of extension on valganciclovir-related toxicity (leukopenia) and transplant outcomes.

There were 177 D+/R- PTRs in the study period (historic:98, current:79). Prophylaxis extension resulted in significant reduction of CMV infection from 25.4% to 10.9% at 6 months, (57% reduction, p = .021). However, 1-year rates of CMV infection (historic:31% vs current:36%) and end-organ disease (historic:7.7% vs current:6.9%) were not different (p = .93). Prophylaxis extension significantly increased leukopenia (white blood cell count<3 K/uL) at 6 months (historic:9.5% vs current:28.6%, p = .018). On multivariable analysis prophylaxis extension was not associated with reduced rates of CMV infection (p = .99) or CMV end-organ disease (p = .3). Additionally, there was no significant difference in rejection (p = .2), graft survival (p = .08), death-censored graft survival(p = .07) or patient survival (p = .6).

Prophylaxis extension in D+/R- PTRs appears to delay time to first CMV but not reduce overall incidence. These findings suggest a hybrid approach, incorporating antiviral withdrawal and protocolized monitoring, may be needed to improve CMV-related outcomes.

Leukopenia is a common complication after kidney transplantation. The etiology is multifactorial, with medication adverse effects and cytomegalovirus infection as main causes. Optimal strategies to prevent or treat posttransplant leukopenia remain unknown. We aimed to identify risk factors for leukopenia and to investigate the benefit of switching the immunosuppressive therapy to hydrocortisone as a continuous infusion.

We retrospectively evaluated all patients with leukopenia after kidney transplantation between 2007 and 2017 at our center relative to age- and sex-matched controls.

Leukopenia was associated with the degree of rejection therapy before leukopenia, the immunosuppressive therapy before transplantation, and an induction therapy with rabbit antithymocyte globulin. Patients with leukopenia exhibited increased mortality, an increased incidence of bacterial and viral infections, and more acute rejections. Switching to hydrocortisone as a continuous infusion in patients with severe leukopenia decreased the duration of leukopenia and the incidence of subsequent viral infections, especially with cytomegalovirus.

Leukopenia is a risk factor for infectious complications and mortality, and it is associated with acute rejection. Switching immunosuppressive therapy to hydrocortisone as a continuous infusion is a safe approach to reduce the duration of leukopenia and the incidence of viral infections.

In clinical practice, conversion from universal cytomegalovirus prophylaxis (CMV PPX) with valganciclovir (VGC) to targeted therapy (preemptive monitoring, PEM) is often pursued in the setting of leukopenia. It is unknown if this is an effective strategy.

Adult patients receiving a kidney and/or pancreas transplant were included if converted from PPX to PEM between 9/1/19 and 3/1/20 due to leukopenia. A positive CMV viral load (VL) was defined as CMV PCR greater than the lower limit of quantification (LLOQ) based on local lab testing. A CMV VL of >500 IU/mL was chosen as the preemptive treatment (PET) threshold. Primary objective was to describe the impact of conversion on resolution of leukopenia. Secondary objectives were to assess PEM associated outcomes.

There were 49 patients converted from PPX to PEM due to leukopenia in the study period; 88% were KTRs and 96% received lymphocyte-depleting induction; 84% were seropositive at transplant (R+) and 16% were high-risk (D+/R-). Mean WBC at time of enrollment was 1.4 ± 0.4. After PEM conversion, WBC recovered to >3 in 87.8% of the population in a mean of 26.8 ± 24.5 days. Immunosuppression was modified in 96% of the population and GCSF was required in 46.9% of patients. CMV viremia occurred in 36.7% of the population; 78% were KTRs and 94% were R+. Time from PEM enrollment to PET was 64 ± 34 days. Median VL at first detection was 587 IU/mL, median peak was 1920 IU/mL. Five patients (27.8%) presented with symptoms consistent with CMV syndrome, none had end organ disease. Six patients (33%) presented with a VL <500 IU/mL at first detection, but all subsequently surpassed the threshold and required PET. Mean duration of PET was 25 ± 11 days. Mean change in WBC in response to PET was -0.4 ± 1.3. Immunosuppression required further adjustment in 61% of patients. There were no deaths or graft loss due to CMV at last follow-up.

In kidney and pancreas transplant recipients who undergo PEM conversion due to leukopenia, withholding of VGC can improve leukopenia, but other concomitant measures are necessary. This population should be considered fairly high risk, with a threshold of treatment of first quantifiable replication. Our findings suggest lack of harm from this approach but highlight the importance of close monitoring to prevent symptomatic replication. Larger studies with longer follow-up are needed to better evaluate the impact of PEM conversion on late-onset CMV and patient and graft outcomes.

Introduction: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and hematopoietic stem cell transplantation. Areas covered: This review discusses the safety profiles of currently available and emerging antiviral drugs and the other strategies for HCMV prevention and treatment after transplantation. Expert opinion: Strategies for management of HCMV rely largely on the use of antiviral agents that inhibit viral DNA polymerase (ganciclovir/valganciclovir, foscarnet, and cidofovir/brincidofovir) and viral terminase complex (letermovir), with different types and degrees of adverse effects. An investigational agent, maribavir, exerts its anti-CMV effect through UL97 inhibition, and its safety profile is under clinical evaluation. In choosing the antiviral medication to use, it is important to consider these safety profiles in addition to overall efficacy. In addition to antiviral drugs, reduction of immunosuppression is often generally needed in the management of HCMV infection, but with a potential risk of allograft rejection or graft-versus-host disease. The use of HCMV-specific or non-specific intravenous immunoglobulins remains debated, while adoptive HCMV-specific T cell therapy remains investigational, and associated with unique set of adverse effects.

In the immunosuppressed, detection of viral reactivation at the earliest convenience and molecular monitoring are of paramount importance. Nucleic acid extraction has a major impact on the reliability of results obtained from molecular assays.

The aim of this study was to investigate the accuracy of the new EMAG^® nucleic acid extraction platform and to compare the performance of the new platform to that of the standard NucliSENS^® easyMAG^® instrument in the routine clinical laboratory.

For accuracy testing, reference material and for comparison studies, clinical specimens were used. In addition, a lab-flow analysis including estimation of hands-on time and that for automated extraction was performed.

When accuracy was tested, all 89 results obtained were found to be concordant with the results expected. When 648 clinical results were compared, 85.7% were found to be within ±0.5 log₁₀ unit, 9.5% between ±0.5 and ±1.0 log₁₀ unit, and 4.8% more than ±1.0 log₁₀ unit. The overall time required for nucleic acid extraction of 8 samples in parallel was 94 min for the fully automated extraction mode and 82 min for the partly automated mode with the new platform, and 73 min with the standard instrument. Hands-on time was found to be shorter with the new platform.

The extraction performance of both platforms was found to be similar for EDTA whole blood, BAL, and urine specimens. The total turn-around time for nucleic acid extraction was found to be longer with the EMAG^® platform, whereas hands-on time was reduced.

Drug-induced hematological cytopenia is common in kidney transplantation. Various cytopenia including leucopenia (neutropenia), thrombocytopenia, and anemia can occur in kidney transplant recipients. Persistent severe leucopenia or neutropenia can lead to opportunistic infections of various etiologies. On the contrary, reducing or stopping immunosuppressive medications in these events can provoke a rejection. Transplant clinicians are often faced with the delicate dilemma of balancing cytopenia and rejection from adjustments of immunosuppressive regimen. Differentials of drug-induced cytopenia are wide. Identification of culprit medication and subsequent modification is also challenging. In this review, we will discuss individual drug implicated in causing cytopenia and correlate it with corresponding literature evidence.

Neutropenia is a significant adverse event after heart transplantation (HT) and increases infection risk. Granulocyte colony-stimulating factor (G-CSF) is commonly used in patients with neutropenia. In this work, we assessed the adverse effects of G-CSF treatment in the setting of a university hospital.

Data on HT patients from January 2008 to July 2016 were reviewed. Patients who received G-CSF were identified and compared with patients without a history of therapy. Baseline characteristics, rejection episodes, and outcomes were collected. Data were analyzed by incidence rates, time to rejection and survival were analyzed using Kaplan-Meier curves, and odds ratios were generated using logistic regression analysis.

Two hundred twenty-two HT patients were studied and 40 (18%) received G-CSF for a total of 85 total neutropenic events (0.79 event/patient year). There were no differences in baseline characteristics between the groups. In the 3 months after G-CSF, the incidence rate of rejection was 0.067 event/month. In all other time periods considered free of G-CSF effect, the incidence rate was 0.011 event/month. This rate was similar to the overall incidence rate in the non-GCSF group, which was 0.010 event/month. There was a significant difference between the incidence rates in the G-CSF group at 0 to 3 months after G-CSF administration and the non-GCSF group (p = 0.04), but not for the other time periods (p = 0.5). Freedom from rejection in the 3 months after G-CSF administration was 87.5% compared with 97.5% in the non-GCSF group (p = 0.006).

G-CSF administration was found to be associated with significant short-term risk of rejection. This suggests the need for increased surveillance during this time period.

Neutropenia is associated with a high risk of serious infections in kidney transplant recipients. There are no sufficient studies of using granulocyte colony-stimulating factors, such as filgrastim, in renal transplant recipients to establish a clear, specified role of this off-label indication. Using filgrastim in these patients may increase the risk of rejection by overstimulating the immune system.

To evaluate the use of filgrastim in adult kidney transplant recipients presenting with neutropenia.

Data were obtained from a medication utilization report of filgrastim in kidney transplant recipients at our center from September 2012 to August 2015. Main Outcome Measure(s) and Results: There were 28 cases of neutropenia that were treated with a range of 1 to 5 doses of filgrastim 300 or 480 μg, with a mean of 1.79 doses. The mean total dose of filgrastim administered per episode of neutropenia was 632 μg (8.6 μg/kg). Overall, 87.5% of the cases achieved a white blood cell count of at least 3 × 10⁹ cells/L within 7 days of hospital discharge. There were no cases of infection or acute rejection following treatment.

The use of filgrastim in kidney transplant recipients demonstrated success in reversing neutropenia. Short courses of therapy were required with minimal adverse events. Patients who required readmission were successfully re-treated. Additional studies are required to determine the most effective dose and duration of treatment.

The purpose of this study was to determine the incidence and management strategies for post-transplant leukopenia/neutropenia in kidney recipients receiving alemtuzumab induction during the first year following transplantation.

We prospectively identified 233 adult patients who underwent kidney transplantation with alemtuzumab induction at a single institution. The incidence and severity of leukopenia (white blood cell count [WBC] ≤2500/mm(3)) and neutropenia (absolute neutrophil count [ANC] ≤500/mm(3)) were evaluated at 1, 3, 6, and 12 months post-transplantation. We determined any association with cytomegalovirus (CMV) infection, graft rejection, and infections requiring hospitalization. We also reviewed interventions performed, including medication adjustments, treatment with granulocyte stimulating factor, and hospitalization.

The combined incidence of either leukopenia or neutropenia was 47.5% (n = 114/233) with an average WBC nadir of 1700 ± 50/mm(3) at 131.0 ± 8.5 days and an average ANC nadir of 1500 ± 100/mm(3) at 130.4 ± 9.6 days. No significant difference in graft rejection, CMV infection, or infections requiring hospitalization was found in the leukopenia/neutropenia group vs the normal WBC group (P = .3). The most common intervention performed for leukopenia/neutropenia group was prophylactic medication adjustment. Six patients (5.2%) required a change in >1 medication. The majority of these patients also required granulocyte stimulating factor (61.5%; 32/52), with an average of 2.5 doses given. A total of 25 patients (21.9%) required hospitalization due to leukopenia/neutropenia with an average length of stay of 6 days.

Kidney transplant patients receiving alemtuzumab induction required significant interventions due to leukopenia/neutropenia in the first year post-transplantation. These results suggest the need for additional studies aimed at defining the optimum management strategies of leukopenia/neutropenia in this population.

Colony-stimulating factors (CSFs) are attractive adjunctive anti-infective therapies. Used to enhance innate host defenses against microbial pathogens, the myeloid CSFs increase absolute numbers of circulating innate immune effector cells by accelerating bone marrow production and maturation, or augment the function of those cells through diverse effects on chemotaxis, phagocytosis, and microbicidal functions. This article summarizes the evidence supporting the accepted clinical uses of the myeloid CSFs in patients with congenital or chemotherapy-induced neutropenia, and presents an overview of proposed and emerging uses of the CSFs for the prevention and treatment of infectious diseases in other immunosuppressed and immunocompetent patient populations.

Early postoperative infections are one of the major causes of morbidity and mortality following orthotopic liver transplantation. The severity of these infections may be increased in patients with neutropenia. There are no guidelines on the use of granulocyte colony-stimulating factor (G-CSF) for the treatment of neutropenia in posttransplant liver recipients. However, it has been recommended by several authors. We have herein presented two patients who were treated effectively with G-CSF. Both patients developed severe neutropenia (<500/mm(3)) on the third postoperative day, and received intravenous G-CSF administration for 3 days. The neutrophil counts gradually increased and additional infusions were not needed. The immunosuppressive and prophylactic treatments were not altered. G-CSF administration was used effectively for 3 days in our two patients. No evidence of infectious or acute rejection episode was encountered during or following G-CSF treatment.

Leukopenia is frequently observed in the setting of solid organ transplantation. The risk factors, natural history, and outcomes associated with leukopenia post-transplantation have not been well defined. We retrospectively studied 102 adult kidney and/or pancreas transplant recipients over a one-yr period of time. By defining leukopenia as a white blood cell count < or =3000 cells/mm(3) and neutropenia as an absolute neutrophil count < or =2000/mm(3), the combined incidence of either leukopenia or neutropenia was 58% (59/102); the first episode occurred at a mean of 91 d post-transplant. A significant increase in the incidence of leukopenia was found in patients who either received alemtuzumab induction (42% with alemtuzumab vs. 9% with rabbit anti-thymocyte globulin induction, p < 0.05) and/or had rapid steroid withdrawal in the early post-transplant period (44% with vs. 16% without steroid withdrawal, p < 0.05). The most common intervention performed for leukopenia was reducing the dose of mycophenolate mofetil and/or valganciclovir. When granulocyte stimulating factors were used, a mean of 3.1 doses were needed to successfully manage the leukopenia. Although leukopenia was a common finding in our study of kidney and/or pancreas transplant recipients, there was no difference in the rates of infection or acute rejection in patients with and without leukopenia.

Infections continue to cause significant morbidity and mortality in SOT recipients despite major advances in immunosuppressive and antimicrobial regimens. Immunomodulatory cytokines provide a potential means to augment the host immune response to infection. This review will focus on cytokine therapy for the prophylaxis and treatment of infections in solid organ transplant recipients, and will speculate on the potential for further advances in the field.

In kidney and liver transplant recipients, granulocyte colony-stimulating factor (G-CSF) has been used successfully to reverse ganciclovir-induced neutropenia or cytomegalovirus-induced neutropenia. Although G-CSF also reversed corticosteroid-induced suppression of the neutrophil respiratory burst in vitro, prophylactic G-CSF failed to reduce infections or mortality in nonneutropenic solid organ transplant recipients. Published clinical experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) in this population has been limited to case reports and a small case series, whereas the use of macrophage colony-stimulating factor (M-CSF) or interferon-gamma (IFN-gamma) has not been systematically investigated in controlled clinical trials.

Despite encouraging results in vitro and in preclinical models, immunomodulatory cytokines have not met expectations when administered to SOT recipients. Nonetheless, the principle of selective enhancement of innate immunity for the prevention and treatment of infections in this patient population has promise and warrants further study.

Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both ''direct'' and ''indirect'' effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre-emptive therapy, whereby anti-CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at-risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established.

A committee of international experts was convened to review the available data regarding CMV prophylaxis and to compare preventative strategies for CMV after transplantation from seropositive donors or in seropositive recipients.

Pre-emptive therapy requires frequent monitoring with subsequent treatment of disease and associated costs, while universal prophylaxis results in greater exposure to potential toxicities and costs of drugs. The advantages of prophylaxis include suppressing asymptomatic viremia and prevention of both direct and indirect effects of CMV infection. Meta analyses reveal decreased in mortality for patients receiving CMV prophylaxis. Costs associated with prophylaxis are less than for routine monitoring and pre-emptive therapy. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations including donor-seropositive/recipient-seronegative renal transplants and in CMV-infected lung and heart transplantation.

Prophylaxis is beneficial in preventing direct and indirect effects of CMV infection in transplant recipients, affecting both allograft and patient survival. More studies are necessary to define optimal prophylaxis regimens.

Viruses are among the most common causes of opportunistic infection after transplantation and the most important. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Viral infection, both symptomatic and asymptomatic, causes the "direct effects" of invasive disease and "indirect effects," including immune suppression predisposing to other opportunistic infections and oncogenesis. Rapid and sensitive microbiologic assays for many of the common viruses after transplantation have replaced, for the most part, serologic testing and in vitro cultures for the diagnosis of infection. Furthermore, quantitative molecular tests allow the individualization of antiviral therapies for prevention and treatment of infection. This advance is most prominent in the management of cytomegalovirus, Epstein-Barr, hepatitis B, and hepatitis C viruses. Diagnostic advances have not been accompanied by the development of specific and nontoxic anti-viral agents or effective antiviral vaccines. Vaccines, where available, should be given to patients as early as possible and well in advance of transplantation to optimize the immune response. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections.

Oncolytic viruses have been considered as a potential form of cancer treatment throughout the last century because of their ability to lyse and destroy tumor cells both in tissue culture and in animal models of cancer. However, it is only during the past decade that new molecular technologies have become available and understanding of genetic and molecular components of these viruses has increased to the point that they can be manipulated and made safe for use in treatment in humans. Thus there has been a revival of the concepts of conditionally replication-competent viruses and suicide gene therapy to supplement currently existing cancer therapies. While a wide variety of viruses have been closely studied for this purpose, herpes simplex virus type-1 (HSV-1) has received particularly close attention. The inherent cytotoxicity of this virus, if harnessed and made to be selective in the context of a tumor microenvironment, makes this an ideal candidate for further development. Furthermore, its large genome size, ability to infect cells with a high degree of efficiency, and the presence of an inherent viral-specific thymidine kinase gene add to its potential capabilities. This review explores work performed in this field and its potential for application in the treatment of cancers in humans.

Phagocyte respiratory burst capacity in response to pathogenic fungi and the in vitro effects of granulocyte colony-stimulating factor (G-CSF) were examined in 15 normal volunteers and 39 transplant recipients (4 autologous and 4 allogeneic bone marrow, 3 heart, 10 liver, 8 lung, and 10 kidney). Chemiluminescence was measured for reaction mixtures of diluted whole blood, opsonized fungi, and luminol, with and without in vitro incubation with r-metHuG-CSF (Filgrastim). Transplant patients exhibited significantly impaired respiratory burst responses to conidia and yeast compared with controls, but this was reversed with Filgrastim. Responses to hyphae were low for both groups, and G-CSF had little or no effect. There was excellent correlation between responses to fungi and responses to opsonized zymosan. In vitro respiratory burst capacity is impaired in transplant recipients. This may predict susceptibility to invasive fungal infections. G-CSF can reverse impaired phagocyte function and is of potential benefit in the prevention and/or treatment of fungal infection in transplant patients.

Our understanding of host defense has exploded during the past two decades. It is temping to take advantage of this knowledge by considering the modulation and control of these mechanisms as therapeutic options. In intensive care medicine, the aim is usually to block an overwhelming inflammatory response, which represents the "bad" side of the double-edged sword of host defense. The obvious danger of such treatment strategies is that impairing the inflammatory reaction means impairing host defense in patients exposed to infectious agents. The alternative approach, i.e., strengthening or supplementing favorable host defense mechanism, has so far been little explored clinically. Granulocyte colony-stimulating factor, the granulocyte colony-stimulating factor, combines the unique properties of an anti-infectious and an anti-inflammatory factor. This attractive profile has led us to various approaches to exploit these immunomodulatory activities. In a recently terminated, placebo-controlled, randomized study, we investigated if prophylactic treatment with rh granulocyte colony-stimulating factor (Filgrastim), at the time a risk can be anticipated such as before an operation, may offer protection from immunoinflammatory dyshomeostasis and thus lower the incidence of postoperative sepsis. Perioperative rh granulocyte colony-stimulating factor administration, compared with placebo treatment, resulted in the prevention of postoperative monocyte deactivation, conservation of an adequate Th1/Th2 ratio, as well as a considerable alleviation of the acute phase response. In parallel, there was a clear tendency toward lowering the rate of postoperative septic complications under the administration of Filgrastim.