Viral pneumonia after hematopoietic stem cell transplantation: high-resolution CT findings

Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematologic malignancies and nonmalignant disorders of bone marrow function. Pulmonary infections from bacterial, fungal, and viral organisms are a major cause of morbidity and mortality in patients after HSCT. The radiographic and high-resolution computed tomography (HRCT) findings of the different lower respiratory tract viral infections are quite similar. Findings of viral pneumonia on HRCT include small poorly defined centrilobular nodules and patchy, often bilateral, areas of peribronchial ground-glass opacity and consolidation. Air trapping may be present because of associated bronchiolitis. Interlobular septal thickening, bronchial wall thickening, and tree-in-bud opacities may also be present. Advanced viral pneumonia with diffuse alveolar damage is characterized by patchy or confluent consolidation and ground-glass opacities. Although nonspecific, in the correct clinical setting, these HRCT findings can help suggest the diagnosis of viral pneumonia in recipients of HSCT.     

Antifungal prophylaxis in hematopoietic stem cell transplant recipients

Infections remain a major complication of hematopoietic stem cell transplantation, with recent trends indicating that fungal pathogens have become one of the most common causes of death. Attention has turned to the use of prophylactic antifungal medications to prevent infection with both Candida and Aspergillus species. Recent studies, which are reviewed within, indicate success in preventing infections caused by azole-susceptible Candida species, accompanied by improved transplant-related mortality rates in high-risk patients. Further studies are necessary to develop strategies to prevent infection with Aspergillus species.     

Adenovirus infections in hematopoietic stem cell transplant recipients.

We report a 12% incidence of adenovirus infections among 532 recipients of hematopoietic stem cell transplant (HSCT) from January 1986 through March 1997. The median time from day of stem cell infusion to first positive culture was 41 days. Recipients of allogeneic stem cells, as opposed to autologous stem cell recipients, were more likely to have a culture positive for adenovirus (16% vs. 3%; P<.0001). Pediatric patients were also more likely than adults to have a positive culture (23% vs. 9%; P<.0001). Among stem cell recipients with partially matched related donors, pediatric recipients appear to be at significantly greater risk for infection than adult recipients (P<.001). Positive cultures were associated with evidence of invasion in 64% of cases (41 of 64). A multiple logistic regression analysis showed that isolating adenovirus from more than 1 site correlated with greater risk for invasive infections (P=.002). Invasive infections were associated with poorer chance of survival.     

Choices aplenty: antifungal prophylaxis in hematopoietic stem cell transplant recipients

The incidence of invasive fungal infection (IFIs) in hematopoietic stem cell transplantation (HSCT) recipients ranges from 10 to 25% with an overall case fatality rate of up to 70-90%. Candida and Aspergillus genera remain the two most common pathogens. Although fluconazole prophylaxis in this population has been moderately effective in reducing mortality due to invasive candidiasis, this agent does not have activity against invasive aspergillosis (IA) and other mould. Several new agents such as voriconazole and caspofungin have enhanced potency and broad-spectrum antifungal activity and show promising results against yeasts and filamentous fungi when given as therapy and as chemoprophylaxis. Further, new diagnostic tools to detect circulating fungal antigens in biological fluids and PCR-based methods to detect species or genus-specific DNA or RNA have been developed. Incorporating these techniques along with clinical criteria appear to improve the accuracy of preclinical diagnosis of IFIs. Such approaches may alter the current treatment strategy from prophylaxis to pre-emptive therapy, thereby potentially decreasing cost and toxicity in high-risk patients.     

Acquired factor VII deficiency in hematopoietic stem cell transplant recipients

Acquired factor VII (FVII) deficiency in the absence of vitamin K deficiency, oral anticoagulant therapy, synthetic liver dysfunction, or DIC is rare, with only a handful of cases thus far reported. In the period from 1990 to 1996 we identified eight patients with acquired FVII deficiency, all of whom presented with prolongation of the prothrombin time (PT) in the first 2 weeks following stem cell transplantation (SCT). The mean plasma FVII clotting activity (FVII:c) was 22% (range 8-35%) with an approximately equivalent reduction in FVII antigen (FVII:Ag) level. Mean plasma levels of fibrinogen and factors II, V, IX, and X were normal. Protein C activity was significantly depressed in only one of the three patients in whom it was measured. Several patients experienced bleeding complications, and hemorrhage directly accounted for death in two cases. Veno-occlusive disease of the liver developed in three patients. We conclude that FVII deficiency should be considered in the differential diagnosis of prolonged PT in patients who have recently undergone SCT. The mechanism of this acquired deficiency state remains to be defined.     

Analysis of rotavirus antigenemia in hematopoietic stem cell transplant recipients

Systemic rotavirus infection, such as rotavirus antigenemia, has been found in immunocompetent rotavirus gastroenteritis patients. However, the pathogenesis of rotavirus infection in immunocompromised transplant recipients remains unclear. Enzyme-linked immunosorbent assay was used to measure rotavirus antigen levels in serially collected serum samples obtained from 62 pediatric patients receiving allogeneic hematopoietic stem cell transplants (HSCT). Rotavirus antigen was detected in 43 (6.8%) of 633 serum samples (8 of 62 patients). The duration of rotavirus antigenemia ranged between 1 and 10 weeks, and diarrhea was concurrent with rotavirus antigenemia in Cases 3, 6, 7, and 8. The level of viral antigen in the transplant recipients (0.19 ± 0.20) was significantly lower than that observed in serum samples collected from immunocompetent patients on either day 1 (0.49 ± 0.18, P = 0.0011) or day 3 (0.63 ± 0.09, P = 0.0005). A patient who received a graft from a human leukocyte antigen (HLA)-mismatched donor was at significant risk for rotavirus antigenemia (P = 0.024; odds ratio = 9.44) in comparison to patients who received grafts from HLA-matched donors. Although the duration of antigenemia was clearly longer in HSCT patients than in immunocompetent rotavirus gastroenteritis patients, the levels of viral antigen were not as high. Therefore, mismatched HLA may be a risk factor for rotavirus antigenemia after HSCT.     

Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients

Alveolar hemorrhage (AH) is a frequent, serious complication of hematopoietic stem cell transplantation (HSCT). To study the incidence of AH, its clinical course and outcomes in HSCT patients, a retrospective review of the records of all adult patients who underwent bronchoscopy between January 1, 2002 and December 31, 2004 was carried out and those who underwent bronchoscopy after HSCT identified. A total of 223 patients underwent bronchoscopy after HSCT for diffuse pulmonary infiltrates with respiratory compromise. Eighty-seven (39%) patients had AH. Of these, 53 had AH without any identified organism while 34 had an organism along with hemorrhage on bronchoalveolar lavage (BAL). Six-month survival rate of patients with AH was 38% (95% confidence interval: 27-48%). In 95 of the 223 patients, an organism was isolated from BAL. These patients had poor outcomes compared to patients in whom no organism was identified. Patients with both AH and an organism had the worst prognosis. Mortality of patients with AH is improving and long-term survival of patients with AH is feasible. Isolation of a microbial organism in BAL is a strong predictor of poor outcome.     

Persistent symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients

Sequential nasopharyngeal aspirates from patients without respiratory symptoms undergoing hematopoietic stem cell transplantation (HSCT) were tested for genomic RNA of human metapneumovirus (hMPV). Persistent hMPV infection was documented in most of them and confirmed by virus isolation. hMPV infection etiology was also evaluated during the same period in samples from pediatric patients with acute respiratory diseases (ARDs). Sequence analysis of hMPV in HSCT recipients documented infection by hMPV genotype A and strong interhost similarity; this pattern differs from that observed in pediatric patients with ARDs. The data indicate that HSCT recipients may frequently develop symptomless hMPV infection.     

Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients

Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring voriconazole levels is unclear. Steady-state trough plasma voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once (n=13), twice (n=10), or > or =3 times (n=2) 5-18 days (median 10) after starting voriconazole or dose modification. The 41 voriconazole levels were 0.2-6.8 microg/ml (median 1.6); 6 (15%) were <0.5 (possibly below the in vitro MIC90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase (AST) (r=0.5; P=0.0009) and alkaline phosphatase (r=0.34; P=0.03), but not with creatinine, bilirubin and alanine aminotransferase (ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher voriconazole levels. We conclude that trough voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels.     

Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients

Previous studies have reported mortality rates of about 80% in hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage. This retrospective study describes the clinical course of 48 such patients: mean age 47.7 years, 52% autologous transplant and 67% peripheral stem cell source. The hemorrhage occurred within one month of transplant in 28 patients. Symptoms included dyspnea in 92%, fever in 67%, cough in 56%, and hemoptysis in 15%. Intensive care unit admission was required in 85% and mechanical ventilation in 77%. Most of the patients were treated with intravenous methylprednisolone 1 g daily for 3 days and then tapered off after a median of 22 days. The hospital mortality was 48%. The cause of death was respiratory failure in 15 of the 23 deaths. Mortality was 28% in autologous compared with 70% in allogeneic transplant recipients (p = 0.0040). The mortality rate of patients whose hemorrhage occurred within the first 30 days of transplant was 32% compared with 70% of those with late hemorrhage (p = 0.0096). This study shows that survival rate of hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage is better than previously reported, and that early onset and autologous transplant are favorable prognostic indicators.     

Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients

Adenovirus (AdV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. We treated 16 patients with AdV hemorrhagic cystitis (HC) following HSCT with cidofovir (CDV; 1 mg/kg/day, three times weekly for 3 weeks). Patients included 10 males and six females with a median age of 50 years (range 10-62). Two of the 16 patients were unevaluable because of early death from nonadenoviral causes. CDV therapy cleared AdV from urine in 12 of 14 patients (86%). Of 14 patients, 10 (71%) showed clinical improvements in HC. Among 14 patients, seven (50%) had avoided renal damage, the most important CDV toxicity. One patient previously treated with foscarnet for cytomegalovirus (CMV) required hemodialysis, and CDV treatment was discontinued. In another patient, CDV treatment was discontinued because of grade 2 nephrotoxicity. Four patients became positive for CMV antigenemia while being treated with CDV, and two developed herpes simplex virus (HSV) stomatitis while being treated with CDV. CDV proved effective in treating AdV HC in transplant patients. However, CDV at 1 mg/kg/day given three times weekly failed to prevent breakthrough infection with CMV and HSV in some patients.     

Genetic variability of cytomegalovirus glycoprotein O in hematopoietic stem cell transplant recipients

K. Roubalova, O. Strunecky, A. Vitek, S. Zufanova, B. Prochazka. Genetic variability of cytomegalovirus glycoprotein O in hematopoietic stem cell transplant recipients.
Transpl Infect Dis 2011: 13: 237–243. All rights reserved Abstract: Genetic variation of cytomegalovirus (CMV) strains can correlate with their pathogenicity for immunocompromised patients. Glycoprotein O (gO), together with glycoprotein L and glycoprotein H, mediate the fusion of the viral envelope with the cell membrane and promotes virus penetration, envelopment, and release. The variability of gO might play a role in CMV cell tropism. The goal was a retrospective analysis of gO variability in a cohort of hematopoietic stem cell transplant (HSCT) recipients to determine the distribution of gO genotypes and to investigate their impact on clinical outcome and manifestation of CMV infection. Methods. In archived blood samples from 51 adult allogeneic HSCT recipients with active CMV infection, gO was analyzed by sequencing the N‐terminal domain of the UL74 gene using the dye deoxy termination method. Results. The gO1 and gO2 clades were most common (39% and 20%, respectively, and gO3 was associated with higher risk of symptomatic infection (P=0.026 in multivariant analysis). Despite being associated with higher antigenemia levels (P=0.02), gO4 had the best survival and lower rate of CMV recurrence. No significant differences were found in clinical manifestation and outcome of CMV disease between patients with various gO clades. Because CMV strains sharing an identical gO sequence differed in glycoprotein B genotypes, sequencing the N‐terminal part of the gO gene does not seem to be optimal for the identification of strains. Conclusions. gO genotyping may contribute to the biological characterization of CMV strains in HSCT recipients.     

Clinical approach to diarrheal disorders in allogeneic hematopoietic stem cell transplant recipients

Diarrhea is a common complication of allogeneic hematopoietic stem cell transplant (HSCT), with an average incidence of approximately 40%-50%. A wide variety of etiologies can contribute to diarrhea in HSCT patients, including medication-induced mucosal inflammation, infections, graft-vs-host disease and cord colitis syndrome in umbilical cord blood transplant. Clinical manifestations can vary from isolated diarrheal episodes, to other organ involvement including pneumonia or myocarditis, and rarely multiorgan failure. The approach for diagnosis of diarrheal disorders in HSCT patients depends on the most likely cause. Given the risk of life-threatening conditions, the development of clinically significant diarrhea requires prompt evaluation, supportive care and specific therapy, as indicated. Serious metabolic and nutritional disturbances can happen in HSCT patients, and may even lead to mortality. In this review, we aim to provide a practical approach to diagnosis and management of diarrhea in the post-transplant period.     

Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients

M. Mikulska, V. Del Bono, R. Prinapori, L. Boni, A.M. Raiola, F. Gualandi, M.T. Van Lint, A. Dominietto, T. Lamparelli, P. Cappellano, A. Bacigalupo, C. Viscoli. Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients.
Transpl Infect Dis 2010: 12: 505–512. All rights reserved Abstract: Bacteremia is a well known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients and enterococci are among the most frequently isolated pathogens. The aim of this study was to identify risk factors for enterococcal bacteremia during the first 30 days after allogeneic HSCT. A retrospective case–control study was performed; for each case, 3 controls were randomly selected among 306 patients transplanted during the study period (January 1, 2004 to December 31, 2007). Odds ratios (OR) with 95% confidence intervals (CI) were calculated for variables influencing the risk for bacteremia. Overall, 33 patients developed enterococcal bacteremia, within a median of 9 days after HSCT (range, 2–24). The cumulative incidence was 10.8%. Multivariate analysis identified the following variables as risk factors for enterococcal bacteremia: donor and transplant type (greater risk for mismatched related or cord blood) (OR=8.98, 95% CI, 1.65–48.99 and OR=7.52, 95% CI, 1.56–36.31, respectively, P=0.047); severe (grades 3–4) mucositis (OR=9.04, 95% CI, 1.97–41.52, P=0.018); pharyngeal enterococcal colonization (OR=4.48, 95% CI, 1.11–18.03, P=0.035); and previous empirical therapy with cephalosporins (OR=4.16, 95% CI, 0.93–18.66 for 1–7 days of therapy, and OR=7.31, 95% CI, 1.78–30.12 for 8–23 days, P=0.018). Higher Karnofsky score (≥50) and previous empirical therapy with glycopeptides were associated with a decreased risk (OR=0.25, 95% CI, 0.06–0.97, P=0.045 and OR=0.11, 95% CI, 0.02–0.59, P=0.010, respectively). The crude mortality at 7 and 30 days was 12% (4/33) and 24% (8/33), respectively. Enterococcal bacteremia is frequent after allogeneic HSCT. The factors associated with this infection are type of transplant, pharyngeal colonization, severe mucositis, and use of cephalosporins. Good general conditions and the use of vancomycin were associated with lower risk of enterococcal bacteremia.     

Respiratory viral infections in hematopoietic stem cell and solid organ transplant recipients

Respiratory viral infections (RVIs) are common causes of mild illness in immunocompetent children and adults with rare occurrences of significant morbidity or mortality. Complications are more common in the very young, very old, and those with underlying lung diseases. However, RVIs are increasingly recognized as a cause of morbidity and mortality in recipients of hematopoietic stem cell transplants (HSCT) and solid organ transplants (SOTs). Diagnostic techniques for respiratory syncytial virus (RSV), parainfluenza, influenza, and adenovirus have been clinically available for decades, and these infections are known to cause serious disease in transplant recipients. Modern molecular technology has now made it possible to detect other RVIs including human metapneumovirus, coronavirus, and bocavirus, and the role of these viruses in causing serious disease in transplant recipients is still being worked out. This article reviews the current information regarding epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment of these infections, as well as the aspects of clinical significance of RVIs unique to HSCT or SOT.