Viral infections in immunocompromised patients

The number of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is steadily increasing, and the outcome of this intervention is largely dependent on how well complications in the form of severe infections can be adequately diagnosed and controlled. Adenoviruses (AdV) have emerged as important causes of morbidity and mortality in these patients. Early diagnosis of the infection by detection of viral DNA may improve the prognosis. In paper I we evaluated a surveillance strategy for detection of AdV DNA by real-time PCR in a prospective study of hematological allo-HSCT recipients. In parallel with a routine cytomegalovirus surveillance program, plasma samples from 97 recipients were analyzed by quantitative PCR for detection of AdV DNA. A total of 5% of the patients had detectable AdV DNA in plasma. Only one patient had high titers and none developed AdV disease. Bone marrow as a source of stem cells and myelodysplastic syndrome as the indication for transplantation were independently associated with higher risk of acquiring AdV infection. We concluded that the strategy did not have a significant effect on the clinical outcome in our material, but given the sometimes high incidence of AdV infection and disease in other settings, we do not dismiss the idea of surveillance. With a somewhat different approach to improve the clinical care for patients undergoing immunosuppressive treatment, we investigated the etiology to febrile neutropenia. Chemotherapy-induced neutropenia is one of the major side effects of the treatment of maligancies, and the risk of infection is increased by the severity and duration of neutropenia. The empiric administration of broad spectrum antibiotics has substantially decreased the mortality rate of patients with febrile neutropenia, but in only approximately one-third or fewer of the fever episodes, bacterial infection is documented. It is likely that other pathogens, such as viruses, play an important role as etiological agents, and an overuse of antibiotics could be anticipated. Therefore, in paper II and paper IV we investigated the presence of common viral infections and febrile neutropenia in children with cancer as well as adult patients with hematological disorders. A broad range of respiratory viruses in nasopharyngeal aspirate (NPA) and viruses commonly reactivated in allo-HSCT recipients were sought for. With human rhinovirus (HRV) being the predominant virus, we found an viral agent in half of the cases in the pediatric cohort. Of these, 25% co-ocurred with a bacterial finding. Virus detcted in blood was a rare event. In the adult population, we detected a viral pathogen in 42% of the episodes of febrile neutropenia. This should be compared to 13% in afebrile neutropenic patients that were included as controls. In both groups, approximately half of the viruses were detected in blood. The predominant respiratory virus was HRV, whereas BK virus was the commonest finding in blood. In one-third of the virus-positive cases, a bacterial infection was documented. We furthermore found NPA being superior to a flocked nasal swab for collection of respiratory specimens (paper III). We concluded that the prevalence of viruses was high in neutropenic patients with fever, and it was higher than for neutropenic patients without fever. It is plausible that a number of the patients with febrile neutropenia suffer from viral infections, and are thus not helped by antibiotics. Unfortunately, the presence of virus could not function as a predictor for non-bacterial infection. The findings, however, warrants further research related to the earlier achievements with aim to identify patients where continuous empiric antibiotic treatment could be avoided

Flocked nasal swab versus nasopharyngeal aspirate for detection of respiratory tract viruses in immunocompromised adults: a matched comparative study

<p>Abstract</p> <p>Background</p> <p>Several studies have compared nasal swabs to the more invasive nasopharyngeal aspirate (NPA) for detection of respiratory viruses. Mostly, the comparisons have been performed on immunocompetent children with upper respiratory tract symptoms. The results range from a relatively poor sensitivity for the swabs to an even higher sensitivity than for the NPA. We aimed to investigate the sensitivity of a flocked nasal swab (fNS) on immunocompromised adults with febrile neutropenia.</p> <p>Methods</p> <p>During 16 months, adults with a hematological disorder presenting with febrile neutropenia were enrolled in the study. Paired samples of the fNS and NPA were collected in the outer part of the nasal cavity and the nasopharynx, respectively. The samples were analyzed regarding a panel of 15 respiratory viruses by means of quantitative polymerase chain reaction. Furthermore, as an indirect measure of cell yield by either method, the copy number of the human beta actin gene was also determined. Cohen's kappa was calculated as a measure of agreement of the results obtained from either method. Wilcoxon signed-rank test was used for comparison of cell yield.</p> <p>Results</p> <p>A total of 98 paired samples from a total of 89 patients were collected. Twenty of the pairs had virus detected in at least one of the specimens; 11 in both, 7 in NPA only, and 2 in fNS only. For the fNS, the overall sensitivity for any virus and for rhinovirus only was 65% and 78%, respectively. NPA was significantly superior to the fNS in collecting epithelial cells.</p> <p>Conclusion</p> <p>We found the overall sensitivity of 65% to be too low to replace NPA with this sampling technique in this patient category.</p

Mannose-Binding Lectin 2 Polymorphisms Do Not Influence Frequency or Type of Infection in Adults with Chemotherapy Induced Neutropaenia

BACKGROUND: Mannose-binding Lectin protein (MBL) has been suggested to be relevant in the defence against infections in immunosuppressed individuals. In a Swedish adult cohort immunosuppressed from both the underlying disease and from iatrogenic treatments for their underlying disease we investigated the role of MBL in susceptibility to infection. METHODS: In this cross sectional, prospective study, blood samples obtained from 96 neutropaenic febrile episodes, representing 82 individuals were analysed for single nucleotide polymorphism (SNP) in the MBL2 gene. Concurrent measurement of plasma MBL protein concentrations was also performed for observation of acute response during febrile episodes. FINDINGS: No association was observed between MBL2 genotype or plasma MBL concentrations, and the type or frequency of infection. Adding to the literature, we found no evidence that viral infections or co-infections with virus and bacteria would be predisposed by MBL deficiency. We further saw no correlation between MBL2 genotype and the risk of fever. However, fever duration in febrile neutropaenic episodes was negatively associated with MBL2 SNP mutations (p<0.05). Patients with MBL2 SNP mutations presented a median febrile duration of 1.8 days compared with 3 days amongst patients with wildtype MBL2 genotype. INTERPRETATION: We found no clear association between infection, or infection type to MBL2 genotypes or plasma MBL concentration, and add to the reports casting doubts on the benefit of recombinant MBL replacement therapy use during iatrogenic neutropaenia

Viral Findings in Adult Hematological Patients with Neutropenia

BACKGROUND: Until recently, viral infections in patients with hematological malignancies were concerns primarily in allogeneic hematopoietic stem cell transplant (HSCT) recipients. During the last years, changed treatment regimens for non-transplanted patients with hematological malignancies have had potential to increase the incidence of viral infections in this group. In this study, we have prospectively investigated the prevalence of a broad range of respiratory viruses in nasopharyngeal aspirate (NPA) as well as viruses that commonly reactivate after allogeneic HSCT. METHODOLOGY/PRINCIPAL FINDINGS: Patients with hematological malignancies and therapy induced neutropenia (n = 159) were screened regarding a broad range of common respiratory viruses in the nasopharynx and for viruses commonly detected in severely immunosuppressed patients in peripheral blood. Quantitative PCR was used for detection of viruses. A viral pathogen was detected in 35% of the patients. The detection rate was rather similar in blood (22%) and NPA (18%) with polyoma BK virus and rhinovirus as dominating pathogens in blood and NPA, respectively. Patients with chronic lymphocytic leukemia (CLL) (p<0.01) and patients with fever (p<0.001) were overrepresented in the virus-positive group. Furthermore, viral findings in NPA were associated with upper respiratory symptoms (URTS) (p<0.0001). CONCLUSIONS/SIGNIFICANCE: Both respiratory viral infections and low titers of viruses in blood from patients with neutropenia were common. Patients with CLL and patients with fever were independently associated to these infections, and viral findings in NPA were associated to URTS indicating active infection. These findings motivate further studies on viruses' impact on this patient category and their potential role as causative agents of fever during neutropenia

Characteristics of the parvovirus B19 positive and negative patients.

<p>NOTE. F, female; M, male; PARV4, parvovirus 4; Pos, positive; Neg, negative; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; B19, parvovirus B19; n, number.</p

Endotoxin concentrations with (n = 68) and without (n = 77) prophylactic antibiotics use.

<p>Filled circles indicate febrile episodes and open circles indicate afebrile episodes. *p<0.05.</p

Endotoxin concentrations stratified based on febrile status and microbiological findings.

<p>Endotoxin concentrations measured in febrile (n = 103) and afebrile (n = 42) episodes (A). Endotoxin concentrations in febrile neutropaenic episodes with bacteria (n = 37), virus (n = 28) and FUO (n = 38) (B). * p<0.05, *** p<0.0001.</p