Clinical Significance of Cytomegalovirus Reactivation in Patients With Plasma Cell Dyscrasia Who Were Treated With Anti-CD38 Monoclonal Antibody: A Retrospective Analysis in a Single Institution.

INTRODUCTION: Anti-CD38 monoclonal antibodies (mAbs) have improved the prognosis of patients with plasma cell dyscrasia (PCD), but are also associated with increased infectious adverse events. Cytomegalovirus (CMV) is a common latent pathogen that is reactivated in immunocompromised individuals. Although CMV reactivation has mostly been reported after high-dose chemotherapy followed by stem cell transplantation in patients with PCD, cases of reactivation during anti-CD38 mAb therapy have been reported recently. Due to limited studies, we aimed to determine the frequency and impact of CMV reactivation during anti-CD38 mAb therapy. PATIENTS AND METHODS: This retrospective analysis included 154 consecutive patients with PCD who were treated with anti-CD38 mAbs at a single institution. RESULTS: Seventy-six patients were evaluated for CMV reactivation by CMV pp65 antigen testing, and 29 (38%) patients, including nine with newly diagnosed PCD, showed positive results. Patients who tested positive for the CMV pp65 antigen had substantially lower serum albumin levels than those who tested negative. However, the two groups showed no marked difference in the concurrent anti-PCD medications or baseline absolute lymphocyte count. Although most patients showing positive results in the CMV pp65 antigen test had mild or no symptoms, with fever being the most common symptom, some patients developed CMV end-organ disease. In addition, CMV reactivation interfered with the course of anti-PCD treatment in most patients, necessitating dose reductions, delays, and discontinuation of chemotherapy. CONCLUSION: This study provides an overview of the clinical impact of CMV reactivation in patients with PCD treated with anti-CD38 mAb-containing regimens.

Unilateral methotrexate-induced lung injury with foreign bodies in the airway: A case report.

A 75-year-old woman who had been taking methotrexate presented to our hospital for fever and dry cough. Chest computed tomography showed ground-glass opacity in the upper lobe of the right lung and foreign bodies in the lower lobe of the right bronchus. During bronchoscopy, foreign bodies were removed from the airway. We found increased levels of lymphocytes and a high CD4/CD8 ratio in the bronchoalveolar lavage fluid. Transbronchial lung biopsy revealed lymphocytic infiltration. Methotrexate was discontinued, and the imaging findings improved. Methotrexate-induced lung injury does occur unilaterally. Foreign bodies in the airway might also trigger unilateral methotrexate-induced lung injury.

Postoperative hyperglycemia may negatively impact cytomegalovirus infection in seropositive liver transplant recipients: a retrospective cohort study.

The aim of the study was to evaluate the association between postoperative hyperglycemia and CMV infection. We analyzed 741 CMV seropositive recipients, of livers from seropositive living donors, who underwent preemptive CMV treatment without CMV prophylaxis. The primary outcome was early CMV infection within 1 month after surgery. Hyperglycemia was defined when mean postoperative blood glucose concentration was >180 mg/dl based on previous research and guidelines. Survival analysis was performed using the Fine and Gray model by accounting for the competing risk of CMV infection-unrelated death. Of the 741 recipients (hyperglycemic group, n = 287; nonhyperglycemic group, n = 454), 372 (50.2%) recipients developed cytomegalovirus (CMV) infection within 1 month after surgery. CMV infection risk was significantly higher in hyperglycemic group than in nonhyperglycemic group in univariable analysis [hazard ratio (HR) 1.34, 95% confidence interval (CI), 1.08-1.66; P = 0.007] and in multivariable analysis (HR 1.25, 95% CI 1.0-1.54; P = 0.038). CMV infection risk was also significantly associated with recipient age, graft ischemia time, model for end-stage liver disease score, and preoperative neutrophil-to-lymphocyte ratio (P < 0.05). In conclusion, preventing postoperative hyperglycemia appears to be an important factor decreasing the risk of CMV infection in seropositive liver transplant recipients undergoing preemptive CMV treatment.

Comprehensive Analysis of CD4+ T Cell Responses to CMV pp65 Antigen Restricted by Single HLA-DR, -DQ, and -DP Allotype Within an Individual.

Within an individual, six different HLA class II heterodimers are expressed co-dominantly by two alleles of HLA-DR, -DQ, and -DP loci. However, it remained unclear which HLA allotypes were used in T cell responses to a given antigen. For the measurement of the CD4+ T cell responses restricted by a single HLA allotype, we established a panel of artificial antigen-presenting cells (aAPCs) expressing each single HLA allele of 20 HLA-DRB1, 16 HLA-DQ, and 13 HLA-DP alleles. CD4+ T cell responses to cytomegalovirus (CMV) pp65 restricted by single HLA class II allotype defined in 45 healthy donors. The average magnitude of CD4+ T cell responses by HLA-DR allotypes was higher than HLA-DQ and HLA-DP allotypes. CD4+ T cell responses by DRA*01:01/DRB1*04:06, DQA1*01:02/DQB1*06:02, DPA1*02:02/DPB1*05:01 were higher among the other alleles in each HLA-DR, -DQ, and -DP locus. Interestingly, the frequencies of HLA-DR alleles and the positivity of specific allotypes showed an inverse correlation. One allotype within individuals is dominantly used in CD4+ T cell response in 49% of donors, and two allotypes showed that in 7% of donors, and any positive response was detected in 44% of donors. Even if one individual had several dominant alleles, CD4+ T cell responses tended to be restricted by only one of them. Furthermore, CD8+ and CD4+ T cell responses by HLA class I and class II were correlated. Our results demonstrate that the CD4+ T cell preferentially use a few dominant HLA class II allotypes within individuals, similar to CD8+ T cell response to CMV pp65.

Effectiveness of PCR and Immunofluorescence Techniques for Detecting Human Cytomegalovirus in Blood and Bronchoalveolar Lavage Fluid.

Current diagnostic methods allow a rapid and reliable detection of active human cytomegalovirus (hCMV) infection by identifying the presence of pp65 CMV antigen or CMV DNA in peripheral blood and affected organs. The goal of this study was to evaluate the effectiveness of CMV detection in blood and organ-specific biological material, such as bronchoalveolar lavage fluid (BALF), by comparing two standard diagnostic methods, immunofluorescence (IF) and the real-time polymerase chain reaction (PCR). We evaluated 25 patients with concomitant respiratory disease who were referred to our hospital for diagnosis due to suspected acute CMV infection. The presence of hCMV was concomitantly evaluated by IF and PCR in 16 peripheral blood samples. In two patients, we observed positive results for both IF and PCR, and in two other patients the results were discordant. Of 11 patients, CMV DNA was detected in six BALF samples, and in one blood plasma sample. Real-time PCR detected CMV DNA in 54.6 % of BALF samples and 12.0 % of blood samples, while indirect IF testing confirmed antigenemia in 12.5 % of blood samples. The results from our study suggest that the IF method is as effective as PCR for detecting an ongoing CMV infection in blood samples. However, real-time PCR was much more effective at detecting CMV DNA in BALF compared to blood samples. Our results suggest that the biological material being tested during CMV diagnosis should be derived directly from the virally infected organ(s).

Seroprevalence and Seroconversion Rates of Cytomegalovirus pp65 Antigen and Cord Blood Screening of Pregnant Women in Malatya, Turkey.

OBJECTIVE: The rates of seropositivity, seroconversion and fetal infection with human cytomegalovirus were analyzed in pregnant women and newborn cord blood in this study. The relationships between maternal age, parity, cytomegalovirus serology and polymerase chain reaction results were evaluated. MATERIALS AND METHODS: A total of 217 pregnant women attended our pregnancy clinic between April 2004 and October 2005. During each trimester, 5 cc of maternal blood was obtained and 5 cc of cord blood was collected after birth. An enzyme-linked immunosorbent assay (ELISA) was used to assess these samples for the presence of human cytomegalovirus protein pp65 antigen (in leukocytes) and cytomegalovirus DNA (in plasma). RESULTS: The mean age of the pregnant women in our study was 28.1±5.3 years. No seroconversion was observed. Among the pregnant women, 212 (97.7%) were IgG positive, and 29 (13.4%) were IgM positive. Five of the pregnant women were positive for IgM alone (2.3%), whereas 24 (11.3%) were positive for both IgM and IgG. The 29 IgM-positive patients were reevaluated using the polymerase chain reaction, and no seropositivity was found. None of the cord blood samples were IgM positive, whereas 211 (97.3%) were IgG positive. There was no significant correlation between parity and seropositivity (p=0.487). The relationship between human cytomegalovirus seropositivity and maternal age was evaluated by dividing the pregnant women into two groups, with a cut-off age of 35 years. There was a significant difference in seropositivity between these two groups (p=0.045). CONCLUSION: Clearly, there is no need to screen pregnant women for Human cytomegalovirus (HCMV) in the Malatya region. Confirming serology results using the polymerase chain reaction and antigenemia testing to detect false positive results offers the advantage of avoiding unnecessary invasive interventions.

PP65 antigenemia in the diagnosis of cytomegalovirus infection in AIDS patients

Cytomegalovirus causes significant morbidity and mortality in AIDS patients and those having undergone bone marrow or another transplant. PP65 antigenemia is based on detecting viral antigen in peripheral blood leukocytes through immunochemistry and by monitoring the infection in immunocompromised individuals. The present study aimed to set up this diagnostic technique in AIDS patients with active cytomegalovirus infection and verify its occurrence in the Botucatu region of São Paulo state, Brazil. Fifty patients, 35 men and 15 women aged from 24 to 69 years, were recruited from those attended at the Department of Tropical Diseases of Botucatu Medical School, UNESP, and divided into three groups according to CD4+ T lymphocyte counts and antiretroviral treatment. The control group comprised bone marrow transplant patients. Fourteen AIDS patients with low CD4+ cell counts tested positive for PP65 antigenemia, which could predict cytomegalovirus infection and indicate prophylactic treatment.