Assessment of mimicking by EBV-CMV immunoglobulin M of anti-HLA antibodies.

OBJECTIVE: We aimed to show the cross-reactivity that may occur between immunoglobulin (Ig) M antibodies that form against Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) and human leukocyte antigens (HLA). METHODS: Complement-dependent cytotoxicity (CDC) cross-reactivity between serum samples of 57 patients with IgM positive CMV and/or EBV infections and T and B cells from 15 healthy donors were evaluated. Dithiothreitol was used to distinguish cross-reactivity caused by IgM antibodies from IgG. RESULTS: The cross-reactivity ratio between pathogenic IgM antibodies with T cell of the 12th donor, and B cell of the 3rd, 4th, and 8th donors was significantly higher (p = 0.011, <0.001, <0.001 and 0.013, respectively). The ratio of B cell CDC cross-reactivity of all donors (26.4%) was higher than the ratio of T cell CDC cross-reactivity (5.2%) (p < 0.001). The ratio of T cell CDC cross-reactivity of sera containing both anti-CMV IgM and anti-EBV IgM antibodies was significantly higher than those of sera containing only anti-CMV IgM or only anti-EBV IgM antibodies (p = 0.002 and p < 0.001, respectively). There was no difference between B cell CDC cross-reactivity rates according to the presence of anti-CMV and/or anti-EBV IgM antibodies. CONCLUSION: Cross-reactivity may occur between anti-CMV and anti-EBV IgM antibodies with HLA molecules. Thus, in graft recipients, pathogenic IgMs can also act as de novo anti-HLA antibodies and aggravate the rejection process.

Diagnosis of Epstein-Barr and cytomegalovirus infections using decision trees: an effective way to avoid antibiotic overuse in paediatric tonsillopharyngitis.

BACKGROUND: The incidence of tonsillopharyngitis is especially prevalent in children. Despite the fact that viruses cause the majority of infections, antibiotics are frequently used as a treatment, contrary to international guidelines. This is not only an inappropriate method of treatment for viral infections, but it also significantly contributes to the emergence of antibiotic-resistant strains. In this study, EBV and CMV-related tonsillopharyngitis were distinguished from other pathogens by using machine learning techniques to construct a classification tree based on clinical characteristics. MATERIALS AND METHODS: In 2016 and 2017, we assessed information regarding 242 children with tonsillopharyngitis. Patients were categorized according to whether acute cytomegalovirus or Epstein-Barr virus infections were confirmed (n = 91) or not (n = 151). Based on symptoms and blood test parameters, we constructed decision trees to discriminate the two groups. The classification efficiency of the model was characterized by its sensitivity, specificity, positive predictive value, and negative predictive value. Fisher's exact and Welch's tests were used to perform univariable statistical analyses. RESULTS: The best decision tree distinguished EBV/CMV infection from non-EBV/CMV group with 83.33% positive predictive value, 88.90% sensitivity and 90.30% specificity. GPT (U/l) was found to be the most discriminatory variable (p < 0.0001). Using the model, unnecessary antibiotic treatment could be reduced by 66.66% (p = 0.0002). DISCUSSION: Our classification model can be used as a diagnostic decision support tool to distinguish EBC/CMV infection from non EBV/CMV tonsillopharyngitis, thereby significantly reducing the overuse of antibiotics. It is hoped that the model may become a tool worth considering in routine clinical practice and may be developed to differentiate between viral and bacterial infections.

Flow cytometry assessment of reactive T-cells distinguishes classic Hodgkin lymphoma from benign lymphadenopathy in children.

BACKGROUND: Detection of classic Hodgkin lymphoma (cHL) neoplastic cells using flow cytometric immunophenotyping (FCI) remains limited. We hypothesized that characterization of the reactive infiltrates could assist in diagnosing cHL in children. METHODS: FCI using four-color staining approaches was performed on 156 lymph node specimens with the following histopathologic diagnoses: cHL (25 cases), reactive lymphoid hyperplasia (RLH, 44 cases), and non-Hodgkin lymphoma (87 cases). RESULTS: The overall concordance of FCI data with the histopathologic results of these cases was 81.4%. A reactive expansion of T-cells with increased expression of CD45RO was present in the reactive infiltrate of cHL (CD45RO/CD3, 67.5%) and Epstein-Barr virus (EBV) infected RLH (62.7%) but not in EBV-negative RLH (28.0%). The mean fluorescence intensity (MFI) of CD7 was higher for cHL and differed significantly from EBV-positive RLH (138.5 vs. 63.8). A proposed diagnostic algorithm markedly elevated the overall concordance rate from 81.4% to 97.4%. CONCLUSIONS: Immunophenotyping the reactive infiltrate of lymphoid tissue using flow cytometry is a reliable supplement to histopathology for the rapid diagnosis of pediatric cHL.

Assessment of the Serologic Status in Epstein-Barr Virus in Patients Qualified for Lung Transplantation in the First Half of 2021.

BACKGROUND: The aim of the study was to assessment serologic status of Epstein-Barr virus (EBV) infections in patients qualificated for lung transplantation in the first half of 2021. METHODS: The study included 72 patients qualified for lung transplantation from January to June 2021. The youngest patient was aged 14 years and the oldest was aged 65 years. The study group consisted of 36 women and 36 men. In the serum of patients, a multi-parameter, comprehensive diagnosis of EBV infections was performed using the IIFT BIOCHIP EBV sequence tests. This test is based on a combination of several substrates, enabling the simultaneous evaluation of antibodies against capsid antigens (anti-CA antibodies), both in the IgG and IgM class, early antigens (anti-EA), nuclear antigens and the assessment of the avidity of anti-CA antibodies. The analysis of all diagnostically significant antibodies specific for EBV infections, including the avidity of anti-CA antibodies, increases the diagnostic accuracy in differentiating active and past infection with EBV. RESULTS: In the studied group it was shown that 58 had past EBV infection (80.6%). Twelve patients (16.6%) have anti-EA antibodies, which indicate that the virus is reactivated. Only 2 patients (2.8%) had no antibodies to EBV. CONCLUSIONS: Comprehensive assessment of antibodies against various EBV antigens in patients qualified for lung transplantation is important in the management and further diagnosis of this infection, especially after transplantation, due to the risk of developing post-transplant lymphoproliferative disease.

Liquid biopsy posttreatment surveillance in endemic nasopharyngeal carcinoma: a cost-effective strategy to integrate circulating cell-free Epstein-Barr virus DNA.

BACKGROUND: The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. METHODS: For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. RESULTS: For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. CONCLUSIONS: The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Cost-Effectiveness of Nasopharyngeal Carcinoma Screening With Epstein-Barr Virus Polymerase Chain Reaction or Serology in High-Incidence Populations Worldwide.

BACKGROUND: The incidence of endemic Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) varies considerably worldwide. In high-incidence regions, screening trials have been conducted. We estimated the mortality reduction and cost-effectiveness of EBV-based NPC screening in populations worldwide. METHODS: We identified 380 populations in 132 countries with incident NPC and developed a decision-analytic model to compare 10 unique onetime screening strategies with no screening for men and women aged 50 years. Screening performance and the stage distribution of undiagnosed NPC were derived from a systematic review of prospective screening trials. RESULTS: Screening was cost-effective in up to 14.5% of populations, depending on the screening strategy. These populations were limited to East Asia, Southeast Asia, and North Africa or were Asian, Pacific Islander, or Inuit populations in North America. A combination of serology and nasopharyngeal polymerase chain reaction was most cost-effective, but other combinations of serologic and/or plasma polymerase chain reaction screening were also cost-effective. The estimated reduction in NPC mortality was similar across screening strategies. For a hypothetical cohort of patients in China, the 10-year survival improved from 71.0% (95% confidence interval = 68.8% to 73.0%) without screening to a median of 86.3% (range = 83.5%-88.2%) with screening. This corresponded to a median 10-year reduction in NPC mortality of 52.9% (range = 43.1%-59.3%). Screening interval affected absolute mortality reduction and cost-effectiveness. CONCLUSIONS: We observed decreased NPC mortality with EBV-based screening. Screening was cost-effective in many high-incidence populations and could be extended to men and women as early as age 40 years in select regions. These findings may be useful when choosing among local public health initiatives.

Hopkins criteria for residual disease assessment after definitive radiotherapy in nasopharyngeal carcinoma.

OBJECTIVES: Assessment of viable tumor residue after definitive radiotherapy is essential in patients with nasopharyngeal carcinoma (NPC). This study aimed to investigate the use of Hopkins criteria on positron emission tomography/computed tomography (PET/CT) for posttreatment response evaluation and whether plasma Epstein-Barr virus (EBV) DNA could bring additional value. MATERIALS AND METHODS: NPC patients who underwent FDG-PET/CT scan within 26 weeks after definitive radiotherapy were retrospectively reviewed. Residual disease was evaluated by Hopkins 5-point score. Accuracy of Hopkins criteria before and after incorporating EBV DNA was calculated. Prognostic value for locoregional failure-free survival (LRFFS) and disease-free survival (DFS) was analyzed. RESULTS: One hundred and sixteen patients were evaluated. Median follow-up time was 28.3 months (range 3.3-92.0 months). Residual disease was found in 19 (16.4%) patients. Overall, Hopkins criteria had high specificity (86.6%; 95% CI, 78.2%-92.7%) and negative prognostic value (NPV) (94.4%; 95% CI, 88.7%-97.3%), while sensitivity and positive prognostic value (PPV) was 73.7% (95% CI, 48.8%-90.9%), 51.9% (95% CI, 37.8%-65.6%), respectively. Posttreatment plasma EBV DNA was not predictive of residual tumor (P = .272). PPV and accuracy were 50.0% (95% CI, 32.1%-67.9%) and 83.0% (95% CI, 73.8%-90.0%) after incorporating detectable EBV DNA into the scoring system. Positive PET/CT results were significantly correlated with inferior 3-year LRFFS (95.7% vs 79.5%, P = .043) and 3-year DFS (84.6% vs 54.4%, P = .028). CONCLUSIONS: The Hopkins criteria demonstrated high NPV and specificity in posttreatment assessment, with the potential to be a reliable prognostic indicator for locoregional failure. Combining EBV DNA with PET/CT did not improve diagnostic accuracies. PET/CT should not be performed less than 12 weeks after treatment.

Multilaboratory Assessment of Epstein-Barr Virus Serologic Assays: the Case for Standardization.

IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations.

Comparison of two commercial quantitative PCR assays for EBV DNA detection and their correlation with the first WHO International Standard for EBV.

PURPOSE: There are few data on the performance of automated Epstein-Barr virus (EBV) PCR assays. This study compared EBV quantification for the kPCR PLX EBV DNA (kPCR; Siemens, France) and the EBV R-gene (R-gene; Argene, Biomerieux, France) assays and their correlation with the World Health Organization (WHO) standard. METHODOLOGY: WHO International Standard for EBV (WHO standard) dilution panels in different matrices were submitted to nucleic acid extraction with Versant kPCR Molecular Systems SP followed by the kPCR assay, or to nucleic acid extraction with the MagNA Pure LC System or NucliSENS easyMag followed by the R-gene assay. Seventy-four clinical specimens were tested in both assays. Bland-Altman analysis and linear regression analysis were performed. RESULTS: The correlation between the WHO standard diluted in different matrices and the R-gene and kPCR assays was good (R2 >0.96 and R2 >0.92, respectively). A matrix effect was observed. The correlation of quantitative results between both assays yielded a coefficient of determination R2 higher than 0.74. The quantification differences were within one log10 of the averaged results for 34 of the 38 specimens (89 %). Calibration to the WHO standard did not increase the comparability of quantitative results. CONCLUSIONS: The quantitative results of both assays showed reasonable correlation with each other and a good correlation with the WHO standard.

Comprehensive assessment of peripheral blood TCRß repertoire in infectious mononucleosis and chronic active EBV infection patients.

Epstein-Barr virus (EBV) primary infection is usually asymptomatic, but it sometimes progresses to infectious mononucleosis (IM). Occasionally, some people develop chronic active EBV infection (CAEBV) with underlying immunodeficiency, which belongs to a continuous spectrum of EBV-associated lymphoproliferative disorders (EBV+ LPD) with heterogeneous clinical presentations and high mortality. It has been well established that T cell-mediated immune response plays a critical role in the disease evolution of EBV infection. Recently, high-throughput sequencing of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (T cell receptor ß (TCRß)) has emerged as a sensitive approach to assess the T cell repertoire. In this study, we fully characterized the diversity of peripheral blood TCRß repertoire in IM (n = 6) and CAEBV patients (n = 5) and EBV-seropositive controls (n = 5). Compared with the healthy EBV-seropositive controls, both IM and CAEBV patients demonstrate a significant decrease in peripheral blood TCRß repertoire diversity, basically, including narrowed repertoire breadth, highly expanded clones, and skewed CDR3 length distribution. However, there is no significant difference between IM and CAEBV patients. Furthermore, we observed some disease-related preferences in TRBV/TRBJ usage and combinations, as well as lots of T cell clones shared by different groups (unique or overlapped) involved in public T cell responses, which provide more detailed insights into the divergent disease evolution.

How Should We Treat Early Post-Transplant Lymphoproliferative Disease After Heart Transplantation?

Although post-transplant lymphoproliferative disease (PTLD) is one of the major fatal complications encountered several years after heart transplant (HTx), little is known about early-PTLD emerging within the first year. We here describe the rare case of a 24-year-old female patient who suffered from early-PTLD (DLBCL: diffuse large B-cell lymphoma) associated with an Epstein-Barr virus (EBV) infection, that developed around the jejunum at 7 months after HTx. She suffered from acute abdominal peritonitis due to perforation of the jejunum soon after the first chemotherapy. She was treated successfully by emergent partial resection of the jejunum and colostomy after the discontinuation of everolimus (EVL) and successive low-dose chemotherapy under careful monitoring and adjustment of intravenous immunosuppressant including cyclosporine (CyA) and prednisolone to avoid a rejection reaction. Prophylactic strategies for early-PTLD in HTx recipients should be undertaken with caution.

Epstein-Barr virus DNAemia in Iranian liver transplant recipients and assessment of its variation in posttransplant lymphproliferative disorder patients by quantitative polymerase chain reaction assay.

OBJECTIVES: Epstein-Barr virus primary infection and/or reactivation may play a major role in the incidence of posttransplant lymphoproliferative disorder in organ recipients. We assessed Epstein-Barr virus viral load in liver transplant patients suspected of having Epstein-Barr virus/ posttransplant lymphoproliferative disorder at specified times after transplant and evaluated the clinical findings and posttransplant complications. MATERIALS AND METHODS: In the 696 patients who underwent liver transplant in this retrospective study, Epstein-Barr virus viral load was examined intermittently in 127 liver transplant recipients who were suspected to have Epstein-Barr virus infection/disease. Sampling was performed during 4 years from July 2009 to May 2013 using real-time polymerase chain reaction assay. Clinical and pathologic data were gathered by reviewing medical records. RESULTS: There were 78 of the 127 suspected patients (61%) who exhibited Epstein-Barr virus DNAemia and 19 patients had posttransplant lymphoproliferative disorder. The median EBV viral load of posttransplant lymphoproliferative disorder patients was significantly higher than unaffected patients. Posttransplant lymphoproliferative disorder was diagnosed clinically in 34 subjects (4.9%). Estimated mortality rate of posttransplant lymphoproliferative disorder patients was 35% during 1.5-year follow-up after transplant. CONCLUSIONS: Monitoring Epstein-Barr virus load may enable detection of Epstein-Barr virus infection/disease in liver transplant patients suspected of having the virus, even several weeks before the onset of any clinical manifestations, especially in pediatric patients who have high incidence and mortality from posttransplant lymphoproliferative disorder.

Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure.

The decision to perform liver transplantation (LT) in patients with Epstein-Barr virus (EBV)-induced fulminant hepatic failure (FHF) relies on a precise assessment of laboratory and pathological findings. In this study, we analyzed clinical and laboratory data as well as the pathological features of the liver in order to evaluate the pathogenesis and the need for LT in 5 patients with EBV-induced FHF. According to the King's College criteria, the Acute Liver Failure Early Dynamic (ALFED) model, and the Japanese criteria (from the Acute Liver Failure Study Group of Japan), only 1 patient was considered to be a candidate for LT. However, explanted liver tissues in 3 cases exhibited massive hepatocellular necrosis together with diffuse CD8-positive T cell infiltration in both the portal area and the sinusoid. EBV was detected in the liver, plasma, and peripheral blood mononuclear cells (PBMNCs). In 2 cases indicated to be at moderate risk by the ALFED model, liver biopsy showed CD8-positive and EBV-encoded RNA signal-positive lymphocytic infiltration predominantly in the portal area, but massive hepatocellular necrosis was not observed. These patients were treated with immunosuppressants and etoposide under the diagnosis of EBV-induced hemophagocytic lymphohistiocytosis or systemic EBV-positive T cell lymphoproliferative disease of childhood. EBV DNA was detected at a high level in PBMNCs, although it was negative in plasma. On the basis of the pathological analysis of the explanted liver tissues, LT was proposed for the restoration of liver function and the removal of the EBV-infected lymphocytes concentrated in the liver. Detecting EBV DNA by a quantitative polymerase chain reaction in plasma and PBMNCs was informative. An accurate evaluation of the underlying pathogenesis is essential for developing a treatment strategy in patients with EBV-induced FHF.

Pre-emptive virology screening in the pediatric hematopoietic stem cell transplant population: a cost effectiveness analysis.

BACKGROUND AND OBJECTIVES: Pediatric patients undergoing hematopoietic stem cell transplant (HSCT) are at a uniquely high risk of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections. The pre-emptive treatment model whereby asymptomatic post-transplant patients are routinely screened with treatment initiated if found viremic has recently been shown to be superior in terms of patient mortality when compared to deferring laboratory assessment and treatment until symptoms emerge. This study analyzes the cost-effectiveness of the pre-emptive therapy model in patient care dollars per quality-adjusted life years (QALY). PATIENTS AND METHODS: Utilization and outcome data were compiled as a retrospective cohort study of 96 pediatric patients receiving HSCT at University of California Los Angeles Pediatric Hematology/Oncology Department between the years 2006 and 2010. Two-decision tree models were constructed for each the pre-emptive model and the deferred model wherein costs and probability assumptions were based on either previously published literature or calculated from this study cohort. RESULTS: The pre-emptive model resulted in a five-year survival of 71%, during which time 4% of patients were found to be EBV viremic, while 33% were found to be CMV viremic. The average actual cost of EBV/CMV virology screening per patient in the cohort following the pre-emptive model was $9699 while the expected cost following the deferred model was $19,284. This results in an incremental cost effectiveness ratio illustrating pre-emptive model cost-savings of $2367/QALY. CONCLUSION: These results support the financial viability and prudence of scheduled screening for subclinical viremia for achieving optimal outcomes in a cost-effective manner in the pediatric HSCT population.

[Assessment of detection assays of Epstein-Barr viral Rta-IgG, VCA-IgA, EA-IgA and Epstein-Barr viral DNA at different clinical stages in the diagnosis of nasopharyngeal carcinoma].

OBJECTIVE: To evaluate the values of combined detection method of EB viral Rta-IgG, VCA-IgA, EA-IgA and EB viral DNA in the diagnosis of nasopharyngeal carcinoma (NPC). METHODS: Serum and plasma samples from 131 untreated NPC patients, 52 non-NPC patients with NPC-like symptoms and 148 healthy donors from January to December 2012 were collected. Immunoenzymatic staining was used to detect VCA-IgA and EA-IgA in sera. ELISA was performed to detect Rta-IgG antibody in sera and real-time fluorescent quantitative PCR for measuring EBV DNA in plasma. The clinical characteristics of 3 groups were compared. ROC curve and correlation analyses were performed to assess the detection assays for the diagnosis of NPC. RESULTS: The positive rates of EBV Rta-IgG, VCA-IgA, EA-IgA and EBV DNA in untreated NPC patient group were higher than those in other two groups. The differences were statistically significant (all P < 0.01). The differences of Rta-IgG antibody positive rates, EBV-DNA levels and EBV-DNA positive rates at different clinical stages were statistically significant (all P < 0.05). The positive rates of VCA-IgA and EA-IgA were not related with clinical stages (P > 0.05). Areas under ROC curve for Rta-IgG and EBV-DNA were 0.901 and 0.827 respectively. All four diagnostic assays demonstrated excellent efficiency. The sensitivity and specificity of individual assays were as follows: Rta-IgG: 77.9%, 92.5%; VCA-IgA 93.1%, 91.5%; EA-IgA: 74.8%, 99.5%; EBV-DNA 64.9%, 97.0%. The sensitivity and specificity of combined assays were 97.7% and 83.5% respectively. CONCLUSION: Combined detection method of EB viral Rta-IgG, VCA-IgA, EA-IgA and EB viral DNA are efficient for the diagnosis of NPC.

A clinicopathological analysis of 26 patients with infection-associated haemophagocytic lymphohistiocytosis and the importance of bone marrow phagocytosis for the early initiation of immunomodulatory treatment.

OBJECTIVE: To analyse the clinicopathological presentation, outcome and importance of bone marrow haemophagocytosis in patients with infection-associated haemophagocytic lymphohistiocytosis (IA-HLH) in a tertiary care hospital in Northern India. STUDY DESIGN: Between January 2007 and December 2009, 26 consecutive patients meeting the diagnostic criteria for IA-HLH, based on the HLH2004 protocol of the Histiocyte Society, were followed up for between 12 and 34 months (median 20 months). RESULTS: IA-HLH was diagnosed in three of the five patients who died 5-6 weeks after the onset of the illness, whereas diagnosis in the remaining group was made a median of 2 weeks after the onset of the illness. The predominant presenting features were fever (100%), hepatomegaly (69%), splenomegaly (58%) and anaemia (96%). All patients showed >3% haemophagocytosis on bone marrow studies-in four cases after serial aspiration/biopsies. Twenty-one (80.8%) cases were non-fatal and five (19.2%) patients died. The non-fatal cases included eight (38.1%) cases of viral infection, seven (33.3%) bacterial infections, two (9.6%) fungal and four (19.0%) protozoal infections; whereas four (80%) bacterial infections and one (20%) viral infection were associated with the fatal cases. The mean of the nadir blood counts of white blood cells, absolute neutrophil counts and platelets; the mean of all the peak biochemical parameters of liver function tests, lactate dehydrogenase and ferritin and the lowest fibrinogen values before treatment, differed significantly (p<0.05) between the non-fatal and the fatal group, being worse in the latter. CONCLUSIONS: IA-HLH is important because it can obscure the typical clinical features of the underlying primary disease, thus delaying the diagnosis and having a negative effect on the outcome. Although bone marrow haemophagocytosis is not a mandatory diagnostic criterion, we found it to be a useful tool together with biochemical parameters for early recognition of HLH, especially in developing countries lacking molecular and flow laboratories. The severity of pancytopenia and derangement in biochemical markers were significantly higher in the patients who died.

[Cost-effectiveness evaluation of seven screening strategies for nasopharyngeal carcinoma].

OBJECTIVE: To evaluate the cost-effectiveness of different screening strategies for nasopharyngeal carcinoma (NPC) and recommend a preferable NPC screening strategy. METHODS: A Markov simulation model was constructed based on the natural history of NPC. Seven strategies (A. Annual screening; B. Annual screening for (Epstein-Barr virus, EBV) EBV-seropositive subjects, triennial screening for seronegative subjects; C. Biennial screening; D. Triennial screening; E. 4-year screening; F. 5-year screening; G. 6-year screening) were evaluated. The NPC-pickup rate, cost, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: The ICERs of the 7 strategies were 83 111.6, 47 768.9, 50 164.7, 40 016.2, 34 272.8, 32 215.6, and 32 248.0 Yuan/QALY, respectively. The discounted QALYs of the strategies were 23 079.9, 22 955.6, 22 810.4, 22 636.5, 22 522.7, 22 445.0, and 22 361.9 years, respectively. The ICERs of the strategies were less than three times of the average per capita gross domestic product (89 976 Yuan) in China in 2010. The strategy A achieved a highest NPC pick-up rate (81.7%), a highest discounted QALY and a smallest number of NPC death (681), but a highest discounted cost and a greatest ICER. Compared with the strategy A, the strategy B achieved a little smaller NPC pick-up rate (73.1%), a little smaller number of NPC death (707), however, the ICER of the strategy B decreased by 38.2%. CONCLUSION: The strategy B (annual screening for EB virus seropositive subjects and triennial screening for seronegative subjects) is a preferable option for NPC screening.

An efficacy analysis for nasopharyngeal carcinoma screening of different screening intervals.

OBJECTIVE: To evaluate the impact of different screening intervals on screening for nasopharyngeal carcinoma (NPC). METHODS: A Markov model was constructed, based on the natural history of NPC. The 5-year mortality rate of NPC was the major measurement to evaluate the efficacies of 16 screening strategies. Parameters for the model were derived from published literature. RESULTS: Screening reduced the 5-year mortality rate for NPC by 20.4 - 43.3%, compared with the equivalent rate without screening. The 5 year mortality rate and the NPC pick-up rate with strategy A1 (annual screening) were 23.6% and 83.9%, respectively. Compared with strategy A1, strategy B1 (annual screening for seropositive subjects; biennial screening for seronegative subjects) had a similar 5-year mortality rate (24.0%) and a slightly smaller NPC pick-up rate (81.7%), but led to a 39.3% reduction in total screenings. Compared with all other strategies excluding strategy A1, strategy B1 achieved the lowest 5-year mortality rate and the largest NPC pick-up rate. CONCLUSIONS: Strategy B1 had the highest efficacy for NPC screening.