Validity of claims-based diagnoses for infectious diseases common among immunocompromised patients in Japan.

BACKGROUND: To validate Japanese claims-based disease-identifying algorithms for herpes zoster (HZ), Mycobacterium tuberculosis (MTB), nontuberculous mycobacteria infections (NTM), and Pneumocystis jirovecii pneumonia (PJP). METHODS: VALIDATE-J, a multicenter, cross-sectional, retrospective study, reviewed the administrative claims data and medical records from two Japanese hospitals. Claims-based algorithms were developed by experts to identify HZ, MTB, NTM, and PJP cases among patients treated 2012-2016. Diagnosis was confirmed with three gold standard definitions; positive predictive values (PPVs) were calculated for prevalent (regardless of baseline disease-free period) and incident (preceded by a 12-month disease-free period for the target conditions) cases. RESULTS: Of patients identified using claims-based algorithms, a random sample of 377 cases was included: HZ (n = 95 [55 incident cases]); MTB (n = 100 [58]); NTM (n = 82 [50]); and PJP (n = 100 [84]). PPVs ranged from 67.4-70.5% (HZ), 67.0-90.0% (MTB), 18.3-63.4% (NTM), and 20.0-45.0% (PJP) for prevalent cases, and 69.1-70.9% (HZ), 58.6-87.9% (MTB), 10.0-56.0% (NTM), and 22.6-51.2% (PJP) for incident cases, across definitions. Adding treatment to the algorithms increased PPVs for HZ, with a small increase observed for prevalent cases of NTM. CONCLUSIONS: VALIDATE-J demonstrated moderate to high PPVs for disease-identifying algorithms for HZ and MTB using Japanese claims data.

Validity of claims-based algorithms for selected cancers in Japan: Results from the VALIDATE-J study.

PURPOSE: Real-world data from large administrative claims databases in Japan have recently become available, but limited evidence exists to support their validity. VALIDATE-J validated claims-based algorithms for selected cancers in Japan. METHODS: VALIDATE-J was a multicenter, cross-sectional, retrospective study. Disease-identifying algorithms were used to identify cancers diagnosed between January or March 2012 and December 2016 using claims data from two hospitals in Japan. Positive predictive values (PPVs), specificity, and sensitivity were calculated for prevalent (regardless of baseline cancer-free period) and incident (12-month cancer-free period; with claims and registry periods in the same month) cases, using hospital cancer registry data as gold standard. RESULTS: 22 108 cancers were identified in the hospital claims databases. PPVs (number of registry cases) for prevalent/incident cases were: any malignancy 79.0% (25 934)/73.1% (18 119); colorectal 84.4% (3519)/65.6% (2340); gastric 87.4% (3534)/76.8% (2279); lung 88.1% (2066)/79.9% (1636); breast 86.4% (4959)/59.9% (3185); pancreatic 87.1% (582)/80.4% (508); melanoma 48.7% (46)/42.9% (36); and lymphoma 83.6% (1457)/77.8% (1035). Specificity ranged from 98.3% to 100% (prevalent)/99.5% to 100% (incident); sensitivity ranged from 39.1% to 67.6% (prevalent)/12.5% to 31.4% (incident). PPVs of claims-based algorithms for several cancers in patients ≥66 years of age were slightly higher than those in a US Medicare population. CONCLUSIONS: VALIDATE-J demonstrated high specificity and modest-to-moderate sensitivity for claims-based algorithms of most malignancies using Japanese claims data. Use of claims-based algorithms will enable identification of patient populations from claims databases, while avoiding direct patient identification. Further research is needed to confirm the generalizability of our results and applicability to specific subgroups of patient populations.

Low level of hemoglobin A1c and the increased incidence of herpes zoster: longitudinal study.

Little is known about the association between glycemic status and herpes zoster. The aim of this study was to evaluate whether glycemic status, including both high and low hemoglobin A1c(HbA1c), is associated with subsequent herpes zoster. We conducted a retrospective longitudinal study in a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all participants who underwent voluntary health check-ups at the hospital. Our primary outcome was the incidence of herpes zoster in groups of individuals stratified by HbA1c levels, which were compared using the generalized estimating equation (GEE), adjusting for participants' demographic characteristics, social history, body mass index, and comorbidities. A total of 81,466 participants were included in this study. The mean age (standard deviation) was 46.5 (12.1), and 39,643 (48.7%) participants were male. Among them, 1751 (2.1%) were diagnosed with diabetes prior to their first visits. After a median follow-up of 1784 [interquartile range (IQR), 749-3150] days, 673 (0.8%) participants developed herpes zoster. The incidence of herpes zoster was 1.45 per 1000 person-years. Compared with the reference group (HbA1c of 5.0-6.4%), the lowest HbA1c group (HbA1c of < 5.0%) had a significantly higher adjusted odds ratio (OR) (OR 1.63; 95% confidence interval (CI), 1.07-2.48) of developing herpes zoster. The group with an HbA1c of ≥ 9.5% had a higher but nonsignificant OR than the reference group (OR 2.15; 95% CI, 0.67-6.94). Our longitudinal study demonstrated that individuals in the lowest (< 5.0%) HbA1c group had a significantly higher risk of developing herpes zoster than the reference group (HbA1c of 5.0-6.4%) after adjusting for covariates.

Validation of claims-based algorithms for rheumatoid arthritis in Japan: Results from the VALIDATE-J study.

AIM: Validity of Algorithms in Large Databases: Infectious Diseases, Rheumatoid Arthritis, and Tumor Evaluation in Japan (VALIDATE-J) study examined algorithms for identifying rheumatoid arthritis (RA) in Japanese claims data. METHODS: VALIDATE-J was a multicenter, cross-sectional retrospective study. Disease-identifying algorithms were used to detect RA diagnosed between January 2012 and December 2016 using claims data from two Japanese hospitals. An RA diagnosis was confirmed using one of four gold standard definitions. Positive predictive values (PPVs) were calculated for prevalent (regardless of baseline RA-free period) and incident (preceded by a 12-month RA-free period) cases. RESULTS: Of patients identified using claims-based algorithms, a random sample of 389 prevalent and 134 incident cases of RA were included. Cases identified by an RA diagnosis, no diagnosis of psoriasis, and treatment with any disease-modifying antirheumatic drugs (DMARDs) resulted in the highest PPVs versus other claims-based treatment categories (29.0%-88.3% [prevalent] and 41.0%-78.2% [incident]); cases identified by an RA diagnosis, no diagnosis of psoriasis, and glucocorticoid-only treatment had the lowest PPVs. Across claims-based algorithms, PPVs were highest when a physician diagnosis or decision by adjudicators (confirmed and probable cases) was used as the gold standard and were lowest when American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria were applied. PPVs of claims-based algorithms for RA in patients aged ≥66 years were slightly higher versus a USA Medicare population (maximum PPVs of 95.0% and 88.9%, respectively). CONCLUSION: VALIDATE-J demonstrated high PPVs for most claims-based algorithms for diagnosis of prevalent and incident RA using Japanese claims data. These findings will help inform appropriate RA definitions for future claims database research in Japan.

Infrequent Thrombotic Complications in Japanese Patients with Warm Autoimmune Hemolytic Anemia.

Objective Patients with autoimmune hemolytic anemia (AIHA) are considered to be at an increased risk of thrombosis, and prophylaxis for venous thromboembolism (VTE) is often recommended. However, the occurrence of thrombosis in Asian patients has not been specifically studied. Thrombotic complications and features of Japanese warm AIHA (WAIHA) patients were studied to see if Japanese patients were at an increased risk of thrombosis and should receive prophylaxis for VTE. Patients and Methods Forty-seven consecutive patients with warm WAIHA were retrospectively studied. Twenty-nine patients were diagnosed as primary cases and 18 as secondary cases, and 10 patients were diagnosed with Evans syndrome. Results No patient presented with thrombosis, and over a median observation period of 15 months, 3 patients had ischemic cerebral vascular accidents. However, all three of those patients had other known risks for thrombosis, with only one taking thrombotic prophylaxis. No venous thrombosis occurred in any patients during the follow-up period. There was no mortality associated with thrombosis. D-dimer levels were often elevated in patients with WAIHA, indicating that the coagulation was activated in a considerable number of patients, but not to such a level as to be associated with clinically overt thrombosis. Conclusion Thrombotic complications occur infrequently in Japanese WAIHA patients, and these individuals do not appear to be at a particularly increased risk of thrombosis because of WAIHA. The indication of VTE prophylaxis should be determined individually, considering other risks.

Transient Pseudothrombocytopenia Detected 8 Months After COVID-19 Vaccination.

Pseudothrombocytopenia is an in vitro phenomenon of platelet aggregation due to conformational changes and exposure of cryptic antigens on the platelet surface caused by anticoagulants, leading to the aggregation of platelets and falsely lower automated platelet counts. Although it has no clinical relevance, it can lead to unnecessary fear, diagnostic errors, or unnecessary tests and interventions when unrecognized. Pseudothrombocytopenia was detected in a 25-year-old woman 8 months after the second dose of mRNA COVID-19 vaccine, BNT162b2. The pseudothrombocytopenia was transient and the duration was shorter than 3 months. As pseudothromobocytopenia is not detected unless blood is drawn for other objectives, it is difficult to determine its true occurrence among recipients of vaccines. This case shows that pseudothrombocytopenia may develop transiently even months after COVID-19 vaccination and should be considered when thrombocytopenia is found in recipients of the vaccine to avoid unnecessary fear, diagnostic errors, or unnecessary tests and interventions.

Reticulocyte Hemoglobin Equivalent in Patients with Idiopathic Warm Autoimmune Hemolytic Anemia: Implication in the Development of Macrocytosis.

OBJECTIVE: Patients with warm autoimmune hemolytic anemia (WAIHA) present with anemia that is highly heterogeneous, and often have macrocytic anemia with inappropriately elevated mean corpuscular volume (MCV). The goal of this retrospectivecase study is to elucidate the characteristics of anemia in patients with idiopathic WAIHA. PROCEDURES: The hematological parameters were analyzed by automated hematology analyzers in 19 consecutive patients with idiopathic WAIHA. Thecontent of hemoglobin (Hb) in the reticulocytes was assessed as reticulocyte Hb equivalent (RET-He). Relevant laboratory data and medical records were retrospectively studied. RESULTS: The median MCV was 102.7 fL and ten patients had macrocytic anemia with MCV above 100 fL. There was a significant correlation between the percentage of reticulocytes and MCV. The median RET-He value was 35.9 pg, and the reticulocytes of patients with higher MCV had higher RET-He. There was a significant correlation between red cell volume distribution width (RDW) andMCV, while the association between RDW and RET-He was not significant. Red blood cell agglutination was not seen in any of the patients. Relative folate deficiency was implied to contribute to the increased Hb content in the reticulocytes of WAIHA patients. CONCLUSION: Reticulocytes in WAIHA patients often contain more Hb than normal reticulocytes and become inappropriately large, possibly due to relative folate deficiency. Elevated MCV in WAIHA patients is due to the increase in both the number and the Hb content of reticulocytes.

Prediction of infectious events by high-sensitivity C-reactive protein level before undergoing chemotherapy for acute myeloid leukaemia.

We retrospectively evaluated the serum high-sensitivity C-reactive protein (CRP) level before chemotherapy for the prediction of infectious events during neutropenia in patients with acute myeloid leukaemia. Thirty-eight patients who underwent first induction chemotherapy and 37 patients who underwent first consolidation chemotherapy were analyzed separately. A receiver-operating characteristic (ROC) curve revealed that the serum CRP level just before the first consolidation chemotherapy, but not just before the induction chemotherapy, had a significant predictive value for febrile neutropenia (FN) at a cut-off value of 0.19 mg/dl and documented infection (DI) at a cut-off value of 0.26 mg/dl. The high-sensitivity CRP measurement enabled the detection of slight increases in the serum CRP level, which might reflect a minute inflammation by occult infection, and discriminated high-risk patients for infectious events.

Fludarabine, cyclophosphamide, anti-thymocyteglobulin, and low-dose total body irradiation conditioning enables 1-HLA-locus-mismatched hematopoietic stem cell transplantation for very severe aplastic anemia without affecting ovarian function.

Allogeneic hematopoietic stem cell transplantation for severe aplastic anemia from an alternative donor is associated with higher risks of graft rejection and severe graft-versus-host disease. We developed a conditioning regimen consisting of rabbit anti-thymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Two adult female patients with transfusion-dependent very severe aplastic anemia underwent 1-locus mismatched transplantation using this regimen. Both patients achieved stable engraftment and the clinical course thereafter was uneventful with persistently normal ovarian function. This novel conditioning regimen may be suitable for alternative donor transplantation for severe aplastic anemia, especially in young female patients.

The Relationship Between Mean Platelet Volume and Fasting Plasma Glucose and HbA1c Levels in a Large Cohort of Unselected Health Check-Up Participants.

BACKGROUND: Larger platelets are more active and mean platelet volume (MPV) is an indicator of platelet activation and an independent risk factor of cardiovascular diseases. While MPV is reported to be higher in diabetic patients, the relationship between MPV and glycemic parameters in general population remains inconclusive. METHODS: In this cross-sectional study, we studied relationship between MPV and fasting plasma glucose (FPG) and HbA1c levels in 38,204 unselected participants of general health check-up aged 20 years or older in the year of 2014 who were considered to be representative of the general population. Individuals with known diabetes, coronary artery disease and/or cerebrovascular disease who were on drug therapy and those with platelet counts below 100 × 109/L or above 400 × 109/L were excluded. RESULTS: The mean age of the individuals was 52.3 ± 12.1 years and 46.1% were male. There were positive associations between MPV and both FPG (r = 0.066; P < 0.001) and HbA1c (r = 0.025; P < 0.001) levels when all individuals were analyzed as a whole. While the association was only marginal in individuals with HbA1c levels below 6.5% (r = 0.009; P = 0.068), it was significant in those with HbA1c ≥ 6.5% (r = 0.138; P < 0.001). When the individuals were categorized into four groups according to the HbA1c values: HbA1c < 5.5%, 5.5% ≤ HbA1c < 6.0%, 6.0% ≤ HbA1c < 6.5%, and HbA1c ≥ 6.5%, the mean MPV was virtually same among groups with HbA1c level < 6.5% and that of the individuals with HbA1c ≥ 6.5 was significantly higher than groups with lower HbA1c levels. Multivariate analyses adjusted with age and sex showed the same results. CONCLUSION: FPG and HbA1c appeared to be associated with MPV in unselected health check-up participants; however, the association between glycemic state and MPV was apparent only in individuals with impaired glycemic control and only marginal in those with normal glycemic control. The clinical significance of the associations warrants further study.

Hyperferritinemia: causes and significance in a general hospital.

OBJECTIVE: To elucidate conditions which cause elevation of the serum ferritin, extent of the elevation in each condition, and clinical relevance of hyperferritinemia in general practice. METHODS: We retrospectively studied medical records of all patients who had at least one serum ferritin measurement above 500 µg L-1. Patients who had a marked elevation of the serum ferritin over 10,000 µg L-1 were studied separately. RESULTS: We studied 1394 patients to identify the etiologies of hyperferritinemia. Median serum ferritin level was 1024 µg L-1 and 49.2% had ferritin levels of 501-1000 µg L-1. The most frequent cause of hyperferritinemia was non-human immunodeficiency virus infection followed by solid tumor, liver dysfunction, renal failure, and hematological malignancy. The distributions of the causes were different among groups stratified by the ferritin level. Forty-one percent had multiple causes and there was a tendency that the more underlying causes a patient had, the higher the ferritin level. Each condition led to a wide range of the ferritin level, and some patients could present with marked hyperferritinemia. Seventy percent of 111 patients with marked hyperferritinemia had multiple etiologies and a variety of diseases could lead to marked hyperferritinemia by themselves. DISCUSSION: Patients with hyperferritinemia frequently had multiple conditions. The level of the serum ferritin was determined by the underlying conditions to a certain extent; however, the variation was significant. While patients with marked hyperferritinemia mostly had multiple underlying causes, various diseases could cause hyperferritinemia by themselves. CONCLUSION: Hyperferritinemia is associated with both etiology and the number of underlying causes.

Iron Deficiency Anemia Due to the Long-term Use of a Proton Pump Inhibitor.

A 52-year-old man who had been taking omeprazole, a proton pump inhibitor (PPI), for 25 years developed iron deficiency anemia. An evaluation of the entire gastrointestinal tract did not reveal any possible causes of gastrointestinal blood loss. The cause of the iron deficiency was considered to be a reduction in gastrointestinal iron absorption in association with the reduced secretion of gastric acid due to PPI use. This case demonstrates that long-term PPI use for as long as 25 years may cause iron deficiency anemia and should be considered in the differential diagnosis of iron deficiency anemia in long-term PPI users.

Simultaneous Presentation of Giant Cell Arteritis and Myelodysplastic Syndrome in an Elderly Japanese Man.

An 81-year-old Japanese man presented with constitutional symptoms and anemia and was diagnosed with giant cell arteritis (GCA) and myelodysplastic syndrome (MDS) simultaneously. His symptoms and anemia improved promptly with steroids; however, the MDS rapidly progressed to overt leukemia. While MDS patients are at an increased risk of autoimmune diseases, an association with GCA has rarely been reported. This case illustrates the importance of considering GCA as a cause of anemia in elderly patients if MDS is already diagnosed, even in countries where the prevalence of GCA is very low. The simultaneous development of GCA and MDS suggests a common pathogenetic link between these two diseases.

[Clinical analysis of HLA-DR-negative non-M3 AML].

The type of leukemia was defined as HLA-DR(-) non-M3-AML, when HLA antigens were detected by flow cytometry at an incidence of < 20% of the blast population excluding M3-AML. Out of 109 patients with de novo acute myeloid leukemia, 8 patients had HLA-DR(-) non-AML-M3. According to the French-American-British criteria, 7 patients could be subdivided into 3 patients with M1, 4 patients with M2 and 1 patient with M4. The morphological features of bone marrow aspiration demonstrated no dysplasia and peroxidase stain positivity was noted in over 86% of the blast cells in all patients, the blast cells with fine granularity in 7 patients. The cytogenetic analysis revealed a normal karyotype. There was no expression marker of the blast antigens except CD13, CD14, CD33, CD34 and CD56. All of 7 patients who underwent induction therapy attained complete remission. Overall survival and disease-free survival showed no significant differences between the HLA-DR(-) non- M3-AML group and the HLA-DR(+) AML group.

[A case of rheumatoid arthritis with acute lymphoblastic leukemia].

A 69-year-old male was diagnosed with rheumatoid arthritis(RA) in 1994. Good control of the RA activity had been obtained with sodium aurothiomalate (GST). However, polyarthritis reappeared in January 2003. He was examined at the Division of Rheumatology, Department of Internal Medicine, Saitama Social Insurance Hospital in August 2003. The treatment was switched from GST to salazosulfapyridine (SASP), with improvement of the polyarthritis. Subsequently, in March 2005, the patient developed fever, pancytopenia and liver dysfunction, and was admitted to Saitama Social Insurance Hospital. Since these abnormalities were suspected to be caused by SASP, this drug was stopped and prednisolone (PSL) was started at 10 mg/day. However, since the fever, pancytopenia and liver dysfunction persisted, bone marrow examination was performed and the patient was diagnosed with acute lymphoblastic leukemia (pre B cell type, L2). He was transferred to the Division of Hematology, Omiya Medical Center, Jichi Medical University, on 8(th) April, 2005 for induction chemotherapy. Although the induction therapy needed to be stopped because the patient developed dysphagia and biliary system dysfunction, complete remission (CR) was confirmed. It was difficult to restart chemotherapy in the patient because his general condition remained poor, with repeated episodes of aspiration pneumonia and newly detected stomach cancer. He was, therefore, transferred back to Saitama Social Insurance Hospital on 28(th) September, 2005. The ALL remained in CR and the RA activity had disappeared without therapy, but the patient died of pneumonia on 1(st) August, 2006.

Myelodysplastic Syndrome Developing Presacral Extramedullary Hematopoiesis with Atypical MRI Findings.

A 64-year-old woman was diagnosed to have refractory cytopenia with multilineage dysplasia (RCMD) including an increased number of sideroblasts in the bone marrow (BM). Computed tomography (CT) revealed a presacral mass which showed iso- or high-intensity signals according to T1-weighted and hypo-intensity signals on T2-weighted magnetic resonance imaging (MRI). CT-guided biopsy revealed the presence of hematopoietic tissue with features that correlated with the BM findings. While the formation of extramedullary hematopoiesis in the presacral area is rare, it is important to differentiate it from other parasacral tumors even though such differentiation is often difficult. This patient demonstrated atypical MRI signals possibly due to an increase in the cellular iron content of the erythroid precursors.