Very unusual extremely high ferritin with cytokine release syndrome in a patient with hematological malignancy after experimental chimeric antigen receptor (CAR)-T-Cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, significant toxicities may also be associated with such therapy. Here we report extremely high ferritin in a male patient after such therapy. CASE PRESENTATION: We present a case of a 52 year old male with a history of B-cell acute lymphoblastic leukemia who received chimeric antigen receptor T-cell (CAR-T) therapy with rapcabtagene autoleucel (carvykti). The patient subsequently developed cytokine release syndrome (CRS) which during its resolution results in a hemophagocytic lymphohistiocytosis (HLH)-like syndrome that fell short of being diagnostic. This syndrome tracked closely with the onset and resolution of immune-effector cell-associated neurotoxicity syndrome (ICANS), with close correlation between the severity of laboratory abnormalities, particularly extremely high ferritin (peak value: 81,540 µg/L), and clinical encephalopathy. CONCLUSIONS: Cytokine release syndrome after experimental (CAR) T cell therapy may cause extremely elevated ferritin and hemophagocytic lymphohistiocytosis -like syndrome.

Prevention of potential delayed hemolytic transfusion reaction in two sickle cell patients using intravenous immunoglobulins and steroids before and after red blood cell exchange with antigen positive units and review literature.

Emergent Red Blood Cell (RBC) exchange is indicated in sickle cell disease (SCD) patients with severe acute chest syndrome. However, fully matched RBC units may not be available for patients with multiple RBC antibodies. Intravenous immunoglobulin (IVIG) and steroids were reported for preventing potential delayed hemolytic transfusion reaction (HTR) in simple transfusion of antigen-positive RBCs. We investigated the efficacy and safety of IVIG and steroids in two SCD patients presented with acute chest syndrome receiving RBC exchange with multiple incompatible units. The first patient had multiple historical alloantibodies, including anti-Jsb, although none of them were reactive. IVIG (1 g/kg) was given before and after RBC exchange with methylprednisolone (500 mg IV) one hour before exchange. Her sickle hemoglobin (HbS) was reduced from 89.4% to 17.4% after the exchange with five Jsb-positive units. The patient improved clinically without acute or delayed hemolysis. The second patient had reactive anti-Jsb on two different admissions 18 months apart. Only one of the sixteen units used in the exchanges was Jsb negative. He received the same IVIG regimen during both admissions but 100 mg IV hydrocortisone instead of methylprednisolone. His HbS was reduced from 63.4% to 22.4% after the first exchange. Significant clinical improvements were achieved after both exchanges. No delayed HTR was observed. Our experience of these two patients suggested that IVIG and steroids may be used in preventing potential delayed HTR in some SCD patients with rare antibodies receiving large amounts of antigen-positive RBC products.

Effect of biotin on currently used Beckman thyroglobulin assay and newly reformulated thyroglobulin assay not affected by biotin.

OBJECTIVES: Biotin causes negative interference with thyroglobulin measurement using the Access thyroglobulin assay. Recently, Beckman reformulated the thyroglobulin assay to overcome biotin interference. We investigated the effect of biotin on both current and newly formulated assays. METHODS: Four serum pools were prepared using specimens containing various amounts of thyroglobulin. Then aliquots of each pool were supplemented with various amounts of biotin, and thyroglobulin concentrations were measured by both the current and the new assays. In addition, 3 volunteers ingested 10 mg biotin, and specimens were drawn before and 2 hours after taking biotin. Thyroglobulin concentrations before and 2 hours after taking biotin were measured by both assays. RESULTS: In the presence of biotin, thyroglobulin concentrations were reduced significantly using the current assay, but no significant change was observed using the newly formulated assay. We observed similar results in vivo. CONCLUSIONS: The newly formulated thyroglobulin assay by Beckman is free from biotin interference.

Technical Note: Comparison of Alinity c Hemoglobin A1c Immunoassay with Premier Hb9210 Automated HPLC Assay: A Preliminary Report.

OBJECTIVE: We utilized Premier Hb9210 analyzer (HPLC method; Trinity Biotech, Jamestown, NY) for measuring HBA1c in whole blood. As our laboratory is transitioning to Abbott system, we compared HbA1c values obtained by Alinity c and Premier Hb9210. METHODS: The Premier Hb9210 analyzer is based on boronate affinity high performance liquid chromatography with analytical measurement range of 3.8 to 18.5%. The Alinity c Hemoglobin A1c assay measured both total hemoglobin and HbA1c (enzymatic assay) in whole blood and then calculated %HbA1c. The analytical measurement range of this assay is 4 to 14% of HbA1c. We evaluated the analytical performance of Alinity c HbA1c by evaluating precision and also comparing 77 clinical samples with our reference HPLC method. RESULTS: Both Alinity c HbA1c and Premier HB9210 have excellent total precision. Plotting HbA1c results obtained by the Premier Hb9210 analyzer in the x-axis (currently used reference method) and the corresponding values obtained by the Alinity c assay, we observed the following regression equation: y=0.9473x+0.1548 ( n=77, r=0.99). DISCUSSION: Our result indicates that HbA1c enzymatic assay on the Alinity c analyzer showed values comparable to HPLC method. However, at the decision points (2.8% average negative bias at >6.4% and 3.3% average negative bias at 7%), HbA1c values obtained by the Alinity c analyzer were lower than the reference method. CONCLUSIONS: We conclude that HbA1c assay on the Alinity c analyzer is a viable alternative to HPLC for measuring HbA1c in clinical laboratories but values at the decision points must be interpreted with caution and if necessary should be repeated by a reference HPLC method.

Severe jaundice with life-threatening liver failure after Kratom use: Reversed by plasma exchange.

Kratom is an herbal supplement which is used for its stimulating properties and pain reduction due to interaction with opioid receptors. Kratom overdose may cause fatality. A 56-year-old man was admitted to the emergency department with severe jaundice and liver failure. His total bilirubin reached at 70.6 mg/dL, but extensive workup did not show any liver mass. Family informed that the patient was taking Kratom. Plasma exchange was suggested as an unconventional therapy and consent from the patient was obtained because this procedure has never been performed to treat Kratom toxicity before. After four procedures, his total bilirubin was reduced to 23.9 mg/dL and his clinical condition improved significantly. Finally on day 5 he was discharged at stable condition with a total bilirubin value of 21.3 mg/dL. There is no antidote for Kratom, and treatment is supportive. To our knowledge this is the first report of reversing Kratom poisoning using plasma exchange.

Good correlation between tacrolimus concentrations using improved CMIA on the Alinity i analyzer and LC-MS/MS method from a reference laboratory but unexpected negative bias with another LC-MS/MS method from a different reference laboratory.

OBJECTIVES: We compared tacrolimus concentrations obtained by the more recently US Food and Drug Administration-approved tacrolimus assay (CMIA) on the Alinity i analyzer (Abbott Laboratories) with a liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based method from 2 reference laboratories. We also investigated the correlation between the CMIA tacrolimus and Elecsys tacrolimus assays. METHODS: Tacrolimus concentrations were measured in EDTA whole blood by the chemiluminescent microparticle immunoassay (CMIA) using the Alinity i analyzer, and then 2 aliquots were sent to 2 reference laboratories, both using ascomycin as the internal standard for the LC-MS/MS method. RESULTS: The total precision of the CMIA tacrolimus assay was excellent. When tacrolimus concentrations obtained by the LC-MS/MS method from reference laboratory A were plotted on the x-axis and corresponding CMIA values were plotted on the y-axis, the following regression equation was observed: y = 0.9721x + 1.005 (r = 0.95), indicating no significant bias with the CMIA. However, when tacrolimus values obtained from reference laboratory B were used for comparison, the regression equation was y = 0.7664x + 1.775 (r = 0.93), indicating significant negative bias with the CMIA. When we compared tacrolimus concentrations obtained by reference laboratories A and B, we observed positive bias with tacrolimus concentrations obtained by reference laboratory B. However, tacrolimus concentrations obtained by both CMIA and Elecsys immunoassays were comparable. CONCLUSIONS: Because of good correlation of tacrolimus concentrations using the CMIA and LC-MS/MS from reference laboratory A, our long-term reference laboratory for drug analysis, we concluded that the CMIA on the Alinity i can be used for therapeutic drug monitoring of tacrolimus.

Trend towards reduction of transfusion reactions using prestorage leukocyte-reduced and pooled whole blood-derived platelets and cost savings compared with poststorage whole blood-derived random platelets as evidenced by real-time hemovigilance.

BACKGROUND: Due to chemotherapy-induced neutropenia or hematologic malignancies, immunocompromised cancer patients may have higher incidence of febrile nonhemolytic transfusion reactions compared with the general population and frequently require platelet transfusions. This quality improvement project compared the safety of transfusion using prestorage leukocyte-reduced and pooled whole blood-derived platelets (Acrodose/WBD) with conventionally produced poststorage WBD platelets (RDP) using an active hemovigilance system. METHODS: Every patient receiving a blood product at the hospital was virtually monitored in real time by trained nurses from a remote hemovigilance unit. These nurses monitor a digital dashboard, which populates a watch list of patients from the time blood product administration is initiated until 12 hours posttransfusion. Over the course of 6 months, 371 patients receiving 792 RDP transfusions and 423 patients receiving 780 Acrodose/WBD platelets transfusions were monitored for transfusion reactions. RESULTS: We identified 26 transfusion reactions in RDP but only 12 transfusion reactions in the Acrodose/WBD platelet group. CONCLUSION: Acrodose platelet transfusion was associated with fewer transfusion reactions, which resulted in significant cost savings.

Technical Note: Approach to Identify and Eliminate Biotin Interference in Thyroid Function Tests Using Beckman DXI 800 Analyzer by Taking Advantage of Assay Harmonization with Alinity i Analyzer.

OBJECTIVE: We reported significant interference of biotin in FT3 and FT4 assays using Beckman DXI 800 analyzer. Recently we acquired Alinity i analyzer where TSH, FT3 and FT4 assays are not biotin based. We hypothesized that if thyroid function tests on DXI 800 and Alinity i are harmonized, then it is possible to eliminate biotin interference. METHODS: We investigated assay harmonization by analyzing 35 specimens for TSH, FT4 and FT3 using both analyzers. We prepared one serum pool using left-over specimens where thyroid tests were ordered. Then aliquots of the pool were supplemented with various amounts of biotin followed by measuring thyroid function tests again. RESULTS: We observed assay harmonization between both analyzers for TSH, FT3 and FT4 Tests. TSH assay was not affected in the presence of biotin, but FT3 and FT4 values were significantly elevated using DXI 800 analyzer. In contrast, TSH, FT3 and FT4 assays were not affected by biotin using Alinity i analyzer. CONCLUSIONS: Elevated FT3 and FT4 using DXI 800 analyzer may be due to biotin interference which can be eliminated by observing normal values using Alinity i analyzer. However, normal or slightly elevated TSH with elevated FT3 and FT4 using both analyzers may indicate rare type of TSH producing tumor of pituitary, not biotin interference.

Technical Note: Use of a Novel Bacterial Culture Sampling Device for Pooled Whole Blood Platelets.

OBJECTIVE: Transfusion associated sepsis is a serious risk after platelet transfusion. Although platelet culture can be performed to avoid such risk, culture results are often available after transfusion due to the 4-hour shelf-life after pooling. To decrease such risk, we implemented a needleless closed system device to culture for contamination before pooling and release for transfusion. METHODS: We customized a needleless device to permit sterile sampling of whole blood platelets without retrograde or cross-contamination. Then aliquots of platelets were injected into culture media for detection of aerobic organisms and cultured for 24 hours but released for transfusion after 12 hours of negative culture. RESULTS: In a period of two years, we used this device in 5,741 whole blood derived pooled platelets and only 24 units tested positive (0.4%) but none of initial positive was later confirmed. There were 11 Staphylococcus and 9 Bacillus species identified. All but one of the positive units were discarded; there was no clinical impact in the patient who received the positive unit. CONCLUSION: This device allows for sampling of whole blood derived platelets before pooling, warranting a transfusion of a culture negative unit after 12 hours of negative culture, consequently reducing transfusion of bacterially contaminated whole blood derived pooled platelets.

Significant discordance between point of care BNP values obtained by the i-STAT and the Beckman DXI 800, causing confusion in patient management when both methods are used interchangeably by clinicians.

B-type natriuretic peptide (BNP) is used as a biomarker of heart failure. In our hospital point of care (POCT) BNP test is performed in EDTA whole blood using i-STAT (Abbott Laboratories, Abbott Park, IL, USA) and in the clinical laboratory using EDTA plasma and the DXI 800 analyzer (Beckman, Brea, CA, USA). We compared BNP values in 88 patients obtained by using the i-STAT followed by using the DXI 800. The time difference between the two analyses varied from 32 min to less than 12 h. In addition, 11 specimens were simultaneously analyzed for BNP using both the i-STAT and the DXI 800 analyzer. Plotting BNP concentrations obtained by the DXI 800 in the x-axis (reference method) and the i-STAT values in the y-axis, we observed the following regression equation; y = 1.4758 x + 23.452 (n = 88, r = 0.96), indicating significant positive bias with the i-STAT. In addition, we also observed significant differences between BNP values obtained by the i-STAT and the DXI 800 in 11 specimens analyzed simultaneously. Therefore, clinicians should not use BNP concentrations obtained by the i-STAT interchangeably with BNP concentrations obtained by the DXI 800 analyzer for patient management.

Rare case of benign transient hyperphosphatasemia in a complicated multiorgan adult transplant patient: Case report and literature review.

BACKGROUND: Transient hyperphosphatasemia, characterized by isolated highly elevated alkaline phosphatase (ALP) activity in the absence of liver or bone disease, is typically seen in children but rarely in adults. Here we report highly elevated ALP activity in a complicated multiple-organ transplant patient due to benign transient hyperphosphatasemia. CASE REPORT: A 54-year-old male had a complicated past medical history including a bilateral lung transplant for cystic fibrosis in 2006, colonic resection due to colon cancer in December 2011 and subsequent chemotherapy which ended in June 2022. He also had combined liver and kidney transplant in 2022 at our academic medical center. Post-transplant, he was treated with triple drug immunosuppressant therapy (tacrolimus, mycophenolic acid, and prednisone). Although his alkaline phosphatase (ALP) activity was 83 U/L, it continued to increase three months after combined liver and kidney transplant even though other liver enzymes were mildly elevated but total bilirubin remained within their reference ranges. Flecainide was discontinued but his ALP remained high, peaking at 5904 U/L. Finally, lansoprazole, ergocalciferol (vitamin D2) and vitamin E supplement were discontinued as nonessential medications, and coincidently ALP activity started to decline. CONCLUSIONS: After ruling out all possibilities that may cause elevated ALP, we concluded that this is a rare case of benign transient hyperphosphatasemia in an adult transplant recipient.

Concordance between i-STAT Contemporary Troponin I and Beckman High Sensitivity Troponin I Only when Both Tests Were Performed within Two Hours: A Preliminary Study.

OBJECTIVE: Often in the Emergency Department (ED) of our hospital, troponin I is measured by the i-STAT (contemporary troponin I) followed by analysis of high sensitivity troponin I (hs-TnI) using the Beckman analyzer in the clinical laboratory. In this study, contemporary troponin I concentrations obtained by the i-STAT were compared with the Beckman hs-TnI concentrations in patients with myocardial infarction. METHODS: Troponin I concentrations were determined by both methods in 56 specimens collected from 56 patients admitted to the ED (time between both measurements; <1 h to up to 16 h). RESULTS: When troponin I concentrations determined by the iSTAT-1 were repeated in the laboratory within 2 h, there was concordance between both values using standard regression analysis (y=1.14 x-0.56, n=18, r=0.98; hs-TnI values converted into ng/mL) as well as Passing-Bablock regression analysis (y=0.89 x-0.006). However, overall correlation when all 56 data points were considered was very poor. In addition, we also observed very poor correlation in another 38 specimens when laboratory determinations of hs-TnI were conducted >2 h up to 16 h. CONCLUSION: We concluded that the iSTAT-1 contemporary troponin I concentrations were concordant with hs-TnI values only if measured within 2 h.

Severe complications in a 25-year-old male after brown recluse spider bite treated by therapeutic plasma exchange: A case report and review of other case studies.

Although in the majority of patients (90%), the bite wound of brown recluse spider resolves spontaneously, some patients may experience a severe reaction requiring hospitalization. A 25-year-old male developed severe hemolytic anemia, jaundice, and other complications following a brown recluse spider bite on his posterior right thigh. He was treated with methylprednisolone, antibiotics, and red blood cells (RBCs) transfusion without response. Therapeutic plasma exchange (TPE) was added to the treatment regimen, and his hemoglobin (Hb) was eventually stabilized, leading to significant clinical improvement. The beneficial effect of TPE in the current case was compared to three other reported cases. We recommend close monitoring of Hb levels in patients with systemic loxoscelism during the first week after brown recluse spider bite and early implementation of TPE in the management of severe acute hemolysis when patients do not respond to usual treatment modalities and RBC transfusion.

Significant Interference of Biotin in Thyroid Function Tests Using Beckman Analyzer: How to Identify such Interferences?

OBJECTIVE: Biotin in elevated concentration interferes with biotin-based immunoassays. We studied biotin interferences in TSH, FT4, FT3, total T4, total T3 and thyroglobulin assays both in vitro and in vivo using Beckman DXI800 analyzer. METHODS: Two serum pools were prepared from left-over specimens. Then aliquots of each pool (and serum control) were supplemented with various amounts of biotin followed by measuring thyroid function tests again. Three volunteers each took 10 mg biotin supplement. We compared thyroid function tests before and 2 h after taking biotin. RESULTS: We observed significant biotin interferences in biotin-based assays (positive interference with FT4, FT3, and total T3 assay but negative interference with thyroglobulin) both in vitro and in vivo but non-biotin-based assays (TSH and total T4) were not affected. CONCLUSIONS: Elevated FT3 and FT4 in the presence of normal TSH is inconsistent with hyperthyroidism and should be followed up with total T3 and T4 test. Significant discrepancy between total T3 (falsely elevated value due to biotin) and total T4 (not affected as the assay is not biotin based) maybe an indication of biotin interference.

Perioperative therapeutic plasma exchange in a patient with rare Factor XIII inhibitor.

INTRODUCTION: Factor XIII deficiency is a rare bleeding disorder which could be severe if inherited or less severe if acquired. We report a case of acquired Factor XIII inhibitor in a 75-year-old male with a suspicious left renal mass treated perioperatively with therapeutic plasma exchange (TPE). PATIENT AND METHOD: To perform kidney biopsy and ablation of the renal mass, six daily TPE treatments were performed before and after biopsy to minimize bleeding risk because the patient did not respond to drug therapy. Both thromboelastography (TEG) and laboratory-based coagulation tests were performed to assess coagulation status prior to and after TPE. RESULTS: The biopsy indicated oncocytoma which was removed by surgical procedure. Factor XIII activity remained below 15 % throughout TPE treatments, but Factor XIII inhibitor titer reduced from initial positive value of 1:40 to negative following the third TPE and remained negative through the sixth TPE. Unfortunately, the inhibitor titer was positive at 1:20 in the fifth month and 1:5 in the sixth month during follow-up. CONCLUSIONS: TPE is useful in removing XIII inhibitory factor, but the effects are only short term.

Significant Improvement in Digoxin Immunoassays Over Four Decades: Newer Assays are Less Affected by Interferences.

BACKGROUND: Digitalis glycosides derived from foxglove plants have been used for medicinal purposes since the 16th century. Currently, digoxin derived from foxgloves is used clinically. Owing to the narrow therapeutic range, therapeutic drug monitoring is essential; however, digoxin immunoassays suffer from interference. METHODS: The issue of interference was reviewed for both older polyclonal antibody-based digoxin assays and newer monoclonal antibody-based digoxin assays. A literature search was conducted using PubMed, ScienceDirect, Scopus, Web of Science, and ResearchGate for studies on digoxin immunoassays published in the English language from 1969 to the present. RESULTS: Radioimmunoassays for digoxin in the 1970s and, later, first-generation nonradioimmunoassay methods were liable to several interferences, including digoxin-like immunoreactive substances, spironolactone, potassium canrenoate, and various digoxin metabolites. However, for the last 10-15 years, next next-generation digoxin immunoassays have been virtually free from such interferences. Nevertheless, certain herbal supplements, as well as both Digibind and DigiFab, interfere with serum digoxin measurement, even with the more recently developed digoxin assays. CONCLUSIONS: More recently introduced monoclonal antibody-based digoxin assays are superior to the older polyclonal antibody-based digoxin assays.

Utility of Therapeutic Drug Monitoring in Identifying Clinically Significant Interactions Between St. John's Wort and Prescription Drugs.

BACKGROUND: The general population widely uses herbal medicines, as they are regarded as effective and safe. St. John's wort, which is an effective herbal antidepressant, exhibits both pharmacokinetic and pharmacodynamic interactions with several drugs. The aim of this review was to highlight the clinically significant interactions of St. John's wort with drugs that require to be monitored to assess their therapeutic effect. METHODS: Published literature was searched using electronic databases, such as MEDLINE, PubMed, and Elsevier ScienceDirect using terms such as "herbal medicine," "herbal toxicity," "legislation herbal medicine," "drug-herb interactions," "St. John's wort," and "St. John's wort-drug interactions." Searches were limited to the English language, and there was no restriction on the date of publication. RESULTS: St. John's wort exhibits a number of pharmacokinetic and pharmacodynamic interactions with drugs. The most dangerous interactions occurred when used concurrently with the immunosuppressants, cyclosporine, and tacrolimus (treatment failure or organ rejection) or warfarin (treatment failure resulting in thromboembolic events) or antiretroviral agents (treatment failure and the emergence of new viral variants that are resistant to conventional drugs). CONCLUSIONS: Patients should consult their health care providers before consuming herbal supplements, especially St. John's wort, to avoid potentially dangerous drug-herb interactions.

Unusual Polyclonal IgM in an IgG Deficient Patient with Autoimmune Lymphoproliferative Syndrome: A Case Study and Literature Review.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disease caused germline mutation of FAS gene, gene encoding Fas ligand or Caspase 10 gene. However, in 20% of all ALPS patients, genetic defect is unknown. We presented a case of a 20-year-old male with a history of autoimmune lymphoproliferative syndrome (ALPS; confirmed by genetic study) who came to our medical center with a concern for malignancy. Although no malignancy was detected, his lack of IgA, very low level of IgG (requiring therapy with intravenous IgG) and highly elevated polyclonal IgM (hyperimmunoglobulin M syndrome) were unusual findings because ALPS patients with hypergammaglobulinemia usually demonstrate elevated IgA or IgG.