Severe Leukopenia Research Articles

Hematological and Serum Chemistry of Canine Parvoviral Enteritis in Diverse Breeds of Dogs

Canine Parvovirus enteritis (CPV-2) is a highly infectious viral disease occurring in puppies resulting in high mortality with a myriad of clinical signs, hematological and biochemical changes during the progression of the disease. This study investigated hematological and biochemical changes in 30 CPV-positive dogs in Ibadan, Nigeria. Severe non-regenerative anemia (35.71%) and leukopenia (22 cases) were prevalent. Thrombocytopenia was severe in 73.33% of cases. Further analysis revealed normocytic hypochromic anemia in 42.86%, microcytic hypochromic anemia in 28.57%, and leukopenia categorized as mild (5), moderate (12), or severe (5). Biochemical changes included hyperproteinemia (26.7%), hyperalbuminemia, hyperglobulinemia, and elevated liver enzymes in some cases. Renal dysfunction was evident in 16.7% of dogs with elevated creatinine. Significant differences (p<0.05) were observed between infected and healthy dogs. These findings underscore the critical impact of CPV on hematological and biochemical profiles, necessitating supportive care and emphasizing the crucial role of vaccination in disease prevention.

Metastatic haemangiosarcoma in conjunction with polycystic kidney disease in a 20‐year‐old jenny donkey

AbstractA 20‐year‐old female donkey was referred for further investigation of anaemia, weight loss and lethargy. Ultrasound scanning revealed multiple rounded, well‐delineated, anechoic nodules of varying size (up to 3 cm diameter) within the cortex of both kidneys. Splenic parenchyma demonstrated mixed echogenic complex mass lesions (up to 5 cm diameter) involving the splenic capsule. Bloodwork revealed a severe anaemia and leukopenia. Histopathological analysis of the lesion revealed splenic haemangiosarcoma with metastatic involvement of other organs in combination with polycystic kidney disease. This case details two previously underreported diseases in donkeys that should be considered as differential diagnoses in donkeys admitted with anaemia, weight loss and lethargy.

Dengue Fever in Cancer Patients: A Case Series

Abstract Complications of dengue fever are understudied in oncology. In patients undergoing chemotherapy, the immunosuppressive effects of drugs increase susceptibility to infections, such as dengue, complicating diagnosis and treatment. Here, we report two cases highlighting the challenges and importance of early detection in managing dengue fever alongside chemotherapy-induced immunosuppression. Both patients presented with severe leucopenia and thrombocytopenia, common to both chemotherapy side effects and dengue, complicating clinical management. Early recognition of dengue has allowed for appropriate management, resulting in full recovery.

Impact of Letermovir for Cytomegalovirus Primary Prophylaxis on Myelosuppression and Immunosuppression in Lung Transplant Recipients.

Cytomegalovirus (CMV) is associated with detrimental outcomes after lung transplantation (LTX); primary prophylaxis (PPX) with valganciclovir (VGC) is guideline-recommended. VGC is associated with myelosuppression, spurring interest in letermovir (LTV). Adults undergoing LTX between January 1, 2021, and July 30, 2022 at our institution who were converted from VGC to LTV for PPX were evaluated. Outcomes included antimetabolite dosing during PPX, the incidence and frequency of myelosuppressive events, and the time to the first myelosuppressive event. Twenty-nine LTX recipients met the inclusion criteria. Most patients received non-lymphocyte-depleting induction (96.6%) and had moderate risk CMV serostatus (D+/R+, 48.3%). Patients transitioned from VGC to LTV 177 days (IQR 102 days) post-transplant. After conversion to LTV, patients tolerated higher daily doses of mycophenolate (721mg vs. 1000mg, p = 0.008) or azathioprine (33.3mg vs. 62.5mg, p = 0.478). The incidence of myelosuppressive events was reduced (100.0%vs. 62.1%, p < 0.001) including leukopenia (96.6%vs. 58.6%, p = 0.001), severe leukopenia (82.8%vs 31.0%, p < 0.001) and neutropenia requiring GCSF (96.6%vs. 48.3%, p < 0.001) while on VGC compared to LTV. While on LTV, patients had a reduced rate of myelosuppressive events compared to VGC (1 event per 6.2 patient days vs. 1 event per 14.7 patient days, p < 0.001). While on LTV, one patient had breakthrough viremia (3.4%) that was treated with (val)ganciclovir. In this single-center study, patients tolerated higher doses of antimetabolite immunosuppression, and the incidence and frequency of myelosuppressive events were reduced while on LTV compared to VGC. This evidence expands upon the current literature demonstrating improved tolerability of LTV in LTX recipients.

6472 Methimazole Induced Agranulocytosis: Uncommon Complication of a Common Medication

Abstract Disclosure: R. Kaur: None. L. Kaur: None. A. Sridhar: None. T. Chaudhary: None. N. Patel: None. Methimazole (MMI) induced agranulocytosis is a rare and life threatening adverse effect that usually occurs within 3 months of drug initiation and can rapidly lead to overwhelming infection. It is reported in 0.1 to 0.5 % of patients on treatment with methimazole. MMI is a standard drug used in graves disease and toxic multinodular goiter. We report a case of MMI induced agranulocytosis in an elderly female with recently diagnosed toxic multinodular goiter. A 66 year old female with past medical history of recently diagnosed toxic multinodular goiter for which she was started on methimazole 80mg/day two months ago presented to the emergency department with chief complaint of severe sore throat associated with rapidly increasing pharyngeal pain and fever over the past 24 hours. She was lethargic, febrile with temperature of 102 F, tachycardic with heart rate of 115/minute and hypotensive with blood pressure of 108/64 mm Hg. Physical examination revealed diffuse pharyngeal and tonsillar erythema with bilateral purulent exudate with tender anterior cervical lymphadenopathy. Thyroid was enlarged, firm, irregular and nontender. Pulmonary, cardiac and abdominal exam was unremarkable. Lab work showed severe leukopenia with WBC count of 1,600/mm3, neutropenia with absolute neutrophil count of 0.0 x 1000/ul (normal range 1.8-7.3 x 1000/ul) and erythrocyte sedimentation rate and C reactive protein were both elevated. Blood cultures and fungal cultures showed no growth. Urinalysis and urine culture were both unremarkable. She had an extensive haematological, rheumatological and infectious disease workup for neutropenia, which was largely unrevealing. Rapid streptococcal testing was negative but throat cultures grew beta haemolytic streptococci. Treatment included suspending methimazole, administering antimicrobial therapy with piperacillin - tazobactam, acyclovir and fluconazole. She was also started on a granulocyte colony stimulating factor. Patient presented satisfactory evolution with progressive increase in leukocyte count and remission of symptoms by day 5 of treatment, rendering further bone marrow testing unnecessary. Antibiotics were changed to oral amoxicillin-clavulanic acid after throat culture results were available and the patient was discharged in stable condition. One month after discharge she underwent total thyroidectomy for definitive cure and is currently followed up as an outpatient by endocrinology. The objective of this case report is to present an uncommon case of agranulocytosis secondary to use of methimazole and to increase awareness among the physicians about the need to consider this diagnosis in patients on this medication. It is also advised that these patients be educated about the drugs side effects, a practice that may avert suffering and unnecessary costs. Presentation: 6/3/2024

Neutrophil count as a risk factor for cardiovascular diseases: how can we manage it?

Neutrophils activation plays a pivotal role in the pathogenesis of atherosclerotic plaque formation, progression and rupture. An association between the leukocyte count and the risk of developing myocardial infarction has been well known for many years; however, only recently did Mendelian randomization studies show that a high neutrophil count is a causal risk factor for atherosclerotic cardiovascular disease. On the other hand, experimental studies show that depletion of circulating neutrophils impairs plaque development. Clopidogrel, an antiplatelet agent, is widely used in combination with aspirin to reduce the incidence of ischemic events in patients treated with coronary stenting. Chronic treatment with this drug reduces inflammatory markers and neutrophil numbers, rarely causing severe leukopenia. The purpose of this review is to present recent evidence showing the link between neutrophil number and the development of cardiovascular diseases and to discuss how the clopidogrel-induced reduction in the neutrophil count may be a beneficial off-target effect of this drug.

A Case Study on Canine Heartworm (Dirofilaria immitis)

A four years old Japanese Spitz dog with a history of anorexia, vomiting, diarrhoea, weakness, reluctant to move, respiratory difficulty, and abdominal discomfort was admitted to the Veterinary Teaching Hospital, Nepal Polytechnic Institute, Chitwan, Nepal. The dog underwent clinical examination including hematological investigation. The hematological blood assays revealed severe anaemia, thrombocytopenia, leukopenia, lymphocytopenia, monocytopenia, and eosinopenia. A peripheral blood smear showed undulating movement of larvae of Dirofilaria Immitis which confirmed it as a canine Dirofilaria immitis (canine heart worm) disease. On the first day of presentation in the hospital, since the dog was dehydrated and anorectic, it was given fluids of 400 ml of normal saline and 200 ml of DNS (dextrose normal saline), pantoprazole at 0.7 mg/kg slow IV, ondansetron at 0.5 mg/kg slow IV, and haematinic agent (HB-RON®) at 5 ml BID PO (Iron, vitamin B12, Folic acid, Zinc, L-Lysin). The following day, the dog was dead, even before all the confirmatory diagnoses. That shows heartworm is prevalent in dog so strategic vector control and screening are recommended for the prevention and control of the disease in countries like Nepal.

Novelties for the management of cytomegalovirus after kidney transplantation

Cytomegalovirus (CMV) infection is the main opportunistic infection observed after kidney transplantation. Despite the use of prevention strategies, CMV disease still occurs, especially in high-risk patients (donor seropositive/recipient seronegative). Patients may develop complicated CMV, i.e. recurrent, refractory or resistant CMV infection. CMV prevention relies on either universal prophylaxis or preemptive therapy. In high-risk patients, universal prophylaxis is usually preferred. Currently, valganciclovir is used in this setting. However, valganciclovir can be responsible for severe leucopenia and neutropenia. A novel anti-viral drug, letermovir, has been recently compared to valganciclovir. It was as efficient as valganciclovir to prevent CMV disease and induced less hematological side-effects. It is still not available in France in this indication. Recent studies suggest that immune monitoring by ELISPOT or Quantiferon can be useful to determine the duration of prophylaxis. Other studies suggest that prophylaxis may be skipped in CMV-seropositive kidney-transplant patients given mTOR inhibitors. Refractory CMV is defined by the lack of decrease of CMV DNAemia of at least 1 log10 at 2 weeks after effective treatment. In case of refractory CMV infection, drug resistant mutations should be looked for. Currently, maribavir is the gold standard therapy for refractory/resistant CMV. At 8 weeks therapy and 8 weeks later, it has been shown to be significantly more effective than other anti-viral drugs, i.e. high dose of ganciclovir, foscarnet or cidofovir. However, a high rate of relapse was observed after ceasing therapy. Hence, other therapeutic strategies should be evaluated in order to improve the sustained virological rate.

Use of letermovir for cytomegalovirus primary prophylaxis in lung transplant recipients.

Cytomegalovirus (CMV) is a driver of negative outcomes after lung transplant (LTX) and primary prophylaxis (PPX) with valganciclovir (VGC) is standard-of-care. VGC is associated with myelosuppression, prompting interest in letermovir (LTV). Adults receiving LTX between April 1, 2015, and July 30, 2022, at our institution were evaluated. Patients were excluded if low CMV risk (D-/R-), survived <90 days post-LTX, or transferred care before PPX withdrawal. Primary outcomes were leukopenia (white blood cell count [WBC] ≤ 3.0×109/L), severe leukopenia (WBC ≤ 2.0×109/L), and neutropenia (absolute neutrophil count ≤ 1500 cells/µL) requiring granulocyte-colony stimulating factor (GCSF) on PPX. Secondary outcomes included breakthrough CMV infection and post-PPX CMV infection. 204 patients met inclusion criteria: 175 patients on VGC and 29 patients on LTV (after VGC conversion). Most patients received bilateral LTX (62.7%) with non-lymphocyte-depleting induction (96.6%) and moderate-risk serostatus (D+/R+, 48.5%). Patients transitioned from VGC to LTV after a mean of 178 days (SD 80.8 days) post-transplant. Patients on VGC experienced significantly more leukopenia (82.3%vs. 58.6%, p = 0.008), severe leukopenia (57.1%vs. 31.0%, p = 0.016), and neutropenia requiring GCSF (70.9%vs. 51.7%, p = 0.048). Breakthrough (5.7%vs. 3.4%, p = 0.955) and post-PPX (24.6%vs. 37.9%, p = 0.199) infections were similar. A subgroup analysis of patients with high-risk serostatus showed similar trends, though did not reach statistical significance. In this single-center study, the incidence of leukopenia and neutropenia requiring GCSF were reduced with LTV compared to VGC. Breakthrough and post-PPX infections were not significantly different. This evidence suggests that LTV has comparable efficacy with reduced myelosuppression compared to VGC in LTX recipients, and may be an appropriate alternative for PPX.

Radioprotective activity of the liposomal composition of quercetin in acute radiation syndrome (experimental study)

Background. The targeted search for new effective radioprotective agents, especially among compounds with antioxidant properties, remains relevant. Among them, quercetin which has a high specific activity against oxidative stress (cited as a «universal antioxidant») deserves attention. The transport liposomal composition of quercetin, which significantly improves its bioavailability and is the basis of the licensed drug «Lipoflavon®» (LF), is known, but the radioprotective properties of this drug have not been studied. The purpose of the work is to position Lipoflavon as a radioprotector for the first time based on the study of radioprotective activity in an acute experiment with total irradiation of rats. Materials and methods. The rat model of acute radiation syndrome (ARS) was carried out by short-term bilateral total body irradiation (TBI) on a CLINAC (6 MeV) linear accelerator at doses of 5.5 and 7.0 Gy. The control rats were sham-irradiated. The test sample of LF was used for the studies. LF (1.5 mg/mL) was administered to rats 30 min before TBI through the tail vein. The control TBI rats were injected with physiological saline. Experimental rats were randomly assigned into groups as follows: group 1 – non-irradiated control (intact animals); group 2 – irradiated control at a dose of 5.5 Gy (TBI5.5); group 3 – irradiation at a dose of 5.5 Gy with administration of LF (LF + TBI5.5); group 4 – irradiated control at a dose of 7.0 Gy (TBI7.0); group 5 – irradiation at a dose of 7.0 Gy with administration of LF (LF + TBI7.0). Clinical characteristics of ARS, overall survival, and the mean survival time of the dead animals were determined. The profiles of lethality («peaks of death») were calculated as total rat lethality (%) in certain time periods of the ARS. In hematological studies, LF was administered 24 h prior to TBI and twice a week the next 4 weeks after TBI. The hematological parameters were monitored on days 3, 7, 14 and 21 after TBI. Results. It was established that prophylactic LF administered 30 min before TBI at doses of 5.5 and 7.0 Gy, which were LD20/30 and DL73.3/30, increased the 30-day survival rate of the irradiated rats to 90 and 40% respectively, compared to 80 and 26.7% in irradiated control, and changed the radiation lethality profile of the rats in the model of ARS. The radioprotective activity of LF manifested in the form of the absence of early and late peaks of death of the irradiated rats and the survival time of more than 30 days after the treatment in 40% of rats with LD73,3/30. Prophylactic and therapeutic administration of LF prevented development of severe leukopenia and thrombocytopenia and contributed to a more rapid and sustained recovery of erythrocytes during the period of ARS. The most efficient radioprotective therapeutic effect of LF was observed in rats with a dose of LD73.3/30. Conclusions. The results of the study substantiate the radioprotective activity of Lipoflavon in ARS and help develop the new approaches to using the licensed drug «Lipoflavon®» as an effective pharmacological therapeutic agent for radiation protection in acute radiation.

Age, gender, and infectious status-wise assessments of hematological parameters among patients with dengue infection

BackgroundThe aim of this study was to examine the impact of different stages of dengue infection on immune cell counts among dengue patients and to compare them with cases of non-dengue febrile illness. MethodsThe recruited patients were divided into two groups: the first group served as a control (n = 55), representing non-dengue febrile illness, and the second group was identified as dengue febrile illness (n = 149), which was further divided into three groups based on infection stage. Blood samples were collected from the selected patients and subjected to blood cell component analysis. To find IgG and IgM as well as the dengue virus non-structural antigen-1 (NS1), an immunochromatographic test (ICT) kit was utilized. Additionally, a hematological analyzer was used to determine complete blood cell counts (CBC). Data was thoroughly analyzed using Graph Pad Prism 6 software. The differences in means of different groups were calculated by applying the student's t-test. ResultsThe findings revealed the presence of severe leucopenia and thrombocytopenia at stages 1 and 2, accompanied by lymphopenia at stage 1. Group comparisons indicated that only teenagers exhibited a significantly lower white blood cell count compared to older individuals, while no significant differences were observed in lymphocytes, platelets, and monocytes across all age groups. Comparing different age groups of normal individuals to dengue-infected patients, the results unveiled that leucopenia was most severe in adults, followed by teenagers and children, with no significant difference in the elderly. Furthermore, adults showed the greatest degree of thrombocytopenia, followed by teens and kids, with the elderly showing the greatest degree of thrombocytopenia. Adults and teens showed extreme neutrophilia, whereas young children and the elderly showed no discernible abnormalities. Elderly patients experienced a marked decrease in monocyte count, a phenomenon not observed in other age groups. ConclusionIn conclusion both, leucopenia & thrombocytopenia, are most severe in stages 1 and 2, whereas neutrophilia & lymphopenia are predominantly severe in stage 1. These results imply that the consequences associated with dengue infection are more severe in the early stages and tend to ameliorate as the patient progresses toward recovery.

Methotrexate toxicity in patients with rheumatic diseases: A 10-year evaluation of manifestations, risk factors, and mortality

Methotrexate (MTX) is a commonly used medication in the treatment of rheumatic diseases. MTX toxicity is a serious and at times fatal complication. In this 10-year cohort, we retrospectively evaluated the cases of MTX toxicity among rheumatic patients to identify demographic, clinical, and laboratory characteristics and risk factors of mortality. Through 10 years, patients older than 17 years with a rheumatic disease and at least one major manifestation of MTX toxicity (mucositis, myelosuppression, pneumonitis) were enrolled in the study. Demographic, clinical, and laboratory data were collected. Comparisons were made between patients who recovered and those who passed away. Of the 66 patients, most had rheumatoid arthritis, followed by systemic lupus erythematous. Most patients were females, and their mean age was 63.3±12.4 years. The most common comorbidity was hypertension followed by diabetes mellitus. Most patients were on polypharmacy and were taking MTX incorrectly. Other potential risk factors of toxicity were hypoalbuminemia, decreased renal function, and infection. The outcome of six patients was death and the predictors of mortality were severe leukopenia at admission, infection, especially sepsis, and severe renal impairment. In this study, we observed some potential risk factors for toxicity, namely incorrect MTX use, polypharmacy, renal impairment, hypoalbuminemia, infection, and comorbid conditions such as diabetes mellitus, hypertension, and ischemic heart disease. We also identified the risk factors of mortality, including infection, sepsis, severe leukopenia, high creatinine levels, and severe renal impairment.

Performance evaluation of the digital morphology analyser Sysmex DI-60 for white blood cell differentials in abnormal samples

Sysmex DI-60 enumerates and classifies leukocytes. Limited research has evaluated the performance of Sysmex DI-60 in abnormal samples, and most focused on leukopenic samples. We evaluate the efficacy of DI-60 in determining white blood cell (WBC) differentials in normal and abnormal samples in different WBC count. Peripheral blood smears (n = 166) were categorised into normal control and disease groups, and further divided into moderate and severe leucocytosis, mild leucocytosis, normal, mild leukopenia, and moderate and severe leukopenia groups based on WBC count. DI-60 preclassification and verification and manual counting results were assessed using Bland–Altman and Passing–Bablok regression analyses. The Kappa test compared the concordance in the abnormal cell detection between DI-60 and manual counting. DI-60 exhibited notable overall sensitivity and specificity for all cells, except basophils. The correlation between the DI-60 preclassification and manual counting was high for segmented neutrophils, band neutrophils, lymphocytes, and blasts, and improved for all cell classes after verification. The mean difference between DI-60 and manual counting for all cell classes was significantly high in moderate and severe leucocytosis (WBC > 30.0 × 109/L) and moderate and severe leukopenia (WBC < 1.5 × 109/L) groups. For blast cells, immature granulocytes, and atypical lymphocytes, the DI-60 verification results were similar to the manual counting results. Plasma cells showed poor agreement. In conclusion, DI-60 demonstrates consistent and reliable analysis of WBC differentials within the range of 1.5–30.0 × 109. Manual counting was indispensable in examining moderate and severe leucocytosis samples, moderate and severe leukopenia samples, and in enumerating of monocytes and plasma cells.

A case of successful contribution of therapeutic drug monitoring of valganciclovir as the prophylaxis against cytomegalovirus infection in a lung transplant recipient

BackgroundGanciclovir and its prodrug, valganciclovir, are first-line agents for cytomegalovirus infection prophylaxis after lung transplantation. Although valganciclovir prophylaxis is known to result in severe leukopenia as an adverse effect, dosage adjustment based on therapeutic drug monitoring (TDM) of ganciclovir concentration is not generally implemented in clinical practice.Case presentationIn this report, we describe the case of a female in her fifties after lung transplantation who successfully maintained valganciclovir prophylaxis under TDM with a minimal occurrence of severe leukopenia. Valganciclovir administration was initiated at a conventional dose of 450 mg/day on postoperative day 43 but was reduced to 450 mg/2 days on postoperative day 69 because of a decrease in white blood cell count and an increase in trough ganciclovir concentration. Subsequently, the valganciclovir dose adjustment was switched from label-indicated renal function-guided dosing to TDM-based dosing, targeting a trough level of 300–800 ng/mL. This target range was determined through deliberations with infectious disease specialists and pharmacists based on previously reported data. The TDM-based dose adjustment successfully prevented cytomegalovirus reactivation without causing significant adverse effects. Valganciclovir prophylaxis was completed on postoperative day 256, and the patient was transferred to another hospital for rehabilitation.ConclusionsThe findings of the present case suggest that TDM-based dosing could be helpful for clinicians in optimizing the prophylactic administration of valganciclovir in patients undergoing lung transplantation.

Blinatumomab-induced macrophage activating syndrome (MAS) in adult with B-cell acute lymphoblastic leukemia (B-ALL)

Blinatumomab as a single agent has demonstrated superiority over salvage chemotherapy in patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), with manageable safety and efficacy. Though known to have anticipated drug toxicities including cytokine release syndrome (CRS) and neurotoxicity, there is only one prior report of macrophage activating syndrome (MAS) due to blinatumomab. Case Presentation: We report the first case of blinatumomab-induced MAS in an adult. The patient presented with fever, cough, and weakness on the second cycle of blinatumomab. Complete blood count was notable for severe leukopenia, with comprehensive metabolic panel notable for elevated alkaline phosphatase, AST, ALT, LDH, and hyperferritinemia consistent with MAS. The patient was already in MRD-negative remission at presentation with MAS. She responded rapidly to withholding the drug and administration of both tocilizumab and dexamethasone. She was able to restart therapy with blinatumomab dosed at 9 mcg/day with no recurrence of symptoms. Though MAS is not an expected association with blinatumomab, the risk for CRS is. Secondary MAS in this case likely shares a mechanism with other hyperinflammatory conditions. Management includes holding the offending agent, like blinatumomab, and administering tocilizumab and dexamethasone. Future research will be needed to predict which patients are at highest risk to develop MAS after similar T-cell therapies.

Benzimidazole‐associated pancytopenia in a dog with presumed Heterobilharzia americana infection

AbstractAdverse drug events are classified into type A (dose‐dependent and common) or type B (idiosyncratic and uncommon) reactions. Benzimidazole toxicosis in veterinary medicine typically induces nonspecific signs such as gastrointestinal distress and infrequent myelosuppression. Pancytopenia from benzimidazoles is exceptionally rare, with only one reported case. We present a 12‐year‐old, female, spayed, mixed‐breed dog with acute lethargy, anorexia, pyrexia and severe leukopenia after high‐dose benzimidazole therapy for suspected liver fluke infection. Despite hospitalisation, the dog remained unresponsive to antimicrobial therapies, developed neutropenic sepsis and was euthanized. Bone marrow analysis indicated marked haematopoietic hypoplasia suggestive of a type A adverse drug event secondary to an incidental, high‐dose fenbendazole administration.

First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation.

Polyclonal rabbit antithymocyte globulins (ATGs) are commonly used in organ transplantation as induction. Anti- N -glycolylneuraminic acid carbohydrate antibodies which develop in response to rabbit carbohydrate antigens might lead to unwanted systemic inflammation. LIS1, the first new generation of antilymphocyte globulins (ALGs) derived from double knockout swine, lacking carbohydrate xenoantigens was already tested in nonhuman primates and rodent models. This open-label, single-site, dose escalation, first-in-human, phase 1 study evaluated the safety, T cell depletion, pharmacokinetics, and pharmacodynamics of LIS1. In an ascending dose cohort (n = 5), a primary kidney transplant recipient at low immunologic risk (panel reactive antibody [PRA] < 20%), received LIS1 for 5 d at either 0.6, 1, 3, 6, or 8 mg/kg. After each patient completed treatment, the data safety monitoring board approved respective dose escalation. In the therapeutic dose cohort (n = 5) in patients with PRA <50% without donor specific antibodies, 2 patients received 8 mg/kg and 3 patients 10 mg/kg. CD3 + T cell depletion <100/mm 3 at day 2 was observed in all patients who received 6, 8, and 10 mg/kg of LIS1. The terminal half-life of LIS1 was 33.7 d with linearity in its disposition. Lymphocyte repopulation was fast and pretransplant lymphocyte subpopulation counts recovered within 2-4 wk. LIS1 was well tolerated, neither cytokine release syndrome nor severe thrombocytopenia or leukopenia were noticed. Antibodies to LIS1 were not detected. In this first-in-human trial, genome-edited swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit antidrug antibodies, and caused time-limited T cell depletion in low- and medium-risk kidney transplant recipients.

Clinical profile and laboratory parameters of confirmed pediatric scrub typhus cases in a tertiary health care institute

Background: Scrub typhus is one of the vector borne tropical infectious disease, caused by O. Tsutsugamushi. Because of nonspecific signs and symptoms and variable prevalence of pathognomic sign (eschar), diagnosis is very difficult in early stage. The purpose of present research was to differentiate that whether case presenting at our institution are different from previously conducted research in various regions. Methods: Hospital record of all reported cases of scrub typhus admitted to department of pediatrics at tertiary health care institute in North India over last two years (2018-2019) was retrieved and reviewed. Results: More cases were reported in male. Maximum number of cases were in 5-10 years i.e. 32 (50.0%) and only one case in less than 12 months. Maximum number cases were reported in August to October 53 (82.8%) as shown. Most common presenting complaint was fever. Most of cases reported with fever of duration of 7-14 days in (51.6%). Rash was present in 7 (10.5%) and eschar in 1 (1.5%). In lab parameters reported abnormalities severe hypoalbuminemia, hyperbilirubinemia, elevated transaminases, anemia, thrombocytopenia leucopenia and leucocytosis. Hepatitis in 48 (75%) was most common complication followed by pneumonia. Other reported complications were myocarditis, acute kidney injury, pneumonia, bleeding, meningitis, enchepalopathy , papilledema, ARDS and hemophagocytosis. Conclusions: Pediatrician should keep high index of suspicion for suspect scrub typhus in a child presents with febrile illness and early treat should be started. Hepatitis is most common complication. As Scrub typhus is associated with multisystem involvement, thorough assessment of patient should be done to look for these complications and appropriate management of complications should be provided to prevent mortality.

Prognostication of Large Granular Lymphocytic Leukemia in Clinical Practice: Three New Cases and Literature Review

Large Granular Lymphocytic Leukemia (LGLL) is a rare lymphoproliferative disorder of either CD3+ cytotoxic T-lymphocytes or CD3− natural killer cells with chronic and ill-defined clinical progression. Presentation at diagnosis can include asymptomatic or symptomatic cytopenias, recurrent infections, splenomegaly and rheumatoid arthritis. Multiple cell survival pathways are involved in the pathogenesis of LGLL, and it has been found to be specifically associated with aberrant STAT3 signaling. An increased number of clonal LGL cells in the blood establishes the diagnosis. Treatment regimens historically have included cyclophosphamide, methotrexate, steroids, cyclosporine, and splenectomy, but there are no available targeted therapies or definitive cure available for LGLL. Here we present three cases with varying treatment responses and outcomes that highlight the need for targeted therapy development. All three patients were confirmed to have T-LGLL by flow cytometry analysis. Patient one is a 64 year old female, presented for moderate recurrent symptoms of LGLL, initially diagnosed 17 years prior and treated with 6 months of cyclophosphamide. On the second presentation she was found to have STAT3 missense mutation and was treated for a second time with cyclophosphamide which improved symptoms. She additionally required subcutaneous immunoglobulin for treatment of recurrent infection. Patient two is a 72 year old male, presented for recurrent aphthous ulcers with severe leukopenia and neutropenia, found to have STAT3 negative LGLL. He received multiple courses of cyclophosphamide and was refractory to treatment with persistent symptoms despite improvement in leukopenia. Patient three is a 70 year old male, presented for symptomatic lymphocytosis. He was found on flow cytometry to have LGLL. He improved without further testing or treatment and has remained in remission for several years. These cases show the variation in presentation and response to therapy for patients with T-LGLL. Previous research has demonstrated the heterogeneity of LGLL and has additionally shown that STAT3 mutation was associated with decreased overall survival. This may be as yet simplifying the pathogenesis for targeting as we can still see heterogeneous clinical response even within STAT3 positive patients. One study showed that the size of the mutated clone correlated with degree of clonal expansion and that immunosuppressive therapy may not be able to reduce the clonal burden at high degrees of mutation. Our cases show that STAT3 positive status is not enough to determine prognosis and treatment course. The degree and types of mutation may need to be quantified as well as additional targets identified. While pursuing targeted treatment therapies for LGLL we must also pursue testing to assess disease burden.

Daratumumab for Refractory Autoimmune Leukopenia: A Case Report

Autoimmune leukopenia is a rare disorder but may cause severe life-threatening infections. Here we report a case involving a 58-year-old male with a history of severe autoimmune leukopenia that was highly refractory to therapies targeting T and B linage cells but had a durable response to daratumumab. This case management suggested that targeting plasma cells may be considered for refractory autoimmune leukopenia.