IVIG Treatment Research Articles

Intravenous immunoglobulin therapy: usage patterns and response to treatment in Qatar over ten years

BackgroundIVIg is a blood-derived antibody product initially designed as a replacement therapy in inborn errors of immunity (IEIs). However, over the last 50 years, IVIg has been used to treat a growing range of autoimmune, autoinflammatory, and secondary immunodeficiency disorders. The US FDA has licensed IVIg for use in the treatment of nine clinical indications; although, IVIg global usage extends to off-label indications with variable treatment responses. Data from Qatar on the use of IVIg is scarce; thus, hampering the formulation of local policies. This study aimed to examine the utilization patterns, clinical indications, and safety profile of IVIg usage in Qatar; a nation with a predominantly young population, and to investigate the response rates to short- and long-term IVIg treatment, as well as explore associations between age at first IVIg dose, clinical indication, and treatment response.MethodsA retrospective chart review was conducted of patients who received IVIg between March 2009, and March 2019, in Hamad General Hospital, Qatar. Demographics, immediate adverse effects of IVIg, and treatment response were collected. IVIg clinical indications were categorized into FDA- and/or EMA-approved, those supported by international guidelines; those approved as second-line therapy, and those with low or no supportive evidence.ResultsIVIg was used for 63 indications during the 10-years. The age of patients skewed towards a younger demographic (median (IQR) 24 (44-6) years); however, no significant differences in response to short- and long-term treatment between age groups were observed. Of the 841 patients, 62% received IVIg in concordance with international recommendations, while 14% bestowed the treatment for indications with low or no supportive evidence. Immediate IVIg adverse effects were documented in 4% of patients in all of the infusions received, with headaches being the most prevalent (1.8%). Variable treatment responses were observed, with the highest recovery reported in immune thrombocytopenic purpura (35%), followed by transverse myelitis (28%).ConclusionThis study provided crucial insights into IVIg utilization, safety, and treatment outcomes in Qatar’s young population. Despite variability in treatment responses and off-label use, adherence to international recommendations remained eminent. Further research is warranted to inform local guidelines and optimize IVIg therapy outcomes.

Severity of Acute Kawasaki Disease Can Be Predicted by Evaluating the Body Temperature at the Completion of an Initial Immunoglobulin Treatment.

Objective: We aimed to determine whether the severity of acute Kawasaki disease (KD) can be predicted based on whether a patient remains febrile or becomes afebrile immediately after the completion of initial immunoglobulin treatment (IVIG). Methods: This retrospective cohort study at a single institution involved 306 patients with KD. They were categorized into four groups according to their fever status at two specific time points (end of the initial IVIG treatment and 24-36 h later): Group F-F, patients who remained febrile at both time points; Group F-AF, patients who were febrile at the end of the initial IVIG treatment but became afebrile 24-36 h later; Group AF-F, patients who were afebrile at the end of the initial IVIG treatment but became febrile 24-36 h later; and Group AF-AF, patients who remained afebrile at both time points. The clinical characteristics of the groups were compared. Results: Group F-F (n = 38) showed a significantly higher incidence of CAAs compared to Group AF-F (n = 37), 55.3% vs. 0.0% (p < 0.0001), although both groups were classified as resistant to the initial IVIG. Conclusions: In Japanese patients with acute KD, the presence or absence of fever at the completion of initial IVIG treatment may serve as an early predictor of the occurrence of CAAs. An earlier secondary treatment may be warranted for patients who are in a febrile state immediately after the completion of the initial IVIG treatment. Future research should include a prospective cohort study with a larger number of KD cases across multiple institutions to analyze the effects of other contributing factors related to CAL formation.

Abstract 4136984: Low Occurence of Fetal Extranodal Findings and AV Interval Prolongation in Prospectively Followed High Titer Anti-Ro Pregnancies

. Background: Third-degree atrioventricular block (AVB) is the most common manifestation of Anti-Ro antibody associated fetal cardiac disease. Extranodal findings of isolated cardiac echogenicity, valvulitis with insufficiency and AV interval prolongation have been reported but not described in large prospective series. Aims: To report the occurrence and outcomes of extranodal findings in subjects followed prospectively since 2020 in STOP BLOQ (Surveillance and Treatment to Prevent Fetal AV block Likely to Occur Quickly) and the Registry for Neonatal Lupus (RNL). Methods: We reviewed fetal echo reports from pregnant STOP BLOQ and RNL Anti-Ro antibody subjects. Pregnancies with high (&gt;1000 EU for anti-Ro52 or 60) antibody titers measured in a core research lab underwent surveillance with home fetal heart rate monitoring (FHRM) 3x/day and weekly or bi-weekly fetal echos from 17- 26 gestational weeks. Low titer subjects underwent echo or no surveillance based on local site protocol. We evaluated cardiac function, effusions, cardiac echogenicity and its location, any tricuspid (TV) or mitral (MV) insufficiency trivial or &gt;trivial) and AV conduction times (&lt;150, 150-170 or &gt;170 ms) Results: Echo reports were available in 622 prospectively followed pregnancies (376 high (40/376 with a previously affected child) and 246 low-titer pregnancies. All had subjectively normal ventricular function and none had effusions. Seven fetuses, 2 low and 5 high titer at 19 (range 16.7-21.7) weeks demonstrated cardiac echogenicity (n=6), AV or semilunar valve insufficiency (n=2) or AV interval 150-170 ms (n=2) (Table). Subjects 1 and 2, both high titer and treated with prophylactic Plaquenil (400 mg/d before 10 gestational weeks), had prior fetal AVB. Subject #1 had normal AV conduction but MV and TV echogenicity and moderate insufficiency of both valves which resolved in days after IVIG and dexamethasone (dex) treatment, but 3° AVB developed at 19 weeks after dex wean. Subjects 2-7 received no treatment and extranodal findings did not progress to cardiac dysfunction or AVB. During the same time period, 10 high titer subjects developed 2° or 3° AVB. Conclusion: Anti-Ro associated extranodal findings are rare, occurring in 1% of pregnancies overall and in 5% of pregnancies with a previously affected child. Unlike AVB, extranodal findings can occur in low titer pregnancies. The role of treatment for isolated extranodal findings in the absence of cardiac dysfunction is unclear.

Identifying Hemolytic Disease of the Fetus and Newborn within a Large Integrated Health Care System.

This study aims to identify hemolytic disease of the fetus and newborn (HDFN) pregnancies using electronic health records (EHRs) from a large integrated health care system. A retrospective cohort study was performed among pregnant patients receiving obstetrical care at Kaiser Permanente Southern California health care system between January 1, 2008, and June 30, 2022. Using structured (diagnostic/procedural codes, medication, and laboratory records) and unstructured (clinical notes analyzed via natural language processing) data abstracted from EHRs, we extracted HDFN-specific "indicators" (maternal positive antibody test and abnormal antibody titer, maternal/infant HDFN diagnosis and blood transfusion, hydrops fetalis, infant intravenous immunoglobulin [IVIG] treatment, jaundice/phototherapy, and first administrated Rho[D] Immune Globulin) to identify potential HDFN pregnancies. Chart reviews and adjudication were then performed on select combinations of indicators for case ascertainment. HDFN due to ABO alloimmunization alone was excluded. The HDFN frequency and proportion of each combination were fully analyzed. Among the 464,711 eligible pregnancies, a total of 136 pregnancies were confirmed as HDFN pregnancies. The percentage of the HDFN-specific indicators ranged from 0.02% (infant IVIG treatment) to 34.53% (infant jaundice/phototherapy) among the eligible pregnancies, and 32.35% (infant IVIG treatment) to 100% (maternal positive antibody test) among the 136 confirmed HDFN pregnancies. Four combination groups of four indicators, four combination groups of five indicators, and the unique combination of six indicators showed 100% of HDFN pregnancies, while 80.88% of confirmed HDFN pregnancies had the indicator combination of maternal positive antibody test, maternal/infant HDFN diagnosis, and infant jaundice/phototherapy. We successfully identified HDFN pregnancies by leveraging a combination of medical indicators extracted from structured and unstructured data that may be used in future pharmacoepidemiologic studies. Traditional indicators (positive antibody test results, high titers, and clinical diagnosis codes) alone did not accurately identify HDFN pregnancies, highlighting an unmet need for improved practices in HDFN coding. · A case ascertainment method was developed to identify HDFN from structured and unstructured data.. · The method used in this study may be used in future pharmacoepidemiologic studies.. · The study highlighted an unmet need for improved practices in HDFN coding..

Isolated peripheral neuroleukemiosis mimicking Guillain‐Barré syndrome in an adolescent with relapsed B‐lymphoblastic leukemia

AbstractBackgroundNeuroleukemiosis, leukemic infiltration of the peripheral nervous system (PNS), is rare. Very few cases of isolated neuroleukemiosis, PNS leukemic infiltration without leukemia blasts in the blood or bone marrow, have been reported in pediatrics. Most cases have occurred in adults with acute myelogenous leukemia (AML) in remission who presented with peripheral neuropathy. We describe a pediatric patient presenting with isolated neuroleukemiosis mimicking Guillain‐Barré syndrome.Patient descriptionA 15‐year‐old boy presented 1 month after IVIG treatment for Guillain‐Barre syndrome with worsening ataxia and weakness. He had a past medical history of B‐cell acute lymphoblastic leukemia (B‐ALL) in remission for 8 years. Examination revealed distal greater than proximal weakness of the bilateral lower extremities, areflexia at the Achilles tendon, and 1+ patellar and upper extremity reflexes. Initial magnetic resonance imaging (MRI) of the brain and spine were normal, and lumbar puncture revealed increased protein with uninterpretable white count due to excessive red blood cells. Repeat MRI brain and spinal cord showed extensive enlargement of all nerve roots and enhancement of the cauda equina and portions of cranial nerve VII bilaterally. Repeat lumbar puncture with cytology revealed leukemic blast cells. Blasts were not detected in peripheral blood smear or by flow cytometry. Bone marrow biopsy was also free of blast cells, confirming the diagnosis of relapsed B‐ALL restricted to the nervous system.ConclusionsNeuroleukemiosis is a rare entity with typical clinical features of mono‐ or polyneuropathy. It most often occurs in adults in remission from AML. However, neuroleukemiosis should also be on the differential for pediatric patients in remission from ALL presenting with neuropathy.

Role of leukocyte-associated Ig-like receptor-1 in the pathogenesis of Kawasaki disease and coronary artery aneurysms

ObjectiveTo elucidate the relationship between leukocyte-associated Ig-like receptor-1 (LAIR-1) and the pathogenesis of Kawasaki disease (KD) and coronary artery aneurysms(CAA). MethodsThe study cohort comprises children who were diagnosed with KD and were categorized into two groups: KD patients with CAA (KD-CAA) and KD without CAA (KD-NCAA), with healthy children serving as control group (HC). LAIR-1 on leukocytes was examined via flow cytometry, while serum LAIR-1 (sLAIR-1) was quantified using ELISA. IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-α, IFN-γ and TNF-α were examined by Immunofluorescence assay. ResultssLAIR-1 levels were elevated in the KD and KD-CAA groups compared with those in the HC and KD-NCAA groups (P < 0.05). sLAIR-1 exhibited an area under the curve value of 0.858 for predicting KD (P < 0.001) and 0.628 for predicting CAA (P = 0.055, borderline significance). LAIR-1 was increased on the neutrophils in KD group, whereas it was lower in KD-CAA than that in KD-NCAA, and decreased in KD after IVIG treatment. In contrast, LAIR-1 was reduced on CD4+ and CD8+ T lymphocyte in KD group, and increased in KD after IVIG treatment (all P < 0.05). LAIR-1 on neutrophils showed a positive correlation with IL-5, while on CD4+ T cells, it was negatively correlated with IL-2, IL-6, IL-10, IFN-γ, and IL-8. On CD8+ T cells, LAIR-1 was negatively correlated with IL-2 and IFN-γ. ConclusionsLAIR-1 may serve as a potential biomarker for KD and CAAs, while LAIR-1 might be implicated in KD pathogenesis and CAA.

Combination of low-dose, long-term immunoglobulin and mirtazapine is effective in progressive multifocal leukoencephalopathy caused by JC virus infection

BackgroundProgressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There’s still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case.Case presentationA patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly.ConclusionsWe demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML.

Paternal HLA-Derived Epitopes and Live Birth in SecondaryRecurrent Pregnancy Loss: New Insights FromaClinical Trial.

Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses before the 24th week of gestation, affects 1%-3% of women worldwide. Approximately, 40% of RPL cases are secondary RPL (sRPL), where women have given birth before facing pregnancy losses. The underlying causes of RPL remain unclear, but immune-related factors may play a role. Previously, a randomised controlled trial using immunoglobulin (IVIG) in sRPL women with a history of four pregnancy losses performed in our RPL unit did not show significant effects of IVIG treatment overall. Yet, some evidence suggests potential benefits for a subset of sRPL patients. In the cohort used for the randomised controlled trial, we examined the role of maternal HLA class II-presented fetal HLA-derived epitopes in sRPL using the predicted indirectly recognisable HLA epitopes (PIRCHE-II) algorithm. In the placebo group, sRPL mothers with an anti-HLA antibody response had higher PIRCHE-II scores when having a live birth compared with sRPL women who experienced another pregnancy loss. This difference was not observed in the IVIG-treated group. Furthermore, as a proxy for T-cell memory, the number of overlapping peptides between the two paternal haplotypes in couples having live births without treatment displayed a larger number of overlapping peptides. This effect was primarily driven by class II-derived peptides. These results suggest that specific combinations of sRPL mothers and fathers, particularly those with an anti-HLA antibody response, may generate higher PIRCHE-II scores, which could contribute to successful live births. Understanding these immune interactions may provide insights for personalised diagnostic and therapeutic strategies in sRPL.

Health Care Utilisation in a Cohort of Patients with Primary and Secondary Antibody Deficiency in the United Kingdom

IntroductionThis study investigates the frequency of hospital attendances, emergency care attendances and geographical influences on service interaction in cohorts of patients with primary and secondary antibody deficiency, to inform future service planning and delivery.MethodsThe COVID-19 in Antibody Deficiency (COV-AD) study was a United Kingdom study that enrolled 525 participants between April 2021 and September 2022. Data on health care utilisation was extracted from a screening cohort of participants at one participating site (Birmingham, UK). Hospital attendance (i.e. all outpatient and inpatient care episodes, including hospital-based IVIG treatment) and emergency care attendance patterns were analysed. Geographical differences in travel times to hospitals and associated costs were considered for all participants at all recruiting sites.ResultsIndividuals with antibody deficiency had a median of 7 hospital attendances per year. A diagnosis of secondary antibody deficiency, and antibody deficiency severe enough to require treatment with immunoglobulin replacement were associated with an increased frequency of hospital attendance. 12.7% of the cohort attended the Emergency Department at least once in the preceding twelve months. Individuals with secondary antibody deficiency were at greater risk of requiring emergency care over the preceding one-year and five-year periods. Individuals receiving subcutaneous immunoglobulin lived further from their local immunology centre and were more likely to engage with the COV-AD research study remotely, via dried blood spots sampling.ConclusionThis study highlights the utilisation of emergency and secondary care usage amongst patient with immunodeficiency and may inform service adaptation and development to better accommodate patient needs and circumstances.

Rational use of immunoglobulins (IVIgs and SCIgs) in secondary antibody deficiencies.

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

Serological indication of chronic inflammatory demyelinating polyneuropathy as an extrahepatic manifestation of hepatitis E virus infection

Guillain–Barré syndrome and neuralgic amyotrophy have been associated with hepatitis E virus (HEV) genotype 3 infections, while myasthenia gravis (MG) has been associated with HEV genotype 4 infections. However, whether chronic inflammatory demyelinating polyneuropathy (CIDP) is associated with HEV infections has not been conclusively clarified yet. 102 CIDP patients, 102 age- and sex-matched blood donors, 61 peripheral neuropathy patients (non-CIDP patients), and 26 MG patients were tested for HEV and anti-HEV IgM and IgG. Sixty-five of the 102 (64%) CIDP patients tested positive for anti-HEV IgG and one (1%) for anti-HEV IgM. No other patient tested positive for ati-HEV IgM. In the subgroup of CIDP patients with initial diagnosis (without previous IVIG treatment), 30/54 (56%) tested positive for anti-HEV IgG. Anti-HEV rates were significantly lower in blood donors (28%), non-CIDP peripheral neuropathy patients (20%), and MG patients (12%). No subject tested positive for HEV viremia. CSF tested negative for in 61 CIDP patients (54 patients with primary diagnosis). The development of CIDP but not non-CIDP polyneuropathy may be triggered by HEV exposure in an HEV genotype 3 endemic region. The increased anti-HEV seroprevalence in CIDP patients is not a consequence of IVIG therapy.

Review of adjuvant Intravenous immunoglobulins in patients with refractory pyoderma gangrenosum: a single-centre experience.

This retrospective review assessed adjuvant intravenous immunoglobulin (IVIG) treatment in six patients with refractory pyoderma gangrenosum (PG). All patients reported decreased ulcer size or depth, with one achieving complete healing. Most had a reduction in pain, and an increase in pain coincided with disease flares. IVIG was well tolerated, although two patients required hospitalization for infection management. Results suggest that IVIG is a safe and effective option for refractory PG, with pain reduction potentially serving as a marker for treatment response, although recurrence remains a concern.

IVIg Treatment Ameliorates Inflammation in Patients with Sleep-related Electrical Status Epilepticus (ESES) (P5-14.003)

IVIg Treatment Ameliorates Inflammation in Patients with Sleep-related Electrical Status Epilepticus (ESES) (P5-14.003)

Impact of aspirin dosage on prognosis and coronary artery complications in pediatric Kawasaki disease patients

Kawasaki disease is a common systemic vasculitis in children, and early treatment is critical to prevent coronary artery complications. This study aimed to evaluate the impact of different aspirin dosages on the prognosis of Kawasaki disease. A total of 161 children diagnosed with Kawasaki disease were enrolled and divided into four groups based on the dosage of aspirin: 30–34 mg/kg, 35–39 mg/kg, 40–44 mg/kg, and 45–49 mg/kg. Demographic characteristics, pre-treatment laboratory indicators, post-treatment laboratory indicators, the incidence of coronary artery complications, and the rate of IVIG resistance were compared across the groups. No significant differences were found in baseline characteristics such as age, gender, weight, IVIG treatment choice, IVIG treatment duration, or the proportion of patients diagnosed before the age of 1 year. Laboratory indicators before and after treatment were also similar between groups. However, at 3-4 weeks after the onset of illness, the incidence of coronary artery complications was significantly higher in the high-dose aspirin groups compared to the low-dose aspirin group. Additionally, the high-dose aspirin group had a longer duration of fever and a higher proportion of recurrent fever compared to the low-dose group. The results suggest that although aspirin dosage did not appear to have a clear impact on the overall prognosis of Kawasaki disease, high-dose aspirin administered in the 3-4 weeks following disease onset may increase the risk of coronary artery complications and is associated with a higher incidence of recurrent fever. Caution is therefore advised in selecting aspirin dosages to minimize unnecessary risks.

1092 Postponing early intrauterine transfusion with IVIG treatment in severe hemolytic disease: Individual patient data meta-analysis

1092 Postponing early intrauterine transfusion with IVIG treatment in severe hemolytic disease: Individual patient data meta-analysis

Cutaneous Crohn Disease Presenting as "Knife-Edged" Ulcers: A Case Report

Background. CCD presents as non-caseating granulomas within the skin at a site distant from the GI tract. CCD is a debilitating extraintestinal sequela of CD that can sometimes precede its GI manifestations. In the absence of GI symptoms, the histopathologic and clinical features of CCD can present as a variety of inflammatory skin conditions that can range from ruptured follicle-associated granulomas to cutaneous ulcerations. While a variety of therapeutic options for patients with CCD and concurrent luminal CD have been described in the literature, there is no standard treatment algorithm for the management of refractory CCD with limited or covert GI involvement. Case Report. The authors discuss the case of a 33-year-old female who presented to the wound care clinic with multiple "knife-edged" cutaneous ulcerations involving the intertriginous spaces, found to be consistent with CCD. Her original cutaneous symptoms and diagnosis manifested with minimal GI involvement and responded to IVIG treatment. Conclusions. This case supports the inclusion of CCD in the differential diagnosis in patients with knife-edged granulomatous skin lesions in intertriginous locations. This clinical condition may present in the setting of no or limited GI symptoms. The management of CCD and a proposed treatment algorithm are also presented.

CD14 down-modulation as a real-time biomarker in Kawasaki disease.

The objectives of this study were to investigate the pathophysiology of Kawasaki disease (KD) from immunological and oxidative stress perspectives, and to identify real-time biomarkers linked to innate immunity and oxidative stress in KD. We prospectively enrolled 85 patients with KD and 135 patients with diverse conditions including immune, infectious and non-infectious diseases for this investigation. Flow cytometry was used to analyse the surface expression of CD14, CD38 and CD62L on monocytes, along with a quantitative assessment of CD14down-modulation. Additionally, oxidative stress levels wereevaluated using derivatives of reactive oxygen metabolites (d-ROMs) and antioxidant capacity measured by a free radical elective evaluator system. During the acute phase of KD, we observed a prominent CD14 down-modulation on monocytes, reflecting the indirect detection of circulating innate immune molecular patterns. Moreover, patients with KD showed a significantly higher CD14 down-modulation compared with infectious and non-infectious disease controls. Notably, the surface expression of CD14 on monocytes was restored concurrently withresponses to intravenous immunoglobulin and infliximab treatment in KD. Furthermore, d-ROM levels in patients with KD were significantly elevated compared with patients with infectiousand non-infectious diseases. Following intravenous immunoglobulin treatment, oxidative stress levels decreased in patients with KD. Monitoring CD14 down-modulation on monocytes in real-time is a valuable strategy for assessing treatment response, distinguishing KD relapse from concomitant infections and selecting second-line therapy after IVIG treatment in KD patients. The interplay between inflammation and oxidative stress likely plays a crucial role in the development of KD.

Presentation and Outcome of Children with Kawasaki Disease: Experience in A Tertiary Care Hospital in Bangladesh

Background: Kawasaki disease (KD) is an acute difficult-to-diagnose febrile illness in children caused by self limiting vasculitis in medium and small sized arteries.&#x0D; Objetive: This study has been conducted to analyze its presenting symptoms, clinical course, laboratory findings, and therapeutic options in a tertiary hospital in Bangladesh to aid early diagnosis and optimum management.&#x0D; Methods: This is a retrospective study where the medical records of 31 children admitted and diagnosed with Kawasaki Disease (KD) in Evercare Hospital Dhaka between 2009 and 2020, were assessed. Through a structured form, the demographic information, clinical profile, laboratory results, and echocardiographic data were obtained from the hospital records and then entered into a Microsoft Excel sheet. Cleaned and verified data were transferred to SPSS program version 23 and analyzed to obtain descriptive statistics.&#x0D; Results: Out of total 31 patients with KD enrolled, 64.5% of the patients were between six months to five years of age with a median age of three years; 97% had an age below 6 months. Though 68% of patients met all the required criteria for KD, one-third (32%) were diagnosed as incomplete KD with fewer manifestations. Along with high fever in all cases, the most common clinical features were polymorphous rash (90%) and changes in extremities (90%) followed by changes in the lips and oral cavity (77.4%), cervical lymphadenopathy (68%) and conjunctival injection (61%). Common laboratory abnormalities found were anemia (90%), leukocytosis (65%), thrombocytosis especially in the second week (78%), high ESR (100%), and elevated CRP (84%). About 42% of patients had cardiac abnormalities at the onset. Seven children (63.6%) had coronary artery aneurysms (CAA) whereas 18% had coronary dilatations. In subsequent followups, coronary artery changes remained almost the same up to 6-8 weeks. After 3-6 months, 87.5 % of children recovered from cardiac abnormality.&#x0D; Conclusion: A high index of suspicion for KD and an active search for compatible findings in children with unexplained fever can help in early diagnosis. Timely initiation of IVIG treatment is needed to reduce the risk of cardiac complications. Young infants under six months of age need further careful early suspicion and evaluation because of their incomplete presentation and more vulnerability to developing cardiac complications.&#x0D; DS (Child) H J 2022; 38(2): 70-78

OP95 A Systematic Review Of The Cost And Cost Effectiveness Of Immunoglobulin Treatment In Patients With Hematological Malignancies

IntroductionPatients with hematological malignancies are likely to develop hypogammaglobulinemia (HGG) and subsequent infections. Immunoglobulin (Ig) replacement is commonly given to prevent infections, but the total costs and cost effectiveness of its use are unknown.MethodsA systematic review was conducted following PRISMA guidelines to assess evidence on the costs and cost effectiveness of Ig replacement, administered intravenously (IVIg) or subcutaneously (SCIg), in adult patients with hematological malignancies. This review was registered with PROSPERO (CRD42022321908).ResultsSix studies were included out of a total of 3,612 citations. A narrative synthesis was conducted because of the high level of heterogeneity across the included studies. Two economic evaluations were identified: one cost-utility analysis (CUA) of IVIg versus no Ig and one comparing IVIg with SCIg. The quality of the evidence was low, with most studies having small patient numbers and a high risk of bias. Compared with no treatment, Ig replacement reduced the hospitalization rate in patients with hematological malignancies.One study reported no change in hospitalization rates following a program to reduce IVIg use, and an observational study comparing IVIg with SCIg found more hospitalizations with SCIg but lower total costs per patient. The CUA comparing IVIg with no IVIg suggested that IVIg treatment was not cost effective, but this study was published in 1991 and had significant limitations. The other CUA found that home-based SCIg was more cost effective than IVIg, but model inputs were derived from unpublished data in a very small patient cohort with HGG and different malignancies.ConclusionsOur review highlights key gaps in the literature. The cost effectiveness of Ig replacement in patients with hematological malignancies is still very uncertain. Despite the increasing use of Ig replacement there are limited data regarding its direct and indirect costs, and its optimal use and implications for healthcare resources remain unclear. Given the paucity of data on the cost and cost effectiveness of Ig treatment in this population, further health economic research is warranted.

ITGB1-Expressing Effector Memory CD4 + T-Cell Response Associates with Clinical Recovery in Childhood Immune Thrombocytopenia

Background: The autoimmune bleeding disorder childhood immune thrombocytopenia (ITP) features antibody and T-cell immune responses against platelet self-antigens. This involves activation of B-cells, CD4 + T-cell help, and CD8 + T-cells. Novel prognostic biomarkers are needed to predict recovery and treatment responses. Compared to healthy children, changes in total lymphocytes, CD4 +, regulatory CD4 +, CD8 +T-cells, CD19 + B-cells, and NK cells were described in childhood ITP. Children with transient ITP were also found to have a fewer CD25 hi CD4 + T-cells than those who develop chronic ITP. In contrast, the platelet-stimulated peripheral blood mononuclear cells (PBMC) of children with chronic ITP produced more IL-2 than those of transient ITP. At present, none of these biomarkers have been validated for ITP prognosis, and consequently they are not in clinical use. This emphasizes the need for clinical-grade biomarkers to predict clinical responses in childhood ITP. Aims: To predict spontaneous recovery and IVIg response in newly diagnosed ITP by (1) validating previously suggested changes in immune cell frequencies, and (2) identifying novel immune cell subsets as predictors. Methods: Children with newly diagnosed ITP were randomized 1:1 to observation or IVIg treatment (TIKI trial). Recovery was determined by platelet counts according to IWG criteria 1, 4, 13, 26 and 52 weeks after the diagnosis. For validation, the CD4 +, regulatory CD4 + (CD25 +/CD127 lo), CD8 +, CD19 +, and NK cells were quantified at the time of diagnosis in a centralized laboratory by flow cytometry. For identification of novel predictors, CD4 + central (CD45RO + CD27 +) and effector memory (CD45RO + CD27 -) frequencies were determined. The primary clinical outcome was longitudinal recovery, either spontaneous or after IVIg (adjusted Cox-proportional hazard model). Secondary outcomes included the mean age-adjusted difference between transient/persistent and chronic ITP by multivariate regression, and comparison to age-appropriate healthy control data. Additionally, PBMC (N=6) were analyzed at diagnosis by single-cell RNA sequencing (scRNA-seq) combined with T- and B- cell receptor sequencing (scTCR-seq and scBCR-seq). Results: For validation of previously suggested predictors, the absolute CD3 +, CD4 +, CD8 +, CD19 +, and NK cell counts of newly diagnosed ITP patients were within the age-appropriate healthy reference range (N=158); they were not associated with recovery, and there were no age-adjusted differences between transient/persistent (N=139) and chronic ITP (N=19). The regulatory CD4 + T cell frequency was not reduced compared to age-appropriate reference data; not associated with recovery, and not different between transient/persistent and chronic ITP patients. For identification of novel predictors, we found that high CD4 +effector memory cells numbers were associated with a reduced recovery rate, with an adjusted hazard ratio for complete recovery over a one-year follow-up to be 0.55 (95% CI, 0.35 - 0.85; ≥ median; adjusted for age and treatment; N=150). Chronic ITP patients displayed a mean age-adjusted increase in effector memory CD4 +cells of 1.4 % (95% CI, 0.4 - 2.4; P= 0.005). The association with recovery was independent of a preceding infection, total leukocyte and lymphocyte counts, and the presence of anti-platelet IgG or IgM autoantibodies. ScRNA-seq analysis of 7965 PBMC also showed an effector memory CD4 + T-cell cluster that was expanded in chronic ITP, present in at a frequency of 8.1 ± 1.4 % (mean ± sem) in transient vs 14.8 ± 1.2 % in chronic ITP. This cluster also expressed high levels of fibronectin receptor integrin b1 ( ITGB1) interleukin 32 (IL32) interleukin 7 receptor (IL7R) andlymphotoxin beta (LTB). The effector memory phenotype of CD4 + ITGB1 + T-cells was confirmed by flow cytometry analysis in healthy individuals and ITP patients. Conclusions: Previously suggested changes in T-, B-, or NK cell frequencies could not be validated as predictors of spontaneous recovery or IVIg response. However, we identified the frequency of ITGB1-expressing effector memory CD4 + T cells as an independent predictor of spontaneous recovery and IVIg response. Thus, T cell phenotyping at the time of diagnosis may be suitable to determine prognosis and personalize treatment decisions in newly diagnosed childhood ITP.