Assessment of the phenotypic severity of hemophilia A: using rotational thromboelastometry (ROTEM) and APTT-clot waveform analysis.

BACKGROUND: Hemophilia A (HA) is an X-linked inherited bleeding disorder caused by reduced factor VIII (FVIII) levels. Approximately 10-15% of patients with severe HA (SHA) do not present with the anticipated bleeding pattern. Here, we assessed the phenotypic severity of hemophilia A using rotational thromboelastometry (ROTEM) and activated partial thromboplastin time-clot waveform analysis (APTT-CWA). METHODS: Patients diagnosed with hemophilia A were enrolled. Clinical phenotype assignment was performed according to the published literature, and patients were classified into four phenotypic subgroups. The whole blood sample was first run on ROTEM in INTEM mode using platelet-poor plasma, APTT was run, and the APTT-CWA graph was simultaneously recorded. RESULTS: A total of 66 patients were recruited for this study. Statistically significant differences were observed between the four phenotypically categorized groups using ROTEM and APTT-CWA. On comparing patients with mild/moderate-to-severe phenotypes (Group II) with SHA without inhibitors (Group IV), no significant difference was found for all parameters of ROTEM or APTT-CWA. The MCF, MA30, MAXV, and Alpha angle values using ROTEM were found to be the lowest in patients with SHA with inhibitors, which helped differentiate them from those with SHA without inhibitors. However, these two groups could not be differentiated using the APTT-CWA parameters. CONCLUSION: ROTEM can be used to distinguish patients with SHA with inhibitors from those with SHA without inhibitors using a combination of parameters with high sensitivity and specificity. However, APTT-CWA cannot be used to differentiate these patient groups.

Unique Challenges Faced by a Child with Standard Risk Leukemia in Post-COVID Era: A Case Report.

Children with malignancies are facing new challenges in post-COVID-19 era. We report an interesting case of a child on treatment for acute lymphoblastic leukemia having a very protracted course of illness with complications not often seen with standard therapy. It intends to make pediatric oncologists and intensive care specialists wary of potential newer complications. How to cite this article: Bhayana S, Kalra M, Sachdeva P, Sachdev A, Sachdeva A. Unique Challenges Faced by a Child with Standard Risk Leukemia in Post-COVID Era: A Case Report. Indian J Crit Care Med 2022;26(6):733-735.

Generic romiplostim for children with persistent or chronic immune thrombocytopenia: Experience from a tertiary care centre in North India.

Thrombopoietin receptor agonists are important therapeutic option in children with immune thrombocytopenia (ITP). We evaluated the response, efficacy, safety of a generic form of romiplostim manufactured in India for treating children with persistent/chronic ITP at our centre. Study of 45 children with persistent/chronic ITP was conducted of which 5 discontinued and 40 were included between 2019-2020. Patients received romiplostim for 20 weeks, at a dose of 5 mcg/kg/week. Platelet count at week 1, 3, 20 and 26 was assessed. Predesigned algorithm was used for dose adjustment. After 20 weeks, patients who had platelet count of 50 × 109/L or above were tapered off medication and monitored till 26 weeks. Median platelet count at enrolment was 11 x 109/L (IQR 23 X 109/L). 13/40 children had received >/= three lines of prior ITP therapy. Platelet response (platelet count rise to more than 50×109/L without rescue medications) observed in 26 (65%) patients at week 20. Rescue medication was used in 12/40 children. Sustained platelet response after tapering and stopping romiplostim observed in 22/40 children. No adverse events were considered serious or led to discontinuation of treatment. Our data demonstrated generic romiplostim is well tolerated and efficacious in children with persistent/chronic ITP.

Diagnosis and Management of Acquired Aplastic Anemia: Consensus Statement of Indian Academy of Pediatrics.

JUSTIFICATION: In India, there is a lack of uniformity of treatment strategies for aplastic anemia (AA), and many children are managed only with supportive care due to non-availability of hematopoietic stem cell transplantation (HSCT). PROCESS: Eminent national faculty members were invited to participate in the process of forming a consensus statement in Hyderabad in July, 2016. Draft guidelines were circulated to all members, and comments received in a online meeting in October, 2020 were incorporated into the final draft. These were approved by all experts. Objective: To facilitate appropriate management of children with acquired aplastic anemia. RECOMMENDATIONS: Key recommendations are: i) A bone marrow biopsy is must to make a diagnosis of AA; ii) Rule out inherited bone marrow failure syndromes (IBMFS), connective tissue disorders, viral infections, paroxysmal nocturnal hemoglobinuria (PNH), drug or heavy metal induced marrow suppression in all cases of AA; iii) Conservative approach to transfusions should be followed, with a target to keep hemoglobin >6 g/dL in children with no co-morbidities; iv) HLA-matched sibling donor HSCT is the preferred choice of treatment for newly diagnosed very severe/ severe AA; v) In absence of HLA-matched family donor, a matched unrelated donor (MUD) transplant or immunosuppressive therapy (IST) should be considered as alternate choice based on physician expertise; vi) Fludarabine, cyclophos-phamide and anti-thymocyte globulin (ATG) based conditioning with cyclosporine and methotrexate as graft versus host disease (GvHD) prophylaxis is the preferred regimen; vii) Horse ATG and cyclosporine are the recommended drugs for IST. One should wait for 3-6 months for the response assessment and consideration of next line therapy.

Pediatric Hemophagocytic Lymphohistiocytosis - A Single Center Study.

OBJECTIVE: To describe the epidemiological features, outcomes and prognostic factors in diagnosis of pediatric hemophagocytic lymphohistiocytosis (HLH). METHODS: 118 children fulfilling the inclusion criteria for HLH were identified from review of hospital records for period January, 2010 to December, 2019. RESULT: Median age at diagnosis was 4 years (range13 days-15 years). Presenting features were fever (100%), hepatosplenomegaly (91%), neurological symptoms (23%), bicytopenia (76%), transaminitis (67.3%), increased soluble interleukin-2 receptor) (sIL-2R) (78%) and hemophagocytosis on bone marrow (75%). Median follow-up duration was 13.5 months (3 days to 102 months). Primary HLH was identified in 27 (23%) patients. Etiology of secondary HLH was infections in 53 (45%), rheumatologic illnesses in 21 (18%) and malignancies in 8 (6%) children. Treatment modalities were steroid only (25%), anti-infectious agent (58%), multi-agent chemotherapy (43%) and HSCT (40%); mortality among above treatment groups were 25%, 58%, 43% and 40%, respectively. 15 patients (13%) had relapsed/refractory HLH who were treated with salvage chemotherapy and hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 39%; mortality within 30 days seen in 23%. Estimated overall survival (OS) and event free survival (EFS) at 3 years were 62% and 61%, respectively. CONCLUSION: Pediatric HLH is an aggressive disease with high mortality. Hyponatremia, hyperbilirubinemia, coagulopathy and increased sIL2 receptor level at diagnosis predicts poor outcome.

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India.

Background: Chronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India. Objective: To describe infection patterns, immunological, and molecular features of CGD from multiple centers in India. Methods: A detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed. Results: Of the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)-CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%), and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up. Conclusions: In India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.

Clinical Profile and Outcome of Childhood Autoimmune Hemolytic Anemia: A Single Center Study.

OBJECTIVE: To analyze clinical and laboratory parameters, and treatment outcomes of children with autoimmune hemolytic anemia (AIHA). METHODS: Retrospective analysis of 50 children aged 0-18 years. Monospecific direct antiglobulin test (DAT) and investigations for secondary causes were performed. Disease status was categorized based on Cerevance criteria. RESULTS: Median (range) age at diagnosis was 36 (1.5-204) months. AIHA was categorized as cold (IgM+,C3+/cold agglutinin+) (35%), warm (IgG+ with/without C3+) (28%), mixed (IgG+, IgM+, C3+) (15%) and paroxysmal cold hemoglobinuria (4%). Primary AIHA accounted for 64% cases. Treatment modalities included steroid (66%), intravenous immunoglobulin (IVIg) (4%), steroid+IVIg (4%), and steroid+rituximab (4%). Treatment duration was longer for secondary AIHA than primary (11 vs 6.6 months, P<0.02) and in patients needing polytherapy than steroids only (13.3 vs 7.5 months, P<0.006). During median (range) follow-up period of 73 (1-150) months, 29 (58%) remained in continuous complete remission, 16 (32%) remained in complete remission. CONCLUSIONS: Infants with AIHA have a more severe presentation. Monospecific DAT and a thorough search for an underlying cause help optimize therapy in most patients of AIHA.

High soluble interleukin-2 receptor values in Indian paediatric & adult controls - Need for population-specific threshold in the diagnosis of haemophagocytic lymphohistiocytosis.

Background & objectives: Elevated soluble interleukin-2 receptor (sIL2R) is a diagnostic criterion for haemophagocytic lymphohistiocytosis (HLH). International guidelines propose a 2400 U/ml cut-off or individual laboratory-defined cut-off. However, sIL2R normal values are so far not known in Indians. So, this study was undertaken to measure sIL2R in healthy children and adults to establish age-related reference values. Methods: Healthy controls and cases (participants with persistent fever, organomegaly, cytopenias and biochemical markers of HLH) were prospectively enrolled. Serum sIL2R was measured by double-sandwich enzyme immunoassay in a standardization batch to determine the optimum cut-off value using receiver operator characteristic curve and was subsequently validated. Results: One hundred and forty six age- and sex-matched children (80 controls and 66 suspected HLH cases) and 55 adults (49 controls and 6 suspected HLH cases) were prospectively enrolled. The optimal sIL2R cut-off ≥23 ng/ml was defined as raised sIL2R in the standardization batch. No controls had sIL2R ≥23 ng/ml in the validation batch. In healthy controls, median sIL2R (interquartile range) decreased with increasing age from 9.0 ng/ml (6.6-13.4) below five years of age to 3.2 ng/ml (2.8-5.1) in adults. Proposed upper limit of normal value for sIL2R is 17.4 ng/ml in less than five year, 12.2 ng/ml in 5-9 yr, 6.7 ng/ml in 10-17 yr and 5.2 ng/ml in ≥18 yr. sIL2R accuracy to diagnose HLH marginally improved with age-appropriate cut-off. Interpretation & conclusions: Paediatric controls in India showed higher sIL2R levels than most studies conducted in other countries, except for some reports in Chinese and Russian populations. Age-appropriate reference values of sIL2R in a specific population may be considered to determine elevated sIL2R as a marker of HLH.

Stuttering Priapism in a Teenage Boy: Lesson to be Learnt.

Untreated priapism can lead to ischemic damage of the penis and impotence. This case report describes a 14-year-old boy who presented with a history of priapism for 2 months, which was undiagnosed, ridiculed, and ignored even by medical practitioners. The underlying etiology was later identified to be chronic myeloid leukemia. Despite the usage of multimodal treatment, it took 7 days for control of priapism. The young boy is now left with an erectile dysfunction. The case highlights that priapism in children is a medical emergency needing aggressive evaluation and treatment.

Primary dengue infection triggered haemophagocytic lymphohistiocytosis in a neonate.

Haemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome which has characteristic symptoms and laboratory findings. Infection is a common trigger of HLH. We report a 2700 g male infant with persistent fever, massive hepatosplenomegaly and severe thrombocytopaenia. Laboratory evidence of primary dengue infection was detected. Investigations revealed hypertriglyceridaemia, hypofibrinogenaemia, hyperferritinaemia and elevated soluble CD25. Bone marrow examination revealed haemophagocytes. The diagnostic criteria for HLH were fulfilled. A diagnosis of secondary HLH triggered by primary dengue infection was considered. Dexamethasone was initiated and continued for 8 weeks. He responded clinically with regression of hepatosplenomegaly, was afebrile and platelet counts normalised. Dengue-associated HLH is often missed clinically as treating physicians focus more on the underlying infection and its treatment. In neonates, HLH should be considered as differential diagnosis of sepsis and other viral infections, particularly in situations of inappropriate response to standard management.

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India.

Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGß2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGß2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.

Consensus Statement of the Indian Academy of Pediatrics on Diagnosis and Management of Fragile X Syndrome in India.

JUSTIFICATION: Fragile X Syndrome (FXS) is the most common genetic cause of inherited intellectual disability and autism spectrum disorder (ASD). Early identification results in appropriate management and improvement in functioning. Risk assessment in other family members can lead to prevention of the disorder. This necessitated the formulation of IAP recommendations for the diagnosis and management of FXS in Indian children and adolescents. PROCESS: The meeting on formulation of national consensus guidelines on Fragile X syndrome was organized by the Indian Academy of Pediatrics in New Delhi on 25th February, 2017. The invited experts included Pediatricians, Developmental Pediatricians, Psychiatrists, Pediatric Neurologists, Gynecologists, Geneticists, Clinical Psychologists and Remedial Educators, and representatives of Parent Organizations. Guidelines were framed after extensive discussions. A writing committee was formed that drafted the manuscript, which was circulated among members for critical appraisal, and finalized. RECOMMENDATIONS: The committee recommended that early diagnosis of FXS is crucial for early, timely and appropriate management. The interventions including timely occupational therapy, speech therapy and behavioral modifications help to improve the developmental potential and reduce the maladaptive behavior. Pharmacotherapy may be needed to control and improve behavioral symptoms. In addition, the emergence of targeted treatments such as low dose sertraline, metformin and /or minocycline may also be helpful for behavior, and perhaps cognition. Genetic counselling is helpful to communicate the risk for future children with FXS or permutation involvement.

Consensus Statement of the Indian Academy of Pediatrics in Diagnosis and Management of Hemophilia.

JUSTIFICATION: Despite having standard principles of management of hemophilia, treatment differs in various countries depending on available resources. Guideline for management of hemophilia in Indian setting is essential. PROCESS: Indian Academy of Pediatrics conducted a consultative meeting on Hemophilia on 18th September, 2016 in New Delhi, which was attended by experts in the field working across India. Scientific literature was reviewed, and guidelines were drafted. All expert committee members reviewed the final manuscript. OBJECTIVE: To bring out consensus guidelines in diagnosis and management of Hemophilia in India. RECOMMENDATIONS: Specific factor assays confirm diagnosis and classify hemophilia according to residual factor activity (mild 5-40%, moderate 1-5%, severe <1%). Genetic testing helps in identifying carriers, and providing genetic counseling and prenatal diagnosis. Patients with hemophilia should be managed by multi-specialty team approach. Continuous primary prophylaxis (at least low-dose regimen of 10-20 IU/kg twice or thrice per week) is recommended in severe hemophilia with dose tailored as per response. Factor replacement remains the mainstay of treating acute bleeds (dose and duration depends on body weight, site and severity of bleed). Factor concentrates (plasma derived or recombinant), if available, are preferred over blood components. Other supportive measures (rest, ice, compression, and elevation) should be instantly initiated. Long-term complications include musculoskeletal problems, development of inhibitors and transfusion-transmitted infections, which need monitoring. Adequate vaccination of children with hemophilia (with precautions) is emphasized.

Umbilical Cord Blood Banking: Consensus Statement of the Indian Academy of Pediatrics.

JUSTIFICATION: Practitioners and people need information about the therapeutic potential of umbilical cord blood stem cells and pros and cons of storing cord blood in public versus private banks. PROCESS: Indian Academy of Pediatrics conducted a consultative meeting on umbilical cord blood banking on 25th June 2016 in Pune, attended by experts in the field of hematopoietic stem cell transplantation working across India. Review of scientific literature was also performed. All expert committee members reviewed the final manuscript. OBJECTIVE: To bring out consensus guidelines for umbilical cord banking in India. RECOMMENDATIONS: Umbilical cord blood stem cell transplantation has been used to cure many malignant disorders, hematological conditions, immune deficiency disorders and inherited metabolic disorders, even when it's partially HLA mismatched. Collection procedure is safe for mother and baby in an otherwise uncomplicated delivery. Public cord blood banking should be promoted over private banking. Private cord blood banking is highly recommended when an existing family member (sibling or biological parent) is suffering from diseases approved to be cured by allogenic stem cell transplantation. Otherwise, private cord blood banking is not a 'biological insurance', and should be discouraged. At present, autologous cord stem cells cannot be used for treating diseases of genetic origin, metabolic disorders and hematological cancers. Advertisements for private banking are often misleading. Legislative measures are required to regularize the marketing strategies of cord blood banking.

Diagnosis and Management of Gaucher Disease in India - Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics.

JUSTIFICATION: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients. PROCESS: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics. OBJECTIVES: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population. RECOMMENDATIONS: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid b-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encountered in our population.