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We present a non-vaccinated 2 years and 3 months old female patient with anti-convulsive therapy for Bourneville tuberous sclerosis (TSC) who was hospitalized for fever, polypnea, paroxysmal coughing episodes and post-tussive vomiting, respiratory failure and convulsive status. Basic paraclinical investigations revealed bilateral paramediohilar interstitio-alveolar infiltration, normal liver and renal parameters, elevated CRP and procalcitonin, but the presence of very high white blood cell count with lymphocytosis raised suspicion of leukemia. It was excluded by bone marrow aspirate examination and the diagnosis of convulsive cough was confirmed based on the clinical and laboratory parameters. Molecular genetic test confirmed the diagnosis of tuberous sclerosis type 2. Taking in account that the child had partially controlled seizures and cerebral, cardiac and renal characteristic lesions, this case raised a lot of questions regarding the infectious contact and the possibility of other potentially severe infectious diseases prevention by vaccination. A hope in this case is the new approved in children drug everolimus. In conclusion, pneumonia, a common disease in pediatric age, can raise many diagnostic and therapeutic problems mainly in patients with chronic pathology, requiring multidisciplinary collaboration for successful management of the case. [ABSTRACT FROM AUTHOR]

Summary. Plasma-derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine ® is a high purity double-virus inactivated human plasma-derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open-label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long-term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on-demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half-life. Mean terminal elimination half-life was 27.6 h and 25.0 h, mean incremental recovery (IU dL−1/IU kg−1) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long-term prophylaxis, TOD and when applied after minor and major surgeries. [ABSTRACT FROM AUTHOR]

A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is indispensable. The article presents an eight-year-old girl, with a family history of haemophilia, without significant disease signs (only post-dental extraction bleeding and a shorter stature). Discordantly, however, the investigations revealed a challenging condition: a genotype of 46,X,i(Xq), with an Isochromosome Xq responsible for the Turner syndrome and simultaneously, for the detrimental transformation, interfering with X chromosome inactivation, of an obligate hemophilia carrier into a severe hemophilia case-two distinct and provocative diseases.

(1) Background: Mild and moderate hemophilia, synonymous with non-severe hemophilia (NSH), are of constant interest for the clinicians. Bleeding occurs usually after trauma, injury, surgery, or inhibitor development, sometimes leading to a shift of the clinical phenotype from mild to severe, even with life-threatening and unexpected outcomes. (2) Methods: We performed a retrospective observational study conducted on 112 persons with congenital coagulopathies, 26 of them with NSH, admitted to our clinic in the period 2000 to 2022. For the diagnosis, we used laboratory studies (complete blood cell count, coagulation assays, biochemistry, thromboelastography, genetic tests) and imaging investigations (X-ray, ultrasound, CT, MRI). We selected four cases confronted with pitfalls of diagnosis and evolution in order to illustrate the sometimes provocative field of NSH. (3) Results: Confronted with challenging cases with under-, missed or delayed diagnosis and severe consequences, we aimed at presenting four such selected cases with mild or moderate hemophilia, real pitfalls in our clinical activity. (4) Conclusions: In the field of NSH, if not timely recognized, tending sometimes to remain ignored by caregivers and patients themselves, we can be confronted with challenging diagnostic situations and life-threatening bleeds.

Pediatric acute lymphoblastic leukemia generally carries a good prognosis, and most children will be cured and become long-term survivors. However, a portion of children will harbor high-risk features at the time of diagnosis, have a poor response to upfront therapy, or suffer relapse necessitating more intensive therapy, which may include allogeneic hematopoietic stem cell transplant (HSCT). Recent advances in risk stratification, improved detection and incorporation of minimal residual disease (MRD), and intensification of upfront treatment have changed the indications for HSCT over time. For children in first complete remission, HSCT is generally reserved for those with the highest risk of relapse. These include patients with unfavorable features/cytogenetics who also have a poor response to induction and consolidation chemotherapy, usually reflected by residual blasts after prednisone or by detectable MRD at pre-defined time points. In the relapsed setting, children with first relapse of B-cell ALL are further stratified for HSCT depending on the time and site of relapse, while all patients with T-cell ALL are generally consolidated with HSCT. Alternatives to HSCT have also emerged over the last decade including immunotherapy and chimeric antigen receptor (CAR) T-cell therapy. These novel agents may spare toxicity while attempting to achieve MRD-negative remission in the most refractory cases and serve as a bridge to HSCT. In some situations, these emerging therapies can indeed be curative for some children with relapsed or resistant disease, thus, obviating the need for HSCT. In this review, we seek to summarize the role of HSCT in the current era of immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with several of the authors JB and PM., (Copyright © 2021 Truong, Jinca, Mann, Arghirescu, Buechner, Merli and Whitlock.)

Neutropenia is commonly diagnosed in pediatric clinics. Due to the special vulnerability of neutropenic patients, the assessment of the etiopathogenic background of neutropenia is mandatory. In this retrospective cross-sectional cohort study, we aimed to establish the status of primary autoimmune neutropenia (AIN) from the point of view of its clinical and biological features and its outcome in a cohort of pediatric patients. We recorded all of the 3,488 cases consecutively admitted to our hospital for different diagnoses but presenting neutropenia, during a period of 3 years (January 2016 to December 2018). We had to exclude 224 patients from the analysis due to incomplete data. Our study focused on patients with AIN or chronic benign neutropenia of infancy and childhood. In these patients, a granulocyte antibody screening by granulocyte immunofluorescence test (GIFT) and the granulocyte agglutination test (GAT) were performed. Regarding their pathogenic background, 0.1% of the patients presenting neutropenia were congenital forms, the rest being acquired forms. Primary AIN was encountered in 18 cases, representing approximately 0.5%. The median age at onset for primary AIN was 7.5 months. Male/female ratio in AIN was 1.94. In 72% of the patients with AIN, neutropenia was severe during the course of disease. In 3 patients, both GIFT and GAT were positive and in 8 patients, only GIFT was positive. For the remaining 7 patients (39%), both GIFT and GAT revealed negative results. 50% of the patients needed hospitalization, but only 3 patients presented severe infections. On-demand G-CSF was administered in 22% of the patients. Our study provides insight with regard to neutropenia, showing the high frequency and etiological diversity in childhood. Primary AIN is usually diagnosed by exclusion of the other causes of neutropenia. GIFT and GAT are useful, but rarely available diagnostic tools for the confirmation of primary AIN., (Copyright © 2020, Spandidos Publications.)

Objective:  In countries with low factor concentrate consumption, disabling joint disease remains the major morbidity in patients with haemophilia. The objective of the present analysis is to express the trend and profile of invasive orthopaedic interventions in our country with low usage of factor replacement, lacking the prophylaxis program until recent years., Patients and Methods:  This retrospective descriptive study was conducted in our university centre in Timisoara with long-lasting experience in haemophilia care, which succeeded in developing an exceptionally valuable genuine comprehensive inter-institutional cooperation. This study refers to 115 invasive interventions performed on 97 patients: 83 with haemophilia A, 10 with haemophilia B and 4 with von Willebrand disease in the period of 2001 to 2017; 17 of them had inhibitors, 5 developing inhibitors after the intervention., Results and Discussion:  The cohort of patients consisted mostly of young adults, aged between 7 and 49 years. The vast majority of them, 91.3% of the patients, had the burden of severe chronic arthropathy. This was the reason for 95 interventions, with programmed solution. In 20 cases the cause of invasive interventions was emergency. Knee and hip replacement represented 28% of the major interventions. The complications we encountered were excessive bleeding (12.2%), infection (13%) and inhibitor development (4.3%)., Conclusion:  Surgery is a demanding intervention in patients with haemophilia, which unfortunately cannot be ignored in our country. Hopefully, the improved availability and accessibility to replacement therapy will eliminate the necessity of these interventions, optimizing the outcomes for the next generations., Competing Interests: None to declare. All authors contributed equally to this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Allogeneic hematopoietic stem cell (allo-HSC) transplantation is used in the treatment of malignant hematological diseases. An important tool in monitoring post-transplantation evolution is represented by the percentage of donor's blood cells found in recipient's blood, known as chimersim. This is useful in predicting the graft rejection and the risk of disease relapse. In this study, we present the importance of multiplex STR markers in chimerism monitoring of a 8 year old girl diagnosed with acute lymphoblastic leukemia (ALL)., Methods: In the pre-transplant stage, saliva on buccal swabs and blood samples in EDTA were collected from the donor and recipient and used as reference samples. The DNA extraction from saliva and blood samples was done using the Pure Link Genomic DNA kit (Invitrogen, USA). For the DNA quantification, the Quantifiler Human DNA kit (Applied Biosystems, USA) was used on an ABI 7500 Real-time PCR system (Applied Biosystems, USA). Amplification of the STR markers was performed using the AmpFLSTR NGM SElect kit (Applied Biosystems, USA) on a ProFlex PCR System. The PCR products were separated and detected on an ABI 3500 Genetic Analyzer (Applied Biosytems, USA)., Results: One month post-transplantation of HSC, a mixed chimerism (MC) containing 38% of donor's cells was obtained from a bone marrow aspiration sample. On the 45th day, a new transplantation was performed. On the 15th day after 2nd transplantation, a MC with 91% donor's cells was obtained. On the 21st day after the 2nd transplantation, a complete chimerism (CC) with 100% donor's cells was obtained., Conclusions: Chimerism monitoring is useful in identifying those patients in risk for relapse or graft rejection.

Introduction: the majority of studies of acute gastrointestinal bleeding in children are retrospective, focusing on therapeutic endoscopy. Previous studies performed in adult patients have demonstrated that both scheduled second look endoscopy and high dose continuous omeprazole infusion are effective in the prevention of peptic ulcer rebleeding. The aim of this study was to compare the efficacy of these two strategies using esomeprazole for the prevention of rebleeding following primary endoscopic hemostasis in children with peptic ulcers. The main outcome was to assess the rebleeding rate within 30 days after the initial hemostasis., Methods: consecutive pediatric cases who underwent endoscopic treatment for bleeding peptic ulcers were randomized into two treatment groups following hemostasis. The first group received esomeprazole as an intravenous bolus every 12 hours for 72 hours and a routine second look endoscopy within 12-24 hours with endotherapy retreatment in the case of a persistent stigmata of bleeding. The second group received a continuous high dose esomeprazole infusion for 72 hours without endoscopic reassessment unless required due to rebleeding., Results: a total of 63 children were randomized to the second look endoscopy group and 64 to the esomeprazole infusion group. Rebleeding occurred within 30 days in four patients (6.3%) in the first group and in three patients (4.6%) in the second group (p = 0.7)., Conclusions: a pharmaceutical approach using a high dose continuous esomeprazole infusion in children after an initial endoscopic hemostasis has a similar efficacy compared to second look endoscopy and bolus esomeprazole administration for the prevention of peptic ulcer rebleeding. Thus, the discomfort of a second endoscopy in children can be avoided and is only recommended for selected high risk cases.

Background: Haemophilia is a congenital disorder of coagulation with high economic burden due to its requirement for an expensive, lifelong replacement therapy, with additional costs for the frequent complications and for the severe handicapping consequences. The objective of this cross-sectional study aimed at giving an insight into the health condition of young haemophiliacs in the absence of a regular prophylactic therapy., Methods: It was conducted on a heterogeneous group of 37 children and adolescents (4-24 years of age), with similar on demand therapeutic regimen, coming from the whole country, focusing on the joint status by using the Haemophila Joint Health Score (HJHS) system and on quality of life (QoL) by using the EQ-5D-3L-Y questionnaire., Results: The results revealed an impressive situation: 70.3 % with chronic arthropathy, 19 % with target joints, 69 % with multiple joint involvement, mainly elbow (41 %) and knee (34 %), joint damage starting in the age group 6-12 years (18.18 % arthropathy vs. 96 % in the age group above 12 years). Joint score (6.67 ± 7.92), gait score (0.75 ± 1.14) and HJHS (7.43 ± 8.78) were highly correlated (r = 0.7, p = 0.001) with the annualised bleeding rate ABR (16.2 ± 12.1). They impacted the QoL in all domains, also expressed by a VAS of 68.39 ± 21.6., Conclusion: We concluded that in the situation of an international consensus that prophylactic replacement can prevent cost-effectively and cost-efficiently the deleterious joint damages, our study is supporting the introduction even of secondary and tertiary prophylaxis in young patients in our country., Competing Interests: The authors declare that they have no conflicts of interest., (Schattauer GmbH.)

Unlabelled: Haemophilic arthropathy is a defining feature and a debilitating condition of persons with haemophilia (PwH) in low resource countries. Orthopaedic surgery is unavoidable for patients with high occurrence of joint damage., Aims: We aimed to evaluate the spectrum and outcome of invasive orthopaedic therapies in PwH and von Willebrand diseases (VWD)., Patients and Methods: Our descriptive observational retrospective study included 131 invasive surgical procedures, performed on 76 consecutive patients, most of them (93.4%) with severe disease, treated in Timisoara's Haemophilia Center over a period of 12 years; 17.1% had pre-operation anti-FVIII inhibitors. Invasive elective procedures were predominant (90.8%) as compared to emergency measures (9.2%); according to their invasiveness, 20.6% of interventions were major, 44.3% intermediate and 35.1% minor. Results were good in the majority of cases; significantly reduced joint bleed rate and pain score were the most consistent achievements. The greatest proportion of complications occurred after major (66.7%), compared to moderate (25.6%) and minor (7.7%) interventions. The main threatening complication was the development (3.8%) or increase (4.6%) of inhibitor titer. Local bacterial infections and wound dehiscence complicated the evolution in 4.6% and 0.8 % of cases, respectively; we noticed no blood-borne infections or thrombotic accidents. Low dosage (10.7%) and short duration of substitution (21.4%) led to increased post-surgical bleeding and post-haemorrhagic anaemia., Conclusions: Surgery is a highly demanding intervention in haemophilia, which cannot be ignored in a low resource country. It represents a life or limb-saving and quality of life-improving measure.

Haemophilia, a lifelong congenital bleeding disease, is a highly demanding disorder, due to the costs of its replacement therapy. In the absence of this pivotal treatment, life expectancy and quality of life are deleteriously affected. As illustration, we present a 14 years long follow-up of a patient with severe haemophilia A, treated sporadically with fresh plasma, cryoprecipitate and factor concentrates, who developed a giant iliopsoas pseudotumor. Since he was an infant, under on demand therapy with fresh frozen plasma, cryoprecipitate and low doses of factor concentrates he presented many spontaneous bleedings, developing multiple disabling arthropathies. At the age of 14 years, an iliopsoas hematoma occurred, which relapsed several times, developing an iliopsoas pseudotumour. After 5 years, sepsis with Klebsiella was diagnosed. A CT scan revealed fistula between the pseudotumor and the gut. Under antibiotics, the evolution of sepsis improved, but over a period of 10 months 5 episodes of haematemesis and melena, followed by one episode of macroscopic haematuria occurred; two months later he developed an inguino-crural mass, which fistulized through the abdominal wall. A mixt german-romanian team solved the clinical concern. After 108 hospitalization days and consumption of 104840 IU factor VIII he left the clinic in good condition. One year later, the temporary colostomy with anus praeter was closed. The follow-up reveals now, after almost 10 years with favourable outcome, that the patient is well, active within his family and profession.