Theresa Cole

Outcome of children requiring intensive care following haematopoietic SCT for primary immunodeficiency and other non-malignant disorders

Haematopoietic SCT (HSCT) is curative for many children with primary immunodeficiencies or other non-malignant conditions. Outcome for those admitted to intensive care following HSCT for oncology diagnoses has historically been very poor. There is no literature available specifically regarding the outcome for children with primary immunodeficiency requiring intensive care following HSCT. We reviewed our post-HSCT admission to intensive care over a 5-year period. A total of 111 children underwent HSCT. Median age at transplant was 1 year 4 months. The most common diagnosis was SCID. In all, 35% had at least one intensive care admission and 44% survived to be discharged from intensive care. Also, 73% of admission episodes requiring invasive ventilation but no inotropes or renal replacement therapy resulted in survival to discharge. Children undergoing HSCT for immunological diagnoses had a high rate of admission to intensive care. No factors were identified that could predict the need for admission. Invasive ventilation alone has a much better outcome than that in historical series. However, the need for multi-organ system support was still associated with a poor outcome. This information is useful when counselling families of children that have deteriorated and been admitted to intensive care during the HSCT procedure.

Clinical experience in T cell deficient patients

T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT) now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning.This review will discuss recent progress in our clinical and molecular understanding of a variety of disorders including: severe combined immunodeficiency, specific T cell immunodeficiencies, signaling defects, DNA repair defects, immune-osseous dysplasias, thymic disorders and abnormalities of apoptosis.There is still much to discover in this area and some conditions which are as yet very poorly understood. However, with increased knowledge about how these disorders can present and the particular problems each group may face it is hoped that these patients can be recognized early and managed appropriately, so providing them with the best possible outcome.

Carboplatin Hypersensitivity Reactions in Pediatric Low Grade Glioma Are Protocol Specific and Desensitization Shows Poor Efficacy

The use of carboplatin for the treatment of pediatric low grade gliomas (PLGG) is often limited by the development of carboplatin hypersensitivity. Reported rates of carboplatin hypersensitivity reactions vary between 6% and 32% in these patients. Here we report the frequency of carboplatin hypersensitivity reactions depending on the treatment regimen used, and outcomes of carboplatin desensitization.

Vancomycin dosing in children: what is the question?

Vancomycin has been in clinical use for over 60 years, but it is still not clear what dose should be given to children. Effective treatment with vancomycin requires a serum concentration well above the minimum inhibitory concentration (MIC) of the bacteria being treated. This is predicted by the area under the concentration curve (AUC) divided by the MIC being >400 (AUC/MIC). Recent concerns about increasing MIC in staphylococci have lead to recommendations to aim for higher trough vancomycin levels (15–20 mg/L). In current practice, most children do not achieve these trough levels. Modelling and pharmacokinetic studies in children suggest these trough levels may not be necessary if the MIC of the organisms is 1 mg/L or less. Further, large-scale studies are needed to determine the most appropriate dosing of vancomycin in children. While awaiting these, it is time to consider moving to 15 mg/kg 6 h as a standard starting regime for vancomycin. It is also vital to determine the MIC of the organism being treated, as this may give some guidance about suitable trough levels to be aimed for. There is currently little evidence to guide the use of loading doses or continuous vancomycin infusions in children.

Cognitive ability in children with chronic granulomatous disease: a comparison of those managed conservatively with those who have undergone hematopoietic stem cell transplant.

Chronic granulomatous disease (CGD) is a primary immunodeficiency managed conservatively or with hematopoietic stem cell transplant. Studies have shown people with CGD and those transplanted for primary immunodeficiencies have lower than average cognitive ability. In this study, IQ in children with CGD and those transplanted for it was within the normal range.

Fifteen-minute consultation: Bacillus Calmette–Guérin abscess and lymphadenitis

Bacillus Calmette–Guerin (BCG) vaccine contains a live attenuated strain of Mycobacterium bovis, which provides 64% efficacy against tuberculous meningitis and 78% efficacy against disseminated tuberculosis.1 A number of local adverse reactions are recognised (abscess, suppurative lymphadentitis, keloid formation). An increased number of local complications were reported in the UK and Ireland since the introduction of a new BCG strain in 2002.2 ,3 It is important to distinguish between a normal vaccine response, a local complication and the very rare cases of systemic BCG infection that occur with immunodeficiency. Antibiotics and/or anti-tuberculous medication are rarely needed, except for systemic BCG infection. After intradermal injection, BCG multiplies at the inoculation site, then spreads to regional nodes. A normal reaction is a red indurated area, which progresses to a local lesion that may ulcerate 2–3 weeks after vaccination. A crust is formed around this induration for 3–4 weeks. At 6–10 weeks, the crust falls off, leaving a flat 3 to 7 mm scar. Regional lymphadenopathy <1 cm (95% in the axilla) is considered a normal reaction to the vaccine.4 This ‘simple’ lymphadenitis occurs 63 days (range 16–87) after BCG vaccination5 and resolves spontaneously by 9 months.6 Lymphadenitis may be more common when BCG is given to infants <6 months old compared with older children and adults.5 Local complications occur in one in a thousand people given BCG vaccine.3 ,7 ### Injection site abscess A local abscess (>1 cm in diameter) can develop at the injection site, 30 days (range 4–65) after BCG vaccination.5 Abscess formation is less common when BCG is given to infants less than 6 months old compared with older children and adults. However, abscesses are more likely in infants aged less than 6 months old immunised by …

Germline-activating mutations in PIK3CD compromise B cell development and function

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110&dgr; subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110&dgr; inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110&dgr; inhibitors.

Emotional and behavioural difficulties in chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency, characterised by life-threatening bacterial and fungal infections and inflammatory complications.1 Cognitive difficulties are also described.2 Chronic ill health and cognitive difficulties potentially expose patients to psychological difficulties. We analysed data in a national cohort of patients with CGD to understand how these difficulties might manifest. Physicians enrolled patients in the national CGD registry between 2000 and 2001.1 …

Central venous catheter-related blood stream infections in children undergoing hematopoietic stem cell transplant for primary immunodeficiency and other nonmalignant disorders.

A single-center experience of catheter-related blood stream infections in children undergoing hematopoietic stem cell transplant for primary immunodeficiency is described. The rate of definite central venous catheter infections was 5.31/1000 line days. Staphylococcus epidermidis was the most commonly identified organism. Teicoplanin resistance occurred in 17% of S. epidermidis infections. The central catheter was removed in 21% of infections.

Infections in the Immunocompromised

Infections in the immunocompromised differ significantly from those in the immunocompetent. They can be more serious, more often life threatening, more difficult to diagnose and are caused by more unusual organisms. Children can be immunocompromised for a variety of reasons and the numbers, worldwide, are growing.