Updated Management Guidelines for Adenosine Deaminase Deficiency.

Inherited defects in the adenosine deaminase (ADA) gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies. In recent years, there have been remarkable advances in the management of ADA deficiency. Most ADA-deficient patients can be identified by newborn screening for severe combined immunodeficiency, which facilitates early diagnosis and treatment of asymptomatic infants. Most patients benefit from enzyme replacement therapy (ERT). Allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor or HLA-matched family member donor with no conditioning is currently the preferable treatment. When matched sibling donor or matched family member donor is not available, autologous ADA gene therapy with nonmyeloablative conditioning and ERT withdrawal, which is reported in recent studies to result in 100% overall survival and 90% to 95% engraftment, should be pursued. If gene therapy is not immediately available, ERT can be continued for a few years, although its excessive cost might be prohibitive. The recent improved outcome of hematopoietic cell transplantation using HLA-mismatched family-related donors or HLA-matched unrelated donors, after reduced-intensity conditioning, suggests that such procedures might also be considered rather than continuing ERT for prolonged periods. Long-term follow-up will further assist in determining the optimal treatment approach for ADA-deficient patients.

Finalising the administration of co-SSPedi, a dyad approach to symptom screening for paediatric patients receiving cancer treatments.

OBJECTIVES: Symptom Screening in Pediatrics Tool (SSPedi) is a validated self-report symptom screening tool for patients with cancer 8-18 years of age. Co-SSPedi is a novel dyad approach in which both child and parent complete SSPedi together. The objective was to finalise the approach to co-SSPedi administration with instruction that is easy to understand, resulting in dyads completing co-SSPedi correctly. METHOD: We enrolled child and parent dyads, who understood English and where children (4-18 years) had cancer or were hematopoietic stem cell transplantation recipients. We provided each dyad with instruction on how to complete co-SSPedi together. Mixed methods were used to determine how easy or hard the instruction was to understand. Two raters adjudicated if co-SSPedi was completed correctly. Dyads were enrolled in cohorts of 12 evenly divided by age (4-7, 8-10, 11-14 and 15-18 years). RESULTS: We enrolled 5 cohorts of 12 dyads, resulting in 60 dyads. Following verbal instruction provided in the first cohort, we identified the need for written instruction emphasising children should wait for parent response prior to entering scores. The instruction was iteratively refined based on qualitative feedback until the fifth cohort, where all 12 dyads found the instruction easy to understand and completed co-SSPedi correctly. CONCLUSIONS: We developed a standard approach to dyad symptom screening named co-SSPedi with instruction that is easy to understand, resulting in correct co-SSPedi completion. Future efforts should focus on co-SSPedi validation and understanding how co-SSPedi scores compare to self- or proxy-reported symptom reporting.

Describing taste changes and their potential impacts on paediatric patients receiving cancer treatments.

OBJECTIVES: Taste changes are common among paediatric patients receiving cancer treatments although specific descriptions and associations are uncertain. Primary objective was to describe the number of paediatric patients receiving cancer therapies who experienced taste changes, its impact on food intake and enjoyment of eating, and coping strategies. METHODS: This was a cross-sectional study that included English-speaking paediatric patients aged 4-18 years with a diagnosis of cancer or haematopoietic stem cell transplantation recipients receiving active treatment. Using a structured interview, we asked participants about their experience with taste changes, impacts and coping strategies. The respondent was the paediatric patient. RESULTS: We enrolled 108 patients; median age was 11 years (IQR 8-15). The taste changes reported yesterday or today were food tasting bland (34%), bad (31%), different (27%), bitter (25%), extreme (19%), metallic (15%) or sour (12%). Taste changes were associated with decreased food intake (31%) and decreased enjoyment in eating (25%) yesterday or today. The most common coping strategies were eating food they liked (42%), eating strong-tasting food (39%), drinking liquids (35%), brushing teeth (31%) and sucking on candy (25%). Factors significantly associated with food tasting bad were as follows: older age (p=0.003), shorter time since cancer diagnosis (p=0.027), nausea and vomiting (p=0.008) and mucositis (p=0.009). CONCLUSIONS: Among paediatric patients receiving cancer treatments, taste changes were common and were associated with decreased food intake and enjoyment in eating. Common coping strategies were described. Reducing nausea, vomiting and mucositis may improve taste changes.

Clostridioides difficile infection in paediatric patients with cancer and haematopoietic stem cell transplant recipients.

BACKGROUND: Epidemiology of Clostridioides difficile infection (CDI) in paediatric cancer patients is uncertain. The primary objective was to describe the prevalence of CDI outcomes among paediatric patients receiving cancer treatments. Secondary objectives were to describe clinical features of CDI, propose a definition of severe CDI and to determine risk factors for CDI clinical outcomes. METHODS: A multi-centre retrospective cohort study that included paediatric patients (1-18 years of age) receiving cancer treatments with CDI. Severe CDI definition was achieved by consensus. Univariable and multivariable regression was conducted to evaluate risk factors for CDI outcomes. RESULTS: There were 627 eligible patients who experienced 721 CDI episodes. The prevalence of clinical cure was 82.9%, recurrence was 9.6%, global cure was 75.0% and repeated new CDI episode was 12.8%. The proposed definition of severe CDI was the presence of colitis, pneumatosis intestinalis, pseudomembranous colitis, ileus or surgery for CDI, occurring in 70 (9.7%) episodes. In univariable regression, initial oral metronidazole or initial oral vancomycin were not significantly associated with failure to achieve clinical cure or CDI recurrence. In multiple regression, oral metronidazole was significantly associated with higher odds (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.0-2.7) and oral vancomycin was significantly associated with lower odds (OR 0.4, 95% CI 0.2-0.8) of repeated new episodes. CONCLUSION: The prevalence of clinical cure was 82.9% and recurrence was 9.6% in pediatric patients receiving cancer treatments. Severe CDI, as per our proposed definition, occurred in 9.7% episodes. Initial oral vancomycin was significantly associated with a reduction in repeated new CDI episodes.

Reasons for disagreement between proxy-report and self-report rating of symptoms in children receiving cancer therapies.

PURPOSE: To qualitatively describe reasons for disagreement in ratings of bothersome symptoms between child self-report and parent proxy-report. METHODS: We enrolled child and parent dyads, who understood English and where children (4-18 years of age) were diagnosed with cancer or were hematopoietic stem cell transplantation (HSCT) recipients. Each child and parent separately reported symptoms using self-report or proxy-report Symptom Screening in Pediatrics Tool (SSPedi). We then used semi-structured interviews to elicit reasons for discrepancies in symptom reporting. RESULTS: We enrolled 12 dyads in each of four age cohorts, resulting in 48 dyads. Forty-one dyads (85.4%) had disagreement in rating the presence or absence of at least one symptom. Themes identified as reasons for disagreement included (1) perception, differing perception of symptom or availability or palatability of intervention; (2) understanding, difficulty orienting to time frame or concept of bother; (3) lack of communication, including child not acknowledging or talking about experiences; (4) projection, of how the parent felt or how they assumed the child would feel; and (5) discrepancy, in how the amount of symptom bother that was initially reported on SSPedi, by either child or parent, did not align with what was reported during the dyad discussion. CONCLUSION: We identified themes that explained disagreement in ratings of bothersome symptoms between child self-report and parent proxy-report. Some disagreement may be reduced by enhancing communication about symptom reporting between child and parent. Future research should focus on methods of symptom screening that encourage communication between children with cancer and their caregivers.

Discordance between pediatric self-report and parent proxy-report symptom scores and creation of a dyad symptom screening tool (co-SSPedi).

Symptom Screening in Pediatrics Tool (SSPedi) (age 8-18 years) and mini-SSPedi (age 4-7 years) can be used to self-report and proxy-report bothersome symptoms in pediatric patients receiving cancer treatments. There are limitations of sole child self-report or proxy-report. An approach in which children and parents complete symptom reports together may be useful. The aim of our study was to describe discordance between child self-report and parent proxy-report symptom scores, and to determine how these scores compare to an approach in which reporting is performed together (co-SSPedi). Children and parents completed SSPedi or mini-SSPedi separately. Discordant symptoms were shared with respondents and discussed. Next, the dyad completed co-SSPedi together and were asked which approach they preferred. Discordance was evaluated for each symptom and was defined as a difference of at least 2 points on an ordinal scale ranging from 0 (not at all bothered) to 4 (extremely bothered). Of the 48 enrolled dyads (children, median age, 10.8 years; 54.2% male), 41 (85.4%) had discordance in at least one symptom. There was no clear pattern in discordance by age group. When a dyad approach was used, more co-SSPedi scores agreed with the original child self-report scores (59 dyads, 56.2%) compared to original parent proxy-report scores (15 dyads, 14.3%) for discordant symptoms. Forty-three (89.6%) dyads preferred to complete SSPedi together. Future work should evaluate the psychometric properties of co-SSPedi.

Translating the Symptom Screening in Pediatrics Tool (SSPedi) into French and among French-speaking children receiving cancer treatments, evaluating understandability and cultural relevance in a multiple-phase descriptive study.

OBJECTIVES: Symptom Screening in Pediatrics Tool (SSPedi) is a validated approach to measuring bothersome symptoms for English-speaking and Spanish-speaking children with cancer and paediatric haematopoietic stem cell transplantation (HSCT) recipients. Objectives were to translate SSPedi into French, and among French-speaking children receiving cancer treatments, to evaluate understandability and cultural relevance. METHODS: We conducted a multiphase, descriptive study to translate SSPedi into French. Forward translation was performed by four medical translators. After confirming that back translation was satisfactory, we enrolled French-speaking children with cancer and paediatric HSCT recipients at four centres in France and Canada. PRIMARY AND SECONDARY OUTCOME MEASURES: Understandability was evaluated by children themselves who self-reported degree of difficulty, and by two adjudicators who rated incorrectness. Assessment of cultural relevance was qualitative. Participants were enrolled in cohorts of 10. RESULTS: There were 30 children enrolled. Participants were enrolled from Marseille (n=10, 33%), Ottawa (n=1, 3%), Quebec City (n=11, 37%) and Toronto (n=8, 27%). No child reported that it was hard or very hard to complete French SSPedi in the last cohort of 10 participants. Changes to the instrument itself were not required. After enrolment of 30 respondents, the French translation of SSPedi was considered finalised based on self-reported difficulty with understanding, adjudicated incorrect understanding and cultural relevance. CONCLUSIONS: We translated and finalised SSPedi for use by French-speaking children and adolescents receiving cancer treatments. Future work should begin to use the translated version to conduct research and to facilitate clinical care.

Changes in hunger among pediatric patients with cancer and hematopoietic stem cell transplantation recipients.

PURPOSE: Change in hunger is a common and bothersome symptom among pediatric patients receiving cancer treatments. Objectives were to describe how children and adolescents receiving cancer treatments experience changes in hunger, factors associated with both increases and decreases in hunger, and coping strategies used by these patients. METHODS: We enrolled children and adolescents 4-18 years of age with cancer or hematopoietic stem cell transplantation (HSCT) recipients who were actively receiving treatment or who had completed therapy. Using a single, qualitative, semi-structured interview, we asked participants about the experience of increases or decreases in hunger, including characteristics of the change and identified coping strategies. RESULTS: There were 50 children enrolled; 25 (50%) were 4-10 years of age and 33 (66%) were boys. Most often, patients associated an increase in hunger with corticosteroid administration, while other treatments, accompanying symptoms, inactivity, and the hospital environment were associated with a decrease in hunger. Many reported that no coping strategies were successful. For those who did report successful strategies to manage an increase in hunger, these included sleep and having food available. Strategies used to manage a decrease in hunger included anti-emetic medications, increased caloric intake, varied food choices, encouragement to eat, scheduling or tracking of meals, and physical activity. CONCLUSIONS: Both increases and decreases in hunger were commonly described. Some coping strategies were reported to be successful. Further research should identify and test interventions to manage changes in hunger in pediatric cancer patients.

Changes in taste among pediatric patients with cancer and hematopoietic stem cell transplantation recipients.

PURPOSE: Changes in taste is a common bothersome symptom in children receiving cancer treatments. However, little is known about how pediatric cancer patients experience this symptom. The objective was to describe how children receiving cancer treatments experience taste alterations and the approaches they use to address the issue. METHODS: In this qualitative study, we included English-speaking children 4-18 years of age with cancer or hematopoietic stem cell transplantation recipients who were actively receiving cancer treatment or who had completed therapy. Using a semi-structured questionnaire, we asked questions about the experience of altered taste sensation. We asked about its characteristics, impacts and identified coping strategies. RESULTS: We included 50 children. Children experienced changes in taste in a heterogeneous fashion although commonly described food as tasting "different", "not right" or "funny". While change in food preferences due to taste alterations was common, specific choices varied. Many found changes started with treatment initiation or mid-way through treatment, and some found that symptoms persisted up to 9 months following treatment completion. Actions taken to address taste changes were sucking on candy, brushing teeth and modifying food choices. CONCLUSIONS: The experience of changes in taste was common yet highly variable in its presentation and resultant changes in food preferences. Taste changes did not always resolve soon after treatment completion. Future research should identify ways to manage this symptom in pediatric cancer patients.

Symptom documentation and intervention provision for symptom control in children receiving cancer treatments.

BACKGROUND: Objectives were to describe the proportion of bothersome symptoms self-reported using the Symptom Screening in Pediatrics Tool (SSPedi) documented in the medical records and associated with an intervention. METHODS: Eligible respondents were inpatients aged 8-18 years receiving cancer treatments and expected to be in hospital or clinic three days later. Children self-reported symptom bother using SSPedi. We evaluated symptom documentation and interventions in the medical records proximal to SSPedi administration. RESULTS: There were 168 children included. Symptoms rated as at least 'a lot' bother were documented in the medical record less than 60% of the time for 12 of 15 symptoms. Of these symptoms, the most infrequently documented symptoms were problems with thinking or remembering things (0%), changes in how your body or face look (4.8%), changes in taste (7.7%) and tingly or numb hands or feet (11.1%). Intervention provision for symptoms rated as 'a lot' bother occurred less than 60% of the time for 10 of 15 symptoms. Of these symptoms, the most infrequently treated were thinking or remembering things (0%), changes in how your body or face look (0%), tingly or numb hands or feet (0%), changes in taste (0%), diarrhoea (0%) and feeling tired (1.6%). CONCLUSIONS: Documentation of symptoms and intervention provision were generally infrequent. Symptoms that were almost never documented or treated included problems with cognition, body image, taste changes and peripheral neuropathy. Future efforts should incorporate symptom screening into routine care and facilitate symptom management by improving access to evidence-based clinical practice guidelines.

Taste changes in children with cancer and hematopoietic stem cell transplant recipients.

BACKGROUND: Objectives were to describe bothersome self-reported changes in taste in pediatric oncology and hematopoietic stem cell (HSCT) patients and to identify patient and treatment-related factors associated with bothersome taste changes. METHODS: We prospectively enrolled children and adolescents with cancer or pediatric HSCT recipients 8-18 years of age from three groups: inpatients receiving cancer treatments; outpatients in maintenance therapy for acute lymphoblastic leukemia (ALL); and outpatients in survivorship. Bothersome changes in taste was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi); nausea was self-reported using the Pediatric Nausea Assessment Tool (PeNAT). RESULTS: Among the 502 children included, 226 (45.0%) reported bothersome taste changes and 48 (9.6%) reported severely bothersome taste changes. In multiple regression, factors independently associated with severely bothersome taste changes were: inpatients receiving cancer treatments vs outpatients in survivorship (odds ratio (OR) 12.28, 95% confidence interval (CI) 2.50-222.27), ALL in maintenance vs outpatients in survivorship (OR 7.43, 95% CI 1.06-147.77), current nausea (OR 1.59, 95% CI 1.04-2.42), vomiting (OR 2.18, 95% CI 1.06-4.38), and first language not English (OR 2.09, 95% CI 0.97-4.28). CONCLUSIONS: We found that 45% of children with cancer and pediatric HSCT recipients reported bothersome changes in taste and these were severely bothersome in 9.6% of children. Inpatients receiving cancer treatment, those experiencing more nausea and vomiting and children whose first language was not English were at greater risk of severely bothersome changes in taste. Future work should evaluate systematic symptom screening in clinical practice and identify interventions focused on addressing bothersome taste changes.

Diagnostic Instability and Reversals of Chronic Obstructive Pulmonary Disease Diagnosis in Individuals with Mild to Moderate Airflow Obstruction.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a chronic, progressive disease, and reversal of COPD diagnosis is thought to be uncommon. OBJECTIVES: To determine whether a spirometric diagnosis of mild or moderate COPD is subject to variability and potential error. METHODS: We examined two prospective cohort studies that enrolled subjects with mild to moderate post-bronchodilator airflow obstruction. The Lung Health Study (n = 5,861 subjects; study duration, 5 yr) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study (n = 1,551 subjects; study duration, 4 yr) were examined to determine frequencies of (1) diagnostic instability, represented by how often patients initially met criteria for a spirometric diagnosis of COPD but then crossed the diagnostic threshold to normal and then crossed back to COPD over a series of annual visits, or vice versa; and (2) diagnostic reversals, defined as how often an individual's COPD diagnosis at the study outset reversed to normal by the end of the study. MEASUREMENTS AND MAIN RESULTS: Diagnostic instability was common and occurred in 19.5% of the Lung Health Study subjects and 6.4% of the CanCOLD subjects. Diagnostic reversals of COPD from the beginning to the end of the study period occurred in 12.6% and 27.2% of subjects in the Lung Health Study and CanCOLD study, respectively. The risk of diagnostic instability was greatest for subjects whose baseline FEV1/FVC value was closest to the diagnostic threshold, and the risk of diagnostic reversal was greatest for subjects who quit smoking during the study. CONCLUSIONS: A single post-bronchodilator spirometric assessment may not be reliable for diagnosing COPD in patients with mild to moderate airflow obstruction at baseline.

Addressing the misdiagnosis of asthma in adults: where does it go wrong?

INTRODUCTION: Asthma is diagnosed based on patients' respiratory symptoms of wheeze, cough, chest tightness and/or dyspnea together with physiologic evidence of variable and reversible expiratory airflow limitation. A high prevalence of overdiagnosis, underdiagnosis and misdiagnosis of adult asthma has been reported in the literature. Areas covered: Misdiagnosis of asthma in adults can occur in the community due to physicians' failure to confirm airflow limitation using spirometry, the relatively poor sensitivity of spirometry to absolutely rule in asthma, the complexity of multiple asthma phenotypes and endotypes, and the inherent day to day variability of asthma symptoms and airflow limitation. Consequences of asthma misdiagnosis to the patient and to the healthcare system include increased medication costs, increased potential side effects related to unnecessary use of medications and lost opportunities to diagnose the true cause of patients' respiratory symptoms. Expert commentary: Here we provide a review of the problem of misdiagnosis of adult asthma and suggestions for how to decrease the risk of misdiagnosis.