COVID-19 in Pediatric Patients With Acute Lymphoblastic Leukemia or Lymphoma.

Importance: COVID-19 in pediatric patients with acute lymphoblastic leukemia or lymphoma (ALL/LLy) has not been described in detail and may affect chemotherapy administration and long-term outcomes. Objective: To describe the clinical presentation of COVID-19 and chemotherapy modifications in pediatric patients with ALL/LLy. Design, Setting, and Participants: This is a retrospective case series of patients at St Jude Children's Research Hospital and its affiliate sites with newly diagnosed ALL/LLy who were treated on the Total XVII protocol (NCT03117751) between March 30, 2020, and June 20, 2022. Participants included patients aged 1 to 18 years who were receiving protocol chemotherapy. Acute symptoms and chemotherapy modifications were evaluated for 60 days after the COVID-19 diagnosis, and viral clearance, adverse events, and second SARS-CoV-2 infections were followed up during the 27-month study period. Exposures: SARS-CoV-2; all patients were screened at least weekly and at symptom onset and/or after known exposure to SARS-CoV-2. Main Outcomes and Measures: Description of the spectrum of COVID-19 illness and chemotherapy modifications. Results: Of 308 pediatric patients, 110 (36%) developed COVID-19 at a median age of 8.2 (IQR, 5.3-14.5) years. Sixty-eight patients (62%) were male. Most patients were in the continuation/maintenance phase of chemotherapy (101 [92%]). Severe disease was rare (7 [6%]) but was associated with older age, higher white blood cell counts at ALL/LLy diagnosis, lower absolute lymphocyte counts at COVID-19 diagnosis, abnormal chest imaging findings, and SARS-CoV-2 reinfection. Rare but serious thrombotic events included pulmonary embolism and cerebral venous sinus thrombosis (n = 1 for each). No multisystem inflammatory syndrome in children or death was seen. SARS-CoV-2 reinfection occurred in 11 patients (10%) and was associated with older age and with receiving standard or high-risk vs low-risk ALL/LLy therapy. Chemotherapy interruptions occurred in 96 patients (87%) and were longer for patients with severe disease, SARS-CoV-2 reinfection, and/or a COVID-19 diagnosis during the pre-Omicron variant period vs the post-Omicron period (after December 27, 2021). Conclusions and Relevance: In this case series of COVID-19 in pediatric patients with ALL/LLy, severe COVID-19 was rare, but chemotherapy administration was affected in most patients. Long-term studies are needed to establish the outcomes of COVID-19 in this population.

Longitudinal Impact of a Novel Condolence Expression Curriculum.

Background: Pediatric residents lack training in expressing condolences to bereaved families after a child's death. We previously developed a novel curriculum that improved residents' comfort with expressing condolences, and now we report assessment of the longitudinal impact of this curriculum on residents' practices of condolence expression. Methods: We applied Kern's 6-step approach to develop, implement, and evaluate a condolence expression curriculum. Residents completed surveys before, immediately after, and six months after participating in the educational intervention to assess curricular impact over time. Results: Twenty pediatric residents participated in the curriculum. Residents reported an increase in their practice of expressing condolences following participation in the curriculum, as well as appreciation for the value of the intervention. Conclusion: A condolence expression curriculum has potential to increase residents' practice of condolence expression to bereaved families over time. Future work will focus on the impact of curricular dissemination across pediatric residency programs.

Training in Expression of Authentic Condolences in Healthcare: A Pilot Study.

Background: Bereaved parents value receiving support from their children's health care teams. Pediatric residents are important members of the teams that care for children at end of life and can play a meaningful role in communication with bereaved families. Yet formal training in expressing condolences is currently lacking. Methods: We applied Kern's six step approach to develop, implement, and evaluate an innovative curriculum aimed at increasing pediatric residents' comfort levels with and practice of condolence expression. Results: Twelve residents participated in the pilot study. Quantitative and qualitative data demonstrate that residents' comfort levels with expressing condolences increased after implementation of the curriculum and that residents appreciated and benefitted from receiving this education. Conclusion: We successfully developed and piloted a condolence expression curriculum that was well received by pediatric residents and led to increased comfort level with expressing condolences. Research is ongoing to determine the full impact of this curriculum.

Improving Blood Product Transfusion Premedication Plan Documentation: A Single-institution Quality Improvement Effort.

Introduction: Premedication with acetaminophen and/or diphenhydramine to prevent febrile nonhemolytic transfusion reactions and minor allergic transfusion reactions is a common practice based on historical recommendations. However, recent small randomized-controlled trials showed no benefit of premedication. This inconsistency leads to practice variability, which results in the inefficiency of our institution's blood product ordering process. This project aimed to improve the number of transfusion encounters with premedication plan documentation from a baseline of 19% to 80% in 12 months. Methods: A multidisciplinary quality improvement (QI) team used QI tools to design interventions to improve the efficiency of the ordering process for blood products. Measures were tracked monthly and analyzed using statistical process control. Results: From September 2018 to January 2021, 5,351 blood product transfusion visits were scheduled. At baseline, 34% of patients received premedication, and 19% had premedication plans documented. Interventions included a passive computerized provider order entry alert, clinical care pathway development, and clinician education. Postimplementation, the average number of encounters with a premedication plan increased from 19% to 87%, whereas encounters receiving premedication decreased from 34% to 25%. There was no change in the average number of transfusion reactions (1.8 per 100 transfusions). Conclusions: Using QI methods, our team successfully standardized the blood product premedication plan documentation despite unclear best practices regarding blood product transfusion premedication. The team added premedication plan documentation training to new employee orientation for sustainability.

Hematopoietic cell transplant for reversal of liver fibrosis in a pediatric patient with erythropoietic protoporphyria.

BACKGROUND: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. CASE (METHODS/RESULTS): We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. CONCLUSION: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.

Incidence and predictors of treatment-related conjugated hyperbilirubinemia during early treatment phases for children with acute lymphoblastic leukemia.

Conjugated hyperbilirubinemia (CHB) and liver transaminase elevation are known complications of acute lymphoblastic leukemia (ALL) therapy, but host risk factors are poorly understood. Among 373 children diagnosed with ALL between 2011 and 2016, clinically significant CHB and transaminase elevation were observed in 15 (4.0%) and 12 (3.2%) children, respectively, during induction and consolidation. Body mass index ≥95th percentile (odds ratio 9.20, 95% confidence interval 2.56-32.96) was the only host factor independently associated with CHB, and no host factors were associated with transaminase elevation. Obese patients warrant closer monitoring of hepatic function to facilitate early intervention prior to the development of severe, adverse hepatic events.

Sustained remission with azacitidine monotherapy and an aberrant precursor B-lymphoblast population in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a B-lymphoblast population in JMML does not always progress to acute leukemia.

PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia.

Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.

Transmissible ER stress reconfigures the AML bone marrow compartment.

Successive adaptation of the bone marrow (BM) from homeostatic hematopoietic microenvironment to a self-reinforcing niche is an integral aspect of leukemogenesis. Yet, the cellular mechanisms underlying these functional alterations remain to be defined. Here, we found that AML incursion precipitates compartmental endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in both leukemia and stromal cells. We observed that extracellular vesicles (EV) transmit ER stress in vivo from the AML xenograft to BM stroma, whereby the upregulation of core UPR components drives subsequent osteolineage differentiation of mesenchymal stem cells (MSC). Finally, we show that the underlying mechanism involves quantitative incorporation and cell-cell transfer of Bone Morphogenic Protein 2 (BMP2), a potent osteogenic signal, by AML-EVs. Corroborative studies in AML patient samples support the translational relevance of AML-EVs as a platform for BMP trafficking and source of compartmental crosstalk. Transmissible ER stress was previously identified as a source of chemoresistance in solid tumor models, and this work reveals a role in remodeling the BM niche in AML.

Pediatric Acquired von Willebrand Syndrome in Cardiopulmonary Disorders: Do Laboratory Abnormalities Predict Bleeding Risk?

There are conflicting reports on whether or not laboratory abnormalities in pediatric acquired von Willebrand syndrome (AVWS) predict bleeding manifestations in patients with cardiopulmonary disorders (CPD). We retrospectively reviewed charts of patients with AVWS and CPD (n=16) seen at Texas Children's Hospital from 2003 to 2012. The most common CPD were valve stenoses, ventricular septal defects, and pulmonary hypertension. All patients had loss of high molecular weight multimers. Fifteen (94%) patients presented with bleeding symptoms, with menorrhagia and epistaxis being the most common. Von Willebrand ristocetin cofactor activity (VWF:RCo), as well as the use of anticoagulant or antiplatelet medication, did not predict bleeding manifestations (P=0.70 and 0.84, respectively). VWF:RCo/VWF antigen (Ag) ratio of <0.7 was significantly associated with presence of bleeding symptoms. All patients who had complete repair of their cardiac defect experienced normalization of VWF multimers and VWF:RCo/Ag ratio, as well as bleeding symptom resolution. We conclude that increased bleeding risk is associated with low VWF:RCo/Ag ratio in pediatric AVWS due to CPD. However, other laboratory abnormalities such as VWF:RCo level and qualitative multimer analysis, do not appear to predict bleeding. Future studies exploring quantification of multimer loss may be helpful in further assessing bleeding risk associations.

Stroke radiology and distinguishing characteristics of intracranial atherosclerotic disease in native South Asian Pakistanis.

BACKGROUND: There are no descriptions of stroke mechanisms from intracranial atherosclerotic disease in native South Asian Pakistanis. METHODS: Men and women aged ≥ 18 years with acute stroke presenting to four tertiary care hospitals in Karachi, Pakistan were screened using magnetic resonance angiography/transcranial Doppler scans. Trial of ORG 10172 in Acute Stroke Treatment criteria were applied to identify strokes from intracranial atherosclerotic disease. RESULTS: We studied 245 patients with acute stroke due to intracranial atherosclerotic disease. Two hundred thirty scans were reviewed. Also, 206/230 (89.0%) showed acute ischaemia. The most frequent presentation was with cortically based strokes in 42.2% (87/206) followed by border-zone infarcts (52/206, 25.2%). Increasing degrees of stenosis correlated with the development of both cortical and border-zone strokes (P = 0.002). Important associated findings were frequent atrophy (166/230, 72.2%), silent brain infarcts (66/230, 28%) and a marked lack of severe leukoaraiosis identified in only 68/230 (29.6%). A total of 1870 arteries were studied individually. Middle cerebral artery was the symptomatic stroke vessel in half, presenting with complete occlusion in 66%. Evidence of biological disease, symptomatic or asymptomatic was identified in 753 (40.2%) vessels of which 543 (72%) were significantly (>50%) stenosed at presentation. CONCLUSION: Intracranial atherosclerotic disease is a diffuse process in Pakistani south Asians, with involvement of multiple vessels in addition to the symptomatic vessel. The middle cerebral artery is the most frequent symptomatic vessel presenting with cortical embolic infarcts. There is a relative lack of leukoaraiosis. Concomitant atrophy, silent brain infarcts and recent ischaemia in the symptomatic territory are all frequently associated findings.

Risk factors predisposing to congenital heart defects.

INTRODUCTION: Congenital heart disease (CHD) is associated with multiple risk factors, consanguinity may be one such significant factor. The role of consanguinity in the etiology of CHD is supported by inbreeding studies, which demonstrate an autosomal recessive pattern of inheritance of some congenital heart defects. This study was done to find out the risk factors for CHD. METHODS: A case-control study was done on pediatric patients at a tertiary care hospital, Aga Khan University Hospital, located in Karachi, Pakistan. A total of 500 patients, 250 cases and 250 controls were included in the study. RESULTS: Amongst the 250 cases (i.e. those diagnosed with CHD), 122 patients (48.8%) were born of consanguineous marriages while in the controls (i.e. non-CHD) only 72 patients (28.9%) showed a consanguinity amongst parents. On multivariate analysis, consanguinity emerged as an independent risk factor for CHD; adjusted odds ratio 2.59 (95% C. I. 1.73 - 3.87). Other risk factors included low birth weight, maternal co-morbidities, family history of CHD and first born child. On the other hand, medications used by the mother during the index pregnancy, maternal age and gender of the child did not significantly increase the risk of developing CHD. CONCLUSIONS: Analyses of our results show that parental consanguinity, family history of CHD, maternal co-morbidities, first born child and low birth weight are independent risk factors for CHD.

Evaluation of therapeutic control in a Pakistani population with hypertension.

RATIONALE, AIMS AND OBJECTIVES: Cardiovascular diseases (CVD) are increasing at an alarming rate in South Asia. High blood pressure is a modifiable risk factor for CVD. In this study, we evaluated the control of blood pressure and the prevalence of cardiovascular risk factors in patients with hypertension. METHOD: A cross-sectional study was conducted in 50 primary health care centres throughout Pakistan. Individuals with a documented history of hypertension, receiving pharmacological therapy, were enrolled and evaluated for the control of their blood pressure. RESULTS: The recommended therapeutic control of hypertension (systolic blood pressure <140 mmHg, diastolic blood pressure <90 mmHg) was seen in only 6.4% of the study participants. Values of both the mean systolic and diastolic blood pressures in all subjects were higher than the desired therapeutic levels (P<0.001). There was a high prevalence in the study population of established but modifiable risk factors of CVD, such as smoking (30.5%), hypercholesterolemia (59.5%) and sedentary lifestyle (43.5%). Lack of therapeutic control of systolic blood pressure was found significantly associated with age, hypercholesterolemia and sedentary lifestyle (P<0.05). CONCLUSIONS: Patients being treated at primary health care centres in Pakistan have inadequate control of high blood pressure. Evidence-based continuous education of primary health care physicians is a necessary intervention for optimizing treatment strategies and achieving better therapeutic control of hypertension in our population.

Knowledge of emergency contraception among women of childbearing age at a teaching hospital of Karachi.

OBJECTIVES: To assess knowledge and attitudes about Emergency Contraception among women of childbearing age in Karachi, Pakistan. METHODS: A questionnaire based survey was conducted on 400 married women, attending the family practice clinics at a teaching hospital in Karachi, Pakistan from July to December 2006. Questionnaire was administered to women at the family practice clinic-seeking level of knowledge of emergency contraception (EC) and attitudes towards its use, Ethical requirements of informed consent and confidentiality were ensured Data was entered into Epi data and analyzed in SPSS. RESULTS: Eighty-eight percent of women were not aware of EC. 83% were housewives. Only a small number (11.5%) ever used EC to prevent pregnancy, out of those, the correct timing of effectiveness of post-coital pill was known to only 40% of women while none of these women were aware of the existence of Intra Uterine Contraceptive Device (IUCD) insertion as an option for EC About 50% of women identified general practitioners or family medicine clinics as their main sources of knowledge about EC. Increased advertising was considered desirable by 72% while 37% considered over the counter availability of EC pill desirable and only 36% of women were uncomfortable to use EC because of religious reasons. CONCLUSION: EC has a potential to offer women an important option for fertility control. Lack of women's knowledge about EC use and availability may account in part for its limited use. There is a need to improve women's education about EC. The primary health care providers can play a major role in informing their patients about emergency contraception.

Factors associated with adherence to anti-hypertensive treatment in Pakistan.

OBJECTIVES: Poor adherence is one of the biggest obstacles in therapeutic control of high blood pressure. The objectives of this study were (i) to measure adherence to antihypertensive therapy in a representative sample of the hypertensive Pakistani population and (ii) to investigate the factors associated with adherence in the studied population. METHODS AND RESULTS: A cross-sectional study was conducted on a simple random sample of 460 patients at the Aga Khan University Hospital (AKUH) and National Institute of Cardiovascular Diseases, Karachi, from September 2005-May 2006. Adherence was assessed using the Morisky Medication Adherence Scale (MMAS), with scores ranging from 0 (non-adherent) to 4 (adherent). In addition to MMAS, patient self-reports about the number of pills taken over a prescribed period were used to estimate adherence as a percentage. AKU Anxiety and Depression Scale (AKU-ADS) was incorporated to find any association between depression and adherence. At a cut-off value of 80%, 77% of the cases were adherent. Upon univariate analyses, increasing age, better awareness and increasing number of pills prescribed significantly improved adherence, while depression showed no association. Significant associations, upon multivariate analyses, included number of drugs that a patient was taking (P<0.02) and whether he/she was taking medication regularly or only for symptomatic relief (P<0.00001). CONCLUSIONS: Similar to what has been reported worldwide, younger age, poor awareness, and symptomatic treatment adversely affected adherence to antihypertensive medication in our population. In contrast, monotherapy reduced adherence, whereas psychosocial factors such as depression showed no association. These findings may be used to identify the subset of population at risk of low adherence who should be targeted for interventions to achieve better blood pressure control and hence prevent complications.

Private drug sellers' education in improving prescribing practices.

OBJECTIVE: To determine the education of private drug sellers as an intervention tool in promoting rational use of medicines for diarrhoea at private drug outlets in a rural setting. PLACE AND DURATION OF STUDY: The study was conducted at Mithi, Tharparkar in rural Sindh in August 2005. PATIENTS AND METHODS: Diarrhea was selected to study drug-prescribing habit of private drug sellers. Evidence-based guidelines for control of diarrhea were developed along with simulation cases and keys. In phase-1, simulators were sent to 6 private drug sellers and their prescription was noted. After phase-1, 3 private drug sellers were educated about prescribing, while in the other 3, there was no intervention. In phase-2, simulators were sent again and prescriptions by private drug sellers was noted. RESULTS: The work experience of private drug sellers was between 5 to 15 years. Two private drug sellers were employed at each of the drug outlet with education between matriculation and graduation. All the private drug sellers prescribed medicines to customers with confidence. The private drug sellers prescribed medicines to customers on a daily basis that included all categories of medications. Amoebicidals, Anti-diarrheals, antispasmodics, antibiotics, analgesics and oral rehydration solutions were prescribed by 22(38.6%), 10(17.5%), 3(4.9%), 10(17.5%), 3(5.3%) and 9(15.8%) private drug sellers prior to intervention respectively. It changed to 0(0%), 6 (14%), 0(0%) 0 (0%), 4 (9.3%) and 16(37.2%) postintervention respectively. Referral to hospital for serious cases increased after intervention. CONCLUSION: The rational use of medicines can be promoted by providing education to private drug sellers. Further studies and education programs for private drug sellers are strongly recommended across the country.