Between crises and care: Childhood realities with sickle cell Anemia: A qualitative study.

No abstract available.

Guidelines for the management of the acute painful crisis in sickle cell disease.

HIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub-Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV. The study was a retrospective cohort study (study period 2004-2018). Cases of HIV+and SCD-afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV+controls without SCD (HIV+/SCD-). Thirty-five HIV+/SCD+subjects and 95 HIV+/SCD- controls were analysed (39% female (51/130), age 3.6years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD+had higher though non-significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P=0.20, two-tailed t-test). There were 19 deaths, 6 (17%) HIV+/SCD+and 13 (14%) HIV+/SCD-, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan-Meier analysis showed a slower rate of treatment failures in the HIV+/SCD+cohort (P=0.11, log-rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD+cohort showed a more rapid rise and higher total CD4 count (P=0.012, regression analysis). The study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD+achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.

Cancer antigen (CA) 15-3, which is associated with breast carcinoma, is an epithelial mucin and a product of the MUC1 gene (MUC1) (Hayes et al, 1986). Elevated levels of CA 15-3 also occur in patients with benign conditions such as inflammatory disease (Colomer et al, 1989; Valerio Marzano et al, 1998). Sickle cell disease (SCD) is an inflammatory disorder characterised by chronic haemolysis, endothelial activation and vaso-occlusion (Hebbel et al, 2004). Recent evidence showed that MUC1 was also expressed in the haematopoietic lineages (Rughetti et al, 2003), which prompted us to examine the possible association of CA 15-3 with SCD. Fifty-one patients with homozygous SCD, 15 patients with previously treated active metastatic breast carcinoma, and 20 healthy volunteers, sex and age-matched, were enrolled in the study. The SCD patients were divided into two subgroups: individuals with painful vaso-occlusive crises (n = 17) and those with steady-state disease (n = 34). Patients with active infection, cirrhosis, severe organ dysfunction, cancer, pregnancy or fibrocystic breast disease were excluded from the study. All subjects provided informed consent. Serum CA 15-3 levels were measured with a microparticle immunoassay. Differences were analysed by the Student's t-test, analysis of variance, and the chi-squared test for statistical analysis. Two patients with steady-state SCD had experienced a prior cerebrovascular event. No difference was found among patients with or without painful crisis with respect to transfusion requirement, bone necrosis, hepatomegaly, seropositivity for hepatitis B or hepatitis C virus or the median value of alanine aminotransferase, bilirubin or creatinine peak levels (P > 0·05). All patients had been pretreated with an avarage of three substances (usually hydroxycarbamide, zinc and folic acid). There was no difference between the groups regarding the treatment with hydroxycarbamide (P > 0·05). In both SCD groups and the metastatic breast cancer group, serum CA 15-3 concentrations were elevated when compared with controls (P < 0·001 for all). The subjects with metastatic breast cancer were found to have significantly higher serum CA 15-3 concentrations when compared with the patients with SCD (steady-state disease or painful crisis) (P < 0·001 for both). There was no difference between the serum CA 15-3 levels of the patients with SCD in steady state or painful crisis (P > 0·05) (Table I). Twenty-eight patients (82%) with steady-state SCD and 13 patients (76%) with SCD in painful crisis had CA 15-3 values >30 U/ml. This difference was not statistically significant (P > 0·05). When both groups of patients with SCD were compared with controls, the percentage of CA 15-3 levels ≥30 IU/l was significantly higher than patients with SCD (P < 0·001 for both). However, this percentage in the SCD groups was lower than patients with breast cancer (P < 0·001 for both) (Table I). Among the patients with SCD, serum CA 15-3 levels were not affected by the use of hydroxycarbamide. Possible explanations of our findings, based on the current literature are: (i) in the past two decades, it has been established that SCD is an inflammatory state with abnormal endothelial cell activation (Hebbel et al, 2004). Previous reports have shown that elevated CA 15-3 levels are associated with connective tissue diseases, such as systemic lupus erythematosus (SLE), and systemic sclerosis (Colomer et al, 1989; Valerio Marzano et al, 1998). One study showed that 7% of patients with SLE had serum CA 15-3 concentrations >40 U/ml (Colomer et al, 1989). Pathogenetic mechanisms that cause the elevation of CA 15-3 in patients with an inflammatory disease can also explain the elevation of CA 15-3 in both SCD groups in our study. (ii) In bone marrow differentiating cells, the increase in MUC1 expression has been shown at the mRNA level (Rughetti et al, 2003). MUC1 was expressed strongly but transiently in early erythroid differentiation, however, it was absent in the circulating erythrocytes (Rughetti et al, 2003). Moreover, increased serum CA 15-3 has also been reported among patients with homozygous β-thalassaemia and sickle cell-thalassaemia (Symeonidis et al, 2006). These observations may suggest that in SCD, the erythroid hyperplasia might express MUC1 glycoform similar to those expressed by carcinoma cells. Our data indicates that serum CA 15-3 levels may be elevated in individuals with SCD. The serum concentration of CA 15-3 should thus be considered when malignant disease is suspected.

Background: Sickle Cell Disease (SCD) is a painful disease with long-term transfusion therapy, hydration, hydroxyurea therapy, and primary care parents are severely affected psychologically, socially, cognitively, and economically. This study evaluates the parental Perspectives on the Challenges of Pediatric Sickle Cell Disease. Method and Material: The qualitative phenomenological method was used to determine the parents’ experiences. The study sample included 12 parents who met the inclusion criteria. Individual interviews, an introductory information form and a semi-structured interview form were used for data collection. The data were analyzed with Colaizzi's seven-step method. Results: The mean age of the parents was 44.83±6.08 (min. 34; max. 54); the children were 14.58±3.20 (min. 8; max. 18). Four themes of the interviews were established: psychosocial distress, family relationship, managing pain, and financial burden. Parents stated that their child experienced feelings such as stress, unhappiness, fear of death, demonstrated reluctance to attend check-ups, maternal attachment and constraint. Moreover, parents said that their other children were also affected emotionally exchibiting jealousy and loneliness. For pain management in children, parents reported using non-pharmacological strategies such as encouraging balloon blowing, providing massages, applying hot water bottles to affected areas, and assisting their children with hot showers. Parents also experience economic burdens, primarily due to transportation costs for hospital visits and the increased nutritional needs of both their children and themselves. Conclusions: The results of the study revealed that the parents who have a child with SCD experience several psychological problems, social isolation, difficulty in pain management and large financial cost to health services. Both the healthcare system and medical professionals should be aware of the challenges faced by parents of children with sickle cell disease (SCD) and provide them with appropriate support. It is recommended that interventions be planned and implemented in a way that maximizes the quality of life of children and their families.

The emerging understanding of sickle cell disease.

28-Year-Old Man With Joint Pain

Validation of Patient-Reported Vaso-Occlusive Crisis Day As a Potential Endpoint in Studies of Sickle Cell Disease

Background and objectives: Sickle cell anemia causes painful crises by the occlusion of small blood vessels by spontaneous intravascular sickling. The aim of this study is to determine the possible association of Zinc deficiency with painful crises among patients with sickle cell anemia. Methods: A case – control study included 50 children with sickle cell anemia during painful crisis, 50 with Sickle cell anemia without painful crisis and 50 normal children (control group). Serum zinc was measured for all participants and statistically analyzed to test the presence of a possible significant relation between serum zinc and painful crises in sickle cell anemia. Results: The mean age of all study population was 9.79 ± 4.54 years and male to female ratio was 1.2:1. Weight, height, body mass index, Hemoglobin and packed cell volume are lower in those with sickle cell anemia as compared to controls but the difference is not statistically significant. White blood cells count is significantly higher in those with sickle cell anemia and painful crisis than those with sickle cell anemia but no painful crisis and the normal controls. Liver enzymes alanine aminotransferase and aspartate aminotransferase are significantly higher among patients than controls. Serum zinc is lower in patients with sickle cell anemia and painful crisis than those with sickle cell anemia but without painful crisis and the normal controls (88.84±31.20, 98.62±20.78, 101.38±24.49 µg/dl respectively) and the difference is statistically significant. Conclusion: Zinc deficiency is significantly associated with predisposition to painful crises in children with sickle cell anemia.

Characterization of Medical Conditions of Children with Sickle Cell Disease in the United States: Findings from the 2007-2018 National Health Interview Surveys (NHIS)

Sleep Patterns and Associated Clinical Correlates Amongst Ghanaian Individuals with Sickle Cell Disease

1. Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust 2. Lane Fox Respiratory Unit, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust 3. Department of Haematology, North Middlesex Hospital 4. Department of Paediatric Haematology, Bristol Royal Hospital for Children 5. Department of Haematological Medicine, King’s College Hospital 6. Department of Haematology, Whittington Hospital

Patients with sickle cell disease (SCD) suffer recurrent painful vaso-occlusive crisis (VOC), poor quality of life and a shortened lifespan. Although hydroxyurea and blood transfusion remain the mainstay of SCD therapy, the only cure currently available is allogeneic stem cell transplant (allo-SCT). However, many barriers prevent allo-SCT from being widely offered to adult SCD patients. The SCD patients most in need of allo-SCT transplant are also those at highest risk for transplant-related complications and mortality.1 Other therapeutic approaches are, therefore, much needed. Neutrophils have been implicated in regulating the disease course of VOC. The SCD patients with WBC > 15 × 109/L are more likely to develop stroke,2 acute chest syndrome,3 and premature death.4 Neutrophils in SCD also exhibit higher levels of activation molecules, for example, CD645 and CD11b/CD18,6 and their sera have elevated soluble CD62L.5, 7 Circulating aged neutrophils (CANs), a subset of neutrophils with high surface expression of CXCR4 and low CD62L, are also significantly elevated.7, 8 Both activated and aged neutrophils may be immobilized on endothelium, and form the nidus for sickled erythrocytes to adhere to, eliciting VOC. Several recent observations from our laboratory and others have supported frequent microbial and pathophysiologic changes in the intestines of SCD patients. These include enterocyte injury,7 altered microbial composition,9 increased permeability7 and bacterial overgrowth.10 We have previously proposed that increased translocation of intestinal bacteria/bacterial products into the systemic circulation is responsible for the increased number of activated neutrophils in SCD.11 Others have found intestinal microbiota to regulate CANs in SCD mice.8 Modulating intestinal microbial composition may, therefore, be a therapeutic option in SCD to reduce VOC, by decreasing both activated and aged neutrophils. We recently reported that rifaximin treatment reduced CANs in SCD patients treated in a clinical study (Clinicaltrials.gov: NCT03719729) funded by Bausch Health Companies, Inc.12 Rifaximin also shifted the intestinal microbiome in these patients towards increased abundance of Bacteroides.12 In this current paper, we report the clinical outcome on the same cohort of SCD patients accrued to the study, to determine whether the changes in the intestinal microbiome and reduction in the CANs were translated into clinical benefits of reduction in VOC. This study was approved by the Institutional Review Board of New York Medical College. The SCD patients were eligible for the study if they were 18 years or over, had a diagnosis of SCD (HbSS, HbSC, HbSβ-thalassemia), and had at least two painful crises needing inpatient or outpatient intravenous opioid analgesia (IOA), during the preceding 12 months. Patients may continue on the hydroxyurea or L-glutamine if they were already taking the medication long-term. Patients were only added to the study if their last episode of painful crisis was more than 4 weeks before starting rifaximin. Each patient received 550 mg of rifaximin twice a day for 6 months. The dose of rifaximin chosen was similar to that for preventing hepatic encephalopathy in patients with liver cirrhosis. Each patient was also given a self-reporting diary to record daily ingestion of the medication and associated side effects. All patients were followed up every 4 weeks, or earlier if they developed VOC. Each patient completed the FANLTC (Functional Analysis of Non-life-Threatening Conditions) questionnaire before, and 3 and 6 months after being started on rifaximin. The FANLTC questionnaire consists of four subjective blocks of questions covering physical, emotional, social/family, and functional well-being. Each question scores as follow: 0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much. Efficacy analyses were performed on data obtained from all the patients who completed 6 months of rifaximin. Changes in the number of VOC and days needing IOA during the study period, were compared to those expected for a six-month period, calculated from the average of the previous 12 months. Thirteen adult patients with SCD consented to the study. Their clinical characteristics are shown in Table S1. There were eight males and five females. Ten patients had HbSS, two HbSβ0thal, and one HbSC. Their median age was 29 years (range 24-56). The median number of VOC in the previous 12 months was 4.5 (range 2-13), and the number of days needing IOA was 25.5 days (range 8-198). In 12 of the 13 patients, the VOC was in the form of musculo-skeletal pain typical in distribution for the VOC that normally affected individual patients, and in one patient the VOC was predominantly in the form of recurrent priapism. Five of the patients were already taking hydroxyurea, and none were taking L-glutamine or on a transfusion program. Six patients were taking oral opioid at home for chronic pain. The study ran between November 2018 and early August 2019, covering the winter months when most of the patients reported having most frequent VOC. In all 12 evaluable patients, rifaximin was started during the winter months. Twelve of the 13 patients accrued to the study were evaluable for response. One patient (HbSC) did not return to be started on the rifaximin after consenting for the study. The remaining 12 patients completed 6 months of rifaximin. The mean self-reported medication compliance of the intended doses was 86% (range 50-100). The median number of VOC during the study period decreased from the expected 2.25 (range 1-6.5) per 6 months to one per 6 months (range 0-4) (P = .003) (Figure 1A). The one patient whose VOC was predominantly in the form of priapism did not respond. His self-reported medication compliance was 100%. The median decrease in days needing IOA over the six-month study-period was nine (range 1-55), and the median percent reduction was 82% (range 20%-100%) (P = .008) (Figure 1B). Total number of days needing IOA was reduced from the expected 254 in 6 months to 98 during the study period. Laboratory analyses did not show any significant change in hemoglobin, white cell counts, serum lactate dehydrogenase, bilirubin, or haptoglobin due to rifaximin therapy. There was no significant change in the FANLTC scores in all four well-being blocks of questions when the patients were analyzed as a group. Subset analysis, however, found that functional well-being significantly improved at 6 months, for those who reported below average scores before rifaximin (mean score 11.4+/−1.7 to 14.6+/−2.19) (P = .02). The average score to the question "I am able to enjoy life" increased from 1.4+/−0.5 to 2.1+/−0.69 (P = .046). There was also improvement among those with below average scores for physical well-being. The average score to the question "I have pain" decreased from 3.56+/−0.72 to 2.3+/−1.6 (P = .022) at month three, and from 3.56+/−0.72 to 2.22+/−1.4 (P = .016) at month six. The average score to the question "I feel ill" also improved, decreased from 2.5+/−0.58 to 0.75+/−0.5 (P = .035) at months three and six. Rifaximin was well tolerated. Mild nausea was common in the first 1-2 weeks of rifaximin therapy and occurred in eight of the 12 patients. Other adverse events included self-limiting diarrhea (n = 1) (negative for pathogens by culture, Clostridium difficile by PCR, and gastrointestinal multiplex PCR) which occurred during the first month of therapy, and polydipsia (n = 2). The results of this study, therefore, suggest that rifaximin may potentially benefit patients, as measured by a decrease in the number of VOCs and days needing IOA, in patients with SCD. These clinical benefits were translated into improvement in the QOL, as measured by FANLTC, for those who experienced below average quality of life prior to the study. Reducing the intestinal microbial load using antibiotics has been found beneficial in SCD mice. Mice with SCD acquired by transplantation when treated with an oral combination of ampicillin, neomycin, vancomycin and metronidazole exhibited lower number of CANs, and were protected against tumor necrosis factor-α-induced fatal VOC.8 The identical cocktail of oral antibiotics, when given to the Townes SCD mice reduced intestinal microbial load and SCD-related osteopenia.10 Although the beneficial effects of the combination antibiotics on SCD are likely related to reduction in the intestinal microbial density, because two of the four antibiotics are absorbed into the systemic circulation, any systemic effects of the antibiotics in modifying SCD complications cannot be totally ruled out. Furthermore, while the findings in these two studies were interesting, the approach is clearly not directly translational. It is highly impractical to administer the combination of the four antibiotics long-term to SCD patients. In our study, more than 90% of those consented remained in the study for 6 months. This high retention rate is likely due to two factors. Besides telephone calls to the patients, until the patients answered the call, on the morning of their follow-up appointments, text messages were also sent to the patients. The clinical benefits, in terms of less frequent painful VOC and improved QOL, experienced by the patients may also contribute to the high patient retention rate. We have chosen to test rifaximin in this study for three reasons. First, rifaximin has an established safety profile for long-term use in patients with liver cirrhosis to prevent hepatic encephalopathy.13 Second, the risks for the development of antibiotic-associated Clostridium difficile infection induced by long-term use of antibiotics is likely low, since rifaximin also has activities against Clostridium difficile. Third, being a minimally absorbed antibiotic, rifaximin provided the opportunity to dissect the effect of reducing intestinal microbial load in SCD, from any systemic effect an antibiotic might also have on the disease process. The results of our study using rifaximin, therefore, support the local effects of an antibiotics in the intestine in modifying the course in SCD. The mechanisms responsible for the beneficial effects of rifaximin in reducing VOC remains to be determined. It is likely that rifaximin works via decreasing the intestinal microbial load, and hence reducing translocation of intestinal bacteria/bacterial products into the systemic circulation to activate and age neutrophils, as reported by us previously that CANs in these individuals dropped significantly while taking the rifaximin during the study period.12 Since rifaximin has an anti-inflammatory property,14 the role contributed by a reduction in the inflammatory process associated with enterocyte injury7 and bacteria/bacterial products translocated across the intestinal barrier as a result of improvement in the integrity of the intestinal barrier cannot be totally ruled out. In summary, this is the first human study showing the potential efficacy of microbial modulation on VOC in patients with SCD. Intestinal microbial modulation with rifaximin is also safe and well-tolerated. The major limitations in our work is the small sample size and the single-center single-arm nature of the study. Furthermore, any placebo effects of the intervention on the QOL of the patients cannot be totally ruled out. The intense follow up of the patients may also be responsible in part for the observed clinical improvement. A multicenter placebo-controlled randomized trial is, therefore, warranted to confirm our findings. We would like to thank the following for their critiques and advice during the preparation of the manuscript: Dr. Peter Gillette at State University of New York Downstate Medical School and King's County Medical Center, Dr. Howard Franklin at Salix Pharmaceuticals, and Dr. Robert Israel at Bausch Health Companies, Inc. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Prevention and Management of Sickle Cell Pain Crises: Lessons Learned from Older Adults with Sickle Cell Disease

Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life. This is an updated version of the review. To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease. We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 03 February 2019.Date of last search of other resources (clinical trials registries): 04 April 2019. We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium. Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies. We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence). Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.