Evolution in the management of acute liver failure-associated aplastic anaemia in children: a single centre experience

BACKGROUND/AIMS: Bone marrow failure (BMF) is a potentially life-threatening complication of acute liver failure (ALF). METHODS: To investigate prevalence and evolving management of BMF associated with ALF, we reviewed all cases seen in our centre over 17 years. BMF was classified as: (a) bone marrow hypoplasia, (b) severe aplastic anaemia (SAA) and (c) very severe aplastic anaemia (VSAA), using standard criteria. We compared outcomes in children receiving: (1) medical treatment only with or without immunomodulation (anti-lymphocyte globulin, calcineurin inhibitors, G-CSF); (2) medical treatment with or without immunomodulation plus liver transplantation (LT); (3) haematopoietic stem cell transplantation (HSCT). RESULTS: Of 213 patients with ALF, 20 [(9.4%); 14 (70%) boys] developed BMF after a median of 1 month (range, 0.5 to 7). Seven had VSAA, 7 SAA and 6 bone marrow hypoplasia. Five children were treated medically, including 3 by immunomodulation; 10 (50%) received LT, with immunomodulation in 6; 5 (25%) received HSCT, in one after LT. Four (20%) children died, only one as consequence of AA. There was no difference in recovery, complication rates or outcome among the three groups. CONCLUSIONS: Aggressive management of ALF-associated AA, including immunomodulation, HSCT and LT, is successful in most cases. HSCT has the advantage of removing the risk of late clonal disorders.     

Analysis of clonal rearrangements of the Ig heavy chain locus in acute leukemia

Clonal rearrangements of the Ig heavy chain (IGH) locus occur in nearly all cases of B-cell precursor acute leukemia (BCP-ALL). Some of these rearrangements may be detected by polymerase chain reaction (PCR) using VH gene framework III (FRIII) and JH consensus primers. However, about 20% of BCP-ALLs fail to amplify with this technique. To determine the causes of these PCR failures and to investigate any possible association with specific subgroups of disease, we analyzed 72 acute leukemias of defined immunophenotype and cytogenetics, comparing FRIII with VH-family leader-specific PCR methods and Southern blotting. Of 37 BCP-ALL cases, 6 (16.2%) failed totally to amplify with FRIII and JH primers. None of these cases amplified with VH leader primers. Additionally, all cases retained germline VH6 genes and 5 of 11 rearranged alleles amplified with a consensus DH primer, indicating that these rearrangements represented biallelic DH-JH recombinations. Among the 6 FRIII and VH leader PCR-negative BCP-ALL cases, there was no common immunophenotype or consistent cytogenetic abnormality, although all showed structural chromosomal abnormalities and 3 of 5 successfully karyotyped had abnormalities of chromosome 12p. 13 cases with t(9;22)(q34;q11) Philadelphia chromosome-positive [Ph+]) and IGH rearrangements (9 BCP-ALL and 4 biphenotypic cases) were also analyzed. Of 23 rearranged IGH alleles, 19 (82%) were positive by FRIII PCR, and all 4 remaining alleles were amplified by VH leader primers. Use of the leader primers in these Ph+ cases also detected 3 additional clonal rearrangements that were not anticipated from Southern blotting; such unexpected bands were not observed in 21 other Ph- cases. The additional bands represented "new" and unrelated VH rearrangements rather than VH-VH replacement events. We conclude that biallelic DHJH rearrangements occur in a subgroup of BCP-ALL; in these cases, the activation of the full VHDHJH recombination mechanism had not occurred. Therefore, these cases of BCP-ALL were arrested at an early stage of B- cell differentiation. In contrast, all Ph+ BCP-ALLs and biphenotypic acute leukemias, which may represent the transformation of multipotent hemopoietic stem cells, had undergone VHDHJH recombination. Of 9 Ph+ BCP-ALL cases, 3 also showed ongoing VHDHJH rearrangement, reflecting the persistent expression of the VHDHJH recombinase. Finally, sequence analysis of 33 rearranged VHDHJH genes showed that only 3 including 2 Ph+ BCP-ALL maintained an intact open-reading frame. Loss of the open- reading frame occurred not only because of out-of-frame VHDH and DHJH joining, but also because of VH gene mutation and deletion. These data show that most BCP-ALLs may represent the neoplastic transformation of BCPs destined to die in the bone marrow.     

Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial

Low nocturnal oxygen saturation (SpO₂) is implicated in complications of Sickle Cell Anemia (SCA). Twenty-four children with SCA were randomized to receive overnight auto-adjusting continuous positive airway pressure (auto-CPAP) with supplemental oxygen, if required, to maintain SpO₂ ≥94% or as controls. We assessed adherence, safety, sleep parameters, cognition and pain. Twelve participants randomized to auto-CPAP (3 with oxygen) showed improvement in Apnea/Hypopnea Index (p<0.001), average desaturation events >3%/hour (p=0.02), mean nocturnal SpO₂ (p=0.02) and cognition. Primary efficacy endpoint (Processing Speed Index) showed no group differences (p=0.67), but a second measure of processing speed and attention (Cancellation) improved in those receiving treatment (p=0.01). No bone marrow suppression, rebound pain or serious adverse event resulting from auto-CPAP use was observed. Six weeks of auto-CPAP therapy is feasible and safe in children with SCA, significantly improving sleep-related breathing disorders and at least one aspect of cognition.     

The presence of alpha-thalassaemia trait blunts the response to hydroxycarbamide in patients with sickle cell disease

Hydroxycarbamide (HC), although a key drug therapy in sickle cell disease (SCD), does not result in a clinical response in all patients. Increases in fetal haemoglobin (HbF) and mean corpuscular volume of erythrocytes are standard clinical measures of HC efficacy in SCD. Genetic studies have determined that the majority of HbF regulation occurs outside the beta-globin locus. Approximately 30% of SCD patients have co-inherited alpha-thalassaemia resulting in hypochromic and microcytic erythrocytes. We provide data from 30 SCD patients (10 with alpha-thalassaemia) demonstrating that co-existing alpha-thalassaemia significantly affects several standard measures of HC efficacy in SCD.     

Changing the pattern of children having children

Statistical patterns today reveal that an overwhelming majority of Black children are born to single, teenage mothers. In 1980, for example, 57 precent of births to those were to mothers 15–17 years of age.The infant mortality rates among such births is strikingly high and even for those infants who survive their first year of life, there are studies which show disproportionately high physical and mental deficits among the offspring of teenagers.Few adolescent mothers turn to the fathers of their children for help. They understand that these young men are rarely in a position to support a young mother and child since unemployment among Black male teenagers is in the 47 percent range. Large numbers of these young women never marry and, instead, head their own households in poverty. Others continue to live with mothers, sisters, or other relatives who may themselves be mothers, with children born out of wedlock. The cycle of dependency on public assistance, or low paying jobs is, thereby, passed on to second, and even third generations.Traditional family values must be strengthened if children born today are to be prepared to participate in our ever more complex, and technologically advanced society.Teenage parents who drop out of school, and are not prepared to participate fully in home and community responsibilities, are also unprepared to provide the goals, education, and skills needed by their children.Dorothy I. Height, Ph.D. is President of the National Council of Negro Women.     

The associations between air quality and the number of hospital admissions for acute pain and sickle-cell disease in an urban environment

The clinical severity of sickle-cell disease (SCD) is dependent on genetic and environmental variables. Environmental factors have been poorly studied. We have investigated possible links between air pollution and acute pain in SCD. We retrospectively studied the numbers of daily admissions with acute sickle-cell pain to King's College Hospital, London, in relation to local daily air quality measurements. We analysed 1047 admissions over 1400 d (1st January 1998-31st October 2001). Time series analysis was performed using the cross-correlation function (CCF). CCF showed a significant association between increased numbers of admissions and low levels of nitric oxide (NO), low levels of carbon monoxide (CO) and high levels of ozone (O(3)). There was no association with sulphur dioxide (SO(2)), nitrogen dioxide or PM(10) (dust). The significant results were further examined using quartile analysis. This confirmed that high levels of O(3) and low levels of CO were associated with increased numbers of hospital admissions. Low NO levels were also associated with increased admissions but did not reach statistical significance on quartile analysis. Our study suggests air quality has a significant effect on acute pain in SCD and that patients should be counselled accordingly. The potential beneficial effect of CO and NO is intriguing and requires further investigation.     

The effects of air quality on haematological and clinical parameters in children with sickle cell anaemia

Sickle cell anaemia (SCA; HbSS) is characterised by its clinical variability, which is only partly explained by known genetic factors. Environmental factors are known to contribute to acute problems but their importance in chronic complications has not been analysed. We have studied 93 children with SCA in a single institution, who underwent transcranial Doppler scanning and steady-state blood tests in 2006. These data were correlated with each individual’s exposure to pollution from dust (PM₁₀), nitric oxide (NO) and nitrogen dioxide (NO₂). This exposure was derived from patient postcodes and detailed street-level maps of average pollutant levels in 2006. All the pollutants correlated closely with each other. Increased exposure to pollution correlated with a significant reduction in total bilirubin levels, with a trend towards lower levels of lactate dehydrogenase and aspartate transaminase. There was significant correlation between extracranial internal carotid artery blood velocity and PM₁₀ exposure. These studies suggest that chronic exposure to air pollutants could explain some variability in SCA. The lower levels of bilirubin and other markers of haemolysis with increased exposure to air pollutants could be mediated by increased exposure to NO.     

Successful desensitization to immunoglobulin A in a case of transfusion‐related anaphylaxis

BACKGROUND: A history of anaphylaxis after transfusion of immunoglobulin A (IgA)‐containing blood products in selective IgA‐deficient (sIgAD) patients can be a major problem, particularly in emergencies, when large quantities of blood products are required. CASE REPORT: A 19‐year‐old woman with end‐stage Type 2 autoimmune hepatitis required liver transplantation as her only remaining treatment option. However, she also had sIgAD, anti‐IgA antibodies, and episodes of anaphylaxis after receiving IgA‐containing blood products. Liver transplantation would have been extremely challenging due to the difficulty of obtaining sufficient blood products from suitable IgA‐deficient donors. Hence, it became imperative to devise a protocol to desensitize her to IgA‐containing blood products. RESULTS: Using a continuous infusion of an IgA‐enriched (6 mg/mL IgA) immunoglobulin preparation with gradual increases in concentration, she was successfully desensitized to IgA. Consequently, she was able to receive standard platelets, fresh‐frozen plasma, and red blood cells with no complications. CONCLUSION: This approach could prove very useful in similar cases that may require administration of large quantities of blood products particularly in emergency lifesaving circumstances.