Outbreaks caused by Dengue, Zika and Chikungunya viruses can spread rapidly in immunologically naïve populations. By analysing 92 newly generated viral genome sequences from blood donors and ...recipients, we assess the dynamics of dengue virus serotype 4 during the 2012 outbreak in Rio de Janeiro. Phylogenetic analysis indicates that the outbreak was caused by genotype II, although two isolates of genotype I were also detected for the first time in Rio de Janeiro. Evolutionary analysis and modelling estimates are congruent, indicating a reproduction number above 1 between January and June, and at least two thirds of infections being unnoticed. Modelling analysis suggests that viral transmission started in early January, which is consistent with multiple introductions, most likely from the northern states of Brazil, and with an increase in within-country air travel to Rio de Janeiro. The combination of genetic and epidemiological data from blood donor banks may be useful to anticipate epidemic spread of arboviruses.
OBJETIVO: Descrever os principais resultados do programa de triagem neonatal para a doença falciforme do Estado do Rio de Janeiro em 15 meses de funcionamento (agosto de 2000 a novembro de 2001). ...MÉTODOS: A partir de agosto de 2000, amostras de sangue passaram a ser coletadas de todos os recém-nascidos atendidos em postos de atenção básica à saúde no Estado para triagem neonatal da doença falciforme. Essas amostras são submetidas a cromatografia líquida de alta resolução. Se o cromatograma resultante for compatível com a doença falciforme, a criança e seus pais são encaminhados para confirmação diagnóstica e tratamento. RESULTADOS: De agosto de 2000 a novembro de 2001, 99 260 recém nascidos participaram da triagem. Houve um caso de homozigose para Hb C. Um em cada 27 recém-nascidos triados pelo programa apresentou o traço falciforme (Hb AS). A doença falciforme foi constatada em 83 casos (um caso novo para cada 1 196 nascimentos): 62 Hb S, 18 Hb SC, 3 Hb SD. Uma criança não compareceu para confirmação diagnóstica. As 82 crianças acompanhadas apresentaram 15 intercorrências (infecções de vias aéreas superiores, febre, seqüestro esplênico, síndrome mão-pé e crises de vaso-oclusão), motivando sete internações. Houve necessidade de transfusão sangüínea em 15 crianças, mas nenhuma tornou-se alo-imunizada. Os demais bebês estão evoluindo satisfatoriamente com o uso de penicilina profilática. CONCLUSÕES: Nossos dados evidenciam a importância do diagnóstico precoce da doença falciforme, de forma a prevenir e evitar as freqüentes complicações infecciosas enfrentadas por esses pacientes.
Introduction: Currently, there is a plethora of analgesics on the market that vary in type, method of application, duration of action, side effects and price. Thus we have, among other things, ...NSAIDs, opioids, anesthetics, cannabinoids, gases and venom-derived pain relievers. Formulations include short-acting, long-acting, extended release or controlled release. Administration of analgesia could be oral, topical, parenteral, intrathecal, epidural, rectal, intranasal, epidermal, submucosal, sublingual, etc. Despite the abundance of these drugs in the western world, there is an embarrassing dearth in developing countries. Thus the challenge to find the right analgesic for a specific patient with a specific etiology of pain is often overwhelming. It is within this framework of this complexity that we describe the efficacy of the lidocaine patch in a patient with a severely painful leg ulcer refractory to standard methods of therapy in a patient with sickle cell anemia (SS)
Patient & Methods: The patient is a 35 year-old African Brazilian man, known to have SS presented at the Instituto de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO) in Rio de Janeiro, Brazil with a severely painful leg ulcer over the lateral left malleolus of 11 years duration. Dimensions of the ulcer were: 10 cm long and 6 cm wide and covered with purulent exudate. The pain was constant and stabbing in nature with an intensity score of 10 over 10 on presentation. The pain was partially responsive to oral tramadol and he refused to take opioids. Given the large size of the ulcer and purulent exudate, application of topical opioids was not considered an appropriate option due a potentially barrier effect of the exudate. Accordingly decision was made to treat the pain with lidocaine patch applied peripherally around the ulcer. Direct application of the patch would stick to the ulcer bed thus limiting its analgesic effect and previous studies showed high blood flow in the immediate peri-ulcer area compared to distant unaffected skin. The lidocaine patch was applied daily as follows: The ulcer was first cleaned with warm normal saline and polihexamide, collagenase was applied to the ulcer bed and the lidocaine patch was applied on the skin on the periphery of the ulcer. The lidocaine patch had to be cut to fit the periphery of the ulcer. The patient was instructed to remove the patch 12 hours after its application. He was taught how to remove and reapply the bandage around the ulcer. Moreover, the patient was instructed to keep a written diary of the intensity of the leg ulcer pain one, six and 12 hours after the application of the patch.
Results: On the first day of treatment the intensity of the ulcer pain was 10 over 10 and he did not allow the nurse to apply the bandage because that made the pain much worse. One hour after the application of the lidocaine patch the pain score dropped to 3 over 10 and at 6 and 12 hours post application the pain score was zero. On the next day he presented to the wound center with a pain score of 4 over 10 and this time he allowed the nurse to remove and apply the bandage without complaints. After the daily application of the lidocaine patch he did not require oral tramadol to treat the ulcer pain.
Conclusion: The lidocaine patch seems to be an effective and save method to treat the pain of sickle cell leg ulcers. Moreover, it obviates the need of oral analgesics to treat the pain. Recent studies suggest that nonneuronal tissues, such as skin keratinocytes in particular, express several isoforms of Na+ channels and of the TRPV family of receptors. These findings suggest that skin may play an important role in the pathophysiology of pain. Thus the application of lidocaine to the periphery of the ulcer inhibits the transmission of painful stimuli directly in situ. A potential problem is that the patch is expensive.
No relevant conflicts of interest to declare.
Sickle cell disease (SCD) is a multisystem disorder characterized by a wide spectrum of clinical manifestations and severity. Studies investigating potential effects of co-morbid human ...immunodeficiency virus (HIV) and SCD have produced conflicting results, and additional investigations are needed to elucidate whether the interaction between the two disease states might impact both HIV and SCD clinical outcomes. The association of HIV infection with clinical and laboratory characteristics of patients with SCD was assessed.
This nested case-control study included individuals with SCD with HIV treated at six Brazilian SCD centers. Clinical and laboratory data were abstracted from medical records. HIV positive participants were compared to age, gender, center, and SCD genotype matched HIV negative participants (ratio 1:4). Individual clinical outcomes as well as a composite outcome of any SCD complication and a composite outcome of any HIV-related complication were compared between the two groups.
Fifteen HIV positive participants were included, 12 (80%) alive and 3 (20%) deceased. Most of the HIV positive patients had HbSS (60%; n = 9), 53% (n = 8) were female, and mean age was 30 ± 13 years. The frequency of individual SCD complications of acute chest syndrome/pneumonia, sepsis/bacteremia, pyelonephritis, ischemic stroke, hemorrhagic stroke, abnormal transcranial Doppler (TCD), and pulmonary hypertension was higher in HIV positive participants when compared to HIV negative, although analyzed individually none were statistically significant. HIV positive participants had significantly higher risk of any SCD complication and of a composite HIV-related complication compared to the HIV negative group (HR = 4.6; 95%CI 1.1-19.6; P = 0.04 and HR = 7.7; 95%CI 1.5-40.2; P = 0.02, respectively). There was a non-significant trend towards higher risk of any infections in participants with HIV positive (HR = 3.5; 95%CI 0.92-13.4; P = 0.07). Laboratory parameters levels were not significantly different in individuals with and without HIV.
In summary, our study in SCD patients shows that those with HIV have an increased risk of any SCD complication and HIV-related complications, as well as a suggestive but not significantly increased risk of infections.
Abstract 843
Although deaths among children with sickle cell disease (SCD) have decreased substantially in the United States and Europe, high mortality is still a serious problem in most developing ...nations. Common causes of death in children with SCD include sepsis, splenic sequestration, stroke, and acute chest syndrome (ACS). Hydroxyurea therapy is able to reduce mortality in adult patients with SCD, but no data exist regarding its benefits on mortality among pediatric patients. Since 2000, our center has prospectively offered hydroxyurea to children with SCD who meet criteria established by the Brazilian Ministry of Health. These criteria include: all SCD genotypes ≥3 years of age, with ≥2 ACS or ≥3 painful events in the previous year, persistent oxygen saturation <94%, growth delay, recurrent priapism, sickle retinopathy, transcranial Doppler velocity >200 cm/sec, or overt stroke with transfusion contra-indication or family refusal.
We retrospectively collected morbidity and mortality data for the first 10 years of the hydroxyurea therapy program of the Hematology Institute of Rio de Janeiro, Brazil (HEMORIO). We compared clinical and survival outcome among hydroxyurea-treated and untreated children, but since hydroxyurea was offered only to children ≥3 years of age, all analyses were restricted to patients 3–18 years old. The incidence of clinical events (hospitalization, ER visits, and transfusions) in the 12-month period prior to initiation of hydroxyurea was compared to that during the first year of treatment using the t-test, while survival analyses were done using the Log Rank Test.
Since 2000, 1643 children with SCD (1223 HbSS or HbSβ0-thalassemia, 291 HbSC, 35 HbSD, and 94 HbSβ+-thalassemia) were prospectively followed at our Center; 59% males, median age 7.7 years. Of these, 965 were between the ages of 3 and 18 years, and were therefore included in the analysis. A total of 224 patients (205 HbSS or HbSβ0-thalassemia, 7 HbSC, 3 HbSD, and 9 HbSβ+-thalassemia, 131 males) met criteria to initiate hydroxyurea treatment; median age at initiation was 6.0 years (range, 3.0–17.6). Hydroxyurea was started at 15 mg/kg/day, and escalated to a maximum of 30 mg/kg/day, or less if hematologic toxicity. Monthly visits were performed during dose escalation and then every 2–3 months, equivalent to patients not receiving hydroxyurea. The median treatment duration for the hydroxyurea-treated group was 1.9 years (range, 1.2 – 6.1) and median hydroxyurea dose was 20 mg/kg/day (range, 15 – 28). There was a significant reduction in hospitalization (67.9%, p=0.002), emergency room visits (48.7%, p <0.001), and transfusions (36.3%, p=0.001) during treatment with hydroxyurea. No serious adverse events attributed to hydroxyurea occurred. There were 46 deaths among patients 3 to 18 years of age: 44 (40 HbSS, 4 HbSC) among untreated patients and only two (both HbSS) taking hydroxyurea. The known causes of mortality in the untreated group were: ACS (17), sepsis (17), stroke (5), osteosarcoma (1), and car accident (1). In addition, three other deaths in the untreated group occurred at home for unknown reasons. The two deaths in the hydroxyurea-treated group were both due to ACS: a 6 year-old boy who had been adherent with hydroxyurea for 42 months at the dose of 25 mg/kg/day, and a 13 year-old boy who had been at a stable dose of 15 mg/kg/day for 3 years. The overall cumulative survival rate was 70.1% (95%CI: 56.4 – 87.2%). Cumulative survival rate at 10 and 17.9-years of age among hydroxyurea-treated children were 99.4% (95%CI: 98.2 – 100%) and 97.4% (95%CI: 93.3 – 100%), respectively, in contrast with 97.4% (95%CI: 96.6 – 98.6%) and 66.3% (95% CI: 51.6 – 85.3%) among those not treated (p=0.027). The OR for mortality was 4.6 times higher among untreated patients, in comparison with hydroxyurea-treated children (p=0.03).
These data indicate that 1) mortality for SCD remains high among Brazilian pediatric patients; (2) hydroxyurea therapy for clinical indications is feasible among young patients in Brazil and reduces incidence of acute events; and 3) hydroxyurea therapy may reduce mortality among children with SCD. Despite having a more severe clinical course, hydroxyurea-treated patients had a lower mortality rate in comparison with untreated ones. These are the first data supporting the hypothesis that hydroxyurea is associated with reduced mortality in children with SCD.
Off Label Use: Hydroxyurea to improve outcomes in SCD.
Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and lifethreatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone ...marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.
This study evaluated the oxidative stress and antioxidant capacity markers in sickle cell anemia (SCA) patients with and without treatment with hydroxyurea. We assessed
GSTT1,
GSTM1 and
GSTP1 ...polymorphisms in patients and a control group. The study groups were composed of 48 subjects without hemoglobinopathies and 28 SCA patients, 13 treated with HU SCA (+
HU), and 15 SCA patients not treated with HU SCA (−
HU). We observed a significant difference for
GSTP1 polymorphisms in SCA patients with the V/V genotype that showed higher glutathione (GSH) and Trolox equivalent antioxidant capacity (TEAC) (
p
=
0.0445 and
p
=
0.0360), respectively, compared with the I/I genotype. HU use was associated with a 35.2% decrease in the lipid peroxidation levels of the SCA (+
HU) group (
p
<
0.0001). Moreover, the SCA (+
HU) group showed higher TEAC as compared to the control group (
p
=
0.002). We did not find any significant difference in glutathione-S-transferase (GST) activity between the groups (
p
=
0.76), but the catalase (CAT) activity was about 17% and 30% decreased in the SCA (+
HU) and SCA (−
HU) groups, respectively (
p
<
0.00001). Whereas the plasma GSH levels were ~
2 times higher in the SCA patients than the control group (
p
=
0.0005). HU use has contributed to higher CAT activity and TEAC, and lower lipid peroxidation in patients under treatment. These findings may explain the influence of HU in ameliorating oxidative stress on SCA subjects.
To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has ...demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.
In patients with imatinib-resistant chronic myeloid leukemia (CML) treated with a second generation tyrosine kinase inhibitor (2GTKI), the initial molecular response at 3 months (3m-IMR) has been ...shown to be predictive of long-term outcomes. However, there is no consensus regarding the best cutoff for the BCR-ABL1 transcript levels, with 1% and 10% being proposed in different studies. Also, additional prognostic factors such as baseline tyrosine kinase (TK) mutations and a prognostic scoring system (PSS) (Jabbour, 2011) have been proposed. In this study, we addressed those issues in an homogeneous group of imatinib-resistant CML patients treated in a single center for a median follow-up of 36 months (14-60).
134 patients with a diagnosis of CML treated either with dasatinib (N=64) or nilotinib (N=70) due to imatinib failure were included. Imatinib failure was defined as any of the following: no complete hematologic response at 3 months, no cytogenetic response at 6 months, no major cytogenetic response at 12 months, no complete cytogenetic response (CCR) at 18 months, or loss of hematologic or cytogenetic response at any time. Patients with the T315I mutation were excluded. Molecular analysis was performed in a properly standardized laboratory every 3 months from the beginning of the 2GTKI, and results are presented according to the international scale. The study's primary endpoint was the 3-year event-free survival (EFS) after 2GTKI. Secondary endpoints were the best response levels attained under 2GTKI (BMR). The factors analysed were the 3m-IMR, age, gender, Sokal and EUTOS scores at diagnosis, failure to achieve a complete cytogenetic response, TK mutations, PSS score and type of 2GTKI. A multivariate analysis with the factors significant at P<0.2 in the univariate analysis for EFS was also performed.
There were 74 males and 60 females, with a median age of 46 years (4-79). The Sokal score was available in 93 patients: it was low in 25 (27%), intermediate in 24 (26%) and high in 44 patients (47%). The EUTOS score was low in 61 and high in 32 patients. The best cytogenetic response to imatinib was complete in 32 patients, major in 18, minor in 12, and minimal or no response in 72 patients. The 62 patients who attained at least a minor cytogenetic response lost it before starting the 2GTKI. TK mutations were present in 33 patients (105 tested). The PSS score was low-risk in 59 (44%), intermediate in 61 (46%) and high-risk in 14 (10%) patients. The 3m-IMR was < 1% in 59 (44%) patients, 1% to <10% in 35 (26%) patients and ≥ 10% in 40 patients (30%). During the study period there were 16 deaths and 60 events. The adverse prognostic factors for the 3-year EFS in the univariate analysis were: 3m-IMR response 1% to <10% (HR of 6.15, <0.001), 3m-IMR ≥ 10% (HR 16.98 , P<0.001), failure to achieve a CCR (HR 4.44, P=0.001), presence of TK mutations (HR 1.76, P=0.044) and a high PSS score (HR 3.00, P<0.001). In the multivariate analysis, only the 3m-IMR remained predictive for EFS (HR 7.6 for 1% to<10% and HR 20 for ≥ 10%). Finally, the 3m-IMR was associated with the best response to 2GTKI: CCR of 100%, 49% and 15% (P<0.001); major molecular response of 88%, 31% and 10% (P<0.001), and molecular response 4.0 of 57.6%, 11.4% and 7.5% (P<0.001) for BCR-ABL1 transcript levels < 1%, 1% to < 10% and > 10%, respectively.
BCR-ABL1 transcript levels at 3 months identified a good-risk group (BCR-ABL1< 1%) with 3y-EFS of 87%, an intermediate-risk group (BCR-ABL1 1% to <10%) with 3y-EFS of 47% and a poor-risk group (BCR-ABL1 ≥ 10%) with 3y-EFS of 11% (P<0.001) (figure1). The present results confirm, in an independent series, that the BCR-ABL1 transcript level at 3 months is the most relevant surrogate for response and long-term outcome following 2GTKI after imatinib-failure in CML patients.
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Boquimpani:BMS: Consultancy; Novartis: Consultancy, Research Funding. Lobo:Novartis: Research Funding. Spector:Novartis: Honoraria, Research Funding.
Objectives
Describe the treatment of patients with vaso‐occlusive crises (VOC) in a Brazilian emergency department (ED) and the successful switch from intravenous to oral morphine.
Patients and ...methods
We analyzed records of 315 patients with sickle cell disease using two different protocols for pain: one in March 2010 prescribing intravenous morphine every 4 h throughout their stay, and another in March 2011 and 2012 prescribing one initial dose of intravenous morphine followed by equianalgesic doses of oral morphine every 4 h. Patients were triaged into three groups: mild, moderate, and severe VOC. The mild group was treated within 1 h after triage, the moderate within 30 min and the severe was treated immediately. Patients whose pain was not relieved within 6 h after the first dose of morphine were transferred into a different holding area of the ED where they continued to receive the same treatment for 48 h after which they were hospitalized if still in pain.
Results
The number of patients who stayed <24 h in the ED increased significantly from 63 in 2010 to 87 in 2012, and the number of admissions decreased from 26 in 2010 to 10 in 2012. The incidence of acute chest syndrome decreased from 8.5% in 2010 to 1.9% in 2012.
Conclusion
Patients treated with oral morphine stayed a shorter time in the ED, had more pain relief, were admitted less frequently, and had less acute chest syndrome. These differences may be due to environmental, cultural, psychological, and pharmacogenetic factors.
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