Mês: junho 2017

Crianças com HIV podem ser a chave para cura

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Crianças com HIV podem ser a chave para cura

Um grupo de crianças soropositivas do sul da África pode ajudar a redirecionar a pesquisa por uma cura para o vírus. Elas nunca foram tratadas para o HIV, mas mantêm um sistema imunológico quase normal e não mostram sinais de progressão para AIDS, apesar de continuar a replicação viral.

O relato foi feito por pesquisadores da Universidade de Oxford, na Inglaterra. As 170 crianças analisadas se assemelham a alguns símios, como o macaco-verde africano, que podem ser infectados com o vírus da imunodeficiência símia (SIV) e têm altas cargas virais sem progressão da doença.

Segundo os pesquisadores, as crianças também compartilham três características imunológicas com os animais: apesar da infecção pelo HIV, a sua ativação imunológica é baixa; algumas de suas células imunes têm baixos níveis de CCR5, molécula utilizada pelo vírus como co-receptor para entrar nas células; e alta viremia. No relato, os pesquisadores explicam que o sistema imunológico das crianças está ignorando o vírus.

Tentativas

As tentativas de curar o HIV têm focado em reduzir a persistência do vírus em reservatórios de longa duração e aumentar a imunidade antiviral. Agora, o estudo sugere que a abordagem pode ter que ser combinada com um ataque imunológico.

Os pesquisadores acreditam que explorar novas estratégias terapêuticas além da terapia antirretroviral (ART), que bloqueiem o caminho entre a infecção por HIV e a Aids, pode ser útil na busca de uma cura. O objetivo seria permitir que crianças com HIV “finalmente conseguissem o livre controle antirretroviral da sua infecção.

 

Referências:

4 mitos sobre o antibiótico

Postado em Atualizado em

4 mitos sobre o antibiótico

O antibiótico foi inventado pelos seres humanos? Usar antibiótico por mais tempo é melhor para o paciente? Muito se sabe sobre esses medicamentos, o problema é que boa parte dessas informações não se baseia em nenhuma evidência clínica. Então, o que é realmente o certo? Veja quatro mitos:

Mito 1: humanos inventaram os antibióticos no século 20

O primeiro antibiótico clinicamente seguro e eficaz foi o Prontosil Rubrum, sulfonamina sintetizada em 1931. No entanto, este não foi o primeiro agente.

A análise genética indica que as bactérias inventaram os antibióticos e um mecanismo de resistência a eles há cerca de 2,5 bilhões de anos. As bactérias foram matando umas as outras com estas armas e usando mecanismos de resistência para se protegerem.

Para se ter uma ideia, em 2011 foi publicado um estudo em que pesquisadores exploraram uma caverna profunda no Novo México, nunca antes acessada por seres humanos. Eles cultivaram inúmeros tipos de bactérias nas paredes da caverna. Cada estirpe era resistente a, pelo menos, um antibiótico moderno; a maioria era multirresistente.

Mito 2: uso inapropriado de antibiótico desenvolve resistência

“Se pudéssemos eliminar o uso inapropriado de antibióticos, a resistência bacteriana não se desenvolveria”, esse mito é muitas vezes repetido, no entanto não é isso que mostram as evidências. Todo uso de antibióticos causa pressão seletiva na bactéria. O uso adequado aplica a mesma pressão seletiva do inadequado.

A verdadeira questão é que devemos sim parar o uso inadequado de antibióticos, mas porque este não oferece nenhum benefício. O uso apropriado é necessário para reduzir a mortalidade e morbilidade por infecções bacterianas.

Mito 3: para prevenir a resistência, os pacientes devem tomar todas as doses prescritas, mesmo depois de se sentirem melhor

Não há dados para apoiar a ideia de que continuar tomando antibióticos prescritos, mesmo após a melhora dos sintomas de infecção, reduz o aparecimento de resistência.

Na verdade, diversos estudos indicam que as terapias de curto período são menos propensas a criar resistência aos antibióticos. Cada ensaio clínico randomizado que já comparou terapias de curta duração com as de longo curso, em vários tipos de infecções agudas bacterianas (incluindo sinusite bacteriana aguda, pneumonia associada à ventilação mecânica, infecções do trato urinário, etc), descobriu que as de curto prazo são tão eficazes quanto.

Pacientes que se sentem melhor, sem mais nenhum dos sintomas de infecção, devem ser orientados a retornar ao médico para determinar se os antibióticos podem ser interrompidos mais cedo. Os profissionais de saúde devem estar receptivos a este conceito e não temer a personalização da duração do tratamento.

 

Mito 4: resistência é, geralmente, uma consequência de novas mutações no local da infecção

Este mito provavelmente deriva do conhecimento de que a resistência em tuberculose ocorre no local da infecção, devido à mutações espontâneas do tratamento. No entanto, a doença possui características distintas de outras infecções bacterianas.

No caso da tuberculose, a resistência só pode ocorrer no local de infecção porque não há reservatório ambiental e ela não faz parte da flora natural das pessoas. Suas cavidades também contêm densidades muito elevadas de bacilos (> 1012 por grama), que predispõem o surgimento de resistência em monoterapia.

Quando se utilizam antibióticos típicos (diferentes de isoniazida, que é específico para a tuberculose), eles  inevitavelmente causam uma pressão seletiva na flora bacteriana. Na maioria dos casos, a resistência não surge no local da infecção durante o tratamento, mas sim entre as bactérias no intestino ou na pele.

Orientações

A resistência aos antibióticos é inevitável e, por isso, é muito importante não desperdiçar seu uso. Eles não devem ser prescritos para pacientes sem infecções bacterianas. Além disso, não instrua os pacientes a tomar todas as doses prescritas, mesmo depois de melhora clínica. Explique que eles podem voltar para uma nova consulta e finalizar o tratamento mais cedo.

 

Referências:

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  • Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med. 2013;368:299-302.
  • Bhullar K, Waglechner N, Pawlowski A, et al. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One. 2012;7:e34953.
  • Rice LB. The Maxwell Finland Lecture: for the duration—rational antibiotic administration in an era of antimicrobial resistance and Clostridium difficile. Clin Infect Dis. 2008;46:491-496.
  • Spellberg B. The new antibiotic mantra—”shorter is better.” JAMA Intern Med. 2016;176:1254-1255.
  • Russo TA, Spellberg B, Johnson JR. Important complexities of the antivirulence target paradigm: a novel ostensibly resistance-avoiding approach for treating infections. J Infect Dis. 2016;213:901-903.
  • Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clin Infect Dis. 2004;38:864-870.
  • Girgis NI, Butler T, Frenck RW, et al. Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrob Agents Chemother. 1999;43:1441-1444.
  • Gasem MH, Keuter M, Dolmans WM, Van Der Ven-Jongekrijg J, Djokomoeljanto R, Van Der Meer JW. Persistence of salmonellae in blood and bone marrow: randomized controlled trial comparing ciprofloxacin and chloramphenicol treatments against enteric fever. Antimicrob Agents Chemother. 2003;47:1727-1731.
  • Arjyal A, Basnyat B, Koirala S, et al. Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial. Lancet Infect Dis. 2011;11:445-454.
  • Begum B, Haque MA, Ahmed MS, et al. Comparison between azithromycin and cefixime in the treatment of typhoid fever in children. Mymensingh Med J. 2014;23:441-448.
  • Cenizal MJ, Skiest D, Luber S, et al. Prospective randomized trial of empiric therapy with trimethoprim-sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prevalence of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2007;51:2628-2630.
  • Geisler WM, Pascual ML, Mathew J, et al. Randomized, double-blind, multicenter safety and efficacy study of rifalazil compared with azithromycin for treatment of uncomplicated genital Chlamydia trachomatis infection in women. Antimicrob Agents Chemother. 2014;58:4014-4019.
  • Nathan N, Borel T, Djibo A, et al. Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study. Lancet. 2005;366:308-313.
  • Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis. 2006;42:597-607.
  • Harbarth S, von Dach E, Pagani L, et al. Randomized non-inferiority trial to compare trimethoprim/sulfamethoxazole plus rifampicin versus linezolid for the treatment of MRSA infection. J Antimicrob Chemother. 2015;70:264-272.
  • Kaplan SL, Deville JG, Yogev R, et al; Linezolid Pediatric Study Group. Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children. Pediatr Infect Dis J. 2003;22:677-686.
  • Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C; Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother. 2005;49:2260-2266.
  • Wilcox MH, Tack KJ, Bouza E, et al. Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis. 2009;48:203-212.
  • Duke T, Poka H, Dale F, Michael A, Mgone J, Wal T. Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial. Lancet. 2002;359:474-480.
  • Asghar R, Banajeh S, Egas J, et al; Severe Pneumonia Evaluation Antimicrobial Research Study Group. Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-59 months in low resource settings: multicentre randomised controlled trial (SPEAR study). BMJ. 2008;336:80-84.
  • Ragnar Norrby S. Atypical pneumonia in the Nordic countries: aetiology and clinical results of a trial comparing fleroxacin and doxycycline. Nordic Atypical Pneumonia Study Group. J Antimicrob Chemother. 1997;39:499-508.
  • Mokabberi R, Haftbaradaran A, Ravakhah K. Doxycycline vs. levofloxacin in the treatment of community-acquired pneumonia. J Clin Pharm Ther. 2010;35:195-200.
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  • Jacobson SJ, Griffiths K, Diamond S, et al. A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children. Arch Pediatr Adolesc Med. 1997;151:701-704.
  • Allewelt M, Schuler P, Bolcskei PL, Mauch H, Lode H; Study Group on Aspiration Pneumonia. Ampicillin + sulbactam vs clindamycin +/- cephalosporin for the treatment of aspiration pneumonia and primary lung abscess. Clin Microbiol Infect. 2004;10:163-170.
  • Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest. 2005;127:1276-1282.
  • Rubinstein E, Cammarata S, Oliphant T, Wunderink R; Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis. 2001;32:402-412.
  • Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013;57:1756-1762.
  • Kohno S, Yamaguchi K, Aikawa N, et al. Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcus aureus in Japan. J Antimicrob Chemother. 2007;60:1361-1369.
  • Itani KM, Weigelt J, Li JZ, Duttagupta S. Linezolid reduces length of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents. 2005;26:442-448.
  • Itani KM, Dryden MS, Bhattacharyya H, Kunkel MJ, Baruch AM, Weigelt JA. Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus. Am J Surg. 2010;199:804-816.
  • San Pedro GS, Cammarata SK, Oliphant TH, Todisco T; Linezolid Community-Acquired Pneumonia Study Group. Linezolid versus ceftriaxone/cefpodoxime in patients hospitalized for the treatment of Streptococcus pneumoniae pneumonia. Scand J Infect Dis. 2002;34:720-728.
  • Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012;54:621-629.
  • Freire AT, Melnyk V, Kim MJ, et al; 311 Study Group. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010;68:140-151.
  • Bhavnani SM, Rubino CM, Hammel JP, et al. Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline. Antimicrob Agents Chemother. 2012;56:1065-1072.
  • Antibiotics: 5 Myths Debunked. Medscape. Oct 20, 2016.

Rx de tórax não detecta a maioria das fraturas de costela

Postado em

medico e paciente olhando uma radiografia

Rx de tórax não detecta a maioria das fraturas de costela

A crescente disponibilidade de tomografia computadorizada (TC) na avaliação de pacientes com traumatismo contuso inaugurou uma nova era, na qual os médicos estão diagnosticando muitas mais lesões do que no passado. Embora algumas dessas lesões possam levar a um efeito significativo no atendimento do paciente, a detecção de outras lesões menores pode levar a uma cascata de custos crescentes de atendimento com hospitalizações desnecessárias para o monitoramento.

As costelas são estruturas que, apesar de claramente visíveis à radiografia e TC, frequentemente deixam de ser examinadas pelo radiologista. Neste contexto, um estudo publicado no American College of Emergency Physicians foi realizado com o objetivo de caracterizar fraturas de costela e suas implicações clínicas nos protocolos atuais que frequentemente incorporam TC de tórax.

Dos 8.661 pacientes que tiveram radiografia de tórax e TC de tórax, 2.071 (23,9%) apresentaram fratura de costela e as fraturas de costela foram observadas na TC de tórax somente em 1.368 casos (66,1%). Os pacientes com fratura de costela apresentaram maiores taxas de admissão (88,7% versus 45,8%; diferença média: 42,9%; intervalo de confiança [IC] de 95%: 41,4% a 44,4%) e mortalidade (5,6% versus2,7%; diferença média: 2,9%, IC 95%:1,8 % a 4,0%) do que os pacientes sem fratura de costela.

A mortalidade de pacientes com fratura de costela observada na TC de tórax não foi estatisticamente diferente dos pacientes com fraturas também observadas em radiografia de tórax (4,8% versus 5,7%; diferença média: 0,9%; IC 95%: 3,1% a 1,1%).

Em relação a mortalidade, os pacientes com primeira ou segunda fratura de costela apresentaram mortalidade significativamente maior (7,4% versus 4,1%; diferença média: 3,3%; IC 95%: 0,2% a 7,1%) do que os pacientes com fraturas de costelas 3 a 12.

Com base nos resultados, dois terços das fraturas de costela foram observados apenas na TC de tórax. Pacientes com fraturas nas costelas apresentaram maiores taxas de admissão e mortalidade versusaqueles sem fratura. Primeira ou segunda fratura de costela foram associadas com mortalidade significativamente maior e grande lesão vascular.

Esses dados podem ser utilizados em futuras diretrizes e recomendações em relação à admissão, monitoramento e protocolos de imagem de tórax para pacientes adultos com traumatismo contuso.

 

Autora:

 

Referências:

  • Murphy CE, Raja AS, Baumann BM, Medak AJ, Langdorf MI, Nishijima DK, et al. Rib Fracture Diagnosis in the Panscan Era. Ann Emerg Med. 2017 May 27. pii: S0196-0644(17)30431-6. doi: 10.1016/j.annemergmed.2017.04.011. [Epub ahead of print]

Cirurgia bariátrica é uma opção terapêutica segura?

Postado em

médica medindo circuferencia abdominal de paciente obeso

Cirurgia bariátrica é uma opção terapêutica segura?

obesidade é uma pandemia mundial em rápido crescimento. A prevalência de sobrepeso e obesidade aumentou na população mundial. No Brasil, a prevalência de obesidade aumentou em 60% nos últimos 10 anos, passando de 11,8% em 2006 para 18,9% em 2016. O excesso de peso também subiu de 42,6% para 53,8% no mesmo período.

cirurgia bariátrica oferece uma opção de tratamento mais eficaz para a obesidade, e o número de cirurgias de perda de peso aumentou dramaticamente nos últimos anos. Apesar disso, ainda observa-se uma escassez de dados de mortalidade em estudos de longo prazo.

Recentemente uma revisão sistemática e metanálise foi publicada no Diabetes, Obesity and Metabolism a fim de investigar a mortalidade por todas as causas em curto (≤ 30 dias) e em longo prazo (≥2 anos) após a realização de cirurgia bariátrica.

Foram avaliados ensaios clínicos randomizados (ECRs) e estudos observacionais que relataram dados de mortalidade em pacientes adultos (≥ 18 anos de idade) submetidos à cirurgia bariátrica para obesidade (índice de massa corporal ≥ 35 kg/m2). Para a mortalidade em curto prazo, estudos elegíveis foram ECRs que relataram mortalidade perioperatória. Para a mortalidade em longo prazo, os estudos (ECRs e observacionais) que compararam a mortalidade entre pacientes obesos após a cirurgia bariátrica e controles não operados foram considerados.

A mortalidade por todas as causas em curto prazo baseada em 38 ECRs envolvendo 4.030 pacientes foi de 0,18% (intervalo de confiança [IC] de 95%: 0,04% a 0,38%) e foi maior para pacientes que realizaram cirurgia aberta (0,31%; IC 95%: 0,03% a 0,97%) do que laparoscópica (0,17%; IC 95%: 0,03% a 0,45%).

Para mortalidade em longo prazo, foram avaliados 12 estudos observacionais. Destes, 8 foram elegíveis para a metanálise, contemplando 23.647 pacientes operados e 89.628 controles obesos não operados. Todos os estudos mostraram uma diminuição da mortalidade em longo prazo para pacientes obesos após cirurgia bariátrica. A estimativa do efeito combinado mostrou redução na mortalidade por todas as causas de 41% (hazard ratio: 0,59; IC 95%: 0,52 a 0,67; p<0,001). Além disso, os pacientes operados apresentaram redução na mortalidade relacionada a doenças cardiovasculares (odds ratio [OR]: 0,42; IC 95%: 0,25 a 0,72; p<0,001) e na mortalidade relacionada ao câncer (OR: 0,47; IC 95%: 0,36 a 0,63; p<0,001) em comparação com os controles obesos não-operados.

Desta forma, pode-se concluir que a cirurgia bariátrica é uma opção terapêutica segura para a perda de peso, sendo associada a baixa mortalidade em curto prazo e pode estar associada a reduções em longo prazo na mortalidade por todas as causas, cardiovasculares e relacionada ao câncer.

 

Referências:

  • Cardoso L, Rodrigues D, Gomes L, Carrilho F. Short- and long-term mortality after bariatric surgery: A systematic review and meta-analysis. Diabetes Obes Metab. 2017 Feb 28. doi: 10.1111/dom.12922. [Epub ahead of print]

Mastocytosis

Postado em

  • Author: Jacquiline Habashy, DO, MSc; Chief Editor: Dirk M Elston, MD  more…

Background

Mastocytosis is a disorder characterized by mast cell proliferation and accumulation within various organs, most commonly the skin.

The World Health Organization (WHO) classification of mastocytosis includes the following [1, 2] :

  • Cutaneous mastocytosis – Urticaria pigmentosa, maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, mastocytoma of skin
  • Indolent systemic mastocytosis
  • Systemic mastocytosis with an associated (clonal) hematologic non–mast cell lineage disease
  • Aggressive systemic mastocytosis
  • Mast cell leukemia
  • Mast cell sarcoma
  • Extracutaneous mastocytoma [1, 2]

This article focuses on cutaneous mastocytosis (CM). The single World Health Organization (WHO) major criterion is multifocal dense infiltrates of mast cells in bone marrow and/or other extracutaneous organs. One major and 1 minor criterion or 3 minor diagnostic criteria are needed to establish a diagnosis of systemic mastocytosis. Minor criteria include baseline total tryptase level of greater than 20 ng/mL; greater than 25% of the mast cells in bone marrow aspirate smears or tissue biopsy sections having spindle atypical morphology; mast cells in bone marrow, blood, or other lesional tissue expressing CD25 or CD2; or detection of a codon 816 c-kit point mutation in blood, bone marrow, or lesional tissue. [3]

Types of cutaneous mastocytosis include solitary mastocytoma, diffuse erythrodermic mastocytosis, paucicellular mastocytosis (also termed telangiectasia macularis eruptiva perstans [TMEP]), and urticaria pigmentosa (UP). Urticaria pigmentosa is the most common form and is characterized by oval or round red-brown macules, papules, or plaques ranging in number from a few to thousands (see images below).

Urticaria pigmentosa lesions on the face of a chil Urticaria pigmentosa lesions on the face of a child. Courtesy of Lee H. Grafton, MD.

Urticaria pigmentosa lesions on the back of a chil Urticaria pigmentosa lesions on the back of a child. Courtesy of Lee H. Grafton, MD.

Lesions may vesiculate in infancy (see image below).

Lesion on the scalp of an infant. Lesion on the scalp of an infant.

When a urticaria pigmentosa or mastocytoma lesion is stroked, it typically urticates, becoming pruritic, edematous, and erythematous. This change is referred to as the Darier sign, which is explainable on the basis of mast cell degranulation induced by physical stimulation. Uncontrolled stroking of mastocytomas should be avoided in patients who have had a systemic reaction such as miosis and asthmalike symptoms in their past. [4] The Darier sign usually is not positive in patients with TMEP because the lesions are paucicellular, and, therefore, mast cells may not be present in sufficient numbers for significant degranulation to occur. See the images below.

Positive Darier sign on a child's back. Positive Darier sign on a child’s back.

Urticaria pigmentosa on a child. Urticaria pigmentosa on a child.

Pathophysiology

Mastocytosis is now classified with the myeloproliferative neoplasms. [5] Increased local concentrations of soluble mast cell growth factor in lesions of cutaneous mastocytosis are believed to stimulate mast cell proliferation, melanocyte proliferation, and melanin pigment production. The induction of melanocytes explains the hyperpigmentation that commonly is associated with cutaneous mast cell lesions. The stimulation of pruritus seen in mastocytosis is associated with the production of interleukin (IL)–31. [6] Impaired mast cell apoptosis has been postulated to be involved, as evidenced by up-regulation of the apoptosis-preventing protein BCL-2 demonstrated in patients with mastocytosis. [7] Activating mutations of the proto-oncogene c-kit have been identified but do not explain the initiation of the disease. [8] IL-6 levels have been shown to be elevated and correlated with disease severity, indicating interleukin 6 is involved in the pathophysiology of mastocytosis. [9]

Although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with D816V and other activating c-kit mutations. [10]

Research from 2016 has shown that there are varied gene expressions in patients with mastocytosis and associated allergies. Those with associated food allergies have an elevated expression of the TRAF4 gene. [11] In the same study, patients who had an allergy to insect venom had a decreased gene expression of B3GAT1.

Associated systemic manifestations are believed to reflect the release of mast cell–derived mediators, such as histamine, prostaglandins, heparin, neutral proteases, and acid hydrolases. Symptoms and signs induced by mediators may include headache, neuropsychiatric symptoms (cognitive disorganization), flushing, dizziness, tachycardia, hypotension, syncope, anorexia, nausea, vomiting, abdominal pain, and diarrhea. The skeletal, hematopoietic, gastrointestinal (GI), cardiopulmonary, and central nervous systems may be involved either directly, via mast cell infiltration, or indirectly, via mast cell mediator release.

Epidemiology

Frequency

Of new patients visiting dermatology clinics, 0.1-0.8% have some form of mastocytosis. Maculopapular cutaneous mastocytosis is the most common subgroup found in children, at approximately 47-75% of cases. There are approximately 17-51% of mastocytoma and 1-5% of diffuse cutaneous mastocytoma in pediatric cases as well. [12]

Race

Most reported cases are in whites. The cutaneous lesions of most types of mastocytosis are less visible in persons with more heavily pigmented skin.

Sex

Mastocytosis affects males and females equally (no known sex predilection).

Age

Most patients with mastocytosis are children; 75% of cases occur during infancy or early childhood and usually resolve by puberty. Mastocytosis incidence peaks again in patients aged 30-49 years.

Prognosis

The prognosis depends on the age of onset. Most patients with urticaria pigmentosa (UP) exhibit onset before age 2 years, which is associated with an excellent prognosis, often with resolution by puberty. The number of lesions diminishes by approximately 10% per year. However, acute extensive degranulation rarely can cause life-threatening episodes of shock.

Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Serum baseline total tryptase to predict the need for daily antimediator therapy, hospitalization, and episodic management in an ICU were 6.6, 15.5, and 30.8 μg/L, respectively. [13]

Slight improvement of skin symptoms, reflected by decrease of SCORing MAstocytosis Index, with decline in serum tryptase levels is the typical course in patients with diffuse cutaneous mastocytosis. [14] Systemic mastocytosis may occur more frequently in diffuse cutaneous mastocytosis patients. [15] Patients with adult or adolescent-onset urticaria pigmentosa are more likely to have persistent disease and are at greater risk for systemic involvement. Juvenile-onset systemic mastocytosis has a malignant transformation rate as high as 7%, whereas adult-onset systemic mastocytosis has a malignant transformation rate as high as 30%.

Rarely, mast cell leukemia may develop in young adults with persistent maculopapular cutaneous mastocytosis. [16]

Primary cutaneous mast cell sarcoma due to the transformation of a benign solitary mastocytoma in an adult has been reported. [17]

Cutaneous mastocytosis onset after age 10 years portends a poorer prognosis, because late-onset disease tends to be persistent, is associated more often with systemic disease, and carries a higher risk of malignant transformation.

In patients with systemic mastocytosis, regression of urticaria pigmentosa is associated with a decreased frequency and severity of other symptoms. Bone marrow findings do not change with regression of urticaria pigmentosa.

One study shows that anaphylaxis is common in patients with mastocytosis (4.3-5.5% per year disease duration) and appears higher than in the healthy population. In childhood, the risk of anaphylactic episodes has been shown to be limited to those with extensive blistering skin disease, but nonexistent for children with mastocytoma or limited disease. In adults, anaphylactic episodes generally appear to be more severe in patients with extensive systemic disease. [18]

Patient Education

Instruct cutaneous mastocytosis patients about avoiding physical stimuli and substances that trigger the condition. Additionally, educate patients and/or parents about the signs and treatment of anaphylaxis, especially in patients with systemic disease or severe symptoms.

Advise mastocytosis patients with systemic disease or extensive symptoms to wear a medical alert bracelet and carry injectable epinephrine in case of an acute event causing mast cell degranulation and subsequent shock. Adults have been reported with severe anaphylaxis after insect stings, especially hymenoptera stings. [19]

History

Mastocytosis patients may present with cutaneous lesions, systemic symptoms of an acute nature, and/or chronic systemic symptoms.

Most patients have pruritic cutaneous lesions. Some patients, especially those with extensive cutaneous disease, experience acute systemic symptoms exacerbated by certain activities or ingestion of certain drugs or foods. Possible systemic symptoms include flushing, headache, dyspnea, wheezing, rhinorrhea, nausea, vomiting, diarrhea, and syncope.

Patients also may have chronic systemic symptoms involving various organ systems. Involvement of the skeletal system may be manifested as bone pain or the new onset of a fracture. Long-term exposure to heparin and stem cell factor from degranulated mast cells is believed to put patients at risk for osteoporosis. [20]  Involvement of the central nervous system may produce neuropsychiatric symptoms, as well as nonspecific changes such as malaise and irritability. GI involvement may yield weight loss, diarrhea, nausea/vomiting, and abdominal cramps. Cardiovascular effects can include shock, syncope (resulting from vascular dilatation), or angina. Anaphylactic reactions to hymenoptera stings may be the first sign of mastocytosis.

Physical Examination

The most common physical findings in mastocytosis involve the skin, liver, spleen, and cardiovascular system.

Skin lesion types are as follows:

  • Macules, papules, nodules, and plaques (see image below)

    Lesion on the arm. Courtesy of Lee H. Grafton, MD. Lesion on the arm. Courtesy of Lee H. Grafton, MD.

  • Blisters and bullae in children (see image below)

    Blistering lesion. Blistering lesion.

  • Diffuse induration
  • Isolated nodule or tumor

Skin distribution findings are as follows:

  • Widespread symmetric distribution
  • Trunk involved more than extremities
  • Tendency to spare the face, scalp, palms, and soles; however, a patient with scarring alopecia has been reported [25]

Skin lesion color, quantity, and size findings are as follows:

  • Yellow-tan to red-brown
  • From 1 to more than 1000
  • From 1 mm to several centimeters

Skin special characteristics are as follows:

  • Darier sign: Wheal and surrounding erythema develop in a lesion after rubbing it.
  • Dermatographism: In approximately half the patients, stroking macroscopically uninvolved skin produces dermographia.
  • Flushing: Flushing may occur spontaneously following skin stroke or after ingesting a mast cell degranulating agent.
  • Diffuse cutaneous mastocytosis (DCM): This is rare and is characterized by mast cell infiltration of the entire skin.
  • Other: Large hemorrhagic bullous and infiltrative small vesicular variants occur. Blistering predominates in infancy, whereas grain-leather appearance of the skin and pseudoxanthomatous presentation develop with time. Anaphylactic shock may occur.

Liver findings include possible hepatomegaly, which is present in 40% of adult patients with systemic mastocytosis.

Spleen findings include possible splenomegaly, which is present in 50% of patients with systemic mastocytosis.

Cardiovascular findings include hypotension and tachycardia.

Gastrointestinal findings include abdominal pain, diarrhea, vomiting, and weight loss (frequency of involvement currently uncharacterized in patients with systemic mastocytosis). [26]

Causes

Mastocytosis probably is a hyperplastic response to an abnormal stimulus. Rare cases of familial urticaria pigmentosa have been recorded. [21] Rarer cases of cutaneous mastocytosis have been associated with radiotherapy fields in patients with breast cancer. [22]

One case report describes an apparent temporal association between the development of cutaneous mastocytosis and HIV seroconversion, proposing similarities of immunoglobulin E receptors on mast cells and basophils and the association of basophils in HIV pathophysiology. [23]

Autism spectrum disorders may be increased in children with mastocytosis. [24]

Complications

Complications may include the following:

  • Possible transformation into a hematologic malignancy
  • Death secondary to mast cell degranulation
  • Mast cell leukemia

    Diagnostic Considerations

    Also consider the following:

    • Generalized eruptive histiocytoma
    • Histiocytosis X
    • Non-X histiocytosis of childhood
    • Secondary syphilis
    • Xanthogranuloma [27]
    • Carcinoid [28]
    • Leiomyoma [12]

    Differential Diagnoses

    • Achlorhydria

    • Cafe Au Lait Spots

    • Carcinoid

    • Congenital melanocytic nevus

    • Congenital smooth muscle hamartoma

    • Cutaneous Pseudolymphoma

    • Dermatologic Manifestations of Herpes Simplex

    • Epidermolysis Bullosa

    • Juvenile Xanthogranuloma

    • Leiomyoma

    • Lentigo

    • Linear IgA Dermatosis

    • Lymphocytoma Cutis

    • Nodular Localized Cutaneous Amyloidosis

    • Postinflammatory Hyperpigmentation

      Laboratory Studies

      In many patients, urticaria pigmentosa (UP) can be diagnosed when history and physical examination findings reveal the characteristic lesions that demonstrate the Darier sign. Usually, a skin biopsy is a necessary confirmatory test, typically through a 3- or 4-mm punch biopsy. It may be helpful to complete two biopsies, one of the suspected lesion and the other of unaffected skin, in order to compare the presence of mast cells. For aid in the diagnosis, the following stains are recommended to be completed with biopsy: hematoxylin, eosin, toluidine blue, Giemsa, and monoclonal antibodies to tryptase, CD117 and KIT. [12]

      Consider the following laboratory tests:

      • CBC count: In systemic mastocytosis, CBC counts may reveal anemia, thrombocytopenia, thrombocytosis, leukocytosis, and eosinophilia.
      • Plasma or urinary histamine level: Patients with extensive cutaneous lesions may have 24-hour urine histamine excretion at 2-3 times the normal level.
      • Total tryptase level: Tryptase is a marker of mast cell degranulation released in parallel with histamine. Total tryptase levels in plasma correlate with the density of mast cells in urticaria pigmentosa lesions in adults with systemic mastocytosis. Patients with only cutaneous mastocytosis typically have normal levels of total tryptase. Total tryptase values are recommended by the WHO as a minor criterion for use in the diagnostic evaluation of systemic mastocytosis. [1, 2, 29] The total tryptase level in serum or plasma seems to be a more discriminating biomarker than urinary methylhistamine for the diagnosis of systemic mastocytosis. [29] Most patients with systemic anaphylaxis of sufficient severity to result in hypotension have elevated serum or plasma beta-tryptase levels. During insect sting–induced anaphylactic hypotension, beta-tryptase levels in the circulation are maximal 15-120 minutes after the sting. [29]

      WHO major criteria for the diagnosis of systemic mast cell disease include the following [19] :

      • Multifocal dense infiltrates of mast cells (>15 close to each other) observed in bone marrow biopsy specimens and/or mast cells stained for tryptase in biopsy specimens from other extracutaneous organs.

      WHO minor major criteria for the diagnosis of systemic mast cell disease include the following [19] :

      • Mast cells in bone marrow, or other extracutaneous organs show abnormal (spindling) morphology (>25%) or the presence of greater than 25% atypical mast cells in bone marrow aspirates
      • Demonstration of c- kit point mutation on codon 816 in bone marrow, blood, or other extracutaneous organs
      • CD117 (c-kit receptor)–positive cells, also positive for CD2 and/or CD25
      • Serum tryptase values greater than 20 ng/mL [2]

      Imaging Studies

      Bone scan and radiologic survey

      Obtain a bone scan and radiologic survey in nonpediatric patients or if the CBC count is abnormal in a young child. If a patient has skeletal system symptoms, perform a bone scan and radiologic survey to identify lytic bone lesions, osteoporosis, or osteosclerosis.

      GI workup (upper GI series, small bowel radiography, CT scanning, endoscopy)

      If a patient has GI symptoms, order a GI workup to identify peptic ulcers, abnormal mucosal patterns, or motility disturbances.

      Other Tests

      If a diagnosis of mastocytosis is uncertain, tests for elevated mast cell mediators and degradation products may help establish the diagnosis.

      Serum tryptase level

      Tryptase levels are elevated in patients with mastocytosis. Tryptase levels may be more useful than histamine levels, because histamine can be elevated in hypereosinophilic states.

      Urinary N-methylhistamine (NMH) and N-methylimidazoleacetic acid levels

      Urinary NMH and N-methylimidazoleacetic acid levels [30, 31]  may be more specific and sensitive than urinary histamine levels. NMH levels correlate directly with the extent of skin lesions. NMH levels decrease with age; therefore, consider the patient’s age when interpreting results.

      Urinary prostaglandin D2 metabolite level

      Even during asymptomatic periods, urinary prostaglandin D2 metabolites levels may range from 1.5-150 times higher than normal levels. This test is not widely available.

Novel Nondrug Approach May Help Chronic Pain

Postado em

Nancy A. Melville

PITTSBURGH — An innovative psychotherapeutic intervention involving the deconstruction of the emotional response to pain and the use of mindfulness to gain more control shows some efficacy as a nonpharmacologic approach to not only manage of chronic pain but also  reduce misuse of opioids.

The intervention, called mindfulness-oriented recovery enhancement (MORE), integrates aspects of mindfulness with other facets of psychotherapy, said its developer, Eric Garland, PhD, associate dean for research in the College of Social Work at the University of Utah, Salt Lake City, in presenting the research here at the American Pain Society (APS) 2017 Annual Scientific Meeting.

“MORE unites complementary aspects of mindfulness training, third-wave cognitive-behavioral therapy (CBT), and principles of positive psychology,” he said.

The therapy, detailed on Dr Garland’s website, specifically targets the hedonic dysregulation that occurs with addiction, stress, and chronic pain and focuses on three components: mindfulness, involving attentional control; reappraisal, involving psychological flexibility; and savoring, with a focus on reward processing.

Aspects of the approach specifically strive to deconstruct the emotional responses that can perpetuate and worsen chronic pain and to use visualization tools to gain perspective, Dr Garland said.

“Some chronic pain patients experience pain emotionally as an unchanging entity over which they lay a layer suffering, saying things like ‘Why me?’ and ‘This pain is ruining my life’.”

“We teach patients skills to remove the emotional overlay and to decompose the experience into subcomponent sensory sensations,” he said.

“For example, rather than experiencing the pain as this terrible anguish and emotional experience, we ask patients to focus on the pain as a cluster of sensations of heat, or tightness or tingling, as well as to pay attention to the spaces between such sensations, when there is no sensation at all.

“Coping with any one of the sensations may be more manageable than the monolithic experience of pain as a whole.”

Another session of the intervention involves focusing mindfully on a bouquet of flowers to generate and shift emotional reward from a natural reward as opposed to a drug-related source.

In a randomized, controlled trial of the intervention published in 2014, 115 patients with chronic pain for a mean of 10.4 years were randomly assigned to the MORE intervention or a standard support group for 8 weeks. Those in the MORE group showed significant reductions in pain severity.

Several recent studies have further demonstrated significant improvements in chronic pain associated with the intervention, including an indirect effect of reinterpretation of pain sensations and nonreactivity to aversive experiences, Dr Garland said.

“The studies showed the effects of MORE were driven by the capacity to reinterpret pain as innocuous sensory information as well as having nonreactivity to stressful thoughts and emotions,” he added

A subanalysis published this year in Drug and Alcohol Dependence using data from the study showed intriguing improvements in positive affect and reductions in misuse associated with the intervention.

The findings specifically showed greater improvements in measures of momentary pain (P = .01) and positive affect (P = .004) in the MORE group compared with the support group, and over the course of treatment, patients were significantly more likely to exhibit positive affect regulation (odds ratio, 2.75).

Additionally, improvements in positive affect (but not pain) during the intervention were associated with reduced risk of misusing opioids by post-treatment (P = .02).

Another analysis of the data, published in February in the Clinical Journal of Pain, showed a positive effect of MORE on deficits in hedonic capacity that can occur in chronic pain, characterized by increased sensitivity to aversive states and insensitivity to natural rewards.

In the analysis, dispositional mindfulness among those in the MORE group, assessed with the Five Facet Mindfulness Questionnaire, was associated with hedonic capacity scores, assessed on the Snaith-Hamilton Anhedonia and Pleasure Scale (P < .001).

“In light of this association, it is plausible that interventions that increase mindfulness may reduce pain-related impairment among opioid-using patients by enhancing hedonic capacity,” the authors conclude.

Dr Garland concluded that the MORE approach could have highly powerful effects.

“Teaching patients to ‘take in the good’ and mindfully savor natural, healthy pleasures may provide the learning signal needed to restore adaptive hedonic regulation and, ultimately, reverse addiction,” he said.

Dr Garland has disclosed no relevant financial relationships.

American Pain Society (APS) 2017 Annual Scientific Meeting.  Presented May 20, 2017.

 

Antioxidante no brócolis pode ajudar a combater o diabetes

Postado em

Dra. Veronica Hackethal

Um antioxidante chamado sulforafano, encontrado no brócolis, pode oferecer uma nova opção para o tratamento do diabetes tipo 2, de acordo com um estudo publicado on-line em 14 de junho no periódico Science Translational Medicine.

“Identificamos uma substância denominada sulforafano com ação comprovada na redução da exacerbação da produção hepática de glicose, que é um mecanismo central do diabetes tipo 2”, disse ao Medscape o primeiro autor do estudo, o Dr. Anders Rosengren, médico da Universidade de Gotemburgo (Göteborgs universitet) na Suécia.

O trabalho é o primeiro a demonstrar que o sulforafano tem como alvo o aumento da produção hepática de glicose no diabetes tipo 2.

Esta pesquisa é incomum na medida em que começou como uma pesquisa genética para identificar alguma substância que pudesse ser uma boa candidata, e os pesquisadores então realizaram vários testes em linhagens celulares e em animais, até chegar aos humanos.

“Muitos estudos proclamaram os benefícios de diferentes componentes alimentares, mas poucos investigaram o mecanismo deles”, explicou o Dr. Rosengren.

O estudo utilizou extrato de brócolis muito concentrado, o que equivaleria a comer cerca de cinco quilos de brócolis por dia. Como é quase impossível comer essa quantidade de brócolis, o sulforafano precisa ser tomado como extrato ou concentrado. Estudos anteriores analisaram o extrato de brócolis no câncer e nas doenças inflamatórias, e constataram que ele tem poucos efeitos colaterais.

“Pensamos que o extrato de brócolis pode ser um acréscimo muito interessante aos tratamentos que já temos”, disse o Dr. Rosengren. “Quando o administramos aos pacientes e dosamos a glicemia antes e 12 semanas após o tratamento, observamos melhora significativa da glicemia de jejum e da HbA1c em pacientes obesos com diabetes tipo 2 descompensada.

Os resultados são “muito instigantes”, acrescentou, ressaltando, no entanto, que é necessário realizar mais estudos antes do extrato poder ser recomendado para os pacientes com diabetes.

De ratos a homens…

Os pesquisadores usaram dados de expressão gênica para identificar uma rede de 50 genes que participam da produção hepática exacerbada de glicose no diabetes tipo 2. A seguir, testaram 3.800 substâncias, e usaram modelos matemáticos para ver qual fazia a melhor modulação negativa dos genes com expressão exagerada. Assim o sulforafano foi identificado como o principal candidato.

Outros estudos mostraram que o sulforafano diminuiu a produção da glicose nas células hepáticas de ratos. Os pesquisadores então examinaram o sulforafano em ratos e camundongos com diabetes induzido por dieta, e descobriram que a substância evitou o surgimento da intolerância à glicose. Ela também melhorou a tolerância à glicose nos animais que já tinham intolerância à glicose, em grau similar ao proporcionado pela metformina.

Por fim, os pesquisadores testaram o sulforafano em um ensaio clínico randomizado e duplo-cego, controlado com placebo, em humanos com diabetes tipo 2.

Todos os participantes estavam tomando metformina – 60 tinham diabetes compensado enquanto 37 tinham diabetes descompensado (20 eram não obesos e 17 eram obesos). Os participantes foram randomizados para receber extrato de brócolis ou placebo durante 12 semanas.

No grupo do extrato de brócolis, os níveis de HbA1c diminuíram significativamente após 12 semanas (P = 0,004), enquanto o grupo do placebo não mostrou diferença em relação ao início do estudo (P = 0,5).

Os participantes que iniciaram o estudo com diabetes descompensado apresentaram redução significativa da glicemia de jejum com o extrato de brócolis em comparação com o placebo (P = 0,233). E, especificamente, nos pacientes obesos com diabetes descompensado que receberam extrato de brócolis, tanto a glicemia de jejum quanto a HbA1c diminuíram significativamente em comparação com o placebo (P = 0,036 e P = 0,034, respectivamente).

No entanto, o extrato de brócolis não demonstrou efeito nos participantes com diabetes compensado.

Alguns pacientes que receberam o extrato apresentaram desconforto gastrointestinal e flatulência. Mas estes sintomas desapareceram após os primeiros dias, e não houve diferença significativa de efeitos adversos entre o grupo do extrato de brócolis e o do placebo.

Qual é o potencial mecanismo?

O trabalho também identificou um possível mecanismo para os efeitos do sulforafano nesses pacientes – a modificação de um fator de transcrição chamado fator nuclear 2 (eritroide-2) (Nrf2, do inglês Nuclear factor (erythroid-derived 2)-like 2), que promove modificações hepáticas de modo a diminuir a expressão das principais enzimas envolvidas na produção de glicose.

Os pacientes obesos podem se beneficiar mais do extrato porque a produção hepática de glicose é particularmente exacerbada na obesidade, explicou o Dr. Rosengren.

“Mais estudos são necessários, no entanto, antes de que o extrato de brócolis possa ser recomendado para os pacientes”, reiterou o pesquisador.

Dr. Rosengren e colaboradores planejam agora testar o extrato de brócolis nas pessoas com pré-diabetes para ver se ele pode ajudar a prevenir a doença.

Atualmente, os pesquisadores estão trabalhando com uma organização de fazendeiros suecos chamada Lantmännen para disponibilizar o extrato formulado como alimento funcional.

O estudo foi patrocinado pela Lunds Universitet. A Lantmännen forneceu o extrato de brócolis e o placebo para o estudo, e o Lantmännen Research Fund financiou parte do estudo. A Lantmännen informa não ter nenhuma influência nos procedimentos do estudo, na análise dos dados ou na interpretação de dados. Dr. Anders Rosengren informa não ter conflitos de interesse relacionados ao tema. Dois coautores são inventores de pedidos de patentes apresentados pela Lunds Universitet, que cobrem o uso do sulforafano para o tratamento da produção exacerbada de glicose hepática. Os direitos de uso desta patente foram concedidos para a Lantmännen.

Sci Transl Med. Publicado on-line em 24 de junho de 2017.