Analysis of 9 cases of drug induced hypersensitivity syndrome related hemophagocytic lymphohistiocytosis / 中华儿科杂志

Objective: To analyze the clinical features,treatment and prognosis of drug induced hypersensitivity syndrome related hemophagocytic lymphohistiocytosis (DIHS-HLH). Methods: This was a retrospective case study. Clinical characteristics, laboratory results, treatment and prognosis of 9 patients diagnosed with DIHS-HLH in Beijing Children's hospital between January 2020 and December 2022 were summarized. Kaplan-Meier survival analysis was used to calculate the overall survival rate. Results: Among all 9 cases, there were 6 males and 3 females, with the age ranged from 0.8 to 3.1 years. All patients had fever, rash, hepatomegaly and multiple lymph node enlargement. Other manifestations included splenomegaly (4 cases), pulmonary imaging abnormalities (6 cases), central nervous system symptoms (3 cases), and watery diarrhea (3 cases). Most patients showed high levels of soluble-CD25 (8 cases), hepatic dysfunction (7 cases) and hyperferritinemia (7 cases). Other laboratory abnormalities included hemophagocytosis in bone marrow (5 cases), hypofibrinogenemia (3 cases) and hypertriglyceridemia (2 cases). Ascending levels of interleukin (IL) 5, IL-8 and interferon-γ (IFN-γ) were detected in more than 6 patients. All patients received high dose intravenous immunoglobulin, corticosteroid and ruxolitinib, among which 4 patients were also treated with high dose methylprednisolone, 2 patients with etoposide and 2 patients with cyclosporin A. After following up for 0.2-38.6 months, 7 patients survived, and the 1-year overall survival rate was (78±14)%. Two patients who had no response to high dose immunoglobulin, methylprednisolone 2 mg/(kg·d) and ruxolitinib died. Watery diarrhea, increased levels of IL-5 and IL-8 and decreased IgM were more frequently in patients who did not survive. Conclusions: For children with fever, rash and a suspicious medication history, when complicated with hepatomegaly, impaired liver function and high levels of IL-5 and IL-8, DIHS-HLH should be considered. Once diagnosed with DIHS-HLH, suspicious drugs should be stopped immediately, and high dose intravenous immunoglobulin, corticosteroid and ruxolitinib could be used to control disease.

Transfusion-related acute lung injury associated to intravenous immunoglobulin infusion in a pediatric patient / Lesão pulmonar aguda relacionada à transfusão associada com infusão de imunoglobulina intravenosa em paciente pediátrico

ABSTRACT Case report of a patient with an immunodeficiency who demands regular replacement of intravenous immunoglobulin. She presented an episode of transfusion-related acute lung injury shortly after using an immunoglobulin product different than the one she usually received. The patient evolved with respiratory changes (hypoxia, dyspnea, change in pulmonary auscultation) minutes after the end of the infusion, and received non-invasive respiratory support. She was discharged after 36 hours with good outcome. The patient achieved full recovery, showing no further reactions in subsequent immunoglobulin infusions (no longer receiving the product that was used when she had the episode of transfusion-related acute lung injury). Although rare, this reaction is potentially serious and has no specific treatment other than supportive therapy. The literature is scarce regarding the risk of recurrence. The decision on whether to proceed with immunoglobulin therapy after this adverse effect should be analyzed individually, assessing the possible risks and benefits for the patient.

RESUMO Relato de caso de paciente com imunodeficiência que necessitava de reposição regular de imunoglobulina endovenosa. Ela apresentou um episódio de lesão pulmonar aguda relacionada à transfusão após uso de produto de imunoglobulina diferente daquele que recebia habitualmente. Evoluiu com alterações respiratórias (hipóxia, dispneia e alteração de ausculta pulmonar) minutos após o fim da infusão, necessitando de suporte respiratório não invasivo. A paciente recebeu alta hospitalar após 36 horas, com boa evolução. Obteve recuperação total dos sintomas, sem mais reações nas infusões subsequentes de imunoglobulina (sendo optado por não mais prescrever o produto que foi usado quando ocorreu o episódio de lesão pulmonar aguda relacionada à transfusão). Apesar de rara, essa reação é potencialmente grave, não possui tratamento específico além de terapia de suporte, e há pouca informação na literatura sobre o risco de recorrência. A decisão sobre o seguimento da terapia com imunoglobulina após esse efeito adverso deve ser analisada individualmente, avaliando os possíveis riscos e benefícios para o paciente.

Análise de prescrições de imunoglobulina humana endovenosa para situações clínicas não referendadas nos protocolos clínicos nacionais / Analysis of intravenous human immunoglobulin prescriptions for clinical situations not referenced in national clinical protocols

Objetivo: Avaliar para quais indicações clínicas a imunoglobulina humana está sendo utilizada, considerando ser esse um medicamento de alto custo e autorizado pelos protocolos nacionais para diagnósticos específicos. Métodos: Trata-se de um estudo transversal, retrospectivo, baseado na busca de informações através do prontuário eletrônico dos pacientes do Hospital de Clínicas de Porto Alegre no período de janeiro a dezembro de 2015. Resultados: Foram identificadas 191 prescrições, totalizando 116 pacientes que tiveram prescrita a imunoglobulina humana endovenosa (IGIV). Desses pacientes, 27 casos foram relacionados a 6 tipos de doenças autoimunes e que apresentam protocolos definidos. Esses protocolos auxiliam os profissionais da saúde quanto aos cuidados necessários de manejo medicamentoso. Os demais casos identificados não constam nas indicações previstas nos protocolos do Ministério da Saúde e representam mais de 75% dos pacientes atendidos. Não foram identificados efeitos colaterais sistêmicos ou periféricos em nenhum caso. Conclusão: Foi possível identificar para quais indicações clínicas está sendo realizada a administração de IGIV, evidenciando-se a necessidade de ampliação desse estudo para outras instituições, como forma de sinalizar a necessidade de administração desse hemoderivado devido a segurança e efetividade no tratamento.

Objective: To evaluate clinical indications for human immunoglobulin, taking into consideration that this is a high-cost drug and authorized by national protocols for specific diagnoses. Methods: This was a cross-sectional, retrospective study based on information collected from electronic medical records of patients treated at Hospital de Clínicas of Porto Alegre from January to December 2015. Results: A total of 191 prescriptions of intravenous human immunoglobulin (IVIG) were identified, totaling 116 patients. Of these patients, 27 presented six types of autoimmune diseases that have established protocols. These protocols assist health professionals in taking all the necessary measures during medication management. The remainder of the cases identified had diseases that are not included in the indications of the protocols of the Brazilian Ministry of Health, and they accounted for more than 75% of the patients treated. No systemic or peripheral side effects were identified in any case. Conclusion: It was possible to identify the clinical indications for the prescription of IVIG, evidencing the need to replicate this study in other institutions, as a way of signaling the need to administer this blood product, considering the safety and effectiveness of the treatment.

Esteroides asociados a inmunoglobulina intravenosa en el tratamiento del Síndrome de Stevens-Johnson y necrólisis epidérmica tóxica / Steroids associated with intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis

Introducción: La necrólisis epidérmica tóxica (NET) y el síndrome de Stevens-Johnson (SSJ) son reacciones cutáneas raras, graves y potencialmente mortales asociadas principalmente al uso de medicamentos; sin embargo, se ha señalado la posible relación entre el SSJ con la infección por Mycoplasma pneumoniae o herpes. El tratamiento consiste en la suspensión del fármaco y cuidados de soporte. No existe tratamiento específico que haya demostrado eficacia. Se ha propuesto el uso de inmunoglobulina intravenosa debido a su potencial anti-Fas in vitro, aunque sus efectos reportados no son concluyentes. Objetivo: Describir la respuesta a inmunoglobulina intravenosa en el tratamiento del SSJ/NET en el Hospital de Especialidades Centro Médico Nacional Siglo XXI. Material y métodos: Se realizó un estudio descriptivo retrospectivo en pacientes con SSJ/NET del servicio de Medicina Interna que recibieron inmunoglobulina intravenosa (IV) en el período de marzo de 2008 y abril de 2014. Resultados: Siete pacientes recibieron de 1-3 g/kg de inmunoglobulina IV, 5 mujeres (87.7%) y 1 hombre (14.2%). Todos se relacionaron con ingesta de fármacos, trimetoprim/sulfametoxazol en el 28.5% de los casos. El 71.4% presentó fiebre, 85.7% presentó afección mayor al 10% de la superficie corporal, 100% presentó afección de 2 o más mucosas y 42.8% requirió manejo avanzado de la vía aérea. La estancia hospitalaria promedio fue de 32 días. No ocurrieron defunciones. Una mujer presentó hipertensión asociada a la infusión de inmunoglobulina, así como cefalea, y otra paciente desarrolló neumonía nosocomial. Conclusiones: La respuesta a inmunoglobulina IV fue satisfactoria logrando abortar la progresión del cuadro en 5 pacientes, 85.7% de los casos, sin efectos adversos relevantes(AU)

Background: Toxic epidermal necrolysis (TEN) and Stevens -Johnson syndrome (SJS) are rare but serious and potentially lifethreatening adverse cutaneous drug reactions. However, a possible relationship between SJS with Mycoplasma pneumoniae infection or herpes has been noted. Treatment consists of drug discontinuation and supportive care as there is no specific therapy that has shown efficacy. Intravenous immunoglobulins have been tested as a consequence of the anti-Fas in vitro potential, although its reported effects are inconclusive. Objective: To describe the response to intravenous immunoglobulin in the management of SJS / TEN in Hospital de Especialidades Centro Médico Nacional SXXI. Material and methods: A retrospective descriptive study was conducted in patients with SJS / TEN in the service of Internal Medicine who received intravenous immunoglobulin (IVIG) from March 2008 until April 2014. Results: Seven patients received 1-3 g/ kg IV immunoglobulin, 5 females (87.7 %) and 1 male (14.2 %), all related to ingestion of drugs, trimethoprim/ sulfamethoxazole in 28.5 % of cases. 71.4% had fever, 85.7 % had skin involvement of greater than 10% of the body surface , 100 % had involvement of 2 or more mucous and 42.8 % required advanced airway management . The average hospital stay was 32 days. No deaths occurred. A woman has hypertension associated with immunoglobulin infusion and headache, and another patient developed nosocomial pneumonia Conclusions: Response to IV immunoglobulin was satisfactory as it was associated with cessation of skin and mucosal detachment in 85.7 % of cases without significant adverse effects.

Eventos adversos en 1395 infusiones con diferentes preparados de gammaglobulina intravenosa / Adverse events in 1395 infusions with different intravenous gammaglobulin products

Los procesos de aislamiento y esterilización de la gammaglobulina endovenosa (IVIG) afectan las características del producto terminado y, por lo tanto, su tolerabilidad. Distintos productos tienen diferentes incidencias de reacciones adversas. Este trabajo cuantifica los eventos adversos (EA) inmediatos provocados por distintas preparaciones de IVIG. Analizamos 1395 infusiones en 28 pacientes, con una mediana de 32.5 por sujeto (rango 2-214), utilizando seis preparados distintos de IVIG, con una dosis total promedio de 40.3 ± 8.3 g. Analizamos retrospectivamente 1 031 infusiones y 364 prospectivamente. Los pacientes utilizaron una media de 2.68 ± 1.8 IVIG diferentes, con una mediana de 2 (rango 1-6) por persona. El número de marcas comerciales utilizadas se relacionó con el número de infusiones recibidas, r = 0.73. En 24 (2.3%) de 1031 infusiones analizadas en forma retrospectiva se registraron EA que afectaron a 11 de los 23 casos incluidos, con una media de 2.18 ± 1.08 EA por afectado. De 24 pacientes y de 364 infusiones prospectivas, en 14 pacientes y en 32 (7.2%) procedimientos se observaron EA. Veinticuatro (42.9%) de 56 EA fueron leves, 31 (55.5%) moderados y uno (1.8%) fue grave. La velocidad de infusión fue de 9.04 ± 4.6 g/h para las que presentaron EA vs. 10.6 ± 4.6 g/h para las que no (p = 0.31). La incidencia, la gravedad y la proporción de pacientes afectados con EA para cada marca comercial de IVIG fueron muy diferentes entre sí. Esta información debe ser tomada en cuenta en el momento de selección de la IVIG a utilizar.

The processes of isolation and sterilization of intravenous gamma globulin (IVIG) affect the end product characteristics and, therefore, its tolerability. Different products have different incidences of adverse reactions. The aim of this study was to quantify the immediate adverse events (AE) caused by the different IVIG preparations. We analyzed 1 395 infusions in 28 patients, with a median of 32.5 per subject (range 2-214), using six different IVIG preparations, with an average dose 40.3 ±8.3 g. One thousand and thirty-one infusions were analyzed retrospectively and 364 prospectively. Patients used a mean of 2.68 ±1.8 different IVIGs, with a median of 2 (range 1-6) per person. The number of trademarks used was related to the number of infusions received, r = 0.73. AE presented in 24 (2.3%) of 1 031 infusions retrospectively analyzed, affecting 11 of 23 patients enrolled, with a mean of 2.18 ± 1.08 AE per subject. Of 24 patients and 364 infusions prospectively analyzed, AE were observed in 14 patients and in 32 (7.2%) procedures. Twenty-four (42.9%) of 56 AE were mild, 31 (55.5%) moderate and one (1.8%) severe. The infusion rate was 9.04±4.6 g/h for those presenting AE vs. 10.6±4.6 g/h for those who did not (p = 0.31, NS). The incidence, severity and proportion of patients with AE for each brand of IVIG were very different from each other. This information should be taken into account when selecting the IVIG to be used.

Encefalopatía aguda en un paciente tratado con inmunoglobulina endovenosa por un síndrome de Guillain-Barré / Acute encephalopathy associated with the use of intravenous immunoglobulin. Report of one case

Adverse reactions to intravenous immunoglobulin (ivIg) therapy, such as anaphylaxis, acute encephalopathy, aseptic meningitis, or thrombotic phenomena are uncommon. We report a 58-year-old man with hypertension presenting with muscle weakness which led to paraparesia and respiratory failure. With the diagnosis of Guillain-Barré syndrome (GBS), he was treated with ivIg. He developed an acute encephalopathy few hours after the administration of ivIg, with a decreased level of consciousness and agitation. A CT scan revealed moderate and diffuse brain edema. Encephalopathy resolved 96 hours after ivIg withdrawal and use of plasma exchange. A CT scan performed seven days after showed the resolution of brain edema.

Hiponatremia y terapia con inmunoglobulina endovenosa: a propósito de un paciente consíndrome de sobreposición / Hyponatremia and therapy with intravenous immunoglobulin: about a patient with overlap syndrome

El uso de inmunoglobulina endovenosa está cada vez más difundido, tanto para inmunodeficiencias como para enfermedades de orden autoinmune, infecciosas, así como de tipo neurológico. Si bien la infusión de ésta se asocia con algunos efectos adversos sintomáticos, también es cierto que varios pasan desapercibidos. Se presenta el caso de una paciente con síndrome de sobreposición (polimiositis y esclerodermia), la que durante el procedimiento presenta una pseudohiponatremia asociada a una excelente respuesta clínica a este fármaco. Es importante recalcar que esta complicación sólo corresponde a un hallazgo y no tiene indicación de suspender la terapia.

The use of intravenous immunoglobulin is becoming increasingly widespread, for immunodeficiencies, autoimmune, infectious and neurological diseases. Although this infusion is associated with some symptomatic adverse effects, it is also true that many go unnoticed. A case of a patient with overlap syndrome (polymyositis and scleroderma) is reported, who presented with a pseudohiponatremia associated with excellent clinical response to this. It is important to emphasize that this complication only corresponds to a finding and it is not an indication to discontinue the therapy.

Terapia con inmunoglobulina endovenosa: mecanismos de acción, usos e indicaciones / Intravenous immunoglobulin treatment: mechanisms of action, uses and indications

Los anticuerpos o inmunoglobulinas forman parte de la inmunidad humoral y son producidos por los linfocitos B. Sus funciones incluyen neutralización, opsonización y fagocitosis de microorganismos y toxinas, activación del complemento y citotoxicidad dependiente de anticuerpos (ADCC). Hace más de 50 años las preparaciones de inmunoglobulina humana endovenosa (IGIV) han sido utilizadas tanto como terapias de reemplazo en inmunodeficiencias como en tratamientos inmunomoduladores/antiinflamatorios.Los mecanismos de acción se pueden clasificar en antiinfectivos y en inmunomoduladores-antiinflamatorios. Los primeros se basan en la restauración de los niveles de anticuerpos tanto patógeno-específicos como naturales, lo que lleva al desarrollo de una respuesta inmune humoral normal. El segundo mecanismo es más complejo y comprende la neutralización de autoanticuerpos, modulación de citoquinas e inhibición del complemento, entre otros.Sus indicaciones en la actualidad incluyen algunas inmunodeficiencias primarias y secundarias, además de ciertas enfermedades autoinmunes y desórdenes inflamatorios sistémicos.

Antibodies or immunoglobulins make up part of humoral immunity and are produced by B lymphocytes. Functions include neutralization, opsonization and phagocytosis of microorganisms and toxins, complement activation and antibody-dependent cellular cytotoxicity (ADCC). Preparations of intravenous human immunoglobulin (IGIV) have been used for more than fifty years in both replacement therapies in immunodeficiency and in immunomodulatory / anti-inflammatory treatments. Mechanisms of action can be classified in anti-infective and in immunomodulatory / anti-inflammatory. The first are based on the restoration of both pathogen-specific and natural antibodies, which leads to a normal humoral immune response. The second is more complex and includes antibody neutralization, cytokine modulation and complement inhibition, among others.Present-day indications include primary and secondary immunodeficiencies, as well as certain autoimmune diseases and systemic inflammatory disorders.

Intravenous immune globulin versus intravenous anti-D immune globulin for the treatment of acute immune thrombocytopenic purpura.

OBJECTIVE: The purpose of this study was to compare the efficacy and side effects of intravenous immunoglobulin (IVIG) with intravenous anti-D immunoglobulin for treatment of newly diagnosed acute childhood Idiopathic thrombocytopenic purpura (ITP). METHODS: Children (6 months to 14 years) with newly diagnosed acute ITP and platelet count below 20,000/ microL were randomized to receive single dose intravenous 75 microg/kg anti-D or 1g/kg IVIG for two consecutive days (total dose 2 g/kg). Response rate defined as a platelet count over 20,000 / microL 72 hours after initial treatment. RESULTS: Eighty one patients (52 male and 29 female) with mean age of 5 years and 3 months randomly divided in anti-D group (n=42) and IVIG group (n=39). Mean baseline (pretreatment) platelet counts were 15406 / microL and 15230/ microL in anti-D and IVIG group, respectively. The response rate in IVIG group (98%) was more significant than anti-D group (76%); (P = 0.017). After 7 days the platelet counts of all patients in IVIG group were more than 20,000/ microL while in anti-D group 12% had platelet counts below 20,000/ microL. CONCLUSION: In acute childhood ITP, initial treatment with IVIG (2g/Kg in divided dose) increased platelet count more rapidly and more significant than intravenous anti-D (single dose of 75 microg/kg) within the first 72 hours.

A Case of Deep Vein Thrombosis and Pulmonary Thromboembolism after Intravenous Immunoglobulin Therapy

Although high-dose intravenous immunoglobulin (IVIG) is generally considered a safe medication for various immune-mediated diseases, thrombotic events have been reported as a complication of the therapy. We report a case who developed thrombotic complications after receiving IVIG. A 56-yr-old woman with idiopathic thrombocytopenic purpura received IVIG at a dose of 400 mg/kg/day for five days. Three days after the administration of IVIG, the patient developed painful edema in the left leg. Lower extremity doppler ultrasound revealed deep vein thrombosis in the left leg. Chest computed tomography (CT) scan demonstrated a filling defect indicating thromboembolism of the right pulmonary artery. After three weeks of enoxaparin therapy, her symptoms and pulmonary embolism on CT improved. This case suggests clinicians should be cautious in the development of thromboembolism by administration of IVIG, especially in patients with thrombophilia.

Kawasaki disease: are we missing the diagnosis?

We report 6 cases of Kawasaki disease (KD) diagnosed over a period of one year and review of all the cases reported from India. The diagnosis of KD was based on clinical criteria The mean age of patients was 6.83 years and mean duration of symptoms before diagnosis was 7.5 days. Apart from classical clinical features, elevated transaminases and blood urea along with free fluid in abdomen was present in one case each. Two patients had dilated coronaries that returned to normal on follow up. One patient developed headache and neck stiffness following treatment with intravenous gamma globulins. The outcome was excellent in all the cases.

Acute myocardial ischemia following accidental intravenous administration of epinephrine in high concentration.

Inadvertent and accidental epinephrine overdose might result in potentially lethal complications. We present a case of acute epinephrine toxicity resulting in acute myocardial ischemia in a young boy with combined variable immunodeficiency syndrome who developed severe allergic reaction to intravenous immunoglobulin, and was subsequently given epinephrine by mistake intravenously rather than subcutaneously. He developed significant ischemic changes in standard 12-lead electrocardiogram, transiently raised cardiac enzymes, reduced left ventricular systolic function, pulmonary edema and pulmonary hemorrhage. It is suggested that special precautionary measures should be taken regarding the dose and the route while administering epinephrine to avoid mishaps.

Inmunoglobulinas en sepsis y shock septico / Immunoglobulins in sepsis and septic shock

La eficacia clinica de las inmunoglobulinas poliespecificas o anticuerpos monoclonales para tratar pacientes con sepsis severa o shock septico es un motivo de controversia despues de haberse desarrollado numerosos ensayos clinicos. Solo algunos de ellos han podido demostrar un beneficio directo para reducir la mortalidad o este efecto es evidente tras un meta-analisis. La evidencia sostiene que las inmunoglobulinas G poliespecificas reducen la mortalidad en estos pacientes, siendo este efecto mayor para las inmunoglobulinas enriquecidas con IgM. Las mejores indicaciones son sepsis postquirurgicas o pacientes en shock septico precoz con altos títulos de endotoxinemia. Se recomienda tambien indicar inmunoglobulinas intravenosas en el tratamiento de pacientes con shock toxico estreptococcico, evidencia establecida a traves de estudios caso-control y un ensayo clinico randomizado que mostro una clara tendencia al beneficio. La evidencia no apoya a un impacto favorable en mortalidad para anticuerpos monoclonales dirigidos contra lipopolisacaridos bacterianos, otros antigenos bacterianos o contra FNT-alfa. Mas aun, la infusion de antagonistas del receptor recombinante de IL-1 o receptores solubles de FNT-alfa que pudieran atenuar la respuesta inflamatoria, no han demostrado utilidad despues de numerosos ensayos clinicos. Estas herramientas terapeuticas se caracterizan por un alto costo de adquisicion y aun no se han realizado analisis costo-efectividad

Insuficiência renal aguda após uso de imunoglobulina intravenosa para tratamento de miocardite / Acute renal failure after intravenous use of immunoglobulin to treat myocarditis

Mulher de 60 anos com quadro de insuficiência cardíaca classe funcional III/IV (NYHA) de etiologia imuno-mediada (miocardite autoimune). Após tentativas terapêuticas sem sucesso, foi utilizada imunoglobulina intravenosa, deteriorando a função renal, complicação rara desta terapia. Após hemodiálise a paciente recuperou a função renal e ocorreu melhora da insuficiência cardíaca crônica para classe funcional I.

Compatibility problems after intravenous immunoglobulin--a case report.

Serious incompatibility was noted in a patient diagnosed as acute Guillain Barre syndrome treated with intravenous immunoglobulin. Patient had positive direct and indirect antiglobulin test and the auto control was negative. There was no clinical signs of hemolysis. Patient's blood group was O D positive and cross matched several units of ABO compatible D positive and D negative blood. Only one unit was compatible. These findings suggest that the particular intravenous immunoglobulin contained a mixture of saline and immune antibodies having different specificity. As the number of patients getting treated with intravenous immunoglobulin is on the rise more and more compatibility problems should be anticipated and should be borne in mind during serological testing and evaluation.

Avanços no conhecimento da síndrome de Guillain-Barré / Advances in Guillain-Barré syndrome knowledge

A incidência da síndrome de Guillain-Barré (SGB) parece ser mais alta do que o anteriormente suposto. Human immunodeficiency virus (HIV) e Campylobacter jejuni (C. jejuni) devem ser considerados entre os agentes infecciosos precursores. O mesmo não acontece com a Borrelia burgdorferi. Parece haver correlação entre a SGB "axonal" ("a"), infecção pelo C. jejuni e anticorpos anti-GM1. Outros agentes precursores têm sido referidos. Os achados anátomo-patológicos na SGB "a"são revisados. As alterações sensitivas são freqüentemente subestimadas. O subtrato imunológico necessita ser melhor conhecido, mas a plasmaférese e a imunoglobulina endovenosa humana são eficazes no tratamento da síndrome