RESUMO
BACKGROUND: To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. METHODS: A double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). RESULTS: Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3-63), versus separate arms (57.4 µg/mL: 95 % CI 32.3-102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8-101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had â¼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. CONCLUSION: Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. CLINICALTRIALS: gov identifier: NCT01556945.
Assuntos
Vacinas Antimaláricas , Malária Falciparum , Malária , Adulto , Criança , Humanos , Adjuvantes Imunológicos , Anticorpos Antiprotozoários , Antígenos de Protozoários , Malária/prevenção & controle , Malária Falciparum/prevenção & controle , Proteína 1 de Superfície de Merozoito , Parasitemia , Plasmodium falciparum , Proteínas de Protozoários , Método Duplo-CegoRESUMO
Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A∗01, HLA-B∗08, and HLA-DRB1∗15/∗16) and protection, while another three allele groups (HLA-A∗03, HLA-B∗53, and HLA-DRB1∗07) were significantly associated with lack of protection. It is noteworthy that these 'protective' allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection.
Assuntos
Genótipo , Antígenos HLA/genética , Imunogenicidade da Vacina , Vacinas Antimaláricas/imunologia , Malária Falciparum/genética , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Alelos , Ensaios Clínicos como Assunto , Antígenos HLA/imunologia , Teste de Histocompatibilidade , Humanos , Malária Falciparum/parasitologia , Razão de Chances , VacinaçãoRESUMO
BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.
Assuntos
Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Proteínas Recombinantes , Vacinas Sintéticas/administração & dosagem , Adulto , Animais , Anticorpos Antiprotozoários/análise , Gâmbia/epidemiologia , Humanos , Imunização , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Masculino , Modelos de Riscos Proporcionais , Proteínas de Protozoários , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
Plasmodia infect the liver for about 7 days before subsequently infecting the blood. Present prophylaxis against Plasmodium falciparum malaria employs agents that primarily kill blood stages and must be continued for 28 days after the last exposure. Atovaquone-proguanil (Malarone) is a new antimalarial agent that is licensed in 35 countries as treatment against blood-stage infection, but its components (atovaquone and proguanil) have separately been shown to be active also against liver stages. To determine whether atovaquone-proguanil is sufficiently active against liver stages to be discontinued 7 days after exposure, we challenged 16 volunteers with P. falciparum via infected mosquitoes. Twelve volunteers received atovaquone-proguanil (1 tablet daily) on the day prior to challenge, on the day of challenge, and for the next 6 days; 4 volunteers received matching placebo. All placebo volunteers demonstrated parasitaemia and malarial symptoms beginning on days 11-12 after challenge. No atovaquone-proguanil volunteer acquired malaria. Atovaquone-proguanil is the first licensed antimalarial agent that kills P. falciparum in the liver and that may be discontinued 7 days after the last exposure.
Assuntos
Antimaláricos/uso terapêutico , Hepatopatias Parasitárias/tratamento farmacológico , Malária Falciparum/prevenção & controle , Naftoquinonas/uso terapêutico , Proguanil/uso terapêutico , Adolescente , Adulto , Atovaquona , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naftoquinonas/farmacocinética , Proguanil/farmacocinética , Resultado do TratamentoRESUMO
Neither GMP malaria antigens nor GMP vaccines have been compared for efficacy in monkeys and humans. It is too risky to base categorical (go/no go) development decisions on results obtained using partially characterized (non-GMP) antigens, adjuvants that are too toxic for human use or unvalidated primate models. Such practices will lead to serious errors (e.g. failure to identify and stop flawed efforts, rejection of effective vaccine strategies) and unjustifiable delays. Successful malaria vaccine development will emphasize definitive field trials in populations at risk of malaria to define and improve vaccine efficacy.
Assuntos
Aotus trivirgatus , Ensaios Clínicos como Assunto , Vacinas Antimaláricas , Malária/prevenção & controle , Saimiri , Animais , Antígenos de Protozoários/imunologia , Modelos Animais de Doenças , Humanos , Plasmodium/imunologiaRESUMO
Microscopic detection of parasites has been the reference standard for malaria diagnosis for decades. However, difficulty in maintaining required technical skills and infrastructure has spurred the development of several nonmicroscopic malaria rapid diagnostic devices based on the detection of malaria parasite antigen in whole blood. The ParaSight F test is one such device. It detects the presence of Plasmodium falciparum-specific histidine-rich protein 2 by using an antigen-capture immunochromatographic strip format. The present study was conducted at outpatient malaria clinics in Iquitos, Peru, and Maesod, Thailand. Duplicate, blinded, expert microscopy was employed as the reference standard for evaluating device performance. Of 2,988 eligible patients, microscopy showed that 547 (18%) had P. falciparum, 658 (22%) had P. vivax, 2 (0.07%) had P. malariae, and 1,750 (59%) were negative for Plasmodium. Mixed infections (P. falciparum and P. vivax) were identified in 31 patients (1%). The overall sensitivity of ParaSight F for P. falciparum was 95%. When stratified by magnitude of parasitemia (no. of asexual parasites per microliter of whole blood), sensitivities were 83% (>0 to 500 parasites/microl), 87% (501 to 1,000/microl), 98% (1,001 to 5,000/microl), and 98% (>5,000/microl). Device specificity was 86%.
Assuntos
Antígenos de Protozoários/análise , Imunoensaio/métodos , Malária Falciparum/diagnóstico , Plasmodium falciparum/isolamento & purificação , Proteínas/análise , Animais , Humanos , Malária Falciparum/parasitologia , Parasitemia/diagnóstico , Parasitemia/parasitologia , Kit de Reagentes para Diagnóstico , Fitas Reagentes , Sensibilidade e Especificidade , Fatores de TempoRESUMO
After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups. Of the 41 vaccinees and 23 control subjects who underwent sporozoite challenge, malaria developed in 7 of 10 who received 1 dose, in 7 of 14 who received 2 doses, in 3 of 6 who received 3 standard doses, in 3 of 7 who received 3 one-half doses, in 3 of 4 who received 3 one-fifth doses, and in 22 of 23 control subjects. Overall protective efficacy of RTS,S/SBAS2 was 41% (95% confidence interval, 22%-56%; P=.0006). This and previous studies have shown that 2 or 3 doses of RTS,S/SBAS2 protect against challenge with P. falciparum sporozoites.
Assuntos
Vacinas Antimaláricas , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Feminino , Humanos , Ativação Linfocitária , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Protozoários/genética , Proteínas Recombinantes/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
The RTS,S/SBAS2 vaccine confers sterile protection against Plasmodium falciparum sporozoite challenge. The mechanisms underlying this are of great interest, yet little is known about the immune effector mechanisms induced by this vaccine. The immune responses induced by RTS,S/SBAS2 were characterized in 10 malaria-naive volunteers. Several epitopes in the circumsporozoite protein (CSP) were identified as targets of cultured interferon (IFN)-gamma-secreting CD4+ T cells. RTS,S-specific IFN-gamma-secreting effector T cells were induced in 8 subjects; this ex vivo response mapped to a single peptide in Th2R. CSP-specific CD8+ cytotoxic T lymphocytes were not detected. RTS, S-specific IFN-gamma production was universal, whereas interleukin-4 and -5 production was rare. RTS,S-specific lymphoproliferative responses and antibodies to CSP were strongly induced in all volunteers. Responses waned with time but were boostable. Thus, RTS, S/SBAS2 is a potent inducer of Th1-type cellular and humoral immunity. These results highlight possible immune mechanisms of protection and have important implications for vaccine design in general.
Assuntos
Anticorpos Antiprotozoários/sangue , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Células Th1/imunologia , Vacinas Sintéticas/imunologia , Adulto , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Epitopos/química , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Interferon gama/biossíntese , Ativação Linfocitária , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/prevenção & controle , Pessoa de Meia-Idade , Dados de Sequência Molecular , Peptídeos/imunologia , Linfócitos T Reguladores/imunologia , Vacinação , Vacinas Sintéticas/administração & dosagemRESUMO
The safety and immunogenicity of 2 yeast-derived, blood-stage malaria vaccines were evaluated in a phase l trial. Healthy adults were given 2 or 3 doses of alum-adsorbed vaccine containing the 19 kDa carboxy-terminal fragment of the merozoite surface protein-1 (MSP-1(19)) derived from the 3D7 or the FVO strain of Plasmodium falciparum fused to tetanus toxoid T-helper epitopes P30 and P2. The first 2 doses of MSP-1(19) were well tolerated. Hypersensitivity reactions occurred in 3 subjects after the third dose of MSP-1(19), including bilateral injection site reactions in 2 (one with generalized skin rash), and probable histamine-associated hypotension in 1. Serum antibody responses to MSP-1(19) occurred in 5/16, 9/16 and 0/8 subjects given 20 microg of MSP-1(19), 200 microg of MSP-1(19), and control vaccines (hepatitis B or Td), respectively. Both MSP-1(19) vaccines were immunogenic in humans, but changes in formulation will be necessary to improve safety and immunogenicity profiles.
Assuntos
Epitopos de Linfócito T , Vacinas Antimaláricas/imunologia , Proteína 1 de Superfície de Merozoito/imunologia , Fragmentos de Peptídeos/imunologia , Plasmodium falciparum/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Toxoide Tetânico/imunologia , Vacinas Sintéticas/imunologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Humanos , Ativação Linfocitária , Vacinas Antimaláricas/efeitos adversos , Pessoa de Meia-Idade , Testes CutâneosAssuntos
Antimaláricos/uso terapêutico , Deficiência de Glucosefosfato Desidrogenase/complicações , Malária Falciparum/prevenção & controle , Malária Vivax/prevenção & controle , Complicações Parasitárias na Gravidez/prevenção & controle , Primaquina/uso terapêutico , Antimaláricos/efeitos adversos , Feminino , Humanos , Masculino , Gravidez , Primaquina/efeitos adversosRESUMO
RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.
Assuntos
Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Gâmbia , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/sangue , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/isolamento & purificação , Proteínas de Protozoários/imunologia , Valores de Referência , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
A safe and effective malaria vaccine will greatly facilitate efforts to control the global spread of malaria. This paper discusses the conceptual framework for developing malaria vaccines and some of the difficulties that the various approaches face. It emphasizes the role of pre-erythrocytic malaria vaccines, which are designed to protect against malaria infection, rather than simply prevent clinical disease. It describes recent encouraging results in human subjects with the RTS,S vaccine, a promising pre-erythrocytic malaria vaccine candidate.
Assuntos
Vacinas Antimaláricas , Plasmodium falciparum/imunologia , Animais , HumanosRESUMO
The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.
Assuntos
Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Vacinação , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Intervalo Livre de Doença , Humanos , Interferon gama , Pessoa de Meia-Idade , Proteínas de Protozoários/imunologia , Linfócitos T/imunologia , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: In AIDS, nodular skin disease can result from various causes. OBJECTIVE: To report a new manifestation of microsporidial infection presenting as nodular skin disease with underlying osteomyelitis. DESIGN: Case report. SETTING: Tertiary-care military medical center in Washington, D.C. PATIENT: A 36-year-old woman with late-stage AIDS who presented with disseminated, nodular cutaneous lesions and underlying osteomyelitis. MEASUREMENTS: Disseminated microsporidial infection with an Encephalitozoon-like species was diagnosed by electron microscopic examination of material obtained from the skin lesions. INTERVENTION: The patient received long-term oral clindamycin therapy, which cured her disseminated infection. CONCLUSIONS: Microsporidia can cause disseminated cutaneous infections in AIDS patients. The response of this patient to long-term clindamycin therapy merits further evaluation.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Antibacterianos/uso terapêutico , Antiparasitários , Clindamicina/uso terapêutico , Microsporida/isolamento & purificação , Infecções Oportunistas Relacionadas com a AIDS/complicações , Adulto , Animais , Feminino , Humanos , Osteomielite/complicações , Dermatopatias Parasitárias/complicações , Dermatopatias Parasitárias/diagnósticoRESUMO
Purified rabbit immunoglobulin raised against yeast-expressed recombinant FVO or 3D7 Plasmodium falciparum merozoite surface protein-1 (MSP-1) 19k-D C terminal fragment (MSP-1(19)) was transfused into malaria-naive Aotus nancymai monkeys that were immediately challenged with FVO asexual stage malaria parasites. Control monkeys received rabbit immunoglobulin raised against the sexual stage antigen Pfs25 or Aotus hyperimmune serum obtained from monkeys immunized by P. falciparum infection and drug cure. Passive transfer of rabbit anti-MSP-1(19) failed to protect against homologous or heterologous challenge and, when compared with negative controls, there were no differences in prepatent periods or time to treatment. Interestingly, rabbit anti-MSP-1(19), but not anti-Pfs25, immunoglobulin, and immune monkey serum prevented the development of antibodies directed against MSP-1(19) fragment by infected monkeys, indicating that the antibodies were reactive with native MSP-1(19) antigen in vivo. The prepatent period and time to treatment was greatly delayed in the two monkeys that received Aotus immune serum, both of which developed a chronic intermittent low level infection. In vitro parasite growth inhibition assays (GIAs) confirmed the presence of inhibitory activity (40% maximum inhibition) in concentrated anti-MSP-1(19) immunoglobulin (4.8 mg/ml), but the peak concentrations we achieved in vivo (1 mg/ml) were not inhibitory in vitro. Subinhibitory levels of anti-MSP-1(19) antibodies achieved by passive transfer were not protective against P. falciparum challenge.
Assuntos
Anticorpos Antiprotozoários/imunologia , Imunização Passiva , Proteína 1 de Superfície de Merozoito/imunologia , Plasmodium falciparum/imunologia , Animais , Aotus trivirgatus , Malária Falciparum/prevenção & controle , Plasmodium falciparum/crescimento & desenvolvimento , Coelhos , Proteínas Recombinantes/imunologiaRESUMO
BACKGROUND: The candidate vaccines against malaria are poorly immunogenic and thus have been ineffective in preventing infection. We developed a vaccine based on the circumsporozoite protein of Plasmodium falciparum that incorporates adjuvants selected to enhance the immune response. METHODS: The antigen consists of a hybrid in which the circumsporozoite protein fused to hepatitis B surface antigen (HBsAg) is expressed together with unfused HBsAg. We evaluated three formulations of this antigen in an unblinded trial in 46 subjects who had never been exposed to malaria. RESULTS: Two of the vaccine formulations were highly immunogenic. Four subjects had adverse systemic reactions that may have resulted from the intensity of the immune response after the second dose, which led us to reduce the third dose. Twenty-two vaccinated subjects and six unimmunized controls underwent a challenge consisting of bites from mosquitoes infected with P. falciparum. Malaria developed in all six control subjects, seven of eight subjects who received vaccine 1, and five of seven subjects who received vaccine 2. In contrast, only one of seven subjects who received vaccine 3 became infected (relative risk of infection, 0.14; 95 percent confidence interval, 0.02 to 0.88; P<0.005). CONCLUSIONS: A recombinant vaccine based on fusion of the circumsporozoite protein and HBsAg plus a potent adjuvant can protect against experimental challenge with P. falciparum sporozoites. After additional studies of protective immunity and the vaccination schedule, field trials are indicated for this new vaccine against P. falciparum malaria.
Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Proteínas de Protozoários/imunologia , Vacinas Sintéticas/imunologia , Adjuvantes Imunológicos , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Epitopos , Feminino , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Imunoglobulina G/sangue , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/prevenção & controle , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinas Sintéticas/efeitos adversosRESUMO
OBJECTIVE: To report a case of concomitant meningitis and hepatitis complicating the use of intravenous immune globulin (IVIG). CASE SUMMARY: A 39-year-old African-American woman with an autoimmune syndrome developed both acute meningitis and hepatitis following administration of IVIG. These resolved over several days and left no sequellae. DISCUSSION: This represents the first case of concomitant acute meningitis and hepatitis associated with IVIG. Thorough microbiologic and serologic evaluation of the patient failed to demonstrate an infectious etiology. We postulate that our patient's syndrome resulted from direct toxicity of IVIG. CONCLUSIONS: Both acute meningitis and hepatitis may simultaneously complicate IVIG therapy. The specific mechanism remains unclear.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Imunoglobulinas Intravenosas/toxicidade , Meningite Asséptica/induzido quimicamente , Adulto , Doença Hepática Induzida por Substâncias e Drogas/complicações , Feminino , Humanos , Meningite Asséptica/complicações , SíndromeAssuntos
Granuloma/complicações , Granuloma/diagnóstico , Leucemia Linfocítica Crônica de Células B/complicações , Pneumonia por Pneumocystis/complicações , Pneumonia por Pneumocystis/diagnóstico , Pseudolinfoma/complicações , Idoso , Anti-Infecciosos Urinários/uso terapêutico , Atovaquona , Biópsia , Diagnóstico Diferencial , Quimioterapia Combinada , Granuloma/tratamento farmacológico , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Naftoquinonas/uso terapêutico , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/patologiaRESUMO
The high incidence of opportunistic pulmonary infections in fludarabine-treated patients at Walter Reed Army Medical Center (WRAMC) and in the literature are described. A CancerLit search of fludarabine from June 1983-April 1994 with subsequent cross referencing and a retrospective review of all patients receiving fludarabine at WRAMC was performed. A total of 2,269 patients with low-grade lymphoid malignancies who received 7,547 + cycles of fludarabine were identified from the literature. Seventy-three (3.2%) of these patients developed opportunistic infections. Seventy-one (97%) of these infections occurred in patients who were pretreated with alkylator regimens or corticosteroids. Forty-five (2%) of these were of respiratory origin and associated with a 56% mortality rate. In contrast, 6 of the 21 patients (29%) treated with fludarabine at WRAMC developed opportunistic pulmonary infections which included three Pneumocystis carinii (PCP), one PCP/disseminated Candidiasis, one Mycobacterium avium intracellulare, and one Aspergillus niger pneumonia. These infections developed during and after treatment with fludarabine in alkylator-resistant patients who had received corticosteroids before (n = 6), during (n = 1), or after (n = 4) fludarabine therapy. Lack of PCP prophylaxis was the only significant (P = .018) variable that differentiated patients who developed opportunistic pulmonary infections. Corticosteroid treatment before, during, or after fludarabine treatment in patients with alkylator-resistant, low-grade lymphoid malignancies who have not received PCP prophylaxis is associated with an increased risk of opportunistic pulmonary infections. Aggressive work-up of pulmonary syndromes and PCP prophylaxis in these patients should be considered during and after treatment with fludarabine.