Enfermedades autoinflamatorias / Autoinflammatory diseases

Las enfermedades autoinflamatorias monogénicas son desórdenes raros que resultan en defectos del sistema inmune innato, originando excesiva respuesta a señales de peligro, activación espontánea de vías inflamatorias o pérdida de reguladores inhibitorios. En los últimos 15 años un creciente número de enfermedades inflamatorias monogénicas han sido descriptas y sus respectivos genes responsables identificados. Las proteínas codificadas por estos genes están involucradas en las vías regulatorias de la inflamación y están expresadas fundamentalmente en las células del sistema inmune innato. Si bien un grupo de pacientes exhibe inflamación sistémica episódica (fiebres periódicas), estos desórdenes están mediados por una continua sobreproducción y liberación de mediadores pro-inflamatorios -especialmente la interleucina 1beta- y su conceptualización como enfermedades autoinflamatorias es preferible por sobre la de fiebres periódicas. Las enfermedades más frecuentes son fiebre mediterránea familiar (FMF), TRAPS, deficiencia de mevalonatocinasa/síndrome de hiper IgD (MKD/HIDS) y los síndromes periódicos asociados a criopirina (CAPS). Sus características clínicas frecuentemente incluyen fiebre, erupciones cutáneas, compromiso de serosas y reactantes de fase aguda. Los autoanticuerpos están usualmente ausentes pero pueden observarse en ciertos síndromes. El diagnóstico es clínico y se basa en las características fenotípicas. El diagnóstico genético es muy importante pero debe ser realizado de manera juiciosa e interpretado con cautela. El tratamiento con agentes biológicos que bloquean citocinas pro-inflamatorias, particularmente IL-1, ha demostrado ser efectivo en muchos pacientes. Sin embargo, en otros tantos casos no se descubren anormalidades genéticas y el tratamiento es subóptimo, planteando la posibilidad de mutaciones patogénicas en genes y vías aún no explorados.

The monogenic autoinflammatory diseases are rare, genetic disorders resulting in constitutive innate immune defects leading to excessive response to danger signals, spontaneous activation of inflammatory mediators or loss of inhibitory regulators. During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, notably IL-1β, and are best considered as autoinflammatory diseases rather than periodic fevers. The most common autoinflammatory diseases are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) and the cryopyrin-associated periodic syndromes (CAPS). Clinical features often include fever, cutaneous rash, serosal involvement and acute phase reactants. Autoantibodies are usually absent but may accompany certain syndromes. Diagnosis remains clinical and is based on the different phenotypic features. Genetic diagnosis is of utmost importance, but must be performed judiciously and interpreted cautiously. Treatment with biologic agents that block proinflammatory cytokines, particularly IL-1, has proved to be dramatically effective in many patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways.

Three suitable antigens for delayed-type hypersensitivity skin testing in a tropical country like Thailand.

Delayed type hypersensitivity (DTH) skin test is a standard tool to assess in vivo cell-mediated immunity. Mantoux method using 4-5 common recalled antigens is recommended. However, not all antigens are widely available and appropriate antigens for tropical countries are not known. The objective of this study is to investigate what and how many antigens should be included in the DTH testing panel that suitable for Thailand and may be for this region. The DTH skin tests were done by Mantoux method in a double blinded fashion. Average induration size of > or = 5 mm defined as a positive test. Antigens included purified protein derivative (PPD), Candida albicans, tetanus toxoid (TT), Trichophyton mentagrophytes and hepatitis B vaccine (HBV). The negative control was normal saline. Of 95 healthy subjects, all showed DTH positive to > or = 1 antigen. The positivity to C. albicans, tetanus toxoid, PPD, T. mentagrophytes, and HBV was 92.6%, 83.2%, 82.1%, 50.5%, and 5.3%, respectively. When three antigens: PPD, TT and C. albicans were analyzed, 100% of subjects showed a positive response to > or = 1 antigen and 96.8% showed a positive response to > or = 2 antigens. When only PPD and TT were analyzed, 100% of subjects showed > or = 1 antigen positive and 68.4% showed both antigens positive. C. albicans antigen at 1:100 was associated with a high incidence of fever (2/20) and large local reaction (7/20), 1:500 was found to be the optimal concentration. PPD, TT and C. albicans are suitable to be included in a DTH skin testing in a tropical country like Thailand. However, in a setting where C. albicans extract is not available, testing with only two antigens of PPD and tetanus toxoid may be an alternative, but with a lower sensitivity.

Manejo del paciente neutropénico febril / Management of children with fever and neutropenia

Las infecciones en pacientes con cáncer y neutropenia en países en vías de desarrollo continúan siendo causadas en su mayoría por bacilos gramnegativos. Las alteraciones inmunológicas que se presentan después de la administración de la quimioterapia o radioterapia o ambas, son múltiples y son responsables de la adquisición de infecciones. Es probable que las infecciones nosocomiales sean causa de un número importante de casos de infección por bacilos gramnegativos en aquellos lugares donde éstos ocupan un lugar importante de los aislamientos clínicos. El manejo de este tipo de pacientes debe ser multidisciplinario y es importante identificar a aquellos pacientes de alto y bajo riesgo (duración de la neutropenia mayor de 7 días y menor de 7 días respectivamente). La exploración física minuciosa es una parte importante en el abordaje clínico, así como el seguimiento a lo largo del tratamiento antibiótico. El tratamiento empírico inicial debe ser racional y estar dirigido de acuerdo a la epidemiología de cada lugar. En centros hospitalarios donde los bacilos gramnegativos continúan siendo la etiología más frecuente, el tratamiento combinado que incluya un betalactámico y un aminoglucósido debe seguir siendo el tratamiento de elección. El tratamiento con un solo antibiótico no es recomendable en nuestro medio. Las infecciones por hongos deben sospecharse en pacientes con neutropenia y fiebre que no mejoran a pesar de un manejo antibiótico adecuado al cuarto o quinto día de haberse iniciado éste. La colitis neutropénica es una complicación grave que puede presentarse en pacientes con neutropenia, su manejo implica una vigilancia estrecha debido a la mortalidad asociada con un tratamiento no oportuno.

Seroprevalence of scrub typhus infection in patients with pyrexia at some malaria clinics in three western provinces of Thailand.

In Thailand, the epidemiological data on scrub typhus infection represents only "the tip of an iceberg" especially in malaria clinics where patients come to seek attention because of other febrile illnesses that may have initial clinical signs that are indistinguishable from malaria. The objectives of this study were to determine the prevalence of antibody titers to Orientia tsutsugamushi, and its various strains, among patients at some malaria clinics in three western provinces of Thailand. The sample was represented by 200 patients from 6 malaria clinics in Ratchaburi, Petchaburi and Kanchanaburi provinces between June and November, 1994. Blood specimens were collected with their consent. Immunofluorescent antibody assays (IFA) were used for measuring IgM and IgG antibody titers for scrub typhus infection. The results showed that the prevalence rate for scrub typhus infection (IgM and/or IgG titer > or = 50) was 59.50% (119 cases). The immunofluorescent antibody response to various strains of O. tsutsugamushi showed that co-infections with the Karp, the Gilliam and the Kato strains were the most common (found in 68.10% of cases). Geometric mean antibody titers (GMT) were highest for the Karp strain, followed by the Gilliam then Kato strains. In conclusion, this study indicates that the prevalence rate of scrub typhus is not rare in these areas.

Comparative study of immunoglobulin G and immunoglobulin M among neonates in caesarean section and vaginal delivery.

The present study comprised 50 cases of normal vaginal delivery and 50 cases of caesarean section. The cord blood level of immunoglobulin G was significantly higher in normal vaginal delivery cases than in caesarean section cases (mean level is 1653.2 +/- 443.1 mg/dl and 898.3 +/- 415.6 mg/dl respectively). The immunoglobulin G was low in cord blood but had higher concentration in all the 7 cases in study group who had fever with rigor in antenatal period. Thus the babies delivered with caesarean section had lower immunoglobulin level than normal vaginal delivery.

Febrile response in malnutrition

The febrile response to a standard dose of triple (DPT) vaccine was assessed in sixteen malnourished children before and after recovery. The increase in temperature was significantly lower in the malnourished children (p < 0.005)

Natural killer cells in dengue hemorrhagic fever/dengue shock syndrome.

Natural killer (NK) cell activity against K-562 target cells and HNK-1+ cell levels were serially determined in peripheral blood of 62 Thai children with dengue hemorrhagic fever/dengue shock syndrome aged 4-12 years and 59 age-matched normal controls. The studies were performed on febrile stage, 1st and 2nd day of subsidence of fever (shock stage), 3rd and 4th day of subsidence of fever (early convalescent stage) and once again on the late convalescent stage (approximately 14-18 days after subsidence of fever). The study revealed that during the course of disease the NK cell activity was not changed significantly from the normal controls. In contrast, the levels of HNK-1+ cells, which exhibited almost all NK and killer cell functional activities, were significantly decreased in the febrile and the shock stages and were normal in the early and late convalescent stages. The NK cell activity, on the per-cell basis, was significantly increased in the early disease stage when compared to that of the later period of the disease and of the normal controls. The study also revealed that patients with grade III of disease severity exhibited significantly more NK cell functional activities per cell than grade II on febrile stage and the first day of shock. These results suggest that natural killer cells were active in defense against dengue viral infection and might play some role in the pathogenesis of dengue hemorrhagic fever/dengue shock syndrome. Their functions might also determine the severity of the disease.