Inmunodeficiencia combinada severa: es tiempo de su detección precoz / Severe combined immunodeficiency: the time for newborn screening has come

Las inmunodeficiencias primarias (IDP) son un conjunto de cerca de 350 enfermedades genéticas que afectan el funcionamiento del sistema inmunológico. Los avances en diagnóstico genético han permitido describir nuevos defectos en el sistema inmune, ampliando el espectro de manifestaciones de las IDP más allá de la susceptibilidad a infecciones. Aunque la mayoría de las IDP se presentan con infecciones recurrentes u oportunistas, un subgrupo puede presentarse por el desarrollo precoz de fenómenos autoinflamatorios, tumorales y, paradojalmente, la coexistencia de autoinmunidad e inmunodeficiencia en un mismo paciente. Al igual que sus manifestaciones clínicas, la severidad de las IDP es variable. La inmunodeficiencia combinada severa (IDCS), caracterizada por una falla en la respuesta humoral y celular, es una de las formas más graves de IDP y el único tratamiento curativo disponible en Latino-América es el trasplante de precursores hematopoyéticos. La IDCS es 100% letal durante los dos primeros años de vida si no se diagnostica y trata oportunamente. Por el contrario, si se trasplantan precozmente, estos pacientes pueden alcanzar una sobrevida normal. Pese a los avan ces en el diagnóstico de IDP que se han observado en nuestro país en los últimos años, los recursos diagnósticos no se encuentran disponibles en todas las regiones, lo que dificulta el reconocimiento temprano de la IDCS y otras IDP en grandes áreas del país. El objetivo de esta actualización es revisar conceptos generales sobre la fisiopatología de la IDCS, diagnóstico, manejo inicial y plantear la nece sidad de la implementación del tamizaje neonatal de IDCS en Chile.

Primary immunodeficiencies (PIDs) are a set of about 350 genetic disorders that affect the normal function of the immune system. Advances in genetic diagnosis have allowed the description of new defects in the immune system, broadening the clinical spectrum of PIDs' manifestations beyond susceptibility to infection. Although most PIDs present with recurrent or opportunistic infections, a subgroup of them may be recognized by the early development of auto-inflammatory events, tumors and, paradoxically, the coexistence of autoimmunity and immunodeficiency in the same patient. As their clinical manifestations, the severity of PIDs is highly variable. Severe combined immunodefi ciency (SCID), a PID that affects cellular and humoral immunity, is one of the most severe forms of PIDs and the only available curative treatment in Latin America is hematopoietic stem cells trans plantation. All patients affected by SCID die during the first two years of life if they are not diagnosed and treated opportunely. In contrast, early transplantation of patients with SCID can lead to excellent survival outcomes. Despite recent advances in the diagnosis of PIDs in Chile, diagnostic resources are not available throughout the country, making the early diagnosis of SCID and other forms of PID difficult in big areas of Chile. The objective of this article is to review general concepts on the patho physiology, diagnosis, and initial management of SCID and raise the need for the implementation of neonatal screening for SCID in Chile.

[Severe combined immunodeficiency: The time for newborn screening has come]. / Inmunodeficiencia combinada severa: Es tiempo de su detección precoz.

Primary immunodeficiencies (PIDs) are a set of about 350 genetic disorders that affect the normal function of the immune system. Advances in genetic diagnosis have allowed the description of new defects in the immune system, broadening the clinical spectrum of PIDs' manifestations beyond susceptibility to infection. Although most PIDs present with recurrent or opportunistic infections, a subgroup of them may be recognized by the early development of auto-inflammatory events, tumors and, paradoxically, the coexistence of autoimmunity and immunodeficiency in the same patient. As their clinical manifestations, the severity of PIDs is highly variable. Severe combined immunodefi ciency (SCID), a PID that affects cellular and humoral immunity, is one of the most severe forms of PIDs and the only available curative treatment in Latin America is hematopoietic stem cells trans plantation. All patients affected by SCID die during the first two years of life if they are not diagnosed and treated opportunely. In contrast, early transplantation of patients with SCID can lead to excellent survival outcomes. Despite recent advances in the diagnosis of PIDs in Chile, diagnostic resources are not available throughout the country, making the early diagnosis of SCID and other forms of PID difficult in big areas of Chile. The objective of this article is to review general concepts on the patho physiology, diagnosis, and initial management of SCID and raise the need for the implementation of neonatal screening for SCID in Chile.

Neumoparotiditis o neumoparótida en el niño: Un diagnóstico diferencial a considerar / Pneumoparotitis or pneumoparotid: A differential diagnosis to consider

Childhood parotid swelling has a number of differential diagnosis mostly of inflammatory origin. Pneumoparotitis is an uncommon cause of parotid inflammation. It is caused by an excessive increase of intraoral pressure and secondary passage of air into the Stensen or Stenon duct and its glandular branches. Diagnostic clues can usually be obtained by a directed anamnesis. Ultrasonography (US) and computed tomography are essential diagnostic tools for this condition that has a benign course with spontaneous resolution in most cases. We present four cases of pneumoparotitis diagnosed by US in children 5 to 13 years of age. One of the cases occurred after the child chewed gum and made bubbles for a prolonged timeperiod and the other three after inflating baloons, making bubbles inside a pool and after playing the flute. All cases resolved spontaneously after two days. We suggest to consider pneumoparotitis in the differential diagnosis of parotid swellig in children.

Infection with Trypanosoma cruzi during pregnancy in rats and a decrease in chronic myocardial lesions in their infected offspring.

To ascertain whether maternal infection with Trypanosoma cruzi may influence the course of the parasitic infection in offspring, two groups of female 1 rats were mated with syngeneic sires. One group of females was infected with 10(6) trypomastigotes of T. cruzi three times at weekly intervals. All offspring were nursed by their mothers until weaning and then separated into two groups of young, one to be infected with the same dose of T. cruzi, and the other to remain uninfected. Infection of pregnant rats caused no aggravated disease but resulted in a self-controlled infection that did not cause any deaths or affect their reproductive capacity. The number of young delivered, litter size, fertility coefficient, and offspring weights at weaning were also unaffected by maternal infection; however, the survival coefficient decreased in comparison with values recorded in the offspring of uninfected mothers. The latter finding is likely due to neonatal transmission, since bloodstream forms of T. cruzi were observed in a few offspring of infected mothers. While infected offspring whose mothers had been inoculated with T. cruzi during pregnancy were not protected from acute infection, the occurrence of chronic focal myocarditis was less prevalent when compared with that recorded in chronically infected offspring born to uninfected mothers.

Evaluation of an attenuated Trypanosoma cruzi strain in rats: analysis of survival, parasitemia and tissue damage

El objetivo de este trabajo fue detectar infección y daño tisular en una línea endocriada de ratas, inducidos por formas vivas de una cepa de T. cruzi cultivada in vitro (TCC). Se inocularon: a) ratas cultivadas in vitro (TCC). Se inocularon: a) ratas lactantes (S), de 3-5 días de edad por vía i.p. con 10**6 TCC (S1), 10**7 TCC (S2) y 10**8 TCC (S3); b) ratas al destete, de 21-25 días de edad por vía s.c. con 10**6 TCC (W1), 10**7 TCC (W2) y 10**8 TCC (W3). Los cultivos tenían como máximo un 2// de trypomastigotes; c) testigos por vía i.p. o s.c. con 10**6 trypomastigotes sanguiíneos de la cepa Tulahuén (SC y WC); se incluyeron testigos normales. La sobrevida fue del 100// en S1, S2 y S3 y 0// en SC en el día 13 post-infección (p.i.). Estos animales murieron con signos de enfermedad de Chagas aguda. La sobrevida fue del 100// en el grupo W. En los primeros 30 días p.i. los parásitos fueron detectados en los grupos S1, S2, S3 y W1, W2 y W3 por búsqueda exhaustiva. Los parásitos se encontraron rápidamente en los testigos SC y WC hasta el día 13. Los xenodiagnósticos fueron positivos (5/5) a los 2 meses p.i. y negativos a los 6 meses p.i. (W1, W2, W3, 0/23; WC, 0/5) Tabla 1). Se observó un leve aumento de la frecuencia de miocarditis crónica focal en algunos animales infectados, independientemente a la dosis (S1, S2, S3, 26//; W1, W2, W3, 46//) que no fue significativo en comparación con la de los testigos y no alcanza el porcentaje de lesión obtenida habitualmente en WC (61,3//). La menor virulencia y patogenicidad observadas en las ratas, especie no estudiada hasta ahora, sugieren que la cepa TCC tiene una importante atenuación después de largo tiempo de cultivo in vitro (AU)

Evaluation of an attenuated Trypanosoma cruzi strain in rats: analysis of survival, parasitemia and tissue damage

El objetivo de este trabajo fue detectar infección y daño tisular en una línea endocriada de ratas, inducidos por formas vivas de una cepa de T. cruzi cultivada in vitro (TCC). Se inocularon: a) ratas cultivadas in vitro (TCC). Se inocularon: a) ratas lactantes (S), de 3-5 días de edad por vía i.p. con 10**6 TCC (S1), 10**7 TCC (S2) y 10**8 TCC (S3); b) ratas al destete, de 21-25 días de edad por vía s.c. con 10**6 TCC (W1), 10**7 TCC (W2) y 10**8 TCC (W3). Los cultivos tenían como máximo un 2// de trypomastigotes; c) testigos por vía i.p. o s.c. con 10**6 trypomastigotes sanguiíneos de la cepa Tulahuén (SC y WC); se incluyeron testigos normales. La sobrevida fue del 100// en S1, S2 y S3 y 0// en SC en el día 13 post-infección (p.i.). Estos animales murieron con signos de enfermedad de Chagas aguda. La sobrevida fue del 100// en el grupo W. En los primeros 30 días p.i. los parásitos fueron detectados en los grupos S1, S2, S3 y W1, W2 y W3 por búsqueda exhaustiva. Los parásitos se encontraron rápidamente en los testigos SC y WC hasta el día 13. Los xenodiagnósticos fueron positivos (5/5) a los 2 meses p.i. y negativos a los 6 meses p.i. (W1, W2, W3, 0/23; WC, 0/5) Tabla 1). Se observó un leve aumento de la frecuencia de miocarditis crónica focal en algunos animales infectados, independientemente a la dosis (S1, S2, S3, 26//; W1, W2, W3, 46//) que no fue significativo en comparación con la de los testigos y no alcanza el porcentaje de lesión obtenida habitualmente en WC (61,3//). La menor virulencia y patogenicidad observadas en las ratas, especie no estudiada hasta ahora, sugieren que la cepa TCC tiene una importante atenuación después de largo tiempo de cultivo in vitro

Evaluation of an attenuated Trypanosoma cruzi strain in rats. Analysis of survival, parasitemia and tissue damage.

Infection and tissue damage induced by parasites of an attenuated Trypanosoma cruzi culture strain (TCC) were studied in "I" line of inbred rats. Suckling rats (S), 3-5 day old were inoculated i.p. with 10(6) TCC (S1), 10(7) TCC (S2) and 10(8) TCC (S3). Weaned rats (W), 21-25 day old were inoculated s.c. with 10(6) TCC (W1), 10(7) TCC (W2) and 10(8) TCC (W3). The cultures yielded up to 2% of trypomastigotes. Controls inoculated either i.p. or s.c. with 10(6) blood form trypomastigotes (SC and WC) as well as normal controls (NC) were included. Survival was 100% in S1, S2 and S3, and 0% in SC on day 13 post-infection (p.i.). The latter animals died with acute Chagas disease signs. Survival was 100% in the W groups. In the first 30 days p.i. parasites were detected in S1, S2 and S3 and W1, W2, W3 groups after exhaustive examination. Parasites were easily found in WC and SC until day 13. Xeno-diagnoses were positive (5/5) at 2 months p.i. and negative at 6 months p.i. (W1, W2, W3, 0/23; WC, 0/5). Only cardiac lesions were slightly increased. The frequency of focal chronic myocarditis seemed to be increased in a dose-independent manner (S1, S2, S3, 26%; W1, W2, W3, 46%) but was not significant in comparison with NC, and even was lower than usually found in WC (61.3%). The reduced virulence and pathogenicity suggest that the TCC strain suffered a remarkable attenuation after long term in vitro culture.

Evaluation of an attenuated Trypanosoma cruzi strain in rats. Analysis of survival, parasitemia and tissue damage.

Infection and tissue damage induced by parasites of an attenuated Trypanosoma cruzi culture strain (TCC) were studied in [quot ]I[quot ] line of inbred rats. Suckling rats (S), 3-5 day old were inoculated i.p. with 10(6) TCC (S1), 10(7) TCC (S2) and 10(8) TCC (S3). Weaned rats (W), 21-25 day old were inoculated s.c. with 10(6) TCC (W1), 10(7) TCC (W2) and 10(8) TCC (W3). The cultures yielded up to 2

of trypomastigotes. Controls inoculated either i.p. or s.c. with 10(6) blood form trypomastigotes (SC and WC) as well as normal controls (NC) were included. Survival was 100

in S1, S2 and S3, and 0

in SC on day 13 post-infection (p.i.). The latter animals died with acute Chagas disease signs. Survival was 100

in the W groups. In the first 30 days p.i. parasites were detected in S1, S2 and S3 and W1, W2, W3 groups after exhaustive examination. Parasites were easily found in WC and SC until day 13. Xeno-diagnoses were positive (5/5) at 2 months p.i. and negative at 6 months p.i. (W1, W2, W3, 0/23; WC, 0/5). Only cardiac lesions were slightly increased. The frequency of focal chronic myocarditis seemed to be increased in a dose-independent manner (S1, S2, S3, 26

; W1, W2, W3, 46

) but was not significant in comparison with NC, and even was lower than usually found in WC (61.3

). The reduced virulence and pathogenicity suggest that the TCC strain suffered a remarkable attenuation after long term in vitro culture.

Efecto de la reinfeccion sobre la evalucion de ratas infectadas con Trypanosoma cruzi / Effect of reinfection on the evolution of rats infected with Trypanosoma cruzi

El objetivo de este trabajo fue comprobar si una de las variables medio-ambientales, la reinfeccion, puede modificar el comportamiento observado en un modelo de rata a nivel de parasitemia, anticuerpos sericos, manifestaciones electrocardiograficas y/o lesion miocardica. Los grupos experimentales fueron: GI: ratas infectadas al destete com 1 x "10 POT 6" T. cruzi; GR: igual a GI mas reinfecciones cada 30 dias hasta los 150 dias post-infeccion inicial (p.i.i.); "GI IND 1". Los xenodiagnosticos fueron negativos en los tres grupos. Los anticuerpos sericos no se modificaron significativamente en GR respecto de GI, salvo en los anticuerpos 7S, pues los del GR presentaron titulos superiores en algunos de los dias estudiados. Los ECG basales no mostraron cambios distintivos en las ratas infectadas. La pruieba de ajmalina mostro una disminucion de la FC independiente del tratamiento; el PR, QaT y QRS se prolongaron significativamente en todos los grupos respecto del basal (p < 0.05), salvo el QaT en el GT; ademas el cambio de PR y QaT fue mayor en los infectados (p < 0.05). En los grupos infectados hubo tambien una amplia variacion en la orientacion del eje electrico respecto del valor basal, acompanado de cambios morfologicos mas manifiestos emGR. La proporcion de lesion cardiaca detectada histologicamente en los grupos

[Effect of reinfection on the development of rats infected with Trypanosoma cruzi]. / Efecto de la reinfección sobre la evolución de ratas infectadas con Trypanosoma cruzi.

The present study was undertaken in order to demonstrate that reinfection could modify parasitemia, serum antibodies, electrocardiographic patterns and/or myocardial lesions already observed in a rat model. Experimental groups IG: rats infected at weaning with 1 x 10(6) T. cruzi; RG: same as IG plus reinoculations each 30 days until completion on day 150; IG1: 51 day old infected rats; C: controls. A high parasitemia was detected in IG and RG until day 20 showing a tendency to become negative on day 30. No parasites were observed in RG after the first reinoculation which could not be attributed to the old age of the host since there was no parasitemia in IG1. Xenodiagnosis were negative in all three groups. Serum antibodies were not significantly modified in RG in comparison with IG, except for 7S antibodies, since RG showed higher titres in some days under study. No distinct patterns of basal ECG were observed in infected rats. The ajmaline test reduced the heart rate (HR) showing no treatment dependence. The PR, QaT and QRS were significantly lengthened in all groups regarding the basal one (p less than 0.05), except for the QaT in C. Besides, the PR and QaT alterations were greater in the infected rats (p less than 0.05). There was also present a wide variety of electric axis orientations, regarding the basal value, accompanied by morphological changes more evident in the RG. The incidence of cardiac lesions histologically detected in the infected group was significantly higher than in C (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

[Delayed cutaneous response to different antigens in household contacts of leprosy patients and controls]. / La respuesta cutánea tardía a diferentes antígenos en convivientes de pacientes lepromatosos y testigos.

The delayed type hypersensitivity (DTH) response to PPD, candidin and histoplasmin, and Mitsuda reaction (MR) in household contacts (HC) of multibacillary (HCM) and paucibacillary (HCP) leprosy patients, and non exposed controls was studied. Intradermal tests with 0.1 ml. of each antigen were performed and read after 48 hours. Late nodular reaction to ML (MR) was evaluated at the 21st day post-challenge. As we had formerly demonstrated, MR was depressed in HCM. Interestingly, this reaction was also depressed in HCP to a lesser magnitude. HCM had a lower DTH response to histoplasmin in relation to PPD and candidin when persons were simultaneously challenged with the three antigens. According to these results we conclude that: a), HCM have a depression in late lepromin reaction; b), in HCP the depression in MR is of a lower magnitude. We hypothesize that in healthy contacts of bacilliferous patients an active mechanism of immunosuppression to mycobacterial antigens may be produced. Alterations in the skin response to histoplasmin is discussed.