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.

Vacunación BCG e inmunodeficiencias primarias: ¿es momento de un cambio? / BCG vaccine administration schedule and primary immunodeficiencies: Is it time for a change?

Resumen: Los pacientes con Inmunodeficiencias primarias (IDP) tienen un riesgo elevado de complicaciones severas por la vacuna BCG, incluso mortalidad. Es necesario evaluar periódicamente el riesgo versus beneficio de la vacunación universal BCG en el periodo neonatal. Chile es un país con baja incidencia de tuberculosis (TB) pero cuya epidemiología ha cambiado recientemente con un aumento de los casos. Cambios en esquemas de vacunación BCG en países con incidencias mayores o similares de TB y con coberturas de vacunación menores han sido posibles sin aumento de los casos graves de TB que son los que previene la BCG. El cambio ha evitado complicaciones graves en pacientes con IDP. Creemos que un análisis crítico de la fecha de vacunación BCG debe realizarse hoy en Chile. Más aún dada la posibilidad técnica de realizar screening neonatal de IDP.

Abstract: Patients with Primary Immunodeficiencies (PID) are at a higher risk of developing severe morbidities and mortality due to the administration of BCG vaccine. Risk-to-benefit of universal BCG vaccina tion of newborns must be assessed periodically. Chile has a low incidence of tuberculosis (TB) but the local epidemiology has recently changed with an increase of TB cases. Changes in the BCG vaccine schedule have been made in countries with similar or higher TB incidences and lower BCG vaccine coverage, with no increase in the severe TB cases, which are prevented by BCG. These changes have prevented serious complications in PID patients. We propose a critical analysis of the BCG adminis tration date in Chile due to the technical possibility of performing neonatal PID screening.

Infección diseminada por Bacilo Calmette-Guérin en un lactante con inmunodeficiencia: reporte de caso / Disseminated infection by Bacillus Calmette-Guérin in an immunodeficient infant: case report

RESUMEN La vacuna Bacillus Calmette-Guerin (BCG) que se administra a los recién nacidos de países con alta incidencia de tuberculosis puede ocasionar reacciones locales hasta infección diseminada en pacientes inmunocomprometidos. Reportamos el caso de un lactante varón de seis meses con antecedente de haber recibido vacuna BCG al nacer, y presentar cuadros infecciosos a repetición, nódulos violáceos blandos en tronco y extremidades con presencia de bacilos ácido alcohol resistentes (BARR) en la histopatología y en cultivo de piel; el estudio molecular reportó la presencia de Micobacterium bovis BCG. En la tomografía se observó opacidades intersticiales en pulmones y en el lavado gástrico se identificó BAAR. El estudio genético del paciente y de la madre reveló la presencia de mutación en el gen IL2RG confirmando el diagnóstico de inmunodeficiencia combinada severa, recibe tratamiento con inmunoglubolina humana y esquema antituberculosis con isoniacida, rifampicina y etambutol. Presentamos el caso por la implicancia en el pronóstico de vida de estos pacientes y por la necesidad de un diagnóstico preciso y oportuno.

ABSTRACT The Bacillus Calmette-Guerin (BCG) vaccine given to newborns in countries with a high incidence of tuberculosis may cause local reactions up to disseminated infection in immunocompromised patients. We report the case of a six-monthold male infant with a history of having received the BCG vaccine at birth, and presenting repeated infectious, soft violet nodules in the trunk and extremities with the presence of acid-alcohol-resistant bacilli (BAAR) in histopathology and skin culture; the molecular study reported the presence of Mycobacterium bovis BCG. In the tomography, interstitial opacities were observed in the lungs and in the gastric lavage BAAR was identified. The genetic study of the patient and the mother revealed the presence of a mutation in the IL2RG gene confirming the diagnosis of severe combined immunodeficiency. Received treatment with human immunoglobulin and anti-tuberculosis scheme with isoniazid, rifampicin, and ethambutol. We present the case because of the implication in the life prognosis of these patients and because of the need for an accurate and timely diagnosis

Síndrome de Edwards asociado a inmunodeficiencia combinada / Edwards' syndrome associated to combined immunodeficiency

El síndrome de Edwards es originado por un desbalance cromosómico representado por una trisomía 18. Alrededor de 95 por ciento de los pacientes corresponden a trisomía completa, donde están presentes múltiples malformaciones en órganos y sistemas. El 5 por ciento restante pertenece a trisomía parcial o mosaicismo, con un fenotipo incompleto por la ausencia de algunas anomalías típicas del síndrome. La inmunodeficiencia es una manifestación poco frecuente del síndrome Edwards. Se presenta el caso de una paciente de 9 meses de edad con trisomía 18 parcial e infecciones severas recurrentes desde la etapa neonatal, asociadas a anemia, linfopenia, trombocitopenia y neutrofilia. La ecografía mostró una hipoplasia del timo. Se encontraron cifras disminuidas de linfocitos TCD4+, CD8+ y de células asesinas naturales. La cuantificación de linfocitos B fue normal. Se hallaron concentraciones normales de inmunoglobulinas séricas IgM e IgG y disminuidas de IgA. Se encontró una disminución de la actividad hemolítica total de la vía clásica del complemento. No se encontraron alteraciones en la función opsonofagocítica. Se diagnosticó una inmunodeficiencia combinada asociada, hecho que demostró la heterogeneidad de la expresión clínica del síndrome Edwards y la relación entre el defecto cromosómico y la formación del sistema inmune en el período intrauterino

Edwards' syndrome is caused by a chromosomal imbalance represented by trisomy 18. Complete trisomy accounts for 95 percent of patients who present multiple malformations in organs and systems. The remaining 5 percent presents partial trisomy or mosaicism, with incomplete phenotype due to lack of some typical anomalies of this syndrome. Immunodeficiency is a rare manifestation of Edwards' syndrome. The case of a 9-months old female patient with partial trisomy 18 and recurrent severe infections since the neonatal phase, all associated to anemia, lymphopenia, thrombocytopenia and neutrophilia, was presented in this paper. The echographic test indicated tymus hypoplasia. There were reduced numbers of TCD4+, CD8+ lymphocytes and of natural killer cells. The lymphocyte B count was normal. Normal concentrations of serum IgM and IgG immunoglobulins as well as decreased concentrations of IgA were found. The total hemolytic activity of the classical complement pathway declined. No alteration was found in the opsonocytophagic function. The diagnosis was associated combined immunodeficiency, which proved the heterogeneity of the clinical expression of Edwards' syndrome and the relationship between the chromosomal defect and the formation of immune system in the intrauterine period

Successful treatment of disseminated BCG infection in a SCID patient with granulocyte colony stimulating factor.

Severe combined immunodeficiencies (SCID) are disorders with impairment of humoral and cellular immune functions. The prognosis of disseminated bacillus Calmette-Guérin (BCG) infection in immunocompromised host is unfavorable since response to standard therapy is poor. We report a successful treatment of disseminated BCG infection with granulocyte colony stimulating factor (G-CSF) in a patient with severe combined immunodeficiency. The patient failed to response to intensive anti-tuberculous (anti-TB) therapy. After 2 months of G-CSF, in addition to anti-TB treatment, the clinical signs of disseminated BCG infection were improved. Since serious BCG infections in SCID are not uncommon in developing countries, where BCG vaccination is mandatory to all newborns, the combination of G-CSF and anti-TB drugs should be considered in immunocompromised patients with protracted mycobacterial infection.

Disseminated Bacille Calmette-Guérin disease as the initial presentation of X-linked severe combined immunodeficiency--a case report.

Bacille Calmette-Guerin (BCG) vaccination is used to prevent severe M. tuberculosis infection. It has been used in many countries for a long time. However, complications do occur, including localized abscesses, regional lymphadenitis and disseminated disease. The latter is often associated with underlying immunodeficiency. We report an 8-month-old male infant presenting with cough and fever who had had a generalized pigmented skin rash for one month. Skin biopsy revealed mycobacterial infection, but his response to treatment was poor and he had a persistent mild fever. Immunological studies revealed an IgG of 49 mg/dl, IgA 4 mg/dl, IgM 28 mg/dl, IgE < 1 mg/dl, CD3 1.1%, CD4 0.6%, CD8 0.6%, CD19 93.9%, CD57 1.1%, activated T cells 0.9%, and CH50 < 6.3%. These findings are compatible with the diagnosis of T(-)B(+)NK- severe combined immunodeficiency. Sequence analysis was performed and showed the presence of missense mutation in IL2Rgamma gene. An X-linked recessive inheritance pattern was proved by sequence analysis of his mother and grandmother. In order to identify the strain of the microorganism, we reviewed pathology of the skin biopsy which consisted of diffuse histiocytic infiltrate with poorly formed granulomas and no necrosis and used polymerase chain reaction (PCR) with the stain-positive clinical specimen and verify the organism found in the child's biopsy as M. bovis BCG strain. The diagnosis of disseminated BCG disease must be considered in any infant with cutaneous mycobacterial lesions, especially with atypical histologic findings. Such a patient's immunologic status should be evaluated and further family study is suggested. A high index of suspicion is needed to make a timely diagnosis, as early intervention with intensive treatment and bone marrow transplantation may be life-saving.

Trasplante de médula ósea en pacientes portadores de inmunodeficiencias severas combinadas / Bone marrow transplantation in patients with severe combined immunodeficiency

La inmunodeficiencia severa combinada (IDSC) es una inmunodeficiencia primaria cuya evolución clínica es mortal si no se realiza un tratamiento con trasplante de médula ósea (TMO). En los últimos 8 años cuatro pacientes de sexo masculino han sido sometidos a TMO, dos de ellos con donante idéntico (hermanos) y los otros dos con médula obtenida de sus respectivas madres (haploidéntico). Como elementos de importancia deben mencionarse la presencia de diseminación de la vacuna BCG en dos de ellos, una paraproteinemia de predominio IgM en un caso y la identificación de una quimera por linfocitos maternos en otro niño. En los cuatro casos existía compromiso pulmonar de importancia, con secuelas tipo bronquiectasias en dos de ellos. Dos pacientes que recibieron TMO idéntico normalizaron su trastorno inmunológico al mes y tres meses de haber recibido el TMO, encontrándose en la actualidad sanos con un tiempo de seguimiento de 1 y 7 años respectivamente. Los otros dos enfermos trasplantados con médula no idéntica fallecieron de complicaciones atribuibles a infecciones y al daño pulmonar existente, al 1 y 2 meses de efectuarse el TMO. Las implicancias prácticas del diagnóstico de la IDSC y los aspectos más importantes del TMO son comentados

Cardiac malignant lymphoma in severe combine immunodeficient mice.

Extranodal malignant lymphomas are known to occur with increased frequency in patients with human immunodeficiency virus infection. Although cardiac malignant lymphomas are rare, recently an increasing number of patients with acquired immune deficiency syndrome (AIDS) and cardiac lymphoma have been reported. To clarify the relationship between AIDS and cardiac lymphomas, we used 60 severe combine immunodeficient (SCID) mice as animal models in whom five different types of human lymphoma cell lines were injected. Primary lymphomas at the site of cell line injection developed within 14-30 days in 58 mice. Cardiac malignant lymphoma was detected in 10 cases (17%), among which tumour was macroscopically evident in 2. Tumour was present on the pericardial aspects of the heart extending into the myocardium in most cases, but no intracavitary lesion was observed. In one case, obstructive features were marked near the root of the great vessels by direct pressure of the growth. This study indicates that lymphomas have a predilection to invade the heart in immunocompromised conditions.

Effect of interferon-gamma treatment on interstitial pneumonia in a patient with severe combined immunodeficiency

In severe combined immunodeficiency disease, both T and B cell functions are diminished or absent and affected usually succumb to overwhelming infection within the first year of life. We are reporting a case with severe combined immunodeficiency, Swiss type who suffered from interstitial pneumonia which cleared by treatment with recombinant human interferon gamma. In this case, we don't know the exact mechanism which caused the clearing of the interstitial pneumonia. However, we can speculate that antiviral action and activated macrophages or monocytes, through the recombinant human interferon gamma, might exert its effect on interstitial pneumonia. Though we should extend its application to more cases of SCID with interstitial pneumonia, this report may suggests a new application for interferon-gamma as a potential corrective and therapeutic agent for interstitial pneumonia in congenital immunodeficiency diseases.