Manejo clínico y diagnóstico para pacientes con enfermedades de inmunodeficiencia primaria por déficit de producción de anticuerpos / Clinical management and diagnosis for patients with primary immunodeficiency diseases due to deficiency of antibody production

1. INTRODUCCIÓNLas inmunodeficiencias primarias son un grupo de más de 400 enfermedades, en las cuales el sistema inmune pierde sus funciones de reconocimiento de patógenos o funciona de forma inapropiada. Algunas de ellas son relativamente comunes; mientras otras son raras. Estas enfermedades son en ocasiones de por vida, debilitantes y costosas1,2.Sin embargo, muchos progresos se han hecho desde su des-cripción original en el año de 1952. Se han dado grandes pasos en cuanto a su entendimiento de las Inmunodeficiencias Pri-marias a nivel genético, de sus características, y tratamiento. Algunos tipos afectan un único tipo de célula; otros afectan más de un componente del sistema inmune2,3.Tomando en cuenta que la aproximación es entre 1-2% de la población, a nivel país se puede decir que un aproximado entre 170 000 a 340 000 pacientes en el país no cuentan con un diagnóstico y muchos mueren por falta de este. El número de afiliados al Instituto Ecuatoriano de Seguridad Social hasta julio de 2021 es de 3 672,611 por lo que se considera que un estimado de 36 726 a 73 452 pacientes podrían presentar este tipo de enfermedades y requerir de atención por infecciones a repetición, enfermedad autoinmune y enfermedades linfopro-liferativas, además de que sin un tratamiento específico po-drían fallecer debido a infecciones graves o tener discapacidad permanente, lo que implica mayor carga para el sistema de Seguridad Social en subsidios y menores ingresos. Ecuador, cuenta con 86 pacientes diagnosticados, según la base de datos de la Sociedad Latino-Americana de Inmunodeficiencias4.Algunas terapias, como la de reemplazo para inmunoglobu-linas, a la que es tributaria más del 60% de estas patologías permite que la esperanza de vida y la morbilidad casi alcancen a aquellos que no presentan la enfermedad5­7.

1. INTRODUCTIONPrimary immunodeficiencies are a group of more than 400 diseases, in which the immune system loses its pathogen recog-nition functions or functions inappropriately. Some of them are relatively common, while others are rare. These diseases are sometimes lifelong, debilitating, and costly1,2. However, much progress has been made since its original description in 1952. Great strides have been made in understanding Primary Immunodeficiencies at the genetic level, their characteristics, and treatment. Some types affect only one type of cell; others affect more than one component of the immune system2,3. Considering that the approximation is between 1 to 2% of the population, at the country level we could say that approximately between 170 000 to 340 000 patients in the country do not have a diagnosis and many die due to lack of it. The number of social security affiliates until July 2021 is 3 672,611, so we could consider that approximately 36 726 to 73 452 patients could present this type of disease and require care for recurrent infections, autoimmune disease and lymphoproliferative diseases, in addition to the fact that without specific treatment they could die due to serious infections or have permanent disability, which implies a greater burden for the social security system in subsidies and lower income. Currently the country has 86 diagnosed patients, according to the database of the Latin American Society of Immunodeficiencies4. Many of the therapies, such as immunoglobulin replacement therapy, to which more than 60% of these pathologies are de-pendent, allow life expectancy and morbidity to almost reach those who do not have the disease 5­7.

Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome / 中国当代儿科杂志

OBJECTIVES@#To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM).@*METHODS@#A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT.@*RESULTS@#After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04).@*CONCLUSIONS@#Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

Recurrent fever, hepatosplenomegaly and eosinophilia in a boy / 中国当代儿科杂志

A 2-year-old boy was admitted into the hospital because of cough and fever. Lymph node tuberculosis was noted when he was 2 months old and he was subsequently hospitalized several times because of cough and fever. After hospitalization the laboratory examination showed an increased eosinophia level in blood. The immune function tests shows decreased levels of IgG, IgA, and IgM. The patient had no response to anti-tuberculosis, anti-bacterial, and anti-fungal treatment, resulting in recurrent fever and progressive enlargement of the liver and spleen. Jam-like stools were noted 35 days after admission. B ultrasonography showed suspected intussusception. Laparotomy, reduction of intussusception and ileocecum angioplasty, biopsies of intestinal wall nodules and lymphoglandulae mesentericae, and hepatic biopsy were then performed under general anesthesia. The patient eventually died because of postoperative severe liver damage, disseminated intravascular coagulation and electrolyte disorder. Both the blood culture and hepatic biopsy tests showed Penicillium marneffei infecton. Immunodeficiency gene test was performed on the patient, his bother and their parents. T→G base substitution mutation (IVS1-3 T→G) in the CD40L gene was found in the patient. X-linked hyper-IgM syndrome was thus diagnosed in the patient. His mother was a carrier of the mutated CD40L gene, but his father was normal in the gene test. Hemizygous mutation in the CD40L gene was found in both the patient and his bother.

Analysis of isotype-specific antibody responses to bovine herpesviruses 1.1 and 1.2a allows to estimate the stage of infection

Specific IgM, IgA, IgG1, IgG2, as well as neutralizing antibody responses were evaluated in sera of calves experimentally infected with two isolates of bovine herpesvirus type 1 (BoHV1) of distinct subtypes (subtype 1, BoHV1.1; subtype 2a, BoHV-1.2a). No significant differences were observed in the antibody responses induced by each BoHV-1 subtype. The antibody responses following primary acute infection were characterized by an increase in specific IgM and IgA levels between days 2 and 14 post inoculation (pi). IgG1 was detected from days 11 to 30 pi. IgG2 was detected on the sample taken on day 30 pi. Reactivation of infection following dexamethasone administration induced a significant rise in IgA levels, whereas IgG1 and IgG2 levels, which were at high levels from the beginning of the reactivation process, showed a slight alteration after corticosteroid treatment. These results suggest that it is possible to estimate the dynamics of BoHV-1 infections with basis on the analysis of class- and subclass-specific antibody responses. Such information may be particularly useful for the study of the kinetics of the infection in a herd and to aid in the adoption of appropriate control measures..

Incidencia de la infección por el virus de la hepatitis A diagnosticadas en la ciudad de Maracaibo estado Zulia Venezuela / Incidence of infection by the hepatitis A virus diagnosed in the city of Maracaibo state Zulia Venezuela

La infección por el virus de la hepatitis A (VHA) sigue siendo un problema de salud pública en los países en vías de desarrollo. El objetivo de la presente investigación fue determinar la incidencia de la infección por el VHA en individuos de la ciudad de Maracaibo, estado Zulia, Venezuela. Durante el periodo comprendido entre enero 2004 a diciembre 2007 se seleccionaron 1056 pacientes en edades de 1 a 60 años de ambos sexos (media ± DS: 27,48 ± 5,24), procedentes de los municipio Maracaibo y San Francisco ubicados en la ciudad de Maracaibo estado Zulia, Venezuela. La presencia de anticuerpos anti-IgM contra el virus de la hepatitis A se determinó mediante métodos convencionales de micro partículas enzimoinmunoanalisis (MEIA). Los resultados encontrados indican una seropositividad en 73 (35,1%), 76 (28%), 66 (24,3%), 35 (20,3%) individuos de las zonas Norte, Sur, Este, Oeste respectivamente, correspondientes al municipio Maracaibo y 31 (23,3%) correspondiente al municipio San Francisco. La mayor prevalencia fue observada en pacientes del sexo femenino menor de 20 años (47,3%), y en pacientes del sexo masculino menor de 10 años (53,7%), siendo el signo clínico más frecuente la ictericia (95,7%). Las deficientes medidas de saneamiento ambiental y sanitario fueron factores aparentemente determinantes en la diseminación del VHA

Hepatitis A virus (HAV) infection continues to be a public health problem in developing countries. The aim of this study was to determine incidence of the hepatitis A virus infection in a population from Maracaibo, Venezuela. From January, 2004 until December, 2007, this study was carried out on 1056 individuals, whose ages were between 1-60 years (average ± DS: 27.48 ± 5.24 years), coming from the Maracaibo and San Francisco municipalities, Venezuela. The IgM antibody against HAV was determined by the ELISA technique. The overall incidence was 26.6%. The North, South, East and West areas of the Maracaibo Municipality and the San Francisco Municipality in the city of Maracaibo showed incidences of 73 (35.1%), 76 (28%), 66 (24.3%), 35 (20.3%) and 31 (23.3%), respectively. The highest incidences were observed in females under 20 years (47.3%) and males under 10 years (53.7%). The most frequent clinical sign was jaundice in 95.7% of patients. Deficient sanitary conditions and hygiene habits seemed to be the main risk factors in spreading HAV infection

A Case of Neuroendocrine Carcinoma and Childhood Myelodysplastic Syndrome in Hyper-IgM Syndrome / 대한혈액학회지

Congenital immunodeficiency is one or combined immune defect in immunoglobulin, leukocyte, and complement. These patients have increased susceptibility to respiratory infection. Hence, their infection must be taken care of, tried to gene therapy and stem cell transplantation. We present here a case of hyper-IgM syndrome in an 11-year-old male patient who complained of abdominal distension and abdominal pain. Multiple abdominal masses were detected by abdominal computed tomography (CT) and he was diagnosed with neuroendocrine carcinoma by mass biopsy. There was no evidence of metastasis of cancer cells to the bone marrow, but a dysgranulopoietic feature was noted and he was diagnosed with childhood myelodysplastic syndrome. This is the first report that neuroendocrine carcinoma is associated with childhood myelodysplastic syndrome in hyper-IgM syndrome.

Spectrum of primary immune deficiency at a tertiary care hospital.

OBJECTIVE: To report various primary immune deficiencies diagnosed in children at a tertiary care hospital, their clinical manifestations and laboratory profile. METHODS: Case records of children diagnosed to have primary immunodeficiency disorders over a period of 24 months at a tertiary care hospital in northern India were evaluated. RESULTS: Twenty-seven children (M: F=3.5: 1) with mean age of 5.4 +/- 4.6 yrs (2 mo-16 yr) were diagnosed to have primary immunodeficiency. Thirteen children had chronic granulomatous disease (CGD), 4 had severe combined immunodeficiency (SCID), 4 had hypogammaglobulinemia, 2 had Ataxia telangiectasia, and one each had DiGeorge syndrome, Wiskott Aldrich syndrome, hyper IgM syndrome and leukocyte adhesion defect. Common mode of presentation were recurrent/ persistent pneumonia in 19, recurrent/ persistent diarrhea in 10, deep seated abscesses in 8, allergy in 3, disseminated tuberculosis infection in 2, extensive fungal infections in 2 and 1 each of disseminated cytomegalovirus (CMV) infection, disseminated BCG disease, otitis media and meningitis. Family history of sibling deaths was elicited in 2 families. Infectious agents were isolated in 16 cases. CONCLUSION: From a single center 27 patients with primary immune deficiency could be identified by chart review, suggesting need for high index of suspicion for diagnosis of primary immune deficiency in India. Though the exact prevalence is not known there is need to make a registry to document the magnitude of problem of these disorders.

Adverse reaction following intravenous immunoglobulin in primary immunodeficiency patients

Intravenous immunoglobulin is used for primary immunodeficiency disorders. There have been some reports that intravenous immunoglobulin causes side effects. The aim of this study was to investigate intravenous immunoglobulin side effects in immunodeficiency patients. The study utilized the data of 29 primary immunodeficiency patients that were referred to allergy and immunology department in Medical Children Center in Tehran. 29 patients having completed record data files in the hospital, were the subjects of this study. Of 29 immune deficiency patients [aged 15 months to 55 years], they were 19 Males [65/51%] and 10 [34/48%] Females. Prevalence of disorders include common variable immunodeficiency 16 [55/17%], Bruton disease 8 [27/58%], hyper IgM 4 [13/79%] and severe combined immunodeficiency 1 [3/44%]. Based on the recorded data, the duration of infusion has been 5 months to 15 years. 15 patients had reported side effects [51/72%]. 34 infusions from the total of 1,626 infusions accompanied with side effects [2/09%]. Most side effects were occurred during 30 minutes onset of infusion and most were caused by rapid infusion. Most side effects were mild reactions [fever, chills and ...]. Intravenous immunoglobulin is a rather safe drug with mild side effects. With an appropriate technique and proper infusion, these side effects can be reduced

A Clinical Study of Primary Immunodeficiency Disease in a Single Center in Seoul from 1996 to 2004 / 소아알레르기및호흡기학회지

PURPOSE: Although primary immunodeficiency disorders are relatively rare, early diagnosis provides the opportunity to reduce morbidity and mortality. The aim of this study was to investigate disease distribution, clinical manifestations, genetic mutation, treatment and prognosis of primary immunodeficiency disorders of childhood. METHODS: We retrospectively reviewed the medical records of 15 cases with primary immunodeficiency disorders between 1996 and 2004 in Samsung Seoul Hospital, Seoul, Korea. RESULTS: The most common primary immunodeficiency was common variable immunodeficiency (CVID) (n=7), followed by X-linked agammaglobulinemia (XLA) (n=3), severe combined immunodeficiency (SCID) (n=2), hyper IgM syndrome (n=1), selective IgA deficiency (n=1), and chronic granulomatous disease (CGD) (n=1). Most cases had recurrent infections such as otitis media, bacterial pneumonia, sinusitis and other respiratory infections during infancy. The age at diagnosis ranged from 4 months to 17 years with a median age of 5 years. The male to female ratio was 11 to 4. Eleven patients were diagnosed with primary immunodeficiency diseases following respiratory infection, while the other 4 patients had pulmonary tuberculosis, perianal abscess, bacterial meningitis, septic arthritis. All the patients with XLA and CVID were regularly treated with IVIG. Two cases of SCID underwent successful bone marrow transplantation without complications. The patients with hyper IgM syndrome died due to severe infection even after bone marrow transplantation. CONCLUSION: Fifteen variable cases of primary immunodeficiency were diagnosed during 9 years. A high index of suspicion is required in children with recurrent or severe infections for the diagnosis of primary immunodeficiency, because early diagnosis and treatment can reduce mortality and morbidity.

Characterization of B Cells of Lymph Nodes and Peripheral Blood in a Patient with Hyper IgM Syndrome

PURPOSE: Hyper IgM syndrome(HIGM) is characterized by severe recurrent bacterial infections with decreased serum levels of IgG, IgA, and IgE but elevated IgM levels. Recently, it has been classified into three groups; HIGM1, HIGM2 and a rare form of HIGM. HIGM1 is a X-linked form of HIGM and has now been identified as a T-cell deficiency in which mutations occur in the gene that encodes the CD40 ligand molecule. HIGM2 is an autosomal recessive form of HIGM. Molecular studies have shown that the mutation of HIGM2 is in the gene that encodes activation-induced cytidine deaminase(AID). Recently, another rare form of X-linked HIGM syndrome associated with hypohydrotic ectodermal dysplasia has been identified. We encountered a patient with a varient form of HIGM2. To clarify the cause of this form of HIGM, we evaluated the peripheral B cells of this patient. METHODS: The lymphocytes of the patient were prepared from peripheral blood. B cells were immortalized with the infection of EBV. Cell cycle analysis was done with the immortalized B cells of the patient. Peripheral mononuclear cells were stained with monoclonal anti-CD40L antibody. Total RNA was extracted from the peripheral mononuclear cells. After RT-PCR, direct sequencing for CD40L gene and HuAID gene were done. Immunostainings of a lymph node for CD3, CD23, CD40, Fas-L, bcl-2, BAX were done. RESULTS: The peripheral B cells of this patient showed normal expression of CD40L molecule and normal sequencing of CD40L gene, and also normal sequencing of AID gene. Interestingly, the peripheral B cells of this patient showed a decreased population of G2/mitosis phase in cell cycles which recovered to normal with the stimulation of IL-4. CONCLUSION: We suspect that the cause of increased serum IgM in this patient may be from a decrease of G2/mitosis phase of the peripheral B cells, which may be from the decreased production or secretion of IL-4. Therefore, this may be a new form of HIGM.