Katia Abarca

IRF8 Mutations and Human Dendritic-Cell Immunodeficiency

BACKGROUND The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).

Endemic scrub typhus-like illness, Chile.

TOC Summary: Rickettsiae closely related to the scrub typhus agent are present in the Western Hemisphere.

Partial recessive IFN-γR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds

We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.

Parásitos intestinales en caninos y felinos con cuadros digestivos en Santiago, Chile: Consideraciones en Salud Pública

Protozoa were found in 64.8% of dogs and in 66.5% of cats;helminthes in 24% of dogs and 45.2% of cats. The species found in dogs were Blastocystis sp. in 36%,Ameba sp. in 31%, Giardia intestinalis in 22%, Toxocara canis in 11%, Chilomastix sp. in 10%,Isospora sp. in 9%, Trichuris vulpis in 9%, Trichomonas sp. in 5%, Sarcocystis sp. in 4%, Dipylidiumcaninum in 2%, Ancylostomideos in 2%, Toxascaris leonina in 1%, Physaloptera sp. in 1%, Taeniasp. in 0.4%. Species found in cats were Blastocystis sp. in 37%, Ameba sp. in 30%, G intestinalis in19%, Chilomastix sp. in 12%, Isospora sp. in 12%, Toxocara cati in 10%, D caninum in 7%,Sarcocystis sp. in 5%, Trichomona sp. in 5%, Toxoplasma gondii in 4%, Taenia sp. in 2% andPhysaloptera sp. in 1%. Forty eight percent of parasites found in dogs and 49% found in cats havezoonotic potential. In dogs younger than six months Blastocystis sp., Ameba sp., G intestinalis,Chilomastix sp., Isospora sp. and T canis were significantly more common; the same was observedfor Isospora in young cats. Approximately 60% of infected animals bore more than one parasite.

Safety, tolerability, pharmacokinetics, and immunogenicity of motavizumab, a humanized, enhanced-potency monoclonal antibody for the prevention of respiratory syncytial virus infection in at-risk children.

Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children. Motavizumab is an investigational humanized monoclonal antibody for RSV prophylaxis. Methods: A dose-escalation study was conducted followed by assessment of safety, tolerability, serum concentrations, and immunogenicity during a second consecutive RSV season. In season 1, premature infants aged ≤6 months or children ≤24 months with chronic lung disease of prematurity received monthly motavizumab (3 or 15 mg/kg). In season 2, children who received ≥3 motavizumab doses in season 1 were randomized to receive monthly motavizumab or palivizumab 15 mg/kg. Results: Of 217 children enrolled in season 1, 211 (97.2%) received motavizumab 15 mg/kg and 205 (94.5%) patients completed the study through 90 days after the final dose. In season 2, 136 children were randomized to receive motavizumab (n = 66) or palivizumab (n = 70). The most commonly reported related adverse event was transient injection site erythema. In season 1, mean trough motavizumab concentrations were 7.9 and 50.2 &mgr;g/mL after the 3- and 15-mg/kg doses, respectively. Trough concentrations increased with repeated motavizumab dosing; a similar pattern was seen in season 2. Antimotavizumab reactivity occurred infrequently (3.3%) in season 1. In season 2, no treatment group–specific antidrug antibody was detected through 90 to 120 days after dosing with either product. Conclusions: The pharmacokinetic profile of motavizumab was similar to that of other IgG1 antibodies. Increased adverse reactions or immunogenicity were not observed during and after a second season of treatment with motavizumab. Safety findings from these studies supported the continued development of motavizumab.

Anaplasma platys in Dogs, Chile

We conducted a 16S rRNA nested PCR for the genus Ehrlichia and Ehrlichia spp. with blood samples from 30 ill dogs in Chile. Phylogenetic analysis was performed by using groESL gene amplification. We identified Anaplasma platys as 1 of the etiologic agents of canine ehrlichiosis.

Prevalencia y presencia de factores de riesgo de leptospirosis en una población de riesgo de la Región Metropolitana

BACKGROUND Leptospirosis is a zoonotic disease and its incidence is known in Chile since 2002, when it was incorporated as a disease that must be reported to health authorities. A serologic survey for leptospirosis was performed in humans and animals from a farm in a semi urban area in Santiago Chile, after the death of a farmer due to Weil disease in that place. AIM To report the prevalence of antibodies against leptospirosis and to determine exposure to infection risk factors in the humans and domestic animals studied in this survey. MATERIAL AND METHODS Antibodies were detected by IgM immunodot and indirect haemagglutination test in 61 humans (43 male, aged 5 to 70 years) and by microscopic agglutination test (MAT) in 44 animals. A questionnaire was applied to determine their exposure to risk factors for infection with Leptospira. RESULTS Seventy two percent of the studied population were farm workers and 70% had activities that required contact with water from canals, 41% cleaned closed places where rodents were present. Other risk factors detected were lack of sewage and waste disposal, high level of rodent infestation and disposal of faeces into canals used for watering. Two humans (3.3%) and six animals (1 bovine and 5 rodents) had positive antibodies. Among animals, antibodies against Leptospira serovar pomona and icterohaemorragiae were detected. CONCLUSIONS In Chile, leptospirosis exists not only in rural areas but semi urban ones close to Santiago, although the prevalence is low. Education is necessary among semi urban population to avoid infection.

A phase 2, randomized, double-blind safety and pharmacokinetic assessment of respiratory syncytial virus (RSV) prophylaxis with motavizumab and palivizumab administered in the same season

BackgroundRespiratory syncytial virus (RSV) is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide. High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb). In preclinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab. Motavizumab is currently under review for licensing approval. Since both MAbs may be available concurrently, this study evaluated their safety and tolerability when administered sequentially during the same RSV season.MethodsBetween April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intramuscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control). Adverse events (AEs, serious AEs [SAEs]), development of antidrug antibody (ADA), and serum drug trough concentrations were assessed.ResultsMost children received all 5 doses (246/260 [94.6%]) and completed the study (241/260 [92.7%]). While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9% M/P, 8.4% P/M, 11.8% motavizumab only; level 3 AEs: 15.7% M/P, 6.0% P/M, 6.5% motavizumab only). This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen. Frequencies of AEs judged by the investigator to be related to study drug were similar among groups. Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug. Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1% or less of any group).ConclusionsThe conclusions drawn from this study are limited by the small sample size per group. However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season.Trial Registrationclinicaltrials.gov NCT00316264

Dengue-1 Virus Isolation during First Dengue Fever Outbreak on Easter Island, Chile

Dengue virus was detected for the first time in Chile, in an outbreak of dengue fever on Easter Island. The virus was isolated in tissue culture and characterized by reverse transcription–polymerase chain reaction as being dengue type 1.

Prevalencia de anticuerpos contra Bartonella henselae en niños, en adolescentes y en una población de riesgo ocupacional en Chile

Assuming that seroprevalence indicates level ofexposure to Bartonella henselae, these results suggest that this infection is endemic in Chile and,for this reason, the best antibody titer to diagnose acute cat-scratch disease should be higherthan the figure recommended by the Centers for Disease Control in the in United States (RevMed Chile 2006; 134: 863-7).(