Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis / 中华医学杂志(英文版)

BACKGROUND@#Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA.@*METHODS@#A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease.@*RESULTS@#The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production.@*CONCLUSION@#Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.

Allergic bronchopulmonary aspergillosis complicating childhood asthma.

While Allergic bronchopulmonary aspergillosis (ABPA) is known to complicate asthma in adults, its association with childhood asthma is very rare. We present two patients, a four-and half year old boy who presented with severe asthma and a 12 year-old girl whose previous chest radiographs revealed fleeting opacities. Both were diagnosed to be suffering from ABPA.

Pulmonary hypertension as a presenting manifestation of allergic bronchopulmonary aspergillosis.

The case of a 46-year-old lady who presented with respiratory failure and pulmonary hypertension in the absence of clinical signs of asthma or bronchiectasis, and in whom a diagnosis of allergic bronchopulmonary aspergilloma [ABPA] was made subsequently on the basis of radiological and laboratory investigations is reported. Symptomatic and objective improvement was seen with corticosteroid therapy. To the best of the authors' knowledge, such an occurrence has not been reported previously. This case highlights the importance of keeping a high index of suspicion while investigating a patient with pulmonary hypertension in whom the aetiology is not apparent on initial evaluation. Identification of the disease, in its early-stage, can prevent progression to bronchiectasis and fibrotic lung disease, and thus, patients can be saved from the morbidity related to end-stage disease.

Caso clínico: aspergilosis pulmonar invasiva tratada con Voriconazol en paciente con Síndrome de Inmunodeficiencia Adquirida / Clinical case: invasive pulmonary aspergillosis treated with Voriconazol in an AIDS patient

Se reporta un caso clínico de aspergilosis pulmonar invasiva en un paciente de 29 años VIH(+) en etapa SIDA, sin antecedentes mórbidos conocidos, con diagnóstico inicial de neumonía por Pneumocystis jirovecii. Fue tratado con éxito, pero sin asistir a controles posterior a su alta . Tres meses después ingresa al servicio de Urgencias del Hospital Gustavo Fricke con tos productiva mucopurulenta, disnea progresiva, fiebre intermitente y compromiso del estado general. La radiografía de tórax sugirió neumonía atípica, detectándose en los exámenes Pneumocystis jirovecii y Enterobacter aerógenes , por lo que se inicia tratamiento con Cotrimoxazol y Ertapenem. En los cultivos en agar Sabouraud se detectó abundante desarrollo de Aspergillus fumigatus , por lo que se empieza tratamiento con anfotericina B en dosis crecientes hasta alcanzar 50 mg/día, sin embargo, por reacciones adversas severas se decidió tratamiento con Voriconazol intravenoso y luego oral, con buena respuesta clínica, radiológica y de laboratorio. Es dado de alta con tratamiento con Voriconazol oral, además de profilaxis secundaria para P. jirovecii y Mycobaterium avium.

A clinical case of an invasive pulmonary aspergillosis in a 29 aged VIH (+) patient, at an AIDS stage, lacking any known morbid data, and bearing an initial diagnosis of pneumonia by Pneumocystis jirovecii is herein described. Was successfully treated even though he failed to attend subsequent health controls. Three months later he is admitted in the Hospital Gustavo Fricke, showing productive mucupurulent cough, progressive disnea, intermittent fever and his overall health condition resulting deeply compromised. Thorax X-ray revealed an atypical pneumonia together with the presence of P. jirovecii and Enterobacter aerogenes, and decided to treat him with Cotrimoxazol and Ertapenem. Meanwhile in agar cultures a heavy development of Aspergillus fumigatus was detected, thus the patient was given Anfotericina B in increasing doses up to reach 50mg/day; however due to some severe adverse reactions, the treatment with intravenous and later oral Voriconazol, which rendered satisfactory clinical, radiological and laboratory responses was ultimately preferred. The patient is discharged from the hospital and advised to continue with oral Voriconazol besides undergoing secondary profilaxis for P. jirovecii and Mycobaterium avium.

Aspergillus-associated hypersensitivity respiratory disorders.

The mould Aspergillus is responsible for a gamut of respiratory diseases ranging from saprobic colonisation to rapidly invasive disseminated disease. The clinical spectrum of Aspergillus-associated hypersensitivity respiratory disorders includes Aspergillus induced asthma, allergic bronchopulmonary aspergillosis (ABPA), allergic Aspergillus sinusitis (AAS) and hypersensitivity pneumonitis. Inhalant allergens, in patients with allergic asthma, play a key role in bringing about the inflammation present in the airways, and fungi are increasingly being recognised as important inhalant allergens. Aspergillus is linked to asthma in more ways than one. In the asthmatic subjects, the fungal spores are trapped in the thick and viscid secretions that are usually present in the airways. This generally develops in atopic subjects and is sustained by continuous inhalation of Aspergillus antigens, triggering asthma that may be more severe in form. Aspergillus induced asthma is yet to receive the recognition that it deserves. Allergic bronchopulmonary aspergillosis is the best known form of allergic aspergillosis and is an emerging disease in India. An immunologically mediated lung disease, ABPA occurs predominantly in patients with asthma. A set of diagnostic criteria is required as there is no single test that establishes the diagnosis apart from demonstration of central bronchiectasis with normal tapering bronchi, a feature considered to be pathognomonic of ABPA. Radiologically, ABPA is characterised by 'transient pulmonary infiltrates' or 'fleeting shadows', often confused with pulmonary tuberculosis. A comparatively more recently recognised clinical entity, AAS is characterised by mucoid impaction in the paranasal sinuses which is akin to that in ABPA. Although it appears that the patient with ABPA provides a favourable milieu for the occurrence of AAS, it is perhaps surprising that in spite of similar histopathological features the co-existence of both these diseases has not often been reported. Aspergilloma, a fungal ball that appears in a pre-existing cavity due to saprobic colonisation of Aspergillus species, can often present with asthma. The association of ABPA and aspergilloma is also known. Although cavitation can occur in ABPA, the co-existence of ABPA with aspergilloma is rather uncommon. Aspergillomas may function as a nidus for antigenic stimulation in a genetically predisposed individual resulting in the occurrence of ABPA. Contemporaneous occurrence of ABPA, AAS and aspergilloma has also been reported. Screening all asthmatic subjects for Aspergillus sensitisation could identify those with a severe form of the disease as well as those at risk for developing ABPA. Furthermore, concomitant occurrence of ABPA and AAS is now being increasingly recognised, and AAS must be excluded in all patients with ABPA.

A novel mutation of the CYBB gene resulting in severe form of X-linked chronic granulomatous disease.

We evaluated a boy who had multiple Salmonella septicemia, Aspergillus pneumonia and brain abscesses. His nitroblue tetrazolium (NBT) test was reportedly abnormal. The dihydrorhodamine (DHR) flow cytometry assay was compatible with typical X-linked chronic granulomatous disease (X-CGD). CYBB analysis revealed a novel complex mutation atggacg --> ttca in exon 12 (base pairs 1532-1538). As a result, 3 amino acids Tyr 511, Gly 512 and Arg 513 were deleted and replaced by 2 amino acids, Phe and Gln. The DHR and mutation analysis of his mother showed normal DHR pattern and no mutations in exon 12 of CYBB gene. In conclusion, any children with multiple Salmonella and Aspergillus infection should be suspected of CGD. NBT test, DHR assay and gene analysis are helpful toolsto confirm the diagnosis e v en i n the case of de novo mutation.

Allergic Bronchopulmonary Aspergillosis Coupled with Broncholithiasis in a Non-asthmatic Patient

Allergic bronchopulmonary aspergillosis (ABPA), an asthmatic disease, is caused primarily by hypersensitivity to Aspergillus species. ABPA is rarely observed in the absence of asthma, which is, in fact, the principle criterion for its diagnosis. Here, we report the case of a 36-yr-old woman without a history of bronchial asthma, who manifested a localized pneumonic consolidation, coupled with broncholithiasis. Pathologic examinations of bronchoscopic biopsy specimens and resected surgical specimens revealed features typical of ABPA. This is a very rare case of ABPA coupled with broncholithiasis in a non-asthmatic individual.

Diagnóstico de ABPA em pacientes portadores de fibrose cística: utilidade clínica da pesquisa de IgE específica contra alérgenos recombinantes do Aspergillus fumigatus / ABPA diagnosis in cystic fibrosis patients: the clinical utility of IgE specific to recombinant Aspergillus fumigatus allergens

OBJETIVO: A aspergilose broncopulmonar alérgica (ABPA) é um fator complicador da fibrose cística que pode determinar uma combinação devastadora na evolução da doença pulmonar. A sobreposição de sinais e sintomas das duas enfermidades dificulta o diagnóstico, mesmo aplicando critérios padronizados. O objetivo deste trabalho foi identificar, em grupo de portadores de fibrose cística, os casos de ABPA através da detecção de IgE específica contra os alérgenos recombinantes do Aspergillus fumigatus e confrontar esse método com os critérios preconizados pela Cystic Fibrosis Foundation. MÉTODOS: Cinqüenta e quatro pacientes de 2 a 20 anos, com características que poderiam estar isoladamente presentes na ABPA, foram avaliados sistematicamente, incluindo: dados clínicos, tomografia computadorizada de tórax, teste cutâneo de hipersensibilidade imediata para A. fumigatus; dosagem de IgE sérica total, RAST para A. fumigatus, e IgE sérica específica para alérgenos recombinantes r Asp f1, f2, f3, f4 e f6. RESULTADOS: Foram elegíveis para o estudo 39 pacientes. Destes, 32 foram investigados. Houve sensibilização ao A. fumigatus em 34 por cento. Ambos os métodos, o critério da Cystic Fibrosis Foundation e a pesquisa de IgE específica contra antígenos recombinantes, determinaram três casos de ABPA; entretanto, o diagnóstico foi concordante em apenas dois pacientes. CONCLUSÃO: A detecção de IgE específica contra antígenos recombinantes do A. fumigatus foi ferramenta útil para detecção precoce da sensibilização e diagnóstico de ABPA. No entanto, a confirmação diagnóstica não pôde ser desvinculada da condição clínica, e sua utilização para diagnóstico, detecção de recidivas e critério de cura ainda requer estudos longitudinais, envolvendo maior número de pacientes.

Aspergilosis broncopulmonar alérgica en niños con enfermedad pulmonar crónica y fibrosis quística / Allergic bronchopulmonary aspergillosis in children with chronic lung disease and cystic fibrosis

Introducción: La aspergilosis broncopulmonar alérgica (ABPA) es infrecuente en pediatría, sin embargo, es necesario tener presente el diagnóstico e instaurar un tratamiento precoz, con la finalidad de evitar mayor deterioro de la función pulmonar. Objetivo: presentar nuestra experiencia en el diagnóstico y manejo de la ABPA en niños portadores de enfermedad pulmonar crónica (EPC) postviral y fibrosis quística (FQ). Pacientes y Método: 6 pacientes con ABPA diagnosticados entre los años 2000-2003, de 9 a 17 años de edad (promedio 13 años), 4 de sexo masculino y 2 femenino. El estudio se realizó en pacientes con EPC postviral o FQ que presentaban un cuadro clínico sugerente y se confirmó con dos o más cultivos positivos para Aspergillus sp, con la presencia de hifas y al menos un criterio primario. Resultados: La totalidad de los pacientes presentaron IgG específica elevada, 5 con test cutáneo positivo y eosinofilia. Los 6 niños mostraron nuevos infiltrados pulmonares y en 2 bronquiectasias centrales. Fueron tratados con prednisona 2 mg/kg/d durante un mes, luego igual dosis en días alternos por 4 meses e itraconazol 2-5 mg/kg/d durante 5 meses. Evolucionaron con mejoría clínica, de la saturometría y flujometría, y en 4 pacientes la espirometría. Todos disminuyeron los infiltrados pulmonares, negativizaron los cultivos y la IgG específica. No observamos efectos adversos con el tratamiento empleado. Conclusión: En pediatría la ABPA es poco frecuente, sin embargo, empeora la función pulmonar, por lo que debe ser considerada en niños portadores de asma bronquial, EPC o FQ. Nuestros pacientes se beneficiaron con el tratamiento utilizado.

Aspergilosis broncopulmonar alérgica: complicaciones poco usuales de la afección / Allergic bronchopulmonary aspergillosis: unusual complications

Se revisa definición, etiología, etapas clínicas, tratamiento y complicaciones de la Aspergilosis Broncopulmonar Alérgica (ABPA). En el Instituto Nacional del Tórax se han seguido 35 casos de ABPA durante un promedio de 15 años. De esta serie se presentan dos pacientes de sexo femenino que corresponden a ABPA complicada por infección por Mycobacterium avium-intracellulare (MAI). Las pacientes que tenían 71 y 72 años de edad respectivamente, presentaron una infección pulmonar por MAI, 3 y diez años después de habérseles diagnosticado ABPA. El diagnóstico de ABPA se basó en sus características clínicas, radiológicas y en sus pruebas inmunológicas (prueba cutánea y Elisa IgG + para A. fumigatus). En ambos casos la infección pulmonar por MAI -confirmada por dos cultivos positivos- estuvo asociada a agravación clínica y radiológica. Las pacientes fueron tratadas exitosamente con claritromicina y etambutol durante 12 meses; este tratamiento estuvo asociado a estreptomicina y minociclina durante los primeros dos meses. La infección por MAI es una complicación poco frecuente de la ABPA. Esta asociación se debe sospechar si una TAC de alta resolución muestra nódulos asociados a bronquiectasias difusas ubicadas más allá de las bronquiectasias centrales (lesiones típicas de la ABPA no complicada). La infección pulmonar por MAI debe ser confirmada a través de cultivos de MAI en expectoración o en el líquido de lavado broncoalveolar.

Manifestacion de Aspergilosis Pulmonar Angioinvasiva como Sindrome de Vena Cava Superior / Angioinvasive aspergilosis as superior cava vein syndrome

En este artículo se presenta el caso de un paciente de diez años de edad con diagnóstico previo de anemia de Fanconi y antecedente de trasplante de médula ósea, manejado con inmunosupresores, quien manifiesta un cuadro clínico respiratorio rápidamente progresivo, acompañado de síndrome de vena cava superior secundario a infección por Aspergillus, variedad angioinvasiva. No se conocen casos similares reportados en el medio colombiano ni en la bibliografía médica actual.Aquí se refieren los hallazgos por imagen, el resultado histológico y la revisión bibliográfica

Nasal septal perforation in a patient with allergic bronchopulmonary aspergillosis and rhinitis on long term corticosteroids.

A 22-year-old male, referred to us as a case of multi-drug resistant tuberculosis was diagnosed as allergic bronchopulmonary aspergillosis (ABPA) after serological and computed tomography confirmation. He was initiated on oral as well as inhaled corticosteroids along with nasal corticosteroid spray for his nasal complaints. One year subsequently, he developed a nasal septal perforation. Biopsy taken from the site did not reveal any granulomatous or atrophic changes and cultures of the biopsy did not yield any organism. The septal defect, repaired surgically by Hazeltine's method healed completely within 6 weeks. There have been anecdotal reports of septal perforation in patients with rhinitis on intranasal corticosteroids but hitherto not in patients with ABPA. A periodic examination of the nasal septum should be undertaken in patients with ABPA and rhinitis on long term inhaled oral and intranasal corticosteroids along with oral corticosteroids.

Allergic bronchopulmonary aspergillosis.

A 38 year old male was diagnosed to have allergic bronchopulmonary aspergillosis which responded remarkably to prednisolone therapy.

Aspergillary bronchopneumonia: an unusual cause of atelectasis and asphyxia in a leukemic patient

Aspergilose pulmonar: causa infrequente de atelectasia e asfixia em paciente leucêmico. Paciente de 22 anos em primeira recidiva de leucemia linfóide aguda de tipo T desenvolveu febre e infiltrado pulmonar após 23 dias de granulocitopenia. Apesar do uso de Anfotericina B, houve progressäo da doença pulmonar com aparecimento de expectoraçäo purulenta, atelectasia do pulmäo direito e insuficiência ventilatória. Esta foi resolvida após eliminaçäo de rolha brônquica espessa. Culturas de escarro revelaram Candida Albicans e Staphylococcus epidermidis; a microscopia óptica da rolha revelou a presença de hifas de aspergilos. O paciente foi a óbito 9 dias após, por infecçäo disseminada por aspeergilos, confirmada por necrópsia

Aspergilosis pulmonar, aspectos clínico-radiológicos

Se realizó un estudio descriptivo, retrospectivo, en 31 pacientes con aspergiloma pulmonar observados en un período de 12 años; 25 de ellos tenían radiografías. Se analizaron sus características clínicas, de laboratorio y radiológicas al momento del diagnóstico y durante el seguimiento del tratamiento con itraconazol. La condición preexistente más frecuente fue la tuberculosis (61.3 por ciento); el síntoma más común al momento de la consulta fue la tos productiva (83.9 por ciento); 21 pacientes (66.7 por ciento) presentaron hemoptisis,la cual disminuyó en frecuencia (21.4 por ciento) con el tratamiento (p>0.05). La alta positividad (64 por ciento) de las pruebas serológicas al comienzo del estudio, cayó posteriormente a 7 por ciento (p>0.05). En 23 pacientes (91 por ciento) las radiografías de tórax mostraron engrosamiento pleural y patrón intersticial anormal. Se demostró, además, cómo cuatro de los siete aspergilomas clásicos disminuyeron o desaparecieron con el tratamiento. Se concluye que la forma de presentación del aspergiloma en nuestro medio es similar a la descrita en otros países y que el itraconazol oral es una opción terapéutica aceptable