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• W2907355946 abstract "Case PresentationA 3-year-old girl was referred to a pediatric pulmonologist for dyspnea and recurrent upper respiratory tract infections (RTIs). The patient was born full term to unrelated Dutch parents after an uneventful pregnancy and birth. The year before presentation, she had suffered from pneumonia and > 10 upper RTIs. Apart from the recurrent RTIs, which started in infancy, her medical history was not significant and did not include allergies or eczema. An adenotonsillectomy was performed at the age of 2 years, and she was treated with multiple antibiotic regimens and inhalation therapy with salbutamol and corticosteroids, with no relief of symptoms. A 3-year-old girl was referred to a pediatric pulmonologist for dyspnea and recurrent upper respiratory tract infections (RTIs). The patient was born full term to unrelated Dutch parents after an uneventful pregnancy and birth. The year before presentation, she had suffered from pneumonia and > 10 upper RTIs. Apart from the recurrent RTIs, which started in infancy, her medical history was not significant and did not include allergies or eczema. An adenotonsillectomy was performed at the age of 2 years, and she was treated with multiple antibiotic regimens and inhalation therapy with salbutamol and corticosteroids, with no relief of symptoms. A dyspneic girl was seen. She had a small stature (−1.7 standard deviations for age), but her weight was appropriate for her age and height. Chest examination revealed mild intercostal retractions and bilateral rhonchi, crackles, and wheezing. Examination of the heart and abdomen showed a regular cardiac rate without murmurs and a nontender abdomen with enlargement of spleen and liver. The patient did not have palpable lymph nodes. A chest radiograph showed bilateral pulmonary infiltrations. A spirometry-controlled inspiratory and expiratory high-resolution chest CT scan showed compression of the left main bronchus by an undefined subcarinal mediastinal mass as well as diffuse bronchiectasis with atelectasis (Fig 1). A chest MRI scan confirmed the mediastinal mass and indicated it was not a cyst. It also showed bilateral hilar lymphadenopathy. Ultrasound of the abdomen showed hepatosplenomegaly without lymphadenopathy or other abnormalities. Examination of the trachea by bronchoscopy revealed tracheal deviation to the right from compression, nodular hyperplasia of the bronchial mucosal surface, and purulent secretion. Pathological evaluation of the bronchoalveolar lavage fluid showed no signs for malignancy. The total cell number was 6.4 × 106 cells in 10 mL, of which 10% was CD15+ (majority neutrophilic granulocytes), with 44% T cells (reference, 5.9% ± 7.7) and 8% B cells (reference, <5%) with a normal kappa/lambda ratio. Microbiological examination of sputum was positive for Streptococcus pneumoniae. Cultures were negative for Mycobacterium tuberculosis and atypical mycobacteria. Serum levels of immunoglobulins were normal, but the antibody response to pneumococcal polysaccharide vaccination was insufficient. Also, despite previous vaccination, antibodies against poliovirus, pneumococcal conjugate vaccination, and Haemophilus influenzae were not detected in serum. The patient was further evaluated by a pediatric immunologist. Upon immunological evaluation, reduced memory B-cell subsets were found in the peripheral blood together with an inversed CD4/CD8 ratio and increased transitional B cells (Table 1), compatible with the possibility of an antibody deficiency. To rule out malignancy and provide decompression of the trachea, the mediastinal mass was removed by uncomplicated thoracoscopic surgery under full anesthesia without any complications. Macroscopically, the mass seemed to consist of multiple lobular lymph nodes. Pathological review confirmed the mass to be lymphatic tissue with dysplastic germinal centers. No malignant cells were found. Other diagnostic tests revealed no signs of viral, bacterial, atypical mycobacterial or yeast infections, or most common immunological diseases.Table 1Immunophenotyping of Peripheral Blood at Time of Presentation at ImmunologistImmunophenotyping of Lymphocyte Subsets%Absolute Count (×109/L)Normal Values (2-5 y)WBC count5.4Lymphocytes19.31.01.7-6.9CD3+ T lymphocytes0.840.9-4.5CD16.56+CD3– NK cells0.270.1-1.0CD19+ B lymphocytes0.230.2-2.1B-cell subsets Transitional B (CD38high/CD24high)60.013824-333 Naive mature (CD38dim/CD24dim/IgD+/CD27–)28.666170-1691 MZ/natural effector (CD38dim/CD24dim/IgD+/CD27+)5.81316-226 Memory (CD38dim/CD24dim/IgD–/CD27+)1.5320-149IgM28%3%-32%IgG36%13%-63%IgA36%4%-42% Plasmablast3.9T-cell subsets CD4+ T lymphocytes29.90.30.5-2.4Naive (CD45RO–CCR7+CD27+CD28+)6.4Central memory (CD45RO+CCR7+CD27+CD28+)5.8Effector memory (CCR7–)87.5 CD8+ T lymphocytes57.50.50.3-1.6Naive (CD45RO–CCR7+CD27+CD28+)2.8Central memory (CD45RO+CCR7+CD27+CD28+)0.5Effector memory (CCR7–)95.0CD4/CD8 ratio0.5 Open table in a new tab What is the diagnosis? Diagnosis: Activated PI3Kdelta syndrome Over the past several years, multiple patients with gain-of-function mutations in PI3Kdelta have been described. These patients suffer from activated PI3Kdelta syndrome (APDS) and share clinical characteristics such as recurrent RTIs, bronchiectasis, hepatosplenomegaly, generalized lymphadenopathy, and antibody deficiency. Because 96% of patients with APDS suffer from recurrent RTIs, many will be examined by the pulmonologist first. Infections are not the only thoracic problem in these patients. Most have pulmonary damage including bronchial wall thickening, tree-in-bud opacities, and/or bronchiectasis, which are seen on chest CT scans from a young age onward and that are not in all cases related to the severity of RTIs. Additionally, lymphadenopathy is a common problem in APDS because of the fast proliferation but poor differentiation of B and T cells. Lymphadenopathy can present in the form of nodular lymphoid hyperplasia in the mediastinum, intestines, and in the mucosal tissue of the bronchus. Mediastinal lymphadenopathy may cause severe obstruction of the airways, increasing the risk of RTIs and secondary pulmonary damage. Because of the wide spectrum of possible clinical manifestations, including bronchiectasis, lymphoproliferation, and autoimmune disease, patients with APDS need a thorough preoperative screening. Recent cohort studies show that, besides infections, patients with APDS often have autoimmunity (34% of patients) and lymphoid malignancy (13% of patients); furthermore, viral infections can have a more severe course. Epstein-Barr virus and cytomegalovirus infections are especially poorly controlled. This may result in severe illnesses such as encephalitis and disseminated infections. Recurrent Epstein-Barr virus infections also increase the risk for lymphoma; therefore, it is crucial that these patients are carefully monitored by both the pulmonologist and immunologist. APDS is caused by dysregulation of the PI3K-AKT pathway. Heterozygous gain-of-function mutations in two genes (PIK3CD and PIK3R1), which together encode the heterodimer PI3Kdelta, cause hyperactivation of the PI3K-AKT pathway in patients’ lymphocytes. Analysis of the phosphorylation status of AKT by Phospho-Flow can show increased activation of the PI3K-AKT pathway in patients with APDS. The hyperactivation causes fast proliferation and differentiation of naive T cells into short-lived effector T cells, skewing the subset distribution of CD4+ and CD8+ T cells and reducing the memory T-cell subset. Within the B-cell compartment, there is increased apoptosis and reduced memory formation, leading to antibody deficiencies. Patients with antibody deficiencies are treated with immunoglobulin replacement therapy and preventive antimicrobial agents. Because APDS not only causes an immune deficiency but also dysregulation, some of the symptoms respond well to steroid treatment; however, specifically in young children, long-term use of prednisone and related drugs can cause serious side effects. Other treatment options are currently being investigated. The mammalian target of rapamycin (mTOR) signaling pathway is downstream of PI3K-AKT signaling. In APDS, dysregulated mTOR signaling is one of the driving mechanisms of disease, causing fast proliferation and differentiation and preventing memory formation in the immune system. Rapamycin inhibits mTOR signaling and is therefore considered a possible treatment to reduce immune dysregulation. Rapamycin is currently used by both pediatric and adult immunologists in the treatment of APDS. Additionally, specific PI3Kdelta inhibitors might be of use to inhibit PI3K-AKT hyperactivation. The first results of trials with these inhibitors as a treatment for APDS in adults are promising; furthermore, inhalation therapy with PI3Kdelta-inhibitors might prevent extensive pulmonary damage. One-and-a-half years after removal, the mediastinal mass was back to its original size. Meanwhile, the patient received subcutaneous immunoglobulin substitution and maintenance antibiotics, although these did not entirely prevent RTIs. Her symptoms responded well to steroid treatment and she became prednisone dependent. After the discovery of APDS in 2013, the patient’s DNA was sequenced, revealing an APDS-causing mutation in PIK3CD, exon 13 (c.1537G>A), resulting in an amino acid substitution p.E525K. Treatment with rapamycin was started and prednisone was tapered and stopped. The frequency of RTIs decreased and she rarely needed antibiotic treatment. She and her mother reported she was more energetic and her height growth increased. Physical examination revealed no more hepatosplenomegaly. She is carefully monitored by the pulmonologist and immunologist because of her current pulmonary damage, future risks of autoimmunity and malignant transformation, and for the effects of long-term rapamycin treatment. 1.Patients with APDS commonly suffer from recurrent RTIs (96%) and therefore will usually present first at the pulmonologist.2.A mediastinal mass as part of generalized lymphadenopathy may obstruct the airways in APDS, increasing the risk of pulmonary infections and persistent severe damage.3.Patients who with APDS-induced pulmonary problems benefit from dual treatment with immunoglobulin and immune suppression.4.Rapamycin is a treatment option in children with APDS who are steroid dependent. Steroid treatment in especially young children can have severe effects on growth and development. In adults, PI3Kdelta inhibitors can be considered. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. v. d. B. received a VIDI grant of the Netherlands Organization For Scientific Research (NWO) in relation to this work. None declared (M. W., D. P., C. V., L. D., G. J. D.). Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met." @default.
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• W2907355946 title "A 3-Year-Old Girl With a Mediastinal Mass" @default.
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