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• W2065432350 abstract "A 9-month-old boy presented with respiratory distress. He had been previously diagnosed with a cow's milk protein allergy when he presented to his pediatrician with bloody stools. This resolved after his formula was changed to Nutramigen (Mead Johnson Nutritionals, Evansville, IN). He had normal growth and development and no prior history of thrush, chronic diarrhea or infections. Although the patient was born in the United States, both of his parents were born in the Philippines. Prenatal testing had been normal including a negative maternal human immunodeficiency virus antibody test. At 9 months of age, he developed loose stools and fever up to 37.9°C for 3 days. One day before admission, he developed increased work of breathing and slept more than usual. On the day of admission, he began to have shallow and rapid respirations with intermittent cough and posttussive emesis, prompting his mother to take him to his pediatrician. In the pediatrician's office, he was noted to be in respiratory distress and appeared cyanotic. Initial oxygen saturation was <70%, but this improved to 90% with supplemental oxygen. The patient was transferred to Children's Memorial Hospital where he was admitted with respiratory distress and hypoxia. On admission, the patient had a temperature of 37.3°C, a respiratory rate of 30 breaths/min, a blood pressure of 85/37 mm Hg, an oxygen saturation of 94% while receiving 5 liters/min of oxygen via nasal cannula, a weight of 8.5 kg (10–25%) and a height of 74 cm (50–75%). Physical examination was remarkable for moderate respiratory distress with diffuse bilateral crackles on auscultation of his lung fields, a liver edge that was palpable 2 cm below the costal margin and a delayed capillary refill (∼3 seconds). Laboratory studies included a white blood cell count of 23,900/mm3 with a differential count of 56% segmented neutrophils, 31% lymphocytes (absolute lymphocyte count, 7409/mm3) and 13% monocytes; hemoglobin of 14.3 g/dL; and platelet count of 461,000/mm3. Chemistry panel and liver function tests were unremarkable. A chest radiograph showed a diffuse bilateral interstitial infiltrate. Despite empiric administration of cefuroxime and azithromycin, his respiratory distress and hypoxia increased while receiving 100% O2 via a nonrebreather mask. He subsequently required mechanical ventilation. Endotracheal tube aspirate revealed <10 white blood cells with no bacteria on Gram-stained smear; bacterial culture was negative. Rapid influenza and respiratory syncytial virus tests were negative. Rapid shell vial and viral culture were negative. He remained afebrile until the 7th hospital day when he developed a fever to 38.5°C. Because of frequent desaturations and increasing need for ventilatory support, he underwent bronchoscopy and bronchoalveolar lavage on the 8th hospital day. A Gram-stained smear showed no bacteria and <10 white blood cells; rare Enterobacter cloacae grew from the bronchoalveolar lavage specimen. Specimens obtained for KOH preparation and acid-fast bacillus staining were negative. Rapid shell vial and viral culture were both negative. In addition, a qualitative polymerase chain reaction for cytomegalovirus from the blood was negative. A laboratory test result returned on hospital day 10 prompting further evaluation, which led to the child's diagnosis. For denouement see p. 1089. Denouement Continued from p. 1085 The prior diagnosis of a cow's milk protein allergy had prompted testing of quantitative serum immunoglobulins. IgA, IgG and IgE were undetectable; the IgM was low at 8.38 mg/dL (normal, 32–120 mg/dL). Flow cytometry obtained on hospital day 11 for T and B cells revealed no CD4+, CD8+ or natural killer cells. The only CD3+ cells were also positive for DR antigen with a total of 55/mm3 (normal, 130–860/mm3). The remaining lymphocytes were all CD19+ cells (pan B cells) with a total of 5453/mm3 (normal, 858–3744/mm3). Based on these findings, the patient was diagnosed with severe combined immunodeficiency (SCID). After hypogammaglobulinemia was diagnosed on day 10, the specimen from the bronchoalveolar lavage was reevaluated by performing a Gomori methenamine silver stain which revealed Pneumocystis jiroveci pneumonia (PCP). The patient was treated with corticosteroids and intravenous pentamidine. Pentamidine was used instead of trimethoprim/sulfamethoxazole because of the immunologists’ concern that the latter would adversely impact transplantation. Intravenous immunoglobulin was also administered. The patient's respiratory status improved and he was extubated on day#18. Genetic sequencing revealed that the patient had a deletion of 2 base pairs in exon 4 of the interleukin (IL)-2 receptor gene (IL-2RG). Mutations in IL-2RG are characteristic of X-linked SCID, and this particular deletion results in a frame shift, making the receptor nonfunctional. Analysis of the patient's mother revealed heterozygosity for the same mutation. Six weeks after SCID and Pneumocystis infection were diagnosed, the patient underwent allogeneic stem cell transplantation from a matched unrelated cord blood specimen. The transplant successfully engrafted without complications, and for 1 year after stem cell transplantation, he has done well without need for immunoglobulin administration. SCID is a syndrome resulting from many different genetic defects that typically result in lymphopenia with deficiencies in the numbers and function of T and B cells.1 All patients with SCID lack T cells and have reduced or absent serum immunoglobulins; B cells and natural killer cells are present in some genetic variations of SCID.1 These deficiencies impair both cell-mediated and humoral immunity. Genetic defects in SCID include mutations in cytokine-receptor genes (IL-2RG, JAK3, and IL-7Rα), antigen receptor genes (RAG1, RAG2, Artemis, CD3δ and CD3ε), proteins that detoxify the metabolic products of the purine salvage pathway (adenosine deaminase) and a regulator of signal thresholds in immune cells (CD45).2 The most common defect is IL-2RG followed by adenosine deaminase deficiency.1,2 The mutation noted in our patient, IL-2RG, encodes a common γ-chain shared by IL-2, IL-4, IL-7, IL-9 and IL-15 cell surface receptors.3 Two-thirds of the patients with IL-2RG mutations have missense or nonsense mutations with the remainder splice mutations, insertions or deletions.3 In the majority of patients, no family history of X-linked transmission can be determined.3 A laboratory finding that has been useful in diagnosing SCID is the presence of an absolute lymphocytopenia. A critical distinction is that lymphocyte counts should be compared with the published age-related normal values.4 The lower range of normal lymphocyte counts at birth is 2000/mm3 which subsequently rises to 4500/mm3 at 8–10 months of age before falling toward adult values.5 With the use of age-appropriate normal values, at least 90% of infants with SCID have lymphocytopenia.4,6 Before our patient was diagnosed with SCID, his absolute lymphocyte counts ranged between 4750 and 10,000/mm3, well within the published age-appropriate normal range. Our patient's lymphocyte counts were also higher than the mean lymphocyte count of <2000/mm3 for IL-2RG deficiency.6 Transplacental passage of maternal lymphocytes and clonal expansion can occur and may account for a normal lymphocyte count6 but would not explain selective expansion of B cells without T cells as seen in our patient. One patient with SCID with an oligoclonal B cell expansion has previously been reported6; the clonality of the B cells in our patient was not examined. Clinical features sometimes seen with persistent maternal T cells include rash, splenomegaly, eosinophilia7 and even lymphocytosis.6 Patients with adenosine deaminase deficiency have the lowest numbers of lymphocytes, whereas IL-2RG mutations typically have higher B cell numbers.6 In addition, a recent report describes 2 patients with SCID who had normal numbers of T lymphocytes, B lymphocytes and natural killer cells.8 In these patients, serum immunoglobulin values were normal. Despite normal values of lymphocytes and immunoglobulins, both patients developed Pneumocystis infection. Sequencing of the γc gene revealed a R222C mutation, which may result in suboptimal binding of IL-2 and other cytokines.8 Symptoms commonly seen in patients with SCID include failure to thrive, fever and persistent diarrhea. Infectious complications include pulmonary infections, thrush and other opportunistic infections such as Pneumocystis.7 In addition to unusual infections, SCID patients may have difficulty controlling and overcoming common viruses such as rotavirus.9,10 Failure to thrive usually occurs within 3–6 months but rarely can occur as late as 12 months.11 Most patients are diagnosed within the first 4–7 months of life.6,7 Bone marrow or stem cell transplantation is a life-saving treatment for patients with SCID. Greater than 80% survival can be achieved with transplantation of either HLA-identical or T cell-depleted haploidentical cells from a related donor, but many require continued intravenous immunoglobulin administration.12 One recent study suggested that if no HLA-identical related donor can be found, survival and long term immune function are better with matched unrelated donors than with mismatched related donors.13 When graft versus host disease occurs, ∼70% of the time it occurs in patients in whom transplacentally transferred maternal T cells persist.1 Outcomes with transplantation are better for children transplanted within the first 28 days of life.14 This has prompted some experts to consider the cost effectiveness of and methods for universal newborn screening for SCID.15,16" @default.
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• W2065432350 title "A Nine-Month-Old Boy with Severe Interstitial Pneumonia" @default.
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• W2065432350 doi "https://doi.org/10.1097/01.inf.0000242967.30801.7d" @default.
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