X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by loss-of-function variants in Bruton’s tyrosine kinase (BTK) on the X chromosome. This defect disrupts B cell development, resulting in low or undetectable immunoglobulin levels. Rarely, patients may present with atypical features, including normal immunoglobulin levels. We report a case of XLA with normal immunoglobulin levels. A 12-year-old male with a history of asthma and a maternal half-brother with XLA was admitted to the hospital for an asthma exacerbation in the setting of pneumonia. He had recently been hospitalized within the past month for similar symptoms and was treated with antibiotics for pneumonia. His infection history was unremarkable until the age of 12, when he began to experience frequent upper respiratory infections in the months leading up to his presenting illness. An immunologic evaluation was performed that revealed the following immunoglobulin (Ig) levels: lgG 572 mg/dL, IgA 184 mg/dL, and IgM 50 mg/dL. Lymphocyte subsets were performed showing a CD3 count of 1,041 cells/μL (93%), a CD4 count of 688 cells/μL (59%), a CD8 count of 359 (31%), CD16 and CD56 counts of 58 cells/μL (5%), and a CD19 count of 3 cells/μL (0%). Specific antibodies to streptococcus pneumoniae, measles, mumps, and varicella were not protective. His antibody levels to diphtheria and tetanus were equivocal, but antibodies to rubella were protective. After resolution of his acute infection, examination in clinic was notable for presence of tonsillar tissue and small palpable submandibular and cervical lymphadenopathy. Repeat immunoglobulins revealed an IgG 802 mg/dL, IgA 271 mg/dL, and IgM 44 mg/dL. Next-generation sequencing revealed a hemizygous pathogenic mutation in BTK (c.82C>T and pArg28Cys). XLA typically manifests with severe hypogammaglobulinemia and absent mature B cells in peripheral blood. However, this case highlights an atypical presentation with normal total immunoglobulin levels. A review of the existing literature reveals that atypical presentations are rare but have been increasingly described as a manifestation of this disease. Clinicians should recognize the significant phenotypic and immunologic variability with XLA and consider the diagnosis in patients with recurrent infections, poor specific antibodies, but normal total immunoglobulin levels.

Adenosine deaminase (ADA) deficiency is an autosomal recessive severe combined immunodeficiency that typically presents within the first year with severe infections. Other features of ADA deficiency include the following: autoimmunity, myeloid dysplasia, pulmonary disease, neurodevelopmental delay, skeletal dysplasia, hepatic dysfunction, and lymphoma. 1 Kohn D.B. Hershfield M.S. Puck J.M. et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019; 143: 852-863 Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Hematopoietic stem cell transplant (HSCT) and gene therapy (GT) have been successful in the treatment of ADA deficiency. 2 Scott O. Kim V.H. Reid B. et al. Long-term outcome of adenosine deaminase-deficient patients—a single-center experience. J Clin Immunol. 2017; 37: 582-591 Crossref PubMed Scopus (14) Google Scholar ,3 Cagdas D. Gur Cetinkaya P. Karaatmaca B. et al. ADA deficiency: evaluation of the clinical and laboratory features and the outcome. J Clin Immunol. 2018; 38: 484-493 Crossref PubMed Scopus (11) Google Scholar Enzyme replacement therapy (ERT) has traditionally been used as a bridge to HSCT or GT and not as first-line, long-standing treatment. However, compliance is essential for long-term successful ERT.

Common variable immunodeficiency is a heterogenous disorder of the immune system associated with immunodeficiency, lymphoproliferation, autoimmunity, and malignancy. Certain laboratory characteristics of common variable immunodeficiency patients can be associated with an increase of related clinical sequelae, though there is limited data on predictive characteristics for clinical sequelae in CVID patients. The purpose of this study was to analyze a unique large CVID patient cohort for predictive laboratory characteristics of clinical sequelae. A retrospective chart review was performed of a longitudinal cohort of CVID patients treated at a single institution, largely by a single provider with higher dose replacement immunoglobulin, that has not been previously described. 219 CVID patients were followed for 1,990 patient-years. 86% of the patients were on immunoglobulin with an average IgG trough of 1260 mg/dL. Low IgG at time of diagnosis, low CD19 absolute cell count, and poor mitogen induced lymphocyte proliferation were associated with increase of CVID clinical sequelae. In particular, this cohort demonstrates the novel finding that low IgG at time of diagnosis prior to immunoglobulin replacement is associated with a higher incidence of lymphoma, bronchiectasis, granulomatous disease, lymphoid hyperplasia, splenomegaly, and hepatic disease.

Newborn screening for severe combined immunodeficiency (SCID) uses the T-cell receptor excision circle (TREC) assay.1 TRECs are T-cell receptor recombination byproducts, and thus, a low TREC number reflects compromised T-cell development in the thymus. Patients with SCID typically have an undetectable TREC assay, though there are other conditions associated with undetectable TRECs, such as 22q11.2 deletion syndrome, RAC2 deficiency, and trisomy 21.2,3 The TREC assay quantifies a patient's TRECs using real-time quantitative PCR.

Idiopathic angioedema is characterized by local edema involving the deeper dermis and subcutaneous tissue and triggered by the release of mediators that cause vasodilatation and increased capillary permeability. [1] Cicardi M. Bergamaschini L. Zingale L.C. Gioffré D. Agostini A. Idiopathic nonhistaminergic angioedema. Am J Med. 1999; 106: 611-615 Abstract Full Text Full Text PDF Scopus (87) Google Scholar Acute attacks most commonly occur in the periphery, but patients also may experience laryngeal or bowel angioedema. Idiopathic angioedema shares some clinical features with hereditary angioedema (HAE) types I and II and is physiologically distinct in that patients with idiopathic angioedema exhibit normal C4 and C1 esterase inhibitor levels and function. [2] Kaplan A.P. Enzymatic pathways in the pathogenesis of hereditary angioedema: The role of C1 inhibitor therapy. J Allergy Clin Immunol. 2010; 126: 918-925 Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Patients with type III HAE also exhibit normal C4 levels with normal quality and quantity of C1 esterase inhibitor; however, guidelines published by an international expert panel in 2012 on hereditary angioedema with normal C1 inhibitor function require that these patients have a family history significant for angioedema to establish a diagnosis of type III HAE. [3] Zuraw B. Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc. 2012; (Dec 13. [Epub ahead of print]) Google Scholar A subpopulation of patients have a missense mutation in the factor XII gene, [4] Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006; 26: 709-724 Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar which the 2012 consensus requires if family history is not present for the diagnosis of type III HAE. If no other causative factors are elucidated, patients with angioedema who do not qualify as HAE according to the 2012 Consensus guidelines are classified as having idiopathic angioedema.

The two main indications for the use of intravenous gammaglobulin--antibody replacement therapy and immunomodulation--are pertinent only for a few scenarios in HIV-1 infection. The role of gammaglobulin in the treatment of HIV-1 infection has changed significantly with the introduction of highly active antiretroviral therapy. Antiretroviral drugs have not only controlled the progression of disease but also had far-reaching effects on HIV-1-induced immunologic aberrations. Complete or partial immunologic reconstitution and prevention of immunologic damage have been the hallmarks of success for highly active antiretroviral therapy. This article addresses the use of gammaglobulin before and after the era of effective antiretroviral therapies.

Background: Antibody responses to immunization are often compromised in patients infected by HIV-1, and the use of childhood immunization in affected children is controversial. We investigated whether multiple immunizations with a T cell-depen dent neoantigen, bacteriophage Phi X174, induce selective immune attrition and postvaccination viremia.Methods: Seventeen asymptomatic, antiretroviral therapy-naive HIV-1-infected patients with a CD4 cell count of 450 cells/mu l or greater were immunized in 1990/1991 with three intravenous doses of bacteriophage Phi X174. Group 1 received zidovudine (ZDV) during the primary and secondary immunization. Group 2 received ZDV exclusively during the tertiary immunization. Bacteriophage-specific antibodies of the IgM and Ige class, lymphocyte phenotypes (CD4(+), CD8(+), CD4+DR+, CD8+DR+, CD4+CD45RO+ and CD4+45RA+, CD4+CD45RO+DR+) and HIV-1 plasma viremia were measured sequentially.Results: In both patient groups the primary, secondary and tertiary antibody responses, as expressed by geometric mean antibody titres and IgM to IgG switch, were impaired. Booster immunizations resulted in a progressive attrition of specific antibody responses to bacteriophage. Antibodies to tetanus toroid remained stable. The HIV-1 viral loads, which were evaluated in archived specimens from eight patients, increased after immunization but returned to baseline appoximately 4 weeks later. The humoral immune attrition and increases in plasma viremia were blunted by concomitant short courses of ZDV.Discussion: Multiple boosters of immunizations in asymptomatic treatment-naive HIV-l-infected patients may result in a specific immune attrition and vaccine-induced viremia. Short-term monotherapy with ZDV may have blunted these adverse effects. Hyperimmunization of HIV-1-infected patients may be detrimental unless accompanied by antiretroviral therapy. (C) 2000 Lippincott Williams & Wilkins.

Cutaneous manifestations of HIV infections in childhood are common but are not the dermatologic lesions associated with HIV infection in adults. For example, Kaposi's sarcoma, a common finding in adults with AIDS, is rare in children. Other cutaneous manifestations, including bacterial and fungal lesions and viral exanthems, are common in children with AIDS and can be atypical and severe. Because 90% of the pediatric AIDS population acquires the virus via maternal transmission to the fetus, a dysmorphic syndrome associated with intrauterine infection has been described. Physicians caring for and evaluating pediatric patients at risk for AIDS should be aware of these dermatologic manifestations, so that early detection and treatment can be instituted to reduce the morbidity of the complication of HIV infection.

CUNNINGHAM, SANDRA J. MD; CRAIN, ELLEN F. MD, PhD; BERNSTEIN, LARRY J. MD Author Information

1The Division of Pediatric Ambulatory Care (Emergency Medicine), Bronx Municipal Hospital Center 2From the Department of Pediatrics, Division of Allergy and Imnunology. Albert Einstein College of Medicine

We present our experience with 54 episodes of Pneumocystis carinii pneumonia in 50 young children with AIDS, all but one representing congenitally acquired infection. Findings at history and physical examination are not helpful in suggesting the diagnosis. The diagnosis is suggested by marked hypoxemia, diffuse disease on chest radiograph, and elevated serum LDH level. Because important aspects of the history may be withheld, a high index of suspicion may be necessary for the correct diagnosis. The mortality rate for ventilated patients was 50%. Pediatr Pulmonal 1990; 9:251–253.

From the Department of Pediatrics, Albert Einstein College of Medicine, Division of Pediatric Ambulatory Care, Bronx Municipal Hospital Center, New York (Dr. Crain), and the Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine, New York (Dr. Bernstein).

DORFMAN, DAVID H. MD1; CRAIN, ELLEN F. MD, PhD1; BERNSTEIN, LARRY J. MD2 Author Information

The hematologic manifestations of 100 pediatric patients with AIDS/ARC were reviewed. Acute or chronic anemia was present in 94% of all patients. Two patients had autoimmune hemolytic anemia and 1 patient had an aplastic anemia. A positive Coombs test was detected in 40% of all patients. Leukopenia and neutropenia occurred in 50% and 40% of patients respectively. Antineutrophil antibodies were detected in 2 patients. Ten of 13 children developed neutropenia on Bactrim. Forty percent of all children were lymphopenic. Monocytosis and eosinophilia occurred in 66% and 40% of patients respectively. Thrombocytopenia was seen in 33% and of these 25% developed a persistent thrombocytopenia. Platelet antibodies were detected in 10 of 11 patients. Pancytopenia occurred in 20% of children with opportunistic infection (O.I.). Acquired Von Willebrands disease and autoantibodies to Factors X, XI and XII were seen in 2 individuals. Peripheral smears revealed ovalocytes, microcytosis, hypochromia and atypical lymphocytes. Bone marrow examination showed hypercellularity, myeloid hyperplasia and increased plasma cells and lymphocytes. Decreased erythropoeisis, dysmyelopoeisis, dyserythropoeisis and megaloblastic changes were occasionally seen. Bone marrow cultures were positive for mycobacterium avium intra cellulare (4), Candida (2) and CMV (1) in a total of 7 patients.

Pediatric PulmonologyVolume 3, Issue 4 p. 280-281 Case Report Clinical Candida supraglottitis in an infant with AIDS-related complex Dr. Michael R. Bye MD, Corresponding Author Dr. Michael R. Bye MD Divisions of Pulmonary Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkPediatric Pulmonary Medicine, Albert Einstein College of Medicine, Jacobi Hospital Room 817, Pelham Parkway and Eastchester Road, Bronx, NY 10461Search for more papers by this authorAnthony Palomba MD, Anthony Palomba MD Critical Care, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkSearch for more papers by this authorLarry Bernstein MD, Larry Bernstein MD Allergy/Immunology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkSearch for more papers by this authorKiran Shah MD, Kiran Shah MD Allergy/Immunology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkSearch for more papers by this author Dr. Michael R. Bye MD, Corresponding Author Dr. Michael R. Bye MD Divisions of Pulmonary Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkPediatric Pulmonary Medicine, Albert Einstein College of Medicine, Jacobi Hospital Room 817, Pelham Parkway and Eastchester Road, Bronx, NY 10461Search for more papers by this authorAnthony Palomba MD, Anthony Palomba MD Critical Care, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkSearch for more papers by this authorLarry Bernstein MD, Larry Bernstein MD Allergy/Immunology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkSearch for more papers by this authorKiran Shah MD, Kiran Shah MD Allergy/Immunology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New YorkSearch for more papers by this author First published: July/August 1987 https://doi.org/10.1002/ppul.1950030415Citations: 18AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Claesson B, Trollfors B, Ekstrom-Jodal B, et al. Incidence and prognosis of acute epiglottitis in children in a Swedish region. Pediatr Infect Dis 1984; 3: 534–538. 2 MayoSmith MF, Hirsch PJ, Wodzinski SF, Schiffman FJ. Acute epiglottitis in adults. N Engl J Med 1986; 314: 1133–1139. 3 Costigan DC, Newth CJL. Respiratory status of children with epiglottitis with and without and artificial airway. Am J Dis Child 1983; 137: 139–141. 4 CDC. Update: Acquired immunodeficiency syndrome. Morbid Mortal Weekly Rep 32: 688–691. 5 Wood RE. Spelunking in the pediatric airways: Explorations with the flexible fiberoptic bronchoscope. Pediatr Clin North Am 1984; 31: 785. 6 Kobayashi RH, Rosenblatt HM, Carney JM. Candida esophagitis and laryngitis in chronic mucocutaneous candidiasis. Pediatrics 1980; 66: 380–384. 7 Jacobs RF, Yasuda K, Smith AL, Benjamin DR. Laryngeal candidiasis presenting as inspiratory stridor. Pediatrics 1982; 69: 234–236. 8 Hughes WT. Systemic candidiasis: A study of 109 fatal cases. Pediatr Infect Dis 1982; 1: 11–18. Citing Literature Volume3, Issue4July/August 1987Pages 280-281 ReferencesRelatedInformation

Between October, 1985 and May 1987, 29 children (mean age 22 ± 22 months, range 2–54 months) with AIDS or ARC developed acute respiratory illness. The initial diagnostic procedure was flexible fiberoptic bronchoscopy, with bronchoalveolar lavage (BAL). BAL was positive for Pneumocystis carinii in 14 and for respiratory syncytial virus, Staphylococcus aureus , and Escherichia coli in 3 additional patients. Subsequent lung tissue analysis and/or clinical course suggested no false negative lavages. Complications possibly related to the procedure occurred in two patients. We find BAL an effective diagnostic technique in these patients, offering a less invasive alternative to open lung biopsy.