Alan P Knutsen

• MD
• Managing Director at Saint Louis University

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-instituti...

We describe the case of a 10-month-old boy with vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL) association and athymia who developed Omenn syndrome.

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on t...

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB bu...

Background Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium’s (PIDTC’s) prospective and retrospective studies of SCID. Objective Because of the advent of newborn screening for SCID and expanded availa...

A Correction to this paper has been published: https://doi.org/10.1007/s10875-020-00917-0

Purpose: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives we...

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

Background With >36 years of data collected, PIDTC prospective (6901) and retrospective (6902) natural history studies provide an unprecedented opportunity to study hematopoietic cell transplantation (HCT) outcomes for SCID over time. Methods Patients in this 6901/6902 analysis met PIDTC diagnostic criteria for SCID and underwent HCT. Categorial v...

Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of Mucopolysaccharidoses including Morquio A syndrome caused by GALNS deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives which can cause ad...

Introduction Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. Methods We collected data retrospectively from 145 patient...

Cohen syndrome was initially described as a syndrome including obesity, hypotonia, mental deficiency, and facial, oral, ocular and limb anomalies. Leukopenia, especially neutropenia, was later described as a feature of Cohen syndrome. Cohen syndrome is caused by an autosomal recessive (AR) mutation of the vacuolar protein sorting 13 homolog B (VPS1...

In a 250 patient cohort from the US and Canada in the current era (2010-2018), we show that over 90% of patients with severe combined immunodeficiency (SCID) can be genetically-characterized.

Key Points The genetic cause of SCID impacts on survival and immune reconstitution and should be considered in tailoring HCT for individual patients. Total and naive CD4+ cell counts in SCID patients 6 and 12 months post-HCT predict long-term survival and sustained immune reconstitution.

Aim: To assess the safety and efficacy of an intravenous immunoglobulin (IVIG) 10% preparation (Panzyga®; Octapharma AG, Lachen, Switzerland) in predominantly antibody-deficient children with primary immunodeficiency disease. Methods: Data from two prospective, open-label and noncontrolled multicenter Phase III studies of IVIG 10% that included...

This chapter examines a variety of immunologic-mediated lung diseases. Hypersensitivity pneumonitis is caused by exposure to a variety of antigens that elicit a Th1-mediated hypersensitivity response in the lungs. In contrast eosinophilic lung disease is typically a Th2-mediated response manifested by a prominent eosinophilic inflammatory response...

Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2-75 years with common variable immunodeficiency (n =...

Key Points Active infection pretransplant adversely impacts survival (81% in patients with active infection vs 95% in infection-free patients; P = .009). Preparative chemotherapy improved 1-year post-HCT median CD4 counts (P = .02) and freedom from IV immunoglobulin (P < .001).

The treatment of severe combined immunodeficiency (SCID) is immune reconstitution using hematopoietic stem cell (HSC) transplantation early in life. HLA-identical related donors are the preferred source of HSCs. Since sibling donors are available in <30% of patients, other sources of HSCs are considered - mismatched related donor, umbilical cord bl...

Multiple endocrine neoplasia (MEN) type I, an autosomal dominant disorder caused by mutations in the MEN1 gene, is classically associated with parathyroid, pituitary, and pancreatic tumors. Patients with MEN type I also frequently exhibit multiple cutaneous lesions, specifically facial angiofibromas and collagenomas. Herein we describe a patient wi...

Purpose: To assess the efficacy and safety of panzyga® (intravenous immunoglobulin 10%) in preventing serious bacterial infections (SBIs) in patients with primary immunodeficiency diseases (PIDs), a prospective, open-label, multicenter, phase 3 study and an open-label extension study were undertaken. Methods: Initially, the study drug (infusion...

Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sou...

Fungi cause a wide spectrum of fungal diseases of the upper and lower airways. There are three main phyla involved in allergic fungal disease: (1) Ascomycota (2) Basidiomycota (3) Zygomycota. Allergic fungal rhinosinusitis (AFRS) causes chronic rhinosinusitis symptoms and is caused predominantly by Aspergillus fumigatus in India and Bipolaris in th...

Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective in the treatment of patients with primary antibody deficiency disorders (PAD). The purpose of this study was to evaluate Streptococcus pneumoniae (Spn) antibody titres to 14 serotypes in patients receiving IVIG compared to SCIG and to correlate Spn antibody level...

The case is presented of a boy aged 5 years and 10 months with recurrent infections and intermittent thrombocytopenia who had immunoglobulin M (IgM) deficiency and specific antibody deficiency to Streptococcus pneumoniae. Whole exome sequencing was performed and revealed a transmembrane activator and calcium modulator and cyclophilin ligand interac...

Purpose: Recent studies have reported that CD19+CD20+CD27+CD43+CD70-CD5− B cells produce IgG, IgA, and IgM antibodies to Streptococcus pneumoniae (Spn). In one adult patient with specific antibody deficiency (SAD), the percentage of CD5− CD19+CD20+CD27+CD43+CD70− B cells was decreased. The percentages of CD5−of CD19+CD27+CD43+CD70− B cells in child...

There remains a lack of agreement on diagnostic criteria and approaches to treatment of patients with allergic bronchopulmonary aspergillosis (ABPA). The results of a survey of American Academy of Allergy, Asthma, & Immunology members regarding these 2 issues are presented and compared for concordance with published recommendations. The literature...

Background: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effectiv...

We report for the first time on a 3-year-old boy with paternally inherited 212.85 kb-16p11.2 and 7.8 Mb-20p12.2-11.23 interstitial microduplications associated with having congenital cardiac defect, dysmorphic facial features, and combined T-, B-, and NK cell immunodeficiency. In addition the 7.8 Mb-20p12.2-11.23 microduplication is unique showing...

Aspergillus species and principally A. fumigatus cause a spectrum of pulmonary diseases depending on underlying host genetic risk factors. These include invasive aspergillosis, hypersensitivity lung disease, allergic asthma, allergic bronchopulmonary aspergillosis, and mycetomas. These disorders, pathogenesis and host risk factors will be discussed...

The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical...

Pulmonary complications are an extremely common manifestation of primary immunodeficiency disorders (PIDD). Infections are the most common abnormality and can lead to specific pulmonary complications. Patients with PIDD can present with a variety of manifestations such as recurrent bacterial, viral, or fungal pneumonia, bronchiectasis, granulomatou...

We report on an 18-year-old man with common variable immunodeficiency presenting with abdominal pain and vomiting due to gastric ulcers caused by reactivation of varicella-zoster virus (VZV). Endoscopy revealed multiple ulcers in the gastric antrum. Fever and rash developed the next day. Skin biopsy showed multinucleated cells with intranuclear inc...

Ectodermal dysplasia with immunodeficiency (EDI) is an X-linked recessive disorder featuring hypodontia, sparse hair, recurring infections, susceptibility to colitis and rarely severe atopy. Current treatment modalities for colitis, including eosinophilic gastroenteritis (EGE), seen with EDI result in immunosuppression and its complications prompti...

Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold...

Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-κB essential modulator (NEMO; also known as IκB kinase γ subunit [IKKγ]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-κB proteins, resu...

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is common in both atopic asthmatic and CF patients, yet only 1%-2% of asthmatic and 7%-9% of CF patients develop ABPA. ABPA is characterize...

Background and objectives: Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of hig...

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is common in both atopic asthmatic and CF patients, yet only 1-2% of asthmatic and 7–9% of CF patients develop ABPA. ABPA is characterized...

Mannose-binding lectin (MBL) deficiency is relatively common occurring in ∼7% of the general population. Most individuals with MBL deficiency are clinically unaffected due to protective antibody adaptive immunity, and therefore never present for evaluation of recurrent infections. We sought to identify associated immunologic abnormalities in patien...

Several epidemiologic studies in the United States and Europe have linked Alternaria sensitivity to both persistence and severity of asthma. In this study, we examined T cell responses and HLA class II alleles in children with moderate-severe asthma. Ninety-six children with moderate-severe asthma were compared to 90 children with mild asthma. HLA...

We present a 6-year-old boy with recurrent sinopulmonary infections, decreased serum IgG levels, decreased memory and switched B cells, decreased antibody responses to Streptococcus pneumoniae immunization, diarrhea, and abdominal pain. Intravenous immunoglobulin was initiated, which resulted in marked improvement of infections. Plasma interleukin...

Asthma afflicts 6% to 8% of the United States population, and severe asthma represents approximately 10% of asthmatic patients. Several epidemiologic studies in the United States and Europe have linked Alternaria sensitivity to both persistence and severity of asthma. In order to begin to understand genetic risk factors underlying Alternaria sensit...

The objective of this prospective, open-label, single-arm, Phase III study was to assess the efficacy and safety of Privigen ®, the first 10% liquid intravenous immunoglobulin stabilized with L-proline, in patients with primary immunodeficiency. As part of a larger study, 19 children (3-11 years) and 12 adolescents (12-15 years) received Privigen 2...

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a bronchial allergic inflammatory reaction to Aspergillus fumigatus that occurs in a minority of susceptible asthmatic and cystic fibrosis (CF) patients. Previous studies identified that HLA-DR2/DR5 was associated with susceptibility to develop ABPA; however, HLA-DR2/DR5 occurs frequentl...

We present a 5-year-old boy who initially presented during infancy with pulmonary interstitial glycogenosis (PIG) and recurrent sinopulmonary infections. At 3.5 years old, IgG-2 subclass deficiency associated with low IgA level and selective antibody deficiency was diagnosed. Subsequently, the immune deficiency evolved into common variable immunode...

Omalizumab is a monoclonal antibody that decreases IgE levels and has been shown to decrease asthma exacerbations, emergency care visits, and hospitalizations when added on to standard medical therapy for moderate-severe persistent asthma. We describe the results of omalizumab treatment in children 6 to 18 years old with severe asthma at a single p...

We report a 5-month-old Amish girl with atypical recombinase-activating gene (RAG)-deficient severe combined immunodeficiency disease. There was a lys992glu RAG-1 substitution leading to impaired RAG activity. Immunological studies revealed mildly decreased CD3+ T cells, markedly decreased CD4+ T cells, and oligoclonal T-cell receptor-Vβ T cells. B...

We present the case of an 8-year-old boy who developed common variable immunodeficiency (CVID) following rituximab therapy for the treatment of idiopathic thrombocytopenia (ITP). Since rituximab can cause prolonged hypogammaglobulinemia and increased susceptibility to infections, monitoring of immunoglobulin levels, antibody responses, B cells, and...

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disorder of cytotoxic cell function that results in abnormal proliferation of benign lymphocytes and histiocytes in response to infectious stimuli. FHLH generally occurs in very young children, and typically presents with fever, cytopenias, coagulopathy, lymphadenopathy, a...

Patients with DiGeorge anomaly (DGA) have a variety of B-cell immune deficiencies, including IgA deficiency and impaired polysaccharide antibody responses. CD27+ memory B cells have been found to be decreased in a variety of B-cell immunodeficiencies, such as selective antibody deficiency (SAD). We evaluated for a correlation between reduced CD27+...

Hypersensitivity pneumonitis (HP) is an immune-mediated hypersensitivity reaction to a variety of inhaled particles that may lead to acute, subacute, or chronic interstitial pneumonitis and possibly end-stage lung disease. Avian antigens most commonly cause HP in children, but fungi have also been implicated. To describe a 15-year-old girl and her...

Twenty-five patients with hypersensitivity reactions to phenobarbital and/or phenytoin are described. Clinical manifestations uniformly consisted of fever and a pruritic skin rash, and were often accompanied by conjunctivitis and lymphadenopathy. Less frequent complications included exfoliative dermatitis and protein-losing enteropathy. Histologic...