Manish Butte

Curr Opin Infect Dis. 2021 Oct 1. doi: 10.1097/QCO.0000000000000797. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility.

RECENT FINDINGS: PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID.

SUMMARY: We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.

PMID:34608876 | DOI:10.1097/QCO.0000000000000797

Virchows Arch. 2021 Oct 4. doi: 10.1007/s00428-021-03147-w. Online ahead of print.

ABSTRACT

Aberrations of the STK4 gene in humans result in an autosomal recessively inherited primary immunodeficiency. We identified three patients with STK4 deficiency who had presented to our hospital and reviewed their biopsy samples with the goal of detailing the characteristics of STK4 deficiency from a pathology perspective. Case 1 was a 20-year-old male who presented with cervical and supraclavicular lymphadenopathy which showed plasmacytic hyperplasia and a concurrent bronchial mass, with AA amyloidosis and EBV-associated “polymorphic lymphoproliferative disorder (LPD) resembling polymorphic post-transplant LPD.” The second case was an 8-year-old girl with abdominal lymphadenopathy; biopsy revealed a complex lymphoproliferation which consisted of EBV-associated “polymorphic LPD resembling polymorphic post-transplant LPD,” plasmacytic hyperplasia, granulomatous reaction, and a CD4- and PD-1-positive clonal T cell proliferation. The third was a 15-year-old girl with a laryngeal mass, representing a high-grade B cell lymphoma with prominent plasmacytic differentiation. Our cases emphasize the complex and challenging histopathology of lymphoid proliferations in patients with STK4 deficiency.

PMID:34604912 | DOI:10.1007/s00428-021-03147-w

Front Pediatr. 2021 Sep 17;9:757229. doi: 10.3389/fped.2021.757229. eCollection 2021.

ABSTRACT

[This corrects the article DOI: 10.3389/fped.2021.702546.].

PMID:34604146 | PMC:PMC8485753 | DOI:10.3389/fped.2021.757229

Case Reports Immunol. 2021 Sep 24;2021:2767012. doi: 10.1155/2021/2767012. eCollection 2021.

ABSTRACT

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

PMID:34603803 | PMC:PMC8486527 | DOI:10.1155/2021/2767012

Int Immunopharmacol. 2021 Sep 30;100:108044. doi: 10.1016/j.intimp.2021.108044. Online ahead of print.

ABSTRACT

BACKGROUND: The pharmacokinetics of Ig20Gly, a 20% subcutaneous immunoglobulin (IG) therapy, is well characterized in IG-experienced patients with primary immunodeficiency diseases (PID). Data from IG-naïve patients are limited.

OBJECTIVE: Simulate serum total immunoglobulin G (IgG) pharmacokinetic profiles in IG-naïve patients with PID for different Ig20Gly initiation and maintenance dosing regimens.

METHODS: A population pharmacokinetic model developed with data from pivotal phase 2/3 trials of weekly Ig20Gly in PID (NCT01412385, NCT01218438) was used to simulate pharmacokinetic profiles of IgG in various scenarios with 400- or 800-mg/kg total loading doses (administered as split doses over 1-2 weeks) and corresponding 100- or 200-mg/kg weekly maintenance doses, respectively. Endogenous baseline IgG levels (1.5, 2.0, 4.0, 6.0 g/L) were evaluated for each scenario; time to putative therapeutic target IgG trough level (7 g/L) was determined.

RESULTS: Serum IgG levels reached steady-state by approximately Week 12 for all scenarios and baseline endogenous IgG levels. Time to target trough level generally occurred sooner with 1-week versus 2-week loading schemes. Endogenous baseline IgG levels <4 g/L required a 1-week 800-mg/kg total loading dose to achieve target levels within 2 weeks. Both maintenance regimens sustained serum IgG above target level.

CONCLUSIONS: Simulations indicated IG-naïve patients with PID can achieve protective serum IgG levels within 1-3 weeks using appropriate Ig20Gly loading regimens. Patients with low endogenous IgG may benefit most from an 800-mg/kg/month loading dose. 400- or 800-mg/kg/month Ig20Gly maintenance regimens appeared adequate to maintain stable IgG levels. Serum IgG monitoring and clinical status can guide dosing parameters.

PMID:34601202 | DOI:10.1016/j.intimp.2021.108044

Immunol Lett. 2021 Sep 29:S0165-2478(21)00149-8. doi: 10.1016/j.imlet.2021.09.008. Online ahead of print.

ABSTRACT

Primary immune deficiencies (PID) are known to be more than 400 genetic defects caused by the impairment in development and/or functions of the immune system. Common Variable Immunodeficiency (CVID), Ataxia Telangiectasia (AT) and Agammaglobulinemia (AG) are examples of the most common immunodeficiency syndrome. Natural killer (NK) cells are a component of innate immune system and play a major role in the host-rejection of both tumors and virally infected cells. iNKT cells have a role in autoimmune and infectious diseases and controlling of tumor rejection. In this study, NK and iNKT cells and their functions, and intracellular cytokine amount are aimed to determine in patients that suffer CVID, AT and AG. NKp30, NKp46, NKG2D, perforin and granzyme mRNA expression levels were analyzed using RT-PCR. Receptors, cytokine amount of NK cell subset and iNKT were analyzed by flow cytometry. Decreased CD3⁺ T and elevated NK cell subset in pediatric AT were found. Expression of NKp44 was decreased in adult AG, but not in pediatric patients. Low NKp44 expression in CD3^–CD16⁺CD56^dim NK cell subset was found in pediatric AT patients. High HLA-DR, perforin and granzyme expression were found in CD3^–CD16⁺CD56^dim NK cell subset of pediatric CVID and AT patients. Alteration of the number of NK subsets, NK receptor expression and cytokine production were observed in pediatric patients compared to healthy subjects.

PMID:34599947 | DOI:10.1016/j.imlet.2021.09.008

J Immunol Methods. 2021 Sep 28:113159. doi: 10.1016/j.jim.2021.113159. Online ahead of print.

ABSTRACT

In general, the method of choice for evaluating immunity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is detection of antibodies against the virus in patient sera. However, this is not feasible in patients who do not produce antibodies, either due to a primary immunodeficiency or secondary to treatment with immunosuppressive drugs. Assessment of the antiviral T cell response is an alternative to serological tests, but most T cell assays are labor-intensive and unsuitable for a clinical routine laboratory. We developed a flow cytometry-based assay for T cell proliferative responses against SARS-CoV-2, based on the detection of blast transformation of activated cells. The assay was validated on previously SARS-CoV-2 infected individuals and healthy seronegative blood donors, displaying 74% sensitivity and 96% specificity for previous infection with SARS-CoV-2. The usefulness of the assay was demonstrated in a patient with common variable immunodeficiency with a history of COVID-19. The described T-cell assay is a clinically relevant complement to serology in the evaluation of cellular immunity against SARS-CoV-2, which can be emulated by any routine lab with flow cytometric competence.

PMID:34597619 | DOI:10.1016/j.jim.2021.113159

J Allergy Clin Immunol Pract. 2021 Sep 27:S2213-2198(21)01057-6. doi: 10.1016/j.jaip.2021.09.031. Online ahead of print.

ABSTRACT

New emerging pulmonary phenotypes associated with antibody deficiency, such as neutrophilic asthma, frequent exacerbations of chronic obstructive pulmonary disease, and unexplained interstitial lung disease, particularly in younger adults, are discussed in this review through a case-based approach. Also discussed in similar fashion are antibody deficiency syndromes that lead to end-stage lung disease and the indications for lung transplantation in primary immunodeficiency disease. These challenging cases require timely and individualized strategies for genetic and immunologic diagnosis, decisions about therapeutic approaches, and long-term monitoring.

PMID:34592394 | DOI:10.1016/j.jaip.2021.09.031

Brain Behav Immun Health. 2020 Nov 5;9:100170. doi: 10.1016/j.bbih.2020.100170. eCollection 2020 Dec.

ABSTRACT

Individuals with Primary Immunodeficiency Disease (PID) have increased risk for infection, autoimmune conditions, and inflammatory disorders. Cognitive impairment, also referred to as brain fog, has been recognized in other medical conditions and as a side-effect of treatments; however, it has not been previously reported in individuals with PID. The phenomenon of brain fog is recognized in other autoimmune or inflammatory conditions, including lupus, multiple sclerosis, chronic fatigue syndrome, and has resulted from chemotherapy treatment for cancer. This research investigates the self-reported memory function of individuals with a diagnosis of PID. Respondents completed a survey which used reliable and valid questionnaires: Memory Functioning Questionnaire, Beck’s Depression Inventory II, and Beck’s Anxiety Inventory. Of the 292 completed surveys, 133 did not report any comorbid neurological diagnosis or incident of concussion (both of which could influence perceived memory function). When compared to normative scores, the respondents in this study were found to have significantly greater perceived memory impairment. The respondents had a significant higher score for anxiety and depression as compared to non-anxious and non-depressed normative values. This study finds that individuals with a diagnosis of PID have a greater degree of perceived memory impairment, or brain fog, in addition to greater levels of anxiety and depression. Individuals with a diagnosis of PID would benefit from prospective surveillance through a comprehensive neuropsychological assessment to track cognitive status and implement corrective measures, should any decline be identified.

PMID:34589905 | PMC:PMC8474660 | DOI:10.1016/j.bbih.2020.100170

Cureus. 2021 Aug 26;13(8):e17467. doi: 10.7759/cureus.17467. eCollection 2021 Aug.

ABSTRACT

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disease caused by a genetic defect in the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex that affects phagocytes. This leads to recurrent severe bacterial and fungal infections manifested by recurrent pneumonia, also involving soft tissue, bones, and liver. Usually, CGD is presented and diagnosed in the first five years of life. In this case report, we describe a late presentation in an adolescent with multiple liver abscesses, the approach of diagnosis, and management.

PMID:34589361 | PMC:PMC8464347 | DOI:10.7759/cureus.17467