CD4 Lymphopenia Research Articles

S4965 A Case of Intestinal Mycobacterium tilburgii in the Setting of Pancytopenia and Idiopathic CD4 Lymphopenia

S4965 A Case of Intestinal Mycobacterium tilburgii in the Setting of Pancytopenia and Idiopathic CD4 Lymphopenia

Recurrent pulmonary nocardiosis due to Nocardia Otitidiscaviarum in a patient with isolated CD4 lymphocytopenia: a case report

BackgroundIdiopathic CD4 lymphocytopenia (ICL) is an underdiagnosed immunodeficiency syndrome characterised by persistent low CD4 counts in the absence of HIV and other causes of lymphocytopenia. ICL patients are susceptible to opportunistic infections, with human papillomavirus, cryptococcal, and tuberculosis being the most common infections reported. Nocardiosis is rarely reported in patient with ICL.Case PresentationWe herein discuss a 46-year-old female presented with complaints of weight loss, low grade fever and cough with expectoration from last four months. The patient was diagnosed with pulmonary nocardiosis and aspergillosis co-infection four years back; in addition she also had ICL. Subsequently, the patient was lost in follow-up and readmitted four years later. Bronchoalveolar lavage sample shows the presence of acid-fast bacilli in modified gram stain, which later identified as Nocardia otitidiscaviarum by metagenomic next-generation sequencing. Her CD4 counts were still found low (298 cells/mm3). After an initial improvement with trimethoprim-sulfamethoxazole (TMP-SMX), she was commenced on indefinite secondary prophylaxis.ConclusionsNocardiosis without usual risk factors should be evaluated for ICL. This case emphasize the importance of periodic follow-up with CD4 count monitoring and secondary prophylaxis therapy to prevent recurrence or the emergence of new infections in ICL.Clinical trial numberNot applicable.

Isotype deficiencies (IgG subclass and selective IgA, IgM, IgE deficiencies).

Background: Immunoglobulin G (IgG) subclass deficiencies and isolated IgA, IgM, IgE deficiencies have all been described in the literature with variable prevalence. Methods: These isotype deficiencies have a variable presentation from asymptomatic to recurrent infections resistant to prophylactic antibiotics. Results: Atopic disorders and autoimmune diseases are common comorbidities. IgE deficiency has been associated with impaired vaccine response and an increased risk of malignancy, particularly in patients with no allergic comorbidities and those with non-common variable immunodeficiency (CVID) humoral immunodeficiency, IgM deficiency, IgG2 deficiency, and CD4 lymphopenia. Conclusion: Close monitoring for malignancy should be strongly considered for these patients who are at risk. Treatment is variable and may include antimicrobial therapies for illnesses and prophylactic antibiotics in select patients, and immunoglobulin replacement can be considered for patients with refractory, recurrent infections.

Mitochondrial chaperon TNF-receptor- associated protein 1 as a novel apoptotic regulator conferring susceptibility to Pneumocystis jirovecii pneumonia.

Molecular chaperons stabilize protein folding and play a vital role in maintaining tissue homeostasis. To this intent, mitochondrial molecular chaperons may be involved in the regulation of oxidative phosphorylation and apoptosis during stress events such as infections. However, specific human infectious diseases relatable to defects in molecular chaperons have yet to be identified. To this end, we performed whole exome sequencing and functional immune assessment in a previously healthy Asian female, who experienced severe respiratory failure due to Pneumocystis jiroveci pneumonia and non-HIV-related CD4 lymphocytopenia. This revealed that a chaperon, the mitochondrial paralog of HSP90, TRAP1, may have been involved in the patient's susceptibility to an opportunistic infection. Two rare heterozygous variants in TRAP1, E93Q, and A64T were detected. The patient's peripheral blood mononuclear cells displayed diminished TRAP1 expression, but had increased active, cleaved caspase-3, caspase-7, and elevated IL-1β production. Transfection of A64T and E93Q variants in cell lines yielded decreased TRAP1 compared to transfected wildtype TRAP1 and re-capitulated the immunotypic phenotype of enhanced caspase-3 and caspase-7 activity. When infected with live P. jiroveci, the E93Q or A64T TRAP1 mutant expressing cells also exhibited reduced viability. Patient cells and cell lines transfected with the TRAP1 E93Q/A64T mutants had impaired respiration, glycolysis, and increased ROS production. Of note, co-expression of E93Q/A64T double mutants caused more functional aberration than either mutant singly. Taken together, our study uncovered a previously unrecognized role of TRAP1 in CD4+ lymphocytopenia, conferring susceptibility to opportunistic infections.

Micobacterias no tuberculosas: cuando categorizarlas en pediatría

Background: The term "nontuberculous mycobacteria" refers to more than 170 different species of bacteria that are not Mycobacterium tuberculosis or M. leprae. These bacteria can cause a variety of infections in children. Accurate diagnosis is crucial, as they can be confused with other diseases. Treatment can be challenging due to antibiotic resistance in some strains. The literature review focuses on improving the diagnosis and treatment of these infections in the pediatric population. The characterization of these bacteria, through methods such as PCR, is essential for effective treatment. Material and methods: A systematic review was performed to determine the need to categorize nontuberculous mycobacteria in pediatrics. Various databases and Boolean operators were used to search for relevant information. Inclusion and exclusion criteria were applied to select documents. The review covered the period from 2012 to 2023. They focused on pediatric studies on nontuberculous mycobacteria. Results: The article "Idiopathic CD4+ lymphocytopenia and juvenile laryngeal papillomatosis" describes a case of juvenile laryngeal papillomatosis (JLP) that was complicated by idiopathic CD4 lymphocytopenia (ICL). Despite treatments and surgeries, JLP progressed. The patient developed ICL based on the decrease in CD4+ lymphocytes without HIV. After receiving interferon-alpha with partial response, he died. The study "Prevalence and species spectrum of both pulmonary and extrapulmonary nontuberculous mycobacteria isolates" highlights the high prevalence of nontuberculous mycobacteria in India, especially M. abscessus. "Nontuberculous Mycobacteria in Denmark" evaluates the incidence and clinical relevance of NTM in Denmark from 1991 to 2015, finding a stable incidence and differences in age groups and species. These studies enrich the understanding of these medical conditions. Conclusion: The four studies analyzed offer a global vision of the incidence and characteristics of nontuberculous mycobacteria (NTM) in various regions. Although they all address NTM, they reveal geographic variability in their incidence and characteristics. A global increase in the incidence of NTM is observed, raising concerns about its clinical relevance. Furthermore, the study in New York highlights the increase in NTM in densely populated urban environments. Botswana underlines the importance of accurate diagnosis, especially in areas with high prevalence of tuberculosis and HIV. In Denmark, no significant increase in the incidence of NTM is observed, suggesting regional variability. Together, these findings emphasize the need to understand the local epidemiology of NTM and the importance of its prevention and control

A Longitudinal study on the Kinetic of T-cells and certain hematological parameters during the Initiation of antiretroviral therapy and after two years on treatment

Background: T- cell are key regulators of the immune system and their role in the initiating and follow –up of patients on antiretroviral therapy (ART) is primordial. In the present work, we compared T-cells and certain biological parameters after 2 months of ART with those obtained after one year and 2 years of ART. Method: In this prospective cohort study, 150 HIV patients on primo ART treatment and consenting were recruited. Five ml of blood were collected at initiation (M0), after 2 months (M2), after 1 year (M12), and after 2 years (M24) of ART. CD4 cells, CD8 cells, and other hematological parameters were measured according to standard operating procedures. Results: The 88 retained participants included 18 (20.6%) men and 70 (79.4%) women, with a mean age of 35.5 years. After 2 months, there was a significant increase in CD4 count, monocytes, and platelets with p-values of 0.001, 0.02, and 0.04, respectively, while hemoglobin and CD8 cells did not significantly change (p-values of 0.06 and 0.82, respectively). After one year and after two years of therapy, the increases in these parameters were not statistically significant compared to the values obtained at M2. Conclusion: CD4 lymphopenia, monopénia and thrombopenia induced by HIV infection are corrected maximally during the first months after the beginning of ART and tend to stabilize over time, while anemia can continue to persist.

Progressive multifocal leukoencephalopathy secondary to idiopathic CD4 lymphocytopenia treated with pembrolizumab

BackgroundProgressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. MethodsWe present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. ConclusionThis report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

Immune responses to SARS-CoV-2 mRNA vaccination in people with idiopathic CD4 lymphopenia

BackgroundThe immunogenicity of SARS-CoV-2 mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL). ObjectiveDetermine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts. MethodsSamples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti-spike and anti-receptor binding domain antibodies were measured. T-cell-receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T-cell responses. ResultsThe median age of ICL participants was 51-years and their CD4 count was 150 cells/μl; eleven individuals had CD4 ≤100 cells/μL. Anti-spike IgG antibody levels were greater in HVs than in patients with ICL after 2-doses and 3-doses of mRNA vaccine. There was no detectable significant difference, however, in anti-spike IgG between HVs and those with ICL and CD4 >100 cells/μL. The depth of spike-specific T-cell responses, by T-cell receptor sequencing, was lower in individuals with ICL. Activation-induced markers and cytokine production of spike-specific CD4 T-cells in ICL did not differ significantly compared to HVs after two or three vaccine doses. ConclusionPatients with ICL and CD4 count >100 cells/μL can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination, however, those with more severe CD4 lymphopenia have blunted vaccine-induced immunity and may require additional vaccine doses and other risk mitigation strategies.

The Association Between Malignancy, Immunodeficiency, and Atopy in IgE-Deficient Patients

Studies show that IgE-deficient patients (IgE <2.5 kU/L) have a high prevalence of malignancy, but relevant clinical and laboratory characteristics associated with this susceptibility have never been well characterized. To evaluate if there is an association between a malignancy diagnosis and other immunological parameters (atopy or other immune abnormalities) in IgE-deficient patients. We retrospectively analyzed medical records of 408 IgE-deficient adults seen at our institution between 2005 and2020. A malignancy diagnosis was found in 23.5% (96 of 408) of IgE-deficient patients. Among those who had allergy skin testing performed for allergic rhinitis-like symptoms, the nonatopic IgE-deficient patients (negative environmental skin tests) were more likely to have a malignancy diagnosis than the atopic group (odds ratio [OR]= 4.36, 95% confidence interval [CI]: 1.11-17.13, P= .03). The IgE-deficient individuals with an additional non-common variable immunodeficiency (non-CVID) humoral abnormality (n= 75; with low IgG, IgA, or IgM without meeting criteria for CVID) were more likely to have a malignancy diagnosis than those with only a selective IgE deficiency (n= 134; with normal IgA, IgM, and IgG) (OR= 2.79, 95% CI: 1.37-5.68, P= .005). Among the IgE-deficient patients, certain less well-defined immune abnormalities such as IgM deficiency (OR= 2.46, 95% CI: 1.13-5.36, P= .02), IgG2 deficiency (OR= 10.14, 95% CI: 1.9-54.1, P= .007), and CD4 lymphopenia (OR= 7.81, 95% CI: 2.21-27.63, P= .001) were associated with higher malignancy odds than those without these abnormalities. The odds of a malignancy diagnosis are not shared equally by all IgE-deficient patients. Prospective studies are needed to determine the utility of performing skin testing and measuring additional immunological parameters in assessing the long-term malignancy risk in IgE-deficient patients.

Flow Cytometric Analysis of Lymphocyte Subsets of Covid-19 Patients from A Single Centre in Turkey

Background:&#x0D; Lymphocyte counts have been shown to negatively correlate with the severity and different outcomes in Covid-19. The aim of this single centre study is to analyse the distribution of lymphocyte subsets in response to SARS-CoV-2 infection and its relation to the severity, course and prognosis of the disease.&#x0D; Methods:&#x0D; Blood samples were obtained from 67 consecutive patients between April 2020 and July 2020. Data on other laboratory parameters, and clinical course were collected retrospectively from patient files and patints were defined to have as severe or non-severe (mild/moderate) disease. Leukocyte subsets to be studied were identified by using flow cytometric analysis. Patients were allocated into 3 groups based on the day of blood sample collection for the flow cytometric analysis: Days 0-7, Days 8-14 and Days &gt;14 as Group I, Group II and Group III, respectively. In 10 available of 67 patients an additional flow cytometric analysis was done 7-10 days after the initial sampling.&#x0D; Results:&#x0D; Lower total lymphocyte, CD3 positive, CD4 positive and B-cell counts were identified in severe infection compared to non-severe infection group which were also correlated with high serum CRP, D-dimer and ferritin levels. NK and monocyte counts were not different between the two groups. Activation markers CD38 and HLA-DR on CD4 and CD8 positive lymphocytes also were not different in either group. &#x0D; Conclusion:&#x0D; CD3 and CD4 lymphopenia were lower in accordance with previous studies and were associated with severe disease. The expectancy of high activation markers was not met. Future studies with detailed subgroup analyses at different time-points, and immune profiling after vaccination as well as during new infection in vaccinated patients will shed more light on our general knowledge of the immune response to COVID-19 and viruses in general.

Sarcoidosis presenting as progressive multifocal leukoencephalopathy in an apparently immunocompetent adult

Neurological involvement in sarcoidosis is termed as neurosarcoidosis. It usually leads to cranial neuropathies, although it can involve any part of the neuroaxis. Although sarcoidosis is a proinflammatory state, there is an associated anergic state demonstrable by a feeble tuberculin response. Lymphocytic sequestration in granulomas can be associated with peripheral CD4 lymphocytopenia (40% of patients with sarcoidosis) predisposing to opportunistic infections. Here we have described a young, otherwise immunocompetent male presenting with subacute onset right hemiparesis with motor aphasia, who was diagnosed to have progressive multifocal leukoencephalopathy (PML) secondary to pulmonary sarcoidosis. We want to emphasize that PML should be considered as a differential in all cases of secondary demyelination (even apparently immunocompetent individuals) as early diagnosis and treatment of the underlying cause is likely to yield better outcomes.

Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain.

ZAP-70, a protein tyrosine kinase recruited to the T cell receptor (TCR), initiates a TCR signaling cascade upon antigen stimulation. Mutations in the ZAP70 gene cause a combined immunodeficiency characterized by low or absent CD8+ T cells and nonfunctional CD4+ T cells. Most deleterious missense ZAP70 mutations in patients are located in the kinase domain but the impact of mutations in the SH2 domains, regulating ZAP-70 recruitment to the TCR, are not well understood. Genetic analyses were performed on four patients with CD8 lymphopenia and a high resolution melting screening for ZAP70 mutations was developed. The impact of SH2 domain mutations was evaluated by biochemical and functional analyses as well as by protein modeling. Genetic characterization of an infant who presented with pneumocystis pneumonia, mycobacterial infection, and an absence of CD8 T cells revealed a novel homozygous mutation in the C-terminal SH2 domain (SH2-C) of the ZAP70 gene (c.C343T, p.R170C). A distantly related second patient was found to be compound heterozygous for the R170C variant and a 13bp deletion in the ZAP70 kinase domain. While the R170C mutant was highly expressed, there was an absence of TCR-induced proliferation, associated with significantly attenuated TCR-induced ZAP-70 phosphorylation and a lack of binding of ZAP-70 to TCR-ζ. Moreover, a homozygous ZAP-70 R192W variant was identified in 2 siblings with combined immunodeficiency and CD8 lymphopenia, confirming the pathogenicity of this mutation. Structural modeling of this region revealed the critical nature of the arginines at positions 170 and 192, in concert with R190, forming a binding pocket for the phosphorylated TCR-ζ chain. Deleterious mutations in the SH2-C domain result in attenuated ZAP-70 function and clinical manifestations of immunodeficiency.

Monogenic inborn errors of immunity in autoimmune disorders.

To estimate the prevalence of monogenic inborn errors of immunity in patients with autoimmune diseases (AID), the study included 56 subjects (male:female ratio: 1.07) with mean age of onset of autoimmunity 7 years (4 months-46 years). 21/56 had polyautoimmunity. 5/56 patients met the JMF criteria for PID. The different AID referred were hematological (42%) > gastrointestinal (GI) (16%) > skin (14%) > endocrine (10%) > rheumatological (8%) > renal (6%) > neurological (2%). 36/56 reported recurrent infections. 27/56 were on polyimmunotherapy. 18/52 (35%) had CD19 lymphopenia, 24/52 (46%) had CD4 lymphopenia, 11/52 (21%) had CD8 lymphopenia, and 14/48 (29%) had NK lymphopenia. 21/50 (42%) had hypogammaglobinemia; 3 of whom were given rituximab. 28/56 were found to have pathogenic variants among PIRD genes. These 28 patients had 42 AID among which hematological was most common (50%) > GI (14%) =skin (14%)> endocrine (9%) >rheumatological (7%) > renal and neurological (2%). Hematological AID was the most common AID (75%) in children with PIRD. Positive predictive value (PPV) of abnormal immunological tests was 50% and sensitivity of 70%. JMF criteria had specificity of 100% in identifying PIRD and sensitivity of 17%. Polyautoimmunity had a PPV of 35% and sensitivity of 40%. 11/28 of these children were offered transplant. 8/28 were started on sirolimus, 2/28 on abatacept, and 3/28 on baricitinib/ruxolitinib after diagnosis. In conclusion, 50% of children with AID have underlying PIRD. LRBA deficiency and STAT1 GOF were the most common PIRD. Age at presentation, number of autoimmunity, routine immunological tests, and JMF criteria are not predictive of underlying PIRD. Early diagnosis with exome sequencing alters the prognosis and opens new therapeutic avenue.

Disseminated mucocutaneous leishmaniasis in a traveller with idiopathic CD4 lymphocytopenia.

We reported here a case of disseminated cutaneo-mucosal leishmaniasis caused by L. braziliensis in a traveller returning from Bolivia, probably favoured by an underlying idiopathic CD4-lymphocytopenia. Third-line therapy with 51mg/kg total dose of liposomal amphotericin B led to a sustained complete clinical cure.

Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years

BackgroundIdiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations.MethodsWe evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality.ResultsAfter the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher.ConclusionsAmong the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.)

Severe CD8+ T Lymphopenia in WHIM Syndrome Caused by Selective Sequestration in Primary Immune Organs.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an ultra-rare combined primary immunodeficiency disease caused by heterozygous gain-of-function mutations in the chemokine receptor CXCR4. WHIM patients typically present with recurrent acute infections associated with myelokathexis (severe neutropenia due to bone marrow retention of mature neutrophils). Severe lymphopenia is also common, but the only associated chronic opportunistic pathogen is human papillomavirus and mechanisms are not clearly defined. In this study, we show that WHIM mutations cause more severe CD8 than CD4 lymphopenia in WHIM patients and WHIM model mice. Mechanistic studies in mice revealed selective and WHIM allele dose-dependent accumulation of mature CD8 single-positive cells in thymus in a cell-intrinsic manner due to prolonged intrathymic residence, associated with increased CD8 single-positive thymocyte chemotactic responses invitro toward the CXCR4 ligand CXCL12. In addition, mature WHIM CD8+ T cells preferentially home to and are retained in the bone marrow in mice in a cell-intrinsic manner. Administration of the specific CXCR4 antagonist AMD3100 (plerixafor) in mice rapidly and transiently corrected T cell lymphopenia and the CD4/CD8 ratio. After lymphocytic choriomeningitis virus infection, we found no difference in memory CD8+ T cell differentiation or viral load between wild-type and WHIM model mice. Thus, lymphopenia in WHIM syndrome may involve severe CXCR4-dependent CD8+ T cell deficiency resulting in part from sequestration in the primary lymphoid organs, thymus, and bone marrow.

Monogenic inborn errors of immunity in autoimmune disorders

To estimate the prevalence of monogenic inborn errors of immunity in patients with autoimmune diseases. This was a retrospective and prospective cohort study. The study included 56 subjects (Male:Female ratio: 1.07) with mean age of onset of autoimmunity of 7 years (4months-46 years). 21/57 (37.5%) had polyautoimmunity. 5/56 patients met the JMF criteria for PID. The different AID referred were hematological (42%) > GI (16%) > Skin (14%) > Endocrine (10%) > Rheumatological (8%) > Renal (6%) > Neurological (2%). 36/57 (63%) reported recurrent infections. 27/56 were on polytherapy, 46 had received steroids. 18/52 (35%) had CD19 lymphopenia, 24/52(46%) had CD4 lymphopenia, 11/52(21%) had CD8 lymphopenia, 14/48 (29%) had NK lymphopenia. 20/50 (42%) had hypogammaglobinemia. 28/56 (50%) were found to have pathogenic variants among PIRD genes (LRBA:6, STAT1 GOF: 3, CTLA4: 2, ACP5: 2, 1 each with NFKB1, NLRP12, CARD11 GOF, STAT3 GOF, RTEL1, NCF2, ATM, RAG1, BTK, IL12RB1, CR2 and CD55 microdeletion/CHAPEL, FOXP3, PIK3CD, CD40L, ADA2). These 28 patients had 41 autoimmune diseases. Hematological AID was most common (50%)>GI (16%)>Endocrine (9%)>Skin (11%)>Rheumatological (7%)>Renal and neurological (1%). Hematological AID is most common manifestation in almost 75% of children with PIRD. Positive predictive value of abnormal immunological tests was 50% and sensitivity of 70%. JMF criteria had specificity of 100% in identifying PIRD but sensitivity was only 17%. Polyautoimmunity had a positive predictive value of 35% and sensitivity of only 40%. Avg age at initial presentation with autoimmunity in patients with underlying PIRD was 7.4 years vs 6.4 years in those without PIRD. 11/28 of these children were offered transplant out of whom 4 have successful transplants. 8/28 were started on sirolimus, 2/28 on abatacept, 3/28 on baracitinib, 2/29 on ruxolitinib after diagnosis that led to steroid withdrawal. 4 have died. Conclusion: 50% of children with AID have underlying PIRD. LRBA deficiency and STAT1 GOF were the most common PIRD. Age at presentation, number of autoimmunity, routine immunological tests and JMF criteria are not predictive of underlying PIRD. Early diagnosis with exome sequencing alters the prognosis and opens new therapeutic avenue.

Abnormal Newborn Screening for Severe Combined Immunodeficiency due to CD4 T cell lymphopenia associated with Heterozygous FOXN1 Variants in the Forkhead Domain

FOXN1 performs a pivotal role in the development of thymic epithelium. Homozygous FOXN1 deficiency results in T-B+NK+ SCID while FOXN1 haploinsufficiency is associated with T cell lymphopenia and nail dystrophy. We report two patients with variants of uncertain significance (VUS) in FOXN1 who presented with lymphopenia detected on newborn screening.Patient A is a 17-month-old female born to non-consanguineous parents who presented with lowT-cell receptor excision circles (TRECs). At 2 weeks old, her lymphocyte subset panel revealed low T cells, but normal B and NK cells (Table 1). Follow up at 3 months revealed uptrending T cells and significantly decreased B cells. She had no concerning clinical features or infections at that time. By 6 months, her T cells were again downtrending, but her B cells had normalized. She required antibiotics for acute otitis media, which quickly resolved. At 15 months, T cell lymphopenia persisted (Figure 2). Her infection history was reassuring, developmental milestones met and physical exam notable only for spooned nails.Patient B is a 4-month-old female also born to non-consanguineous parents presenting with low TRECs. Initial workup at 5 days revealed T cell lymphopenia, but normal B and NK cells (Table 1). At 2 months, CD4 lymphopenia persisted though CD8T cells normalized (Figure 2). She had a self-limiting upper respiratory infection, but otherwise unremarkable infection history. Development and physical exam were normal.A targeted 429-gene panel for inborn errors of immunity revealed heterozygous FOXN1 VUSs in both Patient A (c.890T > G, p.Ile297Ser) and Patient B (c.890T > C, p.Ile297Thr). Patient A's variant was not present in population databases. Patient B's variant has been observed (gnomAD frequency of 0.007%) but not present in population databases for the patient's ethnicities. Surprisingly, both are located at the same position within the Forkhead domain (Figure 1). Algorithms to predict the effect of missense changes on FOXN1 protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all predicted these variants as likely to be disruptive. Further understanding of the phenotypes associated with heterozygous FOXN1 variants of uncertain significance is crucial to guiding diagnostics, treatment, and prognosis. Table 1Lymphocyte panel results at original presentation (Patient A: 2 weeks old, Patient B: 5 days old). Reference ranges obtained from J Allergy Clin Immunol, Volume 112, Number 5, pp 973–980, November 2003VariantCD4+ CD45RA+ (Naïve CD4+ T Cells, cells/μL)CD4+ CD45RO+ (Memory CD4+ T cells, cells/μL)CD8+ T Cells (cells/μL)CD19+ B Cells (cells/μL)CD16+ CD56+ (NK Cells, cells/μL)Patient Ac.890T>G (p.Ile297Ser)633100518423700Patient Bc.890T>C (p.Ile297Thr)569126122610311Ref range (0–3 months)1200–370060–900560–1700300–2000170–1700 [Display omitted] [Display omitted]

Fatal dermatophytic pseudomycetoma in a patient with non-HIV CD4 lymphocytopenia

ABSTRACT Dermatophytic pseudomycetoma is a rare invasive infection, involving both immunocompetent and immunocompromised individuals. Since the discovery of inherited immune disorders such as the impairment of CARD9 gene, extended dermatophyte infections are mostly ascribed to any of these host factors. This study is to present and explore the potential causes in a fatal dermatophytic pseudomycetoma patient. We present a chronic and deep pseudomycetoma caused by the common dermatophyte Microsporum canis which ultimately led to the death of the patient. Mycological examination, genetic studies and host immune responses against fungi were performed to explore the potential factors. The patient had decreased lymphocyte counts with significantly reduced CD4+ T cells, although all currently known genetic parameters proved to be normal. Through functional studies, we demonstrated that peripheral blood mononuclear cells from the patient showed severe impairment of adaptive cytokine production upon fungus-specific stimulation, whereas innate immune responses were partially defective. This is, to our knowledge, the first report of fatal dermatophytic pseudomycetoma in a patient with non-HIV CD4 lymphocytopenia, which highlights the importance of screening for immune deficiencies in patients with deep dermatophytosis.

Cryptococcal Meningoencephalitis in an HIV-Negative Host Infected With COVID-19: A Case Report

We report a rare case of cryptococcal infection in an immunocompetent adult who initially presented with altered sensorium and acute COVID-19 infection. The suspected diagnosis was encephalopathy due to pneumonia; however, the patient developed new neurologic deficits, warranting further investigation, which revealed cryptococcal meningoencephalitis. HIV testing was negative, but CD4 lymphocytopenia was seen, which resolved after treatment for both COVID-19 and cryptococcal meningoencephalitis. This case illustrates the importance of considering uncommon scenarios in which an opportunistic infection such as cryptococcal meningoencephalitis may present. It also demonstrates the need to frequently consider alternative diagnoses, particularly in the pandemic era.