Idiopathic CD4 Lymphocytopenia Research Articles

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.

Severe cytopenia during adjuvant chemotherapy for early breast cancer in a patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.

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.)

Disseminated nontuberculous mycobacterial infection in a patient with idiopathic CD4 lymphocytopenia and IFN-γ neutralizing antibodies: a case report

BackgroundDisseminated nontuberculous mycobacterial (NTM) infection usually occurs in immunodeficient patients, such as those with human immunodeficiency virus infection and idiopathic CD4 lymphopenia. However, disseminated NTM diseases have also been reported in immunocompetent patients. Autoantibodies to interferon-gamma (IFN-γ) are known to be involved in disseminated NTM disease, although anti-IFN-γ antibodies are mainly seen in immunocompetent patients rather than those with immunodeficiency. Here, we report a rare case of disseminated NTM patient with idiopathic CD4 lymphopenia and anti-IFN-γ antibodies.Case presentationA 64-year-old Asian male presented with fever, back pain, anorexia and weight loss. Physical examination revealed subcutaneous masses in the forehead, sternoclavicular joint, and right inguinal region. Computed tomography showed multiple osteosclerotic changes with soft structures and osteolytic changes. Both blood and sputum cultures were positive for Mycobacterium intracellulare, confirming the presence of disseminated NTM infection. Histopathological evaluation of the subcutaneous mass in the right inguinal region showed numerous granulomas consisting of epithelioid cells with Langhans-type giant cells. He was diagnosed with idiopathic CD4 lymphocytopenia. Interestingly, he also had anti-IFN-γ autoantibodies with suppression of IFN-γ-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation. Two-drug combination therapy with clarithromycin and ethambutol was started for the NTM infection, which resulted in a favorable disease course.ConclusionsIn patients with disseminated NTM infection, idiopathic CD4 lymphocytopenia and anti-IFN-γ autoantibody-positive immunodeficiency can be coexisted. It is necessary to clarify the pathogenesis and clinical course of CD4 lymphocytopenic conditions and IFN-γ neutralizing antibody-positive in the disseminated NTM disease.

Idiopathic CD4 lymphocytopenia manifesting as chronic non-resolving pneumonia.

Idiopathic CD4 lymphocytopenia manifesting as chronic non-resolving pneumonia.

Molluscum contagiosum in an HIV-negative adult with idiopathic CD4 lymphocytopenia easily missed by dermatologists: a case report

Molluscum contagiosum in an HIV-negative adult with idiopathic CD4 lymphocytopenia easily missed by dermatologists: a case report

Idiopathic Immunodeficiency in Cytomegalovirus Reactivation: A Rare Case

Idiopathic CD4 lymphocytopenia (ICL) is a rare condition characterized by an unexplained deficit of circulating CD4 T cells leading to increased risk of serious opportunistic infections. Reactivation and severe symptomatic CMV is also a rare case, except in immunocompromised patient. Patient concerns are 36-year-old male patient complained seizure, fever, cough, and dyspnea. History of chronic urticaria and prolonged Mebhydrolin consumption. HIV was negative. CD4 was low. Diagnosis in this case is Viral encephalitis, Viral pneumonitis, CMV reactivation, hemophagocytic lymphohistiocytosis immunodeficiency state. The results in this study indicate that the patients were treated with conventional therapies for Severe CMV infection with Acyclovir. Steroid was given for the last five days. The first day after administration of therapy showed clinical and laboratory improvement. Laboratory values returned to normal values on the fifth day of therapy. Since the second day after the therapy was given, the patient had no complaints. In cases of CMV reactivation, an immunodeficiency condition should be suspected. A comprehensive history, physical examination, laboratory and radiological examination, adequate therapy and and policy support are required to establish a definite diagnosis and reduce the risk of mortality.

Hepatitis B virus-induced CD4 lymphocytopenia: A rare cause of progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare subacute-onset fatal demyelinating disease of the central nervous system caused by the John Cunningham (JC) virus. It usually occurs in impaired cell-mediated immunity settings such as lymphoproliferative disorders, chronic infective or granulomatous conditions on immunosuppressive medications, and human immunodeficiency virus infection. It also appears very rarely with idiopathic CD4 lymphocytopenia. We present a case of PML with visual field defect, progressive motor impairment, behavioral alteration, and dementia. Magnetic resonance imaging had features of asymmetric non-enhancing hyperintense subcortical white matter lesions in the background of chronic active hepatitis B infection. To the best of our knowledge, this is the first case report of CD4 lymphocytopenia associated PML following chronic hepatitis B infection.

Laryngeal Histoplasmosis in an Immunocompromised Host

Laryngeal histoplasmosis is a rare manifestation of histoplasmosis infection and presents as a diagnostic challenge. It has been documented to occur in immunocompromised and immunocompetent hosts. This is a case of laryngeal histoplasmosis in a patient with idiopathic CD4 lymphocytopenia, an immunocompromising condition that presents similarly to HIV. There is no known cause or standardized treatment of idiopathic CD4 lymphocytopenia, which leaves patients at risk for opportunistic infections and malignancy.

CD4 T cell deficiency results in impaired neutralizing IgG against polyomavirus carrying a frequent PML-associated capsid mutation

Abstract Deficiencies in the CD4 T cell compartment, such as HIV/AIDS, idiopathic CD4 lymphopenia, predispose patients to progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease caused by the JC polyomavirus (JCPyV). PML is associated with immunomodulatory therapies that preferentially diminish CD4 T cells in the CSF (natalizumab) or B cells (rituximab). The connection between CD4 T cells and JCPyV control is unclear. Work by others show that PML patient sera have “blind spots” in neutralizing JCPyV variants with mutations in the VP1 capsid protein. We hypothesized that defects in the humoral response after CD4 T cell depletion led to the emergence of antibody (Ab)-escape PyV variants. Using mouse PyV (MuPyV) to model JCPyV CNS disease, we found immune cell aggregates consisting of B cells, CD4 T cells, and CD8 T cells along the ventricles of PyV-infected WT mice but only a few infected cells. In contrast, CD4 T cell-depleted mice had more infected ependyma but lacked lymphocytic aggregates. There were fewer anti-PyV Ab-secreting B cells in the CNS despite similar B cell numbers in MuPyV-infected WT and CD4 T cell deficient mice brains. CD4 T cells prevent emergence of VP1 mutant PyVs that escape neutralizing Abs. MuPyV infection elicits a CD4 T cell-independent anti-VP1 IgG response that neutralizes WT virus equivalently to IgG from CD4 T cell-sufficient mice. Serum from MHC-II KO and CD4 mAb depleted mice had significantly lower neutralization activity toward a MuPyV with a frequent PML-equivalent VP1 mutation than to WT MuPyV. This data demonstrate that a narrowed antiviral IgG response caused by CD4 T cell deficiency is a critical antecedent for outgrowth of Ab-escape PyV VP1 mutant viruses. Supported by 1. Finkelstein Memorial Student Research Award, Pennsylvania State University College of Medicine, Hershey, PA 2. T32 CA060395 Training Grant (Meyers), NIH/NCI 3. R01 NS088367, NIH/NCI

Invasive Candidiasis in a Case of Late onset Combined Immunodeficiency

Late onset combined immunodeficiency (LOCID) is a recently described variant of common variable immunodeficiency (CVID), involving adult patients presenting with opportunistic infections and/or low CD4+ lymphocyte counts. We present a case of a 38-year, male, unmar-ried, who presented with history of abdominal pain and distension, jaundice and altered sleep- wake cycle suggestive of Decompensated liver disease. Patient developed multiple opportunistic infections in ward course which on further work up turned out to be Late onset combined immunodeficiency. Clinicians should be aware of LOCID, which could be confused with HIV infection/AIDS or idiopathic CD4 lymphocytopenia.

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Idiopathic CD4+ lymphocytopenia (ICL) is a rare disorder characterized by low counts of CD4+ cells (<300/mm3) in absence of other known causes of immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) were reported in association with ICL with variable outcome. We describe the case of a 40 year-old man diagnosed with PML, which showed a monophasic course. Causes of primary and secondary immunodeficiency were ruled out, only a “borderline” ICL was found. This case highlights that a severe immunodepression could not be an absolute prerequisite in developing PML and also points the attention on current definition of ICL.

Choroidal Detachment in Idiopathic CD4 Lymphocytopenia

Choroidal Detachment in Idiopathic CD4 Lymphocytopenia

Combined immunodeficiency (CVID and CD4 lymphopenia) is associated with a high risk of malignancy among adults with primary immune deficiency

Primary immunodeficiency disorders (PID) are a group of heterogeneous disorders characterized by recurrent infections, autoimmunity, increased lymphoproliferative disorders and other malignancies. PID is classified into cellular or humoral disorders or a combination of both. We evaluated the clinical differences among adult patients with three variants of PID: common variable immunodeficiency (CVID), idiopathic CD4 lymphopenia (ICL) and combined immunodeficiency (CID). We retrospectively compared demographics, immunological characteristics, clinical presentations and outcomes of CVID, CID and ICL patients followed from 2012 to 2018. In our cohort, we identified 44 adult patients diagnosed with CVID (22), CID (11) and ICL (11). Malignancy was associated with CID, as seven of 11 patients in this group were diagnosed with malignancy compared to CVID (three of 22) or ICL (two of 11) (P=0·002 and 0·03, respectively). Malignancies were also linked to male gender [odds ratio (OR)=5, 95% confidence interval (CI)=1·12-22·18) P=0·0342] and a low ratio of CD4/CD8<0·8 (OR=5·1, 95% CI=1·22-21·28, P=0·025). Among CID and ICL, two of 11 patients died in each group, while no death was documented among CVID group (P=0·04). Autoimmune manifestations did not differ between groups. Similarly, the rate of infections was similar between groups, although infectious agents vary. CID is associated with a high risk of malignancy compare to CVID or ICL. Among adults with PID, male gender, low CD4 and a CD4/CD8 ratio of<0·8 may serve as risk factors of concomitant malignancy. Surveillance of lymphocyte subpopulations should be considered for all adults.

Characterization of autoantibodies, immunophenotype and autoimmune disease in a prospective cohort of patients with idiopathic CD4 lymphocytopenia

ObjectiveCharacterize autoantibodies and autoimmune diseases in a prospective cohort of patients with Idiopathic CD4 Lymphocytopenia (ICL) a rare immunodeficiency characterized by an absolute CD4+ T count of <300 cells/μl in the absence of HIV or HTLV infection. MethodsSingle-Center prospective study of 67 patients conducted over an 11-year period. Rheumatologic evaluation and measurement of autoantibodies were systematically conducted, and flow cytometry of immune cell subsets was performed in a subset of patients. Results54% of referred patients had clinical evidence of autoimmunity, with 34% having at least one autoimmune disease, most commonly autoimmune thyroid disease. 19%, had autoantibodies or incomplete features of autoimmune disease. Patients with autoimmune disease had more elevated serum immunoglobulins, and more effector memory T cells than those without autoimmunity. ConclusionsEvidence of autoimmunity, including autoimmune diseases, is more prevalent in ICL than the general population, and should be considered part of this syndrome.

Idiopathic CD4 lymphocytopenia presenting as cryptococcal meningitis

A 54-year-old male presented to our center with a 3-month history of headache, giddiness, and blurring of vision. Cerebrospinal fluid examination revealed him to be having cryptococcal meningitis. He was worked up for probable causes of immunosuppression including HIV and other infections and had an autoimmune profile as well as a bone marrow examination, none of which revealed any abnormality. Lymphocyte flow cytometry revealed low counts of CD4 T lymphocytes, likely secondary to idiopathic CD4 lymphocytopenia. He was treated for cryptococcal meningitis. Due to marked immunosuppression, the disease progressed rapidly with deterioration in neurological and hemodynamic status, leading to his demise.

Preserved MAIT cell numbers and function in idiopathic CD4 lymphocytopenia.

Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional, MR1-restricted T-cells involved in antimicrobial responses as well as inflammatory, allergic and autoimmune diseases. Chronic infection and inflammatory disorders as well as immunodeficiencies are often associated with decline and/or dysfunction of MAIT cells. Herein, we investigate the MAIT cells in patients with idiopathic CD4 + lymphocytopenia (ICL), a syndrome characterized by consistently low CD4 T-cell counts (<300 cell/µL) in the absence of HIV infection or other known immunodeficiency, and by susceptibility to certain opportunistic infections. The numbers, phenotype and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Furthermore, administration of IL-7 to ICL patients expanded the CD8 + MAIT cell subset, with maintained responsiveness and effector functions after IL-7 treatment. In conclusion, ICL patients maintain normal levels and function of MAIT cells preserving some antibacterial responses despite the deficiency in CD4 + T cells.

“Borderline” idiopathic CD4+ T-cell lymphocytopenia presenting with atypical progressive multifocal leukoencephalopathy

Idiopathic CD4+ lymphocytopenia (ICL) is a rare disorder characterized by low counts of CD4+ cells (<300/mm3) in absence of other known causes of immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) were reported in association with ICL with variable outcome. We describe the case of a 40 year-old man diagnosed with PML, which showed a monophasic course. Causes of primary and secondary immunodeficiency were ruled out, only a “borderline” ICL was found. This case highlights that a severe immunodepression could not be an absolute prerequisite in developing PML and also points the attention on current definition of ICL.