Disseminated coinfection with Mycobacterium Avium complex and Mycobacterium Kansasii in a patient with idiopathic CD4+ lymphocytopenia: A case report.

Simultaneously disseminated coinfection with two species of nontuberculous mycobacteria (NTM) is extremely rare and had been reported only in immunocompromised individuals. Here, we report a 59-year-old Thai man, previously healthy. He presented with a 2-month history of prolonged fever, constitutional symptoms, and hepatosplenomegaly. His chest and abdomen computed tomography illustrated multiple enlarged mediastinal lymph nodes accompanied with multifocal crazy-paving appearance in both lungs and hepatosplenomegaly. Endobronchial ultrasound-guided transbronchial needle aspiration was performed on the mediastinal nodes. The pathologic findings were necrotizing granulomatous lymphadenitis with numerous AFB-positive bacilli. Blood culture subsequently isolated M. intracellulare, while BAL and lymph node culture isolated M. intracellulare and M. kansasii, which confirmed species by multiplex PCR and 16s rRNA sequencing. Idiopathic CD4+ lymphocytopenia (ICL) was diagnosed as the cause of secondary immune deficiency. Intravenous imipenem, amikacin, and azithromycin were administered as an empirical antibiotic regimen for 4 weeks, then substituted to oral rifampicin, clarithromycin, moxifloxacin, and ethambutol as definitive regimen. Unfortunately, it was found that he had died unexpectedly at home after 4 months of treatment, possibly related to this illness. In our view, patients with severe disseminated NTM disease should be evaluated to explore a secondary immune deficiency disorder. An ICL is a rare heterogenous syndrome but should be considered.

Preserved Mucosal-Associated Invariant T-Cell Numbers and Function in Idiopathic CD4 Lymphocytopenia.

BACKGROUND: 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. METHODS: We investigated 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. RESULTS: The numbers, phenotype, and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Administration of interleukin-7 (IL-7) to ICL patients expanded the CD8+ MAIT-cell subset, with maintained responsiveness and effector functions after IL-7 treatment. CONCLUSIONS: ICL patients maintain normal levels and function of MAIT cells, preserving some antibacterial responses despite the deficiency in CD4+ T cells. CLINICAL TRIALS REGISTRATION: NCT00867269.

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

OBJECTIVE: Characterize 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. METHODS: Single-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. RESULTS: 54% 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. CONCLUSIONS: Evidence of autoimmunity, including autoimmune diseases, is more prevalent in ICL than the general population, and should be considered part of this syndrome.

Successful Cord Blood Transplantation for Idiopathic CD4+ Lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.

"Burnt-out" progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia.

Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by John Cunningham virus (JCV) infection; however, a growing number of PML patients now survive longer and achieve remission, largely due to the advent of combination antiretroviral therapy. Several reports have suggested that the pathology in such patients presents only chronic demyelination without characteristic cellular changes, being referred to as "burnt-out" PML. On the other hand, our knowledge of "burnt-out" PML is still substantially limited, especially in patients with non-human immunodeficiency virus infection. Here, we report a case of PML associated with idiopathic CD4+ lymphocytopenia (ICL) who presented with spontaneous remission and survived for 11 years after onset. Notably, postmortem examination revealed surprisingly broad "burnt-out" lesions lacking the classic histopathological findings. However, pathogenic JCV-specific DNA sequences was still present in the autopsied brain tissue. This case suggests that complete remission can be achieved with a persistent presence of JCV-specific pathogenic sequences, even after a catastrophic infection. Considering that there have been a few reported cases of PML with ICL with long survival, the long-term survival of our case may share a favorable immunological response that is unique to a subgroup of ICL.

Disseminated cryptococcosis with granuloma formation in idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphocytopenia (ICL) is a rare disease characterized by marked loss of CD4 T-cells without human immunodeficiency virus infection. CD4 T-cells play an important role in granuloma formation in cryptococcal infection. Thus far, among ICL patients, it has not been concluded definitely whether granuloma is formed or not. We report the case of a 39-year-old woman with ICL and disseminated cryptococcal infection with granuloma formation. She was referred to our department because of a lung mass, osteolytic lesion, and a subcutaneous mass identified on a computed tomography scan, and an elevated C-reactive protein level. Cryptococcus neoformans was isolated from the tissues. She also had marked CD4 lymphocytopenia (33 cells/µL), without human immunodeficiency virus infection. In a biopsy specimen of the lung mass, granulomas containing CD4 T-cells were observed. The cryptococcosis was treated with liposomal amphotericin B followed by fluconazole and she was found to be cured. The CD4 T-cell count was persistently low. This case showed that granulomas containing CD4 T-cells can be formed in ICL patients with cryptococcal infection despite very low CD4 T-cell counts.

Progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia: A case report and review of literature.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by polyoma virus (JC virus) infection. PML usually occurs in a setting of severe immunosuppression and is most commonly associated with human immunodeficiency virus (HIV) infection. Idiopathic CD4+ lymphocytopenia is a very rare cause of PML and only a few cases have been reported in the literature. We present a case of a 45-year-old man who presented with behavioral alteration followed by progressive weakness of right side of the body. Contrast-enhanced magnetic resonance imaging of the brain revealed confluent irregular areas of T2-weighted/fluid-attenuated inversion recovery hyperintensities in left frontoparietal and right temporoparietal regions. His hematological work up showed a decreased absolute CD4+ count of 217 per microliter, but was negative for HIV serology. Keeping a differential diagnoses of central nervous system lymphoma, brain biopsy was performed. Histopathology revealed demyelination with presence of intranuclear inclusions in the oligodendrocytes, which were positive for SV40 immunostain. Adjacent areas showed reactive gliosis with hypertrophic astrocytes, hence a diagnosis of PML was made. The patient died due to aspiration pneumonia. PML can occur very rarely in association with idiopathic CD4+ lymphocytopenia in the absence of other immunosuppressive illnesses. This report highlights the importance of high index of clinical suspicion and need for a careful histological examination for diagnosis of PML to facilitate adequate patient management.

Progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia.

Progressive multifocal leukoencephalopathy is a central nervous system demyelinating disease caused by infection with John Cunningham virus. It affects predominantly the subcortical white matter, producing progressive neurological deficits and large confluent white matter lesions on imaging. It is usually seen in immunodeficient individuals, such as those suffering from acquired immunodeficiency syndrome, those on treatment with monoclonal antibodies, and those following therapeutic bone marrow suppression. Here, we report a rare case of progressive multifocal leukoencephalopathy in an apparently immunocompetent adult, who was found to have idiopathic CD4 lymphocytopenia upon further investigation.

Clinically HIV but negative serology: Think of idiopathic CD4(+) lymphocytopenia.

idiopathic CD4(+) lymphocytopenia (ICL) is a rare disorder characterized by the presence of depleted CD4 cell line without the presence of HIV infection. Slight male preponderance is noticed and is usually seen in the middle age group. Opportunistic infections are the reason for their discovery and here we describe a case where a man was diagnosed as having Pneumocystis jiroveci pneumonia and oral candidiasis.

Idiopathic CD4 Lymphocytopenia: A Case Report and Literature Review.

Idiopathic CD4 lymphocytopenia (ICL) is a rare condition where CD4 T cell counts are low, similar to advanced human immunodeficiency virus (HIV) infection but without acquired immunodeficiency syndrome (AIDS)-related symptoms. The cause is unknown, and theories suggest issues with T cell production, survival, migration, or immune system dysregulation. Diagnosis involves ruling out other causes of low CD4 T cells. Treatment is based on managing infections and may include immunomodulatory therapies, but evidence is limited. Clinical presentations vary widely, including infections, autoimmune disorders, and malignancies. This study explores challenges in diagnosing persistent fevers and lymphopenia, the role of medical history in treatment, HIV screening issues, UTI management in recurrent cases, and the importance of follow-up care for unresolved symptoms or abnormal lab results. This study utilized a case study approach, focusing on the detailed presentation, evaluation, and management of the patient. Data were collected from the patient's medical records, including laboratory tests. Relevant literature was reviewed to provide context and support for the discussion of diagnostic challenges and management strategies. This case highlights the importance of considering uncommon presentations of common infections in patients with complex medical histories. It underscores the need for thorough evaluation, including comprehensive medical history, diagnostic testing, and follow-up care, to ensure accurate diagnosis and appropriate management. By sharing this case, we aim to enhance the awareness and understanding of such presentations among healthcare providers, leading to improved patient care and outcomes.

Acute Cryptococcal Meningitis in a Patient With Idiopathic CD4 Lymphocytopenia: A Rare Clinical Entity.

Cryptococcal meningitis is a known cause of opportunistic infection in immunocompromised patients, especially those with AIDS. Very few cases exist in literature where cryptococcal meningitis is seen in patients without evidence of HIV infection. Here, we describe a case of an elderly woman presenting with clinical features of meningitis. Our patient tested positive for cryptococcal antigen (CRAg) in the CSF and growth of Cryptococcus neoformans was obtained in CSF culture. Further laboratory investigations revealed CD4 lymphocytopenia (233 cells/µl) in the absence of HIV infection. When we checked the CD4 count, beyond a period of six weeks, it was reported to be low, which confirmed our diagnosis of idiopathic CD4 lymphocytopenia (ICL). She was successfully treated with amphotericin B along with flucytosine for two weeks and discharged on maintenance antifungal therapy for eight weeks. This case emphasizes the need to maintain a high index of suspicion and consider the possibility of opportunistic infections even in the absence of HIV infection for timely diagnosis and treatment.

Progressive disseminated histoplasmosis in idiopathic CD4 lymphocytopenia an underdiagnosed combination - a case report.

Progressive disseminated histoplasmosis (PDH) usually presents as fever, anemia, leukopenia, hepatosplenomegaly, lymphadenopathy and pulmonary symptoms. There are few reports on the association of idiopathic CD4 lymphocytopenia (ICL) with histoplasmosis. We describe a 65-year-old female presented with a history of fever, papulo-nodular rash and significant weight loss and diagnosed as progressive disseminated histoplasmosis. All immunocompromised conditions were ruled out. In addition, her 2 consecutive CD4 counts were below 300. The patient was diagnosed with PDH associated with ICL. The patient showed significant improvement with liposomal amphotericin B and itraconazole. Absolute CD4 counts should be done in all cases of progressive disseminated histoplasmosis even in HIV negative individuals to rule out associated ICL.

Disseminated Histoplasmosis Involving Soft Palate, Duodenum, Sigmoid Colon and Bone Marrow in a Patient With Isolated CD4+ T-Lymphocytopenia.

Idiopathic CD4 T-lymphocytopenia (ICL) is a rare entity that is associated with decreased immunity which predisposes affected individuals to opportunistic infections and malignancies. Autoimmune conditions are common in patients with ICL and they are considered part of its clinical spectrum as well. Treatment of ICL includes treatment of opportunistic infections and prophylaxis against them. Some cases are self-limited while others require long-term monitoring. We present a case of a 60-year-old man who was diagnosed with disseminated histoplasmosis involving soft palate, duodenum, colon and bone marrow in the setting of idiopathic CD4 T-lymphocytopenia.

Idiopathic CD4+ Lymphocytopenia Due to Homozygous Loss of the CD4 Start Codon.

Idiopathic CD4+ lymphocytopenia (ICL) is an extremely rare condition characterized by low numbers of CD4+ cells (<0.3 K/µL) without human immunodeficiency virus (HIV) infection or any other cause of immunodeficiency. In this case report, we report a case of idiopathic CD4+ lymphocytopenia in a 22-year-old woman initially presenting with insomnia, fatigue, and a sore throat. However, this rapidly progressed to shortness of breath and chest pain, ultimately leading to acute respiratory distress syndrome (ARDS) over the span of a few days. Broad-spectrum antimicrobials were administered, resulting in prompt recovery. Serological studies were negative for malignancy and severe infections, including HIV1 and HIV2. Flow cytometry revealed an absence of CD4+ cells and an increase in double-negative T-cells. Further genetic workup revealed that in the second exon of the CD4 gene, the patient had a homozygous c.1ATG>GTG (p.Met1Val; p.M1V) mutation. Family screening showed that the patient's mother, father, and brother all had a single p.M1V mutation, allowing for deleterious effects to be partially offset by the normal copy of the gene. We have provided an organized analysis of the existing literature in addition to a concise overview of this case, with the intention of identifying patterns in presentation, clinical course, and outcomes. This case discusses the effects of the loss of the CD4+ start codon in the patient. Although this specific form of lymphocytopenia is very uncommon, it illustrates the importance of genetic testing and the integral nature of laboratory testing in therapy charting.

MR Target Sign in Cerebral Aspergillosis.

Magnetic resonance (MR) is an effective imaging modality in the evaluation of infectious brain disease, yet findings are often nonspecific. The presence of a diagnostic feature can facilitate early treatment, particularly where mortality is high. We highlight MR apparent diffusion coefficient/T2-weighted target sign in the diagnosis of cerebral aspergillosis.

Evaluation of cellular and humoral autoimmunity before the development of type 1 diabetes in a patient with idiopathic CD4 lymphocytopenia.

A 64-year-old woman developed type 1 diabetes 23 years after the diagnosis of idiopathic CD4 lymphocytopenia. To investigate the etiological interaction between idiopathic CD4 lymphocytopenia and type 1 diabetes, we carried out a longitudinal analysis related to islet-specific autoimmunity. Anti-glutamic acid decarboxylase antibody had been already weakly positive for at least 16 years and started rising at 6 months before the onset of type 1 diabetes. The seroconversion of anti-insulinoma-associated antigen-2 antibody and insulin autoantibody occurred at the time of onset. The ratio of CD8/CD4 had been gradually increasing for 8 years before type 1 diabetes onset. Notably, islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD8+ T cells were detected at type 1 diabetes onset, and the frequency was higher than that in 15 non-diabetic controls (6.75% vs 0.49 ± 0.78%, mean ± SD). The present type 1 diabetes patient, presented with idiopathic CD4 lymphocytopenia and showed an elevated number of CD8+ T cells, including the islet antigen-specific CD8+ T cells that might contribute to autoimmune destruction of pancreatic ß-cells.

Complete Multilineage CD4 Expression Defect Associated With Warts Due to an Inherited Homozygous CD4 Gene Mutation.

Idiopathic T-CD4 lymphocytopenia (ICL) is a rare and heterogeneous syndrome characterized by opportunistic infections due to reduced CD4 T-lymphocytes (<300 cells/µl or <20% T-cells) in the absence of HIV infection and other primary causes of lymphopenia. Molecular testing of ICL has revealed defects in genes not specific to CD4 T-cells, with pleiotropic effects on other cell types. Here we report for the first time an absolute CD4 lymphocytopenia (<0.01 CD4+ T-cells/µl) due to an autosomal recessive CD4 gene mutation that completely abrogates CD4 protein expression on the surface membrane of T-cells, monocytes, and dendritic cells. A 45-year-old female born to consanguineous parents consulted because of exuberant, relapsing, and treatment-refractory warts on her hands and feet since the age of 10 years, in the absence of other recurrent infections or symptoms. Serological studies were negative for severe infections, including HIV 1/2, HTLV-1, and syphilis, but positive for CMV and EBV. Blood analysis showed the absence of CD4+ T-cells (<0.01%) with repeatedly increased counts of B-cells, naïve CD8+ T-lymphocytes, and particularly, CD4/CD8 double-negative (DN) TCRαß+ TCRγδ- T-cells (30% of T-cells; 400 cells/µl). Flow cytometric staining of CD4 using monoclonal antibodies directed against five different epitopes, located in two different domains of the protein, confirmed no cell surface membrane or intracytoplasmic expression of CD4 on T-cells, monocytes, and dendritic cells but normal soluble CD4 plasma levels. DN T-cells showed a phenotypic and functional profile similar to normal CD4+ T-cells as regards expression of maturation markers, T-helper and T-regulatory chemokine receptors, TCRvß repertoire, and in vitro cytokine production against polyclonal and antigen-specific stimuli. Sequencing of the CD4 gene revealed a homozygous (splicing) mutation affecting the last bp on intron 7-8, leading to deletion of the juxtamembrane and intracellular domains of the protein and complete abrogation of CD4 expression on the cell membrane. These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling and point out the need for better understanding the role of CD4 on thymic selection and the immune response.

Difficult to Treat Recurrent Pyogenic Cholangitis With Portal Pylephlebitis in the Setting of Idiopathic CD4+ Lymphocytopaenia.

Recurrent pyogenic cholangitis (RPC) is a disease characterized by multiple strictures of the biliary tree, impaired biliary drainage, formation of intrahepatic biliary pigment stones and recurrent bouts of cholangitis. We report the case of a 39-year-old businessman with diagnosed chronic calcific pancreatitis, who presented to us with recurrent episodes of cholangitis, leading to portal pyaemia, and progressive liver failure, which could not be controlled despite adequate biliary drainage. The patient rapidly developed progressive liver failure and sepsis-related coagulation failure. He was also found to have idiopathic CD4+ T cell lymphocytopenia (ICL), which resulted in refractory sepsis and formation of metastatic abscesses in the lung and spleen. ICL is now recognised in patients with recurrent and difficult to treat opportunistic infections. The combination of RPC, sepsis and liver failure in the setting of an acquired immunosuppressed state makes this a unique management scenario.

[Idiopathic CD4-positive lymphocytopenia-associated progressive multifocal leukoencephalopathy confirmed by brain biopsy following negative results of repeated CSF-JC-virus tests: a case report].

A 75-year-old man presented with dysarthria and left facial paralysis. Brain diffusion-weighted MRI revealed a high-signal intensity in the right precentral gyrus, and he was hospitalized under the diagnosis of cerebral infarction. His symptoms worsened and brain MRI findings were consistent with progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) JC virus (JCV) was undetectable in the DNA polymerase chain reaction (PCR) test four times, but brain biopsy revealed typical PML histopathology. He had no human immunodeficiency virus infection and history of immunosuppressive treatment, but he was found to have CD4+ lymphocytopenia. He was treated with mefloquine and mirtazapine, and died 29 months after symptoms onset. In cases whose repeated DNA PCR results are negative for CSF JCV, brain biopsy may be useful for the diagnosis of PML.