Immunodeficiency Research Articles

Cat scratch disease in children with nocturnal fever: A case report

BACKGROUND Cat scratch disease (CSD) is the most common human infection caused by Bartonella henselae (B. henselae ). The main manifestation is self-limited lymphadenopathy that primarily affects adolescents, and typically resolves without treatment within 2-4 months. However, individuals with compromised immune systems or immunodeficiency require specific antibacterial therapy following diagnosis. Due to its low incidence, nonspecific clinical manifestations, and diagnostic limitations, this condition often poses challenges for clinicians in terms of missed diagnoses and misdiagnoses. CASE SUMMARY The child was ultimately diagnosed with CSD. The primary manifestations included nocturnal fever, enlargement of lymph nodes in the neck, axilla and groin, and suspected brucellosis; however, both brucellosis tests conducted during the course of the illness yielded negative results. Bone marrow cytology indicated stimulated proliferation. Lymph node biopsy indicated hyperplasia of lymphoid tissue in the cervical lymph nodes (right), with combined immunohistochemical findings indicating reactive hyperplasia. Immunohistochemical analysis revealed CD20 B (+), CD3 T (+), BCL-6 (+), and BCL-2 (). CD21 FDC networks were present and Ki67 expression in the germinal center was ~80%. Blood next-generation sequencing indicated B. henselae sequence number was 3. Serological test results demonstrated positive antibody response to B. henselae IgG (+), B. henselae IgM (+), Bartonella quintana (B. quintana ) IgG () and B. quintana IgM (), and the final diagnosis was CSD. CONCLUSION In patients presenting with fever at night and swollen lymph nodes of unknown origin, CSD should be considered.

Agaricus bisporus mannose-binding protein stimulates the innate immune cells

Purpose: A lectin-like protein from the mushroom Agaricus bisporus has been shown to slightly increase the proliferation of RAW 264.7 cells. Following its identification as a mannose-binding lectin, henceforth called A. bisporus mannose-binding protein (Abmb), the protein is hypothesized to stimulate the innate immune cells response. The present work was aimed to substantiate that hypothesis. Furthermore, this study complements Abmb exploration as a potential agent for anti-breast cancer, which its treatment is hampered with compromised immunity of patient receiving chemotherapy. Method: Abmb’s effect on the phagocytic activity of the macrophage was measured with FACS. Nitric oxide production was checked using Griess test while expression of the cytokines in the RAW 264.7 cells was analysed at gene and protein level using PCR and FACS, respectively. Abmb’s effect on the expression of surface markers of the human immune cells in the peripheral blood mononuclear cells was checked with specific antibodies for targeted cluster differentiation and analysed using FACS. Result: Abmb increased the phagocytic activity of the macrophage and NO production. Abmb increased the expression of cytokines i.e. tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10. With the peripheral blood mononuclear cells, Abmb activated dendritic and Natural Killer cells, but not the B- or T-cells. Conclusion: Abmb increased the activity of the macrophage cells and activated the immune cells that are related to the innate immune system, particularly the cellular immunity.

The effective multiplicity of infection for HCMV depends on the activity of the cellular 20S proteasome.

Human cytomegalovirus (HCMV) is a betaherpesvirus capable of infecting numerous cell types and persisting throughout an infected individual's life. Disease usually occurs in individuals with compromised or underdeveloped immune systems. Several antivirals exist but have limitations relating to toxicity and resistance. HCMV replication involves upregulation of host proteasomal activities, which play important roles in the temporal stages of replication. Here, we defined the impact on replication kinetics of the proteasome inhibitor, bortezomib. We demonstrate that bortezomib significantly reduces levels of viral genomes and infectious virions produced from a population of cells. Inhibition reduced expression of viral proteins that are influenced by genome synthesis. When added prior to 24 hpi, we observe decreases in PCNA and Cdk1 while increases in p21 whose regulations contribute to efficient replication. This response synergized with an antiviral, maribavir. Since some replication occurred, we tested the hypothesis that a subset of infected cells might break through inhibition. Initially, we simulated bortezomib activities using a mechanistic computational model of late-lytic replication. Upon reducing multiplicity of infection (MOI) in silico, we observed near-identical simulated results compared to experimental data. Next, we analyzed replication using live-cell imaging. This revealed treated cultures do contain a population of cells with fully developed late-stage cytoplasmic assembly compartments but at significantly lower numbers. We refer to this as the effective MOI. Overall, our studies support a hypothesis in which 20S proteasome inhibition disrupts HCMV replication by reducing the MOI to an effective MOI, defined by a fraction of infected cells capable of progressing to fulminant infection.IMPORTANCEHuman cytomegalovirus (HCMV) infection and reactivation continues to contribute to morbidity and mortality around the world. Antiviral compounds are available but have limitations. Here, we have defined the impact of the proteasome inhibitor bortezomib on HCMV replication. Proteasomal activities play a critical role in temporal changes required for replication. We demonstrate that disrupting these activities inhibits viral replication while likely supporting increased antiviral activity of the anti-HCMV agent, maribavir. Using a combination of live-cell imaging and computational tools, we discover that a subset of infected cells progresses to fulminant infection, which we define as the effective multiplicity of infection, and this subset would otherwise be missed when analyzing the average of the population.

Infections: A Concern for Patients with Multiple Myeloma

Multiple myeloma is an incurable but highly treatable hematologic malignancy characterized by varying degrees of disease- and treatment-related secondary immunodeficiency, which predisposes patients to infection, a major cause of morbidity and mortality.

Lung diseases in adult patients with primary immunodeficiencies with defects of antibody production according to real clinical practice

Introduction. The problem of lung diseases in patients with primary defects in antibody production has not been sufficiently studied, especially depending on the climatic, geographical and demographic conditions of real clinical practice.Aim. To study the structure of lung disorders in adult patients with primary antibodies defects in the Middle Urals in real clinical practice.Materials and methods. Register of adult patients with primary immunodeficiencies (PID) were created in 2013 in the Sverdlovsk region. Now it contains 209 people. The main group of the register is patients with primary antibodies defects (PAD, n = 143, 68.4%: agammaglobulinemia (AGG, n = 11, common variable immune deficiency (CVID, n = 37), PIK3-Kinase deficiency (n = 3), Selective IgA deficiency (SD IgA, n = 92). The diagnosis of PID was established on the criteria for the Russian Association of Allergists and Clinical Immunologists and European Societies of Immunodeficencies, in some cases it has a genetic confirmation. We used medical history of patients, radiological, functional studies to establish lung lesions. We occurred immunological examination for all PID patients.Results. Repeated pneumonia were observed in all patients with AGG and CVID, especially in the onset of PID. Patients also had diseases such as bronchiectasis (up to 37.6% of patients), chronic obstructive lung disease (up to 70.3% of patients), bronchial asthma (only SD IgA), interstitial lung disease (only CVID).Conclusion. According to our data, in the Middle Urals, lung diseases, especially pneumonia and bronchiectasis, are the most common clinical manifestations in patients with DA. Analysis of immunoglobulins' level is necessary in patients with repeated pneumonia, bronchiectasis and interstitial lung disease, bronchial asthma and early onset of chronic obstructive lung disease without smoking status.

Using Deep Learning Techniques to Enhance Blood Cell Detection in Patients with Leukemia

Medical diagnosis plays a critical role in the early detection and treatment of diseases by examining symptoms and supporting findings through advanced laboratory testing. Early and accurate diagnosis is essential for detecting medical problems and then prescribing the most effective treatment strategies, especially in life-threatening diseases such as leukemia. Leukemia, a blood malignancy, is one of the most prevalent cancer types affecting both adults and children. It is caused by the rapid and uncontrolled growth of abnormal white blood cells in the bone marrow. This accumulation interferes with the production of normal blood cells, leading to a weakened immune deficiency, anemia, and bleeding disorders. Conventional leukemia diagnostic methods are time-consuming, manually intensive, and inefficient. This research study proposes an automatic diagnostics prediction of leukemia by analyzing blood images according to the shape of the blast cells using digital image processing and machine learning. The purpose of blood cell detection is to precisely identify and classify diverse blood cells, detecting anomalies associated with blood cancers like leukemia. This supports early diagnosis and monitoring, which leads to more effective treatments and improved results for cancer patients. To accomplish this task, we use digital image processing techniques and then apply the convolutional neural network (CNN) deep learning algorithm to blood sample images. This research employs a multi-stage methodology, including data preparation, data preprocessing, feature extraction, and then classification. While our model is built on a typical CNN architecture, we make significant advances by using preprocessing techniques and hyperparameter tuning. We have modified its layers combination to include convolutional, pooling, and fully connected layers that are optimized for image characteristics. These layers are fine-tuned for better feature extraction and classification accuracy. This study showed that blood cell detection for diagnosing acute leukemia based on images had 99% accuracy and outperformed other advanced models, including DenseNet121, ResNet-50, Incep-tionv3, MobileNet, and EfficientNet. The comprehensive analysis of the results reveals the highest accuracy of leukemia detection as compared to existing studies in the relevant literature.

TUBERCULOSE EXTRAPULMONAR: UMA REVISÃO DE LITERATURA

Tuberculosis (TB) is an infectious disease with very ancient records in the history of civilization and has a natural course that is well described in medicine. It is an infection that mainly affects the respiratory tract, but can affect other organs of the body, even simultaneously. When TB occurs in organ systems other than the lungs, it is called extrapulmonary TB (EPTB). Various forms of EBTB are described in the literature, all with a higher incidence in individuals with a compromised immune system. The diagnosis of forms of EPTB depends on the identification of the etiological agent in infected tissue samples and has become simpler with the advent of nucleic acid amplification tests (NAATs). Drugs for treating TB include bactericidal and bacteriostatic drugs in a directly offered and regular treatment regimen for a prolonged period. It is necessary to strengthen PHC in all areas for adequate control of TB - greater access to technologies that facilitate and make diagnosis faster and greater empowerment in the population's health regarding prevention and greater adherence to treatment.

Management of Secondary Immunodeficiency Following T-Cell-Engaging Immunotherapeutic Agents in B-Cell Non-Hodgkin Lymphoma: Implications for Early-Line Treatment Strategies

Anti-CD19 chimeric antigen receptor (CAR) T-cell and anti-CD20 bispecific antibody therapies (BsAbs) are rapidly moving to earlier treatment lines for patients with B-cell non-Hodgkin lymphoma (B-NHL). The rapid pace of the advancement of these T-cell-engaging therapies is juxtaposed by a lack of a comprehensive understanding of the scope and kinetics of immunodeficiency following these treatments. We review emerging studies detailing the safety and efficacy of CD19 CAR-T and CD20 BsAbs in earlier lines for B-NHL, as well as a discussion of the limited knowledge of immune recovery following these treatments. We integrate the limited consensus prevention and management recommendations, advocating that the management of secondary immunodeficiency following these transformative therapies is an urgent unmet need in immune oncology research. A collaboration between hematologists/oncologists and immunologists in the management of these patients is critical to optimize patient care.

The gut microbiota-independent virulence of noninvasive bacterial pathogen Citrobacter rodentium.

Attaching and effacing (A/E) bacterial pathogens consist of human pathogens enteropathogenic Escherichia coli, enterohemorrhagic E. coli and their murine equivalent Citrobacter rodentium (CR). Emerging evidence suggests that the complex pathogen-microbiota-host interactions are critical in conferring A/E pathogen infection-induced severe symptoms and lethality in immunocompromised hosts; however, the precise underlying mechanisms remain enigmatic. Here we report that CR infection causes severe colitis and mortality in interleukin 22 knockout (Il22-/-) and Rag1 knockout (Rag1-/-) mice under germ-free (GF) conditions. In a gut microbiota-independent manner, CR colonizes in GF Il22-/- and Rag1-/- animals, triggers colonic epithelial tissue damage and systemic dissemination of CR, and results in lethal infections. Pretreatment with cefoxitin, a broad-spectrum antibiotic, exacerbates CR-induced colitis and lethality in specific-pathogen-free (SPF) Il22-/- and Rag1-/- mice. Together our results reveal that CR possesses a gut microbiota-independent virulence, which is better illustrated during infections in immunocompromised hosts associated with severe outcomes.

Chronic Neutrophilic Meningitis in Tuberculous Infection: A Rare Case Presentation and review of the literature

Persistent neutrophilic pleocytosis syndrome is a rare form of tuberculous meningitis that is defined as the persistence of neutrophils in cerebrospinal fluid for more than 7 days, in association with the clinical features of meningitis (headache, fever, and positive meningeal signs).1 The exact pathogenesis of this syndrome is not well known yet, and it has many diverse etiologies, including infectious and noninfectious ones. among infectious ones: bacteria such as Nocardia and Actinomyces, and systemic mycoses such as Aspergillus and the zygomycetes, as well as mycobacterium.2 This entity is very rare in immunocompetent patients, and most of the cases are due to infectious causes in those who are immunocompromised. The usual scenario in such cases is initiating broad-spectrum antimicrobial agents without any improvement, therefore the diagnosis is difficult initially and often delayed. Therefore, the epidemiologic features and clinical profile may offer clues to the etiologic agent, especially in the immunocompromised host.3

HIV-TB Coinfection: A Systemic Review and Meta-analysis Insights

HIV and Tuberculosis (TB) are the leading global causes of death among patients with infectious diseases. They contribute significantly to morbidity around the world because of their impact on shared immune defense mechanisms. Tuberculosis is an infection that exploits the vulnerability of compromised immune systems. Opportunistic infections are illnesses that are more frequent or severe in individuals with compromised immune systems. HIV weakens the immune system, making people more susceptible to tuberculosis. When someone is infected with both HIV and tuberculosis, this is known as HIV/TB coinfection. HIV and tuberculosis represent the primary infectious disease challenges in countries with limited resources. In affected individuals, the interaction between Mycobacterium tuberculosis and HIV exacerbates the effects of each other, hastening the decline of immune function and leading to premature mortality if left untreated. Individuals with HIV are more likely than those without HIV to develop active tuberculosis as a result of untreated latent tuberculosis. Antiretroviral therapy (ART) is the use of HIV medications to protect the immune system and prevent the progression of HIV to acquired immunodeficiency syndrome (AIDS). In people with HIV and latent tuberculosis, combined treatment with HIV and TB medications reduces the likelihood of latent tuberculosis progressing to active tuberculosis. The purpose of this research is to understand better the pathogenesis and pathways of HIV/TB co-infection, as well as to investigate drug-drug interactions in multi-drug therapies.

Empowering a Limpopo rural community to Integrate Ubuntu in caring for PLWHIV/AIDS or TB.

Globally, few studies were conducted mostly in Africa on Ubuntu and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). These studies did not incorporate empowering communities on integrating Ubuntu HIV/AIDS or tuberculosis (TB). As such, this study used empowerment as a tool to raise awareness in the community about how they can integrate Ubuntu when caring for people living with HIV (PLWHIV)/AIDS or TB. This study aimed to empower community members to use Ubuntu philosophy when caring for PLWHIV/AIDS or TB in the rural community of Limpopo province. An integrative qualitative research design was used in which data were collected through a workshop with participants. The population was unemployed matriculants, traditional health professionals and community healthcare workers who were purposefully sampled and divided into eight groups. Data were collected through a focus group discussion and analysed using content analysis. Ethical considerations and measures to ensure trustworthiness were followed. Integrating Ubuntu philosophy can reduce stigma, discrimination and lack of disclosure. This might be achieved through humanity, attitude changing and formation of a support group. The principles of Ubuntu (caring, sharing, support, humility, attitude change) came up strongly in preventing stigma and discrimination in the care of PLWHIV/AIDS or TB.Contribution:Community empowerment and integration of Ubuntu philosophical values might have a positive impact on improving the social status of PLWHIV or TB, their families and the community at large.

Opportunities and Regulatory Challenges of Functional Foods and Nutraceuticals During COVID-19 Pandemic

: The novel Coronavirus has brought global mortality, disruption, and a significant loss of life. A compromised immune system is a known risk factor for all viral influenza infections. Due to the perceived “immune-boosting” properties of nutraceutical products, sales of dietary supplements have grown globally. In recent years, consumers have increasingly demanded nutraceutical products rather than curative synthetic medicines for preventive therapies for the coronavirus disease outbreak of 2019 (COVID-19). Healthy foods and nutraceuticals have become daily diet plans for consumers. Although there has been an increase in demand, there is no such regulation and harmonized process, which stands as a barrier to the approval of these products. Therefore, many misbranded and spurious products are entering the market, which may harm consumers. This article focuses on the role of functional foods and nutraceutical in the management of COVID-19 also focuses on the different nutraceutical regulations in each country and compare the similarities and differences of the following countries: India, the USA (United States of America), the EU (European Union), and China. The comparative study of nutraceutical regulations in India, the USA, Europe, and China shows that there is a difference regarding the nutraceutical regulations; however, despite the differences, it is observed that it has the same underlying objective, i.e., ensuring the safety of the consumers by maintaining the product quality.

Spatio-temporal analysis of pulmonary tuberculosis in Astambul District, South Kalimantan, Indonesia 2020-2021

Respiratory tuberculosis (TB) remains a significant global health concern and ranks among the top 10 leading causes of death worldwide, following human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Globally, it is estimated that 1.2 billion people are at risk of being infected with tuberculosis, and Indonesia is the country that contributes the third-highest number of TB cases worldwide, behind China and India. Tuberculosis is still a significant issue in South Kalimantan, notably in Banjar Regency. This study is a descriptive study that intends to identify respiratory TB clusters spatially and temporally in Astambul District during 2020–2021 with the SatScan application, which is visualized as a map of respiratory TB clusters using the Quantum GIS 3.28 application. Data on respiratory TB cases collected from the Banjar District Health Office were examined using retrospective space-time scan statistics, employing a Poisson probability model for analysis. This study found 4 respiratory TB clusters, and 2 of them had significant results, namely in 2020 (RR=6.90, p-value=0.000030) and 2021 (RR=5.27, p-value=0.00003). Factors that affect these clusters are population density, the physical condition of houses, humidity levels, and the availability of health facilities.

A likely pathogenic homozygous frameshift variant in BLOC1S6 associated with a rare form of congenital Hermansky-Pudlak syndrome 9

Hermansky-Pudlak syndrome (HPS) is a collection of autosomal recessive multisystemic disorders with at least 11 different types, categorized on the basis of involved genes. The disease is mostly characterized by tyrosinase-positive oculocutaneous albinism (OCA), platelet storage deficiency, absence of platelet dense bodies, and immune deficiency. Here we described a 2-month-old female infant with generalized hypotonia, recurrent infections, bilateral optic atrophy, nystagmus, cerebral atrophy, and elevated liver enzymes. Unlike her parents, she had chestnut colored hair, fair skin, and brown eyes. Parents had a consanguineous marriage, and their first child had died with similar symptoms at the age of 5 months. Whole exome sequencing (WES) was performed on DNA extracted from the patient's peripheral blood. Following the bioinformatics analysis, a likely pathogenic novel variant in the fifth exon of the BLOC1S6 gene (NM_001311255: c.506dupT: p. L169Ffs*33) was introduced by the Sadra Medical Genetic Laboratory. This variant was confirmed in the patient and segregated in both parents by Sanger sequencing.This report presented the first congenital case of HPS-9 worldwide that might have led to early neonatal death. Our current patient shows new considerable features related to the BLOC1S6 gene variant and HPS-9, which is a valuable source for future research, prediction, clinical management, genetic counseling, and prenatal diagnosing.

Mpox Keratouveitis: A Clinical Analysis of Host Immune Responses

Purpose: To describe 2 patients with mpox keratouveitis and evaluate their contrasting clinical phenotypes in the context of baseline immune function. Methods: Both patients were subject to longitudinal care by providers at our institution. Qualitative polymerase chain reaction (PCR) analysis was used to confirm their diagnoses, and interval slit-lamp photography was used to document their clinical progression. For case 2, histologic analysis was performed on a corneal biopsy specimen. Results: Case 1 describes a 31-year-old immunocompetent man with cutaneous mpox who developed a unilateral keratouveitis after a cutaneous lesion of the ipsilateral eyelid. His keratitis resolved over 1 week with application of trifluridine eye drops. An anterior uveitis persisted but resolved by 2 weeks after treatment with topical prednisolone and oral tecovirimat. Case 2 describes a 27-year-old man with HIV and a declining CD4+ count who was coinfected with monkeypox virus. Over 3 months, he developed a progressive unilateral keratouveitis that resulted in corneal melt requiring tectonic keratoplasty to preserve globe integrity. On histology, the patient's corneal biopsy specimen was devoid of lymphocytes. Conclusions: Contrary to immunocompetent patients, individuals with profound cell-mediated immunodeficiencies may be unable to mount sufficient lymphocytic responses in corneal tissue to contain mpox lesions. A progressive keratouveitis can develop, leading to corneal melt with an atypical local immune signature. The clinical and histologic phenotype of the cornea in this scenario is analogous to progressive vaccinia of the skin, a rare clinical entity that develops after smallpox vaccination of immunocompromised hosts.

Post-Transplantation Late Complications Increase Over Time for Patients With SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) Landmark Study

Post-Transplantation Late Complications Increase Over Time for Patients With SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) Landmark Study

Activation of the immune deficiency pathway (IMD) reduces the mosquito heart rate via a nitric oxide-based mechanism.

The immune deficiency pathway (IMD) is an important component of the antibacterial, antimalarial and antiviral response in mosquitoes. The IMD pathway also drives the infection induced migration of hemocytes to the heart. During an infection, periostial hemocytes kill pathogens in areas of high hemolymph flow and produce nitric oxide that reduces the heart rate. Here, we investigated the consequences of repressing the IMD pathway by silencing the transcription factor, rel2, or activating the pathway by silencing the negative regulator, caspar, in Anopheles gambiae. In uninfected mosquitoes, repression of the IMD pathway does not affect the circulatory system. However, activating the IMD pathway decreases the heart rate, and this correlates with increased transcription and activity of nitric oxide synthase (NOS), but not increased transcription of the lysozymes, LysC1 or LysC2. In infected mosquitoes, however, activation of the IMD pathway does not affect the heart rate but repression of the pathway decreases the heart rate. This latter phenotype correlates with increased transcription and activity of nitric oxide synthase, which is likely due to an increase in infection intensity. In conclusion, we demonstrate that a major immune signaling pathway that regulates periostial hemocyte aggregation, the IMD pathway, reduces the heart rate via a nitric oxide-based mechanism.

Differential neural network based adaptive average output feedback control design for dosage determination on cancer based immunotherapy treatment

Immunotherapy involves natural and synthetic substances to stimulate the body’s immune response. This treatment approach is practical not only for addressing immune deficiencies but also for combating malignancies. This paper describes a non-parametric approximated adaptive control process for managing cancer dynamics under immunotherapy treatment, utilizing a combination of a differential neural network (DNN) observer and nonlinear control techniques such as sliding mode and local optimal strategies. By employing the state estimation and control methods, close tracking between the estimated states provided by the neural network and the cancer model dynamics is possible. Internal model reconstruction and an observer provided by a variable structure model are essential for controlling unknown plants. Furthermore, the control design has successfully reduced tumor cells despite uncertainties and external perturbations affecting cancer dynamics. This robustness enhances the reliability of the proposed design. A virtual real-time scheme was developed to demonstrate this controller’s feasibility in real clinical scenarios. In this scheme, a simulated patient generates variables of immunotherapy dynamics as electrical signals, which are then analyzed by a real-time project.

Measuring the Effect of Newborn Screening on Survival After Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency: A 36-Year Longitudinal Study From the Primary Immune Deficiency Treatment Consortium.

Measuring the Effect of Newborn Screening on Survival After Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency: A 36-Year Longitudinal Study From the Primary Immune Deficiency Treatment Consortium.