Common Variable Immunodeficiency (CVID) is a heterogeneous group of disorders characterized by low levels of immunoglobulins and recurrent bacterial infections. The exact pathogenesis is unknown in most cases, though approximately 20-25% of cases are now considered monogenic defects. These include mutations affecting B cell development and function, such as ICOS, TACI, BAFF-R, CD19, CD21, CD81, as well as defects in immune regulation genes like PIK3CD, PIK3R1, CTLA4, and LRBA. Affected individuals present with recurrent respiratory infections, gastrointestinal infections, and autoimmunity.
This presentation is an overview of primary and secondary immunodeficiency disorders with highlights on the genetic basis of primary disorders and associated factors underlying secondary disorders, as well a management of these disorders
This presentation is an overview of primary and secondary immunodeficiency disorders with highlights on the genetic basis of primary disorders and associated factors underlying secondary disorders, as well a management of these disorders
This presentation is about chronic infections in patients and earlier diagnosis of immunodeficiency. The goals of the presentation are:
1. Understand the role of innate and adaptive immune systems in the defense against infection
2. Recognize the common presentations of common primary immunodeficiencies
3. Be able to identify patients in an ENT practice that may have a primary immunodeficiency
Presentation by: Dr. Richard L. Wasserman and Dr. Scott Manning
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
4. Epidemiology
•A study compiling and analyzing various national registries to extrapolate
the worldwide prevalence of PID
• Estimated incidence of PID was highest in children (reaching 21.9/100,000 in the
0-4-year age range)
• Overall 69.4% of all new worldwide PID cases are diagnosed at age over 15
years
• More than 50% are diagnosed at ages over 25 years
J Allergy Clin Immunol Pract. Nov-Dec 2016;4(6):1101-1107.
5. Epidemiology
•In a Canadian study, of 381 adult patients referred to the Immune
Deficiency Treatment Center of the McGill University Health Center over a
10-year period, more than half (210) of the patients were found to have a
PID.
•In an earlier study, of 237 patients of all ages referred to the Mount Sinai
Immunology Center, 113 were diagnosed with PID, and within this group,
the mean age of diagnosis was 31.5 years.
J Allergy Clin Immunol Pract. Nov-Dec 2016;4(6):1101-1107.
8. Epidemiology
•There are no precise data on the prevalence of CVID, but it has been
estimated at between 1:100,000 and 1:10,000 of the population.
•The calculated prevalence of CVID in these European countries ranges
from 0.07 to 0.98 patients per 100,000 inhabitants.
• The reported prevalence in Japan is also within this range (0.25:100,000).
•Discrepancies between these reports are likely a result of different
methodologies and their influences on various forms of ascertainment bias.
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
11. Pathogenesis
•The exact mechanism of action remains unknown.
•The percentage of patients with monogenic defects associated with CVID
has increased to about 20%-25%.
•Most pathogenetic studies in CVID address disturbed long lived humoral
memory response.
Stiehm's Immune Deficiencies, 2nd Edition
12. Disturbed long lived humoral memory response
•About 1/3 of CVID patients have a partial block at the preB1 to preB2
transition during central B cell development, possibly suggestive of an
altered (Pre)B-cell receptor (BCR) signaling.
•The inability to produce Ig is a reflection of the deficiency of circulating
isotype-switched memory B cells and plasmablasts.
Stiehm's Immune Deficiencies, 2nd Edition
16. Abbas- Cellular and Molecular Immunology, Tenth Edition
Inducible T cell co-stimulator/ CD278
17. Monogenic defects- Inducible co-stimulator (ICOS)
• Autosomal recessive mutations
• First monogenic cause of CVID, identified in a German cohort of CVID patients.
• ICOS is expressed on activated T cells and is one of the essential co-stimulatory
molecules on TFH cells during the germinal center response.
• In the absence of ICOS, the germinal center responses are not able to fully mature
and T-dependent antibody responses fail.
• The ICOS disease spectrum has expanded from a pure B-cell to combined B and
T-cell immune deficiency, suggesting genetic and environmental modifiers.
Stiehm's Immune Deficiencies, 2nd Edition
19. Monogenic defects
•Transmembrane activator and calcium-modulator and cyclophilin ligand
interactor (TACI, TNFRSF13B)
• TACI, as well as the BAFF-R belong to the TNF receptor family
• Involved in B-cell survival, activation and differentiation
• These are autosomal dominant generally with some variants found in
homozygosity but the same mutations have also been observed in relatives of
patients
• Healthy individuals with normal immunoglobulin levels, rendering TACI an
important modifying but not disease-causing gene in CVID.
Stiehm's Immune Deficiencies, 2nd Edition
21. Monogenic defects- BAFF-R deficiency
•BAFF is the important survival signals are delivered to maturing B cells.
•Maturation of follicular B cells particularly depends on BAFF-BAFFR
signaling.
•AR Inheritance
• Two siblings carrying a homozygous deletion in the BAFF-R gene
• B-cell development is arrested at the stage of transitional B cells and the
numbers of all subsequent B-cell stages are severely reduced
Stiehm's Immune Deficiencies, 2nd Edition
22. Monogenic defects
•Defects of the B cell co-stimulatory receptors:
• Both CD19 and CD81 deficiency presented with childhood onset recurrent
respiratory infections, and sometimes skin (1/10) or gastrointestinal infections
(3/10).
• CD21 deficient patients have a milder phenotype with mainly respiratory tract
infections in the presence of low IgG and variable IgA and IgM levels.
Stiehm's Immune Deficiencies, 2nd Edition
24. Monogenic defects- IKAROS Deficiency
• IKAROS proteins are lymphoid-restricted zinc finger transcription factors,
considered as master regulators of hematopoiesis.
• Somatic and germline mutations have been linked to the occurrence of acute
lymphoblastic leukemia.
• The patients identified had moderate to profound hypogammaglobulinemia, loss
of antibody production and often severe B cell deficiency.
• Most patients have had early onset recurrent bacterial infections, some have
autoimmunity or organ inflammation; a few have had disturbed hematopoiesis or
acute lymphoblastic leukemia (ALL).
Stiehm's Immune Deficiencies, 2nd Edition
26. Monogenic defects- IL21
•Autosomal recessive mutation
•Early onset inflammatory bowel disease with pathology similar to Crohn’s
disease, with oral aphthous ulcers.
•Recurrent infections due to hypogammaglobulinemia (IgG deficiency) in
the only currently identified child.
•Reduced B cell numbers and dramatically reduced class-switched memory
B-cells, but increased serum IgE.
Stiehm's Immune Deficiencies, 2nd Edition
27. Monogenic defects- IL21R
•Autosomal recessive IL21R gene defects were found in five children of
three kindreds.
•Four patients had cryptosporidiosis associated with chronic cholangitis and
severe liver disease affecting survival and transplantation outcome, while
the only child without cryptosporidiosis did well after transplant.
•Reduced class-switched CD27+ memory B cells and impaired specific
antibody responses to immunization antigens.
•Increased serum IgE
Stiehm's Immune Deficiencies, 2nd Edition
28. Monogenic defects- CD27
•CD27 is the surface marker of memory B cells
• is an essential costimulatory molecule that regulates the function and survival of
T-cells and NK cells.
•Homozygous mutations lead to a combined immune deficiency
• Decreased numbers of switched memory B cells
• Hypogammaglobulinemia
• Severe T cell and NK defects leading to persistent EBV viremia.
Stiehm's Immune Deficiencies, 2nd Edition
29. Monogenic defects
•Deficiency in genes linked to immune regulation
• PIK3CD and PIK3R1
• Lipopolysaccharide-responsive beige-like anchor protein (LRBA)
• Cytotoxic T lymphocyte antigen-4 (CTLA4)
• Phospholipase Cg2eAssociated Antibody De ficiency and Immune Dysregulation
(PLCG2)
• Protein Kinase C delta deficiency
• Nuclear factor Kappa-B (NFkB)
Stiehm's Immune Deficiencies, 2nd Edition
30. Monogenic defects- PIK3CD and PIK3R1
• Activated Phosphoinositide 3-kinase delta syndrome (APDS) is due to autosomal
dominant mutations in the catalytic subunit of 110 kDa (PIK3CD) or the 85 kDa
regulatory subunit (PIK3R1).
• Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-
trisphosphate and phosphorylated AKT protein and were prone to activation-
induced cell death.
• Some of the APDS patients present as CVID.
• Laboratory clues may be an elevated IgM.
• Targeted therapies with mTOR inhibitors and selective PI3Kd inhibitors.
Stiehm's Immune Deficiencies, 2nd Edition
OMIM
32. Monogenic defects- Cytotoxic T lymphocyte antigen-4 (CTLA4)
•Patients typically present with an immune dysregulation syndrome
characterized by extended lymphocytic activation and organ infiltration
manifesting in most cases with autoimmune cytopenias, enteropathy and
granulomatous infiltrative lung, even inflammatory CNS lymphoma.
Stiehm's Immune Deficiencies, 2nd Edition
33. Monogenic defects- Cytotoxic T lymphocyte antigen-4 (CTLA4)
•Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte
antigen 4-insufficient subjects
• In total, 14 affected mutation carriers received the CTLA-4 fusion proteins
abatacept or belatacept, 11 of whom responded with an improvement in their
clinical symptoms.
J Allergy Clin Immunol. 2018 Dec;142(6):1932-1946.
34. Monogenic defects- Lipopolysaccharide-responsive beige-like
anchor protein (LRBA)
• LRBA (lipopolysaccharide inducible cytosolic protein) localized in the vesicles
and endoplasmic reticulum of almost all cell types.
• protect CTLA-4 in T cells from lysosomal degradation
• Usually present early in life, a combined immune deficiency, resembling complex
forms of CVID.
• LRBA deficient patients commonly suffer from early onset autoimmunity
(commonly hemolytic anemia or ITP), enteropathy, interstitial lung disease,
splenomegaly and in some cases opportunistic infections.
• Patients may benefit from treatment with targeted immunosuppressive.
Stiehm's Immune Deficiencies, 2nd Edition
36. Epigenetic Changes
•Epigenetic mechanisms can influence gene expression without altering the
germline DNA gene sequences and play an important role in the normal
developmental program of immune cells.
•The mechanisms described to date include DNA methylation, chromatin
modulation, histone modification, transcription factor expression, and
noncoding RNAs (ncRNAs).
J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-34
37. Epigenetic Changes
•A study of monozygotic twins who were discordant for a diagnosis of CVID
revealed a higher degree of DNA methylation in the switched and
nonswitched memory B cells of the patient when compared with the healthy
sibling.
J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-34
41. Infection (Respiratory System)
•The upper and lower respiratory tract are the most common sites of
infection.
•Bronchiectasis and interstitial lung disease are major lung complications
that manifest after recurrent and severe lung infections.
•Organism
• Streptococcus pneumoniae, H. influenzae, Moraxella catarrhalis, Mycoplasma
J Investig Allergol Clin Immunol. 2020;30(1):14-34
42. Infection (Gastrointestinal System)
•Gastrointestinal tract infections manifest in form of chronic or acute
diarrhea.
•Organism
• Giardia lamblia
• is the most commonly identified pathogen
• Campylobacter jejuni
• Salmonella species
J Investig Allergol Clin Immunol. 2020;30(1):14-34
43. Late-Onset Combined Immune Deficiency (LOCID)
•A Subset of Common Variable Immunodeficiency with Severe T Cell Defect
•Severe T Cell Defect
• Experienced OIs AND/OR had a CD4 T cell count <200 cells/L
Clin Infect Dis. 2009 Nov 1;49(9):1329-38.
48. Autoimmune Hematologic Disease
•Autoimmune cytopenia, occurring in 4% to 20% of patients, usually with
immune thrombocytopenic purpura (ITP), sometimes autoimmune
hemolytic anemia (AIHA).
•Autoimmunity may be the first manifestation of the immune defect in an
occasional patient who has never had a significant infection.
•The treatment strategies used for cytopenias in CVID are essentially the
same as applied for immune-competent patients.
Ann Allergy Asthma Immunol 123 (2019) 454-460
50. Autoimmune Pulmonary Disease
•Interstitial lung disease
• Incidence is unclear
• Associated with evidence of systemic immune dysregulation, including previous
cytopenias, lymphadenopathy, and splenomegaly
• Requires biopsy to diagnose
• Follicular bronchiolitis, lymphocytic interstitial pneumonitis, and nodular lymphoid
hyperplasia
• Granulomatous inflammation -> Granulomatous and lymphocytic interstitial lung
disease (GLILD)
Ann Allergy Asthma Immunol 123 (2019) 454-460
51. Autoimmune Pulmonary Disease
•Low doses of corticosteroids may be used acutely but have limited benefit
long term.
•Therapy targeting both T and B cells concurrently, such as
cyclophosphamide, cyclosporine, or azathioprine combined with rituximab,
is required.
Ann Allergy Asthma Immunol 123 (2019) 454-460
52. Autoimmune Gastrointestinal Disease
•Stomach
• Autoimmune gastritis
• à Pernicious anemia
•Small Bowel and Colon
• Inflammatory bowel disease (IBD) resembling Crohn’s or ulcerative colitis
Ann Allergy Asthma Immunol 123 (2019) 454-460
53. Autoimmune Gastrointestinal Disease
• IBD-like disease
• Investigation
• Stool fecal calprotectin
• Stool alpha-1 antitrypsin
• Absence of detectable serum antibodies against gliadin, reticulin, tissue transglutaminase, and
endomysium
• Endoscopic features
• Longitudinal ulcers and cobblestone appearance
• Histopathology
• Intraepithelial lymphocytosis, lymphoid aggregates, granulomas, and crypt distortion
• Lack of plasma cells
Ann Allergy Asthma Immunol 123 (2019) 454-460
54. Autoimmune Gastrointestinal Disease
•IBD-like disease
• Treatment
• Difficult to control and unresponsive to standard IBD therapies
• Immunoglobulin replacement does not ameliorate the IBD-like disease.
• Low-dose corticosteroids can be used, although higher doses can lead to a significant
risk of infections.
Ann Allergy Asthma Immunol 123 (2019) 454-460
55. Autoimmune Gastrointestinal Disease
•IBD-like disease
• Treatment
• Antibiotics to eliminate bacterial overgrowth.
• Oral budesonide, and immunosuppressants, including 5-aminosalicylate agents, 6-MP,
and AZA
• Targeted biological therapies in gastrointestinal inflammation, such as anti-TNF alpha,
IL-12, and IL- 23 antagonist, have been used with some benefit in severe cases
Ann Allergy Asthma Immunol 123 (2019) 454-460
56. Autoimmune Gastrointestinal Disease
•Liver
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Nodular regenerative hyperplasia
• Treatment for autoimmune liver disease in CVID includes corticosteroids or
immunomodulators and ursodeoxycholic acid if biliary damage is present.
Ann Allergy Asthma Immunol 123 (2019) 454-460
57. Autoimmune Rheumatologic Disease
• Adult and juvenile forms of chronic inflammatory arthritis (most common)
• Less frequently reported
• SLE
• Raynaud’s syndrome vasculitis
• Mixed connective tissue disorder
• Inflammatorymyositis
• Behcet’s disease
• Sjogren’s syndrome
• Treated in the same fashion as for patients without CVID
Ann Allergy Asthma Immunol 123 (2019) 454-460
62. Malignancy
•Meta-analysis from 48 studies including 8123 CVID patients
• Overall prevalence of malignancy was 8.6%
• The prevalence of lymphoma, gastric cancer and breast cancer in CVID patients
were 4.1%, 1.5%, and 1.3%, respectively.
Expert Rev Clin Immunol. 2019 Oct;15(10):1105-1113.
67. The ESID/ PAGID diagnostic criteria 1999
•Probable CVID
• Male or female patient who has a marked decrease of IgG (at least 2 SD below
the mean for age) and a marked decrease in at least one of the isotypes IgM or
IgA, and fulfils all of the following criteria:
• Onset of immunodeficiency at >2 years of age
• Absent isohemagglutinins and/or poor response to vaccines
• Defined causes of hypogammaglobulinemia have been excluded
Clin Immunol. 1999;93(3):190-7.
68. The ESID/ PAGID diagnostic criteria 1999
•Possible CVID
• Male or female patient who has a marked decrease (at least 2 SD below the
mean for age) in at least one of the major isotypes (IgM, IgG, and IgA) and fulfils
all of the following criteria:
• Onset of immunodeficiency at >2 years of age
• Absent isohemagglutinins and/or poor response to vaccines
• Defined causes of hypogammaglobulinemia have been excluded
Clin Immunol. 1999;93(3):190-7.
69. Defined causes of hypogammaglobulinemia
•Drug induced
•Single gene and other defects
•Chromosomal anomalies
•Infectious diseases
•Malignancy
•Other systemic disorders
71. Defined causes of hypogammaglobulinemia
• Single gene and other defects
• Ataxia telangiectasia
• Autosomal-recessive forms of SCID and
other forms of combined
immunodeficiency
• Hyper-IgM syndromes
• Transcobalamin II deficiency
• Hypogammaglobulinemia X-linked
• Agammaglobulinemia X-linked
• Lymphoproliferative disorder (EBV-
associated) X-linked SCID
• Some metabolic disorders
• Chromosomal anomalies
• Chromosome 18q- syndrome
• Monosomy 22
• Trisomy 8
• Trisomy 21
72. Defined causes of hypogammaglobulinemia
• Infectious diseases
• HIV
• Congenital infection with rubella virus
• Congenital infection with cytomegalovirus
• Congenital infection with Toxoplasma
gondii
• EBV
• Malignancy
• Chronic lymphocytic leukemia
• Immunodeficiency with thymoma
• Non-Hodgkin lymphoma
• Monoclonal gammopathy (mutiple
myeloma, Waldenstrom
macroglobulinemia)
• Other systemic disorders
• Immunodeficiency caused by excessive
loss of immunoglobulins (nephrosis,
severe burns, lymphangiectasia, protein-
losing enteropathy)
73. The diagnostic criteria of Ameratunga 2013
A. Must meet all major criteria
• Hypogammaglobulinaemia: IgG below 5 g/l for adults
• No other cause identified for immune defect
• Age > 4 years
B. Clinical sequelae directly attributable to in-vivo failure of the immune system (one
or more criteria)
C. Supportive laboratory evidence (three or more criteria)
D. Presence of any one of relatively specific histological markers of CVID (not
required for diagnosis but presence increases diagnostic certainty)
Clin Exp Immunol. 2013 Nov;174(2):203-11.
74. The diagnostic criteria of Ameratunga 2013
B. Clinical sequelae directly attributable to in-vivo failure of the immune
system (one or more criteria)
• Recurrent, severe or unusual infections
• Poor response to antibiotics
• Breakthrough bacterial infections in spite of prophylactic antibiotics
• Infections in spite of immunization with the appropriate vaccine, e.g. HPV
disease
• Bronchiectasis and/or chronic sinus disease
• Inflammatory disorders or autoimmunity
Clin Exp Immunol. 2013 Nov;174(2):203-11.
75. The diagnostic criteria of Ameratunga 2013
C. Supportive laboratory evidence (three or more criteria)
• Concomitant deficiency or reduction of IgA (<0.8 g/l) and/or IgM (<0.4 g/l)
• Presence of B cells but reduced memory B cell subsets and/or increased CD21 low
subsets by flow cytometry
• IgG3 deficiency (<0.2 g/l)
• Impaired vaccine responses compared to age-matched controls
• Transient responses to vaccines compared to age-matched controls
• Absent isohaemagglutinins (if not blood group AB)
• Serological support for autoimmunity in section B, e.g. positive Coombs’ test
• Sequence variations of genes predisposing to CVID, e.g. TACI, BAFFR, MSH5, etc.
Clin Exp Immunol. 2013 Nov;174(2):203-11.
76. The diagnostic criteria of Ameratunga 2013
D. Presence of any one of relatively specific histological markers of CVID
(not required for diagnosis but presence increases diagnostic certainty)
• Lymphoid interstitial pneumonitis
• Granulomatous disorder
• Nodular regenerative hyperplasia of the liver
• Nodular lymphoid hyperplasia of the gut
• Absence of plasma cells on gut biopsy
Clin Exp Immunol. 2013 Nov;174(2):203-11.
77. The diagnostic criteria of Ameratunga 2013
A. Must meet all major criteria
• Hypogammaglobulinaemia: IgG below 5 g/l for adults
• No other cause identified for immune defect
• Age > 4 years
B. Clinical sequelae directly attributable to in-vivo failure of the immune system (one
or more criteria)
C. Supportive laboratory evidence (three or more criteria)
D. Presence of any one of relatively specific histological markers of CVID (not
required for diagnosis but presence increases diagnostic certainty)
Probable CVID - ABC or ABD
(should be treated with IVIG/scIG)
Possible CVID- A alone, AB or AC or AD
Clin Exp Immunol. 2013 Nov;174(2):203-11.
78. Revised ESID diagnostic criteria 2014
•At least one of the following:
• Increased susceptibility to infection
• Autoimmune manifestations
• Granulomatous disease
• Unexplained polyclonal lymphoproliferation
• Affected family member with antibody deficiency
http://esid.org/Working-Parties/Registry/Diagnosis-criteria
79. Revised ESID diagnostic criteria 2014
• Marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured
at least twice)
• At least one of the following
• Poor antibody response to vaccines (and/or absent isohemagglutinins); i.e., absence of protective
levels despite vaccination where defined
• Low switched memory B cells (<70% of age-related normal value)
• Secondary causes of hypogammaglobulinemia have been excluded
• Diagnosis is established after the fourth year of life (but symptoms may be present before)
• No evidence of profound T-cell deficiency, defined as two out of the following
• CD4 numbers/microliter: 2–6 y < 300, 6–12 y < 250, >12 y < 200
• % Naive CD4: 2–6 y < 25%, 6–16 y < 20%, >16 y < 10%
• T-cell proliferation absent
http://esid.org/Working-Parties/Registry/Diagnosis-criteria
80. ICON criteria 2016
1. At least 1 of the characteristic clinical manifestations
2. Hypogammaglobulinemia
3. IgA or IgM level must also be low.
(some experts prefer a more narrow definition requiring low IgA level in all patients.)
4. All patients with an IgG level of more than 100 mg/dL should be studied for
responses to T-dependent (TD) and T-independent (TI) antigens.
5. Other causes of hypogammaglobulinemia must be exclude
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
81. ICON criteria 2016
1. At least 1 of the characteristic clinical manifestations
• Infection
• Autoimmunity
• Lymphoproliferation
However, a diagnosis of CVID may be conferred on asymptomatic individuals who
fulfill criteria 2 to 5, especially in familial cases
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
82. ICON criteria 2016
2. Hypogammaglobulinemia
•should be defined according to the age adjusted reference range
•IgG level must be repeatedly low in at least 2 measurements more than 3
weeks apart in all patients.
•Repeated measurement may be omitted if the level is very low (<100-300
mg/dL depending on age), other characteristic features are present
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
83. ICON criteria 2016
4. All patients with an IgG level of more than 100 mg/dL should be studied
for responses to T-dependent (TD) and T-independent (TI) antigens
• There must be a demonstrable impairment of response to at least 1 type of
antigen (TD or TI).
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
84. ICON criteria 2016
Unspecified IgG deficiency
• Or unspecified hypogammaglobulinemia
• Patients with a low IgG level and impaired vaccine responses but IgA or IgM level
is not low
• IgG and IgA levels may be low, but vaccine responses may appear normal by
standard criteria
• Many patients with abnormal immunoglobulin levels and/or functional antibody
responses not meeting criteria for CVID may have a significant burden of
infections and should be assessed for benefit from IgG replacement.
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
87. Late-Onset Combined Immune Deficiency (LOCID)
•A Subset of Common Variable Immunodeficiency with Severe T Cell Defect
•Severe T Cell Defect
• Experienced OIs AND/OR had a CD4 T cell count <200 cells/L
Clin Infect Dis. 2009 Nov 1;49(9):1329-38.
92. B-Cell Pattern Classification (2011)
• Divided into 5 distinct groups based on their B-cell subsets
• Group 1- decreased numbers of transitional B cells along with a reduction in
memory B cells
• Group 2 - reduced number of transitional B cells, as well as naive, marginal zone–
like, and memory B cells
• Group 3 - reduced marginal zone–like and memory B cells
• Group 4 - only decreased memory B cells
• Group 5 - normal marginal zone–like and memory B cells in combination with a
reduced plasmablast count
Blood. 2011 Dec 22;118(26):6814-23.
93. Chapel Classification
•According to this classification, patients are divided into 5 distinct clinical
phenotypes including
• No complications
• Autoimmunity
• Polyclonal lymphocytic infiltration
• Enteropathy
• Lymphoid malignancy
Blood. 2008 Jul 15;112(2):277-86.
95. Immunoglobulin replacement therapy
•Dose
• Starting dose of 0.4 to 0.5 g/kg/month for both intravenous immunoglobulin(IVIG)
and 0.4 to 0.6 g/kg/month for subcutaneous immunoglobulin (SCIG)
• Preexisting bronchiectasis à 0.6 g/kg/month
• Enteropathy or splenomegaly à 0.6-0.8 g/kg/month
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
96. Immunoglobulin replacement therapy
•Adverse events
• Acute reactions
• Headaches, nausea and vomiting, flushing, hives, chills, myalgia, arthralgia, or
abdominal and/or back pain
• Severe, life-threatening anaphylactoid reactions are very rare
• Delayed reactions
• can occur up to 72 hours after the infusion
• Fatigue, headache, myalgias
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
97. Immunization
•Routine boosters of tetanus or diphtheria toxoids or pneumococcus are
probably not necessary for individuals receiving IgG replacement therapy
•Therapeutic IgG contains significant amounts of neutralizing antibodies to
the most commonly used live viral vaccines
• such as measles, mumps, rubella, polio, and varicella
•Less commonly used inactivated vaccines do not pose any risk to patients,
but efficacy is unknown.
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
98. Immunization
•Live attenuated polio vaccine, may cause disease in patients with CVID.
•Efficacy and safety of less frequently used live-agent vaccines have not
been studied in patients with CVID, and they are usually considered to be
contraindicated.
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.
101. Treatment of complications-Rhinosinusitis
•Routine saline nasal rinses may be used to aid in mucus clearance.
•Antibiotic prophylaxis for chronic or recurrent rhinosinusitis and/or otitis
media
• no controlled trials have been conducted
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.