Materiały źródłowe

• #1 Diagnosing PI | Immune Deficiency Foundation

  https://primaryimmune.org/advancing-pi-research-and-clinical-care/diagnosing-pi

  No matter your specialty, you may have patients with undiagnosed primary immunodeficiency (PI). […] Primary immunodeficiencies (PIs), also known as inborn errors of immunity (IEI), are a group of more than 550 rare and chronic disorders caused by genetic variants. Patients average 9-15 years from symptom onset to diagnosis and experts estimate that 70% of individuals with a PI remain undiagnosed. […] You can be the provider that puts the picture together and makes a difference. […] Collect a detailed patient history, including family history. […] Order complete blood count with differential and compare absolute counts of lymphocytes, neutrophils, eosinophils, and monocytes to age-adjusted reference ranges. […] Order serum immunoglobulin (Ig) test to assess the patients overall IgG, IgA, and IgM levels, and antibody titers to vaccine antigens.

• #2 Diagnostic tests for primary immunodeficiency disorders: Classic and genetic testing

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11425801/

  Primary immunodeficiency diseases encompass a variety of genetic conditions characterized by a compromised immune system and typically results in increased susceptibility to infection. […] Currently, the number of recognized monogenic primary immunodeficiency disorders is set at 500 different entities, owing to the exponential use of unbiased genetic testing for disease discovery. […] Although the clinical symptoms of immunodeficiency disorders are broad, an early diagnosis and tailored management strategies are essential to mitigate the risk of infections and prevent disease-associated morbidity. […] Generally, the medical history and physical examination can provide useful information that can help delineate the possibility of immune defects. […] This article focuses on the strategies for optimally using laboratory tests, both classic and genetic, in the diagnosis of PID.

• #3 Primary Immunodeficiency Disease (PID) | Takeda U.S. Medical

  https://www.takedamedconnect.com/diseases-and-conditions/rare-immunology/primary-immunodeficiency-disease

  Primary immunodeficiency disease (PID) refers to a group of mostly inherited conditions that involve impairment of the immune system and require ongoing management. Currently, more than 550 different genetic defects of PID have been identified, often presenting with hallmark recurrent and unusual infections. PIDs are significantly underreported, and estimates suggest that 70-90% of patients are undiagnosed worldwide, largely because it is not top of mind. According to a U.S. survey, the average time from symptom onset to diagnosis of all types of PID was 25 years based on 977 respondents. Diagnosing an antibody production deficit relies on a thorough medical and family history, physical examination and should be supplemented with diagnostic screening tests (e.g. complete blood count with differential white blood cell count, serum antibody levels, vaccine response) to help identify specific PID types.

• #4 Center for Adult Primary Immunodeficiency : Johns Hopkins Center for Innovative Medicine

  https://www.hopkinscim.org/initiatives/about-pi/

  Approximately 1 in 1,200 individuals suffer from a weak immune system, and thousands more go undetected. A major consequence of a weak immune system is the inability to fight off infections; consequently people suffer from recurrent, severe, persistent or unusual infections. […] It is not uncommon for patients to suffer from recurrent illnesses for many years before receiving a diagnosis. It is estimated that 70-90% of persons living with Primary Immunodeficiency remain undiagnosed, with about 500,000 undiagnosed patients in the United States. […] In additional to significantly reducing pain, suffering, and long-term disability, early diagnosis and treatment would save approximately $110,000 per patient per year, by reducing infections, hospitalizations, antibiotic use, COPD exacerbations, and time off from work. […] One of the only centers of its kind, we are a leader in treating adults whose quality of life has been hindered by immune disorders. With a focus on patient care, key areas of study for the center include early recognition and diagnosis, as well as multidisciplinary approaches to therapy.

• #5 Primary immunodeficiency – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/symptoms-causes/syc-20376905

  One of the most common signs of primary immunodeficiency is having infections that are more frequent, longer lasting or harder to treat than are the infections of someone with a typical immune system. […] If you or your child has frequent, recurrent or severe infections or infections that don’t respond to treatments, talk to your health care provider. Early diagnosis and treatment of primary immune deficiencies can prevent infections that can cause long-term problems.

• #6 Evaluation of Primary Immunodeficiency Disease in Children | AAFP

  https://www.aafp.org/pubs/afp/issues/2013/0601/p773.html

  One in 2,000 children younger than 18 years is thought to have a primary immunodeficiency disease. […] When an immunodeficiency disease is suspected, initial laboratory screening should include a complete blood count with differential and measurement of serum immunoglobulin and complement levels. […] If laboratory results are abnormal, or if clinical suspicion continues despite normal laboratory results, children should be referred for further evaluation. […] The overall incidence in the United States is 10.3 per 100,000 person-years; the median interval from onset of symptoms to diagnosis is 2.7 years. […] Physicians should suspect a primary immunodeficiency disease in children who have unusually severe and recurrent infections with common pathogens, or infections with unusual pathogens.

• #7 Approach to the Patient With Suspected Immunodeficiency – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/approach-to-the-patient-with-suspected-immunodeficiency

  Immunodeficiency typically manifests as recurrent infections. Both clinical and laboratory findings are needed for diagnosis. Primary immunodeficiencies are classified by the main component of the immune system that is deficient, absent, or defective: Humoral immunity, Cellular immunity, Combined humoral and cellular immunity, Phagocytic cells, Complement proteins. Immunodeficiency should be suspected when recurrent infections are severe, complicated, in multiple locations, refractory to standard treatment, caused by unusual organisms, or present in family members. History and physical examination are helpful but must be supplemented by immune function testing. Initial testing should include complete blood count (CBC) with manual differential, quantitative immunoglobulin (Ig) measurements, antibody titers, and skin testing for delayed hypersensitivity. If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder. Tests are needed to confirm a diagnosis of immunodeficiency. If results are normal, immunodeficiency (especially Ig deficiency) can be excluded. If results are abnormal, further tests in specialized laboratories are needed to identify specific deficiencies. Gene sequencing techniques can be used to elucidate immunodeficiency disorders with unusual features. An increasing number of primary immunodeficiency disorders can be diagnosed prenatally using chorionic villus sampling, cultured amniotic cells, or fetal blood sampling, but these tests are used only when a mutation in family members has already been identified.

• #8 About Primary Immunodeficiency (PI) | Primary Immunodeficiency (PI) | CDC

  https://www.cdc.gov/primary-immunodeficiency/about/index.html

  People with primary immunodeficiency (PI) have an immune system that doesn’t work correctly. […] Talk to your healthcare provider if you think you or your child could have PI. […] Finding and treating PI early can prevent or delay some health problems that PI causes. […] All states include testing for one type of PI called severe combined immunodeficiency (SCID) as part of newborn screening. […] Talk to your healthcare provider if you think that you or your child has signs of PI. Your healthcare provider might refer you or your child to a clinical immunologist, a healthcare provider who specializes in the immune system. […] Early diagnosis can help prevent or delay some of the health problems caused by PI. […] Left untreated, some types of PI can result in serious health problems, including organ damage, and even death. […] Treatments vary, depending on the type of PI, and can include treatments to prevent infections. […] Treatments that help your immune system work better (including immunoglobulin replacement therapy and interferon-gamma therapy). […] Treatments might be available that are specific to your PI.

• #9 Primary immunodeficiency – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/diagnosis-treatment/drc-20376910

  Your doctor will ask about your history of illnesses and whether any close relatives have an inherited immune system disorder. Your doctor will also perform a physical examination. […] Tests used to diagnose an immune disorder include: […] Blood tests can determine if you have typical levels of infection-fighting proteins (immunoglobulins) in your blood and measure the levels of blood cells and immune system cells. Having numbers of certain cells in your blood that are outside of the standard range can indicate an immune system defect. […] Blood tests can also determine if your immune system is responding properly and producing proteins that identify and kill foreign invaders such as bacteria or viruses (antibodies). […] Parents who have a child with a primary immunodeficiency disorder might want to be tested for certain immunodeficiency disorders during future pregnancies. Samples of the amniotic fluid, blood or cells from the tissue that will become the placenta (chorion) are tested for problems. […] In some cases, DNA testing is done to check for a genetic defect. Test results make it possible to prepare for treatment soon after birth, if necessary.

• #10 Evaluation of Primary Immunodeficiency Disease in Children | AAFP

  https://www.aafp.org/pubs/afp/issues/2013/0601/p773.html

  When a primary immunodeficiency disease is suspected in a child, initial laboratory testing should include a human immunodeficiency virus test, complete blood count with differential, and measurement of serum immunoglobulin and complement levels. […] A basic laboratory workup that includes testing for human immunodeficiency virus (HIV) antibody, complete blood count with differential, and measurement of serum immunoglobulin and complement levels can identify children who need further testing and referral to a subspecialist for a suspected immunodeficiency disease. […] T-cell disorders are characterized by lymphocytopenia. […] Primary immunodeficiency disease should be suspected if the neutrophil count is less than 1,500 per mm3. […] Patients with B-cell disorders have low serum immunoglobulin levels and decreased production or response of immunoglobulins to vaccination. […] Complement disorders are screened by checking the components of the classic and alternative pathways. […] In 2010, the U.S. Department of Health and Human Services recommended routine screening for SCID in newborns.

• #11 Primary Immunodeficiency: Types & Symptoms

  https://my.clevelandclinic.org/health/diseases/17964-primary-immunodeficiency

  Primary immunodeficiency refers to a group of disorders that prevent your immune system from working correctly. […] Your healthcare provider will diagnose PIDD based on your personal and family medical history, a physical examination and laboratory testing. […] To confirm your diagnosis, your provider may order tests that include: Blood tests to identify specific immune system abnormalities. […] Genetic tests to find mutations on genes. […] Flow cytometry, which uses a special laser to examine samples of immune system cells. […] In addition, all U.S. states include testing for a type of PIDD called severe combined immunodeficiency (SCID) as part of newborn screening.

• #12 How is Primary Immunodeficiency diagnosed? – ImmUnity Canada

  https://immunitycanada.org/info/how-is-pi-diagnosed/

  People with PI often become their own greatest advocates. […] Your doctor may refer you to a clinical immunologist for specialist testing and diagnosis. […] The diagnosis process varies, but common steps and diagnostic testing may include the following: Evaluation of symptoms (see symptoms and warning signs of Primary Immunodeficiency), Medical history and physical exam, Complete blood count and blood smear, Lymphocyte proliferation assays and flow cytometry, Measurement of serum immunoglobulin (Ig) levels, Evaluation of antibody responses to vaccine antigens (tetanus, diphtheria, pneumococcus), Neutrophil function assays and stimulation assays for cytokine responses.

• #13 Laboratory tests | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/diagnosis/laboratory-tests

  Laboratory tests that measure different parts of the immune system are important for diagnosing an individual with primary immunodeficiency (PI) and determining which of the more than 550 different conditions they may have. […] Laboratory tests are necessary to determine if an individual has a primary immunodeficiency (PI). These tests are usually prompted by the individual experiencing clinical symptoms, particularly recurrent and/or chronic infections. […] The most common laboratory tests used to evaluate immune disorders identify: Antibody deficiencies, Cellular (T cell) defects, Neutrophil disorders, Complement deficiencies. […] Another emerging laboratory test for the diagnosis of PI is genetic testing. […] The standard screening tests for humoral immune function start with measuring immunoglobulin (Ig), or antibody, levels in the blood serum.

• #14 Diagnostic tests for primary immunodeficiency disorders: Classic and genetic testing

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11425801/

  Initial screening for a suspected humoral immunodeficiency involves quantitation of circulating serum immunoglobulins (immunoglobulin G [IgG], IgA, IgM, and IgE). […] The results must be compared with age-matched controls that typically are provided as 95% confidence intervals. […] Ruling this out may be accomplished by evaluating the serum albumin level to exclude protein loss as a cause of low immunoglobulin levels. […] To accurately evaluate B-cell function, specific antibody production must be measured. […] For specific antibody evaluation, antibody titers to specific antigens from vaccines or natural infections represent the most reliable approach. […] Flow cytometry is used to quantitatively evaluate B lymphocyte counts and their maturation status. […] Initial evaluation includes a complete blood cell count, with the differential focusing on the absolute lymphocyte count compared with age-matched control ranges for proper interpretation.

• #15 Primary immunodeficiencies

  https://www.rch.org.au/clinicalguide/guideline_index/Primary_immunodeficiencies/

  Primary immunodeficiencies (PIDs) present with a variety of symptoms depending on which part of the immune system is affected […] Careful stepwise investigation in consultation with specialists allows for accurate diagnosis and prompt management […] PIDs should be considered in all children with severe infection, infection with unusual or opportunistic organisms, recurrent infection – more than expected for age […] Children aged 2 years presenting with invasive pneumococcal disease (sepsis, meningitis, complicated pneumonia or septic arthritis) with no clear predisposing condition, and all children with recurrent IPD should be investigated for immunodeficiency […] Any child with normal first-line investigations but high suspicion of PID should be referred to a paediatric immunologist for evaluation and consideration of second-line testing […] Children with suspected PID should not be administered live vaccines (this includes varicella, MMR, rotavirus and BCG vaccine).

• #16 Top 3 Tests Used to Diagnose Primary Immunodeficiency – IgCares

  https://igcares.com/home/education-how-is-primary-immunodeficiency-diagnosed.html

  The standard screening test for antibody deficiency starts with measurement of immunoglobulin (Ig) levels in the blood serum, evaluated through testing of blood samples. […] These tests measure how well the immune system responds to vaccines. […] Additional studies used to evaluate patients with antibody deficiencies include measuring the different types of lymphocytes in the blood by marking those cells with molecules that can identify the different types. […] The laboratory evaluation of cellular or T-cell immunity focuses on determining the numbers of different types of T-cells and evaluating the function of these cells. […] The simplest test to evaluate possible decreased or absent T-cells is a complete blood count (CBC) and differential to establish the total blood (absolute) lymphocyte count.

• #17 Primary Immunodeficiency (PID) | Binding Site

  https://www.thermofisher.com/bindingsite/us/en/clinical-applications/immune-system-disorder/primary-immunodeficiency.html

  Because antibody defects are more common than any other immune defect, the first emphasis should be placed on investigation of serum immunoglobulins and antibody production. […] It is important to determine if antibodies which are being produced are functionally relevant. This can be performed by using vaccination as a diagnostic test for specific antibody formation. […] Evaluation of the complement system is appropriate for patients with episodes of bacteremia, meningitis or systemic Neisserial infections. […] Analysis of lymphocyte surface markers, using monoclonal antibodies and flow cytometry, can identify T and B cells, subpopulations of T cells and NK cells and monocytes and macrophages. […] There is often a significant delay in the diagnosis of immunodeficiency. PID is widely under-diagnosed in most countries. In PID, delays of over seven years between first presentation and final diagnosis are common. […] Early diagnosis comes with many benefits for both the clinicians or laboratories and the patients.

• #18

  https://journals.lww.com/imed/fulltext/2024/02010/approach_to_primary_immunodeficiency_disorders.3.aspx

  The initial evaluation in suspected antibody deficiency required quantitative estimation of serum immunoglobulins immunoglobulin G (IgG), IgA, IgM, and IgE. […] Further, to assess in vivo intact antibody production, it is necessary to immunize with protein or polysaccharide vaccine and measure antibody titer after 3-4 weeks of immunization. There should normally be a 4-fold increase of antibody titer post-vaccination. […] However, molecular diagnosis is often required for confirmation of the underlying defect.

• #19 Primary Immunodeficiency (PI) Subclass | Labcorp

  https://www.labcorp.com/immunodeficiency

  Because they are prevalent in varying serum concentrations, a deficiency may be masked when only measuring total IgG. Many patients with PI are undiagnosed, underdiagnosed, or misdiagnosed. […] For this reason, the measurement of IgG subclass concentrations is important in the assessment of the immune system. Early diagnosis results in decreased morbidity and mortality and in lower costs, estimated to be annual savings to the health care system for each diagnosed patient of $85,882. […] A patient may have a normal total IgG yet still have a significant decrease in one subclass. […] Some clinically significant IgG subclass deficiencies occur in patients who have IgA deficiency.

• #20 Laboratory tests | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/diagnosis/laboratory-tests

  To test specific antibody production, the person is immunized with these common vaccines, and blood samples are obtained immediately prior to and approximately four weeks after the immunization to evaluate how well the individual forms specific antibodies. […] The ability to evaluate the antibody response in a person already receiving Ig replacement therapy is more difficult. […] In someone whose diagnosis of an antibody immunodeficiency is unclear, however, it may be necessary to stop Ig replacement therapy for a period of 4-6 months so that the individuals humoral immunity can be adequately assessed. […] Many types of PI affecting cellular immunity are associated with specific genetic variants. This is particularly true of SCID, in which more than 20 different genetic causes have been identified. These can all be evaluated using genetic testing, which is the most accurate means to establish a definitive diagnosis.

• #21 Diagnostic tests for primary immunodeficiency disorders: Classic and genetic testing

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11425801/

  Flow cytometry to evaluate the T cells represents the next step in assessing suspected T-cell or combined T- and B-cell defects. […] Advanced flow cytometry by using monoclonal antibodies specific for activated cells (CD25+, CD69+) can help with the characterization of several PIDs. […] Newborn screening for SCID has been implemented to identify severe T-cell quantitative defects in the newborn period. […] Because PIDs are defined as genetic diseases with increased susceptibility to infections, immune dysregulation (including autoimmunity, allergy, and autoinflammation), and cancer, molecular testing plays an essential role in establishing these diagnoses. […] Multiple genetic testing modalities exist, ranging from single variant/single gene Sanger sequencing to massively parallel sequencing/next-generation sequencing.

• #22 Flow Cytometry Applied to the Diagnosis of Primary Immunodeficiencies | IntechOpen

  https://www.intechopen.com/chapters/69757

  Flow cytometry is a standard laboratory tool in the evaluation and identification of leukocyte populations and specific lymphocyte subpopulations. […] The clinical application is broad for routine use in diagnostic laboratories, which facilitates the assessment of patients with suspected primary immunodeficiencies. […] When an immune system disorder is suspected, immunophenotyping of the patients peripheral blood mononuclear cells (PBMCs) is one of the initial steps in the diagnostic work-up. […] The basic immunophenotype analyzing T (CD3), B (CD19), and natural killer (NK) (CD56+CD16+) lymphocytes leads to a potential diagnosis of severe combined immunodeficiencies (SCID) resulting in four general categories of disease defined by the impact on lymphocyte populations: T/B/NK, T/B/NK+, T/B+/NK, and T/B+/NK+.

• #23 Flow Cytometry Applied to the Diagnosis of Primary Immunodeficiencies | IntechOpen

  https://www.intechopen.com/chapters/69757

  Overall, patients with adenosine deaminase (ADA) deficiency and reticular dysgenesis demonstrate the T/B/NK immunophenotype and typically have the most profound lymphocytopenia among SCID patients. […] The use of larger cytometric panels can include a higher number of lymphocyte subpopulations of interest in the diagnosis of other groups of PID, such as predominantly antibody deficiencies and immune dysregulation diseases among others. […] The expression of isoforms CD45RA, CD45RO in T cells should also be included in the study of patients with suspected SCID. […] The use of flow cytometry has gradually replaced gold standard methods such as lymphocyte proliferation by incorporating [3H] thymidine into the DNA of dividing cells and measured using a liquid scintillation counter, which is proportional to the amount of cell proliferation. […] Flow cytometry can provide rapid and accurate identification of expanded lymphocyte subpopulations, which play an important role in the evaluation and understanding of complex disorders such as primary immunodeficiencies and other immunomediated diseases.

• #24 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  A diagnosis of PID should be suspected in both children and adults who have recurrent pneumonias and/or ear, sinus and cutaneous infections as listed in Table 2. […] The immunologist will perform a comprehensive immune evaluation that often begins with a complete blood count (CBC) and blood smear. […] Significant lymphopenia, for example, may be the first indication of T-cell (cellular) immunodeficiency. […] Other important diagnostic tools include lymphocyte proliferation assays and flow cytometry which allow for the enumeration of B-cells, T-cells, and NK cells, and the evaluation of lymphocyte markers, T-cell variability, and adhesion receptors that may be associated with specific immune defects. […] The initial evaluation of patients with suspected B-cell (antibody-deficiency) disorders involves the measurement of serum IgG, IgA, IgM, and IgE levels.

• #25 Laboratory tests | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/diagnosis/laboratory-tests

  The laboratory evaluation of neutrophils begins by obtaining a series of white blood cell counts (WBC) with differentials. […] Laboratory testing to diagnose CGD relies on the evaluation of a critical function of neutrophils that kills certain bacteria and fungi—the creation of reactive oxygen. […] The standard screening test for deficiencies in the classical complement pathway is the total hemolytic complement assay or CH50. […] Laboratory tests are also available to measure the function of various elements of innate immunity.

• #26 Top 3 Tests Used to Diagnose Primary Immunodeficiency – IgCares

  https://igcares.com/home/education-how-is-primary-immunodeficiency-diagnosed.html

  The measurement of the number of T-cells is often accompanied by cell culture studies that evaluate T-cell function. […] Many immune deficiencies are associated with specific genetic defects. […] This is particularly true of Severe Combined Immune Deficiency (SCID) where more than 12 different genetic causes for SCID have been identified. […] The laboratory evaluation of the neutrophil begins by obtaining a series of white blood cell counts (WBC) with differentials. […] This is the most common abnormal laboratory finding when a patient presents with a clinical history that suggests defective neutrophil immunity. […] Currently, several states have adopted the T-cell receptor excision circle (TREC) assay as part of their routine newborn screening programs. […] T-cell receptor excision circles (TREC) are circular DNA molecules formed within T-cells developing in the thymus.

• #27 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  The best approach for confirming a diagnosis of an antibody-deficiency disorder is the measurement of serum-specific antibody titers (usually IgG) in response to vaccine antigens. […] Neutrophil function assays (e.g., dihydrorhodamine 1,2,3 response [DHR]) and stimulation assays for cytokine responses are helpful for confirming a diagnosis of innate disorders. […] Initiation of treatment should progress while genetic testing is pursued since many patients with clinical and laboratory evidence of PID do not, as of yet, have an identified single gene defect. […] Once the diagnosis is established, it is important that therapy be initiated as soon as possible, since delays can lead to permanent organ damage or even death from overwhelming infection.

• #28 Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114901

  Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. […] In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach.

• #29 Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome – UpToDate

  https://www.uptodate.com/contents/genetic-testing-in-patients-with-a-suspected-primary-immunodeficiency-or-autoinflammatory-syndrome

  Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome […] Achieving a molecular diagnosis provides the most comprehensive understanding of a patient’s primary immune dysregulation, allowing for tailored interventions and personalized surveillance strategies. […] The diagnostic process to uncover a molecular etiology, however, can be complicated by numerous testing strategies and modalities, each with their own nuances and limitations. […] This topic reviews the fundamentals of genetic testing and provides a clinical approach to molecular diagnosis for individuals with suspected primary immunodeficiency or autoinflammatory syndromes (inborn errors of immunity [IEI]). […] The importance of securing a molecular diagnosis in patients with primary immunodeficiency cannot be understated. Identifying a genetic diagnosis can drive a decision toward hematopoietic cell transplantation (HCT) if the suspected diagnosis is confirmed or lead to use of other treatment modalities.

• #30 Diagnostic tests for primary immunodeficiency disorders: Classic and genetic testing

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11425801/

  NGS tests, including PID genetic panels, whole exome sequencing (WES), and whole genome sequencing (WGS), are now widely used for PID diagnosis. […] When focused on NGS testing, the diagnostic yield is higher for patients with more severe phenotypes, in families with more than one affected individual, under conditions of consanguinity, or when trios (index and parents) are tested. […] Clinicians should be aware that each of the NGS tests discussed has its own pros and cons in terms of variant detection sensitivity and specificity, and this should be balanced with the needs of their patients. […] Classic and genetic laboratory testing in PID has shed light on critical defects of the immune system. […] The identification of specific mutations and altered pathways provides valuable insights for early diagnosis, which, in turn, should result in targeted therapeutic interventions.

• #31 Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome – UpToDate

  https://www.uptodate.com/contents/genetic-testing-in-patients-with-a-suspected-primary-immunodeficiency-or-autoinflammatory-syndrome

  The strength of single-gene testing is that it is typically a cost-effective approach to molecular diagnosis for an individual when sufficient phenotypic specificity is present. […] Panels are typically composed of a set of genes that have clinically overlapping phenotypes or that serve as the cause of a particular disease or group of related conditions. […] Genome sequencing (coding and noncoding DNA, approximately 3.5 gigabases) or exome sequencing (all of the coding exons, approximately 1.5 percent of the genome or approximately 50 megabases) uses an advanced sequencing technique known as next-generation sequencing (NGS). […] A five-tier classification system is widely used by clinical genetic testing laboratories and recommends reporting predicted variant effects with the modifiers „pathogenic,” „likely pathogenic,” „uncertain significance,” „likely benign,” and „benign.”

• #32 Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome – UpToDate

  https://www.uptodate.com/contents/genetic-testing-in-patients-with-a-suspected-primary-immunodeficiency-or-autoinflammatory-syndrome

  In one study of 280 families with primary immunodeficiency, use of whole exome sequencing identified a probable molecular diagnosis in 40 percent and altered the preliminary diagnosis in 55 percent of cases, resulting in a change in clinical management in 25 percent. […] Genotype-specific management in primary immunodeficiency […] Management of primary immunodeficiency patients can be impacted by genotype. […] Establishing a molecular diagnosis also allows medical care providers to provide affected families and individuals with critical information regarding the natural history of the disease, recurrence risk, and involvement of extra-hematopoietic systems. […] Genetic testing has the highest diagnostic yield in situations where the clinical phenotype is probably caused by one or more known genetic conditions.

• #33 Top 3 Tests Used to Diagnose Primary Immunodeficiency – IgCares

  https://igcares.com/home/education-how-is-primary-immunodeficiency-diagnosed.html

  The absence of T-cell and antibody immunity causes severe infections, diarrhea and failure to thrive. […] Knowing how SCID is inherited has permitted some families, often following tragic loss of an affected infant due to infection, to make the diagnosis in subsequent affected children at birth, or even before birth. […] Laboratory studies can be helpful in establishing the possible role of genes or chromosomes in a particular PI disease. […] In many primary immunodeficiency diseases, carrier parents can be identified by laboratory tests.

• #34 Primary Immunodeficiency | Boston Children’s Hospital

  https://www.childrenshospital.org/conditions/primary-immunodeficiency

  Since these disorders are genetic, it is also important for us to obtain a full medical history of both your child and your family. […] This is important to look for signs of infection or other findings that can provide clues regarding specific PIDDs. […] Blood tests we perform will help us determine which immune system components responsible for fighting off infection are affected, such as white blood cells or antibodies. […] The type of abnormality identified will help determine what type of PIDD your child has. […] For mothers who have already had a child with a PID, prenatal testing can be done for subsequent pregnancies. […] Currently, HSCT is the only non-experimental cure available. […] The only known cure is hematopoietic stem cell transplantation or gene therapy.

• #35 Primary Immunodeficiency: Diagnosis And Treatment – Klarity Health Library

  https://my.klarity.health/primary-immunodeficiency-diagnosis-and-treatment/

  Testing blood to look at the immune system defects is not the most conclusive test for PIDs. Throughout many years of developing DNA sequencing technologies, scientists have identified variants in over 350 genes that cause PIDs and are discovering more every year. Genetic testing allows suspected diagnoses to be confirmed as the genetic mutations can be detected. […] In cases where parents have a child with PID, they may consider prenatal tests when pregnant to assess whether the next child may have certain types of PIDs. This means they can be prepared and can start treatment soon after birth if needed. […] Methods of diagnosis include blood tests and genetic tests. There is also the option to have prenatal tests to prepare for a child’s potential future treatment.

• #36 Rational laboratory diagnostics of primary immunodeficiency disorders

  https://www.degruyterbrill.com/document/doi/10.1515/labmed-2015-0050/html?lang=en&srsltid=AfmBOoqij6qBSC3nHNww9ojnEepbA7DPCdy8N064r6QT9u-8DDyT2X44

  Today, the most common approach to diagnosing PIDs employs first the clinical examination of the patient, including family history, followed by the functional characterization of immunological components. […] Identification of the genetic cause further allows prenatal diagnosis and carrier identification and therefore permits presymptomatic identification of patients affected with life-threatening forms of PIDs, allowing early interventions. […] Although there are limitations at present, NGS approaches have proven their efficiency, accuracy, and applicability in the molecular diagnostics of PIDs.

• #37 Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

  https://www.mdpi.com/2075-4418/11/3/532

  We present case studies to discuss how the diagnostics of PIDs moved from a straightforward sequence, which led from the clinical picture to hematological and flow cytometry diagnostics, to a more articulated multidisciplinary workflow connecting various clinical specialties and requiring the collaboration between laboratory immunologists and geneticists. […] This article could scarcely describe the complex field of PIDs and is not intended to give diagnostic recommendations. […] It is just meant to discuss how the diagnostics of PIDs is moving in the era of NGS, requiring an intimate collaboration among various specialists in multidisciplinary teams.

• #38 Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114901

  Diagnosis of PIDs is highly complex due to substantial clinical, immunological and genetic heterogeneity. With the advent of next-generation sequencing, testing multiple genes in a single assay becomes possible, providing great opportunities for screening and diagnosing conditions with a heterogeneous genetic background. […] In this study we have used a selector-based sequencing capture assay to identify disease-causing mutations in 179 known PID genes. By sequencing 18 individuals with known mutations, we show that the developed sequence capture assay is capable of finding 83% of the causal variants, resolving the mutation status for 78% of individuals tested in one single assay. […] We propose a stepwise approach for PID diagnostics: in a first stage, resolve most cases by a rapid and at low cost targeted enrichment assay, and then, in a second stage, follow up unexplained cases using whole transcriptome and whole genome sequencing.

• #39 Improving the Detection of Primary Immune Deficiency Diseases for Better Treatment | Institut Pasteur

  https://www.pasteur.fr/en/international/international-programs/improving-detection-primary-immune-deficiency-diseases-better-treatment?language=fr

  As a result of the actions of the first phase targeting the Central and Southern regions of the country, the average annual number of confirmed cases increased by 26% compared to previous years. […] The second phase of the ATun-DIPs project was launched in 2021, in a virtual presence of representatives from all project stakeholders. […] Thanks to the excellent results of the first phase, particularly in terms of the number of diagnosed patients, the project team will expand its scope to cover the entire Tunisian territory. […] To further improve the accuracy of PID diagnosis, more innovative molecular techniques will be employed. […] In the first phase, the molecular diagnosis was based on the „candidate gene” approach, where each gene known to be potentially responsible for PIDs was sequenced for each patient to identify the source of the genetic defect.

• #40 Improving the Detection of Primary Immune Deficiency Diseases for Better Treatment | Institut Pasteur

  https://www.pasteur.fr/en/international/international-programs/improving-detection-primary-immune-deficiency-diseases-better-treatment?language=fr

  In the second phase, the project team will introduce two new high-throughput sequencing technologies through a collaboration with the BIOMICS platform at the Institut Pasteur (Paris). […] The first approach will systematically search for genetic defects in a panel of 300 known genes for each patient, including some identified during phase 1. […] The second technology will, in case the results are inconclusive, perform whole-genome sequencing to search for mutations responsible for PIDs. […] In addition to confirming the diagnosis, this additional research will help identify new genes associated with PIDs.

• #41 Expediting primary immunodeficiency diagnosis with artificial intelligence

  https://www.aaaai.org/tools-for-the-public/latest-research-summaries/the-journal-of-allergy-and-clinical-immunology/2022/expediting

  Many individuals with primary immunodeficiency (PI) suffer prolonged and costly diagnostic odysseys, excessive morbidity and impaired quality of life due to delayed diagnosis. […] Given these challenges, novel methods for disease screening are needed. Artificial/augmented intelligence (AI) approaches offer one such solution to systematically ascertain risk for underlying PI given their proven ability to analyze healthcare data and make predictions at the patient level. […] The investigators note that 1036 individuals (0.2% of total cohort) were given a new PI diagnosis during the study period, with a significantly greater proportion of those coming from the initial high-risk group. […] Importantly, this 2-step AI approach is generalizable and can be embedded into a care coordination workflow to provide a systematic means by which any health system can quantify PI risk at the individual level. […] Their AI platform is expected to facilitate early PI diagnosis while also driving healthcare value for patients with an existing diagnosis.

• #42 Next Generation Sequencing to Diagnose Primary Immunodeficiency | Blogs | CDC

  https://blogs.cdc.gov/genomics/2021/01/22/next-generation-sequencing/

  Primary immunodeficiencies (PI) are a group of more than 400 genetic disorders that alter the ability of the immune system to fight off infection and affect 1 out of 1,200 births in the United States. […] Initial identification of PI in a patient can be challenging as presentations can vary widely and symptoms can overlap with other conditions. Even after PI is diagnosed or suspected, obtaining a precise diagnosis can be difficult. Knowing the specific PI that a patient has can be important in optimizing treatments and improving health outcomes. […] A pilot study by the Jeffrey Modell Foundation (JMF) used next generation sequencing (NGS) to identify the genetic cause of PI in patients with diagnosed or suspected PI. […] The study identified pathologic or likely pathologic variants in 52 of 158 (33%) participants, and 28 (18%) received a molecular diagnosis.

• #43 Growth in diagnosis and treatment of primary immunodeficiency within the global Jeffrey Modell Centers Network | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-022-00662-6

  This global analysis of physician-reported data on patients with PI demonstrates an increase in both diagnosed and treated patients. […] The JMCN provides a critical platform that facilitates the education of physicians and patients, awareness initiatives, and research advances, through collaboration and connectivity, ultimately resulting in improved outcomes and QOL for patients with PI. […] Despite advancements in research, genetic sequencing, molecular diagnosis, and treatments that increased our grasp of the immune system and bettered quality of life (QOL) for individuals with PI, awareness of PI remains a critical issue for physicians and the public alike. […] The JMCN provides a platform to optimize research advances, earliest diagnosis, enhanced treatments, and implement standard-of-care and best practices through maximized connectivity, resulting in a better quality of life and improved outcomes for patients with PI.

• #44 Improving the Detection of Primary Immune Deficiency Diseases for Better Treatment | Institut Pasteur

  https://www.pasteur.fr/en/international/international-programs/improving-detection-primary-immune-deficiency-diseases-better-treatment

  Primary Immune Deficiency diseases (PIDs) constitute a heterogeneous group of over 300 diseases in which a genetic defect of the immune system leads to an increased susceptibility to infections, sometimes jeopardizing the vital prognosis. […] The lack of awareness among the medical community about these diseases results in them remaining significantly underdiagnosed, both in children and in milder forms in adults. […] Due to the difficulty of making a diagnosis, it is estimated that the majority of Tunisian patients remain undiagnosed or get a late diagnosis. […] Under the ATun-DIPs project, over a hundred physicians (pediatricians and general practitioners) have been trained to improve their expertise in recognizing disease warning signs and establishing an early diagnosis. […] The trained personnel were prepared to relay the useful information to their colleagues once returned to their institutions or facilities.

• #45 Growth in diagnosis and treatment of primary immunodeficiency within the global Jeffrey Modell Centers Network | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-022-00662-6

  The JMCN was developed by JMF to meet the rising need for specialized centers to accommodate the increasing patient population and to create the infrastructure needed to promote research, early diagnosis, and proper treatment. […] The considerable growth in patients can likely be attributed to newborn screening, education and awareness activities, molecular diagnosis, and increased availability of genetic diagnostics including NGS platforms. […] The substantial growth described above is partially due to newborn screening, molecular diagnosis, and NGS, and may need additional evaluation in the future. […] The SPIRIT Analyzer identifies at-risk patients by matching 352 ICD-10 codes to JMFs 10 Warning Signs of PI. […] The initiation of SCID newborn screening programs, improvements in diagnostics, and advancements in genomic technologies over the past few decades have allowed for better prevalence estimates and have resulted in improved comprehension of PI and the causal mechanisms leading to monogenic defects of the immune system. […] This comprehensive global analysis of physician-reported data on patients with PI demonstrates an increase in the diagnosis of numerous genotypes throughout the JMCN.

• #46 Improving the Detection of Primary Immune Deficiency Diseases for Better Treatment | Institut Pasteur

  https://www.pasteur.fr/en/international/international-programs/improving-detection-primary-immune-deficiency-diseases-better-treatment

  As a result of the actions of the first phase targeting the Central and Southern regions of the country, the average annual number of confirmed cases increased by 26% compared to previous years. […] The second phase of the ATun-DIPs project was launched in 2021, in a virtual presence of representatives from all project stakeholders. […] Thanks to the excellent results of the first phase, particularly in terms of the number of diagnosed patients, the project team will expand its scope to cover the entire Tunisian territory. […] To further improve the accuracy of PID diagnosis, more innovative molecular techniques will be employed. […] In the first phase, the molecular diagnosis was based on the „candidate gene” approach, where each gene known to be potentially responsible for PIDs was sequenced for each patient to identify the source of the genetic defect.

• #47 GAMMAGARD LIQUID [Immune Globulin Infusion (Human)] 10%

  https://www.gammagard.com/hcp/diagnosing-treating-pi

  PI can affect anyone, regardless of age or gender. Although some types of PI are diagnosed at birth or soon after, other types are often not recognized and diagnosed until later in life. […] People with PI may live many years with recurrent infections before they are accurately diagnosed. […] There are as many as 500,000 undiagnosed cases of PI in the US alone. However, awareness of PI is low among both physicians and the general public, and many patients are left undiagnosed. […] Patients may live many years with PI before they are accurately diagnosed. […] If you have a patient you suspect may have PI, the AAAAI and ACAAI guidelines recommend that you consider: An immunological evaluation, beginning with a thorough medical history and physical exam including family history. […] Levels below the normal range for a patient raise the index of suspicion for an antibody deficiency. However, a patient may present with normal levels and still have an antibody deficiency. […] Some people diagnosed with PI can have normal IG levels, such as patients with SAD. Because of this, vaccine response testing is needed to confirm a diagnosis.

• #48 Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-evaluation-frequency-diagnostic-delay-primary-S0301054620300641

  Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran […] The prevalence of undiagnosed primary immunodeficiency diseases is remarkably high and contributes to increasing the rate of morbidity and mortality among this group of patients. […] To examine the 10 warning sign scoring system in patients suspected of primary immune deficiency and also estimate the diagnostic delay in patients with proven disease. […] The mean diagnostic delay among primary immune deficient patients was 2.051.7 years. […] There is a meaningful delay in diagnosis of primary immune deficiencies especially in antibody deficiency defects which seeks further upgrading of knowledge in physicians.

• #49 Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-evaluation-frequency-diagnostic-delay-primary-S0301054620300641

  Primary immune deficiency disorders (PID) are related to a group of disorders caused by a genetic defect in the immune system which makes the body susceptible to recurrent infections. […] Despite recent advancement in diagnostic modalities, early recognition of these disorders is still highly challenging and as a result a delay in diagnosis is frequently seen. […] The delay in diagnosis is mainly due to insufficient knowledge of physicians about PIDs. […] The cornerstone of PID diagnosis is the presence of recurrent infectious disease, and thus family physicians as well as infectious diseases specialists are the first to encounter patients with a possible underlying immunodeficiency. […] Therefore, new strategies for increasing the knowledge of various specialties are warranted for better understanding of PID manifestations by these physicians.

• #50 Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-evaluation-frequency-diagnostic-delay-primary-S0301054620300641

  In addition, factors including type of infection, affected organ, allergies and vaccine-related adverse effects should also be added to the list of PID warning signs. […] Future larger studies are needed to propose a new diagnostic paradigm for early recognition of PID and reduce the diagnostic delay.

• #51 Diagnosing PI | Immune Deficiency Foundation

  https://primaryimmune.org/advancing-pi-research-and-clinical-care/diagnosing-pi

  Consider referral to an immunologist/allergist even if initial diagnostic labs appear normal. […] Healthcare providers can connect for free with an immunologist specializing in PI to go over the diagnosis, treatment, or management of patients with PI. […] The Immune Deficiency Foundation improves the diagnosis, treatment, and quality of life for every person affected by primary immunodeficiency.

• #52 Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

  https://www.mdpi.com/2075-4418/11/3/532

  Primary immunodeficiencies (PIDs) are a large and growing group of disorders commonly associated with recurrent infections. […] Alongside this conceptual development, there has been technical advancement, given by the new but already established diagnostic possibilities offered by new genetic testing (e.g., next-generation sequencing). […] Fundamental is the integration between different specialties and the development of multidisciplinary and flexible diagnostic workflows. […] The availability of specific immunological phenotyping in the last twenty years of the 20th century led to a significant advance in the diagnosing of this group of disorders. […] Even after the identification of causative genes for several defects, laboratory immune evaluation remained crucial for diagnosis of many PIDs due to the prompt availability of the results and to the functional significance of assays that could reflect the severity of the underlying molecular defect.

• #53

  https://indianpediatrics.net/june2013/june-579-586.htm

  Diagnosis of specific PID from a large spectrum of disorders requires expertise in clinical and laboratory evaluation. Wide array of assays are available for evaluation of immune system which help immensely in the diagnosis of PIDs. Knowledge of clinical presentation of these disorders, correct interpretation of initial results of immunophenotyping of lymphocytes is essential for choosing the appropriate test for specific diagnosis.

• #54

  https://indianpediatrics.net/june2013/june-579-586.htm

  In this review we have highlighted the important clinical manifestations of PIDs including the pattern of infections which would alert the clinicians to suspect PID and the laboratory approach required for further evaluation of some common categories of PID. […] Careful clinical evaluation is crucial for recognition of patients with PID. It is important to know the presenting features and warning signs of PID in order to decide the need for further investigations. […] Although this does not include comprehensive list of all signs and symptoms of PID, patients showing these signs must be evaluated further for an underlying PID. […] The results of the initial tests usually give an important clue to the underlying immune defect. Patients with low T cell counts are likely to have combined T and B cell defects (CID). Patients with low or absent B cell and low Immunoglobulin levels with normal T cell fall in the category of predominantly antibody deficiency.

• #55

  https://indianpediatrics.net/june2013/june-579-586.htm

  Primary immunodeficiency disorders (PIDs) are a heterogeneous group of inherited disorders that affect different components of the immune system. There are more than 150 different disorders which have been described till date. Despite major advances in the molecular characterization of PIDs over the last 20 years, many patients remain undiagnosed or are diagnosed too late with severe consequences. Recognizing different clinical manifestations of PID is the first most important step. It should be followed by use of appropriate diagnostic tools from a vast number of investigations available. This review will focus on important presenting features of PID and laboratory approach for diagnosis of suspected cases of PID. […] Prompt and accurate diagnosis of PID not only helps to direct the most appropriate treatment, and predict prognosis, but also it is important for further genetic counseling for the family.

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