Dr. Kitcharoensakkul talks about how to recognize the most comment types of primary immunodeficiencies. She describes the critical warning signs of undiagnised immunodeficiencies and when to initiate an immune workup in pediatric practice or make an immunology referral.
It's so nice to see familiar names on the audience list today and thank you for being here. So, I'm an associate professor of pediatrics. Uh, I did a fellowship in both rheumatology and also allergy immunology. So I see a wide range of patients with immune deficiency and also immune dysregulation. And I will try to make this talk, uh, as practical as possible for, uh, pediatricians. I have no relevant financial interest to disclose regarding this talk today, but I have research support from, uh, farming health which is not relevant to this talk today. By the end of this talk, I hope you, it will help you recognize the critical warning signs and symptoms of undiagnosed primary immunodeficiencies in practice. Also help identify and describe the most common types of immunodeficiencies. Decide when to initiate immune workup in pediatric practice or making an immunology referral. And finally, explain the roles of pediatricians in managing IEI patients. Um, So in the past, we used to call this group of disorders as primary immunodeficiency, and it's still the term that I use when we talk to patients and families. However, there's a tremendous effort over the past 10 to 15 years to Changed to preferred terms of either inborn errors of immunity or IEI or genetic errors of immunity or GEI. So when you read the literatures, you will see this word more commonly than primary immunodeficiency. The reason for that is because this is not considered monogenic disorders that can cause either immunodeficiency or immune dysregulation or both. And so far, as of 2025, there have been at least 550 genetic defects known to cause immunodeficiency. So that's why there's a push to call this as a genetic errors of immunity. Um, and then you can see there's an exponential growth after the discovery for immunodeficiency over the past 10 years. Before we go to the common types of IEI, uh, I just would like to go over, uh, the main components of the immune system. This is to give you a background when you see patient because patients who have either primary or acquired defect of these organs or these cells can lead to increased susceptibility of infection and also immune dysregulation. So for human immune system, we have primary lymphoid organs which are bone marrows and thymus, which is like a birthplace of our white blood cell, including lymphocytes. Then we have secondary lymphoid organs, which is like spleen, lymph node, or mucosa associated lymphoid tissue from respiratory tract or GI tract or genital urinary tract. So if there's any like primary defect that lead to defect of a bone marrow, spleen, thymus, um, Uh, like, uh, airways, GI tract, that they may also be, uh, the immune system may also be involved or if you have acquired immune deficiency because patient has spleen removed, uh, they receive medication to suppress their bone marrow, that also can lead to those. Symptoms because they have like acquired suppression of their bone marrow. Now, when we look closer into the microscopic level of our immune system, then we have cells and chemicals that we call cytokines, which work like a messengers to help communicate um messages between all these important cells that we can largely divide these components into innate immunity and also an adaptive immunity. Adaptive immunity consists of B cells and T cells, which is the cells that we have a majority of the clinical testing that we have available and to test the number and function of these two cells, since we know that B cells produce antibodies, so we can check immunoglobulin levels, we can check specific vaccine responses to check that B cell function. And then for T cell, we can check T cell number, and we have a couple of indirect ways that we use to assess our T cell function. Um, including check B cell function because B cells need T cell to, to work appropriately. Uh, then we have innate immune defect. Um, and this is a group of disorders that are very hard to diagnose by clinical testing. Most, uh, testing that we have available is done through genetics, uh, because there's no best clinical testing available. Fortunately, most of the immunodeficiency that we see in clinical practice will mainly involve adaptive immune defect, but there's a rise in the recognition of innate immunity defect in the world of immunodeficiency. In terms of types of IEI or immunodeficiency, uh, currently, we have 10 different defects, and this list like keep expanding over time. Uh, what we call this list we call IUIS phenotypic classification. So what does it mean? It means IUIS is a society that they have meetings every 2 years, try to validate novel gene or novel defect to see if they Can cause immuno, um, uh, to see if they cause immunodeficiency. And then they keep adding the number of each defect into each group based on the main component of the immune system that's affected by that gene. So the first line, you will see the defect on T cell and B cell. When there's a T cell defect in T cell, we call combined immunodeficiency, because when patients have T cell defect, it tend to also affect that B cell function. So we call combined immunodeficiency, and we divided them into syndromic features and without syndromic features. There's an example that you will see commonly in practice would be the jaw syndrome or chromosome 70 to Q11 deletion, that they also can have a midlife defect or they have defect of the thymus cause them to have low T cells and sometimes also involve and DVD deficiency, increase their risk of having infection. Then we have a combined immunodeficiency with our other organ involvement. The example be like skin, severe combined immunodeficiency. Then we have primary and DVD deficiency that primarily caused by B cell defect. Then the second line would be the group that you have defect of mainly innate immune system like neutrophil phagocytes, complement other components of innate immune defect. Then the third line will be more like a mixed bags, including autoinflammatory disorders, which is a group that we mainly see in rheumatology, but we also see immunology. For example, when you see patients with recurrent fevers that you have concern for uh puric fever syndromes, uh, that someone would be primary immune dysregulation, they will be the group of disorder that patients. The primary symptoms will be autoimmunity. The example will be like APEC syndrome, for example, that they have uh defects that from uh FOS P3 deficiency cause them to have no regular, no functioning regular T T cells, so cause them to have enteropathy, endocrinopathy early in life. Then we have bone marrow failure syndrome that mainly seen by hematology. And then we have phenocopies of IEI which is a very small number of patients will fit into this category. So that will not be uh the primary goals of our talk today. Now, when we look at the clinical features, the majority of us recognize that when we have patients with recurrent CV atypical infection, you think about immunology or primary immunodeficiency, but about 1/4 of the patients may present mainly with immune dysregulation at that range of autoimmunity, autoinflammation, granulomas from unclear etiology, severe atopy, lymphoroliferation. Malignancy, HLH and then bone marrow failure. So if you have a patient who have infection plus one of these, or patient have multiple sides of these circles of immune dysregulation, also suggests your concern for IEI. Clinically, we can largely define IEI to be the group that mainly patients present with infection, which is still the majority of patients we see in practice that we call primary immunodeficiency disorder. And then we have another group that mainly they present with autoimmunity that we call PERD or primary immune regulatory disorder. Um, and that affect, uh, the treatment because like if patient really have infection, our goal is to protect them from infection, treat infection or transplant them. And then for patients who have mainly immune dysregulation besides protect them from infection, we also need sometime we need to give them immunosuppression or immune modulation. We try to uh keep the balance between infection and immune dysregulation. And ultimately, the goal is also for cure if it's possible by doing a transplant in selected patients. In terms of patients who see clinical practice based on the 10 categories that we talked about a few slides ago, The most common is still going to be primary antibody deficiency, which are the tests that you can test for in clinical practice by sending immunoglobulin level and vaccine titers in patients who have received vaccines. And then we, and then the next one will be T cell defect, which we call combined immunodeficiency, either syndromic or non-syndromic. And then the rest would be going to be about 1/4 of the patient with immunodeficiency. Uh, so we're gonna try to involve, um, all of the clinical aspect that important for a pediatrician to know in this talk today. In terms of warning signs of symptoms and sizes of IEI, this list also has expanded over time. Uh, they are mainly for clinical presentation of patients with IEI. They have mostly just to present with symptoms like they come to see us or they get referred because they have infection and or immune dysregulation. But we also see patients who presented with abnormality on screen for skin, which we will talk about. Uh, in the last part of the talk today, and then, uh, less than 5% will present with only positive family history or abnormal labs. Um, so we will start with symptoms of how to approach patients who come to your practice with symptoms and when to think about immuno uh IEI. So based on a very big database of more than 10,000 European registry, it showed that uh infection remained the most common symptom despite the expanded list of many new molecular defects of causing IAI. So 70% of patients will present like with infection. However, about 1/4 of the patients, you can see a present present in green will present with immune dysregulation with and without infection. So it's also important to recognize what the symptoms of immune dysregulation, uh, that should raise your concern for immunodeficiency with, uh, uh, population that have low consanguinity and family history will be the primary symptom in less than 5% of patients as mentioned earlier. In terms of infection, if you type on your search engine warning signs of IEI or primary immunodeficiency, this list will pop up. And if patients have 2 of these 10 warning signs, then we should consider immune workup or refer to immunology. And this list include uh 4 or more new ear infections within 1 year, 2 or more serious sinus infection within 1 year, 2 or more months on antibiotic with little effect, 2 or more chest X-ray confirmed pneumonia, not only by auscultation within 1 year, failure to thrive after exclusion of other etiologies, recurrent abscesses, persistent thrush in mouth or fungal infection on skin. Need for IV antibiotic to clear infection, 2 or more deep-seated infection, and a family history of IEI. If you uh don't have opportunity to uh uh search, uh, one, on the, you know, website, one of the things that you can use is to think about IEI when you have patients have recurrent severe, persistent, unusual, or associated with other features listed here, they have more than one of these, they need to think about IEI. In terms of autoimmunity, which type of autoimmunity. So this can be from head to toe, but the one that's the most common would be autoimmune cytopenia, particularly if they have ITP plus AIHA or auto hemolytic anemia, or we call in short Evans syndrome, uh, up to half of the patients in pediatric patients may have underlying immunodeficiency. Or patients who have early onset endocrinopathy, uh, interstitial lung disease of, uh, from unclear etiology, bronchi bronchitisis from unclear etiology, early onset enteropathy, or per anal fistula, or refractory unexplained skin lesion, and then a systemic disease is such as rheumatology multiple rheumatologic diagnosis. So this is only the example and then um just want to give you a tips uh in for, for prac for practicing, uh, we should consider immune workup or referral to immunology if you have patients in your practice with a combined autoimmunity and infection or a proportion of immunosuppression they are on, early onset. Autoimmunity, for example, early onset IBD when you have patients who have inflammatory bowel disease diagnosed before 6 years of age, uh, to raise a concern for AEI although only like 10 to 20% of them may have underlying, uh, immunodeficiency, multiple autoimmunity, rheumatology diagnosis with a typical manifestation. And that would be probably rheumatology will help rheumatologist will help you uh make those decisions, recurrent inflammation from unclear etiology, early onset endocrinopathy, severe or multiple atopy with infection or with autoimmunity, and recurrent or childhood onset HOH that they, that for HOH that you should trigger genetic testing and immune testing on this patient. So once you have patients uh in your clinic with meet with either warning signs of infection, or immune dysregulation for IEI, there are two steps that you can take. Number one, you can think about go ahead, we will refer to immunology, or you want to go ahead and send initial lab testing. So I'll give you the list of uh some of the common labs that we use for initial immunology screening. Now, after you send the testing, Uh, if it's normal, but you continue to have suspicion for AI, you still can refer to immunology. We're always happy to see your patients. Um, just to keep in mind that it's also important to look for other causes of infection on those patients. Uh, we try our best to look for immunodeficiency or IEI in patient that referred to our clinic, but they use still probably like 10 to 15% of them end up to have that to have immunodeficiency. Many of them end up having other diagnosis. The most common we see would be like uncontrolled asthma that make them look like they have recurrent uh pneumonia, or sometimes they have like uncontrolled uh allergic rhinitis cause them to look like they have recurrent sinusitis, and sometimes can be a combination of both. Sometimes her patients have both or more than one diagnosis exists in one patient. Um, in terms of initial labs, if you decide to send before referral, uh, that would include CBC and differential, mainly to look at the, uh, cytopenia. In terms of white blood cells, we want to look for both neutropenia and also uh lymphopenia, low lymphocyte count, uh, quantitative immunoglobulin levels, very important to use age reference level because the lower limit of normal change by age. And also if patient receive vaccine before is to check vaccine titers, if patient Did not get vaccine, um, usually, it's very low yield to send the test because you don't know they have low titers because they never received a vaccine. Uh, on the contrary, you might want to see if they have natural protection from infection, but usually, we highly recommend to get that vaccine up to date before send vaccine titers. And the vaccine titers that we commonly order uh tetanus and strep pneumo. If patient less than less than 5 or 6 years old, you also can send hip titers. Uh, it's not uncommon to see low or undreable hepatitis in an older patient, because usually it's not a common infection in older kids and usually the, uh, HIPAA certificate usually doesn't last that long. So usually, like, uh, in terms of like hepatitis, usually we send in the younger kids, but in older kids 5 years and older, you then you send tetanus and strep pneumo. Usually, we don't send vaccine title to viral vaccine like varicella, measles, mumps, unless you send for other reasons. The reason for that, many patients, even though they receive up to-date vaccine, they may have equivocal or low titers because the response to those vaccines they be like. On T cell, and we have no great way to test our T cell function. Um, we, you know, there are no test that we can incubate, incubate like T cell with the vaccine and then see if the patient T cell periphery. There's no, no, there's some tests like that, but doesn't apply to our vaccine yet. Um, and then send flow cytometry to look at a subset of lymphocytes. This is really depends on your level of comfort in terms of interpreting, interpreting test results. Um, one, caveat about sending lymphocyte subset is that it's a test that's sensitive to illness. If you stand too close during the time the patient has illness, sometimes it's patient can have transient lymphopenia. Uh, look like that's gonna raise your concern for immunodeficiency. But, however, you may have more concern if it's persistent. If after recover from illness or from after steroids for at least 6 weeks, if it's still persistent, then that will raise the concern. It's very common, particularly in young children, to have transient neutropenia, lymphopenia, very acute illness, and usually pop back up after you follow up 6 to 8 weeks later. And then other labs in specific cases, we will talk about briefly today. In terms of, in terms of vaccine, I want to mention a little bit about the pneumococcal vaccine. Since now we have several pneumococcal vaccines available. And it's important if you want to send vaccine titers in your practice, you kind of need to know which serotype that uh patient received, like which Prevnar, uh, do, did they receive 1315 or 20 because you want to interpret the result based on the serotypes that vaccine the patient received before. Um, and, uh, for Pneumovax, we, we still use it, uh, to test for specific antibody deficiency in patients who's 2 years and older. Although I understand it may not be available in, uh, many practices now since we have Prevnar 20 available. Uh, to consider normal response, we use serotype, we cut off at least 1.3 in at least 70% of serotypes in the vaccine that patients received before in patients at 6 years and older. In patients older than 6 years old, and at least 50% of stereotypes in patients 2 to 6 years old. In terms of other labs, it really depends on your clinical suspicion. Uh, if you have a concern for CGD or chronic grano metastasis, you can send, uh, neutrophiliosity burst test, or we call the HR dihydroruamine test in patient with recurrent, uh, persistent or severe bacteria and fungal infection. But when you send this test, many times you need a control and it's sometimes it's hard for external lab to find control to send the patient samples. And then to test for a classical and alternative complement pathway or we call CH50 and AH50 in patients who suffer from severe encapsulated bacterial infection, particularly neisseria infection. If patients have low IgG also need to consider, do they have protein loss, cause them to have acquired low I acquire condition, uh leading to low IgG that include look at the serum albumin to look at the protein losing enteropathy, total protein, and urinalysis to look for uh nephrotic syndrome, uh, in patients who have consistent symptoms. And then HIV testing for patients who have persistent lymphopenia. We rarely see HIV now in clinical practice, but, uh, we do send test if we find patients who have a lot of opportunistic infection, who have persistent lymphopenia. And then in our emergency clinic, we also send genetic testing more and more often these days, uh, due to increased recognition of IEI that can present with various presentations. So this is a common step of evaluation when you refer a patient to see us in immunology clinic, uh, we see patient for clinical evaluation, determine what tests should be done, and see if, if they should send you to testing too, or we should hold off, analyze all these testing results, and then see, uh, how like if they have, uh, immunodeficiency or they do not. And if they have immunodeficiency, then that will lead to treatment. So, uh, I will just, the last, uh, half an hour, I will just give you a case study, uh, about the, um, uh, patient that, uh, may present to your clinic and hopefully they'll give you some case examples, uh, how to approach this patient in clinical practice. The first one would be a 12 year old with recurrent syop pulmonary infection, which is one of the most common referral we see in immunology. So this is 12-year-old vaccinated male with recurrent pneumonia confirmed by chest X-ray. Recurrent or that is media. This is post 3 sets of ear tubes and also recurrent sinusitis 3 to 4 times per year. So if you look at the warning signs on the list uh for you earlier, patient will need about 32 to 3. So we said if it's 2, we should think about immunodeficiency. So we send immune testing and CBC showed no cytopenia. So we send immunoglobulin level, and then immunoglobulin level show low IgG and low IgA. And then when you send a vaccine titer response to tetanus was normal, but response to pneumo after booster with pneumovax was low, less than 70%, uh, which is low for 12 year old patients. So that will raise your concern for antibody deficiency because besides low number, they also have low specific antibody responses. You also send neutrocuriosity burst to look for uh CGD and that's come back normal because of, of the history of pneumonia. Uh, before we move on to what diagnosis this patient has, I just want to give you, uh, some, a reminder of when we interpret immunoglobulin levels. It's very important to use reference values, uh, because you can see the lower limit of normal increased by age. IgG level of 350 will be normal for 3 years old, will be considered low for 10 years old, for example. And sometimes, When you send a patient to get labs at LabCorp or Quest, they will use a dull reference range. So when the results come back, you want to make sure you look up and I give you a reference here. There are several references available, including Mayo, Harriet Lane and up to date, also have their own lower limit of normal. That's quite comparable, but there's some differences. And one is low. Uh, usually we want to confirm at least one more time and to make sure it's persistent. And uh once we've confirmed that patient have hypogamma globulinemia, we want to see this primary from IEI or they have secondary hypogamma globulinemia, or both. Now, this is a common acquired causes of hypogamma globulinemia, including rheumatologic medication. B cell depleting therapy, for example, rituximab, if patient received them for autoimmune etiology, also can lead to low B cell count, also low IgG, long-term use of corticosteroid, several anti-epileptic drugs also can cause hypogamma globulinemia and of course chemotherapy. There are also some non-medication causes of acquired hypogammaglobulinemia, for example, nephrotic syndrome, protein lucid neuropathy, lymphoma, and in adults, uh, lymph chronic lymphocytic leukemia and with multiple myeloma also will be in differential diagnosis. So back to our patient, uh, we get that results back. It showed that it's come back low. So we check Ig albumin to make sure this is not low because of protein loss. The fact that patient have normal tetanus probably is not from the protein loss, it's important to confirm. And then have normal urinalysis, uh, others to, to look for, to make sure the patient doesn't have protein loss. Then we look for T and B cell count, and they were all normal. And we again review history to make sure there's no acquire causes of hypogamma globulinemia. At this point, we feel comfortable to diagnose this patient, what we call common variable immunodeficiency or CVID. And this CVID is one of the most common immunodeficiency that they diagnose in adult uh immunology patients, but we also see them in uh pediatric population. Let's talk a little bit about CVID. Uh, CVID, majority of them in adults, as mentioned, about 1/5% of cases will be diagnosed in adulthood. And to diagnose this patient needs to be at least 4 years and older. That way that we can rule out transient hypogamma globulinemia of infancy. And besides low IgG, they usually have at least also low IgA or IgM and they have poor and deeply respond to at least 1 vaccine if they are vaccinated, and also need to exclude other causes. CVAD is an example of the disease in the group that we call primary antibody deficiency. And as mentioned earlier, this is a group that you see most commonly in clinical practice. Patients can present with either infection and or immune dysregulation. That include recurrent cytop pulmonary infection, gastroenteritis, septic arthritis, mostly bacterial, but they also can have infection from enteroviruss, particularly meningitis, GIa lambar, mycoplasma, and also from cryptosporidium. In terms of immune dysregulation, they can present with non-sever bronchiectasis, um, multiple autoimmunity, particularly cytopenia, lymphadenopathy, or granulomas. And the disease in this group can be largely divided into five categories. Uh, the one that we talked about is CVID, but the more severe phenotype called a gamma globulinemia called XLA or X gamma globulinemia. That they have virtually absent immunoglobulin level and also B cell count. Then we have hypogamma globulinemia that have a low IgG, but they have normal vaccine responses. Then we have a specific antibody deficiency that we can diagnose in patient 2 years and older. Uh, when they have normal immunoglobulin level and poor response only to polysaccharide vaccine, i.e., Pneumovax. Then we have selective IgA deficiency. Also a reminder to diagnose undetectable IgA, they need to be at least 4 years old. To have undetectable IgA in patient less than 4. And usually we, we see that as a part of a celiac screen, that usually not a red flag for immunodeficiency. Uh, and for to diagnose CT HA deficiency, they need to be undectable as less than 7. So in summary from the first case, you get to see a patient who presently had no pulmonary infection that ultimately diagnosed with CVID and then we ultimately syn genetic testing and it came back negative. So patients start on immunoglobulin uh replacement therapy and usually does require long-term treatment and also monitor for symptom of immune dysregulation that can develop in this patient over time. Now for the second case, this patient presented with multiple autoimmunity in rheumatology clinic with no history of infection. So this is an 11 year old, a girl who presents with a history of GAA. This is her elbows. You can see the enhanced. Be a carcinophil membrane here. Uh, she was diagnosed with, uh, JRA since she was 17 months old. And at the time, you know, since she's gonna be on immunosuppression, we check her liver enzymes. She also thought to have hepatitis, and the additional workup showed that there's not exact infection, and she has positive and high smooth muscle that is a concern for autoimmune hepatitis. Now, at 11 years old, 10 years later, her JA was well controlled, but then on uh anti-TNF and uh DMARD leflunomide, but then she was admitted for vasletic rash, looked like typical HSP, you know she like purpura, uh, but also flare of her arthritis, or that can be a part of HSP too. So given, uh, multiple autoimmunity with like liver, and in our skin, even though she has no history of infection, we send repeat testing for like lupus and the test came back negative. Uh, as you know, NAI is only a screening test, but her specific antibody to lupus were negative. So we sent additional immunology testing, and the tests that I, uh, listed to you earlier all come back normal and remarkable, except she has only mild. Uh, B cell lympmphopenia, that has the B cell a little bit low, which is usually not like a, not to the degree that we're concerned about primary antibody deficiency. However, the family now reported multiple family members on the dad's side with autoimmunity, very limited history of infection, measures multiple autoimmunity, including AIHAITP, Crohn's disease, multiple myeloma. Uh, JRARA sarcoidosis. So that raised a concern for IEI as mentioned, despite without infection, if they, if they have multiple autoimmunity, concerning family history, should raise a concern for eye. So we sent genetic testing and patient found to have a rare condition that we called CTLFO haplo insufficiency inherited from father. So that also led to diagnosis in her father too. So what is this disease? This is a disease that can present within within any medical specialty. Since the CTUA4 used to inhibit T cell activation. So when patients have deficiency of this protein, patient will have a lot of T cell activation that cause autoimmunity. Uh, and, uh, patient will also have increased risk of lymphoma, multiple myeloma, and gastric cancer, even though, even the carriers who are symptomatic, they also can have increase of cancer. So they need to be followed in cancer predisposition clinic. And it's very important to make this diagnosis because there are, there's specific therapy available that we call Abatacept, which is a CTOF4 immunoglobulin that we already used to treat patients with rheumatoid arthritis and GRA and many other autoimmune conditions. So there's a specific treatment available. And uh So for this patient, it's just an example that um to have the the diagnosis, they will lead to the target therapy. So in terms of her treatment, after she was diagnosed with a CTOA4 heloinsufficiency, then we switched her medication to the target therapy with Avata. And her liver enzymes are normalized two months after starting her on therapy and have have remained within normal limit at the last follow-up, and she has no recurrence of HSP which can be incidental or can be a part of the presentation of CTLFO heploin sufficiency. Um. This is to give you an example of diagnosis of IEI on this patient led to target therapy, uh, make, make curative therapy option possible for them because there's an increasing report of uh transplant for these patients also change. In disease monitoring, like we, we refer patients to cancer predisposition clinic to monitor for uh cancer and also genetic counseling for the family, uh, with the reproductive rate, 50% rate of passing on to the next generation. So the second case is an example of patients who have immunodeficiency or IEI even though they don't have any infection despite on immunosuppression, but they have multiple autoimmunity at such a young age that lead to a diagnosis and treatment for immunodeficiency. Now, the last 10 minutes, I just would like to talk about our approach for patient with abnormal born spleen for ate, or like what happened to them after you referred this patient to see us in immunology. As you know, we have newborn screening in both Illinois and Missouri. And that's what it usually looks like when you receive the report from the state uh newborn screen. Uh, so this is a 5 year old male who presented, you receive a card, the patient normal newborn screen. Patient born full term, completely healthy, no family history of immunodeficiency, agreeing to older healthy siblings, normal vital sign, normal growth, uh, exam findings. Admission, but the patient was flagged to have abnormal newborn screen. So what do they do? You can see here they show up as a cycle threshold. This is a PCR cycle threshold. So if it's a PCR cycle higher than 37, it means they have very diluted protein that we call TREC. And TRAC stands for T cell receptor cigen circle, which is a marker of new T cell production. So it means that patients have lower trait, which means they have lower new T cell production, that there's a concern for skin. So trick, uh, that used in newborn screening, this is a, um, it usually fun during new T cell production during the process of VDJ recombination. This is the process that needs to occur to create diversity of a T cell receptor and we can respond and react to various These kinds of germs. So when patients have low trick, it means they have low T cells, it doesn't mean they have skipped. So some patients have many patients may have false positive screening because they can have low T cell or lower new T cell production from various causes. And I will show you examples. And when they have undetectable trait of highly abnormal newborns for screen, we think about two conditions, it's a skid or a thymia. So both of them can cause low T cells because our lymphocyte we produce some bone marrow, and after that they need to migrate to thymus to make. Tissue and develop into naive T cells. So when you, when we have no low T cell, this can be a defect from thymus or we call a thymia, for example, the, or can be a defect from the bone marrow that we call skid. That's how we, uh, term it a little bit differently, but most patients have low T cell. Um, sulfa skid is a genetic disorder caused by defect in T cell differentiation in bone marrow, and sometimes it also affects B cell and and K cell, but both of them will cause very low T cell production. The reason for us to differentiate between the two because the treatment is different because um when we have low T cell, we have uh the additional testing that we do, including genetic testing to see what type of defect because if patient have Uh, skid from bone marrow defect, they need bone marrow transplant. But if they have thymic defect, they'll need thymic transplant, um, suddenly to a different form of treatment, uh, and usually we determine that by genetic testing, um, or other tests, or the other tests. In 10 years before, before we have newborn screen for ski in Missouri and Illinois, patients uh will present with infection. However, if after newborn screen, many patients who can have infection despite newborn screen. Sometimes it takes time to get to transplant and also, uh, sometimes there are also very 1% of cases, very low rate of uh patients missed from newborn screen. So you see we're gonna want to have index of suspicion of skin in patient who have history of hospitalization for opportunistic infection, for example, like PJP pneumonia, that this patient have a pneumocystis pneumonia. Chronic diarrhea and failure to thrive after our other etiology, recurrent or pers persistent oral thrush, and usually it's a thick, deep thrush like that, like, uh, this patient with BRAC1 deficiency, failure to thrive as mentioned, and some of them also have uh syndromic uh features including neurology of skeletal involvement. Um, if you have, uh, newborns or infants with persistent lymphopenia, as mentioned, it's very common to see transient lymphopenia when they have. Viral illnesses, but you happen to repeat and then they remain persistent, uh, below 1000 all the time in young kids, in very young kids like infants, uh, as mentioned, absolute lymphocyte count change over time to the lower limit of normal, kind of need to think about skid or immunodeficiency too. Also important to keep in mind that majority of patients with Skiet do not have positive family history. Many of them are new mutation or they form autosomal resistive disease. The parents are carrier, but they don't have disease. The other manifestation I want to point out in case you have a patients present in your clinic with diffused erythroderma, uh, from unclear etiology, one of the, uh, this can be potential manifestation of skin, uh, that we call leaky skin because they have residual T cell number and function left over that cause them to have immune discirculation, cause them to like they have severe eczema, but it's very red, very scaly. Uh, some patients also can have a low pitch here, also can have splenomegaly from lymphocyte infiltrate in the lymphoid organs. Um, if you check labs, they also can have eosophia and elevated serum IGE because they have TH2 deviation from immune dysregulation. This also can be a manifestation of skin patients. Luckily, you know, we have in Missouri, we have newborn screened for skid since 2017 and in, in Illinois, we have it since 2014, but we start pilot a year or two before that in Missouri. So as of now, uh, newborns are screened for skid in the US. The reason because usually patient, patients are symptomatic at birth, and we want to diagnose them, I'm so sorry, we want to diagnose them before they have their first infection. Uh, which is like, uh, and also before they have a rotavirus live vaccine. Uh, that, and there's a treatment available, which is mentioned as a bone marrow transplant or thymic transplant or other treatment. It's also been shown recently that if we diagnose patients by one screen, the red line here, they have a better survival, better than if they already diagnosed because they have clinical infection, their 5-year survival can go down from 92% to 80%. It's even better to diagnose uh through newborn screening than from from family history. So it has been shown that newborn screening helps improve survival of patients in the US and Canada. Now, I mentioned earlier, earlier, some patients who have abnormal liver screen for scared. They do not have scare. So what they end up having, they can be completely having normal lymphocytes, but they also can have confirmed they have other syndrome like trisomy, which can be obvious on exam, but also So the George uh testedangi uh it can be from the diabetic, uh, infant of diabetic mother, uh, various syndromes also can be from security T cell lymphopenia from a thirst space loss, uh, from maternal immunosuppression such as like azathioprine, uh, or from chemotherapy or from leukemia. So there are many other secondary causes can cause patients to have false positively screen for skin. Uh, so in summary, When we have patients with abnormal skin screen, what we will do the next step, we will do confirmation. It doesn't mean they will always have skin, uh, but we need to send tests. However, if it's highly abnormal, then likely they will have skip. Then there are 3 possible outcome. Uh, about 40% will be completely normal, we call false positive. Half of them have low T cell, but they do not have skip, but they have other causes for them to have skip. And then about 10%, this is a data at children's uh that we published 5 years ago, about 10% turned up to have skin or complete jaws require specific treatment. So patient can present to you in, in two fashion. Most of them will present with abnormality on screen, but some of them will present with clinical manifestation. So if you have patient concern for skin in your practice, it's important to send CBCs, look for lymphopenia, and also send fluocytometry, and that also can be referred to as in immunology, and we can assist with, uh, specific testing. And then, uh, usually we also send genetic testing that will lead to specific treatment on those patients. So on on our index patient, we sent flow cy dormetry to look for a TB and NKSL. And as you can see here, patients have a detectable T cell and very low NKSL. So we call minus because they don't have T cell, B+, they have normal B cell count and N scale. So this is consistent with Xing um skid uh for mutation of uh. Uh, to receptor gamma genes, so this patient ultimately gets transplant and he's about 76, 7 years old now. He's doing very well. So in summary, you learn about 3 different cases, we have 3 different presentation, including infection, immune dysregulation, and abnormal newborn screen. In terms of treatment, currently, treatment as available as of 2025, it includes supportive treatments such as we do anti antimicrobial prophylaxis, immunoglobulin replacement therapy, immunization, Um, curative treatment, we have transplant, as mentioned, and gene therapy. Target therapy, if available, for example, like biologic agent like this patient with CTLL4 CTL CTLL4 hapco insufficiency as mentioned earlier. Or other specific treatment listed here. So it's the main three treatment options we have. So sometimes when we have complicated patients come to our clinic, we try to seek, to see like, you know, if they will be eligible for this treatment option, but that really start to submit diagnosis before we can jump to treatment. In terms of pediatrician, the role of a general practitioner in help managing IEI would include regular health screenings. Uh, sometimes the immunology be very focused on the immunology and sometimes, and we try to be as thorough as possible, but we want to remain in close communication with patients, pediatricians, um, including immunization that, uh, you also can help. Diagnose and treat acute infection, monitor for complication of disease and other comorbidities, modify other risks for illness including mental health. As is with ordering IVIG, we don't do this that often, but sometimes, uh, you know, if we don't have license in certain states, sometimes we need help with pediatrician to help with IVIG order. And uh for vaccination, I would like you to give you, so if you type immunodeficiency Foundation, there will be a handout available for pediatric uh for general practitioner in terms of diagnostic and clinical care guidelines for primary immunodeficiency. And they will give you some recommendation. Live vaccine usually allow except if patients have severe T cell defect or severe activity defect. Other than that, you should attend, we tend to allow patients. If you're not sure, you also can reach out to us. Um. For a family member, usually we encourage them to receive vaccine, including yearly influenza vaccine. However, certain vaccine caution must maybe need to be, must be exercised in some patients who have severe T cell immunodeficiency or severe antibody defect. And again, don't hesitate to reach out to us. So in summary, a clinicians play a very important role in identifying IEI and we're talking about warning symptom and size today. And uh it's essential to raise the concern for IEI in patient, not only with infection, but if infection, but particularly patient with infection and autoimmunity or multiple autoimmune disease, very early onset autoimmunity. And a newborn screening is vital and it has been shown to be helpful in improving. Uh, prognosis of patient with scare. And genetic testing has become a very important component of the immune workup for diagnosis of IEI. Uh, in, and I would like to show, uh, pictures of our group here. I cannot do anything, everything by myself is a group effort and actually we have a bigger group of both allergy and rheumatology, uh, taking care of inpatient. But for outpatient, we have a solid group of, uh, Dr. Cooper, who is our division director. Then you have Doctor Horner, Doctor Beneski, who transplant majority of our patients with immunodeficiency, Dr. Schmidt, Doctor Fogel, and Kate, uh, Catherine Baron, who also Uh, see our immunology patient in clinic also inpatient, and we have dedicated nurse and scheduling staff and research coordinator for immunodeficiency. And um I'm welcome any questions. Thank you.
Related Presenters
