Primary immunodeficiencies: when to worry about your child's immune system?

Primary immunodeficiencies: when to worry about your child's immune system? One of the most frequent concerns from the parents of my little patients (and I am sure this is valid for all pediatricians) is that their child is having too many infections. Where do we draw the line and start being concerned? When we shouldn't worry anymore? What to do to find out? In order to be able to say that a child has too many infections, it's mandatory for pediatricians to know what is normal with regard to the type, frequency, severity and localization of the infections in healthy children in the area where the patient lives. This is important because like this we avoid unnecessary studies and we can properly diagnose a primary immunodeficiency. Early diagnosis is paramount for a good prognosis of the patients and the responsibility of raising the concern belongs to the general pediatricians, who follow the babies and children regularly. Every general pediatrician who sees a usual number of around 20-30 patients per day has at least one patient with a primary immunodeficiency and this number increases in populations with high degree of consanguinity. This is why awareness is important not only for patients and parents, but also for health professionals. What are the PIDs? Primary immunodeficiencies are defined by an increased susceptibility to infections (more frequent, more severe or produced by microorganism which are usually not harmful to healthy people) or an inadequate response to various situations, with predisposition to develop allergies, autoimmune phenomena, failure to thrive, malignancy (mostly lymphatic), among other manifestations. They imply abnormalities in the quality and the quantity of different mechanisms involved in the immunological response. The word primary means that the patient is born with the condition, even if the clinical manifestations appear later in life. One cannot catch or develop a PID. How are PIDs classified? This field of knowledge is pretty new and more and more diseases are being defined every year. We are currently able to diagnose more than 200 different entities, with known genetic or molecular defect in more than half of them. The International Union of Immunological Societies (IUIS) Expert Committee for Primary Immunodeficiency periodically revises and classifies all known immune deficiencies. In their last document, published in April 2014 (http://primaryimmune.org/wp-content/uploads/2014/05/iuis-classification-april- 1

2014.pdf), nine major groups of PIDs are defined: Combined immunodeficiencies Combined immunodeficiencies with associated or syndromic features Predominantly antibody deficiencies Diseases of immune dysregulation Congenital defects of phagocyte number, function, or both Defects in innate immunity Autoinflammatory disorders Complement deficiencies Phenocopies of PID Are they frequent? The more severe PIDs, like the severe combined immunodeficiency, are rare diseases, seen in about 1 in 30.000 newborns, but the milder ones, like the selective immunoglobulin A deficiency, are seen in around 1 in 400 newborns. The real problem of PIDs is that they are severely under-diagnosed (it's calculated that only 10% of them are diagnosed), because of the rarity of some and because of the lack of proper training among health professionals. The predominantly antibody deficiencies group is the largest, comprising more than half of PIDs. How to suspect a PID? What are the alarm signs? What happens when we get in contact with a microorganism is the result of a very fragile balance between the microorganism itself (how strong and virulent it is, how many of them we get in contact with) and the activity of our immune system, or defenses against these potential killers. It's important for health professionals to keep a high suspicion for PIDs whenever they evaluate a patient. The Jeffrey Modell Foundation (http://www.info4pi.org), a nonprofit global patient organization established in 1987 by the parents of Jeffrey, a child who died at the age of fifteen from complications of primary immunodeficiency, publish the periodically revised warning signs on immunodeficiency, which should be known by all pediatricians, but also by parents. 10 WARNING SIGNS OF PRIMARY IMMUNODEFICIENCY 1. Four or more new ear infections within 1 year. 2. Two or more serious sinus infections within 1 year. 3. Two or more months on antibiotics with little effect. 4. Two or more pneumonias within 1 year. 5. Failure of an infant to gain weight or grow normally. 6. Recurrent,deep skin or organ abscesses. 7. Persistent thrush in mouth or fungal infection on skin. 8. Need for intravenous antibiotics to clear infections. 9. Two or more deep-seated infections including septicemia. 10. A family history of PI. Primary Immunodeficiency (PI) causes children and adults to have infections that come back frequently or are unusually hard to cure. 1:500 persons are affected by one of the known Primary Immunodeficiencies. If you or someone you know is affected by two or more of the following Warning Signs, speak to a physician about the possible presence of an underlying Primary Immunodeficiency. From the Jeffrey Modell Foundation: http://info4pi.org 2

For adults, these signs are a little different: 10 WARNING SIGNS OF PRIMARY IMMUNODEFICIENCY FOR ADULTS 1. Two or more new ear infections within 1 year. 2. Two or more new sinus infections within 1 year, in the absence of allergy. 3. One pneumonia per year for more than 1 year. 4. Chronic diarrhea with weight loss. 5. Recurrent viral infections (colds, herpes, warts, condyloma). 6. Recurrent need for intravenous antibiotics to clear infections. 7. Recurrent, deep abscesses of the skin or internal organs. 8. Persistent thrush or fungal infection on skin or elsewhere. 9. Infection with normally harmless tuberculosis-like bacteria. 10. A family history of PI. Primary Immunodeficiency (PI) causes children and adults to have infections that come back frequently or are unusually hard to cure. 1:500 persons are affected by one of the known Primary Immunodeficiencies. If you or someone you know is affected by two or more of the following Warning Signs, speak to a physician about the possible presence of an underlying Primary Immunodeficiency. From the Jeffrey Modell Foundation: http://info4pi.org When studying a patient suspected of PID, the patient's and family's medical history is of extreme importance and pediatricians, as well as physicians caring for adults, need to know what to look for. A complete physical examination looking at characteristics commonly forgotten completes the initial phase of raising the suspicion for PID. At what age are PIDs diagnosed? Although PIDs are congenital, the clinical manifestations can appear in newborn and very young babies, as well as older children and even adults. The age when the first symptoms appear is useful in orienting towards a specific diagnosis. Usually, severe forms of PIDs, such as the severe combined immunodeficiency, start to create problems very early in life, while patients with milder forms can reach adult age with no significant symptoms. Antibodies deficiencies usually manifest themselves after 6-8 months, when there is a significant decrease of the maternal antibodies in the baby's immune system. Some PIDs require a minimum age to be diagnosed, like, for example, the immunoglobulin A deficiency, which cannot be diagnosed in a child younger than 4 years, or the immunoglobulin G subclass deficiency, diagnosed in children older than 7 years. There are also many partial, also called hypomorphic defects, which can manifest a lot later than usually and probably with milder symptoms. Which microorganisms are associated with PIDs? Virtually all. The classic, severe PIDs, are usually associated with infections produced by germs which are harmless for healthy children and adults. Other PIDs can mean simply having a lower capacity to respond to usual germs, having more complications or slower healing than in healthy people. There are also specific disorders which imply susceptibility to only a few very determined microorganisms, while having a good immune response to others. The type of microorganism and the course of the diseases are helpful hints towards finding a correct diagnosis. How are PIDs diagnosed and studied? Testing for a PID usually means complicated, expensive and rare tests, that can be done only in specialized laboratories. Nevertheless, most PIDs, together with the clinical pictures, can be ruled out with a 3

very simple blood test, consisting of a complete blood count and plasmatic immunoglobulins. It is very important for physicians to know the normal range for these values, since they vary a lot with age. Clinical data which may raise a suspicion of PID (examples) Family history Consanguinity (when both parents come from the same family) Family history of PID Children deaths in the family due to non accidental causes Severe allergies, severe atopy or severe asthma Autoimmunity Recurrent miscarriages in the family Frequent or severe infections Growth problems, mental delay Patient's history and physical examination Recurrent ear and sinus infections Repeated pneumonias, meningitis, septicemia Failure to thrive Recurrent abscesses Severe eczema Delay in the shedding of primary teeth Petechiae Absence of tonsils, lymph nodes Gingivitis, periodontal disease Low-set ears, uvula bifida, congenital heart disease Albinism, nistagmus, photofobia Telangiectasia (spider veins), big or in unusual places Hair and nails abnormalities, short stature Any genetic disease, especially autosomal recessive forms Same or related PIDs Various PIDs associated with susceptibility to infections or malignancy X-linked diseases, especially in male children's death Immune dysregulation PIDs Autoinflammatory and immune dysregulation PIDs Chromosomal diseases Various PIDs associated with susceptibility to infections Chromosomal diseases Predominantly antibody deficiencies Predominantly antibody deficiencies Many PIDs Phagocyte defects, immune dysregulation, Hyper IgE syndrome Omenn syndrome, Hyper IgE syndrome Hyper IgE syndrome Wiskott-Aldrich syndrome Severe combined immune deficiency Phagocyte defects Di George syndrome Chédiak-Higashi syndrome Ataxia-telangiectasia syndrome Cartilage-hair hypoplasia, T-cell immunodeficiency, congenital alopecia, and nail dystrophy syndrome What treatments are available for PIDs? PIDs are a huge group of lots of very different diseases. This is why, depending of the type, severity, age of the patient and other factors, there are several treatment options: Immunoglobulin substitutive treatment: done periodically through intravenous or subcutaneous injections. They are the base of the treatment for PIDs with antibodies deficiencies, such as the X- linked agammaglobulinemia (or Bruton's disease), common variable immunodeficiency or combined immunodeficiencies. Antibiotics and antifungals as prophylaxis (to prevent infections) can be used in selected cases, adapted to the patient's characteristics and needs. Bone marrow transplantation is a treatment option for more severe PIDs and the only curative one. Gene therapy is also promising for some specific PIDs like adenosin-deaminase (ADA) deficiency or other forms of severe combined immunodeficiency. Specific therapy such as enzyme replacement or immunomodulatory treatments are options for treatment, depending on the underlying PID. For example, adenosin-deaminase (ADA) replacement in ADA deficiency (a form of sever combined immunodeficiency) and interferon-gamma in some patients with chronic granulomatous disease or complement deficiencies. For all patients, preventing, diagnosing and treating early complications and unrelated illnesses is mandatory for a good outcome. There are no effective OTC immune boosters or enhancers and no product has been proven to 4

help prevent infections in patients with a primary immunodeficiency and while some are showing promising results in healthy children, like probiotics, we don't have enough information yet to be able to recommend any similar product for PID patients, who can even experience a worse outcome. Key messages: Primary immunodeficiencies can be very serious, some even deadly without a proper treatment. Early diagnosis is paramount for a good prognosis of the patients. Anything out of the ordinary about infections, regarding the frequency, severity and complications should be an alarm sign to suspect a PID. Some PIDs don't necessarily mean more or more severe infections, but an inadequate response to microorganisms, with excessive or uncontrolled inflammation, allergic phenomena, autoimmunity, malignancy and other manifestations. Awareness for PIDs is important to be able to identify patients early (see the alarm signs). Pediatricians need to know in which patients to start an immunological study and which patients should be referred to an experienced centre in pediatric PIDs. A basic immune study consisting of a complete blood count and immunoglobulins, together with the properly oriented clinical information, can rule out most immunodeficiencies. Most PIDs manifest themselves in childhood, but some can be diagnosed in adults. If you think you or your child have any of the alarm signs or any other concerns regarding the immune system, discuss this with your physician. References Primary immune deficiencies - principles of care. Chapel H, Prevot J, Gaspar HB, Español T, Bonilla FA, Solis L, Drabwell J; Editorial Board for Working Party on Principles of Care at IPOPI. Front Immunol. 2014 Dec 15;5:627. doi: 10.3389/fimmu.2014.00627. ECollection 2014. Consanguinity and primary immunodeficiencies. Al-Herz W, Aldhekri H, Barbouche MR, Rezaei N. Hum Hered. 2014;77(1-4):138-43. doi: 10.1159/000357710. Common dermatologic manifestations of primary immune deficiencies. Relan M, Lehman HK. Curr Allergy Asthma Rep. 2014 Dec;14(12):480. doi: 10.1007/s11882-014-0480-2. Pulmonary manifestations of primary immunodeficiency disorders in children. Jesenak M, Banovcin P, Jesenakova B, Babusikova E. Front Pediatr. 2014 Jul 25;2:77. doi: 10.3389/fped.2014.00077. ECollection 2014. Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment. Ochs HD, Hagin D. Ann Allergy Asthma Immunol. 2014 Jun;112(6):489-95. doi: 10.1016/j.anai.2014.04.007. [Primary immunodeficiencies: they need to be kept in mind] Immunodeficiències primaries: cal pensar-hi. A. Martín Nalda, P. Soler- Palacín, F. Caracseghi, M. Hernández, M. Martínez-Gallo, C. Figueras Nadal. Pediatr Catalana 2011;71:23-29. Primary Immunodeficiency Diseases. N. Rezaei, A. Aghamohammandi, L. Notarangelo. Berlin: Springer, 2008 5