A Review of Primary Immune Deficiency Disorders

Authors: Talin Darian,1 Joudeh B. Freij,1 Divya Seth,2 Pavadee Poowuttikul,2 *Elizabeth Secord2

1. Wayne State University School of Medicine, Detroit, Michigan, USA 2. Department of Pediatrics, Division of Allergy, Asthma and Immunology, Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, USA *Correspondence to [email protected]

Disclosure: The authors have declared no conflicts of interest.

Received: 04.03.20

Accepted: 14.05.20

Keywords: Agammaglobulinemia, deficiency, , innate immune deficiency, newborn screening (NBS), primary disorders (PIDD), deficiency.

Citation: EMJ Allergy Immunol. 2020;5[1]:70-77.

Abstract This scenario-based review of diseases (PIDD) discusses the differential diagnosis, usual presentations, work-up, and treatment of children with the most commonly encountered immune disorders. Newborn screening (NBS) for severe combined immunodeficiency (SCID) is covered, as are later presenting disorders caused by B cell defects and disorders of the innate immune system.

2 INTRODUCTION have different manifestations of the disease. Diagnosis thus requires a thorough knowledge of Primary immunodeficiency diseases (PIDD)patient history, a physical exam, and appropriate can broadly be described as a group of various laboratory tests (which can be nonspecific). There defects of the immune system which lead to a are several guidelines in place to help physicians variable clinical picture of immune dysregulation.1 make a proper diagnosis, such as the Jeffrey 3 The clinical picture present depends upon the Modell Foundation and the American Academy 4 specific immune deficiency, but may involve of Allergy, Asthma, and Immunology. some combination of recurrent infections, Given the complexity of PIDD, this review autoimmunity, atopy, lymphoproliferative provides a scenario-based review of the major disorders, or malignancy. Prevalence of PIDD PIDD, stating common presenting symptoms, is variable depending on the specific immune a differential diagnosis, laboratory tests, and deficiency; studies performed in Korea, Sweden, the treatment and management of the most Taiwan, South Africa, and Singapore all found common PIDD. primary deficiencies to be most common, followed by defects in phagocytosis.1 SCENARIO ONE Because these diseases are very rare, diagnosing them can be difficult and late diagnosis can lead Eli is 9 months-old and has a “constant cold.” He to a worse prognosis and a delay in life-saving has had thick nasal discharge for 2 months and treatment. Further, the same genetic defect can two ear infections that have required antibiotics in

70 ALLERGY & IMMUNOLOGY • August 2020 EMJ the last 3 months. He has never been hospitalised. sequelae, such as autoimmune disease.10,12,13 It is There is no family history of PIDD and his 2-year- a heterozygous disease affecting B cells.14 The old sibling is healthy. Eli was born full-term, and most commonly known defects are mutations newborn T cell receptor excision circle (TREC) in the transmembrane activator and calcium screening for severe combined immunodeficiency modulator, the inducible costimulator receptor, (SCID) was normal. He was born at the 50th and some defects of the cluster of differentiation percentile and is now at the 10th percentile. (CD)-19 molecule.8,11 These defects all affect late B-cell function, and patients with CVID typically B-cell defects or deficiencies may manifest at this have normal total B cells, but many will have age as maternal are waning. The usual low memory B cells (CD19+CD27+IgM-).14 CVID transplacental transfer of maternal IgG occurs cannot be diagnosed before the age of 4 years during the third trimester. A preterm baby may and can only be diagnosed after other identifiable not have received all the usual IgG, but this full- causes of hypogammaglobinemia have been term baby would have received maternal IgG and excluded.11,15 According to the diagnostic criteria should have been making his own at this time. there should also be a two-standard deviation Transient hypogammaglobulinemia of infancy decrease of IgG and either IgM or IgA and an (THI) is commonly identified in the first year inability to make specific antibodies.11,15 of life but some infants have low IgG until they Agammaglobulinemia, which is most often are several years old. Total Ig is low but specific caused by a mutation in the Bruton’s tyrosine antibodies are present.5 Historically this has kinase gene (BTK), typically presents at around been considered a normal variant and some 6-9 months of age when maternal antibody increased incidence of infection may be because levels decline, and the infant fails to produce of THI or it may be coincidental.1,2 THI is a antibodies.16,17 Recurrent respiratory infections diagnosis of exclusion.6 because of encapsulated bacteria, such as Selective serum IgA deficiency is relatively Streptococcus pneumoniae and Haemophilus common in children and adults. The estimated influenzae Type B, are the most common prevalence is between one in 200 and one in infections.2,11,17 Definitive diagnosis requires 1,000.7,8 IgA deficiency is typically asymptomatic the presence of hypogammaglobinemia or but can present with recurrent respiratory agammaglobulinemia and <2% CD19+ B cells in the infections from encapsulated organisms and peripheral blood. X-linked agammaglobulinemia gastrointestinal infection and, although it (XLA) can also be confirmed by the absence of is controversial, there may by an increased the BTK gene.11 incidence of reaction to blood transfusions Mutations in other genes involved in the because of IgG antibodies targeting IgA.9 development of the early B cell can also cause Selective IgA is thought to be symptomatic only agammaglobulinemia.18 These genes include in individuals who cannot make mucosal IgA.9 the μ heavy chain gene (IGHM), λ5 (IGLL1), IgA may be the first Ig class to fall Ig α (CD79A), Igβ (CD79B), and BLNK.9,16 The in the development of common variable autosomal recessive mutations result in a clinical immunodeficiency (CVID). IgA deficient patients picture similar to XLA. are, therefore, usually periodically screened The absence of tonsils has been an important for progression to CVID. Typically, diagnosis finding in XLA research and sometimes aids of IgA deficiency is made after the fourth diagnosis.9,18 Eli presented with recurrent upper year of life and requires that other causes of respiratory infections and recurrent sinusitis, hypogammaglobulinemia and T-cell defects be but cases of meningitis, osteomyelitis, and excluded.9 Eli was 9 months-old and the absence septicaemia because of encapsulated bacteria of IgA would still be physiologic. are common infections, especially in untreated CVID is a primary immunodeficiency that agammaglobulinemia.2,11,19 Patients can also be usually presents in the second or third decade at risk for chronic diarrhoea because of of life with increased infections. The estimated Campylobacter jejuni and Giardia lamblia prevalence is one in 20,000 to one in 50,000.10,11 infection.2,11,19 Because agammaglobulinemia CVID can also present with noninfectious patients have a functional T-cell system,

Creative Commons Attribution-Non Commercial 4.0 August 2020 • ALLERGY & IMMUNOLOGY 71 most viral infections are cleared without SCENARIO TWO any difficulty. However, they are susceptible to enterovirus infection and when the oral Michael is 6 days old and was born full-term poliovirus vaccine was in common usage, it could via vaginal delivery to a healthy mother with no cause meningoencephalitis in individuals with perinatal complications or prenatal illnesses. He 2,11 undiagnosed agammaglobulinemia. is breastfeeding well. His parents receive a phone Increased autoimmunity can be seen in patients call that NBS for SCID is positive. They are asked with XLA but has typically been thought to bring him to the immunologist office at the to occur at a lower frequency compared to local university health centre. 20 other primary . Patients NBS for SCID detects TREC, circular DNA with agammaglobulinemia have a higher remnants that are byproducts of newly formed rate of inflammatory conditions such asnaive T cells.22 The TREC assay was piloted rheumatoid arthritis or Crohn’s disease than the in 2008 in Wisconsin23 and is now utilised general population.20 for NBS throughout the USA and in some other countries.24,25 Some patients present later than the classic 6–9 months because of liberal use of antibiotics Most positive TREC screens are from preterm for less severe infections. It is important not to infants who are not yet making competent T dismiss the diagnosis in older children before cells because of prematurity and/or illness. Some investigation. It is also important to be aware infants have a transient T-cell lymphopenia and of XLA cases reported with, what used to be severe illnesses not associated with PIDD, which classified as “hypo IgM,” normal IgG and IgA but may result in low T cells.24,25 poor specific antibody formation.21 DiGeorge syndrome (DGS), most often because Treatment of XLA involves lifetime replacement of 22q11.2 chromosomal deletion, is a common of Ig intravenously or subcutaneously.2,11 Standard cause of a positive TREC. DGS varies and can dosing requires an initial dose of 400 mg/ affect not only the immune system but also kg every 3–4 weeks and subsequent dosing cause facial anomalies, cardiac defects, and individualised to the patient as determined by parathyroid abnormalities. Complete DGS IgG levels. The goal of treatment is to minimise renders the infant with essentially no T cells infections. Aggressive antibiotic therapy needs because of a lack of the thymic tissue necessary to be initiated when any infection is suspected.2,11 for negative and positive selection of T cells Haematopoietic stem cell transplant (HSCT) is for maturation.26 Although chest X-ray may be not routinely recommended for patients with utilised to evaluate for thymic tissue (‘sail sign’ XLA, despite the wide use in other PIDD, because or thymic shadow), it is not a reliable tool for intravenous IG therapy is so successful and the diagnosis because thymic tissue may be very limited studies on the efficacy of HSCT do not small or in an ectopic location.26 Flow cytometry support its use for agammaglobulinemia.2,11 for T-cell markers is more reliable than a chest X-ray and less invasive than a CT scan for Complete blood count with differential and IgG, verification of a functioning thymus. Flow IgA, and IgM are sent. He has an IgA level <7 mg/ cytometry is utilised to enumerate CD3+ T cells dL, an IgG of 107 mg/dL (lower-limit of normal for in circulation. Mitogen proliferation, especially this age is 217 mg/dL), and IgM is undetectable. to phytohemagglutinin (PHA), is utilised to On examination it is noted that there is no determine if the T cells present are functional.26 tonsillar tissue present. Lymphocyte enumeration is ordered. Eli has no CD19 B cells. Genetic testing The preferred treatment for complete DGS is 26 confirms a defect in Bruton’s tyrosine kinase thymic transplant, with survival rates of 58–75%. which stops maturation of B cells. Eli will have an Thymic transplant is not readily available for most excellent prognosis if treatment is begun as soon patients as it is approved at only a few centres. DGS patients most often have other conditions as possible. that must be treated prior to transplant, most commonly unstable congenital heart disease.

72 ALLERGY & IMMUNOLOGY • August 2020 EMJ Partial DGS, or incomplete DGS, can also trigger a The infant with SCID will not be able to respond positive TREC in infants with low but functioning to vaccines and will be started on replacement T cells. Recovery of adequate T-cell numbers Ig as maternal antibodies wane. They should occurs over time. There is evidence that patients not receive vaccines, especially live vaccines with incomplete DGS are more likely than the which may do harm. Other persons in the home general population to develop autoimmune should receive the influenza vaccine to avoid disease later in life, and it is advisable to monitor endangering the infant.31 these individuals.27 All mothers should be counselled to stop PIDD other than SCID that have variably low breastfeeding until their CMV IgG and IgM T cells, such as ataxia-telangiectasia or even serology is known. It is controversial to advise hypomorphic forms of SCID, may trigger a low breastfeeding if the mother has CMV negative TREC.28 , which is sometimes titers. Some would argue that the mother may associated with a heterozygous defect in the develop CMV. Viral infections, in particular CMV, rearrangement of the recombination-activating remain the most common cause of death for gene (RAG), was often difficult to diagnose infants with SCID. If mothers are seropositive, they before TREC NBS because the infants had a should avoid breastfeeding entirely and the infant severe eczematous rash, lymphadenopathy, should have a CMV PCR performed weekly.31,32 eosinophilia, hepatosplenomegaly, and T and B There are several measures of prophylaxis for cells that are present but nonfunctioning, which infants with SCID. Ig replacement should be 28 are now identified by NBS. started when maternal antibodies wane. Infants with a positive TREC are evaluated to Trimethoprim-sulfamethoxazole for Pneumocystis determine the etiology of the low T cells and to jiroveci pneumonia prophylaxis after all neonatal determine if the cause is SCID. The morbidity jaundice is cleared, fluconazole for fungal and mortality for SCID transplant is decreased prophylaxis, and acyclovir for prophylaxis of if performed prior to 3 months of age, and herpesvirus should be administered. Palivizumab prior to any infectious complications of SCID.29 may be given during the respiratory syncytial Flow cytometry is used to further delineate the virus season. If blood products are needed they number of T-, B-, and natural killer (NK)- should be irradiated, leukocyte depleted, and 30 lymphocytes in infants with a low TREC.30 CMV negative.

Michael’s exam reveals a healthy appearing 6-day- In a study conducted after initiation of NBS, 19% old boy with no heart murmur. Family history is of infants with SCID had X-linked SCID, but this negative for PIDD and Michael has no siblings. type was previously reported to be approximately half of all cases. The same report revealed that Laboratory testing is ordered for lymphocyte other types of SCID are more common than enumeration and mitogen proliferation. Blood previously believed, and the incidence of SCID is is drawn and held for genetic screening. overall much higher than previously reported.24 Breastfeeding is discussed and the mother’s The less prevalent types of SCID were apparently cytomegalovirus (CMV) IgG and PCR are sent to missed prior to the start of routine screening.24,25 the lab. X-linked SCID is caused by defects in the If flow cytometry supports SCID there are common γ-chain of the IL receptor. Mutations in precautions that should be taken for the infant this gene result in absent T and NK cells. These such as protective isolation. Hospitalisation is patients have the typical SCID phenotype, with encouraged by some, but infants can be at home presentation in the newborn period characterised under strict precautions if hospitalisation is not by recurrent severe infections, chronic diarrhoea, practical. When considering whether or not and failure to thrive if not diagnosed via NBS.32,33 to hospitalise the infant prior to transplant, it is important to determine if there are other young Janus kinase-3 (JAK3) deficiency is the other children in the home and if the parents are able T-B+NK--SCID, but it is inherited in an autosomal to strictly supervise the infant until definitive recessive fashion. JAK3 encodes for a tyrosine treatment of stem cell or bone marrow transplant kinase that is coupled to cytokine receptors that can be done. are essential for lymphoid cell development.

Creative Commons Attribution-Non Commercial 4.0 August 2020 • ALLERGY & IMMUNOLOGY 73 This deficiency is virtually indistinguishable from leukocyte antigen-matching for bone marrow X-linked SCID, with the exception that females transplant or stem cell transplant. could be affected.32

If flow cytometry shows absent T, B, and NK cells, SCENARIO THREE suspicion for adenosine deaminase deficiency (ADA) increases. ADA-deficient SCID accounts Hallie is 3 years old and her mother is concerned for 10–15% of all cases.28 ADA-SCID is a purine about mannose binding lectin deficiency metabolism disorder that kills lymphocytes (MBL-D), an immune problem that she read by build-up of toxic metabolites. It affects the about on the internet. Hallie had an abscess in immune system but is not a genetic defect her nappy area about 1 year ago that required intrinsic to the immune system.30 This type of drainage and intravenous antibiotic. Her mother SCID is usually diagnosed in infancy but 15–20% believes they told her it was a methicillin-resistant are diagnosed later in life as infections occur. Staphylococcus aureus (MRSA) infection. She ADA can be missed on NBS if lymphocyte counts has also had several skin abscesses requiring oral have not yet fallen when the NBS card is collected, antibiotic. She has not had other infections and which has prompted some states to add ADA there is no family history of PIDD. Her umbilical enzyme screening to NBS. stump separated at 1 week of age. Dentition appears normal. Before lab results are available SCID that is T- and B-cell negative may be caused Hallie develops a fever of 103° Fahrenheit and by RAG1 and 2 deficiency. RAG are expressed by shortness of breath and is hospitalised. Physical lymphocytes and help to mediate double strand exam reveals a respiratory rate of 50, hypoxia, DNA breakage at recombination sites.28,32,33 and crepitations in the right posterior lung Inherited in an autosomal recessive pattern, RAG field. A chest X-ray reveals a right lower lobe deficiency is one of the defects that can also pneumonia. She is started on antibiotics cause Omenn syndrome. It is sometimes missed to cover pneumococcus and community prior to NBS for SCID because there are often acquired pneumonia. lymphocytes present which may be of maternal origin or clonally expanded T cells of infant The is part of the innate origin that are poorly functioning.33 RAG defects immune system, although the classical can also cause leaky SCID, a less severe form of complement pathway is primarily activated SCID that is characterised by low, but not absent, by antigen-antibody complexes. The alternate T cells.33,34 pathway’s main trigger is bacterial endotoxin. Some components of yeast cell wall and mold, There are now >50 genetic defects associated typically Aspergillus, also trigger the alternate with SCID. Genetic testing is important because pathway. The lectin pathway is activated when of preparation for bone marrow transplant or lectin recognises carbohydrate residues on stem cell transplant, especially if the defect bacteria and activates the complement system is in the DNA repair genes.32,35 If there is a trial by binding to MBL. Neisseria and Salmonella or open for genetic therapy for the type of SCID yeast are most commonly recognised by MBL. identified, the family may opt to apply for that All three complement pathways promote lysis, therapy, which may go on to become standard of opsonisation, and phagocytosis of bacteria.37,38 care in the near future.36 Primary complement deficiencies can lead The laboratory results reveal normal absolute to increased infections and autoimmune count of B cells, but nearly absent CD3+ T cells disease. C2 component deficiency is one of and absent CD3-CD56+CD16+ NK cells. The few the most common complement disorders. T cells present are predominantly CD45RO+, It can be asymptomatic or can present with indicating memory cells of maternal origin. sinopulmonary infections or bacterial meningitis. Mitogen proliferation to PHA is very low. The About 10% of patients with C2 deficiency will genetic screen for this patient is positive for JAK3 have autoimmune disease, most commonly deficiency. Gene therapy for JAK3 deficiencies lupus erythematosus.39 Terminal complement are currently being researched, but no trial is component deficiencies leave patients prone open to this family. Testing is initiated for human to Neisseria meningitis.39 Deficiencies have

74 ALLERGY & IMMUNOLOGY • August 2020 EMJ been described in C3 and C4 components of exit the bone marrow and reach the circulation complement, and these may present as infection but lack the CD18 (β-2 integrin-chain) function or autoimmune disease. Most complement necessary for extravasation to infected deficiencies are autosomal recessive, buttissues. 48-50 Patients have a poor ability to form deficiency, an alternate pathway abscesses. Patients with severe LADI often have deficiency, is X-linked and results in susceptibility late umbilical cord separation, omphalitis, and to fulminant meningococcal infections.40 severe periodontal disease.48,51 With moderate- to-severe LADI, leukocyte counts are elevated Complement disorders other than MLB-D are because of the inability to extravasate.48 There is rare. MBL-D affects 5–10% of the population variability of LADI with extreme severe disease and is usually asymptomatic.41 If MBL-D is presenting in the first weeks of life. Without present with another condition, such as cystic early intervention of stem cell or bone marrow fibrosis or HIV, it can hasten the primary disease transplant mortality is high, but some children with progression or susceptibility.42,43 It is controversial less severe disease present in later childhood.48,52 whether the defect/deficiency alone can lead to Flow cytometry is utilised to detect CD18 increased infections, but patients with no other on leukocytes.50 disorder than MBL-D have been reported to have increased infections. LADII, a glycosylation disorder, is characterised by cognitive deficiency and severe growth There are many secondary causes of failure.53,54 LADIII, an integrin activating protein staphylococcal abscesses of the skin (e.g., chronic disorder, is associated with a severe bleeding skin conditions such as atopic dermatitis, burns, disorder caused by platelet dysfunction.55 Neither and trauma). Some PIDD are characterised by LADII or LADIII seem likely in Hallie's case. presentation with staphylococcal abscesses. Autosomal dominant hyper IgE syndrome is a Chronic granulomatous disease (CGD) is a deficiency of signal transducer and activator disorder of the NADPH oxidase system which of transcription-3 (STAT3), and affects many usually forms hydrogen peroxide (H2O2) and systems including skin, skeletal, and immune reactive chloride species.56,57 Patients are prone systems. The disorder was characterised long to infection with catalase positive organisms such before the genetic defect was discovered as Staphylococcus, Serratia, and Aspergillus.58,59 but this has allowed earlier recognition of the NADPH oxidase is formed of multiple subunits 44,45 disease. Patients typically have high serum and there are several known defects in these IgE, elevated eosinophils, frequent fractures subunits, the most common being a defect in the and skeletal anomalies, eczematous skin, and gp91 phox unit, which is an X-linked mutation. frequent staphylococcal and fungal infections. Some female carriers of this mutation have later The abscesses are usually deep without active onset and less severe disease. The autosomal neutrophils. Neutrophil chemotaxis is often poor recessive forms lead to the same types of in patients with STAT3 deficiency. The abscesses infection. Patients with CGD may also suffer from must be drained before they are flocculent, and granulomas that are thought to be secondary to awareness of this issue is key to decreasing chronic inflammation, which may cause organ 46 morbidity and mortality. A multisystem obstructions and chronic pain.59,60 scorecard is utilised for initial diagnosis of STAT3 deficiency, and genetic testing confirms the The most accurate assay for the diagnosis of CGD diagnosis.47 This patient does not have a high involves measurement of hydrogen peroxide in score on the initial evaluation but gets extra phagocytes by dihydrorhodamine reductase. points for young age because symptoms worsen The assay is performed by flow cytometry. with time. Genetic testing for some X-linked and autosomal recessive forms is available.61 Leukocyte adhesion deficiency (LAD) is another PIDD that can lead to staphylococcal abscesses. Her immunology labs return. IgG, IgA, IgM, and LAD is rare and there are several subtypes, all IgE are all within normal limits for her age. Her autosomal recessive in inheritance, which lead lymphocytes subsets are within normal range by to increased abscess formation. In the most percentage and by absolute counts. Her recall common subtype, LADI, the neutrophils can antibodies to pneumococcal and tetanus are

Creative Commons Attribution-Non Commercial 4.0 August 2020 • ALLERGY & IMMUNOLOGY 75 protective. Her CH50 is 95% (normal), and her The pneumonia improves and she is placed on mannose binding lectin is normal. Her oxidative staphylococcal prophylaxis as well as fungal burst by dihydrorhodamine assay is very low, prophylaxis prior to discharge. Discussion of showing a population of granulocytes that do not possible use of interferon-γ is also presented to stimulate and have poor oxidative burst. Antibiotic the family. Genetic testing is sent to verify the coverage is changed to include Staphylococcus. type of autosomal recessive CGD.

Morbidity and mortality of CGD has improved significantly since studies supporting that CONCLUSION staphylococcal prophylaxis treated with trimethoprim-sulfamethoxazole and fungal NBS for SCID now helps identify many severe prophylaxis treated with itraconazole are of immune deficiency cases early in life, but providers benefit.62,63 Shortly before the antimicrobial must still be vigilant for signs and symptoms of prophylaxis studies were released, interferon-γ PIDD such as infections, autoimmune disease, was shown to be of benefit in decreasing infection and failure to thrive. Family history of PIDD is but has exhibited controversial benefit when always an indication to investigate for PIDD. As paired with prophylaxis.59,64,65 Bone marrow or time goes by more defects of the immune system, stem cell transplant remains a possibility for CGD either humoral, cellular, or innate, are appreciated patients, particularly those with severe recurrent and defined. infection, and gene therapy trials for X-linked CGD is under investigation.11

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