Diagnostic criteria for primary immunodeficiencies

Clinical ImmunologyVol. 93, No. 3, December, pp. 190 –197, 1999Article ID clim.1999.4799, available online at http://www.idealibrary.com on Diagnostic Criteria for Primary Immunodeficiencies Mary Ellen Conley, Luigi D. Notarangelo, and Amos Etzioni Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)1 The identification of many genes responsible for pri- tions in the same gene. This new information allows us mary immunodeficiencies has provided us with a new to reevaluate the criteria that we use to make diag- perspective to evaluate these disorders. It has clarified the clinical and laboratory findings that are most con- The diagnostic criteria are meant to establish sim- sistently associated with a specific gene, demonstrated ple, objective, and clear guidelines that ensure that the spectrum of clinical severity seen in a particular different physicians and scientists are using the same disorder, and shown that not all of the patients with definitions when they include patients in research identical clinical and laboratory findings have muta- studies. These criteria may also help physicians formu-late a diagnosis in patients with abnormalities of the immune system. The diagnostic criteria are divided The following individuals participated in the development of the diagnostic criteria: Francisco A. Bonilla, Children’s Hospital Medical into three categories: definitive, probable, and possible.
Center, Boston, MA; Rebecca H. Buckley, Duke University Medical To guard against the inclusion of patients who have Center, Durham, NC; A. Wesley Burks, Jr., Arkansas Children’s polymorphic variants in the genes associated with im- Hospital, Little Rock, AR; Jean-Laurent Casanova, INSERM, Hos- munodeficiency and to specify the clinical or laboratory pital Necker, Paris, France; Helen M. Chapel, Oxford Radcliffe Hos-pital, Oxford, United Kingdom; Mary Ellen Conley, University of finding that is most consistently abnormal in a partic- Tennessee College of Medicine and St. Jude Children’s Research ular disorder, the patient must fulfill an inclusion cri- Hospital, Memphis, TN; Max D. Cooper, University of Alabama, terion that is characteristic of the disorder.
Birmingham, AL; Coleen K. Cunningham, SUNY Health Science Patients with a definitive diagnosis are assumed to Center, Syracuse, NY; Charlotte Cunningham-Rundles, Mount Sinai have a greater than 98% probability that in 20 years Medical Center, New York, NY; Martha M. Eibl, University of Vi-enna, Vienna, Austria; Teresa Espanol, Hospital Vall D’Hesooh, they will still be given the same diagnosis. Mutation Barcelona, Spain; Amos Etzioni, Rambam Medical Center, Haifa, detection is the most reliable method of making a di- Israel; Alain Fischer, INSERM, Hospital Necker, Paris, France; agnosis. In some disorders the absence of the specific Ramsay Fuleihan, Yale University, New Haven, CT; Diana Garcia de mRNA or protein is diagnostic. In others, the mRNA Olarte, University of Antioquia, Medellin, Columbia; Richard A.
Gatti, UCLA Medical Center, Los Angeles, CA; Raif S. Geha, Chil- and/or protein may be only transiently expressed or dren’s Hospital Medical Center, Boston, MA; Rolf Gustafson, Hud- may be produced at very low levels, or clinically useful dinge University Hospital, Sweden; Lennart Hammarstrom, Center assays may not yet have been developed. The clinical for Biotechnology, Novum, Sweden; A. K. Junker, University of Brit- and laboratory findings in several of the X-linked im- ish Columbia, Vancouver, British Columbia, Canada; Barbara Li-sowska-Grospierre, INSERM, Hospital Necker, Paris, France; Ste- munodeficiencies are sufficiently distinctive that these findings, when coupled with a family history of disease Philadelphia, PA; Luigi D. Notarangelo, University of Brescia, Bres- that is specific to X-linked inheritance, can be used to cia, Italy; Hans D. Ochs, University of Washington, Seattle, WA; make a definitive diagnosis. In families with a known Savita Pahwa, North Shore University Hospital, Manhasset, NY;Robert Roberts, UCLA Medical Center, Los Angeles, CA; Dirk Roos, mutation in a particular gene, mutation detection can University of Amsterdam, Amsterdam, The Netherlands; Richard be used to provide a definitive diagnosis in a newborn Schiff, Miami Children’s Hospital, Miami, Florida; Paul R. Scholl, Children’s Memorial Hospital, Chicago, IL; Harry W. Schroeder, Jr., Patients with a probable diagnosis are those with all University of Alabama, Birmingham, AL; Klaus Schwarz, Universityof Ulm, Ulm, Germany; Reinhard Seger, University Children’s Hos- of the clinical and laboratory characteristics of a par- pital, Zurich, Switzerland; William T. Shearer, Texas Children’s ticular disorder but who do not have a documented Hospital, Houston, TX; C. I. Edvard Smith, Karolinska Institute, abnormality in the gene, the mRNA, or the protein that Huddinge, Sweden; Ricardo U. Sorensen, Louisiana State Univer- is known to be abnormal in the disorder. They are sity, New Orleans, LA; John L. Sullivan, University of Massachu-setts, Worcester, MA; Kathleen E. Sullivan, Children’s Hospital of assumed to have a greater than 85% probability that in Philadelphia, Philadelphia, PA; Diane W. Wara, UCSF Medical Cen- 20 years they will be given the same diagnosis. Pa- ter, San Francisco, CA; David Webster, Royal Free Hospital, London, tients with a possible diagnosis are those that have United Kingdom; Kenneth Weinberg, Children’s Hospital of Los some but not all of the characteristic clinical or labo- Angeles, Los Angeles CA; and Jerry A. Winkelstein, Johns HopkinsUniversity, Baltimore, MD.
ratory findings of a particular disorder.
Copyright 1999 by Academic PressAll rights of reproduction in any form reserved.
DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES Not all of the patients with mutations in a specific gene will fulfill the criteria for a probable or even a Differential Diagnosis of Hypogammaglobulinemia possible diagnosis of the disorder associated with that gene. To indicate the range of findings in patients with mutations in a specific gene or who are diagnosed as having a particular syndrome, a short description of the spectrum of disease has been included for each disorder. However, the description is not meant to be Information about the family history can be useful in making a diagnosis of immunodeficiency; however, caution should be used. Approximately 50% of patients with an X-linked immunodeficiency, documented by mutation detection, do not have a family history of immunodeficiency because they are the first manifes- Transcobalamin II deficiency and hypogammaglobulinemiaX-linked agammaglobulinemia tation of a new mutation. The presence of consanguin- X-linked lymphoproliferative disorder (EBV associated) ity increases the possibility that a patient has a rare autosomal recessive immunodeficiency, but many pa- tients with rare disorders are compound heterozygotes (have different mutations on the maternal and pater- nal alleles). In a patient with atypical clinical or labo- ratory findings, the presence of a sibling with more typical disease can suggest a diagnosis but does not permit a definitive diagnosis in the absence of muta- A differential diagnosis is provided for many syn- Congenital infection with Toxoplasma gondiiEpstein–Barr virus dromes. For some disorders, exclusion criteria are in- Chronic lymphocytic leukemiaImmunodeficiency with thymomaNon-Hodgkin lymphoma Common Variable Immunodeficiency (CVI)
Immunodeficiency caused by hypercatabolism of immunoglobulin Immunodeficiency caused by excessive loss of immunoglobulins (nephrosis, severe burns, lymphangiectasia, severe diarrhea) Male or female patient who has a marked decrease (at least 2 SD below the mean for age) in serum IgG 2. Absent isohemagglutinins and/or poor response to and IgA and fulfills all of the following criteria: 1. Onset of immunodeficiency at greater than 2 3. Defined causes of hypogammaglobulinemia have 2. Absent isohemagglutinins and/or poor response to 3. Defined causes of hypogammaglobulinemia have Most patients with CVI are recognized to have im- munodeficiency in the second, third, or fourth decade oflife, after they have had several pneumonias; however, children and older adults may be affected. Viral, fun-gal, and parasitic infections as well as bacterial infec- Male or female patient who has a marked decrease tions may be problematic. The serum concentration of (at least 2 SD below the mean for age) in one of the IgM is normal in about half of the patients. Abnormal- major isotypes (IgM, IgG, and IgA) and fulfills all of the ities in T cell numbers or function are common. The majority of patients have normal numbers of B cells;however, some have low or absent B cells. Approxi- 1. Onset of immunodeficiency at greater than 2 mately 50% of patients have autoimmune manifesta- tions. There is an increased risk of malignancy.
DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES IgA Deficiency
thrush in the first 2 to 7 months of life. Pneumocystis pneumonia, significant bacterial infections, and dis-seminated BCG infection are common presenting ill- Male or female patient greater than 4 years of age nesses. Occasional patients do not have failure to who has a serum IgA of less than 7 mg/dL (0.07 g/L) but thrive and are not recognized to have immunodefi- normal serum IgG and IgM and in whom other causes ciency until late in the first year of life. SCID is fatal in of hypogammaglobulinemia have been excluded (see the first 2 years of life unless the patient is treated with Table 1). These patients have a normal IgG antibody extremely restrictive isolation, hematopoietic stem cell transplant, or therapy that replaces the abnormal geneor gene product.
Male or female patient greater than 4 years of age who has a serum IgA at least 2 SD below normal for age but normal serum IgG and IgM and in whom other causes of hypogammaglobulinemia have been excluded (see Table 1). These patients have a normal IgG anti- 6. Cartilage hair hypoplasia.
7. MHC Class II deficiency.
Patients with IgA deficiency have an increased inci- DiGeorge Syndrome
dence of upper respiratory tract infections, allergies,and autoimmune disease. Many individuals with IgA deficiency are asymptomatic. Others have persistent orrecurrent infections and some develop CVI over time.
Male or female patient with reduced numbers of CD3ϩ T cells (less than 500/mm3) and two of the threefollowing characteristics: Severe Combined Immunodeficiency (SCID)
1. Conotruncal cardiac defect (truncus arteriosus, tetrology of Fallot, interrupted aortic arch, or ab- Male or female patient less than 2 years of age with either (a) engraftment of transplacentally acquired 2. Hypocalcemia of greater than 3 weeks’ duration maternal T cells or (b) less than 20% CD3ϩ T cells, an absolute lymphocyte count of less than 3000/mm3, and 1. Mutation in the cytokine common gamma chain Male or female patient with reduced numbers of CD3ϩ T cells (less than 1500/mm3) and a deletion of 4. Mutation in IL-7R␣5. ADA activity of less than 2% of control or muta- Male or female patient with reduced numbers of CD3ϩ T cells (less than 1500/mm3) and at least one ofthe following: Male or female patient less than 2 years of age with (a) less than 20% CD3ϩ T cells, an absolute lymphocyte count of less than 3000/mm3, and proliferative re- 2. Hypocalcemia of greater than 3 weeks’ duration sponses to mitogens less than 10% of control or (b) the presence of maternal lymphocytes in the circulation.
3. Dysmorphic facies or palatal abnormalities.
Patients with SCID usually develop failure to thrive The majority of patients with DiGeorge syndrome and persistent diarrhea, respiratory symptoms, and/or are recognized to have immunodeficiency in the first DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES few months of life when they are being evaluated for mon. The four genetic disorders that result in this cardiac malformations that are highly associated with syndrome are clinically indistinguishable. In most DiGeorge syndrome and/or deletions of chromosome cases, there is no Class II expression; however, in oth- 22q11.2. A few patients present with persistent viral or ers the intensity of expression may be as high as 5% of fungal infections or with hypocalcemic tetany. The se- normal. Patients with higher expression tend to have a verity of the T-cell defect varies greatly. In many pa- milder course; these patients may survive beyond early tients the immunodeficiency resolves in the first few childhood. Hepatic abnormalities, particularly scleros- years of life. Dysmorphic facial features and mental retardation are common. Autoimmune disorders maybe seen in older patients.
Leukocyte Adhesion Defects (LAD)
MHC—Class II Deficiency
A male or female patient with decreased intensity of expression of CD18 on neutrophils (less than 5% of Male or female patient with decreased intensity of normal) and at least one of the following: expression (less than 5% of normal) of HLA-DR or DP 1. Mutation in the ␤ integrin gene.
on B cells or monocytes and a mutation in one of the 2. Absence of ␤ integrin mRNA in leukocytes.
following genes: CIITA, RFX-B, RFX-5, or RFX-AP.
A male or female patient with defective expression of Male or female patient with decreased intensity of CD18 on leukocytes (less than 5% of normal) and all of expression (less than 5% of normal) of HLA-DR or DP on B cells and monocytes and all of the following: 1. Recurrent or persistent bacterial or fungal infec- 1. Failure to thrive, opportunistic infections, or per- 2. Leukocytosis (WBC greater than 25,000/mm3).
2. Normal numbers of T cells and B cells.
3. Delayed separation of the umbilical cord and/or 3. Normal proliferative responses to mitogens.
Male or female patient with decreased intensity of Infant with marked leukocytosis (WBC greater than expression (less than 5% of normal) of HLA-DR or DP on B cells or monocytes, and normal numbers of T cellsand B cells, who has at least one of the following: 1. Recurrent bacterial infections.
2. Severe deep-seated infection.
3. Absence of pus at sites of infection.
2. Normal mitogen responses but absent T-cell pro- 3. Reduced numbers of CD4ϩ cells.
4. Failure of mononuclear cells to stimulate a mixed Marked leukocytosis and recurrent bacterial infec- tions are the hallmarks of LAD. Staphylococcus,gram-negative enteric bacteria, and fungal infec- tions are particularly troublesome. Periodontitis is avery common persistent finding. In the severe form, MCH Class II deficiency, which is seen most often in no expression of CD18 is detected on neutrophils and patients from around the Mediterranean Sea, results early death occurs without BMT. In the moderate in a clinical phenotype that is very similar to SCID.
form, a small amount of CD18 is expressed and pa- Patients usually develop severe infections and pro- tients can survive to adulthood. Some patients may tracted diarrhea in the first 6 months of life. Pseudo- have normal CD18 expression with defective CD18 monas, CMV, and cryptosporidium infections are com- DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES 1. Normal CD18 and CD15a expression on neutro- X-Linked Severe Combined Immunodeficiency
1. Chronic granulomatous disease.
2. SLeX deficiency (LAD II).
Male patient with either (a) engraftment of transpla- centally acquired maternal T cells or (b) less than 10% Chronic Granulomatous Disease (CGD)
CD3ϩ T cells, less than 2% CD16/56ϩ NK cells, and more than 75% CD19ϩ B cells and who has one of thefollowing: Male or female patient with abnormal NBT or respi- 1. Mutation in the cytokine common gamma chain ratory burst in activated neutrophils (less than 5% of 2. Absent ␥c mRNA on Northern blot analysis of 1. Mutation in gp91, p22, p47, or p67 phox.
3. Absent ␥c protein on the surface of lymphocytes or 2. Absent mRNA for one of the above genes by 4. Maternal cousins, uncles, or nephews with severe 3. Maternal cousins, uncles, or nephews with an ab- Male patient with less than 10% CD3ϩ T cells, less Male or female patient with abnormal NBT or respi- than 2% CD16/56ϩ NK cells, and more than 75% ratory burst in activated neutrophils (less than 5% of CD19ϩ B cells who has all of the following: 1. Onset of failure to thrive before 1 year of age.
1. Deep-seated infection (liver, perirectal, or lung 2. Serum IgG and IgA more than 2 SD below normal abscess; adenitis; or osteomyelitis) due to Staph- ylococcus, Serratia marcescens, Candida, or As- 3. Persistent or recurrent diarrhea, URI, or thrush.
2. Diffuse granulomata in respiratory, gastrointesti- 3. Failure to thrive and hepatosplenomegaly or Male patient with greater than 40% CD19ϩ B cells in the peripheral circulation and one of the following: 1. Engraftment of transplacentally acquired mater- 2. Maternal cousins, uncles, or nephews with a his- Patients with the X-linked form of CGD (60 –70% of tory of severe combined immunodeficiency.
patients) tend to present earlier and have more severedisease than patients with autosomal recessive forms.
Most patients with X-linked CGD develop failure to thrive, severe bacterial adenitis, abscesses, or osteomy-elitis within the first year of life. Pneumonia and Males with XSCID usually develop persistent respi- lymphadenitis due to catalase-positive organisms (par- ratory infections, diarrhea, and failure to thrive by 4 ticularly staphylococcus) or fungi are the most common months of age and are recognized to have immunode- infections. Symptoms of intestinal or urinary tract ob- ficiency by 6 or 7 months of age. Candidiasis is com- struction can be caused by granuloma formation.
mon. Many patients have normal serum IgM, but IgG Rarely, in both the X-linked and autosomal recessive and IgA are usually very low. Some but not all patients forms, the first severe symptoms are not recognized with engraftment of transplacentally acquired mater- nal T cells show signs of GVH such as rash and ele- DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES vated liver function tests. Occasional patients may de- mg/dL (2 g/L) and the IgG and IgA concentrations are velop some autologous T and/or NK cells.
generally less than 20 mg/dL (0.2 g/L). Approximately20% of patients present with a dramatic, overwhelm- ing infection, often with neutropenia. Another 10 –15%have higher concentrations of serum immunoglobulin than expected or are not recognized to have immuno- deficiency until after 5 years of age.
X-Linked Agammaglobulinemia (XLA)
All other causes of hypogammaglobulinemia listed in Male patient with less than 2% CD19ϩ B cells and at 2. Absent Btk mRNA on Northern blot analysis of X-Linked Hyper IgM (XHIM)
3. Absent Btk protein in monocytes or platelets.
4. Maternal cousins, uncles, or nephews with less Male patient with serum IgG concentration at least 2 SD below normal for age and one of the following: Male patient with less than 2% CD19ϩ B cells in 2. Maternal cousins, uncles, or nephews with con- 1. Onset of recurrent bacterial infections in the first 2. Serum IgG, IgM, and IgA more than 2 SD below Male patient with serum IgG concentration at least 2 SD below the normal for age and all of the following: 3. Absent isohemagglutinins and/or poor response to 1. Normal number of T cells and normal T cell pro- 4. Other causes of hypogammaglobulinemia have 2. Normal or elevated numbers of B cells but no 3. One or more of the following infections or compli- cations:Recurrent bacterial infections in the first 5 years Male patient with less than 2% CD19ϩ B cells in whom other causes of hypogammaglobulinemia have Pneumocystis carinii infection in the first year of been excluded (see Table 1) and at least one of the 1. Onset of recurrent bacterial infections in the first 2. Serum IgG, IgM, and IgA more than 2 SD below 4. Absent CD40 ligand cell surface staining on acti- vated CD4ϩ T cells as assessed by binding tosoluble CD40 or by binding of monoclonal anti- Most patients with XLA develop recurrent bacterial infections, particularly otitis, sinusitis, and pneumo-nia, in the first 2 years of life. The most common Male patient with serum IgG concentration at least 2 organisms are Streptococcus pneumonea and Hemophi- SD below normal for age, normal numbers of T cells lus influenzae. The serum IgG is usually less than 200 and B cells, and one or more of the following: DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES 1. Serum IgM concentration at least 2 SD above 2. Serum IgA at least 2 SD below normal for age.
2. P. carinii infection in the first year of life.
3. Alpha fetoprotein more than 2 SD above normal 3. Parvovirus-induced aplastic anemia.
4. Cryptosporidium-related diarrhea.
4. Increased chromosomal breakage after exposure 5. Severe liver disease (sclerosing cholangitis).
Patients with XHIM have recurrent bacterial and opportunistic infections starting in the first year of life.
AT is a progressive neurologic disorder. Most pa- P. carinii pneumonia is a common presenting infection.
tients begin to have difficulty walking at the end of the Some patients may have chronic, profuse diarrhea re- first year of life and are wheelchair-bound by the teen- quiring parenteral nutrition. Over 50% of patients age years. Ocular or facial telangiectasia is usually have chronic or intermittent neutropenia, often associ- noted at 4 – 8 years of life. Many patients have recur- ated with oral ulcers. Cryptosporidium infection may rent respiratory infections. Leukemia or lymphomas lead to severe bile duct disease and hepatic cancer.
are seen in 10 –15% of patients and may be the pre- Serum concentration of IgG is usually less than 200 senting finding. Some patients are not recognized to mg/dL; IgM may be low, normal, or elevated. Atypical have AT until the second decade of life.
cases may present with recurrent infections, anemia,or hepatitis in the second or third decade of life.
1. Defects in T cell activation (i.e., defective expres- sion of CD69 or CD25 after in vitro T cell activa- Wiskott–Aldrich Syndrome (WAS)
2. Human immunodeficiency virus infection.
3. Congenital rubella infection.
4. MHC class II deficiency.
Male patient with congenital thrombocytopenia (less than 70,000 platelets/mm3), small platelets, and at 6. Drug or infection exposure known to influence the 1. Mutation in WASP.
2. Absent WASP mRNA on Northern blot analysis of Ataxia Telangiectasia (AT)
3. Absent WASP protein in lymphocytes.
4. Maternal cousins, uncles, or nephews with small Male or female patient with either increased radia- tion-induced chromosomal breakage in cultured cellsor progressive cerebellar ataxia and who has disablingmutations on both alleles of ATM.
Male patient with congenital thrombocytopenia (less than 70,000 platelets/mm3), small platelets, and at Male or female patient with progressive cerebellar ataxia and three of the following four findings: 2. Abnormal antibody response to polysaccharide 2. Serum IgA at least 2 SD below normal for age.
3. Alpha fetoprotein at least 2 SD above normal for 3. Recurrent bacterial or viral infections.
4. Increased radiation-induced chromosomal break- 5. Lymphoma, leukemia, or brain tumor.
Male or female patient with progressive cerebellar Male patient with thrombocytopenia (less than ataxia and at least one of the following four findings: 70,000 platelets/mm3) and small platelets, or male pa- DIAGNOSTIC CRITERIA FOR PRIMARY IMMUNODEFICIENCIES tient splenectomized for thrombocytopenia, who has at lymphohistiocytic disorder and who has a mutation in 2. Abnormal antibody response to polysaccharide 3. Recurrent bacterial or viral infections.
Hodgkin disease, immunodeficiency, aplastic anemia, or lymphohistiocytic disorder following acute EBV in- 5. Lymphoma, leukemia, or brain tumor.
fection and having maternal cousins, uncles, or neph-ews with a history of similar diagnoses following acute Congenital thrombocytopenia with small platelets is the diagnostic hallmark of Wiskott–Aldrich syndrome.
Many patients present with bloody diarrhea in the first month of life. Eczema, which occurs in some but not all Hodgkin disease, immunodeficiency, aplastic anemia, patients, may be the predominant clinical problem.
or lymphohistiocytic disorder following acute EBV in- Otitis and sinusitis, and infections due to herpes sim- plex and EBV, are particularly troublesome. Many pa-tients have increased IgE and IgA with low IgM. T cell numbers and function decline with age. There is anincreased incidence of autoimmune manifestations Males with XLP are usually asymptomatic until they (vasculitis, hemolytic anemia, glomerulonephritis) and develop EBV infection, which may cause fulminant tumors (leukemia, lymphoma, EBV-related brain tu- hepatitis (60% of all patients), particularly in young mor). Occasional patients have moderate thrombocyto- children. Hodgkin or non-Hodgkin lymphoma (30%) penia (50,000 to 100,000 platelets/mm3) and no other and/or immune deficiency with low serum IgG and abnormal NK cell function (30%) are more likely todevelop in older patients. Less common manifestations X-Linked Lymphoproliferative Syndrome (XLP)
include EBV-associated hemophagocytic syndrome and vasculitis. The vast majority of patients die in child-hood; survival rate is very poor for males with fulmi- Male patient with lymphoma/Hodgkin disease, fatal nant hepatitis (Ͻ5%) and higher for those with isolated EBV infection, immunodeficiency, aplastic anemia, or

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