IDF Diagnostic and Clinical Care Guidelines - Final

7/30/2019 IDF Diagnostic and Clinical Care Guidelines - Final

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Immune Deficiency Foundatio

Diagnostic & ClinicCare Guidelinefor Primary Immunodeficiency Disea

IMMUNE DEFICIENCY FOUNDATION


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The mission of the Immune Deficiency Foundation is to

improve the diagnosis and treatment of patients with primary immunodeficiency diseases through research,education and advocacy.

Readers may redistribute this article to other individuals for non-commercial use, provided the text, htmlcodes, and this notice remain intact and unaltered in any way. The Immune Deficiency FoundationDiagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases may not be resold,reprinted or redistributed for compensation of any kind without prior written permission from theImmune Deficiency Foundation.

Copyright I mmune Deficiency Foundation 2006


40 WEST CHESAPEAKE AVENUE SUITE 308 TOWSON, MARYLAND 21204 www.primaryimmune.org [email protected](800) 296-4433 (410) 321-6647 FAX (410) 321-9165


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In 1990, The Institute of Medicine defined practice guidelines as systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. Guidelinesmay also be used for quality improvement and payment policy making.

The Immune Deficiency Foundation, in partnership withexpert immunologists, developed these guidelines to enhance earlier diagnosis, improve health outcomes and increase access to specialized health care and optimal treatment for patients with primary immunodeficiency diseases. The development of the guidelines was funded by an educational grant from Talecris Biotherapeutics.

Table of ContentsIntroduction 2

Antibody Production Defects 3

Cellular or Combined Defects 9

Phagocytic Cell Immune Defects 13

Complement Defects 16

Practical Aspects of Genetic Counseling:General Considerations 19

Life Management Considerations 21

Health Insurance 22

Glossary 25



Editor:Rebecca H. Buckley, MDDuke University School of Medicine

Contributors:Mark Ballow, MD Women and Childrens Hospital of BuffaloDivision of Allergy and Immunology

Melvin Berger, MD, PhDCase Western Reserve University Rainbow Babies and Childrens HospitalR. Michael Blaese, MDInstitute for Inherited Disease Research

Francisco A. Bonilla, MD, PhDChildrens Hospital, Boston

Mary Ellen Conley, MDUniversity of Tennessee College of MedicineSt. Jude Childrens Research Hospital

Charlotte Cunningham-Rundles, MD, PhDMt. Sinai School of Medicine

Thomas A. Fleisher, MDDepartment of Laboratory Medicine, CCNational Institutes of Health, DHHS

Erwin W. Gelfand, MDNational Jewish Medical and Research Center

Steven M. Holland, MDLaboratory of Clinical Infectious Diseases - NIAIDNational Institutes of Health

Richard Hong, MDUniversity of Vermont School of MedicineDepartment of Pediatrics

Richard B. Johnston, Jr., MDUniversity of Colorado School of MedicineNational Jewish Medical and Research Center

Roger Kobayashi, MD

Allergy, Asthma and Immunology AssociatesUCLA School of Medicine

David Lewis, MDStanford University School of Medicine

Harry L. Malech, MDGenetic Immunotherapy SectionLaboratory of Host Defenses - NIAIDNational Institutes of Health

Bruce Mazer, MDMcGill University Health CenterMontreal Childrens Hospital

Stephen Miles, MD All Seasons Allergy, Asthma and Immunology

Hans D. Ochs, MDDepartment of PediatricsUniversity of Washington School of Medicine

Jennifer Puck , MDNational Human Genome Research InstituteNational Institutes of Health

William T. Shearer, MD, PhD Texas Childrens Hospital

E. Richard Stiehm, MDMattel Childrens Hospital at UCLAUCLA Medical Center

Kathleen Sullivan, MD, PhD The Childrens Hospital of Philadelphia

Jerry A . Winkelstein, MD Johns Hopkins University School of Medicine


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The hallmarks of primary immunodeficiency are recurrent orunusual infections. Some of the infections may be persistentand some may be due to unusual microorganisms that rarely cause problems in healthy people. The primary immunodeficiency diseases are a group of more than 130 genetically determined conditions that have an identified or tobe determined molecular basis. Because most of these are lifelong conditions, it is very important to perform a detaileddiagnostic evaluation before initiating therapies that will becontinued in an open-ended fashion. The guidelines that

follow are intended to provide practical information forpatients and health care providers who are concerned abou whether or not an individuals immune system is functionnormally. Currently, no screening is performed for thesedefects at birth, during childhood or in adulthood. Therefimmunodeficiency diseases are usually detected only afteindividual has experienced recurrent infections that may omay not have caused permanent organ damage. There isobviously a great need for the early detection of these def

2 IMMUNE DEFICIENCY FOUNDATION

Introduction

KEY CONCEPTSSITE OF INFECTIONS POSSIBLE CAUSE SCREENING DIAGNOST

Upper Respiratory Tract Antibody or Complement Deficiency Immune globulin levels, Antibodto vaccines; isohemagglutinins; CH50Lower Respiratory Tract Antibody or Complement Deficiency; Immune globulin levels, Antibo

T Cell Deficiency; vaccines; isohemagglutinins; CH50;Phagocytic Cell Defect WBC with manual differential to coun

neutrophils, lymphocytes and platelets;Respiratory Burst Assay

Skin, internal organs Phagocytic Cell Defect Respiratory Burst Assay/CD11/CD Assay

Blood or Central Nervous System Antibody or Complement Deficiency Immune globulin levels, Antibo(meninges) vaccines; CH50

Suspect a primary immunodeficiency if:y There are recurrent infections or there is an unusual or persistent infectiony A usually mild childhood disease takes a turn for the worse (may become life-threatening)y Blood cell counts are low or persistently high

Persistent

Consider a PrimaryImmunodeficiency

Disease

RECURRENTINFECTIONS

Low Blood Cell CountsUnusual or Less Virulent Infectious

Agents


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Part A: Recognition and Assessment An infection recurring in a single site is generally not indicative of aprimary immunodeficiency disease. Rather it suggests an anatomicabnormality. On the other hand, several types of infections affecting various organ systems may be indicative of an underlyingimmunologic deficiency. These infections and conditions include:

y Recurrent sinopulmonary infections- Pneumonia with fever- Sinusitis documented by X-ray or Computerized tomography

(C-T) scan- Otitis media (Although frequent ear infections are seen in

normal children, an evaluation may still be indicated forindividuals on a case by case basis.)

y Meningitis and/or sepsis (blood stream infection)y Gastrointestinal infectionsy Cutaneous (skin) infections

The occurrence of infections with unusual organisms also suggeststhe presence of a primary immunodeficiency disease. This is how some patients are diagnosed. Examples are atypical mycobacteria, which would suggest an IFN-yR defect, or Pneumocystis carinii, which would suggest Severe Combined Immunodeficiency (SCID) or

Hyper IgM syndrome.In addition, certain types of autoimmune conditions may beassociated with some types of antibody deficiency. Examples includeautoimmune disorders including autoimmune endocrine disorders,rheumatic conditions, and autoimmune hemolytic anemia orthrombocytopenia (low platelet count). These autoimmune disordersare seen especially in patients with IgA deficiency and Common Variable Immunodeficiency (CVID). Allergic disorders can also beseen in IgA deficiency.

Useful Physical Examination Findingsy Absence or reduced size of tonsils and lymph nodes in X-linked

agammaglobulinemia and in X-linked Hyper IgM syndromey Enlarged lymph nodes and splenomegaly in CVID and autosomal

recessive Hyper IgM syndromey Scarred tympanic membranes

y Unusual skin changes such as, complete absence of eyebrowhair, severe eczema resistant to treatment, mouth thrush resistto treatment after 4 months of age, petechiae, vitiligo, recurrepersistent warts or severe molluscum contagiosum

y Rales and rhonchi in lungs, clubbing of the fingers

Useful Diagnostic Screening Testsy Complete blood count and manual differential

These tests are of great clinical importance because they allthe physician to know whether the lymphocyte, neutrophil aplatelet counts are normal. Many immune defects can be rulout by these simple tests. In the setting of immunodeficiencydisorders, the manual differential is more reliable than anautomated differential.

y Quantitative serum immunoglobulin (IgG, IgA, IgM and IgEQuantitation of immune globulin levels can beperformed atCLIA (Clinical Laboratories Improvement Act) approvedlaboratory. However, the assay results should be evaluated incontext of the tested patients age and clinical findings. Animportant problem exists for IgA levels, which may berepothe value at the lower limit of sensitivity of the method but mactually be zero. Most commercially available assays for IgAnot sensitive enough to distinguish between very low and ab

levels. Results of all immune globulin levels must also becompared with age-adjusted normal values to evaluate theirsignificance. IgG subclass measurements are rarely helpful.

y Measurement of specific antibodies to vaccines These tests are of crucial importance in determining whethethere is truly an antibody deficiency disorder when the serumimmunoglobulins are not very low or even if they are low. Itimportant to test for antibodies to both protein (i.e. tetanus odiphtheria) and polysaccharide (i.e. pneumococcalpolysaccharides) antigens. Isohemagglutinins (antibodies toblood cells) are natural anti-polysaccharide antibodies; if the

missing this also suggests an antibody deficiency disorder. When these screening tests are not conclusive and the clinicalsuspicion of an immunodeficiency is strong, the patient shouldreferred to an immunologist for further evaluation.


Antibody Production Defects

ANTIBODY PRODUCTION DEFECTSDISEASE COMMON NAME ICD 9 CODE

X-Linked Agammaglobulinemia (Brutons) Agammaglobulinemia, XLA 279.Common Variable Immunodeficiency (CVID) Late Onset Hypo- or Agammaglobulinemia, CVID 27 X-Linked or Autosomal Hyper IgM Syndrome Hyper IgM Syndrome 279.0Selective IgA Deficiency IgA Deficiency 279.01


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Part B: Management, Expectations,Complications and Long TermMonitoring With the exceptions of selective IgA deficiency and transienthypogammaglobulinemia of infancy, patients with an identifiedantibody deficiency disorder are generally treated on a periodicbasis throughout life with replacement immune globulin,intravenously or subcutaneously. The intervals between doses givenare generally 2 to 4 weeks for the intravenous route of administration and more frequently (7 to 14 days) for the

subcutaneous route. An immunologist should participate in thedetermination of the proper dose and interval for each patient. Typical total monthly doses are in the range of 400 to 800mg/kgbody weight. Trough (pre-dose) blood levels of IgG can be evaluatedmore frequently initially and at least once a year after that todetermine if there has been a change in the pharmacokinetics andresultant blood levels of IgG in a specific individual. Doseadjustments are obviously necessary during childhood related tonormal growth or during pregnancy. However, once a dose has beenestablished for an adult, it is not usually necessary to routinely evaluate the trough IgG level unless the patient is not doing wellclinically. The trough level should be at least at or above the lowerrange of normal for IgG levels or >500 mg/dl. This may vary depending on the judgment of an immunologist as to the patientsclinical condition. For example, in one study, when IgG trough levelsin patients with agammaglobulinemia were maintained above 800mg/dl, serious bacterial illness and enteroviral meningoencephalitis were prevented. Higher trough levels (>800 mg/dl) may also havethe potential to improve pulmonary outcomes. It is important torecognize that for virtually all confirmed antibody deficiencies, lifelong immune globulin replacement is required.Immune globulin replacement is preventive, not a treatment. Many patients with antibody production disorders also benefit from the

use of prophylactic antibiotics or adjunctive therapy with full doseantibiotics rotating on a monthly schedule. Patients with antibody deficiencies are at risk for developing chronic lung disease;therefore, it is best to obtain an annual assessment of pulmonary function and chest x-rays or perhaps high resolution C-T scans.Families should expect that their affected relative will havedecreased absences from school and/or work with proper therapy.However, while sepsis and meningitis attacks will stop withimmune globulin treatment, sinopulmonary and gastrointestinalinfections may continue to occur, although with less frequency.If there is evidence of bronchiectasis in an individual with anantibody deficiency disorder, a high resolution C-T scan of the

lungs should be obtained and repeated periodically to monprogression.Spirometry (lung breathing tests) should also be performedannually or at 6 month intervals if the disease appears to beprogressing adversely at a more rapid rate. Liver and renal fublood tests should be checked prior to beginning immune gltreatments and at least once a year thereafter.In the face of any abnormal neurologic or developmental finbaseline lumbar puncture (spinal tap) for the examination offluid may be helpful in detecting an insidious meningoencep(brain) infection due to enterovirus, particularly in patients w

linked (Brutons) agammaglobulinemia. Developmentalassessments of such children should also be obtained annual6 month intervals if the disease appears to be progressing adat a more rapid rate.From a prognostic point of view, antibody deficient patientsdetermined to have B cells by flow cytometry (e.g. likely to CVID) are also at risk for autoimmune disease complicationGranulomatous lesions in the skin, liver, spleen and lungs in with CVID may be misdiagnosed as sarcoid.Patients with CVID or Brutons agammaglobulinemia may p with chronic diarrhea and have malabsorption due to infecti

parasites, e.g. Giardia lamblia or overgrowth in the small int with certain types of gram negative bacteria, e.g. C. difficile

Immune Globulin Therapy When DiagnosisUncertain When there is uncertainty of the diagnosis, and immune globreplacement has already been started, it is useful to reassess need for immune globulin treatment. This is particularly truepatients serum contains IgA, IgM and IgE, which are not prsignificant amounts in immune globulin preparations. If theypresent in the patients serum, this means that the patient isproducing these immunoglobulins. To further evaluate whethpatient can produce antibodies normally, the patient can bechallenged with a neoantigen (e.g. vaccines not routinely usas rabies or Bacteriophage PhiX174) for which it is extremeunlikely that the specific antibody would be present in the im globulin preparation. Alternately, only under the advisementimmunologist, immune globulin treatment can be stopped inspring or summer when infection risks are less. Then, the pacan be reimmunized with standard killed vaccines and the antiters to these vaccines tested after three months. If immune globulin and antibody titers to bacteriophage PhiX174 and/o vaccine antigens are found to be in the normal range,then




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immune globulin replacement is not necessary. Skin testing forallergies is also useful; individuals who have positive allergy skintests are producing IgE antibodies to the allergens and are notlikely to need immune globulin replacement.

Monitoring Immune Globulin Therapy in Antibody Deficient PatientsFrequency of testing for trough levelsy Monitor IgG levels at least once a year (more often if the patient

is having infections) just before the next infusion. Be aware that gastrointestinal tract infection with the parasite Giardia lambliacan cause enteric loss of IgG leading to unexpectedly low IgGlevels. Generally, once the optimal dose of immune globulin hasbeen established in a patient, monthly monitoring of the IgGlevel is not indicated unless there is protein loss through the GIor urinary tracts.

Long-term follow up of patients on immune globulin therapy y Evaluations regarding hepatitis A, B, and C by PCR (polymerase

chain reaction) screening may be indicated. Yearly PCR screening for hepatitis C is the standard of care in EuropeanUnion countries.

Adverse event monitoring on immune globulin therapy y Every 6-12 months creatinine level and liver function tests are

useful.

Other ScreeningsCancer screening may be indicated on a periodic basis, as it is forindividuals with intact immune systems. Some subgroups of those with a primary immunodeficiency disease, such as those with chroniclymphadenopathy may merit baseline MRI and/or PET scans andmore intensive screening. Lymphoma evaluation is the same as forthose without hypogammaglobulinemia. Useful diagnostic screeningtests include determination of uric acid, LDH (lactic dehydrogenase)

and ESR (erythrocyte sedimentation rate).

VaccinationsPatients receiving regular infusions of immune globulin therapy possess passive antibodies to the agents normally given in vaccines. Thus, while a patient is receiving immune globulin therapy, there isno need for immunizations. Some immunologists recommendinfluenza vaccination, but the patient is unlikely to respond to it withantibody production. However, all household contacts should receiveregular immunizations with killed vaccines, particularly annualinfluenza immunizations. Live virus vaccines, even if attenuated, posea substantial risk to certain individuals with primary

immunodeficiency diseases. These vaccines include the oral vaccine, mumps, measles and German measles (Rubella) vac(MMR), yellow fever vaccine, and the chickenpox vaccine (V).In addition, FluMist, an intranasal, attenuated live influenza vaccmay also harm vulnerable populations such as those with primimmunodeficiency. Agents used to counteract bioterrorism su vaccinia vaccine to provide immunity to smallpox may also bharmful to a person with associated T cell defects.

Part C: Practical Aspects of Gene

Counseling The genetic bases of many of the common antibody producdefects are currently unknown. This is especially true for mpatients with Common Variable Immunodeficiency and SeleIgA deficiency. For this reason, genetic counseling can becomplicated in families affected by these disorders. Theinheritance pattern and recurrence risk to family members idifficult to predict without a molecular diagnosis, but an accfamily history may be helpful in this aspect. It should be nohowever, that these disorders can also occur sporadically anfamily history in those cases would be negative. Even thouginheritance pattern for some disorders may not be clearly understood, research has shown that family members of pat with CVID and Selective IgA deficiency also have an increof antibody deficiencies and autoimmune disorders. It is alsimportant to note that, when the gene defect has not beenidentified for a specific disorder, prenatal diagnosis is not an The genetic bases of other antibody production defects are knand these disorders include patients with absent B cells andagammaglobulinemia and most cases of the Hyper IgM syndr These disorders can follow either an X-linked recessive or anautosomal recessive inheritance pattern. Please see the genera genetic counseling section for a more detailed explanation ofinheritance. Because mutations in a variety of different genescause these conditions, molecular testing is important to deterthe specific gene involved and its mutation. This can help preclinical manifestation of the disorder in the affected individua gene identification along with an accurate family history wildetermine the pattern of inheritance in the family, risks for fammembers that could be affected, as well as identification of atcarrier females of X-linked disorders. Genetic testing is curreavailable in specialized labs for diagnostic confirmation, carrand prenatal diagnosis of some of these diseases. For a currenthese laboratories, consult your immunologist or contact theImmune Deficiency Foundation.



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1. Will my child outgrow the disease? While it is unlikely that your child will outgrow a primary immunodeficiency disease, identifying changes in yourchilds medical condition and their management is bestperformed by your immunologist.

2. What is IGIV?IGIV stands for immune globulin, intravenous, a family of plasma proteins that help fight infections. The name refers

to the intravenous (in the vein) form of IgG antibodiespurified from blood or plasma donations fromapproximately 60,000 donors per batch.

3. Is there a need for extra immune globulin duringinfections, such as pneumonia, and duringsurgery?During an infection, the antibodies to that infectious agentare rapidly used up, so there may be a need for additionalamounts of immune globulin during that illness. It may also provide broad protection against infections that may occur during invasive surgery. Appropriate antibiotic

coverage should also be considered during surgery. 4. Can immune globulin be given orally and is there

any place for this as a treatment?Some researchers have given immune globulin by mouthto patients trying to mimic the situation in very younganimals where the infant animal receives protectiveantibodies in mothers milk. While immune globulin hasbeen given by mouth to some patients, there are noresearch trials that confirm its usefulness.

5. Is there protection in IGIV from West Nile Virus?

At the present time, this is unknown. However, there is norisk of transmitting the virus by IGIV.

6. What is the safety of IGIV? There is a remote or theoretical possibility of blood bornedisease transmission. However, laboratory screeningmethods are very good and can identify infected donors as well as those developing infection. In addition, themanufacturing of IGIV separates and may inactivatepotentially contaminating viruses. To date, there has beenno evidence of prion (the agent of Mad Cow Disease) orHIV transmission.

7. Why is it important to record the brand, infusiorate and lot numbers of IGIV that is infused?On rare occasions, a problem is identified in a specificof IGIV from a specific manufacturer. With good recokeeping, you can know if the potential problem affectsor you can avoid infusing the specific lot. The best walearn about these types of problems when they happento sign up for the Patient Notification System, by calli 1-888-UPDATE-U (1-888-873-2838).

8. Is it appropriate to have a central vascular IGIV (port) implanted to receive IGIV treatments? While surgically implanted central lines may makeinfusions easier, they carry real risks of infection and bclotting that could severely complicate the care of aperson with a primary immunodeficiency disease. Therefore, central lines are not recommended if only tused for this purpose. When standard venipuncturesmade to start IV lines for the infusion of IGIV, it is hel younger patients to apply a topical anesthetic cream liEMLA 30 to 60 minutes before the stick.

9. Can IGIV be given in any way besides by vein? There have been a number of studies over the years thdemonstrate that immune globulin (IG) can be infusedsubcutaneously (SQ), under the skin in restricted volu with good clinical results. Use of SQIG may be a goochoice for those with poor vascular access, very youngchildren and those with numerous reactions to theintravenous infusions. Immunology specialists will befamiliar with this technique and can advise you whethnot it is appropriate for you. In 2006, an immune globupreparation for subcutaneous administration was licensin the United States.

10. What are some types of reactions to immune globulin?Reactions are common during the first infusions of IGafter the diagnosis has been established. They are of several different types. True allergic reactions are rare,occur early during the time of the infusion and arecharacterized by hives, chest tightening, difficulty inswallowing or breathing, feeling faint, abdominaldiscomfort and blood pressure or pulse changes. The fresponse should be to stop the infusion. Your medical



Part D: Frequently Asked Questions


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provider may then take additional steps if thesymptoms do not rapidly subside.Lot-to-lot and product-to-product reactions may includeheadache, flushing, lightheadedness, nausea, vomiting,back or hip pain and fatigue. These side effects aremore common and are usually rate related, occurring generally at the higher infusion rates.Headaches may be a significant complication and mostoften occur within 24 hours of an IGIV infusion. Someheadaches can be managed with milder analgesicagents like acetaminophen (Tylenol), aspirin oribuprofen. However, some headaches represent asyndrome of aseptic meningitis. Severe headachesoccur most frequently in individuals with a prior history of migraine headaches.For specific information about less common but seriousreactions, you should refer to the specific IGIV packageinsert.Patients experiencing reactions should NOT be treatedat home. Newly diagnosed patients or patients using anew product should receive their first infusion in amedical setting.

11. How is IGIV reimbursed? Ask your provider for an itemized bill to help clarify billing questions, or ask your insurance company for anExplanation of Benefits (EOB). Reimbursement for IGIVmay vary from year to year and from insurance plan toinsurance plan. It is very important to understand yourplan and its coverages.

12. As more patients receive their IGIV infusionsin the home, what is the recommendation for follow up with an immunology specialist? An immunologist should follow up most patients every 6 to 12 months, but patients with secondary complications, such as chronic lung or gastrointestinaldisease may need more frequent follow-up and/ormore than one specialist.

13. What expectations should the patient withantibody deficiencies have once he or she ison immune globulin therapy?Immune globulin therapy should protect the patient from sepsis (blood stream infection), meningitis

(infection of the coverings of the brain) and otherserious bacterial infections. In addition, school/work absences will decline. However, do not expect allinfections to stop. There may still be a need for the useof antibiotics. Children in general fare better thanadults. Quality of life should be greatly improved onimmune globulin therapy.

14. What is the role of antibiotics in antibody deficiency diseases? Antibiotics may be used chronically if there is evidencof chronic infection or permanent damage to the lungs(bronchiectasis) or sinuses. The antibiotics should be given in full treatment doses. Often, different antibioti will be prescribed on a rotating schedule on a monthlybasis. Prophylactic antibiotic therapy may beparticularly helpful for selective IgA deficiency, asimmune globulin therapy is not indicated.

15. What is the role of over the counter immunestimulants? There is no evidence that these stimulants have any helpful effects.

16. Is it OK to exercise and play sports? Yes. Physical activity and sports may help improve yoor your childs sense of well-being as you participate isome of lifes enjoyable activities.

17. Is it OK to have pets? Yes, but be aware that animals may carry infectionssuch as streptococcal infections that can be transmittedto humans. Also, live vaccines may be given todomestic pets and could potentially pose a risk to theperson with primary immunodeficiency.

18. Can IGIV be given during pregnancy? Yes, and it should be given as when not pregnant.



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TreatmentImmune Globulin Replacement

IgA < 11mg/dL

IgM > 200or < 40mg/dL

Referral to an immunologist for further evaluation, diagnosis and development of a care plan

IgG < 400mg/dL

LABORATORY EVALUATION

May be a primaryimmunodeficiency



TYPES OF INFECTIONSRecurrent Otitis and Sino-Pulmonary Infections with Fever

MeningitisSepsis

Cutaneous InfectionsGI Infections

Autoimmune Disorders: Immune Cytopenias

One site of infection > Two sites of infection

May be a primaryimmunodeficiency

Generally NOT a primaryimmunodeficiency

Findings on PhysicalExamination

Absent tonsils or Lymph nodes

Generally a primaryimmunodeficiency

Low age-adjusted absoluteLymphocyte, Neutrophil or

Platelet Counts

Tonsils and Lymph nodes present

ANTIBODY PRODUCTION DEFECTS

IgE > 1000IU/ml

CBC and DifferentialQuantitative Immunoglobulins

Specialized Testing


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Part A: Recognition and Assessment These individuals have abnormal T cell function and, as aconsequence, also have problems with antibody production. Affectedindividuals have both common and unusual infections. Typically, thepatient is an infant or a young child and would not survive withoutearly medical diagnosis and intervention(s). Some affected individualspresent clinically in the nursery, such as those with severe or completeDiGeorge syndrome or some with the Wiskott-Aldrich syndrome.However, most other infants with severe T cell defects have nooutward signs to alert anyone to their problem until infections begin. Those with the most severe forms of cellular or combined defectsrepresent a true pediatric emergency and should receive promptreferral to an immunologist so that plans can be made for treatment often a transplant to achieve immune reconstitution. Early diagnosiscan avoid infections and make survival more likely. Patients may:y Appear illy Have facial dysmorphia (DiGeorge syndrome)y Fail to thrive

- Weight is a more important determinant than lengthy Have congenital heart disease (heart murmur at birth, cyanosis,

DiGeorge syndrome)y Have rashes

- Severe diaper rash or oral candidiasis (thrush)- Eczema as in Wiskott-Aldrich syndrome or Graft versus Host

Disease (GVHD)- Red rash as in GVHD or Omenns syndrome- Telangiectasia (prominent blood vessels)- Petechiae in Wiskott-Aldrich syndrome

y Have chronic intractable diarrheay Develop intractable viral infections due to Respiratory syncitial

virus (RSV), parainfluenza, cytomegalovirus (CMV), Epstein Barr Virus (EBV), or adenovirus

y Have infections not accompanied by lymphadenopathy exceptin the Wiskott-Aldrich syndrome

y Have adverse reactions after live vaccines such as Varivto prevent chicken pox y Have neurological findings such as ataxia or tetany of t

newborn (DiGeorge syndrome)y Have Polyendocrinopathy, Immunodysregulation, Enter

X-linked (IPEX) syndrome, or chronic mucocutaneous y Need to have a diagnosis of Human Immunodeficiency

(HIV) infection excludedSome combined defects, though ultimately fatal without treare not initially as severe so do not present as early as SCIDare zeta-associated protein (ZAP) 70 deficiency, purine nucphosphorylase (PNP) syndrome, Wiskott-Aldrich syndromefactor of kappa B essential modulator (NEMO) deficiency. recognition of Ataxia Telangiectasia may also be delayed, adevelop progressively during the first several years of life.

Laboratory Testing A white blood cell count with a manual differential shouldobtained to determine whether the patient has a low absolulymphocyte count (i.e. is lymphopenic). Age-appropriate n values must be considered.

These tests would also reveal whether the patient has too neutrophil count (i.e. is neutropenic) or has an elevated necount, as is seen in leukocyte adhesion deficiency (LAD)counts and platelet size measurements may also be useful out Wiskott-Aldrich syndrome. Referral to an immunologbe made for more detailed lymphocyte analysis by flow c T cell functional testing is of greatest importance. Quantitimmune globulin and antibody testing should also be perfGenetic testing is complicated by the fact that there are at eleven differentmolecular causes of SCID. If a diagnosis of SCID is suspected, the infant should be kept away from osmall children and those with infections.


Cellular or Combined Defects

DEFINITION OF LYMPHOPENIA Birth < 2500/ L 56 Months up to 1 year < 4000/ L Adult < 1000/ L

CELLULAR OR COMBINED DEFECTSDISEASE COMMON NAME ICD 9 CODE

Severe Combined Immunodeficiency Bubble Boy Disease, SCID 279.2DiGeorge Syndrome also known as Thymic Aplasia 279.11 22q11 Deletion Syndrome Ataxia Telangiectasia AT 334.8

Wiskott-Aldrich Syndrome WAS 279.12


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Part B: Management, Expectations,Complications and Long TermMonitoringOnly irradiated (5000 RADS), CMV-negative, leukocyte-depletedblood products should be used in managing the patient with SCIDor other suspected T cell deficiencies. No live virus vaccines shouldbe administered to any member of the household, including thepatient. This includes no oral polio, Measles, Mumps, Rubella(MMR), FluMist, or Varivax vaccines and no Bacillus CalmetteGuerin (BCG) in countries where these practices are

recommended. However, all household contacts should receiveregular immunizations with killed vaccines, particularly annualinfluenza immunizations. Typical serious, often overwhelming orfatal infections in SCID are PJP (Pneumocystis jiroveci pneumonia),candida, Respiratory syncitial virus (RSV), parainfluenza 3,cytomegalovirus (CMV), Epstein Barr virus (EBV) and adenovirus. If an infant is suspected of having SCID, he or she should be placedon PJP prophylaxis with trimethoprim/sulfamethoxazole. If there isa family history of an early death due to infection, a diagnosis orexclusion of SCID in a subsequent birth can be done by performing a white blood cell count and a manual differential onthe cordblood to look for a low lymphocyte count. If the count islow, flow cytometry, a specialized laboratory test, should beperformed to see if T cells are present.

Immune reconstitution in SCID generally requires bone marrtransplantation early in life. Gene therapy has been tried witnotable success, but there have been serious adverse events.SCID patients who have received successful bone marrow transplants require at least annual follow up by an immunoloat a specialized center. There may be unanticipatedcomplications and patients should also have the opportunity benefit from new therapeutic developments.Patients with combined immune deficiencies who have low not absent T cell function may additionally fail to make antinormally despite normal or elevated immune globulin levels They also require immune globulin replacement therapy. Foexample, although Wiskott-Aldrich patients may have normaimmune globulin levels, they are usually treated with immun globulin because their ability to make antibodies is abnormathe complete form of DiGeorge syndrome there is no T cellfunction and thymic transplantation is the recommendedtreatment. The long-term outcome for partial DiGeorgesyndrome is generally satisfactory from an immunologicperspective, however, susceptibility to other complications ssevere autoimmune disease or EBV induced lymphoma rem AT (Ataxia Telangiectasia) patients should minimize theirexposure to ionizing irradiation, as they have an increased ri

chromosomal breakage and its complications.



Part C: Practical Aspects of GeneticCounseling The genetic basis is known for many of the cellular or combinedimmune defects. Many of these disorders follow X-linkedinheritance; others follow autosomal recessive inheritance. Pleaserefer to the general genetic counseling section for an explanationof inheritance patterns. A special consideration for geneticcounseling of families affected by these disorders is the fact thatthere are several different genes that, when mutated, result in thesame clinical disorder. For example, it is currently known thatmutations in one of at least eleven genes can cause SCID. Themost common form of SCID follows X-linked inheritance; allother forms of SCID follow autosomal recessive inheritance. It istherefore crucial that genetic testing be done to determine thespecific gene involved in these disorders to provide accurateestimates of risks for family members being affected. However, genetic testing should not delay initiation of appropriatetreatment. Genetic testing for many of the cellular or combined

immunodeficiency disorders is only available in specializedlaboratories in the U.S. and abroad. For more specific informrefer to the general section on genetic counseling.DiGeorge syndrome is one of the few primary immunodeficdiseases that may follow autosomal dominant inheritancehowever, most cases are sporadic. It is caused by a deletedportion of a region on chromosome 22 in more than half of tcases, by mutations in a gene on chromosome 10 in another and is of unknown cause in the other cases; it affects both mand females. While many of these cases occur as new mutatin the genes responsible on chromosome 22, it is also importo do molecular testing of the parents of a child with thiscondition because there can be clinical variability and an affparent may have previously gone undiagnosed. Whether or nthe chromosome defect is inherited or due to a new mutationhas significant impact on recurrence risk for a family. Genettesting for chromosome 22 deletions is widely available inlaboratories across the United States.


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Part D: Frequently Asked Questions 1. What happens if my child is exposed to chickenpox?

You need to let your physician know immediately so your child can receive VZIG (Varicella Zoster Immune Glohyperimmune globulin within 48 hours of exposure. The incubation period of varicella is 11 to 21 days. If your a vesicular rash which looks like small blisters, he or she will need to be treated with acyclovir, an antiviral agen(IV) acyclovir is superior to oral.

2. What is the risk to those with primary immunodeficiency diseases if attacks of bioterrorism occur?Individuals with T cell defects are at serious risk if widespread smallpox immunization programs are initiated. Aantibodies in immune globulin therapy may offer some protection. Research is being conducted to find additionaand vaccinia hyper-immune globulin is being developed.

3. What kind of vaccines can my child receive? All of the killed vaccines are safe, but he or she should not receive any live vaccines such as oral polio, measlesrubella, varicella (chicken pox), yellow fever or intranasal influenza. Antibodies in IGIV may give protection agof these viruses. In general, immunodeficient patients who are receiving IGIV should not be given vaccines, althimmunologists give influenza immunizations. If the patient is immune deficient enough to need IGIV, he or she would not be able to respond with antibody production. It is uncertain whether there would be a T cell responsebe helpful. The antibodies present in IGIV would neutralize most vaccines so that they would be ineffective.



14/3212 IMMUNE DEFICIENCY FOUNDATION


Laboratory Testing

Refer toImmunologist

TreatmentImmune Globulin

Replacement TherapyBone Marrow Transplantation

Gene Therapy

Complete blood countand manual differential

LymphopeniaBirth < 2500/L,

5 6 Months < 4000/L, Adults < 1000/L,

Thrombocytopenia orNeutropenia

Failure to thriveand gain weight

Adverse reactionsafter live vaccines

Intractable diarrhea, viral infections

Cutaneousfindings

Absence of lymphoid tissue

PhysicalExamination

Common or unusualinfections in an infant or

young child

CELLULAR ORCOMBINED

DEFECTS


15/32IMMUNE DEFICIENCY FOUNDATION

Part A: Recognition and AssessmentSigns of defects in the phagocytic cells are manifest in many organ systems. The onset of symptoms is usually in infancy orearly childhood.y Skinboils and/or cellulitis with or without pus formationy Lymph nodesmay be swollen and contain pusy In LAD (leukocyte adhesion deficiency) there may be

delayed shedding of the umbilical cord or omphalitisy Osteomyelitisan infection of boney Hepatic Abscessan infection in the liver may be seen in

Chronic Granulomatous Diseasey LungsAspergillus (mold) lung disease is insidious;

pneumonia may also occur due to bacterial pathogens(Staph or Serratia) that do not usually result in infections innormal hosts

y Gastrointestinal tract antral outlet and/or urinary tractobstruction resulting in abdominal or back pain is oftenseen in Chronic Granulomatous Disease, as is constipation

y Mouth (gingivitis)gum inflammation, mouth ulcersy Unexplained fever without identifiable causey Malaise and fatiguey Albinism may be seen in Chediak Higashi syndrome

Laboratory TestsDefects in phagocytic cells can be due to an insufficientnumber of such cells, an inability of the cells to get to aninfected area, or to an inability to kill ingested bacteria or funginormally.y A complete blood count and differential are needed to

determine whether phagocytic cells (neutrophils) arepresent in normal number. In the case of cyclic

neutropenia, the test (absolute neutrophil count) has to repeated sequentially (e.g. 2 times per week for 1 monty A test for CD11/CD18 expression on white cells is nee

to exclude LAD.y A Respiratory Burst Assay (the replacement for the NB

assay) should be performed to determine if phagocyticcells can produce oxygen radicals needed to kill bacteriand fungi.

Part B: Management, ExpectationComplications and Long TermMonitoringIn general, neutropenia (reduced numbers of phagocytes)is most commonly secondary to a drug or an infection andthe patient should be referred to a hematologist or otherspecialist for management. In individuals with a primary immunodeficiency disease affecting phagocytic cells,prophylactic antibiotics may be appropriate. Theseantibiotics include trimethoprim sulfamethoxizole andcephalexin. CD40 Ligand deficient patients are often

profoundly neutropenic. Individuals with KostmannsSyndrome may be responsive to granulocyte colony stimulating factor (G-CSF), as may be the neutropeniaassociated with CD40 Ligand deficiency. Prophylacticantifungal agents are often administered in ChronicGranulomatous Disease (CGD).

It is important to obtain bacterial cultures in these patientto direct antibiotic treatment. With appropriate antibiotictherapy, individuals with CGD should live into their 40s older. However, there are differences in infectionsusceptibility in terms of the X-linked and autosomal

recessive types, with somewhat more frequent infections ithe X-linked type. Meticulous medical care from an exper

Phagocytic Cell Immune Defects

PHAGOCYTIC CELL IMMUNE DEFECTSDISEASE COMMON NAME ICD 9 COD

Leukocyte Adhesion Defect LAD 288.9

Chronic Granulomatous Disease CGD 288.1

Chediak Higashi Syndrome CHS 288.2Cyclic NeutropeniaKostman Disease Neutropenia 288.0



in immunology will increase the patients chances of longersurvival. Typically, hemogloblin, hematocrit, ESR (erythrocyte sedimentation rate) and/or CRP(C-reactiveprotein) and a chest X-ray should be followed regularly inCGD. If there is any fever, malaise or change in health status,the patient requires immediate medical evaluation. Patients with CGD have normal T cell and B cell function. Therefore,they are not susceptible to viral infections, can receive live virus (but not BCG) vaccines, and can attend school and visitpublic areas such as malls.Gamma-interferon has been used to treat CGD. There is nochange inin vitro tests of phagocytic cell function with thistreatment, although some clinical benefit (e.g. reducednumber of serious infections) has been reported. Bonemarrow transplantation has been successful in children withCGD when there is a matched sibling donor.

Part C: Practical Aspects of GeneCounseling The genetic basis is known for most of the phagocytic celimmune defects. However, as with SCID, mutations inmultiple genes are responsible for a clinically similar condFor example, four genes (when mutated) are known to cauChronic Granulomatous Disease. The most common formthis disorder follows X-linked recessive inheritance and thother forms follow autosomal recessive inheritance. A detfamily history may be helpful in determining the type of CHowever, genetic testing is again crucial in determining thspecific gene involved. With this information, the clinicalprognosis can be assessed and patterns of inheritancedetermined in the family. Genetic testing for the phagocytcell immune defects is only available in specializedlaboratories. Please see the general section on geneticcounseling for more information about testing.

Phagocytic Cell Immune Defects

Part D: Frequently Asked Questions 1. What activities and places should my child avoid?

There is no general recommendation for avoiding infections, however swimming in lakes or ponds should be avExposure to aspergillus and mold that is associated with gardening that involves digging and handling or being ashould also be avoided. These and any other activities that will expose the child with a phagocytic cell primary immunodeficiency to potentially harmful bacteria or fungi should be avoided.

2. Can my child receive all types of vaccines? Yes, except for BCG, because patients with CGD have normal T and B cell function.



Skin Gastrointestinal Tract

Respiratory Burst Assay

CD11/CD/18 byflow cytometry

Serum IgE Levels

Lymphadenopathy Musculoskeletal Pulmonary ConstitutionalSymptoms

Antibiotics Anti Fungal Agents

Bone Marrow Transplantation

Gamma-Interferon

CBC and Manualdifferential

ESR or CRP

Treatment

If abnormal, refer to an immunologist for further evaluation, diagnosis and treatment

Physical Examination

PHAGOCYTIC CELLIMMUNE DEFECTS

Laboratory Tests


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Evaluation of the complement system is appropriate forpatients with recurrent episodes of bacteremia (positiveblood culture), meningitis or disseminated gonorrhea, which suggest a late complement component deficiency.Recurrent Neisserial infections warrant immediate testingof the complement system.y C2, C3 or C4 deficiencies may present with

pneumococcal disease, i.e. otitis or pneumonia. Therecan also be concomitant antibody deficiency due topoor antigen uptake by dendritic cells which normally interact with antigen-antibody complexes bearingcomplement components. Systemic lupuserythematosus is much more common than infectionsas a manifestation of early complement componentdeficiencies.

y C3 deficiency is very rare but is characterized by recurrent serious bacterial infections and developmentof membranoproliferative glomerulonephritis.

y Neisseria infections in children and adolescents suggestC5-7 deficiencies:

- Recurrent Central Nervous System (CNS) infectionsare more common in African Americans thanCaucasians with complement componentdeficiencies.

- Genitourinary tract infections are also seen.- Cutaneous lupus and other manifestations of

autoimmunity are observed, particularly withdeficiencies of subcomponents of C1, C2, or C4.

Hereditary Angioedema is due to a deficiency of C1esterase inhibitor. Patients may experience recurrentepisodes of abdominal pain, vomiting and laryngealedema. The diagnosis can be made based on the clinicaloccurrence of angioedema (swelling) and the repeated finding of decreased quantities of C1 inhibitor protein oractivity and reduced levels of C4. C1q when measuredconcomitantly is normal.

Laboratory TestsDiagnosis: CH50 and AH50y In the work up for complement deficiency, the CH50 i

excellent screening test, but the blood needs to behandled carefullysee below. Alternative Pathway defcan be screened for with the AH50 test. Identification the particular component that is missing will requirestudies in a research or specialized laboratory.

y For diagnosis, proper specimen collection of bloodsamples is very important. Complement is very heat laIn general, if the CH50 is undetectable, the patient likehas a deficiency in a complement component, howeverthe CH50 is just low, it is more likely that the specime was not handled properly or that the patient has anautoimmune disease.


Complement Defects

COMPLEMENT DEFECTSDISEASE COMMON NAME ICD 9 CODE

C1 Esterase Inhibitor Deficiency Hereditary Angioedema 277.6Complement Component Deficiencies(e.g. C2, C3, C4, C5, C6, C7, etc.)

Part A: Recognition and Assessment

Complement deficiency 279.8


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Part B: Management, Expectations,Complications and Long TermMonitoringProphylactic antibiotics may be appropriate for deficiencies of any of the components of the complement cascade.Meningococcal immunization and/or prophylaxis may behelpful for immunization of any person diagnosed with a C5through C9 deficiency. All complement deficient patients should receiveimmunization with Prevnar or Pneumovax or both forpneumococcal infection prevention. Early recognition of feversand prompt evaluation (including blood cultures) is very important.Complications of complement deficiency includeautoimmune disease, especially systemic lupuserythematosus, lupus-like syndromes, glomerulonephritis, andinfections.Mannose binding lectin, a protein of the innate immunesystem, is involved in opsonisation and phagocytosis of micro-organisms. Most of those with the Mannose Binding Lectindefect are healthy except for skin infections, but someresemble patients with early complement component defects.In the setting of recurrent infection with suspected mannosebinding lectin deficiency, a specialty laboratory must diagnosethis defect.

Part C: Practical Aspects of GeneCounseling The genetic basis is known for all of the complement defbut testing is only available in specialized laboratories. Aforms of inheritance have been reported for the complemdefects and it is very important to determine the specificcomplement factor involved as well as its molecular basi The genetic basis of hereditary angioedema is known andfollows autosomal dominant inheritance. Please see the general genetics section for a more complete description

autosomal dominant inheritance. Family history is imporin the evaluation of angioedema. Genetic testing is availafor C1 Esterase Inhibitor deficiency and can be importandistinguishing the hereditary form of the disorder from thacquired forms.


Part D: Frequently Asked Questions 1. Can my child receive all types of vaccines?

Yes, individuals with complement defects usually have normal T and B cell function.

2. Are there infection risks if my child with a complement defect attends public school or goes to publNo, in general the problems with infections are due to those that your child would come in contact with in a varisettings. However, if there is a known outbreak of pneumonia or meningitis in your community, it may be pruden your child at home out of the school environment and administer antibiotics recommended by the public health a



Complement Defects

Treatment

Prophylactic Antibiotics,

Monitor for AutoimmuneDiseases

Prophylaxis with

Androgens and/or EACA,Infusion of C1 Esterase

Inhibitor for Acute Attacks

C1 EsteraseInhibitor

Complement Screening Assays: CH50, AH50

Specific Assays:Complement Components

Treatment

If abnormal, refer to an immunologist for further evaluation, diagnosis and treatment

Angioedema,laryngeal edema,abdominal pain

Laboratory TestsLaboratory Tests

Ear infections,Pneumonia

Meningitis,Gonorrhea

COMPLEMENT COMPONENT orINHIBITOR DEFECTS


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Due to the genetic nature of the primary immunodeficiency diseases, genetic counseling for the individual affected by thesediseases, as well as family members, is very important in providingcomprehensive care. Genetic counseling is typically providedonce the individual has been diagnosed with a specific primary immunodeficiency disease. While most immunologists areknowledgeable about the genetic aspects of primary immunodeficiency disease, it is sometimes helpful to refer theindividual or family member to a genetic counselor who hasexpertise in providing complex information in an unbiased andeasily understood manner. Issues addressed in genetic counselingfor a primary immunodeficiency disease should include:

y Discussion of the diagnosis and the gene(s) responsible forthe disorder, if known.

y Determination of available molecular genetic testing forconfirmation of the diagnosis, if applicable, depending onthe disorder in question.

y An accurate intake of the patients family history, preferably in the form of a pedigree.

y Determination and discussion of inheritance pattern andrecurrence risk for future children.

y Identification of family members who may be at risk of being

affectedwith the disorder or at risk of being carriers.y Brief discussion of the availability of prenatal diagnosis

options for the particular primary immunodeficiency. Thiscan be discussed again in more detail in future geneticcounseling sessions when appropriate.

y Discussion of whether the family should save the cord bloodof future infants born to them. If the infant is affected, this would not be helpful. If the infant is normal, the cord bloodcould be used as a source of stem cells for affected HLA-identical members of the family who might need atransplant for immune reconstitution.

Patterns of Inheritance The pattern of inheritance is very important when evaluating thepatient with a primary immunodeficiency disease. Many of theprimary immunodeficiency diseases follow X-linked recessiveinheritance. This means that the genes responsible for thesedisorders are located on the X chromosome and these conditionspredominantly affect males. Affected males have either inheritedthe gene defect from their mothers who were carriers of the genedefect or the gene defect occurred as a new mutation for the firsttime in the affected male.

About one third of all X-linked defects are identified as nmutations. In these cases, the mothers are not carriers or athe first affected (carrier) member of the family and the fahistory is otherwise negative. Female carriers of the genedefect do not typically show clinical symptoms. Howeverof all boys born to female carriers may be affected with thdisorder and half of the daughters may be carriers like themothers. Therefore, in families with X-linked disorders, itimportant to determine whether the gene defect is inheriteor is a new mutation, because this will greatly affect therecurrence risk to other family members.

The other most common pattern of inheritance for primarimmunodeficiency diseases is autosomal recessive. Disordfollowing this pattern are caused by gene defects on any o 22 pairs of numbered chromosomes (not the X or Y) andtherefore, affect both males and females. In this type of inheritance, the condition is only expressed when bothparents are carriers of the gene defect and both have passethe defective gene on to their child. These couples have ain four chance of having an affected child with eachpregnancy.


Practical Aspects of Genetic Counseling:General Considerations

Normal Affected Normal CarrierMale Male Female Female

Normal Affected Carrier Normal Affected CarrierMale Male Male Female Female Female

X-LINKED RECESSIVE INHERITANCE

AUTOSOMAL RECESSIVE INHERITANCE


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Some primary immunodeficiency diseases follow autosomal dominant inheritance. These disorders arecaused by gene defects on any of the numberedchromosomes and affect both males and females. Unlikeautosomal recessive inheritance, only one copy of the genedefect needs to be present for the condition to beexpressed in an individual. The defective copy overrides theindividuals normal copy of the gene. Individuals affected with these disorders have a 50% chance of passing the gene defect on to each of their children, regardless of gender. It is important to note that some of these disordersoccur as new mutations in the affected individual and a

family history may be negative.Genetic counseling for primary immunodeficiency diseases is complicated by a number of factors. It isimportant that the process of genetic counseling forprimary immunodeficiency diseases be done by either animmunologist or genetic counselor knowledgeable aboutthe specific intricacies of these disorders. Some of thecomplicating factors include:

y Primary immunodeficiency diseases are a group of more than 130 different disorders and there are at leastthat many genes involved in these disorders.

y Some primary immunodeficiency diseases have thesame or similar clinical presentation, but different genetic causes. This impacts the accuratedetermination of inheritance pattern and recurrencerisk to other family members.

y The genetic basis is still not known for many of theprimary immunodeficiency diseases, including someof the most common disorders, making it difficult toaccurately determine inheritance patterns and risk toother family members. This also makes it difficult tooffer prenatal diagnostic options.

y Very few commercial laboratories perform moleculardiagnostic procedures for primary immunodeficiency diseases and, for those that do, costs may be $2500- 3000 or more per family. Genetic testing is alsopossible in some research laboratories. Theseconsiderations may impact accessibility to testing as well as timely receipt of test results. For a current list of

laboratories performing genetic testing of primary immunodeficiency diseases, consult yourimmunologist or contact the Immune Deficiency Foundation.

Genetic counseling also involves a psychosocialcomponent. This is true when providing genetic counselinto families affected by the primary immunodeficiency disorders. The emotional aspect of having a genetic diseain the family can be a heavy burden and this can beexplored in a genetic counseling session. In addition, thediscussion of prenatal diagnostic options can be a sensitivtopic, since interruption of a pregnancy may be aconsideration. Prenatal diagnosis for primary immunodeficiency diseases may be an option if the genetic defect is known in the family. This could be donethrough a chorionic villus sampling performed in the firsttrimester of pregnancy or through amniocentesisperformed in the second trimester. Each of theseprocedures has a risk of miscarriage of the pregnancy associated with it, so these risks need to be discussedthoroughly by the genetic counselor. Prenatal diagnosis foa primary immunodeficiency disease may be considered when a couple wants to better prepare for the birth of an

infant with the disease in question. For example, knowingthat a fetus is affected can give a couple time to startlooking for a match for a bone marrow donor if this is thetherapy for the disease. Knowing that a fetus is unaffectedcan offer great relief to the couple for the rest of thepregnancy. Prenatal diagnosis may also be considered when a couple would choose to terminate a pregnancy of an affected fetus. Again, these considerations arethoroughly discussed in a genetic counseling session.Finally, the discussion of gene therapy may be addressed the genetic counseling of a family affected by a primary immunodeficiency disease. The anticipation is that genetherapy will become available for several diseases over thcoming years. However, even if the treatment is perfectedand found to be safe, it cannot be done unless theabnormal gene is known in the family.


Practical Aspects of Genetic Counseling:General Considerations


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Diagnosis InformationPatients need a hard copy description of their diagnosisand therapy and/or a MedicAlert badge (if applicable, areavailable at: www.medicalert.org). In addition, individualsshould consider acquiring a Personal Health Key from theMedicAlert organization. This USB enabled key stores yourhealth record and can be carried on a key chain or in apurse.

Travel Recommendations Travel outside the United States may require medicalregimens or vaccinations. Patients should consult with theirimmunologist to determine which vaccines can be safely administered and about the advisability of travel to various geographic areas of the world. As an example, be awarethat yellow fever vaccine is a live vaccine so it should notbe given to patients with T cell defects or members of theirimmediate household. In addition, IGIV would be of nobenefit for protection against yellow fever, as it lacksantibody to this viral agent.

Psychosocial Concerns The challenges of living with a primary immunodeficiency disease can cause significant stress and have a great impacton the psychological well being of the person affected withthe disease and his/her caregivers and family members.Learning effective coping strategies can benefit all who areaffected by these chronic illnesses. Establishing a goodsupport system through family members, friends, healthcare team members and other peers affected by primary immunodeficiency disease is essential to coping effectively with the disease. It is important for health care providers topay close attention to signs of more serious psychologicalconcerns, such as clinical depression, in a patient affectedby a primary immunodeficiency or his/her caregiver. Thisrecognition can help the individual and family seek appropriate intervention in a timely manner.

Education The transition from infant/toddler to school aged child cabe particularly challenging for a family affected by aprimary immunodeficiency disease. Communicationbetween parents and caregivers, the health care team andschool professionals is very important. This should includeducating school personnel about the childs particulardisease, management of infections, vaccine restrictions,prescribed therapy and precautionary measures that canbe taken to minimize infection in the school. Parents andhealth care providers should be familiar with the federal

regulations enacted to promote equal education forchildren with chronic diseases, such as primary immunodeficiency diseases, that may qualify as disabilitieFor more information about these regulations, pleasecontact the Immune Deficiency Foundation.

Employment Adults with primary immunodeficiency diseases aresometimes faced with the problem of employmentdiscrimination because of their diseases. Both patients an

health care providers should be familiar with the Americans with Disabilities Act and how it protects U.S.citizens with health conditions such as primary immunodeficiency diseases, that may qualify as disablingconditions. For more information about federal regulationplease contact the Immune Deficiency Foundation.


Life Management Considerations


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Great progress has been made in the treatment of primary immunodeficiency diseases. Life-saving therapies are now available for many of the primary immunodeficiency diseases. However, primary immunodeficiency diseasesdiffer from acute health conditions, as many of thetherapies necessary to treat these conditions are life-long. Therefore, it is essential that patients affected by thesediseases have adequate health insurance coverage forthese chronic therapies. In many cases, if therapy is notadministered on a regular basis, the cost of healthcomplications and subsequent hospitalizations could beextremely burdensome.

Reimbursement and coverage of the treatments andservices for primary immunodeficiency diseases can vary considerably, depending on the type of health insurance apatient has. Therefore, maintenance of health insurancecoverage requires a close working relationship on the partof the patient, the health care provider and the healthinsurance administrator. Patients or their caregivers need topay particular attention to the following issues when working with their health insurance providers:

y Obtain a complete copy of the patients healthinsurance policy and understand services andtreatments that are covered under the policy andthose that are excluded.

y Know the patients specific diagnosis, including theICD-9 code for the diagnosis. This information isavailable through the physicians office.

y Know if the insurance policy requires physicianreferrals and/or prior authorization for coverage of medical treatments, services or procedures beforeadministration of the treatment is scheduled to takeplace.

yConsider establishing a case manager through thehealth insurance provider to maintain consistency when seeking advice on the patients policy.

y Maintain a good understanding of out of pocketexpenses, including annual deductible amount,coinsurance amount and copayments for prescriptiondrugs, office visits and any other services.

y Know if the health insurance policy has a lifetimelimit/maximum on benefits and if so, know themaximum amount.

y Know if the health insurance policy has any pre-existing condition waiting periods.

y Know patients rights under the Health InsurancePortability and Accountability Act (HIPAA) and how these protect insurance coverage.

y If the patient is covered by Medicare, selecting theoption of Part B coverage is necessary for properreimbursement of many of the therapies for primary immunodeficiency diseases. Additionally, sincecoverage of these therapies is usually limited to 80%,is also important that a patient considers selecting aMedigap policy to help defray the cost of the 20% for which the patient is typically responsible.

Since reimbursement for therapies is constantly changingit is important to keep up with any changes in eachindividuals health insurance policy. In some cases,coverage for therapies may be denied and the patient mayhave to appeal for reconsideration of coverage. Patientsshould read their health plans Summary Plan Document

to know the appeals process and timelines associated with filing an appeal. Resources are often available for this typof assistance through manufacturers of the therapies. Inaddition, the resources below can be of assistance topatients going through this process. Sample letters forpatients and providers are attached below for guidancethrough the insurance appeals process.

y Immune Deficiency Foundation: www.primaryimmune.orgor (800) 296-4433

y State Departments of Insurance: www.naic.org/state_web_map.htm

y Centers for Medicare and Medicaid Services: www.cms.hhs.gov


Health Insurance



Patient Sample Insurance Appeal Letter

(Date )

(Contact Name )(Insurance Company Name )( Address )(City, State, ZIP )

Re: (Name of Patient )

( Type of Coverage )(Group Number/Policy Number )(Dates of Service )

Dear (Name of contact person at insurance company ):

Please accept this letter as my appeal to (insurance company name )s decision to deny coverage for (name of specific treatment/procedure denied ). I understand, based on your letter dated (insert date ), this was deniedbecause:

(specific reason for denial as stated in the denial letter )

I have been a member of your (name of PPO, HMO, etc. ) plan since (Date ). During that time I have participated within the network of physicians listed by the plan. However, my primary care physician, Dr. (name ) believes that thebest care for me at this time would be (therapy prescribed for your condition ).

I have enclosed a letter from Dr. (name of primary care physician ), explaining why (he/she ) recommends(name of therapy ). I have also enclosed a letter from Dr. (name of specialist ) explaining the therapy in detail,(his/her ) qualifications and experience, and several peer-reviewed articles discussing the use of (name the therapy )for my condition.

Based on this information, I am asking you to reconsider your previous decision and allow me to continue with thetreatment prescribed by Dr. (physician name ). If you require any additional information, please do not hesitate tocontact me at (phone number ). I look forward to hearing from you soon.

Sincerely,

( Your name )

Enclosures: (number )

cc: (medical director )(your physician )(local legislators )(state insurance commissioner )


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(Date )

(Contact Name )(Insurance Company Name )( Address )(City, State, ZIP )

Re: (Name of Patient )(Diagnosis )(Dates of Service )( Type of Coverage )

(Group Number/Policy Number )(Claim Number)

Dear (Name, Division, Administrator, or other appropriate title ):

I am writing to request a review of a claim for (patients name ), who was recently denied treatment for (patientsdisease ). It is my belief there is sufficient cause to fully reimburse the above-mentioned claim to the allowable limit of(dollar amount from payers fee schedule for the therapy and related services). Your company has denied this claim for following reason (s) listed on the attached EOB: (date from EOB). ( Attachment #1 .)

In my professional opinion, (patients name ) has required the administration of (name of therapy such as IGIV ) totreat (his/her ) unresolved (name of disease ). I believe this therapy has particular urgency for this patient. (Brieflydescribe patients history, emphasizing progression of disease ).

During the course of (his/her ) treatment, (patients name ) has experienced (describe positive outcomes ). I haveenclosed a summary of (patients name ) medical history and treatment notes to date ( Attachment #2 ), as well as a copy of the products package insert ( Attachment #3 ) to support this appeal. Moreover, the clinical literature supports the use of (name of therapy ) in such cases as described in the attached documentation ( Attachment #4, compendiamonographs, peer-reviewed articles ).

(Describe any other circumstances that support reimbursement of therapy for this particular patient,including other patients with similar conditions who received the same treatment with positive results. )

Enclosed you will find the following information to help you make your decision: EOB, package insert, treatment notesmonographs, peer-reviewed articles, and published coverage policy.

Administration of (name of therapy ) is an essential therapy for this patient. I trust the enclosed information, along with mymedical recommendations, will suffice in establishing the necessity of payment and coverage of (patients name )s claim.

Sincerely,

(Physicians name/ID number )

Enclosures: (number )

cc: (medical director )(patient )(local legislators )(state insurance commissioner )


Physician Sample Insurance Appeal Letter


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Acute a descriptive term used to describe an illness which is usually short in duration Agammaglobulinemia an almost total lack of immunoglobulins or antibodies Amniocentesis involves the withdrawal of fluid surrounding a fetus usually in order to perform pren genetic testing Antibodies protein molecules that are produced and secreted by certain types of white cells (lymphoin response to stimulation by an antigen; their primary function is to bind and help eliminate or neutrbacteria, viruses, toxins, and other substances foreign to the body Antigen any foreign substance that provokes an immune response when introduced into the body; timmune response usually involves both T lymphocytes and B lymphocytes Ataxia an unsteady gait caused by neurological abnormalities Autoimmune disease- a disease that results when the bodys immune system reacts against a persons

tissue Autosomes- any chromosome (numbered 1-22) other than a sex chromosome (X or Y)

Bacteria- single cell organisms (microorganisms) that can be seen only under a microscope; while babe useful, many bacteria can cause disease in humansB lymphocytes (B cells)- white blood cells of the immune system derived from bone marrow and invothe production of antibodiesBone marrow - soft tissue located in the hollow centers of most bones that contain developing red anblood cells, platelets and cells of the immune systemBronchiectasis damage to the tubes (bronchi) leading to the air sacs of the lung; usually the consequrecurrent infection

CD 40 ligand a protein found on the surface of activated T lymphocytes; Individuals with X-linkedSyndrome have a deficiency in this proteinCellular immunity - immune protection provided by the direct action of the immune cellsChromosomes- physical structures in the cells nucleus that house genes; each human has 23 pairs ochromosomes 22 pairs of autosomes and a pair of sex chromosomesChronic- descriptive term used to describe an illness or infection that may be recurrent or lasting a lChorionic villus sampling involves the retrieval of a sample of the developing placenta from the womorder to perform prenatal genetic or biochemical testingCombined immunodeficiency immunodeficiency resulting from when both T and B cells are inadeqor lackingComplement- a complex series of blood proteins that act in a definite sequence to effect the destructbacteria, viruses and fungiCongenital present at birthCord blood blood obtained from the placenta at birth, usually by removal from the umbilical cordCryptosporidium an organism that can cause severe gastrointestinal symptoms and severe liver diseasepresent in drinking water; the organism is resistant to chlorine, so even chlorinated water can carry this

DNA (deoxyribonucleic acid) the carrier of genetic information contained in chromosomes found in cell nucleus

Eczema- skin inflammation with redness, itching, encrustations and scaling


Glossary

A

B

C

D

E


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Fungus- member of a class of relatively primitive microorganisms including mushrooms, yeast and mGamma interferon- a cytokine primarily produced by T-cells that improves bacterial killing by phagoused as treatment for Chronic Granulomatous DiseaseGene- a unit of genetic material (DNA)Gene (or genetic) testing testing performed to determine if an individual possesses a specific gene o genetic trait; may include studies of whether the gene is altered (mutated) in any way Gene therapy - treatment of genetic diseases by providing the correct or normal form of the abnormacausing the diseaseGraft-versus-host disease- a life-threatening reaction in which transplanted or transfused immunocom T cells attack the tissue of the recipient

Graft rejection the immunologic response of the recipient to the transplanted tissue resulting in rejethe transplantGranulocyte- a white cell of the immune system characterized by the ability to ingest (phagocytize) material; a granulocyte is identified by the presence of many granules when seen under a microscopeneutrophils, eosinophils, and basophils are examples of granulocytes

Haplotype a series of gene clusters on one human chromosome 6 that encodes a set of histocompat(HLA) antigensHelper lymphocytes (Helper T cells)- a subset of T cells that help B cells and other immune cells to fuoptimally Humoral immunity - immune protection provided by soluble factors, such as antibodies, which circulbodys fluidHypogammaglobulinemia- lower than normal levels of immunoglobulins and antibodies in the bloodlevels need to be assessed as to whether the level requires replacement immune globulin therapy; thiassessment is best made by a qualified experienced immunologist

IgA - an immunoglobulin found in blood, tears, saliva, and fluids bathing the mucous membranes of rand intestinal tractsIgD- an immunoglobulin whose function is poorly understood at this timeIgE- an immunoglobulin found in trace amounts in the blood; antibodies of this type are responsible reactionsIgG- the most abundant and common of the immunoglobulins; IgG functions mainly against bacteriasome viruses; it is the only immunoglobulin that can cross the placenta

IgM- an immunoglobulin found in the blood; IgM functions in much the same way asIgG but is formed earlier in the immune response; it is also very efficient in activating complementImmune response- the activity or response of the immune system against foreign substancesImmunodeficiency - a state of either a congenital (present at birth) or an acquired abnormality of the system that prevents adequate immune responsivenessImmunoglobulins (Ig) the antibody proteins; there are five major classes: IgG, IgA, IgM, IgD, and IIntravenous immunoglobulin immune globulin therapy injected directly into the vein

Killer lymphocytes T lymphocytes that directly kill microorganisms or cells that are infected withmicroorganisms, also called cytotoxic T lymphocytes


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Leukemia type of cancer of the immune systemLive vaccines live viruses are used in the vaccine; live vaccines (particularly oral polio and the chicke vaccine) when injected into immunodeficient individuals, can transmit the diseases they were designeLess virulent agents organisms that do not generally infect humans; they may cause disease in indiv with weak immune systems, these are called opportunistic infectionsLeukocyte (white blood cell)- a group of small colorless blood cells that play a major role in the bodyimmune system; there are five basic white blood cells: monocytes, lymphocytes, neutrophils, eosinobasophilsLymph fluid made up of various components of the immune system; it flows throughout tissues of via the lymph nodes and lymphatic vesselsLymph nodes- small bean-sized organs of the immune system, distributed widely throughout the bodlymph node contains a variety of specialized compartments that house B cells, T cells and macrophanodes unite in one location the several factors needed to produce an immune responseLymphocytes- small white cells, normally present in the blood and in lymphoid tissue, that bear the mresponsibility for carrying out the functions of the immune system; there are three major forms of lyB cells, T cells and natural killer (NK) cells, each of which have distinct but related functions in genimmune responseLymphoma type of cancer of the immune system

Macrophages- phagocytic cells found in the tissue, able to destroy invading bacteria or foreign materMetabolism a general term which summarizes the chemical changes within a cell resulting in eitherbuilding up or breaking down of living materialMicroorganisms- minute living organisms, usually one-cell organisms, which include bacteria, protozoaMolecules- the smallest unit of matter of an element or compoundMonocyte- phagocytic cell found in the blood that acts as a scavenger, capable of destroying invadinor other foreign material; these cells develop into macrophages in tissuesMucosal surfaces surfaces that come in close contact with the environment, such as mouth, nose, gastrointestinal tract, eyes, etc. IgA antibodies protect these surfaces from infection

Neutropenia a lower than normal amount of neutrophils in the blood Neutrophils- a type of granulocyte, found in the blood and tissues that can ingest microorganisms

Opportunistic infection- an infection caused by a usually benign or less virulent agent, but resulting those organisms become established under certain conditions, such as in immunodeficient individualOrganism an individual living thingOsteomyelitis infection of the bone

Parasite a plant or animal that lives, grows and feeds on or within another living organismPersistent infections infections marked by the continuance of an infectious episode despite approprimedical interventionsPetechiae pinhead sized red spots resulting from bleeding into the skin, usually caused by low platenumbers (thrombocytopenia)


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Phagocyte- a general class of white blood cells that ingest microbes and other cells and foreign partimonocytes, macrophages and neutrophils are types of phagocytesPlasma cells- antibody-producing cells descended from B cellsPlatelets- smallest of the blood cells; their primary function is associated with the process of blood cPolysaccharides complex sugarsPrimary immunodeficiency immunodeficiency that is intrinsic to the cells and tissues of the immunsystem, not due to another illness, medication or outside agent damaging the immune systemProphylactic- medical therapy initiated to prevent or guard against disease or infectionProtein- a class of chemicals found in the body made up of chains of amino acids (building blocks);immunoglobulins (antibodies) are proteins

Recurrent infections infections, such as otitis, sinusitis, pneumonia, deep-seated abscess, osteomyelbacteremia or meningitis, that occur repeatedly

Secondary immunodeficiency immunodeficiency due to another illness or agent, such as humanimmunodeficiency virus (HIV), cancer or chemotherapy Sepsis- an infection of the bloodSpleen- an organ in the abdominal cavity; it is directly connected to the blood stream and like lymphcontains B cells, T cells, and macrophagesStem cells- cells from which all blood cells and immune cells are derived; bone marrow is rich in ste The stem cells referred to in this glossary, do not include embryonic stem cells, which are involved i

generation of all cells and tissuesSubcutaneous infusion administration of a drug or biologic (e.g. immunoglobulin) slowly, directly uskin often using a small pump

Telangiectasia dilation of small blood vessels Thrombocytopenia low platelet count Thrush- a fungal disease on mucous membranes caused by Candida albicans infections Thymus gland- a lymphoid organ located behind the upper portion of the sternum (breastbone) wheredevelop; this organ increases in size from infancy to adolescence and then begins to shrink T lymphocytes (or T cells)- lymphocytes that are processed in the thymus; they have a central role in cout the immune response

Unusual infectious agents these are normally non-pathogenic agents or those not generally found inhumans which can cause serious disease in immunocompromised patients

Vaccine a substance that contains components from an infectious organism which stimulates an immresponse in order to protect against subsequent infection by that organism Virus a submicroscopic microbe causing infectious disease which can only reproduce in lining cells

White blood cells see leukocyte


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IDF Diagnostic and Clinical Care Guidelines - Final

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