Continuing Education Activity

Immunodeficiency results from a failure or absence of elements of the immune system, including lymphocytes, phagocytes, and the complement system. Immunodeficiencies can be primary or secondary. Primary immunodeficiency is subdivided into types that cause T-cell deficiency, B-cell deficiency, both T-cell and B-cell deficiency, complement deficiency, phagocyte deficiency, and immunoglobulin A deficiency. Primary immunodeficiencies leading to T-cell deficiency include DiGeorge syndrome, also known as congenital thymic aplasia, chronic mucocutaneous candidiasis, hyper-immunoglobulin M syndrome, and interleukin-12 receptor deficiency. Primary immunodeficiency leading to B-cell deficiency includes X-linked agammaglobulinemia, also called Bruton agammaglobulinemia. Primary immunodeficiencies leading to both T-cell and B-cell deficiency include severe combined immunodeficiency disease, Wiskott-Aldrich syndrome, immunodeficiency with ataxia-telangiectasia, and Major Histocompatibility Complex deficiency. Primary immunodeficiencies leading to complement deficiency include hereditary angioedema, deficiency of C3, deficiency of membrane attack complex, and C2 or C4 deficiency secondary to autoimmunity. Primary immunodeficiencies leading to phagocyte deficiency include chronic granulomatous disease and leukocyte adhesion deficiency syndrome. Selective immunoglobulin A deficiency is also a primary immunodeficiency. Secondary causes of immunodeficiency include steroids, nutrient deficiency, obesity, acquired immune deficiency syndrome (AIDS), or other viral infections. This activity reviews the different immunological disorders, their evaluation, and management, and highlights the role of the interprofessional team in caring for affected individuals.

Objectives:

• Outline the immunodeficiency disorders.
• Describe the presentation of a patient with an immunodeficiency disorder.
• Review the treatment options for immunodeficiency disorders.
• Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients with immunodeficiency disorders.

Introduction

Immunodeficiency results from a failure or absence of elements of the immune system, including lymphocytes, phagocytes, and the complement system. These immunodeficiencies can be either primary, such as Bruton disease, or secondary, as the one caused by HIV infection.[1][2]

Primary Immunodeficiency

B-cell Deficiencies

X- linked Agammaglobulinemia (Bruton disease)[3]

• First described by Bruton
• X-linked disorder
• Found in male babies expressed around 5 to 6 months of age (maternal IgG disappears)
• In boys, pre-B cells did not differentiate into mature B lymphocytes
• There is a mutation in the gene that encodes for a tyrosine kinase protein
• A low level of all immunoglobulins (IgG, IgA, IgM, IgD, and IgE) is present
• Infants with X-linked agammaglobulinemia suffer from recurrent bacterial infections: otitis media, bronchitis, septicemia, pneumonia, and arthritis, and Giardia lamblia causes intestinal malabsorption.
• Intermittent injections of large amounts of IgG keep the patient alive, but a patient may die at a younger age if infection with antibiotic-resistant bacteria occurs.
• Bone marrow transplantation is critical.

Selective Immunoglobulin IgA Deficiencies

• IgA deficiency is more common than other deficiencies of immunoglobulins.[4]
• These patients are more prone to recurrent sinus and lung infections.
• A malfunctioning in heavy-chain gene switching may cause this problem.
• Treatment should not include gammaglobulin preparations to prevent hypersensitivity reactions. 

T-cell Immunodeficiencies

Congenital thymic aplasia (DiGeorge syndrome)[5]

• Tetany is present.
• Fungal and viral infections are common.
• A transplant of the fetal thymus is needed to correct this deficiency.

 Chronic Mucocutaneous Candidasis[6]

• Selective defect in the functioning of T-cells. 
• Patients with this disorder usually have a normal T-cell mediated immunity to microorganisms other than Candida.
• B-cell function is normal.
• Disorders affect both genders, and it is inherited.
• Patients, in addition to the above, will have other disorders like parathyroid deficiencies.
• Antifungals are useful.

 Hyper-IgM syndrome[7]

• This disorder is characterized by bacterial infections, including pneumonia, meningitis, otitis, among others that start in early childhood.
• High levels of IgM.
• Other immunoglobulins are defective.
• Lymphocytes are normal in numbers.
• The gene encoding the CD40 ligand on T lymphocytes is faulty.
• B and T lymphocyte cooperation in the immune response are compromised.
• The failure to interact with CD40 results in an inability of the B cell to switch from the production of IgM to the other classes of antibodies.
• Immunoglobulin therapy is recommended.

Interleukin-12 receptor deficiency

• Mycobacterial infections are frequent due to the lack of the interleukin-12 receptor.
• Treatment involves selective antimicrobials.

T-cell and B-cell Deficiencies

Severe combined immunodeficiency disease (SCID)[8]

• There is a failure of early stem cells to differentiate into T and B lymphocytes.  
• Deficiency of the interleukin-2 receptor is the most prevalent.  
• Other problems are due to defective genes encoding ZAP-70, Janus kinase 3, and the genes involved in the DNA recombination of immune cells receptors: RAG1 and RAG2.
• Clinically characterized by a variety of infections, including those caused by opportunistic pathogens.
• Selective antibiotics, antivirals, and antifungals are available after the pathogen identification.
• Immunosuppressive therapy is not needed after allograft transplantation.

Wiskott-Aldrich syndrome[9]

• This syndrome is associated with normal T-cell numbers with reduced functions, which get progressively worse.
• IgM concentrations are reduced, but IgG levels are normal.
• Both IgA and IgE levels are elevated.
• These patients have a defective WASP, which is involved in actin filament assembly.

Immunodeficiency with ataxia-telangiectasia[10]

• This is a deficiency of T-cells associated with a lack of coordination of movement (ataxia) and dilation of small blood vessels of the facial area (telangiectasis).
• T-cells and their functions are diminished to various degrees.
• B-cell numbers and IgM concentrations are normal to low. 
• IgG is often reduced, and IgA is considerably reduced.
• There is a high incidence of malignancy, especially leukemias, in these patients.

MHC deficiency (Bare leukocyte syndrome)[11]

• This subjects have fewer CD4+ or CD8+ T lymphocytes that predispose these individuals to be prone to recurrent infections.
• Antibody production is affected and predispose to bacteremia.

Complement Deficiencies

Hereditary angioedema[12]

• This disease has an autosomal dominant genetic pattern.
• Caused by C1 inhibitor deficiency
• Clinically characterized by generalized edema including the one leading to acute suffocation
• Therapy with oxymetholone and danazol can be helpful in correcting the defect.

Recurrent infections

• Frequent infections by extracellular bacteria may be caused by C3 deficiency. C5 deficiency predisposes to viral infections. 
• Patients with a deficiency of the membrane attack complex (MAC) are particularly susceptible to bacteremia caused by Neisseria species.  

Autoimmune diseases[13]

• This is caused by C2 and C4 deficiencies and mimics systemic lupus erythematosus.

Phagocyte Deficiencies 

Chronic granulomatous disease (CGD)[14]

• It is mostly an X-linked disorder.   
• It is clinically characterized by a defective NADPH that interferes with the intracellular ability of neutrophils to kill engulfed bacteria species.
• NADPH oxidase is required for the generation of peroxidase and superoxides that will kill the organisms.
• The intracellular survival of the organisms leads to the formation of a granuloma, an organized structure consisting of mononuclear cells.
• These granulomas can become large enough to obstruct the stomach, esophagus, or bladder.
• Patients with this disease are very susceptible to opportunistic infections by certain bacteria and fungi, especially with Serratia and Burkholderia.  
• Nitroblue tetrazolium (NBT) dye reduction test confirms the diagnosis of CGD and the dichlorofluorescein (DCF) test is also useful. 
• Aggressive therapy with wide-spectrum antibiotics and antifungal agents is required. 

Leukocyte adhesion deficiency syndrome[15]

• It is characterized by pyogenic infections, including pneumonia and otitis.
• It is an autosomal recessive disease, and the faulty gene encodes for an integrin.
• There is an impaired adhesion and defective phagocytosis of bacteria.
• Treatment involves the use of selective antibiotics.

Secondary Immunodeficiency

Use of Drugs (Steroids)[16]

• Administration of steroids has direct effects on immune cell traffic and functions.
• T cells are more affected than B cells.
• Cytokine synthesis is inhibited.

Nutrient Deficiencies[17]

• They are associated with an impaired immune system.
• Affects cell-mediated immunity, antibody production, phagocyte function, complement system, and cytokine synthesis.
• Aggravated by infections
• Multiple enzymes with important roles require zinc, iron, and other micronutrients.

Obesity

• It may cause impaired immune responses.
• There is altered NK function.
• Cytotoxicity is compromised and the ability of phagocytes to kill microorganisms.

Acquired Immune Deficiency Syndrome (AIDS)[18]

• Caused by the human immunodeficiency virus (HIV), which is a retrovirus transmitted sexually, perinatally, or blood products.
• Immune dysfunction results from the direct effects of HIV and the impairment of CD4 T cells.
• HIV proteins may act as superantigens.
• There are decreased responses to antigens and mitogens.
• Interleukin-2  and other cytokines are decreased.
• Infected cells may be killed by HIV-1 specific CD8+ T cells.
• In HIV-1 infection, neutralizing antibodies appear to be ineffective in controlling viral replication and infection.

Etiology

Primary immunodeficiency diseases result from intrinsic defects in immune cells, including T cells, complement components, and phagocytes. Recurrent pneumonia caused by extracellular bacteria suggests antibody deficiency. On the other hand, recurrent fungal infections may be caused by a lack of T lymphocytes.

Severe combined immunodeficiency disorders (SCID) are incompatible with life, and affected children usually die within the first 2 years. SCID is more common in the male. It is caused by a gene defect on the X chromosome in more than 50% of cases. The defective gene encodes the gamma chain of the interleukin-2 (IL-2) receptor. This chain forms a molecular part of the receptors for IL-2, IL-4, IL-7, IL-11, IL-15, and IL-21. On the other hand, few cases of SCID are caused by defective genes that encode for adenosine deaminase or nucleoside phosphorylase. The deficiency of these enzymes causes ribonucleotide reductase inhibition leading to a defect in DNA synthesis and cell replication. Mutation in the genes encoding RAG1 or RAG2 causes an autosomal recessive form of SCID.[8] 

The DiGeorge anomaly arises from a defect in the third and fourth pharyngeal pouches that causes a developmental abnormality of the thymus. The T-cell defect is variable depending on the severity of the thymic lesion. These infants have partial monosomy of 22q11-pter or 10p.

In the bare leukocyte syndrome, there is a mutation in the gene that encodes for the MHC class II transactivator (CIITA), resulting in the absence of class-II MHC molecule on antigen-presenting cells including macrophages and dendritic cells. A mutation in the gene that encodes for a transport-associated protein (TAP) results in the lack of class-I MHC molecule expression, which is manifested by a deficiency of CD8+ T lymphocytes.

Secondary immunodeficiency may be caused by drugs, including steroids, cyclophosphamide, azathioprine, mycophenolate, methotrexate, leflunomide, ciclosporin, tacrolimus, and rapamycin, which affect the functions of both T and B lymphocytes. Viral infections can cause immunodeficiency. For example, HIV causes AIDS, which mainly affects CD4+T cells and downregulates cellular immune responses that produce opportunistic infections and cancers, which are threatening to human health.[19]

Malnutrition is a cause of secondary deficiency, for example, protein-energy malnutrition affects cell-mediated immunity and phagocytosis, the ingestion of microorganisms is intact, but the ability of phagocytic cells to kill intracellular organisms is impaired. Nutritional deficiency can result from cancer, burns, chronic renal disease, multiple trauma, and chronic infections. Zinc and iron deficiencies have a variety of effects on immunity, including a reduction in delayed cutaneous hypersensitivity. Vitamin supplementation (B6 and B12), selenium, and copper are also important for the normal function of the immune system.[17]

Epidemiology

In Korea, a total of 152 patients with primary immunodeficiencies (PID) observed from 2001 to 2005. The prevalence was 11.25 per million children. The most frequent immunodeficiencies found were antibody deficiencies, 53.3% (n = 81), followed by phagocytic disorders, 28.9% (n = 44).[20] Sweden carried out a study of the frequency of this problem during the period 1974 through 1979 and resulted in 201 reported cases.[21] Antibody deficiencies were the most frequent (45.0%), followed by phagocytic disorders (22.0%) and combined T-cell and B-cell deficiencies (20.8%). In a Taiwan tertiary hospital from January 1985 to October 2004, 37 patients with primary immunodeficiencies were identified: the highest prevalence corresponded to antibody deficiency (46%), followed by defective phagocyte function (24%) and T-cell immunodeficiencies (19%).[22] In South Africa, a study was conducted on 168 patients diagnosed with PID from 1983 to 2009, antibody deficiencies predominated (51%).[23] Similarly, in Singapore between 1990 and 2000, 39 patients with PID were identified, and antibody deficiency (41%) was the most prevalent. The prevalence of common variable immunodeficiency (CVID) varies widely worldwide.

The most prevalent secondary immunodeficiency is the one caused by HIV and causes the acquired immunodeficiency syndrome, which prevalence varies worldwide. There were approximately 37 million individuals living with HIV at the end of 2016.[24] There were 20.9 million people infected that were receiving antiretroviral therapy (ART) by mid-2017. Seven out of 10 pregnant women living with HIV received antiretroviral treatment. A massive expansion of antiretroviral therapy (ART) has reduced the global number of people dying from HIV-related causes to about 1.1 million in 2015, 45% fewer than in 2005. Since 2003, annual AIDS-related deaths have decreased by 43%. In the world’s most affected region, eastern and southern Africa, there were 10.3 million people on treatment, this number of people has doubled since 2010. Deaths due to opportunistic infections and other AIDS-related illnesses have decreased by 36% since 2010. The population at high risk of HIV/AIDS includes men who have sex with men, people in prisons and other closed settings, individuals who inject drugs, sex workers, transgender people, patients receiving blood transfusions or blood products, and infants born to HIV-infected mothers.

Pathophysiology

Immune cells include B and T lymphocytes. B-cells transform into plasma cells that produce large amounts of antibodies. These antibodies or immunoglobulins fight extracellular microorganisms. That explains why in B-cells deficiencies, including X-linked agammaglobulinemia, there is a high susceptibility to pneumonia, otitis, and other infections caused by extracellular bacteria. SCID can be caused by RAG-1/2 deficiency and characterized by defective VDJ recombination due to a defect of recombinase activating gene RAG1 or RAG2. May present with Omenn syndrome.[8]

T-cells differentiate into helper, cytotoxic, or suppressor T cells. Helper T cells stimulate antibody production. In T-cell deficiencies, including DiGeorge syndrome, the antibody production may be compromised to an extent. T-cells fight intracellular microorganisms, including fungi, viruses, and also tumors, which infect or proliferate in individuals with HIV/AIDS, SCID, hyper-IgM syndrome, and other T-cell deficiencies.

The innate immune response is the first line of defense against infections. It is comprised of phagocytic cells, complement system proteins, and a large number of cytokines and their receptors. Innate immunity plays a key role in helping B and T lymphocytes to accomplish their fundamental functions. Deficiencies of the innate immunity characterized by susceptibility to infections by rare and opportunistic pathogens, failure to thrive, and certain inflammatory or autoimmune disorders, for example, C4 deficiency is linked to the occurrence of lupus-like syndromes.

Most immunodeficiencies are congenital and have an X-linked or autosomal recessive inheritance pattern. For example, immunodeficiency with ataxia-telangiectasia is an autosomal recessive disease caused by mutations in the genes that encode DNA repair enzymes. The defects arise from breakage in chromosome 14 at the site of TCR and Ig-heavy chain genes.

Histopathology

A curious case of immunodeficiency is the hyper-IgM syndrome that results in a medical problem where individuals are IgG and IgA deficient but secrete a large amount of IgM. The gallbladder in these patients shows a submucosa that is filled with cells with pink-staining cytoplasm and eccentric nuclei. These cells synthesize and secrete IgM.

In SCID in the microscopical examination, numerous Giardia lamblia parasites can be seen swarming over the mucosa of the jejunum. In the thymic stroma, there is not the presence of lymphoid cells, and no Hassall's corpuscles are seen. The gland has a fetal appearance.[8]

In AIDS, small bowel biopsies from patients with diarrhea caused by cryptosporidia show intermediate forms of cryptosporidia, which are small pink dots on the surface of the mucosa. Pneumonia caused by P. jiroveci is the most frequent opportunistic infection seen in AIDS, and the diagnosis is made histologically. P. jiroveci stain brown to black with the Gomori methenamine silver stain and with Giemsa or Dif-Quik stain on cytologic smears, the dot-like intracystic bodies are seen.

Cytomegalovirus (CMV) is frequently a disseminated opportunistic infection seen with AIDS. It causes pneumonia and other problems. The presence of large cytomegalic cells that have enlarged nuclei that contain a violaceous intranuclear inclusion surrounded by a clear halo distinguish CMV. Sometimes, basophilic stippling is present in the cytoplasm.

Lymphoid atrophy is a prominent morphological feature of malnutrition. Histologically, the lobular architecture is ill-defined, there is a loss of corticomedullary demarcation, and there are fewer lymphoid cells. Hassall's corpuscles are enlarged and degenerate; some may be calcified. Atrophy is observed in the thymus-dependent periarteriolar areas of the spleen and the paracortical section of the lymph nodes.

History and Physical

In immunodeficiency disorders, there is a history of[25][26]:

• Male sex
• Recurrent infections
• Infections caused by rare microorganisms
• Opportunistic infections
• Frequent use of antimicrobials without noticeable improvement
• Infection and inflammation of internal organs 
• Blood disorders, such as anemia and low platelet count

The physical findings include[25][26][19]:

• Sinus and lung infections, e.g., pneumonia
• Otitis media
• Meningitis
• Septicemia
• Arthritis
• Bacteremia
• Fever
• Cough
• Malaise
• Intestinal malabsorption
• Bronchiectasis
• Autoimmunity
• Graft versus host reaction
• Recurrent tonsillitis
• Acute suffocation
• Extensive cutaneous viral and bacterial (Staphylococcal) infections
• Severe atopy 
• Multiple organ failures, e.g., biliary and liver disease and nephropathy
• Multiple gross defects, e.g., asymmetrical orbits and cleft palate
• Absence of tonsils
• Rheumatoid disease
• Sore throat
• Purulent conjunctivitis
• Granuloma
• Skin abnormalities, e.g., pyodermitis
• Hepatomegaly  
• Splenomegaly
• Multiple cancers, e.g., brain tumor and colorectal carcinoma
• Eczema  
• Failure to thrive 
• Diarrhea    
• Tuberculosis    
• Hematological abnormalities, e.g., petechia, anemia, and bone marrow failure
• Short stature 
• Laryngeal edema    
• Ataxia    
• Telangiectasia   
• Opportunistic cancer, e.g., Kaposi's sarcoma   
• Lymphoproliferative disorders     
• The absence of lymph nodes    
• Bleeding
• Thymic aplasia or hypoplasia  
• Facial abnormalities, for example, low set ears and facial dysmorphisms  
• Recurrent abscess  
• Tetany  
• Cachexia    
• Oral candidiasis and elsewhere  
• Lupus-like syndrome   
• Angioedema   
• Malnutrition   
• Cardiac abnormalities, e.g., cardiac murmur and conotruncal malformation
• Hypothermia   
• Septic shock    
• Asthenia  
• Anorexia   
• Loss of weight   
• Headache
• Convulsions    
• Anaphylaxis   
• Hypoparathyroidism  
• Obesity  
• Aphthous stomatitis
• Urinary sepsis
• Fetal demise
• Intrauterine infection
• Hydrops fetalis
• Denture abnormalities
• Pruritus
• Psychological problems, for example, anxiety or depression
• Vasculitis
• Microcephaly
• Costochondral junction flaring
• Hearing impairment and deafness
• Erythroderma
• Myopathy
• Hypohidrosis
• Hypotrichosis 
• Intrauterine growth retardation
• Alopecia
• Dwarfism
• Lymphocytic interstitial pneumonitis
• Albinism
• Glomerulonephritis
• Hemolytic-uremic syndrome
• Macroglossia 
• Cafe-au-lait spots
• Exocrine pancreatic insufficiency
• Serositis
• Spondiloepiphyseal dysplasia
• Congenital ichthyosis
• Bamboo hair
• Osteoporosis and fractures
• Scoliosis
• Hyperextensible joints 
• Poor wound healing 
• Mental retardation
• Nail dystrophy
• Adrenal disease
• Late-onset primary encephalopathy
• Early-onset diabetes
• Thyroiditis  
• Palmoplantar hyperkeratosis   
• Urogenital abnormalities 
• Venous telangiectasias of trunk and limbs  
• Chondrodysplasia  
• Amyloidosis
• Delayed cord separation 
• Periodontitis   

Evaluation

The immunological investigation of a patient with immunodeficiency includes the assessment of immunoglobulins, including isohemagglutinins and antibody activity, B and T-lymphocyte counts, lymphocyte stimulation assays, quantification of components of the complement system, and phagocytic activity.[25][8][26]

Quantitative Serum Immunoglobulins

• IgG
• IgM
• IgA
• IgE

IgG Sub-Classes

• IgG1
• IgG2
• IgG3
• IgG4

Antibody Activity 

IgG antibodies (post-immunization)

• Tetanus toxoid
• Diphtheria toxoid
• Pneumococcal polysaccharide
• Polio

IgG antibodies (post-exposure)

• Rubella
• Measles
• Varicella zoster

Detection of isohemagglutinins (IgM)

• Anti-type A blood
• Anti-type B blood

Other assays

• Test for heterophile antibody
• Anti-streptolysin O titer
• Immunodiagnosis of infectious diseases (HIV, hepatitis B, and C, HTLV and dengue)
• Serum protein electrophoresis

Blood lymphocyte subpopulations

• Total lymphocyte count
• T lymphocytes (CD3, CD4, and CD8)
• B lymphocytes (CD19 and CD20)
• CD4/CD8 ratio

Lymphocyte stimulation assays

• Phorbol ester and ionophore
• Phytohemagglutinin
• Antiserum to CD3

Phagocytic function  

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

• Unstimulated
• Stimulated

Neutrophil mobility

• In medium alone
• In the presence of chemoattractant

Complement System Evaluation

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

• C3 serum levels
• C4 serum levels
• Factor B serum levels 
• C1 inhibitor serum levels

Hemolytic assays

• CH50
• CH100
• AH50

Complement system functional studies

• Classical pathway assay (using IgM on a microtiter plate)
• Alternative pathway assay (using LPS on a microtiter plate)
• Mannose pathway assay (using mannose on a microtiter plate)

Measurement of complement-activating agents

• Circulating immune complexes
• Cold agglutinins 

Assays for complement-binding

• C1q autoantibody ELISA
• C1 inhibitor autoantibody ELISA

Others complement assays

• LPS activation assay
• Specific properdin test
• C1 inhibitor activity test

Autoimmunity Studies[13]

• Anti-nuclear antibodies (ANA)
• Detection of specific auto-immune antibodies for systemic disorders (anti-ds DNA, rheumatoid factor, anti-histones, anti-Smith, anti-(SS-A) and anti-(SS-B)
• Detection of anti-RBC, antiplatelet, and anti-neutrophil
• Testing for organ-specific auto-immune antibodies

Microbiological studies

• Blood (bacterial culture, HIV by PCR, HTLV testing)
• Urine (testing for cytomegalovirus, sepsis, and proteinuria)
• Nasopharyngeal swab (testing for Rhinovirus)
• Stool (testing for viral, bacterial, or parasitic infection)
• Sputum (bacterial culture and pneumocystis PCR)
• Cerebrospinal fluid (culture, chemistry, and histopathology)

Coagulation tests 

• Factor V assay
• Fibrinogen level
• Prothrombin time
• Thrombin time
• Bleeding time

Other investigations of immunodeficiency disorders 

• Complete blood cell count    
• Tuberculin test
• Bone marrow biopsy
• Histopathological studies
• Liver function test
• Blood chemistry
• Tumoral markers
• Levels of cytokines
• Chest x-ray
• Diagnostic ultrasound
• CT scan
• Fluorescent in situ hybridization (FISH)
• DNA testing (for most congenital disorders)

Treatment / Management

Immunoglobulin Therapy[8] 

• X- linked agammaglobulinemia
• Transient hypogammaglobulinemia of infancy
• Variable common immunodeficiency
• Selective immunoglobulin deficiencies, except for IgA
• Hyper-IgM syndrome
• Lupus-like syndromes

Use of Transfer Factor (Dialysable Leukocyte Extract)[19]

• Interstitial pneumonia in acquired immunodeficient states
• Recurrent viral infections in immunodeficiency syndromes
• Chronic mucocutaneous candidiasis
• Primary tuberculosis with immunodeficiency
• Wiskott-Aldrich syndrome
• Severe combined immunodeficiency disease
• Chronic active hepatitis
• Coccidioidomycosis
• Behcet disease
• Aphthous stomatitis
• Familial keratoacanthoma 
• Malignancy  

Use of Antibiotics

• Primary and secondary antibody deficiencies
• Hyper-IgM syndrome  
• Chronic mucocutaneous candidiasis      
• Interleukin-12 receptor deficiency      
• Severe combined immunodeficiency diseases     
• MHC deficiency       
• Complement system deficiencies   
• Chronic granulomatous disease    
• Leukocyte adhesion deficiency syndrome      
• HIV/AIDS     
• Nutrient deficiencies (zinc and iron)

Use of Antifungal Drugs

• DiGeorge syndrome  
• Chronic mucocutaneous candidiasis 
• Severe combined deficiency diseases
• Chronic granulomatous disease
• Use of immunosuppressors 
• Obesity
• HIV/AIDS
• Malignancy

Use of Antiviral Drugs

• DiGeorge syndrome
• HIV/AIDS
• Severe combined deficiency diseases
• C5 deficiency
• CMV in transplant recipients  
• Recurrent viral infections in immunodeficiency syndromes

Use of Immunosuppressors[27] 

• Systemic lupus erythematosus (SLE)  
• Wiskott-Aldrich syndrome  
• Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy   
• Autoimmune lymphoproliferative syndrome
• Idiopathic CD4+ lymphocytopenia
• Complement system deficiencies
• Malignancy

Transplantation

Bone marrow transplant[28]

• RAG-1/RAG-2 SCID
• ADA-SCID  
• Artemis SCID
• Wiskott-Aldrich syndrome
• X-linked agammaglobulinemia
• Acute leukemia

Thymus transplant

• DiGeorge syndrome

Use of Cytokines in the Immunotherapy of Advanced Malignancies[29]

• Interleukin-2
• Interleukin-7
• Interleukin-12
• Interleukin-18
• Interleukin-21

Use of Nutritional Supplements (Vitamins A, C, E and B6, Iron, Zinc, Selenium, and Copper)

• Primary immunodeficiency with malnutrition
• Lymphoma
• Malignancies in general 
• Graft-versus-host reaction
• Diseases with impaired cell-mediated immunity 
• Recurrent and chronic bacterial infections
• SCID
• HIV/AIDS
• Burns  

Phase III Clinical Trials of the Bruton Tyrosine Kinase (BTK) Inhibitor Ibrutinib[30]

• Relapsed or refractory chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Relapsed or refractory Mantle cell lymphoma
• Newly diagnosed non-germinal center B-cell subtype of diffuse large B-cell lymphoma

Use of Interferon Gamma

• Chronic granulomatous disease
• Bladder carcinoma
• Melanoma
• Chagas disease
• HIV/AIDS 
• Cryptococcal meningitis

Differential Diagnosis

These disorders are characterized by bacterial infections including pneumonia, meningitis, otitis, diarrhea, urinary sepsis, septicemia, osteomyelitis, cellulitis, conjunctivitis, hepatitis, gastroenteritis and in some Giardia lamblia causes intestinal malabsorption. They start in early childhood and include X-linked agammaglobulinemia, IgG selective deficiencies, transient hypogammaglobulinemia of infancy, common variable immunodeficiency, hyper-IgM syndrome and certain types of SCID.

They can be ruled out as follow: X-linked agammaglobulinemia is seen in male babies around 5-6 months of age, when maternal IgG disappears. There is a low level of all immunoglobulins (IgG, IgA, IgM, IgD, and IgE) and DNA studies show Bruton's tyrosine kinase (BTK) mutations that cause B lymphocyte precursors in the bone marrow fail to develop into mature B lymphocytes. This mutation is a distinctive trait of this immunodeficiency, and therefore others immunodeficiencies can be ruled out.   

Transient hypogammaglobulinemia of infancy is caused by a physiological immaturity of the immune system and manifests similarly to X-linked agammaglobulinemia, but recurrent bacterial infections stop once the infants start producing their own immunoglobulins.

IgG selective deficiencies predispose to bacterial recurrent infections but they can be ruled out by the demonstration of absence or low serum levels of one or more IgG subclasses. This problem is corrected by the administration of gammaglobulins or intravenous immunoglobulins.

Common variable immunodeficiency is a cause of recurrent bacterial infections or more rarely viral infections, but it is ruled out because the infections start later in life and mostly after childhood. All causes of antibody deficiency most be rule out before considering the diagnosis of this problem.

Hyper-IgM syndrome is characterized by the presence of recurrent bacterial infections as those that appear in X-linked agammaglobulinemia but the cause of this illness is a mutation in the gene encoding for CD40 on T lymphocytes that causes a failure in T and B lymphocyte cooperation, which is important for B cell switching from IgM to other classes of immunoglobulins. A genetic study diagnoses this immunodeficiency.

Severe combined immunodeficiency diseases (SCID) are mostly characterized by the presence of recurrent bacterial infections, but they are rule out because they are other manifestations such as malignancies and recurrent viral, fungal, parasitic and opportunistic infections.[8]  

Prognosis

B-cells deficiencies have a better prognosis if they can be treated with intravenous immunoglobulins (every few weeks) and subcutaneous infusion that is needed once or twice a week. T-cells deficiencies such as DiGeorge syndrome have a poor prognosis, but if thymus transplantation is successfully done, a better prognosis occurs. SCID has the poorest prognosis unless bone marrow transplantation is successfully performed. Immunodeficiency with some congenital disabilities can be treated with surgery and can attain a better prognosis by the concomitant administrations of immunotherapy (for example, the use of immunomodulators). In general, for improving the quality of life of patients with primary immunodeficiencies, long-term treatment with antimicrobials, antiviral, and/or antifungal drugs is needed. Most primary immunodeficiencies are rare and require personalized management, especially if gene mutations or a missing enzyme cause them. Currently, the use of gene therapy and stem cell transplantation offers a promising outcome that can be reflected in a better prognosis.[8]

In secondary immunodeficiency such as HIV/AIDS, long-term treatment with anti-retroviral is required, as well as prophylaxis for fungal infections. If patients are malnourished, healthcare professionals must implement a balanced diet high in proteins, and they must administer vitamins, minerals, and other nutrients. In drug-related immunodeficiencies, the prognosis is reserved, especially in those patients with auto-immune disorders, inflammatory diseases, and organ transplants. The prognosis of patients with malignancies varies and depends on the type of cancer, evolution, staging and grading, and the response to treatment modalities, including chemotherapy, radiotherapy, and even the use of natural products.

Complications

• Life-threatening overwhelming infections caused by bacteria, viruses, fungi, and parasites
• Opportunistic malignancy
• Septic shock
• Anaphylactic shock
• Bleeding disorders
• Cardiac failure
• Acute and chronic renal failure
• Respiratory insufficiency
• Multi-organ failure
• Obstetric problems such as intrauterine growth retardation and fetal demise
• Systemic lupus erythematosus  or other systemic rheumatic disorders
• Endocrinopathy
• Congenital disabilities
• Metabolic disturbances
• Neurological complications including seizures and coma
• Acidosis/alkalosis
• Premature death

Deterrence and Patient Education

Patients with genetic or rare immunodeficiencies must be educated about the likelihood of giving birth to children with similar medical problems. They must also learn about different therapeutic modalities available to treat such disorders as well as pregnancy monitoring and therapeutic abortion if needed. Parents must be counseled about the importance of avoidance of offspring with consanguineous family.

Patients with HIV/AIDS can have a family but must be educated about the importance of being monitored and tested for HIV load and CD4 count at every stage of the intrauterine life, delivery, and breastfeeding and treated consequently to prevent vertical transmission. Lifestyle changes and practices to diminish the HIV transmission and viral load, including the use of condoms, sexual abstinence, and the avoidance of intravenous drugs, must be advised.

Enhancing Healthcare Team Outcomes

The management of immunodeficiency disorders is with an interprofessional team that includes nurses and pharmacists. The majority of such disorders are inherited, but in adults, a common cause is AIDS- thus testing for the human immunodeficiency virus is important.

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Disclosure: Angel Justiz Vaillant declares no relevant financial relationships with ineligible companies.

Disclosure: Ahmad Qurie declares no relevant financial relationships with ineligible companies.