Immunodeficiency results from a failure or absence of elements of the immune system including lymphocytes, phagocytes and complement system. These immunodeficiencies can be either primary such as Bruton’s disease or secondary as the one caused by HIV infection.
X- linked Agammaglobulinemia (Bruton’s disease)
Selective Immunoglobulin IgA Deficiencies
Congenital thymic Aplasia (DiGeorge Syndrome)
Chronic Mucocutaneous Candidasis
Interleukin-12 receptor deficiency
T-cell and B-cell Deficiencies
Severe combined immunodeficiency disease (SCID)
Immunodeficiency with ataxia-telangiectasia
MHC deficiency (Bare leukocyte syndrome)
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency syndrome
Use of Drugs (Steroids)
Acquired Immune Deficiency Syndrome (AIDS)
Primary immunodeficiency diseases result from intrinsic defects in immune cells including T cells, complement components, and phagocytes. Recurrent pneumonia caused by extracellular bacteria suggest antibody deficiency. On the other hand, the recurrent fungal infection 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. Deficiency of these enzymes causes ribonucleotide reductase inhibition leading to a defect in the DNA synthesis and cell replication. Mutation in the genes encoding RAG1 or RAG2 cause an autosomal recessive form of SCID.
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 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.
Malnutrition is a cause of the secondary deficiency, for example, the 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 a normal function of the immune system.
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). Sweden carried out a study of the frequency of this problem during the period 1974 through 1979 and resulted in 201 reported cases. 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%). In South Africa a study was conducted on 168 patients diagnosed with PID from 1983 to 2009, antibody deficiencies predominated (51%). 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. 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 others 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.
Immune cells include B and T lymphocytes. B-cells transform in plasma cells that produce large amounts of antibodies. These antibodies or immunoglobulins fights extracellular microorganisms. That explains why in B-cells deficiencies including X-linked agammaglobulinemia there is 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.
T-cells differentiate into helper, cytotoxic or suppressor T cells. Helper T cells stimulate the 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 others T-cell deficiencies.
The innate immune response is the first-line of defense against infections. It comprises of the phagocytic cells, complement system proteins and a large number of cytokines and their receptors. The innate immunity plays a key role in helping B and T lymphocytes to accomplish their fundamental functions. Deficiencies of the innate immunity characterize 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.
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 are not the presence of lymphoid cells, and no Hassall's corpuscles are seen. The gland has a fetal appearance.
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.
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.
Quantitative Serum Immunoglobulins
IgG antibodies (post-immunization)
IgG antibodies (post-exposure)
Detection of isohemagglutinins (IgM)
Blood lymphocyte subpopulations
Lymphocyte stimulation assays
Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)
Complement System Evaluation
Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting
Complement system functional studies
Measurement of complement-activating agents
Assays for complement-binding
Others complement assays
Other investigations of immunodeficiency disorders
Use of Transfer Factor (Dialysable Leukocyte Extract)
Use of Antibiotics
Use of Antifungal Drugs
Use of Antiviral Drugs
Use of Immunosuppressors
Bone marrow transplant
Use of Cytokines in the Immunotherapy of Advanced Malignancies
Use of Nutritional Supplements (Vitamins A, C, E and B6, Iron, Zinc, Selenium, and Copper)
Phase III Clinical Trials of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib
Use of Interferon Gamma
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.
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 has 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, use of immunomodulators). In general, for improving the quality of life of patients with primary immunodeficiencies a 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 offer a promising outcome that can be reflected a better prognosis.
In secondary immunodeficiency such as HIV/AIDS a 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 transplant. 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.
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 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.
|||Comprehensive activities to increase recognition of primary immunodeficiency and access to immunoglobulin replacement therapy in Poland., Pac M,Bernatowska E,, European journal of pediatrics, 2016 Aug [PubMed PMID: 27357411]|
|||Primary immunodeficiencies: 2009 update., Notarangelo LD,Fischer A,Geha RS,Casanova JL,Chapel H,Conley ME,Cunningham-Rundles C,Etzioni A,Hammartröm L,Nonoyama S,Ochs HD,Puck J,Roifman C,Seger R,Wedgwood J,, The Journal of allergy and clinical immunology, 2009 Dec [PubMed PMID: 20004777]|
|||Autoimmunity and inflammation in X-linked agammaglobulinemia., Hernandez-Trujillo VP,Scalchunes C,Cunningham-Rundles C,Ochs HD,Bonilla FA,Paris K,Yel L,Sullivan KE,, Journal of clinical immunology, 2014 Aug [PubMed PMID: 24909997]|
|||Moschese V,Chini L,Graziani S,Sgrulletti M,Gallo V,Di Matteo G,Ferrari S,Di Cesare S,Cirillo E,Pession A,Pignata C,Specchia F, Follow-up and outcome of symptomatic partial or absolute IgA deficiency in children. European journal of pediatrics. 2019 Jan [PubMed PMID: 30269248]|
|||Lambert MP,Arulselvan A,Schott A,Markham SJ,Crowley TB,Zackai EH,McDonald-McGinn DM, The 22q11.2 deletion syndrome: Cancer predisposition, platelet abnormalities and cytopenias. American journal of medical genetics. Part A. 2018 Oct [PubMed PMID: 28940864]|
|||Carey B,Lambourne J,Porter S,Hodgson T, Chronic mucocutaneous candidiasis due to gain-of-function mutation in STAT1. Oral diseases. 2018 Apr 27 [PubMed PMID: 29702748]|
|||Yazdani R,Fekrvand S,Shahkarami S,Azizi G,Moazzami B,Abolhassani H,Aghamohammadi A, The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clinical immunology (Orlando, Fla.). 2019 Jan [PubMed PMID: 30439505]|
|||Severe Combined Immunodeficiency Disorders., Chinn IK,Shearer WT,, Immunology and allergy clinics of North America, 2015 Nov [PubMed PMID: 26454313]|
|||Neuropsychological Profile of a Girl with Wiskott-Aldrich Syndrome., Byrne AM,Schechter T,Westmacott R,, Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 2018 Mar [PubMed PMID: 29561314]|
|||Liptai Z, [Ataxia telangiectasia. A prototype of neurological involvement in primary immune deficiencies]. Orvosi hetilap. 2018 Dec [PubMed PMID: 30525879]|
|||Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India., Aluri J,Gupta M,Dalvi A,Mhatre S,Kulkarni M,Hule G,Desai M,Shah N,Taur P,Vedam R,Madkaikar M,, Frontiers in immunology, 2018 [PubMed PMID: 29527204]|
|||Modern complement analysis., Kirschfink M,Mollnes TE,, Clinical and diagnostic laboratory immunology, 2003 Nov [PubMed PMID: 14607856]|
|||Autoimmunity and Immunodeficiency., Dosanjh A,, Pediatrics in review, 2015 Nov [PubMed PMID: 26527628]|
|||A Cohort of 169 Chronic Granulomatous Disease Patients Exposed to BCG Vaccination: a Retrospective Study from a Single Center in Shanghai, China (2004-2017)., Zhou Q,Hui X,Ying W,Hou J,Wang W,Liu D,Wang Y,Yu Y,Wang J,Sun J,Zhang Q,Wang X,, Journal of clinical immunology, 2018 Mar 20 [PubMed PMID: 29560547]|
|||Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications., De Rose DU,Giliani S,Notarangelo LD,Lougaris V,Lanfranchi A,Moratto D,Martire B,Specchia F,Tommasini A,Plebani A,Badolato R,, Clinical immunology (Orlando, Fla.), 2018 Mar 13 [PubMed PMID: 29548898]|
|||Ocon AJ,Bhatt BD,Miller C,Peredo RA, Safe usage of anakinra and dexamethasone to treat refractory hemophagocytic lymphohistiocytosis secondary to acute disseminated histoplasmosis in a patient with HIV/AIDS. BMJ case reports. 2017 Oct 4 [PubMed PMID: 28978596]|
|||Rehman AM,Woodd SL,Heimburger DC,Koethe JR,Friis H,PrayGod G,Kasonka L,Kelly P,Filteau S, Changes in serum phosphate and potassium and their effects on mortality in malnourished African HIV-infected adults starting antiretroviral therapy and given vitamins and minerals in lipid-based nutritional supplements: secondary analysis from the Nutritional Support for African Adults Starting Antiretroviral Therapy (NUSTART) trial. The British journal of nutrition. 2017 Mar [PubMed PMID: 28393746]|
|||Tchatchouang S,Nzouankeu A,Donkeng V,Eyangoh S,Ngando L,Penlap V,Fonkoua MC,Pefura-Yone EW,Njouom R, Prevalence of Opportunistic Pathogens Pneumocystis jiroveci and Tubercle Bacilli in HIV-Infected Patients with Respiratory Infections in Yaounde, Cameroon. AIDS research and human retroviruses. 2019 Feb 14 [PubMed PMID: 30618276]|
|||Use of transfer factor in patients with depressed cellular immunity and chronic infection., Rocklin RE,, Birth defects original article series, 1975 [PubMed PMID: 1096987]|
|||Rhim JW,Kim KH,Kim DS,Kim BS,Kim JS,Kim CH,Kim HM,Park HJ,Pai KS,Son BK,Shin KS,Oh MY,Woo YJ,Yoo Y,Lee KS,Lee KY,Lee CG,Lee JS,Chung EH,Choi EH,Hahn YS,Park HY,Kim JG, Prevalence of primary immunodeficiency in Korea. Journal of Korean medical science. 2012 Jul [PubMed PMID: 22787376]|
|||Fasth A, Primary immunodeficiency disorders in Sweden: cases among children, 1974-1979. Journal of clinical immunology. 1982 Apr [PubMed PMID: 6978347]|
|||Lee WI,Kuo ML,Huang JL,Lin SJ,Wu CJ, Distribution and clinical aspects of primary immunodeficiencies in a Taiwan pediatric tertiary hospital during a 20-year period. Journal of clinical immunology. 2005 Mar [PubMed PMID: 15821893]|
|||Naidoo R,Ungerer L,Cooper M,Pienaar S,Eley BS, Primary immunodeficiencies: a 27-year review at a tertiary paediatric hospital in Cape Town, South Africa. Journal of clinical immunology. 2011 Feb [PubMed PMID: 20859665]|
|||Tsang HF,Chan LW,Tong JC,Wong HT,Lai CK,Au TC,Chan AK,Ng LP,Cho WC,Wong SC, Implementation and new insights in molecular diagnostics for HIV infection. Expert review of molecular diagnostics. 2018 May [PubMed PMID: 29641941]|
|||[Discriminant analysis to predict the clinical diagnosis of primary immunodeficiencies: a preliminary report]., Murata C,Ramírez AB,Ramírez G,Cruz A,Morales JL,Lugo-Reyes SO,, Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993), 2015 Apr-Jun [PubMed PMID: 25958376]|
|||ICON: the early diagnosis of congenital immunodeficiencies., Routes J,Abinun M,Al-Herz W,Bustamante J,Condino-Neto A,De La Morena MT,Etzioni A,Gambineri E,Haddad E,Kobrynski L,Le Deist F,Nonoyama S,Oliveira JB,Perez E,Picard C,Rezaei N,Sleasman J,Sullivan KE,Torgerson T,, Journal of clinical immunology, 2014 May [PubMed PMID: 24619621]|
|||Gamboa F,Rivera JM,García-Bragado F,Rodríguez Yoldi M, [Pneumocystis carinii pneumonia. Complications of cytotoxic treatment in a systemic vasculitis]. Anales de medicina interna (Madrid, Spain : 1984). 1995 Nov [PubMed PMID: 8804172]|
|||Shamriz O,Chandrakasan S, Update on Advances in Hematopoietic Cell Transplantation for Primary Immunodeficiency Disorders. Immunology and allergy clinics of North America. 2019 Feb; [PubMed PMID: 30466768]|
|||Mechanisms and applications of interleukins in cancer immunotherapy., Anestakis D,Petanidis S,Kalyvas S,Nday CM,Tsave O,Kioseoglou E,Salifoglou A,, International journal of molecular sciences, 2015 Jan 13 [PubMed PMID: 25590298]|
|||Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies., Ponader S,Burger JA,, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014 Jun 10 [PubMed PMID: 24778403]|