View source for Immunodeficiency

{{Short description|Lack of or compromised immune system}}
{{More citations needed|date=November 2007}}
{{Infobox medical condition (new)
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| synonyms        = Immunocompromisation, immune deficiency
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'''Immunodeficiency''', also known as '''immunocompromisation''', is a state in which the [[immune system]]'s ability to fight [[infectious disease]]s and [[cancer]] is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include [[HIV]] infection and [[environmental factor]]s, such as [[nutrition]].<ref name="pmid20042227">{{cite journal | vauthors = Chinen J, Shearer WT | title = Secondary immunodeficiencies, including HIV infection | journal = The Journal of Allergy and Clinical Immunology | volume = 125 | issue = 2 Suppl 2 | pages = S195–203 | date = February 2010 | pmid = 20042227 | pmc = 6151868 | doi = 10.1016/j.jaci.2009.08.040 }}</ref> Immunocompromisation may also be due to [[genetic diseases]]/flaws such as [[Severe combined immunodeficiency|SCID]].

In clinical settings, [[immunosuppression]] by some drugs, such as steroids, can either be an [[adverse effect]] or the intended purpose of the treatment. Examples of such use is in [[organ transplant]] surgery as an anti-[[transplant rejection|rejection]] measure and in patients with an overactive immune system, as in [[autoimmune disease]]s. Some people are born with intrinsic defects in their [[immune system]], or [[primary immunodeficiency]].<ref>{{cite web | title = Primary immunodeficiency | publisher = Mayo Clinic | date = 30 January 2020  | url = https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/symptoms-causes/syc-20376905 | access-date = 13 May 2020}}</ref>

A person who has an immunodeficiency of any kind is said to be '''immunocompromised'''. An immunocompromised individual may particularly be vulnerable to [[opportunistic infection]]s, in addition to normal [[infection]]s that could affect anyone.<ref>{{Cite journal|last1=Meidani|first1=Mohsen|last2=Naeini|first2=Alireza Emami|last3=Rostami|first3=Mojtaba|last4=Sherkat|first4=Roya|last5=Tayeri|first5=Katayoun|date=March 2014|title=Immunocompromised patients: Review of the most common infections happened in 446 hospitalized patients|journal=Journal of Research in Medical Sciences |volume=19|issue=Suppl 1|pages=S71–S73pmc=4078380|pmid=25002900|pmc=4078380 }}</ref> It also decreases [[cancer immunosurveillance]], in which the immune system scans the body's cells and kills [[neoplastic]] ones. They are also more susceptible to infectious diseases owing to the reduced protection afforded by [[vaccines]].<ref>{{cite journal |last1=Lee |first1=Ainsley Ryan Yan Bin |last2=Wong |first2=Shi Yin |last3=Chai |first3=Louis Yi Ann |last4=Lee |first4=Soo Chin |last5=Lee |first5=Matilda Xinwei |last6=Muthiah |first6=Mark Dhinesh |last7=Tay |first7=Sen Hee |last8=Teo |first8=Chong Boon |last9=Tan |first9=Benjamin Kye Jyn |last10=Chan |first10=Yiong Huak |last11=Sundar |first11=Raghav |last12=Soon |first12=Yu Yang |title=Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis |journal=BMJ |date=2 March 2022 |volume=376 |pages=e068632 |doi=10.1136/bmj-2021-068632 |pmid=35236664 |pmc=8889026 }}</ref><ref>{{cite journal |last1=Zbinden |first1=Delphine |last2=Manuel |first2=Oriol |title=Influenza vaccination in immunocompromised patients: efficacy and safety |journal=Immunotherapy |date=February 2014 |volume=6 |issue=2 |pages=131–139 |doi=10.2217/imt.13.171 |pmid=24491087 }}</ref>

==Types==

===By affected component===
* [[Humoral immune deficiency]] (including B cell deficiency or dysfunction), with signs or symptoms depending on the cause, but generally include signs of [[hypogammaglobulinemia]] (decrease of one or more types of antibodies) with presentations including repeated mild [[respiratory infection]]s, and/or [[agammaglobulinemia]] (lack of all or most antibody production) which results in frequent severe infections and is often fatal.<ref>{{cite web | url = https://www.utoronto.ca/kids/Immunodeficiency.htm | archive-url = https://web.archive.org/web/20130710053320/https://www.utoronto.ca/kids/Immunodeficiency.htm | archive-date = 10 July 2013 | title = Immunodeficiency | url-status = dead | first = Saul | last = Greenberg | name-list-style = vanc | publisher = University of Toronto }}</ref>
* [[T cell deficiency]], often causes secondary disorders such as [[acquired immune deficiency syndrome]] (AIDS).<ref name=Schwartz2011>{{cite journal | url = http://emedicine.medscape.com/article/888372-overview | journal = Medscape | title = T-cell Disorders | first = Robert A | last = Schwartz | editor-first = Harumi | editor-last = Jyonouchi | name-list-style = vanc | date = 2019-10-22 }}</ref>
* {{anchor|granulocyte}}''Granulocyte deficiency'', including decreased numbers of [[granulocyte]]s (called as [[granulocytopenia]] or, if absent, [[agranulocytosis]]) such as of [[neutrophil granulocyte]]s (termed [[neutropenia]]). Granulocyte deficiencies also include decreased function of individual granulocytes, such as in [[chronic granulomatous disease]].
* [[Asplenia]], where there is no function of the [[spleen]]
* [[Complement deficiency]] is where the function of the [[complement system]] is deficient

In reality, immunodeficiency often affects multiple components, with notable examples including [[severe combined immunodeficiency]] (which is primary) and [[acquired immune deficiency syndrome]] (which is secondary).

{|class="wikitable"
|+Comparison of immunodeficiencies by affected component
|-
|
! Affected components !! Main causes<ref name=Bannister2006>If not otherwise specified in boxes, then reference for entries is: [https://books.google.com/books?id=iPuvQDcqW88C&pg=PA432 Page 432], Chapter 22, Table 22.1 in: {{cite book | last1 = Jones | first1 = Jane | last2 = Bannister | first2 = Barbara A. | last3 = Gillespie | first3 = Stephen H. | name-list-style = vanc |title=Infection: Microbiology and Management |publisher=Wiley-Blackwell |year=2006 |isbn=978-1-4051-2665-6 }}</ref> !! Main pathogens of resultant infections<ref name=Bannister2006/>
|-
! [[Humoral immune deficiency]]
[[B cell deficiency]]
| [[B cell]]s, [[plasma cell]]s or [[antibody|antibodies]]
|
* [[Primary humoral immune deficiency|Primary humoral]]
* [[Multiple myeloma]]
* [[Chronic lymphoid leukemia]]
* [[AIDS]]
|
* ''[[Streptococcus pneumoniae]]''
* ''[[Hemophilus influenzae]]''
* ''[[Pneumocystis jirovecii]]''
* ''[[Giardia intestinalis]]''
* ''[[Cryptosporidium parvum]]''
|-
! [[T cell deficiency]]
| [[T cell]]s
|
* [[Hematopoietic stem cell transplantation|Marrow]] and other [[organ transplant|transplantation]]
* [[AIDS]]
* [[Cancer chemotherapy]]
* [[Lymphoma]]
* [[Glucocorticoid]] therapy
| [[Intracellular pathogen]]s, including ''[[Herpes simplex virus]]'', ''[[Mycobacterium]]'', ''[[Listeria]]'',<ref name=Bannister2006-435>[https://books.google.com/books?id=iPuvQDcqW88C&pg=PA435 Page 435] in: {{cite book | last1 = Jones | first1 = Jane | last2 = Bannister | first2 = Barbara A. | last3 = Gillespie | first3 = Stephen H. | name-list-style = vanc |title=Infection: Microbiology and Management |publisher=Wiley-Blackwell |year=2006 |isbn=978-1-4051-2665-6 }}</ref> and intracellular [[fungal infections]].<ref name=Bannister2006/>
|-
! [[Neutropenia]]
| [[Neutrophil granulocyte]]s
|
* [[Chemotherapy]]
* [[Bone marrow transplantation]]
* Dysfunction, such as [[chronic granulomatous disease]]
|
* ''[[Enterobacteriaceae]]''
* Oral ''[[Streptococci]]''
* ''[[Pseudomonas aeruginosa]]''
* ''[[Enterococcus]]'' species
* ''[[Candida (fungus)|Candida]]'' species
* ''[[Aspergillus]]'' species
|-
! [[Asplenia]]
| [[Spleen]]
|
* [[Splenectomy]]
* [[Trauma (medical)|Trauma]]
* [[Sickle-cell anemia]]
|
* [[Polysaccharide encapsulated bacteria]],<ref name=Brigden2001/> particularly:
** ''[[Streptococcus pneumoniae]]''<ref name=Brigden2001>{{cite journal | vauthors = Brigden ML | title = Detection, education and management of the asplenic or hyposplenic patient | journal = American Family Physician | volume = 63 | issue = 3 | pages = 499–506, 508 | date = February 2001 | pmid = 11272299 }}</ref>
** ''[[Haemophilus influenzae]]''<ref name=Brigden2001/>
** ''[[Neisseria meningitidis]]''<ref name=Brigden2001/>
* ''[[Plasmodium]]'' species
* ''[[Babesia]]'' species
|-
! [[Complement deficiency]]
| [[Complement system]]
|
* Congenital deficiencies
|
* ''[[Neisseria]]'' species
* ''[[Streptococcus pneumoniae]]''
|}

===Primary or secondary===
The distinction between primary versus secondary immunodeficiencies is based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it.

====Primary immunodeficiency====
{{Main|Primary immunodeficiency}}

A number of [[rare disease]]s feature a heightened susceptibility to [[infection]]s from childhood onward.  Primary Immunodeficiency is also known as congenital immunodeficiencies.<ref name="BasicImmunology">Basic Immunology: Functions and Disorders of the Immune System, 3rd Ed. 2011.</ref>  Many of these disorders are [[genetic disorder|hereditary]] and are [[autosomal recessive]] or [[Sex linkage|X-linked]]. There are over 95 recognised primary immunodeficiency syndromes; they are generally grouped by the part of the immune system that is malfunctioning, such as [[lymphocyte]]s or [[granulocyte]]s.<ref>{{cite journal | vauthors = Rosen FS, Cooper MD, Wedgwood RJ | title = The primary immunodeficiencies | journal = The New England Journal of Medicine | volume = 333 | issue = 7 | pages = 431–40 | date = August 1995 | pmid = 7616993 | doi = 10.1056/NEJM199508173330707 | s2cid = 39699189 }}</ref>

The treatment of primary immunodeficiencies depends on the nature of the defect, and may involve antibody infusions, long-term antibiotics and (in some cases) [[Hematopoietic stem cell transplantation|stem cell transplantation]]. The characteristics of lacking and/or impaired antibody functions can be related to illnesses such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency <ref name=":0">{{Cite web|url=http://primaryimmune.org/|title=Immune Deficiency Foundation|website=primaryimmune.org|access-date=2017-04-17}}</ref>

====Secondary immunodeficiencies====
{{Further|Immunosuppression}}
{{anchor|acquired}}Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various [[immunosuppression|immunosuppressive]] agents, for example, [[malnutrition]], [[aging]], particular medications (e.g., [[chemotherapy]], [[disease-modifying antirheumatic drug]]s, [[immunosuppressive drug]]s after [[organ transplant]]s, [[glucocorticoid]]s) and [[environmental toxins]] like [[Mercury (element)|mercury]] and other [[heavy metals]], [[pesticide]]s and [[petrochemicals]] like [[styrene]], [[dichlorobenzene]], [[xylene]], and [[ethylphenol]]. For medications, the term ''[[immunosuppression]]'' generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term ''immunodeficiency'' generally refers solely to the adverse effect of increased risk for infection.

Many specific diseases directly or indirectly cause immunosuppression. This includes many types of [[cancer]], particularly those of the bone marrow and blood cells ([[leukemia]], [[lymphoma]], [[multiple myeloma]]), and certain chronic infections. Immunodeficiency is also the hallmark of [[AIDS|acquired immunodeficiency syndrome]] (AIDS),<ref name="BasicImmunology" /> caused by the [[HIV|human immunodeficiency virus]] (HIV). HIV directly infects a small number of [[T helper cell]]s, and also impairs other immune system responses indirectly.

Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism and hyperglycemia.

Smoking, alcoholism and drug abuse also depress immune response.

Heavy schedules of training and competition in athletes increases their risk of immune deficiencies.<ref>{{cite journal |last1=Gleeson |first1=Michael |last2=Nieman |first2=David C |last3=Pedersen |first3=Bente K |title=Exercise, nutrition and immune function |journal=Journal of Sports Sciences |date=January 2004 |volume=22 |issue=1 |pages=115–125 |doi=10.1080/0264041031000140590|pmid=14971437 |s2cid=84378380 }}</ref>

==Causes==
The cause of immunodeficiency varies depending on the nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions.<ref>{{cite web
 | url =https://www.hsph.harvard.edu/nutritionsource/nutrition-and-immunity/
 | title =Nutrition and Immunity
 | website =The Nutrition Source
 | date =May 2020
 | publisher =Harvard T.H. Chan School of Public Health
 | access-date =8 November 2020 }}</ref><ref>{{cite journal | vauthors = Bourke CD, Berkley JA, Prendergast AJ | title = Immune Dysfunction as a Cause and Consequence of Malnutrition | journal = Trends in Immunology | year=2016 | volume = 37 | issue = 6 | pages = 386–398 | doi=10.1016/j.it.2016.04.003 | pmid = 27237815 | pmc = 4889773 | doi-access = free }}</ref> Only for some genetic causes, the exact genes are known.<ref>{{cite book |last1=Charles A Janeway |first1=Jr |last2=Travers |first2=Paul |last3=Walport |first3=Mark |last4=Shlomchik |first4=Mark J. |title=Immunobiology |date=2001 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27109/ |chapter=Inherited immunodeficiency diseases |publisher=Garland Science }}</ref>

== Immunodeficiency and autoimmunity ==
{{More citations needed section|date=November 2016}}
There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation.<ref>{{cite journal | vauthors = Grammatikos AP, Tsokos GC | title = Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus | journal = Trends in Molecular Medicine | volume = 18 | issue = 2 | pages = 101–8 | date = February 2012 | pmid = 22177735 | pmc = 3278563 | doi = 10.1016/j.molmed.2011.10.005 }}</ref>
One example is [[common variable immunodeficiency]] (CVID) where multiple autoimmune diseases are seen, e.g., [[inflammatory bowel disease]], autoimmune [[thrombocytopenia]], and autoimmune thyroid disease.
[[Familial hemophagocytic lymphohistiocytosis]], an autosomal recessive primary immunodeficiency, is another example. [[Pancytopenia|Low blood levels of red blood cells, white blood cells, and platelets]], rashes, [[lymphadenopathy|lymph node enlargement]], and [[hepatosplenomegaly|enlargement of the liver and spleen]] are commonly seen in these patients. Presence of multiple uncleared viral infections due to lack of [[perforin]] are thought to be responsible.
In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in [[X-linked agammaglobulinemia]] (XLA).
Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in [[chronic granulomatous disease]] (CGD) as well. CGD is caused by a decreased production of [[nicotinamide adenine dinucleotide phosphate]] (NADPH) oxidase by [[neutrophil]]s.
Hypomorphic RAG mutations are seen in patients with [[midline granulomatous disease]]; an autoimmune disorder that is commonly seen in patients with [[granulomatosis with polyangiitis]] and NK/T cell lymphomas.
[[Wiskott–Aldrich syndrome]] (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma.
In [[autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy]] (APECED) also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis.
Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena.

==Diagnosis==

Medical History and Physical Examination:
A physician will inquire about past illnesses and family history of immune disorders to identify inherited conditions.                                                                                                                                                                                         A detailed physical examination helps recognize symptoms indicative of an immune disorder.                                    Blood Tests: these tests are instrumental in diagnosing immunodeficiency as they measure: Infection-fighting proteins (immunoglobulins): Essential for robust immune defense, these protein levels are measured to evaluate immune function.<ref>{{cite web |title=Primary immunodeficiency - Diagnosis and treatment |website=[[Mayo Clinic]] |url=https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/diagnosis-treatment/drc-20376910}}</ref>                                                                                                               Blood cell counts: Deviations in specific blood cells can point to an immune system anomaly.                                                              Immune system cells: These assessments are used to measure the levels of various immune cells. Genetic testing involves collecting samples from patients for molecular analysis when there is a suspicion of inborn errors in immunity. Most Primary Immunodeficiency Disorders (PIDs) are inherited as single-gene defects.<ref>{{cite web |title=Laboratory tests |url=https://primaryimmune.org/understanding-primary-immunodeficiency/diagnosis/laboratory-tests |publisher=Immune Deficiency Foundation}}</ref> The key genes associated with immunodeficiency diseases include CD40L, CD40, RAG1, RAG2, IL2RG, and ADA. Here is a summary of some methods utilized to identify genetic anomalies:
Sanger Sequencing of Single Genes:
Sanger sequencing is widely recognized as the benchmark method for accurately identifying individual nucleotide changes, as well as small-scale insertions or deletions in DNA. It is particularly valuable for confirming known familial genetic variations, for validating findings from next-generation sequencing technologies, and in specific scenarios that require sequencing of single genes. An example is its use to confirm mutations in the Bruton tyrosine kinase (BTK) gene, which are linked to X-linked agammaglobulinemia  (XLA)<ref>{{cite web |last1=FERNANDEZ |first1=JAMES |title=Overview of Immunodeficiency Disorders. Merck Manuals Consumer Version |url=https://www.merckmanuals.com/home/immune-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders}}</ref> 
•	Targeted Gene Sequencing Panels (tNGS): This technology is ideal for examining genes in specific pathways or for follow-up experiments (targeted resequencing) from whole genome sequencing (WGS). It is rapid and more cost-effective than WGS, and because it allows for deeper sequencing.<ref>{{cite journal |last1=von Hardenberg |first1=Sandra |last2=Klefenz |last3=Steinemann |title=Current genetic diagnostics in inborn errors of immunity |journal=Frontiers in Pediatrics |date=2024 |volume=12 |doi=10.3389/fped.2024.1279112 |doi-access=free |pmid=38659694 |pmc=11039790 }}</ref>
•	Whole Exome Sequencing (WES): is a commonly used method which captures the majority of coding regions of the genome for sequencing, as these regions contain the majority of disease-causing mutations Useful for identifying mutations in specific genes<ref>{{cite journal |last1=von Hardenberg |first1=Sandra |title=Pediatric Immunology Volume 12 |journal=Frontiers in Pediatrics |date=2024 |volume=12 |doi=10.3389/fped.2024.1279112 |doi-access=free |pmid=38659694 |pmc=11039790 }}</ref> 
•	Trio or Whole-Family Analyses: In some cases, analyzing the DNA of the patient, parents, and siblings (trio analysis) or the entire family (whole-family analysis) can reveal inheritance patterns and identify causative mutations<ref>{{cite document |title=Solo VS extended family analysis in consanguineous populations |publisher=BMC Medical Genomics|doi=10.1186/s12920-020-00743-8 |doi-access=free }}</ref>

==Treatment==
Available treatment falls into two modalities: treating infections and boosting the immune system.

Prevention of [[Pneumocystis pneumonia]] using [[trimethoprim/sulfamethoxazole]] is useful in those who are immunocompromised.<ref>{{cite journal | vauthors = Stern A, Green H, Paul M, Vidal L, Leibovici L | title = Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD005590 | date = October 2014 | pmid = 25269391 | doi = 10.1002/14651858.CD005590.pub3 | pmc = 6457644 }}</ref> In the early 1950s Immunoglobulin(Ig) was used by doctors to treat patients with primary immunodeficiency through intramuscular injection. Ig replacement therapy are infusions that can be either subcutaneous or intravenously administered, resulting in higher Ig levels for about three to four weeks, although this varies with each patient.<ref name=":0" />

==Prognosis==
Prognosis depends greatly on the nature and severity of the condition.  Some deficiencies cause early mortality (before age one), others with or even without treatment are lifelong conditions that cause little mortality or morbidity.  Newer stem cell transplant technologies may lead to gene based treatments of debilitating and fatal genetic immune deficiencies.  Prognosis of acquired immune deficiencies depends on avoiding or treating the causative agent or condition (like AIDS).

== See also ==
* [[Acquired immune deficiency syndrome]] (AIDS)
* [[Immune disorder]]
** [[Autoimmune disease]], immune response to self-proteins
** [[Allergy]], immune response to harmless non-self proteins
*** [[Histamine]]
* [[Immunosenescence]], age-associated immune deficiency
* [[Glucocorticoid|Steroids]], commonly administered drugs like [[prednisone]] that suppress the immune system
* [[Human genetic enhancement#To prevent the possibility of catching particular diseases|Human genetic enhancement]]
* [[Immune system]]
* [[Immunology]]

== References ==
{{reflist}}

== External links ==
{{Medical resources
| DiseasesDB      = 21506
| ICD10           = {{ICD10|D|84|9|d|80}}
| ICD9            = {{ICD9|279.3}}
| ICDO            =
| OMIM            =
| MedlinePlus     =
| eMedicineSubj   =
| eMedicineTopic  =
| MeshID          = D007153
| SNOMED CT       = 234532001
}}
* [http://www.primaryimmune.org/ Immune Deficiency Foundation]
* [http://www.esid.org/ The European Society of Immunodeficiencies]

{{Immune system}}
{{Lymphoid immunodeficiency}}
{{Myeloid and complement immunodeficiency}}
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[[Category:Immunodeficiency| ]]