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Combined immune deficiency (CID)

Combined immune deficiencies (CID) are a group of primary immunodeficiencies in which both T cells and B cells of the adaptive immune system are either low or function poorly.


There are many different genetic variants that can cause CID. These variants lead to moderate to severe susceptibility to infections, and they can sometimes also cause inflammatory disease or autoimmune manifestations due to immune dysregulation. Preventative treatments such as immunoglobulin (Ig) replacement therapy and prophylactic antibiotics can be helpful, and immunosuppressive and anti-inflammatory drugs may be needed to control immune dysregulation. However, several forms of CID require definitive therapy with hematopoietic stem cell transplantation (HSCT).


CID is a group of rare genetic disorders of the immune system that results in impaired immunity. CID is referred to as 'combined' because both T cells and B cells are affected. Unlike severe combined immunodeficiency (SCID), T cells are usually detectable in CID, and their function can be variably affected. 

The clinical spectrum of CID is wide, with some disorders causing mild to moderate disease and others causing severe susceptibility to infections, as well as inflammatory complications due to immune dysregulation (dysfunction of the immune system in which lymphocytes may be present but not work well, allowing for the development of excessive autoreactivity and resultant autoimmune disease and inflammation). Unfortunately, the prognosis of CID is not always easy to determine at the level of the affected individual. This becomes important when considering the relative potential risks vs. the potential benefits of a particular treatment strategy. Fortunately, the success rate of HSCT, particularly for those without an HLA-matched sibling donor, has improved substantially over the past few years, so the risk of this treatment has become much more acceptable for less severely affected individuals.

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Clinical features

Individuals with CID often present in the first two years of life with recurrent infections and/or immune dysregulation and specific findings associated with the different syndromes. 

Individuals with milder defects, however, may not present until later in childhood or even early adulthood. An increased incidence of hematologic malignancy and solid tumors has also been reported, especially in adulthood. Individuals with CID may present with infections that are typical of deficits of cellular immunity, like chronic viral infections (CMV, HPV, EBV), mycobacterial disease, fungal, parasitic, or other opportunistic infections. However, many instead may be uniquely affected by infections characteristic of a deficit of humoral immunity, such as recurrent bacterial sinopulmonary infections. The spectrum of severity is variable, ranging from life-threatening and disseminated infections characteristic of SCID to milder infections that respond to conventional therapy and do not require hospitalization. Diarrhea and failure to thrive are present in only half of those affected. 

Interestingly, some individuals with CID may not present with infections but rather with autoimmunity, tissue inflammation, and allergic disorders as a consequence of immune dysregulation. Multiple autoimmune manifestations in the same individual, with typical patterns of presentation with specific genetic variants, have been documented in CID. Autoimmune manifestations are due to different mechanisms, including T cell dysfunction leading to self-reactivity against the subject’s own tissues, or B cell dysfunction with consequent autoantibody production and organ damage. In many forms of CID, functional impairment of regulatory T cells (a subgroup of T cells that are able to control and suppress self-reactive lymphocytes) has also been documented. 

Autoimmune diseases frequently seen are autoimmune cytopenias (autoimmune hemolytic anemia, thrombocytopenia, and neutropenia), enteropathy, endocrinopathies, liver disease, vitiligo, alopecia, nephritis, and central nervous system autoimmunity. Endocrine glands are often affected, leading to high rates of hypo- and hyperthyroidism, diabetes, hypoparathyroidism, and adrenal insufficiency. 

Granuloma formation is another manifestation of immune dysregulation. Granulomas are mainly localized in the skin, but the mucosa, lymphoid tissue, and internal organs may also be affected. Individuals with early onset multiple autoimmunity and/or granulomas should be investigated for possible immune defects. Neutralizing autoantibodies against specific cytokines, important molecules that help fight infections, may be present in those patients leading to a significant increase in infection rate. Specific syndromes, particularly hyper IgE, predispose individuals with CID to severe eczema and allergies. 

Finally, individuals with CID are at higher risk of developing malignancies as a consequence of uncontrolled cellular proliferation and/or altered immune surveillance. The most common forms of cancer in CID are hematologic malignancies including lymphomas, lymphoproliferative disease, and leukemias, which are often (but not always) associated with EBV infection. An increased frequency of solid tumors has also been documented. Those who develop HPV-associated warts are at high risk of squamous cell carcinoma of the skin. Basal cell carcinoma of the skin is also more frequent. Furthermore, an increased incidence of carcinomas of the liver, pancreas, and gut has been documented.


CID is often first suspected due to clinical symptoms as described above, including frequent or unusual infections, autoimmune disease, and severe allergic disease. Sometimes it may be diagnosed due to a known family history of immunodeficiency. The diagnosis of CID can be very challenging, as lab results may vary widely between the different types of CID. General immunologic blood testing may demonstrate low T and/or B cell numbers, and altered distribution of lymphocyte subsets. In some cases, lymphocyte numbers may be normal in spite of poor cellular function. Poor B cell function is often reflected by low immunoglobulins and/or poor vaccine responses. 

Newborn screening for severe combined immunodeficiency (SCID) is routinely done in the U.S. Although newborn screening, which looks for a lack of T cells, is very sensitive for SCID, it does not uncover the majority of the forms of CID. This is because T cells are often present in many forms of CID. Therefore, a normal newborn screen does not eliminate the possibility of CID. 

Genetic testing is considered to be the most definitive method of diagnosing CID. Genetic testing involves sequencing (reading) genes that cause CID to look for variants (changes). Most current genetic tests involve sequencing using a panel of genes known to be related and disease-causing for SCID and CID, or providers may opt to sequence all the protein-encoding regions of the genome (whole exome sequencing). This test is often performed on blood but may also be done using a cheek swab. Sequencing may show variants that have been described in other individuals with CID or variants that are entirely new. Predictive analysis can provide some assistance in interpreting new changes, though specialist interpretation and additional testing are often needed to determine if a new variant is likely disease-causing. Sequencing of additional family members can often help in this regard as well.


There are many different forms of CID, and they are inherited in several different ways. Most (but not all) forms of CID are inherited in an autosomal recessive manner. Some forms of CID are caused by a variant in only one copy of a gene, which is known as autosomal dominant inheritance. Since males only have a single X chromosome, a single variant in a gene located on the X chromosome may result in disease in males, but not in females. This is known as X-linked inheritance.


Prophylaxis, or preventative treatment, against infections is indicated for CID, depending on the degree of immunodeficiency. If an antibody deficiency is present, then Ig replacement therapy should be started. Similarly, depending on the degree of cellular dysfunction, prophylaxis against opportunistic infections, such as herpes viruses, fungi, and Pneumocystis jirovecii, may be indicated. Use of immunosuppressive drugs may be necessary in individuals with significant manifestations of immune dysregulation. 

Specific treatment varies but will likely be based on the underlying genetic variant. Our ability to genetically diagnose diseases has transformed treatment for these disorders, as specific inhibitors or promoters of the poorly functioning protein may be available. Recent publications show the beneficial effects of specific inhibitors in certain diseases, although it remains to be proven whether these medications will sustain long-term remission of symptoms. 

If the condition is very severe and not amenable to prophylaxis or medications, then a referral for HSCT may be considered. As many of these disorders are newly described, the collective experience with transplantation for any specific type of CID may be limited. It will be important to discuss with the affected individual’s healthcare team how effective transplantation has been in this disease, as well as what the long-term outcome is expected to be with prophylaxis alone or if specific medications for the disease are available. It is likely that indications for transplant or for new medications will continue to change as more is learned about these disorders.


CID is a growing group of disorders, and within many of these disorders, there is a great deal of variability in the disease findings. Supportive therapies are often helpful in reducing complications, and as more is known about these disorders, the recommendations regarding which individuals should be referred for HSCT as well as best methods of transplantation are likely to change.

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA