In order to ascertain if an individual has activated PI3K delta syndrome, usually one finds atypical levels of immunoglobulins. Methods to determine the condition are the following:

- Genetic testing

- Laboratory findings

- Symptoms exhibited

The diagnosis of Nezelof syndrome will indicate a deficiency of T-cells, additionally in ascertaining the condition the following is done:

The differential diagnosis for this condition consists of acquired immune deficiency syndrome and severe combined immunodeficiency syndrome

The basic tests performed when an immunodeficiency is suspected should include a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three most important types of antibodies: IgG, IgA and IgM).

Other tests are performed depending on the suspected disorder:

- Quantification of the different types of mononuclear cells in the blood (i.e. lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRαβ and TCRγδ), groups of B lymphocytes (CD19, CD20, CD21 and Immunoglobulin), natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells).

- Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells

- Tests for B cell function: antibodies to routine immunisations and commonly acquired infections, quantification of IgG subclasses

- Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity.

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories.

Criteria for diagnosis were agreed in 1999. For instance, an antibody deficiency can be diagnosed in the presence of low immunoglobulins, recurrent infections and failure of the development of antibodies on exposure to antigens. The 1999 criteria also distinguish between "definitive", "probable" and "possible" in the diagnosis of primary immunodeficiency. "Definitive" diagnosis is made when it is likely that in 20 years, the patient has a >98% chance of the same diagnosis being made; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. "Probable" diagnosis is made when no genetic diagnosis can be made, but the patient has all other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85-97%. Finally, a "possible" diagnosis is made when the patient has only some of the characteristics of a disease are present, but not all.

Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels (gammaglobulins) are often deficient.

In terms of the treatment for ativated PI3K delta syndrome, generally primary immunodeficiencies see the following used:

- Bacterial infection should be treated rapidly(with antibiotics)

- Antiviral therapy

- Modify lifestyle(exposure to pathogens need to be minimized)

XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tract, through childhood. This is due to humoral immunodeficiency. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker CD19 and/or CD20), as well as low levels of all antibody classes, including IgG, IgA, IgM, IgE and IgD.

When XLA is suspected, it is possible to do a Western Blot test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy.Although the symptoms of a XLA and other primary immune diseases (PID) include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years.

Infusions of immune globulin can reduce the frequency of bacterial infections, and G-CSF or GM-CSF therapy improves blood neutrophil counts.

As WHIM syndrome is a molecular disease arising from gain-of-function mutations in CXCR4, preclinical studies identified plerixafor, a specific CXCR4 antagonist, as a potential mechanism-based therapeutic for the disease. Two subsequent clinical trials involving a handful of patients with WHIM syndrome demonstrated that plerixafor could increase white blood cell counts and continues to be a promising targeted therapy.

A woman with spontaneous remission of her WHIM syndrome due to Chromothripsis in one of her blood stem cells has been identified.

In support of these studies, a 2014 phase I clinical trial treated 3 patients diagnosed with WHIM syndrome with plerixafor twice a day for 6 months. All three patients presented with multiple reoccurring infections before treatment and all had an increase in their white blood cell count post treatment. One patient (P3) had a decrease in his infections by 40% while the remaining 2 patients (P1 and P2) had no infections throughout the entirety of the treatment. Plerixafor may also proof to have anti-human papillomavirus (HPV) properties as all patients experienced a shrinkage or complete disappearance of their warts. While this treatment shows promise in treating neutropenia (decreased white blood cells), this trial showed no increase of immune globulins in the body. A phase III clinical trial has been approved to compare the infection prevention ability of plerixafor versus the current treatment of G-CSF in patients with WHIM.

Early diagnosis of Severe Combined Immunodeficiency is rare because doctors do not routinely count each type of white blood cell in newborns.

The following types of CVID have been identified, and correspond to mutations in different gene segments.

Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic. However, patients younger than 6 months of age may have very low to non-detectable IgE levels. Eosinophilia is also a common finding with greater than 90% of patients having eosinophil elevations greater than two standard deviations above the normal mean. Genetic testing is available for "STAT3" (Job's Syndrome), "DOCK8 (DOCK8 Immunodeficiency or DIDS)", "PGM3" (PGM3 deficiency), "SPINK5" (Netherton Syndrome - NTS), and "TYK2" genetic defects.

According to a European registry study, the mean age at onset of symptoms was 26.3 years old. As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if:

- the person presents with a marked decrease of serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA;

- the person is four years of age or older;

- the person lacks antibody immune response to protein antigens or immunization.

Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Diagnosis is difficult because of the diversity of phenotypes seen in people with CVID. For example, serum immunoglobulin levels in people with CVID vary greatly. Generally, people can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production. Additionally, B cell numbers are also highly variable. 12% of people have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range. In general, people with CVID display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected, and are associated with specific disease features. Although CVID is often thought of as a serum immunoglobulin and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cell. Notably, approximately 10% of people display CD4 T cell counts lower than 200 cells/mm; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency), and has a poorer prognosis than classical CVID.

About half of US states are performing screening for SCID in newborns using real-time quantitative PCR to measure the concentration of T-cell receptor excision circles. Wisconsin and Massachusetts (as of February 1, 2009) screen newborns for SCID. Michigan began screening for SCID in October 2011. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not diagnosed until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mother's antibodies for the first few weeks of life and SCID babies look normal.

A survey of 10,000 American households revealed that the prevalence of diagnosed primary immunodeficiency approaches 1 in 1200. This figure does not take into account people with mild immune system defects who have not received a formal diagnosis.

Milder forms of primary immunodeficiency, such as selective immunoglobulin A deficiency, are fairly common, with random groups of people (such as otherwise healthy blood donors) having a rate of 1:600. Other disorders are distinctly more uncommon, with incidences between 1:100,000 and 1:2,000,000 being reported.

Most patients with hyper IgE syndrome are treated with long-term antibiotic therapy to prevent staphylococcal infections. Good skin care is also important in patients with hyper IgE syndrome. High-dose intravenous gamma-globulin has also been suggested for the treatment of severe eczema in patients with HIES and atopic dermatitis.

Serology (detection on antibodies to a specific pathogen or antigen) is often used to diagnose viral diseases. Because XLA patients lack antibodies, these tests always give a negative result regardless of their real condition. This applies to standard HIV tests. Special blood tests (such as the western blot based test) are required for proper viral diagnosis in XLA patients.

It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio, or the measles, mumps, rubella (MMR vaccine). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack normal ability to maintain immune memory.

XLA patients are specifically susceptible to viruses of the Enterovirus family, and mostly to: polio virus, coxsackie virus (hand, foot, and mouth disease) and Echoviruses. These may cause severe central nervous system conditions as chronic encephalitis, meningitis and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus (EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection. Patients with XLA are also more likely to have a history of septic arthritis.

It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodies.There is no special hazard for XLA patients in dealing with pets or outdoor activities. Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.

Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood.

XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency ("Bubble boys").A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene, and exhibit a similar, yet milder, immune deficiency as in XLA.

Health professionals must look at a person's history, symptoms, physical exam and laboratory test in order to make a diagnosis. If the results show patients with low levels of lymphocytes, absence of granulocytes or absence of thymus then the patient may be suspected to have RD.

The diagnostic work up usually includes and MRI of the brain, an EEG, ophthalmic examination and a cardiac ECHO.

Muscle biopsy - which is not commonly done - may show storage of abnormal material and secondary mitochondrial abnormalities in skeletal muscle. Other features that may be seen on muscle biopsy include variability in fibre size, increase in internal and centralized nuclei, type 1 fibre hypotrophy with normally sized type 2 fibres, increased glycogen storage and variable vacuoles on light microscopy

The diagnosis is confirmed by sequencing of the EPG5.

This includes Ataxia-telegiectasia, Chédiak-Higashi syndrome, DiGeorge syndrome, Griscelli syndrome and Marinesco-Sjogren syndrome.

Treatment for "B cell deficiency"(humoral immune deficiency) depends on the cause, however generally the following applies:

- Treatment of infection(antibiotics)

- Surveillance for malignancies

- Immunoglobulin replacement therapy

In terms of diagnosis of "humoral immune deficiency" depends upon the following:

- Measure "serum immunoglobulin levels"

- B cell count

- Family medical history

The only treatment for Omenn syndrome is chemotherapy followed by a bone marrow transplantation. Without treatment, it is rapidly fatal in infancy.

No cure currently exists; however, gene therapy has been proposed.

Though BLSII is an attractive candidate for gene therapy, bone marrow transplant is currently the only treatment.

The mainstay of treatment consists of thymectomy and immunoglobulin replacement with IVIG (Kelesidis, 2010). Immunodeficiency does not resolve after thymectomy (Arnold, 2015). To treat the autoimmune component of the disease, immune-suppression is sometimes used and it is often challenging to determine if a patient’s symptoms are infectious or autoimmune (Arnold, 2015).

Patients should have serological testing for antibodies to toxoplasma and cytomegalovirus. If receiving a transfusion, CMV negative blood should be used in those with negative serological testing. Live vaccines should also be avoided (Kelesidis, 2010). The CDC recommends pneumococcal, meningococcal, and Hib vaccination in those with diminished humoral and cell-mediated immunity (Hamborsky, 2015).

Some have advocated treating prophylactically with TMP-SMX if CD4 counts are lower than 200 cells/mm^3, similar to AIDS patients (Kelesidis, 2010).