First and foremost is high level of clinical suspicion especially in young adults showing abnormal behavior as well as autonomic instability. The person may have alteration in level of sensorium and seizures as well during early stage of the illness. Clinical examination may further reveal delusions and hallucinations

In addition to tests corresponding to the above findings (such as EMG for neuropathy, CT scan, bone marrow biopsy to detect clonal plasma cells, plasma or serum protein electrophoresis to myeloma proteins, other tests can give abnormal results supporting the diagnosis of POEMS syndrome. These included raised blood levels of VEGF, thrombocytes, and/or erythrocyte parameters.

Patients diagnosed as having Castleman disease but also exhibiting many of the symptoms and signs of POEMS syndrome but lacking evidence of a peripheral neuropathy and/or clonal plasma cells should not be diagnosed as having POEMS syndrome. They are better classified as having Castleman disease variant of POEMS syndrome. These patients may exhibit high blood levels of the interleukin-6 cytokine and have an inferior overall survival compared to POEMS syndrome patients. Treatment of patients with this POEMS syndrome variant who have evidence of bone lesions and/or myeloma proteins are the same as those for POEMS syndrome patients. In the absence of these features, treatment with rituximab, a monoclonal antibody preparation directed against B cells bearing the CD20 antigen, or siltuximab, a monoclonal antibody preparation directed against interleukin-6, may be justified.

Flow cytometry with monoclonal antibodies is used to screen for deficiencies of CD18.

In the presence of suspicious symptoms a number of test are helpful in the diagnosis:

- Muscle enzymes are often elevated, i.e. creatine kinase

- Anti-Jo-1 antibody testing

- Electromyography

- Muscle biopsy

- Pulmonary function testing

- Lung biopsy

In certain situations, testing of other antibodies, specific imaging (MRI, thoracic high resolution computed tomography), and swallowing evaluation may be needed.

Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens. Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease.

The number of new cases a year is unknown. According to the California Encephalitis Project, the disease has a higher incidence than its individual viral counterparts in patients younger than 30. The largest case series to date characterized 577 patients with anti-NMDA receptor encephalitis. The epidemiological data were limited, but this study provides the best approximation of disease distribution. It found that women are disproportionally affected, with 81% of cases reported in female patients. Disease onset is skewed toward children, with a median age of diagnosis of 21 years. Over a third of cases were children, while only 5% of cases were patients over the age of 45. This same review found that 394 out of 501 patients (79%) had a good outcome by 24 months. 30 patients (6%) died, and the rest were left with mild to severe deficits. The study also confirmed that patients with the condition are more likely to be of Asian or African origin.

In the heart, there are two forms of the hypereosinophilic syndrome, endomyocardial fibrosis and Loeffler's endocarditis.

- Endomyocardial fibrosis (also known as Davies disease) is seen in tropical areas.

- Loeffler's endocarditis does not have any geographic predisposition.

Numerous techniques are used to diagnose hypereosinophilic syndrome, of which the most important is blood testing. In HES, the eosinophil count is greater than 1.5 × 10/L. On some smears the eosinophils may appear normal in appearance, but morphologic abnormalities, such as a lowering of granule numbers and size, can be observed. Roughly 50% of patients with HES also have anaemia.

Secondly, various imaging and diagnostic technological methods are utilised to detect defects to the heart and other organs, such as valvular dysfunction and arrhythmias by usage of echocardiography. Chest radiographs may indicate pleural effusions and/or fibrosis, and neurological tests such as CT scans can show strokes and increased cerebrospinal fluid pressure.

A proportion of patients have a mutation involving the "PDGFRA" and "FIP1L1" genes on the fourth chromosome, leading to a tyrosine kinase fusion protein. Testing for this mutation is now routine practice, as its presence indicates response to imatinib, a tyrosine kinase inhibitor.

A diagnosis of Waldenström's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.

Additional tests such as computed tomography (CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between WM and multiple myeloma. Anemia is typically found in 80% of patients with WM. A low white blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with WM.

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström's macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström's macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström's macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström's macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Criteria for diagnosis of Waldenström's macroglobulinemia include:

1. IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma

2. Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.

All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.

There are 3 possible ways to test the fetal antigen status. Free Cell DNA, Amniocentesis, and Chorionic Villus Sampling. Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.

- Free Cell DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol. Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.

- Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.

- CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:

In the absence of symptoms, many clinicians will recommend simply monitoring the patient; Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström's macroglobulinemia.

But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also suffered from Waldenström's macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.

Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection that also have a spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease. A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of hepatitis b-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease.

Testing for HDN involves blood work from both mother and father, and may also include assessment with amniocentesis and Middle Cerebral Artery scans.

Unfortunately, treatment for the anti-synthetase syndrome is limited, and usually involves immunosuppressive drugs such as glucocorticoids. For patients with pulmonary involvement, the most serious complication of this syndrome is pulmonary fibrosis and subsequent pulmonary hypertension.

Additional treatment with azathioprine and/or methotrexate may be required in advanced cases.

Prognosis is largely determined by the extent of pulmonary damage.

Because the CD18 gene has been cloned and sequenced, this disorder is a potential candidate for gene therapy.

The protein electrophoresis test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey (X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence Jones protein and perform a bone marrow biopsy. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis). Although patients with MGUS have sometimes been reported to suffer from Small Fiber Neuropathy in monoclonal gammopathy of undetermined significance:a debilitating condition which causes bizarre sensory problems to painful sensory problems. peripheral neuropathy, no treatment is indicated.

There is currently minimal therapeutic intervention available for BENTA disease. Patients are closely monitored for infections and for signs of monoclonal or oligoclonal B cell expansion that could indicate B cell malignancy. Splenectomy is unlikely to reduce B cell burden; peripheral blood B cell counts rose significantly in three patients who underwent the procedure. It remains to be determined whether immunosuppressive drugs, including B cell-depleting drugs such as rituximab, could be effective for treating BENTA disease.

Cytokine release syndrome is an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies. Severe cases have been called "cytokine storms", a term borrowed from discussions of the pathophysiology of immune disorders and infectious disease.

CRS has been known since the approval of the first monoclonal antibody drug, Muromonab-CD3, which causes CRS, but people working in the field of drug development at biotech and pharmaceutical companies, regulatory agencies, and academia began to more intensely discuss methods to classify it and how to mitigate its risk following the disastrous 2006 Phase I clinical trial of TGN 1412, in which the six subjects experienced severe CRS.

Criteria for the clinically defined diagnosis of lymphocyte-variant hypereosinophilia have not been strictly set forth. Diagnosis must first rule out other causes of eosinophilia and hypereosinophilia, such as those due to allergies, drug reactions, infestations, and autoimmune diseases as well as those associated with eosinophilic leukemia, clonal eosinophilia, systemic mastocytosis, and other malignancies (see causes of eosinophilia). Criteria for the diagnosis include findings of: a) long term hypereosinophila (i.e. eosinophil blood counts >1,500/microliter) plus physical findings and symptoms associated with the disease; b) bone marrow analysis showing abnormally high levels of eosinophils; c) elevated serum levels of Immunoglobulin E, other immunoglobulins, and CCL17; d) eosinophil infiltrates in afflicted tissues; e) increased numbers of blood and/or bone marrow T cells bearing abnormal immunophenotype cluster of differentiation markers as defined by fluorescence-activated cell sorting (see above section on Pathogenesis); f) abnormal T cell receptor arrangements as defined by polymerase chain reaction methods (see above section on Pathogenesis); and g) evidence of excessive IL-5 secretion by lymphocytes (see above section on Pathogenesis). In many clinical settings, however, studies on the T cell receptor and IL-5 are not available and therefore not routine parts of the diagnostic work-up or criteria for the disease. The finding of T cells bearing abnormal immunophenotype cluster of differentiation markers is critical to making the diagnosis.

CRS is an adverse effect of some drugs and is a form of systemic inflammatory response syndrome.

The Common Terminology Criteria for Adverse Events classifications for CRS as of version 4.03 issued in 2010 were:

Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic syndrome associated with a broad variety of tumors including lung cancer, ovarian cancer, breast cancer, Hodgkin’s lymphoma and others. PCD is a rare condition that occurs in less than 1% of cancer patients.

As is the case with other paraneoplastic syndromes, PCD is believed to be due to an autoimmune reaction targeted against components of the central nervous system, mostly to Purkinje cells.

It is thought to be triggered when tumor cells (in PCD, most commonly ovarian or breast cancer) ectopically express proteins normally expressed in the cerebellum. This is believed to trigger an anti-tumor immune response that may be clinically significant, but also an anti-neural immune response. A broad spectrum of neuronal and glial proteins has been identified as target antigens in PCD.

Neurological symptoms may include, among others, dysarthria, truncal, limb and gait ataxia and nystagmus. Symptoms often develop subacutely and progress rapidly over a period of weeks or months to a plateau period that can last for months to years and which often reflects complete loss of Purkinje cells.

Of particular note, PCD symptoms precede the diagnosis of the underlying cancer in the majority of cases, and often present insidiously and progress rapidly for weeks to months to a severely disabled state followed by a variable plateau period that can last for months to years. Therefore, newly developing cerebellar ataxia should always prompt proper diagnostic measures to exclude PCD.

Tumor removal is still the therapeutic mainstay with very early treatment being essential to prevent irreversible neuronal loss. Immunosuppressive or immunomodulatory treatments are often ineffective. There may be a role for high-dose gammaglobulin therapy in the treatment PCD, but due to the rare occurrence of this disease, controlled trials of this therapy may be difficult.

The majority of patient peripheral blood mononucleated cells are polyclonal naïve mature B cells, with a significant increase in immature, transitional B cell numbers (identified as CD10+). Percentages of circulating class-switched and memory B cells are very low, and "in vitro" studies show poor B cell differentiation and immunoglobulin secretion. Serum IgM is low in most patients, while total IgG and IgA may be on the low end of normal. Patients demonstrate defective antibody production against T cell-independent, polysaccharide-based vaccines. Some patients may not mount protective antibody titers to other vaccines, such as measles and varicella zoster virus.

T cell counts are generally within or just above the normal range. "In vitro" stimulation of T cells demonstrates that both CD4+ and CD8+ T cells are less responsive than normal, suggesting mild T cell anergy in patients.

A diagnosis of leukemia can generally be ruled out in these patients based on the unremarkable appearance of small resting lymphocytes in the blood; however, patients must be closely monitored for any signs of monoclonal or oligoclonal B cell expansion because there may be an increased risk for B cell malignancy. Specifically, one patient with BENTA disease was reported as having developed B cell chronic lymphocytic leukemia (B-CLL) as an adult.