How should I interpret a positive result for serum cryoglobulins?

Cryoglobulins (CGs) are immunoglobulins that precipitate in the blood under cold conditions (<37◦ C) and redissolve upon warming1.  The term “cryoglobulinemia” is commonly used to describe patients with a systemic inflammatory syndrome that is often associated with small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. Although some patients with cryoglobulinemia may be asymptomatic, most present with a range of diseases characterized by fatigue, arthralgia, skin rashes or necrosis, purpura, neuropathy, bowel wall ischemia and/or glomerulonephritis and kidney failure.

Wintrobe and Buell are credited for first describing cryglobulinemia in 1933 when assessing a patient who ultimately was found to have multiple myeloma2. Since then the spectrum of diseases associated with CG has expanded to also include seemingly disparate conditions such as hepatitis C, autoimmune disorders and monoclonal gammopathy of undetermined significance (MGUS).  A commonly cited classification scheme for CG is shown (Table)3.   It should be emphasized that some CGs may not fit neatly into this scheme.

In our patient, the positive CG serum test should be interpreted in the clinical context in which it was obtained while searching for risk factors as well as signs and symptoms that may be associated with cryoglobulinemia.


Table. Classification of cryoglobulinemia

Category Description Examples
Type I Isolated monoclonal immunoglobulin, either IgM or IgG (less commonly IgA or free immunoglobulin light chains Multiple myeloma, Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS)
Type II Mixture of monoclonal IgM and polyclonal IgG Hepatitis C, HIV, other viral infections
Type III Polyclonal mixture IgM and IgG Autoimmune disorders, hepatitis C


  1. Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
  3. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974; 57:775-88.


Contributed by Kirstin Scott, Medical Student, Harvard Medical School

How should I interpret a positive result for serum cryoglobulins?

My 65 year old patient has had several bouts of bacterial pneumonia in the past 2 years. Her total serum immunoglobulins are within normal range. Could she still be immunodeficient?

Absolutely! Besides HIV infection which should be excluded in all patients with recurrent bouts of bacterial pneumonia irrespective of age, “selective polysaccharide antibody deficiency”, also known as “specific antibody deficiency” or SAD, should also be excluded (1-3). SAD in adults with recurrent pneumonia is not rare, having been reported in about ~8% of such patients (4).  

Think of SAD when your adult patient presents with recurrent bouts of bacterial pneumonia  despite having normal serum total immunoglobulin (IgG, IgA, and IgM) levels and IgG subtypes (1-3).  These patients have a normal response to tetanus toxoid (a protein) but cannot mount adequate antibody response against polysaccharide antigens of pathogens such as pneumococcus.  

One way to diagnose SAD in a suspected patient is through vaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV23).  In patients with low baseline antibody titers to many of the capsular types of pneumococcus included in the PPSV23,  a suboptimal response (defined by the lab) 4 weeks after vaccination with PPSV23 is suggestive of SAD. Remember that if your patient has already been vaccinated with the 13 valent pneumococcal conjugate vaccine (PCV13), you can only evaluate for the response to serotypes included in the  PPSV23 only.

Although there are no randomized-controlled studies and treatment should be individualized, immunoglobulin replacement may reduce the risk of future bouts of pneumonia in SAD (2-3). 


1. Cohn JA, Skorpinski E, Cohn JR. Prevention of pneumococcal infection in a patient with normal immunoglobulin levels but impaired polysaccharide antibody production. Ann Allergy Asthma Immunol 2006;97:603-5.

2. Cheng YK, Kecker PA, O’Byrne MM, Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Alergy Asthma Immunol 2006;97:306-311.

3. Perez E, Bonilla FA, Orange JS, et al. Specific antibody deficiency: controversies in diagnosis and management. Front Immunol 207;8:586.

4. Ekdahl K, Braconier JH, Svanborg C. Immunoglobulin deficiencies and impaired immune response to polysaccharide antigens in adult patients with recurrent community acquired pneumonia. Scand J Infect Dis 1997;29:401-7.

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My 65 year old patient has had several bouts of bacterial pneumonia in the past 2 years. Her total serum immunoglobulins are within normal range. Could she still be immunodeficient?