Q:

10/30/2013
My question is regarding the significance of a highly elevated C4a level (>20,000). The patient is a 31 year old man, history of childhood asthma, referred to me for evaluation of persistent skin sxs, which turn out to be consistent with dermatographia. The dermatographia started rather abruptly about 5 years ago when he was diagnosed with lyme and babesiosis and placed (unfortunately) on 4 years of high dose abx. Someone ordered a C4a level, as noted. I have read the other comments re complement mediated defense against spirochetes, and C4a as a reflection of persistent inflammation. Is there an association between highly elevated C4a and dermatographia, especially 4 years after diagnosis? Or a relationship to profound fatigue, which is still ongoing for him? Other work-up all negative and he does participate in daily activities.

A:

Thank you for your inquiry.

To my knowledge, and after a review of the literature, the causes of elevations in C4a are fairly limited and include the following:
1. Acute pancreatitis
2. Rheumatologic disorders such as systemic lupus erythematosus and rheumatoid arthritis as well as immune complex diseases such as serum sickness.
3. Exercise.
4. As you mentioned, spirochete infection especially Lyme disease.
5. AIDS (see references and abstracts copied below).

Although treatment of Lyme disease is associated with a fall in C4a, chronic elevations can occur, and this would appear to be the most likely cause in your patient.

I am unaware of, nor could I find any evidence in the literature, of an elevation of C4a related to dermographic urticaria. So I don't believe the dermographia is the cause.

Thank you again for your inquiry and we hope this response is helpful to you.

Scand J Immunol. 2009 Jan;69(1):64-9. doi: 10.1111/j.1365-3083.2008.02191.x.
Complement split products c3a and c4a in chronic lyme disease.
Stricker RB, Savely VR, Motanya NC, Giclas PC.
Source
International Lyme and Associated Diseases Society, Bethesda, MD, USA.
Abstract
Complement split products C3a and C4a are reportedly elevated in patients with acute Lyme disease. We have now examined these immunologic markers in patients with chronic Lyme disease compared to appropriate disease controls. The study population consisted of 29 healthy controls, 445 patients with chronic Lyme disease, 11 patients with systemic lupus erythematosus (SLE) and six patients with AIDS. The Lyme disease patients were divided according to predominant musculoskeletal symptoms (324 patients) or predominant neurologic symptoms (121 patients). C3a and C4a levels were measured by radioimmunoassay. All patients with chronic Lyme disease and AIDS had normal C3a levels compared to controls, whereas patients with SLE had significantly increased levels of this marker. Patients with predominant musculoskeletal symptoms of Lyme disease and AIDS patients had significantly increased levels of C4a compared to either controls, patients with predominant neurologic symptoms of Lyme disease or SLE patients. Response to antibiotic therapy in chronic Lyme disease was associated with a significant decrease in the C4a level, whereas lack of response was associated with a significant increase in this marker. In contrast, AIDS patients had persistently increased C4a levels despite antiretroviral therapy. Lyme patients with positive single-photon emission computed tomographic (SPECT) scans had significantly lower C4a levels compared to Lyme patients with normal SPECT scan results. Patients with predominant musculoskeletal symptoms of Lyme disease have normal C3a and increased C4a levels. This pattern differs from the increase in both markers seen in acute Lyme disease, and C4a changes correlate with the response to therapy in chronic Lyme disease. C4a appears to be a valuable immunologic marker in patients with persistent symptoms of Lyme disease.

Int Arch Allergy Immunol. 2008;146(3):255-61. doi: 10.1159/000116362. Epub 2008 Feb 13.
Complement split products C3a and C4a are early markers of acute lyme disease in tick bite patients in the United States.
Shoemaker RC, Giclas PC, Crowder C, House D, Glovsky MM.
Source
Center for Research on Biotoxin Associated Illnesses, Pocomoke, Md., USA.
Abstract
Background: Current laboratory markers do not readily detect acute Lyme disease. We assessed the utility of complement and its split products as markers of Lyme disease in patients shortly after a tick bite.
Methods: Thirty-one consecutive acute Lyme disease patients, 14 with and 17 without erythema migrans (EM) skin rash, seen by a physician within 96 h of a tick bite were matched with 24 consecutive tick bite patients without Lyme disease symptoms and 46 healthy control subjects. Complement and split products measured included factor B, Bb, C4, C3c, C3a(des Arg), C4a(des Arg), C1q- and C3d-containing immune complexes, and C2.
Results: C2, C4, C3 and factor B levels were within normal ranges in all groups. C3a and C4a levels were significantly higher in acute Lyme disease patients than in tick bite and healthy control groups (both p < 0.001). All acute Lyme disease patients, regardless of EM, had elevated levels of C3a or C4a. Few tick bite controls had elevated levels of C3a (2/20) or C4a (5/24) and only 1 of the healthy control subjects had elevated C3a (0/46) or C4a (1/32).
Conclusions: These findings suggest that C3a and C4a may be useful markers of Lyme disease in patients seen shortly after tick bite, even in those without EM.

Clinica Chimica Acta
Volume 179, Issue 1, 13 January 1989, Pages 45-48.
Complement activation after prolonged exercise

Glovsky M, Ward P, Johnson K:
Complement determinations in human disease.
Ann Allergy
Asthma Immunol 2004; 93: 513-525, 605.

Gloor B, Stahel P, Muller C, Schmidt O,
Buchler M, Uhl W: Predictive value of complement activation fragments C3a and
sC5b-9 for development of severe disease in patients with acute pancreatitis.
Scand J Gastroenterol 2003; 38: 1078-1082.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology