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Q:

6/23/2020
My question is about low CH50. Patient is a 54 year-old male with history of infection that include spinal meningitis at 13, Legionnairre disease at age 30, and three hospitalizations for pneumonia in his adult life. His mother told him he had an immunodeficiency at age 4 and he received immunoglobulin replacement for 6 months. He had a recent hospitalization in January for epiglottis (s/p emergent tracheostomy, negative blood cultures and negative strep screen). The ICU team during hospitalization ordered immunodeficiency labs including CH50. CH50 was low, which I suspected due to improper handling.

I saw him in clinic recently for a CVID evaluation. I decided to recheck CH50 and advised patient to go to Labcorp lab to get the lab done in hopes they process the blood draw correctly. His repeat CH50 was low (<10 u/mL), but with normal C3 and C4 level. It is hard for me to know if this specimen was processed correctly. I am wondering with his clinical history if I should investigate further for complement deficiency. If so, is this something that should be further evaluated with checking complement levels (C1q, C1s, C1r, C2, C5, C6, C7, C8, C9) and genetic testing?

Of note, his immunoglobulin levels (IgG, IgM, and IgA) are normal with isolated low IgG4 and appropriate Tetanus/Diphtheria titers. He has low pneumococcal titers and is awaiting vaccination and post vaccination titers.

A:

Complement deficiencies are rare but there are well defined associations of immune dysfunction, both susceptibility to infection and autoimmune disease, with various complement disorders. In my experience, CH50 is seldomly due to improper handling and with a confirmation I am confident this is a complement defect. The infections you describe are more diverse than what would be expected with late complement defects, C5-9, in which recurrent gram negative, Neisserial infections are typical. Early complement defects, including C3, are associated with more diverse susceptibility to infection but usually are encapsulated organisms such as Streptococcus pneumonia and Hemophilus influenza. Several questions in the Ask the Expert archives related to hypocomplementemia are included below. The question from 7/11/2012 emphasizes the association with IgG2 subclass deficiency and specific IgG2 allotypes influencing disease expression. Partial C4 deficiency is probably the most common defect but is not consistently associated with disease. C2 deficiency is the most likely for the clinical presentation described, although occurs in 1:20,000 (1,2). C3 deficiency or an abnormality of a regulatory protein would be another consideration. If multiple complement components are low, I would suggest checking an alternative pathway assay (AH50) and specific regulatory proteins, e.g. Factor H, FactorI, or alternative pathway deficiency such as Factor B, Factor D, or properidin.

In summary, I suggest checking C4, C3, C2 and C1q which are commercially available. I do not have concern about the IgG4 and assume that IgG2 is normal. There is an association with autoimmune disease with early complement defects, but I would not check autoantibodies unless there are clinical reasons to raise concern. As opposed to CH50, I do find that mishandling of samples may contribute to decreased levels. If all of these values are normal, then I would consider checking C1r,s, C5, C6, C7 and C8 and AH50.

I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI, FACAAI

1, Systemic lupus erythematosus, complement deficiency, and apoptosis.
Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ
Adv Immunol. 2000;76:227.

2. Infections of people with complement deficiencies and patients who have undergone splenectomy.
Ram S, Lewis LA, Rice PA
Clin Microbiol Rev. 2010;23(4):740.

The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as "nonself" in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes "tagged" with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

7/11/2012
Question: I have 5 years old child with Complement C2 defic. but never has been ill with any pyogenic infections. No FTT issues either. Healthy otherwise. Fhx neg. for Immunedefic. except his 3 yrs old sister also has C2 defic. with recurrent Strep. pneumo meningitis issues. Child's C3/C4, CH50, AH50, MBL, MAC complement levels normal. Ig's, T & B cell panel also normal. Good protective abs response to H flu, Strep. pneumo, Tetanus/Dipth. He has been fully vaccinated again including Meningoccal vaccine. ID put him on prophylactic Amoxicillin which is giving him more diarrhea issues.

Will appreciate your input:
A. Does this child need prophylactic Amoxil?
B. Besides vaccination to polysacch. ags, does he need any further work up?

Answer: Although Complement 2 deficiency has been traditionally more closely associated with autoimmune disease than immunodeficiency, increased susceptibility to infections certainly occurs in the setting of Complement 2 deficiency.

The largest series of such patients, to my knowledge, was reported from Sweden in 2005 (see abstract copied below).

Since I have no personal experience in dealing with this issue, I am going to ask the lead author of this article, Dr. Goran Jonsson, for help in answering your question. When we hear from Dr. Jonsson, we will forward his response to you.

Medicine (Baltimore). 2005 Jan;84(1):23-34.
Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease.
Jönsson G, Truedsson L, Sturfelt G, Oxelius VA, Braconier JH, Sjöholm AG.
Abstract
Although frequently asymptomatic, homozygous C2 deficiency (C2D) is known to be associated with severe infections and rheumatic disease. We describe the clinical findings in 40 persons with C2D from 33 families identified in Sweden over 25 years. Medical records covering 96% of the accumulated person-years were reviewed, giving a mean observation time of 39 years (range, 1-77 yr). Severe infection was the predominant clinical manifestation in the cohort: 23 patients had a past history of invasive infections, mainly septicemia or meningitis caused by Streptococcus pneumoniae, and 12 patients had repeated infections of this kind. Nineteen patients had at least 1 episode of pneumonia, and recurrent pneumonia was documented in 10 patients. Repeated infections occurred mainly during infancy and childhood. Systemic lupus erythematosus was found in 10 patients. Another 7 patients had undifferentiated connective tissue disease (n = 4) or vasculitis (n = 3). We found no correlation between susceptibility to invasive infection and rheumatologic disease. Cardiovascular disease occurred at a high rate, with a total of 10 acute myocardial infarctions and 5 cerebrovascular episodes in 6 patients. Causes of death among the C2D patients were infection (n = 5), acute myocardial infarction (n = 3), and cancer (n = 1). We suggest that severe infection may be the principal clinical manifestation of C2D. We also provide novel evidence for a possible role of C2D in the development of atherosclerosis consistent with findings in mannan-binding deficiency and experimental C3 deficiency. In addition, we confirm the well-known association between C2D and systemic lupus erythematosus.

We received a response from Dr. Goran Jonsson regarding your recent Ask the Expert inquiry. Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Goran Jonsson:
Thank you for your mail. I will do my best to answer the questions. About 25% of all C2D patients are health and live a completely normal life. This seems to be the case for the 5 year-old child. However, the relatively high risk for a severe infection may still occur up to the age of about 12 years. Then the risk for a severe infection declines with age but is increased compared to the general population. The Gm-allotype may be used as a prognostic marker for an increased risk for severe infections. The genotype Gm (n-n) is highly protective. (see JI 2006, Homozygosity for the IgG2 Subclass Allotype G2M(n) Protects against Severe Infection in Hereditary C2 Deficiency) This genotype is linked to the IgG2-subclass production and quality. This means that the ability to mount a strong and rapid antibody response against encapsulated bacteria may compensate for the defects seen in C2D with regard to the risk of severe infections. As previously observed by Alper et al, C2D patient with an increased risk for infection also in some cases show a very low IgG2 concentration in serum. So, I strongly recommend that all C2D patients should be vaccination against encapsulated bacteria such as pneumococci, HIB and N meningitidis. For reference see our latest study in Clinical Immunology June 2012 Vaccination against encapsulated bacteria in and opsonization due to antibody-dependent complement activation.

With regard to the 3 y older sister I would check her IgG2-subclass level. If here the age-related concentration is low she should be treated with gammaglobulin substitution. This may be the best option even if her IgG2 is normal since a measurement of the concentration do not give the whole picture. I do not usually use prophylactic antibiotic regimes but if gammaglobulin treatment do not work or is not available it could of cause be used. The substitution with gammaglobulin can usually be terminated at the age of about 12 years.

Best regards,
M.D. PhD. Göran Jönsson,

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