[CIS-PAGID] low ch50 with normal complement levels, another case.

[Anita Gewurz]

Re:  undetectable total classical pathway C activity, as determined by  
the conventional sensitized sheep erythocyte hemolysis assay, another  
possibility is cold-induced, ex vivo C consumption.  This phenomenon,  
described by us and others — notably Mathews KP et al. Journal of  
Clinical Immunology (1992) — is associated with blood coagulation at  
temperatures of <37°C during routine specimen handling; curiously, the  
CH50 of matched EDTA patient plasma, identically handled, is normal.   
It was, in our clinical C laboratory experience,  a fairly common  
phenomenon, but of unknown cause and clinical significance.

Anita Gewurz MD
Section of Allergy & Immunology
Department of Immunology/Microbiology
Rush University Medical Center
1725 W Harrison St - 117
Chicago IL 60612
TEL (312) 942-6296
EMAIL agewurz at rush.edu

On Nov 23, 2010, at 10:04 AM, <dmvascon at usp.br> <dmvascon at usp.br> wrote:


> Dear Nancy

>

> Previous comments were very elucidative. With these new results it  

> is important to wonder that in the case of C6 deficiency, APH50 will  

> be probably low as CH50.

> Deficiency of Membrane attack complex components usually present  

> with infectious manifestations associate to encapsulated bacteria,  

> most commonly meningococcus.

> C9 deficient patients are usually asymptomatic, as MAC formed by C5b  

> through C8 is sufficient to lysis bacteria. Moreover, C9 deficiency  

> is very common in asians (in Japan is approximately 1:1000, if I  

> remember well).

>

> All the best,

>

> Dewton Vasconcelos

>

> University of Sao Paulo School of Medicine

>

>

> Citando Nancy Kingston <nwk19 at yahoo.com>:

>

>>  Thanks for your comments so far.  Regarding these, I looked again  

>> through the patients multiple past labs and found corrected  

>> results...C6 and C9 are low.  The labs are reported as follows:

>> C1 function 151970 units/ml (75672-190932 Units/ml) performed by  

>> Cleveland Clinic

>> C2 1.4 mg/dL(1.0-4.0 mg/dl) performed by Cleveland Clinic

>> C3 158 mg/dl (77-143 mg/dl) (Akron Children's)

>> C4 24 mg/dl (7-40 mg/dl) (Akron Children's)

>> C5 10 mg/dl (6-20 mg/d/) performed by Quest, Cleveland Clinic.

>> C6 Functional 16 units/ml (32-57 units/ml) from Mayo

>> C7 11 mg/dL (4-11mg/dl) ARUP

>> C8 15.4 mg/dL (10.7-24.9 mg/dL) Quest/Cleveland Clinic

>> C9 26 unit/ml (37-61 unit/mL) Mayo/Cleveland Clinic

>>

>> C6 and C9 were both performed at Mayo, but the C6 is reported as  

>> functional and the C9 is not.  Is anyone familiar with the Mayo lab  

>> that could answer this?  I will have my lab investigate this.  I am  

>> anxiously awaiting the rest of the results (AH50, MBL and the  

>> Factor I and P).

>> Thank you for your comments,

>> Nancy

>> --- On Mon, 11/22/10, Patsy Giclas <giclasp at njhealth.org> wrote:

>>

>>

>> From: Patsy Giclas <giclasp at njhealth.org>

>> Subject: Re: [CIS-PAGID] low ch50 with normal complement levels,  

>> another case.

>> To: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>

>> Date: Monday, November 22, 2010, 9:03 PM

>>

>>

>> Re the question on anti-complement antibodies:

>>

>> Autoantibodies have been documented for the collagen-like region  

>> (CLR) of

>> C1q, associated with HUVS and SLE, C1-inhibitor - various regions,

>> associated with acquired angioedema, C3bBb (=C3NeF), associated  

>> with MPGN2

>> and SLE, factor H, associated with aHUS, factor B (maybe a variant  

>> of C3NeF)

>> also with aHUS, and sporadic unconfirmed antibodies against other  

>> complement

>> proteins. Most of these antibodies are associated with decreased  

>> function of

>> the antigen-component, but some, like C3NeF, enhance function.   

>> Most of

>> these antibodies don't result in CH50 of 0 but it could easily be  

>> low,

>> especially if the resulting immune complex activated complement in  

>> addition

>> to inhibiting a component.

>>

>> Re Dr Wasserbauer's patient:

>>

>> There are dysfunctional forms of several of the complement  

>> components, so I

>> support Dr Raasch's question about doing the functional assay. I'd  

>> wait

>> until the AH50 results are in, though, rather than doing all the  

>> components.

>>

>> Patsy Giclas

>>

>> Patricia C. Giclas. Ph.D.

>> Director, Complement Laboratory

>> Advanced Diagnostic Laboratories

>> Professor, Pediatrics Dept,  Allergy and Immunology Division

>> National Jewish Health

>> 1400 Jackson St., Denver, CO 80206 U.S.A.

>>

>> Office: D409, Neustadt Building

>> Phone: 303-398-1217

>> Fax: 303-270-2128

>> Email: giclasp at njhealth.org

>>

>>

>>> From: "raas0027 at umn.edu" <raas0027 at umn.edu>

>>> Reply-To: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>

>>> Date: Mon, 22 Nov 2010 12:51:52 -0700

>>> To: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>

>>> Subject: Re: [CIS-PAGID] low ch50 with normal complement levels,  

>>> another case.

>>>

>>> Hi Nancy,

>>>

>>> You mentioned that previous levles of C1-4, C7-9 were normal. Were  

>>> these

>>> levels from FUNCTIONAL hemolytic assays, QUANTITATION of the  

>>> individual

>>> proteins (e.g. by RID or nephelometry) or both?

>>>

>>> TO ALL: Autoantibodies to some complement components have been  

>>> described

>>> (e.g. C1q and C3 nephritic factor). What about C1-9, for example?

>>>

>>> Regards,

>>>

>>> Jason

>>>

>>> Jason Raasch, MD

>>>

>>> Midwest Immunology Clinic

>>> 15700 37th Ave N

>>> Suite 110

>>> Plymouth, MN 55446

>>>

>>> (Phone) 763.577.0008

>>> (FAX)   763.5770192

>>>

>>>

>>> On Nov 22 2010, Nancy Kingston wrote:

>>>

>>>> Dear Colleagues,

>>>   I, too have been referred a patient this month with a CH50 of  

>>> 0.  I would

>>> like to refer you to a helpful review on the work up of complement

>>> deficiency. (J Allergy Clin Immunol. 2004 Apr;113(4):585-93; quiz  

>>> 594.) I

>>> would like your suggestions on my patient as well.

>>>>

>>>   The patient is a 3 yo male with history of recurrent sinus  

>>> infections

>>> requiring IV antibiotics since about 1 1/2 yrs old. There is no  

>>> family hx

>>> of immune deficiency or autoimmune disorder.   He had been seeing an

>>>  infections disease specialist  for this and,  on one occasion,  had

>>> gotten a dose of IVIG.  In the last six months his CH50 has been  

>>> checked 3

>>> times and has been 0.  ID has sent C1, C2, C3, C4, C7, C8, C9 on the

>>> pateint and the levels were all normal.  He had been seen my another

>>> immunologist within the last year and had normal immunoglobulins and

>>> several normal antibody titers (tetanus, pneumococcal, h.  

>>> influenza).

>>> They had also checked neutrophil function, which was normal.

>>>>

>>>   He does have subtle inflammation in the lower extremities and  

>>> knee joints

>>> comfirmed by an orthopod.

>>>>

>>>   He recently complained of headache, back pain and  

>>> photosensitivity, s/p

>>> one week of ceftriaxone, but on exam/ work up,  was negative for

>>> meningitis.  He was also on prophylactic bactrim at the time.

>>>>

>>>   He recently has sinusitis symptoms, but when I checked and xray,  

>>> it was

>>> completely normal.

>>>>

>>>   I have gotten back a normal C5 and C 6 this week.  I am awaiting  

>>> AH50,

>>> MBL, Factor I and Factor P.

>>>> As mentioned, I do have him on antibiotic prophylaxis as well as  

>>>> naproxen.

>>>   The mother is hoping for IgG replacement as she thought that the  

>>> dose he

>>> had gotten previously was helpful.  On literature review, I have  

>>> only seen

>>> prophylactic antibiotics as the therapy in general.

>>>> What are your thoughts on IgG replacement for this patient?

>>>> Pending the above labs, do you have any further suggestions for  

>>>> lab work?

>>>> Thank you for your suggestions,

>>>>

>>>> Nancy Wasserbauer, DO

>>>> Akron Children's Hospital

>>>> Allergy/Immunology

>>>>

>>>>

>>>>

>>>> From: Anita Gewurz <agewurz at rush.edu>

>>>> Subject: Re: [CIS-PAGID] low ch50 with normal complement levels?

>>>> To: pagid at list.clinimmsoc.org

>>>> Cc: "Ashish Kumar" <Ashish.Kumar at cchmc.org>

>>>> Date: Tuesday, November 16, 2010, 2:25 AM

>>>>

>>>>

>>>> Dear Ashish,

>>>>

>>>   Like Drs. Vasconceles and Gonzalez, I suspect the problem is  

>>> homozygous C2

>>> deficiency and would also check the AH50.

>>>>

>>>   Undetectable CH50 levels can certainly result from complement  

>>> activation,

>>> as suggested by Dr. Verbsky, but in the situation you describe a  

>>> congenital

>>> C defect is most likely.  Homozygous deficiency of an early-acting

>>> classical or mannose-binding lectin pathway component may present in

>>> infancy with infection or lupus-like disease.  Normal alternative  

>>> pathway

>>> hemolytic activity (AH50) excludes deficiency of C3, C5, C6, C7,  

>>> C8 or C9.

>>>>

>>>   Patricia Giclas PhD, Director of the Complement Laboratory at  

>>> National

>>> Jewish can help

>>> http://www.nationaljewish.org/research/diagnostics/adx/labs/complement.aspx

>>> .

>>>>

>>>> Sincerely,

>>>>

>>>> Anita Gewurz MD

>>>> Section of Allergy and Immunology

>>>> Department of Immunology/Microbiology

>>>> Rush Medical College

>>>> Chicago IL 60612

>>>>

>>>>

>>>> On Nov 15, 2010, at 7:11 PM, <dmvascon at usp.br> wrote:

>>>>

>>>>> Dear Ashish

>>>>>

>>>     I would suggest to test for APH50, in order to evaluate  

>>> alternate

>>> pathway function. The combination of both functional screening  

>>> tests (CH50

>>> and APH50) is very useful to drive the evaluation of complement  

>>> defects:

>>>>>

>>>>> CH50 indetectable, APH50 normal: defects of classical pathway  

>>>>> activation

>>>>> CH50 normal, APH50 indetectable: defects of alternate pathway  

>>>>> activation

>>>>> CH50 and APH50 indetectable: defects of membrane attack complex.

>>>>>

>>>     These functional tests are fundamental, due to the fact that  

>>> in a

>>> qualitative defect of any component of complement (without  

>>> quantitative

>>> defect), there will be a reduction of the value of the screening  

>>> test,

>>> without reduction of the quantitation of any component by any

>>> immunochemical method (nephelometry, turbidimetry etc.).

>>>>>

>>>     Usually complement deficiencies present clinical  

>>> manifestations later in

>>> life (usually autoimmunity in classical pathway activation  

>>> components - C1,

>>> C4, C2) and infections by encapsulated bacteria - mainly Neisserial

>>> infections - with alternate pathway or membrane attack complex  

>>> component

>>> deficiencies.

>>>>>

>>>     Therefore it is important to test for other possible  

>>> complement defects

>>> and follow-up these patients closely to detect any possible  

>>> clinical and

>>> immunological manifestation as early as possible.

>>>>>

>>>>> Best regards,

>>>>>

>>>>> Dewton

>>>>>

>>>>>

>>>>> Citando Ashish Kumar <Ashish.Kumar at cchmc.org>:

>>>>>

>>>>>> Dear Friends,

>>>>>>

>>>      I recently saw a set of twin girls who were born at 32 weeks  

>>> with

>>> twin-twin transfusion syndrome; the smaller of the two has needed  

>>> a couple

>>> hospitalizations with URIs due to hypoxia. She has chronic  

>>> rhinorrhea, a

>>> history of wheezing that responds to bronchodilator therapy. Someone

>>> checked her ch50 and it was <10; recheck showed the same. Her twin  

>>> was then

>>> checked and hers too was <10. Their complement levels are all  

>>> normal,

>>> except I don't have results on C2. They are 18 months old, have  

>>> normal

>>> immune globulins, lymphocyte numbers and no serious infections.  

>>> The smaller

>>> twin hasn't needed hospitalization since March, even though she  

>>> has had a

>>> couple URIs since then - probably because of the season, growth  

>>> and better

>>> asthma control. So, they were sent to me for consult because of  

>>> the low

>>> ch50. Since the testing is sensitive to sample handling, I thought  

>>> to

>>> repeat it and it is still low. I cannot reconcile the history of  

>>> no serious

>>> infections with low

>>>    ch50 but normal complement levels. Is this just a testing  

>>> aberration? Any

>>> suggestions/ideas?

>>>>>>

>>>>>> Thanks!

>>>>>> Ashish Kumar

>>>>>>

>>>>>> Ashish Kumar, MD, PhD

>>>>>> Assistant Professor

>>>>>> Cincinnati Children's Hospital Medical Center

>>>>>> Cincinnati, OH

>>>>>>

>>>>>>

>>>>>

>>>>>

>>>>> <dmvascon.vcf>

>>>>

>>>>

>>>>

>>>>

>>>>

>>>

>>> --

>>> Jason Raasch, MD

>>>

>>> Midwest Immunology Clinic

>>> 15700 37th Ave N

>>> Suite 110

>>> Plymouth, MN 55446

>>>

>>> (Phone) 763.577.0008

>>> (FAX)   763.5770192

>>>

>>

>>

>>

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