Q:

9/6/2012
I am seeing a 40 year old male who received 24 vials of Cro-Fab in May 2010 to treat a rattle snake bite. He spent 2 weeks in ICU and amputation of his leg was discussed. However, he has completely recovered and did not lose his limb. His PCP has been following a low total protein (5.2 in July 2012) and as part of the evaluation she sent total immunoglobulin levels. Results showed IGG < 75, IgM < 7, IgA < 7. He has no history of recurrent infections. I have spoken to lab as well as confirmed lab results by repeating. How might Cro-Fab interfere with immunoglobulin lab testing? What would be a best next step for this patient? Thank you.

A:

Thank you for your inquiry.

Actually, I do not believe that the administration of CroFab is in any way related to your patient’s hypogammaglobulinemia.

Although it is reasonably rare, there have been several case reports of patients with markedly low immunoglobulin levels who have remained asymptomatic. I have personally encountered one of these who is now in his early 70’s, is asymptomatic, in excellent health, and has been known to have hypogammaglobulinemia for over two decades. There is a nice report of three such cases in the Annals of Allergy (1).

My personal experience is limited to this one case, but in this instance, I have not initiated immunoglobulin replacement, but follow the patient approximately every six months to make sure that he does not develop problems with recurrent infections. I have also checked for any evidence of organ damage (e.g., bronchiectasis) or chronic infection (e.g., sinusitis) in this patient and have found none.

The Annals article does not state whether the authors treated their patients with replacement immunoglobulin.

I am going to therefore write Dr. Arnold Levinson, who is a coauthor on this paper, and ask him to share his experience and his philosophy regarding the need for replacement therapy in such patients. When we receive Dr. Levinson’s response, we will forward it to you.

In the meantime, I would consider evaluating this patient’s immune response by getting baseline pneumococcal antibody titers followed by immunization with Pneumovax, and by doing flow cytometry for T cell markers.

Thank you again for your inquiry. Once again, I will forward Dr. Levinson’s response as soon as we hear from him.

Reference:
1. Glaum MC and Levinson AI. Asymptomatic long-standing panhypogammaglobulinemia with impaired antibody responses. Annals of Allergy, Asthma and Immunology 2008; 100(4):396-397.

Sincerely,
Phil Lieberman, M.D.

We received a response from Dr. Arnold Levinson. Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Arnold Levinson:
This is indeed an unusual and challenging patient. My assessment and recommendations for this patient are outlined below.
 
1) Agree that Cro-Fab is not an issue
 
2) Check patient's recent serum albumin to rule out protein-losing enteropathy (important to do even in absence of GI symptoms) although this severe degree of panhypogammaglobulinemia is not typical of protein loss. Of note, panhypogammglobulinemia secondary to protein loss is not typically associated with recurrent infections as such patients usually retain protective titers of antibodies against microbes.
 
3) Check patient's former medical records to see if total globulins were ever measured. If significantly reduced, it's reasonable to surmise that the decrease was due to the low gamma globulins and current panhypogam is longstanding. Such a finding would help the doc estimate how long the patient has been hypogammaglobulinemic and inform recommendations concerning the introduction of immunoglobulin replacement therapy.
 
4) The severe degree of panhypogam is not typically caused by other secondary causes like CLL or NHL, but would check to make sure CBC normal and no evidence of lymphadenopathy or splenomegaly.
 
5) However, the severe panhypogam could be associated with a thymoma – Good's syndrome- even in the absence of recurrent bacterial infections. Therefore, the doc must get a chest CT (chest x-ray too insensitive), if not already done, to rule out this diagnosis. The patient is of the age that is typical for presentation of this syndrome.

6) Rule out medications that may cause hypogammaglobulinemia, e.g., anticovulsants, gold, lithium, etc.

7) If all of the above diagnostic approaches are negative, we can assume the patient has an atypical form of CVID. In that case, to complete the workup, would check baseline IgG titers to Strep pneumonia (12 serotypes), Haemophilus influenzae, and tetanus toxoid. Then immunize with pneumovax, HiB and tetanus toxoid and wait 4 weeks to repeat titers looking to see if patient is capable of making protective immune responses (highly unlikely). By the way, should the patient turn out to have CLL, NHL or thymoma, I think it's worth completing the same workup. In addition to enumerating T cell subsets in blood, would also immunopehotype for CD19 or CD20 B cells. Numbers of total B cells are typically normal in CVID and NHL, very high in CLL and very low/absent in Good's syndrome.

8) Regarding immunoglobulin replacement therapy, would discuss risks/benefits with the patient. If the above workup is most consistent with CVID and patient lacks protective titers, she is a priori at risk for recurrent bacterial infections unless there is evidence of longstanding panhypogamma (low gamma globulins x several years). If duration of panhypogam cannot be established, most of our colleagues would initiate immunoglobulin replacement therapy if the patient agrees following informed consent. Needless to say, one must consider whether patient has additional medical conditions that augment the risks of IgG replacement therapy.
 
I hope the above comments help the consulting doc deal with this challenging patient. Please let me know if you have any questions about the above suggestions and keep me posted on the results of the completed diagnostic workup.
 
Warmest regards,
Arnold I. Levinson, MD
Associate Dean for Research
Emeritus Professor of Medicine and Neurology
Perelman School of Medicine
University of Pennsylvania

AAAAI - American Academy of Allergy Asthma & Immunology