Q:

6/3/2013
I had a 42 year-old woman who was seen as of low-grade fevers and frequent sinus infections. On immunologic evaluation, she was found to have Manose binding lectin deficiency. Her CH 50 is normal as are C3 and C4. Her post pneumococcal vaccine titers were excellent. She also has an enlarged thymus gland and is followed at Dartmouth.  She has daily fevers - generally a temperature of 99-100. I have asked her to document them. I checked an interleukin-1 level which was normal. Circulating immune complexes are normal. Have you heard of thymoma or enlarged thymus gland presenting with fevers? Or MBL deficiency? They have been going on for over a year. She has had a CAT scan of her chest. And would IVIG be of any value? As always thank you very much for your expertise.

A:

Thank you for your inquiry.

For your interest, I have copied below a response to an inquiry to our website regarding the treatment of mannose-binding lectin deficiency. Very little has changed in this regard since that response. Although it does not directly deal with the specific questions you posed, it should be of interest to you.

Also of interest to you would be a nice summary of this condition, which can be found on “UpToDate” by M. W. Bronkhorst and Lee H. Bouwman. In that article, they do mention the existence of a preparation of mannose-binding lectin that has been used as replacement therapy, but it is only experimental at this time.

Having made these introductory remarks, I will try and respond specifically to your questions as best I can.

1. I am not aware of a thymoma or enlarged thymus gland presenting with fevers, nor could I find any reference to such with a literature search.
2. I could find no link between thymoma, thymus gland enlargement, and mannose-binding lectin deficiency. A literature search using these terms failed to turn up any association.
3. There is no report in the literature to my knowledge (and based on a literature search) of immunoglobulin replacement therapy being used specifically to treat mannose-binding lectin deficiency. However, there is a report in the literature (abstract copied below) of immunoglobulin replacement therapy in patients with immunoglobulin subclass deficiency. Buried within this report is the response of patients with mannose-binding lectin deficiency coexisting with IgG subclass deficiency in their patient population. They were not treating mannose-binding lectin deficiency specifically, but immunoglobulin subclass deficiency. Nonetheless, they did find that, as with patients who had immunoglobulin subclass deficiency alone, those with mannose-binding lectin deficiency were benefited. But, as I mentioned, there is no data that I am familiar with or could find in the literature that has looked specifically at immunoglobulin replacement therapy for mannose-binding lectin deficiency.

In summary:
1. I could find no entity in the literature which reports a patient such as you have described, and no link between thymoma (thymus gland enlargement) and mannose-binding lectin deficiency or fevers.
2. There is no definite evidence in the literature that I could find to document a beneficial response of immunoglobulin replacement therapy in patients with mannose-binding lectin deficiency.

Finally, however, I mention parenthetically that immunoglobulin replacement therapy has been employed for treatment of thymoma with associated hypogammaglobulinemia (Good’s syndrome). However, your case, because you have not mentioned hypogammaglobulinemia per se, does not, at least in this point in time, fit this diagnosis. But over time, your patient may begin to develop hypogammaglobulinemia related to her thymoma. I have also copied below a recent abstract discussing this issue. Therefore, you should of course follow her immunoglobulin levels and should consider flow cytometry to type her B-cell population.

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

Management of mannose-binding lectin deficiency
Question:
Thanks for your help. I have a 4 yo patient scheduled to see me with history of mannose binding lectin deficiency. Reports are her levels for MBL are in the 80s and trending down. The family is driving quite a distance to come see me and I want to make sure I order the correct labs when they come so that I don't have to bring them back. I don't have additional history but am assuming there's a significant infection history. I plan to vaccinate with menactra and Pneumovax if they haven't already received these. Any other advice? I know its preliminary since I haven't seen the patient yet but since they will be traveling a long way, I'd like to have everything available for when they arrive. Thanks.

Answer:
Thank you for your recent inquiry.

Unfortunately, I know of no specific therapy for mannose-binding lectin deficiency at this time. There are studies of replacement therapy being performed, but to my knowledge, no preparation is clinically available at this time. Thus management measures are limited to appropriate use of antibiotics and immunizations with polysaccharide bacterial vaccines as you have planned. In addition, if it has not been done, you should of course check the child for other sources of recurrent respiratory tract infections if that is the presenting history (e.g., measure immunoglobulins).

One of the best clinical reviews of this condition that I have seen is in UpToDate. If you do have a subscription to this text, I think you will find this reference extremely helpful and would probably answer most of your questions.

Comprehensive reviews on this subject are sparse. However, I have copied for you below a recent review which is an in-depth discussion of more basic aspects of the condition (whereas the UpToDate article is very clinically oriented).

Finally, I am going to take the liberty of contacting Dr. Damon Eisen, who is an internationally recognized authority in mannose-binding lectin deficiency to see if he would share his thoughts with us regarding your inquiry. When I receive a response from Dr. Eisen, I will of course forward it to you immediately.

I did not know if you were aware of a new feature of our website which is entitled "Consult with a Clinical Immunologist." This site is intended specifically for inquiries regarding immune deficiency. The site is linked to the Immune Deficiency Foundation. Because the information that I have been able to find for you in this regard is rather nonspecific and admittedly sparse, I would suggest that you submit the same question to the Clinical Immunology Consult section of the website. You will find the submission link on the "Ask the Expert" page just below the submission for the "Ask the Expert" (allergist) site.

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

J Innate Immun. 2010 Feb;2(2):114-22. Epub 2009 Jul 7.
Mannose-binding lectin deficiency and respiratory tract infection.
Eisen DP.
Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Vic., Australia.
Abstract
Mannose-binding lectin (MBL) is an innate immune system pattern recognition protein that kills a wide range of pathogenic microbes through complement activation. A substantial proportion of all human populations studied to date have MBL deficiency due to MBL2 polymorphisms, which potentially increases susceptibility to infectious disease. MBL binds numerous respiratory pathogens but the capsule of Streptococcus pneumoniae abrogates its efficient binding. Clinical studies in humans have shown that MBL deficiency appears to predispose to severe respiratory tract infection. A recent meta-analysis shows that MBL deficiency was associated with death in patients with pneumococcal infection after adjusting for bacteraemia and comorbidities. Human clinical studies have also shown associations between MBL deficiency and various less common respiratory infections. Intracellular infections like tuberculosis may be less common with MBL deficiency because of reduced opsonophagocytosis. Lung secretions contain small amounts of MBL that are potentially sufficient to activate complement, but their measurement is confounded by dilution inherent in collection techniques. Therefore, if this protein does play a role in pulmonary immunity it is presumably through prevention of haematogenous dissemination of respiratory pathogens while adding to mucosal defences. Ficolins are collectins that are structurally and functionally related to MBL and are either present in serum or expressed in tissues including the lung. Limited variation in serum levels of L- and H-ficolin result from the presence of FCN2 and FCN3 polymorphisms. Initial studies on the impact of FCN2 polymorphisms or low L-ficolin levels do not seem to show major associations with respiratory infection. MBL is being developed as a new immunotherapeutic agent for prevention of infection in immunocompromised hosts. The available literature suggests that it may also be of benefit in MBL deficient patients with severe pneumonia. This review concentrates on clinical associations between MBL deficiency and susceptibility to respiratory tract infection

Sincerely,
Phil Lieberman, M.D.

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

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Damon Eisen:
It is certainly the case that there is no replacement therapy for MBL. Clinical development of the recombinant human form has been ceased as the product had not met critical milestones including, presumably, results from early phase studies in liver transplantation and cancer chemotherapy patients. An earlier project exploring plasma derived MBL (that I was involved with in Australia) was also curtailed as the commercial partner did not believe there was an appropriate market to pursue.

A level of MBL of 80 (presumably ng/ul) is definitely in the deficient range. My work and others indicates that this level of MBL is associated with a broad range of infections. It is probably the case though that these clinical studies have unmeasured confounders and the direct effect of low MBL cannot be measured in humans. Animal model data does show that knockout mice are susceptible to S. aureus bacteremia, invasive aspergillosis and HSV2 infection.

I agree with Dr Lieberman that a workup for other causes of recurrent infection is required. Vaccination as you plan is appropriate. Prophylactic antibiotics should be prescribed according to established guidelines for other defined immunodeficiencies if they are present.

There is no role for repeated measurement of MBL in this patient as the levels are not going to alter with time. The optimum approach is to ensure that no other treatable immunodeficiency is present and to optimise vaccine coverage.

Kind regards
Associate Professor Damon Eisen
Victorian Infectious Diseases Service
Royal Melbourne Hospital
Grattan St, Parkville, Victoria, Australia Department of Medicine, RMH University of Melbourne Parkville

Int Arch Allergy Immunol. 2009;149(3):267-74. doi: 10.1159/000199723. Epub 2009 Feb 12.
Efficacy of intravenous gammaglobulin for immunoglobulin G subclass and/or antibody deficiency in adults.
Abdou NI, Greenwell CA, Mehta R, Narra M, Hester JD, Halsey JF.
Source
Center for Rheumatic Disease and Center for Allergy and Immunology, Kansas City, Mo. 64111, USA.
Abstract
Background: The clinical significance and efficacy of treating patients who have immunoglobulin (Ig) G subclass deficiency and/or antibody deficiency with Ig-replacement therapy has been debated. There are no clear guidelines to recommend intravenous gammaglobulin (IgIV) in these patients as there are few published studies documenting its efficacy.
Methods: We studied in an open-label protocol 10 adult patients with recurrent respiratory infections and IgG subclass and/or antibody deficiency. All patients received monthly IgIV for 12 months and then were observed for 3 months without IgIV infusions. We studied quality of life, incidence of infections, need for antibiotics, frequency of hospitalizations due to infections, IgG subclass and antibody (tetanus and pneumococcal) levels. Innate immunity was evaluated by studying the status of Toll-like receptors and polymorphisms, mannan-binding lectin levels and genotypes. Correction of the immune defects during IgIV therapy was evaluated.
Results: Monthly IgIV significantly improved quality of life, decreased the number of infections and the need for antibiotics, and improved IgG subclass and antibody serum levels. No consistent finding of innate immunity could be detected.
Conclusions: IgIV could be beneficial in patients with IgG subclass or antibody deficiency.

J Microbiol Immunol Infect. 2012 Nov 28. pii: S1684-1182(12)00208-3. doi: 10.1016/j.jmii.2012.09.003. [Epub ahead of print]
Intravenous immunoglobulin replacement therapy to prevent pulmonary infection in a patient with Good's syndrome.
Wang CH, Chan ED, Perng CL, Chian CF, Chen CW, Perng WC, Su WL.
Source
Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan.
Abstract
Good's syndrome is an acquired immunodeficiency state associated with thymoma and characterized by recurrent pulmonary infections. We describe a 67-year-old woman who presented with respiratory symptoms caused by concomitant disseminated cytomegalovirus infection and Pneumocystis jiroveci pneumonia 38 months after thymectomy for a thymoma. Immunologic analysis revealed hypogammaglobulinemia with absent B-cell population as demonstrated by flow cytometry, consistent with Good's syndrome. Following treatment with sulfamethoxazole/trimethoprim and ganciclovir, the patient improved with resolution of her respiratory symptoms. However, the patient subsequently experienced additional infections, necessitating additional subsequent hospital admissions. During the last admission, intravenous immunoglobulin (IVIG) replacement therapy was initiated and continued after discharge. Infection has been prevented for one year after beginning IVIG replacement therapy. This case reveals that in patients with combined humoral and cell-mediated immune deficiency, concomitant infection with different pathogens is not unusual, and immediate specific therapy is important. Periodic IVIG infusion, to maintain adequate Ig levels, is recommended.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology