Q:

3/29/2013
52 y/o female with 10 year history of chronic sinusitis, AR, sinus polyposis and Asthma. Historically with occasional elevation in eos. (approx. 1000 23%) Was on AIT and Xolair prior to being seen in my office. Had been seen and evaluated by several allergist. Has had several sinus surgeries and tympanostomy tubes. In 2011 moved to California basic AR/Asthma regimen continued. Pt began to have increased issues with sinusitis, severe otitis, and asthma. Immune work up reveals fluctuating IgG lowest at 642. IgA and IgM levels normal. Ab to tetanus, rubeola well protected. Has appropriate hemagglutinin. Pneumovax response marginal and titers decreasing over time. Lymph subset CD4, CD8, CD3, CD 15 and 56 WNL. CD 19 was very low at 2% absolute count 23. She was seen by Heme/Onc who agreed possible evolving immune deficiency. Mitogen studies low-normal to candida, low to tetanus, normal to con A, and normal to Pokeweed. IgE and stool for O and P all WNL. Due to sporadic elevations of eos and hx of an infiltrate on Chest CT a diagnosis of Churg Strauss was also entertained. ANCA's have been negative on multiple occasions. She has seen 2 local rheumatologists. ANA fluctuates highest 1:640. Will be seeing a "vasculitis specialist" next week. Currently on standard asthma medications and prednisone. Not on Xolair. Recently had a repeat Lymph subset panel and CD 19 1% <20 absolute count. CD3,CD4,CD8,CD 16/56 remain normal.
Specialists seen: Allergy/immunology, Pulmonary medicine, Infectious disease, ENT, Rheumatology.

-Significantly depressed CD19,
-fluctuating IgG but not profoundly depressed,
-Ab's to tetanus and rubeola present with appropriate Hemagglutinis. Waning pneumococcal ab titers after pneumovax (twice).
-T cell depressed Mitogen studies.
-Clinically has recurrent Upper respiratory illness(sinusitis/otitis) and asthma.

1. Does she need a Bone marrow with her lack of CD19 cells?
2. I have recommended Prevnar and will reassess S.pneumo ab's after vaccine.
3. Any role for Xolair?
4. Any role for gammaglobulin replacement?
5. Any additional studies recommended?

Thank you.

A:

Thank you for your inquiry.

Before I begin the response, I would like to call your attention to two previous entries posted on our Ask the Expert website which deal with the issue of recalcitrant asthma, eosinophilia, and pulmonary infiltrates. These entries will speak to this issue in terms of the suggested workup of this disorder and also lead you to previous entries and references which are germane to your question. I have used a quote from one of these entries to directly answer your Question Number 3 (see below).

Previous entries:
“Asthma, pneumonia, and eosinophilia” - Posted 3/18/2013

“Recalcitrant asthma with hypereosinophilia” - Posted 2/14/2013

Having said that, I think your inquiry can be divided into two distinct subcategories of questions. The first subcategory, and perhaps the easiest to answer, relates to the well known syndrome of resistant asthma, chronic sinusitis, eosinophilia, and on occasion pulmonary infiltrates. As noted, there are several entries (see above) on our website that discuss this symptom complex in detail. These entries will lead you to references and additional possible studies that might be of help in response to your Question Number 5.

However, I think that you have done an extensive workup and due diligence in your evaluation. The probability that any further workup for this syndrome will be of help to you is highly doubtful.

But in direct response to your Question Number 3 (Any role for Xolair?), I have copied below our answer to a very similar inquiry regarding the asthma/eosinophilia/sinusitis/pulmonary infiltrate syndrome. As you can see, I do feel there is a role for omalizumab in your patient.

Quote from entry posted on 2/14/2013:
"Recalcitrant asthma with hypereosinophilia (Ask the Expert, posted on 2/14/2013)
Q: 1. Do you agree with a trial of Xolair?

A: Yes. As you can see from the abstract copied below, Xolair has been reported to be effective in both nonallergic and allergic asthmatics. Your patient, although having a single positive skin test, is more than likely a nonallergic or “intrinsic” asthmatic. The article abstracted below postulates that there may be local IgE synthesis in the respiratory tract. Another explanation for this phenomenon is the presence of IgE anti-staphylococcal antigens in patients with asthma (J Allergy Clin Immunol 2012; 130:376-381).

Even patients with nondetectable significant allergy on skin testing could have an IgE-mediated response in part responsible for their symptoms. Thus, I feel a trial of Xolair is warranted.

Reference/Abstract:

J Allergy Clin Immunol. 2013 Jan;131(1):110-116.e1. doi: 10.1016/j.jaci.2012.07.047. Epub 2012 Sep 27.
Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.
Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, Hellings P, Brusselle G, De Bacquer D, van Cauwenberge P, Bachert C.
Source
Upper Airways Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium.
Abstract
Background: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma.
Objective: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma.
Methods: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels.
Results: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy.
Conclusion: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways."

Thus, in summary to one subcategory of your inquiry which deals with the asthma/eosinophilic syndrome, there are other studies which you might consider which are detailed in the entries mentioned above, but which are unlikely to be helpful. And, I do feel there is a role for omalizumab in the treatment of your patient.

The other subcategory of your inquiry deals with the possibility that this patient may have common variable immunodeficiency based on the single finding of a low CD19 (since the immune response studies and immunoglobulin levels themselves do not clearly establish this diagnosis). As you know, CD19 is a B cell marker which is present on B cell precursors all the way through the development of the B cell until the plasma cell stage. This marker has long been known to assist in the diagnosis of various B cell neoplasms. The presence of CD19 has usually been used to raise suspicions that a B cell neoplasm exists. However, B cell neoplasms can also be characterized by low CD19 (see Yang, et al., Diminished Expression of CD19 in B-cell Lymphomas,” abstracted below).

In addition, antibody deficiency syndrome can be due to mutations in the CD19 gene (see van Zelm, et al., “An antibody-deficiency syndrome due to mutations in the CD19 gene,” abstracted below).

Also diminishing CD19 on B cells is also a harbinger of B cell deficiency (see Salzer, et al., “B cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta,” abstracted below).

Thus, the low CD19 in your patient is significant for the possibility that she may be developing common variable immunodeficiency either as the primary abnormality or as a result of a B cell neoplasm.

Thus, a bone marrow would possibly be indicated for this reason, but certainly not in regards to the asthma/hypereosinophilia component of her problem.

With this in mind, I would think that the oncologist who is following her with you should be the physician that makes the determination as to whether or not a bone marrow would be of help, with your input in this regard.

It should be mentioned that I am not aware of, nor could I find in the literature, any link between low CD19 and the asthma/eosinophilia component of her disease. I would speculate therefore that these two symptom complexes are separate; not related to one another.

Perhaps the most difficult question to answer is your Question Number 4 (Any role for gammaglobulin replacement?). On the basis simply of the clinical presentation, her immune response, and the immunoglobulin levels, I would answer no to this question; at least for the present time. That is, I would follow her immunoglobulin levels over time and further assess her clinical status in terms of recurring infections. At this time, the only end-organ involvement that you have mentioned that could be related to an immune deficiency is her sinusitis, but more than likely the most important component of her sinusitis is not of infectious origin per se, but rather of an eosinophilic nature exhibiting a TH2 cytokine profile (Hamilos DL. Asthma Proceedings 1996; 17(5):293 and Dykewicz and Hamilos. J Allergy Clin Immunol 2010 (February); 125(2):S103-S115).

Thus there is little to suggest the need for immunoglobulin replacement at this time other than the CD19. However, I believe that you might receive a different opinion in this regard depending on who was asked the question. That is, I believe some workers in the field of immunodeficiency might suggest, on the basis of the patient’s manifestations, a more liberal use of immunoglobulin replacement therapy.

In summary:
1. The indication for a bone marrow would be based upon the low CD19, and I think the oncologist following her should have input with your consultation as to whether a bone marrow is indicated at this time. The reason for doing so, of course, would be to look for a B cell malignancy.
2. I do believe that there is an indication for omalizumab.
3. Whether or not immunoglobulin replacement therapy is indicated is a debatable issue, but at this time I would personally withhold immunoglobulin treatment until one had more evidence for the frequency and severity of bacterial infections and end-organ involvement. However, again, you may receive conflicting opinions in this regard.
4. I doubt any additional studies would be helpful, but the entries submitted to our website noted above will lead you to a discussion of the workup of her eosinophilic asthmatic syndrome.

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

Cytometry B Clin Cytom. 2005 Jan;63(1):28-35.
Diminished expression of CD19 in B-cell lymphomas.
Yang W, Agrawal N, Patel J, Edinger A, Osei E, Thut D, Powers J, Meyerson H.
Source
University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio, USA.
Abstract
Background: CD19 is expressed on most B-cell lymphomas; however, the frequency and types of B-cell lymphomas with low-level expression of CD19 are not well characterized.
Methods: We reviewed flow cytometric histograms specifically for decreased CD19 expression on 349 cases analyzed by the Flow Cytometry Laboratory at University Hospitals of Cleveland (Cleveland, Ohio). Results of flow cytometry were correlated with the morphologic diagnosis.
Results: Of the cases reviewed, 125 (36%) showed a visible decrease in CD19 expression compared with normal B lymphocytes. Decreased CD19 expression was noted in 79% of follicular lymphomas (27 of 34), 36% of small lymphocytic lymphomas/chronic lymphocytic leukemias (82 of 228), 31% of mantle cell lymphomas (4 of 13), 24% of diffuse large B-cell lymphomas (8 of 33), and 13% of marginal zone B-cell lymphomas/lymphoplasmacytoid lymphomas (4 of 30) and was not observed in any Burkitt lymphoma (0 of 5) or hairy cell leukemia (0 of 6). Decreased CD19 expression was significantly more frequent in follicular lymphomas than in other lymphoma subtypes (P < 0.001). No significant difference was observed in the frequency of decreased CD19 expression based on histologic grade of follicular lymphoma.
Conclusions: Diminished expression of CD19 expression occurs frequently in B-cell lymphomas, in particular follicular lymphoma, and may be helpful in identifying B-cell lymphoma cells in complex cell mixtures such as bone marrow specimens.

N Engl J Med. 2006 May 4;354(18):1901-12.
An antibody-deficiency syndrome due to mutations in the CD19 gene.
van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJ, Franco JL.
Source
Department of Immunology, Erasmus MC, The Netherlands.
Abstract
Background: The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen.
Methods: We evaluated four patients from two unrelated families who had increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of mature B cells in blood. We found a mutation in the CD19 gene in all four patients. The CD19 gene in the patients and their first-degree relatives was sequenced, and flow-cytometric immunophenotyping of B cells, immunohistochemical staining of lymphoid tissues, and DNA and messenger RNA analysis were performed. B-cell responses on the triggering of the B-cell receptor were investigated by in vitro stimulation; the antibody response after vaccination with rabies vaccine was also studied.
Results: All four patients had homozygous mutations in the CD19 gene. Levels of CD19 were undetectable in one patient and substantially decreased in the other three. Levels of CD21 were decreased, whereas levels of CD81 and CD225 were normal, in all four patients. The composition of the precursor B-cell compartment in bone marrow and the total numbers of B cells in blood were normal. However, the numbers of CD27+ memory B cells and CD5+ B cells were decreased. Secondary follicles in lymphoid tissues were small to normal in size and had a normal cellular composition. The few B cells that showed molecular signs of switching from one immunoglobulin class to another contained V(H)-C(alpha) and V(H)-C(gamma) transcripts with somatic mutations. The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired, and in all four patients, the antibody response to rabies vaccination was poor.
Conclusions: Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective.

Blood. 2013 Jan 14. [Epub ahead of print]
B cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta.
Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, Garncarz W, Müllauer L, Kain R, Boztug H, Heitger A, Arbeiter K, Eitelberger F, Seidel MG, Holter W, Pollak A, Pickl WF, Förster-Waldl E, Boztug K.
Source
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
Abstract
Primary B cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family, suffering from recurrent infections and severe lupus-like autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, defective class switch indicated by low numbers of IgM- and IgG-memory B cells as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase delta (PRKCD), causing absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) was decreased and mRNA levels of nuclear factor interleukin-6 (NF-IL6) and IL6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B cell deficiency with severe autoimmunity.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology