For the question "Immunoglobulin replacement therapy in Waldenström’s macroglobulinemia" Did Dr. Steven Treon ever reply? I have a duplicate patient and would love to hear the response. This is becoming more common. Also does doing a High Resolution CT of the Chest help looking for Bronchiectasis as a sign of Immune Deficiency help? Related article under "Rituxan" in your search engine suggest that but the experts were not quoted in detail. Thanks.


Thank you for your inquiry.

The answer to your second question is much easier to obtain than the first. That is, high resolution CT of the chest is a very helpful test in detecting bronchiectasis. I have copied for you below abstracts from articles assessing the use of high resolution CT in this condition.

As to whether or not to begin immunoglobulin replacement therapy in patients receiving Rituxan, regardless of cause, opinions vary and data are limited. However, as more results are reported, it appears that replacement therapy can be useful in such patients, and necessary in some.

Unfortunately we did not receive a response from Dr. Treon in regards to the question you cited, but we did receive a response more recently from Dr. Cunningham-Rundles who, as you know, is an internationally known expert in adult immunodeficiency disorders. This response concurred with our assessment of immunoglobulin replacement therapy in patients on Rituxan to an inquiry in this regard. It was posted on January 6, 2012, and is entitled "Hypogammaglobulinemia related to rituximab administration". As you can see from my response to this inquiry, and Dr. Cunningham-Rundles' concurrence, the use of immunoglobulin replacement therapy in patients on rituximab can be accepted therapy.

The issues involved are discussed in the abstracts that I have copied below, but in brief, in a patient receiving rituximab who has hypogammaglobulinemia, if there is any sign of recurrent bacterial infection, then I believe immunoglobulin replacement therapy can be warranted based upon the data expressed in the literature to date.

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

AJR Am J Roentgenol. 1999 Jul;173(1):47-52.
Bronchiectasis: accuracy of high-resolution CT in the differentiation of specific diseases.
Cartier Y, Kavanagh PV, Johkoh T, Mason AC, Müller NL.
Department of Radiology, University of British Columbia and Vancouver Hospital and Health Sciences Centre, Canada.
Objective: The aim of the study was to determine whether various causes of bronchiectasis can be differentiated by the pattern and distribution of abnormalities seen on high-resolution CT.
Materials and Methods: The retrospective study included 82 consecutive patients who had a specific diagnosis of bronchiectasis proven by appropriate clinical and laboratory criteria. All patients underwent high-resolution CT scanning (1- to 1.5-mm collimation). The CT scans were assessed for the presence, extent, type, and anatomic distribution of bronchiectasis by two independent observers who were not aware of the clinical data. The observers recorded their most likely diagnosis and the degree of confidence in that diagnosis.
Results: The two independent observers made a correct diagnosis in 61% of cases (100/164 interpretations). On average, a correct diagnosis was made in 19 (68%) of 28 cases of cystic fibrosis, 16 (67%) of 24 cases of previous tuberculosis, six (43%) of 14 cases of previous childhood infection, five (56%) of nine cases of allergic bronchopulmonary aspergillosis, and four (57%) of seven cases of other causes of bronchiectasis. We found moderate agreement between the observers for the correct diagnosis (kappa = .53) and good agreement for the presence or absence of bronchiectasis in each lobe (kappa = .71).
Conclusion: The pattern and distribution of abnormalities revealed by high-resolution CT in patients with bronchiectasis are influenced by the underlying cause. Bilateral, predominantly upper lobe, bronchiectasis is seen most commonly in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis, unilateral upper lobe predominance in patients with tuberculosis, and lower lobe predominance in patients after childhood viral infection.

Radiol Clin North Am. 2009 Mar;47(2):289-306.
Javidan-Nejad C, Bhalla S.
Section of Cardiothoracic Imaging, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, St. Louis, MO, USA.
Bronchiectasis is defined as irreversible bronchial dilatation, leading to chronic cough, sputum formation, and recurrent infections. HRCT plays a major role in diagnosis of bronchiectasis. Most bronchiectasis is either idiopathic or a result of prior infections. Cystic fibrosis, allergic bronchopulmonary aspergillosis, and traction bronchiectasis caused by prior tuberculosis, sarcoidosis, and silicosis with progressive massive fibrosis have an upper lobe distribution. A lower lobe distribution is mostly seen in chronic aspiration, hypogammaglobulinemia, Mounier-Kuhn syndrome, primary ciliary dyskinesia, and traction bronchiectasis caused by usual interstitial pneumonitis and nonspecific interstitial pneumonitis. The right middle lobe and lingula are preferentially involved in atypical mycobacterial infections and sometimes in primary ciliary dyskinesia and Kartagener syndrome. A location-based approach may help lead to a specific diagnosis.

J Clin Pathol. 2010 Mar;63(3):275-7.
Does rituximab aggravate pre-existing hypogammaglobulinaemia?
Diwakar L, Gorrie S, Richter A, Chapman O, Dhillon P, Al-Ghanmi F, Noorani S, Krishna MT, Huissoon A.
Department of Immunology, Heartlands Hospital, Birmingham B9 5SS, UK.
Rituximab, an anti-CD20 chimeric antibody, is the first monoclonal agent to be used in the therapy of cancer. It has been hailed as one of the most important therapeutic developments of the decade. While transient peripheral B cell depletion is common after rituximab therapy, immunoglobulin levels are generally not affected. This is because CD20 is expressed on pre-B and mature B lymphocytes but not on stem cells or plasma cells. Two adult patients with pre-existing primary antibody deficiency who presented with recurrent infections immediately following rituximab use for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) are described. Both were previously treated with various immunosuppressive agents without any notable infective problems. However, a few weeks after treatment with rituximab, these patients presented with clinically significant immunodeficiency requiring intravenous immunoglobulin replacement therapy. This striking temporal relationship between rituximab administration and onset of infections suggests that rituximab has accelerated the presentation of immune deficiency in these patients. Increased vigilance around the use of newer immunomodulatory agents such as rituximab is recommended.

Br J Haematol. 2009 Jun;146(1):120-2. Epub 2009 May 9.
Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin.
Cooper N, Davies EG, Thrasher AJ.

Rheumatol Int. 2011 Dec 30. [Epub ahead of print]
Sustained hypogammaglobulinemia under rituximab maintenance therapy could increase the risk for serious infections: a report of two cases.
Besada E, Bader L, Nossent H.
Revmatologisk avdeling, Nevro-og ortopediklinikken, Universitetssykehuset Nord-Norge, Postboks 14, 9038, Tromsø, Norway.
We report two patients with granulomatosis with polyangiitis in remission with rituximab maintenance therapy with sustained hypogammaglobulinemia. Both patients had serious infections and were admitted to the intensive therapy unit. The patients had at least low IgM levels prior to the initiation of rituximab. They received cyclophosphamide and prednisolone at induction and at maintenance. They had lung affection, low level of both IgM and IgG and a cumulative dose of rituximab over 7 g at the time of the severe infection. Our patients have features similar to common variable immunodeficiency patients, and therefore prolonged very low levels of immunoglobulins could heighten the risk for severe infections.

Int J Infect Dis. 2011 Jan;15(1):e2-16. Epub 2010 Nov 11.
Does rituximab increase the incidence of infectious complications? A narrative review.
Kelesidis T, Daikos G, Boumpas D, Tsiodras S.
Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., CHS 37-121, Los Angeles, CA 90095, USA.
Background: Rituximab has increasingly been used for the treatment of hematological malignancies and autoimmune diseases, and its efficacy and safety are well established. Although clinical trials have shown conflicting results regarding the association of rituximab with infections, an increased incidence of infections has recently been reported in patients with lymphomas being treated with rituximab. However, clinical experience regarding the association of rituximab with different types of infection is lacking and this association has not been established in patients with rheumatoid arthritis.
Methods: All previous studies included in our literature review were found using a PubMed, EMBASE, and Cochrane database search of the English-language medical literature applying the terms 'rituximab', 'monoclonal antibodies', 'infections', 'infectious complications', and combinations of these terms. In addition, the references cited in these articles were examined to identify additional reports.
Results: We performed separate analyses of data regarding the association of rituximab with infection in (1) patients with hematological malignancies, (2) patients with autoimmune disorders, and (3) transplant patients. Recent data show that rituximab maintenance therapy significantly increases the risk of both infection and neutropenia in patients with lymphoma or other hematological malignancies. On the other hand, data available to date do not indicate an increased risk of infections when using rituximab compared with concurrent control treatments in patients with rheumatoid arthritis. However, there is a lack of sufficient long-term data to allow such a statement to be definitively made, and caution regarding infections should continue to be exercised, especially in patients who have received repeated courses of rituximab, are receiving other immunosuppressants concurrently, and in those whose immunoglobulin levels have fallen below the normal range. Few data are available concerning the risk of organ transplant recipients developing infections following rituximab therapy. Data from case reports, case series, and retrospective studies correlate rituximab use with the development of a variety of infections in transplant patients.
Conclusions: Further studies are needed to clarify the association of rituximab with infection. Physicians and patients should be educated about the association of rituximab with infectious complications. Monitoring of absolute neutrophil count and immunoglobulin levels and the identification of high-risk groups for the development of infectious complications, with timely vaccination of these groups, are clearly needed.

Phil Lieberman, M.D.

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