Patients with hypogammaglobulinemia requiring immunoglobulin replacement should be monitored clinically for infection rates, infective complications, malignancy, and other complications. There is no published consensus on the ideal frequency of monitoring tests, but the following is generally used:
CBC, liver function tests, and IgG trough levels measured at least every 3 to 6 months
Viral hepatitis screening (HBsAg, hepatitis B and C polymerase chain reaction) and lymphocyte subsets performed annually
Serum saved annually or with any change of immunoglobulin product
Pulmonary function tests performed at least annually
Regular CT scans of the chest (with fewer cuts as appropriate); frequency of scanning as clinically indicated, and balanced against lifetime radiation risk as some primary immunodeficiencies are radiosensitive (e.g., ataxia-telangiectasia, common variable immunodeficiency)[69]Vorechovsky I, Scott D, Haeney MR, et al. Chromosomal radiosensitivity in common variable immune deficiency. Mutat Res. 1993 Dec;290(2):255-64.
http://www.ncbi.nlm.nih.gov/pubmed/7694117?tool=bestpractice.com
[70]Aghamohammadi A, Moin M, Kouhi A, et al. Chromosomal radiosensitivity in patients with common variable immunodeficiency. Immunobiology. 2008;213(5):447-54.
http://www.ncbi.nlm.nih.gov/pubmed/18472053?tool=bestpractice.com
Other investigations performed as needed.
Patients with milder forms of hypogammaglobulinemia (e.g., IgA deficiency, impaired specific antibody deficiency) who do not require immunoglobulin replacement require monitoring of symptoms and immunoglobulin levels to ensure disease is not progressing.
There are increasing reports of prolonged and symptomatic hypogammaglobulinemia following certain treatments, including biologics such as rituximab and other B-cell targeted therapies.[20]Levy R, Mahévas M, Galicier L, et al. Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature. Autoimmun Rev. 2014 Oct;13(10):1055-63.
http://www.ncbi.nlm.nih.gov/pubmed/25183241?tool=bestpractice.com
[21]Christou EA, Giardino G, Worth A, et al. Risk factors predisposing to the development of hypogammaglobulinemia and infections post-rituximab. Int Rev Immunol. 2017 Nov 2;36(6):352-9.
http://www.ncbi.nlm.nih.gov/pubmed/28800262?tool=bestpractice.com
[22]Khan DA. Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist. Ann Allergy Asthma Immunol. 2016 Aug;117(2):115-20.
https://www.annallergy.org/article/S1081-1206(16)30263-0/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27499538?tool=bestpractice.com
[23]Ottaviano G, Marinoni M, Graziani S, et al. Rituximab unveils hypogammaglobulinemia and immunodeficiency in children with autoimmune cytopenia. J Allergy Clin Immunol Pract. 2020 Jan;8(1):273-82.
http://www.ncbi.nlm.nih.gov/pubmed/31377437?tool=bestpractice.com
[55]Wijetilleka S, Jayne DR, Mukhtyar C, et al. Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases. Rheumatology (Oxford). 2019 May 1;58(5):889-96.
https://academic.oup.com/rheumatology/article/58/5/889/5262287?login=false
http://www.ncbi.nlm.nih.gov/pubmed/30590695?tool=bestpractice.com
[56]Wijetilleka S, Mukhtyar C, Jayne D, et al. Immunoglobulin replacement for secondary immunodeficiency after B-cell targeted therapies in autoimmune rheumatic disease: systematic literature review. Autoimmun Rev. 2019 May;18(5):535-41.
http://www.ncbi.nlm.nih.gov/pubmed/30844552?tool=bestpractice.com
Patients receiving rituximab should have their immunoglobulin levels monitored regularly (e.g., every 6 months).[22]Khan DA. Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist. Ann Allergy Asthma Immunol. 2016 Aug;117(2):115-20.
https://www.annallergy.org/article/S1081-1206(16)30263-0/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27499538?tool=bestpractice.com
[23]Ottaviano G, Marinoni M, Graziani S, et al. Rituximab unveils hypogammaglobulinemia and immunodeficiency in children with autoimmune cytopenia. J Allergy Clin Immunol Pract. 2020 Jan;8(1):273-82.
http://www.ncbi.nlm.nih.gov/pubmed/31377437?tool=bestpractice.com
[57]Barmettler S, Ong MS, Farmer JR, et al. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018 Nov 2;1(7):e184169.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2712179
http://www.ncbi.nlm.nih.gov/pubmed/30646343?tool=bestpractice.com
[58]Khojah AM, Miller ML, Klein-Gitelman MS, et al. Rituximab-associated hypogammaglobulinemia in pediatric patients with autoimmune diseases. Pediatr Rheumatol Online J. 2019 Aug 28;17(1):61.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712749
http://www.ncbi.nlm.nih.gov/pubmed/31462263?tool=bestpractice.com
[82]Md Yusof MY, Vital EM, McElvenny DM, et al. Predicting severe infection and effects of hypogammaglobulinemia during therapy with rituximab in rheumatic and musculoskeletal siseases. Arthritis Rheumatol. 2019 Nov;71(11):1812-23.
https://eprints.whiterose.ac.uk/146972
http://www.ncbi.nlm.nih.gov/pubmed/31131994?tool=bestpractice.com
Additionally, there is increasing data that pediatric patients treated with rituximab may be at higher risk for hypogammaglobulinemia and should be monitored.[23]Ottaviano G, Marinoni M, Graziani S, et al. Rituximab unveils hypogammaglobulinemia and immunodeficiency in children with autoimmune cytopenia. J Allergy Clin Immunol Pract. 2020 Jan;8(1):273-82.
http://www.ncbi.nlm.nih.gov/pubmed/31377437?tool=bestpractice.com
[58]Khojah AM, Miller ML, Klein-Gitelman MS, et al. Rituximab-associated hypogammaglobulinemia in pediatric patients with autoimmune diseases. Pediatr Rheumatol Online J. 2019 Aug 28;17(1):61.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712749
http://www.ncbi.nlm.nih.gov/pubmed/31462263?tool=bestpractice.com