IgG;

My patient with COPD on prednisone with recurrent pneumonia has a low serum IgG level.  Can corticosteroids lower serum immunoglobulin levels?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

Yes! Both exogenous and endogenous hypercortisolism may be associated with a drop in serum immunoglobulin levels, particularly IgG, which may persist even after discontinuation of steroid treatment.1-4 This means that a low serum IgG level in a patient on corticosteroids should be interpreted with caution and may not necessarily suggest primary antibody deficiency.

Although some early studies did not find a significant impact of corticosteroids on immunoglobulin levels, several subsequent studies found otherwise.  A 1978 study involving atopic asthmatic patients (averaging 16.8 mg prednisone daily) found that mean serum IgG significantly decreased (-22%) with milder drop in IgA levels (-10%) and no drop in serum IgM levels.2 Of interest, IgE level increased significantly initially but later dropped as well. More importantly, mean serum IgG levels remained significantly decreased an average of 22 days after corticosteroids were discontinued.

More recently, in a study involving patients with giant cell arteritis and polymyalgia rheumatica on corticosteroids, 58% developed antibody deficiency with the great majority involving IgG, either alone or along with other immunoglobulins.3 The reduction of IgG persisted even after discontinuation of corticosteroids in nearly 50% of patients, and observed in nearly one-quarter of patients for at least 6 months! Whether low serum immunoglobulins due to corticosteroids alone significantly increase susceptibility to infections is unclear, however.

In our patient with COPD on prednisone, if serum IgG level is found to be low and a primary antibody deficiency is still suspected, a functional assessment of the antibody production after active immunization (eg, polysaccharide pneumococcal vaccine, tetanus toxoid) may be necessary. 1 An adequate antibody response to active immunization makes primary immunodeficiency unlikely. 

 

Bonus Pearl: Did you know that corticosteroid-induced hypogammaglobulinemia may be in part related to reduced IgG production as well as an increase in IgG catabolism?1,4

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References

  1. Sarcevic J, Cavelti-Weder C, Berger CT, et al. Case report-secondary antibody deficiency due to endogenous hypercortisolism. Frontiers in Immunology 2020;11:1435. https://www.frontiersin.org/articles/10.3389/fimmu.2020.01435/full
  2. Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immunoglobulins. J Allergy Clin Immunol 1978;62: 162-6. https://www.jacionline.org/article/0091-6749(78)90101-X/pdf
  3. Wirsum C, Glaser C, Gutenberger S, et al. Secondary antibody deficiency in glucocorticoid therapy clearly differs from primary antibody deficiency. J Clin Immunol 2016;36:406-12. https://link.springer.com/article/10.1007/s10875-016-0264-7
  4. McMillan R, Longmire R, Yelenosky R. The effect of corticosteroids on human IgG synthesis. J Immunol 1976;116:1592-1595. https://www.jimmunol.org/content/116/6/1592

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My patient with COPD on prednisone with recurrent pneumonia has a low serum IgG level.  Can corticosteroids lower serum immunoglobulin levels?

My patient with peripheral neuropathy was just diagnosed with monoclonal gammopathy of unclear significance (MGUS). Can these two conditions be related?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

The presence of MGUS in patients with peripheral neuropathy (PN) may be either coincidental or causal. Younger age group (<50 y) and the presence of IgM MGUS increase the likelihood of a causal relationship between MGUS and peripheral neuropathy. 1

The likelihood of a causal relationship is higher in the younger age group because of the very low prevalence of M proteins (less than 1.5%) in this population making coincidental presence of MGUS and PN much less likely. In contrast, this relationship may just be coincidental in older patients because of higher baseline prevalence of MGUS (7% in those over 70 y old). 1  

Similarly, a causal relationship between MGUS and PN may be more likely when the M protein is IgM (vs IgG or IgA). In a study of patients with MGUS and peripheral neuropathy,  31% of patients with IgM MGUS had neuropathy vs 14% for IgA and 6% for IgG MGUS. In fact, among patients with PN without an obvious cause, the prevalence of an M protein may be as high as 10%.2  Whether the relationship between non-IgM MGUS and PN is causal remains unclear.3

Although the exact mechanism of MGUS-related PN is not known, pathologic studies in Waldenstrom macroglobulinemia and multiple myeloma have demonstrated demyelination and widened myelin lamellae associated with monoclonal IgM deposits.1

But before you implicate MGUS as the cause of PN, make sure to exclude common causes of PN, such as diabetes mellitus, alcoholism and potential drugs.

 

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References

  1. Chaudhry HM, Mauermann ML, Rajkumar SV. Monoclonal gammopathy—associated peripheral neuropathy: diagnosis and management. Mayo Clin Proc 2017; 92:838-50. https://www.mayoclinicproceedings.org/article/S0025-6196(17)30118-0/pdf
  2. Kelly JJ Jr, Kyle RA, O’Brien PC, et al. Prevalence of monoclonal protein in peripheral neuropathy. Neurology 1981;31:1480-83. https://www.ncbi.nlm.nih.gov/pubmed/6273767
  3. Nobile-Orazio E, Barbien L, Baldini L, et al. Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta neurol Scand 1992;85:383-90. https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.1992.tb06033.x
My patient with peripheral neuropathy was just diagnosed with monoclonal gammopathy of unclear significance (MGUS). Can these two conditions be related?

Should my patient with COPD and recurrent exacerbations undergo evaluation for antibody deficiency?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

Although there are no consensus guidelines on when to evaluate patients with COPD for antibody deficiency, we should at least consider this possibility in patients with recurrent exacerbations despite maximal inhaled therapy (long-acting beta-2 agonist-LABA, long-acting muscarinic antagonist-LAMA and inhaled corticosteroids).1

Couple of retrospective studies of common variable immunodeficiency (CVID) in patients with COPD have reported a prevalence ranging from 2.4% to 4.5%. 1 In another study involving 42 patients thought to have had 2 or more moderate to severe COPD exacerbations per year—often despite maximal inhaled therapy— 29 were diagnosed  with antibody deficiency syndrome, including 20 with specific antibody deficiency (SAD), 8 with CVID and 1 with selective IgA deficiency.2  Although systemic corticosteroids may lower IgG and IgA levels, the majority of the patients in this study were not taking any corticosteroids at the time of their evaluation.

In another study involving patients undergoing lung transplantation, pre-transplant mild hypogammaglobulinemia was more prevalent among those with COPD (15%) compared to other lung conditions (eg, cystic fibrosis), independent of corticosteroid use.3  A favorable impact of immunoglobulin therapy or chronic suppressive antibiotics on reducing recurrent episodes of COPD exacerbation in patients with antibody deficiency has also been reported, supporting the clinical relevance of hypogammaglobulinemia in these patients. 2,4 

Remember that even normal quantitative serum immunoglobulin levels (IgG, IgA, and IgM) do not necessarily rule out antibody deficiency. Measurement of IgG subclasses, as well as more specific antibodies, such as those against pneumococcal polysaccharides may be required for further evaluation.

See a related pearl at https://pearls4peers.com/2015/07/12/my-65-year-old-patient-has-had-several-bouts-of-bacterial-pneumonia-in-the-past-2-years-her-total-serum-immunoglobulins-are-within-normal-range-could-she-still-be-immunodeficient/.

Contributed in part by Sydney Montesi, MD, Mass General Hospital, Boston, MA.

References

  1. Berger M, Geng B, Cameron DW, et al. Primary immune deficiency diseases as unrecognized causes of chronic respiratory disease. Resp Med 2017;132:181-188. https://www.sciencedirect.com/science/article/pii/S0954611117303554
  2. McCullagh BN, Comelias AP, Ballas ZK, et al. Antibody deficiency in patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD). PLoS ONE 2017; 12: e0172437. https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0172437
  3. Yip NH, Lederer DJ, Kawut SM, et al. Immunoglobulin G levels before and after lung transplantation 2006;173:917-21.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662910/
  4. Cowan J, Gaudet L, Mulpuru S, et al. A retrospective longitudinal within-subject risk interval analysis of immunoglobulin treatment for recurrent acute exacerbation of chronic obstructive pulmonary disease. PLoS ONE 2015;10:e0142205. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142205

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Should my patient with COPD and recurrent exacerbations undergo evaluation for antibody deficiency?

My patient with erythema multiforme has tested positive for Mycoplasma pneumoniae IgM antibody. Does this mean she has an acute M. pneumonia infection as the cause of her acute illness?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , Leave a comment

Not necessarily! Although detection of IgM in the serum of patients has proven valuable in diagnosing many infections during their early phase, particularly before IgG is detected, less well known is that false-positive IgM results are not uncommon. 1

More specific to M. pneumoniae IgM, false-positive results have been reported in 10-80% of patients without a clinical diagnosis of acute M. pneumoniae infection 2-4 and 3-15% of blood donors. 4

False-positive IgM results may also occur when testing for other infectious agents, such as the agent of Lyme disease (Borrelia burgdorferi), arboviruses (eg, Zika virus), and herpes simplex, Epstein-Barr, cytomegalovirus, hepatitis A and measles viruses. 1,5  

Reports of false positive IgM results include a patient with congestive heart failure and mildly elevated liver enzymes who had a false-positive hepatitis IgM which led to unnecessary public health investigation and exclusion from an adult day care center. 1 Another patient with sulfa rash had a false-positive measles IgM antibody resulting in callback of >100 patients and healthcare providers for testing!5

There are many potential mechanisms for false-positive IgM results, including polyclonal B cell activation, “vigorous immune response”, cross-reactive antibodies, autoimmune disease, subclinical reactivation of latent viruses, influenza vaccination, overreading weakly reactive results, and persistence of antibodies long after the resolution of the acute disease. 1,2

In our patient, a significant rise in M. pneumoniae IgG between acute and convalescent samples several weeks apart may be more helpful in diagnosing an acute infection accounting for her erythema multiforme.

 

References

  1. Landry ML. Immunoglobulin M for acute infection: true or false? Clin Vac Immunol 2016;23:540-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933779/
  2. Csango PA, Pedersen JE, Hess RD. Comparison of four Mycoplasma pneumoniae IgM-, IgG- and IgA-specific enzyme immunoassays in blood donors and patients. Clin Micro Infect 2004;10:1089-1104. https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)63853-2/pdf
  3. Thacker WL, Talkington DF. Analysis of complement fixation and commercial enzyme immunoassays for detection of antibodies to Mycoplasma pneumoniae in human serum. Clin Diag Lab Immunol 2000;7:778-80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC95955/
  4. Ryuta U, Juri O, Inoue Y, et al. Rapid detection of Mycoplasma pneumoniae IgM antibodies using immunoCard Mycoplasma kit compared with complement fixation (CF) tests and clinical application. European Respiratory Journal 2012; 40: P 2466 (Abstract). https://erj.ersjournals.com/content/40/Suppl_56/P2466 
  5. Woods CR. False-positive results for immunoglobulin M serologic results: explanations and examples. J Ped Infect Dis Soc 2013;2:87-90. https://www.ncbi.nlm.nih.gov/pubmed/26619450

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My patient with erythema multiforme has tested positive for Mycoplasma pneumoniae IgM antibody. Does this mean she has an acute M. pneumonia infection as the cause of her acute illness?