My patient with primary Sjogren’s syndrome has now been diagnosed with COPD despite lack of a significant smoking history. Is there a connection between Sjogren’s syndrome and COPD?

Increasing body of evidence suggests that COPD in patients with primary Sjögren’s syndrome (PSS) is not uncommon even among those who never smoked (1).

 
A 2015 study of patients with PSS reported that overall 41% of patients with PSS, including 30% of those who never smoked, fulfilled the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD. More specifically, pulmonary function tests (PFTs) showed decreased vital capacity (VC), forced expiratory volume in 1 second (FEV-1)  and DLCO in patients with PSS. Importantly, lab inflammatory and serological features were poorly associated with PFT results, while radiographic signs of interstitial lung disease (ILG) were absent in one-half of patients with PSS and COPD (1).

 
A longitudinal study with a mean follow-up of 11 years found a 37% rate of development of COPD among patients with PSS (2). Another related study reported a poor correlation between respiratory symptoms and COPD disease as assessed by PFTs in PSS, with the authors recommending that PFTs be performed “liberally” in all patients with PSS regardless of symptoms (3).

 
Lastly, a population-based cohort study of female adults found significantly higher rate of COPD among patients with PSS compared to controls (4).

 
Although the exact pathogenic mechanism behind PSS-associated COPD is unclear, xerotrachea and impaired mucocilliary clearance, as well as inflammatory infiltrates in the exocrine glands of the airways, all leading to physical obstruction and bronchial hyperreactivity have been suggested (1).

 

Bonus Pearl: Did you know that COPD is associated with many other autoimmune diseases (eg, rheumatoid arthritis and systemic lupus erythematosus), and a genetic link has been implicated between COPD and autoimmunity? (5,6).

 

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References
1. Nilsson AM, Diaz S, Theander E, et al. Chronic obstructive pulmonary disease is common in never-smoking patients with primary Sjögren’s syndrome. J Rheumatol 2015;42:464-71. https://www.researchgate.net/publication/270907531_Chronic_Obstructive_Pulmonary_Disease_Is_Common_in_Never-smoking_Patients_with_Primary_Sjogren_Syndrome
2. Mandl T, Diaz S, Ekberg O, et al. Frequent development of chronic obstructive pulmonary disease in primary SS-result of a longitudinal follow-up. Rheumatology 2012;51:941-46. https://www.researchgate.net/publication/221760110_Frequent_development_of_chronic_obstructive_pulmonary_disease_in_primary_SS-results_of_a_longitudinal_follow-up
3. Bolmgren VS, Olssson P, Wollmer P, et al. Respiratory symptoms are poor predictors of concomitant chronic obstructive pulmonary disease in patients with primary Sjögren’s syndrome. Rheumatol Int 2017;37:813-18. https://link.springer.com/content/pdf/10.1007/s00296-017-3678-5.pdf
4. Shen TC, Wu BR, Chen HJ, et al. Risk of chronic obstructive pulmonary disease in female adults with primary Sjögren’s syndrome. A nationwide population-based cohort study. Medicine 2016; 95:1-6. http://europepmc.org/abstract/MED/26962839
5. Hemminki K, Liu X, Ji J et al. Subsequent COPD and lung cancer in patients with autoimmune disease. Eur Respir J 2011;37:463-74. https://www.ncbi.nlm.nih.gov/pubmed/21282811
6. Ji X, Niu X, Qian J, et al. A phenome-wide association study uncovers a role for autoimmunity in the development of chronic obstructive pulmonary disease. Resp Cell Mol Biol 2018;58:777-79. https://www.atsjournals.org/doi/10.1165/rcmb.2017-0409LE

My patient with primary Sjogren’s syndrome has now been diagnosed with COPD despite lack of a significant smoking history. Is there a connection between Sjogren’s syndrome and COPD?

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?

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?

In my patient with a serious infection, when should I worry about a primary immunodeficiency disorder?

You may consider a primary immunodeficiency disorder (PID) when 2 or more of the following “warning signs” are present: 1

  • ≥ 4 ear infections in 1 year
  • ≥ 2 serious sinus infections in 1 year
  • ≥ 2 pneumonias in 1 year
  • Recurrent, deep skin or organ abscesses
  • Persistent thrush in mouth or persistent fungal infection on the skin
  • ≥ 2 deep-seated infections, including septicemia
  • ≥ 2 months on antibiotics with little effect
  • Need for IV antibiotics to clear infections
  • Failure of an infant to gain weight or grow normally
  • Family history of primary immunodeficiency

Other infectious conditions that may be a clue to PID include those in unusual locations (eg, pneumococcal arthritis) or caused by unusual pathogens (eg, Pneumocystis jirovecii).

Among non-infectious conditions, history of granulomas in multiple organs, early-onset eczema refractory to therapy, and autoimmunity (eg, autoimmune cytopenias, autoimmune thyroiditis, celiac disease, vitiligo, type I diabetes mellitus) may also be potential clues.2

But before you embark on searching for PID,  rule out local barrier disorders of the skin or mucosa (eg, foreign body, bronchiectasis, cystic fibrosis) and secondary causes of immunodeficiency (eg, HIV), syndromes of protein loss/deficiency (eg, cirrhosis, nephrotic syndrome, malnutrition), splenectomy, malignancy, and medications (eg, steroids, chemotherapy, tumor necrosis factor inhibitors).2

Final Fun Fact: Did you know that PID affects 1 in 1,200 people in the US? 3

References:

  1. Arkwright PD, Gennery AR. Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. Ann N Y Acad Sci 2011; 1238:7-14 http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2011.06206.x/abstract
  2. Hausmann O, Warnatz K. Immunodeficiency in adults a practical guide for the allergist. Allergo J Int. 2014; 23: 261–268 https://link-springer-com.ezp-prod1.hul.harvard.edu/article/10.1007/s40629-014-0030-4
  3. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol 2007; 27:497  https://link.springer.com/article/10.1007/s10875-007-9103-1

 

Contributed by Yousef Badran, MD, Mass General Hospital, Boston, MA.

In my patient with a serious infection, when should I worry about a primary immunodeficiency disorder?