Prednisone;

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?

Does my patient on chronic prednisone need stress doses of corticosteroids perioperatively?

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

There are wide-ranging opinions on stress doses of corticosteroids (CS) in patients on chronic prednisone undergoing surgery, largely due to lack of adequately-sized randomized controlled studies.  Most experts seem to agree, however, that the age-old practice of routinely administering very high doses of hydrocortisone (eg, 100 mg IV every 8 hours) with prolonged taper postoperatively is excessive. 1-7

Couple of questions to consider before you decide on stress doses of CS for your patient with CS-induced (not primary) adrenal suppression. First, is your patient likely to have a suppressed adrenal function? And if so, what type of surgery is he or she about to undergo?

As for the first question, keep in mind that exogenous CS suppress the production of corticotropin (ACTH) and can induce adrenal atrophy that may persist for up to 12 months, an effect that’s dependent not only on their dose but also on their duration and may vary greatly from person to person. 2,4

Generally, a daily prednisone dose of 5 mg or less —irrespective of the duration— is considered unlikely to cause adrenal suppression (unless it’s given at bed time) and therefore should not require stress doses of CS.1 Conversely, clinical features of Cushing’s syndrome and prednisone doses of 20 mg or more daily for more than 3 weeks are likely to be associated with hyphothalamic-pituitary-adrenal (HPA) axis suppression.  Due to possible delay in the recovery of the HPA axis after discontinuation of exogenous CS, you should review not only your patient’s current dose and duration of CS but his or her regimen during the previous year. 2

When in doubt, particularly in patients receiving intermediate doses (eg, between 5 to 20 mg of prednisone daily) or duration of CS, testing the HPA axis (eg, by cosyntropin stimulation) has been suggested by some with the caveats that it’s a grade 2C (weak recommendation, low quality evidence) recommendation,7 and the results may not necessarily predict clinical adrenal insufficiency or be available before surgery. 4  

Once you have decided that your patient may be at risk of adrenal insufficiency during the perioperative period, the stress dose and duration of CS will likely depend on the type of surgery: “minor” (eg, inguinal herniorrhaphy); “moderate” (eg, total joint replacement, peripheral vascular surgery) and “major” (eg, pancreatoduodenectomy, cardiac surgery with cardiopulmonary bypass). 

A popular online resource suggests the following:4

  • Minor surgery or local anesthesia: Give only the morning maintenance dose of CS without any stress doses
  • Moderate surgery: Give the usual morning dose plus hydrocortisone IV 50 mg (or equivalent) just before the procedure followed by 25 mg IV every 8 hours for 24 hours, followed by the maintenance regimen
  • Major surgery: Give the usual morning dose plus hydrocortisone 100 mg IV before anesthesia induction, followed by 50 mg IV every 8 hours for 24 hours, tapering the dose by half each day to maintenance.

Alternatively, for minor and moderate procedures, other authors suggest usual daily dose plus hydrocortisone 50 mg IV before incision, followed by hydrocortisone 25 mg IV every 8 h for 24 h, then the usual daily dose.1  Yet others have recommended giving IV hydrocortisone 25 mg/day for 1 day for minor surgeries, 50-75 mg/day x 1-2 days for moderate surgeries, and 100-150 mg/day for 2-3 days for major surgeries.2-4 Whichever regimen you chose, make sure to give the morning maintenance dose.  

Why is less aggressive stress dosing being favored in these patients? Several reasons come to mind, including:

  •  In normal subjects, endogenous cortisol production rarely rises above 150-200 mg /day even in response to major surgery 2-4   
  • High doses of CS, particularly with long taper, may unnecessarily subject patients to adverse effects, such as hyperglycemia and poor wound healing 3,4
  • Published reports of CS-treated patients having complications such as hypotension or even death in the postoperative period have generally only implicated, not proven, adrenal insufficiency as a cause. 1-4

 

Bonus pearl: Did you know that the hypotension of secondary adrenal insufficiency in patients treated with CS is not caused by mineralocorticoid deficiency? Instead, it may in part be related to the action of CS in enhancing vascular responsiveness to vasopressors (eg, catecholamines).2 

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References

  1. Liu MM, Reidy AB, Saatee S, et al. Perioperative steroid management: Approaches based on current evidence. Anesthesiology 2017;127:166-72. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2626031
  2. Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin N Am 2003;32:367-83. http://pggweb.com/doc/glucocorticoids.pdf
  3. Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 1997;219:416-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1243159/
  4. Shaw M. When is perioperative ‘steroid coverage’ necessary? Clev Clin J Med 2002;69:9-11. https://www.ncbi.nlm.nih.gov/pubmed/11811727
  5. Urmson K. Stress dose steroids: the dogma persists. Can J Anesthe 2019;September 23. https://www.ncbi.nlm.nih.gov/pubmed/31549340
  6. Wax DB. One size fits all for stress-dose steroids. Anesthesiology 208;128:674-87. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2672525
  7. Hamrahian AH, Roman S, Milan S. The management of the surgical patient taking glucocorticoids. Uptodate 2019, accessed October 21, 2019. https://www.uptodate.com/contents/the-management-of-the-surgical-patient-taking-glucocorticoids
Does my patient on chronic prednisone need stress doses of corticosteroids perioperatively?

When should I consider prophylaxis for Pneumocystis pneumonia (PCP) in my patient on prednisone?

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

It is generally recommended that patients on ≥20 mg of daily prednisone (or its equivalent) for ≥1 month be considered for PCP prophylaxis. 1

Couple of studies in 1990s helped define the dose and duration of corticosteroids (CS) that should prompt PCP prophylaxis. A Mayo Clinic study of patients without AIDS found that a median daily CS dose of 30 mg of prednisone or equivalent—with 25% of patients receiving as little as 16 mg of prednisone daily— was associated with PCP.2  The median duration of CS therapy before PCP was 12 weeks. A similar study found a mean CS dose of 33 mg of prednisone or equivalent with mean duration of 7 months (range 1-154 months) among patients with PCP without AIDS. 3

A 2018 retrospective study4  of patients with rheumatic diseases receiving prolonged high-dose CS therapy (≥30 mg prednisone for ≥4 weeks) found that PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) resulted in 93% reduction in the incidence of PCP with an overall number needed to treat (NNT) of 52. It was suggested that PCP prophylaxis could be discontinued in patients receiving < 15 mg of prednisone daily.

Bonus Pearl: Did you know that TMP/STX may be given either as double-strength 3x/week or single-strength daily? 5,6

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References

1. Limper AH, Knox KS, Sarosi SA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128. https://www.ncbi.nlm.nih.gov/pubmed/21193785

2. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc 1996;71:5-13. https://www.sciencedirect.com/science/article/abs/pii/S0025619611649148

3. Arend SM, Kroon FP, van’t Wout JW. Pneumocystis carinii pneumonia in patients without AIDS, 1980 through 1993: An analysis of 78 cases. Arch Intern Med 1995;155:2436-2441. https://www.ncbi.nlm.nih.gov/pubmed/7503602

4. Park JW, Curtis JR, Moon J, et al. Prophylactic effect of trimethoprim-sulfamethoxazole for Pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoieds. Ann Rheum Dis 2018;77:664-9. https://www.ncbi.nlm.nih.gov/pubmed/29092853

5. Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.http://www.pneumon.org/assets/files/789/file483_273.pdf

6. Stern A, Green H, Paul M, Leibovici L. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients (Review). Cochrane data of Systematic Reviews 2014, issue 10. DOI: 10.1002/14651858.CD005590.pub3. https://www.ncbi.nlm.nih.gov/pubmed/25269391

 

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 or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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!

 

 

When should I consider prophylaxis for Pneumocystis pneumonia (PCP) in my patient on prednisone?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

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

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected in CIG.

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References

  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60. https://www.ncbi.nlm.nih.gov/pubmed/5638121
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF

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 or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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 exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

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

The presence of hepatitis B surface antibody (HBsab) in patients who also test positive for core antibody does not necessarily confer full protection against hepatitis B virus (HBV) reactivation during immunosuppression (incidence 4.3%). 1 This is because despite having HBsab and no HB surface antigen,  a small portion of patients continue to have detectable HBV DNA in the serum and are therefore at risk of reactivation during severe immunosuppression. 2

In fact, the American Gastroenterological Association recommends against using anti-HBs status to guide antiviral prophylaxis in anti-HBc-positive patients. 1

Overall, antiviral prophylaxis may reduce the risk of HBV reactivation by 87% (C.I. 70%-94%). Antiviral drugs with a high barrier to resistance (eg, entecavir) are preferred over lamivudine.

Immunosuppressants often requiring HBV prophylaxis include: 1-3

  • B cell-depleting agents (eg, rituximab, ofatumumab)
  • Anthracycline derivatives (eg, doxorubicin, epirubicin)
  • Prednisone (4 weeks or more)
  • Tumor necrosis factor inhibitors (eg, etanercept, adalimumab, certolizumab, infliximab)
  • Other cytokine or integrin inhibitors (eg, abatacept, ustekinumab, natalizumab, vedolizumab)

Traditional immunosuppressive agents such as azathioprine, 6-mercaptopurine and methotrexate are often considered “low-risk” and do not generally require prophylaxis. 1

Fun Fact: Did you know that hepatitis B virus is very old and probably originated in birds when dinosaurs roamed the earth? 4

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References

  1. Reddy KR, Beavers KL, Hammond SP, et al. American Gastroenterological Association Institute Guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:215-19. https://www.ncbi.nlm.nih.gov/pubmed/25447850
  2. Gigi E, Georgiou T, Mougiou D, et al. Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab. HIPPOKATRIA 2013;17:91-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738290/
  3. Kim EB, Kim DS, Park SJ, et al. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat 2008;40:36-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699087/
  4. Suh A, Brosius J, Schmitz J, et al. The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B virus. Nature Communications 2013; Article no. 1791. http://www.nature.com/articles/ncomms2798

 

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 or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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!

Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

Does corticosteroid therapy impact the results of interferon-gamma release assays—IGRAs— in patients screened for latent tuberculosis?

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

 

The weight of the evidence to date suggests that immunosuppressive therapy, including corticosteroids, other oral immunosuppressants and anti-tumor-necrosing factor (TNF) drugs, may negatively impact IGRA results.1-5

Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 2-4 In a study of patients with autoimmune disorders, 27% of patients on daily prednisolone dose of 10 mg or more had indeterminate QuantiFeron Gold In-Tube test compared to 1% of patients not taking prednisolone.4

A meta-analysis of the performance of IGRAs (including T-SPOT.TB) in patients with inflammatory bowel disease concluded that these assays were negatively affected by immunosuppressive therapy.5

So, be cautious in interpreting a negative or indeterminate results of IGRAs in patients on corticosteroid therapy or other immunosuppressants.

See also a related P4P post: https://pearls4peers.com/2020/01/20/my-patient-with-rheumatoid-arthritis-might-have-been-exposed-to-tuberculosis-does-immunosuppressive-therapy-affect-the-results-of-interferon-gamma-release-assay-igra-testing-for-latent-tuberculosis/

Bonus Pearl: Did you know that IGRA is not affected by prior Bacillus Calmette-Guerin (BCG) vaccination, a significant advantage over PPD skin tests?

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References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  3. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
  4. Belard E, Semb S, Ruhwald M, et al. Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the Tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis 2011;17:2340-2349. https://academic.oup.com/ibdjournal/article/17/11/2340/4631016 
  5.  Shahidi N, Fu Y-T, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-2042. https://www.researchgate.net/publication/265093409_Performance_of_Interferon-gamma_Release_Assay_for_Tuberculosis_Screening_in_Inflammatory_Bowel_Disease_Patients
Does corticosteroid therapy impact the results of interferon-gamma release assays—IGRAs— in patients screened for latent tuberculosis?