Proton pump inhibitors (PPIs) have been associated with increased risk of Clostridium difficile infection, as well as acute gastroenteritis (AG) caused by Salmonella, Campylobacter, and most recently, norovirus. 1,2
A recent prospective study1 of over 38,000 patients (mean age ~ 70 y) found a significant association between PPI use and AG leading to hospitalization with a dose-response relationship. PPI use increased the risk of Salmonella, Campylobacter, and C. difficile infections. Of note, H2 receptor antagonists were not associated with AG-related hospitalization in this study.
A 2017 retrospective case-control study also showed an association between PPI use and norovirus infection in hospitalized patients (mean age ~80 y in both groups). Most cases occurred during epidemic years with a median hospital stay of 5 days before onset of symptoms. Given the usually short incubation period of norovirus AG (typically 12-48 h), many of these cases likely acquired the infection during their hospital stay.
Besides reducing the acidity of gastric juice, PPIs may increase the risk of AG by causing an overgrowth of bacteria in the GI tract, reduce its motility and adversely affect the immune response, including neutrophil chemotaxis. 3
Does your patient really need a PPI?
- Chen Y, Liu B, Glass K, et al. Use of proton pump inhibitor and the risk of hospitalization for infectious gastroenteritis. PLoS One 2016;11:e0168618. Doi:10.1371/journal.pone. 0168618. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168618
- Prag C, Prag M, Fredlund H. Proton pump inhibitors as a risk factor for norovirus infection. Epidemiol Infect 2017;145:1617-23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426289/pdf/S0950268817000528a.pdf
- Wandall JH. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. Gut 1992;33:617-21. https://www.ncbi.nlm.nih.gov/pubmed/1319381
Yes! Besides expanding the circulatory plasma volume by raising the oncotic pressure, albumin appears to have a vasoconstricting effects by binding to endotoxins, nitric oxide (NO), bilirubin and fatty acids1,2.
Splanchnic vasodilatation, a feature of decompensated cirrhosis (eg ascites, bleeding varices, hepatorenal syndrome, and hepatic encephalopathy), is accentuated by superimposed infections through cytokine-mediated release of endothelial vasodilators3. By binding to potential vasodilators such as bile acids, endotoxins and NO, albumin may also help restore endothelial function and act as a vasoconstrictor.
In a cool study involving patients with SBP randomized to either albumin or hydroxyethyl starch (HS, a synthetic volume expander), the albumin (not HS) group had a significant increase in mean arterial pressure, right atrial pressure, pulmonary artery pressure, systolic volume, left ventricular stroke work, and systemic vascular resistance3.
Albumin may also have an immune-modulating activity in patients with cirrhosis or acute liver decompensation by binding to prostaglandin E-2 (PGE-2), generated as a result of inflammatory reaction in the liver and bacterial translocation4. PGE-2 is a suppressor of macrophage cytokine secretion and bacterial killing. By binding to PGE-2, albumin can reverse this immunosuppression by reducing the availability of serum PGE-2.
- Baraldi O, Valenini C, Donati G, et al. Hepatorenal syndrome: update on diagnosis and treatment 2015;4:511-20. https://www.ncbi.nlm.nih.gov/pubmed/26558188
- Angeli P, Volpin R, Piovan D, et al. Acute effects of the oral administration of midodrine, an α-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. Hepatology 1998;28:937-43. https://www.ncbi.nlm.nih.gov/pubmed/9755229
- Fernandez J, Monteagudo J, Bargallo X, et al. A randomized unblended pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005;42:627-634. https://www.ncbi.nlm.nih.gov/pubmed/16108036
- Gleeson, MW, Dickson RC. Albumin gains immune boosting credibility. Clin Transl 2015;6:e86;doi:10.1038/ctg.2015.11. http://www.nature.com/ctg/journal/v6/n4/full/ctg201511a.html
The most significant risk factor for PCP prophylaxis is defect in cell-mediated immunity including high-dose glucocorticoid (HDGC, ≥20 mg of prednisone daily) treatment1. A systematic review concluded that at a PCP rate of 6.2% in control groups, PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) is highly effective (85% risk reduction) in non-HIV patients with acute leukemia or solid organ/autologous bone marrow transplantation (number needed to treat 19)2.
Other Indications for PCP prophylaxis include1:
- HDGC treatment for ≥1month plus another cause of immunocompromise.
- Combination of immunosuppressive drugs, such as tumor-necrosing factor- α inhibitors plus HDGC or other immunosuppression.
- Polymyositis/dermatomyositis with interstitial pulmonary fibrosis on glucocorticoids.
- Certain primary immunodeficiencies (eg idiopathic CD4-lymphopenia, hyper-IgM syndrome).
- Granulomatosis with polyangiitis (Wegener’s) on methotrexate and HDGC
- Rheumatologic diseases on HDGC and a second immunosuppressive drug
- T-cell depleting agents (eg, fludarabine)
- Severe malnutrition
TMP/STX may be given either as double-strength 3x/week or single-strength daily1,2.
- Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.
- 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.
The risk of infection in patients on glucocorticoids (GCs) is likely determined not only by the dose and duration of treatment but also by the nature of the underlying disease requiring GC therapy (eg, asthma, autoimmune disease, malignancy), use of additional immunosuppressants, as well as individual host sensitivity to the effects of GCs1,2. For these reasons, it is often difficult to determine how much GCs will be too much for a specific patient when discussing opportunistic infections such as PCP in patients without HIV infection.
In patients with an autoimmune disease such as ours, as little as 12 mg/day of prednisone on presentation or as few as 5 days of GC therapy has been associated with PCP3. Because the critical amount of immunosuppression necessary for PCP to cause disease is unclear4, and autoimmunity is often associated with T-cell dysregulation5, it is prudent to consider PCP in the differential of diagnosis of dyspnea (along with fever or pulmonary infiltrates if present) in this patient despite not receiving “high” doses of prednisone daily. It is also important to remember that many cases of PCP occur during GC taper4.
- Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet 2003;362:1828-38.
- Youssef J, Novosad SA, Winthrop KL. Infection risk and safety of corticosteroids. Rheum Dis Clin N Am 2016; 42; 157-176.
- 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.
- Sepkowitz KA, Brown AE, Armstrong D. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. Arch Intern Med 1995;1125-28.
- Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human immunodeficiency diseases. Blood 2002;99:2694-2707.
Worldwide prevalence of SI may be as high as 100 million people, with an increasing number seen in developed countries among immigrants (including those from Latin America), refugees, and travelers. “Autoinfection” by Strongyloides allows it to complete its life cycle between the GI tract and the lung without leaving the host, and is often associated with chronic asymptomatic infection in the immunocompetent persons1.
Immunocompromised patients, however, particularly those treated with corticosteroids (including systemic courses as short as 6 days, or local injection) are at increased risk of developing an accelerated form of autoinfection due to SI, also known as hyperinfection syndrome (HIS)1,2. HIS has been reported as late as 64 years after leaving an endemic area!1. When Strongyloides larvae disseminate away from the lung or GI tract into other organs (e.g. brain) the mortality rate may approach 100%, if untreated.
Due to the potential complications associated with untreated SI, particularly in the immunocompromised , routine screening of anyone with a potential Strongyloides-exposure history (irrespective of symptoms or years since exposure) has been advocated1,3. In our patient with COPD, screening for asymptomatic SI by a highly sensitive test (eg serology) should be considered (as early as possible if corticosteroids are being considered for treatment of his COPD). Some have also advocated empiric treatment with ivermectin in “at risk patients” in whom testing is not feasible or practical1,4.
- Mejia R, Nutman TB. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis 2012;25:458-463.
- Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208-217.
- CDC. Strongyloides. http://www.cdc.gov/parsites/strongyloides/helath_professionals/ , accessed September 20, 2016.
- Santiago M, Leitão B. Prevention of strongyloides hyperinfection syndrome: a rheumatologic point of view. Eur J Intern Med 2009;20:744-748.
There is relative dearth of data addressing this very important issue. A decreased IG response after mitogen stimulation during treatment with oral prednisolone has been reported (1). 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 (1). A meta-analysis of the performance of IGRAs (including T-SPOT.TB) concluded that these assays were negatively affected by immunosuppressive therapy (2). So, until more data becomes available, caution is advised in interpreting lack of positive test or indeterminate results of IGRAs in patients on corticosteroid therapy.
1. 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.
2. 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.