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Association of Community-Acquired Pneumonia With Antipsychotic Drug Use in Elderly Patients: A Nested Case–Control Study

Gianluca Trifirò, MD, PhD; Giovanni Gambassi, MD, PhD; Elif F. Sen, MSc; Achille P. Caputi, MD; Vincenzo Bagnardi, PhD; Jose Brea, PhD; and Miriam C.J.M. Sturkenboom, PharmD, PhD
[+] Article and Author Information

From Erasmus University Medical Center, Rotterdam, the Netherlands; University of Messina and IRCCS Centro Neurolesi “Bonino-Pulejo,” Messina, Università Cattolica del Sacro Cuore, Rome, and University of Milano-Bicocca and European Institute of Oncology, Milan, Italy; and Universidad de Santiago de Compostela, Santiago de Compostela, Spain.


Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1541.

Reproducible Research Statement:Study protocol and statistical code: Available from Dr. Trifirò (e-mail, g.trifiro@erasmusmc.nl). Data set: Not available.

Requests for Single Reprints: Gianluca Trifirò, MD, PhD, Department of Medical Informatics, Erasmus University Medical Center, PO Box 1738, 3000 DR, Rotterdam, the Netherlands; e-mail, g.trifiro@erasmusmc.nl.

Current Author Addresses: Drs. Trifirò and Sturkenboom and Mr. Sen: Department of Medical Informatics, Erasmus University Medical Center, PO Box 1738, 3000 DR, Rotterdam, the Netherlands.

Dr. Gambassi: Centro Medicina Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Largo Francesco Vito, 1-00168 Rome, Italy.

Dr. Caputi: Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Via Consolare Valeria, Gazzi, 98125 Messina, Italy.

Dr. Bagnardi: Department of Statistics, University of Milano-Bicocca, Via Bicocca degli Arcimboldi, 8-20126 Milan, Italy.

Dr. Brea: Industrial Pharmacology Institute, Department of Pharmacology, School of Pharmacy, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

Author Contributions: Conception and design: G. Trifirò, G. Gambassi, A.P. Caputi, M.C.J.M. Sturkenboom.

Analysis and interpretation of the data: G. Trifirò, G. Gambassi, A.P. Caputi, V. Bagnardi, J. Brea, M.C.J.M. Sturkenboom.

Drafting of the article: G. Trifirò, G. Gambassi, E.F. Sen, A.P. Caputi, J. Brea, M.C.J.M. Sturkenboom.

Critical revision of the article for important intellectual content: G. Trifirò, G. Gambassi, A.P. Caputi, V. Bagnardi, M.C.J.M. Sturkenboom.

Final approval of the article: G. Trifirò, G. Gambassi, E.F. Sen, A.P. Caputi, V. Bagnardi, M.C.J.M. Sturkenboom.

Statistical expertise: G. Trifirò, G. Gambassi, V. Bagnardi, M.C.J.M. Sturkenboom.

Administrative, technical, or logistic support: E.F. Sen, M.C.J.M. Sturkenboom.

Collection and assembly of data: M.C.J.M. Sturkenboom.


Ann Intern Med. 2010;152(7):418-425. doi:10.7326/0003-4819-152-7-201004060-00006
Text Size: A A A

Background: According to safety alerts from the U.S. Food and Drug Administration, pneumonia is one of the most frequently reported causes of death in elderly patients with dementia who are treated with antipsychotic drugs. However, epidemiologic evidence of the association between antipsychotic drug use and pneumonia is limited.

Objective: To evaluate whether typical or atypical antipsychotic use is associated with fatal or nonfatal pneumonia in elderly persons.

Design: Population-based, nested case–control study.

Setting: Dutch Integrated Primary Care Information database.

Patients: Cohort of persons who used an antipsychotic drug, were 65 years or older, and were registered in the IPCI database from 1996 to 2006. Case patients were all persons with incident community-acquired pneumonia. Up to 20 control participants were matched to each case patient on the basis of age, sex, and date of onset.

Measurements: Risk for fatal or nonfatal community-acquired pneumonia with atypical and typical antipsychotic use. Antipsychotic exposure was categorized by type, timing, and daily dose, and the association with pneumonia was assessed by using conditional logistic regression.

Results: 258 case patients with incident pneumonia were matched to 1686 control participants. Sixty-five (25%) of the case patients died in 30 days, and their disease was considered fatal. Current use of either atypical (odds ratio [OR], 2.61 [95% CI, 1.48 to 4.61]) or typical (OR, 1.76 [CI, 1.22 to 2.53]) antipsychotic drugs was associated with a dose-dependent increase in the risk for pneumonia compared with past use of antipsychotic drugs. Only atypical antipsychotic drugs were associated with an increase in the risk for fatal pneumonia (OR, 5.97 [CI, 1.49 to 23.98]).

Limitations: Antipsychotic exposure was based on prescription files. Residual confounding due to unmeasured covariates or severity of disease was possible.

Conclusion: The use of either atypical or typical antipsychotic drugs in elderly patients is associated in a dose-dependent manner with risk for community-acquired pneumonia.

Primary Funding Source: None.

Figures

Grahic Jump Location
Appendix Figure.
Study flow diagram.

Case patients with incident community-acquired pneumonia and matched control participants were selected by using the Integrated Primary Care Information database.

* 6 case patients were not included in the analyses because they could not be matched to a control participant.

Grahic Jump Location

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Comments

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Community-acquired pneumonia and antipsychotic drug use
Posted on April 13, 2010
Matt P Wise
University Hospital of Wales, Cardiff, UK.
Conflict of Interest: None Declared

Trifiro and colleagues recently reported the results of a nested case -control study assessing the risk of developing community-acquired pneumonia (CAP) in elderly patients administered antipsychotic drugs (1). The authors concluded that the use of both typical and atypical antipsychotic therapy was associated with CAP in a dose dependent manner. The mechanisms of pneumonia are unknown but the authors speculated that anti-cholinergic and H1-receptor blocking effects might be important. It was suggested that blocking muscarinic cholinergic receptors would lead to a dry mouth, impaired oropharyngeal bolus transport and pulmonary aspiration, whilst sedation through H1-receptor blocking would facilitate this process. Poor oral hygiene is a risk factor for pneumonia and reduced salivary flow promotes plaque formation, however antipsychotic medication, particularly clozapine, is frequently associated with excessive salivation or sialorrhea (2). Although both typical and atypical agents increased the incidence of pneumonia there was heterogeneity amongst typical antipsychotic drugs with butyrophenones having a much lower risk of CAP (1). A common side-effect of antipsychotic drugs is the development of hyperglycaemia and although frequently described with atypical agents, also occurs with phenothiazines but not butyrophenones (3). Hyperglycaemia in non-diabetic patients increases the risk of CAP by 6-10% for each 1mmol/L rise in plasma glucose above baseline (4). In health lung airway fluid glucose is maintained 10 times lower than plasma by an active transport mechanism. The latter has a threshold such that glucose appears in airway fluid when plasma glucose exceeds 6.7-9.7mmol/L and this is associated with bacterial growth in the lung. Modest hyperglycaemia induced by antipsychotic agents represents an eloquent mechanism whereby the risk of CAP may be increased. The American Diabetes Association consensus statement makes a number of recommendations on baseline measurement and frequency of follow up of metabolic parameters in patients initiated on antipsychotic medication (5). Despite these guidelines less than a quarter of patients initiated on atypical antipsychotic agents have a baseline glucose measured and only one third has an annual glucose measurement. In view of the current study (1) we suggest that clinicians initiating antipsychotic drugs in the elderly should adhere closely to these recommendations.

References

1. Trifiro G, Gambassi G, Sen EF, Caputi AP, Bagnardi V, Brea J, et al. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients. Ann Intern Med. 2010;152:418-425.

2. Freudenreich O. Drug-induced sialorrhea. Drugs Today (Barc). 2005;41:411-8.

3. Vidarsdottir S, de Leeuw van Weenen JE, Frolich M, Roelfsema F, Romijn JA, Pijl H. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab. 2010;95:118-25.

4. Benfield T, Jensen JS, Nordestgaard BG. Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome. Diabetologia. 2007;50:549-554.

5. American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596- 601.

Conflict of Interest:

None declared

Additional Risk Factors for Community Acquired Pneumonia in Patients Receiving Antipsychotics
Posted on May 3, 2010
James R. Webster
Feinberg School of Medicine of Northwestern University
Conflict of Interest: None Declared

TO THE EDITOR: I believe the manuscript by Trifiro et.al. (1), documenting that antipsychotic drug use in the elderly is associated with an increased risk for community acquired pneumonia did not discuss several clinically important associations. Their data shows that the "Case Patients" were significantly more likely (< 0.001) to have COPD, to use corticosteroids and to have a housebound life style which may be a proxy for frailty. These are all risk factors for pneumonia and should be appreciated by physicians treating the elderly, especially when prescribing antipsychotics. In addition I was disappointed that they did not discuss whether or not the patients in their study had received Pneumococcal vaccine which, although its efficacy has been called into question, is still recommended for the elderly (2).

References

1. Trifiro G, Gambassi G, Sen EF, et al. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: A nested control study. Ann Intern Med. 2010;152:418-425.

2. MMWR QuickGuide, January 9, 2009/Vol. 57/No. 53

Conflict of Interest:

None declared

Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study.
Posted on July 6, 2010
Arvinder P. Gagneja
Meritcare
Conflict of Interest: None Declared

Dear Sir,

I read with great interest the article by Trifiro, et al. (1), published in the April 6th 2010 issue of the Journal: Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study. The authors concluded that the use of either atypical or typical antipsychotic drugs in elderly patients is associated in a dose-dependent manner with risk for community-acquired pneumonia.

I noted two possible confounding factors that were not discussed in the article. The first was COPD, which was present in 19.4 % of case patients, and in 11.2% of control participants, and this difference was statistically significant (p< 0.001). The second was corticosteroid use (although it is not clear if this was inhaled form or other), which was present in 6.6 % of case patients, and 2.5 % of controls, and this difference was also statistically significant (p< 0.001). Both COPD (2, 3, 4) and inhaled corticosteroid use (2, 3) have been shown to be an independent risk factors for community-acquired pneumonia.

The authors also mentioned that residual confounding due to unmeasured covariates was possible. Some of these could have been asthma, inhalation therapy, oxygen therapy, and usual contact with children, all of which have been shown to be independent risk factors for community- acquired pneumonia (2). Also alcohol abuse has been shown to be an independent risk factor for community-acquired pneumonia (4).

A possible hypothesis to explain the association between antipsychotic medications and community-acquired pneumonia in some elderly patients is the presence of underlying medical conditions (specifically those that independently increase the risk of community-acquired pneumonia) that may also increase the risk of other conditions which lead to the use of antipsychotic medications.

Therefore I believe that further studies are required to clarify whether antipsychotic medications cause community-acquired pneumonia in elderly patients and these future studies should eliminate the confounding risk factors to the fullest extent as possible. But in the meanwhile, I agree with the author's recommendation that, clinicians who start treatment with antipsychotic drugs in elderly patients should carefully monitor for community-acquired pneumonia.

References:

1. Trifiro G, Gambassi G, Sen EF, Caputi AP, Bagnardi V, Brea J, Sturkenboom MC; Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study. Ann Intern Med April 6, 2010 152:418-425.

2. Almirall J, Bolibar I, Serra-Prat M, Roig J, Hospital I, Carandell E, Agusti M, Ayuso P, Estela A, Torres A; New evidence of risk factors for community-acquired pneumonia: a population-based study. Eur Respir J. 2008 Jun;31(6):1274-84.

3. Almirall J, Bolibar I, Balanzo X, Gonzalez CA; Risk factors for community-acquired pneumonia in adults: a population-based case-control study. Eur Respir J. 1999 Feb;13(2):349-55.

4. Ruiz M, Ewig S, Marcos MA, Martinez JA, Arancibia F, Mensa J, Torres A; Etiology of community-acquired pneumonia: impact of age, comorbidity, and severity. Am J Respir Crit Care Med. 1999 Aug;160(2):397- 405.

Conflict of Interest:

None declared

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Summary for Patients

Antipsychotic Use and Community-Acquired Pneumonia

The summary below is from the full report titled “Association of Community-Acquired Pneumonia With Antipsychotic Drug Use in Elderly Patients. A Nested Case–Control Study.” It is in the 6 April 2010 issue of Annals of Internal Medicine (volume 152, pages 418-425). The authors are G. Trifirò, G. Gambassi, E.F. Sen, A.P. Caputi, V. Bagnardi, J. Brea, and M.C.J.M. Sturkenboom.

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