Pneumocystis jirovecii Genotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia - - Emerging Infectious Disease journal - CDC
Table of Contents
Volume 19, Number 1–January 2013
CME ACTIVITY
Pneumocystis jirovecii Genotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia
Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit.
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/eid; (4) view/print certificate.
• Distinguish the rate of dihydropteroate synthase (DHPS) mutations among patients with Pneumocystis jirovecii pneumonia (PCP) in the current study
• Analyze patient characteristics associated with a higher rate of DHPS mutations
• Assess variables associated with sulfa resistance among cases of PCP in the current study
• Evaluate the effects of DHPS mutations on the risk of death among cases of PCP in the current study.
Pneumocystis jirovecii causes severe pneumonia in immunocompromised patients, including HIV-infected persons, transplant recipients, patients receiving high-grade chemotherapy for hemato-oncologic diseases, and persons with autoimmune diseases who are treated with immunosuppressive drugs. Cotrimoxazole, the combination of sulfamethoxazole and trimethoprim (SMX/TMP), is the drug of choice for prevention of and treatment for Pneumocystis pneumonia (PCP). SMX/TMP targets enzymes involved in the biosynthesis of folic acid, dihydropteroate synthase (DHPS), and dihydrofolate reductase.
Several investigators have reported an association between failure of prophylaxis when using sulfa drugs and substitutions of 2 aa within the putative sulfa binding site of DHPS at positions 55 (Thr to Ala, mutation M1) and 57 (Pro to Ser, M2) (1–4). These mutations were observed either as single (M1 or M2) or double (M3) mutation. This association strongly suggested that P. jirovecii DHPS mutations conferred a level of sulfa resistance sufficient to cause failure of anti-PCP prophylaxis. However, the mutations might have also conferred a clinically substantial resistance to sulfa treatment for overt PCP.
To investigate the issue, many studies have analyzed the effect of the mutations on the outcome of PCP. About half of those studies did not detect any association between the mutations and an increased risk of death caused by PCP (5–8) or a decreased response to sulfa drugs (3,9–11). Conversely, other studies detected an association with a poor outcome (12,13): sulfa treatment failure (14,15); more severe symptoms and need of assisted ventilation (13); or a trend for a worse prognosis (16). Thus, the effect of these mutations on PCP outcome is unclear and justifies investigation to improve PCP treatment and prognosis.
The possibility of other parameters influencing PCP outcome has also been explored. P. jirovecii genotype Ne of the internal transcribed spacers (ITSs) of the nuclear rRNA operon has been associated with milder disease (17), failure of PCP prophylaxis (18), and failure of PCP treatment (9). One ITS genotype observed in Australia was associated with reduced severity of PCP (13). Specific P. jirovecii genotypes defined by single-nucleotide polymorphisms in 3 loci were associated with low or high burden during the course of PCP (19). In comparison, some studies did not detect any associations between P. jirovecii genotypes, including Ne genotype, and several clinical parameters, such as severity and survival at 3 months (15,20). These observations suggested that some P. jirovecii genotypes might be more virulent or resistant to drugs, but further studies are needed to provide better understanding the issue.
We previously examined P. jirovecii DHPS polymorphisms in clinical specimens of 158 immunosuppressed patients from 5 hospitals in the city of Lyon in France (7). We detected an association between DHPS mutation M2 and failure of prophylaxis when pyrimethamine/sulfadoxine was used but not between DHPS mutations and death caused by PCP. In this study, we further observed the proportion of the organisms harboring DHPS mutations (36%) and of death attributed to PCP (20%) among these 158 patients. We investigated in more detail the effect of DHPS mutations on PCP prognoses, taking into account more clinical parameters. Moreover, to test the hypothesis of variable virulence of some P. jirovecii genotypes, we identified those present in the specimens. Because the disease signs and symptoms vary considerably between HIV-infected and HIV-uninfected patients, we limited our analyses to the HIV-infected patients.
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/eid; (4) view/print certificate.
Release date: December 14, 2012; Expiration date: December 14, 2013
Learning Objectives
Upon completion of this activity, participants will be able to:• Distinguish the rate of dihydropteroate synthase (DHPS) mutations among patients with Pneumocystis jirovecii pneumonia (PCP) in the current study
• Analyze patient characteristics associated with a higher rate of DHPS mutations
• Assess variables associated with sulfa resistance among cases of PCP in the current study
• Evaluate the effects of DHPS mutations on the risk of death among cases of PCP in the current study.
CME Editor
Jean Michaels Jones, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Jean Michaels Jones has disclosed no relevant financial relationships.CME Author
Charles P. Vega, MD, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.Authors
Disclosures: Meja Rabodonirina, MD, PhD; Laetitia Vaillant, MD; Patrick Taffé, PhD; Aimable Nahimana, PhD; René-Pierre Gillibert, PhD; and Philippe Hauser, PhD, have disclosed no relevant financial relationships. Philippe Vanhems, MD, PhD, has disclosed the following relevant financial relationships: received grants for clinical research from Sanofi Pasteur.CME ACTIVITY
Pneumocystis jirovecii Genotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia
Meja Rabodonirina, Laetitia Vaillant, Patrick Taffé, Aimable Nahimana, René-Pierre Gillibert, Philippe Vanhems, and Philippe M. Hauser
Suggested citation for this article Abstract
Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations have been associated with failure of sulfa prophylaxis; their effect on the outcome of patients with P. jirovecii pneumonia (PCP) remains controversial. P. jirovecii DHPS polymorphisms and genotypes were identified in 112 cases of PCP in 110 HIV-infected patients by using PCR single-strand conformation polymorphism. Of the 110 patients observed, 21 died; 18 of those deaths were attributed to PCP. Thirty-three percent of the PCP cases involved a P. jirovecii strain that had 1 or both DHPS mutations. The presence or absence of DHPS mutations had no effect on the PCP mortality rate within 1 month, whereas P.jirovecii type 7 and mechanical ventilation at PCP diagnosis were associated with an increased risk of death caused by PCP. Mechanical ventilation at PCP diagnosis was also associated with an increased risk of sulfa treatment failure at 5 days.Several investigators have reported an association between failure of prophylaxis when using sulfa drugs and substitutions of 2 aa within the putative sulfa binding site of DHPS at positions 55 (Thr to Ala, mutation M1) and 57 (Pro to Ser, M2) (1–4). These mutations were observed either as single (M1 or M2) or double (M3) mutation. This association strongly suggested that P. jirovecii DHPS mutations conferred a level of sulfa resistance sufficient to cause failure of anti-PCP prophylaxis. However, the mutations might have also conferred a clinically substantial resistance to sulfa treatment for overt PCP.
To investigate the issue, many studies have analyzed the effect of the mutations on the outcome of PCP. About half of those studies did not detect any association between the mutations and an increased risk of death caused by PCP (5–8) or a decreased response to sulfa drugs (3,9–11). Conversely, other studies detected an association with a poor outcome (12,13): sulfa treatment failure (14,15); more severe symptoms and need of assisted ventilation (13); or a trend for a worse prognosis (16). Thus, the effect of these mutations on PCP outcome is unclear and justifies investigation to improve PCP treatment and prognosis.
The possibility of other parameters influencing PCP outcome has also been explored. P. jirovecii genotype Ne of the internal transcribed spacers (ITSs) of the nuclear rRNA operon has been associated with milder disease (17), failure of PCP prophylaxis (18), and failure of PCP treatment (9). One ITS genotype observed in Australia was associated with reduced severity of PCP (13). Specific P. jirovecii genotypes defined by single-nucleotide polymorphisms in 3 loci were associated with low or high burden during the course of PCP (19). In comparison, some studies did not detect any associations between P. jirovecii genotypes, including Ne genotype, and several clinical parameters, such as severity and survival at 3 months (15,20). These observations suggested that some P. jirovecii genotypes might be more virulent or resistant to drugs, but further studies are needed to provide better understanding the issue.
We previously examined P. jirovecii DHPS polymorphisms in clinical specimens of 158 immunosuppressed patients from 5 hospitals in the city of Lyon in France (7). We detected an association between DHPS mutation M2 and failure of prophylaxis when pyrimethamine/sulfadoxine was used but not between DHPS mutations and death caused by PCP. In this study, we further observed the proportion of the organisms harboring DHPS mutations (36%) and of death attributed to PCP (20%) among these 158 patients. We investigated in more detail the effect of DHPS mutations on PCP prognoses, taking into account more clinical parameters. Moreover, to test the hypothesis of variable virulence of some P. jirovecii genotypes, we identified those present in the specimens. Because the disease signs and symptoms vary considerably between HIV-infected and HIV-uninfected patients, we limited our analyses to the HIV-infected patients.
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