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Original Research |

The Clinical Presentation of Fusobacterium-Positive and Streptococcal-Positive Pharyngitis in a University Health Clinic: A Cross-sectional StudyPresentation of Bacterial Pharyngitis in a University Health Clinic

Robert M. Centor, MD; T. Prescott Atkinson, MD, PhD; Amy E. Ratliff, MLS; Li Xiao, PhD; Donna M. Crabb, MT (ASCP); Carlos A. Estrada, MD, MS; Michael B. Faircloth, MD; Lisa Oestreich, DO; Jeremy Hatchett, MD; Walid Khalife, PhD; and Ken B. Waites, MD
[+] Article, Author, and Disclosure Information

From Huntsville Regional Medical Campus, University of Alabama at Birmingham, and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, and Sparrow Hospital, Lansing, Michigan.

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the U.S. Department of Veterans Affairs.

Acknowledgment: The authors thank the medical and nursing staff of the University of Alabama at Birmingham Student Health Clinic for their assistance in participant enrollment and specimen collection. They also thank the entire staff of the University of Alabama at Birmingham Student Health and Wellness Center for their hard work in contributing to data collection.

Financial Support: By the University of Alabama at Birmingham and the Justin E. Rodgers Foundation.

Disclosures: None. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1305.

Reproducible Research Statement:Study protocol: Available from Dr. Centor (e-mail, rcentor@uab.edu). Statistical code and data set: Available from Dr. Estrada (e-mail, cestrada@uab.edu).

Requests for Single Reprints: Robert M. Centor, MD, Professor, General Internal Medicine, Faculty Office Tower 720, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294-3407; e-mail, rcentor@uab.edu.

Current Author Addresses: Dr. Centor: Professor, General Internal Medicine, Faculty Office Tower 720, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294-3407.

Dr. Atkinson: Birmingham Children's Hospital, Children's Park Place M220, 1601 4th Avenue South, Birmingham, AL 35233.

Ms. Ratliff, Ms. Crabb, and Dr. Waites: Diagnostic Mycoplasma Laboratory, 1720 2nd Avenue South, SHEL 407, Birmingham, AL 35294.

Dr. Xiao: Diagnostic Mycoplasma Laboratory, 1720 2nd Avenue South, SHEL 476, Birmingham, AL 35294.

Dr. Estrada: Division of General Internal Medicine, University of Alabama at Birmingham, 732 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35294-3407.

Drs. Faircloth: University of Alabama at Birmingham Student Health and Wellness Center, 1714 9th Avenue South, Birmingham, AL 35294.

Dr. Oestreich: Assistant Professor, University of Alabama at Birmingham Student Health and Wellness Center, 1714 9th Avenue South, Birmingham, AL 35294.

Dr. Hatchett: 159 Moss Stone Lane, Calera, AL 35040.

Dr. Khalife: Department of Laboratories, Sparrow Hospital, 1215 East Michigan Avenue, Lansing, MI 48909.

Author Contributions: Conception and design: R.M. Centor, T.P. Atkinson, J. Hatchett, K.B. Waites.

Analysis and interpretation of the data: R.M. Centor, T.P. Atkinson, A.E. Ratliff, L. Xiao, D.M. Crabb, C.A. Estrada, W. Khalife, K.B. Waites.

Drafting of the article: R.M. Centor, T.P. Atkinson, C.A. Estrada, W. Khalife, K.B. Waites.

Critical revision of the article for important intellectual content: R.M. Centor, T.P. Atkinson, A.E. Ratliff, L. Xiao, D.M. Crabb, C.A. Estrada, M.B. Faircloth, L. Oestreich, K.B. Waites.

Final approval of the article: R.M. Centor, T.P. Atkinson, A.E. Ratliff, D.M. Crabb, C.A. Estrada, K.B. Waites.

Statistical expertise: C.A. Estrada.

Obtaining of funding: R.M. Centor.

Administrative, technical, or logistic support: R.M. Centor, T.P. Atkinson, A.E. Ratliff, L. Xiao, D.M. Crabb, K.B. Waites.

Collection and assembly of data: T.P. Atkinson, A.E. Ratliff, L. Xiao, D.M. Crabb, M.B. Faircloth, L. Oestreich, J. Hatchett, K.B. Waites.


Ann Intern Med. 2015;162(4):241-247. doi:10.7326/M14-1305
Text Size: A A A

Background: Pharyngitis guidelines focus solely on group A β-hemolytic streptococcal infection. European data suggest that in patients aged 15 to 30 years, Fusobacterium necrophorum causes at least 10% of cases of pharyngitis; however, few U.S. data exist.

Objective: To estimate the prevalence of F. necrophorum; Mycoplasma pneumoniae; and group A and C/G β-hemolytic streptococcal pharyngitis and to determine whether F. necrophorum pharyngitis clinically resembles group A β-hemolytic streptococcal pharyngitis.

Design: Cross-sectional.

Setting: University student health clinic.

Patients: 312 students aged 15 to 30 years presenting to a student health clinic with an acute sore throat and 180 asymptomatic students.

Measurements: Polymerase chain reaction testing from throat swabs to detect 4 species of bacteria and signs and symptoms used to calculate the Centor score.

Results: Fusobacterium necrophorum was detected in 20.5% of patients and 9.4% of asymptomatic students. Group A β-hemolytic streptococcus was detected in 10.3% of patients and 1.1% of asymptomatic students. Group C/G β-hemolytic streptococcus was detected in 9.0% of patients and 3.9% of asymptomatic students. Mycoplasma pneumoniae was detected in 1.9% of patients and 0 asymptomatic students. Infection rates with F. necrophorum, group A streptococcus, and group C/G streptococcus increased with higher Centor scores (P < 0.001).

Limitations: The study focused on a limited age group and took place at a single institution. Asymptomatic students—rather than seasonal control participants—and a convenience sample were used.

Conclusion: Fusobacterium necrophorum–positive pharyngitis occurs more frequently than group A β-hemolytic streptococcal–positive pharyngitis in a student population, and F. necrophorum–positive pharyngitis clinically resembles streptococcal pharyngitis.

Primary Funding Source: University of Alabama at Birmingham and the Justin E. Rodgers Foundation.

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Sore throat: avoid overcomplicating the uncomplicated and avoid undercomplicating the rare complicated.
Posted on March 4, 2015
Jan Matthys MD, Marc De Meyere MD, An De Sutter MD
dr. Matthys J, dr. De Meyere M and dr De Sutter A: Department of General Practice, University Hospital Gent, Belgium.
Conflict of Interest: None Declared
Dear editor,
We thank Robert Centor and colleagues for their interesting and important new data on causes of pharyngitis (1). As authors of the Belgian guideline on acute sore throat (2), we agree with the editorial of Jeffrey Linder (3), who argues that the new findings on Fusobacterium necrophorum are not a necessary condition to reconsider the American guidelines.

The proposition of Centor (1) implies more testing and more antibiotics, but is not based on evidence. Even a positive culture of Fusobacterium necrophorum is not a definitive proof of infection, and arguments are lacking that treating Fusobacterium necrophorum with antibiotics decreases symptoms or prevents the Lemierre syndrome (3). As for the Fusobacterium necrophorum culture, we know that a positive culture of GABHS is not definitive evidence of infection. Moreover, just like a positive culture for GABHS is not a proof of infection, but may as well indicate carriership, this may also be the case for a positive culture of Fusobacterium necrophorum.

Together with Linder we take notice of the very slow decrease in antibiotic prescribing for pharyngitis, but more encouraging is the fact that in the US, sore throat visits decreased from 7.5% of primary care visits in 1997 to 4.3% of visits in 2010 (4) without as far as we know an increase in (severe) complications .

More and more European guidelines consider acute sore throat as a self-limiting disease. (2) Antibiotics are prescribed immediately only when the patient has risk factors or decreased immunocompetence and in case of very ill patients (approximately 5%). When the patient does not improve within two or three days, the physical examination must be repeated to exclude a peritonsillar abscess and even Lemierre syndrome. It is the merit of Centor that with this publication, he helps the clinician to take the possibility of the feared Lemierre syndrome into consideration in the process of a scientific medical decision making.

1. Centor RM, Atkinson TP, Ratliff AE et al.The Clinical Presentation of Fuso-bacterium-Positive and Streptococcal-Positive Pharyngitis in a University Health Clinic: A Cross-sectional Study. Ann Intern Med. 2015;162:241-7. doi: 10.7326/M14-1305.
2. Matthys J, De Meyere M, van Driel ML, De Sutter A. Differences among international pharyngitis guidelines: not just academic. Ann Fam Med. 2007;5:436-43. Review.
3. Linder JA. Sore throat: avoid overcomplicating the uncomplicated. Ann Intern Med. 2015;162:311-2. doi: 10.7326/M14-2899.
4. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010.JAMA Intern Med. 2014;174:138-40. doi: 10.1001/jamainternmed.2013.11673.
Real-Time Fusobacterium necrophorum PCR, Throat Swabs
Posted on March 6, 2015
James R. Uhl, Daniel R. Gustafson, Stefanea L. Rucinski, Robin Patel
Mayo Clinic, Rochester, MN, 55905
Conflict of Interest: RP has received research funding from Accelerate, 3M, Actavis, Curetis, Cubist and nanoMR, has served as a consultant to Curetis, has patents on a method and apparatus for device sonication, an antibiofilm substance and Bordetella pertussis/parapertussis PCR, has received royalties from UpToDate and is an editor for the Journal of Clinical Microbiology.
We developed a real-time PCR assay for detection of Fusobacterium necrophorum in throat swabs; assay evaluation yielded findings that support and expand those of Centor et al. (3).
Between November 2010 and January 2011, 239 swabs submitted for Streptococcus pyogenes PCR (7), were tested for F. necrophorum using culture and PCR targeting ptsI using FRET hybridization probes. For PCR, swabs were cut into 50l 0.1mm glass beads and 600l TRIS buffer and processed using an Eppendorf ThermoMixer for 6min at 95C, 1400rpm. For culture, 5ml fastidious anaerobe broth with 1g/ml norfloxacin, 4g/ml vancomycin and 3g/ml josamycin was added to swab pledgets, incubated anaerobically at 37C for 2d, and sub-cultured to fastidious anaerobe agar plates with the same supplementation. Colonies consistent with F. necrophorum were identified by16S ribosomal RNA gene PCR/sequencing (2). Nine (4%) and 84 (35%) swabs were PCR-positive for F. necrophorum and S. pyogenes, respectively. Culture confirmed 8/9 F. necrophorum PCR-positive specimens. No F. necrophorum culture-positive, PCR-negative results were observed. The age of patients with F. necrophorum detected was 15-51years (average, 28years), while those with S. pyogenes detected were 2-72years, with 64% being 2-15years old. One subject was positive for both. Among subjects aged 0-14, 15-30 and 31-77years, 0/123 (0%), 4/42 (10%) and 4/73 (5%), respectively were positive for F. necrophorum. We tested throat swabs from 106 asymptomatic volunteers (Mayo Clinic employees) using F. necrophorum PCR and culture. Four (4%) were PCR-positive, of which one was culture-positive.

PCR can detect F. necrophorum in throat swabs faster than culture (1, 3). As with S. pyogenes, positive results occur in asymptomatic individuals. F. necrophorum was detected in a similar percentage of adolescents and young adults with presumed pharyngitis to that previously reported (4). In our opinion, a placebo-controlled evaluation of antibiotic treatment should be considered in adolescents and young adults with pharyngitis in whom F. necrophorum is detected to determine whether treatment affects duration and severity of symptoms, likelihood of progressing to Lemierre syndrome and/or peritonsillar abscess and contagiousness. The antimicrobial agent that should be evaluated is debatable. Between November 2011 and December 2014, susceptibility testing on 30 F. necrophorum isolates showed that 74% were susceptible to penicillin (MIC≤0.5µg/ml), whereas all were susceptible to metronidazole and clindamycin (≤8 and ≤2µg/ml, respectively).

Our data, derived from a Minnesota population, add to the evidence suggesting that F. necrophorum may cause pharyngitis (5, 6). Seasonality, why this organism is primarily found in adolescents and young adults, and whether treatment is indicated are unknown.
Adolescent and young adult sore throats are complicated
Posted on April 2, 2015
Robert M. Centor, MD, Prescott Atkinson, MD, Ken B. Waites, MD
University of Alabama at Birmingham
Conflict of Interest: None Declared
We thank Dr. Matthys and colleagues for their comment concerning our paper - The Clinical Presentation of Fusobacterium-Positive and Streptococcal-Positive Pharyngitis in a University Health Clinic: A Cross-sectional Study. We do believe that Fusobacterium necrophorum both causes adolescent and young adult pharyngitis and deserves antibiotic treatment.

While the evidence is circumstantial, we believe antibiotics would be prudent. The Lemierre Syndrome is a devastating disease that has an estimated death rate of 5% with very significant short term and long-term morbidity.(1) Chirinos reported that Fusobacterium necrophorum causes approximately 80% of the Lemierre Syndrome.(2) In most patients, the syndrome occurs a few days after developing a sore throat.

We have strong evidence that Fusobacterium necrophorum causes pharyngitis. Several European studies showed an association of the organism with pharyngitis. We reported a summary of 6 patients who had pharyngitis and Fusobacterium necrophorum bacteremia but without internal jugular thrombophlebitis.(3) Our current report shows that as the Centor score increased, the probability of a positive PCR for Fusobacterium necrophorum increased.

While we cannot prove that Fusobacterium necrophorum pharyngitis precedes the Lemierre Syndrome, the circumstantial evidence makes that postulate highly likely. While we cannot prove that treating Fusobacterium necrophorum pharyngitis with appropriate antibiotics would decrease the probability of the Lemierre Syndrome, the biological plausibility seems high.

Since we estimate that 1 in 400 Fusobacterium necrophorum pharyngitis(1), a randomized controlled trial would take over 10,000 patients to prove that we can prevent the Lemierre Syndrome. In such a trial, approximately 12 or 13 patients would develop the Lemierre Syndrome. We believe that one could legitimately question the ethics of this proposed trial.

Does this mean that we would need to treat a large number of patients with antibiotics? We reiterate that this bacterium rarely causes pharyngitis in pre-adolescents – and Dr. Uhl and colleagues confirm this in their comment. We hope to have a rapid test in the future, but in the meantime would favor empiric treatment of 50% of adolescent and young adult pharyngitis, because we believe the Lemierre Syndrome deserves prevention.

We agree with Dr. Uhl and colleagues that we should collect much more epidemiologic data on this organism in adolescent and young adult pharyngitis patients. We do not favor a randomized control trial, as the Lemierre Syndrome often presents with devastating metastatic infections.



1. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009 Dec 1;151(11):812–5.
2. Chirinos JA, Lichtstein DM, Garcia J, Tamariz LJ. The evolution of Lemierre syndrome: report of 2 cases and review of the literature. 2002 Nov 1;81(6):458–65.
3. Centor RM, Geiger P, Waites KB. Fusobacterium necrophorum bacteremic tonsillitis: 2 Cases and a review of the literature. Anaerobe. 2010 Dec;16(6):626–8.
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