---------------------------------------------------------------------------
 Emerging Infectious Diseases * Volume 3 * Number 1 * January-March 1997
---------------------------------------------------------------------------
 
Dispatches

Exudative Pharyngitis Possibly Due to Corynebacterium pseudodiphtheriticum,
a New Challenge in The Differential Diagnosis of Diphtheria

---------------------------------------------------------------------------

      Corynebacterium pseudodiphtheriticum has rarely been reported
      to cause disease in humans, despite its common presence in the
      flora of the upper respiratory tract. We report here a case of
      exudative pharyngitis with pseudomembrane possibly caused by
      C. pseudodiphtheriticum in a 4-year-old girl. The case
      initially triggered clinical and laboratory suspicion of
      diphtheria. Because C. pseudodiphtheriticum can be easily
      confused with Corynebacterium diphtheriae in Gram stain,
      clarification of its role in the pathogenesis of exudative
      pharyngitis in otherwise healthy persons is of public health
      importance. Simple and rapid screening tests to differentiate
      C. pseudodiphtheriticum from C. diphtheriae should be
      performed to prevent unnecessary concern in the community and
      unnecessary outbreak control measures.

Among the pathogenic nondiphtheria corynebacteria, Corynebacterium
pseudodiphtheriticum has rarely been reported to cause disease in humans,
despite its frequent presence in the flora of the upper respiratory tract
(1,2). C. pseudodiphtheriticum was first isolated in humans by Von
Hoffmann-Wellenhof from the throat of a patient in 1888 (2). The organism
exhibits little pleomorphism. It appears as short gram-positive rods that
often lie in parallel rows on smear preparation. We report here a case of
exudative pharyngitis in a 4-year-old girl with a pseudomembrane possibly
caused by C. pseudodiphtheriticum, which initially triggered suspicion of
diphtheria, and provide a summary of previously published case reports.

Case Report

On November 6, 1994, a 4-year-old girl was admitted to the Emergency Room
of St. Mary's Hospital in Rogers, Arkansas, with fever and generalized
lymphadenopathy. Two other children in her home day care, including the
patient's sibling, also had lymph node enlargement and fever. Her mother
reported that the patient had not been immunized against any of the common
childhood diseases but had an unremarkable medical history, with the
exception of hand-foot-and-mouth disease at 3 years of age; she had never
received antibiotics. Her developmental milestones were achieved on time.
The family included the patient, her mother, father, and a 3-year-old
sibling.

The patient's posterior pharynx was erythematous with swelling of the
posterior palate and with a thick grayish white membranous exudate adhering
to the posterior wall of the pharynx. The pseudomembrane had almost
completely detached and was gone, leaving behind ulcerated tissue. A
discrete adenopathy in the neck and palpable nodes in the axillary,
epitrochlear, and inguinal regions were observed.

The initial white blood cell count was 7,000 per ml, with 50%
polymorphonuclear cells and 17% lymphocytes. A rapid screening test for
group A streptococci and a Paul-Bunnell test for Epstein- Barr virus had
negative results. Routine throat and nasopharyngeal swabs were collected
and submitted to the hospital's clinical microbiology laboratory, where
they were injected into blood agar and blood chocolate agar (special media
for diphtheria culture were unavailable). From the throat swab, there was
light growth of Streptococcus pneumoniae and light growth of gram-positive
rods; a mixture of normal flora was also present. Gram-positive rods were
also isolated from the nasopharyngeal swab. Subsequently, when subcultured
on cystine-tellurite agar, these gram-positive rods grew as black colonies.
Subcultures were then sent to the state laboratory, which confirmed them as
C. pseudodiphtheriticum. After ambulatory treatment with cefprozil and
erythromycin, the patient recovered in 4 days.

  Investigation of Contacts
Because of its resemblance with C. diphtheriae, a C. pseudodiphtheriticum
isolate was not immediately identified, and the case was initially thought
to be diphtheria. Consequently, 36 children and adults who had recently
been in contact with the patient in day care, at the fitness center, or at
the church were cultured for diphtheria. C. diphtheriae was not found, but
C. pseudodiphtheriticum was found in the patient's 3-year-old sibling and
in three additional persons: a 1-year-old girl and her 3-year-old brother,
who lived in the same building as the patient and shared her day care, and
a 54-year-old woman who attended the same church.

  Microbiology and Molecular Characterization
The C. pseudodiphtheriticum isolate from the initial patient was forwarded
to the Centers for Disease Control and Prevention (CDC), where it was
assayed by phenotypic and genotypic methods. The identification was
confirmed on the basis of growth characteristics and biochemical
properties. The isolate was assayed by polymerase chain reaction (PCR),
which detects 248 base pair fragments of the A subunit of the diphtheria
toxin gene (3), and the result was negative. Additional PCR assays were
performed with 12 sets of primers that cover the entire diphtheria toxin
gene (tox) and diphtheria toxin regulatory element (dtxR); 560 base pairs
of the dtxR were detected. However, the PCR results of its five prime and
three prime ends were negative, indicating that the gene was nonfunctional.

Previous Case Reports 1

Since 1932, only 83 cases of disease possibly caused by C.
pseudodiphtheriticum in humans have been reported. Until 1981, the only
reported disease associated with this organism was endocarditis in the
presence of anatomic abnormalities of the heart. Since then, this organism
has been increasingly recognized as a pathogen of the lungs and bronchi,
particularly in patients with underlying immunosuppressive conditions and
preexisting pulmonary diseases and in patients undergoing endotracheal
intubation.

Among reported cases, 19 were endocarditis (4-17); 61 involved infections
of the lungs, trachea, or bronchi (18-32); one was a urinary tract
infection (33); one involved a skin infection (34); and one was a vertebral
discitis (35). All but three patients had underlying medical conditions,
including functional or anatomic abnormalities of the heart (N=27), lung
and tracheobronchial diseases (N=28), endotracheal intubations (N=3), and
immunosuppressive conditions including prolonged steroid use (N=6) and AIDS
(N=4).

Most patients showed good clinical response to various antimicrobial drugs:
penicillin, ampicillin, cefazolin, vancomycin, gentamicin, tobramycin,
norfloxacin, and others. Nineteen (23%) deaths were reported overall.
Information on sex was available for 80 cases; 54 (68%) were in males. Only
five (6%) cases occurred in children <18 years of age; no cases were
reported among children <5 years of age.

      1 A table listing all published case reports is available upon
      request from Dr. Hector Izurieta, Mail Stop A32, Centers for
      Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA
      30333.

Since the early 1990s, diphtheria has returned in epidemic proportions in
the former Soviet Union and is likely to be imported into other countries.
Two cases of exudative upper respiratory tract infections with a
pseudomembrane, in which the main organism isolated was C.
pseudodiphtheriticum, have been reported. The first case was in a
54-year-old man with necrotizing tracheitis in 1991 (32). Santos et al.
(36) reported isolation of C. pseudodiphtheriticum from a 32-year-old male
Uzbek national who had a severe sore throat and dysphagia of 2 days
duration. His tonsils were enlarged bilaterally, and a grayish-white
exudate extended from the tonsil to the posterior pharyngeal wall. The
uvula and soft palate were erythematous and edematous, and tender cervical
lymphadenopathy was present. The presumptive clinical diagnosis in this
patient was respiratory diphtheria.

Although the presence of a grayish pseudomembrane in the upper respiratory
tract associated with isolation of C. pseudodiphtheriticum in these two
cases and in the case we described is not proof that the isolated
corynebacterium caused the pharyngitis or tracheitis, these accumulating
case reports suggest that C. pseudodiphtheriticum may have played a
pathogenic role.

The isolate from our patient was nontoxigenic by PCR. The diphtheria toxin
is considered to be the main virulence factor of C. diphtheriae that causes
the formation of the pseudomembrane in faucial diphtheria (37). Several
possibilities could explain the presence of a pseudomembrane in infections
with nontoxigenic corynebacterium strains. First, toxigenic and
nontoxigenic colonies of the same species can coexist in a patient; this
phenomenon has been reported in diphtheria (38). Multiple colonies would
have to be tested to confirm this hypothesis in this case. Second,
nontoxigenic forms of C. diphtheriae can produce invasive disease (39,40).
It is possible that the symptoms in our patient were caused by a
nontoxigenic C. pseudodiphtheriticum and that the pseudomembrane was simply
an inflammatory exudate. This has been reported for Arcanobacterium
haemoliticum (formerly Corynebacterium haemoliticum), which has also been
associated with production of a grayish pharyngeal pseudomembrane (41,42).
In 1960, Barksdale et al. reported a pseudomembrane in two laboratory
workers contaminated with known nontoxigenic forms of C. diphtheriae (43).
Third, we cannot exclude the possibility that the symptoms were caused by
other organisms, including S. pneumoniae, which was found in the throat
culture of our patient (29). However, this is unlikely because the growth
of S. pneumoniae in our patient's throat culture was light, and the
organism was not found in the nasopharyngeal swab. Furthermore, S.
pneumoniae has not been reported to produce a pseudomembrane (44,45).

Because several other Corynebacterium spp. have been identified as
potentially pathogenic for humans, routine screening for C. diphtheriae and
other members of the Corynebacterium spp. in clinical samples of patients
with respiratory infections should be encouraged (46). Full identification
of gram-positive rods isolated from the respiratory tract, especially when
they appear on original plates as the predominant organisms or
copredominant with another species, should be carried out at the local,
state, or reference level. Simple screening tests, such as negative
cysteinase and positive pyrazinamidase, in addition to inability to ferment
glucose, maltose, and sucrose quickly differentiate C. pseudodiphtheriticum
from C. diphtheriae. These tests should be a part of improved training of
laboratory personnel. Clinical and laboratory experience gained through
this process will not only provide information about death rates for these
organisms, but would be invaluable in preventing unnecessary concern in the
community and the extraordinary measures needed to control dissemination of
diphtheria.

Acknowledgments

We acknowledge Drs. Cynthia Whitman and Rosalind Carter, New York City
Department of Health, and Dr. Robert S. Holzman, New York University
Medical Center, for sharing information regarding a suspected case of
diphtheria in New York; and Elizabeth Laborde, Alabama State Health
Department's Laboratory, and Mary Beth Young, St. Mary's Hospital
laboratory, Rogers, Arkansas, for sharing information regarding cultures
for C. pseudodiphtheriticum.

Hector S. Izurieta,* Peter M. Strebel,* Thomas Youngblood, Dannie G.
Hollis,* and Tanja Popovic*
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Rogers
Pediatric Clinic, Rogers, Arkansas, USA

References

  1. Clarridge JE, Speigel CA. Corynebacterium, and miscellaneous irregular
     gram-positive rods, Erysipelothrix, and Gardnerella. In: Manual of
     clinical microbiology, 6th ed. Murray PR, Baron EJ, Pfaller MA,
     Tenover FC, Yolken RH, editors. Washington (DC): American Society for
     Microbiology, 1995:357-78.
  2. Austrian R. Streptococcus pneumoniae. In: Gorbach SL, Bartlett JG,
     Blacklow NR, editors. Infectious Diseases. Philadelphia: W.B. Saunders
     Company, 1992:1412-15.
  3. Mikhailovich VM, Melnikov VG, Mazurova IK, Wachsmuth IK, Wenger JD,
     Wharton M, et al. Application of PCR for detection of toxigenic
     Corynebacterium diphtheriae strains isolated during the Russian
     diphtheria epidemic, 1990 through 1994. J Clin Microbiol 1995;3061-3.
  4. Tow A, Wechsler HF. Diphtheroid bacillus as the cause of acute
     endocarditis. American Journal of Diseases of the Child
     1932;44:156-61.
  5. Olinger MG. Mixed infections in subacute bacterial endocarditis:
     report of two cases. Arch Intern Med 1948;81:334-41.
  6. Morris A, Guild I. Endocarditis due to Corynebacterium
     pseudodiphtheriticum: five case reports, review, and antibiotic
     susceptibilities of nine strains. Reviews of Infectious Diseases
     1991;13:887-92.
  7. Johnson WD, Kaye D. Serious infections caused by diphtheroids. Ann NY
     Acad Sci 1970;174:568-76.
  8. Rubler S, Harvey L, Avitabile A, Abenavoli T. Mitral valve obstruction
     in a case of bacterial endocarditis due to Corynebacterium hofmannii:
     echocardiographic diagnosis. New York State Journal of Medicine.
     1982;82:1590-4.
  9. Wilson ME, Shapiro DS. Native valve endocarditis due to
     Corynebacterium pseudodiphtheriticum. Clin Infect Dis 1992;15:1059-60.
 10. Barrit DW, Gillespie WA. Subacute bacterial endocarditis. BMJ
     1960;1:1235-9.
 11. Blount JG. Bacterial endocarditis. Am J Med 1965;38:909-22.
 12. Johnson WD, Cobbs CG, Arditi LI, Kaye D. Diphtheroid endocarditis
     after insertion of prosthetic heart valve: report of two cases. JAMA
     1968;203:919-21.
 13. Boyce JMH. A case of prosthetic valve endocarditis caused by
     Corynebacterium hofmannii and Candida albicans. British Heart Journal
     1975;37:1195-7.
 14. Wise JR, Bentall HH, Cleland WP, Goodwin JF, Hallidie-Smith KA, Oakley
     CM. Urgent aortic-valve replacement for acute aortic regurgitation due
     to infective endocarditis. Lancet 1971;2:115-21.
 15. Leonard A, Raij L, Shapiro FL. Bacterial endocarditis in regularly
     dialyzed patients. Kidney Int 1973;4:407-22.
 16. Lindner PS, Hardy DJ, Murphy TF. Endocarditis due to Corynebacterium
     pseudodiphtheriticum. New York State Journal of Medicine
     1986;86:102-4.
 17. Cauda R, Tamburrini E, Venture G, Ortona L. Effective vancomycin
     therapy for Corynebacterium pseudodiphtheriticum endocarditis
     (letter). South Med J 1987;80:1598.
 18. Donaghy M, Cohen J. Pulmonary infection with Corynebacterium hofmannii
     complicating systemic lupus erythematosus. J Infect Dis 1983;147:962.
 19. Miller RA, Rompalo A, Coyle MB. Corynebacterium pseudodiphtheriticum
     pneumonia in an immunologically intact host AIDS patients. Lancet
     1992;340:114-5.
 20. Cimolai N, Rogers P, Seear M. Corynebacterium pseudodiphtheriticum
     pneumonitis in a leukaemic child. Thorax 1992;47:838-9.
 21. Roig P, Lpez MM, Arriero JM, Cuadrado JM, Martn C. Neumona por
     Corynebacterium pseudodiphtheriticum en paciente diagnosticado de
     infeccin por VIH. An Med Interna 1993;10:499-500.
 22. Douat N, Labbe M, Glupczynski G. Corynebacterium pseudodiphtheriticum
     pneumonia in an anthracosilicotic man. Clinical Microbiology
     Newsletter 1989;11:189-90.
 23. Andavolu RH, Venkita J, Lue Y, McLean T. Lung abcess involving
     Corynebacterium pseudodiphtheriticum in a patient with AIDS-related
     complex. New York State Journal of Medicine 1986;86:594-6.
 24. Cohen Y, Force G, Grox I, Canzi AM, Lecleach L, Dreyfuss D.
     Corynebacterium pseudodiphtheriticum pulmonary infection in AIDS
     patients. Lancet 1992;340:114-5.
 25. Yoshitomi Y, Higashiyama Y, Matsuda H, Mitsutake K, Miyazaki Y,
     Maesaki S, et al. Four cases of respiratory infections caused by
     Corynebacterium pseudodiphtheriticum. Kansenshogaku Zasshi-Journal of
     the Japanese Association for Infectious Diseases 1992;66:87-92.
 26. Rikitomi N, Nagatake T, Matsumoto K, Watanabe K, Mbaki N. Lower
     respiratory tract infections due to nondiphtheria corynebacteria in 8
     patients with underlying lung disease. Tohoku J Exp Med
     1987;153:313-25.
 27. Freeman JD, Smith HJ, Haines HG, Hellyar AG. Seven patients with
     respiratory infections due to Corynebacterium pseudodiphtheriticum.
     Pathology 1994;26:311-4.
 28. Manzella JP, Kellogg JA, Parsey KS. Corynebacterium
     pseudodiphtheriticum: a respiratory tract pathogen in adults. Clin
     Infect Dis 1995;20:37-40.
 29. Ahmed K, Kawakami K, Watanabe K, Mitsushima H, Nagatake T, Matsumoto
     K. Corynebacterium pseudodiphtheriticum: a respiratory tract pathogen.
     Clin Infect Dis 1995;20:41-6.
 30. Craig TJ, Maguire FE, Wallace MR. Tracheobronchitis due to
     Corynebacterium pseudodiphtheriticum. South Med J 1991;84:504-6.
 31. Williams EA, Green JD, Salazar S. Pneumonia caused by Corynebacterium
     pseudodiphtheriticum. J Tenn Med Assoc1991;84:223-4.
 32. Colt HG, Morris JF, Marston BJ, Sewell DL. Necrotizing tracheitis
     caused by Corynebacterium pseudodiphtheriticum: unique case and
     review. Reviews of Infectious Diseases 1991;13:73-6.
 33. Nathan AW, Turner DR, Aubrey C, Cameron JS, Williams DG, Ogg CS, et
     al. Corynebacterium hofmannii infection after renal transplantation.
     Clin Nephrol 1982;17:315-8.
 34. Lockwood BM, Wilson J. Corynebacterium pseudodiphtheriticum isolation.
     Clinical Microbiology News 1987;9:5-6.
 35. Wright ED, Richards AJ, Edge AJ. Discitis caused by Corynebacterium
     pseudodiphtheriticum following ear, nose and throat surgery. Br J
     Rheumatol 1995;34:585-6.
 36. Santos MR, Gandhi S, Vogler M, Hanna BA, Holzman RS. Suspected
     diphtheria in an Uzbek nacional: isolation of C. pseudodiphtheriticum
     resulted in a false positive presumptive diagnosis. Clin Infect Dis
     1996;22:735.
 37. Fontanarosa PB. Diphtheria in Russia a reminder of risk. JAMA
     1995;273:1245.
 38. Simmons LE, Abbot JD, Macaulay ME. Diphtheria carriers in Manchester:
     simultaneous infection with toxigenic and nontoxigenic mitis strains.
     Lancet 1980;2:304-5.
 39. Tiley SM, Kociuba KR, Heron LG, Munro R. Infective endocarditis due to
     nontoxigenic Corynebacterium diphtheriae: a report of seven cases and
     review. Clin Infect Dis 1993;16:271-5.
 40. Efstratiou A, Tiley SM, Sangrador A, Greenacre E, Cookson BD, Chen
     SCA, et al. Invasive disease caused by multiple clones of
     Corynebacterium diphtheriae. Clin Infect Dis 1993;17:136.
 41. Kain KC, Noble MA, Barteluck RL, Tubbesing RH. Arcanobacterium
     hemoliticum infection: confused with scarlet fever and diphtheria. J
     Emerg Med 1991;9:33-5.
 42. Robson JMB, Harrison M, Wing LW, Taylor R. Diphtheria: may be not!
     Communicable Disease Intelligence1996;20:64-6.
 43. Barksdale L, Garmise L, Horibata K. Virulence, toxinogeny, and
     lysogeny in Corynebacterium diphtheriae. Ann NY Acad Sci
     1960;88:1093-108.
 44. Austrian R. Streptococcus pneumoniae. In: Gorbach SL, Bartlett JG,
     Blacklow NR, editors. Infectious Diseases. Philadelphia: W.B. Saunders
     Company 1992:1412-15.
 45. Feery BJ, Forsell P, Gulasekharam J. Streptococcal sore throat in 
     general practice--a controlled study. Med J Aust 1976;1:989-91.
 46. Clarridge JE. When, why and how far should coryneforms be identified? 
     Clinical Microbiology Newsletter 1986;8:32-4. 

---------------------------------------------------------------------------

Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA