Emerging Infectious Diseases
[Volume 5 No.5 / September - October 1999]

Letters

A Case of Corynebacterium pseudodiphtheriticum
Nosocomial Pneumonia

To the Editor: Corynebacterium pseudodiphtheriticum
has seldom been isolated from patients with upper
respiratory tract infections and pneumonia. Most
reported infections are community acquired and occur
in patients with underlying disease and
immunosuppression (1). We report a case characterized
by hospital-acquired pneumonia in a debilitated
patient. Review of the literature indicates that C.
pseudodiphtheriticum should be regarded an emerging
pathogen.

On April 1, 1998, a 68-year-old woman was admitted to
the intensive care unit for acute respiratory
distress. She had a 14-month history of amyotrophic
lateral sclerosis. Three weeks before admission, she
had been hospitalized for Staphylococcus aureus
pneumonia and had recovered after treatment with
amoxicillin and clavulanic acid plus ciprofloxacin. At
the time of admission, the patient had a temperature
of 38C. Systolic blood pressure was 120 mm Hg.
Ventilation was spontaneous, with respirations 24 per
minute; pulmonary sibilants were noted. Respiratory
acidosis was also identified, with a pH of 7.35, SaO2
92%, PaO2 60 mm Hg, and PaCO2 60 mm Hg. Laboratory
data included 18,000 leukocytes per ml (90%
polymorphonuclear cells) and a serum fibrin level of 7
g/L. A chest X-ray showed pneumopathy of the lower
segment of the right lung, which was compatible with
the diagnosis of inhalation pneumopathy. On day 2 of
admission, the patient's temperature was 39C, and she
had paresis of the vocal cords. After C.
pseudodiphtheriticum infection was diagnosed,
treatment with intravenous cloxacillin (l g 3
times/day) and amoxicillin plus clavulanic acid (l g 3
times/day) was started. On day 3 after admission, the
patient's breathing worsened, a radiograph showed
bilateral pneumopathy, and she was intubated for
mechanical ventilation. Two days later, her breathing
improved, and a second bronchic aspiration was
sterile. The patient eventually died of unrelated
complications.

Direct microscopy examination of a Gram-stained
bronchial aspiration sample showed numerous
polymorphonuclear cells and gram-positive bacilli in
parallel rows, which did not show pleomorphism. After
48 hours of incubation at 37C, 10(sup 6) colony-forming
units/ml of a coryneform bacillus further identified
as C. pseudodiphtheriticum grew in pure culture on
blood agar gelose (BioMrieux, La Balme les Grottes,
France) under a 5% CO2 atmosphere and did not produce
hemolysis. The test for catalase was positive, and the
following biochemical characteristics were obtained by
using a commercial identification strip (ApiCoryne,
BioMrieux): absence of carbohydrate fermentation,
urea hydrolysis, and nitrate reduction compatible with
C. pseudodiphtheriticum. Minimum inhibitory
concentrations (disk diffusion method) were 2 mg/L for
amoxicillin, 2 mg/L for cefalotin, 0.09 mg/L for
doxycycline, 0.03 mg/L for gentamicin, <4 mg/L for
vancomycin, 16 mg/L for erythromycin, and 20 mg/L for
trimethoprim-sulfamethoxazole. Identification was
confirmed by analysis of the cell-wall fatty acid
profile by the Sherlock system, by the trypticase soy
broth agar database 3.9 (MIDI Inc., Newark, DE), and
by 16S rRNA sequence analysis under previously
described conditions (2). The 16S rRNA gene sequence
was compared with all eubacterial 16S rRNA sequences
available in the GenBank database by using the
multisequence comparison Advanced Blast NCBI. The
sequence had a 99% similarity to that of C.
pseudodiphtheriticum (1039/1047 base pairs).

Eighty-nine cases of infection possibly caused by C.
pseudodiphtheriticum have been identified in the last
57 years. Of these, 57 (62.9%) were upper respiratory
infections, which included rhinosinusitis, tracheitis,
tracheobronchitis, and bronchitis; 19 (21.3%) were
pneumonia (3-7). Ten (11.2%) cases of endocarditis
were reported (8); there was also one case each of
urinary tract malakoplakia after renal transplantation
(9), lung abcess (10), diskitis (11), and
lymphadenitis (12).

Unlike C. diphtheriae, C. pseudodiphtheriticum is a
commensal bacterium that does not produce toxins and
needs predisposing factors to become a pathogen
causing pneumonia. Of patients with hospital-acquired
C. pseudodiphtheriticum upper respiratory tract
infections and pneumonia (7 of 26 upper respiratory
tract infections and 2 of 14 cases of pneumonia
reported in the early 1990s), all had underlying
pathologic features. Predisposing factors were as
follows: 33.7% had lung and tracheobronchial diseases,
including chronic obstructive pulmonary disease,
angina (5), chronic emphysema, asthma, and bronchitis
(6); 32.5% had congestive heart failure (5). Of those
with immunodepression, 5% had AIDS, 7.2% had undergone
chemotherapy or prolonged steroid use; and 18.2% had
other pathologic features, disseminated intravascular
coagulation (6), chronic renal failure, diabetes
mellitus (5), and connective tissue disease (5,6).

The first source of pneumonia is usually inhalation,
as was the case for our patient, who had paresis of
the vocal cords. She was not immunosuppressed but was
debilitated by amyotrophic lateral sclerosis. The
second factor is often an endotracheal intubation, as
reported in a previously healthy 29-year-old trauma
victim who contracted pneumonia due to C.
pseudodiphtheriticum after 7 days of intubation (7).
An increase in cases reported from 1932 to 1998
indicates the emergence of infections due to C.
pseudodiphtheriticum. Thirty-four cases were reported
from 1932 to 1989 (57 years), and 55 cases were
reported from 1990 to 1998 (8 years). Reasons for the
emergence of C. pseudodiphtheriticum infections may
include confusion between C. diphtheriae and C.
pseudodiphtheriticum infections. For example, two
cases of C. pseudodiphtheriticum exudative upper
respiratory tract infections with a pseudomembrane
were first diagnosed as respiratory diphtheria. In the
first case, C. pseudodiphtheriticum was isolated from
a 32-year-old Uzbek man who had a severe sore throat
and dysphagia lasting 2 days (3). In a second case, a
4-year-old girl had exudative pharyngitis with a
pseudomembrane, which was possibly caused by C.
pseudodiphtheriticum (4). The availability of
commercial strips for the identification of C.
pseudodiphtheriticum and 16S rRNA sequencing
eliminates such confusion.

Ccile Martaresche, Pierre-Edouard Fournier, Vronique
Jacomo, Marc Gainnier, Alain Boussuge, and Michel
Drancourt

Hpital Salvator, Assistance Publique-Hpitaux de
Marseille, Marseille, France

References

1. Brown AE. Other Corynebacteria and Rhodococcus. In:
Mandell GL, Bennett JE, Dolin R, editors. Principles
and practice of infectious diseases. 4th ed. New York:
Churchill Livingstone; 1995. p. 1874.

2. Weisburg WC, Barns SM, Pelletier DA, Lane DJ. 16S
ribosomal DNA amplification for phylogenetic study. J
Bacteriol 1991;173:697-703.

3. Santos MR, Ghandi S, Vogler M, Hanna BA, Holzman
RS. Suspected diphtheria in a Uzbek national;
isolation of C. pseudodiphtheriticum resulted in a
false positive presumptive diagnosis. Clin Infect Dis
1996;22:735.

4. Izurieta HS, Strebel PM, Youngblood T, Hollis DG,
Popovic T. Exudative pharyngitidis possibly due to C.
pseudodiphtheriticum, a new challenge in the
differential diagnosis of diphtheria. Emerg Infect Dis
1997;3:65-8.

5. Manzella JP, Kellog JA, Parsey KS. Corynebacterium
pseudodiphtheriticum: a respiratory tract pathogen in
adults. Clin Infect Dis 1995;20:37-40.

6. Ahmed K, Kawakami K. Corynebacterium
pseudodiphtheriticum: a respiratory tract pathogen.
Clin Infect Dis 1995;20:41-6.

7. Miller RA, Rompalo A, Coyle MB. Corynebacterium
pseudodiphtheriticum pneumonia in an immunologically
intact host. Diagn Microbiol Infect Dis 1986;4:165-71.

8. Wilson ME, Shapiro DS. Native valve endocarditis
due to Corynebacterium pseudodiphtheriticum. Clin
Infect Dis 1992;15:1059-60.

9. Nathan AW, Turner DR, Aubrey C, Cameron JS,
Williams DJ, Ogg CS, et al. Corynebacterium hofmannii
infection after renal transplantation. Clin Nephrol
1982;17:315-8.

10. Andavolu RH, Venkita J, Lue Y, McLean T. Lung
abscess involving Corynebacterium pseudodiphtheriticum
in a patient with AIDS-related complex. New York State
Journal of Medicine 1986;86:594-6.

11. Wright ED, Richards AJ, Edje AJ. Discitis caused
by Corynebacterium pseudodiphtheriticum following ear,
nose and throat surgery. Br J Rheumatol 1995;34:585-6.

12. LaRocco M, Robinson C, Robinson A. Corynebacterium
pseudodiphtheriticum associated with suppurative
lymphadenitis. European Journal of Clinical
Microbiology 1987;6:79.

Family Outbreak of Rickettsia conorii Infection

To the Editor: Over a 15-day period, three young siblings were
separately taken to an emergency room in Israel, with symptoms
suggesting a contagious viral illness (fever, maculopapular rash,
hepatosplenomegaly, lymphadenopathy, neutropenia, and
thrombocytopenia). None of the children had been in direct contact
with animals. Specific immunoglobulin (IgM) immunofluorescence assay
(IFA) 7 to 8 days after admission of each child confirmed the
diagnosis of Rickettsia conorii infection.

Spotted fever is the generic name given to a variety of tickborne
rickettsial diseases distributed worldwide. In Mediterranean
countries, including Israel, spotted fever is caused by members of
the R. conorii complex. Spotted fever has been endemic in Israel for
more than 40 years, with several hundred cases reported annually. In
1997, two fatal cases were reported (1). Spotted fever is caused by
a variant member of R. conorii, which is transmitted by the dog tick
Rhipicephalus sanguineous (2,3). The disease has a broad spectrum of
clinical signs, from asymptomatic to fatal (4,5). Symptoms and signs
include fever, headache, vomiting, myalgia, conjunctivitis, and a
typical maculopapular or purpuric rash. The tache noir at the site
of the tick bite, which is found in patients in Europe, is seldom,
if ever, seen in Israel.

The first patient, a 6-year-old boy, was taken to the pediatric
emergency room with high fever and a diffuse rash, approximately 1
week after visiting a cousin who had similar complaints. Physical
examination showed temperature of 40C, chills, diffuse
maculopapular rash all over the body, including the hands and feet,
hepatosplenomegaly, and lymphadenopathy. Blood tests showed
neutropenia, thrombocytopenia, and hyponatremia. Because Rickettsia
was included in the differential diagnosis, immunofluorescent assay
(IFA) for Rickettsia was performed and intravenous doxycycline (2
mg/kg/day) was initiated. One week later, the boy's 8-month-old
sister was brought to the emergency room with similar complaints,
and 2 days afterwards his 2-year-old sister began to have the same
symptoms. A detailed history revealed that all children had played
on a lawn frequented by dogs.

All three siblings had fever, chills, and diffuse maculopapular rash
all over the body, including the hands and feet. An IgM IFA test for
R. conorii from the first child was negative on the day of admission
and became positive 8 days later. On the day of the boy's hospital
discharge, his 8-month-old sister was taken to the emergency room.
Her serology test was negative on admission but became positive 7
days later. The third (2-year-old) sibling's first blood test was
negative, and the family did not agree to a second blood test. All
three children responded well to doxycycline (2 mg/kg/day, with a
double dose the first day) for 5 to 7 days. Most symptoms subsided
within 48 hours.

Spotted fever is usually a sporadic illness and is not spread from
person to person. Clusters of cases have been reported. Yagupsky
reported spotted fever in Israel in a few children living near each
other in an agricultural settlement (6). A report from the Delaware
Division of Public Health described a group of children who had been
camping together where contact with ticks was likely (7). This case
illustrates that spotted fever may be acquired even without direct
contact with animals, through exposure to ticks in places frequented
by infected animals. Our report suggests that Rickettsial illness
should be considered in the differential diagnosis of fever with
rash in disease-endemic areas, even if the timing of similar
complaints in several family members suggests a contagious viral
illness.

G. Shazberg, J. Moise, N. Terespolsky, and H. Hurvitz
Bikur Cholim General Hospital, Jerusalem, Israel

References

1. Spotted fever. Jerusalem, Israel: Ministry of Health, Department
of Epidemiology; 1997.

2. Goldwasser RA, Steiman Y, Klinberg W, Swartz TA, YJingberg MA.
The isolation of strains of Rickettsiae of the spotted fever group
in Israel and their differentiation from other members of the group
by immunofluorescence methods. Scand J Infect Dis 1974;6:53-62.

3. Manor E, Ighbarieh J, Sarov B, Kassis 1, Regnery R. Human and
tick spotted fever group rickettsia isolated from Israel: a
genotypic analysis. J Clin Microbiol 1992;30:2653-6.

4. Wolach B, Franci S, Bogger-Goren S, Drucker M, Goldwasser RA,
Sadan N, et al. Clinical and laboratory findings of spotted fever in
Israeli children. Pediatr Infect Dis J 1989;8:152-5.

5. Yagupsky P, Wolach B. Fatal Israeli spotted fever in children.
Clin Infect Dis 1993;17:850-3.

6. Agupsky P, Sarov B, Sarov I. A cluster of cases of spotted fever
in a kibbutz in southern Israel. Scand J Infect Dis 1989;21:155-60.

7. Rotz L, Callejas L, McKechnie D, Wolfe D, Gaw E, Hathcock L, et
al. An epidemiologic and entomologic investigation of a cluster of
Rocky Mountain spotted fever cases in Delaware. Del Med J
1998;70:285-91.

Iron and the Role of Chlamydia pneumoniae in Heart Disease

To the Editor: Chronic infection of the coronary arteries by
Chlamydia pneumoniae has been proposed as a heart disease risk
factor (1). One reason for this proposal is the organism's
association with one or more other risk factors for heart disease
(2). However, an independent pathogenic role for C. pneumoniae in
heart disease is unlikely if its presence is only a marker for
another risk factor. In the Helsinki Heart Study (3), markers of
chronic C. pneumoniae infection were a significant risk factor for a
cardiac event, independent of most traditional risk factors;
however, some association with known risk factors was seen,
including a positive association with smoking and an unexpected
negative association with spare-time physical activity.

We postulate a key role for iron, a proposed risk factor for heart
disease (4-6), in promoting the growth of C. pneumoniae in coronary
arteries. Iron is an essential growth factor for nearly all
pathogenic microorganisms (7). In particular, the growth of C.
pneumoniae in a human lung cell line and in Hep-2 cells is strongly
inhibited by iron restriction or by use of the iron chelator
deferoxamine (8, P. Saikku, pers. comm.). Excess iron is present in
atherosclerotic lesions. Seven times more iron is present in
atherosclerotic than in healthy arteries (9).

Among proposed risk factors for heart disease, iron provides the
most conceptually straightforward explanation for the presence of C.
pneumoniae in coronary vessels. We propose that chronic infection of
coronary arteries by C. pneumoniae occurs only if excess iron is
present in vivo. Excess iron is defined as stored iron or iron in
excess of the amount needed to maximize hematocrit. This implies
that C. pneumoniae can establish infection in the coronary arteries
only if a threshold level of available iron is present. Confirmation
of the hypothesis could explain an association of C. pneumoniae with
coronary atherosclerosis and, more generally, with ischemic heart
disease and would be consistent with the greater susceptibility of
men than women to C. pneumoniae infection (2) and myocardial
infarction. Moreover, confirmation of the hypothesis would leave
open the question of whether C. pneumoniae is directly atherogenic
or merely finds fertile ground for growth in arteries because of the
presence of iron above some threshold level.

Until age 20, men and women show few differences in prevalence of
antibody titers against C. pneumoniae. After age 20, the prevalence
of markers diverges sharply, with men showing a much steeper rise
than women. This is similar to the patterns observed for both stored
iron levels and rate of myocardial infarction in men and women,
especially between the ages of 20 and 50 years (4,5). In later
years, prevalence rates for C. pneumoniae markers do not rise as
steeply for women as the curves for stored iron level or myocardial
infarction rates (2). These patterns are compatible with
associations between stored iron, myocardial infarction rate, and
markers for infection with C. pneumoniae. Another relevant
observation is the negative association of markers with spare-time
physical activity (2). Such activity is associated with lower stored
iron levels (10), which may decrease vulnerability to C. pneumoniae.

The presence of excess iron in regulating susceptibility to C.
pneumoniae does not readily explain the geographic gradient in the
frequency of antibodies (2). C. pneumoniae infection seems to be
more prevalent near the equator. In general, acquisition of stored
iron is more problematic among impoverished persons, many of whom
live near the equator. Parasitic infections that cause chronic iron
loss from bleeding in the gut and bladder, along with limited
availability of easily absorbed heme iron in meat, tend to minimize
iron acquisition in these areas. C. pneumoniae may be endemic in
populations near the equator, especially among children in tropical
urban slums, because of other factors that eliminate any
differential effects on the basis of iron levels. In these areas
chlamydial antibodies may be a good marker for invasion but not
necessarily for disease.

We suggest that, above a modest threshold level of stored iron in
vivo, C. pneumoniae acquires the ability to colonize coronary
arteries. Invasion and colonization by the organism in vivo probably
require a concentration of available iron similar to that needed for
growth in cell culture. Even in a state of total iron depletion,
iron is still present in the body in abundance. However, in iron
depletion virtually all iron in the body is functional iron.
Functional iron, i.e., iron in hemoglobin, may not be readily
accessible to the organism. Our hypothesis implies that stored iron
can be mobilized by C. pneumoniae for growth. An approach to testing
the hypothesis would involve comparing the ability of C. pneumoniae
to colonize macrophages from stored iron-replete persons with those
from persons without stored iron. If the hypothesis is confirmed,
maintenance of an iron-depleted state under medical supervision
could be recommended as a preventive strategy against recolonization
after a course of antibiotic therapy.

Acknowledgment

We thank Jane E. Raulston for review of the manuscript and for
useful suggestions.

Jerome L. Sullivan* and Eugene D. Weinberg

*University of Florida College of Medicine, Gainesville, Florida,
USA; and Indiana University, Bloomington, Indiana, USA

References

1. Saikku P, Mattila K, Nieminen MS, Huttunen JL, Leinonen M, Ekman
M-R, et al. Serological evidence of an association of a novel
Chlamydia, TWAR, with chronic coronary heart disease and acute
myocardial infarction. Lancet 1988;ii:983-5.

2. Saikku P. The epidemiology and significance of Chlamydia
pneumoniae. J Infect 1992;25 Suppl I:27-34.

3. Saikku P, Leinonen M, Tenkanen L, Linnanmaki E, Ekman MR,
Manninen V, et al. Chronic Chlamydia pneumoniae infection as a risk
factor for coronary heart disease in the Helsinki Heart Study. Ann
Intern Med 1992;15;116:273-8.

4. Sullivan JL. Iron and the sex difference in heart disease risk.
Lancet 1981;1:1293-4.

5. Sullivan JL. Iron versus cholesterolperspectives on the iron and
heart disease debate. J Clin Epidemiol 1996;49:1345-52.

6. Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R,
Salonen R. High stored iron levels are associated with excess risk
   [ of myocardial infarction in eastern Finnish men. Circulation
1992;86:803-11.

7. Weinberg ED. Patho-ecologic implications of microbial acquisition
of host iron. Reviews in Medical Microbiology 1998;9:171-8.

8. Freidank HM, Billing H. Influence of iron restriction on the
growth of Chlamydia pneumoniae TWAR and Chlamydia trachomatis.
Clinical Microbiology and Infection 1997;3 Suppl 2:193.

9. Thong PSP, Selley M, Watt F. Elemental changes in atherosclerotic
lesions using nuclear microscopy. Cell Mol Biol 1996;42:103-10.

10. Lakka TA, Nyyssnen K, Salonen JT. Higher levels of conditioning
leisure time physical activity are associated with reduced levels of
stored iron in Finnish men. Am J Epidemiol 1994;140:148-60.

Filth Flies Are Transport Hosts of Cryptosporidium parvum

To the Editor: Infection with Cryptosporidium parvum, a zoonotic and
anthroponotic coccidian parasite (1), may be fatal for persons with
impaired immune systems (2), for whom a low number of oocysts can
initiate life-threatening diarrhea (1). Insects such as
promiscuous-landing synanthropic flies (i.e., coprophilic filth
flies) are recognized transport hosts for a variety of parasites
(3-5), but not for C. parvum. We assessed the role of synanthropic
flies in the mechanical transmission of C. parvum oocysts.

Bovine diarrheic feces (20-ml specimens) containing 2.0 x 105
oocysts/ml were placed in petri dishes in each of five 4-liter paper
cages with approximately 250 pupae of laboratory-reared house flies
(Musca domestica F58WTZ strain). Three days after the flies emerged,
fecal specimens were collected on glass microscope slides placed in
each cage. Thirty flies aspirated from each cage on days 3, 5, 7, 9,
and 11 after emergence were eluted, and the eluants were processed
by the cellulose acetate membrane (CAM)-filter dissolution method
(6). Digestive tracts dissected from randomly selected flies and the
glass slides with fly excreta were examined by immunofluorescent
antibody (IFA) (7), and C. parvum oocysts were counted (8). Maggots
of M. domestica were reared in fly larvae medium (PMI FEEDS, Inc.,
St. Louis, MO) contaminated with calf diarrheic feces (50 ml)
containing 2.0 x 105 C. parvum oocysts/ml. Resulting pupae were
eluted, the eluants were processed by the CAM-filter dissolution
method (6), and C. parvum oocysts were identified by IFA (7) and
counted (8). Diarrheic fecal specimens from a C. parvum-uninfected
calf were used as negative controls in similar experiments. Randomly
selected samples containing fly-derived C. parvum oocysts were
processed with acid-fast stain (AFS) (8) to check for normal
cellular morphologic features.

Ten Victor-type flying-insect traps (Woodstream, Lititz, PA) were
baited with rotten fish and placed inside a barn (approximately 880
m2) in which a male Holstein calf infected with C. parvum (AUCP-1
strain) was housed. The traps were emptied weekly, the flies were
counted and identified (5,9), and the inside surfaces of the traps
(containing fly excreta), along with the flies, were eluted with 200
ml of eluting fluid (6). The eluting fluid was filtered through a
CAM (Millipore, Bedford, MA) (6,8), which was then processed (6),
and C. parvum oocysts were identified by IFA (7) and counted (8).

The mean number of C. parvum oocysts per droplet of M. domestica was
4 to 20 (mean 7.0 + 3.2), and the number of droplets increased over
time. All flies harbored C. parvum oocysts on their external
surfaces. On average, 14.0 + 6.8 fly excreta were counted per 1.0
cm2 of glass slide. From 1 to 8 C. parvum oocysts were detected in
digestive tracts of flies exposed to feces with oocysts. C. parvum
oocysts were also numerous on maggot and pupa surfaces;
approximately 150 and 320 oocysts were recovered per maggot and
pupa, respectively.

Wild-caught flies belonged to the families Calliphoridae (96% of
total flies), Sarcophagidae (2%), and Muscidae (2%). An average of
eight flies was caught per trap, and more than 90% of flies harbored
C. parvum oocysts. The number of trap-recovered C. parvum oocysts
per fly was 2 to 246 (mean 73 oocysts per fly).

Synanthropic flies that breed in or come in contact with a fecal
substrate contaminated with C. parvum oocysts can harbor these
oocysts both externally and internally and will mechanically deposit
them on other surfaces. Therefore, synanthropic flies can serve as
mechanical vectors for C. parvum oocysts and under poor sanitary
conditions could be involved in the transmission of human and animal
cryptosporidiosis. The biology and ecology of synanthropic flies
indicate that their potential for mechanical transmission of C.
parvum oocysts can be high. The morphologic and AFS and IFA staining
characteristics of C. parvum oocysts recovered from the exoskeletons
of flies and identified in their fecal spots suggest that oocysts
are still viable.

Thaddeus K. Graczyk,* Ronald Fayer, Michael R. Cranfield,*
Barbara Mhangami-Ruwende,* Ronald Knight,* James M. Trout, and
Heather Bixler

*Johns Hopkins University, Baltimore, Maryland, USA; The Baltimore
Zoo, Druid Hill Park, Baltimore, Maryland, USA; U.S. Department of
Agriculture, Beltsville, Maryland, USA; and University of
Pennsylvania, School of Veterinary Medicine, Philadelphia,
Pennsylvania, USA

References

1. Fayer R, Speer CA, Dubey JP. The general biology of
Cryptosporidium. Cryptosporidium and cryptosporidiosis. In: Fayer R,
editor. Boca Raton (FL): CRC Press; 1997. 1-42.

2. Graczyk TK, Fayer R, Cranfield MR. Zoonotic potential of
cross-transmission of Cryptosporidium parvum: implications for
waterborne cryptosporidiosis. Parasitol Today 1996;13:348-51.

3. Wallace GD. Experimental transmission of Toxoplasma gondii by
filth-flies. Am J Trop Med Hyg 1971;20:411-3.

4. Hedges SA. Flies, gnats and midges. In: Malis A, editor. Handbook
of pest control. Cleveland (OH): Franzak & Foster Co.; 1990. p.
621-84.

5. Greenberg B. Flies and diseases, biology and disease
transmission. Princeton (NJ): Princeton University Press; 1973. p.
221.

6. Graczyk TK, Cranfield MR, Fayer R. Recovery of waterborne oocysts
of Cryptosporidium parvum from water samples by the membrane-filter
dissolution method. Parasitol Res 1997;83:121-5.

7. Graczyk TK, Cranfield MR, Fayer R. Evaluation of commercial
enzyme immunoassay (EIA) and immunofluorescent antibody (IFA) test
kits for detection of Cryptosporidium oocysts of species other than
Cryptosporidium parvum. Am J Trop Med Hyg 1996;54:274-9.

8. Graczyk TK, Fayer R, Cranfield MR, Owens R. Cryptosporidium
parvum oocysts recovered from water by the membrane filter
dissolution method retain their infectivity. J Parasitol
1997;83:111-4.

9. Borror DJ, DeLong DM, Triplehorn CA. An introduction to the study
of insects. Philadelphia (PA): Saunders College Publishing; 1981. p.
827.

The Cost-Effectiveness of Vaccinating against Lyme Disease

To the Editor: The recent article by Meltzer and colleagues (1) is
an important contribution to a pertinent public health issue: who
should receive the newly licensed Lyme disease vaccine. Answering
this question is a daunting task, given the scarcity of valid data.
Estimates of the spectrum and prevalence of the long-term sequelae
of Lyme disease remain controversial (2-4). In generating their
cost-effectiveness model, Meltzer et al. examined the cost savings
involved in preventing three categories of classic organ-specific
Lyme disease sequelae (cardiovascular, neurologic, and arthritic);
however, they did not take into account the potential cost savings
from preventing cases of a generalized symptom complex known as
post-Lyme syndrome, which includes persisting myalgia, arthralgia,
headache, fatigue, and neurocognitive deficits. These generalized
sequelae, which are recognized by the National Institutes of Health
as late sequelae of Lyme disease, have been found to persist for
years after antibiotic therapy (5,6). Two population-based
retrospective cohort studies (7,8) among Lyme disease patients whose
illness was diagnosed in the mid-1980s determined that one third to
half had clinically corroborated post-Lyme syndrome symptoms years
after the initial onset of disease. Although these studies were
conducted 15 years ago, when optimal antibiotic regimen guidelines
were still evolving, the estimated cost of averting these
often-disabling nonorgan-specific symptoms should also be taken into
account in estimated sensitivity analyses of vaccine
cost-effectiveness. The cost of treating sequelae is weighted
heavily in the cost-effectiveness models presented by Meltzer and
colleagues, which adds importance to considering post-Lyme syndrome.
Nevertheless, we recognize the difficulty of this modeling,
especially in the absence of validated cost-of-treatment data for
these generalized symptoms.

A point of correction is that Meltzer et al. erroneously cite one of
these studies (7) to infer that the long-term clinical sequelae of
Lyme disease lasted a mean of 6.2 years from the onset of disease.
In this retrospective study, Shadick et al. evaluated 38 persons
with a clinical history of Lyme disease a mean of 6.2 years from the
onset of disease regardless of the presence of persisting symptoms;
25 of these patients had no residual symptoms at follow-up. To
accurately estimate the duration of clinical sequelae, longitudinal
evaluations of representative populations of Lyme disease patients
will be required because late manifestations have been demonstrated
months to years after diagnosis (9,10).

Dimitri Prybylski

University of Maryland School of Medicine, Baltimore, Maryland, USA

References

1. Meltzer MI, Dennis DT, Orloski KA. The cost-effectiveness of
vaccinating against Lyme disease. Emerg Infect Dis 1999;5:321-8.

2. Ellenbogen C. Lyme disease. Shift in the paradigm? Arch Fam Med
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3. Liegner KB. Lyme disease: the sensible pursuit of answers. J Clin
Microbiol 1993;31:1961-3.

4. Sigal LH. Persisting symptoms of Lyme diseasepossible
explanations and implications for treatment [editorial]. J Rheumatol
1994;21:593-5.

5. National Institute of Allergy and Infectious Diseases. Research
on chronic Lyme disease. National Institutes of Health Office of
Communications Fact Sheet; May 1997.

6. National Institute of Allergy and Infectious Diseases. Emerging
infectious diseasesNIAID research. National Institutes of Health
Fact Sheet; Mar 1998.

7. Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF,
Berardi VP, et al. The long-term clinical outcomes of the disease. A
population-based retrospective cohort study. Ann Intern Med
1994;121:560-7.

8. Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme
disease: an infectious and post-infectious syndrome. J Rheumatol
1994;21:454-61.

9. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic
manifestations of Lyme disease. N Engl J Med 1990;323:1438-44.

10. Szer IS, Taylor E, Steere AC. The long-term course of Lyme
arthritis in children. N Engl J Med 1991;325:159-63.

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

URL: ftp://ftp.cdc.gov/pub/EID/vol5no5/ascii/letters.txt

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