Differentiating Kawasaki Syndrome From Microbial Infection

Transcription

IIM_07012008_00311.ps 6/16/08 10:56 AM Page 311
DIFFERENTIAL DIAGNOSIS
Differentiating Kawasaki Syndrome
From Microbial Infection
Michael E. Ryan, DO, Terrah Keck, DO, Mary Frances Musso, DO, and Kimberly C. Capp, DO
Kawasaki syndrome (KS) is a serious disorder affecting
children aged 1 to 8 years. It mimics a range of other diseases
of childhood. Diagnosis is based on physical examination
findings coupled with the exclusion of other causes. To provide
optimal care for patients, it is important to be aware of the
differential diagnoses of KS, which include bacterial and viral
infections; rheumatological diseases, which may be secondary
to infectious diseases; and other causes, such as antimicrobial
drug reactions. [Infect Med. 2008;25:311-316]
fronted with a child in whom KS is
suspected. KS should be considered
in any child with fever for more than
5 days, especially if the child has a
rash and nonpurulent conjunctivitis.
The differential diagnosis of KS is extensive and includes bacterial and
viral infections and rheumatological
diseases, among other causes.
Bacterial infections
Key words: Kawasaki syndrome ■ Vasculitis ■ Hypersensitivity syndrome
■ Febrile rash
awasaki syndrome (KS), also
known as mucocutaneous
lymph node syndrome, the
cause of which is unknown, is a common vasculitis seen in the pediatric
population. Epidemiologically, it is
similar to an infectious disease in
that it has a seasonal occurrence and
has been implicated in epidemics.
Clinically, it is a vasculitis that is unresponsive to antibiotics. Two important aspects of KS are that it develops in healthy children and is the
most common cause of acquired cardiac disease in the developed world.
In fact, chronic cardiac complications
develop in 20% to 25% of children in
whom KS goes untreated. The most
common and dangerous cardiac
complication is coronary artery di-
K
latation, which may result in rupture
and exsanguination. Children also
may experience a prolonged course
of arthritis, arthralgias, and cramping abdominal pain. Therefore, it is
very important to diagnose KS with
certainty, treat it appropriately, and
follow up patients meticulously.
DIFFERENTIAL DIAGNOSES
Since there is no specific diagnostic
test for KS, the diagnosis hinges on
meeting 4 of the 5 criteria as well as
the presence of fever for 5 days. Because the diagnostic features often
have different presentations, the diagnosis of KS may be difficult even
for the experienced clinician. Thus, it
is always important to consider the
differential diagnosis when con-
Dr Ryan is chairman of pediatrics for the Geisinger Health System in Danville, Pa. Dr Keck and
Dr Musso are residents and were medical students at Geisinger at the time the manuscript was
prepared. Dr Capp is a medical/pediatric resident at Geisinger.
Bacterial infections that play into
the differential diagnosis include
scarlet fever; staphylococcal scalded
skin syndrome (SSSS); toxic shock
syndrome (TSS); Rocky Mountain
spotted fever (RMSF) and other
forms of rickettsial infection, such
as typhus; leptospirosis; rat-bite
fever; and Yersinia pseudotuberculosis
infection.1-10
Scarlet fever is a syndrome that
results from erythrogenic exotoxin A
production by group A Streptococcus.
It is similar to KS in that it causes
desquamation with time, including
periungual desquamation. Infection
also can cause cervical adenopathy,
exudative tonsillitis, and strawberry
tongue.
A few distinguishing features
help differentiate scarlet fever from
KS. Although a desquamating rash is
a characteristic of both diseases, the
rash associated with scarlet fever
may become blanched. It is diffusely
erythematous, resembling a sunburn, and is rough with a sandpaper
July 2008 INFECTIONS in MEDICINE 311
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KAWASAKI SYNDROME OR INFECTION? continued
Figure 1 – The appear-
ance of Pastia sign
helps distinguish
scarlet fever from
other causes of rash.
Figure 2 – Subconjuncti-
val hemorrhage may
appear as a symptom
of toxic shock syndrome
(TSS). Its appearance
helps distinguish
TSS from Kawasaki
syndrome.
texture. The rash is most intense on
the axillae and on the groin, abdomen, and trunk. It generally appears about 24 hours after the onset
of fever. It is first seen on flexor surfaces of the extremities and becomes
generalized in 24 to 48 hours. Pastia
sign (Figure 1), nonblanching skin
folds, and circumoral pallor also
may be noted. Cephalic to caudal
desquamation occurs about a week
after the onset of rash. Finally, if
physical findings are not sufficient to
determine a diagnosis, checking antistreptolysin O titers can be helpful
because levels may be elevated in
patients with scarlet fever.
SSSS is another toxin-mediated
disorder. It shares with KS the characteristics of a desquamating truncal
rash and an erythematous, peeling,
fissured “sunburst” rash around the
mouth. Unlike KS, SSSS is preceded
312 INFECTIONS in MEDICINE July 2008
by an initial infection of the upper
respiratory tract. Another distinguishing characteristic is that the
rash of SSSS usually spares the
palms, soles, and mucous membranes. The peeling is confined to
areas around body orifices.
One to 2 days after the rash manifests, bullae may appear and exfoliate in sheets, which is referred to as a
positive Nikolsky sign. Isolation of
staphylococci from a site other than
the blisters (eg, conjunctivae or nasopharynx) or from the blood will
aid in the diagnosis.
TSS is generally caused by Staphylococcus aureus. Similarities between
TSS and KS include edema of the
face, palms, and soles. In addition,
desquamation of the skin 1 to 2
weeks after illness onset, strawberry
tongue, and bulbar conjuctival hyperemia are present in both illnesses.
Distinguishing characteristics of TSS
include shock, a widespread blanching erythroderma eruption that is
most prominent on the trunk and extremities, and possible subconjunctival hemorrhage (Figure 2). Approximately 85% of TSS patients have S
aureus isolated from their mucosa or
wound sites, but isolation of the organism is not required to make the
diagnosis.
RMSF, a rickettsial infection, is
caused by the spirochete Rickettsia
rickettsii. It is transmitted through the
bite of a tick and is most prevalent in
the southeastern and central Mississippi valley regions of the United
States, with North Carolina and
Oklahoma having the highest incidence. Similarities to KS include
fever, maculopapular rash with involvement of palms and soles, and
conjunctival hyperemia. In contrast
to KS, RMSF causes a peripherally
distributed eruption beginning on
the ankles, wrists, and forehead, in
which the initial lesions may blanch
and appear as small red macules that
rapidly progress to maculopapules
and finally to petechiae. The onset of
rash is preceded by a 3- to 7-day prodrome of chills, fever, and severe
frontal headache, malaise, and
anorexia. Thrombocytopenia, hyponatremia, elevated aminotransferase
levels, hyperbilirubinemia, leukopenia, and coagulopathies might
emerge. Serum antibodies reactive to
R rickettsii may be detected by indirect immunofluorescence assay, but
diagnostic levels might be undetectable until the second week after
syndrome onset.
Febrile rickettsial infection includes epidemic and murine typhus,
and it is transmitted by fleas or lice
harboring Rickettsia species. Similarities to KS include high fever, a maculopapular petechial eruption, and
cervical adenopathy. Some distinguishing characteristics include a 4to 6-day prodrome with high fever,
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KAWASAKI SYNDROME OR INFECTION?
chills, headache, and generalized
aches and pains. In addition, the
maculopapular rash is often centrally distributed, and neuroretinitis
may be found. The indirect fluorescent antibody test is often used to
confirm the diagnosis.
Leptospirosis is caused by the
spirochete Leptospira interrogans,
which is transmitted by dogs, swine,
rodents, and contaminated water.
Similarities to KS include a maculopapular rash with peripheral
desquamation, conjunctivitis, cervical lymphadenopathy, and pharyngitis. One of the distinguishing characteristics is conjunctivitis with episcleral injection and uveitis that may
be unilateral or bilateral and usually
involves the entire uveal tract. The
rash is maculopapular to generalized and may be petechial or purpuric. Erythema nodosa also may be
noted.
The anicteric form of leptospirosis
is the most common form and is associated with biphasic fever, myalgias, and chills. Acalculous cholecystitis or intense jaundice is occasionally seen in children. Laboratory
studies that may aid in the diagnosis
include those that evaluate for leukocytosis, hematuria, proteinuria, azotemia, and hyperbilirubinemia.
Rat-bite fever is a very rare syndrome caused by either Spirillum
minus or Streptobacillus moniliformis.
Similarities to KS include intermittent fever, rash on the palms and
soles, and lymphadenopathy. It has
many distinguishing characteristics,
including a waxing and waning pattern of fever of 3 to 4 days’ duration
alternating with afebrile periods lasting 3 to 9 days; this cycle may persist
for weeks. The rash often develops 1
to 8 days after fever onset. Laboratory tests may indicate leukocytosis
and may yield false-positive results
for venereal diseases.
Y pseudotuberculosis is transmitted
by the ingestion of incompletely
cooked pork, unpasteurized milk, or
contaminated well water or by indirect contact with infected animals.
This bacterium causes a fever, rash,
lymphadenitis, and conjunctivitis
similar to those seen with KS. Some
distinguishing characteristics of Y
pseudotuberculosis infection include
varying degrees of fever, a scarlatiniform rash, and mesenteric adenitis
(which may mimic acute appendicitis). It is also associated with Parinaud oculoglandular syndrome,
which includes unilateral conjunctivitis with conjunctival granulomas,
ptosis, preauricular adenopathy,
photophobia, and external signs of
inflammation. Of interest, 75% of
patients with clinically apparent Y
pseudotuberculosis infection are children younger than 15 years.
Viral infections
Viral infections that are symptomatically similar to KS include
adenovirus infections as well as
measles, German measles, roseola
infantum, erythema infectiosum,
and mononucleosis.1,2,4-7
Adenovirus infections, like KS,
are characterized by a persistent
high fever, pharyngitis (Figure 3),
conjunctivitis, cervical lymphadenopathy, and rash.
Distinguishing characteristics of
adenovirus infections include sore
throat, rhinitis, and unilateral conjunctivitis that can include serous
discharge, subconjunctival hemorrhages, and the formation of a grayish pink friable membrane on the
palpebral conjunctiva. The conjunctivitis also is associated with an itching, burning, foreign-body sensation
that is not seen in KS.
The discrete generalized erythematous maculopapular rash of adenovirus infections often appears while
the child is febrile. Adenoviruses
also can cause right iliac fossa abdominal pain. Direct antigen testing
or viral culture can be used to detect
adenoviruses.
Measles, caused by the rubeola
virus, shares similarities with KS in
that it is characterized by swelling of
the hands and feet, a maculopapular
rash with desquamation, conjunc-
Figure 3 – Pharyngeal manifestations, including erythema, tonsillitis, and exudates, also are
indicative of adenovirus infection.
IIM_07012008_00314.ps 6/16/08 10:56 AM Page 314
tivitis, and fever that persists for 5 to
7 days. Some unique characteristics
of measles include a 3- to 4-day prodrome of fever, conjunctivitis, coryza, and severe cough. In contrast to
KS, the conjunctivitis of measles is
exudative. The brick-red rash of
rubeola starts on the face, the neck,
and behind the ears; it then extends
down the trunk and onto the extremities. The rash is initially maculopapular and becomes more confluent before it begins to fade after 3
days, leaving behind a distinctive
brownish hue. This is often followed
by a branny desquamation that does
not involve the hands and feet. In addition, Koplik spots on the buccal
mucosa and a central, white coating
of the tongue with an erythematous
tip and margins may be seen.
Similarities between KS and German measles, which is caused by the
rubella virus, include a maculopapular rash, adenopathy, and fever. German measles is distinguished from
KS by a nonspecific prodrome of
fever, coryza, sore throat, arthralgias,
and adenopathy that occurs 1 to 5
days before exanthem onset, but this
is more common in adolescents and
adults than in infants and young
children.
The rash is characterized by a
nondesquamating, pale pink, morbilliform maculopapular eruption
that begins on the face and neck and
progresses down the trunk to the extremities. The rash is generalized in
24 to 48 hours, lasts 1 day in each
area, and fades rapidly. In addition
to cervical adenopathy, postauricular and occipital lymphadenopathy
and arthralgias also may be noted.
Roseola infantum is caused by
human herpesvirus 6 and usually occurs in children aged 6 to 36 months.
It is characterized by persistent fever
of 3 to 5 days’ duration, followed by
rash and lymphadenopathy. Distinguishing features of roseola infantum include an erythematous and
morbilliform rash that consists of
rose-colored macules appearing on
the neck, trunk, and buttocks and
less frequently on the face and extremities that begins as the fever
abates. The mucous membranes are
often spared, and the rash resolves in
1 to 2 days. Patients with roseola infantum also are at increased risk for
febrile convulsions. Laboratory studies often show leukopenia.
Erythema infectiosum (also called
fifth disease) is caused by Parvovirus
B19. Like KS, it is characterized by
fever, adenopathy, and rash. Unlike
KS, a prodrome of malaise, pharyngitis, coryza, and fever precedes the
illness. The characteristic “slapped
cheek” rash generally follows about
10 days later. In the second phase of
the illness, the rash spreads to extremities and becomes symmetrical,
morbilliform, and lacelike or annular
with central clearing and is often
mildly pruritic. It spares the mucous
membranes, palms, and soles. In its
final phase, the rash may remit and
recur for weeks with stress, exercise,
or bathing. Complications of erythema infectiosum include arthritis, hemolytic anemia, aplastic crisis, and
nonimmune hydrops in the fetus
and newborn.
Mononucleosis is caused by the
Epstein-Barr virus (EBV). Similarities to KS include fever, rash, and
cervical lymphadenopathy. Mononucleosis is typically characterized
by a triad of membranous tonsillitis
with or without exudates, cervical
lymphadenopathy, and splenomegaly. The rash of mononucleosis is
rare (5% to 10% of patients with EBV
infection) and may appear as 2 different exanthems. The first type of
exanthem is erythematous, maculopapular, and rubella-form and is
more prominent on the trunk and
proximal upper extremities (occasionally it is seen on the face, forearms, and legs). This is the classic,
non–antibiotic-related EBV rash. The
second type is an erythematous or
copper-colored ampicillin-associated rash that begins on the trunk and
spreads to the face and extremities.
EBV infection can be diagnosed in
the clinic with the monospot test or
with specific EBV antibody tests.
Rheumatological diseases
A few rheumatological diseases
cause symptoms similar to those of
KS, including Gianotti-Crosti syndrome, Henoch-Schönlein purpura
(HSP), and juvenile rheumatoid
arthritis (JRA).8
Gianotti-Crosti syndrome, an infantile, papular acrodermatitis originally associated with hepatitis B
surface antigen that may occur after
viral infection, is caused by pathogens such as EBV, cytomegalovirus,
enteroviruses, and respiratory syncytial virus. Like KS, this syndrome
includes a desquamative rash and
lymphadenopathy. The rash is characterized by a sudden eruption of
symmetric, flat-topped, discrete,
nonpuritic, skin-colored to erythematous papules on the malar face, extremities, and buttocks (Figure 4)
that spares the trunk, mucous membranes, and antecubital and popliteal
fossae. The lesions then fade and
desquamate spontaneously within 2
to 3 weeks but may remain for up to
8 weeks. The lymphadenopathy is
generalized and inguinal, and maxillary nodes can be enlarged for 2 to 3
months after onset.
HSP is a systemic vasculitis with
deposition of IgA-containing immune complexes throughout the
body. Like KS, HSP is characterized
by fever; rapidly fading rash;
swollen hands, feet, and periorbital
areas; arthritis; and abdominal pain.
Unlike KS, HSP is classically described as intermittent purpura,
arthralgias, abdominal pain, and
renal disease. HSP also may be preceded by an upper respiratory tract
infection, mild fever, and headache.
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KAWASAKI SYNDROME OR INFECTION?
The initial lesions are symmetrical,
blotchy, erythematous macules that
become urticarial and then purpuric
within a day. The palpable purpuric
lesions are seen on the buttocks, extensor surfaces of extremities, back,
scrotum and, occasionally, the face.
In a child younger than 2 years,
edema of the scalp, hands, feet, and
periorbital tissues may develop before the appearance of purpuric lesions. Cutaneous hemorrhage may
be the sole manifestation of any attack, with arthralgia and arthritis
noted as a migratory, periarticular
swelling of the knees and ankles. Patients also may have colicky abdominal pain associated with vomiting
and melena, and mild renal involvement with transient proteinuria,
hematuria, and focal glomerular involvement. Abnormal findings on
laboratory tests include leukocytosis,
thrombocytosis, and elevated erythrocyte sedimentation rate (ESR).
Skin biopsy specimens show IgA,
C3, and fibrin deposits.
JRA has characteristics similar to
those of KS, including lymphadenopathy, rash, and high, spiking
fevers. These fevers are dramatic,
with sweats and chills, and temperatures often spike to 40°C (104°F) before plunging to several degrees
below normal (picket fence temperature). The rash is a transient, evanescent, salmon-colored, nonpruritic
rash that is primarily noticeable on
the chest and abdomen. It often appears and disappears with the fever
spikes. Many patients may initially
complain of mild sore throat and
joint symptoms that become a progressively destructive arthritis primarily affecting the wrists. Hepatosplenomegaly during the rash,
anemia, and leukocytosis also may
be present.
Other differential diagnoses
Other syndromes with characteristics similar to those of KS include
Figure 4 – The rash
associated with
Gianotti-Crosti
syndrome is
desquamative like
that of Kawasaki
syndrome. However,
it is uniquely
characterized by a
sudden eruption of
symmetrical, flat-topped,
discrete, nonpuritic,
skin-colored to erythematous papules on the
malar face, extremities,
and buttocks.
Stevens-Johnson syndrome (SJS),
acrodynia, and convulsant hypersensitivity syndrome (CHS).6,9,10
SJS is a condition caused by a severe allergic reaction to drugs such
as sulfonamides, NSAIDs, and
phenytoin and by infections such as
those caused by Mycoplasma pneumoniae and herpes simplex virus. Like
KS, SJS is characterized by pharyngitis, fever, conjunctivitis, a maculopapular rash involving the hands
and feet, and hemorrhagic lips. The
rash tends to be vesicular with crusting of edematous, erythematous
eruptions involving the face, hands,
and feet. Bullous erythema multiforma, with lesions that may slough off
as large pieces of skin, also may be
noted. Stomatitis is an early and conspicuous symptom, beginning with
vesicles on the tongue, lips, and buccal mucosa (Figure 5). This later becomes more severe and includes
pseudomembranous exudation, excessive salivation, and ulcerations.
Rhinitis with epistaxis and crusting
of the nares also may be seen. The
conjunctivitis of SJS is bilateral and
often exudative. Laboratory testing
may indicate an increased ESR, although the ESR is not as high as that
seen in KS.
Acrodynia, also known as erythredema polyneuropathy or pink disease, is caused by mercury poisoning
IIM_07012008_00316.ps 6/16/08 10:57 AM Page 316
KS is a coronary artery aneurysm.
Aneurysms may lead to sudden
death, often within the first 30 days
after the onset of KS. Usually IVIG is
followed by a prompt end to most
symptoms the child is having. On occasion, a second dose of IVIG is required. Any child whose status does
not improve after a second dose of
IVIG should be reevaluated. ❖
Figure 5 – Stomatitis is
an early symptom of
Stevens-Johnson
syndrome (SJS) and helps
distinguish SJS from
Kawasaki syndrome.
Vesicles develop on
the tongue, lips, and
buccal mucosa. Extensive
stomatitis, crusting, and
erythematous eruptions
are depicted here.
that usually occurs in infancy. Similar to KS, it is characterized by
painful swelling of the hands and
feet, a maculopapular rash, and irritability. Unlike KS, the erythema is
blotchy and diffuse. Hands and feet
also may be cold, clammy, pink or
dusky red, and pruritic. In addition,
hemorrhagic puncta may be seen.
Laboratory studies may demonstrate albuminuria, hematuria, and
the presence of mercury in urine.
CHS is a systemic reaction to anticonvulsant therapy. Like KS, it is
characterized by fever, maculopapular rash, and lymphadenopathy. It
includes involvement of visceral organs, and fulminant hepatitis may
develop. The lymphadenopathy is
generalized. The rash usually begins
2 to 8 weeks after the drug is begun
and usually resolves when the drug
is stopped. CHS may be followed by
an eosinophilic colitis. Helpful findings from laboratory tests include
leukocytosis with eosinophilia and a
normal ESR.
TREATMENT
High-dose intravenous gamma globulin (IVIG) (2 g/kg) as a single dose
along with high-dose aspirin (100
mg/kg/d) for 10 to 14 days followed
by low-dose aspirin (5 mg/kg/d)
until acute inflammatory mediators
return to normal is the standard of
care for KS.1 This therapy has been
shown to reduce the incidence of
coronary artery disease. The most serious complication associated with
Therapeutic agents
mentioned in this article
Ampicillin
Aspirin
Intravenous gamma globulin
Phenytoin
REFERENCES
1. American Academy of Pediatrics. Summaries
of Infectious Diseases. In: Pickering LK, ed. Red
Book: 2003 Report of the Committee on Infectious
Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:412-415.
2. Darmstadt GL, Marcy SM. Erythematous macules and papules. In: Long SS, Pickering LK,
Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 2nd ed. New York:
Churchill Livingstone; 2003:432-434.
3. Gomez HF, Cleary TG. Yersinia species. In:
Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases.
2nd ed. New York: Churchill Livingstone; 2003:
839-843.
4. Demmler GL. Adenoviridae. In Long SS, Pickering LK, Prober CG, eds. Principles and Practice
of Pediatric Infectious Diseases. 2nd ed. New
York: Churchill Livingstone; 2003:1076-1080.
5. Maldonado YA. Rubeola virus. In: Long SS,
Pickering LK, Prober CG, eds. Principles and
Practice of Pediatric Infectious Diseases. 2nd ed.
New York: Churchill Livingstone; 2003:11481155.
6. Cohen BA, ed. Pediatric Dermatology. 3rd ed.
Philadelphia: Elsevier Health Sciences; 2005:
161-200.
7. Davis HW, Michaels MG. Infectious disease. In:
Zitelli BJ, Davis HW, eds. Atlas of Pediatric Physical Diagnosis. 4th ed. St Louis: Mosby; 2002:396454.
8. McIntire SC, Urbach AH, Londino Jr AV.
Rheumatology. In: Zitelli BJ, Davis HW, eds.
Atlas of Pediatric Physical Diagnosis. 4th ed. St
Louis: Mosby; 2002:225-256.
9. Committee on Injury and Poison Prevention
American Academy of Pediatrics. Handbook of
Common Poisonings in Children. Elk Grove Village, IL: American Academy of Pediatrics; 1994:
216-219.
10. Le J, Nguyen T, Law AV, Hodding J. Adverse
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period. Pediatrics. 2006;118:555-562.
IIM_07012008_000320RR.ps 6/24/08 10:36 AM Page 320
CASE REPORT
Fever and Rash:
Infection or Kawasaki Syndrome?
Michael E. Ryan, DO, Terrah Keck, DO, Mary Frances Musso, DO, and Kimberly C. Capp, DO
Kawasaki syndrome (KS) is a common and serious disorder
that most often affects children aged 1 to 8 years but mimics
a range of other diseases of childhood. Diagnosis of KS is
based on physical examination findings coupled with the
exclusion of other causes. To provide optimal care for patients,
it is important to be aware of the differential diagnosis of KS.
We report a case of a 4-year-old boy who presented with
persistent fever and cervical lymphadenitis; later, mucous
membrane changes, rash, and conjunctival injection
characteristic of KS developed. [Infect Med. 2008;25:320-322]
Key words: Kawasaki syndrome ■ Vasculitis ■ Hypersensitivity syndrome
■ Febrile rash
awasaki syndrome (KS) is a
common vasculitis seen in
the pediatric population. It
also is known as mucocutaneous
lymph node syndrome, and the
cause is unknown. Epidemiologically, it is similar to an infectious disease; it has a seasonal occurrence and
has been implicated in epidemics.
Clinically, it is a vasculitis unresponsive to antibiotics. KS develops in
healthy children and is the most
common cause of acquired cardiac
disease in the developed world.
Chronic cardiac complications develop in 20% to 25% of children with
untreated KS, and the most common
and dangerous cardiac complication
is coronary artery dilatation. It may
K
result in rupture of the arteries and
exsanguination. KS also may cause
children to experience a prolonged
course of arthritis, arthralgias, and
crampy abdominal pain. Therefore,
it is very important that KS is diagnosed accurately and treated appropriately and that clinicians are diligent about follow-up.
Case report
A 4-year-old boy with a past medical
history of recurrent otitis media initially presented with a complaint of
right ear pain and fever. Otitis media
of the right ear was diagnosed, and
amoxicillin therapy was begun. Four
days later, the patient presented to
his primary care physician because
Dr Ryan is chairman of pediatrics for the Geisinger Health System in Danville, Pa. Dr Keck and
Dr Musso are residents and were medical students at Geisinger Health System at the time the
article was prepared. Dr Capp is a medical/pediatric resident at Geisinger Health System.
of persistent fever and enlargement
of a left anterior cervical node. The
ear pain had resolved, however. The
patient was not taking in an adequate amount of fluids and thus was
mildly dehydrated.
The patient’s temperature was
38.7°C (101.6°F). His right tympanic
membrane was slightly red, with
fluid behind it. His tonsils were more
than 3 mm in diameter and were erythematous. He had an enlarged (2
cm in diameter) left anterior cervical
node. His skin turgor was decreased
and no rash was noted.
The patient was admitted with
suspected retropharyngeal abscess
and for receipt of intravenous fluids
and further evaluation and therapy.
Intravenous clindamycin was administered immediately. His initial
laboratory studies revealed a white
blood cell count of 18,480/µL, with
53% polymorphonuclear cells, 30%
lymphocytes, 11% monocytes, and
6% eosinophils. His hemoglobin level was 10.8 g/dL, and the platelet
count was 370,000/µL. The C-reactive protein level was 27 mg/L.
A CT scan of the neck showed
no retropharyngeal abscess, but pansinusitis, bilateral middle ear opacification, and bilateral cervical adenopathy were evident. Further
laboratory studies revealed an antistreptolysin O titer of less than 20
IU/mL, alanine aminotransferase
level of 8 U/L, and aspartate amino-
IIM_07012008_00321.ps 6/16/08 10:58 AM Page 321
FEVER AND RASH
tient’s condition rapidly
improved. He became afebrile, his rash resolved, and
his eyes and lips improved.
He began to eat and drink
normally, and the cervical
adenopathy resolved. He
was discharged home on
the fifth hospital day with
instructions to continue
taking aspirin and to follow up with the pediatric
infectious disease clinic in
1 week. At the follow-up
visit, peeling of the hands
and feet was observed. The
patient continued to do
well with no evidence of
coronary abnormalities.
Discussion
The diagnosis of KS is defined by the presence of
fever of at least 5 days’ duFigure 1 – These images illustrate the characteristic white ration and 4 of the 5 fol(top) and red (bottom) strawberry tongue seen in Kawa- lowing characteristics: consaki syndrome.
junctival hyperemia, mucous membrane changes,
distal extremity changes,
polymorphous exanthema, and certransferase level of 22 U/L. Test revical adenopathy. The fever characsults were negative for Epstein-Barr
teristic of KS is high and spiking. It
virus and Parvovirus.
is not affected by antibiotics or antiThe patient remained febrile after
pyretics and resolves within 24 to
3 days of intravenous clindamycin
48 hours of IVIG therapy. The onset
therapy. On the third hospital day, a
diffuse macular rash developed. The
patient’s lips were cherry red and
dried, and his eyes were marked
by a nonpurulent conjunctival injection. Cervical adenopathy was unchanged, and no swelling of the
hands or feet occurred.
Findings on echocardiography
were normal. The albumin level was
2.6 g/dL, and the erythrocyte sedimentation rate (ESR) was 78 mm/h.
Intravenous clindamycin therapy
was stopped, and the patient was
given aspirin, 100 mg/kg/d, and intravenous immunogammaglobulin
(IVIG), 2 g/kg.
Over the next 18 hours, the pa-
of fever is considered the first day
of the illness, from which all other
events are measured.1
The conjunctival hyperemia seen
in KS is characteristically nonexudative and is most apparent in the bulbar conjunctiva, with sparing of the
limbic region around the iris. Hyperemia is noticeable a few days after
the onset of fever and may persist for
1 to 2 weeks if left untreated.
Effects of KS on mucous membranes are extensive and include diffuse erythema of the oral and pharyngeal mucosa without discrete ulcerative lesions. The lips also may
be injected, dried, or fissured, and
the patient may have a strawberry
tongue (Figure 1).
The distal extremity changes of
KS are progressive and include erythema of the palms and soles along
with indurative edema of the hands
and feet. Periungual desquamation
(Figure 2) of the fingers and toes follows the swelling and is noticed on
days 10 to 25. Beau lines (transverse
grooves across the fingernails) may
appear 2 to 3 months after disease
onset.
The polymorphous exanthema of
KS is characterized by macules and
papules without any vesicle or bullae formation. It is prominent on the
trunk and extremities. In two-thirds
Figure 2 – Periungual
desquamation follows
swelling in Kawasaki
syndrome, as seen here
on a child’s fingertips.
IIM_07012008_00322.ps 6/16/08 10:58 AM Page 322
FEVER AND RASH continued
Figure 3 – Perineal accentuation
of exanthema occurs in two-thirds
of cases of Kawasaki syndrome.
of cases, it is accentuated in the perineal
area (Figure 3). Fever
and sore throat manifest 2 to 5 days before
the rash appears, and
the rash fades without residua within 10
days.
The least prominent sign of KS is
cervical adenopathy,
which is present in
about 50% of children
with KS (other signs
and symptoms discussed are present in
about 90% of patients). This cervical adenopathy is
characterized by an erythematous,
Therapeutic agents
Amoxicillin
Clindamycin
Intravenous
immunogammaglobulin
Figure 4 – Cervical adenopathy,
characterized by an erythematous,
indurated, nonsuppurative anterior
cervical node of at least 1.5 cm in
diameter, is less prominent than
other signs or symptoms of Kawasaki
syndrome. Nevertheless, it occurs
in up to 50% of affected children.
indurated, nonsuppurative anterior
cervical node of at least 1.5 cm in diameter (Figure 4).
Additional characteristics of KS
include constitutional symptoms (irritability, fatigue, and anorexia), GI
symptoms (abdominal pain with or
without vomiting and diarrhea, hepatic dysfunction with possible hydrops of the gallbladder, and pancreatitis), skeletal symptoms (arthritis
or tympanitis with possible hearing
loss), and lymphoid symptoms (ex-
udative tonsillitis).
Laboratory abnormalities may include an elevated ESR or increases in
other acute phase reactants, elevated
transaminase levels, thrombocytosis,
and hypoalbuminemia. ❖
REFERENCE
1. American Academy of Pediatrics. Summaries
of infectious diseases. In: Pickering LK, ed. Red
Book: 2003 Report of the Committee on Infectious
Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:412-415.
IIM_07012008_00323.ps 6/16/08 11:00 AM Page 323
IDAlert
■ What You Need to Know About the ACIP’s
Recommendations on Herpes Zoster Vaccination
[Infect Med. 2008;25:323-325]
The CDC’s Advisory Committee on
Immunization Practices (ACIP)
recommends that all persons
older than 60 years be immunized
against the varicella-zoster virus
that causes herpes zoster with a
single dose of the live, attenuated
virus vaccine Zostavax (Merck &
Co, Inc, Whitehouse Station, NJ).
Furthermore, it urges clinicians
to offer the vaccine on the first
available clinical encounter.
The recommendations, which will
appear in Morbidity and Mortality
Weekly Report (MMWR), can be
accessed online.1 These recommendations are the first made by the
ACIP advocating use of a live, attenuated virus vaccine for prevention of
herpes zoster. The hope—promised
by results of several clinical trials
cited in the MMWR article—is that
routine immunization of older
adults will significantly ameliorate
the incidence of and morbidity
associated with herpes zoster.
About 1 million cases of herpes
zoster are diagnosed annually in the
United States. Many of them will be
associated with postherpetic neuralgia (PHN), stated the ACIP, which
summarized various other complications in its recommendations statement. Included are ocular symptoms
and sequelae (ie, herpes zoster
ophthalmicus); varicella-zoster virus
viremia; and serious, potentially
fatal neurological conditions and
viral dissemination to viscera that
can occur in persons who are
immunocompromised. Older persons (beginning at about age 50) are
particularly at risk for development
of herpes zoster, with 2 studies calculating that 50% of persons who
live to age 85 years will have experienced this condition and subsequent
PHN.2,3
The Vaccine and Vaccination
Each 0.65-mL dose of the zoster
vaccine (when reconstituted and
stored at room temperature for up
to 30 minutes) contains a minimum
of 19,400 plaque-forming units of the
Oka/Merck strain of varicella-zoster
virus. This vaccine is appreciably
more potent than the varicella
vaccine routinely used in children to
prevent chickenpox (ie, Varivax, also
manufactured by Merck & Co, Inc).
It is administered subcutaneously to
the deltoid area. A single dose is all
that is required (booster doses are
not licensed for use).
Zoster vaccine should be stored in
a freezer that maintains an average
temperature of 15°C (5°F) or colder. Once reconstituted, the vaccine
should be used immediately: within
30 minutes. After this time, the
potency degrades. If unused, the
reconstituted vaccine should be
discarded.
The zoster vaccine is licensed for
use only in persons 60 years and
older. It is safe for use in persons
receiving blood products. Persons
who already have received immunization against varicella-zoster
virus should not be re-immunized;
however, the ACIP stated that
concern regarding unintentional
re-immunization in persons 40 years
and older was slight because
varicella vaccination did not begin in
the United States until 1995. The
ACIP also noted that clinicians need
not question older patients about a
history of chickenpox or conduct
serological testing for varicella
immunity before administering the
vaccine. Persons who have had an
episode of herpes zoster in the past
can receive the vaccine, but it should
not be used to treat acute herpes
zoster or PHN or be used as prophylaxis against PHN. Precluding
contraindications and precautions
related to health status, persons
with chronic renal failure, diabetes
mellitus, rheumatoid arthritis,
chronic pulmonary disease, or other
chronic conditions can receive the
vaccine.
Vaccine Coadministration
Although the zoster vaccine can
be administered along with the
trivalent inactivated influenza
vaccine without compromising the
effectiveness of either one, no data
are available on the effects of administering the zoster vaccine with
other vaccines that are routinely
recommended for persons 60 years
and older. Because simultaneous
administration of most commonly
used live, attenuated and inactivated
vaccines, in general, has yet to be
associated with impaired immune
response and has not been associated with an increased rate of adverse
events,4 the zoster vaccine can be
administered in the setting of other
indicated (inactivated) vaccines
during the same office visit.
The ACIP reminded clinicians
that when multiple vaccines are to
IIM_07012008_00324.ps 6/16/08 11:00 AM Page 324
IDAlert continued
Table – Who should not receive the zoster vaccine because
of immunocompromise
Persons who should not
receive the vaccine
Exceptions
Persons with HIV/AIDS
Persons with leukemia,
lymphomas, or other malignant
bone marrow or lymphatic
neoplasms
Persons in whom leukemia is
in remission and who have not received
chemotherapy or radiation for at least
3 months4
Persons receiving immunosuppressive therapy, including
high-dose corticosteroids
(> 20 mg/d of prednisone or
equivalent) for 2 weeks or more
At least a month should elapse between
discontinuation of the immunosuppressive therapy and zoster vaccination4,a
Persons with evidence of any
unspecified cellular
immunodeficiency
Persons with impaired humoral
immunity, such as hypogammaglobulinemia or dysgammaglobulinemia
Persons undergoing hematopoietic stem cell transplant
Clinical discretion may be applied,
but if a decision to vaccinate is made,
the vaccine should be administered at
least 24 months after the transplant
procedure
Persons receiving recombinant
human immune mediators
and immune modulators
(adalimumab, infliximab, and
etanercept)
Vaccination should either occur weeks
before therapy is initiated or at least
1 month after therapy is discontinued
a
Patients receiving short-term (< 14 days) or low to moderate doses of corticosteroids (< 20 mg/d
of prednisone or equivalent) or topical, intra-articular, bursal, or tendon injections or long-term
alternate-day low to moderate doses of short-acting systemic corticosteroids can receive the
zoster vaccine. In addition, low-dose methotrexate (< 0.4 mg/kg/wk), azathioprine (< 3 mg/kg/d),
or 6-mercaptopurine (< 1.5 mg/kg/d) therapy is not a contraindication for administration of zoster
vaccine.
be administered during a single
office visit, they should be administered to different anatomic sites
using separate syringes. Although
the zoster vaccine can be administered at any time along with an
inactivated virus vaccine, it should
be administered at least 4 weeks
before or after administration of another live, attenuated virus vaccine.
Who Should Not Be
Vaccinated
Because the risk of morbidity and
mortality from herpes zoster is
heightened in immunocompromised persons, eligible patients
who are scheduled to begin immunosuppressive therapy should
be immunized at least 14 days
(and preferably a month, according
to some experts5) before immunosuppressive therapy is initiated.
Otherwise, immunization is contraindicated in immunocompromised persons, including those
receiving immunosuppressive
drugs. However, exceptions and
caveats to these guidelines exist
(Table).
Although a history of neomycinassociated contact dermatitis is not
a contraindication to receiving the
zoster vaccine, persons who have
a history of anaphylactic reaction
to any component of the vaccine,
including neomycin, should not
receive it.4 Pregnant women—who
are not in the target age group
for herpes zoster immunization
anyway—also should not receive
the vaccine. Clinicians should
be aware that the CDC and the
vaccine’s manufacturer have
established a registry to monitor
maternal-fetal outcomes of pregnant women who inadvertently
have been administered live, attenuated varicella-zoster virus–type
vaccines within a month of becoming pregnant. The telephone number of the registry is 800-986-8999.
Persons who are receiving an
antiviral medication, such as
acyclovir, famciclovir, or valacyclovir, should not be vaccinated in
the setting of active therapy. Rather,
therapy should be discontinued for
at least 24 hours before the zoster
vaccine is administered and at least
14 days should elapse postvaccination before antiviral therapy is
resumed.4 Because antiviral agents
are active against herpesviruses,
they could interfere with vaccine
effectiveness.
IIM_07012008_00325.ps 6/16/08 11:00 AM Page 325
Additional Notes and
Caveats
Clinicians are asked to document
all immunizations in the patient’s
medical record, per the ACIP’s
General Recommendations on
Immunization, published in 2006.4
The type of vaccine, the vaccine’s
manufacturer, anatomic site and
route of delivery, the date of
vaccine administration, lot number
of the vaccine, and name of the
administering facility should be
recorded. In addition, to help avoid
inadvertent re-immunization,
patients should be given a copy of
the document containing a record
of the vaccination.
If the zoster vaccine was
inadvertently administered to a
child, the ACIP recommends that
the dose be counted as a single
valid dose of varicella vaccine. If
the erroneously administered dose
of zoster vaccine was given instead
of the first dose of varicella vaccine,
a second dose of varicella vaccine
is required. The ACIP has requested that such errors be reported to
the Vaccine Adverse Event Reporting System (VAERS) whether or
not an adverse event occurs.
Conversely, if a clinician mistakenly administers varicella vaccine
to a person for whom the zoster
vaccine was indicated, no specific
safety concerns apply; however, the
dose should be considered invalid,
and the patient should immediately be given a dose of zoster vaccine.
If a delay in recognition of the error
occurs, the zoster vaccine should be
promptly administered 28 days
after the varicella vaccine was
given.
As with other vaccines, clinically
significant adverse events should
be reported to VAERS even if a
causal relation to vaccination is
questionable. Clinicians are encouraged to enter reports electronically
at https://secure.vaers.org/
VaersDataEntryintro.htm. The
Web site of the VAERS is www.
vaers.hhs.gov and the telephone
number is 800-822-7967.
REFERENCES
1. Centers for Disease Control and Prevention.
Prevention of herpes zoster. Recommendations of the Advisory Committee on Immunization Practices (ACIP). www.cdc.gov/
mmwr/preview/mmwrhtml/rr57e0515a1.
htm?s_cid=rr57e0515_e. Accessed June 10,
2008.
2. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in
Canada and the United Kingdom. Epidemiol
Infect. 2001;127:305-314.
3. Schmader K. Herpes zoster in older adults.
Clin Infect Dis. 2001;32:1481-1486.
4. Centers for Disease Control and Prevention.
General recommendations on immunization
of the Advisory Committee on Immunization
Practices. MMWR. 2006;55(RR-15):1-48.
5. Ihara T, Kamiya H, Torigoe S, et al. Viremic
phase in a leukemic child after live varicella
vaccination. Pediatrics. 1992;89:147-149.
IIM_07012008_00326.ps 6/16/08 11:01 AM Page 326
ImagesinInfectiousDisease
Pill Impaction Mimicking
Appendicitis in HIV-Positive Patient
45-year-old Hispanic man who acquired HIV infection in April 2003 presented with a 24-hour history of worsening right lower quadrant pain accompanied by fever, decreased appetite, nausea, and
vomiting. The pain was described as sharp, constant, and
nonradiating. He denied any accompanying diarrhea,
constipation, urinary frequency, dysuria, dyspepsia, reflux symptoms, or previous episodes of abdominal pain.
There was no history of recent travel. His current CD4+
cell count was 239/µL. In May 2003, he had a CD4+ cell
count nadir of 133/µL. His HIV RNA level has remained
undetectable at less than 50 copies/mL since starting firstline antiretroviral therapy in June 2003. Therapy consists
of coformulated zidovudine/lamivudine/abacavir and
efavirenz. He has never had opportunistic infections or
other major medical illnesses.
Physical examination revealed a temperature of 38.2ºC
(101°F); pulse rate, 106 beats per minute; 10 out of 10
tenderness over the right lower quadrant with muscle
guarding; and positive Rovsing, obturator, and psoas
signs. Rectal examination showed tenderness over the
right rectal vault.
Laboratory analysis demonstrated a white blood cell
count of 13 106/L (76% neutrophils). Findings from uri-
A
Figure 1
Figure 2
nalysis were normal. Findings on a CT scan of the abdomen with contrast were normal with no evidence of
appendicitis. Because of persistent abdominal pain with
normal findings on the CT scan of the abdomen, colonoscopy was performed. Figures 1, 2, and 3 are images
taken at the level of the terminal ileum. Figure 1 shows an
impacted pill in the appendiceal orifice. Figure 2 shows
the removal of the pill using forceps. Figure 3 shows mild
residual inflammation of the appendiceal orifice after removal of the impacted pill.
Discussion
Abdominal pain is a frequent presenting symptom
among HIV-positive patients seeking care at emergency
departments. The incidence is estimated to be 12% to
45%.1 In one retrospective study conducted in 1997 at San
Francisco General Hospital, abdominal pain was the sole
complaint in 18% of the patients.1 The majority, however,
reported other accompanying symptoms. The most common were nausea/vomiting (58%), diarrhea (32%), and
fever (21%).
Evaluation of the cause of abdominal pain rests on
thorough history taking and physical examination. The
differential diagnosis of right lower quadrant pain in
IIM_07012008_00329.ps 6/16/08 11:01 AM Page 329
ImagesinInfectiousDisease
a non-immunocompromised, HIV-negative patient includes appendicitis; diverticular disease and its complications; intra-abdominal abscesses; kidney stones; sexually transmitted diseases; enterocolitis; and intestinal
obstruction from mechanical causes, such as strictures,
masses, volvulus, and intussusception.
The differential diagnosis of right lower quadrant pain
among HIV-positive patients also includes malignancies,
such as lymphoma and Kaposi sarcoma, and opportunistic infections, such as those caused by mycobacteria (ie,
Mycobacterium tuberculosis and Mycobacterium avium-intracellulare) and cytomegalovirus. Immune reconstitution
syndrome associated with recent introduction of antiretroviral therapy also may produce atypical presentations
of disease. The list of differential diagnoses becomes more
lengthy and complex as the CD4+ cell count declines.
Workup of abdominal pain in a patient with HIV infection is the same as that for the noninfected patient.2
However, because of the vast differential diagnoses, the
probability of coexisting conditions caused by multiple
pathogens,3 and atypical presentations of common disorders,4 radiological imaging such as CT and abdominal
sonography should be used early in the assessment of abdominal pain in HIV-positive patients.2
Normal findings on a CT scan of the abdomen may
lead the clinician to consider endoscopic procedures (ie,
esophagogastroduodenoscopy or colonoscopy). Colonoscopy, in this case, served both diagnostic and therapeutic purposes.
Pill impaction that causes inflammation in the intesFigure 3
tinal mucosa is an unusual cause of abdominal pain. The
impacted pill was removed endoscopically. The patient
was given metoclopramide, a prokinetic agent, for a
week. Pill impaction has not recurred. To our knowledge,
this is the first reported case of pill impaction presenting
clinically as an appendicitis mimic in a patient who is
HIV-positive.
It is unknown what causes pill impaction among HIVpositive patients. Varying degrees of enteropathy develop in HIV-infected patients, especially those who have
advanced disease. AIDS patients have been shown to
have delayed gastric emptying5 with impairment of both
intestinal absorption and permeability,6 factors that may
promote pill impaction with resulting local mucosal inflammation. None of the medications that are used to
treat HIV infection have been shown to significantly affect intestinal function (absorption, permeability, and inflammation) or alter intestinal transit times.5
Recurrent pill impaction should warrant manometric
studies with or without gastric or small-intestine biopsies
to determine the cause and appropriate treatment. Prokinetic agents, such as metoclopramide and erythromycin, and also octreotide provide short-term, symptomatic
relief. ❖
The case and images were submitted by Mauro Torno, MD, and
Michael Shallman, MD, of Long Beach Health Department and
St Mary Medical Center in Long Beach, Calif.
REFERENCES
1. Yoshida D, Caruso JM. Abdominal pain in the HIV infected patient. J Emerg
Med. 2002;23:111-116.
2. Wilcox CM, Friedman SL. Gastrointestinal manifestations of the acquired
immunodeficiency syndrome. In: Feldman M, Sleisenger MH, Scharschmidt
BF, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 6th ed. Philadelphia: WB Saunders; 1998:387-409.
3. Slaven EM, Lopez F, Weintraub SL, et al. The AIDS patient with abdominal
pain: a new challenge for the emergency physician. Emerg Med Clin North
Am. 2003;21:987-1015.
4. Kuhlman JE, Fishman EK. Acute abdomen in AIDS: CT diagnosis and triage.
Radiographics. 1990;10:621-634.
5. Sharpstone D, Neild P, Crane R, et al. Small intestinal transit, absorption,
and permeability in patients with AIDS with and without diarrhoea. Gut.
1999;45:70-76.
6. Bjarnason I, Sharpstone DR, Francis N, et al. Intestinal inflammation, ileal
structure and function in HIV. AIDS. 1996;10:1385-1391.
YOUR CONTRIBUTIONS
ARE INVITED!
Send slides or prints with a short description of what
is shown. An honorarium will be awarded for each
published photograph or set of photographs. Send to:
Images, Infections in Medicine, 330 Boston Post Road,
PO Box 4027, Darien, CT 06820-4027.
IIM_07012008_000330R.ps 6/23/08 12:50 PM Page 330
PediatricBulletin
Streptococcus pneumoniae 19A:
An Emerging Threat
Benjamin Estrada, MD
University of South Alabama, Mobile
[Infect Med. 2008;25:330, 334]
Key words: Heptavalent pneumococcal conjugate vaccine (PCV7) ■ Streptococcus pneumoniae 19A
■ Multidrug resistance
ince the licensure of the heptavalent pneumococcal
conjugate vaccine (PCV7) in 2000, the prevalence of
invasive pneumococcal disease (IPD) among children in the United States has decreased significantly. The
incidence of IPD caused by pneumococcal serotypes associated with PCV7 among children younger than 5 years
decreased from 80 cases per 100,000 population in 1998 to
1999 to 4.6 cases per 100,000 population in 2003.1 Various
studies have demonstrated that nasopharyngeal colonization with pneumococcal serotypes covered by the
vaccine also has decreased. However, several studies suggest that in some settings, these bacterial populations
have been replaced with Streptococcus pneumoniae serotypes not covered by the vaccine.2,3
Among the various pneumococcal serotypes (19A, 6A,
3, and 15) that have been recognized as emerging threats
during recent years, S pneumoniae 19A is, by far, the most
prominent. This serotype has been associated not only
with the development of IPD but also with a high level
of resistance to multiple antibiotic classes.2,4,5
IPD surveillance in Massachusetts during 2001 to 2006
identified a significant increase in cases caused by serotypes not covered by the PCV7.2 The percentage of infections caused by serotype 19A increased from 10% during
2001 to 2003 to 41% during 2005 to 2006. In Alaska,
serotype 19A was the cause of 28.3% of cases of IPD among
children younger than 2 years between 2004 and 2006.3
In addition to IPD, multiresistant serotype 19A also has
been linked to the development of otitis media. As evidenced by Pichichero and Casey5 and by Jacobs and colleagues6 in 2 separate studies, a significant challenge related to this clinical situation is the high level of resistance
that many of these isolates have to antibiotics (such as
amoxicillin, trimethoprim, macrolides, clindamycin, oral
S
cephalosporins, and ceftriaxone) most commonly used to
treat otitis media in children.
The direct effect of PCV7 in serotype selection or replacement is not yet fully understood. Although serotype
selection induced by lack of effectiveness of PCV7 against
serotype 19A is believed to be 1 of the main factors associated with serotype 19A proliferation, it is not the only
factor. Moore and colleagues7 have suggested that antibiotic resistance, clonal expansion, and capsular switching
also have contributed to the emergence of this serotype
as the predominant cause of IPD in the United States. In
addition, it is important to emphasize that according to a
recent study by Hwa Choi and colleagues,8 multidrugresistant 19A serotypes began to increase in South Korea
before the introduction of PCV7.
The introduction and widespread administration of
PCV7 to children in the United States has led to a significant decrease in the incidence of IPD. However, it is
important for clinicians to recognize that because of
multiple factors, multidrug-resistant serotype 19A has
emerged as a significant cause of pneumococcal disease.
Clinicians need to consider the presence of this serotype
in situations in which IPD is observed. In addition, infection with S pneumoniae 19A should be considered in children with otitis media who fail to respond to antibiotic
therapy. ❖
REFERENCES
1. Centers for Disease Control and Prevention. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine
on incidence of invasive pneumococcal disease—United States, 1998-2003.
MMWR. 2005;54:893-897.
2. Centers for Disease Control and Prevention. Emergence of antimicrobialresistant serotype 19A Streptococcus pneumoniae—Massachusetts, 2001-2006.
MMWR. 2007;56:1077-1080.
3. Singleton RJ, Hennessy TW, Bulkow LR, et al. Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children with
Dr Estrada is professor of pediatrics, division of pediatric infectious diseases, University of South Alabama, Mobile.
continued on page 334
IIM_07012008_00331.ps 6/16/08 11:04 AM Page 331
MENINGITIS
A Differential Diagnosis of
Drug-Induced Aseptic Meningitis
Clair Cascella, MD, Sara Nausheen, MD, and Burke A. Cunha, MD
Drug-induced aseptic meningitis should be included in the
differential diagnosis of viral/aseptic meningitis. Clinicians
should use historical clues in patients presenting with signs and
symptoms of viral meningitis to aid in the differentiation of
drug-induced aseptic meningitis from other causes of aseptic
meningitis. Viruses are the most common cause of aseptic
meningitis, with enteroviruses being the most common among
viruses in cases presenting as aseptic meningitis. Ibuprofen is
currently the most common cause of drug-induced aseptic
meningitis. Drug-induced aseptic meningitis is a benign condition without long-term sequelae. The diagnosis of druginduced aseptic meningitis is made by establishing a causal
relationship between the use of the drug and the onset of signs
and symptoms, supported by negative tests for infectious
causes of symptoms and rapidity of resolution after the drug
is discontinued. [Infect Med. 2008;25:331-334]
Key words: Drug-induced aseptic meningitis ■ Enteroviral meningitis
septic meningitis refers to a
nonbacterial inflammation of
the leptomeninges.1 Viruses
are the most common cause of aseptic meningitis, and the most common
viruses that cause aseptic meningitis
are enteroviruses. Drug-induced
aseptic meningitis is rare but probably more common than the literature
would suggest; therefore, it should
be included in the differential diagnosis of aseptic meningitis, par-
A
ticularly if aseptic meningitis develops in association with the use of
NSAIDs or other offending drugs
(Table 1) and if clinical recovery is
rapid following cessation of the drug
or if results of viral studies are
negative.
The pathogenetic mechanisms of
drug-induced aseptic meningitis are
not fully understood, but 2 major
mechanisms have been proposed.
One proposed mechanism is that the
Dr Cascella is a first-year medical resident in the department of medicine at Winthrop-University
Hospital in Mineola, NY. Dr Nausheen is a second-year fellow in the infectious disease division at
Winthrop-University Hospital. Dr Cunha is chief of the infectious disease division at WinthropUniversity Hospital and professor of medicine at State University of New York School of Medicine in Stony Brook.
meninges are directly irritated by the
intrathecal administration of drugs.
The other is that the meninges are
expressing an immunological hypersensitivity—most often a type 3 or
type 4 hypersensitivity reaction—to
the offending drug.2
An association between hypersensitivity reactions and underlying
collagen-vascular disease or rheumatological disease has been reported.1-10 Typically, the cerebrospinal
fluid (CSF) profile in drug-induced
aseptic meningitis is that of a neutrophilic pleocytosis accompanied
by a normal CSF lactic acid level
and a variably elevated CSF protein
level.1,3 Patients who have druginduced meningitis may have eosinophils present in the CSF (fewer
than 5%).
THE CLINICAL PICTURE
Patients who have drug-induced
aseptic meningitis typically present
with fever, headache, and nuchal
rigidity. Signs and symptoms usually appear within 24 to 48 hours after
drug ingestion, but symptoms may
not occur until 2 years post-therapy.2,6 Drug-induced aseptic meningitis may develop in a patient who initially was able to tolerate the causative drug.1,6
In patients who have drug-induced aseptic meningitis, the typical
CSF profile reveals a neutrophilic
pleocytosis, with several hundred to
several thousand white blood cells
IIM_07012008_000332R.ps 6/23/08 12:50 PM Page 332
ASEPTIC MENINGITIS continued
Table 1 – Medications known to cause aseptic meningitis
Medications
Common
Uncommon
Rare
NSAIDs
Ibuprofen
Sulindac
Naproxen
Diclofenac
Rofecoxib
Ketoprofen
Salicylatesa
Tolmetin
Piroxicam
Celecoxib
Antimicrobials
Trimethoprim/
sulfamethoxazole
Trimethoprim
Sulfonamides
Cephalosporins
Penicillin
Amoxicillin
Amoxicillin/clavulanate
Isoniazid
Ciprofloxacin
Metronidazole
Pyrazinamide
Valacyclovir
Indinavir
Ornidazole
Immunomodulating agents
Monoclonal
antibody OKT3
Intravenous IgG
Azathioprine
Levamisole
Efalizumab
Infliximab
Sulfasalazine
Intrathecal agents
Metrizamide
Cytarabine
Methylprednisolone
acetate
Methotrexate
Gentamicin
Iophendylate
Iopamidol
Iohexol
Hydrocortisone
Baclofen
Gadolinium
Diethylenediamine
pentaacetic acid
Spinal anesthesia
Other
Carbamazepine
Monovalent mumps and
rubella vaccine
Hepatitis B vaccine
Ranitidine
Famotidine
Dexchlorpheniramine
Phenazopyridine
Radiolabeled albumin
Lamotrigine
Allopurinol
Pentoxifylline
Methotrexate
a
With serum levels ≈ 70 mg/dL.
Adapted from Hopkins S, Jolles S. Expert Opin Drug Saf. 20053; Marinac J. Ann Pharmacother. 1992.4
per microliter; normal glucose levels; and variably elevated protein
levels.1,2,4-7 Results of CSF Gram stain
and cultures are negative, and lymphocytic or eosinophilic pleocytosis
may occur. Drug-induced aseptic
meningitis is reversible, with most
signs and symptoms resolving within 24 to 48 hours after the drug
is discontinued.2,4-7
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of aseptic
meningitis is extensive and includes
infectious and noninfectious causes
(Table 2).1-10 Drug-induced aseptic
IIM_07012008_00333.ps 6/16/08 11:04 AM Page 333
ASEPTIC MENINGITIS
Table 2 – Causes of acute aseptic meningitis
Common
Uncommon
Rare
Bacterial
Lyme disease
Leptospirosis
Mycobacterium
tuberculosis infection
Subacute bacterial
endocarditis
Parameningeal infection
(epidural subdural
abscess, sinus or
ear infection)
Partially treated bacterial
meningitis
Treponema pallidum
infection
Mycoplasma pneumoniae
infection
Rocky Mountain
spotted fever
Brucellosis
Ehrlichiosis
Borrelia recurrentis
infection (relapsing fever)
Spirillum minus infection
(rat-bite fever)
Nocardiosis
Actinomyces infection
Viral
Echovirus infection
Coxsackievirus infection
Mumps
St Louis encephalitis
Eastern equine encephalitis
Western equine encephalitis
California encephalitis
Herpes simplex virus
type 1 infection
Herpes simplex virus
type 2 infection
HIV infection
Lymphocytic
choriomeningitis
Poliovirus infection
Epstein-Barr virus
infection
Adenovirus infection
Cytomegalovirus infection
Varicella
Measles
Rubella
Parainfluenza virus infection
Rotavirus infection
Vaccinia virus infection
West Nile virus infection
Human herpesvirus 6 infection
Japanese B encephalitis
Murray Valley encephalitis
Fungal
Cryptococcosis
Coccidioidomycosis
Histoplasmosis
Candidiasis
Blastomycosis
Aspergillosis
Sporotrichosis
Parasitic
Angiostrongylus
cantonensis infection
Toxoplasmosis
Cysticercosis
Trichinella spiralis infection
Systemic diseases
Neurosarcoidosis
Behçet disease
Systemic lupus
erythematosus
Vogt-Koyanagi-Harada
syndrome
Sjögren syndrome
Rheumatoid arthritis
Neurosurgical
procedures
Neurosurgery (posterior
fossa syndrome)
Intrathecal agents
Infectious causes
Noninfectious causes
Neoplastic diseases
Medications
Intracranial tumors
Lymphoma
Leukemia
Metastatic carcinomas
See Table 1
Adapted from Chaudhry HJ, Cunha BA. Postgrad Med. 19911; Connolly KJ, Hammer SM. Infect Dis Clin North Am. 1990.8
IIM_07012008_00334.ps 6/16/08 11:04 AM Page 334
ASEPTIC MENINGITIS continued
meningitis is a diagnosis of exclusion. It is important to obtain a history of medical disorders such as systemic lupus erythematosus, the most
frequent underlying condition associated with drug-induced aseptic
meningitis.7 It is also important to
make inquiries about recent vaccinations that may be implicated in the
development of aseptic meningitis.2
Patients with enteroviral meningitis often present with an early neutrophilic pleocytosis, although a shift
to lymphocytic pleocytosis usually
occurs within the first 48 hours.1,4,7,10
In normal hosts, enteroviral meningitis has a benign course, usually
lasting about 2 weeks. Recovery is
typically characterized by decreasing frequency of headaches and stiff
neck within the 2-week period.7,9
The condition may be diagnosed by
polymerase chain reaction testing of
the CSF, by viral culture of throat
and rectal specimens, or by serological tests for enteroviruses. CSF lactic
acid levels readily differentiate bacterial from viral meningitis.9
Quick resolution of symptoms is
an important sign that distinguishes
drug-induced aseptic meningitis
from viral meningitis, in which recovery usually requires 10 to 14
days.7 CSF glucose levels are usually normal in drug-induced aseptic
meningitis, which may help in differentiating it from bacterial meningitis in which glucose levels usually
are low.4,6,7,10
Analysis of C-reactive protein
(CRP) levels also may be helpful in
distinguishing bacterial from a druginduced aseptic meningitis because
CRP levels are usually highly elevated in bacterial meningitis compared
with drug-induced aseptic meningitis.2,5 The diagnosis of drug-induced
aseptic meningitis is made by establishing a temporal relationship with
the administration of the drug and
onset of clinical symptoms and rapid
resolution of the syndrome after
drug withdrawal.2-4,7,10
The most common cause of druginduced aseptic meningitis is
NSAIDs. The list of medications that
cause drug-induced aseptic meningitis continues to increase and currently includes a wide variety of
medications (Table 1).11-28
REFERENCES
1. Chaudhry HJ, Cunha BA. Drug-induced aseptic meningitis: diagnosis leads to quick resolution. Postgrad Med. 1991;90:65-70.
2. Jolles S, Sewell WA, Leighton C. Drug-induced
aseptic meningitis: diagnosis and management. Drug Saf. 2000;22:215-216.
3. Hopkins S, Jolles S. Drug-induced aseptic
meningitis. Expert Opin Drug Saf. 2005;4:285297.
4. Marinac J. Drug- and chemical-induced aseptic
meningitis: a review of the literature. Ann Pharmacother. 1992;26:813-822.
5. Nettis E, Calogiuri G, Colanardi MC, et al.
Drug-induced aseptic meningitis. Curr Drug
Targets Immune Endocr Metabol Disord. 2003;3:
143-149.
6. Rodríguez SC, Olguín AM, Miralles CP, Viladrich PF. Characteristics of meningitis caused
by Ibuprofen: report of 2 cases with recurrent
episodes and review of the literature. Medicine
(Baltimore). 2006;85:214-220.
7. Moris G, Garcia-Monco JC. The challenge of
drug-induced aseptic meningitis. Arch Intern
Med. 1999;159:1185-1194.
8. Connolly KJ, Hammer SM. The acute aseptic
meningitis syndrome. Infect Dis Clin North Am.
1990;4:599-622.
9. Cunha BA. The diagnostic usefulness of cerebrospinal fluid lactic acid levels in central nervous system infections. Clin Infect Dis. 2004;39:
1260-1261.
10. Kepa L, Oczko-Grzesik B, Stolarz W, SobalaSzczygiel B. Drug-induced aseptic meningitis
in suspected central nervous system infections.
J Clin Neurosci. 2005;12:562-564.
11. Bonnel RA, Villalba ML, Karwoski CB, Beitz J.
Aseptic meningitis associated with rofecoxib.
Arch Intern Med. 2002;162:713-715.
12. Papaioannides DH, Korantzopoulos PG, Giotis
CH. Aseptic meningitis possibly associated
with celecoxib. Ann Pharmacother. 2004;38:172.
13. Wittmann A, Wooten GF. Amoxicillin-induced
aseptic meningitis. Neurology. 2001;57:1734.
14. Mateos V, Calleja S, Jiménez L, Suárez-Moro R.
Recurrent aseptic meningitis associated with
amoxicillin-clavulanic acid [in Spanish]. Med
Clin (Barc). 2000;114:79.
15. Fobelo MJ, Corzo Delgado JE, Romero Alonso
A, Gómez-Bellver MJ. Aseptic meningitis related to valacyclovir. Ann Pharmacother. 2001;35:
128-129.
16. Mondon M, Ollivier L, Daumont A. Aseptic
meningitis ornidazole-induced in the course of
infectious endocarditis [in French]. Rev Med Interne. 2002;23:784-787.
17. Kashyap AS, Kashyap S. Infliximab-induced
aseptic meningitis. Lancet. 2002;359:1252.
18. Mäkelä A, Nuorti JP, Peltola H. Neurological
disorders after measles-mumps-rubella vaccination. Pediatrics. 2002;110:957-963.
19. Ishihara O, Omata T. A case of famotidineinduced aseptic meningitis [in Japanese]. Rinsho Shinkeigaku. 2000;40:48-50.
20. Lafaurie M, Dixmier A, Molina JM. Aseptic
meningitis associated with intravenous administration of dexchlorpheniramine. Ann Med Interne (Paris). 2003;154:179-180.
21. Greenberg LE, Nguyen T, Miller SM. Suspected
allopurinol-induced aseptic meningitis. Pharmacotherapy. 2001;21:1007-1009.
22. Mathian A, Amoura Z, Piette JC. Pentoxifylline-induced aseptic meningitis in a patient
with mixed connective tissue disease. Neurology. 2002;59:1468-1469.
23. Peter JB. Ibuprofen meningitis. Neurology. 1990;
40:866-867.
24. Lee RZ, Hardiman O, O’Connell PG. Ibuprofen-induced aseptic meningoencephalitis.
Rheumatology (Oxford). 2002;41:353-355.
25. Hawboldt J, Bader M. Intramuscular methotrexate-induced aseptic meningitis. Ann Pharmacother. 2007;41:1906-1911.
26. Khan S, Sharrack B, Sewell WA. Metronidazole-induced aseptic meningitis during Helicobacter pylori eradication therapy. Ann Intern
Med. 2007;146:395-396.
27. Kluger N, Girard C, Gonzalez V, et al. Efalizumab-induced aseptic meningitis. Br J Dermatol.
2007;156:189-191.
28. Nesseler N, Polard E, Arvieux C, et al. Aseptic
meningitis associated with lamotrigine: report
of two cases. Eur J Neurol. 2007;14:e3-e4.
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high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA.
2007;297:1784-1792.
4. Farrell DJ, Klugman KP, Pichichero M. Increased antimicrobial resistance
among nonvaccine serotypes of Streptococcus pneumoniae in the pediatric
population after the introduction of 7-valent pneumococcal vaccine in the
United States. Pediatr Infect Dis J. 2007;26:123-128.
5. Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA. 2007;298:1772-1778.
6. Jacobs MR, Good CE, Sellner T, et al. Nasopharyngeal carriage of respiratory pathogens in children undergoing pressure equalization tube placement
in the era of pneumococcal protein conjugate vaccine use. Laryngoscope. 2007;
117:295-298.
7. Moore MR, Gertz RE Jr, Woodbury RL, et al. Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J Infect Dis. 2008;197:1016-1027.
8. Hwa Choi E, Hee Kim S, Wook Eun B, et al. Streptococcus pneumoniae serotype
19A in children, South Korea. Emerg Infect Dis. 2008;14:275-281.
IIM_07012008_00335.ps 6/16/08 11:05 AM Page 335
Clinical MycologyUpdate
Department Editor
Duane R. Hospenthal, MD, PhD
Diagnostic Nucleic Acid Testing
for Invasive Fungal Infections
Rupal Mody, MD and Michael Zapor, MD, PhD
[Infect Med. 2008;25:335-338]
Key words: Nucleic acid testing ■ Polymerase chain reaction ■ Diagnosis ■ Fungal infections
ver the past 2 decades, there has been an alarming
increase in opportunistic fungal infections with an
associated rise in morbidity and mortality. This
trend has been attributed to the growing number of patients who are immunocompromised because of bone
marrow or solid organ transplant, immunosuppressive
drugs, AIDS, and hematological malignancies. Advances
in trauma and critical care medicine that lead to longer
survival of more patients with immunocompromising
conditions also play a role.
Historically, the most common opportunistic mycotic
infections have been those associated with Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans.
A number of fungal pathogens, including non-fumigatus
Aspergillus species and other septate moulds, as well as
members of the Zygomycetes class are emerging as important causes of fungal disease.1,2 These infections are
frequently fatal. Early recognition of these pathogens is
critical to initiating prompt, appropriate therapy.
Because all antifungal drugs, including the newer
agents, have gaps in coverage, most pathogens should be
identified at the species level when devising a therapeutic strategy. However, conventional reliance on culture
and histopathology for diagnosis of invasive fungal infections is time-consuming and frequently insensitive.
For this reason, nucleic acid–based assays are gaining attention as potentially sensitive, accurate, and rapid tests
for the diagnosis of fungal infections.
O
Dr Mody is an infectious disease fellow at the Walter Reed Army Medical Center in Washington, DC, and Dr Zapor is staff physician in the infectious disease service at the medical center. The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US
Government. The authors are employees of the US Government. This
work was prepared as part of their official duties and, as such, is not subject to copyright.
Overview of molecular diagnostics
Methods that are currently used to diagnose fungal infections include direct observation (smears, histopathology); culture of clinical specimens; and antigen/antibody
assays for detecting the cell wall components galactomannan (GM) and -glucan. More recently, polymerase
chain reaction (PCR) amplification and its variants (including multiplex PCR, nested PCR, and real-time PCR)
have been used to detect fungal pathogens, such as Candida and Aspergillus species, by amplifying genomic sequences unique to each organism.3-6
Multiplex PCR provides increased sensitivity over
standard PCR by using multiple primer pairs per reaction
to amplify more than 1 target sequence.4 Nested PCR, in
which the original target sequence is amplified and then
used as a template for additional amplifications with a
second set of primers, is more specific than conventional
PCR. Nested PCR has been used clinically for the detection of Candida species and Histoplasma capsulatum.7-10
Real-time PCR couples the assay with an amplification
product detection system (typically a fluorescent label)
and has been used to detect and quantify DNA from several fungal pathogens, including Aspergillus species, Candida species, and C neoformans.4,11-15
Fungal nuclear, mitochondrial, and ribosomal genes,
as well as RNA sequences, have been used as templates
in PCR and similar assays.16 The sensitivity of these assays is enhanced when the target sequence has multiple
copies within the genome.14,16 Ribosomal targets possess
both sequences, which are highly conserved among the
fungi and species-specific variable internal transcribed
spacer regions. Recent studies have focused on 5.8S, 18S,
and 28S ribosomal RNA and DNA genes for the detection
of Candida and Aspergillus species.7,8,10,11,13,15-17
Once target sequences are amplified by PCR, the
amplicons can be further characterized by other molecuJuly 2008 INFECTIONS in MEDICINE 335
IIM_07012008_00336.ps 6/16/08 11:05 AM Page 336
Clinical MycologyUpdatecontinued
lar biology techniques, including restriction fragment
length polymorphism analysis, nucleic acid sequencing,
Southern and Northern blot analysis, electrophoretic
karyotyping, and DNA microarray genotyping.4,5,18
Clinical application of molecular diagnostics
Although PCR assays can be used to detect any fungi,
their clinical application has mostly been applied to the
detection of Candida and Aspergillus species.13,15,19,20-26
PCR assays for Candida are very sensitive and can detect
DNA from as few as 10 organisms/mL of blood. Similarly, PCR assays for Aspergillus can detect DNA from 10 to
100 conidia/mL of blood.24
Pryce and colleagues13 suggested that real-time PCR
testing, which can detect DNA quantity over time, might
be useful for monitoring response to antifungal therapy.
Klingspor and Jalal15 also found real-time PCR assays to
be both sensitive and specific for the detection of Candida
and Aspergillus species in clinical specimens. In their
study, clinical samples (blood, sputum, tissue, cerebrospinal fluid, bronchoalveolar lavage fluid, pleural
fluid, ascites, bile, and urine) from transplant recipients
with suspected invasive fungal infections were assayed
by PCR. Of 1650 specimens assayed, 114 (6.9%) were
PCR-positive for either Candida species (n = 86) or Aspergillus species (n = 28), whereas 62 (3.8%) were culturepositive for either Candida species (n = 57) or Aspergillus
species (n = 5). Of the PCR samples positive for Candida,
72% were identifiable to species.
Ahmad and colleagues7 found semi-nested PCR to be
99% specific and more sensitive than culture in diagnosing candidemia. White and colleagues17 found that PCR
testing, when compared with latex agglutination and enzyme-linked immunosorbent assay, detected Candida infection earlier, was more sensitive, and was comparably
specific.
It has been suggested that environmental contaminants might cause false-positive PCR results when used
in the diagnosis of fungal infections.17 This has been substantiated in a study by Ljungman and colleagues21 in
which blood samples from patients with leukemia were
assayed weekly by PCR for Cytomegalovirus and fungi.
Real-time PCR results were positive in 9 samples taken
from 8 of 35 patients (3 samples positive for Aspergillus
and 5 samples positive for Candida, with 1 sample being
positive for both).21 However, only 3 of the 4 samples in
which Aspergillus species were detected corresponded
with suspicion for Aspergillus infection based on the presence of pulmonary infiltrates on a chest CT scan.21
In the same study, of 3 cases of proven fungemia attributed to Candida species, in only 1 case was the blood
PCR-positive for Candida.21 Six samples from 5 patients
were PCR-positive for Candida species.21 Two samples
came from 1 patient who had bacteremia, 1 sample came
from an asymptomatic patient, 1 sample each came from
2 patients with fever of unknown origin, and 1 sample
came from a patient with candidemia. Hence, Candida
was never recovered in culture of specimens taken from
4 of the 5 patients whose blood was PCR-positive for
Candida.21 The PCR test results may represent true positives, although, even in the absence of growth in culture,
Candida species are not always recovered from the blood
of patients with candidiasis.
Another technique useful for the diagnosis of fungal
infections is fluorescence in situ hybridization (FISH).
This assay uses fluorescein-labeled peptide nucleic acid
(PNA) probes specific for the ribosomal RNA sequences
of C albicans.27 The FDA approved 1 of these assays, the C
albicans PNA FISH (AdvanDx, Inc, Woburn, Mass), in
2004 for use in rapidly (ie, within 2.5 hours) differentiating albicans from non-albicans Candida species isolated
from blood. In one study, the reported sensitivity and
specificity of this technique was 99% and 100%, respectively.27 The same company also manufactures a dual
color C albicans/Candida glabrata FISH assay for simultaneous identification of both organisms from blood culture. The sensitivity and specificity of this dual assay are
similar to those of the C albicans PNA FISH.28
The value of PCR in the diagnosis of invasive aspergillosis has been evaluated in several studies (Table).
The sensitivity, specificity, negative predictive value, and
positive predictive value vary widely between studies depending on the pretest probability of infection and type
of PCR used (eg, real-time vs nested).22-25 The low positive
predictive value of PCR assays when bronchoalveolar
lavage specimens are used (range, 38% to 83.5%) likely reflects the difficulty in distinguishing airway colonization
from infection.22-25
The sensitivity of PCR assays in detecting Aspergillus
in serum varies from 40% to 92.3%, with improved sensitivity on serial testing.19,20,26,29 The low sensitivity of the
assay described in some studies (especially in early infection) might be attributed to transient fungemia, low-level
fungemia (ie, below the detection limits of the assay), and
a short half-life of fungal DNA (because of rapid degradation or clearance). PCR testing fares better in detecting
Aspergillus invasion of tissue, such as lung tissue, with a
reported sensitivity of 100% in one study.26
Comparisons of the GM assay and real-time PCR assay
in detecting Aspergillus infections have shown conflicting
results. Buchheidt and colleagues29 reported that the nested PCR assay is more sensitive than the GM assay, whereas both Kawazu and colleagues30 and Costa and colleagues31 reported the GM assay to be superior. If valid,
IIM_07012008_00337.ps 6/16/08 11:05 AM Page 337
Table – Reported performance of PCR in the detection of Aspergillus species
from clinical specimens
Assay
Samples (N)
Source
Sensitivity
Specificity
PPV
NPV
Real-time PCR25
96
BAL,
blood
43%
NP
NP
NP
Real-time PCR29
> 1522
BAL,
blood,
other
63.6%
63.5%
NP
NP
Real-time PCR30
1251
Blood
55%
93%
40%
96%
16
Blood
69.6% - 82.1%
(depending on
primers)
80.4% - 91.1%
(depending on
primers)
NP
NP
Real-time PCR20
401
Blood
92.3%
94.6%
60%
99.3%
Real-time PCR35
1193
Blood
100%
65%
NP
NP
PCR-ELISA26
241
Blood,
BAL,
tissue
Proven infection:
40% - 100%;
probable
infection:
44% - 66%
Proven infection:
100%; probable
infection: 100%
100%
44% - 58%
PCR-ELISA19
1205
Blood
63.6%
89.7%
63.6%
89.7%
Conventional
PCR22
197
BAL
93.9%
94.4%
83.8%
98.1%
Conventional
PCR23
68
BAL
Proven infection:
80%; probable
infection: 64%
Proven infection:
93%; probable
infection: 93%
Proven
infection:
38%;
probable
infection:
52%
Proven
infection:
99%;
probable
infection:
96%
Real-time
PCR24
PCR, polymerase chain reaction; PPV, positive predictive value; NPV, negative predictive value; BAL, bronchoalveolar lavage; NP, not provided; ELISA, enzyme-linked immunosorbent assay.
the findings of the latter 2 studies might reflect greater
shedding of fungal antigen relative to the presence of
Aspergillus nucleic acid in the blood of patients with
fungemia.
Merits and limitations of molecular diagnostics
When compared with culture and histopathology for the
diagnosis of invasive fungal infections, PCR coupled with
various hybridization techniques offers the potential of
enhanced sensitivity, specificity, and relative rapidity.
Moreover, real-time PCR such as the LightCycler PCR detection system (Roche Applied Science, Mannheim, Germany) confers the advantage of quantifying fungal DNA
and potentially might be used to monitor disease progression as well as response to therapy.25,26 PCR testing
also permits identification of individual species and
strains as well as amplification of specific sequences for
further study (eg, nucleic acid sequencing) and manipulation (eg, cloning).
However, there are drawbacks to using PCR testing in
the diagnosis of infection. The techniques for extracting
and amplifying DNA are not currently standardized,
and the reactions are expensive and vulnerable to falsepositive results due to contamination. Most important,
positive PCR results may not distinguish between contamination, colonization, or true infection, nor between
DNA extracted from dead versus viable organisms.32
Lack of recovery of live organisms also removes the option of performing antifungal susceptibility or retrospective virulence or strain testing. Nevertheless, a great
potential value of PCR derives from its negative predictive value.
continued
IIM_07012008_00338.ps 6/16/08 11:05 AM Page 338
Clinical MycologyUpdatecontinued
Conclusions
Studies show PCR assays to be both sensitive and specific in the diagnosis of infections caused by fungi such as
Aspergillus and Candida; sensitivity is typically greater
with tissue than with blood. The diagnostic value of PCR
testing may be further enhanced in the appropriate clinical setting or when the test is done in conjunction with
other tests, such as culture and the GM assay. When done
serially, quantitative PCR testing might be useful for
monitoring disease progression or response to therapy,
and potentially it could be used to differentiate colonization from infection. In addition, PCR testing has shown
promise in the diagnosis of infections caused by other
fungi, such as C neoformans, H capsulatum, and Pneumocystis jiroveci.9,33,34 However, the sensitivity of these assays
predispose them to false-positive results, and true-positive results may not distinguish between contamination,
colonization, and infection. Further clinical studies are
needed before PCR testing alone can be advocated for the
diagnosis of fungal infection. ❖
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26. Lass-Flörl C, Gunsilius E, Gastl G, et al. Diagnosing invasive aspergillosis
during antifungal therapy by PCR analysis of blood samples. J Clin Microbiol. 2004;42:4154-4157.
27. Forrest GN, Mankes K, Jabra-Rizk MA, et al. Peptide nucleic acid fluorescence in situ hybridization-based identification of Candida albicans and its impact on mortality and antifungal therapy costs. J Clin Microbiol. 2006;44:33813383.
28. Wu FP, Della-Latta R, Addison B, et al. Dual color PNA FISH assay for simultaneous identification of Candida albicans and Candida glabrata directly
from positive blood culture bottles. In: Proceedings from Infectious Disease
Society of America 2006 General Meeting; October 12-15, 2006; Toronto. Abstract 06-LB2053.
29. Buchheidt D, Hummel M, Schleiermacher D, et al. Prospective clinical evaluation of a LightCycler-mediated polymerase chain reaction assay, a nested-PCR assay and a galactomannan enzyme-linked immunosorbent assay
for detection of invasive aspergillosis in neutropenic cancer patients and
haematological stem cell transplant recipients. Br J Haematol. 2004;125:196202.
30. Kawazu M, Kanda Y, Nannya Y, et al. Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1–>3)-beta-D-glucan test in
weekly screening for invasive aspergillosis in patients with hematological
disorders. J Clin Microbiol. 2004;42:2733-2741.
31. Costa C, Costa J, Desterke C, et al. Real-time PCR coupled with automated
DNA extraction and detection of galactomannan antigen in serum by enzyme-linked immunosorbent assay for diagnosis of invasive aspergillosis.
J Clin Microbiol. 2002;40:2224-2227.
32. Bretagne S. Molecular diagnostics in clinical parasitology and mycology: limits of the current polymerase chain reaction (PCR) assays and interest of the
real-time PCR assays. Clin Microbiol Infect. 2003;9:505-511.
33. Bialek R, Weiss M, Bekure-Nemariam K, et al. Detection of Cryptococcus neoformans DNA in tissue samples by nested and real-time PCR assays. Clin
Diagn Lab Immunol. 2002;9:461-469.
34. Larsen H, Masur H, Kovacs J, et al. Development and evaluation of a quantitative, touch-down, real-time PCR assay for diagnosing Pneumocystis carinii
pneumonia. J Clin Microbiol. 2002;40:490-494.
35. Hebart H, Löffler J, Meisner C, et al. Early detection of Aspergillus infection
after allogeneic stem cell transplantation by polymerase chain reaction
screening. J Infect Dis. 2000;181:1713-1719.
IIM_07012008_00339.ps 6/16/08 11:07 AM Page 339
CASE REPORT
Acute Suppurative Thyroiditis in a
Patient With Aplastic Anemia
Yoo Seung Chung, MD, Jun-Ho Choe, MD, Wonshik Han, MD, Dong-Young Noh, MD,
Yeo-Kyu Youn, MD, and Seung Keun Oh, MD
Acute suppurative thyroiditis (AST) is a rare inflammatory
complication in patients with hematological malignancy.
Infection spreads to the thyroid from a distant site through
the bloodstream or the lymphatics. Defects such as persistent
thyroglossal duct and pyriform sinus fistula are associated
with the development of AST. Ultrasonography, barium
swallow testing, CT, and fine-needle aspiration are used
for diagnosis. Treatment includes the administration of
parenteral antibiotics, drainage, and excision. We describe
a patient with aplastic anemia and bacteremic AST.
[Infect Med. 2008;25:339-342]
Key words: Acute suppurative thyroiditis
cute suppurative thyroiditis
(AST) is a rare inflammatory
disease. The rarity of this disease can be attributed to several factors. The thyroid is well encapsulated, which may hinder the transmission of infection from surrounding
tissue to the thyroid. In addition,
a rich blood supply and lymphatic
drainage within the thyroid may be
protective against bacterial infection. Furthermore, high iodine levels within the thyroid gland may
create an environment that is unfavorable to bacterial growth.1 Reports
of AST are uncommon in patients
who have hematological malignancy. Only 9 cases have been reported
in the literature.2,3
A
Case report
A 27-year-old man presented to our
hospital with symptoms of general
weakness and fatigue. His blood test
results were positive for anemia (hemoglobin level, 2.9 g/dL). A bone
marrow biopsy specimen showed
cellularity values of 0% to 10%, a
range that is considered hypocellular
for the patient’s age; erythropoiesis,
granulopoiesis, and megakaryocyte
production were decreased. Aplastic
anemia was diagnosed, and the patient was treated with a consecutive
5-day regimen of antithymoglobulin
(ATG). At the start of chemotherapy,
the absolute neutrophil count (ANC)
was 1534/mL.
Five days after the administration
Dr Chung and Dr Choe are fellows and Dr Han, Dr Noh, Dr Youn, and Dr Oh are professors of medicine in the department of general surgery at Seoul National University College of Medicine,
South Korea.
of ATG (day 1), sudden fever and
sore throat developed. The patient’s
temperature was 39.9ºC (103.8ºF).
Blood pressure was 110/70 mm Hg,
with a pulse rate of 96 beats per
minute. Symptoms of influenza
were absent, but the patient complained of a sore throat and rightsided neck pain. No skin change or
discoloration of the neck area was
observed; however, swelling and
tenderness of the neck developed.
The ANC was 252/mL. A thyroid
function test revealed high free thyroxine levels (2.37 ng/dL; normal,
0.70 to 1.80 ng/dL), depressed thyroid-stimulating hormone levels
(0.12 mIU/L; normal, 0.4 to 4.1
mIU/L), and normal total triiodothyronine levels (91 ng/dL; normal,
87 to 184 ng/dL). A blood culture
was performed, and piperacillin
and tobramycin were administered
empirically.
Radiological examination revealed cystic lesions of the thyroid
gland with decreased enhancement;
a thyroid abscess was therefore suspected (day 3; Figure 1). No pyriform sinus fistula (PSF) was detected
by laryngoscopy or CT. Because the
blood culture grew methicillin-sensitive Staphylococcus aureus (MSSA),
cefazolin was added to the therapeutic regimen. Despite this antibiotic
therapy and ultrasonography-guided aspiration (day 6; Figures 2 and
3), the patient’s condition did not
IIM_07012008_00340.ps 6/16/08 11:07 AM Page 340
ACUTE SUPPURATIVE THYROIDITIS continued
The pathology laboratory reported a
chronic active inflammation with an
abscess in the base of an adenomatous goiter (AG) (Figure 5).
After the operation, the patient’s
fever persisted and he reported hip
joint pain, which seemed to be
caused by bacteremia. A chest CT
scan revealed multiple nodules with
cavitation in both lungs, which was
associated with a ground-glass opacity in both upper lobes and minimal
bilateral pleural effusion. These
symptoms suggested septic pneumonia and superinfection with Pneumocystis jiroveci. Nafcillin, piperacillin/tazobactam, and trimethoprim/
sulfamethoxazole were administered. When the patient’s symptoms
improved and the bacteremia resolved, the patient was discharged
from the hospital on the 51st postoperative day.
Figure 1 – This neck
CT scan shows a
cystic lesion of the
thyroid gland
with decreased
enhancement.
Figure 2 – A sonogram
at the time of aspiration
indicates diffuse
heterogeneous
echogenecity in the
lower right pole of the
thyroid gland, including
a multiseptated
cystic portion.
Discussion
Figure 3 – A microscopic
photograph of the
aspiration specimen
of the thyroid gland
demonstrates the
suspected abscess
with numerous
neutrophils and
necrotic debris
(hematoxylin-eosin
stain, original
magnification 400).
improve. Surgery was performed to
manage the thyroid abscess (day 8).
During surgery, necrotic tissue
was discovered in the lower right
pole of the thyroid gland. The left
side of the gland was lesion-free. We
performed necrosectomy of the friable necrotic tissue and drained yellow pus. Ultimately, a right subtotal
thyroidectomy was performed (Fig340 INFECTIONS in MEDICINE July 2008
ure 4). We irrigated the thyroid bed
with normal saline solution and applied a Jackson-Pratt closed-suction
drain. The volume of drainage decreased successively from 20 mL to
10 mL to 5 mL over the course of
3 days postoperatively, and the
wound was clean. Thyroid tissue
culture revealed MSSA, as did cultures of blood and aspirated mucus.
Because of its rich blood supply, lymphatic drainage, abundant iodine,
and protective fibrous capsule, the
thyroid gland is very resistant to infection.1 However, AST develops in
several settings. One setting is when
infection spreads from a distant site
to the thyroid via the bloodstream or
lymphatic system.4 Also, AST may
develop secondary to trauma and
persistent thryoglossal duct and by
direct extension of infection from a
neighboring structure to the thyroid.4 Preexisting thyroid disease, including AG, nodular goiter, Hashimoto thyroiditis, and thyroid cancer,
can precede thyroid infection.1,5 AG
can be the indirect cause of a thyroid
abscess.
In our patient, S aureus was isolated from blood and thyroid tissue cultures. Bacteremia was attributed to
immunosuppression during chemotherapy with ATG. It is recommended that patients in whom fever develops following ATG administration be treated with broad-spectrum
IIM_07012008_00341.ps 6/16/08 11:07 AM Page 341
ACUTE SUPPURATIVE THYROIDITIS
antibiotics.6 Also, some investigators
have recommended that patients at
high risk for infection should be
given prophylactic antibiotic and antifungal therapy, although there is a
concern that this strategy may aggravate emergence of antibiotic resistance.6-10 Because of this caveat,
our hospital does not use prophylactic antibiotic therapy in neutropenic
patients during ATG chemotherapy.
AST is a rare complication of
chemotherapy in hematological malignancy: Of the 9 cases reported in
the literature, 5 were attributed to
fungal infection (all associated with
Candida species).2,3 Of the 4 cases
attributed to bacterial infection, a
causative bacterial pathogen was
confirmed in only 1 case. Blood and
tissue cultures yielded Salmonella.2
Numerous imaging methods,
such as ultrasonography, barium
swallow tests, and CT, are used to
diagnose AST. Ultrasonography is
thought to be an important method
for diagnosing thyroid abnormalities.11 PSF, in particular, is considered
to be one of the most common underlying abnormalities in AST. Barium swallow is an essential diagnostic tool for confirming PSF.12 However, Bernard and colleagues11 have
suggested that CT is extremely useful in diagnosing AST in its early
phase, claiming that it provides more
accurate mapping than ultrasonography. In our case, we used CT as the
first-line imaging modality to evaluate the suspected thyroid abnormality and any other pathological cervical lesions. Because laryngoscopy
and CT did not detect PSF and because bacteremia was the suspected
cause of symptoms, we performed
the operation before ingravescence.
Treatment should include administration of parenteral antibiotics,
drainage of the abscess, and excision
of the affected area. There is no significant difference in the course of
disease or survival among patients
Figure 4 – This photo-
graph shows the friable
necrotic tissue excised
during a right subtotal
thyroidectomy.
Figure 5 – A microscopic
photograph of the thyroid
gland specimen after
right subtotal thyroidectomy demonstrates
chronic active inflammation with abscess formation (hematoxylin-eosin
stain, original magnification 40).
Therapeutic agents
Antithymoglobulin
Cefazolin
Nafcillin
Piperacillin
Piperacillin/tazobactam
Tobramycin
Trimethoprim/sulfamethoxazole
treated with antibiotics, drainage, or
a combination of both.5 Because the
mortality rate of AST is 8.6%5 and because no improvement was seen
after administration of antibiotic
therapy and aspiration of exudates,
surgical management was an appropriate decision in our case.
Few studies discuss the relationship between hematological malignancy and thyroid disease in longterm follow-up. Moskowitz and colleagues13 reported that autoimmune
disorders such as Graves disease,
Hashimoto thyroiditis, toxic multinodular goiter, and idiopathic hyJuly 2008 INFECTIONS in MEDICINE 341
IIM_07012008_00342.ps 6/16/08 11:07 AM Page 342
ACUTE SUPPURATIVE THYROIDITIS continued
pothyroidism are closely associated
with acute leukemia. Toubert and
colleagues14 reported that hypothyroidism could occur after bone marrow transplant without total body
irradiation. Therefore, follow-up thyroid function testing should be performed and hormonal therapy, if
needed, should be administered. ❖
REFERENCES
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid, A Fundamental and Clinical
Text. 9th ed. Philadelphia: Lippincott Williams
& Wilkins; 2005:541-547.
2. Dai MS, Chang H, Peng MY, et al. Suppurative
salmonella thyroiditis in a patient with chronic
lymphocytic leukemia. Ann Hematol. 2003;82:
646-648.
3. Imai C, Kakihara T, Watanabe A, et al. Acute
suppurative thyroiditis as a rare complication
of aggressive chemotherapy in children with
acute myelogeneous leukemia. Pediatr Hematol
Oncol. 2002;19:247-253.
4. Hazard JB. Thyroiditis: a review. Am J Clin
Pathol. 1955;25:289-298.
5. Berger SA, Zonszein J, Villamena P, et al. Infectious diseases of the thyroid gland. Rev Infect
Dis. 1983;5:108-122.
6. Marsh JC, Ball SE, Darbyshire P, Mittman N.
7.
8.
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14.
Guidelines for the diagnosis and management
of acquired aplastic anaemia. Br J Haematol.
2003;123:782-801.
Gafter-Gvili A, Fraser A, Paul M, Leibovici L.
Meta-analysis: antibiotic prophylaxis reduces
mortality in neutropenic patients. Ann Intern
Med. 2005;142(12, pt 1):979-995.
Liberati A, D’Amico R, Pifferi S, et al. Antibiotic prophylaxis to prevent nosocomial infections
in patients in intensive care units: evidence that
struggle to convince practising clinicians. Intern
Emerg Med. 2006;1:160-162.
Gafter-Gvili A, Fraser A, Paul M, et al. Antibiotic prophylaxis for bacterial infections in
afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev. 2005;
(19):CD004386.
Lo N, Cullen M. Antibiotic prophylaxis in
chemotherapy-induced neutropenia: time to
reconsider. Hematol Oncol. 2006;24:120-125.
Bernard PJ, Som PM, Urken ML, et al. The CT
findings of acute thyroiditis and acute suppurative thyroiditis. Otolaryngol Head Neck Surg.
1988;99:489-493.
Miyauchi A, Matsuzuka F, Kuma K, Takai S.
Piriform sinus fistula: an underlying abnormality common in patients with acute suppurative thyroiditis. World J Surg. 1990;14:400-405.
Moskowitz C, Dutcher JP, Wiernik PH. Association of thyroid disease with acute leukemia.
Am J Hematol. 1992;39:102-107.
Toubert ME, Socié G, Gluckman E, et al. Shortand long-term follow-up of thyroid dysfunction after allogeneic bone marrow transplantation without the use of preparative total body
irradiation. Br J Haematol. 1997;98:453-457.
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Differentiating Kawasaki Syndrome From Microbial Infection

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