NEJMcps 2401526

The n e w e ng l a n d j o u r na l of m e dic i n e
Clinical Problem-Solving
Caren G. Solomon, M.D., M.P.H., Editor
Going Down the Rabbit Hole

Kendall J. Burdick, M.D., William Ealick, M.D., M.P.H.,
Hector Vargas Acevedo, M.D., Theodore C. Sectish, M.D.,
and Thomas J. Sandora, M.D., M.P.H.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert
clinician, who responds to the information by sharing relevant background and reasoning with the reader
(regular type). The authors’ commentary follows.
From the Department of Pediatrics A previously healthy 8-year-old girl was transferred from Nantucket (off the coast of
(K.J.B., W.E., H.V.A., T.C.S., T.J.S.) and Massachusetts) to a Boston hospital in the summer with a 12-day history of fevers
the Division of Infectious Diseases
(K.J.B., W.E., H.V.A., T.C.S., T.J.S.), Bos- and sore throat. On day 1 of illness, she was seen at a Nantucket emergency depart-
ton Children’s Hospital, the Department ment (ED) for fever, pharyngitis, and cervical lymphadenopathy. She had a rapid
of Pediatrics, Boston Medical Center strep test that was negative, but she was discharged with a course of amoxicillin for
(K.J.B., W.E.), and the Department of Pe-
diatrics, Harvard Medical School (K.J.B., presumed bacterial pharyngitis. She continued to have fevers, and intermittent
W.E., H.V.A., T.J.S.) — all in Boston. Dr. emesis developed. On day 4, she presented to the ED, where she was noted to have
Burdick can be contacted at kendall persistent cervical lymphadenopathy and pharyngitis. Culture from the throat
.burdick@childrens.harvard.edu or at Bos-
ton Children’s Hospital, 300 Longwood swab obtained during the previous ED visit was negative, as were a monospot test
Ave., Boston, MA 02115. and a test for Lyme antibodies. Her antibiotic was changed to doxycycline for em-
Drs. Burdick and Ealick contributed equally pirical treatment of tickborne illnesses, and she was discharged home. On day 6, she
to this article. was seen again in the ED for similar symptoms and admitted with concern about
N Engl J Med 2024;391:454-9. possible peritonsillar abscess, although documentation indicated her examination
DOI: 10.1056/NEJMcps2401526 was more consistent with viral pharyngitis. She received dexamethasone and was
Copyright © 2024 Massachusetts Medical Society.
discharged on day 7. She remained afebrile for 4 days after discharge.
CME
The differential diagnosis for pharyngitis in children is broad and includes both
infectious and noninfectious causes. Fever is suggestive of infection; symptoms of
conjunctivitis, rhinitis, cough, and laryngitis can be useful in suggesting viral
rather than bacterial causes and avoiding unneeded antibiotics. Rapid tests for
streptococcal antigen have high specificity but can be falsely negative. In this case,
the lack of response to amoxicillin makes streptococcal pharyngitis less likely. A
negative monospot test does not rule out Epstein–Barr virus (EBV) infection; its
sensitivity is in the range of 70 to 90% among children older than 4 years of age
but depends on timing after infection. Other infectious causes of cervical adenop-
athy in an 8-year-old child include cytomegalovirus (CMV), bacterial lymphadenitis
(e.g., due to Staphylococcus aureus), or toxoplasma (although fever is often absent).
Nontuberculous mycobacterial adenitis is uncommon in children older than 5 years
of age, is not typically associated with pharyngitis, and is more subacute in nature.
Autoimmune or autoinflammatory causes of sore throat (with or without ulcer-
ation) in school-age children include systemic lupus erythematosus and PFAPA
(periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome.
Finally, oncologic causes of cervical adenopathy (e.g., Hodgkin’s lymphoma) should
not be missed.
454 n engl j med 391;5 nejm.org August 1, 2024
The New England Journal of Medicine

Downloaded from nejm.org by SANGRAM BIRADAR on July 31, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
On day 11 of illness, fevers and symptoms re- adherent, leather-like pharyngeal pseudomem-
curred, including new headaches. The patient re- brane; and toxic appearance with a “bullneck.”
turned to the same ED. Her examination was This patient had no identified exposure, and her
notable for bilateral tonsillitis with overlying exu- tonsillar exudates and overall appearance were
dates, and large, tender cervical lymph nodes. Her not characteristic of diphtheria.
white-cell count was 25,000 cells per microliter
with a neutrophilic predominance. A blood cul- On admission to the hospital, the patient reported
ture was sent. Computed tomography (CT) of the decreased oral intake, neck pain, headache, and
neck showed extensive peritonsillar edema, bilat- sore throat. She was febrile to 41.0°C and had
eral soft-tissue edema with possible abscesses, rigors. Her voice sounded muffled. There was no
and a 2.4-cm lymph node on the left side. Of note, stridor or drooling. She had bilateral subconjunc-
she was incompletely vaccinated. She had received tival hemorrhages without conjunctivitis, dry lips
one tetanus–diphtheria–acellular pertussis (Tdap), with erythema, erythema of the posterior oro-
three polio, two measles–mumps–rubella–varicella pharynx with tonsillar exudate, and marked bilat-
(MMR-V), two hepatitis B, and two coronavirus eral cervical lymphadenopathy without overlying
disease 2019 vaccines but not a third dose of hepa- erythema or tenderness to palpation. There was
titis B vaccine, any additional doses of tetanus– no cardiac murmur, and capillary refill was nor-
diphtheria or Tdap vaccine, or any doses of rotavi- mal. Respirations were unlabored with clear breath
rus, Haemophilus influenzae type B, pneumococcal sounds in both lungs. Her abdomen was soft and
conjugate, hepatitis A, or influenza vaccine. She nontender, with no hepatosplenomegaly. She had
received one dose of ampicillin–sulbactam in the no edema of the arms or legs and no rash.
ED, which was transitioned to clindamycin on She was started on intravenous ampicillin–
admission. After discussion with local pediatric sulbactam, and a repeat blood culture was ob-
otolaryngology consultants, she was transferred tained. The otolaryngology service was consulted
to our hospital for consideration of surgical inter- and reviewed the CT of the neck from the outside
vention for possible peritonsillar abscess. hospital. The service team believed that there was
no drainable collection and that her illness was
Group A streptococcus is the most common more consistent with uncomplicated bacterial
bacterial cause of pharyngitis in children and is pharyngitis or infectious mononucleosis.
diagnosed by means of rapid antigen test or The white-cell count was 15,000 cells per micro-
culture. The presence of an associated sandpa- liter with 9660 neutrophils per microliter and no
per-like rash suggests scarlet fever. In this pa- atypical lymphocytes, the hemoglobin level 10.5 g
tient, the persistence of symptoms despite ap- per deciliter with a mean corpuscular volume of
propriate treatment for streptococcal pharyngitis 77 fl, and the platelet count 391,000 cells per mi-
requires consideration of other infectious causes. croliter. The results of routine chemical tests were
Less common bacterial causes include Yersinia within normal limits. The C-reactive protein (CRP)
pestis, Francisella tularensis, Arcanobacterium haemo- level was 8.6 mg per deciliter (normal value, ≤0.5),
lyticum, and Fusobacterium necrophorum. Although and the procalcitonin level was 1.1 ng per millili-
not relevant to this patient, gonococcal or ter (normal value, ≤0.09). A polymerase-chain-
syphilitic pharyngitis should also be considered reaction (PCR) panel for respiratory viruses
in sexually active adolescents. Peritonsillar and (including severe acute respiratory syndrome
retropharyngeal abscesses are important com- coronavirus 2) and EBV and CMV serologic tests
plications of pharyngitis that should not be were negative. A blood parasite smear, repeat EBV
missed. For this patient who is incompletely serologic test, blood adenovirus PCR assay, and
vaccinated, diphtheria also warrants consider- blood Anaplasma phagocytophilum PCR assay were
ation. Factors that would raise suspicion for sent. The infectious diseases service was consulted.
diphtheria include recent travel to areas in which
the disease is endemic (including Haiti, the Do- The mild leukocytosis, mild anemia with low
minican Republic, Asia and the South Pacific, mean corpuscular volume, and elevated levels of
eastern Europe, and the Middle East); insidious inflammatory markers suggest an infectious or
onset of disease with low-grade fever; a firmly inflammatory state. Given the prolonged fever
n engl j med 391;5 nejm.org August 1, 2024 455

without a clear source, it is reasonable to expand A detailed exposure history was obtained by the
the workup. The differential diagnosis of pro- infectious diseases consult service. The patient
longed fever that does not respond to initial had multiple recent contacts who had received a
antibiotic therapy includes not only less typical diagnosis of infectious mononucleosis. At home,
infectious diseases but also rheumatologic dis- she had a pet lizard and dog but no birds or cats.
ease and cancer. A thorough history taking and The patient had not traveled outside New England
physical examination should direct decisions in the past 6 months.
about laboratory testing and imaging. Her parents noted that there were multiple
dead rabbits near their home, that the patient
On day 14 of illness, the patient had new tender- spent a lot of time outside, and that she had mul-
ness over the maxillary sinuses. A CT scan showed tiple tick bites that summer. In addition, the fam-
enlargement and hyperenhancement of the ton- ily reported that their water came from a well and
sils with related mild paranasal sinus disease and that earlier in the summer they had traveled to a
enlarged and heterogeneously enhancing upper nature preserve in Nantucket where the patient
cervical lymph nodes with areas of hypoattenua- drank from natural springs. Because of these ex-
tion. Biopsy of the cervical lymph node was con- posures and her continued fevers despite multiple
sidered but was deferred while other investigations days of ampicillin–sulbactam, she was transitioned
were pursued. to intravenous gentamicin at a dose of 2.5 mg per
On day 15 of illness, the white-cell count in- kilogram of body weight every 12 hours for em-
creased to 25,000 cells per microliter and the CRP pirical treatment of presumed tularemia while
level to 15 mg per deciliter, despite intravenous confirmatory testing was pending.
ampicillin–sulbactam. Out of concern about in-
complete Kawasaki’s disease, an echocardiogram A history of tick bites could suggest anaplasma
was obtained and revealed normal function and or Rocky Mountain spotted fever, but prominent
no evidence of coronary-artery dilation. An ab- pharyngitis would not be expected in those in-
dominal ultrasonogram that was obtained to fections. The patient has no specific manifes-
evaluate for gallbladder hydrops (which can be tations of Lyme disease (e.g., erythema migrans,
seen in Kawasaki’s disease) did not show that cranial-nerve palsy, or signs of meningitis). Ba-
finding but did show splenomegaly. besia is also transmitted by tick bite and could
cause fever and splenomegaly, but she had a
Kawasaki’s disease is an acute self-limited vas- negative blood parasite smear. Tests for other
culitis of unknown cause, occurring predomi- common infections in which splenomegaly might
nantly in children younger than 5 years of age. be seen (e.g., EBV and CMV) were negative. Nec-
The diagnosis is clinical and requires at least rotizing lymphadenitis can occur in tuberculosis
5 days of fever associated with at least four of and cat scratch disease, but her exposure history
these clinical features: bilateral limbic-sparing did not suggest these infections. The history of
conjunctival injection, mucosal changes, cervical tick bites, proximity to rabbits, and ingestion of
lymphadenopathy (single node >1.5 cm), poly- both well and spring water are important clues
morphous rash, and erythema and induration of to a potential diagnosis of tularemia.
the hands and feet followed by desquamation.
Incomplete Kawasaki’s disease refers to mani- On day 16 of illness, a radiologist reviewed the
festations that do not fully meet these diagnostic previous cross-sectional imaging and noted that
criteria. Patients with Kawasaki’s disease can the cervical nodes showed characteristics of
have a diffusely erythematous oropharynx, but necrotizing lymphadenitis, potentially consistent
tonsillar exudates are not usually seen. Leukocy- with tularemia. After 48 hours of gentamicin
tosis and elevated levels of inflammatory mark- treatment, the patient was afebrile, had better oral
ers, which this patient has, are typical. Because intake, and had reduced lymphadenopathy on
coronary-artery aneurysms are a complication of physical examination. Laboratory tests showed a
Kawasaki’s disease, it is important to diagnose decrease in her white-cell count and levels of in-
and treat the disease early to prevent cardiac flammatory markers. She continued receiving gen-
sequelae. This patient’s echocardiogram was tamicin for presumed oropharyngeal tularemia.
normal. On day 22 of illness (after 8 days of gentamicin),

she lost intravenous access. Through shared deci- early fall.2 As climate change affects animal hosts
sion making with the family and the treating and insect vectors, the geographic range and in-
physicians, she was transitioned to oral cipro- cidence of tickborne illnesses (including tulare-
floxacin (250 mg twice daily) and was discharged mia) and other zoonotic diseases are expected to
home to complete a total 10-day antibiotic treat- increase.3-5
ment course. Tularemia manifests in six clinical syndromes:
ulceroglandular, glandular, oculoglandular, oro-
Aminoglycosides and tetracyclines have tradi- pharyngeal, pneumonic, and typhoidal. Ulcero-
tionally been used to treat tularemia; beta- glandular disease is the most common, whereas
lactams are ineffective. Gentamicin is preferred the typhoidal syndrome has the highest mortal-
for the treatment of severe tularemia. In milder ity.6 The syndrome at presentation corresponds
cases, or once a patient with severe disease has with the mode of acquisition of the causative
had a good clinical response, fluoroquinolones organism (Fig. 1). Oropharyngeal tularemia is
or doxycycline can be given orally to complete unusual in the United States. It occurs after
therapy. transmission of the organism by ingestion of
contaminated food (e.g., undercooked rabbit meat)
Three days after discharge, a test for F. tularensis or water (e.g., released into springs or well water
antibody was reported as positive at a titer of from infected animals).7 Because none of the
1:1280 (reference range, <1:20). The family was patient’s family members were symptomatic, it
notified and reported that the patient had com- appears more likely that the contaminated water
pleted the antibiotic course and was feeling well, source was the natural spring from which the
with a decrease in neck swelling (presumed to patient drank, rather than the home well water.
be resolving lymphadenopathy) and no residual Public health prevention measures in the context
symptoms. of diagnosed cases of oropharyngeal tularemia
may include testing and treatment of municipal
or private water sources. Oropharyngeal tulare-
C om men ta r y
mia is difficult to diagnose because it has non-
This patient presented to our hospital with 11 specific manifestations characterized by sore
days of illness that included fever, pharyngitis, throat, cervical lymphadenopathy, and tonsilli-
and cervical lymphadenopathy. Initially, she was tis; in some cases, there is a grayish-white mem-
thought to have either a viral or a common bac- brane involving the posterior pharyngeal wall
terial infection, but she did not have a response and surrounding structures, which can mimic
to routine antibiotic therapy. After a thorough findings with other infectious diseases (e.g.,
history taking that elicited exposure to rabbits group A streptococcal or A. haemolyticum pharyn-
and ticks and ingestion of well and spring water, gitis).
the correct diagnosis of oropharyngeal tularemia Definitive diagnosis of tularemia relies on
was presumed, leading to directed therapy that microbiologic tests. A confirmed case requires
resulted in resolution of symptoms. isolation of the organism in a clinical specimen
Tularemia — also known as rabbit fever, or a change in serum antibody titer by a factor
hunter’s disease, and deer fever, among others of four or more between acute and convalescent
— is a rare zoonotic infection that is endemic on serum specimens. A case is considered to be
multiple continents, including North America, probable when a patient has a clinically compat-
Europe, and Asia.1 Tularemia is caused by sev- ible presentation and a single elevated antibody
eral subspecies of F. tularensis, an aerobic, facul- titer of greater than 1:160 or detection by im-
tative intracellular, gram-negative coccobacillus; munofluorescence or PCR assay from a clinical
F. tularensis subspecies tularensis is the most highly specimen. In this patient’s case, the very high
virulent subspecies. In the United States, tulare- titer and the rapid response to appropriate anti-
mia is most prevalent in south-central and west- biotics further support the diagnosis. Serocon-
ern states and is relatively uncommon in Massa- version usually occurs only after 2 to 3 weeks, so
chusetts. However, reported cases in Massachusetts an elevated antibody titer may not be present if a
often occur on Cape Cod, Martha’s Vineyard, or patient is tested early in the course of infection.2,8
Nantucket, generally during the summer and Titers peak 4 to 6 weeks after symptom onset

Pneumonic tularemia
Oculoglandular tularemia
Occurs after inhalation of
Introduced to the eyes by touching of aerosolized bacteria and
the face with contaminated hands manifests as fever, cough,
and respiratory distress
Oropharyngeal tularemia
Occurs after ingestion of food or
water contaminated with organism
Infected animal
Contaminated
water
Infected
droppings
aerosolize
Francisella tularensis
Typhoidal tularemia
Acquired by the same routes as other forms
and is characterized by systemic symptoms
without any localizing symptoms
Ulceroglandular and glandular tularemia

Patients with the ulceroglandular form present
with a skin ulcer at the site of entry, accompanied Deerfly
by enlargement of regional lymph nodes; glandular
disease is similar but without an ulcer.
Bites from
American infected arthropods
Dog Tick
Contact with infected animals

(e.g., rabbits and rodents)

Figure 1 (facing page). Tularemia — Modes of Acquisi-

Gentamicin is the preferred treatment of se-
tion and Manifestations. vere tularemia in both adults and children, and
The syndrome at presentation corresponds with the clinical experience with this agent supports that
mode of acquisition of the organism. Ulceroglandular it is highly effective.11,12 In milder cases, fluoro-
and glandular tularemia primarily occur through the quinolones or doxycycline can be given orally to
bite of infected arthropods (e.g., ticks and deerflies) complete therapy. Ciprofloxacin has been shown
or contact with infected animals (e.g., rabbits and ro-
dents). Patients with the ulceroglandular form present
to be effective for treatment of children with
with a skin ulcer at the site of entry, accompanied by tularemia.13 Ten days is the recommended dura-
enlargement of regional lymph nodes; glandular dis- tion of gentamicin or ciprofloxacin therapy if a
ease is similar but without an ulcer. Oropharyngeal patient has an adequate clinical response. Given
tularemia occurs after transmission of the organism studies that show a higher likelihood of thera-
by ingestion of contaminated food or water (e.g., re-
leased into springs or well water from infected ani-
peutic failure with doxycycline than with fluo-
mals). Pneumonic tularemia occurs after inhalation of roquinolones,14 the Centers for Disease Control
aerosolized bacteria and manifests with fever, cough, and Prevention recommends a duration of 14 to
and respiratory distress. Typhoidal tularemia is ac- 21 days if doxycycline is used.8 The likelihood
quired by the same routes as other forms and is char- of clinical failure is increased when diagnosis
acterized by systemic symptoms without any localizing
symptoms of the other manifestations.
and treatment are delayed beyond 16 days of
illness, and, in such cases, surgical intervention
(e.g., debridement or drainage of a necrotic
lymph node or associated abscess) may be war-
and decline slowly over time but may remain ranted.
detectable for years.9 Blood cultures are rarely This case highlights the value of a detailed
positive in tularemia10; they were obtained in exposure history and the importance of main-
this patient early in her clinical investigation to taining a broad differential diagnosis in cases in
rule out bacteremia from more typical patho- which initial antibiotic therapy does not yield the
gens. However, in patients with suspected tula- expected response.
remia, the laboratory should be notified about Disclosure forms provided by the authors are available with
this suspicion when any culture is sent; the or- the full text of this article at NEJM.org.
ganism is highly virulent, and laboratory per- We thank the members of the health care team involved in
the diagnosis and treatment of this case, including Fabienne
sonnel who handle specimens must take special Bourgeois, M.D., Kathryn Carpenter, M.D., Grace Porter, M.D.,
precautions to avoid acquiring infection. Alexa Altchek, M.D., and Tomas Conrads, M.D.
References
1. Hughes WT Jr, Etteldorf JN. Oropha- 5. Thomson MC, Stanberry LR. Climate tidious bacteria. Clin Infect Dis 2000;30:
ryngeal tularemia. J Pediatr 1957;51:363-72. change and vectorborne diseases. N Engl 166-73.
2. Massachusetts Department of Public J Med 2022;387:1969-78. 11. Cross JT Jr, Schutze GE, Jacobs RF.
Health. Tularemia. August 27, 2017 6. Evans ME, Gregory DW, Schaffner W, Treatment of tularemia with gentamicin
(https://www.mass.gov/doc/ McGee ZA. Tularemia: a 30-year experi- in pediatric patients. Pediatr Infect Dis
t ularemiapdf). ence with 88 cases. Medicine (Baltimore) J 1995;14:151-2.
3. Balci E, Borlu A, Kilic AU, Demiraslan 1985;64:251-69. 12. Enderlin G, Morales L, Jacobs RF,
H, Oksuzkaya A, Doganay M. Tularemia 7. Kaya A, Uysal IÖ, Güven AS, et al. Cross JT. Streptomycin and alternative
outbreaks in Kayseri, Turkey: an evalua- Treatment failure of gentamicin in pedi- agents for the treatment of tularemia:
tion of the effect of climate change and atric patients with oropharyngeal tulare- review of the literature. Clin Infect Dis
climate variability on tularemia out- mia. Med Sci Monit 2011; 17(7): CR376- 1994;19:42-7.
breaks. J Infect Public Health 2014;7:125- CR380. 13. Johansson A, Berglund L, Sjöstedt A,
32. 8. Centers for Disease Control and Pre- Tärnvik A. Ciprofloxacin for treatment of
4. Andersen LK, Davis MDP. Climate vention. Tularemia. December 13, 2018 tularemia. Clin Infect Dis 2001;33:267-8.
change and the epidemiology of selected (https://www.cdc.gov/tularemia/index.html). 14. Rojas-Moreno C, Bhartee H, Vasude-
tick-borne and mosquito-borne diseases: 9. Maurin M. Francisella tularensis, tu- van A, Adiga R, Salzer W. Tetracyclines
update from the International Society of laremia and serological diagnosis. Front for treatment of tularemia: a case series.
Dermatology Climate Change Task Force. Cell Infect Microbiol 2020;10:512090. Open Forum Infect Dis 2018;5(9):ofy176.
Int J Dermatol 2017;56:252-9. 10. Doern GV. Detection of selected fas- Copyright © 2024 Massachusetts Medical Society.


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The n e w e ng l a n d j o u r na l of m e dic i n e

Caren G. Solomon, M.D., M.P.H., Editor

Going Down the Rabbit Hole

454 n engl j med 391;5 nejm.org August 1, 2024

The New England Journal of Medicine

n engl j med 391;5 nejm.org August 1, 2024 455

456 n engl j med 391;5 nejm.org August 1, 2024

The New England Journal of Medicine

n engl j med 391;5 nejm.org August 1, 2024 457

Ulceroglandular and glandular tularemia

Contact with infected animals

458 n engl j med 391;5 nejm.org August 1, 2024

The New England Journal of Medicine

Figure 1 (facing page). Tularemia — Modes of Acquisi-

n engl j med 391;5 nejm.org August 1, 2024 459

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