The n e w e ng l a n d j o u r na l of
Case Records of the Massachusetts General Hospital
From the Departments of Medicine
(J.T.C., E.P.H.), Radiology (R.H.), and Pa‑
thology (S.E.T.), Massachusetts General
Hospital, and the Departments of Medi‑
cine (J.T.C., E.P.H.), Radiology (R.H.), and
Pathology (S.E.T.), Harvard Medical School
— both in Boston; and the Department
of Medicine, Alpert School of Medicine,
Brown University, Providence, RI (F.J.S.).
This article was updated on July 20, 2017,
at NEJM.org.
N Engl J Med 2017;377:268-78.
DOI: 10.1056/NEJMcpc1616399
Copyright © 2017 Massachusetts Medical Society.
268
Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors
Case 22-2017: A 21-Year-Old Woman
with Fever, Headache, and Myalgias
Jacqueline T. Chu, M.D., Rydhwana Hossain, M.D., Frederic J. Silverblatt, M.D.,
Emily P. Hyle, M.D., and Sarah E. Turbett, M.D.​​
Pr e sen tat ion of C a se
Dr. Nkemdilim Mgbojikwe (Medicine): A 21-year-old woman was admitted to this
hospital during the winter because of fever, headache, and myalgias.
The patient had been well until 4 days before this admission, when fever, chills,
fatigue, malaise, retro-orbital headache, and photophobia developed. On presenta-
tion to a clinic affiliated with the university where she was a student, she reported
that, 6 days earlier, she had returned from a trip to Indonesia. A blood-smear
examination for malaria was negative, and the patient was advised to take acetamin-
ophen and ibuprofen. Over the next 2 days, her symptoms worsened, and abdominal
pain in the left lower quadrant and arthralgias affecting the knees developed. On
the third day of illness, she presented to the emergency department of another
hospital for evaluation.
On examination at the other hospital, the temperature was 41.0°C. The blood
lactic acid level and results of liver-function tests were normal; other laboratory
test results are shown in Table 1. Tests for heterophile antibodies, influenza, and
Clostridium difficile were negative. Blood and urine specimens were obtained for
culture, and a lumbar puncture was performed; on cerebrospinal fluid analysis,
the white-cell and red-cell counts and protein and glucose levels were normal.
Dr. Rydhwana Hossain: Chest radiography revealed no evidence of focal consolida-
tion, pulmonary edema, or hilar adenopathy. Abdominal radiography revealed
multiple air-filled loops of small bowel but no evidence of abnormal bowel dilata-
tion, obstruction, or free air. Four hours later, computed tomography (CT) of the
abdomen and pelvis, performed after the administration of intravenous contrast
material, revealed the presence of a few subcentimeter mesenteric lymph nodes in
the right lower quadrant. There was no bowel-wall thickening, obstruction, ascites,
or hepatosplenomegaly. The kidneys were heterogeneous in appearance.
Dr. Mgbojikwe: Acetaminophen was administered, and the patient was admitted
to the hospital. High temperatures persisted; cooling blankets were applied, and
more than 7 liters of fluid were administered intravenously. On the second hospi-
n engl j med 377;3 nejm.org  July 20, 2017
The New England Journal of Medicine
 Case Records of the Massachuset ts Gener al Hospital
tal day, intravenous doxycycline and ceftriaxone
were administered. Three blood-smear examina-
tions for malaria, a stool culture for enteric
pathogens, and a stool examination for ova and
parasites were negative; other laboratory test re-
sults are shown in Table 1. By the third hospital
day, cough and mild chest pain had developed,
and hypoxemia was reportedly present; supple-
mental oxygen was administered, initially through
a nasal cannula at a flow rate of 4 liters per
minute and then through a nonrebreather face
mask at a flow rate of 15 liters per minute.
Dr. Hossain: Repeat chest radiography revealed
diffuse, hazy opacities, predominantly in the
lower lobes, with new opacification of the left
hemidiaphragm (Fig. 1A).
Dr. Mgbojikwe: Headache and photophobia per-
sisted. A CT scan of the head was normal.
Doxycycline was continued, ceftriaxone was dis-
continued, and vancomycin and piperacillin–
tazobactam were administered intravenously.
The patient was transferred to the intensive care
unit (ICU) at the other hospital.
In the ICU, the blood levels of lactic acid, amy-
lase, lipase, and creatine kinase were normal, and
tests for rheumatoid factor, antinuclear antibod-
ies, and antineutrophil cytoplasmic antibodies
were negative; other laboratory test results are
shown in Table 1. An electrocardiogram and a
transthoracic echocardiogram were normal. Furo-
semide was administered intravenously, and the
patient had 3 liters of urine output. Therapy with
oral oseltamivir and a continuous intravenous
infusion of sodium bicarbonate was begun, and
the patient was transferred by helicopter to the
medical ICU at this hospital.
On admission to this hospital, the patient re-
ported that fevers had occurred without period-
icity and that photophobia, headache, and diffuse
myalgias persisted. She had a history of anxiety
and exercise-induced asthma and a remote his-
tory of tonsillectomy and adenoidectomy. Her
only medication was citalopram, and she had no
known allergies. She was a college student and
lived with roommates in a rural area of New
England. Twenty-seven days before the onset of
illness, she had returned from a 10-day trip to
the U.S. Virgin Islands. Six days before the onset
of illness, she had returned from a 16-day ecol-
ogy tour in rural Indonesia; she had traveled
through the United Arab Emirates in transit to
Indonesia, and the passenger seated next to her
n engl j med 377;3 nejm.org  July 20, 2017
The New England Journal of Medicine
Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
on the flight from the United Arab Emirates to
Indonesia coughed intermittently during the trip.
The patient did not receive any vaccinations be-
fore the trip and did not take malaria prophy-
laxis. While she was in Indonesia, she used
mosquito netting during sleep but received mul-
tiple mosquito bites. She drank boiled water and
pasteurized milk and ate rice and beans, thor-
oughly cooked meat, and fruit that had been
washed but not peeled. She visited jungles and
plantations and had contact with elephants, a
bovine calf, and a juvenile macaque. She also
observed but did not have contact with cats,
dogs, bats, chickens, and cattle. She swam in
jungle streams, ponds, and a waterfall pool. She
reported that at the midpoint of the trip, a mild,
nonpainful, nonpruritic rash developed; the rash
first appeared on the wrists, spread centripetally
and became diffuse, and then resolved. She was
monogamous with her boyfriend, and they used
condoms inconsistently. She did not smoke to-
bacco, but she smoked marijuana occasionally
and drank alcohol rarely.
On examination, the patient was irritable and
appeared tired. The temperature was 37.2°C, the
pulse 80 beats per minute, the blood pressure
112/57 mm Hg, the respiratory rate 22 breaths
per minute, and the oxygen saturation 97% while
she was receiving supplemental oxygen through a
high-flow nasal cannula (at a flow rate of 50 liters
per minute, with a fraction of inspired oxygen of
0.5). She had a few petechiae on the palate, pal-
pebral conjunctival injection, and mild neck stiff-
ness. On auscultation of the chest, there were
rales over both lung bases. There was mild, dif-
fuse abdominal tenderness that was worst in the
left lower quadrant, as well as a very faint blanch-
ing, macular rash on the thighs, arms, and lower
abdomen (Fig. 2). Application of a tourniquet to
an arm for 5 minutes did not precipitate the
development of petechiae. The remainder of the
physical examination was normal. The red-cell
indexes, anion gap, and blood levels of glucose,
lactic acid, lactate dehydrogenase, and lipase were
normal, as were the results of liver-function tests.
Other laboratory test results are shown in Table 1.
A rapid test for malaria antigen, a pregnancy
test, and a polymerase-chain-reaction (PCR) test
for influenza were negative. Urinalysis showed
slightly cloudy yellow urine, with 1+ ketones, 1+
occult blood, a specific gravity of 1.012, and a pH
of 5.0; on microscopic examination, amorphous
269
 270
Table 1. Laboratory Data.*

Reference Range, On Presentation, Day 2, Day 3, On Admission,

Variable Adults† Other Hospital Other Hospital Other Hospital This Hospital
Hematocrit (%) 36.0–46.0 38.9 (ref 37.0–47.0) 34.2 31.8 30.8
Hemoglobin (g/dl) 12.0–16.0 13.0 (ref 11.5–15.5) 11.4 10.6 10.3
White-cell count (per μl) 4500–11,000 8800 (ref 4100–10,800) 4800 4300 5260
Differential count (%)
Neutrophils 40–70 83 (ref 45–72) 47 70 72.2
Band forms 0–10 10 27 17
Lymphocytes 22–44 3 (ref 25–45) 17 8 17.7
Monocytes 7–11 4 (ref 2–12) 7 5 8.7
Eosinophils 0–8 0.8
Basophils 0–3 1 0.4
The

Metamyelocytes 1 (ref 0)
Platelet count (per μl) 150,000–400,000 202,000 (ref 130,000– 171,000 158,000 191,000
400,000)
Red-cell count (per μl) 4,000,000–5,200,000 4,270,000 (ref 4,200,000– 3,720,000 3,470,000 3,460,000
5,400,000)
Description of peripheral-blood smear Vacuolated polymorpho‑ Burr cells, toxic granu‑ Burr cells, toxic granula‑
nuclear leukocytes, lation tion, poikilocytosis,
Döhle bodies elliptocytes, polychro‑
masia
Erythrocyte sedimentation rate (mm/hr) 0–20 33 (ref 0–15) 36
n e w e ng l a n d j o u r na l

Prothrombin time (sec) 11.0–14.0 13.7

The New England Journal of Medicine

of

Prothrombin-time international normalized ratio 0.9–1.1 1.1

Activated partial thromboplastin time (sec) 22.0–35.0 35.3

n engl j med 377;3 nejm.org  July 20, 2017

Sodium (mmol/liter) 135–145 132 (ref 136–144) 134 138
Potassium (mmol/liter) 3.4–5.0 3.2 (ref 3.6–5.1) 3.6 3.6

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Chloride (mmol/liter) 98–108 99 (ref 101–111) 107 104

Carbon dioxide (mmol/liter) 23–32 25 (ref 22–32) 18 18
Calcium (mg/dl) 8.5–10.5 8.7 (ref 8.5–10.1) 7.8 8.6
Phosphorus (mg/dl) 2.6–4.5 2.8 (ref 2.5–4.6) 2.1
Magnesium (mg/dl) 1.7–2.4 1.5 (ref 1.8–2.4) 1.5
Glucose (mg/dl) 70–110 171 (ref 74–106) 113 97
Urea nitrogen (mg/dl) 8–25 10 (ref 8–26) 14 9

Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
 Reference Range, On Presentation, Day 2, Day 3, On Admission,
Variable Adults† Other Hospital Other Hospital Other Hospital This Hospital
Creatinine (mg/dl) 0.60–1.50 1.13 (ref 0.4–1.0) 1.44 1.16
Estimated glomerular filtration rate (ml/min/1.73 m2)‡ >60 >60 46 59
Protein (g/dl)
Total 6.0–8.3 6.9 (ref 6.5–8.1) 5.4
Albumin 3.3–5.0 3.6 (ref 3.5–5.0) 3.0
Globulin 1.9–4.1 2.4
Troponin T (ng/ml) <0.03 0.01 (ref <0.05) 0.05 <0.01
B-type natriuretic peptide (pg/ml) 355 (ref 0–100)
N-terminal pro–brain natriuretic peptide (pg/ml) 0–450 2659
C-reactive protein (mg/liter) <8.0 288.8 (ref <10.0) 287.1 242.2
Procalcitonin (ng/ml) 0.74 (ref <0.1) 23.00
Arterial blood gases
Fraction of inspired oxygen Not specified Not specified
pH 7.35–7.45 7.29 7.41
Partial pressure of carbon dioxide (mm Hg) 35–42 34 29
Partial pressure of oxygen (mm Hg) 80–100 67 59
Base excess (mmol/liter) 0–3.0 −9.6 −5.6
Oxygen saturation (%) 94.0–99.9 92.3

* The term ref denotes the reference range at the other hospital; these ranges are listed when they differ from those at Massachusetts General Hospital. To convert the values for calcium

n engl j med 377;3 nejm.org  July 20, 2017

to millimoles per liter, multiply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to millimoles per liter,

The New England Journal of Medicine

multiply by 0.4114. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To
convert the values for creatinine to micromoles per liter, multiply by 88.4.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults
who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
‡ If the patient is black, multiply the results by 1.21.
Case Records of the Massachuset ts Gener al Hospital

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
271
 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 2. Clinical Photograph.

A photograph of the patient’s arm, which was taken on
examination at this hospital, shows a faint blanching,
macular rash. (Photograph courtesy of Dr. Jeffrey A.
Gelfand.)

Figure 1. Chest Radiographs.
A chest radiograph obtained on the third day at the other
hospital (Panel A) shows new diffuse, hazy opacities,
predominantly in the lower lobes, with opacification of
the left hemidiaphragm. A chest radiograph obtained
on admission to this hospital (Panel B) shows rapidly
progressing confluent perihilar opacities that are more
prominent on the left side than on the right side, as
well as a new small pleural effusion on the left side.
Differ en t i a l Di agnosis
Dr. Jacqueline T. Chu: In this previously healthy 21-
year-old woman, an acute, severe febrile illness
developed 6 days after she had returned from
travel abroad. In developing a differential diag-
nosis of potential infections to explain this pa-
tient’s illness, it is helpful to consider her health
status, epidemiologic factors that are unique to
the geographic areas she visited, and the incu-
bation periods associated with common patho-
gens that she is likely to have encountered.

crystals and mucin were present, and there were
0 to 2 red cells per high-power field, no white
cells per high-power field, and 0 to 2 hyaline
casts per low-power field.
Dr. Hossain: Chest radiography revealed rapidly
progressing confluent perihilar opacities that were
more prominent on the left side than on the
right side, as well as a new small pleural effu-
sion on the left side (Fig. 1B). The left hemidia-
phragm was completely obscured, possibly be-
cause of consolidation or atelectasis.
Dr. Mgbojikwe: A diagnostic test was performed.
Health Status
In any traveler with a possible infection, the first
step is to define the underlying health status. To
our knowledge, this patient was not immuno-
compromised; she was healthy enough to under-
take an active, adventurous trip. However, she
did not seek medical care before travel; thus, she
presumably was not immunized against vaccine-
preventable diseases (e.g., typhoid or influenza)
and did not receive prophylaxis for infections
that are relevant to her travel itinerary. Further-
more, she may not have been adequately educated
about appropriate precautions regarding food
and insect exposures.

272 n engl j med 377;3 nejm.org  July 20, 2017

The New England Journal of Medicine

Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital

University This
clinic hospital
Time of possible exposure First rash Other
Time of expected disease onset (exact timing uncertain) hospital

Clinically well Sick

–37 –27 –22 –6 0

New
U.S. Virgin Islands Indonesia New England
England

Malaria

Influenza

MERS

Dengue

Chikungunya

Zika Virus

Murine Typhus

Enteric Fever

Leptospirosis

–37 –27 –22 –6 0

Days before Onset of Illness

Figure 3. Timeline of Possible Exposures to Infectious Agents and Associated Incubation Periods in This Patient.
Shown is a timeline of the patient’s travel relative to the onset of illness, as well as the time of possible exposure (dotted lines) and time
of expected disease onset (solid lines), which is based on the incubation period, for each infectious cause included in the differential diag‑
nosis. MERS denotes Middle East respiratory syndrome.

Epidemiologic Factors tation? This patient’s symptoms developed 27 days

I will consider the most common causes of infec-
tion in each region of exposure: the U.S. Virgin
Islands, Indonesia, and the patient’s home in
New England. I will also consider rare illnesses
that can cause severe complications or death or
may not remit without antibiotic therapy. In the
regions of exposure, the likelihood of specific
infections is based on the patient’s participation
in high-risk activities. For this patient, the epi-
demiologic exposures that stand out the most
include eating fruit that had been washed but
not peeled and swimming in freshwater streams,
ponds, and a waterfall pool in Indonesia.
Incubation Periods
One of the most useful clues in the diagnosis of
infection in a returning traveler is knowledge of
the incubation periods of commonly encountered
diseases. What pathogens could this patient have
been exposed to that would cause infection in a
time frame consistent with this patient’s presen-
after her return from the U.S. Virgin Islands and
between 6 and 22 days after potential exposures
in Indonesia. Exposures in New England were
scattered therein. Some diseases in the differen-
tial diagnosis can be ruled out on the basis of
their incubation periods, whereas others remain
possible (Fig. 3).
Malaria
Malaria transmission is highly unusual in the
U.S. Virgin Islands, but the disease is endemic in
the eastern provinces of Indonesia and in rural
Borneo. In view of this patient’s progressive and
ultimately severe symptoms, her history of mos-
quito exposure, and her lack of chemoprophy-
laxis, malaria should be a strong consideration
in this case. The patient’s presenting symptoms
of fevers (with high temperatures), retro-orbital
headache, myalgias, and fatigue are all commonly
seen in patients with malaria, and the typical
incubation period of 6 to 30 days would fit with

n engl j med 377;3 nejm.org July 20, 2017 273

The New England Journal of Medicine
Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

a possible exposure in Indonesia. In patients with tion periods for these diseases are too short for
severe malaria, pulmonary edema, metabolic aci- the patient to have been infected while she was
dosis, and acute renal dysfunction may occur. on the U.S. Virgin Islands, but they are compat-
Hemolytic anemia, which often accompanies ible with infection in Indonesia. The patient’s
malaria, was absent in this case, as was the clas- initial syndrome of fever, severe retro-orbital
sic fever associated with Plasmodium falciparum headache, and myalgias would be consistent with
malaria (with spikes in temperature every 48 any of these three arboviral infections. Her later,
hours), although this fever pattern is often not more severe illness with renal failure and pul-
observed in early infection. However, the nega- monary edema would be less consistent with
tive predictive value of one Giemsa blood-smear chikungunya and Zika virus, which typically
examination is 98.2%1; therefore, the four nega- cause mild disease. Dengue, however, can cause
tive blood-smear examinations for malaria, as well severe illness in some patients, especially those
as the negative rapid test for malaria antigen and with immunity from a previous infection. In such
the clinical improvement without appropriate patients, dengue hemorrhagic fever may occur;
treatment, essentially rule out a diagnosis of this condition is marked by increased vascular
malaria in this case. permeability that leads to shock, along with co-
agulopathy, disseminated intravascular coagula-
Viral Respiratory Diseases tion, and severe bleeding. This patient did not
This patient traveled from New England during have a history of dengue, and although she be-
the winter and was at risk for acquiring viral came severely ill, she did not have coagulopathy
respiratory infections. Her respiratory findings or hemorrhage.
— including cough, chest pain, pulmonary rales,
hypoxemia, and pulmonary opacities on chest Rickettsial Diseases
imaging — prompt consideration of influenza The clinical presentation of rickettsial diseases
and other viral respiratory infections. However, depends on the infecting species, which vary
these respiratory findings did not develop until geographically. Murine typhus is an emerging
the fifth day of illness. In contrast, if a commu- cause of undifferentiated fever in Indonesia,2 and
nity-acquired respiratory virus were the causative this patient had many of the classic (although
agent, respiratory symptoms would have been nonspecific) clinical findings, including fever,
expected to occur at the onset of illness. headache, myalgias, and abdominal pain. Some
During one flight, the patient sat next to a patients with murine typhus have a maculopapu-
coughing passenger from the United Arab Emir- lar rash, occasionally with a petechial compo-
ates; this raises the possibility of exposure to the nent, which was present in this patient. The
Middle East respiratory syndrome (MERS) coro- causative organism of murine typhus, Rickettsia
navirus. MERS is a respiratory illness that is typhi, is carried by rat fleas. The incubation pe-
marked by fever, cough, and shortness of breath riod for murine typhus is 1 to 2 weeks, and this
and is often accompanied by gastrointestinal timeline fits with possible exposure in Indonesia
symptoms. However, as with other viral respira- in this patient. Most cases are mild, and more
tory diseases, MERS is unlikely in this patient severe disease occurs in older adults. This pa-
because respiratory symptoms were initially ab- tient is young, and therefore, if her illness were
sent. Furthermore, the incubation period for MERS caused by murine typhus, a presentation this
ranges from 2 to 14 days, and this patient’s severe would be unexpected.
symptoms began 22 days after any possible ex-
posure. Enteric Fever
Typhoid and paratyphoid, which are also known
Arboviral Diseases as enteric fever, are caused by Salmonella enterica.
Several arthropod-borne viruses — including The majority of cases reported in the United
dengue, chikungunya, and Zika — are transmit- States occur in returning travelers; in more than
ted by mosquitos in both Indonesia and the U.S. half of such cases, they are returning from the
Virgin Islands, and dengue is a common cause Indian subcontinent, and in a growing propor-
of febrile illness in these regions. The incuba- tion of cases, they are returning from Southeast

274 n engl j med 377;3 nejm.org  July 20, 2017

The New England Journal of Medicine

Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital
Asia.3,4 The disease spreads through contaminat-
ed water or food, and this patient may have con-
sumed unpeeled fruit in Indonesia. Furthermore,
she did not receive an immunization against ty-
phoid before her trip, although it should be noted
that the protection afforded by this vaccine is
incomplete. The incubation period for enteric
fever is typically 7 to 18 days, which is consistent
with a possible exposure in Indonesia in this
patient. She had the nonspecific but hallmark
clinical findings of fever (with high tempera-
tures), abdominal pain, rash, and headache; in
enteric fever, these symptoms can progress to
shock and organ damage. However, she did not
have the classic stepwise fever (which increases
in severity over days or weeks), pulse–tempera-
ture dissociation, or relative bradycardia. Finally,
the “rose spots” (faint salmon-colored macules)
on the trunk and abdomen that are characteristic
of typhoid were absent. Despite the absence of
these differentiating features, this patient’s ill-
ness and the relatively high prevalence of this
disease in Indonesia make enteric fever a high-
probability diagnosis.
Leptospirosis
Leptospirosis, which has been reported world-
wide, is increasingly recognized as a clinically
important and potentially life-threatening illness.
It is most prevalent in the tropics, with outbreaks
occurring after heavy rain or flooding. The spiro-
chete that causes leptospirosis can be free-living
in water, soil, or mud or associated with animal
hosts, often rodents. The organism is transmit-
ted to humans through mucous membranes or
skin abrasions during swimming or bathing in
freshwater contaminated by rodent urine. Expo-
sure is more common among persons with cer-
tain professions, such as farmers, sewage work-
ers, and slaughterhouse workers; it is also more
common among persons who participate in ad-
venture sports or tourism activities in freshwater.
While this patient was in Indonesia, she swam
in jungle streams, ponds, and a waterfall pool,
places where she may have encountered this or-
ganism.
One distinguishing feature of leptospirosis is
that it may be associated with a biphasic presen-
tation. The first phase of illness is an acute
bacteremic illness. After the spirochetes are dis-
seminated through various tissues, antibodies
n engl j med 377;3 nejm.org  July 20, 2017
The New England Journal of Medicine
Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
are produced, and the second phase of illness
(the immune phase) may lead to vascular dam-
age and increased vascular permeability. In this
patient, the initial rash may have signified the
first phase of illness, with the disease becoming
clinically quiescent until after her return home.
After her return home, she may have entered the
second phase of illness, which was characterized
by fever (with high temperatures), headache, cough,
rash, myalgias, arthralgias, and abdominal pain.
This syndrome evolved into a severe illness, which
included the development of pulmonary–capil-
lary leak and acute kidney injury (with a creati-
nine level of 1.4 mg per deciliter [124 mmol per
liter]). Other findings developed in this patient
that were nonspecific but also suggestive of lep-
tospirosis; these included urinary abnormalities
(which can be present in the second, immune
phase) and conjunctival erythema (which may be
suggestive of conjunctival suffusion, a commonly
reported finding in leptospirosis).
Summary
Murine typhus, enteric fever, and leptospirosis
are all associated with the nonspecific triad of
fever, headache, and myalgias. However, the epi-
demiologic clue of freshwater exposure and the
pulmonary complications, renal insufficiency,
and biphasic rash seen in this patient all make
leptospirosis the most likely diagnosis in this
case. I suspect that the diagnostic test was either
a urinary PCR assay for leptospira DNA or a
blood test for leptospira antibodies.
Dr. Virginia M. Pierce (Pathology): Dr. Silverblatt,
what was your clinical impression when you
evaluated this patient?
Dr. Frederic J. Silverblatt: When I saw this patient,
she was lethargic and had temperatures as high
as 40.6°C. The initial presentation of fever in a
returning traveler usually offers few clues to help
differentiate between specific causes, and diag-
nostic clues often lie in information obtained
from a detailed history. In this case, the key
question was, “What did you do during your stay
in Indonesia?” Her answer directed my attention
toward infections associated with freshwater ex-
posure, such as leptospirosis. I also considered
malaria, typhoid fever, rickettsial infections, and
viral infections, including dengue, chikungunya,
and Zika virus infection. While the results of the
diagnostic studies were pending, I recommend-
275
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. CDC Case Definition for Leptospirosis.*

Criterion Present in This Patient

Clinical criteria
Fever during the previous 2 weeks Yes
Plus ≥2 of the following:
Myalgias Yes
Headache Yes
Jaundice
Conjunctival suffusion without purulent discharge Yes
Rash Yes
Or ≥1 of the following:
Aseptic meningitis
Gastrointestinal symptoms Yes
Pulmonary complications Yes
Cardiac arrhythmias or abnormalities on electrocardiography
Renal insufficiency Yes
Hemorrhage
Jaundice with acute renal failure
Laboratory criteria
Supportive (≥1 of the following):
Detection of a leptospira agglutination titer of 200–800 in one or more serum speci‑
mens by means of a microscopic agglutination test
Detection of antileptospira antibodies in a clinical specimen by means of an indirect im‑
munofluorescence assay
Detection of leptospira in a clinical specimen by means of dark-field microscopy
Detection of antileptospira IgM antibodies in an acute-phase serum specimen Yes
Confirmed (≥1 of the following):
Isolation of leptospira from a clinical specimen
Detection of a leptospira agglutination titer in a convalescent-phase serum specimen
that is ≥4 times the titer detected in an acute-phase serum specimen analyzed at the
same laboratory
Detection of leptospira in tissue by means of a direct immunofluorescence assay
Detection of a leptospira agglutination titer of ≥800 in one or more serum specimens by
means of a microscopic agglutination test
Detection of pathogenic leptospira DNA in a clinical specimen by means of polymerase-
chain-reaction assay
Epidemiologic linkage
Involvement in an exposure event (e.g., adventure race, triathlon, or flooding) associated
with known laboratory-confirmed cases
Case classification
Probable: A clinically compatible case with ≥1 of the following:
Involvement in an exposure event associated with known cases
Presence of supportive laboratory findings but no confirmatory laboratory evidence of Yes
leptospira infection
Confirmed: Presence of confirmatory laboratory evidence of leptospira infection

* Data are from the Centers for Disease Control and Prevention (CDC).8

276 n engl j med 377;3 nejm.org  July 20, 2017

The New England Journal of Medicine

Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital
ed doxycycline to treat possible leptospirosis or
rickettsial infection and ceftriaxone to treat pos-
sible typhoid fever. The next day, hypoxemia de-
veloped, and the patient was transferred to the
ICU. At that point, the decision was made to
initiate therapy with broader-spectrum antibiot-
ics and transfer the patient to this hospital.
Cl inic a l Di agnosis
Leptospirosis.
Dr . Jac quel ine T. Chu’s
Di agnosis
Leptospirosis.
Pathol o gic a l Discussion
Dr. Sarah E. Turbett: The diagnostic test, which was
performed on the sixth day of illness, was a
positive enzyme immunoassay for the detection
of IgM antibodies to leptospira antigens.
A PCR assay of a whole-blood sample drawn
from the patient on the fourth day of illness was
not positive for leptospira DNA. In some in-
stances, PCR assays have been found to be less
sensitive than serologic tests; the discordance
is attributed to the timing of sample collection
in relation to the relatively short-lived period of
leptospiremia.5,6 Other factors affecting the sen-
sitivity of PCR assays include the sample type
(whole blood vs. serum) and pretreatment with
antibiotics.6,7 In this case, the timing of sample
collection, the sample type, and the previous ad-
ministration of antibiotics may have contributed
to the undetectable result.
The Centers for Disease Control and Preven-
tion has developed a case definition to assist in
making the diagnosis of leptospirosis on the
basis of clinical and laboratory criteria and a
concomitant epidemiologic exposure (Table 2).8
This patient met the criteria for probable acute
leptospirosis.
Discussion of M a nagemen t
Dr. Emily P. Hyle: An estimated 1.3 million cases
of leptospirosis occur annually, with a case fatal-
ity rate of 6.85%. However, these are probably
underestimates, given the challenges associated
with diagnosis, especially in resource-limited Probable acute leptospirosis.
n engl j med 377;3 nejm.org  July 20, 2017
The New England Journal of Medicine
Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
settings, where the disease is most prevalent.9
The protean clinical manifestations make lepto-
spirosis difficult to distinguish from other com-
mon tropical diseases. Severe leptospirosis can
be manifested by meningoencephalitis or multi-
organ failure, including cardiac (e.g., myocardi-
tis), pulmonary (e.g., hemorrhage), hepatic (e.g.,
direct bilirubinemia), and renal (e.g., tubular
damage or acute renal injury) manifestations.10-12
Because this patient had acute kidney injury, she
met the criteria for severe disease.
Four published studies have compared the
effects of antibiotics with those of placebo in
patients with leptospirosis.13 In these studies, the
mortality rates were low, but many patients with
severe disease were excluded; thus, there is insuf-
ficient evidence to determine whether the use of
antibiotics results in lower mortality than the ad-
ministration of supportive care alone. The duration
of illness is likely to be shortened with the use
of antibiotics.13 For patients with severe disease,
antibiotics are typically recommended. Penicillin,
ceftriaxone, and doxycycline are the most fre-
quently prescribed antibiotics for leptospirosis.
This patient’s illness could have been prevent-
ed. Doxycycline is commonly prescribed for ma-
laria prophylaxis and can also prevent leptospi-
rosis.14 However, the patient had not seen a
provider for pretravel health advice because of
the cost associated with such a visit.
Dr. Pierce: Dr. Mgbojikwe, what happened with
this patient?
Dr. Mgbojikwe: By the second hospital day, the
patient’s fever had diminished, but her headache,
myalgias, and dyspnea persisted. The antimicro-
bial regimen was changed to ceftriaxone, doxy-
cycline, and levofloxacin. Her clinical status
continued to improve over the next 3 days; her
headache diminished and her hypoxemia re-
solved. She was discharged home with a 2-week
course of doxycycline for the treatment of sus-
pected leptospirosis.
Four days later, the patient was seen in the
infectious diseases clinic at this hospital. Since
returning home, she had remained afebrile, and
the myalgias, arthralgias, and respiratory symp-
toms had resolved. A mild, intermittent retro-
orbital headache without photophobia persisted.
Fina l Di agnosis
277
 Case Records of the Massachuset ts Gener al Hospital

This case was presented at the Medical Case Conference. Disclosure forms provided by the authors are available with
No potential conflict of interest relevant to this article was the full text of this article at NEJM.org.
reported.

References
1. Stauffer W, Cartwright CP, Olson D,
et al. Superior diagnostic performance of
malaria rapid diagnostic tests as com-
pared to blood smears in U.S. clinical
practice. Clin Infect Dis 2009;​49:​908-13.
2. Gasem MH, Wagenaar JF, Goris MG,
et al. Murine typhus and leptospirosis as
causes of acute undifferentiated fever, In-
donesia. Emerg Infect Dis 2009;​15:​975-7.
3. Basnyat B, Maskey AP, Zimmerman
MD, Murdoch DR. Enteric (typhoid) fever in
travelers. Clin Infect Dis 2005;​41:​1467-72.
4. Lynch MF, Blanton EM, Bulens S,
et al. Typhoid fever in the United States,
1999-2006. JAMA 2009;​302:​859-65.
5. Jorgenson JH, Pfaller MA, Carroll KC,
et al., eds. Manual of clinical microbiol-
ogy. 11th ed. Washington, DC:​ASM Press,
2015.
6. Thaipadungpanit J, Chierakul W,
Wuthiekanun V, et al. Diagnostic accuracy
of real-time PCR assays targeting 16S
rRNA and lipL32 genes for human lepto-
spirosis in Thailand: a case-control study.
PLoS One 2011;​6(1):​e16236.
7. Agampodi SB, Matthias MA, Moreno
AC, Vinetz JM. Utility of quantitative poly-
merase chain reaction in leptospirosis
diagnosis: association of level of leptospi-
remia and clinical manifestations in Sri
Lanka. Clin Infect Dis 2012;​54:​1249-55.
8. Leptospirosis (Leptospira interrogans) 2013
case definition. Atlanta:​Centers for Dis-
ease Control and Prevention (https:/​/​w wwn​
.cdc​.gov/​nndss/​conditions/​leptospirosis/​
case-definition/​2013/​.)
9. Costa F, Hagan JE, Calcagno J, et al.
Global morbidity and mortality of lepto-
spirosis: a systematic review. PLoS Negl
Trop Dis 2015;​9(9):​e0003898.
10. Abgueguen P, Delbos V, Blanvillain J,
et al. Clinical aspects and prognostic fac-
tors of leptospirosis in adults: retrospective
study in France. J Infect 2008;​57:​171-8.
11. Craig SB, Graham GC, Burns MA,
Dohnt MF, Smythe LD, McKay DB. Hae-
matological and clinical-chemistry mark-
ers in patients presenting with leptospiro-
sis: a comparison of the findings from
uncomplicated cases with those seen in
the severe disease. Ann Trop Med Parasi-
tol 2009;​103:​333-41.
12. Haake DA, Levett PN. Leptospirosis in
humans. Curr Top Microbiol Immunol
2015;​387:​65-97.
13. Brett-Major DM, Coldren R. Antibiot-
ics for leptospirosis. Cochrane Database
Syst Rev 2012;​2:​CD008264.
14. Infectious diseases related to travel:​
leptospirosis. Atlanta:​Centers for Disease
Control and Prevention, 2016 (https:/​ /​
wwwnc​.cdc​.gov/​t ravel/​yellowbook/​2016/​
infectious-diseases-related-to-travel/​
leptospirosis).
Copyright © 2017 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

278 n engl j med 377;3 nejm.org  July 20, 2017

The New England Journal of Medicine

Downloaded from nejm.org by MARIA DOLORES HERRERO MENDOZA on October 28, 2020. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.