The n e w e ng l a n d j o u r na l of
Clinical Problem-Solving
From the Department of Medicine
(C.D.O., C.R.O., J.J.), Section of Hematol-
ogy (A.I.L.), and the Department of Pa-
thology, Section of Digestive Diseases
(D.J.), Yale School of Medicine, New
­Haven, CT. Address reprint requests to
Dr. Odio at ­camila​.­odio@​­nih​.­gov.
N Engl J Med 2020;383:68-74.
DOI: 10.1056/NEJMcps1817531
Copyright © 2020 Massachusetts Medical Society.
68
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
m e dic i n e
Caren G. Solomon, M.D., M.P.H., Editor
Cryptic Cachexia
Camila D. Odio, M.D., Corey R. O’Brien, M.D., Jeremy Jacox, M.D., Ph.D.,
Dhanpat Jain, M.D., and Alfred I. Lee, M.D., Ph.D.​​
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.
A 57-year-old man with a history of rectal adenocarcinoma for which he had under-
gone colostomy presented to the emergency department with an unintentional 22.6-kg
weight loss and malaise, occurring over a period of 6 months. During this time, his
body-mass index (the weight in kilograms divided by the square of the height in
meters) dropped from 23.9 to 16.6. Progressive weakness developed, limiting his
ability to complete activities of daily living. He noted abdominal distention and leg
pain. He reported no nausea, vomiting, anorexia, joint pains, fevers, or cough. He
noted soft, brown, formed colostomy output without associated blood, mucus, or
oiliness.
Unintentional weight loss in a middle-aged man arouses concern about a possible
cancer. It is critical to review this patient’s rectal-cancer treatment and surveil-
lance. The differential diagnosis also should include prostate cancer and lung
cancer, which are common in this age group. Alternatively, failure to thrive could
result from heart failure, cirrhosis, adrenal insufficiency, diabetes mellitus, or
malnutrition. Infections such as human immunodeficiency virus (HIV) infection
and tuberculosis can be manifested insidiously. A detailed social history should be
obtained. Furthermore, malabsorption syndromes such as celiac and inflamma-
tory bowel disease are associated with altered bowel habits that may be obscured
in a patient with a colostomy.
Six years earlier, the patient received a diagnosis of stage IIIB (tumor–node–metas-
tasis classification, T3N1aM0) rectal adenocarcinoma after undergoing a colonos-
copy for hematochezia. His treatment consisted of neoadjuvant chemotherapy,
­external-beam radiation therapy, and an abdominoperineal resection, resulting in a
colostomy. Regular surveillance colonoscopies (most recently, 3 years before the cur-
rent presentation), computed tomographic (CT) imaging (9 months earlier), and
carcinoembryonic antigen (CEA) measurements (6 months earlier) were negative for
recurrence. The patient was a lifetime nonsmoker and reported no alcohol or recre-
ational drug use. He did not have a history of homelessness, imprisonment, or
known tuberculosis exposure. He reported no changes in eating habits and followed
a well-balanced diet.
The patient lived alone, worked as a mechanic, and had had no sexual contact in
more than 2 years. The family history included stomach cancer in his mother. He was
born in Puerto Rico and was of European ancestry; he moved permanently to Con-
necticut at the age of 19 years and last visited Puerto Rico 8 months before the current
n engl j med 383;1  nejm.org  July 2, 2020
The New England Journal of Medicine
 Clinical Problem-Solving

presentation. His only medication was ibuprofen,

taken a few times weekly for low back pain,
which had occurred sporadically for many years.
The back pain had worsened slightly after his
cancer diagnosis but was ameliorated with physi-
cal therapy.

Since the patient’s symptoms developed after his

last cancer surveillance testing, a repeat CEA
measurement should be obtained. Whole-body
imaging may identify local or metastatic sites of
recurrent rectal cancer and can be used to screen
for other chest abnormalities, including pleural
effusions suggestive of heart failure. The inci-
dence of tuberculosis in Puerto Rico is lower than
that in the continental United States; still, tuber-
culosis remains part of the differential diagno- Figure 1. Photograph of the Patient’s Legs.
sis, as does HIV infection. Histoplasmosis should Melanoderma is evident, with hypopigmented macules and patches.
also be considered, since it is endemic in Puerto
Rico, has been reported in Connecticut, and may
be manifested as unintentional weight loss. drome. Addison’s disease is possible, given the
systemic symptoms, but is typically associated
The temperature was 37°C, the heart rate 110 beats with diffuse hyperpigmentation, particularly in-
per minute, and the blood pressure 94/60 mm Hg. volving skin creases or the oral mucosa; vitamin
The patient had tachypnea, with shallow breaths. B12 deficiency in rare cases leads to hyperpig-
He appeared cachectic, with wasting of the arm, mentation of the hands and feet. The horizontal
leg, and temporal muscles. Horizontal nystagmus nystagmus arouses concern about the possibility
was noted. The buccal mucosa was normal, with- of a central neurologic problem.
out cheilosis or abnormal pigmentation. No cervi-
cal, axillary, or inguinal adenopathy was noted. The white-cell count was 7900 per cubic millime-
His abdomen was protuberant and nontender, ter, with 94% neutrophils and 2.5% lymphocytes.
with shifting dullness; a colostomy bag in the left The hemoglobin level was 9.0 g per deciliter, the
lower quadrant had a pink, patent ostomy with mean corpuscular volume 82.6 fl, the red-cell
brown, formed stool. There was hyperpigmenta- distribution width 19.9%, and the reticulocyte
tion of the distal lower extremities, with hypopig- count 1%. The platelet count was 164,000 per
mented macules and no edema (Fig. 1); no other cubic millimeter. A peripheral-blood smear
hyperpigmentation was observed. Motor strength showed hypochromic, normocytic red cells with
was 4/5 in the hips and shoulders and 5/5 in the increased bands. The iron level was 19 μg per
biceps and knees. deciliter (3.4 μmol per liter; reference range, 60 to
179 μg per deciliter [10.7 to 32.1 μmol per liter]),
Weight loss and temporal-muscle wasting sup- ferritin 322 ng per milliliter (reference range, 18 to
port a catabolic state due to cancer, chronic in- 370), vitamin B12 621 pg per milliliter (458 pmol
fection, inflammation, malnutrition, or a mal- per liter; reference range, 180 to 914 pg per milli-
absorptive syndrome such as celiac disease. The liter [133 to 674 pmol per liter]), and folate 20.5 ng
abdominal examination suggests ascites, raising per milliliter (46.5 nmol per liter; reference range,
the possibility of cirrhosis. The tachycardia and >5.9 ng per milliliter [>13.4 nmol per liter]). The
hypotension suggest intravascular depletion. The blood urea nitrogen, creatinine, and total biliru-
decreased proximal muscle strength could be bin levels were normal. The alanine aminotrans-
explained by lassitude, a proximal myopathy, or ferase level was 84 U per liter (reference range, 0 to
a paraneoplastic syndrome. The shin hyperpig- 34), the aspartate aminotransferase level 82 U per
mentation could represent vascular insufficiency, liter (reference range, 0 to 34), and the alkaline
an endocrine disorder, or a malabsorptive syn- phosphatase level 157 U per liter (reference range,

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 The n e w e ng l a n d j o u r na l
A
B liver contour makes this diagnosis unlikely.
Figure 2. CT Scan of the Chest, Abdomen, and Pelvis.
Panel A shows large amounts of ascites (white arrow)
and retroperitoneal lymphadenopathy (encircled), with
normal bowel and kidneys (black arrows). Panel B shows
a normal liver contour (arrow).
30 to 130). The serum albumin level was 1.6 g per
deciliter (reference range, 3.5 to 5.0), and the total
protein level was 6.4 g per deciliter (reference
range, 6.0 to 8.3). The prealbumin level was 7.6 mg
per deciliter (reference range, 18 to 35). The CEA
level was 1.0 ng per milliliter (reference value,
<3.0). The morning cortisol, thyrotropin, and gly-
cated hemoglobin levels were normal. Serologic
tests for tissue transglutaminase IgA antibodies
(to identify the presence or absence of celiac dis-
ease), HIV, and hepatitis A, B, and C viruses were
negative. Urine testing for histoplasma antigen
was negative. The C-reactive protein level was
86.9 mg per liter (reference range, 0.1 to 3.0). Uri-
nalysis showed trace protein; the protein-to-creat-
inine ratio in a spot urine sample was 0.9 mg of
protein per milligram of creatinine (reference
range, <0.1). A CT scan of the chest, abdomen,
and pelvis showed large amounts of ascites and
retroperitoneal lymphadenopathy, with no abnor-
70 n engl j med 383;1
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of m e dic i n e
malities in the lungs, liver, spleen, bowel, and
kidneys (Fig. 2).
The normal CEA level decreases the likelihood
of recurrent rectal cancer, but the CT findings of
ascites and lymphadenopathy merit further in-
vestigation. The hypoproliferative anemia, with
a low iron level, normal ferritin level, and ele-
vated C-reactive protein level, suggests anemia
of chronic disease. The constellation of hypoal-
buminemia, transaminitis, and ascites arouses
concern about possible cirrhosis, but the normal
Paracentesis can distinguish ascites due to por-
tal hypertension from another cause, such as
cancer, tuberculosis, or heart failure. The severe
hypoalbuminemia and low prealbumin level may
be due to anorexia, malabsorption, protein-losing
enteropathy, or nephropathy. Fecal fat and stool
alpha1-antitrypsin measurements should be ob-
tained, and the elevated protein-to-creatinine
ratio in the spot urine sample merits further
quantification with a 24-hour urine study. The
difference between the total serum protein and
albumin levels (known as the globulin gap or
gamma gap) is 4.8 g per deciliter, which exceeds
the reference value of less than 4 g per deciliter,
indicating increased nonalbumin serum proteins
such as acute-phase reactants or immunoglobu-
lins. Serum and urine protein electrophoresis
should be performed, with immunofixation and
quantitative measurements of immunoglobulins
and serum free light chains, to distinguish
between a monoclonal and a polyclonal gam-
mopathy.
Paracentesis showed a serum–ascites albumin
gradient of 0.6 g per deciliter and a white-cell
count of 47 per cubic millimeter (after red-cell
correction); the neutrophil count was 12 per cubic
millimeter, and the lymphocyte count was 10 per
cubic millimeter. The total protein level in a sam-
ple of ascitic fluid was 4.5 g per deciliter, with an
adenosine deaminase level of 24.4 U per liter
(reference range, <7.6). Cytologic examination
showed no malignant cells. A 24-hour urinary
protein measurement showed 410 mg of protein.
The stool alpha1-antitrypsin level exceeded 1.13 mg
per gram of stool (reference range, <0.50). Serum
and urine protein electrophoresis with immuno-
fixation revealed no discrete monoclonal gam-
nejm.org July 2, 2020
 Clinical Problem-Solving
mopathy; the serum free light-chain ratio (ratio of
kappa to lambda light chains) was normal. Quan-
titative immunoglobulin measurement showed
an IgG level of 2080 mg per deciliter (reference
range, 768 to 1632), an IgM level of 30 mg per
deciliter (reference range, 35 to 263), and an IgA
level of 1360 mg per deciliter (reference range,
68 to 408). Analysis of IgG subclasses showed
an IgG1 level of 1224 mg per deciliter (reference
range, 382 to 929) and an IgG4 level of 194.2 mg
per deciliter (reference range, 3.9 to 86.4).
A serum–ascites albumin gradient of less than
1.1 g per deciliter rules out portal hypertension.
Elevated ascitic fluid levels of total protein (≥2.5 g
per deciliter) and adenosine deaminase may be
seen in patients with peritoneal tuberculosis
(although adenosine deaminase levels are typi-
cally higher than that observed in this patient)
but also occur in other conditions, including
hepatocellular carcinoma and spontaneous bac-
terial peritonitis. The corrected ascites neutro-
phil count of less than 250 cells per cubic milli-
meter makes a diagnosis of spontaneous
bacterial peritonitis unlikely. Additional analysis
of the ascitic fluid, including a smear for acid-
fast bacilli, mycobacterial culture, and nucleic
acid amplification, is required to test for tuber-
culosis. The 24-hour urinary protein level is incon-
sistent with nephrotic syndrome. The elevated
stool alpha1-antitrypsin level suggests a protein-
losing enteropathy. The paraprotein studies argue
against a plasma-cell dyscrasia. The markedly
elevated IgA level could reflect inflammation or
an intestinal source of chronic infection. The
elevated IgG4 level with retroperitoneal lymph-
adenopathy arouses concern about the possibil-
ity of an IgG4-related disease; a retroperitoneal
lymph-node biopsy should be performed.
Staining of ascitic fluid for acid-fast bacilli and a
polymerase-chain-reaction (PCR) assay for tuber-
culosis were negative; a sample of ascitic fluid
was submitted for mycobacterial culture. Exami-
nation of a specimen from a CT-guided retroperi-
toneal lymph-node biopsy revealed nonnecrotiz-
ing epithelioid granulomas and a polymorphous
lymphoid population. Gram’s and acid-fast bacilli
stains were negative for bacterial organisms;
pathological examination showed no evidence of
malignant cells and no increase in IgG4-positive
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plasma cells. Grocott methenamine–silver stain-
ing and periodic acid–Schiff (PAS) staining were
negative for fungal and other organisms.
The differential diagnosis for nonnecrotizing
granulomas includes an array of autoimmune
and infectious diseases. The negative ascitic
fluid test for tuberculosis makes intestinal tu-
berculosis unlikely but does not rule it out.
Colonoscopy with biopsies may be helpful, since
the majority of intestinal tuberculosis cases have
ileocecal involvement, with the duodenum spared.
An upper endoscopic examination would rule
out celiac disease (even though it is unlikely ow-
ing to the negative serologic tests), tropical
sprue, and Whipple’s disease.
A colonoscopy with biopsy showed mild, active
colitis without granulomas, crypt abscesses, or
dysplasia. Esophagogastroduodenoscopy with
biopsies showed gross evidence of diffuse, active
duodenal inflammation, with no increase in in-
traepithelial lymphocytes and no flattening of
intestinal villi. Staining for acid-fast bacilli and a
PCR assay for tuberculosis were negative. An ex-
tensive focal collection of foamy histiocytes in the
lamina propria of the duodenum was identified
and showed diffuse uptake on PAS staining (Fig. 3).
Foamy histiocytes in an intestinal-biopsy sample
may occur in histiocytic disorders and reactive
diseases such as xanthomatosis, as well as in
Whipple’s disease. The latter condition, due to
Tropheryma whipplei infection, commonly affects
the duodenum, and the classic presentation in-
cludes weight loss, diarrhea, abdominal pain,
and arthralgia. This patient has some of those
features, along with protein-losing enteropathy,
lymphadenopathy, and melanoderma, all of which
are seen in Whipple’s disease.
A PCR assay of the duodenal biopsy specimen was
positive for T. whipplei. A magnified view of the
PAS-stained specimen showed rodlike structures
that are characteristic of Whipple’s disease
(Fig. 3D). Repeat physical examination revealed
episodic convergence nystagmus (medial drift
of both eyes) on mastication, a finding that is
consistent with oculomasticatory myorhythmia
(rapid, rhythmic contractions of the face and jaw
along with convergence movements of the eyes)
71
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 3. Duodenal Biopsy Specimen.

On hematoxylin and eosin staining, a low-magnification view of the duodenal biopsy specimen (Panel A) shows
slightly broadened villi with focal collections of macrophages (arrows); a high-magnification view (Panel B) shows
aggregates of foamy histiocytes. On periodic acid–Schiff (PAS) staining (Panel C), the collection of foamy histio-
cytes in the lamina propria shows strong cytoplasmic positivity; a high-magnification view of the foamy histiocytes
(Panel D) shows many PAS-positive globules that vary in size and many rodlike structures, features that are charac-
teristic of Whipple’s disease.

and suggestive of central nervous system (CNS)
involvement. A lumbar puncture to confirm CNS
infection was unsuccessful. The patient was treat-
ed with an extended course of ceftriaxone for CNS
coverage (2 g daily for 4 weeks). Two days after the
start of ceftriaxone therapy, fever, bandemia, re-
spiratory failure, and hypotension developed,
which were thought to represent a Jarisch–Herx-
heimer reaction and necessitated intubation and
the use of a pressor. After 4 days, the patient was
successfully weaned from the ventilator but re-
quired intermittent treatment with bilevel positive
airway pressure for an additional 2 weeks.
After 1 month of ceftriaxone therapy, mobility
had improved and lower back pain had lessened,
the BMI had increased to 17.9, and the nystagmus
had resolved. The albumin level had increased to
2.3 g per deciliter, and liver enzyme levels had
normalized, although ascites persisted and the
patient remained anemic. He was transitioned to
suppressive treatment with oral cotrimoxazole
for a planned 1-year course. After completion
of inpatient rehabilitation, the patient relocated
to Puerto Rico and did not follow up at our insti-
tution.
C om men ta r y
This case describes a patient, originally from
Puerto Rico, with rectal cancer in remission, in
whom profound weight loss and weakness de-
veloped. Evaluation revealed ascites due to hypo-
albuminemia with protein-losing enteropathy and
retroperitoneal lymphadenopathy, suggesting the
possibility of cancer or tuberculosis. Endoscopic
biopsy ultimately identified Whipple’s disease,

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 Clinical Problem-Solving
with oculomasticatory myorhythmia, arousing
concern about the possibility of CNS involve-
ment. Several weeks of ceftriaxone treatment
resulted in clinical improvement, although the
patient’s course was complicated by the Jarisch–
Herxheimer reaction.
T. whipplei is a ubiquitous environmental or-
ganism.1 The bacterium has been identified in
fecal samples in up to 20% of asymptomatic
persons, but clinical manifestations of infection
occur in only 1 case per 1 million persons annu-
ally.2,3 Immunologic variation may influence sus-
ceptibility to active disease.3,4 The infection shows
a male predominance and typically affects per-
sons of European ancestry.5
Whipple’s disease classically involves arthral-
gia, abdominal pain, and diarrhea, although large
case series suggest that arthralgia and diarrhea
each occur in 70 to 80% of patients, and ab-
dominal pain occurs in about 55%.5 Some other
features of the disease are as common or more
common, including weight loss (in 92% of pa-
tients), hypoalbuminemia (in 91%), anemia (in
85%), and lymphadenopathy (in 60%). Many of
these features develop over a period of 6 to 8 years
before diagnosis.2,5 Less common findings, which
were also present in this patient, include oculo-
masticatory myorhythmia (in 20% of patients),
melanoderma in sun-exposed areas of the body
(in 40%), nonnecrotizing granulomas of the
lymph nodes (in 9%), and ascites (in 8%).3,6,7 Up
to 50% of patients have CNS disease. Back pain
due to spondylitis has been observed in rare
cases and typically affects the lumbar spine.2
Diagnostic tests for Whipple’s disease include
histologic examination for PAS-positive macro-
phages, a PCR assay for T. whipplei (specifically
the 16S ribosomal RNA), and immunohisto-
chemical binding of T. whipplei–specific antibody;
a diagnosis of Whipple’s disease requires at least
two of these three tests to be positive.5 PAS-
positive foamy macrophages (histiocytes) are a
nonspecific finding, occurring with histiocytic
and reactive disorders and other infections, includ-
ing Mycobacterium avium and histoplasma infec-
tions.7 In contrast, immunohistochemical exam­
ination and a PCR assay have high sensitivity
and specificity for T. whipplei infection (>90%).
False positive results may occur, owing to bac-
terial colonization in the absence of active in-
fection.8,9
The diagnosis of Whipple’s disease is often
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delayed because of its rarity and many nonspe-
cific symptoms and signs. The disease is fatal if
left untreated. Prolonged antibiotic regimens with
blood–brain barrier penetration cure most pa-
tients. Standard therapy is a 14-day course of
ceftriaxone (or a longer course if the CNS is in-
volved), followed by a 1-year course of trime-
thoprim–sulfamethoxazole. A small clinical trial
showed a 95% remission rate at a median of 89
months with this treatment approach (with re-
mission defined as resolution of clinical symp-
toms, negative results on PCR testing of affected
tissue, and normalization of macrophages in a
duodenal biopsy specimen).10 One patient had a
recurrence 3 years after receiving treatment with
ceftriaxone plus trimethoprim–sulfamethoxazole,
but remission was achieved after the administra-
tion of an alternative treatment regimen (merope-
nem, followed by trimethoprim–sulfamethoxa-
zole for 1 year).
In a subsequent trial comparing a 1-year
course of trimethoprim–sulfamethoxazole with
a 3-month course (after initial treatment with
ceftriaxone for 14 days in all patients), no sig-
nificant differences in cure or relapse rates were
observed.11 Shorter treatment regimens may be
considered in patients with prompt and marked
clinical improvement (resolution of symptoms
and normalization of inflammatory markers)
and patients in whom antibiotic treatment has
adverse effects. An alternative regimen of doxy-
cycline plus hydroxychloroquine for 12 months,
with trimethoprim–sulfamethoxazole for CNS
disease, has been associated with high cure rates
in small retrospective studies12 and in a small
clinical trial involving patients who did not have
a response to ceftriaxone plus trimethoprim–
sulfamethoxazole.13 However, data are lacking
from studies directly comparing these regimens.
The Jarisch–Herxheimer reaction, which oc-
curred in this patient, is rare and has been re-
ported after a patient has started antibiotic
treatment. The reaction is characterized by fever,
hypotension, altered mental status, and respira-
tory failure and is attributable to an inflamma-
tory response to endotoxins released on bacte-
rial death.14
Although there are no standard surveillance
guidelines for Whipple’s disease, experts recom-
mend duodenal biopsy at 6 months and 12
months after treatment, with histologic analysis
and PCR testing.3 Alternative therapy should be
73
 Clinical Problem-Solving

considered if the specimen from the surveillance
biopsy has PAS-positive macrophages or is posi-
tive for T. whipplei on PCR testing.3 Lifelong re-
lapse rates were previously reported to be as
high as 30%3 but appear to be substantially
lower with current standard regimens,2 although
lifelong clinical surveillance remains prudent.3
Neurologic relapse leading to fatal encephalitis
has been reported in rare cases.2 Patients who
have a relapse should be treated with a different
antibiotic regimen than that previously used.2,3
In this case, diagnosing Whipple’s disease and
promptly initiating appropriate antibiotic therapy
resulted in marked clinical improvement within
1 month, although the patient was subsequently
lost to follow-up. All patients treated for Whip-
ple’s disease should be aware of the risk of re-
currence and the potentially fatal outcome if the
recurrence is untreated. They should be encour-
aged to remain vigilant, in partnership with
their clinicians.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. Maiwald M, Schuhmacher F, Ditton
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2. Dolmans RAV, Boel CHE, Lacle MM,
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