A patient with diarrhea, arthralgias, and fever

1993;105:923-930

GASTROENTEROLOGY

CLINICAL CHALLENGES Mark A. Peppercorn, M.D. Clinical Challenges Editor Beth Israel Hospita1 330 Brookline Avenue Boston. Massachusetts 02215

A Patient With Diarrhea, Arthralgias, and Fever JAIME

ZIGHELBOIM,*

HERSCHEL

*Division of Gastroenterology Minnesota

A. CARPENTER,*

Case Report A 28-year-old abdominal abdominal

carpenter

pain and bloating.

temperatures fatigue

sometimes sweats.

and

wrists,

and

would

usually only involve

excellent

aspirin

suppression

He was married, mitted

disease

mother

German;

na1 disease.

the proximal

knees,

joints.

up to 4 g/day, from

tarsal

arthralgias

of the arthralgias, He denied

as wel1 as with

5 to 10 mg daily, with although

not com-

use of other medications. of sexually

or illicit drug use. His father there was no family history

gastrointestinal

ankles,

The

and there was no history

The

of

joint area. He had been treated

in a dose ranging

plete relief of the fevers.

with

a single joint at a time with pain

1-4 days in a given enteric-coated

with

associated

involving

elbows,

metatarsophalangeal

prednisone

a 5-year his-

there was a 5-year history

arthralgias

joints,

mid-

in the evenings, 103’F

and

the pas-

with crampy

He also reported

reaching

areas,

with

with diarrhea He reported

primarily

In addition,

migratory

interphalangeal

lasting

presented

daily, associated

tory of fever. This occurred drenching

review

of systems

bleeding,

weight

trans-

was Italian

and

of gastrointesti-

revealed

no history

loss, skin

rash,

of

or other

symptoms. On examination, muscular

his temperature

and healthy

appearing.

mal. The skin and mucous reveal

any abnormalities.

was 36.9”C.

NO pallor

examination

revealed

and

examination

was

examinations or clubbing

no masses

normal.

Neurological Laboratory

did not was noted.

or tenderness,

There

smal1 nontender axillary nodes bilaterally prominent inguinal nodes, but no cervical thy. On cardiac click was heard,

He was

The vita1 signs were nor-

membrane

Abdominal recta1

were

several

results

was normal.

were as fellows

count,

J. TALLEY*

Mayo Clinic and Mayo Foundation,

(4.1-10.9)

593 X 109/L

rate, 52 mm/h era1 blood slight

(0-22);

smear

abnormalities keratocytes normal;

serum

folate,

6.1 g/dL

(6.3-7.9);

phosphatase,

159 U/L

ase, 25 u/L

(12-31);

direct bilirubin, (4.3-8.0); hemoglobin,

total

stranded

1.0 mg/dL

antinuclear

DNA,

nonreactive.

some fatty crystals.

Cultures

albumin,

and

3.3 g/

rapid

fecal

factor,

negative;

~30

anti-double

plasma

was negative;

of urine

(0.1-1.1);

(5.0-12.5);

rheumatoid

antibody

for parasites

alkaline

uric acid, 4.2 mg/dL

(0.8-1.2);

53 U (0-70);

Stool

total protein, aminotransfer-

6.5 pg/dL

stool (0-2);

(135-

9 mg/dL

(70-100);

0.4 mg/dL

(0.0-0.3);

thyroxine,

1.6 mg/g

(0-39);

(2.5-4.5);

78 mg/dL

total bilirubin,

creatinine,

iron satura(281-1079);

calcium,

(98-25 1); aspartate

0.1 mg/dL

dL (3.5-5.0);

total

137 mEq/L

(3.6-4.8);

glucose,

elec-

(50-150);

ng/L

sodium,

4.9 mEq/L

phosph orus, 4.6 mg/dL

(8.9-10.1);

IU/mL

(2-20);

367

and

hemoglobin

(250-400);

B,,,

cells

macrocytes,

9 pg/dL

266 pg/dL

7.0 pg/L

145); potassium,

regenerating

iron,

periph-

red blood

and stomatocytes;

vitamin

platelet

sedimentation

1.1% (0.6-1.8);

microcytic

serum

capacity,

3% (14-50);

differential;

erythrocyte

including

schizocytes, iron binding

normal

reticulocytes,

showed

trophoresis tion,

with

(184-370);

Rochester,

reagin

there

and blood

were

were nega-

tive. Chest and spine radiographs trointestinal stomach jejunal

barium

but minimally folds.

“lymphoid

A barium follicles”

were normal.

series showed thickened enema

a normal duodenal

showed

in the cecum

and

An upper

gas-

esophagus

and

and proximal

slightly

prominent

ascending

colon.

and several less lymphadenopa-

auscultation, an inconstant soft systolic but no murmurs or rubs were detected.

examination

NICHOLAS

9.2 X lO”/L

pain for the past 4 months.

sage of 4-6 loose stools

and

and Internal Medicine, and *Division of Medical Pathology,

(normal

values

in pa-

rentheses): hemoglobin, 9.1 g/dL (12.9-16.6); mean corpuscular volume, 65.7 fL (81.2-95.1); white blood cel1 count,

Abbreviations used in this paper: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; PAN, polyarteritis nodosa; PAS, periodic acid-Schijf; PCR, polymerase chain reaction; rRNA, ribosomal ribonuclelc acid. 0 1993 by the American Gastroenterological Association

0016-5085/93/$3.00

924

ZIGHELBOIM

Proctoscopy performed.

ET AL.

GASTROENTEROLOGY

was normal

to 10 cm. A diagnostic

test was

is familial

referred

Dr. laime Zighelboim: This 5-year history

of diarrhea

in an autosomal

young

of fever and peripheral

history

paroxysmal

to as familial

polyserositis,

mediterranean

No. 3

commonly

fever.” This dis-

ease is found mainly in Israel (among Sephardic Jews), Armenia, Italy, and Northern Africa, and is inherited

DifferentialDiagnosis

4-month

pain

Vol. 105,

man

had a

by recurrent

arthralgias,

and a

pain, arthralgias,

and abdominal

pain.

The

recessive

attacks

ules. These

fashion.

of fever,

and painful

attacks

usually

It is characterized

abdominal

pain,

lower extremity last 24-48

chest

skin nod-

hours,

although

best way to approach the differential diagnosis in this case is to consider those diseases that can affect the

in some patients they may last for a week, and recur anytime from once a month to once a year. Pathologi-

joints

cally,

and the gut, or so called

tis”.’ The differential considering

those

cause chronic

“enteropathic

can be narrowed conditions

that

arthri-

even further can,

in addition,

fever.

Inflammatory

bowel

disease

the axial and peripheral

joints;

arthritis

occurs

and in Crohn’s

disease

in which

when

is involved.*

cerative more the

colitis

common extraintestinal

present

before

manifestations the onset

axial arthritis,

uveitis, other

whereas

thema

nodosum,

in 3%23%

can affect both in ulit is

Some of

of IBD

that

may

of bowel

symptoms

include

and primary

sclerosing

cholan-

systemic

arthritis,

disease activity.2

(IBD)

the colon

gitis,

peripheral

by

manifestations

pyoderma

and episcleritis Overall,

such

gangrenosum, arthritis

bowel

is present

of cases of IBD; it predominantly

involves

the lower extremity joints, particularly the knees and ankles, is often migratory, and is rarely erosive or destructive.”

It usually

inflammation

this

tion

reduces

cause

condition.

Chronic

the occurrence

familial

mediterranean

The systemic that

can manifest

gastrointestinal can present

with

symptoms. with

cluding fever, ache, myalgias,

fever,

cystitis,

and hepatic

or pancreatic

extremely

poot-,

mately

involvement with

Shigella, Salmonella, Campylobacter, and

infections,

and

Yersinia species

have al1 been implicated. The lower extremity joints are predominantly involved. However, symptoms usually resolve within weeks to months in over 90% of cases,’ and it would be unusual for the arthritis to precede the diarrhea. The absente of other manifestations of Reiter’s syndrome (conjunctivitis, urethritis, mucocutaneous lesions) in our patient makes this an unlikely diagnosis. An entity to consider in a patient of Italian ancestry with unexplained fever, arthralgias, and abdominal

infarction.

and hypertension

and (PAN) inheadman-

a 5-year

treatment.”

an unlikely

diagnosis.

hypersensitivity

survival

in

PAN is

of approxi-

to over 50% with diarrhea and the

or hypertension Henoch-Schönlein

vasculitis

Evidente

is present

of untreated

lO%, although it improves The predominant

lack of renal involvement

with enteric

nodosa

ifestations can include nausea, vomiting, abdominal pain, bleeding, bowel infarction, perforation, chole-

of cases. The prognosis

scopy findings did not identify colitis. Another condition that causes fever, diarrhea, and joint pain is Reiter’s syndrome or reactive arthritis.5

arthralgias,

weight loss, malaise, weakness, and arthralgias.” Gastrointestinal

30%60%

and abdominal pain by several years, which would be unusual in IBD, and the colon radiograph and procto-

of dis-

signs and symptoms

Nonsteused in

of diarrhea

attacks

group

Polyarteritis

nonspecific

cussion,

in association

are another

symptoms are treated. drugs are sometimes

the onset

painful

fever most unlikely.

vasculitides

of renal

preceded

administra-

tacks of abdominal or chest pain, and the prominent diarrhea in the our case would make a diagnosis of

steroid

This occurs

of acute

sur-

afflicted

and may prevent the development of amyloidosis.“s The lack of a family history, the absente of acute at-

refractory cases, but these agents can potentially reactivate quiescent colitis. 4 However, in the case under disthe arthralgias

in patients

colchicine

flare and

during

of the serosal

occurs

a colitis

develops

abates when the bowel roidal anti-inflammatory

with

orders as

ery-

tend to parallel

peripheral

a nonspecific

faces of unknown

that can present

makes PAN purpura

is a

with gastro-

intestinal symptoms and signs, including nausea, vomiting, diarrhea, constipation, hematochezia, and bowel intussusception. ” Polyarthralgias are also a prominent finding. However, palpable purpura is present in virtually al1 cases, usually distributed over the buttocks and lower extremities, and such findings were absent in our patient. Behcet’s syndrome should be considered in patients presenting with fever and arthritis; the latter is not deforming and usually affects the knees and ankles. Gastrointestinal involvement typically consists of mucosal ulceration of the gut, which usually occurs in the terminal ileum and cecum, and can cause bleeding, perforation, fistulas, and strictures.‘* However, the absence of recurrent oral and genital ulceration and the

September

1993

A PATIENT

lack of skin and eye involvement drome an unlikely Johnson syndrome of skin lesions

and the chronicity

An additional lymphoma.

due

bowel, with

important to

diffuse

lymphatic

lymphomas

prominent

the barium

probably

represented

are a common

incidental

dren.‘” These ferentiated

benign

with

certainty

lonic lymphoma polyposis without segment.

finding,

lymphoid

In the case under

and peripheral

deterioration In addition, lymphoma.

would

observed

in chilbe dif-

diffuse

co-

however,

preceded

fever

the onset

without

treatment.

migratory arthralgias are rare in intestinal Thus, this diagnosis can be essentially disfurther

consideration

Subacute

bacterial

endocarditis

by George

in our case. can present

fïndings,

in our patient

biopsy.

tient with

arthritis,

cough,

absorption,

and

mesenteric

this disease

This

entity

and mesenteric

lymph

ence of rod-shaped ration.

weight

lymphadenopathy.

deposits nodes.

organisms

Since Whipple’s

He also noted

cases have been described.“,” ease that typically

description, males

the prevalente though others in the HLA disease

mediated mechanism, causing a sterile, moderately severe inflammatory synovitis. Auscultation wil1 usually detect

a cardiac

murmur;

only rarely

are no murmurs

audible. Our patient only had a systolic click; the absence of any cardiac murmurs, the prolonged course of the disease, and the negative blood cultures argue against a diagnosis of endocarditis. Patients with the acquired immunodeficiency syndedrome (AIDS) can have al1 of the manifestations scribed in this patient. Fever, fatigue, arthralgias, diarrhea, and lymphadenopathy are common symptoms and signs in patients with AIDS. In addition, patients with AIDS are prone to infection with Mycobacterium avium-intracellulare,which can be confused with Whipple’s disease endoscopically and histologically.‘* We are not told whether a human immunodeficiency virus

to be

of HLA-B27 has been reported,22 alhave been unable to detect differences types

between

patients

with

Whipple’s

and the genera1 population.23

ease include

manifestations

diarrhea,

which

of Whipple’s is present

pain and bloating.

or immune-

disfourth

are no established cases of In addition, an increase in

tients

The latter may be due to a hypersensitivity

prepa-

over 700

and fifth decade of life. The disease is not thought contagious, because there direct human transmission.

hemorrhages, arthritis.

the pres-

in their

and

splinter

propia

It is an uncommon

affects white

cutaneous

splenomegaly,

He

on a silver stained

original

mal-

because

in the lamina

Melena has been reported occult blood loss is more

(petechiae,

he rec-

lipodystrophy”

from emboli to the mesenteric vessels and its branches. Physical examination may occasionally reveal muconodules),

there-

was first

loss, diarrhea,

mately 75% of cases.20,2’,24,2s It is usually malodorous and is often associated with

lesions

is Whip-

test should

ously with fever, night sweats, weakness, weight loss, and arthralgias. “,” Acute abdominal pain can occur

subcutaneous

how-

in 1907,‘” when

“intestinal lipid

Gastrointestinal insidi-

while had no

to the HIV virus.

and laboratory

Whipple

925

ognized the presence of “frothy cells” (macrophages) that extensively infiltrated the lamina propia in a pa-

of the associated

which

by years, and therefore, if this it is likely that marked clinical

missecl from

described

polyps,

other causes of colonic of the involved colonic

have occurred

for exposure

be a smal1 bowel

named

cannot

discussion,

fore

FEVER

our patient

and the next diagnostic

in our patient

primary

lymphadenopathy

of intestinal symptoms were due to lymphoma,

over-

malignan-

especially

polyps

from

or from a biopsy

smal1

stenosis

follicles

lymphoid

risk factors

Based on the clinical

gastrointestinal

examination

benign

apparent

AND

on our patient;

must be considered,

ple’s disease,

localized

lymphoid

enema

test had been performed

this diagnosis

ever, the most likely diagnosis

and bacterial

of the

ARTHRALGIAS,

and malabof the

or

contents

(HIV)

DIARRHEA,

is intestinal

for < 1% of al1 gastrointestinal

cies.14 The during

with diarrhea

obstruction,

Primary

tract account

syn-

of the symptoms.”

involvement

stasis of intestinal

growth.

Behcet’s

consideration

This can present

sorption

makes

diagnosis in our patient. Steven’sis also unlikely in view of the lack

WITH

frequently

complain

dis-

in approxiwatery and steatorrhea.

in several patients, although common.26 In addition, paof nonspecific

abdominal

Extraintestinal manifestations are frequent and can precede the onset of gastrointestinal symptoms by many years. In a recent review of 29 patients diagnosed at the Mayo Clinic over a 30-year period, arthritis was present in 82% of patients for a mean of 9 years, fever in 54% for a mean of 4 years and weight loss in 89% for a mean of 8 months before the diagnosis was susand is pected. 2s Fever occurs in >50% of patients usually monly,

low grade and intermittent, although less coma high, spiking, or sustained temperature ele-

or frank arthritis are vation can occur. 24 Arthralgias reported by >80% of patients, and in more than 30% of cases can be present for longer than 5 years before joints are most ofthe diarrhea appears. 24,2sPeripheral ten involved in a migratory or intermittent fashion. Almost patient

90% of patients complain of weight 10s~~‘; our maintained a stable weight, and this may have

926

ZIGHELBOIM

confused

GASTROENTEROLOGY

ET AL.

his previous

physicians

the correct diagnosis. Other extraintestinal

systems

include ment

making

Cardiac

chronic

cough

involvement failure

can be manifested

with lung or cardiac The

most

dreaded

mately

10% of patients organ

nerve,

disease. visual,

cord,

blood

duodenal

cluding

and

glossitis,

wasting,

dehydration,

in patients

with

hypoalbuminemia,

cult

in-

cheilosis, ascites and is probain

50% of cases;20,2’,24,25 the lymph

nodes

can be moderately enlarged and are typically nontender, and freely movable. Heart murmurs

firm, occur

due

to endocardial

valvular

infiltration

index,

of macro-

many

is p thalassemia normal

erosions

anemia

iron and a low saturation

capacity

state. The nor-

was probably

due to the

disease, which can infectieus, or neo-

minor.

This cannot

be ruled

electrophoresis

out by a

in a patient

with

iron deficiency because when iron deficiency coexists with p thalassemia minor, the hemoglobin A2 levels may be normal. 31 Our patient’s pe ri p heral blood smear revealed

slight

abnormalities

cells, which

al1 erythrocytes,

in the shape

represented

and probably

of the red

only a smal1 fraction were not of clinical

phage

ple’s disease. The abdomen may be distended or slightly tender, and a periumbilical mass is sometimes

DNA, and zymogen particles has been reported patient with Whipple’s disease.33,34 In addition,

palpated

normal

abnormalities, ataxia, posterior column signs, or peripheral neuropathy.27,28 The most common laboratory abnormalities, present in >70% of cases, include a low serum carotene, steatorrhea, hypoalbuminemia, iron deficiency anemia, and an elevated erythrocyte sedimentation rate.2” The former three are due to malabsorption and protein losing enteropathy, although the levels of serum albumin do not correlate with the enteric protein 10s~. In our patient, fatty crystals were identified in the stool; because up to 14 g of stool fat per 24 hours can be

and

and oc-

had a microcytic

systolic click, which was probably due to mitral valve prolapse rather than cardiac involvement by Whip-

and nerve

with

of the arthralgias

of an iron deficiency

hemoglobin

vance.32

wil1 vary depending on the site of involvement may reveal signs of dementia, confusion, cranial

with

patients

including Whipple’s disease. Anplastic condition, other common condition that can cause a microcytic anemia, particularly in individuals of Italian ancestry,

friction

representing enlarged mesenteric lymph e al and splenomegaly have also rarely nodes*24beenHepatom reported.2” g ‘Th e neurological examination

of

anti-inflammatory

coexistence of an anemia of chronic occur in any chronic inflammatory,

blood

had an inconstant

and in ap-

may be a cause

the gastric

patient

with a low serum

suggestive

phages leading to stenosis or insufficiency,24 but flow murmurs are more common due to anemia; pericardial rubs are rare. Our patient

Our

Gastric

loss in some patients

treatment

may explain

bleeding.

or occult

occurring

disease take nonsteroidal

fever, which

in-

blood

drugs for symptomatic

associated

tract.

However,

disease.

as

Whip-

present

was nonspe-

smal1 bowel

are very common,

mal total iron binding with

in the ab-

disease can be due to iron

65% of cases,3o and

of

cranial nerve

29 this finding

the gastrointestinal

erosions intermittent

Whipple’s

and occasionally,

Lymphadenopathy peripheral edema. 20~2’*24,2s bly the most common physical sign, being approximately

Whipple’s

of malabsorption

hyperpigmentation, hypotension,

severe

chronic,

the

or more often

peripheral

loss from

dis-

treatment

syndromes

in the proximal

proximately

in the clinical

hypothalamic,

can show evidente

muscle

patients

in approxi-

successful

Cortical,

spinal

by congestive

volvement have al1 been described. The physical examination in patients ple’s disease

of diarrheal

in Whipple’s

malabsorption

most

occurs

involvement, after

The anemia

pain.

involving

and can present

the first sign of relapse

involvechest

of Whipple’s

particularly

system. 27,28 This

of other

in a variety

No. 3

cific.

are asymptomatic.

complication disease,

nervous

intestinal

However,

involvement

centra1 absente

and pleuritic

or pericarditis.

ease is neurological

found

sence of fat malabsorption that can be involved

the lungs and heart.20~2’~24Pulmonary causes

heart

and delayed

Vol. 105,

A defect in peripheral degradation of

OKT4/OKT8

blood bacterial

ratio

of rele-

monocyte and macroproteins, bacterial

and

increases

in one an ab-

in intrae-

pithelial lymphocytes in smal1 bowel biopsy samples from patients with Whipple’s disease have been noted.35 Rod-shaped bacilli and bacterial products are found

in the cytoplasm

of macrophages

present

in the

lamina propia, suggesting impaired phagocytosis and intracellular processing of bacterial remnants.3”-35 On the other hand, humoral defense mechanisms appear to be intact. Despite these cellular defense abnormalities, patients are not at increased risk for acquiring other infections but appear to have a specific and unusual susceptibility to the organism causing Whipple’s disease.24 The endoscopic appearance of the duodenum in Whipple’s disease can be characterized by yellowwhite plaques and a pale yellow shaggy mucosa in ap-

September

50% of cases. 30 The mucosa

proximately

friable

A PATIENT WITH DIARRHEA, ARTHRALGIAS, AND FEVER 927

1993

and erythematous,

or there

Less than 20% of patients upper

endoscopy

abnormalities starting

tend to improve

appropriate

within

antibiotic

normal

these endoscopic a few months

of

therapy. radiograph

wil1 show

thickening

of the plicae

circulares

with a gra-

of decreased

involvement

distally

marked dient

may be erosions.

wil1 have completely

exams.30 In general,

Radiologically,

may be mildly

mately

a smal1 bowel

75% of patients

with

in approxi-

Whipple’s

disease.25

fact, the terminal

ileum

is almost

always

spared.

bowel

can

be present

but

is usually

dilatation

In

Smal1 not

marked. These changes typically revert with successful therapy+21,24.25 The upper gastrointestinal radiograph in our patient ized proximal with

showed

smal1 bowel,

Whipple’s

barium

involvement. raphy

disease.

study would

dalities

mild

useful

lymph

the centra1

nervous

magnetic

resonance

show contrast

be consistent

a full smal1 bowel to assess the extent

diagnostic

which

nodes,

of the visual-

would

disease include

of the abdomen,

mesenteric

which

However,

be required

Other

in Whipple’s

thickening

radiologie computed

often

computed

imaging

enhancing

mo-

enlarged disease

tomography

of the head,

mass lesions

which

and arthralgias tinal

preceding,

symptoms,

sensitive

or

diagnostic

may

in the brain.

portion

combination

of the

of fever of intes-

the iron defiproximal smal1

were together

of Whipple’s

An upper endoscopy stomach, and duodenal

very sugges-

disease.

the

circular

folds

were

thickened, and the mucosa was friable on gentle contact. These changes persisted distally to the leve1 of the ligament

of Treitz.

the dissecting

The villi appeared

microscope.

thickened

Smal1 bowel biopsy

under samples

were obtained.

Pathological

but not with

Nite

bacilli.

findings

Findíng

Dr. Herschel A. Carpenter:

endoscopic

biopsy specimen from the distal duodenal mucosa showed distention and clubbing of the villi due to infiltration of the lamina propia by foamy macrophages. The lacteals were dilated and lipid droplets were present in the interstitium, reflecting lymphatic obstruction (Figure 1). The macrophages contained smal1 sickle-shaped bacilli, which stained with periodic

Blue, a are

The differential diagnosis of PAS-positive diastaseresistant macrophages in the lamina propia of the

mosis,

and

in addition

Whipple’s

bacillus.

distinguished by

beaded

shape

M. avium-intracellulare

Although

examination

be done for confìrmation. capsdattlm is PAS-positive

disease, histoplas-

rods that are larger

than the

they can frequently

from the organism on

to Whipple’s disseminated

macroglobulinemia.

are long, straight,

of Whipple’s

of PAS/diastase an acid-fast

be

disease stained

stain should

The capsule of Histoplasma diastase-resistant. In dissemimacrophages are filled with

nated histoplasmosis, however, the organisms are large, these organisms; round, and easily distinguished from Whipple’s bacil-

lus. In macroglobulinemia, a plasma cel1 dyscrasia, PAS-positive diastase-resistant immunoglobulin accumulates in macrophages; however, this stains homogePAS-positive macrophages are neously. *’ Occasional present

An

These

disease.

slides at high magnification,

revealed a normal esophagus, bulb. Beginning in the second

duodenum,

of Whipple’s

smal1 bowel includes,

the lymphadenopathy, and the thickened

tive of a diagnosis

(PAS)/diastase stain for acid-fast

M. avium-intracellulareinfection,

by years, the onset

ciency anemia, bowel folds by radiograph

acid-Schiff

of

Cllnical Impression Dr.Nícholas J. Talley: The

lamina propia by macrophages. The villi are distended. Lipid droplets are dispersed among the macrophages, the result of lymphatic obstruction (H&E stain: original magnification x 100). (Insert) Highpower view showing free Whipple’s disease-associated organisms (arrows) in the lamina propia (PAS-diastase stain; original magnification X600).

tomog-

reveals

and in Whipple’s

system,

of

Figure 1. Smal1 bowel biopsy specimen showing infiltration of the

these

in otherwise usually

sickle-shaped

stain

normal faintly,

smal1 bowel

mucosa,

and the inclusions

as they are in Whipple’s

but

are not

disease.

Outcome Dr. Nicholas J. Talley: The patient was given a 6-week course of oral erythromycin ethylsuccinate, 400 mg four times a day, followed by oral trimethoprim-sulphamethoxasole, 160 mg/800 mg twice a day.

928

ZIGHELBOIM

A 2-month

ET AL.

course

GASTROENTEROLOGY

of iron

day was also prescribed. therapy,

the

diarrhea

sulfate,

After and

325 mg orally

1 month

abdominal

per

of antibiotic pain

had

re-

solved, and the joint symptoms and fever were markedly improved. He was re-examined during the eighth month

of antibiotic

but his physical enlarged serum

treatment.

examination

axillary

and

hemoglobin

normal

He was asymptomatic, stil1 revealed

inguinal

2 mm/h.

An upper

duodenal

biopsies

macrophages

lymph

had improved

MCV. The erythrocyte showed

sulphamethoxasole months. Further

nodes.

to 15.3 g/dL, sedimentation

endoscopy

in the lamina

minimally

rate was

was normal; persistent

propia.

The with a

however,

PAS-positive

The trimethoprim-

was continued for an additional 16 clinical evaluations at 1 and 2 years

after the diagnosis

were unremarkable.

Comment Drs.Jaime Zighelboim and Nicholas 1. Talley: Whipple’s

disease

was a uniformly

fata1 disease

the recognition

that antibiotic

There

a rapid and dramatic

is usually

therapy

until

was effective.

clinical

improve-

The evaluation of which

antibiotic

primarily deed,

of the treatment

response,

agents are chosen,

on clinical

and

the smal1 bowel

biopsy

be based

parameters.

may remain response

50% of patients

No. 3

regardless

should

laboratory

for years in spite of an optimal approximately

Vol. 105,

In-

abnormal

to treatment;

wil1 have persistent

his-

tological abnormalities after successful antibiotic treatment.30*35 Thus, the presence of PAS-positive macrophages

alone in the absente

tion during a higher

follow-up

risk of centra1

ever, the reappearance in the lamina

propia

in an asymptomatic The organism

of clinical

may not imply nervous

system

of the typical may herald

deteriora-

active disease or relapse.

How-

Whipple’s

bacilli

an impending

relapse

patient.39 that causes Whipple’s

disease has not

been reproducibly

grown

Whipple’s

bacillus

has been identified

using polymer-

ase chain

reaction

(KR)

Portions

bacterial

in culture,

but recently,

technology.

16s or smal1 subunit

ribosomal

the of al1

RNA

(16s

rRNA) genes are highly conserved, but this gene accumulates random mutations over time. Thus, the evolutionary

distance

from one organism

to another

can be

ment within several weeks of starting treatment with antibiotics. The aim of antibiotic therapy is twofold: to

estimated

treat

used a primer designed to amplify a 721-base segment of bacterial 16s ribosomal DNA on nucleic acids ob-

the disease

and

to prevent

relapse.

In a large

study, relapse occurred in 35% of patients despite antithat longbiotic therapy. 36 Thus, there is consensus term antibiotic treatment for at least 1 year is required,25 remain

although empirical

the

treatment

and anecdotal.

recommendations Indeed,

there

is stil1

controversy in the literature regarding the optimal duration of treatment and choice of antibiotic agent.36*37 An

initial

2-week

treatment

with

parenteral

antibi-

otics has been recommended using streptomycin and procaine penicillin G,2’,25 mainly because no centra1

ferences

tained

by comparing in their

from

the number

16s rRNA

a smal1 bowel

of nucleotide

sequences.

biopsy

Wilson

sample

difet a1.4n

of a patient

with Whipple’s disease. From uct, a lb-base oligonucleotide

the resulting PCR prodthat was unique to the

Whipple’s-associated

organism

and used DNA

bacterial

as a specific

primer

was identified

for a second

PCR

on

obtained

from smal1 bowel tissue from the same they used another nonspecific patient. In addition, primer directed at the eubacterial kingdom for PCR, as a control.

Both primers

yielded

a specific

nucleotide

nervous system relapses have been reported in patients treated initially with these antibiotics. However, these drugs do not cross the blood-brain barrier in the presence of uninflamed meninges, as is the case in Whipple’s disease. 21 Newer parenteral antibiotics, including

sequence not found in other known bacterial organisms. This DNA sequence was closely related to Rhodococcus,Arthrobacter, and Streptomycesspecies (8 9%-9 1%) ,

the third generation cephalosporins such as ceftriaxone, can also be used initially and are particularly attractive because of once or twice a day administration, fewer side effects, and excellent centra1 nervous system penetration. 3s In general, we w ould recommend longterm treatment with a drug that penetrates the bloodbrain barrier as first line therapy to try and prevent neurological relapse; trimethoprim-sulfamethoxasole would be a good choice. In patients allergie to sulfas, ceftriaxone, trimethoprim alone, chloramphenicol, and ampicillin are other options.

base bacterial 16s rRNA sequence from tissue obtained from a smal1 bowel biopsy sample in another

as wel1 as the mycobacteria (84%86%). Relman et a1.41 used PCR to amplify a unique

1321-

patient with Whipple’s disease. They then isolated an almost identical 16s rRNA sequence in four additional patients with the disease. In three of these patients, PCR was performed on DNA extracted from lymph node tissue, thus reflecting the presence of a true pathogen rather than possible contamination with an organism from the intestinal lumen. They also performed KR using a specific primer, which failed to amplify a visible product in 10 different control tissues

September

from

1993

patients

A PATIENT WITH DIARRHEA, ARTHRALGIAS,

without

Whipple’s

tide sequence of their only two discrepancies sitions

in which

disease.

The nucleo-

16s rRNA PCR product among the 525 nucleotide

this sequence

could be compared

had powith

that obtained by Wilson et a1.40 They named the newly discovered bacillus Tropberyma whippelii, from the Greek

trophe

(nourishment)

and eryma

cause of the malabsorption

syndrome

(barrier),

be-

that it causes.

As KR technology becomes more widely available for genera1 clinical use, in the future it should become possible

to apply this powerful

tic tool in Whipple’s ble to document after antibiotic likely

disease.

complete therapy

technique

as a diagnos-

It may also become

eradication and predict

possi-

of the organism who wil1 be most

to relapse.

Final Diagnosis The final diagnosis

was Whipple’s

disease.

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Received January 22, 1993. Accepted May 11, 1993. Address requests for reprints to: Nicholas J. Talley, M.D., Ph.D., Gastroenterology Unit, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905.