IM - ORIGINAL

Relationship between previous treatments and onset of symptomsin patients with Whipple’s disease

Lucia Trotta • Federico Biagi • Michele Di Stefano •

Gino Roberto Corazza

Received: 17 April 2012 / Accepted: 26 May 2012

� SIMI 2012

Abstract The clinical features of Whipple’s disease

(WD) consist of arthropathy that precedes the involvement

of other organs, such as the gastrointestinal tract, nervous

system and heart. It has been shown that gastrointestinal

manifestations can be precipitated by immunosuppressive

therapy used to control the arthropathy. In the present

study, we investigated the clinical features of the Italian

population of patients affected by WD. The clinical his-

tories of 22 patients with WD were reviewed. Relationship

between previous treatments and onset of symptoms was

analysed. 20/22 patients suffered from arthropathy that had

started before gastrointestinal complaints; gastrointestinal

symptoms were present in 18 patients and neurological

involvement was found in 5. WD must always be taken into

account in male patients with long-standing ill-defined

arthropathy, and it should be ruled out before starting

immunosuppressive or antibiotic treatment that can make

correct diagnosis and management very difficult.

Keywords Whipple’s disease � Tropheryma whipplei �Immunosuppressive therapy � Small bowel

Introduction

Whipple’s disease (WD) is a rare, systemic infection due to

Tropheryma whipplei (TW), a PAS positive rod-shaped

bacterium that has recently been identified and cultivated

[1–4]. Since it was found that TW is very common in the

environment and is characterized by a wide genetic het-

erogeneity [5–7], the discrepancy between the widespread

presence of TW and the rarity of this disease is likely to be

explained with immunogenetic host factors and individual

susceptibility to the infection. This is supported by the

observation that WD is associated with HLA DRB1*13 and

DQB1*06 and impaired monocyte function, and impaired

interferon-production was shown not only in some patients

with WD but also in non-affected first-degree relatives

[8, 9].

The most common clinical manifestations are arthrop-

athy, malabsorption, weight loss, and lymphadenopathy.

Other symptoms, such as neurological, ophthalmologic,

and cardiovascular manifestations are less common, but

are nevertheless very important from a prognostic point

of view [10–12]. Diagnosis is based on tissue biopsy

showing the macrophages with characteristic periodic

acid-Schiff (PAS) inclusion in the lamina propria. The

use of polymerase chain reaction (PCR) to amplify the

sequences of bacterial 16S ribosomal DNA is very

helpful in looking for TW in those locations in which

biopsies cannot easily be taken, such as the central ner-

vous system [4, 13].

Since WD is such a rare disease, diagnostic delay can be

long, and the treatment, that should start as soon as possible

to prevent neurological involvement, is often delayed.

Therapy with ceftriaxone for 14 days or, alternatively,

meropenem followed by at least 1 year with trimethoprim-

sulfamethoxazole is recommended [14]. On the other hand,

as a result of treatment failure and relapses in the long term

despite oral trimethoprim-sulfamethoxazole, other author-

ities suggest treating WD patients with at least 12 months

of bactericidal antibiotic therapy and then maintaining

them on lifelong antibiotic prophylaxis with doxycycline

[15].

L. Trotta � F. Biagi (&) � M. Di Stefano � G. R. Corazza

First Department of Internal Medicine, Coeliac Centre,

Fondazione IRCCS Policlinico San Matteo, University of Pavia,

P.le Golgi, 19, 27100 Pavia, Italy

e-mail: f.biagi@smatteo.pv.it

123

Intern Emerg Med

DOI 10.1007/s11739-012-0799-4

It is known that the clinical features of WD usually

consist of arthropathy that usually precedes gastrointestinal

manifestation by many years. More precisely, according to

a German study, the appearance of gastrointestinal mani-

festations was precipitated by the immunosuppressive

therapy used to control the arthropathy [16]. In the present

study, we investigated the clinical features of the Italian

population of patients affected by WD.

Patients and methods

We studied 22 consecutive patients (4 female, mean age at

diagnosis 53.7 ± 11.7 years) affected by WD. The patients

were seen in our hospital between August 2000 and July

2011. A complete medical history was obtained and

physical examination was performed. The diagnosis of WD

in 21 patients was confirmed by the presence of a typical

pattern showing PAS positive macrophages infiltrating the

duodenal mucosa or lymph nodes. Only in one patient WD

was diagnosed by PCR positive for TW on a heart valve,

while the duodenal mucosa did not show PAS positive

infiltrating the macrophages [4, 13].

The clinical notes of the patients were reviewed and the

following data were collected: date of birth, gender, date of

diagnosis of WD, overall diagnostic delay (months

between onset of symptoms leading to diagnosis of WD

and diagnosis itself), duration of arthralgia (months

between its onset and diagnosis of WD), duration of gas-

trointestinal symptoms (months between their onset and

diagnosis of WD), therapies before and after the diagnosis

of WD, complications, date and cause of death (if the

subject is still alive, date of the last time he/she was seen in

clinic).

All patients were grouped according to their previous

treatment regimen. Group A consisted of 15 patients who

received immunosuppressive therapy because of long-

lasting arthropathy. Azathioprine, cyclosporine, metho-

trexate, corticosteroids, and biological drugs in addition

to non-steroidal anti-inflammatory drugs have been used.

Other drugs were hydroxychloroquine that was used in

three patients because of arthropathy, and diaminocil-

line used for 3 years in 1 patient for suspected post-

streptococcal fever. Group B consisted of seven patients

who had never been treated with immunosuppressive

agents.

The study was approved by the local ethics committee of

Fondazione IRCCS Policlinico San Matteo. The procedures

followed were in accordance with the ethical standards of the

responsible committee on human experimentation and with

the Helsinki Declaration of 1975, as revised in 1983.

Results

Duration of therapy before diagnosis and diagnostic

delay

In group A, the mean duration of immunosuppressive

therapy before the diagnosis of WD was 42.4 ± 33.1

months. Diagnostic delay was higher in group A than in

group B (78.4 ± 36 months vs. 33 ± 39.8 months, student

T test p = 0.01). Further details of the patients are given in

Table 1.

Main clinical features investigated

Although age at diagnosis was higher in patients of group

A than in group B (56.3 ± 11.4 vs. 48.1 ± 11.2 years)

and, similarly, the age at onset of the first symptoms was

higher in group A than in group B (49.8 ± 10.8 vs.

45.4 ± 13.2 years), these differences were not statistically

significant.

Twenty out of 22 patients suffered from arthropathy

that, typically, had started a few years before gastrointes-

tinal complaints (median 57 months, range 0–264). They

were usually migratory and affected peripheral joints

(ankles, shoulders, knees, wrists and hands). In group A,

patients had experienced a history of arthropathy of median

72 months (IQR 31.5–119.5), while in group B it was of

median 18 months (IQR 2–35.25). The Mann–Whitney test

was statistically significant (p = 0.02).

Gastrointestinal symptoms, characterized by diarrhoea

and abdominal pain, usually occurred after the onset of

joint symptoms. In the 13 patients of group A, diarrhoea

lasted for a median of 2 months (IQR 1–3.75); in the 5

patients of group B, it lasted for a median of 3 months (IQR

2.75–8.25). This was not statistically different. Weight loss

and fever were seen in most patients (81.8 and 77.2 %).

Table 2 shows the clinical features of the two groups of

patients. Neurological manifestations included psychiatric

symptoms, loss of memory, ataxia, and ocular involve-

ment. The three patients with cardiac involvement suffered

from endocarditis, myocarditis, and the last one had a

pericardial effusion.

Sixteen patients out of 22 improved after therapy with

ceftriaxone and trimethoprim-sulfamethoxazole. Evidence

of immune reconstitution inflammatory syndrome (IRIS)

was found in 5 out of 22 patients (5 male, mean age

58.4 ± 11.9 years) [15]. A possible relapse of clinical

disease occurred in one patient who developed neurologi-

cal manifestations after the suspension of trimethoprim-

sulfamethoxazole. However, liquor PCR was negative for

TW.

Intern Emerg Med

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Discussion

In this study, we investigated the clinical features of an

Italian population of patients affected by WD and fol-

lowed-up in our centre for the last 10 years.

We observed that many features are similar in the

German and in the Italian groups, such as age at diagnosis

and age of onset of the first symptoms [16]. We also

confirmed that arthropathy usually preceded the gastroin-

testinal manifestations for many years. Moreover, the

duration of arthropathy prior to diagnosis was longer in

group A than in group B. Digestive symptoms, consisting

of abdominal pain, diarrhoea and weight loss, usually

developed later on.

The interval between the onset of early symptoms

(mainly arthralgia) and the steady-state stage of WD with

organ involvement is generally about 6 years [1, 16]. We

also confirmed this data in our population (group A?B) in

which diagnostic delay was about 5.3 years. However,

other studies show that this interval is usually shorter in

patients receiving immunosuppressive treatments, includ-

ing TNF antagonist [16–19]. We could not confirm these

findings. In our group A, diagnosis of WD was made 78.4

months after symptom onset, while in group B diagnosis of

WD was made 33 months after symptoms onset. The mean

period of duration of gastrointestinal symptoms was very

similar in both group A and group B.

It is difficult to explain these differences. It is possible

that development of gastrointestinal symptoms in our

patients was delayed by other drugs. Three patients

belonging to group A received hydroxychloroquine, a drug

known to be active on TW [15], and that could have slowed

down the progression of WD. In addition, one patient

received diaminocilline for 3 years for suspected post-

streptococcal rheumatic fever. A study performed on five

patients in whom diagnosis of WD was made during

treatment with biological drugs offered similar results [20].

Alternatively, we can hypothesise that patients included in

group A were those with the most severe arthropathy and

so the most likely to be considered affected by a primary

arthropathy, refractory to standard therapies and thus

requiring immunosuppressive therapy. Thus, labelling

these patients as affected by a primary arthropathy can

have made the recognition of the correct diagnosis more

difficult, thus increasing the diagnostic delay in a similar

way to other gastrointestinal conditions, like coeliac dis-

ease [21]. Finally, to explain these differences on the basis

of a different genetic background between Italian and

Table 1 Clinical features of

patients affected by Whipple’s

disease

AD age at diagnosis of

Whipple’s disease, WL weight

loss, LAP lymphoadenopathy,

DVT deep venous thrombosis,

PIMT previous

immunosuppressive therapy

Sex AD Arthralgia Diarrhoea WL LAP Other symptoms PIMT

1 M 39 Yes Yes Yes Yes Yes

2 M 57 Yes Yes Yes Yes DVT Yes

3 F 57 Yes Yes Yes No Myocarditis, erythema nodosum Yes

4 M 72 Yes Yes Yes No Yes

5 M 40 Yes Yes Yes No Pericardial effusion, hypoacusia,

psychiatric symptoms

Yes

6 M 65 Yes Yes Yes Yes DVT, recidivating pneumonia, systemic

candidosis

Yes

7 M 40 Yes Yes Yes Yes Ataxia, uveitis, orchiepididymitis Yes

8 M 58 Yes Yes No Yes Yes

9 M 72 Yes Yes Yes No Yes

10 M 51 Yes Yes Yes No Yes

11 F 50 Yes Yes Yes No Yes

12 M 50 Yes Yes Yes Yes Yes

13 M 71 Yes No No No DVT Yes

14 F 66 Yes No Yes Yes Endocarditis Yes

15 M 57 Yes Yes Yes Yes Loss of memory Yes

16 M 39 Yes No Yes Yes Psychiatric symptoms No

17 F 60 No No Yes No No

18 M 35 No Yes Yes No Oculomotor paralysis No

19 M 62 Yes Yes Yes No Oesophageal candidosis No

20 M 47 Yes Yes Yes No No

21 M 38 Yes Yes Yes No Melanodermia No

22 M 56 Yes Yes Yes Yes Oesophageal candidosis, gastrointestinal

bleeding

No

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123

German patients with WD is very difficult, because we

showed that there is no difference between Italians and

Germans as far as HLA is concerned [8].

In conclusion, WD must always be taken into account in

male patients with long-standing ill-defined arthropathy,

and it should be ruled out before starting immunosup-

pressive or antibiotic treatment that can make correct

diagnosis and management very difficult.

Acknowledgments We are grateful to Susan West for reading and

correcting the manuscript. This project was funded by the 5th

Framework Programme of the European Commission (ref. QLG1-CT-

2002-01049).

Conflict of interest None.

References

1. Fennolar F, Puechal X, Raoult D (2007) Whipple’s disease.

N Engl J Med 356:55–66

2. Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F,

Raoult D (2008) Whipple’s disease: new aspects of pathogenesis

and treatment. Lancet Infect Dis 8:179–190

3. Relman DA, Schmidt TM, MacDermott RP, Falkow S (1992)

Identification of the uncultured bacillus of Whipple’s disease.

N Engl J Med 327:293–301

4. Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H,

Roux V, Piette JC, Vandenesch F, Vital-Durand D, Marrie TJ

(2000) Cultivation of the bacillus of Whipple’s disease. N Engl J

Med 342:620–625

5. Schoniger-Hekele M, Petermann D, Weber B, Muller C (2007)

Tropheryma whipplei in the environment: survey of sewage plant

influxes and sewage plant workers. Appl Environ Microbiol

73:2033–2035

6. Lagier JC, Fenollar F, Lepidi H, Raoult D (2011) Evidence of

lifetime susceptibility to Tropheryma whipplei in patients with

Whipple’s disease. J Antimicrob Chemother 66:1188–1189

7. Li W, Fennolar F, Rolain J-M, Fournier P-E, Feurle GE, Muller

C, Moos V, Marth T, Altwegg M, Calligaris-Maibach RC,

Schneider T, Biagi F, La Scola B, Raoult D (2008) Genotyping

reveals a wide heterogeneity of Tropheryma whipplei. Microbi-

ology 154:521–527

8. Martinetti M, Biagi F, Badulli C, Feurle GE, Muller C, Moos V,

Schneider T, Marth T, Marchese A, Trotta L, Sachetto S, Pasi A,

De Silvestri A, Salvaneschi L, Corazza GR (2009) The HLA

alleles DRB1*13 and DQB1*06 are associated to Whipple’s

disease. Gastroenterology 136:2289–2294

9. Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C,

Strober W, Zeitz M, Schneider T (2002) Dysregulated peripheral

and mucosal Th1/Th2 response in Whipple’s disease. Gastroen-

terology 123:1468–1477

10. Fennolar F, Raoult D (2001) Whipple’s disease. Clin Diagn Lab

Immunol 8:1–8

11. Dutly F, Altwegg M (2001) Whipple’s disease and ‘‘Tropherymawhippelii’’. Clin Microbiol Rev 14:561–583

12. Di Stefano M, Jorizzo RA, Brusco G, Cecchetti L, Sciarra G,

Loperfido S, Brandi G, Gasbarrini G, Corazza GR (1998) Bone

mass and metabolism in Whipple’s disease: the role of hypogo-

nadism. Scand J Gastroenterol 33:1180–1185

13. Raoult D, La Scola B, Lecocq P, Lepidi H, Fournier PE (2001)

Culture and immunological detection of Tropheryma whippeliifrom the duodenum of a patient with Whipple disease. JAMA

285:1039–1043

14. Feurle GE, Junga NS, Marth T (2010) Efficacy of ceftriaxone or

meropenem as initial therapies in Whipple’s disease. Gastroen-

terology 138:478–486

15. Lagier JC, Fenollar F, Lepidi H, Raoult D (2011) Evidence of

lifetime susceptibility to Tropheryma whipplei in patients with

Whipple’s disease. J Antimicrob Chemother 66:1188–1189

16. Mahnel R, Kalt A, Ring S, Stallmach A, Strober W, Marth T

(2005) Immunosuppressive therapy in Whipple’s disease patients

is associated with the appearance of gastrointestinal manifesta-

tions. Am J Gastroenterol 100:1167–1173

17. Feurle GE, Moos V, Schinnerling K, Geelhaar A, Allers K, Biagi

F, Blaker H, Moter A, Loddenkemper C, Jansen A, Schneider T

(2010) The immune reconstitution inflammatory syndrome in

Whipple disease. A cohort study. Ann Intern Med 153:710–717

18. Lamparter S, Dittrich C, Koehler HH (2008) Exacerbation of WD

by immunosuppressants. J Clin Gastroenterol 42:760–761

19. Kneitz C, Suerbaum S, Beer M, Muller J, Jahns R, Tony HP

(2005) Exacerbation of Whipple’s disease associated with inf-

liximab treatment. Scand J Rheumatol 34:148–151

20. Hoppe E, Masson C, Audran M, Drillon M, Andreu M, Saraux A,

Berthelot JM, Maugars Y, Hmamouchi I, Morel J (2010) Whip-

ple’s disease diagnosed during biological treatment for joint

disease. Joint Bone Spine 77:335–339

21. Corazza GR, Brusco G, Andreani ML, Biagi F, Di Stefano M,

Gasbarrini G (1996) Previous misdiagnosis and diagnostic delay

in adult celiac sprue. J Clin Gastroenterol 22:324–325

Table 2 Characteristics of the WD patients grouped according to

their previous treatment regimen

All patients Group A Group B

Number 22 15 7

Sex

Male 18 12 6

Female 4 3 1

Age at diagnosis of

WD (years)

53.7 ± 11.7 56.3 ± 11.4 48.1 ± 11.2

Age at the onset of

symptoms (years)

48.4 ± 11.5 49.8 ± 10.8 45.4 ± 13.2

Arthropathy 20 15 5

Fever 18 14 4

Diarrhoea 18 13 5

Weight loss 20 13 7

Central nervous

system involvement

5 3 2

Cardiac involvement 3 3 0

Lymphadenopathy 10 6 4

Diagnosis

Duodenal biopsy 21 14 7

Lymphonodal biopsy 1 0 1

PCR positive on

cardiac valve

1 1 0

Course and outcome

Remission 15 8 7

Relapses 1 1 0

IRIS 5 5 0

Death 1 1 0

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