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Original Research |

The Immune Reconstitution Inflammatory Syndrome in Whipple Disease: A Cohort Study

Gerhard E. Feurle, MD; Verena Moos, PhD; Katina Schinnerling, Dipl Biol; Anika Geelhaar, Dipl Biol; Kristina Allers, PhD; Federico Biagi, MD; Hendrik Bläker, MD; Annette Moter, MD; Christoph Loddenkemper, MD; Andreas Jansen, MD; and Thomas Schneider, MD, PhD
[+] Article and Author Information

From DRK Krankenhaus Neuwied, Neuwied, Germany; Medizinische Klinik I and Institut für Medizinische Mikrobiologie und Hygiene and Institut für Pathologie, Charité-Universitätsmedizin Berlin, and Robert Koch-Institut, Abteilung für Infektionsepidemiologie, Berlin, Germany; Pathologisches Institut, Ruprecht-Karls Universität Heidelberg, Heidelberg, Germany, and Coeliac Unit/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.


Note: Drs. Feurle and Moos contributed equally to this study.

Acknowledgment: The authors thank Seher Kücükköylü, MD, Dusseldorf, Germany, for providing the clinical data for patient 7; Hans-Heinrich Kreipe, MD, Professor, Hannover, Germany, for providing paraffin sections from patient 8; Michael Hummel, MD, Assistant Professor, for clonal analysis of the B-cell repertoire of patient 8; Andrea Herbst, Neuwied, Germany, for data management; Diana Bösel, Martina Seipel, Simone Spiekermann, and Annett Petrich, Berlin, Germany, for technical assistance in the laboratory; and the 5th Framework program of the European Commission and Deutsche Forschungsgemeinschaft for financial support.

Grant Support: By the 5th Framework Program of the European Commission (grant QLG1-CT-2002-01049) and Deutsche Forschungsgemeinschaft (grants KFO 104 and SFB633).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1513.

Reproducible Research Statement:Study protocol: Available from Dr. Feurle (e-mail, g.e.feurle@t-online.de). Statistical code: Available from Dr. Jansen (e-mail, Andreas.Jansen@ecdc.europa.eu). Data set: Available from Dr. Moos (e-mail, verena.moos@charite.de).

Requests for Single Reprints: Verena Moos, PhD, Charité, Campus Benjamin Franklin, Medizinische Klinik I, Hindenburgdamm 30, D-12203 Berlin, Germany; e-mail, verena.moos@charite.de.

Current Author Addresses: Dr. Feurle: DRK Krankenhaus Neuwied, Marktstrasse 104, 56564 Neuwied, Germany.

Drs. Moos, Allers, and Schneider; Ms. Schinnerling; and Ms. Geelhaar: Medizinische Klinik I, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, D-12203 Berlin, Germany.

Dr. Biagi: Coeliac Unit/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, 27100 Pavia, Italy.

Dr. Bläker: Pathologisches Institut, Ruprecht-Karls Universität Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany.

Dr. Moter: Institut für Medizinische Mikrobiologie und Hygiene, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Charitéstrasse 1, 10117 Berlin, Germany.

Dr. Loddenkemper: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum Rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany.

Dr. Jansen: Scientific Advice Unit, European Centre for Disease Prevention and Control, Tomtebodavägen 11A, 171 83 Stockholm, Sweden.

Author Contributions: Conception and design: G.E. Feurle, V. Moos, A. Jansen, T. Schneider.

Analysis and interpretation of the data: G.E. Feurle, V. Moos, K. Schinnerling, A. Geelhaar, K. Allers, H. Bläker, C. Loddenkemper, A. Jansen, T. Schneider.

Drafting of the article: G.E. Feurle, V. Moos, A. Jansen, T. Schneider.

Critical revision of the article for important intellectual content: G.E. Feurle, V. Moos, C. Loddenkemper, T. Schneider.

Final approval of the article: G.E. Feurle, V. Moos, F. Biagi, H. Bläker, A. Moter, A. Jansen, T. Schneider.

Provision of study materials or patients: G.E. Feurle, F. Biagi, A. Moter, C. Loddenkemper, T. Schneider.

Statistical expertise: G.E. Feurle, A. Jansen.

Obtaining of funding: G.E. Feurle, V. Moos, C. Loddenkemper, T. Schneider.

Administrative, technical, or logistic support: A. Moter, C. Loddenkemper, T. Schneider.

Collection and assembly of data: G.E. Feurle, V. Moos, K. Schinnerling, A. Geelhaar, F. Biagi, A. Moter, C. Loddenkemper, T. Schneider.


Ann Intern Med. 2010;153(11):710-717. doi:10.7326/0003-4819-153-11-201012070-00004
Text Size: A A A

Background: Whipple disease, which is caused by infection with Tropheryma whipplei, can be treated effectively with antimicrobials. Occasionally, inflammation reappears after initial improvement; this is often interpreted as refractory or recurrent disease. However, polymerase chain reaction for T. whipplei in tissue is sometimes negative during reinflammation, indicating absence of vital bacteria, and this reinflammation does not respond to antimicrobials but does respond to steroids.

Objective: To demonstrate that the immune reconstitution inflammatory syndrome (IRIS) occurs in patients treated for Whipple disease.

Design: Cohort study. (International Standard Randomised Controlled Trial Number Register registration number: ISRCTN45658456)

Setting: 2 academic medical centers in Germany.

Methods: 142 patients treated for Whipple disease out of a cohort of 187 were observed for reappearance of inflammatory signs after effective antibiotic therapy. Definitions of IRIS in HIV infection, tuberculosis, and leprosy were adapted for application to Whipple disease.

Results: On the basis of study definitions, IRIS was diagnosed in 15 of 142 patients. Symptoms included fever, arthritis, pleurisy, erythema nodosum, inflammatory orbitopathy, small-bowel perforation, and a hypothalamic syndrome. Two patients died. There was a positive correlation with previous immunosuppressive treatment and a negative correlation with previous diarrhea and weight loss.

Limitations: The study was observational and thus has inherent weaknesses, such as incomplete and potentially selective data recording.

Conclusion: The immune reconstitution inflammatory syndrome was diagnosed in about 10% of patients with Whipple disease in the study cohort; the outcome varied from mild to fatal. Patients who had had previous immunosuppressive therapy were at particular risk. An immune reconstitution syndrome should be considered in patients with Whipple disease in whom inflammatory symptoms recur after effective treatment. Early diagnosis and treatment with steroids may be beneficial; prospective studies are needed.

Primary Funding Source: European Commission and Deutsche Forschungsgemeinschaft.

Figures

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Figure.
Study flow diagram.

“Fulfilled criteria 1 and 3” indicates effective antibiotic treatment of Whipple disease; “fulfilled criteria 1 and 2” indicates ineffective treatment of Whipple disease; and “fulfilled criteria 1, 2, and 3” indicates effective treatment of Whipple disease and IRIS. IRIS = immune reconstitution inflammatory syndrome.

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Management of Whipple's disease and immune reconstitution inflammatory syndrome
Posted on January 13, 2011
Didier Raoult
Unite de Recherche de Maladies Infectieuses et Tropicales Emergentes
Conflict of Interest: None Declared

The manuscript of Feurle et al. (1) presents a study in which an immune reconstitution inflammatory syndrome (IRIS) was diagnosed in about 10% of patients with Whipple's disease (WD). The authors, themselves, recognized several limitations to their report. We have also some concerns.

First, our therapeutic experiences for WD are discrepant with that of the authors (2-4). In contrast to those of Feurle, reporting the cure of nearly all the patients (2), we have been frequently consulted for patients who have relapsed or failed using similar treatments with bacterial documentation (4). A strain has been isolated in our laboratory from the cerebro-spinal fluid of one of his patients relapsing considered cured (Unpublished data). The existence of these discrepancies that is public justifies to be specified in a manuscript relating the management of patients with WD (3).

The second limitation is the omission of a series of 113 patients with classic WD reporting 2 IRIS (5;6). It is also important to underline that corticosteroids failed to improve one of the patients, only thalidomide successfully induces rapid improvement as in erythema nodosum leprosum (6).

The third limitation is that their conclusions are not clear and seem to promote a dangerous idea to treat an infectious disease by corticosteroids without antibiotics. Indeed, they suggest that early treatment with corticosteroids may be life-saving and should not be delayed while waiting for biopsy and PCR results. There is no evidence that the death reported for their 2 patients is linked to IRIS. In contrast, it has been clearly shown that a quicker clinical progression occurs for patients with WD receiving corticosteroids alone (5). One of our patients died after the initiation of corticosteroids before the diagnosis of WD (5).

For unknown reasons, patients treated for WD do not present any more 16S rRNA in spite of the detection of bacteria using PAS-staining and immunohistochemistry, but after the stopping treatment, they relapse (4). Thus, the negativity of 16S rRNA is not a sign of cure of WD and it is necessary to be extremely cautious before concluding to cure.

Finally, in controversial topics, specifically recommending therapeutic strategies, it should be mandatory to explore very comprehensively the recent literature in the best journals not to neglect to balance the conclusions.

References.

1. Feurle GE, Moos V, Schinnerling K, Geelhaar A, Allers K, Biagi F et al. The immune reconstitution inflammatory syndrome in whipple disease: a cohort study. Ann Intern Med. 2010;153:710-717. [PMID: 21135294]

2. Feurle GE, Junga NS, Marth T. Efficacy of Ceftriaxone or Meropenem as Initial Therapies in Whipple's Disease. Gastroenterology. 2010;138:478- 86. [PMID: 19879276]

3. Fenollar F, Raoult D. How should classic Whipple's disease be managed? Nat Rev Gastroenterol Hepatol. 2010;7. [PMID: 20442732]

4. Lagier JC, Fenollar F, Lepidi H, Raoult D. Failure and relapse after treatment with Trimethoprim-Sulfamethoxazole in classic Whipple's disease. J Antimicrob Chemother. 2010;65:2005-12. [PMID: 20639526]

5. Lagier JC, Lepidi H, Raoult D, Fenollar F. Clinical presentation of 142 patients with systemic Tropheryma whipplei infections diagnosed or confirmed in a reference center. Medicine. 2010;89:337-45. [PMID: 20827111]

6. Lagier JC, Fenollar F, Lepidi H, Liozon E, Raoult D. Successful treatment of immune reconstitution inflammatory syndrome in Whipple's disease using thalidomide. J Infect. 2010;60:79-82. [PMID: 19852981]

Conflict of Interest:

Our point of vue about the therapeutic management of WD is highly discrepant than those of Feurle et al..

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