Marth T. Complicated Whipple’s disease and endocarditis following tumor necrosis factor inhibitors. World J Cardiol 2014; 6(12): 1278-1284 [PMID: 25548618 DOI: 10.4330/wjc.v6.i12.1278]
Corresponding Author of This Article
Thomas Marth, MD, Professor of Internal Medicine, Division of Internal Medicine, Krankenhaus Maria Hilf, Maria-Hilf-Straße 2, 54550 Daun, Germany. t.marth@krankenhaus-daun.de
Research Domain of This Article
Cardiac & Cardiovascular Systems
Article-Type of This Article
Case Control Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Thomas Marth, Division of Internal Medicine, Krankenhaus Maria Hilf, 54550 Daun, Germany
ORCID number: $[AuthorORCIDs]
Author contributions: Marth T solely contributed to this manuscript.
Correspondence to: Thomas Marth, MD, Professor of Internal Medicine, Division of Internal Medicine, Krankenhaus Maria Hilf, Maria-Hilf-Straße 2, 54550 Daun, Germany. t.marth@krankenhaus-daun.de
Telephone: +49-6592-7152221 Fax: +49-6592-7152501
Received: July 30, 2014 Revised: September 2, 2014 Accepted: November 17, 2014 Published online: December 26, 2014 Processing time: 46 Days and 19.8 Hours
Abstract
AIM: To test whether treatment with tumor necrosis factor inhibitors (TNFI) is associated with complications of Tropheryma whipplei (T. whipplei) infection.
METHODS: Because unexplained arthritis is often the first Whipple’s disease (WD) symptom, patients may undergo treatment with TNFI before diagnosis. This may influence the course of infection with T. whipplei, which causes WD, because host immune defects contribute to the pathogenesis of WD. A literature search and cross referencing identified 19 reports of TNFI treatment prior to WD diagnosis. This case-control study compared clinical data in patients receiving TNFI therapy (group I, n = 41) with patients not receiving TNFI therapy (group II, n = 61). Patients from large reviews served as controls (group III, n = 1059).
RESULTS: The rate of endocarditis in patient group I was significantly higher than in patient group II (12.2% in group I vs 1.6% in group II, P < 0.05), and group III (12.2% in group I vs 0.16% in group III, P < 0.01). Other, severe systemic or local WD complications such as pericarditis, fever or specific organ manifestations were increased also in group I as compared to the other patient groups. However, diarrhea and weight loss were somewhat less frequent in patient group I. WD is typically diagnosed with duodenal biopsy and periodic acid Schiff (PAS) staining. PAS-stain as standard diagnostic test had a very high percentage of false negative results (diagnostic failure in 63.6% of cases) in group I. Polymerase chain reaction (PCR) for T. whipplei was more accurate than PAS-stainings (diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01).
CONCLUSION: TNFI trigger severe WD complications, particularly endocarditis, and lead to false-negative PAS-tests. In case of TNFI treatment failure, infection with T. whipplei should be considered.
Core tip: Arthritis frequently is the first symptom of Whipple’s disease (WD). Therefore, many patients are treated with anti-inflammatory drugs or tumor necrosis alpha inhibitors (TNFI) before diagnosis. As host immune defects contribute to the pathogenesis of WD, immunosuppressive therapy may deteriorate the course of Tropheryma whipplei (T. whipplei) infection. In this study, it is shown that treatment with TNFI is associated with severe complications of T. whipplei infection, particularly with endocarditis. TNFI therapy may lead to false negative periodic acid-Schiff-tests and thereby hinder the diagnosis of WD. T. whipplei infection should be considered in case of TNFI treatment failure.
Citation: Marth T. Complicated Whipple’s disease and endocarditis following tumor necrosis factor inhibitors. World J Cardiol 2014; 6(12): 1278-1284
Tropheryma whipplei (T. whipplei) is an actinobacteria that may cause Whipple’s disease (WD), a chronic and systemic infection. WD in its classical form mostly occurs in middle-aged Caucasian men and is clinically characterized by weight loss, diarrhea and arthritis. A broad range of other symptoms such as abdominal pain, melena, fever, cardiac symptoms, cough, lymphadenopathy and symptoms of the central nervous system (CNS) may be observed[1,2].
Classical WD is very rare, although T. whipplei occurs ubiquitiously in the environment. This discrepancy has been explained in part by cellular immune defects and a certain human leucocyte antigen type that predisposes individuals for infection[3]. The genome of T. whipplei is very small, and shows some specific features such as a lack of thioredoxin pathway and a high variability of surface structures which point to a host dependency and a “parasitic“ nature of the bacterium[4]. Diagnosis of WD is usually established by duodenal biopsy and histological stain for periodic acid-Schiff (PAS), and/or a T. whipplei specific polymerase chain reaction (PCR)[5].
Localized (“isolated”) clinical forms of WD (i.e., without gastrointestinal or systemic symptoms) may be manifestations of the CNS or endo-/pericarditis. These clinical manifestations are difficult to diagnose and are associated with a poor prognosis, and therefore require an intensive treatment and follow-up[3,5].
It is well known that the first symptoms in patients with WD in approximately two-thirds of patients are seronegative, migratory and non-destructive arthropathies, which precede other symptoms by approximately 8 years[1,5,6]. Many patients with arthropathies are treated with non-steroidal anti-inflammatory drugs (NSAIDs), or with other non-biological disease-modifying anti-rheumatic drugs (DMARDs) prior to the diagnosis of WD. It has been previously shown that intestinal manifestations (i.e., diarrhea) of WD may be triggered by DMARDs[6].
As treatment with NSAID or DMARDs lacks a prolonged clinical effect in patients with T. whipplei infection, patients may be subsequently treated with biological DMARDs, mostly with tumor necrosis factor alpha inhibitor (TNFI). Although TNFI are reasonable safe immunosuppressive drugs[7], therapy with TNFI may be associated with an increased rate of infections, particularly with opportunistic infections and the activation of latent tuberculosis[8-11]. We aimed to examine data on the clinical course and frequency of symptoms and complications in patients with WD who had received TNFI therapy prior to diagnosis compared to WD patients who had not received such treatment.
MATERIALS AND METHODS
For this case-control study, a literature search was performed with the following keywords in the PubMed and Cochrane databases in all combinations: Whipple, Whipple disease, Whipple’s, Whipple’s disease, intestinal lipodystrophy, Tropheryma, T. whipplei, biological therapy, tumor necrosis factor alpha, TNF antagonist, TNF inhibitor, anti-TNF, TNF blocker, etarnecept, infliximab, adalimumab, certolizumab, golimumab, immunosuppressant, immunosuppressive, and immunosuppression.
In total, 15 publications were identified in which WD patients were treated with TNFI[12-26]. Another four unlisted references, mostly abstracts or non-English articles, could be tracked by cross-referencing[27-30]. In several instances, the authors of the reports were contacted for more detailed information on the WD patients.
The patients in this case-control study were stratified according to their prior treatment and compared to large databases of reviews. In patient group I, WD patients (n = 41; 19 publications) were treated with non-biological DMARDs and with TNFI. Patient group IIconsists of WD patients (n = 61; same 19 publications) treated with non-biological DMARDs, but not with TNFI. Groups I and II were compared to WD patients from large reviews (patient group III, n = 1059)[31-33]. One citation is a monography (696 patients)[31], another review covers patients (238 patients) from this monography and presents some more details[32], and one paper is a follow-up case analysis to the monography (n = 363)[33]. In group III, few patients were treated with DMARDs (mostly steroids), but not with TNFI.
The clinical course of the patients were compared including major symptoms (arthralgia, weight loss, and diarrhea) and complications (such as fever, septic temperatures, endocarditis, pericarditis, immune-mediated symptoms, gastrointestinal complications, neurologic symptoms, skin manifestations, lymphadenopathy, and eye complications). Other less frequent symptoms could not be compared systematically due to the protean features of WD in many patients.
Statistical analysis
Statistical analysis of differences between patient groups and for the comparison of the PAS- and PCR-tests was performed with the Pearson’s χ2 test. Significance levels are expressed as two-sided P values. In parallel, the Fisher’s exact test was performed which did not show different significance levels.
RESULTS
Forty-one patients were identified in whom TNFI were used to treat unexplained arthritis, and in whom the diagnosis of WD was established later (patient group I, Table 1). These patients received non-biological DMARDs prior or in parallel to therapy with TNFI.
Table 1 Frequency of the symptoms at the time of diagnosis of Whipple’s disease.
When patients in group I were compared to patients in group II (non-biological DMARD therapy, but no therapy with TNFI), there was a highly significant increase in the rate of endocarditis (P < 0.05). Additionally, compared to patients from large literature reviews (group III), the percentage of patients with endocarditis in patients treated with TNFI was dramatically higher (50 times higher, 12.2% in patient group I vs 0.16% in patient group III, P < 0.01). Additionally, pericarditis in patient group I was more frequent than in patient group III (P < 0.01). Pericarditis had an inflammatory course in all reported patient courses.
The rate of patients with diarrhea in group I was lower than in group II, and less than half in group III. Additionally, and as a possible consequence of the reduced rate of diarrhea, weight loss was less frequent in group I than in other patients. The immune reconstitution inflammatory syndrome (IRIS), which mostly occurs after medical immunosuppression[14-16], was observed in comparable percentages in the patients of groups I and II (16% and 22.9%, respectively). The remaining signs or symptoms of patients treated with TNFI (patient group I) were similar to the other patient groups (Table 1). The details of group I patients (19 publications reporting 41 individuals) are given in Table 2.
Table 2 Summary of cases treated with tumor necrosis factor alpha inhibitor and later diagnosis of Whipple’s disease.
Patients (n)(sex, age, yr)
TNFI/time from treatment start of TNFI to diagnosis of WD
Other DMARDs
Clinical picture at the time of diagnosis of WD (after TNFI treatment)
Therapy for WD/outcome
Ref.
1 (F, 33)
Etarnecept; 6 mo
NSAID, MTX
Chronic inflammation, ankylosing spondylitis, arthritis, diarrhea, fever, weight loss
CFA + CTM; resolution
[12]
1 (M, 57)
Etarnecept; “mo“
Leflunomide, MTX
Endocarditis, aortic valve replacement
DCN, HCQ; resolution
[13]
1 (M)
Etanercept; not stated
Steroids, others not specified
Arthralgia, diarrhea, others not specified, IRIS after Abx
CFA + CTM, amelio-ration, but remaining cognitive sequelae, headache
[26]
In 63% of group I patients severe systemic or local complications were observed (1.88 complications per patient, Table 3). Very often, fever or septicemia occurred. In addition to endocarditis, pericarditis or IRIS, a broad range of of complications, e.g., spondylitis, colitis, lymphadenopathy, and CNS symptoms was observed. The outcome of the patients treated with TNFI (group I) was lethal in one patient (out of 19 patients with reported outcome), and two other patients had severe long-term sequelae (Table 3).
Table 3 Whipple’s disease related symptoms and outcome after therapy with tumor necrosis factor alpha inhibitor.
Despite TNFI therapy, arthralgia persisted or clinical detereoration developed within mo in many patients in group I. This often led to intensified diagnosic procedures, especially to endoscopy with duodenal biopsies. Subsequent PAS staining or PCR tests finally led to the diagnosis of WD. When analyzing the accurracy of diagnostic tests for patients who were diagnosed and treated with WD, there was a very high rate of false-negative PAS tests. Therefore, only 8/22 PAS tests (36.4%) either before or after TNFI therapy were true positive. Conversely, 14 out of 22 PAS stains (63.6%) were negative in patients for whom WD was diagnosed by other means. In contrast, 10 out of 11 PCR tests were positive for the diagnosis of WD before or after the initiation of TNFI therapy (Tables 4 and 5). Therefore, PAS stainings was significantly more unreliable than PCR-testing. Taken together, PCR for T. whipplei was much better as compared to PAS stain (diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01).
Table 4 Lack of reliability of standard diagnostic procedures in patient group I: Different situations ("settings") of the diagnostic procedures.
In this case-control study we demonstrate that the risk of severe T. whipplei-associated complications, particularly the rate of endocarditis, is increased by TNFI therapy in patients with a later diagnosis of WD. This observation is of interest for several reasons. First, endocarditis with T. whipplei is one of the major reasons for serious or lethal outcomes of WD, and requires prolonged and intensive antibiotic treatment regimens[1,3,34]. Second, T. whipplei seems to have a certain tropism for heart valves. Endocarditis with T. whipplei - a bacterium that occurs ubiquitously in the environment - has been described to be the fourth most frequent cause of culture-negative endocarditis[35]. With the availability of T. whipplei specific PCR, a higher diagnostic frequency of WD endocarditis in the future seems probable[31,32,36]. Third, the risk of bacterial endocarditis may be increased somewhat by TNFI therapy in general, because certain genetic haplotypes in the tumor necrosis factor gene (single nucleotide polymorphisms) predispose patients for bloodstream infections or endocarditis[37], and signals of increased rates of endocarditis after TNFI therapy have been observed in a treatment registry[38]. Therefore, in patients with endocarditis under biological DMARD therapy, the possibility of TNFI therapy-associated T. whipplei endocarditis should be considered, and the rate of endocarditis following TNFI should be monitored in patient series.
Infectious complications including opportunistic infections may occur after therapy with TNFI, which disturbs the important host defense mechanisms[10]. Latent tuberculosis can be activated,because TNFI breach the cellular integrity, disturb granuloma formation, and viable mycobacteria in granulomas become released[39]. Therefore, it is mandatory to exclude tuberculosis before initiating therapy with TNFI. As another example for activation of infection, TNFI therapy reduces interferon (IFN)-gamma levels which may lead to salmonella septicemia[40].
T. whipplei is an ubiquitously occurring bacterium that can be detected via stool PCR, e.g., in asymptomatic carriers (4%, healthy population), in sewage plant workers (20%), and in relatives of WD patients (38%)[1,41,42]. It causes acute infections such as fever and diarrhea in children, occurs as localized infection (e.g., endocarditis or in the CNS), or causes the rare, classical WD[1,3,43]. The hallmarks of classical WD are the long-term persistence of the viable bacteria in duodenal macrophages, and reduced T helper cell 1 responses in patients[5,44,45]. In analogy to latent tuberculosis, TNFI therapy may disturb the balanced immunological control, impair IFN-gamma further, and subsequently lead to an activation or deterioration of the systemic (e.g., sepsis, IRIS) or local (e.g., endocarditis) T. whipplei infection. Our data therefore provide further hints to the opportunistic nature of T. whipplei from the clinical point of view. Our data also expand the pathogenetic understanding and concept of T. whipplei infection, because it remained unclear why the wide-spread, low-pathogenic organism would infrequently lead to clinical manifestations, i.e., to systemic WD. With respect to our results, immunosuppression plays a role in the progression of asymptomatic T. whipplei infection to chronic and systemic WD.
The observations in this study also require attention because WD diagnosis by duodenal biopsies with PAS stain is unreliable in TNFI pretreated patients. Therefore, in this situation diagnosis should be based on PCR, and screening strategies in the future may apply stool PCR[46] before and during therapy with TNFI.
The reason that PAS-staining is apparently much less frequently diagnostically accurate under biological DMARD therapy is unclear. Additionally, it remains unclear why the percentage of common clinical WD symptoms such as diarrhea and (subsequent) weight loss following TNFI therapy is lower, and the severe systemic complications of WD are more frequent. These observations could be due to the suppression of gastrointestinal involvement of T. whipplei and an induction of the systemic spread of the bacteria by TNFI treatment. These open questions should be clarified in future investigations which could also target the limitations of this study, i.e., the retrospective data analysis in a rare disorder.
In conclusion, our study shows that TNFI therapy may activate latent or asymptomatic infection with T. whipplei, leading to an aggressive course of WD and high rate of endocarditis. Therefore, clinical practice before TNFI therapy should be modified, so that T. whipplei is excluded before therapy with TNFI in patients with unexplained arthritis. Moreover, if TNFI treatment failure or paradoxical therapy effects are observed, the possibility of T. whipplei infection should be considered. These safety concerns should be monitored in TNFI therapy registers.
COMMENTS
Background
Whipple’s disease (WD) is a rare systemic infection with Tropheryma whipplei (T. whipplei), and host immune defects contribute to the pathogenesis. WD is typically diagnosed by duodenal biopsy and periodic acid-Schiff (PAS) stain. As unexplained arthritis is often the first WD symptom, patients may receive treatment with anti-inflammatory drugs or tumor necrosis alpha inhibitors (TNFI) before diagnosis. It remained unclear whether TNFI therapy is associated with a more complicated course of T. whipplei infection.
Innovations and breakthroughs
This study shows that treatment with TNFI may trigger severe complications of T. whipplei infection, particularly endocarditis. Medical immuno-suppression plays a role in the progression of asymptomatic T. whipplei infection to chronic and systemic WD. TNFI therapy may also lead to false-negative PAS-tests in WD and thereby hinder the diagnosis. In this situation, polymerase chain reaction has an important diagnostic role.
Applications
In case of treatment failure or paradoxical effects of TNFI treatment in patients with unclear arthritis, infection with T. whipplei should be considered.
Peer review
This is certainly an interesting and potentially important retrospective case control studies that had been investigated by the authors to look at the potential negative impact of using biological immunosuppression of arthritis patients without checking them for an undiagnosed Whipple‘s disease.
Footnotes
P- Reviewer: Al-Mohammad A, Chen LZ, Oteo JA S- Editor: Gou SX L- Editor: A E- Editor: Wu HL
Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple’s disease.N Engl J Med. 1992;327:293-301.
[PubMed] [DOI][Cited in This Article: ]
Bentley SD, Maiwald M, Murphy LD, Pallen MJ, Yeats CA, Dover LG, Norbertczak HT, Besra GS, Quail MA, Harris DE. Sequencing and analysis of the genome of the Whipple’s disease bacterium Tropheryma whipplei.Lancet. 2003;361:637-644.
[PubMed] [DOI][Cited in This Article: ]
Mahnel R, Kalt A, Ring S, Stallmach A, Strober W, Marth T. Immunosuppressive therapy in Whipple’s disease patients is associated with the appearance of gastrointestinal manifestations.Am J Gastroenterol. 2005;100:1167-1173.
[PubMed] [DOI][Cited in This Article: ]
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.JAMA. 2006;295:2275-2285.
[PubMed] [DOI][Cited in This Article: ]
Kneitz C, Suerbaum S, Beer M, Müller J, Jahns R, Tony HP. Exacerbation of Whipple’s disease associated with infliximab treatment.Scand J Rheumatol. 2005;34:148-151.
[PubMed] [DOI][Cited in This Article: ]
Weisfelt M, Oosterwerff E, Oosterwerff M, Verburgh C. Whipple’s disease presenting with neurological symptoms in an immunosuppressed patient.BMJ Case Rep. 2012;2012.
[PubMed] [DOI][Cited in This Article: ]
Legoupil N, Jourdan C, Poyart C, Ariche L, Puechal X, Job-Deslandre C, Kahan A. Attentei cutanee au cours der la Maladie de Whipple: une manifestation exceptionelle.Rev Rhumatisme. 2006;73:1232.
[PubMed] [DOI][Cited in This Article: ]
Soulie C, Drillon M, Peret M, Bouvier J, Andeu MR. Maladie de Whipple sous etarnecept.Rev Med Interne. 2008;29:S114.
[PubMed] [DOI][Cited in This Article: ]
Miksche LW, Blümcke S, Fritsche D, Küchemann K, Schüler HW, Grözinger KH. Whipple’s disease: etiopathogenesis, treatment, diagnosis, and clinical course. Case report and review of the world literature.Acta Hepatogastroenterol (Stuttg). 1974;21:307-326.
[PubMed] [DOI][Cited in This Article: ]
Fenollar F, Lepidi H, Raoult D. Whipple’s endocarditis: review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis.Clin Infect Dis. 2001;33:1309-1316.
[PubMed] [DOI][Cited in This Article: ]
Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic.Rheumatology (Oxford). 2005;44:714-720.
[PubMed] [DOI][Cited in This Article: ]
Netea MG, Radstake T, Joosten LA, van der Meer JW, Barrera P, Kullberg BJ. Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression.Arthritis Rheum. 2003;48:1853-1857.
[PubMed] [DOI][Cited in This Article: ]
Schöniger-Hekele M, Petermann D, Weber B, Müller C. Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers.Appl Environ Microbiol. 2007;73:2033-2035.
[PubMed] [DOI][Cited in This Article: ]
Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T. Dysregulated peripheral and mucosal Th1/Th2 response in Whipple’s disease.Gastroenterology. 2002;123:1468-1477.
[PubMed] [DOI][Cited in This Article: ]
