Tropheryma whippelii (Whipple's Disease)
Authors: Vera Moos, Ph.D. and David N. Fredricks, M.D.
Previous Authors: David N. Fredricks, M.D., David A. Relman, M.D.
Whipple's disease is a rare, chronic, systemic illness first described in a 36-year-old physician by George Whipple in 1907 (98). Whipple named the disorder "intestinal lipodystrophy" based on his belief that altered fat metabolism played a role in its pathogenesis. He also noted numerous rod-shaped organisms in a silver stained lymph node from his case, but the significance of this observation was not apparent in 1907. The infectious nature of Whipple`s disease was not made apparent until the 1950s when trials of antibiotics demonstrated that patients could be cured of this usually fatal disease (71). Electron microscopy later revealed the presence of unique bacillary structures within tissues from patients with Whipple`s disease. Clinical response to antibiotics was associated with disappearance of bacilli. Reappearance of bacilli heralded clinical relapse (93). Despite the accumulated evidence of a bacterial etiology for Whipple`s disease, initially no organism was reproducibly cultured from tissues of affected patients.
Further characterization of the Whipple bacillus became possible through the application of nucleic acid amplification technology and molecular phylogenetic analysis. A portion of a previously uncharacterized bacterial 16S ribosomal RNA gene was amplified with the polymerase chain reaction (PCR) directly from human Whipple`s disease tissues using primers directed against highly conserved regions of the bacterial gene (79, 99). The same sequence was not detected in tissues from persons without Whipple`s disease. A phylogenetic tree with inferred evolutionary relationships was created from a set of aligned 16S rDNA sequences that included the amplified Whipple's bacillus sequence. The Whipple bacillus was assigned to the actinomycete group of bacteria. The name Tropheryma whippelii was proposed, derived from the Greek words "trophe" for nourishment and "eryma" for barrier, and "whippelii" in honor of George Whipple. After the stable cultivation and genotypical characterization of a first strain of “Tropheryma whippelii”, the name was corrected toThropheryma whipplei (52).
Microbiology
Until the end of the last millenium, attempts to grow T. whipplei in axenic media, cell culture, and animal hosts have failed. Laboratory cultivation of T. whipplei has first been reported 1997 by co-cultivation of bacteria with deactivated human macrophages, but continuous cultivation was not achieved (87). A subsequent report used co-cultivation with fibroblasts to establish a continuous bacterial culture (74). Stable cultivation enabled the sequencing of the whole genome of T. whipplei (7, 75). And based on the genetic organization and the metabolic pathways of T. whipplei, an axenic medium was developed (80). Analyses of rRNA operon sequences from different T. whipplei infected tissues have revealed several unique sequence types (43, 56) and today, a number of different stable strains of T. whipplei have been isolated and characterized based on their genomic structure (23, 47). However, no geographical or clinical pattern of disease has emerged that correlates with a particular bacterial sequence type (53).
Although mice can be infected transiently with the organism (2), an appropriate animal model of the disease is still lacking, Thus, Koch's postulates for establishing microbial disease causation, as originally constructed, still cannot be fulfilled.
T. whipplei measures 0.20 micron in diameter, and 1.5-2.5 microns in length (15). No flagella are apparent. A 20-nm-thick cell wall lies external to a cytoplasmic membrane and contains peptidoglycan. A second phospholipid membrane is external to the cell wall. Although an outer membrane is typical of Gram negative bacilli, the symmetric appearance and lack of lipopolysaccharide in the T. whipplei outer membrane, and the thickness of the cell wall, distinguish this bacterium from the Gram negative group.
Epidemiology
Whipple`s disease mainly affects Caucasians, preferentially males with a mean age of about (16, 48). As causative genetic risk factors cytokine gene polymorphisms (8) and a HLA-association that seems to influence the course of the disease (63) have been identified.
There is no known natural reservoir or animal host for T. whipplei other than man. Disease in neighbors (54) and in a father-son and father-daughter pair have been described (20, 72). Today, there is evidence of person-to-person transmission of the agent (24, 46). However, the contact or even temporary infection with T. whipplei only leads to Whipple`s disease very rarely. T. whipplei has been detected in waste water from sewage treatment plants and its workers in Germany, France and Austria (25, 57, 88); but replication of the organism in this environment has not been demonstrated (57).
Today, based on elaborate PCR systems, it has been shown that there are different forms of infection with -, or carriage of T. whipplei. Several reports have described PCR detection of T. whipplei in saliva, gastric juice, or intestinal biopsies from patients without Whipple`s disease (19, 21, 90). On the other hand, another PCR study showed that T. whipplei was not found in any of 342 small intestinal biopsies obtained from patients without Whipple`s disease (58). Results of the group of D. Raoult revealed an incidence of healthy carriage of T. whipplei of 0.6% for saliva (82) and 4% for stool (25) and higher values might be explained by unspecific PCR primers (82).
In addition to asymptomatic carriage, T. whipplei was detected during several symptomatic self-limiting conditions: The agent can be detected in 15% of stool samples of French children with gastroenteritis (76), it has been found in 3% of bronchio-alveolar lavages of patients with pneumonia (12), and T. whipplei bacteraemia was associated with fever and cough in rural west Africa (26, 41). However, T. whipplei was not assured as the only causative agent in these conditions, since not all possible other causes of symptoms were excluded.
The prevalence of T. whipplei in stool samples is enhanced under poor hygienic conditions (25, 27, 88). Thus, it might be a commensal bacterium acquired through faecal-oral transmission (46) and spread by human-to-human transmission (26, 27). No particular bacterial sequence type has been identified that correlates with geographical or clinical pattern of disease or carriage of T. whipplei (53).
Clinical Manifestations
Classical Whipple’s Disease
Classical Whipple`s disease primarily affects the small intestine. However, the clinical manifestations of classical Whipple's disease are diverse. Patients may have neurological or rheumatological symptoms, lymphadenopathy, peritoneal or pleural effusions, uveitis or skin manifestations without the classical gastrointestinal symptoms (16, 31, 32, 48). The symptoms may be isolated but in the majority of cases, multiple organ systems including brain, lymph node, heart, lung, eye, liver, spleen, skin, bone, and synovium (59) are affected. Heart valves not only can be infected during isolated T. whipplei induced endocarditis, but also in combination with “classical” symptoms. Patients often suffer from migratory arthritis or arthralgia that precedes gastrointestinal symptoms by years and subsequent misdiagnosis with immunosuppressive treatment (55).
Eventually, patients may develop diarrhea, malabsorption, weight loss, malaise, fever, or abdominal pain. Signs of cachexia, lymphadenopathy, abdominal tenderness, peripheral edema, and fever may be apparent. Laboratory abnormalities may include anemia, thrombocytosis, hypoalbuminemia, electrolyte disturbances, and increased stool fat content.
In 10 to 40% of patients with classical Whipple`s disease neurological symptoms evolve and represent the most serious manifestations of Whipple`s disease (16, 18, 39, 48, 70). Headache and cognitive dysfunctions are the most common unspecific abnormalities during CNS disease while only disturbances of the ocular movement, in particular progressive supranuclear ophthalmoplegia (SNO) in conjunction with oculomasticatory myorhythmia (OMM) or oculofacioskeletal myorhythmia are considered pathognomonic for neurological Whipple’s disease (18). More rarely insomnia, epilepsy, focal cerebral lesions, ataxia, seizures, cerebellar ataxia,and meningitic features may be present and the spinal cord or peripheral nerves may be involved (39) CNS manifestation may be the initial symptom of the disease (70), but infection of the cerebrospinal fluid (CSF)affects approximately 40% of patients even in the absence of any symptoms (32, 48). This observation forms the basis for selecting antibiotics for treatment that cross the blood-brain barrier and justifies the need of a PCR from CSF in any case before the initiation of antimicrobial treatment.
T. whipplei Endocarditis
The most frequent isolated infection with T. whipplei seems to be endocarditis without other signs of Whipple`s disease (22, 28, 37, 48, 61). The infection may also affect implants (17, 38). Since the infection is slowly progressive and the agent cannot be cultured by standard methods, it often does not meet the major clinical criteria for infective endocarditis (52). Thus, diagnosis requires valve explantation followed by T. whipplei-specific PCR or histological examination (22, 28, 48, 61).
Laboratory Diagnosis
PAS-staining
The histologic hallmark of classical Whipple`s disease are periodic acid-Schiff (PAS) reactive vacuoles in macrophages within the lamina propria of the small bowel (96). The magenta stain indicates carbohydrate within these vacuoles. It is believed that PAS reagent reacts with intact and partially degraded bacterial cell wall polysaccharide remnants. The reactivity of Whipple`s disease tissue persists after treatment with diastase, indicating that a non-starch polysaccharide is present (96). T. whipplei can be visualized with Giemsa stain and some silver stain methods (e.g. Gomori), but not with acid-fast staining procedures and T. whipplei stains weakly Gram positive. Tissues with PAS-positive macrophages should be subjected to acid-fast staining to exclude mycobacteria (e.g. Mycobacterium avium complex), which may also be PAS reactive (60). Infection with Rhodococcus equi may also produce PAS-positive macrophage inclusions, usually in the lung (42). Besides diagnosis, PAS-staining is superior to monitor treatment success, since the morphology of the infected macrophages changes obviously in the course of effective treatment (96).
Although PAS-positive, acid fast stain-negative macrophage inclusions found in the small intestine, synovial tissue or lymph nodes are diagnostic of Whipple`s disease, PAS-positive, diastase-resistant macrophages found in e.g. colon or brain are not specific for Whipple`s disease (59). Other methods and/or alternative specimens should be used to confirm the diagnosis of Whipple`s disease at colon or brain.
PCR
Within the last years, PCR has become more important for the diagnosis of Whipple`s disease. First PCR systems were based on the 16S rRNA gene of T. whipplei and the sequencing of the complete genome enabled PCR with an increased sensitivity by using repeated sequences (29, 69, 79, 95). However, there are many technical pitfalls, and its use should be limited to accredited laboratories where the amplified DNA should be verified by sequencing or testing for multiple targets (29). Due to asymptomatic CNS involvement, PCR from CSF is important in any case before the initiation of treatment. PCR from affected tissues is reasonable as therapy control since it should become negative during antibiotic treatment (95).
However, there are some major limitations for PCR. Due to healthy carriage of T. whipplei, a positive PCR from gastrointestinal samples has to be confirmed by histology or by a second PCR from specimen without environmental contact (e.g. CSF or synovial fluid) to avoid that other important differential diagnoses are obscured. In addition, today only DNA-based PCR systems are used, thus, there might be a positive signal from remnants of dead bacteria even after successful treatment. A persistently positive PCR after treatment should be controlled suspiciously and eventually the viability and antibiotic resistance of the bacteria should be checked (6, 9).
Sometimes patients with clinical evidence of classical Whipple`s disease fail to have convincing histological evidence of disease from small intestinal biopsies. However, this is very improbable for cases with classical Whipple`s disease with gastrointestinal symptoms. Yet, T. whipplei DNA can be detected in alternative tissue samples by PCR (81). PCR is strongly recommended to detect T. whipplei in all specimens like e.g. CSF, synovium, lymph node, blood and other tissues that are not in direct environmental contact. In addition, from all solid specimens, PAS.staining should be conducted.
Immunohistochemistry
Specific antibodies against T. whipplei improved the histological detection (5). Specific immunohistochemistry is more sensitive and allows the identification of T. whipplei in PAS-negative tissues (5). Especially as said before, PAS-staining of brain and colon biopsies might be unspecific and misinterpreted as T. whipplei inclusions and thus, additional immunohistochemistry is a valuable evaluation.
Fluorescence In Situ Hybridization
Diagnosis by fluorescence in situ hybridization (FISH) is highly probative through direct molecularbiological identification of T. whipplei RNA within its histological context as it differentiates between contaminations and true infection (26). In addition, since it is based on the detection of RNA it targets preferentially viable bacteria. However, FISH for T. whipplei is not a routine method and only available in specialized laboratories.
Electron Microscopy
Although also no routine diagnostic method, examination of affected tissues by electron microscopy can also be helpful in confirming a diagnosis of Whipple`s disease since T. whipplei has a characteristic ultrastructural morphology (89).
Culture
The slow growth rate of T. whipplei in the laboratory hinders routine use of cultivation as a routine diagnostic approach at the present time, since it is limited to specialized research laboratories (74, 87). However, cultivation can be useful for testing of antibiotic susceptibility or viability of bacteria in selected cases with persistent problems after initiation of treatment.
Diagnostic Approaches
Different antigenic proteins were identified (59) and T. whipplei-specific antibodies can be detected in serum samples of healthy controls and carriers of T. whipplei (16, 55). While the serological reactivity of Whipple`s disease patients rather is reduced compared to carriers (16, 55). The presence of T. whipplei-specific IgA in stool and supernatants of intestinal biopsies seems to be more specific to patients (10, 35). Thus, serology seems only suitable for diagnosis in combination with the quantification of T. whipplei DNA in stool samples (10) and is currently not routinely valuable for clinical decision-making. PCR from saliva or stool specimens may be used for a diagnostic screening (29), however patients without gastrointestinal involvement will be missed and due to the existence of healthy carriage false positive results are probable.
Pathogenesis
The existence of asymptomatic carriage and self-limiting infection with T. whipplei with only a minority evolving to chronic manifestations hints at an underlying predisposition of affected patients (27, 76). T. whippleimight penetrate the body after human-to-human transmission (26, 27) and the first infection might occur early in life and might be asymptomatic or result in self-limiting gastroenteritis, fever, or cough (25, 76).Consequently, most of the infected persons seem to develop a protective humoral and cellular immune response (10, 35, 66).
However, there are predisposed persons with an immune deficiency that allows systemic spread and persistence of the pathogen. In these predisposed persons classical Whipple`s disease develops in the course of many years and decades. The entry of T. whipplei to immunological protected sites (e.g. the CNS) might be achieved by the pass of infected monocytes through the endothelial barrier (77). The predisposition of patients impairs the activity of dendritic cells (83) and the production of IL-12 (44) and advocates the development of macrophages with an alternative activated phenotype expressing IL-10 (35, 36, 67). Type 1 interferon and IL-16 are important growth factors for T. whipplei: Type I interferon maintains infection in macrophages (3) and IL-16 prevents the maturation of phagosomes (40) and has been identified as a growth factor for T. whipplei (14). As a result, intestinal macrophages ingest but seem to be unable to kill invading bacteria or to induce protective immune responses. Further, the number of duodenal lymphocytes is reduced (67) and the activity of T-helper cells of type 1 (Th1) is impaired (62).
As a consequence of impaired cellular immune responses, a reduced amount of T. whipplei–specific immunoglobulins is secreted (10) and the cytokine milieu in the serum and gastrointestinal mucosa is anti-inflammatory (44, 67, 84), This inhibition of Th1 activity in the periphery and the duodenum is T. whipplei-specific (66). These aberations might be influenced by inefficient antigen-presentation since certain HLA alleles are associated with Whipple`s disease (63) and by cytokine gene polymorphisms (8). By contrast, functional Th2 responses and the activity of regulatory T cells increase in peripheral and mucosal lymphocytes (62, 84), in line with the early observation that T. whipplei replicates in macrophages deactivated by IL-4 and –10 (87).
Thus, the absence of an inflammatory- and Th1 response against T. whipplei and the alternative activation of macrophages allow the establishment of a chronic infection in predisposed patients. Since these immunological abnormalities persist even if the disease is successfully treated, a lifetime susceptibility seems probable (49).
SUSCEPTIBILITY IN VITRO AND IN VIVO
T. whipplei has been successfully cultivated within fibroblasts and on cell-free media; Both cultivation techniques allow some measurement of in vitro antibiotic susceptibility (11, 64, 94). For the commonly used therapeutic trimethoprim-sulfamethoxazole (TMP-SMX), only SMX is effective (11), since T. whipplei lacks the target of TMP (13). Acquisition of resistance against SMX may result in treatment failures (6, 30, 50). Based on the high efficiency of doxycycline in combination with hydroxychloroquine in vitro, it has been suggested and successfully applied in patients (51).
ANTIMICROBIAL THERAPY
Prior to the first successful use of chloramphenicol in 1952 (71) Whipple`s disease was uniformly fatal. Subsequent reports have noted successful responses to penicillin, plus streptomycin, aampicillin, amoxicillin (4),ceftriaxone (31, 32), gentamicin, the tetracyclines (tetracycline, doxycycline), sulfonamides, trimethoprim, trimethoprim/sulfamethoxazole (TMP-SMX), erythromycin, neomycin, rifampin plus other antibiotics, and salicylazosulfapyridine (45). Tetracycline was the drug of choice for many years, but a high relapse rate and a poor response to re-treatment of CNS relapse were reported (45). Better results were achieved with TMP-SMX or a combination of penicillin and streptomycin (18, 33). Two prospective treatment trial published today proved the effectiveness of an intravenous induction therapy for 14 days with either meropenem or ceftriaxone in combination with an oral continuation therapy with TMP-SMX for 12 months (32) and 3 months (31) respectively. To clear T. whipplei from the CNS primary treatment should include antibiotics, which attain high CSF levels (e.g. ceftriaxone or penicillin G) (32). In case of allergic reactions to ceftriaxone, penicillin G, carbapenems, or chloramphenicol are possible alternatives.
However, until now it cannot be decided which the best antibiotic treatment for Whipple`s disease is. The efficiency of doxycycline and SMX was demonstrated in vitro and doxycycline in combination withhydroxychloroquine achieved the best bactericidal results (11). Based on these encouraging in vitro results, one alternative treatment option is doxycycline in combination with hydroxychloroquine (51, 85). In an ongoing study currently the combination of ceftriaxone and TMP-SMX with this sole oral regime is compared.
With respect to the suggested continuation therapy with TMP-SMX, one should remember that only SMX is effective (11), since T. whipplei lacks the target of TMP (13). Acquisition of resistance against SMX may result in treatment failures (6, 30). Therefore, alternatives to TMP-SMX or SMX alone could be useful. In cases of CNS involvement oral TMP-SMX should be added till PCR of the CSF turns negative. Based on all data available, combination therapy seems to be superior to monotherapy in Whipple`s disease.
Upon treatment, clinical improvement is often dramatic and most patients recover from classical symptoms completely (18, 32). However, neurological defects are more difficult to reverse resulting from irreversible tissue damage (70). It should be mentioned at this point that isolated suspected CNS-manifestations of Whipple`s disease which do not respond to treatment have to be critically re-evaluated.
Drug of Choice
Recognizing the significant limitations of the data, we recommend an antibiotic regimen of intravenous induction therapy for 14 days with 2g daily ceftriaxone in combination with an oral continuation therapy with TMP-SMX (160 mg/800 mg 2x daily) for 12 months (32). In addition, based on the promising in vitro data and first empiric applications, another alternative would be a sole oral treatment with doxycycline (2 x 100mg/day) in combination with hydroxychloroquine (3 x 200mg/day) (1, 51). In cases of CNS involvement oral TMP/SMX may be added till PCR of the CSF turns negative.
To clear T. whipplei from the CNS primary treatment should include antibiotics, which attain high CSF levels. Thus, in case of allergic reactions to ceftriaxone, meropenem, penicillin G, carbapenems, orchloramphenicol are possible alternatives.
One year of antimicrobial therapy is curative in most patients. However, clinical judgment may dictate longer courses of treatment in special cases.
Alternative Therapy
Alternative therapies are parenteral penicillin, either 1.2 million units procaine penicillin IM or 6-24 mU penicillin G IV, per day concurrent with streptomycin 1.0 gram per day for 10-14 days, followed by oral TMP/SMX one double strength tablet twice daily for 1 year (Table 1).Even lifetime treatment with doxycycline has been suggested to prevent subsequent new infection in identified patients (49, 51). For the patient who is intolerant of TMP-SMX, doxycycline (100 mg po bid) in combination with hydroxychloroquine or penicillin VK (500 mg po qid) may be used for consolidation oral treatment after parenteral penicillin plus streptomycin.
Special Situations
The most common and severe complications during the treatment of Whipple`s disease are unspecific inflammatory processes defined as immune reconstitution inflammatory syndrome (IRIS) (34). IRIS manifests as long-lasting fever, or other recurrent inflammatory processes (e.g. orbitopathy, arthritis, gut perforation) after initiation of antimicrobial treatment in ca. 10% of patients. Additional application of corticosteroids in these cases may be organ- or even lifesaving (34). Although treatment has not been evaluated prospectively, an additional corticosteroid treatment with 1,5 mg/kg/day prednisolone results in prompt relief from IRIS symptoms (34). According to our experience, particularly long lasting immunosuppressive medication prior to the diagnosis of Whipple`s disease with low initial CD4+ T cell numbers followed by an imbalances reconstitution of the CD4+ T cell compartment predisposes for the development of IRIS (34, 68).
A second group of patients that profits from corticosteroid treatment are cases with severe CNS-manifestations and cerebral lesions. Adjunctive therapy with corticosteroids may reduce local inflammation and oedema as well as endothelial damage and the guidelines for the treatment of tuberculous meningitis should be considered (92).
A Herxheimer-type reaction has been described with initiation of antibiotics, marked by a brief clinical deterioration (fever, hypotension) and a rise in acute phase reactants (78, 91).
Underlying Diseases
There is no evidence that Whipple`s disease is more prevalent in immunocompromised patients, or that treatment should be modified in this population.
ADJUNCTIVE THERAPY
In cases of relapsing disease despite adequate antibiotic treatment, in dependence from the first medication, alternative treatment regimes should be considered. In documented relapses, in which IRIS and inflammatorycerebral lesions are excluded, an additional supportive therapy with IFNg might be beneficial (86).
ENDPOINTS FOR MONITORING THERAPY
Clinical response to antibiotics is usually observed in the first days to week of therapy. Cessation of diarrhea and fever are usually the first objective signs of improvement. Within one month, significant weight gain usually occurs and arthralgia resolves. Correction of laboratory and histologic abnormalities lag behind the clinical gains. Intestinal epithelial cells begin to normalize within days of treatment, and extracellular bacilli disappear within the first few weeks (65). However, the architecture of the intestinal mucosa usually remains abnormal for many months. PAS staining macrophages may persist in the lamina propria for years after successful treatment. However, the morphology of the stained cells changes and treatment success can easily be monitored by an experienced observer (96). Laboratory abnormalities usually resolve within 6-18 months.
It is reasonable to obtain an intestinal biopsy in the patient with gastrointestinal disease just prior to terminating antibiotic treatment (e.g. at one year of antibiotics). The histologic picture observed at this time can serve as a new baseline for comparison to future biopsies obtained when disease relapse is a concern. The presence of PAS positive macrophages in the lamina propria at termination of treatment does not by itself indicate persistent disease. On the contrary, these abnormal macrophages will continue to be found in most patients for years, albeit with changing histology and in decreasing numbers (96).
If the patient is thought to be compliant but fails to improve, one should consider antibiotic failure or false diagnosis. Although laboratory and histological abnormalities may persist for months, a trend towards normalization should be evident rapidly on effective treatment. A patient who shows evidence of worsening laboratory parameters such as anemia, hypoalbuminemia, rising ESR, or steatorrhea should have his or her diagnosis and treatment plan re-evaluated.
PCR based assays for T. whipplei may be useful for diagnosing Whipple`s disease and monitoring response to antibiotics (73). Although T. whipplei DNA may persist in intestinal tissue for weeks or months after initiation of antibiotics, microbial DNA disappears from tissues more rapidly than the rate at which histological abnormalities resolve (96). One caveat is that the eradication of T. whipplei DNA from intestinal tissue does not exclude the possibility of ongoing CNS disease. A PCR based assay of cerebrospinal fluid should be used to diagnose and monitor the treatment of CNS Whipple`s disease (97).
VACCINES
There is no commercially available vaccine. Because the disease appears to be quite rare and the identification of high risk patients difficult, justification of such a strategy would be difficult.
PREVENTION OR INFECTION CONTROL MEASURES
Population-wide prevention is not necessary, since the majority of people are not susceptible for Whipple`s disease. However, for diagnosed patients
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Tables
Table 1: Recommended Antimicrobial Regimens for Whipple`s disease
I. Induction plus consolidation therapy |
|---|
Induction (10-14 days): Ceftriaxone 2 grams IV Consolidation (1 year): TMP/SMX 160 mg/800 mg po 2x |
II. Sole oral treatment |
Doxycycline 100 mg po 2x plus Hydroxychloroquine 200 mg po 3x for one year In case of CNS involvement: additional TMP/SMX 160 mg/800 mg |
TMP-SMX = Trimethoprim-sulfamethoxazole
What's New
GeiBdorfer W, et al. Tropheryma whipplei Endocarditis. In the Literature Section, Clin Infect Dis 2012;55:iii.
Raoult D, et al. Tropheryma whipplei in Children with Gastroenteritis. Emerg Infect Dis. 2010 May;16:776-82.