Gerhard E. Feurle

An evaluation of antimicrobial treatment for Whipple's disease : tetracycline versus trimethoprim-sulfamethoxazole

Whipples disease is a multisystemic disorder in which almost all organ systems can be invaded by rod-shaped bacteria. Without extended antimicrobial therapy, its course is lethal. Empirically, treatment consists of tetracyclines given for one to two years. Trimethoprim-sulfamethoxazole, a compound that crosses the blood-brain barrier, has been suggested as an alternative when patients were observed with progressive cerebral involvement. There has never been a formal evaluation of the selection of antibiotics for the treatment of Whipples disease. In the present nonrandomized, partially retrospective study, we compared the result of two treatment regimens in 30 patients, all examined personally. Twenty-two patients were treated with tetracycline and eight patients with trimethoprim-sulfamethoxazole. In five patients, therapy with tetracycline was changed to another antimicrobial agent because of treatment failure or drug intolerance. The main treatment measure was disappearance of the clinical symptoms such as weight loss, arthritis, malabsorption, fever, edema, central nervous system manifestations, lymphadenopathy, and congestive heart failure. Drug intolerance requiring a change of medication was also considered a treatment failure. We found that trimethoprim-sulfamethoxazole induced complete clinical remission in 12 of 13 treatment cycles, tetracycline in 13 of 22 treatment cycles (P<0.05; mean difference 33%; 95% confidence interval 8% to 58%). Trimethoprim-sulfamethoxazole was also more efficacious than tetracycline in the treatment of cerebral Whipples disease. However, trimethoprim-sulfamethoxazole did not prevent cerebral manifestations in all cases. The only deaths due to Whipples disease occurred in patients with cerebral involvement. It is concluded that treatment with trimethoprim-sulfamethoxazole was significantly superior to that with tetracycline in inducing clinical remission of Whipples disease. A more active antimicrobial regimen is necessary to treat cerebral involvement.

Efficacy of Ceftriaxone or Meropenem as Initial Therapies in Whipple's Disease

BACKGROUND & AIMS Whipples disease is a chronic infection caused by the actinomycete Tropheryma whipplei. We conducted a randomized controlled trial of the efficacy of antimicrobials that are able to cross the blood-brain barrier and to which T whipplei is susceptible. METHODS Patients from central Europe with previously untreated Whipples disease (n = 40) were assigned randomly to groups given daily infusions of either ceftriaxone (1 x 2 g, 20 patients) or meropenem (3 x 1 g, 20 patients) for 14 days, followed by oral trimethoprim-sulfamethoxazole for 12 months. The primary outcome measured was maintenance of remission for 3 years, determined by a composite index of clinical and laboratory data as well as histology. RESULTS All patients were observed for the entire follow-up period (median, 89 mo; range, 71-128 mo); all achieved clinical and laboratory remission. Remission was maintained in all patients during the time of observation, except for 2 who died from unrelated causes. A single patient with asymptomatic cerebrospinal infection who was resistant to both treatments responded to chloroquine and minocycline. The odds ratio for the end point (remission for at least 3 years) was 0.95 (95% confidence interval, 0.05-16.29; P = 1.0). CONCLUSIONS This was a randomized controlled trial to show that treatment with ceftriaxone or meropenem, followed by trimethoprim-sulfamethoxazole, cures patients with Whipples disease. One asymptomatic individual with infection of the cerebrospinal fluid required additional therapy.

Reduced Peripheral and Mucosal Tropheryma whipplei-Specific Th1 Response in Patients with Whipple’s Disease

Whipple’s disease is a rare infectious disorder caused by Tropheryma whipplei. Major symptoms are arthropathy, weight loss, and diarrhea, but the CNS and other organs may be affected, too. The incidence of Whipple’s disease is very low despite the ubiquitous presence of T. whipplei in the environment. Therefore, it has been suggested that host factors indicated by immune deficiencies are responsible for the development of Whipple’s disease. However, T. whipplei-specific T cell responses could not be studied until now, because cultivation of the bacteria was established only recently. Thus, the availability of T. whipplei Twist-MarseilleT has enabled the first analysis of T. whipplei-specific reactivity of CD4+ T cells. A robust T. whipplei-specific CD4+ Th1 reactivity and activation (expression of CD154) was detected in peripheral and duodenal lymphocytes of all healthy (16 young, 27 age-matched, 11 triathletes) and disease controls (17 patients with tuberculosis) tested. However, 32 Whipple’s disease patients showed reduced or absent T. whipplei-specific Th1 responses, whereas their capacity to react to other common Ags like tetanus toxoid, tuberculin, actinomycetes, Giardia lamblia, or CMV was not reduced compared with controls. Hence, we conclude that an insufficient T. whipplei-specific Th1 response may be responsible for an impaired immunological clearance of T. whipplei in Whipple’s disease patients and may contribute to the fatal natural course of the disease.

Genotyping reveals a wide heterogeneity of Tropheryma whipplei.

Tropheryma whipplei, the causative agent of Whipples disease, is associated with various clinical manifestations as well as an asymptomatic carrier status, and it exhibits genetic heterogeneity. However, relationships that may exist between environmental and clinical strains are unknown. Herein, we developed an efficient genotyping system based on four highly variable genomic sequences (HVGSs) selected on the basis of genome comparison. We analysed 39 samples from 39 patients with Whipples disease and 10 samples from 10 asymptomatic carriers. Twenty-six classic gastrointestinal Whipples disease associated with additional manifestations, six relapses of classic Whipples disease (three gastrointestinal and three neurological relapses), and seven isolated infections due to T. whipplei without digestive involvement (five endocarditis, one spondylodiscitis and one neurological infection) were included in the study. We identified 24 HVGS genotypes among 39 T. whipplei DNA samples from the patients and 10 T. whipplei DNA samples from the asymptomatic carriers. No significant correlation between HVGS genotypes and clinical manifestations of Whipples disease, or asymptomatic carriers, was found for the 49 samples tested. Our observations revealed a high genetic diversity of T. whipplei strains that is apparently independent of geographical distribution and unrelated to bacterial pathogenicity. Genotyping in Whipples disease may, however, be useful in epidemiological studies.

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

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.

Localization of Xenin-immunoreactive Cells in the Duodenal Mucosa of Humans and Various Mammals

Xenin is a 25-amino-acid peptide extractable from mammalian tissue. This peptide is biologically active. It stimulates exocrine pancreatic secretion and intestinal motility and inhibits gastric secretion of acid and food intake. Xenin circulates in the human plasma after meals. In this study, the cellular origin of xenin in the gastro-entero-pancreatic system of humans, Rhesus monkeys, and dogs was investigated by immunohistochemistry and immunoelectron microscopy. Sequence-specific antibodies against xenin detected specific endocrine cells in the duodenal and jejunal mucosa of all three species. These xenin-immunoreactive cells were distinct from enterochromaffin, somatostatin, motilin, cholecystokinin, neurotensin, and secretin cells, and comprised 8.8% of the chromogranin A-positive cells in the dog duodenum and 4.6% of the chromogranin A-positive cells in human duodenum. In all three species, co-localization of xenin was found with a subpopulation of gastric inhibitory polypeptide (GIP)-immunoreactive cells. Immunoelectron microscopy in the canine duodenal mucosa demonstrated accumulation of gold particles in round, homogeneous, and osmiophilic secretory granules with a closely adhering membrane of 187 ± 19 nm diameter (mean ± SEM). This cell type was found to be identical to the previously described canine GIP cell. Immunocytochemical expression of the peptide xenin in a subpopulation of chromogranin A-positive cells as well as the localization of xenin immunoreactivity in ultrastructurally characterized secretory granules permitted the identification of a novel endocrine cell type as the cellular source of circulating xenin.

Distribution, formation, and molecular forms of the peptide xenin in various mammals.

In the present investigation we isolated the recently discovered pentacosapeptide xenin from gastric mucosa of man, dog, pig, guinea pig, rat, and rabbit. HPLC, mass spectrometry, and amino acid sequence analysis showed xenin-25 in concentrations of 54-144 pmol/g tissue in gastric mucosa of each species. Extraction with 2% TFA followed by analytical C18 HPLC revealed 0.02-84 pmol/g xenin-25 also in hypothalamus, lung, liver, heart, kidney, adrenal gland, pancreas, testicle, skin, and duodenal, jejunal, ileal, and colonic mucosa of dog and man, respectively. Digestion of these acid extracts with pepsin liberated xenin-25 in concentrations from 2 up to 166 pmol/g tissue. Gel chromatography revealed a large molecular weight precursor of xenin-25 and evidence for an endogenous acid protease coeluting with pepsinogen capable of releasing xenin-25 from its precursor. Maximal concentrations of xenin-25 were obtained when canine gastric mucosa was incubated with 2% TFA at room temperature for 2 h. Longer incubation times led to a decline of xenin-25 concentration and to formation of xenin-16 and xenin-9, both C-terminal fragments of xenin-25. We conclude that xenin-25 is present not only in human gastric mucosa but also in the stomach of various other mammals. Xenin-25 is further present in low concentrations in many other organs where a pepsin-like protease generates xenin-25 from a large precursor and processes it to smaller fragments.

Intravenous ceftriaxone, followed by 12 or three months of oral treatment with trimethoprim-sulfamethoxazole in Whipple's disease

BACKGROUND There is no agreement on how and for how long Whipples disease should be treated. In a randomized trial it was shown that patients can be cured with ceftriaxone or meropenem followed by trimethoprim-sulfamethoxazole for 12 months. The present study tested whether trimethoprim-sulfamethoxazole for three months is sufficient. METHODS In the time from July 2004 to July 2008, 40 untreated patients from central Europe were sequentially admitted to an open-label, non-randomized extension of the previous trial with essentially an identical protocol. The modified treatment consisted of 2 g ceftriaxone intravenously once daily for 14 days followed by oral trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 months. Primary endpoint was treatment efficacy compared with the previous study. RESULTS Twelve months of treatment with trimethoprim-sulfamethoxazole was not more effective than 3 months as indicated by clinical findings, laboratory (p = 0.405, p = 0.631, resp.), and histological data (p = 0.456). 36 of 37 surviving patients including 14 with cerebrospinal infection were in remission without evidence of recurrence after a median follow-up time of 80 months. In one patient, Tropheryma whipplei arthritis recurred 63 months after initial therapy. Secondary endpoints indicate that histology of intestinal biopsies was a more useful indicator to determine eradication of T. whipplei than PCR. In submucosal and extra-intestinal tissue, the diagnostic value of the PCR was superior. Prospective data disclosed a heterogeneous spectrum of clinical presentation and course of Whipples disease. CONCLUSION This study indicates that ceftriaxone followed by three months of trimethoprim-sulfamethoxazole is highly efficacious in the treatment of Whipples disease.

Xenin plasma concentrations during modified sham feeding and during meals of different composition demonstrated by radioimmunoassay and chromatography

UNLABELLED Xenin is a 25 amino acid peptide produced by specific endocrine cells of the duodenal mucosa. Xenin has multiple biological actions in the gastrointestinal tract. It modulates intestinal motility, affects exocrine pancreatic secretion, and gastric secretion of acid. In the present investigation, we studied plasma concentration of xenin in volunteers after modified sham feeding and after meals of different composition. Plasma xenin concentrations were determined by radioimmunoassay in unextracted plasmas and after acidic extraction using C-18 Sep-Pak chromatography and after neutral extraction using affinity filtration. Both extraction methods were followed by C 18 r.p. HPLC chromatography. Xenin plasma concentrations in unextracted and in extracted plasma rose significantly after modified sham feeding when the food was brought to the volunteers from another room immediately before sham feeding started. When the volunteers had the opportunity to observe the preparation of the meal, xenin plasma concentrations during fasting were high and no further rise was observed after sham feeding. Isocaloric feeding resulted in elevated xenin concentrations in unextracted plasma and after high-pressure liquid chromatography. The methods of extraction, acidic or neutral, did not affect the results. CONCLUSION Cephalic factors, investigated by modified sham feeding, stimulate release of xenin into the circulation. Xenin may participate in the central nervous regulation of gastrointestinal function.

Effect of Rising Intragastric ph Induced by Several Antacids on Serum Gastrin Concentrations in Duodenal Ulcer Patients and in a Control Group

The interrelationship of the effects of antacids and of rising intragastric pH on serum gastrin levels was examined by comparing the effect of three antacids (Mg(OH)2Al(OH)3, and CaCO3), and their nonbuffering chloride compounds (MgCl2, AlCl3, and CaCl2), on serum gastrin and intragastric pH in duodenal ulcer patients. In the case of calcium, the effect of CaCl2 with a pH of 10, and in another group, CaCl2 with a pH of 2, was studied. In the case of magnesium, a control group was also investigated. In another group, the effect of a nonionized suspension (BaSO4) was studied in order to assess the contribution of intragastric volume. Serum gastrin was determined radioimmunologically, and pH measurements were performed in vitro using a glass electrode. Serum gastrin concentrations rose significantly whenever intragastric pH was raised. Serum gastrin also rose after MgCl2, AlCl3, and CaCl2 with a pH of 2, when intragastric pH was not significantly altered. This rise, however, was significantly smaller than after administration of the antacids, except in the MgCl2-Mg(OH)2 and in the CaCl2 pH 10-CaCO3 groups. No significant rise of serum gastrin levels was observed after BaSO4. In nonulcer subjects, gastrin response was smaller than in the duodenal ulcer patients. The results suggest that administration of nonbuffering Mg-, Al-, and Ca-chlorides leads to elevated serum gastrin levels in duodenal ulcer patients; rising intragastric pH, however, exerts an additional serum gastrin response.