Impaired intracellular pathogen clearance and inflammatory joint disease: Is Whipple's disease a guiding light?

Whipple's disease can mimic spondyloarthritis (SpA) or rheumatoid arthritis (RA) for many years and, in a few cases, induces the development of antibodies to cyclic citrullinated peptides. The causative agent Tropheryma whipplei can smolder within cells, including macrophages, by suppressing the xenophagic process, a type of selective autophagy that targets pathogens. Other inflammatory joint diseases may also stem from impaired xenophagy with persistence of bacteria or viruses that can eventually migrate from the mucous membranes to the joints and entheses, where they may exert adverse effects on immune responses, even if they fail to replicate. Xenophagy interferes with the loading of peptides (including self-peptides) onto major histocompatibility complex proteins. Another effect of xenophagy is the induction of citrullination, which accelerates pathogen clearance but can also contribute to loss of self-tolerance. Pathogens react to citrullination by becoming dormant. These facts suggest a role in SpA and RA for impaired xenophagy with migration of pathogens to joints and entheses, where they may remain dormant. Studies of fibroblast-like synoviocytes showed alterations in autophagy that correlated with citrullination of vimentin, alpha-enolase, and filaggrin, which are targets of RA-specific autoantibodies. Compared to autoimmune responses (T-cell or B-cell clones, autoantibodies) alone, metastatic spread of pathogens initially located in the mucous membranes as the event inducing inflammatory joint disease would constitute a better explanation to the heterogeneous distribution of the joint involvement, palindromic onset in some cases (as seen in Whipple's disease), occurrence of flares, and possible development of escape phenomenon to immunomodulating drugs in a manner reminiscent of delayed antibiotic resistance.

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease.

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

Whipple's disease.

Whipple's disease is a rare, chronic, systemic infectious disorder with prominent intestinal manifestations. It presents with weight loss, arthralgia, diarrhea, and abdominal pain. There are different entities of infection or carriage, respectively, classical Whipple's disease, localized WD, and Isolated Neurological WD. The disease is commonly diagnosed by biopsy of lymph node or small-bowel. Histological detection within duodenal biopsies with "Periodic acid Schiff" (PAS) staining still is first choice for the diagnosis of classical Whipple's disease. PCR or immunohistochemistry can identify the agent more specifically, and DNA sequencing for Tropheryma whipplei on lymphocytes from blood and cerebrospinal fluid from PCR-positive specimens, is essential. Cell-mediated immunity in active and inactive Whipple's disease has subtle defects that might predispose some individuals to symptomatic infection with this bacillus. Successful treatment can be achieved in most of the cases by antimicrobial therapy. WD can be progressive lethal. Immune reconstitution inflammatory syndrome (IRIS) might complicate the course of treatment and in worst case end fatal.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) mimicking Whipple's disease: a case report and literature review.

INTRODUCTION: Diffuse leptomeningeal glioneuronal tumor is a new entity under the neuronal and mixed neuronal-glial tumors in the WHO 2016 updated classification and commonly found in children and adolescents. The initial diagnosis is challenging because of its non-specific radiologic feature and negative CSF cytology analysis. A 17 years male was presented with intractable headache subsequently followed by back pain and joint pain. MRI showed enhancement of arachnoid membrane at basal cistern, bilateral sylvian fissure and cerebral cistern with slight enlargement of ventricles. There were no evidences of infection in CSF and blood samples. Based on the duodenal biopsy and prodromal symptom of joint pain, the patient was suspected of having Whipple's disease. Eleven months after the onset, a small mass lesion was observed at the anterior horn of right lateral ventricle. The histology was remarkable for anaplastic oligodendroglioma. Immunostainings revealed positivity for GFAP, Olig2, synaptophysin and negativity for IDH1 mutation, H3K27M. MIB1 labeling index was 40% and 1p19q FISH analysis showed only 1p deletion. Therefore, a final diagnosis of DLGNT was made. CONCLUSION: DLGNT should be included as a differential diagnosis of patients with leptomeningeal-enhanced and high CSF protein level with normal white blood cell count.

Neurological and neuropsychological complications in the course of chronic Whipple's disease - case report. / Objawy neurologiczne i neuropsychologiczne w przewleklej postaci choroby Whipple'a ­ opis przypadku.

INTRODUCTION: Whipple's disease (WD) is a chronic, multisystemic infectious disease caused by Gram-positive bacillus Tropheryma whipplei (T.w.). Its common symptoms arise in the digestive system, however, during the infection the CNS (Central Nervous System) may also be affected. AIM: The aim of this work is to present a case report of a patient diagnosed with Whipple's disease with dominant neuropsychological and behavioural complications in the late phase. CONCLUSIONS: Whipple's disease is a rare disease with possible neurological and neuropsychiatric complications. Neurological disorders (eye movement disorders, myoclonus, oculoskeletal miorhythmia, progressive dementia) may develop in spite of correct pharmacological treatment. Apart from its classical symptoms, unspecified cognitive function disorders and autonomic nervous system disorders may develop. Providing right antibiotic treatment may not always lead to complete remission or prevent neuropsychiatric complications. However, early diagnosis and clinical alertnessallow to administer right treatment and improve further prognosis.

Gastrointestinal diagnosis of classical Whipple disease: clinical, endoscopic, and histopathologic features in 191 patients.

Classic Whipple disease (CWD) is a systemic infection caused by Tropheryma whipplei. Different diagnostic tools have been developed over the last decades: periodic acid-Schiff (PAS) staining, T whipplei-specific polymerase chain reaction (PCR), and T whipplei-specific immunohistochemistry (IHC). Despite all these advances, CWD is still difficult to diagnose because of a variety of clinical symptoms and possibly a long time span between first unspecific symptoms and the full-blown clinical picture of the disease. Herein, we report an observational cohort study summarizing epidemiologic data, clinical manifestations, and diagnostic parameters of 191 patients with CWD collected at our institution. Gastrointestinal manifestations are the most characteristic symptoms of CWD affecting 76% of the cohort. Although the small bowel was macroscopically conspicuous in only 27% of cases, 173 (91%) patients presented with characteristic histological changes in small bowel biopsies (in 2 patients, these changes were only seen within the ileum). However, 18 patients displayed normal small bowel histology without typical PAS staining. In 9 of these patients, alternative test were positive from their duodenal specimens (ie, T whipplei-specific PCR and/or IHC). Thus, in 182 patients (95%) a diagnostic hint toward CWD was obtained from small bowel biopsies. Only 9 patients (5%) were diagnosed solely based on positive T whipplei-specific PCR and/or IHC of extraintestinal fluids (eg, cerebrospinal fluid, synovial fluid) or extraintestinal tissue (eg, lymph node, synovial tissue), respectively. Thus, despite efforts to diagnose CWD from alternative specimens, gastroscopy with duodenal biopsy and subsequent histological and molecular-biological examination is the most reliable diagnostic tool for CWD.

Magnetic resonance imaging of Whipple's disease confined to the CNS presenting with multiple intracerebral mass lesions.

We report a patient diagnosed with Whipple's disease (WD) who presented only with neurological symptoms. Neuroimaging (MRI) showed lesions with marked mass effect similar to infiltrative tumors, which were hypersignal on long TR and hyposignal on short TR images, located in several areas of the brain. In serial controls, lesions resolved with gliosis and atrophic changes as well as migration of active infiltrative-like lesions to new areas. MR findings of the brain WD are discussed, which confirmed by stereotactic brain biopsy. Familiarity with the range of possible MR imaging appearances of WD enables the radiologist to place WD more effectively on the differential diagnosis which motivates the clinician to consider both the diagnosis and early initiation of treatment; so, this may significantly impact outcome. Moreover, repeated MR investigations may serve as a valuable method to evaluate efficacy of treatment and long term follow-up of WD involving the CNS.

Are prevalent self-reported cardiovascular disorders associated with delayed recovery from whiplash-associated disorders: a population-based cohort study.

OBJECTIVES: The aim of this cohort study was to investigate the association between self-reported cardiovascular disorders (CVD) and recovery from whiplash-associated disorder (WAD) after a traffic collision. MATERIALS AND METHODS: This study was based on the Saskatchewan Government Insurance cohort, including individuals over 18 years of age, who made a traffic-injury claim or received health care after a traffic injury, between 1997 and 1999. Participants completed a baseline questionnaire and were followed up by telephone interviews at 6 weeks, 3 months, 6 months, 9 months, and 12 months after injury. Our sample includes a subcohort of 6011 participants who reported WAD (defined as answering "yes" to the question "Did the accident cause neck or shoulder pain") at baseline. The outcome, self-perceived recovery, was measured at all follow-up interviews. The presence of CVD and its effect on health was classified into 3 exposure categories: (1) CVD absent, (2) CVD present with no or mild effect on health, and (3) CVD present with moderate or severe effect on health. The association between CVD and recovery from WAD was assessed with Cox regression, and adjusted for potential confounders. RESULTS: We found a crude association between comorbid CVD with moderate or severe effect on health in women. However, the adjusted association was weak and potentially affected by residual confounding. We found no association in men. DISCUSSION: Our results suggest that CVD does not have an impact on the recovery of individuals with WAD.

Common subclinical hypothyroidism during Whipple's disease.

BACKGROUND: Classic Whipple's disease is caused by T. whipplei and likely involves genetic predispositions, such as the HLA alleles DRB1*13 and DQB1*06, that are more frequently observed in patients. T. whipplei carriage occurs in 2-4% of the general population in France. Subclinical hypothyroidism, characterized by high levels of TSH and normal free tetra-iodothyronine (fT4) dosage, has been rarely associated with specific HLA factors. METHODS: We retrospectively tested TSHus in 80 patients and 42 carriers. In cases of dysthyroidism, we tested the levels of free-T4 and anti-thyroid antibodies, and the HLA genotypes were also determined for seven to eight patients. RESULTS: In this study, 72-74% of patients and carriers were male, and among the 80 patients, 14 (17%) individuals had a high level of TSH, whereas none of the carriers did (p<0. 01). In the 14 patients with no clinical manifestations, the T4 levels were normal, and no specific antibodies were present. Four patients treated with antibiotics, without thyroxine supplementation, showed normal levels of TSHus after one or two years. One patient displayed a second episode of subclinical hypothyroidism during a Whipple's disease relapse five years later, but the subclinical hypothyroidism regressed after antibiotic treatment. HLA typing revealed nine alleles that appeared more frequently in patients than in the control cohort, but none of these differences reached significance due to the small size of the patient group. CONCLUSION: Regardless of the substratum, classic Whipple's disease could lead to subclinical hypothyroidism. We recommend systematically testing the TSH levels in patients with Whipple's disease.

Postural stability in subjects with whiplash injury symptoms: results of a pilot study.

CONCLUSIONS: Posturographic tests can be used to assess and confirm the body's imbalance in subjects with whiplash injury. Further studies with larger cohorts are necessary to confirm this pilot study. OBJECTIVES: To verify through a posturographic exam the qualitative and quantitative alterations of postural stability in subjects with previous cervical trauma in comparison with healthy subjects. METHODS: A total of 42 subjects were analysed for the study; 22 as the control group (NM) and 20 (WM) with a positive anamnesis of whiplash injury from 3 to 12 month from diagnosis through a force platform. Centre of pressure (CoP) movements of the two groups with their eyes open and closed were recorded. RESULTS: During the closed eye test, the subjects with cervical injuries displayed a significant increase in the anterior-posterior oscillation velocity (p < 0.05) compared with the control group, with a significant reduction (p < 0.01) of the ratio between the shifting length (SL) of CoP on the polygon support and the total envelope area (EA, mm(2)) of CoP movements in the polygon support (SL/EA-ratio, mm(-1)).

Tropheryma whipplei and Whipple's disease.

Since its identification, information concerning Tropheryma whipplei, the causative agent of Whipple's disease (WD), has increased. Although T. whipplei is commonly infecting humans, WD is rare. The bacterium is most likely transmitted among humans via the oro-oral and the feco-oral routes. Infections result in chronic conditions such as asymptomatic carriage, disseminated Whipple's disease, which is usually preceded by arthralgias, and localized infections, such as endocarditis or encephalitis. T. whipplei is associated with acute infections including gastroenteritis, pneumonia, and/or bacteremia. Screening, based on the combined analyses of saliva and stool specimens using specific quantitative PCR, is useful if WD is suspected. Doxycycline and hydroxychloroquine for 12 months is the best treatment for WD; it should be followed by life-long treatment with doxycycline, as potentially fatal relapses can occur. T. whipplei seems to be an opportunistic bacterium that causes chronic infections in susceptible patients with as yet unknown predisposing factors.

[Whipple's disease in a patient with infantile cerebral palsy and hepatitis B virus cirrhosis].

The paper describes a patient who has developed Whipple's disease in the presence of infantile cerebral palsy and hepatitis B virus cirrhosis. After 5-year treatment with co-trimoxazole (480 mg b.i.d.), the clinical manifestations subsided and PAS-positive macrophages were no longer detectable in the small intestinal mucosal biopsy specimens. Subsequent worsening of the patient's condition was associated with the progression of liver cirrhosis.

Evaluation of arginine metabolism for the analysis of M1/M2 macrophage activation in human clinical specimens.

BACKGROUND: Macrophage heterogeneity reflects their plasticity in response to environmental stimuli. Usually human macrophages are characterized by analysis of surface molecules or cytokine expression while functional assays are established in the mouse system but lacking for various human specimens. METHODS: To evaluate the value of analysis of arginine metabolism for characterization of human macrophage differentiation, we analyzed nitrite production and arginase activity in plasma, duodenal biopsies, and in vitro differentiated macrophages of patients with classical Whipple's disease. RESULTS: We demonstrate that it is feasible to determine the content of urea in supernatants of stimulated duodenal biopsies, arginase activity in fresh duodenal biopsies and plasma samples, and arginase activity and nitrite production in lysates and supernatants of in vitro differentiated macrophages. However, only selected tests are appropriate to define macrophage polarization in human specimens. CONCLUSION: Analysis of arginine metabolism is not suitable for the characterization of in vitro differentiated human macrophages. Besides the measurement of nitrite in duodenal biopsy supernatants, the determination of arginase activity in human plasma seems to be a reasonable functional test to detect enhanced M2 macrophage activation and, thus, is of great value for the analysis of macrophage activity with a minimum of material and costs.

Whipple's disease.

This article reviews the microbiology, pathophysiology, epidemiology, clinical manifestations, diagnostic testing, and treatment of Whipple's disease, an illness caused by Tropheryma whipplei and characterized by multivariate clinical manifestations including an inflammatory arthropathy. Diagnosis is confirmed by tissue sampling with periodic acid-Schiff staining and/or polymerase chain reaction. Clinical manifestations most frequently manifest in the gastrointestinal tract, musculoskeletal system, neurologic system, heart, and eyes, but can affect any site. Successful therapy with appropriate antibiotics is potentially curable, but recurrences may occur.

Whipple's disease-associated pulmonary hypertension with positive vasodilator response despite severe hemodynamic derangements.

Pulmonary hypertension (PH) associated with Whipple's disease (WD-PH) is extremely rare, and the underlying pathophysiological processes are incompletely understood. Alterations in hemodynamics can be severe, with right ventricular (RV) dysfunction being common. A case involving a 23-year-old man with WD-PH who exhibited a dramatic vasodilator response during right heart catheterization despite severely altered pulmonary hemodynamics and concomitant RV dysfunction is reported. While the patient's symptoms responded poorly to treatment with nifedipine and sildenafil, significant improvement in dyspnea, RV dysfunction and pulmonary pressures were noted following antibiotic therapy. The present report highlights that despite severely elevated pulmonary artery pressures and RV dysfunction in WD-PH patients, a highly significant vasodilator response and dramatic improvement with antibiotic therapy may be observed. Furthermore, the case highlights the phenomenon of PH in the setting of inflammation, suggesting that adequate control of the inflammatory response can be accompanied by a marked improvement in hemodynamics in certain types of PH.

Whipple's disease.

A 74 year old male patient with weight loss, diarrohea, loss of appetite, anemia, thrombocytopenia and culture negative endocarditis was diagnosed to have Whipple's disease. We are reporting this case, as it is a rare disease with fewer than 1000 validated cases reported in literature.

The amnesic syndrome of primary Whipple disease of the brain.

OBJECTIVE: To describe a case of primary Whipple disease (WD) of the brain, which may manifest as an amnesic syndrome. MATERIALS AND METHODS: A 46-year-old woman developed primary WD of the brain. The onset was characterized by a short-term amnesic syndrome for several months before the onset of generalized tonic-clonic seizures. Her amnesia was stable throughout her illness. RESULTS: Our patient had impairment of verbal and visual memory tasks with reduced learning. Her amnesic syndrome was secondary to asymmetric bilateral hippocampal atrophy with gliosis involving the mesial temporal structures-all secondary to primary WD of the brain. CONCLUSIONS: WD may present as an amnesic syndrome and needs to be thought of as a treatable cause of cognitive dysfunction in young adults.

Enfermedad de Whipple: una infrecuente causa bacteriana de demencia / Whipple’s Disease: an uncommon cause of dementia

Presentamos un caso de demencia diagnosticada como Alzheimer, cuya evolución condujo al diagnóstico final de una enfermedad de Whipple cerebral (AU)

We present a dementia case, diagnosed as Alzheimer type. Nevertheless, the final diagnosis of Whipple’s disease was delayed (AU)