Novel Patterns in High-Resolution Computed Tomography in Whipple Pneumonia.

With the use of metagenomic next-generation sequencing, patients diagnosed with Whipple pneumonia are being increasingly correctly diagnosed. We report a series of 3 cases in China that showed a novel pattern of movable infiltrates and upper lung micronodules. After treatment, the 3 patients recovered, and lung infiltrates resolved.

Susceptibility of nucleotide-binding oligomerization domain 2 mutations to Whipple's disease.

OBJECTIVES: Whipple's disease (WD) results from infection of the bacteria Tropheryma whipplei (TW). This disease is characterized by macrophage infiltration of intestinal mucosa and primarily affects Caucasian males. Genetic studies of host susceptibility are scarce. Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is an innate immune sensor, resides mainly in monocytes/macrophages and contributes to defense against infection and inflammatory regulation. NOD2 mutations are associated with autoinflammatory diseases. We report the association of NOD2 mutations with TW and WD for the first time. METHODS: A multicenter, retrospective study of three patients with WD was conducted. Patients received extensive multidisciplinary evaluations and were cared for by the authors. NOD2 and its association with infection and inflammation were schematically represented. RESULTS: All patients were Caucasian men and presented with years of autoinflammatory phenotypes, including recurrent fever, rash, inflammatory arthritis, gastrointestinal symptoms, and elevated inflammatory markers. All patients underwent molecular testing using a gene panel for periodic fever syndromes and were identified to carry NOD2 mutations associated with NOD2-associated autoinflammatory disease. Despite initially negative gastrointestinal evaluations, repeat endoscopy with duodenal tissue biopsy ultimately confirmed WD. After initial ceftriaxone and maintenance with doxycycline and/or hydroxychloroquine, symptoms were largely controlled, though mild relapses occurred in follow up. CONCLUSION: Both NOD2 and TW/WD are intensively involved in monocytes/macrophages. WD is regarded as a macrophage disease. NOD2 leucin rich repeat-associated mutations in monocytes/macrophages cause functional impairment of these cells and consequently may make the host susceptible for TW infection and WD, especially in the setting of immunosuppression.

The spectrum of central nervous system involvement in Whipple's disease.

BACKGROUND AND PURPOSE: To assess the clinical spectrum of central nervous system (CNS) involvement as well as cerebrospinal fluid (CSF) and neuroimaging findings in patients with Whipple's disease (WD) and to analyze the association of neurological symptoms with CSF and imaging findings. METHODS: Neurological involvement was retrospectively analyzed in a series of 36 patients diagnosed with WD at a single center between 1992 and 2019. Findings of 81 comprehensive CSF examinations from 36 patients, including polymerase chain reaction (PCR) tests for Tropheryma whipplei (TW) in CSF from 35 patients, were systematically evaluated. The prevalence of ischemic stroke in patients with WD was compared to a matched control cohort. RESULTS: Neurological symptoms occurred in 23 of 36 (63.9%) patients, with cognitive, motor, and oculomotor dysfunction being most frequent. TW was detected by PCR in CSF of 13 of 22 (59.1%) patients with and four of 13 (30.8%, p = 0.0496) patients without neurological symptoms. Total CSF protein (p = 0.044) and lactate (p = 0.035) were moderately elevated in WD with neurologic symptoms compared with WD without. No intrathecal immunoglobulin synthesis was observed. Three of 36 (8.3%) patients had hydrocephalus due to aqueductal stenosis. Patients with WD had an unexpectedly high prevalence of ischemic stroke (10/36, 27.7%) compared to matched controls (10/360, 3.2%). CONCLUSIONS: Neurological involvement in patients with WD is common. Detection of TW DNA in CSF is only partly associated with neurological symptoms. Elevated CSF parameters suggest CNS parenchymal infection. Stroke is a hitherto underrecognized manifestation of WD. These findings suggest that mechanisms beyond CNS infection contribute to the spectrum of CNS involvement in WD.

Whipple's disease presenting as weight gain and constipation in a Chinese woman.

BACKGROUND: Whipple's disease is a chronic infection due to Tropheryma whipplei, commonly reported in the Caucasian but not in the Chinese population. CASE PRESENTATION: A 52-year-old female with good past health, was diagnosed with Whipple's disease, presenting with constipation, unintentional weight gain, and fleeting polyarthralgia. Investigations prior to admission showed raised CA125 and computed tomography of the abdomen showed multiple retroperitoneal mesenteric lymphadenopathies. Extensive investigations performed on secondary causes of weight gain were unrevealing. Subsequent PET-CT scan revealed generalized lymphadenopathy involving the left deep cervical, supraclavicular, and retroperitoneal mesenteric area. Excisional biopsy of the left supraclavicular lymph node was performed, with histology showing infiltrations of Periodic acid-Schiff positive foamy macrophages. T. whipplei DNA was detected in her serum, saliva, stool, and lymph node by PCR targeting the 16S ribosomal RNA gene. She was started on intravenous ceftriaxone, and then stepped down to oral antibiotics for a total of 44 months. The recurrence of fever after 12 days of ceftriaxone raised the suspicion of Immune Reconstitution Inflammatory Syndrome (IRIS). Serial imaging showed a gradual reduction in the size of retroperitoneal lymphadenopathies. Literature review on Whipple's disease in the Chinese population identified 13 reports of detectable T. whipplei DNA in clinical specimens. The majority of the cases were pneumonia, followed by culture-negative endocarditis, encephalitis, and skin and soft tissue infection. However, most patients with pneumonia were diagnosed based on next generation sequencing alone, with the resolution of pulmonary infiltrates without adequate duration of antibiotics, suggesting the possibility of colonization instead of infection. The recommendation of long-term doxycycline suppression after treatment may be supported by the slow response of retroperitoneal lymphadenopathies to antibiotics in our patient. CONCLUSIONS: Unintentional weight gain and constipation could be atypical presentations of Whipple's disease. It is a rare disease in the Chinese population despite the advancement of molecular techniques in the diagnosis of infections. A prolonged course of antibiotics may be required due to slow clinical response as documented by serial imaging in our case. The possibility of IRIS should be considered in patients with breakthrough fever during treatment of Whipple's disease.

An unusual presentation of a rare disease: acute upper limb ischemia as the presenting symptom of Whipple's Endocarditis, a case report.

BACKGROUND: Whipple's disease is known to cause multiple varied systemic symptoms, and is a well-documented cause of culture-negative endocarditis. Endocarditis secondary to Whipple disease, however, has rarely been known to present primarily as a cause of acute limb ischemia. We describe such a case here. CASE PRESENTATION: A previously healthy 40 year old man presented to the emergency department with acute-onset right arm paresthesias. On exam, he was found to be tachycardic with a VI/VI systolic ejection murmur. He was diagnosed with critical limb ischemia and severe aortic regurgitation, and echocardiography showed a large mass on his bicuspid aortic valve. Thrombectomy was performed urgently, with aortic valve repair the following day. As blood cultures and valvular tissue culture remained unrevealing, the patient remained on empiric vancomycin and ceftriaxone for culture-negative endocarditis. 16 s rRNA nucleic acid amplification testing (NAAT) of his formalin-fixed, paraffin-embedded valvular tissue detected T. whipplei, after which the patient was transitioned to ceftriaxone and trimethoprim-sulfamethoxazole for a year of therapy. He continues to do clinically well. CONCLUSIONS: We report an unusual presentation of Whipple endocarditis as an acute upper limb ischemia, absent other classic symptoms of Whipple's disease, and with diagnosis made by 16 s rRNA NAAT of valvular tissue in the setting of culture-negative endocarditis.

Uptake of Tropheryma whipplei by Intestinal Epithelia.

BACKGROUND: Tropheryma whipplei (TW) can cause different pathologies, e.g., Whipple's disease and transient gastroenteritis. The mechanism by which the bacteria pass the intestinal epithelial barrier, and the mechanism of TW-induced gastroenteritis are currently unknown. METHODS: Using ex vivo disease models comprising human duodenal mucosa exposed to TW in Ussing chambers, various intestinal epithelial cell (IEC) cultures exposed to TW and a macrophage/IEC coculture model served to characterize endocytic uptake mechanisms and barrier function. RESULTS: TW exposed ex vivo to human small intestinal mucosae is capable of autonomously entering IECs, thereby invading the mucosa. Using dominant-negative mutants, TW uptake was shown to be dynamin- and caveolin-dependent but independent of clathrin-mediated endocytosis. Complementary inhibitor experiments suggested a role for the activation of the Ras/Rac1 pathway and actin polymerization. TW-invaded IECs underwent apoptosis, thereby causing an epithelial barrier defect, and were subsequently subject to phagocytosis by macrophages. CONCLUSIONS: TW enters epithelia via an actin-, dynamin-, caveolin-, and Ras-Rac1-dependent endocytosis mechanism and consecutively causes IEC apoptosis primarily in IECs invaded by multiple TW bacteria. This results in a barrier leak. Moreover, we propose that TW-packed IECs can be subject to phagocytic uptake by macrophages, thereby opening a potential entry point of TW into intestinal macrophages.

[Chronic Tropheryma whipplei infection: an important differential diagnosis of refractory polyarthritis]. / Chronische Tropheryma-whipplei-Infektion: Eine wichtige Differentialdiagnose der therapierefraktären Polyarthritis.

BACKGROUND: Refractory arthritis is a common problem in routine rheumatology practice, and can be a diagnostic challenge. In these cases, chronic Tropheryma whipplei (T. whipplei) infection is an important differential diagnosis that should be considered. OBJECTIVE: Based on five clinical cases, this case-based review describes the diagnostic and therapeutic principles in the management of chronic T. whipplei infection. RESULTS: Whipple's disease is a multisystemic infectious disease caused by the bacterium T. whipplei. The disease typically manifests with arthralgia, weight loss and diarrhoea. Joint involvement often develops years before gastrointestinal symptoms occur. In addition to systemic manifestations ("classic Whipple's disease"), T. whipplei can also lead to localized joint infections without gastrointestinal involvement. Articular manifestations of systemic and localized T. whipplei infections are commonly misdiagnosed as a sign of various forms of autoimmmune arthritis. DISCUSSION: Whipple's disease and localized T. whipplei joint infection should be considered in the diagnostic work-up of refractory arthritis. Synovial fluid analysis by means of specific polymerase chain reaction-based testing for T. whipplei is diagnostically ground-breaking.

Subcutaneous Nodules Caused by Tropheryma whipplei Infection.

To help clarify the clinical manifestations, diagnosis, and treatment for Whipple disease, we report a case of a man in China infected with Tropheryma whipplei. The patient had multiple subcutaneous nodules as the only manifestation, which was not consistent with the typical symptoms of T. whipplei infection.

Tropheryma whipplei in the stool samples of children with acute diarrhea: a study from Tehran, Iran.

BACKGROUND: Recently, Tropheryma whipplei has been suggested as one of the causative agents of diarrhea among children worldwide. Limited data is available on the prevalence of T. whipplei among children with diarrhea in most countries such as Iran. This study was conducted to evaluate the prevalence of T. whipplei in children with acute diarrhea in Iran. METHODS: In this study, the stool samples were collected from 130 children under 10 years old with acute diarrhea from children's hospitals in Tehran city. Genomic DNA was extracted from stool samples and was tested for the presence of DNA of T. whipplei using the SYBR Green Real-time PCR method. Positive T. whipplei samples were finally confirmed by PCR Product sequencing. RESULTS: The mean age of participants was 32.5 months, and 54.6% of children were female. Using the SYBR Green Real-time PCR, 9.23% (12/130) of samples were positive for T. whipplei, which were confirmed by sequencing. 66.67% of positive cases were males. The duration of diarrhea in infected children with T. whipplei (83.3%) was significantly longer (OR: 5.93, 95% CI 1.24-28.22) compared to children with negative results (45.8%). Other demographic factors and clinical signs had not a statistically significant relationship with T. whipplei infection. CONCLUSIONS: In this study, T. whipplei was detected in stool samples of children with acute diarrhea. The results indicated that T. whipplei could be associated with childhood diarrhea in Iran. The health care system and physicians should be aware of the presence of T. whipplei infection in Iran, especially in childhood diarrhea.

Rapidly progressive dementia and intractable diarrhea: a teaching case report and a systematic review of cognitive impairment in Whipple's disease.

OBJECTIVE: Whipple's disease (WD) is a systemic, chronic, relapsing disease caused by Tropheryma whipplei, which can mimic signs and symptoms of various clinical entities. Typical manifestations are represented by gastrointestinal and systemic symptoms, among which neurological ones are frequent. We present the case of a patient with WD and rapidly progressive cognitive impairment and a review of literature aimed to report epidemiological, clinical, neuroimaging, and laboratory findings of cognitive impairment associated with WD. METHODS: A systematic review of medical literature published until November 22, 2020, was performed. Full-text, peer-reviewed case reports and series in English language presenting patients with WD and cognitive impairment were included. Data concerning demographic, clinical, neuroimaging, and laboratory characteristics were collected and synthesized qualitatively. RESULTS: The patient was a 54-year-old male who developed rapidly progressive dementia, fluctuating arousal disturbances, and supranuclear ophthalmoparesis associated with chronic diarrhea and fever spikes. T. whipplei was detected in the cerebrospinal fluid, and appropriate antimicrobial therapy was given with progressive clinical benefit. The systematic review of 114 case reports/series identified 147 patients with WD and cognitive impairment; this latter was rarely isolated. Neurological symptoms associated with cognitive decline were psychiatric disturbances, supranuclear ophthalmoplegia, hypothalamic involvement, and consciousness disorders. Brain imaging and cerebrospinal fluid findings were heterogeneous and nonspecific. CONCLUSIONS: Cognitive impairment represents one of the most common neurological features associated with WD. The clinical suspicion of this disease in patients with rapidly progressive dementia is crucial to guide diagnostic strategies and proper antimicrobial therapy, which may revert the clinical deterioration.

Whipple's disease orbitopathy: case report and review of literature.

A 59-year-old female patient was diagnosed with Whipple's disease (WD) after several months of constitutional complaints and adenopathies that were initially misinterpreted as sarcoidosis. Initial treatment included doxycycline, hydroxychloroquine and prednisolone, which was suspended due to long-term clinical stability. Four months after prednisolone suspension, the patient presented with right periorbital oedema and erythema. Ophthalmological examination revealed restricted eye movements. A computed tomography (CT) scan demonstrated signs of myositis. The patient was treated with anti-inflammatory and antibiotic drugs, that induced remission of the orbitopathy. During the following two years, she presented three relapses, affecting both the right or the left eyes. The last episode was also associated with systemic corticosteroid tapering. Orbitopathy is a rare form of WD presentation and the diagnosis of this condition may be challenging. As the clinical spectrum may range from an incidentaloma to a severe compressive neuropathy, proper recognition and management of WD orbitopathy is essential.

Tropheryma whipplei in Feces of Patients with Diarrhea in 3 Locations on Different Continents.

We examined fecal specimens of patients with diarrhea from 3 continents for Tropheryma whipplei and enteropathogens. T. whipplei was most common in South Africa, followed by Singapore and Germany. Its presence was associated with the presence of other pathogens. An independent causative role in diarrhea appears unlikely.

Phenotypic diversity of Tropheryma whipplei clinical isolates.

Tropheryma whipplei is a bacterial pathogen responsible for a wide range of infections in humans, covering asymptomatic carriage, acute infections, chronic isolated infections and classic Whipple's disease. Although the bacterium is commonly found in the environment, it very rarely causes disease. Genetic comparison of clinical isolates has revealed that main variations were found in region encoding T. whipplei surface glycoproteins called WiSP. However, no association has been made between the genetic diversity and the clinical manifestations of the infection. In this study we evaluated the phenotypic diversity of 26 clinical isolates from different origins and taken from patient with different infection outcomes. MRC5 and macrophages cells were infected, and bacterial uptake, survival and the pro-and anti-inflammatory potential of the different clinical isolates was assessed. No significant difference of phagocytosis was found between the different isolates; however, we found that bacterial replication was increased for bacteria expressing high molecular weight WiSP. In addition, we found that the expression of the genes coding for IL-1ß and TGF-ß was significantly higher when MRC5 cells were stimulated with isolates from chronic infections compared to isolates from localized infections while no significant differences were observed in macrophages. Overall, our study revealed that, as previously observed at the genetic level, phenotypic diversity of T. whipplei isolates is associated with the expression of different WiSP, which may result in subtle differences in host responses. Other host factors or genetic predisposition may explain the range of clinical manifestations of T. whipplei infections.

Whipple's disease: the great masquerader-a high level of suspicion is the key to diagnosis.

BACKGROUND: Whipple's disease is a chronic infectious disease that primarily affects the small intestine, but several organs can simultaneously be involved. The disease is caused by a gram-positive bacterium called Tropheryma whipplei. The disease is difficult to suspect because it is rare with unspecific and long-term symptoms; it can be lethal if not properly treated. CASE PRESENTATION: We here present three patients who presented with a plethora of symptoms, mainly long-standing seronegative arthritis and gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy. They were after extensive investigations diagnosed with Whipple's disease, in two of them as long as 8 years after the first occurrence of joint manifestations. The diagnosis was made by PCR targeting the T. whipplei 16S rRNA gene from small bowel specimen in all three patients, and, besides from histopathologic findings from the duodenum and distal ileum in one and mesenteric lymph nodes in another patient. CONCLUSIONS: This report aims to raise awareness of a very rare disease that presents with a combination of symptoms mimicking other and significantly more common diseases.

[A 3-week history of intestinal symptoms in a 67-year-old male patient with chronic arthralgia]. / Seit 3 Wochen bestehende intestinale Beschwerden bei einem 67-jährigen Patienten mit chronischen Arthralgien.

Whipple disease is an infection caused by the bacterium Tropheryma whipplei. Due to its unspecific clinical symptoms, it is difficult to diagnose and often remains undetected for a long time. The case of a patient who presented with acute intestinal symptoms to the authors' department is reported. The diagnosis of classic Whipple disease was established. The symptoms subsided under antibiotic therapy. Complications in the form of immune reconstitution inflammatory syndrome (IRIS) occurred, requiring immunosuppressive treatment.

Whipple disease - systemic disease with gastrointestinal manifestations.

Whipple disease is rare, potentionally life-threatening disease with broad scale of possible symptoms and therefore wide differential diagnosis. Localized forms as well as systemic manifestations are possible. Etiological agent is bacteria Tropheryma whipplei. The most common manifestations include arthralgias, fever, diarrhea, abdominal pain, malabsorption syndrome and weight loss. In my article I present literature review and a case report of the pacient with relatively typical course of the disease.

Clinical manifestations of Whipple's disease mimicking rheumatic disorders.

Whipple's disease is a rare, chronic, systemic disorder caused by Tropheryma whipplei infection. The most common symptoms are weight loss, arthralgia, diarrhea and abdominal pain. Other organ involvement can also occur in the patients. Joint manifestations may mimic rheumatoid arthritis or spondyloarthritis. Arthalgia, arthritis, spondylodiscitis, bursitis and/or tenosynovitis are seen in the majority of the patients. This explains why some of the symptoms are misdiagnosed as those of rheumatic diseases. Understanding of Whipple's disease is important for differential diagnostics of several rheumatic symptoms.

Whipple disease diagnosed by enteroscopy: first case report in Colombia of an underdiagnosed disease and literature review.

BACKGROUND: Whipple's disease is a rare systemic disease caused by a gram-positive bacillus called Tropheryma whipplei. First described in 1907 as an intestinal lipodystrophy with histological finding of vacuoles in the macrophages of the intestinal mucous. Usually the symptoms are localized according to the compromised organ. The differential diagnosis is wide. It can be fatal without proper treatment. Recurrence can occur in up to 33% of the cases and usually compromises the neurological system. CASE PRESENTATION: This article reports the case of a 46-year-old female patient with a history of a 6-month hypochromic microcytic anemia of unknown cause. She consulted for a 6-months oppressive abdominal pain located in the mesogastrium as well as abdominal distention associated with nausea and liquid stools; in addition, she had an 8-month small and medium joint pain, without edema or erythema. Physical examination without relevant findings. Multiple esophagogastroduodenoscopies with normal gastric and duodenal biopsies findings and a normal colonoscopy were performed. Endoscope capsule showed red spots in the duodenum and ulcerations in the jejunum and proximal ileum covered by fibrin; histological report showed macrophages with positive periodic acid-schiff reaction staining (PAS staining), disgnosing Whipple's disease. Antibiotics were initiated. The patient is currently in the second phase of treatment without gastrointestinal and joint symptoms. CONCLUSION: This is the first case reported in Colombia. It is a rare entity and difficult to diagnose reason why it is important to continue with clinical investigations to give more clarity about the onset and appropriate diagnose to avoid the delay in treatment of this entity.

Thrombocytopenia and endocarditis in a patient with Whipple's disease: case report.

BACKGROUND: Whipple's disease (WD) is a rare multisystem infectious disorder that is caused by the actinomycete Tropheryma whipplei. It presents with joint pain followed by abdominal pain, diarrhea, malabsorption and finally failure to thrive. Diagnosis requires tissue sampling and histology with periodic acid-Schiff [PAS] staining. Thrombocytopenia associated with endocarditis associated with WD has been reported twice. CASE PRESENTATION: A 56 year old Caucasian male presented with years of steroid treated joint pain and recent onset diarrhea, weight loss and abdominal pain. Ultimately he was found to have a platelet count of 4000 with concomitant endocarditis and embolic stroke. Small bowel biopsy confirmed the diagnosis of WD approximately 1 year after his first visit. His platelets improved with antibiotic treatment but he eventually expired 16 months after his initial consult and 5 months after his definitive diagnosis. CONCLUSION: WD can remain undiagnosed and untreated until late in the course of the illness. A high index of suspicion is recognized as necessary for early diagnosis to begin treatment. Critical thrombocytopenia associated with endocarditis is a rare and potentially poor prognostic sign in late stage Whipple's disease.

Whipple's disease scleral nodules: a novel presentation in 2 consecutive patients.

BACKGROUND: Whipple's disease (WD) is a rare, chronic, infection caused by gram-positive filamentous aerobic actinobacterium Tropheryma whipplei occurs classically in the gastrointestinal tract and shows histopathologically foamy macrophages with typical numerous PAS-positive, non-acid fast particles. Ocular WD in the form of uveitis may occur in the absence of systemic disease but has not been reported to present with scleral manifestation. We describe for the first time to the best of our knowledge 2 cases of scleral nodules with typical histopathological morphology of WD and without systemic involvement. CASE PRESENTATION: The first was a 53-year old diabetic male farmer who presented with 2 nontender right eye scleral nodules for 3 months, had a negative systemic workup, and surgical excision showed Periodic acid Schiff (PAS)-positive eosinophilic structures inside macrophages. Grocott's methenamine silver (GMS) stain and acid-fast bacilli (AFB) stain of the tissue itself were negative. The second case was a 60-year old male who presented with an asymptomatic superior scleral nodule for 4 months, which showed similar appearance and negative GMS and AFB stains. CONCLUSION: WD should be included in the differential diagnosis of scleral nodules even in the absence of systemic symptoms. Surgical excision without systemic treatment resulted in successful outcome without recurrence.