Campylobacter Jejuni Enteritis Research Articles

Antecedent infections and vaccinations in chronic inflammatory demyelinating polyneuropathy: A European collaborative study.

Chronic inflammatory demyelinating polyneuropathy (CIDP) may be rarely preceded by infection. A causative link remains unproven, in contrast to Guillain-Barré syndrome (GBS), which is commonly postinfectious with well-demonstrated pathophysiological mechanisms of molecular mimicry following Campylobacter jejuni enteritis. Uncommonly, infections are reported before the onset of CIDP. In this study we aimed to determine the frequency and characteristics of CIDP occurring after antecedent infections or vaccinations in two large European cohorts. We reviewed the records of 268 subjects with "definite" or "probable" CIDP from the Inflammatory Neuropathy Clinic, Birmingham, UK (129 subjects), and from the Serbian national CIDP database (139 subjects). Twenty-five of 268 (9.3%) subjects had a respiratory or gastrointestinal infection in the 6 weeks preceding CIDP onset, and 3 of 268 (1.1%) had received an influenza vaccination. CIDP disease onset occurred at a younger age (mean [standard deviation], 44.25[17.36] years vs 54.05[15.19] years; P < .005) and acute-onset CIDP was more common (42.9% vs 12.1%; odds ratio, 5.46; 95% confidence interval, 2.35-12.68; P < .001) in subjects with preceding infections or vaccinations. No differences in CIDP subtype, rates of cerebrospinal fluid protein level elevation, disability, or likelihood of treatment response, were observed. Antecedent infections or vaccinations may precede about 10% of cases of CIDP and are more common in younger subjects. Acute-onset CIDP is more frequent after antecedent events. These findings may suggest specific pathophysiological mechanisms in such cases.

SY7.2. Electrophysiological features in GBS and CIDP

GBS is currently classified into axonal and demyelinating categories. Acute motor axonal neuropathy (AMAN), an axonal subtype of GBS, was widely recognized in the 1990s. Whereas in Europe and North America, acute inflammatory demyelinating polyneuropathy (AIDP) is considered the major subtype of GBS, in East Asia, and Central and South America, AMAN is found for 30–80% of GBS cases. Over the past 20 years, major advances have been made in understanding the immunopathogenesis and pathophysiology of AMAN. Clinically, AMAN is characterized by pure motor involvement, frequent antecedent Campylobacter jejuni enteritis, and serum anti-ganglioside antibodies. Electrophysiological studies frequently reveal, as well as axonal degeneration, rapidly reversible nerve conduction block/slowing (resolved within days to a few weeks); the time-course suggests functional or microstructural changes at the nodes of Ranvier. It is now established that disrupted nodal sodium channel clusters, and paranodal myelin detachment is responsible for conduction block in AMAN. CIDP is currently classified into “typical CIDP” and other variants such as “multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)”. Typical CIDP is a classic form, clinically characterized by symmetric proximal and distal muscle weakness and motor- dominant manifestation. In typical CIDP, demyelination predominantly affects the distal nerve terminals and nerve roots, presumably because of the lack of the blood-nerve barrier in these regions, and this could be responsible for the “non-nerve length-dependent” distribution of muscle weakness. These findings suggest an importance of humoral immunity in typical CIDP. In contrast, MADSAM is characterized by multifocal demyelination in the intermediate nerve trunks. In MADSAM neuropathy, cellular immunity may be predominantly involved in breakdown of the blood-nerve barrier at the site of conduction block. Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. The understanding of the pathophysiology of each CIDP subtype is important for appropriate immune treatments.

Understanding hyper-reflexia in acute motor axonal neuropathy (AMAN)

Hyper-reflexia is occasionally seen in acute motor axonal neuropathy (AMAN), but its pathophysiology is unclear. We report a patient with AMAN following Campylobacter jejuni enteritis, who showed generalized hyper-reflexia, bilateral Hoffmann sign and right Babinski sign. MRI and transcranial magnetic stimulation of the motor cortex disclosed no corticospinal tract involvement. An extensive electrophysiological investigation documented α-motoneuron hyperexcitability and dysfunction of the interneuronal inhibitory circuits in the spinal anterior horn. We propose an immune-mediated damage of the spinal inhibitory interneuronal network as possible mechanism inducing hyper-reflexia in AMAN.

Cytopenia in Campylobacter jejuni Enteritis Patients

Campylobacter jejuni (C. jejuni) enteritis is generally self-limited, but occasionally triggers extraintestinal associated sequelae. We examined whether cytopenia is associated with C. jejuni enteritis. A retrospective case-controlled study of C. jejuni and Escherichia coli (E. coli) enteritis patients, who were microbiologically confirmed in our hospital from February 2006 to October 2017, was conducted. Leukocytopenia and thrombocytopenia were defined as statuses less than 4.0 × 109/L and 130 × 109/L during their clinical courses, respectively. Clinical and microbiological data were collected. Risk factors for cytopenia were assessed by a multivariate analysis. The two eligible cohorts comprised 138 C. jejuni (71 inpatients) and 35 E. coli (34 inpatients) enteritis patients. The prevalence of leukocytopenia or thrombocytopenia in the C. jejuni patients was 7.9% (11/138) and 5.0% (7/138), and that in the E. coli patients was 0% (0/35) and 5.7% (2/35), respectively. Leukocytopenia was more prevalent in the C. jejuni enteritis inpatients than in the E. coli inpatients, but there were no significant differences in thrombocytopenia in both cohorts. The mean minimum leukocyte values were determined after an average of three admission days in the C. jejuni inpatients. The elevations of C-reactive protein and creatinine were risk factors for thrombocytopenia and leukocytopenia, respectively. Hemophagocytosis was detected in a C. jejuni enteritis patient with cytopenia. The present study suggested that leukocytopenia is a possible extraintestinal sequela in some C. jejuni enteritis patients. Hemophagocytosis should be considered as one of underlying mechanisms when cytopenia is found in these patients.

Distal limb weakness phenotype of Guillain-Barré syndrome

ObjectiveSeveral regional variants of Guillain-Barré syndrome (GBS) have been proposed in western countries, but other variants remain unclear, especially among mildly disabled cases. The aim of this study was to identify unvalidated GBS phenotypes among Japanese patients with mild GBS. MethodsRetrospective study of a cohort of patients at a University Hospital in Japan. ResultsAmong 107 GBS patients, 25 (23%) were classified as having mild GBS (GBS disability scale ≤ 2 at nadir). A review of mild cases identified 8 patients (7.5% of all GBS and 32% of mild GBS) with an unusual phenotype, namely a distal limb weakness form of GBS (DL-GBS), which showed limited distribution of limb weakness within hands and feet with preserved strength in proximal limb muscles. The patients with DL-GBS were characterized by mild-to-moderate weakness in distal parts of limbs especially fingers, lacking or mild sensory disturbance at distal limbs, sometimes hyperreflexia at legs, and having prior Campylobacter jejuni enteritis. Among the patients with GBS after C. jejuni enteritis, DL-GBS patients were characterized by frequent detection of anti-GM1 antibodies without anti-GD1a antibodies, whereas the others were often positive for the two antibodies. ConclusionsDL-GBS is a distinct regional phenotype of GBS, which should be differentiated from cervical myelopathy. It can be generally categorized as a mild type of GBS after C. jejuni enteritis, which has characteristic pattern of anti-ganglioside autoantibodies.

Anti-ganglioside Antibodies in Peripheral Nerve Pathology.

Anti-ganglioside antibodies are principally associated with autoimmune peripheral neuropathies. In these disorders, immune attack is inadvertently directed at peripheral nerve by autoantibodies that target glycan structures borne by glycolipids, particularly gangliosides concentrated in nerve myelin and axons. The most thoroughly studied disorder is the acute paralytic disease, Guillain-Barré syndrome (GBS) in which IgG autoantibodies against gangliosides arise following acute infections, notably Campylobacter jejuni enteritis. Additionally, chronic autoimmune neuropathies are associated with IgM antibodies directed against many glycolipids including gangliosides. This introductory chapter briefly summarizes the immunological and pathological features of these disorders, focusing on the methodological development of antibody measurement and of animal models.

Distal limb weakness variant of Guillain- Barré syndrome: A mild form of acute motor axonal neuropathy after Campylobacter jejuni enteritis

Background: Distal limb weakness of Guillain-Barré syndrome (DL-GBS) is a recently proposed reginal variant of GBS, which shows muscular weakness limitedly at distal limbs (wrists, hand, ankles, and toes) with preserved muscle power at proximal limbs (shoulders, elbows, hips, and/or knees) throughout the disease course.

Campylobacter jejuni-Induced Intussusception Recurrence Within a 30-hour Period

Intussusception represents the most common etiology for intestinal obstruction in early childhood. It represents telescoping of the small bowel potentially resulting in ischemia and perforation. It is recognized as potentially recurrent in up to 10% of cases. A mass lesion providing a lead point is a risk factor for recurrence. Symptoms include acute intermittent abdominal pain, and bloody stools. Campylobacter jejuni is a gram-negative bacterium that causes enteritis and is known to cause intussusception. However, there are no reported cases of Campylobacter causing recurrent intussusception within a 30 hr period. We report a previously healthy 2 year old male who presented with a 7 day history of diarrhea, fever, 3 day history of bloody stools, spasmodic abdominal pain, and 1 self-limited episode of rectal prolapse. He was seen on 3 occasions in an emergency department. At the first visit, he was sent home with a kit for stool study, as he was unable to produce a bowel movement. On final return, an abdominal ultrasound reported short segment intussusception in the right lower quadrant. He developed recurrent ileocolic intussusception (3 recurrences total within 30 hours). All 3 episodes were successfully reduced via barostatic enema. For suspected lead point, he underwent exploratory laparoscopy; none was identified. After exploratory laparoscopy, his parent developed bloody stools prompting stool studies from our patient for investigation of infectious etiologies which were positive for Campylobacter jejuni. He was treated with Azithromycin. Small bowel obstruction from intussusception can complicate several luminal processes resulting in bowel wall thickening or mass acting as a lead point. While infectious etiologies are a risk factor for intussusception, this is the first report of recurrent intussusception associated with Campylobacter jejuni enteritis. In this case, stool collection for studies was unsuccessful until his parent presented with similar symptoms. Despite there being no recommendations currently for stool studies in the evaluation of intussusception in society guidelines, the authors would speculate that stool studies for enteric pathogens should be routinely obtained in children presenting with intussusception and treated wherever identified, potentially impacting the risk of recurrence. Current treatment recommendations for complicated cases of bacterial enteritis secondary to Campylobacter jejuni include macrolide antibiotics.

Insights into Campylobacter jejuni colonization and enteritis using a novel infant rabbit model.

A lack of relevant disease models for Campylobacter jejuni has long been an obstacle to research into this common enteric pathogen. Here we used an infant rabbit to study C. jejuni infection, which enables us to define several previously unknown but key features of the organism. C. jejuni is capable of systemic invasion in the rabbit, and developed a diarrhea symptom that mimicked that observed in many human campylobacteriosis. The large intestine was the most consistently colonized site and produced intestinal inflammation, where specific cytokines were induced. Genes preferentially expressed during C. jejuni infection were screened, and acs, cj1385, cj0259 seem to be responsible for C. jejuni invasion. Our results demonstrates that the infant rabbit can be used as an alternative experimental model for the study of diarrheagenic Campylobacter species and will be useful in exploring the pathogenesis of other related pathogens.

Clinical Phenotypes in Guillain-Barré Syndrome

Guillain-Barré syndrome can be classified into several phenotypes according to the type of predominantly disturbed nerve fibers, distribution of muscular weakness, and electrophysiological and pathological findings. Although several regional variants including Fisher syndrome and pharyngeal-cervical-brachial weakness were initially reported in Western researchers, many labor-intensive studies by Japanese researchers have significantly contributed to defining and highlighting these variants. This review summarizes the several regional variants of Guillain-Barré syndrome while highlighting the substantial contributions made by Japanese investigators. Furthermore, a new regional variant named "distal limb weakness" is proposed, in which regional weakness of hands and feet is observed throughout the disease course. It is considered a mild phenotype of acute axonal motor neuropathy after Campylobacter jejuni enteritis.

Molecular Mimicry and Guillain-Barré Syndrome

One-thirds of patients develop Guillain-Barré syndrome subsequent to Campylobacter jejuni enteritis. Molecular mimicry exists between C. jejuni lipo-oligosaccharides and human peripheral nerve gangliosides GM1 and GD1a. IgG antibodies against GM1 or GD1a are produced in one out of 5,000 patients with C. jejuni enteritis. The autoantibodies bind to gangliosides at the nodes of Ranvier in the peripheral motor nerves and activate complement in situ. This is followed by the disappearance of the voltage-gated sodium channel clusters at the nodes and disruption of axo-glial junctions at the paranodes. This results in the development of motor nerve conduction failure and muscle weakness in the four limbs.

Association of Anti-GT1a Antibodies with an Outbreak of Guillain-Barré Syndrome and Analysis of Ganglioside Mimicry in an Associated Campylobacter jejuni Strain.

An outbreak of Guillain-Barré syndrome (GBS), subsequent to Campylobacter jejuni enteritis, occurred in China in 2007. Serum anti-ganglioside antibodies were measured in GBS patients and controls. Genome sequencing was used to determine the phylogenetic relationship among three C. jejuni strains from a patient with GBS (ICDCCJ07001), a patient with gastroenteritis (ICDCCJ07002) and a healthy carrier (ICDCCJ07004), which were all associated with the outbreak. The ganglioside-like structures of the lipo-oligosaccharides of these strains were determined by mass spectrometry. Seventeen (53%) of the GBS patients had anti-GT1a IgG antibodies. GT1a mimicry was found in the lipo-oligosaccharides of strain ICDCCJ07002 and ICDCCJ07004; but a combination of GM3/GD3 mimics was observed in ICDCCJ07001, although this patient had anti-GT1a IgG antibodies. A single-base deletion in a glycosyltransferase gene caused the absence of GT1a mimicry in ICDCCJ07001. The phylogenetic tree showed that ICDCCJ07002 and ICDCCJ07004 were genetically closer to each other than to ICDCCJ07001. C. jejuni, bearing a GT1a-like lipo-oligosaccharide, might have caused the GBS outbreak and the loss of GT1a mimicry may have helped ICDCCJ07001 to survive in the host.

Ambiguous value of anti-ganglioside IgM autoantibodies in Guillain-Barré syndrome and its variants.

Anti-ganglioside autoantibodies of the IgG type are detected in a half of patients with Guillain-Barré syndrome (GBS), and their detection strongly supports the diagnosis of GBS. In contrast, anti-ganglioside IgM antibodies are also often detected in GBS patients, but it remains unclear whether IgM antibodies indicate a diagnosis of GBS. We identified four GBS patients (3.3%) who tested positive for IgM antibodies but negative for IgG antibodies among 122 patients with GBS and its variants. These four patients were all adolescents or young adults (age 13-22 years), experienced preceding gastrointestinal symptoms, and had serological and/or bacterial evidence of recent Campylobacter jejuni enteritis. Serum IgG reacted strongly with the lipo-oligosaccharide (LOS) of the C. jejuni isolates from these patients' stool specimens. Thin-layer chromatography with immunostaining showed that their serum IgG reacted with resorcinol-positive portion of LOS, suggesting that these patients had IgG autoantibodies against sialic acid-containing epitopes, probably unrecognized ganglioside-like structures on the bacterial LOS. We also examined anti-ganglioside autoantibodies in 22 patients with C. jejuni enteritis without subsequent neurological disorders and detected IgM antibodies in seven (32%) patients. Our data indicate that anti-ganglioside IgM antibodies can be detected in C. jejuni enteritis without complication of GBS, and that the detection of anti-ganglioside IgM antibodies does not always support a diagnosis of GBS. IgG autoantibodies against unrecognized gangliosides might play a role in the development of disease in patients with GBS in whom only anti-ganglioside IgM antibodies are detected by routine clinical testing.

Glycoconjugates and neuroimmunological diseases.

A wide range of neuroimmunological diseases affect the central and peripheral nervous systems. These disorders are caused by autoimmune attack directed against structurally and functionally diverse nervous system antigens. One such category comprises peripheral nervous system (PNS) diseases, termed peripheral neuropathies, in which the target antigens for autoantibody-directed nerve injury are glycan structures borne by glycoproteins and glycolipids, particularly gangliosides that are concentrated in peripheral nerve. The archetypal PNS disorder is the acute paralytic disease, Guillain-Barré syndrome (GBS) in which autoantibodies against glycolipids arise in the context of acute infections that precede the clinical onset, notably Campylobacter jejuni enteritis. In addition, several chronic autoimmune neuropathies are associated with IgM antibodies directed against nerve glycans including sulphated glucuronic acid epitopes present on myelin-associated glycoprotein and sulphated glucuronyl paragloboside, a range of disialylated gangliosides including GD1b and GD3, and GM1 ganglioside. This chapter describes the immunological, pathological and clinical features of these disorders in the context of our broader knowledge of the glycobiology underpinning this neuroimmunological field.

44. Electrodiagnostic features in Guillain–Barré syndrome after Campylobacter jejuni enteritis

44. Electrodiagnostic features in Guillain–Barré syndrome after Campylobacter jejuni enteritis

Acute Pancreatitis Associated With Campylobacter jejuni Enteritis: A Case Report

A 62-year-old male developed pancreatitis including elevation of pancreatic enzymes and evidence of pancreatic inflammation on imaging in association with Campylobacter jejuni enteritis. Hyperamylasemia in association with C. jejuni enteritis has been reported occasionally. Though many reports in the literature are incomplete, to our knowledge, only a single prior report of pancreatitis associated with Campylobacter jejuni enteritis included radiographic evidence of pancreatic inflammation. doi:10.4021/jmc541w

Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy.

In the Guillain-Barré syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement-mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement-mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were trafficked to recycling endosomes and lysosomes. Consequently, complement-mediated cytotoxicity was attenuated. Importantly, we observed the same AGAb endocytosis and protection from cytotoxicity in live mouse nerve terminals. AGAb uptake was attenuated following membrane cholesterol depletion in vitro and ex vivo, indicating that this process may be dependent upon cholesterol-enriched microdomains. In contrast, we observed minimal AGAb uptake at nodes of Ranvier, and this structure thus remained vulnerable to complement-mediated injury. These results indicate that differential endocytic processing of AGAbs by different neuronal and glial membranes might be an important modulator of site-specific injury in acute AGAb-mediated Guillain-Barré syndrome subforms and their chronic counterparts.

Acute Pancreatitis Associated With Campylobacter jejuni Enteritis: A Case Report

A 62-year-old male developed pancreatitis including elevation of pancreatic enzymes and evidence of pancreatic inflammation on imaging in association with Campylobacter jejuni enteritis. Hyperamylasemia in association with C. jejuni enteritis has been reported occasionally. Though many reports in the literature are incomplete, to our knowledge, only a single prior report of pancreatitis associated with Campylobacter jejuni enteritis included radiographic evidence of pancreatic inflammation. J Med Cases. 2012;3(3):167-168 doi: https://doi.org/10.4021/jmc541w

Guillain–Barré syndrome and anti-ganglioside antibodies: a clinician-scientist’s journey

Guillain–Barré syndrome (GBS) is the most frequent cause of acute flaccid paralysis. Having seen my first GBS patient in 1989, I have since then dedicated my time in research towards understanding the pathogenesis of GBS. Along with several colleagues, we identified IgG autoantibodies against ganglioside GM1 in two patients with GBS subsequent to Campylobacter jejuni enteritis. We proceeded to demonstrate molecular mimicry between GM1 and bacterial lipo-oligosaccharide of C. jejuni isolated from a patient with GBS. Our group then established a disease model for GBS by sensitization with GM1 or GM1-like lipo-oligosaccharide. With this, a new paradigm that carbohydrate mimicry can cause autoimmune disorders was demonstrated, making GBS the first proof of molecular mimicry in autoimmune disease. Patients with Fisher syndrome, characterized by ophthalmoplegia and ataxia, can develop the disease after an infection by C. jejuni. We showed that the genetic polymorphism of C. jejuni sialyltransferase, an enzyme essential to the biosynthesis of ganglioside-like lipo-oligosaccharides determines whether patients develop GBS or Fisher syndrome. This introduces another paradigm that microbial genetic polymorphism can determine the clinical phenotype of human autoimmune diseases. Similarities between the clinical presentation of Fisher syndrome and Bickerstaff brainstem encephalitis have caused debate as to whether they are in fact the same disease. We demonstrated that IgG anti-GQ1b antibodies were common to both, suggesting that they are part of the same disease spectrum. We followed this work by clarifying the nosological relationship between the various clinical presentations within the anti-GQ1b antibody syndrome. In this review, I wanted to share my journey from being a clinician to a clinician-scientist in the hopes of inspiring younger clinicians to follow a similar path.

Guillain–Barré syndrome associated with normal or exaggerated tendon reflexes

Areflexia is part one of the clinical criteria required to make a diagnosis of Guillain-Barré syndrome (GBS). The diagnostic criteria were stringently developed to exclude non-GBS cases but there have been reports of patients with GBS following Campylobacter jejuni enteritis with normal and exaggerated deep tendon reflexes (DTRs). The aim of this study is to expand the existing diagnostic criteria to preserved DTRs. From the cohort of patients referred for anti-ganglioside antibody testing from hospitals throughout Japan, 48 GBS patients presented with preserved DTR at admission. Thirty-two patients had normal or exaggerated DTR throughout the course of illness whereas in 16 patients the DTR became absent or diminished during the course of the illness. IgG antibodies against GM1, GM1b, GD1a, or GalNAc-GD1a were frequently present in either group (84 vs. 94%), suggesting a close relationship between the two groups. We then investigated the clinical and laboratory findings of 213 GBS patients from three hospital cohorts. In 23 patients, eight presented with normal tendon reflexes throughout the clinical course of the illness. Twelve showed hyperreflexia, with at least one of the jerks experienced even at nadir, and exaggerated reflexes returning to normal at recovery. The other three had hyperreflexia throughout the disease course. Compared to 190 GBS patients with reduced or absent DTR, the 23 DTR-preserved patients more frequently presented with pure motor limb weakness (87 vs. 47%, p=0.00026), could walk 5m independently at the nadir (70 vs. 33%, p=0.0012), more frequently had antibodies against GM1, GM1b, GD1a, or GalNAc-GD1a (74 vs. 47%, p=0.014) and were more commonly diagnosed with acute motor axonal neuropathy (65 vs. 34%, p=0.0075) than with acute inflammatory demyelinating polyneuropathy (13 vs. 43%, p=0.0011). This study demonstrated that DTRs could be normal or hyperexcitable during the entire clinical course in approximately 10% of GBS patients. This possibility should be added in the diagnostic criteria for GBS to avoid delays in diagnosis and effective treatment to these patients.