Whipple's disease

Whipple's disease is a rare chronic multi-system pathology of infectious origin. Most common with it are general practitioners( therapists) and gastroenterologists, because the most common reason for primary treatment to a specialist are signs of joint and gastrointestinal tract damage.

Earlier Whipple's disease was lethal in 100% of cases, but now it has a favorable prognosis. Adequately selected antibiotic regimens allow not only to save patients life, but also to significantly improve its quality even at severe stages of the disease.

Historical background

Whipple's disease is a bacterial disease that is transmitted by the fecal-oral route.

Whipple's disease was isolated as an independent pathology not so long ago, it is named after the name of the first described English pathologist, George H. Whipple( George Hoit Whipple).In 1907, he published an article with a posthumous pathological anatomical analysis of a clinical case of J. Hopkins Hospital.

D. Whipple discovered a complex of unusual changes in the organs of a 36-year-old patient who suffered from fever, lymph node enlargement, persistent cough, chronic diarrhea and progressive weight loss for 5 years before death. He was diagnosed with:

• signs of affection of all serous membranes( polyserosite);
• significant plural enlargement of the lymph nodes in the abdominal cavity;
• atypical deposition of lipids in the wall of the intestine and lymphoid tissue;
• a significant increase in the number of macrophage cells and the appearance in them of foamy structures with argyrophilic rod-shaped inclusions.

Whipple called the identified disease intestinal lipodystrophy and suggested that it is infectious. But the etiology of this pathology was reliably detected only in the second half of the 20th century, and already after receiving positive results from antibiotic therapy.

Currently, according to the ICD-10, Whipple's disease belongs to the class of diseases of the digestive system and is coded by K 90.8, if necessary, additional codes are used to indicate developed extraintestinal manifestations. At the moment, just over 1000 cases have been confirmed, and only about 2000 observations of patients with symptoms of Whipple's disease have been described in the medical literature.

The aetiology of

Whipple described the characteristic changes in the lymph nodes and intestinal wall and isolated the disease as a separate nosological unit, but he could not unambiguously prove its bacterial etiology, although he pointed out the presence of microorganisms similar in spirochaetes in the tissues of the small intestine. Whipple mistakenly believed that the cause of the disease - a violation of lipid metabolism.

In 1949, with the biopsy of lymph nodes, so-called PAS-positive macrophages were identified, the inclusions in the foamy cytoplasm of which are similar to the products of bacterial cell disintegration. The bacterial nature of the disease was also confirmed by the favorable results of massive antibacterial therapy. Several researchers have detected rod-shaped bacterial inclusions in macrophages, but could not verify them.

The causative agent was determined much later, at the very end of the 20th century, using a polymerase chain reaction. They turned out to be a gram-positive bacterium, related to one of the families of actinomycetes. It was called Tropheryma whipplei( T. whipplei or TW), which comes from the Greek.words trophe - food, eryma - barrier.

Tropheryma whipplei has an elongated shape and a 3-layered cell wall, about 0.2x2.0 μm in size( sometimes up to 3.0 μm).The small genome of this bacterium is located in a single ring chromosome, and its surface antigens are similar to human tissue antigens and therefore do not provoke a pronounced immune response. This is an important point in the pathogenesis of the disease.

Epidemiology

Tropheryma whipplei is a common bacterium, but still the largest number of cases belongs to the population of North America and Central Europe. At the same time, only some strains are pathogenic to humans, and their entry into the body does not always lead to the development of the disease. Tropheryma whipplei is often sown from the feces of absolutely healthy people.

The prevalence of Whipple's disease is approximately 0.5-1 per million people. At the moment, only about 1000 episodes are officially registered( and confirmed) in the world.80% of the cases were men 40-50 years old. At the same time, it is assumed that there is a certain number of healthy carriers in the population, many of them, most likely, were infected as early as childhood. But the normal host-infection immune response in their organisms does not allow the causative agent to actively propagate and spread.

Pathogenesis. The role of immune disorders

Human infection occurs by the fecal-oral route. The causative agent for penetration through the walls of the gastrointestinal tract does not require the presence of mucosal defects. Most likely, the entrance gates are the tissues of the small intestine, here the most pronounced changes are noted. In this case, enterocytes( cells of the intestinal mucosa) are not primarily affected, the main disorders occur in the thickness of the tissues and in the regional mesenteric( mesenteric) lymph nodes.

Tropheryma whipplei for reproduction and distribution requires special cells of the immune system - macrophages. It is the violation of their functioning that is the key to the pathogenesis of Whipple's disease.

Normally, macrophages capture foreign cells penetrating the body, surrounding them with outgrowths and then, as it were, plunging into their cytoplasm. This process resembles the nutrition of amoeba and is called phagocytosis. As a result, pathogens appear in a vial inside the cytoplasm of the macrophage, where they are killed and cleaved by enzymes. But with the Tropheryma whipplei, this protective mechanism does not work.

It is believed that the prerequisite for the development of Whipple's disease are certain immune disorders that are initially present in a person who has become infected. Such a defect is very specific and does not lead to an increased risk of developing other infections. It is supplemented by other immunity disorders that arise after the introduction of T. whipplei.

• Macrophages in Whipple's disease retain the ability to phagocytose the pathogen, but they can not then liquefy( dissolve) them. Therefore, Tropheryma whipplei gets the opportunity not only to remain viable in the cytoplasm of these immune cells, but also to actively multiply. In fact, macrophages become a receptacle and a transporter for bacteria, creating conditions for their dissemination( diffuse spread) throughout the body.
• A change in the ratio between regulatory subpopulations of CD4 and CD8 T-lymphocytes.
• Decrease in the ability of macrophages and some other immune cells to produce specific antibodies, which is due to a violation of the recognition of surface antigens Tropheryma whipplei.
• Activation of the production of interleukin-16( IL-16), which reduces the productivity of macrophage lysis and simultaneously promotes enhanced replication of the genome of the pathogen. The higher the concentration of this cytokine in the blood, the higher the activity of the disease.

All these immunological disorders contribute to the generalization of infection in Whipple's disease. Therefore, the symptoms are chronic, progressive and multisystemic.

Mechanism for the development of basic symptoms

The mandatory sign of Whipple's disease is the destruction of the walls of the small intestine. They are infiltrated by multiple clusters of large malfunctioning macrophages, which significantly worsen the lymph drainage from the intestinal villi and the process of assimilation of fats. As a result, malabsorption of all nutrients( panmalabsorption syndrome) develops with the corresponding intestinal symptoms, and fatty inclusions begin to settle in the tissues. Affected areas of the intestine are stretched and densified, the villi in these areas are shortened and thickened.

Absorbed bacteria macrophages migrate throughout the body, overcome tissue barriers and form fat-containing infiltrates in other organs. Settling on the serous membranes, they lead to the development of serosites and polyarthritis. And in a number of cases, this symptomatology has a recurrent-progressive character and precedes the typical intestinal manifestations of the disease.

At a certain stage of the disease, the affected macrophages penetrate the blood-brain barrier. The changes that occur in the brain include:

• Infiltration of the brain tissue along vessels of different calibers. Multiple different-caliber foci of defeat occur in both white and gray matter.
• Appearance in the cortex and subcortical structures of microglial nodules with astrocytosis on the periphery. The cells that form them contain PAS-positive inclusions( as in the cytoplasm of macrophages) or even the bacteria themselves.
• When the process grows, the neural network is involved in the process. Demyelination of the nerve processes, vacuolation of cells and appearance of bacterial inclusions in their cytoplasm are noted. Progressively decreases the amount of brain tissue, decreases the productivity of the brain.

The occurrence of microcirculation in various locations is also possible, which exacerbates neurological symptoms. This is due to the clogging of small-caliber vessels in the brain with embolic cardiac( cardiogenic) origin.

Without treatment, pathological changes in Whipple's disease are progressing steadily and rapidly enough, the patient's death occurs against the background of multiple critical brain disorders and multiple organ failure.

Clinical picture of

In the early stages of the disease, joint pains appear in the person, peripheral lymph nodes increase, and symptoms of general intoxication develop.

The duration of the incubation period at the moment is not known reliably. Whippl's disease has 3 clinical stages:

1. The initial phase, or stage of nonspecific manifestations. It is characterized by damage to the joints, peripheral lymph nodes, joints, skin, muscles, general toxication symptoms. Despite the inevitable damage to the walls of the digestive tract, Whipple's disease in the vast majority of cases debuts with extraintestinal manifestations. Symptoms appear and grow gradually, their presence is often attributed to banal infections or the patient's existing pathology.
2. Deployed or abdominal stage, characterized primarily by the development of intestinal disorders. At the same time, the already existing symptoms are accompanied by impaired absorption with the development of malabsorption syndrome, abdominal pain, chronic diarrhea( usually by the type of steatorrhoea due to an excess of undigested fat in the feces), flatulence. This leads to increasing hypovitaminosis and anemia, contributes to violations of water and mineral metabolism and generally depletes the sick.
3. The stage of generalization of infection, with the defeat of many organs. The heart valves, endocardium, pleura, lung tissue, the central nervous system( primarily the brain) and the shells of the eyeballs are usually involved in the process. It is not excluded the appearance of fatty infiltrates and other localization. Symptom becomes polymorphous, increasing. The condition is steadily becoming heavier, and without adequate treatment Whipple's disease leads to the death of the sick person.

The total duration of the disease can be different. The total duration of stages 1 and 2 can reach 20-25 years. An unfavorable sign, indicating a significant weighting and a clear progression of the disease - the attachment of neurological symptoms. After their appearance, stage 3 is diagnosed, the duration of this stage without treatment usually does not exceed 5 years.

At the same time, neurological symptoms are sometimes found before characteristic intestinal disorders. This does not serve as a criterion for exclusion in the diagnosis of Whipple's disease, but is regarded as a prognostically unfavorable symptom.

Neurological manifestations of Whipple's disease

Neurological symptoms in Whipple's disease are rather polymorphic. Its nature and severity depends on the localization and size of infiltrates and hemorrhages formed in the brain, the severity of atrophic processes.

Neurological manifestations of Whipple's disease include:

• Increasing intellectual-mnestic( cognitive) decline of , often reaching the degree of dementia( dementia).Disturbances are cortical-subcortical in character and irreversible even after removal of the infectious agent. Cognitive decline of varying severity with time develops in 50% of patients with Whipple's disease.
• Hyperkinetic syndrome, usually in the form of myoclonium .Most often, oculofascial myorrhythmia develops-a combination of spontaneous pendulum convergent( convergent) nystagmus and rhythmic movements of the lower jaw, soft palate, lips, tongue, and eyelids. Such synchronous myoclonies of eyeballs and facial muscles are considered by many physicians as pathognomonic for Whipple's symptom symptom, although they are noted in about 20% of patients. In rhythmic hyperkinesia, the muscles of the neck, various parts of the extremities, and the trunk can also be involved, in this case they speak of the development of skeletal myorrhythmia.
• Supranuclear Ophthalmoplegia , diagnosed in approximately 40-50% of cases. It is characterized by a restriction of the arbitrary movement of the eyeballs, mainly a paresis of the vertical gaze. At the same time there is no double vision( diplopia) and strabismus, reflex combined movements are preserved. The syndrome of ophthalmoplegia is associated with the defeat of the nerve structures that are responsible for the innervation of the oculomotor muscles and are located above the nuclei of the corresponding cranial nerves.
• Seizure syndrome with the development of generalized or partial epileptiform seizures.
• Hypothalamic disorders .Polydipsia( excessive water intake), bulimia( uncontrolled eating of excessive amounts of food), various types of insomnia( sleep disorders), sexual disorders, amenorrhea in women can be noted. Clinical signs of the defeat of the hypothalamic region are noted in about 30% of cases. Cerebellar ataxia .In varying degrees, there are almost ¼ patients with Whipple's disease.

Less common are cortical visual impairment, hemiparesis, myelopathy caused by lower spastic paraparesis, hypokinesia.

In a significant percentage of cases, there are also mental disorders, and they can occur at different stages of Whipple's disease. Possible anxiety and depressive conditions, psychotic symptoms.

Diagnosis

Half of people with Whipple's disease develop mental disorders, up to dementia.

The main way to confirm Whipple's disease is to study the biopsy of the small intestine. At the same time morphologically in the tissues are found:

• Infiltrates of the intestinal mucosa plate, which are formed by the CHEC( or PAS) -positive large macrophages with a foamy cytoplasm and coarse-grained inclusions.
• Thickening, shortening and changing the shape of the villi of the intestinal mucosa. They become clavate, with excessive amounts of lymph and fatty inclusions.
• Extra- and intracellular accumulation of fat in the mucosa of the small intestine.
• The presence of rod-shaped bacteria in the intercellular space and inside the cells, which is revealed mainly in the electronic microscopy of the biopsy.

Morphological study is recommended to be supplemented by PCR, which allows to verify the causative agent reliably. For this, different biological material can be used: biopsies of the intestine, kidneys, liver, lymph nodes, samples of the cerebrospinal fluid and synovial fluid. PCR has a high sensitivity and specificity, allowing to diagnose the disease even with questionable and false-negative results of pathomorphological examination.

All other methods of research give only indirect and nonspecific data. Therefore, general clinical and biochemical blood tests, coprograms, instrumental methods of visualization of tissues can not act as a way to confirm or exclude Whipple's disease.

Treatment of

Whipple's disease at any stage requires systemic antibacterial therapy, it was the beginning of the use of antimicrobial agents in its time allowed to reduce the lethality of this pathology. Prescribed antibiotics must have a bactericidal action, it is good to penetrate into all tissues, into the joint fluid and into the liquor.

According to modern clinical recommendations, treatment of Whipple's disease includes:

• The starting period( the first 2 weeks of therapy), during which the preference is given to parenteral administration of antibacterial drugs. Ceftriaxone( 2 g / day) or meropenem( 3 g / day) or a combination of benzylpenicillin( 12 million units / day) with streptomycin( 1 g / day) can be used.
• Supportive treatment( during the following year, sometimes up to 2 years).Most often, co-trimoxazole is used, when signs of patient resistance appear, they are transferred to a combination of doxycycline and hydroxychloroquine. And in the presence of neurologic symptoms, the treatment regimen is supplemented with sulfadiazine up to 4 mg / day.

If necessary, symptomatic is added to such etiotropic treatment. It can be aimed at correcting violations of water-salt metabolism and deficiency of vitamins and basic nutrients, alleviating the existing symptoms. At the initial stages of treatment, a diet is necessary.

Forecast

Without properly selected antibiotic therapy, Whipple's disease is unequivocally lethal. The introduction of antimicrobial agents into the scheme of treatment is effective even at the stage of infection generalization. At present, the prognosis for Whipple's disease is generally favorable.

Against the background of adequate antibiotic therapy, the intensity of intestinal disorders and fever usually decreases by the end of the first week of treatment. Within a month the articular syndrome is leveled, there is a positive dynamics in case of eye damage. The overall well-being improves quickly, weight gain begins. But neurologic symptoms can rarely be completely eliminated, although they can gradually soften against a background of long-term combination therapy.

Even with a good response to antibacterial treatment and patient compliance with all medical recommendations, the development of relapses, treatment of which is carried out according to the scheme of starting antibacterial therapy, is not ruled out.

Currently, the selection of effective and effective methods of diagnosis and treatment of Whipple's disease continues.

The doctor-gastroenterologist E. N. Zinovieva presents the report on the topic "Whipple's disease":