Inflammatory syndrome

The inflammatory response is responsible for a syndrome of both clinical and biological. Its mechanisms are complex, resulting from cellular and humoral phenomena. Most authors define the inflammatory response, which can be local or general, as a phenomenon of non-specific defense response to aggression, which aims to maintain the integrity of the self. We must distinguish the inflammatory response of the immune response, although there is a close link with it because the inflammatory response is involved in natural immunity and promotes the induction of specific immune response.

All causes of cellular aggression can trigger an inflammatory response. The agents most frequently encountered initiators are hypoxia (ischemia most often), physical agents (eg, trauma, burns, frostbite, radiation), chemical agents (eg caustics), the microbial agents (for example exotoxins and endotoxins bacteria, the cytopathogenic effect of the virus), immunological reactions (eg, autoimmune diseases). Sometimes the cause of inflammation may be unknown.Some cytokines have a central role in the induction of inflammatory reaction. Cytokines are soluble polypeptides which carry messages to cells to cells. They are secreted by cells activated during the inflammatory reaction. Same cytokine can be secreted by various cell types. Similarly, targets and functions are usually multiple.

Main cytokine inflammation are interleukin-6 (IL-6), interleukin 1 (IL-1), Tumor Necrosis Facto r α (TNF), the γ-interferon (IFN) and the Transforming Growth Factor β (TGF). These cytokines, IL-6 in mind, stimulate hepatic synthesis of acute phase proteins and are responsible for the clinical signs of inflammatory syndrome described below.

inflammatory syndrome

inflammatory syndrome

DIAGNOSTIC:

Clinical manifestations:

Localized inflammatory reaction:

For centuries, rubor, calor, tumor and dolor (redness, heat, swelling, pain), the four cardinal clinical signs of inflammation are in the medical treatises.

These clinical signs that match a localized inflammatory reaction, however, are inconsistent, and, depending on etiology, many inflammatory reactions are only expressed by general clinical manifestations.

General symptoms:

Fever that accompanies many inflammatory reactions can be explained by the direct action on hypothalamic thermoregulatory centers pyrogens from the aggressor agent, eg lipopolysaccharide of Gram-negative bacteria. But more often, they are pyrogenic cytokines synthesized in the context of the inflammatory response involved. These cytokines act at some endothelial structures in the hypothalamus where they initiate the secretion of prostaglandin E2 (PGE2).

The cytokines of the inflammatory reaction are also responsible for other general clinical signs of inflammation: asthenia, somnolence, anorexia, weight loss, failure to thrive in children. Finally, tissue deposition of AA protein can complicate certain persistent inflammatory reactions (eg during chronic infections or in inflammatory diseases such as rheumatoid arthritis), resulting in amyloid A. AA protein derived from serum amyloid A (SAA ) which increases in concentration during the inflammatory reaction.

Biological events:

They observe so all the more clear that the inflammation develops long.

Hyposideremia and ferritin:

They result from an iron sequestration in macrophages. Ferritin increases during the inflammatory reaction, and can even often mask true iron deficiency that would be associated with the inflammatory response (for example in colon cancer accompanied both an inflammatory response and chronic bleeding) . In this case the assay of transferrin, or better of the soluble transferrin receptor, will provide useful information.

Anemia:

It is non-regenerative, normochromic and microcytic if the inflammation persists. However, it is rare that the hemoglobin is less than 8 g / dL.

Thrombocytosis:

It can reach 106 platelets / mm3 and can reach its maximum rate the convalescence phase, that is to say, it may continue to increase for several days while the disease is cured (thrombocytosis called “rebound “or” post-infectious “).There is no recommendation on the therapeutic approach to an intense reaction thrombocytosis. The majority of practitioners do not offer antiplatelet therapy without other associated thrombosis risk factors (eg bed rest or thromboembolic history).

Leukocytosis:

It is inconsistent, often very marked, and very dependent on the etiology of the inflammatory reaction. It can be very important during inflammatory reactions that accompany certain bacterial infectious diseases (especially in case of deep abscess) or certain systemic diseases (Still’s disease in particular). Conversely, certain inflammatory reactions are accompanied leukopenia (e.g., a viral infection or systemic lupus erythematosus).

Liver function disturbances:

Elevated alkaline phosphatase of hepatic origin is observed in some important inflammatory reactions, for example in case of bacterial infection, during kidney cancers (when there is no liver metastasis), or in GCA.

Demonstration of inflammatory syndrome:

There is no specific rule prescribing additional tests for the diagnosis of inflammatory reaction. Their prescription is often based on local laboratory capabilities. C-reactive protein (CRP) is the most commonly used measure, it is preferred because of its rapid and synchronous kinetics of the inflammatory process, and its greater reliability than the erythrocyte sedimentation rate (ESR). For many authors, the increase in CRP is sufficient to affirm the inflammatory syndrome. For others, it is necessary, in addition to the increase of this marker, the observed increase of at least one further protein of the inflammatory reaction (PRI): haptoglobin, orosomucoid fibrinogen. The VS is also easily used, but this has its limits.

Erythrocyte sedimentation rate:

Normal VS increases with age and is higher in females. From a large population of adults aged 20 to 65, a simple formula was established to calculate the upper limit of normal VS according to age and sex:

– For men: [age in years] / 2;

– For women: [age in years + 10] / 2.

If the VS has the advantage of simplicity of implementation and low cost, this method has the disadvantage of not always sensitive nor specific: there are inflammatory reactions with a normal ESR, and the VS increases when there is no inflammation.

Caution: elevated ESR is not synonymous with inflammatory reaction, and a normal ESR does not rule out with certainty the existence of an inflammatory response. The VS can not be interpreted only by using more specific assays: immunoglobulins and proteins of the inflammatory reaction.

Proteins of the inflammatory reaction:

The PRI can be defined as proteins whose plasma concentration range of at least 25% in the first 5 to 7 days of onset of inflammation. This may be especially increase but also decrease:

– PRI most useful in the detection of the inflammatory reaction are those whose rate increases, the CRP in clinical practice foremost, but also orosomucoid, haptoglobin and fibrinogen; kidney (when there is no liver metastasis), or GCA.

Demonstration of inflammatory syndrome:

There is no specific rule prescribing additional tests for the diagnosis of inflammatory reaction. Their prescription is often based on local laboratory capabilities. C-reactive protein (CRP) is the most commonly used measure, it is preferred because of its rapid and synchronous kinetics of the inflammatory process, and its greater reliability than the erythrocyte sedimentation rate (ESR). For many authors, the increase in CRP is sufficient to affirm the inflammatory syndrome. For others, it is necessary, in addition to the increase of this marker, the observed increase of at least one further protein of the inflammatory reaction (PRI): haptoglobin, orosomucoid fibrinogen. The VS is also easily used, but this has its limits.

Erythrocyte sedimentation rate:

Normal VS increases with age and is higher in females. From a large population of adults aged 20 to 65, a simple formula was established to calculate the upper limit of normal VS according to age and sex:

– For men: [age in years] / 2;

– For women: [age in years + 10] / 2.

If the VS has the advantage of simplicity of implementation and low cost, this method has the disadvantage of not always sensitive nor specific: there are inflammatory reactions with a normal ESR, and the VS increases when there is no inflammation.

Caution: elevated ESR is not synonymous with inflammatory reaction, and a normal ESR does not rule out with certainty the existence of an inflammatory response. The VS can not be interpreted only by using more specific assays: immunoglobulins and proteins of the inflammatory reaction.

Proteins of the inflammatory reaction:

The PRI can be defined as proteins whose plasma concentration range of at least 25% in the first 5 to 7 days of onset of inflammation. This may be especially increase but also decrease:

– PRI most useful in the detection of the inflammatory reaction are those whose rate increases, the CRP in clinical practice foremost, but also orosomucoid, haptoglobin and fibrinogen;

– MICs whose rate is lowered when the inflammatory reaction (MICs “negative”) are albumin, prealbumin, and transferrin.

Serum protein electrophoresis:

The increase of MICs may be demonstrated, rather coarse manner, by serum protein electrophoresis which shows an increase of α1-globulin (as orosomucoid) and especially α2-globulins (as haptoglobin). In fact, this electrophoresis may appear normal if the inflammatory response is moderate. CRP migrates γ area but the concentrations are too low to make changes in its rate are visible on the electrophoretic path. The fibrinogen component of the plasma is not studied by this technique performed with serum.

Warning: One of the main interests of the serum protein electrophoresis is to allow the detection of a polyclonal or monoclonal immunoglobulin elevation which, as we have seen, can increase the VS alone.

C reactive protein :

C-reactive protein is distinguished from other PRI by its very rapid kinetics: it increases from the 6th hour of an inflammatory reaction, and normalizes within a few days after his disappearance.

This property allows you to quickly assess the effectiveness of a therapeutic in an inflammatory response, while the return to normal of the VS, haptoglobin or fibrinogen may request more than 2 or 3 weeks.

Warning: it often leads to the CRP a sorting option “elevated in bacterial infections and not in viral infections,” or “high in cases of infectious complication but not in case of disease flare in SLE patients’ . Although this assertion can be integrated in a diagnostic approach should be used with caution these concepts too caricatured and especially never base a diagnostic decision (eg rule out appendicitis before normal CRP) or therapeutic (eg decide antibiotic therapy because the CRP is high) on this single parameter. Indeed, as with any supplementary examination, it is the clinical history and physical examination that matter to the diagnostic and therapeutic decision, the result of a bioassay that can be caught out.

C3 fraction of the complement:

The fraction of complement C3 is a PRI slow kinetics. Its concentration increases in the inflammatory reaction. The interest of its dosage is to seek, in an inflammatory reaction already established context, reduced then “paradoxical” concentration.

This decrease then turned to certain diseases: endocarditis Osler, systemic lupus erythematosus thrust some glomerulonephritis, cryoglobulinemia.

Procalcitonin:

Recent studies reported the benefit of procalcitonin in the evaluation of inflammatory conditions. This prohormone of calcitonin is not currently metered everywhere in current practice. Instead of his determination in the investigation of an inflammatory reaction to be determined. The majority of publications reports a specific increase in the serum level of this marker during systemic bacterial infections. However, a repeat bioassay can be caught out and that it is the clinical history and physical examination that matter to the diagnostic and therapeutic decision.

Protein profile:

The result of the simultaneous determination of MICs can be presented as a group, in the form of a graph called protein profile. The results are expressed in percentage of the normalized values, allowing to correlate the changes in serum protein each other, and to integrate the information provided by these concentration changes. This profile, described as “etiopathogenic orientation” may embrace 10 proteins 3 proteins of the humoral immune response (IgM, IgG, IgA), 4 positive PRI (CRP orosomucoid, haptoglobin, complement C3), and 3 negative PRI (albumin , prealbumin, transferrin). This is a very rich examination information, but expensive and therefore prescribed in case of diagnostic problem.

Modification of the inflammatory reaction of proteins out of the inflammatory response:

Other causes that inflammation can affect the plasma concentration of the PRI:

– Although albumin may drop to 22 g / L during the inflammatory response, below this figure must prudently seek another cause of hypoalbuminemia: liver failure, malnutrition, malabsorption; urinary leakage, capillary, digestive or skin;

– If transferrinemia increases (instead of falling parallel to albumin in the inflammatory response), look for iron deficiency;

– If haptoglobin fall (instead of increasing in parallel with orosomucoid during the inflammatory response), look hemolysis;

– Fibrinogen may decrease when corticosteroids, if consumed upon activation of coagulation (eg disseminated intravascular coagulation) or as part of a macrophage activation syndrome.

It can actually increase with estrogen therapy, or renal impairment where it is common to observe an increase in the VS;

– Hepatocellular deficiency decreases the concentration of all MICs default synthesis;

– Nephrotic syndrome is accompanied by an increased synthesis of MICs, but does not alter CRP. Levels of haptoglobin and fibrinogen are high. However, albumin and orosomucoid are lowered: their increased hepatic synthesis is masked by their significant urinary leakage due to their low molecular weight;

– Orosomucoid complexes to basic molecules, in particular certain drugs, eg antibiotics, β-blockers or furosemide. A collapse orosomucoid can thus be observed in polymedicated patients.

When seeking an inflammatory syndrome:

In practice, the search for an inflammatory reaction will occur in three clinical situations:

– In a patient with a symptom of unknown etiology (eg, arthralgia, headache, fever, weight loss): the highlight of an inflammatory reaction is an argument in favor of an organic pathology;

– In a patient with unexplained elevations of VS: the detection of an increase in PRI confirms the inflammatory origin of the increase in VS. A serum protein electrophoresis (or protein profile) is essential realization here to stop a raised ESR due to an abnormality of immunoglobulins; in a patient with a known inflammatory disease: the biological parameters of the inflammatory reaction are used as markers of progressive disease, and in particular allow for assessing the effectiveness of proposed treatments.

Warning: it is not recommended to use markers of inflammation such as “test of a health problem” in asymptomatic subjects integrating a VS or CRP measurement in a routine checkup . In other words, these markers can be seen as risk factors for possible disease coming and still asymptomatic. For example it is well demonstrated that the detection of an elevated ESR in an asymptomatic patient will come to no diagnostic benefit (but instead explorations have wasted time and money, not to mention the anxiety that armature with patients such situations).

Ferritin is also not to be used as screening inflammatory marker.

TO BEHAVE :

With a disease diagnosis already established:

There is of course no other diagnostic procedures to be undertaken in this case. Monitoring the evolution of the inflammatory reaction confirms the healing clinical data or aggravation. If the clinical course is discordant with respect to that of the biological markers of the inflammatory reaction, especially if clinical signs of the disease regress and biological parameters of inflammation persist or deteriorate, we will look for a problem superimposed ( for example the occurrence of infectious complications and cancer in a patient treated for temporal arteritis in clinical remission).

In the absence of diagnostic orientation:

The identification of the underlying condition is a medical practice often very tedious, akin or sometimes overlaps with the search for the cause of prolonged fever (see Chapter prolonged fever, Part I).

The diagnostic approach can be broken down as follows.

We must first control the persistence of inflammatory syndrome:

Indeed, it often happens that the inflammation is found at the waning of a past mild disease unnoticed or forgotten by the patient, eg a seasonal infection, gastroenteritis or gout. This inflammation will be transitory. If, after examination and clinical examination, the patient is actually asymptomatic, so it is useful to monitor the persistence of inflammation, before undertaking a sophisticated etiological. The CRP testing here will be more useful than the VS which can remain elevated for several weeks after the disappearance of the inflammatory reaction.

Table I. Examples of clinical symptoms not to ignore (and easily forgotten!) When examining a patient with persistent inflammation of unknown origin.

The investigation always starts with the history and clinical examination data:

If the inflammation persists, then you must always start the investigation by the meticulous collection of clinical history and physical examination. This is the first and essential step in the diagnostic process. This clinical analysis sometimes allows a diagnosis, and especially is essential to guide the strategy prescribing additional tests.

He must not forget to weigh the patient at the first consultation, the evolution of the weight curve is an important element in assessing the gravity and making possible empirical explorations or aggressive treatment decision. Clinical examination is complete from head to toe, including pelvic examination. Review all clinical abnormalities that could be highlighted in the context of the clinical examination of a patient with a persistent inflammatory syndrome without obvious cause would be particularly indigestible and somewhat didactic. On the other hand, include some clinical signs that need particular attention (Table I), because that can easily go unnoticed.

Additional examinations are prescribed based on clinical analysis:

Additional tests will be directed by clinical data, although some will be systematically prescribed (Box 1). It is irrelevant to want to include an exhaustive list of additional tests that can be prescribed in a patient with persistent inflammation of unknown etiology. This list is probably incomplete for some patients, but especially propose unnecessary examinations for the majority of patients. Here we must remember that the risk of a false positive test result is even higher than the investigations multiply 1. As always when interpreting a supplementary examination results, we must ensure that it is consistent with the clinical data. So do require that additional tests that are justified by the data of the interrogation and physical examination. However, if no track can be raised and the inflammation persists, the practice of a scanner (thoracolumbar) Abdominopelvic be systematic (deep research cancer or lymphoma), as well as performing a biopsy temporal artery in a subject over 60 years (due to the GCA frequency).

1. If for example the terminals of a test values are determined to include 95% of the normal population, it can be expected that one normal individual 20 is a result of which the value is outside these bounds, ie a false positive. If we multiply the tests, the risk of obtaining a false positive increases all.

Box 1. Investigations prescribed for the diagnosis of unexplained persistent inflammatory response (indicative list)
routine provision of first line
liver biology
creatinine
Cytobacterioligical urine exam
Abdominal ultrasound
Serum protein electrophoresis
systematic blood cultures
intradermal tuberculin
Lactase dehydrogenase, creatine phosphokinase
Blood count and platelets, with smear
proteinuria
Chest radiography
Prescription oriented clinical data
Neutrophil cytoplasmatic antibody
antinuclear antibodies, rheumatoid factor
colonoscopy
bone marrow biopsy, bone marrow aspiration
Venous Doppler ultrasound of the lower limbs
Echocardiography
Eye exam
Sinus radiography and dental panoramic
bronchoscopy
upper gastrointestinal endoscopies
HLA B27 shots and sacroiliac
tumor markers
infectious serology, not to mention HIV
Small bowel
gastric aspirate (BK)
Scanner thoraco-abdominal-pelvic *
Temporal artery biopsy *
* These examinations can be prescribed immediately in the absence of guidance if the inflammation persists and remains isolated.

What to do when everything is negative?

First, be aware resume examination and clinical examination in full, since new clinical elements have appeared over time. Also, do not hesitate to call on other colleagues who will bring a new and often useful analysis of the situation, if only to reinforce its own approach. In the absence of etiological diagnosis, the course of action will be decided case by case, guided by the patient’s clinical condition.

Basically two attitudes will be considered.

Simple clinical and laboratory monitoring:

Either we decide a simple clinical and laboratory monitoring: it is possible if the patient’s clinical condition is satisfactory, if there is no sign of severity, no breach of the condition or of threatening visceral involvement. Passing time will sometimes be a “further examination” useful, allowing for the emergence of new signs that will guide the diagnosis. Often remain without etiological diagnosis, knowing the prognosis of persistent unexplained inflammatory reactions is usually satisfactory, changes they most often toward healing within weeks without sequelae.

Test treatment:

Either we decide to establish a test treatment: it is the patient’s clinical condition which compels them, by the appearance of an impaired general condition source of functional impairment and / or cachexia which no longer allows the waiting. Two main treatments are to discuss: corticosteroid therapy or TB treatment. The choice is never easy, and is to some extent arbitrary, and possibly intuition and clinical experience. It will help clinical and epidemiological data, eg the high risk of exposure to tuberculosis in a patient from a country with low levels of hygiene, or the possibility of temporal arteritis with biopsy of negative temporal artery in the elderly. For TB treatment, some teams recommend using triple therapy with isoniazid, pyrazinamide and ethambutol, that is to say with only specific anti-tuberculosis (so no rifampicin may act on other bacteria) in the to improve the interpretability of the therapeutic test. This treatment should be continued for at least three months before being able to judge its effectiveness. For corticosteroids, it is considered only after excluding an infectious etiology. There is no recommendation as to the dose to be used, it will be appropriate to the gravity of the clinical situation. A dose equivalent to that used in attack GCA, 0.7 mg / kg / day could be an adequate dose for adults. If it is favorable, the therapeutic response is usually rapid (within days); there is probably no point in continuing treatment over 15 days in the absence of improvement.

Remember that it must be cautious in interpreting the improvement, corticosteroid having non-specifically a favorable effect on fever and on the PRI rate.