Brazilian purple fever

What is Brazilian purple fever?

Brazilian purple fever was first reported in one of the districts of São Paulo in 1984. Since then, there have been occasional outbreaks of the disease in the cities of São Paulo. Similar cases of the disease recorded in Australia. Currently, there is little information about the bacteria that cause the infection and how to transmit the disease, but fever always affects children under the age of 10 years.

Causes of Brazilian purple fever

The causative agent of Brazilian purple fever is small (0.3-0.4 x1.5 µm in diameter) fixed, non-spore-forming gram-negative coccobacilli, which, when deeply stained, can be seen as gram-positive. Gram-stained bacteria of the genus Haemophilus appear as small pale-colored Gram-negative rods, sometimes forming thin filaments. Small size, cellular polymorphism and insufficient staining with safranin can significantly complicate the detection of hemophilic bacilli, so some authors suggest that, along with Gram-staining, be stained with methylene blue. In this case, microorganisms (MOs) have a blue color on a gray-blue background. Bacteria are facultative anaerobes. Of the six capsular serotypes (from a to f), type b (Hib) is more common. Non-encapsulated strains, which are called non-typeable, are also isolated. Hemophilus sticks, mostly non-typeable strains, often form part of the normal microflora of the mucous membranes of the upper respiratory tract in healthy adults and children. The frequency of nasopharyngeal carriage in adults varies widely, reaching in some cases 75%. In the United States, prior to the introduction of a conjugate vaccine, Hib strains were detected in the nasopharynx of 3-5% of children. In Russia, the carrier frequency in children is no more than 5%, and non-typeable forms colonize the oropharynx of healthy children with a frequency of 35-78%, depending on age. Non-typable strains of H. influenzae often colonize the lower airways in patients with COPD and cystic fibrosis. H. influenzae is a human exclusively pathogen. Infection occurs by airborne droplets or by contact with a contaminated material. In humans, 8 hemophilic species can be distinguished, the main pathogens of which are H. influenzae and H. ducreyi.

Haemophilus influenzae (Afanasyev-Pfeiffer wand) causes respiratory and meningeal infections, endocarditis, abscesses, arthritis, skin, nails and eyes.

Haemophilus influenzae biovar aegyptius (Koch Wicks stick) causes conjunctivitis and Brazilian purple fever in children.
Haemophilus ducreyi (Ducrey-Unna’s wand) is the causative agent of venereal disease known as chancroid.

H. influenzae is highly whimsical when cultivated on artificial nutrient media. Its growth requires growth factors contained in red blood cells (which reflects the name Haemophilus – “blood loving”), in particular X and V. However, in the native sheep and human blood there are enzymes (NADase) that destroy the V factor. Therefore, V-dependent hemophilic species does not grow at all well or not at all on blood agar (CA) prepared on the basis of mutton or human blood. On a SV prepared on the basis of horse or rabbit blood, hemophilic rods can grow in the form of the smallest point colonies. They possess cytochrome oxidase and catalase activity. The presence of a specific mouse odor is characteristic of a pure culture of hemophilus bacilli.

To improve the release of H. influenzae from clinical material, it is recommended to use chocolate agar. The probability of the release of MO from clinical material of the lower respiratory tract increases with the use of nutrient media containing bacitracin (either ready commercial media or those prepared on the basis of chocolate agar can be used). Commercial saponinobacitracin discs or bacitracin discs (10 U) can also be used. The high concentration of this antibiotic inhibits the growth of most other MOs, which are representatives of the microflora of the respiratory tract (staphylococci, streptococci, etc.), which makes it possible to obtain the growth of a hemophilic rod from highly contaminated clinical material. The optimal incubation conditions for H. influenzae are a humid atmosphere with a high content of CO2 (5-10%) and a temperature of 35-37 ° C. Such conditions can be created in a CO2 thermostat or when the cups are incubated in a desiccator with a lit candle. As a result of the candle burning, the oxygen concentration decreases and the CO2 level rises, reaching 3%. However, even with the strictest adherence to the recommendations of the National Committee on Clinical Laboratory Standards NCCLS, when testing H. influenzae for macrolides, the disco-diffusion method reveals more than 50% of errors in the interpretation of results, therefore it is recommended to use E-tests as the most reliable and simple quantitative method. Due to the fact that the hemophilic bacillus is distinguished by its low viability in the external environment, it is recommended to use vehicles and immediately (no later than 2 hours) deliver the material to the clinical laboratory.

Pathogenesis during Brazilian purple fever

The pathogenicity of hemophilus varies in different strains. The main factors of pathogenicity of H. influenzae are: capsule (especially in H. influenzae serotype b) and drank. Flagella contribute to the adherence of MO with the surface of the mucous membrane of the respiratory tract and further penetration into the submucous membrane, which leads to the development of an inflammatory reaction. The capsule polysaccharide makes it difficult for bacteria to be absorbed by phagocytes and facilitates adhesion to the mucous membrane of the upper respiratory tract, while endotoxin (lipopolysaccharide) damages mucous membrane cells, causes inflammation in the tissues of the central nervous system and triggers the development of sepsis. Non-typeable strains cause the disease by damaging the surface of the respiratory epithelium cells. Strains exhibiting increased virulence are able to migrate to the lymph and bloodstream.

H. influenzae cause a large number of different infections, including life-threatening patients. In general, all infections caused by hemophilic bacilli can be divided into 2 types: invasive and non-invasive.

Non-invasive infections occur in the process of the spread of MO through the mucous membrane of the respiratory tract. Acute sinusitis, acute otitis media and exacerbation of chronic bronchitis, as a rule, are complications of viral infections that reduce local immunity and impair mucociliary clearance.
Most non-invasive infections cause non-typeable strains, for which the presence of the outer membrane protein P2 is a major virulence factor.
Invasive infections, especially meningitis and epiglottitis, are predominantly produced by Hib strains and are of hematogenous origin. A type b capsule consists of polyribosylribitol phosphate (PRF), that is, it contains pentose (ribose) as a monomer, unlike other types containing hexose. This is probably what determines the higher virulence; it is the most important virulence factor, since it protects the MO from phagocytosis, opsonization, and complementary lysis. The low incidence of invasive infections in children during the first two months of life is due to the presence of maternal antibodies to PRF. With an increase in the population of people with antibodies to PRP, the frequency of invasive infections also decreases. In the case of the development of a disease caused by M. сatarrhalis, infection occurs endogenously due to the spread of MO from adjacent mucous membrane areas, however, the mechanisms of the development of these infections have not been significantly studied. Most often, M. catarrhalis is excreted in diseases of the upper respiratory tract, conjunctivitis and pneumonia in children. Among the adult population, in most cases it is found in laryngitis, bronchitis and pneumonia in patients with COPD. Of the etiological agents in chronic bronchitis, M. catarrhalis is inferior only to H. influenzae and S. pneumoniae, and in 54.6% of all patients with infection caused by M. catarrhalis, COPD is diagnosed. In patients with immunodeficiency states, this MO can cause endocarditis, pericarditis, and septic arthritis.

Symptoms of Brazilian purple fever

The disease begins with purulent conjunctivitis. In some cases, there are fever, vomiting, abdominal pain and a purple rash, other symptoms are similar to meningococcal infection. If the disease is not treated, sepsis can develop.
Bacteria can be detected in the blood and cerebrospinal fluid.

Characterized by systemic lesions and rashes (without petechiae). Mortality reaches 70%.

Diagnosis of Brazilian purple fever

The principles of isolation of the pathogen are similar to those in infections caused by H. Influenzae. Gram-negative pleomorphic sticks are found in stained smears. The final identification of the isolated pure culture is carried out in the agglutination reaction (RA) with rabbit serum immunized with museum strains of Koch sticks.

Brazilian Fever Treatment

According to the results of studies conducted, infections caused by H. influenzae strains that do not produce β-lactamase have aminopenicillins (ampicillin, amoxicillin) that can be considered the means of choice, since they are not inferior to inhibitor-resistant penicillin and cephalosporin II.

The sensitivity of H. influenzae to other AMPs varies. High sensitivity persists to fluoroquinolones. Although most strains of H. influenzae are susceptible to macrolide antibiotics, these drugs cannot be regarded as effective against this MO. This is due to the fact that macrolides are characterized by borderline values ​​of BMD in relation to H. influenzae (from 1 to 8 mg / l). Concentrations of macrolide antibiotics in the blood, sputum, and tissues of the bronchopulmonary system are usually lower than their BMD values ​​for H. influenzae, which does not allow for the eradication of the pathogen. This is characteristic of all macrolides, including azithromycin, which is considered as the most active in vitro against H. influenzae. This statement was confirmed in a clinical study in which it was shown that the use of azithromycin does not result in eradication of the pathogen from the middle ear cavity in patients with acute otitis media (R. Dagan, 1997).

With respect to strains producing β-lactamase, protected aminopenicillins, 2nd generation cephalosporins and other more advanced β-lactams are highly active. However, in light and moderate respiratory tract infections, the use of III-IV generation cephalosporins and carbapenems can hardly be considered justified. In fact, the choice must occur between aminopenicillins, on the one hand, and protected aminopenicillins, as well as second generation cephalosporins, on the other. Clear advantages have protected aminopenicillins and second generation cephalosporins due to the relatively high frequency of production of β-lactamase (on average in Europe – 14.5%). In severe infections (meningitis, epiglotitis, sepsis), the most reliable means are third-generation cephalosporins (ceftriaxone, cefotaxime).

Treatment of M. catarrhalis infections is not associated with significant problems. MO shows a high level of natural sensitivity to the majority of ILA. M. catarrhalis is highly sensitive to most β-lactam antibiotics (aminopenicillins, cephalosporins, carbapenems), however, the effectiveness of semi-synthetic penicillins is limited to β-lactamase, which is produced by more than 90% of the strains. The enzyme is effectively suppressed by known inhibitors and is not capable of destroying cephalosporins, which almost determines the 100% sensitivity of the strains studied in the framework of the Alexander Project study to amoxicillin / clavulanate and cephalosporins.

M. catarrhalis is highly sensitive to macrolides and fluoroquinolones. Sensitivity to tetracyclines, co-trimoxazole, chloramphenicol remains, and acquired resistance to the listed antibiotics (according to Alexander Project research results) either does not occur at all or occurs in 2-3% of cases (to co-trimoxazole).

Prevention of Brazilian purple fever

To prevent severe, life-threatening infections caused by Hib strains, conjugated vaccines have been developed that are characterized by high safety and immunogenicity, including in children younger than 18 months.

Currently, the conjugated Hib vaccine is included in the immunization schedule for children in the United States, Great Britain, Finland and other countries. The new vaccination schedule of Ukraine, approved at the beginning of 2006, also provides for triple vaccination of children against Hib infection at the 3rd, 4th and 5th months of life. The possibility of including Hib vaccination in the expanded WHO immunization program is being discussed.

An article in The Pediatric Infectious Diseases Journal published an article on the epidemiological characterization of non-type b infections caused by H. influenzae. Due to the widespread use of the vaccine against hemophilic type b infection in the twentieth century, the number of diseases caused by these MOs has sharply decreased. Thus, H. influenzae, not belonging to type b, is a rare pathogen in children, but in the era of vaccination against H. influenzae type b, this pathogen becomes a more frequent cause of disease in fully vaccinated children.

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