Ministry of Health of the Russian Federation Izhevsk State Medical Academy

CHLAMYDIA INFECTION ETIOLOGY, PATHOGENESIS, CLINICAL CHARACTERISTICS, DIAGNOSIS AND TREATMENT

GUIDE FOR PRACTICAL DOCTORS, REFRESHER COURSE TRAINEES, OBSTETRICIAN-GYNECOLOGISTS, UROLOGISTS, PEDIATRICIANS, REGISTRARS AND INTERNS

IZHEVSK

“EXPERTIZA”

2000

Redactors: Head Dermatovenereology Chair Izhevsk State Medical Academy, c.m.s. R.M. Zagrtdinova, Assistant Professor Gynecology and Obstetrics Chair T.A. Kravchuk, Head Female Venereology Deaprtment of the Republic Dermatovenereology Despensary N.Yu Bychkova, dermatovenereologist RDVD A.A. Petrov, Head Male Venereology Deaprtment of the Republic Dermatovenereology Despensary, N.A. Vilkova, dermatovenereologist RDVD L.V. Petukhova, docent Dermatovenereology Chair ISMA E.I. Kasikhina

Review: assistant professor Obstetrics and Gynecology Chair ISMA, c.m.s. F.K. Tetelyutina; leading dermatovenereologist, Physician-in-Chief RDVD V.A.Merzlyakov

CHLAMYDIA INFECTION. ETIOLOGY, PATHOGENESIS, CLINICAL CHARACTERISTICS, DIAGNOSIS AND TREATMENT. Guide. Izhevsk: Expertiza, 2000 – 36 pages

The guide tackles the epidemiological, etiological, pathogenesis and clinical issues of urogenital chlamydia infection. Modern methods of diagnosis and therapy are presented.

Printed by approval of the Senate, Izhevsk State Medical Academy.

The guide is recommended for doctors, dermatovenereology refresher-course trainees, obstetricians-gynecologists, pediatricians, registrars and interns

INTRODUCTION

Epidemiology situation with sexually transmitted diseases (STD) in the Russian Federation tends to remain grave.

Urogenital chlamydia infection remains the most widespread STD. According to WHO data 89 mln persons contracted urogenital chlamydiasis in 1995 worldwide. 166111 chlamydia infection cases were reported in our country in 1998 which is 8.3% of all STD [E.A. Batkayev, E.V. Lipova]

Urogenital chlamydiasis (UGC) is the second malady among 8 most common venereal diseases (trichomoniasis, chlamydiasis, genital papillomavirus, gonorrhea, genital herpes, HIV infection, syphilis, soft chancre).

According to WHO experts the gravest situation will prevail in the areas where these maladies are hyperendemic, i.e. the places characterized by endemic pesthole of trachoma. Isn't it we (Udmurt Republic) referred to by the WHO researchers. It is here, in Udmurtia, there resides an endemic hotbed of trachoma, which raged 70 years ago. Perhaps this is the reason why our children die of chlamydiasis with the Russian health centers being unable to help us. They feel perplexed by our perinatal chlamydiasis as well as the hemorrhagic fever with renal syndrome and Russian tic-borne encephalitis!

For the last decade chlamydiasis has spread vastly acquiring clear-cut characteristics of an epidemic, increasingly affecting general health statistics and reproductive ability of population. It poses a tangible health risk for people and badly affects the reproductive losses figures.

The survey aimed at revealing the cause of reproductive losses (including abortions and before-one-year-old deaths) which was initiated several years ago in joint effort pediatrics pathomorphologists yielded appalling results: chlamydiasis was reported in 30% of 500 autopsies. In 1998 chlamydia infection was found responsible for 58.3% fetal infections in stillborns and accounted for 32% of malformation cases. The yearly statistics of neonate (0 to 7 days old) deaths steadily deteriorate with chlamydia infection being reported the cause in 27% of cases.

The effects of latent and unattended chlamydia infection include economic and demographic losses which going beyond the domain of health care problems make it a challenge of primary social importance.

The common character of chlamydia infection and steady growth of incidence, especially among young people, is the cause of worry among medical community in many countries, as the most serious aftermath of the untreated chlamydia infection include persistent infertility, incompetent pregnancy, grave gynecological diseases resulting in loss of reproductive organs, a wide spectrum of pregnancy, natal and postnatal complications for mother and child, including perinatal and neonatal deaths.

EPIDEMIOLOGY

According to statistics by the All-Russian Chlamydiasis Center, UGC accounts for 20-70% of nongonococcal urethritis cases, 40%-80% of postgonococcal urethritis cases, 30%-40% of cystourethritis cases, 30%-50% of Reiter’s disease cases, 25%-30% of salpinginitis cases, 5%-14% of conjunctivitis cases, 7-20% of pneumonia in neonates. During prevention screening chlamydia was found in 5% of healthy males [Richinal et al., 1972] and in 7% of females [Holnes et al., 1975]. S. Hillis and co-authors (1996) launching an independent study demonstrated high chlamydia infection incidence in sexually active adolescent females (above 10%), in young females of reproductive age (5%), and in males receiving STD treatment (15-20%). There is a pronounced growth trend in extragenital forms of chlamydiasis: proctitis, pharyngitis, otitis, pneumonia, conjunctivitis, Reiter’s disease.

Chlamydia infection in females is often complicated by deterioration of reproductive function. According to expert estimations 15%-40% females with UGC develop pelvic inflammatory disease (PID). 20% females with PID are diagnosed as infertile, 9% suffer from ectopic pregnancy, 18% complained of pain localized in pelvis minor [S. Krotov, V.Krotov, S. Yuriev, 1997].

Researchers worldwide report that chlamydia was found in 50% females suffering from infertility, while in cases of tubal sterility this figure grew to 70%-75% (Brunham et al., 1985)

Chlamydiasis incidence in pregnant females may range from 10 to 30-40% depending on the patient body being screened, the probability of passing on the infection to the child approaching 40-50%. According to D.A. Ott Research Institute for Obstetrics and Gynecology 84% of children with intrauterine infection develop rhinitis, nasopharyngitis (52,6%), vulvitis (43%), conjunctivitis (33%), gastrointestinal tract diseases (33%), otitis (17.6%).

Persistent form of chlamydia infection was observed in 57% full term children and in 75% immature children who either did not receive specific treatment or underwent insufficient treatment [M.A. Bashmakova et al, 1991]. Almost all researchers confirm sexual transmission of chlamydia infection.

About 70% females who had contact with males having chlamydia infection also test positive for chlamydia. Proportion of females and males with chlamydia infection is 5 : 2. Both males and females infected by chlamydiae are the source of infection for their sexual partners.

According to recommendations by WHO the indications for chlamydia examination are as follows:

1. Chronic inflammatory diseases of the genitourinary system, that do not respond to traditional therapy.
2. Background diseases of uterine cervix
3. Pregnancy
4. Reactive arthritis
5. Chronic conjunctivitis
6. Atypical anemia
7. Fever of unclear nature
8. Disordered menstrual cycle (meno-, metrorrhagia)
9. Spontaneous abortions, premature delivery
10. Therapeutic and diagnostic intrauterine interventions
11. Neonates with chlamydia infection found in mother
12. Neonatal pathology
13. Presence of STD
14. Sexual contacts with chlamydia infected persons
15. Frequent change of sexual partners
16. Persons subject to compulsory occupational pre-hiring and regular on-the-job STD screening under provisions of Ministry of Health directive No.286 of 12/07/1993.

ETIOLOGY AND PATHOGENESIS

The causative agent of urogenital chlamydiasis is Chlamydia trachomatis of serotypes D-K.

Chlamydiae are immobile, gram-negative, cocco-like bacteria, capable of proliferation inside a cell only.

The main characteristics of chlamydiae are intracellular energy-dependent parasitism and unique cycle of development.

Chlamydiae are obligate pathogenic bacteria that parasitize in basal cells of columnar and transitional epithelium. Chlamydiae are not a part of normal human flora and their presence is an indication of infection. The development cycle of a chlamydia cell is unique and peculiar to chlamydia only. Chlamydia can exist in two froms: elementary bodies EB (infectious form) and reticular bodies RB (vegetative form). EBs have average diameter 250-300nm are of orbed shape and are enclosed in a cell wall, containing a firm eccentric nucleoid and protoplast. EBs are a highly contagious agent, adapted for extracellular existence.

One of the most crucial moments in the infection process is attachment of EBs to the surface of a host cell. This is an intricate process which involves:

• Lipopolysaccharides ensuring fusion of the bacterial cell with the target cell;
• Proteins of the chlamydia outer membrane and the membrane proteins of the host cell;
• Electrostatic, hydrophobo-hydrophilic interactions.

The EBs that penetrated into a cell are phagocyted forming an intracellular vacuole or phagosome which does not intermix with the lisosome.

Thus the EB agent becomes immune against the lisosome activity of the host cell and using the energy resources of the affected cell pass the transitional stage of a Transient Body (TB) turning into an RB.

The RB is an entirely different lifeform of chlamydia: it is non-contagious and is well adapted to intracellular existence being metabolically active.

Morphologically the RB refers to gram-negative bacteria of 400-800 by 800-1200nm size, oval or amorphous in shape, with a mobile cell wall and cytoplasmatic membrane. It has a centrally located nucleoid. RB starts binary replication transforming back into EB. RBs replicate from 8 to 11 times generating up to 1000 new infectious bodies (EBs) within one cycle.

The chlamydia development cycle in cytoplasmatic embedments lasts 48-72 hours and normally ends with rupture of the embedment membrane killing the host cell. The content of the embedment spills into the intercellular space and the EBs infect new cells.

Chlamydia shows pronounced sensitivity to UV rays and high temperature. Urogenital chlamydia strains are highly sensitive to 70% ethanol, 0.5% phenol solution, 0.05% silver nitrate solution, 0.5% solution of potassium permanganate, peroxide, ethyl ether. At the same time chlamydiae were observed to survive on a cotton cloth for 48 hours at 18-19C ambient temperature.

Reliable inactivation of chlamydiae is achieved through use of non-titrated sodium hypochlorite solution.

Manifested development of the disease depends on:

1. Initial condition of immunity
2. Massiveness of infection
3. Combination of harmful agents
4. Destabilization of the microbiocenosis in the urogenital tract
5. Deterioration of the structural and functional integrity of the target cell membranes and microcirculations in the affected area.
6. Impairment of the homeostasis system (hormonal and antioxidation state)

During chlamydia infection the body responds with complex immunity sustained only for the time when the infectious agent is present. It is a peculiarity of chlamydia infection that phagocytosis being an important cell immune mechanism which combats bacteria does not work. The reason for that rests in antilisosomal ferments produced by chlamydia cell which prevent digestion of the phagosome content by the host cell. The above factors ensure the persistence of the agent, its circulation in lymphatic and blood systems and onset of a multi-spot infection.

Urogenital chlamydia infection normally proceeds without clear-cut manifestations of acute local inflammatory reaction.

GENERATION OF ANTIBODIES DURING CHALMYDIA INFECTION

At the early stages of primary immune response there start to appear traces of IgM antibodies the overwhelming majority of which is found in vascular streamways. This protects the system against dissemination of infection. Diagnostically meaningful level of contra-chlamydia IgM antibodies can be readily found on the fifth day of the disease with the peak of the IgM content growth in blood occurring by the 8^th – 10^th day. Later, concentration of IgM antibodies drops while IgA antibodies appear. For a short period of time both IgM and IgA antibodies can be regenerated simultaneously which testifies to the climax of the infection process.

About 40% of IgA antibodies are found in blood. The mucous membranes of the urogenital tract produce secretory IgA which prevent attachment of chlamydia to the surface of the mucous membrane cells thus precluding chlamydia from penetration into tissue. Presence or absence of the secretory IgA serves a good prognostic criterion for the course of the disease. Later a steady growth of IgG presence can be observed, accompanied by gradual decrease of IgA levels. The diagnostically meaningful blood levels of the IgG antibodies start to occur by the 15^th – 20^th day of the disease.

Simultaneous presence of the IgA and the IgG in the diagnostically meaningful blood serum titres is a clear evidence of a chronic character of the disease.

With fresh chlamydia infection the IgA and IgG antibodies titres may either increase or decrease while during chronic disease the IgA and IgG antibody levels remain steady.

In a number of cases (3 to 10% according to various authors) during chronic chlamydia infection low IgA antibodies titres are registered in blood for several weeks before appearance of the IgG antibodies.

In asymptomatic patients when IgG and IgA serum titres remain invariably low (in absence of other Ig ) for several weeks there is a good reason to assume a possibility of persistent form of chlamydia infection.

Prolonged circulation of IgG antibodies in a low “border” titre provide evidence that the person went through chlamydia infection long ago.

The persistent form of UGC is determined as retention of atypical minor RBs in the target cells, remaining viable without growth and proliferation for a certain time period with the available chlamydia population existing in unfavorable conditions (L-forms).

CLINICAL MANIFESTATIONS

At present time there are over 20 nosologic forms of diseases associated with chlamydia infection.

The peculiar characteristic of UGC is either a very slight appearance or total absence of symptoms which makes it difficult to determine the moment when the disease is contracted. UGC is very rarely present as a monoinfection and in the majority of cases it is the associated infection that provides the clinical manifestations of an inflammation process against the background of inhibited immune response from the system. The diagnosis should be based on the results of laboratory tests with clear identification of the main affected areas and presence of complications at the moment of examination.

The International Classification of Diseases (ICD-X) identifies the following clinical forms of UGC:

1. UGC of lower areas of the genitourinary system
• Vulvovaginitis (in children)
• Vestibulitis
• Bartholinitis
• Ecto- and endocervitis
• Urethritis
2. Pelvic UGC and UGC of other areas of genitourinary system
• Endomiometritis
• salpingo-oophoritis
• pelviperitonitis
• cystitis
• epididymitis
• orchitis
• orchoepididymitis
• prostatitis
• vesiculitis
3. Extragenital Chlamydia Infection
• Rhinitis
• Tonsillitis
• Pharyngitis
• Nasopharyngitis
• Bronchitis
• otitis
• conjunctivitis, ophtalchlamydiasis
• pneumonia
• arthritis
• Reiter’s syndrome
• Perihepatitis (Fitz-Hugh-Curtis syndrome)
• Chlamydia infection in anorectal area
• Affliction of gastrointestinal tract
• Pyelonephritis

The chlamydiasis agent is usually transmitted through sexual contacts. Life (household) transmission of chlamydia infection is most typical for children of small age. Physical transmission of chlamydia onto mucus membranes of eyes may lead to ophtalmic chlamydiasis. Life transmission of the disease may occur in pools, public baths (conjunctivitis), or include occupational transmission when an obstetrician-gynecologist contracts a disease during operation, delivery or abortion.

Oral sex may lead to pharyngitis, tonsillitis while anal sex contacts may result in proctitis and/or paraproctitis. Intrauterine transmission of the infection has also been confirmed. With chlamydiae residing in the cervical canal of a pregnant woman there is a 50% probability that fetus will be infected, the remaining 50% account for neonate infections during delivery. Thus the basic ways of chlamydia infection spread are:

1. Canal ascending spread (including pregnancy cases)
2. Lymphatic
3. Hematogenic (including pregnancy cases)
4. Spermatozoon assisted
5. Therapeutical or diagnostic intrauterine intrusions
6. Protozoa-assisted (incomplete phagocytosis)
7. Transplacental (during pregnancy)

During UGC incubation period lasts 5 to 30 days, averaging to 21 days.

The infection is most common in people 20-40 years of age. Sexual partners of infected persons test positive for chlamydiae in 70% cases. Human being has neither natural nor acquired post-recovery immunity against chlamydia infection.

UROGENITAL CHLAMYDIASIS IN MEN

In men the infection may reside in urethra, epididymis (epididymitis), rectum (proctitis), conjunctiva (conjunctivitis) and elsewhere (Reiter’s disease).

Two general types of UGC are recognized fresh and chronic, there are cases of hosting chlamydiae, though.

In considerable number of patients chlamydia is a cofactor alongside with other STDs. REGISTRARS AND INTERNS

Chronic chlamydial urethritis in men proceeds along the chronic course with lighter effects than in gonococcal urethritis. The infection starts with negligible signs. Patients complain of white and mucous discharge from the urethral canal, itching and pain in urethra, frequent urge to void urine. During urethritis with insignificant manifestation there may be a scant discharge in form of a “morning drop”. Some authors believe that a reliable symptom to diagnose chlamydiasis is presence of more than 10 leucocytes per high-power field or finding more than 15 polymorphous leucocytes in the first voided urine sediment. Urethroscopy reveals soft infiltrate, transitional infiltrate and littrei.

Chlamydial epididymitis is a result of canal spread of chlamydiae from the posterior urethra. It develops as a cofactor to a main urethral infection as well as prostatitis and vesiculitis. Chlamydial epididymtis usually follows the sequence urethritis – prostatitis – vesiculitis resulting in canal spread of chlamydiae to epididymis affecting the epithelium lining the walls of the seminal duct. Some patients develop symptoms of vasitis and funiculitis. The inflamed seminal duct is palpable as an extremely tender cord. In case of funiculitis the spermatic cord is a sore consolidation. Chlamydial epdidymitis exists in acute, subacute or chronic forms. The chronic form of epididymitis may come either as independent illness or stem from acute and subacute forms. Acute epididymitis is characterized by temperature rising to 39^oC, severe pain in epididymis, radiating to lumbosacral region. The scrotum skin on the side of the affected epididymis is reddened and edematous while the epididymis feels swollen and tuberous to the touch. The subacute form of epididymitis is manifested by moderate pain, subfebrile temperature, and signs of intoxication. Chronic chlamydial epididymitis is characterized by normal temperature, negligible pain, moderate enlargement and uniform consolidation of the epididymis.

Chlamydial orchoepididymitis. Inflammation may affect the membranes of the testes causing orchoepididymitis. The scrotum becomes edematous, red, severely tender to palpation and hot. Patients with chronic unilateral orchoepididymitis in conjunction with prostatitis, vesiculits and vasitis may develop potency and ejaculation troubles.

Chlamydial prostatitis. Chlamydial prostatitis is a common complication of chlamydial urethritis and, as a rule, is a chronic, torpid process. Patients complain of discharge from the urinary canal, sometimes taking place during defecation or after urination, itching in the urinary canal, rectum, sporadic pains in the inguinal region, scrotum, sacrum. Depending on the character and degree of the lesion there may be distinguished catarrhal (affecting the glandular ducts), follicular (affecting the gland follicules,i.e. secretory/incretory epithelium of acinus) and parenchimatous (inflammation spreads beyond the glandular tissue affecting the parenchima of the prostate) prostatitis.

With catarrhal prostatitis the gland is tender to palpation, though reveals no enlargement and is of normal consistency. In case of follicular prostatitis the gland is not enlarged, though palpation may reveal tender nodes (swelling of inflamed follicules) of different consistency. During parenchimatous prostatitis enlargement and tenderness of the gland or one of its lobes, changes in its shape and consistency (hard, soft, flabby) are determined through palpation. The glandular secretion of the prostate contains chlamidyae, small amount of leucocytes and small number or no lecitin inclusions.

Apart from chlamydia, prostatitis may be caused by mixed gonococcal, trichomonadal, mycoplasmatic, viral and bacterial infections.

Chlamydial paraurethritis, vesiculitis and other local complications, as a rule, do not have any particulars or noticeable manifestations.

Chlamydial proctitis comes as a result of chlamydiae inoculation during anal sex. Most commonly chlamidya invasion causes asymptomatic infectious proctitis. Clinically the diease manifests itself through slight pains in rectum, mucuos discharge, pulling rectal pains and sporadic proctorrhagia.

Chlamydiae play an important part in male autoimmune infertility. High incidence of chlamydia infection (39,3%) is typical for men with childless marriage bonds. Males with chlamydial urethritis very frequently test positive for U. Urealiticum (25%-52%).

Very common combination of chlamydia infection with HIV observed lately implies increased susceptibility of chlamydia patients to HIV infection. There are several peculiarities in the immune response to chlamydia in persons with HIV infection. Among other things, growth of the 1gG antichlamydia antibodies titre has been reported in asymptomatic AIDS patients, and low level of antichlamydial 1gA in progressive AIDS cases.

It is suggested that C. trachomatis may facilitate transmission of HIV infection during sexual contacts (vaginal and rectal). Such possibility is accounted for by increased level of the C3 component in persons with chlamydia infection which increases cell invasion capability of HIV.

Reiter's disease is characterized by a combined lesion of genitourinary organs in form of nongonococcal uroprostatitis, inflammatory conditions of eyes and joints in form of assymetric reactive arthritis. Reiter's diease usually ocurrs in persons with genetic predisposition, most commonly in bearers of HLA-B27 hystocompatibility antigen, getting infected through sexual contact.

The classic triad falls far short from being observed in all patients (the so called incomplete Reiter's disease). Symptoms may develop not at the same time ocurring sequentially sometomes after lengthy time intervals. Reiter's disease may take form of tetrad rather than triad, being aggravated by skin and mucus membrane lesions. Visceral and neurological complications are also possible.

Reiter's disease is a common risk for sexually active young males (20-25 years of age), though there have been reports about cases observed in children, teenagers, eldery males and females. Female and male incidence ratios of Reiter's disease are 1:20 and 1:100 respectively.

Reiter's disease progresses through two stages. The first stage, infectious-toxical, takes place with the onset of a primary hotbed of apparent or latent infection in genitourinary system, which becomes a source of infection, toxemia and lesion of individual organs, joints first of all. Etiotropic therapy may prove successful at this time. If the treatment proves ineffective, immunopathologic reactions may develop later which then prevail.

At the second, autoimmune stage, when elimination of the infectious agent cannot affect the course of the disease, is characterized by formation of sites with persistent and recurrent immune inflammation in the joints and other organs.

Clinical characteristics of Reiter's diease include urethritis, arthritis and conjunctivitis. In Reiter's disease cases urethritis and prostatitis may proceed with minimal symptoms, causing little trouble, acute urethritis with serious dysurial disturbances being a rare case. Often only an increased number of leucocytes in a mucous membrane scraping, pathological inclusions in urine and urethroscopy data help to prove inflammaion in the urethral canal. Prostatitis during Reither’s disease is noted for by asymptomatic but very persistent character. Traumatic examination of prostate, rough massage frequently lead to exacerbation of other symptoms – arthritis, uveitis. Acute epididymitis, cooperitis, acute cystitis, pyelonephritis are seldom in men with Reiter’s disease.

Affected limbs (mostly joints) are the most pronounced manifestation of Reiter’s disease, prevailing in its clinical picture and determining seriousness of the case and prognosis for the disease. In the beginning the lesion of the joints develops as a monoarthritis, as the time passes, the joint syndrome becomes polyarthricular. Arthritis is characterized by acute inflammation, pronounced edema of periarticular tissue, tenderness, hyperemia and hyperthermia, effusion into the joint cavity. In a number of cases arthritis is accompanied by such general reaction conditions as fever and weakness.

Most common lesion sites are joints of the lower extremities: knees, ankles, as well as the joints of metatarsi and phalanges. In case of toe trouble lesion sometimes affects all the joints of only one toe which is accompanied by a uniform diffuse swelling of tissue giving the toe a ‘hot-dog’ look.

Arthritis asymmetry peculiar to early Reiter’s disease is retained during the generalization stage of the pathology which frequently involves lesion side switching (ex. right ankle arthritis is aggravated by arthritis of the left knee joint). This peculiar feature was called the ‘ladder symptom”. Muscular atrophy develops early and progresses quickly sometimes reaching extreme severity.

Backbone troubles are less common than arthritis of the limb joints, including and often limited to sacroileitis without pronounced clinical manifestations and diagnosed only by means of an x-ray examination.

X-ray examination may not reveal any substantial differences between Reiter’s disease, rheumatic and psoriatic arthritis. Relatively typical are spongy “calcaneal” spurs, “furry” periosteal proliferations at the sites of tendon attachment and inverted comma-shaped spurs on one or two vertebrae resulting from periostitis. Osteoporosis and narrowing of the articular space with usuration of the joint surfaces are frequent phenomena in the troubled joints.

The lesion of eyes comes as an uncomplicated bilateral conjunctivitis lasting for 5-7 days and disappearing without treatment. Some cases have been reported to take longer to heal. Medium severity and severe conjunctivitis comes in combination with episcleritis and keratitis the latter sometimes being complicated by ulceration of cornea. Iridocyclitis and posterior uvetitis are less comon and occur later, though may lead to deterioration of vision and sometimes blindness, retinal detachment, secondary glaucoma.

Skin and mucous membranes lesions in Reiter's disease are numerous. These include circinary and xerotic balantitis, keratodermia of palms and planta, generalized keratodermia, erosion of mucus membranes in the mouth cavity, psoriatic, erithemato-squamous rash, polymorphous erithemas, urticarious and nodulous eruptions, paronichia, lesion of nails. Prolonged cases of Reiter's disease may lead to myocardial dystrophy, polyneuritis, encephaliis. Course of Reiter's disease: the total duration of the disease episode is 2-6 months. The acute form as well as the prolonged one (with the episode lasting up to 1 year) end up in complete clinical rradiation. Chronic Reiter's disease leading to limited employability and/or disability occur more rarely. Prognosis for acute cases is favorable (0.9% to over 6%), lethal outcomes staying below 0.4%.

CLINICAL PICTURE OF FEMALE UROGENITAL CHLAMYDIASIS

UGC does not have specific clinical and pathognomonic signs in almost 2/3 of female infections, which implies late diagnosing and delayed start of treatment. Very often chlamydia triggering development of PID hampers natural barriers and paves the way for opportunistic pathogenic flora, associated and mixed infections. The tragedy of any contemporary STD rests in fact that it almost never comes alone as a monoculture. It means that chlamydia always vegetates together with opportunistic and absolute pathogenes and hence is “characterless”. Its frequent companions are gonorrhea, trichomonosis, mycoplasmae, viruses, bacterial vaginosis. It is next to impossible to single out the leading role of every agent in this chaos. Nevertheless, cylindrical epithelium of the uterine cervix, the transitional area or ectopy remain the main gates for chlamydia infection. It is worth mentioning, though, that chlamydiae are not always present in the cervical epithelium in females with affected internal organs.

The first signs of UGC in women may include endocervicitis and cervicitis. Endocervical canal is lined with columnar epithelium and has glands whose secretory discharge is of alkaline reaction which provides optimal environment for chlamydiae to thrive. Chlamydial endocervicitis is diagnosed in 12-60% of females screened for STD and in 9-48% of women with gynecological diseases [Vee A.S. Twombly – al – Hallong, 1993).

Chlamydial endocervicitis is frequently asymptomatic. Most common complains are pruritus, scant mucous or mucopurulent discharge from genitalia. The discharge macerate the epithelium of endo- and ectocervix, causing its partial desquamation. The uterine neck becomes edemous, hyperemic, ectopies form a “red chaplet” around the orifice of the cervical canal. Often in prolonged UGC cases the so-called “hypertrophic ectopies” are formed on the basis of the colposcopic picture. According to some authors [V.I Kozlova, A.L. Pukhner, 1995] the hypertrophic ectopy porvides a diagnostic sign of chlamydiasis in form of enlarged lymph follicules in the subepithelial strome of uterine. A relation have been established between UGC and precancerous conditions of the uterine neck.

Primary chlamydial vestibulitis and colpitis are very rare, as chlamydia is unable to proliferate in the multilayer flat epithelium and is sensisitve to acid environment of vagina. At the same time physiological and pathological changes in the multilayer epithelium may provoke its being infected (small age, postmenopause, hypoestrogenia, hysterectomy).

Chlamydial urethritis does not have specific manifestations and patients rarely complain of dysuria, itching sensation, painful urination. It has been established that among females with C. Trachomatis found in cervical canal, 25% also host chlamydiae in urethra.

Paraurethritis is normally concomitant to urethritis. Examination reveals hyperemia of the orifices of paraureteric ducts while palpation sometimes results in dischrage of a mucopurulent secretion drop. Inflammatory process in the bladder is accompanied by pulling pains in the lower abdomen and dysuria. There are no specific urethroscopic signs of chlamydia infection.

The term ‘ascending chlamydia infection” embraces lesion of the mucous membranes of the uterine cavity, tubes, ovaries, ligaments, peritonium and liver. Most often infection spreads through canals (via cervical canal into the uterine cavity and the fallopian tubes), with lymph, blood and sperm. Intrauterine invasions with therapeutic and diagnostic purposes also may cause the ascending chlamydia infection.

Chlamydial salpingitis is the most common variant of the ascending chlamydia infection threatening with grave complications. It is characterized by a prolonged latent, subacute and seldom acute progress of the disease. The worst complication is infertility whose onset depends on the frequency and duration of the inflammation process exacerbations. Sterility may either stem from endotubal occlusions or from lesion of ciliary epithelium without impairment of tubal patency. As has been established after analysis of laparoscopy data, tubal occlusion in interstitial part occurs in 71% females with chlamydia infection while in females with common ascending inflammation and gonorrhea tubal occlusion incidence in ampular part is limited to 53% cases with adhesion processes in pelvis minor area being limited to 1-2 degree. [CDVI, Moscow, 1999]. Other tubal complications include tuboovarial abscesses leading to loss of the reproductive organs, ectopic pregnancy, peritubal adhesions (peritonial sterility).

Chlamydial endometritis, most commonly basal, often occurs after intrusions into uterine cavity (diagnostic scraping, after menstruation, abortion, intrauterine contraception). Endometritis of such kind may be accompanied by uterine bleeding causing anemia or uterine synechia. The most common complaints are pains in the lower abdomen extending to anal region and/or sacrum. There are no specific symptoms of chlamydia infection in the upper region of the genitary system. The course of the disease is often asymptomatic. Taking into account presence of associated bacteria the clinical picture may provide a variety of symptoms of acute and then chronic inflammatory process. Possible aftermaths are sterility, tuboovarian abscesses, incompetent pregnancy.

It might be well to point out that negative testing of cervical and urethral material for C. trachomatis cannot be considered reliable as it does not permit to exclude chlamydial infection in the tubes and uterus which further emphasizes importance of laparoscopy, hysteroscopy, aspiration of endometrium enabling sample taking of the tubal, uterine and peritoneum content for C. trachomatis testing. Therefore chlamydial etiology of salpingitis or endometritis may be positively established only after the infectious agent was found in the tubal or uterine secretion.

N.B. Antipova in 1988 and O.N. Arakelova in 1989 obtained interesting data testifying that bacterial flora in the uterine cervix differed from that in the tubes even during acute salpingitis condition. Infiltration of the tubal walls and adhesion of folds lead to tubal occlusion and tubal sterility. Clinical manifestations are scarce.

The main danger of chlamydia infection rests in its prolonged asymptomatic progress ending up in grave anatomical transformations in organs.

PREGNANCY AND FETAL PATHOLOGY

Chlamydiasis in pregnant women deserves particular attention. Being a typical representation of the TORCH complex, that is perinataly important infections causing grave lesions of fetus, chlamydia infection is asymptomatic in 1/3 of cases and is always mixed with any other opportunistic or absolutely pathogenic infectious agents. In other words it is always a complex infection in 60% to 80% cases developing against the backgorund of bacterial vaginosis, mycoplasmosis, ureaplasmosis, candidiasis, pyelonephritis in pregnant women.

Pregnancy in women with untreated or newly contracted chlamydia infection is a tangible life menace for the mother and baby. UGC in pregnant women more commonly (as compared to general population statistics) leads to spontaneous abortions, death and malformation of fetus, premature delivery, pyelonephritis, uteroplacental insufficiency, underweight of neonates, untimely rupture of amniotic fluid, premature placental detachment, tight adhesion of afterbirth, peritonitis after cesarean section, perinatal and neonatal mortality. Noteworthy is the fact that about 40% of women, infected with chlamydiae, give birth to preemies in 30-36 week [S.D. Voropayeva, 1997].

Chlamydiae in pregnant women often reside in the cervical canal, endometrium, tubes, frequently infect the decidual membranes and cause chorioamnionitis. The main ways of the infection attack are the ascending spread from the uterine cervix, lymphatic spread and hematogenous spread. During hematogenous dissemination chlamydiae invade the placenta causing inflammation, placentitis or focal microabscesses in placenta. Overcoming the trophoblastic barrier chlamydiae infect fetus through the umbilical cord. This infection way provides the most menace. Fetal infection can proceed through lymphatic spread via lymphatic canals from the uterine cervix or the apendages. During the ascending spread chlamydiae most often get inside the uterus through the cervical canal, when the protective function of the endocervical mucus is hampered due to general physiological immune deficiency during pregnancy, though, normally the mucus provides a reliable protection against vaginal microflora.

The fetus may become infected in two ways: most commonly during birth when the fetus proceeds through infected maternal passages or before delivery, while still in the uterus. Intrauterine transfer of chlamydia is pregnant with the most severe generalized infection forms associated with antenatal fetal deaths, neonatal mortality, and congenital persistent diseases.

Intrauterine generalization of chlamydia infection develops after organogenesis, though it does not mean that there are no organic lesions in the fetus, as the infection attacks the newly formed organs, spreading through all the canals and ducts. The affected organs and tissues develop proliferative and adhesive processes, leading to narrowing and obturation of canals, hepatocirrhosis, renal insufficiency, severe forms of hydrocephalia, abscesses of the brain and other birth defects.

It is common knowledge that chlamydia is capable to affect the chromosomal set of the cell bringing teratogenic influence to bear on the fetus. There are the following chlamydiasis forms in neonates:

1. Intrauterine sepsis
2. Meningoencephalitis; granulomatous meningitis
3. Fetal pneumonias
4. Gastrointestinal diseases
5. Respiration disturbances syndrome
6. Prolonged conjugational jaundice in neonates
7. Conjunctivitis, blehparitis
8. Nasopharyngitis
9. Otitis
10. Vulvovaginitis etc.

Due to fetal infection risk married pairs are recommended to undergo screening for chlamydia before the planned pregnancy.

CHLAMYDIA INFECTION IN CHILDREN

Increased incidence of chlamydia infection in pregnant women, the challenging character of chlamydial diagnosing and therapy determines the validity of studying the role of this infection in pediatrics [E.N. Patrusheva, 1995]. Taking into account that the risk of being infected during pregnancy or delivery for a child is 40 – 70% at least 6-7% of children get infected by chlamydia [Y. Maychuk, 1993, I.I Yevsyukova et al, 1993, V.S. Zaitsev, 1995, L.K. Glazkova, N.M. Gerasimova, 1996, I.I Yevsyukova,1997].

Chlamydia infection is diagnosed after a comprehensive examination. In the Udmurt Republic chlamydia infection in children and adults alike is diagnosed by examintaion of mucous scrapings from the urethra and posterior vaginal vault by Direct Immunofluorescence (DIF) with monoclonal antibodies, PCR (polymerase chain reaction) or IFT (immunofermental test) for presence of C.trachomatis antigen. Chlamydia infection is diagnosed when two or more laboratory test methods yeild positive results. Urethral examination material is obtained from a girl’s uerthra either by iintroduction of a disposable catheter for 10-15 seconds or by inserting a probe (eye spoon) 0.5-1cm deep into urethra and taking a scraping with a circular motion. Examination material is also taken from the mucous membrane of the vaginal vestibule and the posterior vaginal vault by introduction of a catheter (or Volkmann's small spoon) through the hymen opening. The catheter is introduced into a boy’s urethra 0.5-0.75 cm deep. In case of physiological phimosis the examination material is taken with the foreskin retracted of as far as it will go by application of a glass to the urethral orifice and inner lobe of the prepuce.

Additional clinical examinations that need to be carried out are: examination of genitalia, recto-abdominal examination, bacterioscopy of the urethral and vaginal discharge, cultural examinations for presence of gonococci, trichomonadas, mycoplasmae, culture for flora and its sensitivity to antibiotics.

As of the moment of screening 48% girls with chlamydia infection presented complaints of pruritus, discharge and frequent urination. Thus, asymptomatic disease is found in 25% of cases. About half of vulvovaginitis cases (46%) were of relapsing character with the mothers complaining about ineffectiveness of treatment administered before. Taking into consideration that only15% patients had been referred to be examined by a gynecologists it is safe to assume that neighborhood pediatricians are not well familiar with this pathology. Many mothers noticing daughters ‘ whites consulted doctors but complete examination was not carried out. The vaginal discharge most often was assigned to “peculiarities of age”, allergy or neglect of personal cleanness.

High incidence of UGC (83%) was observed in girls from troubled families. The high probability of contracting chlamydiasis (59%) calls for compulsory screening of all children regardless of sex and age when chlamydia infection is found in parents. We have analyzed dependence of chlamydia incidence of the contingent subject to examination. The highest incidence was observed among children referred to examination in connection with arthritis, polyadenitis and IFT positive reaction (73%). Polyadenitis incidence in case of chlamydia infection is 10 times as high as in common case (21% and 2%). Most frequently enlargement of the cervical, jaw and inguinal lymph nodes can be observed, i.e. those which are in anatomic vicinity to the focal points of infection.

DIAGNOSIS OF CHLAMYDIA INFECTION

Diagnosis of chlamydia infection should be comprehensive. Several methods are used currently, each having its own advantages and limitations.

Cytologic method – smear staining after Romanovski-Giemsa is almost not used any more due to its low sensitivity and specificity.

Culturing have remained the golden tool of diagnosing as it has the highest specificity, though its sensitivity is 80% and below. This method is very labor intensive as chlamydiae do not grow on artificial nutrient. Isolation of chlamydiae on a monolayer of McCoy, L-929 or HeLa cells is used to culture for chlamydiae. This method is indispensable in diagnosing persistent infections, as it is the only test which permits to judge about viability and morphology.

Immunofermental examination (IFE) with IgG is extensively used in screening, but the method becomes more informative with simultaneous determination of IgA, IgM, IgG antibodies and their titre.

IgM antibodies are determined only in case of acute infection. They can be found in blood in 5 days after contracting the infection, reach their peak by the 10^th day and disappear 2-3 months later even without treatment, and are never found in case of recurrent infection. Since IgM cannot penetrate through the placental barrier their presence in neonates is a testimony to congenital infection.

IgA appear in 7-14 days after infection. After successful therapy their level decreases in 2 weeks and as a rule they disappear totally in 4 months. In case of recurrent infection the IgA level rises again. If the level of these antibodies does not drop after administered treatment one can assume the case in point is a persistent disease.

IgG antibodies appear in 20 days after infection. After treatment their level can stay low for many years. In case of a new infection their level increases.

Simultaneous growth of the IgA and IgG titres often attests to persistent infection. In case of a fresh chlamydia infection IgM and IgA may be generated simultaneously for a short period with total absence of IgG. This method is indispensable in diagnosing chlamydia infection residing beyond the lower regions of the urogenital tract (salpingitis, perihepatitis, epididymitis) and diagnosing Reiter’s disease. Currently the laboratories of the Republican DermatoVnerological Dispensary (RDVD) use Medac (Germany) Immunofluorescence test (IFT) systems of two kinds:

1. Genus-specific – for all type of chlamydiae (C.trachomatis, C.pneumoniae, C.pcittaci, C.pecorum);
2. Species-specific – for C.trachomatis only.

Thus, to obtain a final diagnosis with the help of IFT methods it is necessary to test for both IgG and IgA, preferably using paired serum with 14 days interval.

In addition IFT method is employed now for chlamydia testing directly at the place of infection The advantage of the method is that it permits to use any biological fluid of the organism.

Direct Immunofluorescence (DIF) is the simplest, fastest and rather a reliable method extensively employed worldwide. The examination material is taken with the help of special disposable urethral and cervical brushes, which ensure uniform sampling of cylindrical epithelium from the entire circumference of the urethra. The test sensitivity is about 90%. With special instrument unavailble the reliability of the results is lower, since chlamydia being a topical Infection may be absent in the spot where the test cylindrical epithelium is taken but reside in the neighboring site.

The most sensitive and specific at present are the molecular diagnosis methods PCR (polymerase chain reaction) and LCR (Lygase chain reaction), based on determination of the DNA nucleotic sequence in the subject microorganism. The above methods are so superior to other in sensitivity and specificity that any opportunity must be taken to use them for UGC diagnosing.

Sampling technique for PCR and DIF chlamydia screening methods.

In PCR method patients have to abstain from urinating for 1-1.5 hours before giving a sample while during DIF method giving a sample is best within 15-20 minutes after urination. While taking a sample one should bear in mind what regions of cylindrical epithelium in the urogenital tract provide the best media for chlamydiae to thrive (2.5-4 cm deep in the anterior urethra in males and the mucous membrane 1.5cm deep in the cervical canal of females). During sample taking from the uterine neck removal of the mucous plug is the crucial moment. The proper scraping depends very much on how carefully the mucus was removed. The mucous plug is removed with a cotton tampon and forceps, the sample is then collected with a special spatula Cervex-Brush or Voba-Brush, that have a number of advantages, since getting a representative result requires availability of cells from the entire surface of the uterine neck, cervical canal, transformation zone and outer part of the cervix. Applying the PCR method to examination of the first voided urine sediment in screening males yields rather informative results.

While screening girls samples are collected from the mucous membrane of the vagina vestibule and in certain cases from the posterior vaginal vault through the hymen opening. PCR can also be used to examine saliva, sputum, washes from the mucous membranes of eyes, nasopharynx, bronchoalveolar lavage.

TREATMENT OF CHLAMYDIASIS

Treatment of chlamydia infection must be comprehensive including:

• etiological therapy
• pathogenic therapy
• symptomatic therapy and local treatment administered to the affected sites

When practicable simultaneous treatment should be administered to sexual partners. Intracellular parasitism of chlamydia calls for employment of antibiotics capable of blocking the protein synthesis through accumulation in the cells. Such antibiotics include: tetracyclines, macrolides and quinolones (see Table 1)

The antibiotic therapy duration data available in publications are contradictory. Some sources claim effectiveness of a 7 days treatment with doxycycline administered in a 100mg dose once a day while other advocate a single 1g dose of sumamed. Experiments by other researchers show that 10-14 days long treatment proves effective only in 55-60% cases. According to WHO recommendations, in order to achieve sanation of the organism it is necessary to cover 5-7 reporductive cycles of the bacteria. These recommendations are not always followed. So, the duration of UGC treatment with antibiotics is 14 days extending to about 21 days in complicated cases, which permits to achieve a clinicoetiological cure. The recommended duration of the antibiotic therapy is based on the contemporary knowledge about the development cycle of chlamydia and blocking sufficient number of reproductive cycles for satisfactory sanation of the organism.

In some chronic cases chlamydiasis patients are found to have a variety of immune impairments. Prescription of medications influencing various elements of the immunity should be done after immunological examination of the patient and in strict conformity with the found impairments which sometimes is a challenging task in its own. Use of the interferon inductors, possessing pronounced interferogenic and modulator capability in treatment would be appropriate (see Table 2,3). An important role in treatment of chlamydia infection is given to systemic enzymotherapy (tripsin, chimopsin, chimotripsin, wobenzym etc.) which helps to improve permeability of the cell membranes, stops adhesive processes responsible for autoimmune reactions, and ensures antiedematous and analgetic effects. Enzymotherapy promotes early start of reparative processes and enhances effects of antibiotics facilitating their penetration into cells and increasing their concentration in the blood serum by 20-40% (see Table 4).

TABLE 1

ANTIBIOTICS USED FOR TREATMENT OF UROGENITAL CHLAMYDIA INFECTION

MEDICINE	ADMINISTRATION AND DOSAGE
DOXYCYCLINE	2 100mg administrations daily after a meal. 200mg for first administration
TETRACYCLINE	4 administrations daily after a meal. 500mg per administration.
ERITHROMYCINE	4 administrations daily, 1 hour prior to a meal. 500mg per administration.
SUMAMED	250mg once a day.
CLARITHROMYCINE (CLACYDE)	2 administrations daily after a meal. 250mg per administration. 500mg for first administration
ROVAMYCINE (SPIRAMYCINE)	9 MIU in three doses daily, 3 MIU per a dose, in 2 hours after a meal.
ROXITROMICINE (RULIDE)	300mg daily in two 150mg doses
LOMOFLOXACINE (MAXAQUINE)	600mg daily in a single dose after a meal
OFLOXACINE (TARIVIDE)	600mg daily in two 300mg doses after meals
PEFLOXACINE (ABACTAL)	800mg daily in two 400mg doses during meals
VILPRAFEN (JOZAMYCINE)	1000mg daily in two 500mg doses, in 2 hours after a meal.

Note: An increased dose of antibiotic is prescribed for first administration. Doxycycline, tetracycline and fluoquinolone antibiotics shall not be prescribed to pregnant, breast-feeding women and children under 14. Erithromycine and spiramycine are the only macrolide antibiotics allowed for pregnant and breast-feeding females.

To enhance the therapy efficacy local treatment with preparations of silver compounds, Lugole’s solution, solution of chlorhexidine would be appropriate. Use of perftoran solution, antioxidants etc. as well as prescribing vitamins, ferments, adaptogenes and eubiotics are aimed at stimulation of reparative processes.

UNCOMPLICATED CHLAMYDIA INFECTION THERAPY

1^ST PHASE – preparatory phase (7 days)

Immunocorrective measures (in case of impaired immune status). Systemic enzymotherapy (tripsin, wobenzyme). Local therapy – instillations, washing with 0.05% chlorhexin solution. Vitaminotherapy – Undevit 2 pills, thrice a day.

Antioxidants.

2^nd PHASE – basic

Antibioticotherapy (2 weeks) against the background of continued 1^st phase effort. Antimycotics in therapeutical concentrations according to indications. Digestion promotion ferments (Festal, Mezim-Forte etc.)

3d PHASE – recuperative (2 weeks)

Hepatoprotectors (Carsil, Essenciale etc.). restoration of normal biocenosis (Bifikol, 5 doses twice a day orally for 3-4 weeks, native bifidumbacterine, washings, tampons with native lactobacterine etc.) Focal administration of antioxidant preparations or perftoran to lesion spots. Physiotherapy by indications. Administering treatment to background processes in the uterine cervix (criodestruction, laser vaporization).

TREATMENT OF COMPLICATED CHLAMYDIA INFECTION (in the organs of pelvis minor and scrotum)

Acute inflammatory diseases of female genitalia caused by mixed flora including chlamydia is a challenge for urgent gynecology. This fact is sometimes responsible for difficulties in and late identification of chlamydia infection. In addition, UGC complications in females (peritonitis, tuboovarial abscesses) often lead to radical operations ending in loss of reproductive organs and only transitory eradication of the infection source.

Classic cases of acute salpingitis and endometritis with a positively established etiological factor are coped up with by administering a comprehensive therapy aimed at taking care of both traditional factors (antimicrobial, antiinflammatory, immunomodualting, desintoxicating, antimycotic, symptomatic measures as well as those influencing the microcirculation processes, permeability of membranes, vitaminotherapy etc.) and the revealed infectious agents (type of antibacterial medicine).

Clinical experience shows that complicated manifested cases of UGC in females often remain unidentified in the acute phase, making the urgent team prescribe traditional antibiotics of penicillin type. This circumstance will become the main villain in development of a chronic inflammatory process, persistent chlamydiasis as it promotes generation of L-forms (beta-lactam antibiotics cannot affect intracellular chlamydiae). Aminoglycosides do not influence anaerobics, chlamydiae or streptococci. Fluoquinolones are devoid of antianaerobic effect. Tetracyclines being bacteriostatics are notorious for high incidence of acquired tetracycline resistence.

Therefore it is possible to ensure elimination of the entire spectrum of PID causing agents only through administering combinatory therapy. The most reasonable combinations are as follows:

1. Ceftriaxon (Rocefine) + Doxycycline
2. Fluoquinolones (Ofloxacine, zanocine, tarivid, ciphran) + nitroimidazole medications (tiberal, trichopol, metronidazole)
3. The most effective combination: ceftriaxon + doxycycline + nitroimidazole prepaprations [A.L. Tikhomirov, 2000; S.V. Sidorenko, 2000].

Therapy tactics depends on the degree of clinical manifestations.

In cases of pronounced inflammatory manifestations, caused basically by mixed bacterial infection the first, basic phase of treatment would embrace antibioticotherapy, immunocorrective effort (amixine, timaline, timogen etc.), vitamins-antioxidants (vitamins A, E, ascorbic acid).

7-10 days after the treatment commenced systemic enzymotherapy is added. Antimycotics.

The II (recuperative) phase involves hepatoprotectors, physical therapy (exposure of affected organs to ultrasound, laser-magnetic effects). Gialuronydase preparations (lydase 64 units in subcutaneous injections every other day for 3-4 weeks). Instillation, washing with perftoran solution, 0.05% chlorhexidine solution baths, sodium hypochlorite baths administered focally.

In case of slow inflammatory disease the 1^st, preparatory phase includes inductothermia of the affected organs (2-3 weeks), immunocorrective therapy, systemic enzymotherapy (2 weeks dosage schedule), wash with 0.05% chlorhexidine solution, administered focally.

The II basic phase starting in 7-10 days after the treatment commenced introduces antibiotics, antimycotics. Antioxidants. Polyvitamins. Adaptogenes. (potions of eleuterococc, pantocrin, aralia).

The III, recuperative phase involves hepatoprotectors, physical therapy (exposure of affected organs to ultrasound, laser-magnetic emssions). Gialuronidase preparations. Local therapy (instillations, baths) with perftoran, lactobacterine on tampons into vagina, antioxidants.

While administering therapy to female patients with ectopy of the uterine cervix focal treatment involving use of ferments, medications increasing proliferation processes and causing destruction of tissue should be allowed only after the results of thorough colposcopy and smears cytology from ecto- and endocervix excluding precancerous condition become available.

TREATMENT OF UROGENITAL CHLAMYDIA INFECTION IN PREGNANT WOMEN

Treatment of UGC in pregnant women has been a challenge worldwide. Regretfully no standard therapy technique has been developed yet. The reason is that drugs and medications can affect the fetus, the risk being especially high during the first three months of pregnancy.

The traditional antibiotics therapy with erithromycine ( four 0.5g doses daily for 14 days) which is recommended by the WHO researchers (1989) is ineffective, as erithormycine is decomposed by the stomach acid and is suspected to cause jaundice in pregnant women and neonates, the latter fact calling for earnest study.

New generation of antibiotics coming into existence lately are an inspiring alternative to erithromycine. They are characterized by convenience of use, possess beta-lactam security, penetrate into the cell more readily and are active against a wide range of pathogens. Antibiotics should be employed starting with the second trimester of pregnancy (16-18 week).

Macrolides: Rovamycine (Spiramycine) in three 3 MIU doses daily, for 10 days.

Vilprafen (Jozamycine) 1000mg daily in two 500mg doses, for 15 days (admission period can be reduced to 10 days).

An encouraging factor in treating pregnancy chlamydiasis is immunomodulating therapy with recombinant (bioengineering) interferon inductors.

Viferon – 1 suppository twice a day for endovaginal application, 1 week.

The interferonocorrective therapy is comlemented by phytogenic adaptogens (eleuterococc, gin-seng, schizandra, wolfberry), endovenous mielopid injections 1 dose daily for 5-7 days.

Other chlamydiasis therapy principles remain traditional with proper regard to pharmacological influence on the fetus.

Thus a draft schedule for pregnancy chlamydiasis treatment would be as follows:

1. With early identification and woman’s desire to preserve pregnancy, the first trimester is devoted to identification of all associated infections and tender therapy aimed at restoration of vaginal biocenosis (tampons with lactobacterine ¹10-15), adaptogens, polyvitamins.
2. Starting with the 2^nd trimester the basic antibioticotherapy is prescribed with use of the above said drugs (erithromycine, rovamycine, jozamycine) with due regard to the principles of comprehensive treatment:
• Immunocorrection (recombinant interferons, laser therapy, blood UV exposure);
• Antimycotics (nistatine, pimafucine etc.)
• Eubiotics (lacto-, bifidumbacterine) per os and for endovaginal administration;
• Systemic enzymotherapy (wobenzyme, tripsin, chemotripsin, chimopsin) 1-2 times daily in form of micro-enemas during treatment with antibiotics;
• Hepatoprotectors (Karsil);
• Local sanation through administration of chlorine antiseptics (dioxidine shall not be administered during pregnancy): chlorhexidine, sodium hypochlorite.
3. In 2 months an infection elimination test should be carried out.
4. If required, the treatment is repeated during 34-36 weeks using some other antibiotic or interferon corrective therapy is administered;
5. Monitoring the condition of the fetoplacentary system and taking corrective measures
6. Reinfection prevention through treatment of both partners.

At present time chlamydia infection is not viewed as an indication for artificial abortion, though the grave and unpredictable character of this condition force to regard it as a malady even when latent which requires treatment even during pregnancy.

The best strategy to ensure successful pregnancy is pregravidal instruction of married couples.

TREATING CHLAMYDIA INFECTION IN CHILDREN

Medications are prescribed with regard to age, weight and accopmanying infections.

Based upon electronic morphometric study by I.N Lupan (1977) that confirmed practicability of a month-long break in therapy, we recommend a complex therapy consisting of several phases: the first phase envisages use of an immunomodulator, antibiotic and a macrolide antimycotic: dosage being 50mg per kilo of weight daily, rulide (dosage 5-8mg/kg daily), erithromycine (dosage 50mg/kg daily), sumamed (dosage 5mg/kg, 10mg/kg for the first dose), rovamicyne (dosage 10MIU/kg daily), chlacyde (dosage 10mg/kg daily), vilprafen (50mg/kg daily). Duration of antibacterial therapy is 14 days.

After that for one month children must receive preparations promoting intracellular metabolism and membrane stability (antioxidants, adaptogens), improving intestinal functions (eubiotics), enhancing restoration of microcirculations (trental, curatil), favorable for evacuation functions of the kidneys and bile cyst (phytopreparations).

Upon completion of the second phase the condition is monitored with the help of DIF, PCR and IFT tests. In case of negative testing the next examination date is set. Positive test results is a good reason to run the tests again and in case positive testing is confirmed treatment is repeated. This helps to reduce the duration of antibiotic therapy and simultaneously increase the treatment efficacy.

The third phase includes an immunomodulator, antibacterial preparation of some other type (clindamycine, doxycycline), antimycotics, ferments and hepatoprotectors.

Individual immunocorrection is administered in all cases in accordance with found changes. In case of chlamydia infection children reveal acquired complex immunodeficiency with impairment at the cellular level on the background of inadequate cooperation between the elements of the immune system. This was the reason why immunomudulators became a part of the comprehensive therapeutical effort.

Thymical hormone factors (thymopoetine, thymaline, T-activine etc.), interferon-like cytokines (reaferone, viferon, neovir, cycloferon) and synthetic preparations (levamizol, diucifon, pentoxyl, methyluracil) are used with strict control over immune parameters. Taking into consideration variable character of immune deviations in children with urogenital chlamydiasis, immunocorrection must be targeted at confirmed impairments strictly commensurate in each individual case.

To avoid candidiasis antibacterial medications are administered simultaneously with antimycotics (diflukan, nizoral, pimafucine, nistatine). The administration of etiothropics should be accompanied by hypoallergic diet.

Presence of opportunistic pathogenic cofactor (stphylococci, streptococci, protei, Coli etc.) requires administration of homologic bacteriophages (staphylococcal, streptococcal, proteal, clebsiellesic, coliphage). These preparations are prescribed to be taken and for focal application consistent with the type of revealed microflora.

Per os prescriptions are taken in age-dependent dose divided into three administrations 1.5 hours before meals for 7-10 days. Focal application of bacteriophages is carried out in form of 2-5ml daily vaginal instillations for 7-10 days. Sitting baths with phytoteas are recommended in case of pronounced clinical symptoms. To facilitate reparative process oil solution of vitamin A, methyluracil ointment, actovegin gel, phytostimulin cream are employed.

The final phase of focal therapy involves instillations or ointments with alternating eubiotics: bifidumbacterin, acilact or lactobacterin, 5 doses per administration once a day, for 10-12 days.

The recommended variants of comprehensive treatment of chlamydia associated vulvovaginitis permited to achieve 69% recovery after a single phase etiotropic therapy and 97% recovery after a multi-phase treatment.

TABLE ¹2

INTERFERON INDUCTORS USED IN CHLAMYDIASIS THERAPY

MEDICINE	ADMINISTRATION AND DOSAGE
AMIXINE DURING EXACERBATION PERIOD	250mg daily for 2 days, then 125mg every other day for 3-4 weeks
POLUDAN	200mg in daily intramuscular injections for 10 days
CYCLOFERON	200mg in daily intramuscular injections for 10 days
NEOVIR (during exacerbation)	250mg in daily intramuscular injections for 3 days, followed by 2 or 3 250mg intramuscular injections every other day.
RIDOSTINE	Three 8mg intramuscular injections, separated by a 2 days pause
INTERFERON	0.5-1 MIU intramuscular injection every other day for 2-3 weeks
LEUCOFERON (LF)	1 ampoule (10’000 IU) intramuscular injection, 2-3 injections a week for 2-3 weeks.
INTERLOCK	500’000 IU daily intramuscular injections for 2 weeks
REAFERON (INTERFERON ALFA 2A)	1 MIU daily for 2 weeks
REALDIRON (INTERFERON ALFA 2B)	1MIU daily intramuscular injections for 2 weeks

TABLE ¹3

IMMUNOMODULATORS USED IN CHLAMYDIASIS THERAPY

MEDICINE	ADMINISTRATION AND DOSAGE
POLYOXIDONIY	ten 6mg intramuscular injections every other day. In case of persistent UGC antibiotics start to be administered on the tenth day.
TACTIVINE 1.0ML	7 to10 0.5-1.0 hypodermic injections administered every other day
THYMALINE 1.0ML	Ten 1ml daily intramuscular injections
DERINATE 1.5%, 5.0ML	5 to 10 5.0ml intramuscular injections separated by a 2 days pause.

TABLE ¹4

SYSTEMIC ENZYMOTHERAPY

MEDICINE	ADMINISTRATION AND DOSAGE
TRIPSIN	10 to 15 10mg daily intramuscular injections
WOBENZYM TAB.¹40	6 pills daily in 3 doses 40 min. prior to a meal for 2-3 weeks
FLOGENZYM TAB.¹60	6 pills daily in 3 doses 30 min. prior to a meal for 2-3 weeks
LIDAZA 64 units	10 to 15 64 units daily hypodermic injections

Due to frequently ineffective treatment of chlamydia infection the necessity to improve therapy efficacy remains a valid challenge. High incidence of allergies among population, excessive sensibility to many medications, including antibiotics, and increase of antibiotic resistance make development of non-pharmacological therapy methods a topical issue. One of the most promising lines of research is the effect of IR radiation on biological structures. IR-therapy device “URO-BIOPHONE” invented and produced in Russia is a considerable achievement in treatment of urogenital system.

The device is a small size, easy to use instrument. The operating principle is based on changing the electric potential at the cellular membranes of microorganisms, leading to reduction of the produced toxins, which facilitates their neutralization by the immune system and promotes healing.

After completion of R & D process and approval of the medico-technical parameters, the device was subject to comprehensive technical and clinical tests in appropriate health care institutions and was recommended by the Ministry of Health Committee for quantity production. The manufacturer is the Government-owned enterprise ‘Izhevski Mekhanichesky Zavod”.

Therapy session lasts 24 seconds. When put to use the device generates a package of electromagnetic waves in the non-thermal band of IR range. The radiation spectrum of the appliance corresponds to that of a number of pathogenic microorganisms, being inactivated. Operation of the device results in reduction of metabolism intensity between chlamydia and the host cell adversely affecting chlamydia vulnerability.

As a rule urogenital chlamydiasis is always accompanied by a cofactor pathogenic flora. Therefore, to add to the efficacy “URO-BIOPHONE” is designed to inactivate a number of cofactor pathogens: staphylococci, clebsiella, morganella, yersinia, trichomonada, gardnerella, mycoplasma, candida, human papilloma virus. Of course the above microorganisms do not provide an exhaustive list of chlamydia associated pathogens, though their inactivation will be a positive contribution to a comprehensive cure effort. “URO-BIOPHONE” inactivates both the above said pathogens and their L-forms.

We examined 3100 (1650 male and 1550 female) UGC patients admitted in Udmurt Republic Dermatovenereological Dispensary (RDVD), most of them being sexual pairs. Average age of the patients was 28.5 (18 to 45). 1201 male patients showed clinical manifestations of an active urogenital infection: anterior urthritis was observed in 50% cases, total urethritis – in 40% cases, orchoepididymitis – in 16% cases, prostatitis – in 30% cases, prostatovesiculitis – in 5% cases. Clinical manifestations of the disease were observed in 1328 female patients: cervicitis was found inr 60% cases, urethritis - in 39% cases, bartholinitis - in 7%, endometritis – in 16%, salpingitis – in 47%. The disease history varied from 3 months to 13 years (average being 2.5 years). 1922 patients (62%) had antibiotics therapy mentioned in the history of the UGC disease. Etiological identification of chlamydia infection was done through examination of urethral and cervical canal scrapings by DIF with monclonal antibodies “ChlaMonoScreen” of firm “Niarmedic” and by IFT test for presence of group-specific M and G immunoglobulins in blood serum (firm “AO Vector Best”). Topical diagnosing in males was carried out by means of urethroscopy, palpation of prostate and seminal vesicles and examination of their secretion. Topical diagnosing in female cases was carried out by means of bimanual examination, ultrasonic examination of pelvic organs. Common blood, urine, and blood biochemistry test were carried out too. Monotherapy (20 sessions) with the ‘URO-BIOPHONE” device was administered in 2150 cases. Complex treatment: antibiotics (sumamed, rovamycine, rulid) during 14 days and 14 to 20 sessions with BIO-PHONE was administered in 950 cases (see the therapy schedule below).

TREATMENT OF CHLAMYDIA INFECTION WITH URO-BIOPHONE

Antibiotics (doxycycline, vilprafen, rovamycine, rulid etc.) according to common dosage scheme + simultaneous Uro-Biophone therapy: 22-24sec. long sessions every other day during 14 days, followed by two weeks of 22-24sec. long sessions administered once in three days, then 1 session weekly during weeks 5 and 6.

Note: the antibiotic treatment duration is limited to 12-14 days.

In case of intolerance to antibiotics Uro-Biophone therapy is administered as follows:

22-24sec. long sessions administered every other day during 21 days, followed by

a 22-24 sec. session taken once in 3 days during 14 days, winding up with one weekly 22-24sec. session during weeks 6 – 10.

Note: Use of the appliance permit to do without immunostimulating therapy and antimycotics. Ferments are prescribed by indications.

In 2-3 weeks after completion of the main therapy 2853 (92%) patients were subject to adequacy check. 1248 (64%) examinees of total 1950 (80%) who received monotherapy tested negative and 702 (36%) examinees tested positive. In 887 (98%) examinees of total 903 patients who had received complex treatment, DIF and IFT yielded negative results and only 16 (2%) tested positive.

The obtained results permit to recommend employment of “URO-BIOPHONE” in treatment of chlamydia infection.

CURE CHECK

Chlamydiasis monitoring test by DIF method should not be run earlier than 30 days after treatment completion and earlier that 45 days after treatment for PCR test method. Earlier screening may yield false positive results, which cannot be used to appraise the effectiveness of the administered treatment and presence of viable chlamydia, indicating only the availability of cellular walls of microorganisms or their fragments. The culture method can be employed in two weeks after completion of treatment. Serologic study may be run 3 month later after therapy in order to make sure that IgG level is twice as little while IgA antibodies are absent.

Monitoring tests should be administered to all sexual partners who are advised to use barrier contraception until they test negative twice.

LIST OF REFERENCE

1. “Diseases of the uterine neck, vagina and vulva”, under the editorship of prof. V.P. Prilepskaya, Moscow, “MED press”, 1999
2. “Sexually transmitted diseases”, Nizhny.Novgorod State Medical Academy, N.Novgorod,1999
3. V.I. Kozlova, A.F. Pukhner “Viral, chlamydial and mycoplasmic diseases of genitalia”, Moscow, “Avicenta” UNITY press, 1995
4. E.A. Batkayev, E.V. Lipova “Urogenital chlamydiasis: manual”, Moscow, 2000
5. E.K. Ailamazyan “Chlamydia infection in obstetrics”, St. Petersburgh. 1995
6. N.a. Gomberg, I.N. Yesaulova, N.S. Gladkova “Incidence of chlamydia and ureoplasmic infections in reproductive age females with conditions of pelvic organs”, Vestnik Dermatologii, ¹9, 1988
7. Yu.K. Skripkin “Venereal skin diseases”, Guide for Doctors, 1996
8. O.K. Shaposhnikov “Venereal diseases”, Moscow, “Meditsina”, 1980
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10. I. Gromyko “STD epidemic in Eastern Europe countries”, ZPPP, ¹6, 1999
11. K.K. Borisenko “Diagnosis, treatment and prevention of sexually transmitted diseases”, Guidelines, SANAM Ass., 1996
12. A.M. Meshkov “Comprehensive treatment of patients with inflammatory diseases of urogenital tract of chlamydial and ureoplasmic etiology”, synopsis of the candidacy thesis, 1987
13. Manual. “Role of chlamydia in pathology of the urogenital tract (diagnosis and therapy methods)”. Moscow, 1996.
14. Yu.K. Skripkin, V.V. Delectorsky, K.K. Borisenko “Urogenital chlamydiasis, ureaplasmosis, gardnerellasis”, 1998
15. M.N. Shvelidze “Administering comprehensive treatment to females with inflamatory urogenital diseases of trichomonadal-chlamydial-ureoplasmic etiology”, synopsis of the candidacy thesis, 1998
16. N.M. Ovchinnikova, V.N. Bednova, V.V. Delectorsky “Laboratory tests of STD’s”, Moscow, “Meditsina”, 1997
17. “Chlamydiasis. Clinical manifestations, diagnosis and therapy.” Methods guide. Under editorship of prof V.I. Krasnopolsky, prof. V.V. Delectorsky et al.
18. S.D. Voropayeva “Diagnosing and treating genitalia chlamydial infection in females”, Aksherstvo i gynekologiya, ¹5,1997, pp. 60-63
19. M.V. Fyodorova, V.N. Serov, A.N. Strizhakov, T.G. Tarasova “Fetal infections”, Vestnik Rossiyskoy assotsiatsii akusherov i gynekologov, ¹2, 1997, pp.89-99