SPIROCHETES Dr.T.V.Rao MD Dr.T.V.Rao MD.

SPIROCHETES Dr.T.V.Rao MD Dr.T.V.Rao MD

Spirochetes Spirochetes -are elongated motile, flexible bacteria twisted spirally along the long axis are termed spirochetes Contain – endoflegalla which are polar flagella wound along the helical protoplasmic cylinder and situated between the outer membrane and cell wall Dr.T.V.Rao MD

Taxonomy Order: Spirochaetales Family: Spirochaetaceae
Genus: Trepanoma Borrelia Family: Leptospiraceae Genus: Leptospira Dr.T.V.Rao MD

Human pathogen Genera Trepanoma Borreilia Leptospira Dr.T.V.Rao MD

How they appear Dr.T.V.Rao MD

What are Trepanoma Nema Meaning thread Relatively short and slender
Trepos – Turn Nema Meaning thread Relatively short and slender With fine spirals pointed and round ends May be pathogenic or commensals in the mouth Dr.T.V.Rao MD

Spirochaetales Associated Human Diseases
Genus Species Disease Treponema pallidum ssp. pallidum pallidum ssp. endemicum pallidum ssp. pertenue carateum Syphilis Bejel Yaws Pinta Borrelia burgdorferi recurrentis Many species Lyme disease (borreliosis) Epidemic relapsing fever Endemic relapsing fever Leptospira interrogans Leptospirosis (Weil’s Disease) Dr.T.V.Rao MD

Venereal Syphilis Venereal Syphilis caused by T.pallidum Endemic syphilis T. pallidum Yaws T.pertune Pinta T.carateum Dr.T.V.Rao MD

Discovery “Everything” happened mostly in Germany from 1905 to 1910
Discovery “Everything” happened mostly in Germany from 1905 to 1910 ! With a short life of 35 years, Fritz Schaudinn ( ) and Paul E. Hoffmann ( ) discovered Treponema pallidum in serum in 1905. This paper is: F. R. Schaudinn and P. E. Hoffmann:Vorläufiger Bericht über da Vorkommen von Spirochaeten in syphilitischen Krankheitsprodukten und bei Papillomen. Arbeiten aus dem Kaiserlichen Gesundheitsamte, 1905, 22 (2): Paul Ehrlich, father of immunochemistry and his assistent Hati. Fritz Schaudinn Dr.T.V.Rao MD

Syphilis Named from poem published by the Italian physician and poet Girolamo Fracastoro – shepherd from Hispaniola named Syphilis who angered Apollo and was given the disease as punishment Dr.T.V.Rao MD

"He who knows syphilis, knows medicine" Sir William Osler
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Treponema pallidum Described in 1905 by Schaudinn and Hoffman, Hamburg
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Trepanoma pallidum Greek words trepo “turning” & nema “head”
Morphology Motile, sluggish in viscous environments Size: 5 to 20 μm in length & 0.09 to 0.5 μm in diameter, with tapered ends Structure Multilayer cytoplasmic membrane Flagella-like fibrils Cell wall Outer sheath (outer cell envelope) Capsule-like outer coat Dr.T.V.Rao MD

Treponema pallidum. Spiral spirochete that is mobile of spirals varies from 4 to 14 Length 5 to 20 microns and very thin 0.1 to o.5 microns. Can be seen on fresh primary or secondary lesions by dark field microscopy or fluorescent antibody techniques Dr.T.V.Rao MD

General Overview of Spirochaetales
Gram-negative spirochetes Spirochete from Greek for “coiled hair” Extremely thin and can be very long Tightly coiled helical cells with tapered ends Motile by Periplasmic flagella (a.k.a., axial fibrils or endoflegalla) Dr.T.V.Rao MD

General Overview of Spirochaetales
Outer sheath encloses axial fibrils wrapped around protoplasmic cylinder Axial fibrils originate from insertion pores at both poles of cell May overlap at centre of cell in Treponema and Borrelia, but not in Leptospira Differing numbers of endoflegalla according to genus & species Dr.T.V.Rao MD

Trepanoma palladium Physiology Difficult to culture
Maintained in anaerobic medium with albumin, sodium bicarbonate, pyruvate, cysteine Microaerophilic Dr.T.V.Rao MD

Cross-Section of Spirochete with Periplasmic Flagella
Cross section of Borrelia burgdorferi NOTE: a.k.a., endoflegalla, axial fibrils or axial filaments. (Outer sheath) Dr.T.V.Rao MD

Staining with special stains
Staining by Giemsa and Fontana Dr.T.V.Rao MD

Antigenic structure The Antigens are complex
Infection with Treponema will induce 3 types of Antigens Reagin Antibodies – STS Detected by Standard tests for Syphilis 1 Wasserman Test, 2 Kahn Test VDRL Test Dr.T.V.Rao MD

Beef Heart Extracts - Antigen
Lipid Hapten – Cardiolipin Chemically Dipphostidyl glycerol Cardiolipin present in the Trenonems ? Or a product of tissue Damage ? Dr.T.V.Rao MD

Second Group Antigen T.pallidum
Present in T.pallidum and Non pathogenic cultivable treponemes Reiter's Trenonems Dr.T.V.Rao MD

Third Antigen Polysaccharide species specific Positive only in sera of patients infected with pathogenic Treponema Dr.T.V.Rao MD

Dark field Microscopy Dr.T.V.Rao MD

Treponema cannot be cultivated in Culture Media
The inability to grow most pathogenic Treponema in vitro, coupled with the transitory nature of many of the lesions, makes diagnosis of Treponema infection impossible by routine bacteriological methods Dr.T.V.Rao MD

Cultivation of .. ? Although the Treponemes are distantly related to Gram-negative bacteria, they do not stain by Gram's method, and modified staining procedures are used. Moreover, the pathogenic Treponemes cannot be cultivated in laboratory media and are maintained by subculture in susceptible animals. Dr.T.V.Rao MD

Trepanoma pallidum Clinical Infection: Syphilis Transmission
Usually through sexual contact from an infected individual by invading intact mucous membranes or abraded skin Pathogenesis Disease of blood vessel & perivascular areas Primary lesion due to inflammation at site of inoculation Secondary lesion due to inflammation of ectodermal tissues Tertiary lesion due to diffuse chronic inflammation to organ systems Dr.T.V.Rao MD

Trepanoma pallidum Clinical Infection: Syphilis
Clinical Manifestations Primary Disease Chancre: single lesion, non-tender & firm with a clean surface, raised border & reddish color Usually on the cervix, vaginal wall, anal canal Draining lymph nodes enlarged & non-tender Dr.T.V.Rao MD

Pathogenesis of T. pallidum
Tissue destruction and lesions are primarily a consequence of patient’s immune response Syphilis is a disease of blood vessels and of the perivascular areas In spite of a vigorous host immune response the organisms are capable of persisting for decades Infection is neither fully controlled nor eradicated In early stages, there is an inhibition of cell-mediated immunity Inhibition of CMI abates in late stages of disease, hence late lesions tend to be localized Dr.T.V.Rao MD

Pathology Dissemination: Penetration:
Pathogenesis Pathology Penetration: T. pallidum enters the body via skin and mucous membranes through abrasions during sexual contact Also transmitted transplacentally Dissemination: Travels via the lymphatic system to regional lymph nodes and then throughout the body via the blood stream Invasion of the CNS can occur during any stage of syphilis Dr.T.V.Rao MD

Pathology The bacteria rapidly enter the lymphatic's, are widely disseminated via the bloodstream and may lodge in any organ. The exact infectious dose for man is not known, but in experimental animals fewer than ten organisms are sufficient to initiate infection. Dr.T.V.Rao MD

Pathology The bacteria multiply at the initial entry site forming a chancre, a lesion characteristic of primary syphilis, after an average incubation period of 3 weeks Dr.T.V.Rao MD

STAGES OF SYPHILIS Primary Secondary Latent Late or tertiary
Early latent Late latent Late or tertiary May involve any organ, but main parts are: Neurosyphilis Cardiovascular syphilis Late benign (gumma) Dr.T.V.Rao MD

Basic lesion of syphilis
The chancre is painless and most frequently on the external genitalia, but it may occur on the cervix, perianal area, in the mouth or anal canal. Dr.T.V.Rao MD

Stages of syphilis Untreated syphilis may be a progressive disease with primary, secondary, latent and tertiary stages. T. pallidum enters tissues by penetration of intact mucosae or through abraded skin. Dr.T.V.Rao MD

Primary syphilis b) Starts as papule and then erode
a) One or more painless chancres (indurated raise edges & clear bases) that erupt in the genitalia, anus, nipples, tonsils or eyelids. b) Starts as papule and then erode c) Disappear after three to six weeks even without treatment. d) Lymphadenopathy that is either unilateral or bilateral Dr.T.V.Rao MD

Clinical Manifestations Latent disease Early latent (1st 4 years) No signs & symptoms of active syphilis but remain seroactive Late latent (after 4 years) If untreated, 60% continue to be asymptomatic while 40% progress to tertiary stage Dr.T.V.Rao MD

Pathology The chancre is painless and most frequently on the external genitalia, but it may occur on the cervix, peri-anal area, in the mouth or anal canal. Chancres usually occur singly, but in immunocompromised individuals, Dr.T.V.Rao MD

Chancre The chancre usually heals spontaneously within 3-6 weeks, and 2-12 weeks later the symptoms of secondary syphilis develop. These are highly variable and widespread but most commonly involve the skin where macular or pustular lesions develop, particularly on the trunk and extremities. The lesions of secondary syphilis are highly infectious. Dr.T.V.Rao MD

Progress of Disease Relapse of the lesions of secondary syphilis is common, and latent syphilis is classified as early (high likelihood of relapse) or late (recurrence unlikely). Individuals with late latent syphilis are not generally considered infectious, but may still transmit infection to the fetus during pregnancy and their blood may remain infectious. Dr.T.V.Rao MD

Clinical Manifestations Primary Disease Chancre: single lesion, non-tender & firm with a clean surface, raised border & reddish color Usually on the cervix, vaginal wall, anal canal Draining lymph nodes enlarged & non-tender Dr.T.V.Rao MD

PRIMARY SYPHILIS (The Chancre)
Incubation period 9-90 days, usually ~21 days. Develops at site of contact/inoculation. Classically: single, painless, clean-based, indurated ulcer, with firm, raised borders. Atypical presentations may occur. Mostly anogenital, but may occur at any site (tongue, pharynx, lips, fingers, nipples, etc...) Non-tender regional adenopathy Very infectious. May be darkfield positive but serologically negative. Untreated, heals in several weeks, leaving a faint scar. Dr.T.V.Rao MD

Primary Syphilis Dr.T.V.Rao MD

Primary Syphilis- Penile Chancre
Clinical Manifestations Primary Syphilis- Penile Chancre Dr.T.V.Rao MD Source: CDC/ NCHSTP/ Division of STD Prevention, STD Clinical Slides

Primary Syphilis Dr.T.V.Rao MD

Primary Syphilis - Chancre
Dr.T.V.Rao MD

Pathogenesis of T. pallidum (cont.)
Secondary Syphilis Secondary disease 2-10 weeks after primary lesion Widely disseminated mucocutaneous rash Secondary lesions of the skin and mucus membranes are highly contagious Generalized immunological response Dr.T.V.Rao MD

Treponema pallidum Clinical Infection: Syphilis
Clinical Manifestations Tertiary Disease Gummas (3-10 years after secondary disease) Non-progressive, localized dermal lesions Benign tertiary syphilis Pronounced immunologic host reaction Neurosyphilis (>5 years after primary disease) Paralytic dementia, tabes dorsalis, amyotropic lateral sclerosis, meningovascular syphilis, seizures, optic atrophy, gummatous changes of the cord Dr.T.V.Rao MD

Secondary Syphilis Secondary syphilis at 6-8 weeks – diffuse symptoms:
Fever Headache Skin pustules Usually disappears even without treatment Dr.T.V.Rao MD

Treponema pallidum Clinical Infection: Syphilis
Clinical Manifestations Congenital Syphilis Transplacental infection of the developing fetus Abortion occurs during 2nd trimester of pregnancy Early symptoms: Hepatosplenomegaly, jaundice, hemolytic anemia, pneumonia, multiple long bone involvement, snuffles, skin lesions, testicular masses Dr.T.V.Rao MD

Treponema pallidum Clinical Infection: Syphilis Late symptoms:
Clinical Manifestations Congenital Syphilis Late symptoms: Frontal bossae of Parrott, Short maxilla, high palatal arch, Hutchinson’s triad (Hutchinson’s teeth, Interstitial keratitis, eighth-nerve deafness), saddle nose, mulberry molars, Higoumenakis sign, relative protruberance of mandible, rhagades, saber shin, scaphoid scapulas, Clutton’s joint) Dr.T.V.Rao MD

Secondary Syphilis Dr.T.V.Rao MD

Secondary Syphilis Secondary disease 2-10 weeks after primary lesion Widely disseminated mucocutaneous rash Secondary lesions of the skin and mucus membranes are highly contagious Generalized immunological response Dr.T.V.Rao MD

Secondary Syphilis Dr.T.V.Rao MD

Secondary syphilis Dr.T.V.Rao MD

Tertiary Syphilis Affects 2/3 of untreated cases
Gummata: rubbery tumors Bone deformities Blindness Loss of coordination Paralysis Insanity Dr.T.V.Rao MD

Latent Stage Syphilis Following secondary disease, host enters latent period First 4 years = early latent Subsequent period = late latent About 40% of late latent patients progress to late tertiary syphilitic disease Dr.T.V.Rao MD

Tertiary Syphilis Tertiary syphilis characterized by localized granulomatous dermal lesions (gummas) in which few organisms are present Granulomas reflect containment by the immunologic reaction of the host to chronic infection Dr.T.V.Rao MD

Neurosyphilis Late Neurosyphilis develops in about 1/6 untreated cases, usually more than 5 years after initial infection Central nervous system and spinal cord involvement Dementia, seizures, wasting, etc. Cardiovascular involvement appears years after initial infection with resulting myocardial insufficiency and death Dr.T.V.Rao MD

Latent Syphilis Latent syphilis Late syphilis Late, benign syphilis
a) Reactive serologic test b) Asymptomatic until death Late syphilis Three subtypes of Late syphilis Late, benign syphilis *Develops between 1 to 10 years after the infection *Presence of gumma Dr.T.V.Rao MD

Dr.T.V.Rao MD

Mother to Child Transmission
Infection in utero may have serious consequences for the fetus. Rarely, syphilis has been acquired by transfusion of infected fresh human blood. Dr.T.V.Rao MD

Congenital Syphilis Congenital syphilis results from trans placental infection T. pallidum septicemia in the developing fetus and widespread dissemination Abortion, neonatal mortality, and late mental or physical problems resulting from scars from the active disease and progression of the active disease state Dr.T.V.Rao MD

Treponema pallidum and Immunity
Clinical Infection: Syphilis Immunity Syphilis has persistent infection for decades in spite vigorous host response due to: Dense coat (with fibronectin, transferrin, cerruloplasmin) Evasion from PMN detection Inhibition of cell-mediated immunity Relative but unreliable protection from reinfection in untreated patients Minor protection from reinfection in treated patients Dr.T.V.Rao MD

Congenital Syphilis Abnormally shaped teeth Nasal septum collapses
Passed from mother to fetus during pregnancy Abnormally shaped teeth Nasal septum collapses Skeletal abnormalities Dr.T.V.Rao MD

DIAGNOSIS OF SYPHILIS 1. History and clinical examination.
2. Dark-field microscopy: special technique use to demonstrate the spirochete as shiny motile spiral structures with a dark background. The specimen includes oozing from the lesion or sometimes L.N. aspirate. It is usually positive in the primary and secondary stages and it is most useful in the primary stage when the serological tests are still negative. Dr.T.V.Rao MD

Diagnosis of syphilis Direct detection of spirochetes :
Darkfield microscopy (motile bugs + experience + prompt examination) Silver stain Culture : not used Serology: non-specific and specific tests Dr.T.V.Rao MD

Serologic Tests Reveal patients immune status not whether they are currently infected Use lipoidal antigens rather than T. pallidum or components of it; non-treponemal antigen tests RPR; rapid plasma reagin VDRL; Venereal Disease Research Laboratory Dr.T.V.Rao MD

Treponema pallidum Laboratory diagnosis Serologic testing
Nontreponemal Tests (uses Cardiolipin-lecithin as antigen) Complement-fixation tests (Wasserman & Kolmer test) Flocculation tests (Venereal Disease Research Laboratory, (VDRL), Hinton & rapid reagin tests) Dr.T.V.Rao MD

Serologic Tests Positive within 5 to 6 weeks after infection
Strongly positive in secondary phase Strength of reaction is stated in dilutions May become negative with treatment or over decades Dr.T.V.Rao MD

Treponemal Tests (uses syphilitic tissue as complement-fixing antigen) Reiter Protein Complement Fixation Antigen is an extract from nonvirulent treponeme (Reiter strain) Nonreactive in late stages of syphilis Dr.T.V.Rao MD

Non-treponemal tests Antigen: cardiolipin (beef heart) + lecithin + cholesterol Detect nonspecific antibody (Reagin): a mixture of IgM & IgG direct against some normal tissue antigens VDRL (Venereal Disease Research Laboratory) test for serum and CSF samples Dr.T.V.Rao MD

Venereal Disease Research Laboratory - VDRL
Flocculation test, antigen consists of very fine particles that precipitate out in the presence of reagin. Utilizes an antigen which consists of cardiolipin, cholesterol and lecithin. Antigen very technique dependent. Must be made up fresh daily. Serum must be heated to 56 C for 30 minutes to remove anti-complementary activity which may cause false positive, if serum is not tested within 4 hours must be reheated for 10 minutes. Calibrated syringe utilized to dispense antigen must deliver 60 drops/mL +/- 2drops. Dr.T.V.Rao MD

VDRL Each preparation of antigen suspension should first be examined by testing with known positive or negative serum controls. The antigen particles appear as short rod forms at magnification of about 100x. Aggregation of these particles into large or small clumps is interpreted as degrees of positivity Reactive on left, non-reactive on right Dr.T.V.Rao MD

Rapid Plasma Reagin Test - RPR
General screening test, can be adapted to automation. CANNOT be performed on CSF. Antigen VDRL cardiolipin antigen is modified with choline chloride to make it more stable attached to charcoal particles to allow macroscopic reading antigen comes prepared and is very stable. Serum or plasma may be used for testing, serum is not heated. Dr.T.V.Rao MD

Treponema pallidum Laboratory diagnosis
Serologic testing Treponemal Tests (uses syphilitic tissue as complement-fixing antigen) Treponema Pallidum Immobilzation (TPI) Reaginic antibody & complement immobilize a suspension of living and motile treponemes maintained in rabbit testes & determined by darkfield microscopy Difficult, expensive, requires living organisms Positive for nonvenereal treponematoses, bejels, yaws & pinta Dr.T.V.Rao MD

Treponemal Tests (uses syphilitic tissue as complement-fixing antigen) Reiter Protein Complement Fixation Antigen is an extract from nonvirulent treponeme (Reiter strain) Nonreactive in late stages of syphilis Dr.T.V.Rao MD

Specific serological tests of syphilis
A. Reiter protein complement fixation test. B. Fluorescent Treponemal antibody/absorption test, FTA/ABS. the most specific and most sensitive . C. Treponema pallidum haemagglutination test- TPHA- D. Treponema pallidum immobilization test- TPI Dr.T.V.Rao MD

Treponema pallidum haemagglutination (TPHA)
Adapted to micro techniques (MHA-TP) Tanned sheep RBCs are coated with T. pallidum antigen from Nichol’s strain. Agglutination of the RBCs is a positive result. Dr.T.V.Rao MD

Specific serological tests of syphilis
A. Reiter protein complement fixation test. B. Fluorescent Treponemal antibody/absorption test, FTA/ABS. the most specific and most sensitive . C. Treponema pallidum Haemagglutination test- TPHA- D. Treponema pallidum immobilization test- TPI Dr.T.V.Rao MD

Treponemal Tests (uses syphilitic tissue as complement-fixing antigen) Fluorescent Antibody Tests / Fluorescent Treponemal Antibody Absorption (FTA-ABS) Test Uses lyophilized Nichols strain organisms as antigen  mixed with antitreponemal antibody (from test serum) in a slide  flourescein isothiocyanate-labeled antihuman Ig –> presence of antibody determined by darkfield microscopy Used to diagnosed congenital syphilis & late stage syphilis, confirmation of nontreponemal tests Dr.T.V.Rao MD

Fluorescent Treponemal Antibody Absorption Test (FTA-ABS)
Diluted, heat inactivated serum added to Reiter’s strain of T. pallidum to remove cross reactivity due to other Treponemes. Slides are coated with Nichol’s strain of T. pallidum and add absorbed patient serum. Slides are washed, and incubated with antibody bound to a fluorescent tag. After washing the slides are examined for fluorescence. Requires experienced personnel to read. Highly sensitive and specific, but time consuming to perform. Dr.T.V.Rao MD

Positive FTA Test for Syphilis Viewed with a Fluorescent Microscope
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Serologic Tests To improve sensitivity and specificity tests using a specific treponemal antigen devised MHA-TP: microhemagglutination assay for T. pallidum FTA-ABS: fluorescent treponemal antibody absorption test All positive nontreponemal test results should be confirmed with a specific treponemal test Dr.T.V.Rao MD

Treponema pallidum Serologic testing Laboratory diagnosis
Treponemal Tests (uses syphilitic tissue as complement-fixing antigen) Haemagglutination Tests Microhemagglutination assay –T. pallidum (MHA-TP) Dr.T.V.Rao MD

Every Pregnant women Needs Screening
Dr.T.V.Rao MD

Biologic False-Positive Test Results
Positive STS in persons with no history or clinical evidence of syphilis Acute BFP: those that revert to negative in less than 6 months Chronic BFP: persist > 6 months Dr.T.V.Rao MD

BFP Test Results in Syphilis
Acute BFP Vaccinations Infections pregnancy Chronic BFP Connective tissue disease (SLE) Liver disease Blood transfusions IVDA Dr.T.V.Rao MD

Advantage of VDRL: cheap, easy to perform quantitative, screen test
monitor disease course trace theraputic effect, become “-” in m after effective treatment. Dr.T.V.Rao MD

Treatment of Late Syphilis
benzathine penicillin 2.4 million units intramuscularly weekly for 3 weeks. procaine penicillin 1.2 million units intramuscularly daily for 21 days Tetracycline or erythromycin 500 mg 4 times a day – or doxycycline 100 mg x2- by mouth for 30 days Jarrisch-Herxheimer reaction Follow-up Dr.T.V.Rao MD

Prevention & Treatment of Syphilis
Penicillin remains drug of choice WHO monitors treatment recommendations 7-10 days continuously for early stage At least 21 days continuously beyond the early stage Prevention with barrier methods (e.g., condoms) Prophylactic treatment of contacts identified through epidemiological tracing Dr.T.V.Rao MD

Treponema pallidum Treatment & Prevention
Antibiotic treatment DOC: Penicillin (complete recovery for stage I &II) streptomycin, tetracycline, erythromycin (poor passage to fetal circulation) Treatment of case contacts Barrier methods (condom); “safe sex” Dr.T.V.Rao MD

Other Related to Treponemes
Related Treponemes cause the non-venereal treponematoses bejel, or endemic syphilis (T. pallidum endemicum), yaws (T. pallidum pertenue), and pinta (T. carateum). Dr.T.V.Rao MD

Treponema pallidum Other treponemal diseases
Yaws (Frambesia) -Treponema pertenue Resembles syphilis Acquired in childhood other than sexual contact Mother yaw (or framboise), a painless erythematous papule occurs a month after primary infection Secondary lesion resemble primary lesion occurs 1-3 months after Tertiary lesions involve the skin & bones, crab yaws DOC: Penicillin Dr.T.V.Rao MD

Pinta - Treponema carateum Acquired by person-to-person contact & rarely by sexual contact Primary & secondary lesions are flat, erythematous & non-ulcerating; healing first becomes hyper pigmented and later depigmented scarring; occurs in hand, feet & scalp Tertiary lesions are uncommon DOC: Penicillin Dr.T.V.Rao MD

Bejel - Treponema pallidum variant Endemic syphilis Acquired by direct contact during childhood Similar to syphilis DOC: Penicillin Dr.T.V.Rao MD

Programme created by Dr. T. V
Programme created by Dr.T.V.Rao MD for Medical and Health Care Workers in the Developing World Dr.T.V.Rao MD

SPIROCHETES Dr.T.V.Rao MD Dr.T.V.Rao MD.

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