Syphilis

Organism

Syphilis is a systemic disease caused by spirochete bacterium Treponema pallidum.

Incubation period:

  • Nine to 90 days from exposure to primary syphilis.
  • Thirty to 150 days from exposure to secondary stage.
  • Usually five to 35 years from exposure to tertiary stage.

The usual mode of transmission is sexual intercourse. T. pallidum may occasionally be spread by blood contamination, for example by needlestick injuries or the sharing of injecting equipment, and also by direct contact with open lesions.

Contact infectivity for primary, secondary and early latent syphilis is around 20% (there are reports ranging from 10-60%). Late latent and tertiary syphilis are not infectious.

Clinical presentation

Syphilis is a multi-system disease and can go through various stages.;

Test for syphilis in all patients presenting with a genital ulcer. The ulcer (chancre) is characteristically a single indurated painless ulcer which can occur in the genital region or elsewhere on the body (extragenital).

Particularly in endemic communities, consider syphilis if a patient presents with characteristic signs of secondary syphilis, e.g. hair loss, rashes on hands and feet, and painless enlarged lymph nodes.

  • In Australia, syphilis usually presents either as a primary chancre, clinical manifestations of secondary syphilis or through the chance finding of positive serology.
  • Congenital syphilis is rare if there is general screening of antenatal patients (additional testing for syphilish should be offered at any stage in pregnancy if antenatal patients has been exposed to any significant risk throughout pregnancy).
  • Tertiary syphilis is rarely seen.

Special considerations

  • Careful physical examination of the relevant areas, and awareness of its likely presence in endemic communities is crucial to establishing an accurate diagnosis of syphilis.
  • Untreated, early clinical syphilis usually resolves spontaneously, leading to latent disease, which may proceed to late, destructive lesions.

Staging of syphilis

The appropriate course of treatment can only be decided after the clinical stage of the disease has been determined. This requires examination and serological testing. The stages are:

  • Primary syphilis: the signs are an ulcer (chancre) at the site of infection (both genital and extragenital) that is typically solitary, indurated and painless. However chancres may also be multiple, painful, and purulent and can cause syphilitic balanitis of Follmann. 
  • Secondary syphilis: manifestations are a rash that is typically bilaterally symmetrical and non-itchy; ulcers of the mouth, nasal cavity or vulva; enlarged lymph nodes and condylomata lata. Hair loss involves scalp and eyebrows. Cranial nerve palsies and other neurosyphilis manifestations may develop.
  • Latent syphilis: presence of T. pallidum in the body without symptoms or signs. Latent syphilis can be either early (within 24 months of primary infection) or late (more than 24 months since primary infection).
  • Tertiary syphilis: progression of syphilis to involve the heart, nervous system, eye, ear or the development of gummata (granulomatous lesions). The first lesions of tertiary syphilis are usually seen five to 20 years after primary infection, but asymptomatic neurosyphilis may occur within five years.

Presentation of latent syphilis

Positive serology in a patient without symptoms or signs of disease is the most common presentation of syphilis in Australia today.

Usually divided into early and late latent. Early latent syphilis (less than 2 years from infection) is usually infective while late latent syphilis (more than 2 years from infection) is non infectious. 

  • The duration of latency influences potential infectivity of the patient and the treatment required.
  • The problem, with a finding of positive syphilis serology without clinical symptoms or signs, is to distinguish adequately treated syphilis from untreated disease.
  • The duration of latency must be determined by:
    • identifying the occurrence of primary or secondary lesions, if possible
    • asking about previous syphilis serology at the time of blood donations, previous STI diagnosis or pregnancy
    • checking the records of Community Health, PHUs, ACCHS, PathWest, or other medical practitioners.

Note: A clue can also be gained from the RPR titre. Titres of less than 8 are likely to reflect latent syphilis (two years or more from infection) and titres greater than 8 reflect active syphilis, with a proviso that if acute disease is suspected do a repeat blood test in two weeks.

Presentation of tertiary syphilis

Tertiary syphilis should be excluded in any patient with the following conditions:

  • aortic incompetence
  • aneurysm of the ascending arch of the aorta
  • dementia
  • personality change
  • multifocal neurological disorders
  • nerve deafness
  • pupillary abnormalities
  • retinal disease or uveitis.

If tertiary syphilis is suspected, referral to a specialist should occur. Contact details of specialists with appropriate experience are provided on contacts for specialist advice on STIs and HIV.

Cases of suspected tertiary syphilis need to be discussed with specialists because managing patients with tertiary syphilis can be very complex. Such complexities are beyond the scope of these guidelines.

Special considerations

  • Practitioners should maintain an awareness of the possibility of tertiary syphilis.
  • Tertiary manifestations of syphilis may be 'benign', with development of gummata in almost any organ, or more serious, with cardiovascular or central nervous system involvement. Benign gummatous disease is rare. Cardiovascular disease and neurosyphilis occasionally occur from five to 35 years after exposure.

Exclude other STIs

Investigate all patients presenting with possible syphilis for other STIs, including chlamydia, gonorrhoea, HIV, HBV, hepatitis A (HAV) (if symptomatic or if there is any history of male-to-male and/or oro-anal sex and vaccination is contemplated), and HCV (if there is a history of injecting drug use), as coinfection is likely.

In patients with primary syphilis and at risk for HIV, retesting for HIV should occur after three months. The presence of herpes, donovanosis and warts may be detected during clinical examination

STI Atlas (external site)

Investigations

All practitioners should be familiar with the types of syphilis serology tests and their interpretation. Diseases caused by other treponemal organisms, including yaws, will cause the same serological reactions as syphilis.

In a patient seen for the first time with a clinical presentation that suggests primary syphilis do a NAAT (PCR) swab of the ulcer. In addition, syphilis serology should be requested.

Patients being treated for primary and secondary syphilis should have a rapid plasma reagin test (RPR) repeated on the day treatment is commenced to provide an accurate baseline for monitoring treatment.

In a patient seen for the first time without any signs or symptoms of syphilis, request syphilis serology.

    Choice of tests

    Two types of tests are used for syphilis serology: non-treponemal tests and treponemal tests. 
    Non-treponemal tests
  • RPR (monitors disease activity)
  • Venereal Disease Research Laboratory (VDRL) test.
  • These tests do not measure antibodies to T. pallidum (the organism that causes syphilis). Instead, they measure antibodies to another protein called cardiolipin, derived from human cardiolipin, which has been modified by the treponemal infection so that it is perceived as foreign by immune surveillance. These non-treponemal tests are more likely to give false positive results than the treponemal tests because other disease processes can also modify human cardiolipin causing the same antibody development.
  • Both tests are quantified (they indicate how much antibody is present), so they can be used to monitor progress of infection or success of treatment. However, titres on the RPR and VDRL may be different, and cannot be directly compared.
  • VDRL is the only test fully validated for screening cerebrospinal fluid (CSF), although NAAT may be useful in the future.
    Treponemal tests
  • Enzyme immunoassay (EIA) – IgM and IgG
  • Treponema pallidum haemagglutination test (TPHA)/Treponema pallidum particle agglutination test (TPPA)
    These tests detect specific treponemal antibodies (commonly lgG) and, once positive, remain so whether the patient has been treated or not. Hence IgG detection in treponemal tests is not an indication of successful treatment. Proper interpretation of tests for syphilis usually requires a detailed history of the patient's illness, when they may have been infected, their treatment, and their previous test results. The history may come from the patient or from previous treating practitioners. The first test performed by the laboratory will be an EIA or TPPA or TPHA.
     
  • If the result is negative, it is extremely unlikely that the patient has syphilis. However, in the first two weeks after infection, all tests may be negative, so:
    • repeat syphilis serology in two to four weeks where primary syphilis or re-infection is possible, as other tests may become positive or the antibody titres may rise.
  • If the result is positive, and the patient is not known to have been infected previously with syphilis, an RPR and other syphilis specific tests will be carried out. If the patient is known to have been infected previously, it is unnecessary to perform a FTA-Abs lgG.
  • If none of these follow-up tests is positive, the patient may have:
  • a false positive TPHA, TPPA or EIA
  • very early primary syphilis
  • distant past syphilis that may have been treated or untreated.
  • If any of these follow-up tests is positive, this confirms the presence of genuine syphilis antibodies (meaning that the patient is infected or has been infected in the past). A positive RPR may be found in syphilis at any stage, whether or not the patient has been adequately treated. The most common situation in communities with long standing syphilis endemicity is that the clinical picture and serology are consistent with latent or tertiary syphilis, whether treated or untreated. If it is not certain that the patient has been adequately treated in the past, a full course of treatment is indicated. Special considerations
  • Clinical and CSF examination will determine the need for treatment of neurosyphilis.
  • Neurosyphilis should be considered in seropositive patients:
    • with neurological or ophthalmic signs
    • with treatment failures
    • who are HIV-infected
    • who are unable to be treated with any form of penicillin
    • with suspected congenital syphilis.
  • Interpretation of CSF serology, protein level and cell counts should be discussed with a specialist.
  • A chest X-ray is not recommended as a routine investigation for late latent syphilis. Full cardiovascular examination should be undertaken if patients have any cardiovascular symptoms. 
  • Causes of false positive results in non-treponemal tests
  • An acute false positive reaction occurs during or after various acute febrile illnesses (e.g. hepatitis, infectious mononucleosis, measles, malaria), pregnancy, immunisation and in one per cent of clinically normal individuals. The reaction disappears within six months. It is usually low titre.
  • A chronic false positive reaction persists for more than six months. Such a reaction occurs in injecting drug users, autoimmune disease (e.g. systemic lupus erythematosus, immunoglobulin disorders), chronic infections (e.g. leprosy), and malignancy.
    Causes of false positive results in treponemal tests
  • TPHA/TPPA: Pregnancy, some viral infections (e.g. infectious mononucleosis), autoimmune diseases, cancer, injecting drug use and skin diseases.
  • EIA: Causes are less clear, but include pregnancy, old age, some viral infections (e.g. infectious mononucleosis), autoimmune diseases, cancer, injecting drug use, and alcoholic cirrhosis of the liver. 
    Causes of false negative syphilis serology
  • Antibody is not present. This is most likely in recently acquired infections, in which case the test should be repeated at least one month later. Recent antibiotic therapy may also delay the appearance of antibody.
  • The patient is immunosuppressed.
  • A negative RPR occurs in 25 per cent of patients with late syphilis. Therefore, EIA, TPHA or TPPA are the preferred screening tests.
  • A negative RPR may also occur as the result of the ‘prozone reaction’ where the presence of a large antibody response in undiluted serum (as seen in some cases of secondary syphilis) overwhelms the test and renders it inaccurate. Asking the laboratory to retest with diluted serum overcomes this problem.
  • If tests are negative in a patient suspected to have syphilis on clinical grounds, a specialist with appropriate experience should be consulted (see list of contacts in contacts for specialist advice on STIs and HIV). 
Treatment

Penicillin remains the drug of choice in treating syphilis.

It is essential that syphilis serology is repeated at commencement of treatment so the response to treatment can be accurately assessed.

If there is any doubt about the clinical stage of the patient's infection, treat as for late latent syphilis.

Rationale: The effectiveness of penicillin for treating syphilis has been well established and treponemes have not developed penicillin-resistance. There is little evidence showing the effectiveness of non-penicillin regimens, and they must be regarded as inferior to penicillin.

Treatment regimens

Primary, secondary and early latent syphilis (up to 24 months)

  • Benzathine penicillin 1.8 g intramuscularly, as a single dose

        or

  • procaine penicillin 1 g for patients less than 60 kg bodyweight and 1.5 g for patients over 60 kg bodyweight, intramuscularly, daily for 10 consecutive days.

If allergic to penicillin

  • Doxycycline 100 mg orally, 12-hourly for 14 days.

Late latent syphilis (more than 24 months)

  • Benzathine penicillin 1.8 g intramuscularly, once weekly for three doses. If treatment is missed for more than two weeks, must restart

        or

  • procaine penicillin 1 g for patients less than 60 kg bodyweight and 1.5 g for patients over 60 kg bodyweight, intramuscularly, daily for 15 days.

If allergic to penicillin

  • Doxycycline 100 mg orally, 12-hourly for 28 days.

Tertiary syphilis

Tertiary syphilis includes cardiovascular syphilis and neurosyphilis. Specialist advice should be sought (see list of contacts in contacts for specialist advice on STIs and HIV).

Give steroid therapy 48 hours pre-treatment. Prednisolone 20 mg orally 12 hourly.

  • Benzyl penicillin 1.8 g (3 million units) intravenously, four-hourly for 10 days. This can be given as an outpatient where ambulatory antibiotic services are available.

        or

  • if outpatient treatment is unavoidable, procaine penicillin 1.5 g intramuscularly, daily for 20 consecutive days

        plus

  • probenecid 0.5 g orally, six-hourly for 20 days.

Pregnancy

Medicines in pregnancy.

Special considerations

  • Doxycycline should not be used in women who are pregnant or possibly pregnant, or breastfeeding, or in children under nine years of age.
  • An appropriately experienced specialist should be consulted for patients allergic to penicillin (some of whom are also allergic to ceftriaxone).
  • Neither benzathine penicillin nor aqueous procaine penicillin, at the doses recommended, achieve treponemicidal levels in CSF, and should not be used in treating neurosyphilis. Consult specialist for advice regarding treatment of neurosyphilis. 
  • Jarisch-Herxheimer reaction is a common reaction to treatment in patients with primary and secondary syphilis. It occurs six to 12 hours after commencing treatment, and is an unpleasant reaction of varying severity with fever, headache, malaise, rigors and joint pains, and lasts for several hours. Symptoms are controlled with analgesics and rest. Patients should be alerted to the possibility of this reaction and reassured accordingly.
  • Procaine reaction is a rare reaction to procaine penicillin. It is characterised by a sensation of impending doom with hallucinations. The reaction is self-limiting and lasts about 30 minutes. The patient needs to be reassured and given general supportive measures.
  • Patients being treated for primary and secondary syphilis should have RPR repeated on the day treatment is commenced to provide an accurate baseline for monitoring treatment.
  • Co-infection with HIV, see Syphilis in HIV infection (below).

Related links


Education, counselling and prevention

Counselling is important in managing STIs/HIV and should be considered at every contact with the patient.

As a minimum, consider counselling at the first presentation and subsequently during treatment and follow-up.

  • Counselling is an opportunity to educate and support the patient in prevention strategies. This should be done in a confidential setting.
  • The key points are:
    • communicating the confidentiality of the diagnosis
    • communicating the reasons for testing and contact tracing
    • formulating expectations from treatment
    • promoting awareness of risk behaviours.
  • Counselling should also include discussion of the implications of STI testing (i.e. that testing does not prevent transmission). Emotional reactions can accompany a positive STI/HIV diagnosis with delayed reactions sometimes occurring several days after the consultation.

See also general considerations in STI HIV counselling.

Management of partners

It is the responsibility of all health care providers, including doctors, to begin tracing sex partners so that they can be assessed and treated.

This involves counselling to ensure that the patient understands the implications of infection transmission.

Managing sex partners may require referral to another practitioner.

Index case with primary syphilis – sex partners from the previous three months plus duration of index case symptoms should be assessed and treated for syphilis.

Index case with secondary syphilis – sex partners from the previous six months plus duration of the index case symptoms should be assessed and treated for syphilis. This may need to be extended back to previous 24 months depending on the patient's clinical features and the outcomes of contact tracing in the shorter time frame. 

Index case with early latent syphilis – sex partners from the previous 24 months should be assessed and treated for syphilis.

Special considerations

  • Period to trace will depend on the sexual history and clinical stage of the infection.
  • The duration of potential infectivity is up to two years. It is important to stress that people with tertiary or late latent syphilis are not infectious except rarely vertically in the case of females. Important sequelae include neurosyphilis and cardiovascular disease. In the case of congenital syphilis, the duration of infectivity is up to eight years.
  • Syphilis can be transmitted by oral sex.
  • Persons who were sexually exposed to a patient with primary, secondary, or early latent syphilis should be treated presumptively if serological test results are not available immediately and the opportunity for follow-up is uncertain.

See more information about contact tracing.

Follow up

Review all patients initially 3 months after completing treatment, then at 6 months and (if necessary) at 12 months.

The review should consist of:

  • clinical assessment
  • repeat serology.

Tests for follow-up and management of syphilis

For the primary health care provider, diagnosis and clinical management of syphilis depends largely on the interpretation of the RPR test in comparison with previous RPR results, together with the clinical findings.

Assessing the patient's response to treatment also depends on tracking the RPR results, which are expressed as 'titres'. Successful treatment is where the titres fall fourfold.

Therefore, it is essential that RPR is checked at the commencement of treatment in order that changes in titre can be accurately assessed.

The diagnosis of re-infection is based on seroconversion from non-reactive to reactive RPR serology, or on the basis of at least a four-fold (eg four to 16) titre rise in RPR.

Re-treatment and lumbar puncture are indicated if:

  • clinical signs persist or reappear after treatment
  • the RPR titre rises at least four-fold after it has fallen
  • (in early syphilis) the RPR titre does not fall at least four-fold within 12 months.

Syphilis follow-up chart

Special consideration

  • If possible, review all patients who present for STI testing three months later, as this provides an opportunity to repeat blood tests for syphilis, HIV and HBV.
Syphilis in HIV infection

Diagnosis and investigation of patients who are immunosuppressed should be discussed with a specialist with appropriate experience (see contacts for specialist advice on STIs and HIV).

  • HIV-positive patients who are immunosuppressed may not form antibodies, so serological tests for disease may give false negative results. Their management, including the best form of investigation, requires specialist expertise.
  • Published case reports and expert opinion suggest that HIV-infected patients with early syphilis are at increased risk of neurological complications, and have higher rates of treatment failure with currently recommended regimens. These risks are probably small but should be considered.
  • Unusual serological responses have been observed among HIV-infected persons who also have syphilis. Nevertheless, both treponemal and non-treponemal serological tests for syphilis are accurate for most patients with syphilis and HIV co-infection.
  • No treatment regimens have been demonstrated to be more effective in preventing development of neurosyphilis in patients with HIV infection than those recommended for patients without HIV infection.
  • Careful follow-up after therapy is essential. 
Syphilis during pregnancy

All women should have syphilis serology carried out in the first trimester of pregnancy or at the first antenatal visit.

Women at risk of acquiring syphilis should have a further test in the third trimester (preferably at 28 to 30 weeks). If this is not done, they should be tested at delivery.

The serological status of mothers should be documented at least once during confinement.

Cord blood testing offers no advantage over the testing of maternal blood in determining syphilis infection.

  • Screening and treatment of all pregnant women prevents the following complications of syphilis (providing it is done early enough, preferably in the first half of the pregnancy):
    • miscarriage, stillbirth
    • premature labour
    • congenital syphilis in the infant.
  • Seropositive pregnant women should be considered infected unless treatment history is clearly documented in a medical record.
  • Women who are treated for syphilis during the second half of pregnancy are at risk of premature labour and/or fetal distress if their treatment precipitates the Jarisch-Herxheimer reaction. Advise these women to seek medical attention after treatment if they notice any change in fetal movements or if they have contractions.

Treating syphilis during pregnancy

Pregnant women with syphilis should be rapidly assessed and treated with penicillin (category A) according to the diagnosed stage of syphilis (see treatment of syphilis above).

  • If the mother and sexual partner(s) are treated adequately with penicillin during pregnancy, the risk of the infant acquiring congenital syphilis is low.
  • Women who are allergic to penicillin should be managed in consultation with a specialist with appropriate experience.
  • Treatment of syphilis in pregnancy can be considered adequate if:
    • it is completed by at least 30 days before delivery
    • there is a documented four-fold drop in RPR titre.
  • If adequate treatment has not been documented, the patient should be treated for late latent syphilis.

Follow-up after syphilis in pregnancy

Mothers who have been treated for syphilis during pregnancy should be followed up.

  • In subsequent pregnancies, unless there is indication of reinfection and provided the patient has remained HIV negative, no further treatment is indicated.
  • RPR titre should be monitored at 16, 24, 30, 36 weeks and at confinement in subsequent pregnancies.
  • Re-treatment is indicated if:
    • clinical signs persist or reappear after treatment
    • if the RPR titre rises by at least four-fold after it has fallen
    • (in early syphilis) if the RPR titre does not fall at least four-fold within six months.

Pregnancy

Medicines in pregnancy

Congenital syphilis

Congenital syphilis is syphilis acquired by an infant from the mother during pregnancy.

It is diagnosed by demonstrating T. pallidum in clinical specimens of material taken from nasal discharges, skin lesions, or in placental, umbilical cord or autopsy material of a neonate OR by demonstration of raised protein, raised white cells and/or positive VDRL in the neonate's CSF. There are other causes of abnormal CSF findings so it is suggestive, not proof. Positive VDRL is very specific.

Concurrent HIV infection should be excluded. Often clinical manifestations of congenital syphilis are not present at birth. In most cases, they appear within three months.

Early congenital syphilis

A child under two years of age who was infected in utero. Clinical signs are similar to secondary syphilis and may include:

  • hepatosplenomegaly
  • skin rash
  • condylomata lata
  • rhinitis (snuffly babies)
  • bone involvement (osteochondritis)
  • pseudoparalysis (due to epiphysitis)
  • meningitis
  • anaemia
  • failure to thrive.

Late congenital syphilis

A child over two years of age who was infected in utero. The child presents with signs such as:

  • one or more of Hutchinson's triad (interstitial keratitis, defective incisors and nerve deafness)
  • gummata
  • neurosyphilis
  • frontal bossing and anterior bowing of the shins.

Cardiovascular lesions do not occur in congenital syphilis.

Treating congenital syphilis

Treatment for congenital syphilis should be in consult with an experienced paediatrician who has knowledge in treatment for congenital syphilis. 

CSF examination is not routinely recommended for babies born to mothers with positive syphilis serology and investigation should be performed upon advice from a paediatrician. 

Infant should be assessed to determine if high or low risk of acquiring congenital syphilis (see below). 

High risk +/- abnormal CSF

  • Benzyl penicillin 50 mg/kg intravenously (IV), 12-hourly for 10 days.

Low risk

  • Benzathine penicillin 37.5 mg/kg intramuscularly, as a single dose.

No risk

  • No treatment needed 

Special conditions

  • The infant should be treated if test results cannot exclude infection.
  • Infants delivered to mothers with syphilis treated within 30 days of delivery should also receive treatment.
  • Babies should be considered at high risk if:
    • treatment of the mother during pregnancy was not adequate (i.e. the mother's RPR titre fails to fall four-fold after appropriate treatment for early syphilis in pregnancy)
    • maternal treatment was unknown
    • maternal treatment was with a drug other than penicillin
    • the mother's serology at delivery shows previously undiagnosed syphilis
    • examining the baby reveals signs of congenital syphilis
    • the mother has not had all the recommended antenatal and delivery blood tests.
  • Babies should be considered at low risk if:
    • mother had been treated during current pregnancy with penicillin regimen 
    • treatment completed more than 30 days of delivery 
    • adequate response to treatment (4 fold decrease) of mother with positive syphilis serology during pregnancy. 
    • no clinical suspicion of acquiring syphilis in late pregnancy. 
    • clinically no signs of congenital syphilis 
    • RPR titre of infant is same of less than maternal titre at delivery 
  • Babies considered no risk if:
    • all maternal syphilis tests (RPR, TPHA, TPPA, FTA- Abs, IgM) are negative
    • the RPR tests conducted during pregnancy and the last one before pregnancy are all at a titre of 1:4 or less, and all within one titre of each other
    • the mother has documented adequate treatment with penicillin during pregnancy or penicillin/doxycycline before pregnancy and there is no evidence of new infection during this pregnancy. 
  • If no antenatal syphilis serology was performed, and the mother is from a region with a high prevalence of syphilis, the baby should be considered for investigation and treatment while awaiting syphilis serology results.
  • Infants with clinically evident congenital syphilis should have an ophthalmological examination as indicated. 
  • Syphilis serology (including RPR) should be performed on an infant at risk, however care should be taken in the interpretation of the serology, especially in babies with low risk. If any doubt about congenital syphilis, treat the neonate. Passively transferred treponemal antibodies may be present for as long as one year. If they are present for more than a year, the infant should be re-evaluated and treated for congenital syphilis.

Follow-up of congenital syphilis

All neonates who have or are suspected of having congenital syphilis should be followed-up.

  • If the child was considered to be at low or high risk for congenital syphilis or had confirmed congenital syphilis: syphilis serology at 1, 3, 6, 12 and 24 months.
  • If the child has no clinical signs or serological evidence of congenital syphilis: follow-up mother only.
Public health issues

Contact tracing is important to prevent further transmission or reinfection. Always test for other STIs.

If a child is diagnosed with acquired syphilis, issues of sexual abuse and/or sexual assault should be considered.

Notification

This is a notifiable infection. Medical practitioners must complete the appropriate notification forms for all patients diagnosed with a notifiable STI/HIV, as soon as possible after confirmed diagnosis.

Epidemiological reports and real time notification data