One important differential diagnosis to consider is that of rashes that affect the palms and soles. The differential for rashes affecting palms and soles includes:
- Coxsackie virus
- Meningococcemia
- Toxic shock syndrome from staphylococcus aureus
- Lesions from bacterial endocarditis
- Keratoderma blenorrhagicum which can occur with reactive arthritis
- Syphilis
- Rocky Mountain Spotted Fever
- Kawasaki disease
- Measles
The following table outlines the differential diagnosis for rashes affecting the hands, feet, and mouth:
| Category | Etiologies |
| Drug-Related | Drug eruption Arsenic poisoning |
| Infectious | Syphilis – Treponema pallidum Coxsackie virus A6 Enterovirus A71 Varicella zoster Erythema multiforme (hypersensitivity reaction to HSV) Rocky mountain spotted fever Measles virus (rubeola) Scabies Eczema herpeticum Aphthous ulcers Primary HSV gingivostomatitis |
| Inflammatory | Sarcoidosis |
| Other dermatologic causes | Nummular eczema or contact dermatitis Pityriasis lichenoides Pityriasis rosea (salmon or pink colored scaly rash, usually preceded by a viral infection) Psoriasis |
We reviewed that in hand-foot-mouth disease (HFMD), patients typically present with complaints of mouth or throat pain, and if fever is present it is usually below 38.3 degC. This diagnosis of HFMD is more common in children. The oral lesions are more common on the tongue and buccal mucosa and begin as erythematous macules, which progress to vesicles surrounded by a thin halo of erythema. Skin lesions can be macular, maculopapular, or vesicles. Potential etiologies are coxsackie virus or enteroviruses.
We also talked about Rocky Mountain Spotted Fever which is a tick-borne disease for which the pathogen is R. rickettsii, a gram-negative bacteria. Occurs throughout Canada, US, Mexico, Central, South America (Bolivia, Argentina, Brazil, Colombia). Most cases occur in spring and early summer. The incubation is 2-14 days (most 5-7 d) and can present early on with nonspecific symptoms, and can then develop fever, headache, and rash.
In the case that we discussed, investigations returned and diagnosis was made of secondary syphilis. A summary of key points on syphilis is included below.
- Basic Introduction to Syphilis
Syphilis infection is caused by a gram-negative spirochete – Treponema pallidum. It is a sexually transmitted infection, and can also be transmitted through bloodborne means or by vertical transmission during pregnancy and childbirth.
Who should be tested:
- Classic signs or symptoms (see below)
- Patient who is sexually active with an undiagnosed genital ulcer or rash involving hands/feet
- Less specific signs and symptoms such as CN dysfunction, headache, meningitis when another etiology is not identified
We do also test asymptomatic patients in the following scenarios:
- Pregnancy
- Person born to a mother diagnosed with infectious syphilis in pregnancy
- Individuals with HIV
- Sexual partner with early syphilis (also should receive empiric therapy)
- High-risk sexual behaviours
- Sexually active men who have sex with men
2. Syphilis Serology
The following table from Public Health Ontario is very helpful in interpreting syphilis serology. Remember that non-treponemal tests include:
– VDRL – venereal diseases research laboratory
– RPR – rapid plasma reagin
Treponemal test include:
– TPPA – Treponema pallidum particle agglutination assay
– TPHA – Treponema pallidum haemagglutination assay
– FTA-ABS – fluorescent treponemal antibody absorbed
– EIA – enzyme immunoassay
**Some labs may screen syphilis serologic samples by using automated treponemal immunoassays
3. Stages of Syphilis
DOI: 10.1056/NEJMra1901593
The diagram above from NEJM highlights a few key points. Primary syphilis which usually occurs within 3 weeks of infection (range 2- 6 weeks) presents as a painless chancre (usually genital lesion, but can occur at other sites such as perirectal or oral cavity). The lesion is usually indurated and ulcerated with a clean base.
Secondary syphilis can occur within weeks to a few months after chancre (approximately 25 percent of individuals with untreated infection will have secondary syphilis). Patients with secondary syphilis may not have a history of a chancre if asymptomatic or may have been unnoticed. Clinical manifestations of secondary syphilis include secondary rash/condyloma latum, adenopathy, fever, arthralgias/arthritis, headache, meningitis, anterior uveitis/retinitis, Cranial neuropathies, glomerulonephritis, hepatitis, osteitis/periostitis, alopecia, malaise/anorexia.
Tertiary syphilis is untreated infection for several years/decades and later complications can include aortitis, gummatous deposits. Tertiary neurosyphilis includes general paresis, tabes dorsalis, pupillary abnormalities. (Argyll-Robertson pupil – “Can accommodate but won’t react“)
Early neurosyphilis: Occurs within months to a few years after infection, most commonly presenting as meningitis or meningovascular disease
Late neurosyphilis: Occurs years to decades after infection, typically affecting the brain (causing dementia) or spinal cord (causing tabes dorsalis). Tabes doralis presents with sensory ataxia due to involvement of the dorsal columns and decreased vibration/proprioception, as well as sudden, brief stabbing pains.
Latent syphilis is asymptomatic – and when positive serology results without clinical manifestations. Early latent is < 1 year, late latent > 1 year.
4. Management of Syphilis
Patients diagnosed with syphilis and partners should abstain from condomless intercourse until treatment of the index case and (if indicated) all current partners is complete and ideally for (7) days after completion of treatment.
Syphilis is reportable in all provinces and territories and notifiable to Public Health Agency of Canada. Non-infectious syphilis (late latent, cardiovascular, neurosyphilis) may be reportable at provincial/territorial level.
| Stage of syphilis | Treatment | Are there alternatives? |
| Primary, secondary, Early latent | Benzathine penicillin G 2.4 mU IM x 1 | Doxycycline 100 mg po bid x 14 days In exceptional circumstances and when close follow-up is assured: Ceftriaxone 1 g IV or IM daily for 10 days In special circumstances, azithromycin 2 g once orally. |
| Late latent, cardiovascular syphilis and gumma | Benzathine penicillin G 2.4 mU IM weekly x 3 doses (i.e. 3 weeks, once weekly) | – Consider penicillin desensitization – Doxycycline 100 mg PO BID for 28 days – In exceptional circumstances and when close follow-up is assured: Ceftriaxone 1 g IV or IM daily for 10 days |
| NEUROSYPHILIS | Aqueous penicillin 4mU q4 hours IV x 14 days | NO ALTERNATIVE |
INDICATIONS FOR PENICILLIN DESENSITIZATION:
– Neurosyphilis
– Pregnancy
– Consider in late latent or latent of unknown duration, tertiary syphilis
Patients can develop an acute febrile reaction accompanied by headache, myalgia and fever that occurs within 24 hours after the initiation of syphilis therapy, called Jarisch-Herxheimer Reaction.
5. Monitoring Response to Treatment
A few definitions to be aware of when it comes to monitoring:
Treatment failure – failure of titre to drop by at least 4-fold post-treatment. Consider in these settings if there is re-infection and/or rule out neurosyphilis.
Serofast – patient has >= 4-fold reduction in RPR, but RPR does NOT convert to non-reactive by 24 months. Most commonly seen in the setting of HIV infection. In this setting you would still want to rule out neurosyphilis but if the CSF is normal, and if appropriate response with >= 4 fold reduction in RPR, then continue to monitor.
6. RESOURCES:
- Three great articles in CMAJ on primary secondary and neurosyphilis
- NEJM Review Ghanem, K. G., Ram, S., and P. A. Rice The Modern Epidemic of Syphilis. N Engl J Med 2020; 382:845-854 DOI: 10.1056/NEJMra1901593
- PHO https://www.publichealthontario.ca/-/media/documents/lab/lab-sd-057-syphilis-treponema-pallidum-serology-testing.pdf?la=en
- Health Canada: https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis/treatment-follow-up.html
- CDC: https://www.cdc.gov/std/treatment-guidelines/syphilis.htm