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Clinical Infection & Immunity

Case Report

Volume 2, Number 2-3, September 2017, pages 31-35

The Resurgence of Syphilis

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. Known as the “great imposter”, syphilis is a multisystem chronic infectious disease with three stages (primary, secondary, and tertiary) and many different forms of presentation [1, 2]. Initial serological testing for screening is with rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL), followed by confirmatory testing with fluorescent treponemal antibody absorption (FTA-abs) or darkfield microscopy. T. pallidum is a corkscrew shaped spirochete bacteria definitively diagnosed with darkfield microscopy.

In 2012, the World Health Organization (WHO) estimated 18 million cases, among adolescents and adults aged 15 - 49 years [3]. In the United States, between 2000 and 2001, the national rate of reported primary and secondary (P&S) syphilis cases - the most infectious states of disease - was 2.1 cases per 100,000 population, the lowest rate since reporting began in 1941. However, the primary and secondary syphilis rate has increased almost every year since 2000 - 2001. The most recent report from 2014 to 2015 shows the national rate has increased 19.0% to 7.5 cases per 100,000 population, the highest rate reported since 1994 [3].

A 27-year-old Caucasian male with no past medical history, works as a police officer in Queens County, New York, and is sexually active with females only. The patient initially presented to his primary care provider (PCP) with complaint of headache, chills, sore throat, and fatigue. Patient was seen and treated symptomatically as a viral upper respiratory infection.

Patient returned 2 weeks later with upper respiratory symptoms resolved, with new complaint of a rash. Patient stated he first noticed a small 1 × 1 cm patch on his left chest wall (Fig. 1), and then the rash spread across his chest (Fig. 2), abdomen and bilateral arms (Fig. 3), not involving the palms, and not going below the belt or onto the back. Rash was generalized, erythematous, maculopapular and initially treated with topical triamcinolone.

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Figure 1. First spot of rash development.

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Figure 2. Day 35 prior to treatment.

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Figure 3. Spread of rash to arms without palmar involvement.

When the patient returned to his PCP after 1 week with no improvement in the rash, he was screened for sexually transmitted infections. Screening returned a positive RPR titer of 1:128 and the patient was diagnosed with secondary syphilis (Table 1).

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Table 1. Sexually Transmitted Infection Lab Results

Per current Centers for Disease Control (CDC) guidelines, the patient was treated with bicillin L-A (penicillin G) injections, once a week for the next 3 weeks (Table 2), which showed gradual improvement of the rash (Fig. 4) [3].

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Figure 4. Day 42 near resolution of rash.

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Table 2. Timeline of Symptoms and Treatment

Serological testing is readily available. Tests typically become positive 3 - 5 weeks after infection or 1 - 2 weeks after appearance of a chancre. If a test is initially negative, and then becomes positive, it is highly diagnostic of syphilis [2].

Screening can be done with either RPR or VDRL. If the test shows a reactive specimen, quantitative titers are typically drawn, with the highest number showing most strongly positive reaction. Screening in HIV patients frequently shows false-negative results due to the inability to mount an immune response [2, 4].

Reactive results require confirmatory testing with fluorescent treponemal antibody absorption (FTA-abs) or darkfield microscopy. FTA-abs can be performed on biopsied tissue or exudate from a syphilitic lesion. The only definitive diagnosis for T. pallidum is with darkfield microscopy, which identifies the corkscrew shaped spirochete bacteria [4].

Differential diagnosis is extremely broad and varies by stage. Primary syphilis must be differentiated from chancre-type diseases including chancroid, herpes simplex, balanitis, and granuloma inguinale. Secondary syphilis classically resembles other skin manifestations like pityriasis rosea, fungal skin diseases, drug allergic reactions, and alopecia areata. Tertiary syphilitic skin manifestations can appear similar to other granulomatous diseases including tuberculosis, leprosy, sarcoidosis, deep mycoses and lymphoma. Congenital syphilis can present with symptoms similar to atopic eczema, lymphadenopathy, hepatomegaly, and splenomegaly [4].

Parenteral benzathine penicillin G (bicillin L-A) is the standard of treatment at this time. Dosage and length of treatment is dependent on the stage and manifestations of disease. It is important to note the preparation of medication given, as certain combinations cannot access some sites of treponemal sequestration (i.e., the central nervous system and aqueous humor) [3].

Adult patients with primary, secondary, or early latent syphilis should be treated with one dose of bicillin L-A 2.4 million units given intramuscularly [3]. Patients with asymptomatic late latent syphilis, not acquired within the past year, or tertiary syphilis (excluding neurosyphilis), should be given three doses of bicillin L-A 2.4 million units intramuscularly, once a week for three consecutive weeks [5, 6]. The recommended treatment for neurosyphilis is aqueous penicillin G 18 - 24 million units per day given intravenously. It can be divided into six doses given every 4 h or as a continuous infusion for 14 days [6].

For patients with penicillin allergy, there are multiple alternative therapies dependent on the stage. Doxycycline 100 mg twice daily is the standard choice for oral therapy. For early syphilis, it is given for 14 days and late latent syphilis is treated for 28 days [6].

During pregnancy, penicillin G is the only documented effective treatment. Penicillin allergic patients should first be desensitized, and then treated with penicillin [3].

Sexual partners should also be evaluated and treated if indicated. Partners who have been exposed to primary syphilis within the last 90 days, secondary syphilis within 6 months, early latent syphilis within 1 year, or are unlikely to follow up should be treated presumptively for early syphilis. Long-term partners of patients with late latent syphilis should be screened and treated if necessary [3].

Patients should follow up for retesting in 6 - 12 months, with a goal of a fourfold decrease in titer. Data indicate that 15-20% of patients with primary and secondary syphilis do not achieve a fourfold decline 1 year after treatment. Unless these patients are presenting with symptoms of neurosyphilis, they should be retreated with bicillin L-A 2.4 million units given intramuscularly once a week for three consecutive weeks [3].

Syphilis is caused by the spirochete T. pallidum. Infection can be caused by transmission with very few treponemes, leading to a high rate of acquisition estimated to be 30% [5]. The main route of transmission by this organism is through unprotected sexual intercourse. Transmission occurs via exposure to moist mucosal or cutaneous lesions of P&S syphilis, then the organism enters the counterpart’s body through mucous membranes and broken skin, with rapid spread through the body’s vasculature and lymphatic systems [2, 5].

Less common routes of transmission include in utero, blood transfusions and needle stick injuries. In utero transmission can occur at any stage of disease through the mother’s blood supply by crossing the placenta, with documented transmission to the fetus as early as the ninth week of pregnancy [2, 5].

The age group that rates of reported primary and secondary syphilis cases were highest was among the ages of 20 - 29 years. Historically, the majority of reported cases of P&S syphilis were primarily attributable to men, specifically gay, bisexual, and men who have sex with men (MSM). The current resurgence, which began in the early 2000s, is attributed to MSM, in concurrence with an increase in HIV infection [5]. However, the recent 2014 - 2015 data show that the rate increased 18.1% among men and 27.3% among women. The increase in the rate of women is concerning because as the rate of P&S syphilis increases, this tends to increase the rate of congenital syphilis. Despite the increase in syphilis cases seen in women, MSM continues to account for the majority of P&S syphilis cases in 2015 [3].

The race/ethnicity that historically continues to have the highest rates of P&S syphilis is among African Americans followed by Native Hawaiians/Other Pacific Islanders, Hispanics, American Indians/Alaskan Natives, Asians, and Caucasians. P&S syphilis increased in each of these race/ethnicities except for American Indians/Alaska Natives. Native Hawaiians/other Pacific Islanders had the greatest increase of P&S syphilis in 2015 [3].

By region of the United States, in 2015, the West had the highest rate of reported P&S and congenital syphilis cases. The West was followed by the South, Northeast, and the lowest rates were seen in the Midwest. But in each region themselves, the P&S syphilis rates increased. The states with the most reported cases of syphilis were found to be Louisiana and Wyoming [3].

The primary stage of syphilis typically presents with a small red papule which rapidly progresses into a single, shallow, painless chancre. The incubation period of T. pallidum ranges from 9 to 90 days; however, lesions typically develop approximately 3 weeks after contact [2, 5]. This primary chancre heals spontaneously in 4 - 8 weeks. Due to the painless nature and classic location of the chancre on mucous membranes, it commonly goes unnoticed, especially in women [2]. Regional lymphadenopathy, malaise and fever can also be seen [4].

Without treatment, infection progresses to the secondary stage within 4 - 10 weeks with widespread manifestations of the skin and mucous membranes [2]. Classic symptoms of secondary syphilis include fever, malaise, headache, swollen lymph nodes, sore throat, patchy hair loss, myalgia, anorexia with weight loss and skin lesions, also known as syphilides in 75-80% of patients. Syphilides are typically generalized lesions across the patient’s trunk and limbs with palmar and solar involvement. The palmar and solar involvement is important to distinguish from pityriasis rosea, the most common differential diagnosis. Syphilides vary based on the patient’s skin tone but are noted to be symmetrical, non-pruritic, pink macular lesions. Without intervention, they progress to red papular or papulosquamous lesions. When present at mucocutaneous junctions (typically the groin and axilla), due to the excess moisture and friction, these lesions tend to merge forming condyloma lata [2, 5].

Less common manifestations of secondary syphilis include arthritis, periostitis, tenosynovitis, iritis, choroidoretinitis, hepatitis, glomerulonephritis, and neurologic diseases [2]. It is this variety of inflammatory disorders that created the name “the great imposter” when talking about syphilis.

After the resolution of secondary syphilis symptoms, without treatment, patients develop the early latent and late latent stages of syphilis. Early latent is considered to be less than 4 years from the time of initial infection, and late latent is greater than 4 years [4]. This is the time period before the development of tertiary syphilis.

Tertiary syphilis most often develops 3 - 20 years after the onset of primary syphilis. Pre-antibiotic studies indicate that one-third of untreated infection is followed by tertiary complications. Tertiary syphilis can be divided into three subcategories: neurosyphilis, cardiovascular syphilis and late benign syphilis. Neurosyphilis is the most common complication of tertiary disease [5].

There are many forms of neurosyphilis: asymptomatic, meningeal, parenchymatous, and gummatous [5]. It is classically characterized by Argyll Robertson pupils, tabes dorsalis and a positive Romberg sign.

Acute syphilitic meningitis develops due to inflammation of the meninges and ependyma leading to increased intracranial pressure. It presents with cranial nerve (CN) palsy (typically CN III, VI, and VII) in 40% of cases, sensorineural deafness (CN VIII) in 20% of cases and can lead to communicating and obstructive hydrocephalus [5].

Meningovascular syphilis is infarction secondary to syphilitic endarteritis caused by infiltration of lymphocytes and plasma cells leading to concentric proliferation of fibroblasts progressively narrowing the arterial lumen. Common manifestations include hemiparesis or hemiplegia, aphasia and seizures. This can occur concurrently with tabes and may be accompanied by Argyll Robertson pupils [5]. Argyll Robertson pupils are small and irregular due to miosis from a syphilitic lesion in the midbrain. Colloquially they “accommodate but do not react”; this is also known as near-light dissociation. Meningovascular syphilis can also rarely present as spinal syphilis only with symptoms of spastic paraparesis, ankle clonus, hyperreflexia, urinary and fecal incontinence. However, the clinical picture can change due to concurrent tabes dorsalis, general paresis, or thrombosis and develop symptoms similar to the transection of a spinal cord at the thoracic level with flaccid paraplegia and urinary retention [5].

General paresis or meningoencephalitis is the direct treponemal invasion of the cerebrum. Pathology shows chronic thickening of the meninges leading to fibrosis, cerebral atrophy, demyelination of white matter and granular ependymitis. Patients present with a combination of neurologic findings including pupillary abnormalities; flattening of the facial lines; lip, tongue, facial muscle and finger tremors; and psychiatric symptoms, including depression, dementia, defects in judgment, emotional lability delusions, grandiose delusions and megalomania [5].

Tabes dorsalis initially presents neurologically with loss of vibratory sense and feeling of passive movement in joints followed by lightning pains and hyperesthesia of the areas involved, ataxia, paresthesias on the legs and trunk, diminished deep tendon reflexes, and sluggish pupillary reactivity eventually progressing to Argyll Robertson pupils. Ocular manifestations may be the first sign of neurosyphilis. Optic atrophy, frequently seen with tabes dorsalis can also be an isolated manifestation of neurosyphilis. Visceral crises of the epigastrium, intestines and larynx can also present related to lighting pains.

Cardiovascular syphilis is a rare tertiary complication, seen more commonly in men than women (3:1 ratio), and may lead to aortic aneurysm, aortic insufficiency, coronary artery stenosis, and myocarditis. T. pallidum most commonly infiltrates the vascular wall of the aorta producing transmural inflammation similar to endarteritis of meningovascular syphilis. The long-term presence of this inflammation causes necrosis in the adventitia of the vascular wall creating scar tissue continuously over the years of development or “tree-barking”, leaving a perfect fibrous septation for the development of aortic aneurysms. This is the most common manifestation of tertiary syphilis. Aortic insufficiency and coronary artery disease are complications of extensive aortic aneurysm development [5].

The skin lesions of tertiary syphilis are characterized as nodular or gummatous ulcerations which are due to focal granulomatous tissue destruction. Patients rarely complain of “gumma” lesions without secondary bacterial infection [4]. Most lesions occur in skin and bone, with the most common location in the lower leg [2, 5]. Cerebral and myocardial gummas are very rare and mostly seen in HIV-infected persons [5].

What is most concerning about this infection is that it can lead to deadly outcomes if left untreated both in the male and female population. According to Hall et al, “approximately 15% of patients who acquire syphilis and receive no treatment will die of the disease” [4].

Required screening for syphilis in most states has decreased the incidence of cases; however, there are still reported cases due to late presentation for obstetric follow-up and untreated mothers. Fetal blood transmission can occur as early as 9 weeks after conception via the placenta, and T. pallidum can cross the placenta both leading to fetal infection [2, 4]. Stillbirths from untreated mothers are not uncommon. Infants born with T. pallidum may present normally at birth and develop signs of infection within the first 2 years of life. The most common first sign of infection in an infant is the “snuffles” which is due to the perforated septum. Other presentations of infection consist of saddle nose deformity, cutaneous lesions, condyloma lata, bullous eruptions, neurosyphilis and parrot pseudoparalysis or epiphysitis which causes the infant pain and subsequent refusal to move [2]. Mortality rate depends on immunologic resistance, length of infection, and initiation of treatment [4].

Syphilis is a multisystem chronic infectious disease with many varying presentations. Incidence has been drastically increasing since 2001. Treatment is relatively simple, so when caught and treated in the primary and secondary stages, tertiary complications with extensive multisystem involvement and increased mortality can be avoided. This case serves as a reminder of the importance of prevention and prompt treatment of all sexually transmitted infections. Proper, consistent use of male condoms can reduce the risk of transmission; however, the only definitive prevention is regular screening for sexually transmitted infections in both partners or abstinence from sexual intercourse. Together these defenses may decrease the prevalence of syphilis and other sexually transmitted infections in the United States.

Financial Support

No financial support was provided for this project.

Presentation

The content of this manuscript was presented at New York Colleges of Osteopathic Medicine Educational Consortium Grand Rounds Poster competition on May 25, 2017.

Conflicts of Interest

The authors have no conflicts of interest to disclose.

1. CDC Call to Action: let's work together to stem the tide of rising syphilis in the United States. Centers for Disease Control and Prevention. https://www.cdc.gov/std/syphilis/syphiliscalltoactionapril2017.pdf. Updated April 2017. Accessed May 7, 2017.
2. Pancholi P, Pancholi M, Roh EK. Sexually transmitted disease: genital ulcer disease syphilis. In: Schalock P, ed. Lippincott's primary care dermatology. Philadelphia, PA: Lippincott, Williams & Wilkins; 2011; p. 204-207.
3. Syphilis. Centers for disease control and prevention. https://www.cdc.gov/std/syphilis/. Updated February 6, 2017. Accessed March 11, 2017.
4. Hall J. Spirochetal infections. In: Hall B, Hall J. Sauer's manual of skin diseases. Philadelphia, PA: Lippincott, Williams & Wilkins; 2010; p. 220-229.
5. Sparling PF, Swartz MN, Musher D, et al. Clinical manifestations of syphilis. In: Holmes K, ed. Sexually transmitted diseases. 4th ed. New York, NY: McGraw Hill; 2008; p. 661-682.
6. Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-1917.
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