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Year : 2022  |  Volume : 23  |  Issue : 2  |  Page : 145-149

Clinicopathological features of secondary syphilis in a human immunodeficiency virus-infected teenager

1 Internal Medicine Resident, General Hospital ISSSTE, Queretaro, Mexico
2 Department of Dermatopathology, General Hospital SESEQ, Queretaro, Mexico
3 Pediatric dermatologist, Private Practice, Queretaro, Mexico
4 Pediatric Infectologist, Private practice, Queretaro, Mexico

Date of Submission30-Jul-2021
Date of Acceptance26-Dec-2021
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Ana San Juan Romero
ISSSTE Hospital General de Queretaro. Av Tecnologico 101, Las Campanas, 76000 Santiago de Queretaro, Queretaro
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.ijpd_118_21

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Syphilis and human immunodeficiency virus (HIV) are both sexually transmitted diseases that affect the same risk group practices, which make co-infection common. Syphilis-infected individuals typically follow a disease course divided into primary, secondary, latent, and tertiary stages. Atypical manifestations, fulminant presentation, serological irregularities, and treatment failures appear more frequently in HIV-seropositive patients. We present the case of a 15-year-old boy with a penicillin allergy who developed dermatological and systemic manifestations in which laboratorial and histopathological studies corresponded to a syphilis-HIV co-infection with a positive response to treatment.

Keywords: Dermatopathology, human inmunodeficiency virus, secondary syphilis

How to cite this article:
Juan Romero AS, Torres EG, Urtusuástegui García MV, Feìlix Bermuìdez GE. Clinicopathological features of secondary syphilis in a human immunodeficiency virus-infected teenager. Indian J Paediatr Dermatol 2022;23:145-9

How to cite this URL:
Juan Romero AS, Torres EG, Urtusuástegui García MV, Feìlix Bermuìdez GE. Clinicopathological features of secondary syphilis in a human immunodeficiency virus-infected teenager. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 May 17];23:145-9. Available from: https://www.ijpd.in/text.asp?2022/23/2/145/341456

  Introduction Top

In the human immunodeficiency virus (HIV), era new problems have arisen in the diagnosis and treatment of syphilis, and the disease again receives attention. Both are sexually transmitted diseases that affect the same risk group practices, which make co-infection common. It can also be transmitted vertically in pregnant women. The major finding in clinical and histopathological aspects of syphilis is that it is known as "the great imitator" and in HIV patients it has a series of pecularities.[1],[2]

In particular, venereal syphilis still remains a worldwide public health problem.[3] The World Health Organization estimates that 11 million new cases of syphilis occur globally every year in patients between the ages of 15 and 49 years.[4] Furthermore, recent reports show that the frequency of syphilis is increasing especially among HIV-positive patients in many countries. HIV infection disproportionately affects men, primarily homosexual men and other men who have sex with men. The clinical manifestations of syphilis depend on site of infection and immune status of the individual. Infected individuals typically follow a disease course divided into primary, secondary, latent, and tertiary stages over a period of more than 10 years. HIV and syphilis each facilitate infection of the other and aggravate one another's clinical course. Syphilis atypical manifestations, fulminant presentation, serological irregularities, and treatment failures appear more frequently in HIV-seropositive patients.[5],[6],[7],[8]

In this article, we present the histological, clinical, and laboratory findings of a secondary stage syphilis young patient with HIV infection at an early age.

  Case Report Top

A 15-year-old male teenager, with no relevant medical history other than a penicillin allergy, developed over the last month an acute onset of pruritic progressive widespread eruption of erythematous-squamous lesions and hyperpigmented macules that started over palms and soles, spreading 2 weeks afterwards to the face, trunk, and extremities associated with conjunctival erythema [Figure 1]a and [Figure 1]b. There was no fever. He denied having any sexual intercourse or any other risk practices. Physical examination revealed right cervical and bilateral inguinal lymphadenopathy, a nonpainful 5 mm chancre on the right side of glans, several perianal fissures, oral candidiasis, and gingivitis. There were no signs of visceromegalies as well as meningeal or neurological symptoms. Laboratory workup revealed normal cell count (total leukocytic count: 5200/uL, neutrophil count: 2397/uL, lymphocyte count: 2652/uL, platelet count: 150000/uL, and hemoglobin [Hb]: 14.7 g/dL), normal liver and kidney function tests, and coagulation profile.
Figure 1: (a and b) Well circumscribed squamous-erythematous plaques of approximately 0.5 mm on the anterior and posterior trunk, as well as the upper extremities (including palms) and some residual hyperchromic lesions

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The patient was referred for a skin biopsy and histopathological evaluation of the skin lesions. Histopathological examination of a 4-mm punch biopsy taken from one of the hyperpigmented macules in the right arm revealed epidermis with the presence of compact orthokeratosis with areas of parakeratosis with deposits of scarse neutrophils, and a thinning stratum granulosum. Regarding the dermis, pseudoepitheliomatous hyperplasia with long, thinned papillae and elongated rete ridges was observed; and a dense diffuse infiltrate was noticed of atypical medium pleomorphic cells with increased nuclear/cytoplasmic ratio involving the whole dermis without significant epidermotropism. The infiltrate extended around blood vessels and adnexal structures and showed a striking interstitial pattern where cells dissected in between thick sclerotic collagen bundles. These cells were positive for CD138+, confirming they were plasma cells. There was the presence of endothelial swelling and slight hyperplasia that compromised the endothelial lumen [Figure 2]. These findings were compatible with secondary syphillis. To study the presence and localization of treponemes in the biopsy, an immunohistochemical workup was done, which turned out to be positive for Treponema pallidum [Figure 3]. The positive immunohistochemical staining in the the histopathology gave a definitive diagnosis of syphillis. Positive fluorescent treponemal antibody absorption (FTA-ABS) was positive, and the suspected co-infection with HIV was confirmed with a positive enzyme-linked immunoassay test and reconfirmed by the Western blot test.
Figure 2: H and E stain, ×10. Endothelial swelling that compromises the lumen

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Figure 3: Positive immunohistochemical testing for Treponema pallidum (×10)

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The proposed treatment was second line based because of the patient's allergy to penicillin with doxycyline 100 mg twice a day for 2 weeks. Topical miconazole gel was given for 2 weeks for the oral thrush. He was referred to an HIV clinic to start antiretroviral treatment with bictegravir, emtricitabine, and tenofovir. On follow-up, 2 weeks later, oral candidiasis resolved and skin lesions began to diminish. He is currently continuing his HIV treatment. The patient's CD4 count was 564 cells/mm3 at the beginning of treatment and showed a gradual increase to 756 cells/mm3 after 2 months. The viral load was 40 copies/ml (undetectable viral load) after 2 months of antiretroviral treatment. Venereal disease research laboratory (VDRL) test titer was 1/128 at the beginning and 3 months later was 1/64.

  Discussion Top

Syphilis is a relatively frequent sexually transmitted disease caused by T. Pallidum. The occurrence in children is rare; therefore, a diagnosis of syphilis in a child or juvenile warrants an investigation of sexual abuse.[9] This disease has classically been divided into three stages. Primary stage may be asymptomatic or characterized by a unique nonpainful chancre localized in the genital area (95%), such as the balanopreputial sulcus of the penis, the labia majora and minora, cervix, anus; or in extragenital sites such as the oral cavity, nipples or groin area. This lesion resolves in a 2–6 weeks period of time and there is a chance of reappearance. Atypical features of syphilis in HIV-infected patients include multiple chancre lesions instead of a single one, the primary genital lesions may persist until the secondary stage (as in this patient), they are more likely to present initially with manifestations of secondary syphilis and syphilitic gumma can be the presenting symptom as well.[10],[11] In the primary stage, dark-field examination of exudates of skin lesions, polymerase chain reaction, or nontreponemal testing can be done for the diagnosis.[8]

Secondary syphilis presents 3–5 months after the primary infection; however, in HIV patients, syphilis natural evolution shortens and secondary syphillis presents earlier with disseminated manifestations such as headache, fever, lymphadenopathy, patchy alopecia, mucosal ulcerations or erosions, hepatosplenomegaly, and rarely renal or neurological alterations. Diagnosis at this stage can be made with nontreponemal and treponemal testing. Latent syphilis presents when serology is positive in an asymptomatic patient. Tertiary syphilis can present as benign syphilis, neurosyphilis or cardiovascular, this stage can have irreversible sequelae or even death.[5],[8]

Among all these stages, it is the secondary stage that can cause confusion, because it mimics countless infections and other immune-mediated processes. Skin eruptions are the the most frequent manifestation. The diverse cutaneous expressions are macular, maculopapular, papulosquamous, lenticular, corymbose, nodular, annular, follicular, pustular, and impetiginoid.[12] Lesions can mimic other diseases including pityriasis rosea (PR), Rocky Mountain spotted fever, contact dermatitis, erythema multiforme, psoriasis, and drug eruptions.[13] Atypical cutaneous manifestations such as frambesiform lesions, photodistributed papulosquamous lesions, nodular-ulcerative lesions and even a vesicular rash have been reported.[14]

There is evidence to suggest that cellular immunity plays a role in clearance of syphilis infections.[15],[16] Carlson et al.[5] propose that helper T-cells remove the initial chancre of syphilis and it is more likely to progress to secondary and tertiary stages in people with defective cellular immunity, such as patients co-infected with HIV. Therefore, HIV-positive patients with low CD4+ counts may be less likely to control the proliferation of T. pallidum resulting in a higher number of spirochetes. Massive numbers of these bacteria may be found in internal organs, with little or no inflammation.[17]

T. pallidum cannot be cultured in vitro, so diagnosis and proof of cure rely on serological examination. Due to the various clinical presentations, a biopsy is usually performed before serological tests as in this juvenile patient, which makes it essential to identify potential syphilis patients through pathology. Gold standard diagnosis is by treponemal (treponema pallidum particle agglutination, FTA-ABS) or non-treponemal (rapid plasma reagin, VDRL) serological testing. Sensitivity of these tests is near 100% in secondary syphilis, and it decreases in the early and latent stages and in immunocompromised patients. The diagnosis in patients with HIV can be complicated because of the suppressed immune response which generates circulating antibodies deficiency. Therefore, seroconversion does not occur sometimes, and the diagnosis depends on the biopsy.[5] An alternative explanation is the prozone phenomenon, in which the quantity of antibodies produced is so high that the dilutions used in the nontreponemal tests are insufficient for diagnose.[18] Although limited reports have suggested this may occur more often in HIV-infected patients, definitive evidence is lacking.[19] In the present case, this phenomenon did not occur likely due to a normal CD4+ count.

Histopathology of the lesions varies in secondary syphilis. Several studies have shown a nonaffected epidermis, as well as focal ulceration, atrophy, irregular acanthosis, elongated rete ridges, and even hyperkeratosis and parakeratosis. On the other hand, affection of the dermis includes mild edema, endothelial swelling and/or proliferation (shown in several studies as highly specific 88%), interstitial inflammation of lymphocytes and/or plasma cells (shown in several studies as highly specific 94%) or a lichenoid pattern. Lymphoplasmacellular infiltrate is predominantly present and can be admixed with histiocytes, neutrophils, and even eosinophils and usually locates perivascularly in a coat-sleeve-like arrangement or perianexaly. Spread of inflammatory cells into epidermis can occur. Occasionally, there can be a granulomatous infiltration.[1],[20]

All of these are the most common features of secondary syphilis, but how reliably these features can be used to differentiate syphilis from other inflammatory dermatoses is unclear. There are other inflammatory dermatoses that can mimic this infection clinically and histologically such as pityriasis lichenoides (PL), PR, and mycosis fungoides (MF). Some cases can lack plasma cells and could also lack endothelial swelling, although both are considered significant features of syphilis. There is no single distinguishing feature that differentiates reliably between syphilis and PL; however, the presence of interstitial inflammation and elongated rete ridges stand out to suggest syphilis. Neutrophils in the stratum corneum, plasma cells, interface dermatitis lymphocytes and vacuoles and the presence of lymphocytes with ample cytoplasm are characteristics more often present in syphilis than in PR. These features can be used reliably to differentiate syphilis from PR. Lymphocyte atypia and vacuolar interface pattern with a lymphocyte in every vacuole is common in both syphilis and MF, the most helpful features to distinguish them are the presence of lymphocytes with ample cytoplasm and the presence of plasma cells. Lymphocytes in syphilis have a normal appearing nuclei, which distinguishes this entity from true lymphocyte atypia. The presence of plasma cells has previously been mentioned as a helpful clue to differentiate syphilis from MF (plasma cells are found in later stages on MF). Therefore, correlation with clinical morphology, serology, and temporality, as well as ancillary immunostaining or silver staining, should be considered in cases where these findings are encountered histologically.[1],[20],[21]

Silver Steiner staining detection of T. Pallidum method can be used to demonstrate primary syphilis and around 70% of secondary syphilis cases. Treponemes are present throughout the dermis, particularly perivascularly, and in the dermal-epidermal junction zone. They can also be found in the epidermis, but always with microorganisms demonstrable in the dermis. It has low sensibility and is difficult to interpret because of the abundant background. False negatives are common when the number of bacteria is low. Immunohistochemical (IHC) detection (antitreponema polyclonal) can be positive in 70%–90% of cases. It is the only irrefutable proof for diagnosis. Positive IHC testing in this patient confirmed the syphilis diagnosis even before serological testing.[1],[20]

Occurrence of syphilis in patients with depressed immunity modifies the histopathological characteristics of the disease. Findings of high quantities of treponemes (i.e., 100 treponemes/10 hpf) were only present in biopsies from patients with CD4+ counts <250 cells/ml, which supports the hypothesis that CD4+ T-cells are important for the control of the Treponema spirochete.[5] Rosa et al.[17] found that T. pallidum density in skin biopsies by immunohistochemistry was inversely related to peripheral CD4+ counts. All patients exhibit a moderate to robust cutaneous lymphoplasmacytic infiltrate, regardless of CD4+ counts. This patient always had CD4+ counts superior to 500 cells/ml, which could explain the normal density of treponemes found in the biopsy. Although lymphadenopathy can accompany secondary syphilis, a biopsy is rarely performed. However, when performed, it shows the typical luetic lymphadenitis, with marked follicular hyperplasia, inflammatory capsulitis, abundant plasma cells, and vasculopathy. High density of spirochetes is notorius with a perivascular arrangement.[20],[22]

Benzathine penicillin G (BPG) remains the treatment of choice for all stages of syphilis. A single intramuscular injection of BPG (2.4 MU) should be administered in early syphilis. These single doses are sufficient to achieve an adequate serological response. In late latent syphilis, infection of unknown duration or in an HIV-co-infected patient, 3 weekly doses are appropriate. In HIV-negative nonpregnant adults with an allergy to penicillin, tetracycline and doxycycline for 14 days are alternatives for treating early syphilis and have been used for decades with success. Efficacy is compromised by potential nonadherence compared to single dosage BPG. Tetracyclines have not been studied enough in HIV-infected patients, thus are not considered standard therapy; desensitization to penicillin has been proposed.[23],[24] Nonetheless, this patient had a positive response to the alternative treatment supported by the lowering VDRL and clinical improvement. The prognosis of patients is directly related with an early diagnosis and an adequate treatment. After each administration of BPG, the antibody titers should lower, until the report is negative. This normally occurs a year after the beginning of treatment. HIV-positive patients require continued observation and periodic testing because immunosuppression can reactivate syphilis, even after treatment.[25],[26]

In conclusion, the syphilis-HIV co-infection is becoming more common worldwide. Therefore, it is important to know the peculiarities involved as the atypical manifestations, the fulminant presentation, serological irregularities, and treatment failures are more common. It requires a multidisciplinary approach, with dermatological and neurological examinations, not forgetting psychological assessment. The periodic testing and follow-up of each patient marks the prognosis and clearly denotes who will need a second round of treatment.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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