A nodular-ulcerative form of secondary syphilis in AIDS Ofelya Gevorgyan, MD, Benjamin D. Owen, MD, Arvind Balavenkataraman, MD, and Mitchell R. Weinstein, MD
An uncommon variant in the pre-AIDS era, lues maligna is a nodularulcerative form of secondary syphilis. We present a case of a 41-year-old man with HIV infection who developed fever, chills, nausea, vomiting, right upper quadrant abdominal pain, weight loss, watery diarrhea, and a painless, nonpruritic rash. He had diffuse nodular-ulcerative lesions in various stages of development. He was found to have a CD4 count of 101 cells/mm3 (22%), an HIV viral load of 2,735,060 copies/mL, and a positive rapid plasma reagin at 1:64. He was started on emtricitabine, tenofovir, and dolutegravir, as well as doxycycline. He was given benzathine penicillin 2.4 million units intramuscularly and within hours developed a Jarisch-Herxheimer reaction. Skin lesions showed signs of healing, and constitutional symptoms improved 48 hours later.
W
e describe a nodular-ulcerative form of secondary syphilis in a patient with AIDS, characterized by some remarkable clinical and laboratory features. The alarming resurgence of syphilis and high coinfection rates with HIV necessitate clinicians’ familiarity with this manifestation of “the great imitator.” CASE PRESENTATION A 41-year-old man with a history of intravenous drug abuse and untreated HIV infection presented to his primary care physician with complaints of fever, chills, nausea, vomiting, right upper quadrant abdominal pain, weight loss, watery diarrhea, and a diffuse painless, nonpruritic nodular-ulcerative rash. He was malnourished, febrile (101.2°F), tachycardic, and in mild respiratory distress, with tender and enlarged cervical lymph nodes and mild right upper quadrant tenderness. A diffuse nodulo-ulcerative rash was present, with lesions in various stages of development involving the extremities, back, chest, face, and scalp, as well as a few lesions on his soles, but sparing the palms and the oral mucosa (Figure). The patient was found to have a CD4 count of 101 cells/mm3 (22%), an HIV viral load of 2,735,060 copies/mL, a reactive treponemal antibody, and a positive rapid plasma reagin (RPR) titer at 1:64. He reported an unprotected sexual encounter with a male partner 4 months prior to the appearance of the rash. He was started on combination antiretroviral therapy with emtricitabine, tenofovir, and dolutegravir, trimethoprim-sulfamethoxazole for 80
Pneumocystis jirovecii pneumonia prophylaxis, as well as doxycycline for presumptive secondary syphilis, given a reported allergy to penicillin. He was admitted to the hospital a few days later with worsening constitutional symptoms. His white blood cell count was 3.3 k/mm3; hemoglobin, 9.6 k/mm3; aspartate aminotransferase, 81 IU/L; alanine aminotransferase, 64 IU/L; and alkaline phosphatase, 644 IU/L. Right upper quadrant ultrasound was unremarkable. The patient had had a nonanaphylactic cutaneous reaction to penicillin previously. In the hospital he was given benzathine penicillin 2.4 million units intramuscularly. Within hours he developed worsening fever, tachycardia, and tachypnea, thought to be a Jarisch-Herxheimer reaction. Within 48 hours of treatment, his skin lesions showed signs of healing, and significant improvement was noted by the time of hospital discharge 5 days later. He received 2 more weekly penicillin injections as an outpatient, and 1 week after the third injection he reported almost complete resolution of the rash. At that time, his RPR titer was 1:512. He was subsequently lost to follow-up. DISCUSSION Syphilis is well known for its protean cutaneous manifestations, which led early clinicians to christen the disease “the great imitator.” Lues maligna, or nodular-ulcerative syphilis, is a rare but severe manifestation of secondary syphilis first described by Bazin in 1859, with early systematic studies by Haslund and Neisser in the late 1800s (1, 2). The term “malignant” has been used to describe its grotesque clinical features (3). Lues maligna is characterized by marked prodromal constitutional symptoms, as observed in our patient. This is followed by the development of multiple irregularly distributed, erythematous papules that subsequently evolve into well-defined round or oval, necrotic ulcerated plaques on the scalp, face, trunk, and extremities. Lesions in various stages of development, including papules, nodules, pustules, and ulcerations covered From the Department of Medicine, Section of Infectious Diseases, Presence Saint Joseph Hospital, Chicago, Illinois. Corresponding author: Ofelya Gevorgyan, MD, Department of Internal Medicine, Presence Saint Joseph Hospital, 2913 N. Commonwealth Avenue, Suite 204, Chicago, IL 60657-6211 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2017;30(1):80–82
a
b
c
d
Figure. (a) Lesions in various stages of development, including papules, nodules, pustules, and ulcerations, covered with laminated, brown-black rupioid crusts. (b) Characteristic lesions of lues maligna on the trunk of the patient: papules and sharply marginated ulcers with an erythematous halo and a clean-looking base. (c) Sparing of the palms of the patient. (d) Nodules and ulcers present on the soles of the patient.
with laminated, brown-black rupioid crusts are present, and mucosal surfaces may be affected (1). The trunk, palms of the hands, soles of the feet, and mucosal membranes can be involved, but to a lesser degree than in typical secondary syphilis (3). Our patient had a few lesions on the soles, but his palms and mucosal membranes were spared. The liver is the most commonly involved extracutaneous organ (3). Our patient had right upper quadrant abdominal pain and elevation of liver enzymes, likely due to syphilis. Fisher’s criteria are usually used for diagnosing malignant syphilis: 1) compatible gross morphology; 2) a high-titer serologic test for syphilis; 3) a Jarisch-Herxheimer reaction following treatment; and 4) a dramatic response to antibiotic therapy (3). All of these manifestations were present in our patient. The histologic findings in secondary syphilis are as varied as the clinical presentations. Features mimicking persistent gyrate erythema, lichen planus, parapsoriasis lichenoides and varioliformis acuta, erythema exudativum, psoriasis, pustular psoriasis, histiocytoma, and sarcoidosis have been described (4). Lues January 2017
maligna is characterized by occlusion of the blood vessels with resultant fibrinoid necrosis at the dermal-subcutaneous junction. Treponemes are not readily identified in the lesions but have been described in the dermis using a Warthin-Starry stain (3). The incidence of primary and secondary syphilis has been increasing in the USA in the last several years, especially in men who have sex with men, with the largest increases among Hispanic and white men. Despite this shift in epidemiology, the highest rates continue to occur in black men (5). The prevalence of lues maligna was 0.36% in Haslund’s original series (2). In the pre-AIDS era, lues maligna was associated with severe malnutrition, alcoholism, and intravenous drug use (6). Following the AIDS epidemic, the incidence of malignant syphilis significantly increased (6). According to a 1996 multicenter retrospective study, patients with HIV were 60 times more likely to present with ulcerative syphilis compared to historic case series (2). The reasons for atypical manifestations in the setting of HIV are not entirely understood. It is known that the pathogenesis of lues maligna is less dependent on specific treponemal virulence
A nodular-ulcerative form of secondary syphilis in AIDS
81
factors and more influenced by the host’s immune state, as patients can acquire the disease from persons with typical manifestations of syphilis (1). There are also important clinical interactions between syphilis and HIV, as syphilis is associated with the transmission and acquisition of HIV infection. Syphilitic ulcers facilitate transmission of HIV, and syphilis stimulates the immune system, which can lead to an increase in HIV replication and lower CD4 counts (7). An increase in the incidence of Jarisch-Herxheimer reactions has been described among patients with malignant syphilis and patients coinfected with HIV in general. Yang et al described a rate as high as 34.6% in HIV-infected patients (8). The Jarisch-Herxheimer reaction is a transient immunological phenomenon seen commonly in patients during treatment of secondary syphilis; it manifests with constitutional symptoms such as fever, chills, headache, and myalgias in addition to exacerbation of existing cutaneous lesions (9). The reaction usually occurs soon after the administration of an appropriate antibiotic (2–24 hours) and usually resolves without any intervention, generally within 24 hours. Jarisch-Herxheimer reaction is more severe when the number of organisms is abundant (9). No specific tests are available to diagnose Jarisch-Herxheimer reaction. It should be managed symptomatically and does not require discontinuation of the appropriate antimicrobial treatment (9). Corticosteroids have been used to offset the reaction with no conclusive evidence of their benefit (9). Pretreatment with anti–tumor necrosis factor-alfa Fab has been shown to reduce the incidence and severity of the reaction in louse-borne relapsing fever (10), but its role in syphilis and its potential therapeutic value is unknown. The Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines recommend a follow-up nontreponemal serologic test of syphilis patients 6 and 12 months after therapy (11). Repeat syphilis testing before these specified times can create confusion, as the RPR may
82
increase immediately after therapy of early syphilis, and the initial RPR may underestimate the maximal titer (12). In our case, the early rise in RPR posttherapy was uninterpretable, but likely was not significant. Unfortunately, the patient was lost to follow-up, so the subsequent response is unknown. 1.
Balagula Y, Mattei PL, Wisco OJ, Erdag G, Chien AL. The great imitator revisited: the spectrum of atypical cutaneous manifestations of secondary syphilis. Int J Dermatol 2014;53(12):1434–1441. 2. Tucker JD, Shah S, Jarell AD, Tsai KY, Zembowicz A, Kroshinsky D. Lues maligna in early HIV infection: case report and review of the literature. Sex Transm Dis 2009;36(8):512–514. 3. Kumar B, Muralidhar S. Malignant syphilis: a review. AIDS Patient Care STDs 1998;12(12):921–925. 4. Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol 1973;107(3):373–377. 5. Patton ME, Su JR, Nelson R, Weinstock H. Centers for Disease Control and Prevention. Primary and secondary syphilis—United States, 2005– 2013. MMWR Morb Mortal Wkly Rep 2014;63(18):402–406. 6. D’Amico R, Zalusky R. A case of lues maligna in a patient with acquired immunodeficiency syndrome (AIDS). Scand J Infect Dis 2005;37(9): 697–700. 7. Shockman S, Buescher LS, Stone SP. Syphilis in the United States. Clin Dermatol 2014;32(2):213–218. 8. Yang CJ, Lee NY, Lin YH, Lee HC, Ko WC, Liao CH, Wu CH, Hsieh CY, Wu PY, Liu WC, Chang YC, Hung CC. Jarisch-Herxheimer reaction after penicillin therapy among patients with syphilis in the era of the HIV infection epidemic: incidence and risk factors. Clin Infect Dis 2010;51(8): 976–979. 9. Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BS. The JarischHerxheimer reaction: revisited. Travel Med Infect Dis 2013;11(4):231– 237. 10. Fekade D, Knox K, Hussein K, Melka A, Lalloo D, Coxon R, Warrell D. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med 1996;335(5):311–315. 11. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Morb Mortal Wkly Rep 2015;64(RR3):1–137. 12. Holman K, Wolff M, Sena A, Martin D, Behets F, Van Damme K, Leone P, McNeil L, Gehrig M, Hook EW. Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy. Sex Transm Dis 2012;39(8):645–647.
Baylor University Medical Center Proceedings
Volume 30, Number 1
An uncommon variant in the pre-AIDS era, lues maligna is a nodularulcerative form of secondary syphilis. We present a case of a 41-year-old man with HIV infection who developed fever, chills, nausea, vomiting, right upper quadrant abdominal pain, weight loss, watery diarrhea, and a painless, nonpruritic rash. He had diffuse nodular-ulcerative lesions in various stages of development. He was found to have a CD4 count of 101 cells/mm3 (22%), an HIV viral load of 2,735,060 copies/mL, and a positive rapid plasma reagin at 1:64. He was started on emtricitabine, tenofovir, and dolutegravir, as well as doxycycline. He was given benzathine penicillin 2.4 million units intramuscularly and within hours developed a Jarisch-Herxheimer reaction. Skin lesions showed signs of healing, and constitutional symptoms improved 48 hours later.
W
e describe a nodular-ulcerative form of secondary syphilis in a patient with AIDS, characterized by some remarkable clinical and laboratory features. The alarming resurgence of syphilis and high coinfection rates with HIV necessitate clinicians’ familiarity with this manifestation of “the great imitator.” CASE PRESENTATION A 41-year-old man with a history of intravenous drug abuse and untreated HIV infection presented to his primary care physician with complaints of fever, chills, nausea, vomiting, right upper quadrant abdominal pain, weight loss, watery diarrhea, and a diffuse painless, nonpruritic nodular-ulcerative rash. He was malnourished, febrile (101.2°F), tachycardic, and in mild respiratory distress, with tender and enlarged cervical lymph nodes and mild right upper quadrant tenderness. A diffuse nodulo-ulcerative rash was present, with lesions in various stages of development involving the extremities, back, chest, face, and scalp, as well as a few lesions on his soles, but sparing the palms and the oral mucosa (Figure). The patient was found to have a CD4 count of 101 cells/mm3 (22%), an HIV viral load of 2,735,060 copies/mL, a reactive treponemal antibody, and a positive rapid plasma reagin (RPR) titer at 1:64. He reported an unprotected sexual encounter with a male partner 4 months prior to the appearance of the rash. He was started on combination antiretroviral therapy with emtricitabine, tenofovir, and dolutegravir, trimethoprim-sulfamethoxazole for 80
Pneumocystis jirovecii pneumonia prophylaxis, as well as doxycycline for presumptive secondary syphilis, given a reported allergy to penicillin. He was admitted to the hospital a few days later with worsening constitutional symptoms. His white blood cell count was 3.3 k/mm3; hemoglobin, 9.6 k/mm3; aspartate aminotransferase, 81 IU/L; alanine aminotransferase, 64 IU/L; and alkaline phosphatase, 644 IU/L. Right upper quadrant ultrasound was unremarkable. The patient had had a nonanaphylactic cutaneous reaction to penicillin previously. In the hospital he was given benzathine penicillin 2.4 million units intramuscularly. Within hours he developed worsening fever, tachycardia, and tachypnea, thought to be a Jarisch-Herxheimer reaction. Within 48 hours of treatment, his skin lesions showed signs of healing, and significant improvement was noted by the time of hospital discharge 5 days later. He received 2 more weekly penicillin injections as an outpatient, and 1 week after the third injection he reported almost complete resolution of the rash. At that time, his RPR titer was 1:512. He was subsequently lost to follow-up. DISCUSSION Syphilis is well known for its protean cutaneous manifestations, which led early clinicians to christen the disease “the great imitator.” Lues maligna, or nodular-ulcerative syphilis, is a rare but severe manifestation of secondary syphilis first described by Bazin in 1859, with early systematic studies by Haslund and Neisser in the late 1800s (1, 2). The term “malignant” has been used to describe its grotesque clinical features (3). Lues maligna is characterized by marked prodromal constitutional symptoms, as observed in our patient. This is followed by the development of multiple irregularly distributed, erythematous papules that subsequently evolve into well-defined round or oval, necrotic ulcerated plaques on the scalp, face, trunk, and extremities. Lesions in various stages of development, including papules, nodules, pustules, and ulcerations covered From the Department of Medicine, Section of Infectious Diseases, Presence Saint Joseph Hospital, Chicago, Illinois. Corresponding author: Ofelya Gevorgyan, MD, Department of Internal Medicine, Presence Saint Joseph Hospital, 2913 N. Commonwealth Avenue, Suite 204, Chicago, IL 60657-6211 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2017;30(1):80–82
a
b
c
d
Figure. (a) Lesions in various stages of development, including papules, nodules, pustules, and ulcerations, covered with laminated, brown-black rupioid crusts. (b) Characteristic lesions of lues maligna on the trunk of the patient: papules and sharply marginated ulcers with an erythematous halo and a clean-looking base. (c) Sparing of the palms of the patient. (d) Nodules and ulcers present on the soles of the patient.
with laminated, brown-black rupioid crusts are present, and mucosal surfaces may be affected (1). The trunk, palms of the hands, soles of the feet, and mucosal membranes can be involved, but to a lesser degree than in typical secondary syphilis (3). Our patient had a few lesions on the soles, but his palms and mucosal membranes were spared. The liver is the most commonly involved extracutaneous organ (3). Our patient had right upper quadrant abdominal pain and elevation of liver enzymes, likely due to syphilis. Fisher’s criteria are usually used for diagnosing malignant syphilis: 1) compatible gross morphology; 2) a high-titer serologic test for syphilis; 3) a Jarisch-Herxheimer reaction following treatment; and 4) a dramatic response to antibiotic therapy (3). All of these manifestations were present in our patient. The histologic findings in secondary syphilis are as varied as the clinical presentations. Features mimicking persistent gyrate erythema, lichen planus, parapsoriasis lichenoides and varioliformis acuta, erythema exudativum, psoriasis, pustular psoriasis, histiocytoma, and sarcoidosis have been described (4). Lues January 2017
maligna is characterized by occlusion of the blood vessels with resultant fibrinoid necrosis at the dermal-subcutaneous junction. Treponemes are not readily identified in the lesions but have been described in the dermis using a Warthin-Starry stain (3). The incidence of primary and secondary syphilis has been increasing in the USA in the last several years, especially in men who have sex with men, with the largest increases among Hispanic and white men. Despite this shift in epidemiology, the highest rates continue to occur in black men (5). The prevalence of lues maligna was 0.36% in Haslund’s original series (2). In the pre-AIDS era, lues maligna was associated with severe malnutrition, alcoholism, and intravenous drug use (6). Following the AIDS epidemic, the incidence of malignant syphilis significantly increased (6). According to a 1996 multicenter retrospective study, patients with HIV were 60 times more likely to present with ulcerative syphilis compared to historic case series (2). The reasons for atypical manifestations in the setting of HIV are not entirely understood. It is known that the pathogenesis of lues maligna is less dependent on specific treponemal virulence
A nodular-ulcerative form of secondary syphilis in AIDS
81
factors and more influenced by the host’s immune state, as patients can acquire the disease from persons with typical manifestations of syphilis (1). There are also important clinical interactions between syphilis and HIV, as syphilis is associated with the transmission and acquisition of HIV infection. Syphilitic ulcers facilitate transmission of HIV, and syphilis stimulates the immune system, which can lead to an increase in HIV replication and lower CD4 counts (7). An increase in the incidence of Jarisch-Herxheimer reactions has been described among patients with malignant syphilis and patients coinfected with HIV in general. Yang et al described a rate as high as 34.6% in HIV-infected patients (8). The Jarisch-Herxheimer reaction is a transient immunological phenomenon seen commonly in patients during treatment of secondary syphilis; it manifests with constitutional symptoms such as fever, chills, headache, and myalgias in addition to exacerbation of existing cutaneous lesions (9). The reaction usually occurs soon after the administration of an appropriate antibiotic (2–24 hours) and usually resolves without any intervention, generally within 24 hours. Jarisch-Herxheimer reaction is more severe when the number of organisms is abundant (9). No specific tests are available to diagnose Jarisch-Herxheimer reaction. It should be managed symptomatically and does not require discontinuation of the appropriate antimicrobial treatment (9). Corticosteroids have been used to offset the reaction with no conclusive evidence of their benefit (9). Pretreatment with anti–tumor necrosis factor-alfa Fab has been shown to reduce the incidence and severity of the reaction in louse-borne relapsing fever (10), but its role in syphilis and its potential therapeutic value is unknown. The Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines recommend a follow-up nontreponemal serologic test of syphilis patients 6 and 12 months after therapy (11). Repeat syphilis testing before these specified times can create confusion, as the RPR may
82
increase immediately after therapy of early syphilis, and the initial RPR may underestimate the maximal titer (12). In our case, the early rise in RPR posttherapy was uninterpretable, but likely was not significant. Unfortunately, the patient was lost to follow-up, so the subsequent response is unknown. 1.
Balagula Y, Mattei PL, Wisco OJ, Erdag G, Chien AL. The great imitator revisited: the spectrum of atypical cutaneous manifestations of secondary syphilis. Int J Dermatol 2014;53(12):1434–1441. 2. Tucker JD, Shah S, Jarell AD, Tsai KY, Zembowicz A, Kroshinsky D. Lues maligna in early HIV infection: case report and review of the literature. Sex Transm Dis 2009;36(8):512–514. 3. Kumar B, Muralidhar S. Malignant syphilis: a review. AIDS Patient Care STDs 1998;12(12):921–925. 4. Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol 1973;107(3):373–377. 5. Patton ME, Su JR, Nelson R, Weinstock H. Centers for Disease Control and Prevention. Primary and secondary syphilis—United States, 2005– 2013. MMWR Morb Mortal Wkly Rep 2014;63(18):402–406. 6. D’Amico R, Zalusky R. A case of lues maligna in a patient with acquired immunodeficiency syndrome (AIDS). Scand J Infect Dis 2005;37(9): 697–700. 7. Shockman S, Buescher LS, Stone SP. Syphilis in the United States. Clin Dermatol 2014;32(2):213–218. 8. Yang CJ, Lee NY, Lin YH, Lee HC, Ko WC, Liao CH, Wu CH, Hsieh CY, Wu PY, Liu WC, Chang YC, Hung CC. Jarisch-Herxheimer reaction after penicillin therapy among patients with syphilis in the era of the HIV infection epidemic: incidence and risk factors. Clin Infect Dis 2010;51(8): 976–979. 9. Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BS. The JarischHerxheimer reaction: revisited. Travel Med Infect Dis 2013;11(4):231– 237. 10. Fekade D, Knox K, Hussein K, Melka A, Lalloo D, Coxon R, Warrell D. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med 1996;335(5):311–315. 11. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Morb Mortal Wkly Rep 2015;64(RR3):1–137. 12. Holman K, Wolff M, Sena A, Martin D, Behets F, Van Damme K, Leone P, McNeil L, Gehrig M, Hook EW. Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy. Sex Transm Dis 2012;39(8):645–647.
Baylor University Medical Center Proceedings
Volume 30, Number 1
