Lues maligna is a severe form of secondary syphilis also known as malignant syphilis or ulceronodular syphilis. The incidence has decreased since the beginning of the 20th century. However, lues maligna is more common among HIV-infected individuals, and may be associated with early HIV infection. In this article, we describe a case of lues maligna as the initial manifestation of HIV infection in a 41-year-old man who presented in 2007.
CASE REPORT
A 41-year-old man presented with 5 days of right foot pain after a pruritic pimple on the dorsum of his right foot. He reported fatigue, depression, and unquantified weight loss during the past several months. The patient also had a different, darker pruritic rash along his forearms, shins, and trunk that started 14 months before admission. He had subjective fevers, but denied chills, oral lesions, headache, or myalgias.
The patient had a negative HIV enzyme-linked immunosorbent assay (ELISA) test and negative Rapid plasma reagin (RPR) approximately 18 months before presentation, then developed a rash 12 to 14 months before presentation. His rash approximately coincided with inconsistent condom use and several new sexual relationships. He smoked 6 to 7 cigarettes per day and smoked cocaine approximately 2 years prior. The patient denied recent intravenous drug use or methamphetamine use, but did admit to taking a friend’s Adderall.
On examination, the patient was afebrile with stable vital signs. His oropharynx did not show ulcerative lesions or thrush. The skin had 2 distinct rashes: (1) a soft 2 × 3 cm erythematous papule along the dorsum of his right foot with no fluctuance; (2) diffuse frambesiform (granulomatous or “berrylike”) well-demarcated oval nodules, some with associated crusting, along his upper extremities, trunk, and shins (Fig. 1). His neurologic examination showed a normal gait, normal sensation in the extremities, normal ankle jerks, and intact cranial nerves.
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Figure 1.:
Left upper panel, plasma cell predominant infiltrate with endothelial cell swelling and narrowing of vessel luminae; left lower panel, marked psoriasiform epithelial hyperplasia with neutrophilic scale crust and dense inflammatory infiltrate; right lower panel, skin-colored to hyperpigmented nodules on the right inner thigh and skin-colored to hyperpigmented nodules on the bilateral calves.
Laboratory studies revealed the following: hemoglobin 15.7 g/deciliter, white blood cell count 8.0 × 109 cells/L (neutrophils 5.12 × 109 cells/L, lymphocytes 1.84 × 109 cells/L, eosinophils 0.56 × 109 cells/L) and platelets 331 × 109 cells/L. Liver function tests were within normal limits. Erythrocyte sedimentation rate was 57 mm/hour (normal <8 mm/hour) and C-reactive protein was 66 mg/L (normal range 0–17 mg/L). Blood cultures were unremarkable and wound cultures from the right thigh and foot showed methicillin-resistant Staphyloccocus aureus sensitive to bactrim, clindamycin, and tetracyclines. Acid-fast bacilli stains, mycobacterial, bacterial, and fungal cultures were all negative. Urine toxicology screen was positive for amphetamines and negative for cocaine.
The right thigh biopsy pathology showed psoriasiform hyperplasia with neutrophilic rich scale and plasma cell-rich inflammatory infiltrate. Periodic acid-Schiff stain and Grocott’s silver stain for fungal infection, and Brown-Hopps gram stains for bacterial identification were all negative; a Steiner stain was also negative for spirochetes. Rapid plasma reagin was positive at 1:128, and Treponema pallidum particle agglutination assay (TPPA) for confirmation of syphilis was positive. HIV ELISA and Western blot were positive, and the HIV viral load was 1240. CD4 count was 514 cells per cubic millimeter of blood and CD4% was 26%. Rectal and throat swabs for Neisseria gonorrhea culture were negative. The patient received 2.4 × 106 units of intramuscular penicillin G. Formal evaluation by dermatology at 1-month posttreatment revealed substantially improved lesions with some faint hyperpigmented patches and plaques overlying the prior lesions, consistent with a healing process. The patient was noted to have a reduction in serial RPR titers typical to the time course of treated syphilis–titers were noted to be 1:16 at month 2, 1:8 at month 7, 1:4 at month 10, and nonreactive 1 year after the initial infection. The patient will continue to have his RPR titers followed every 3 months for 2 years.
DISCUSSION
The patient was diagnosed concurrently with HIV infection and lues maligna, a severe form of secondary syphilis. This case report is significant because the patient likely had an early HIV infection, and the unusual rash of lues maligna was the initial clinical manifestation of HIV. Although another case report also described concurrently diagnosed HIV and syphilis,1 the timing of syphilis and HIV acquisition was not mentioned. The timeline of having a negative HIV ELISA and syphilis test 18 months prior, followed by a rash at 12 to 14 months suggestive of syphilis, and then positive HIV ELISA and syphilis tests at presentation would make initial lues maligna followed by HIV acquisition the most likely scenario. Unfortunately, the complexity of diagnosing lues maligna has prohibited the many other studies of syphilis/HIV coinfection to easily report on HIV acquisition as it relates to lues maligna or other clinical manifestations of syphilis infection.
Lues maligna has a long history, first described by Bazin in 1859 as a nodular variant of syphilis. The first systematic studies of lues maligna go back to the work of Haslund2 and Neisser3 who differentiated lues maligna as a severe form of secondary syphilis separate from the gummas of tertiary syphilis. The rash of lues maligna is also different from other forms of secondary syphilis in its morphology and location. Lues maligna may present as pustules, nodules, or ulcers with or without mucosal involvement.4 The hallmark skin findings are multiple well demarcated round or oval lesions that may have a lamellar crusting to the edge, similar to the rash of yaws. In contrast, the skin findings present in other forms of secondary syphilis are papulosquamous in nature, often mimicking the rashes associated with other diseases such as viral exanthams, cutaneous lymphomas, mycobacterial infections, or fungal infections. Secondary syphilis can also affect the scalp, resulting in alopecia, which is not seen in lues maligna. In terms of location, both lues maligna and other forms of secondary syphilis can be generally and symmetrically distributed throughout the body, and involve the oral mucosa and palms.
Diagnostic criteria for lues maligna include the following: (1) strongly positive RPR titer; (2) a severe Jarisch-Herxheimer reaction (JHR); (3) characteristic gross and microscopic morphology; and (4) rapid resolution of the lesions with antibiotics.4 In this patient, the diagnosis of lues maligna was confirmed by the positive RPR/TPPA titers, characteristic clinical nodular lesions, a plasma cell-rich inflammatory infiltrate noted on pathology, and rapid resolution of the diffuse rash with antibiotics. The patient did not have any signs or symptoms consistent with a JHR in response to penicillin treatment. The patient’s lack of JHR may have been related to his concurrent immunosuppression, as the absence of this reaction in HIV-infected patients with treated secondary syphilis has been previously reported.5 Although some experts advocate for pretreatment of JHR with supportive measures, there is no good clinical evidence to guide this decision. In the event of a JHR, supportive treatment such as intravenously fluids, antipyretics, and antiinflammatory medication should be administered.6
After the advent of HIV infection, lues maligna has become more common. During the period from the early 1900s to 1988, only 14 cases of lues maligna were reported.7 The prevalence of lues maligna was 0.36% in Haslund’s research.2 A 1996 multicenter retrospective study of 11,368 HIV-infected individuals in Germany found that 151 (1.3%) of all HIV-infected patients had syphilis, 11 (7.3%) of whom had lues maligna.8 Compared with historic syphilis series, patients with HIV were 60 times more likely to present with ulcerating syphilis. This data emphasizes the need to test all patients newly diagnosed with syphilis for HIV, as the presence of syphilis indicates a risk factor for HIV coinfection. In addition, our case suggests that lues maligna may be a risk factor for early HIV infection, but further study is needed to compare the risk of HIV acquisition in patients with lues maligna to other forms of syphilis infection. The extent of inflammatory response elicited in lues maligna may predispose individuals to a greater risk of HIV acquisition. Especially in patients who have high-risk sexual behaviors, frequent monitoring of RPR titers and considering acute HIV infection testing are important clinical concerns.
Although traditional diagnostics are central to lues maligna, substantial variation has been reported in patients with HIV infection. RPR titers of patients with lues maligna may be extremely high (1:8192 in 1 report9), and can stay high despite antibiotic therapy. However, negative RPR serologies from prozone phenomena have been reported in lues maligna patients.10
The histologic characteristics of lues maligna are similar to those of secondary syphilis, but with some subtle differences. For example, we were unable to identify the presence of spirochetes on Steiner stains. There is often a dearth of spirochetes in the pathology specimens associated with lues maligna,11 but if detected, they have been noted most commonly using Warthin-Starry stains.12 As a result, one must rely on other diagnostic criteria such as history and physical exam, serologic titers, and histologic findings. It is also important to perform other special stains such as gram stains, acid-fast bacilli stains, and periodic acid-Schiff stain stains on the tissue biopsy, to rule out other competing diagnoses such as foreign-body infection from intravenous drug use, bacterial, mycobacterial, or fungal infections. Other histologic characteristics of lues maligna include a lymphocytic predominance with plasma cells in the upper and middle dermis; superficial and deep vessels reveal a significant perivascular infiltrate and pronounced endothelial swelling, proliferation, and fibrinoid necrosis. Granulomatous infiltrates and giant cells have been seen in cases of lues maligna in HIV-infected patients, although they are surprisingly rare in HIV-seronegative patients with syphilis.1
Our case highlights the important association between lues maligna and HIV infection. Maintaining a low threshold for RPR and TPPA diagnostic testing in addition to obtaining skin biopsy specimens are essential for the prompt recognition of this clinical entity, as well as to rule out other potential diagnoses. Physicians should be aware that lues maligna is not only a disease seen in patients with established HIV infection, but may also present in early HIV infection.
REFERENCES
1. Kumar B, Muralidhar S. Malignant syphilis: A review. AIDS Patient Care STDS 1998; 12:921–925.
2. Haslund A. Syphilis maligna. Archiv fur Dermatologie und Syphilis 1897; 38:345–392.
3. Neisser A. Malignant syphilis. Br J Dermatol 1897; 9:11–26.
4. Fisher DA, Chang LW, Tuffanelli DL. Lues maligna. Presentation of a case and a review of the literature. Arch Dermatol 1969; 99:70–73.
5. Burdette SD, Waibel JS, Bernstein JM, et al. With this eruption, there is not a second to lues. Skinmed 2005; 4:179–182.
6. See S, Scott EK, Levin MW. Penicillin-induced Jarisch-Herxheimer reaction. Ann Pharmacother 2005; 39:2128–2130.
7. Sands M, Markus A. Lues maligna, or ulceronodular syphilis, in a man infected with human immunodeficiency virus: case report and review. Clin Infect Dis 1995; 20:387–390.
8. Schofer H, Imhof M, Thoma-Greber E, et al; The German AIDS Study Group (GASG). Active syphilis in HIV infection: a multicentre retrospective survey. Genitourin Med 1996; 72:176–181.
9. Gregory N, Sanchez M, Buchness MR. The spectrum of syphilis in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1990; 22:1061–1067.
10. Watson KM, White JM, Salisbury JR, et al. Lues maligna. Clin Exp Dermatol 2004; 29:625–627.
11. Pleimes M, Hartschuh W, Kutzner H, et al. Malignant syphilis with ocular involvement and organism-depleted lesions. Clin Infect Dis 2009; 48:83–85.
12. Shulkin D, Tripoli L, Abell E. Lues maligna in a patient with human immunodeficiency virus infection. Am J Med 1988; 85:425–427.
