A lymphocytic papular eruption associated with primary human immunodeficiency virus infection

ARTICLE

Individuals infected with the human immunodeficiency virus (HIV) can be placed in one of three clinical categories: asymptomatic carrier state, acquired immunodeficiency syndrome (AIDS)-related complex (ARC), and full-blown AIDS [1, 2]. In association with HIV infection, various cutaneous manifestations have been reported, including infectious and neoplastic diseases, and others [2-7]. These skin lesions occur mostly in patients with ARC or AIDS.

Both symptomatic and subclinical primary HIV infections are thought to exist [2, 8, 9]. Symptomatic primary infection with HIV has been documented by virus isolation during acute illness and concurrent or subsequent HIV seroconversion [8-12]. The general symptoms include high temperature, malaise, headache, rigor, arthralgia, myalgia, sore throat, abdominal cramp, diarrhea, lymphadenopathy, lymphocytic meningitis, and encephalitis [8-12]. In addition to these manifestations, a half to two thirds of patients have skin rash [9, 11], which is described as maculopapular, vesicular, pustular, and urticarial eruptions [8-11] with mucous ulcerations [9]. However, skin eruptions associated with the initial exposure to HIV have not yet been well-characterized either clinically or histologically. In this article, we report a retrospectively identified, acute illness possibly associated with primary HIV infection in a Japanese patient with AIDS, focusing on a papular eruption histologically characterized by a massive infiltrate of atypical T-lymphocytes.

Case report

A 42-year-old homosexual Japanese man had been in a good health until December 16, 1991, when he consulted a private hospital for a 3-day-history of acute illness, consisting of a high fever, 38 to 39° C, malaise, diarrhea with abdominal pain, and inguinal lymphadenopathy. His medical history included bone fracture of the right lower leg at delivery. The family history was unremarkable. At this point, the leukocyte number was 4.8 x 10⁹/l with differential counts of 58% neutrophils, 30% lymphocytes, and 12% monocytes. The hemoglobin value was normal, the platelet number was decreased (104 x 10⁹/l; normal, 120-400 x 10⁹/l), and C-reactive protein was 5.6 g/l (normal, < 0.5 g/l). On December 19, the patient developed an erythematous skin rash mainly on the trunk, followed by cough and sore throat. Although the eruption was alleviated, AST (317 IU/l; normal 5-40 IU/l), ALT (339 IU/l; normal, 4-35 IU/l) and LDH (2,210 IU/l; normal 170-450 IU/l) were elevated with a continuing high temperature. The leukocyte count was 4.6 x 10⁹/l with an increased percentage of lymphocytes (63%). Antibody titers against Epstein-Barr virus suggested past infection with this virus. Serum tests for hepatitis B surface antigen and its antibodies, hepatitis C antibodies, and syphilis were negative. On January 10, 1992, while the serum levels of liver enzymes had gradually normalized, his skin eruption became worse. When he was referred and admitted to our hospital on January 28, he had a high temperature (39° C), sore throat, cervical lymphadenopathy and presented with asymptomatic, erythematous papules and vesiculopustules on the trunk and lower extremities (Fig. 1). Bacterial cultures revealed that the pustules were sterile. Throughout January, the leukocyte count fluctuated between 7.2 and 8.9 x 10⁹/l with relatively high percentages of lymphocytes. The blood chemistry showed that the value of LDH (496 IU/l) had decreased with completely normalized AST and ALT levels. Chest X-ray and urinalysis were unremarkable. The patient's skin lesions were tentatively diagnosed as a viral eruption or generalized pustular bacterial infection. After rehydration for several days without any specific treatment, his acute symptoms settled over 2 weeks and he was discharged on March 6.

The biopsy specimen taken on February 6, 1992, from an erythematous papule on the trunk disclosed a massive, focal, perivascular infiltration of lymphocytes of the whole dermis (Fig. 2). Dermal edema gave rise to subepidermal collections of fluid beneath the epidermis. In the upper dermis, there was a marked infiltrate of lymphocytes that invaded the epidermis. The lymphocytes had irregularly shaped, atypical nuclei, some of which showed mitotic figures. The infiltrating lymphocytes in deparaffinized sections were positive for CD45RO (UCHL-1; Dakopatts, Glostrup, Denmark) but not CD20 (L26; Sekagaku Corp., Tokyo, Japan), indicating T cells. The skin specimen taken on February 19, 1992, from a folliculitis-like papule on the trunk also exhibited a lymphocytic infiltrate in the upper dermis and around the follicles with epidermotropism.

Over the next 3 years, his condition remained stable. In early May of 1995, however, the patient began to feel unwell with continuing fever and cough. In June, he developed dizziness, gait disturbance, and vomiting. He was admitted to the department of internal medicine at our university hospital on June 23. The leukocyte count was 2.4 x 10⁹/l with 17% lymphocytes, with a CD4/CD8 ratio of 0.13. A diagnosis of AIDS was made from serum tests showing a positive, enzyme-linked immunosorbent assay and Western blot for HIV-1. His neurological symptoms were diagnosed as HIV encephalopathy. He had severe seborrheic dermatitis on his face, the biopsy specimen of which revealed a lymphocytic infiltrate in the dermis and the presence of Pityrosporum in the follicles as well as the cornified layer. He was infected with Treponema pallidum and hepatitis B virus, because the titers of VDRL and TP-AB were 1 and 1,120, respectively, and hepatitis B s and e antigens were positive although antibodies against these antigens were negative. Although the systemic administration of granulocyte-colony stimulating factor temporarily increased the number of leukocytes, the patient died on August 31, 1995. Autopsy was not performed.

Discussion

It is estimated that AIDS occurs on average 8 years and within 5 years in 20% to 30% of individuals after primary infection [13]. The patient died of AIDS 3 years and 8 months after the onset of acute illness in which an erythematous papular eruption was a salient manifestation. Although neither P24 antigenemia, HIV viremia, nor seroconversion linking the patient's acute illness [9] was proved, it is tempting to suggest that the patient's illness was associated with primary HIV infection for the following reasons. Firstly, the patient's symptoms, including fever, malaise, abdominal pain, sore throat and skin rash are common clinical manifestations of reported cases where primary infection was shown by seroconversion [8-12]. However, since these "mononucleosis-like" [11] manifestations are not specific, we can not exclude the possibility of another viral infection. Secondly, throughout the acute illness of this patient, leukocytes were not decreased in number but rather increased up to 8.9 x 10⁹/l with high percentages of lymphocytes, 4 to 5 weeks after the onset of the illness. Although we could not analyze the numerical change in the number CD4⁺ cells, that there was no reduction in the total number of lymphocytes suggests that the patient's condition was not yet AIDS or ARC at this point. During the course of the acute illness, inversion of CD4:CD8 ratio usually occurs because of increased numbers of circulating CD8⁺ cells, resulting in lymphocytosis approximately 4 weeks after the onset of illness [11]. Thirdly, serum tests for hepatitis B virus and syphilis became positive between the acute illness and admission with AIDS. Given that coincidental infection by these microorganisms is often seen in HIV-positive individuals, this conversion implies that the patient had already been exposed to HIV around the time of the acute illness.

The eruptions associated with primary HIV infection remain uncharacterized both clinically and histologically. A papular type of eruption has also been noted to be associated with AIDS or ARC [14, 15]. However, the skin lesions in our case differed from those of patients with AIDS or ARC in that the papules were clinically larger in size and histologically more active than AIDS- or ARC-related papules [14, 15]. This eruption was strikingly characterized by a massive perivascular infiltrate of atypical T-lymphocytes with marked epidermotropism. After gradual resolution of the acute infection, there was an extraordinary proliferative response associated with the development of atypical lymphocytosis which paralleled the development of lymphadenopathy [11]. Thus, it seems that the papular eruption, with a massive lymphocytic infiltrate occurs as one of consequences resulting from systemic activation of lymphocytes. We could not characterize the skin-infiltrating T cells as CD4⁺ or CD8⁺, because non-fixed specimens for staining were not available. This interesting issue is to be clarified in future studies. Our patient demonstrated that lymphocytic papules with acute illness is an important manifestation to be kept in mind for the diagnosis of primary HIV infection.

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