CASE REPORTS

Syndrome of Severe Skin Disease, Eosinophilia, and Dermatopathic Lymphadenopathy in Patients with HTLV-II Complicating Human Immunodeficiency Virus Infection MARK H. KAPLAN,M.D., WILLIAMW. HALL, Ph.D., M.D., MYRONSUSIN, M.D., SAVITAPAHWA,M.D., Manhasset, New York, S. ZAKISALAHUDDIN,Bethesda, Mary/and, CONRADHEILMAN, Ph.D., Wrnington, De/aware, JAMESFETTEN,M.D., MARIACORONESI, BRUCEF. FARBER,M.D., Manhasset, New York, SHARONSMITH, M.D., EastOrange, NewJersey

Two intravenous drug users dually infected with human immuuodeficiency virus type 1 (HIV-l) and human T-cell leukemia virus type II (HTLV-II) developed an unusual severe dermatitis charact.8rized by progressive brawny induration, fiseuring, and ulceration of the skin, with an associated CD8 cell infiltration iu one patient. Both patients had persistent eoainophilia. Lymph node biopsy revealed dermatopathic lymphadenopathy, an unusual pathologic finding in HIV-l infection but one seen in association with mycosis fungoides and other skin disorders. Two new isolates of HTLV-II virus were eatablished from these patients and were identified as HTLV-II by Southern blotting. This type of skin disease and lymph node pathology has not been found in other intravenous drug users who have been i&&d with HIV-l alone or in patients in other risk groups for HIV-1 infection. HTLV-II may play a role in this unique new disease pattern in patients infected with HIV-l.

From the Departments of Medicine (MHK. WWH, JF. MC, BFF), Pathology (MS), and Pediatrics (SP). North Shore University Hospital, Cornell University Medical College, Manhasset. New York; Laboratory of Tumor and Cell Biology (SZS), National Cancer Institute, Bethesda, Maryland; E.I. DuPont de Nemours and Company (CH), Wilmington, Delaware; and the Departments of Pathology (SS) and Medicine, University of Medicine and Dentistry of New Jersey, East Orange Veterans Affairs Medical Center, East Orange, New Jersey. This study was supported by The Jane and Dayton T. Brown and Dayton T. Brown, Jr., Viral Laboratory. Requests for reprints should be addressed to Mark H. Kaplan, M.D., North Shore University Hospital-Cornell University Medical College, 300 Community Drive, Manhasset. New York 11030. Manuscript submitted May 7. 1990, and accepted in revised form November 19, 1990.

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uman T-cell leukemia virus type I (HTLV-I), H the first human retrovirus to be discovered, has beenshownto be the causeof acute and smoldering adult T-cell leukemia (ATL) [14], tropical spasticparaparesis[l-4], polymyositis [5], and several other hematologic and neurologic conditions. With the use of seroepidemiologicmethods, this virus hasbeenfound to be widely distributed in the Caribbean, Africa, Japan, and other parts of the world, with only a small percentageof patients experiencing significant illness in their lifetime [l]. HTLV-II, the secondhuman retrovirus to be discovered [6,7], initially appearedto have a limited distribution in humans and was associatedwith only variant forms of hairy cell leukemia [8-lo] in which a co-existent T8 cell lymphoproliferative state [ll] occurred.It has also beensuggestedthat HTLV-II-infected intravenousdrug users(IVDUs) may be more susceptibleto soft tissue bacterial infections [12,13]. The sharedimmunologic crossreactivitybetween HTLV-I and HTLV-II made it difficult to distinguish betweenthem using standard enzyme-linked immunosorbent assay (ELISA) technology. This hasresulted in an underestimationof the extent of HTLV-II infection. Earlier studies using competitive ELISA methods suggestedthat HTLV-II was presentin IVDUs in New York and England [13,14]. Recently, methods of gene amplification utilizing the polymerasechain reaction (PCR) [15] have allowedthesevirusesto be readily distinguished.Using this methodology,Leeet al [16]haveshownthat there is a high rate of HTLV-II infection in seropositive IVDUs in New Orleans. We have found that HTLV-II is present in IVDUs in the greater New York area [17,18]who are also infected with human immunodeficiency virus type 1 (HIV-l). Seronegative virus-positive states for HTLV-II have also been discoveredusing PCR with liquid hybridization technology [19]. Reports of dual HTLV-I/HIV-l infections have appeared,many without distinguishableclinical ill-

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nesses [21-271. Several cases have been reported in which HIV-l infection has been associated with unusual or accelerated forms of HTLV-I co-infection, including two patients with HTLV-I-associated CD8 suppressor cell leukemia [28,29], two patients with HTLV-I accelerated ATL, and one patient with progressive HTLV-I polymyositis [32]. No unique clinical disease has previously been associated with dual infection with HIV-l and HTLV-II. In this report, we describe two IVDUs coinfected with these viruses who presented with dermatopathic lymphadenopathy, associated eosinophilia, and severe infiltrative skin disease suggestive of a mycosis fungoides-like state. This clinical triad has not been previously described in HIV-l infection, suggesting that HTLV-II plays a significant role in inducing this unusual complication of acquired immunodeficiency syndrome (AIDS).

MATERIALSAND METHODS Serum was screened for HIV-l antibody using the Abbott ELISA kit, and antibody was confirmed by Western blot using methods previously described [33,34]. Sera were also screened for antibody to HTLV-I using the Biotech HTLV-I ELISA kit. Serum showing antibody to HTLV-I was confirmed to be positive to HTLV-I or HTLV-II using Western blot analysis. Purified HTLV-I HUT102B (Biotech Research Laboratories, Inc.) and HTLV-II MO (Hillcrest Biologicals) viral lysates were separated in sodium dodecyl sulfate (SDS)12.5% polyacrylamide gels in a discontinuous buffer system [33]. Subsequently, protein bands were electrophoretically transferred to nitrocellulose using a modification of the Towbin procedure [35]. The transfer was conducted in 0.025 mol/L TRIS (pH 8.3) containing 0.192 mol/L glycine and 20% (vol/ vol) methanol. Electrotransfer was conducted for 30 minutes at 30 V, then at 100 V for 3 hours. The nitrocellulose sheet was blocked for at least 1 hour with a blotto solution (5% nonfat dry milk dissolved in phosphate-buffered saline [PBS]). Strips cut from the nitrocellulose sheet were incubated with the primary antibody overnight at room temperature in blotto solution, and then washed three times with PBS-containing 0.05% Tween 20 before the addition of a horseradish peroxidase-conjugated anti-human immunoglobulin (Jackson Laboratories) diluted in a 5% blotto solution. After 1 hour of incubation, the strips were washed three times with PBS-Tween 20 and developed with 4 chloro lnaphthol. After color development, the reaction was stopped by rinsing the strips with deionized water. The strips were dried and stored in the dark.

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Cell Culture for HTLV-II-Producing Cell Lines Mononuclear cells from heparinized blood and lymph nodes were separated by Ficoll hypaque density gradients. Lymphocytes were maintained in RPM1 with 20% fetal calf serum after stimulation with 10 rg/mL of phytohemagglutinin (PHA P Difco Laboratories) and 10% T-cell growth factor (TCGF) (Cellular Products). Cultures were split, refed every 5 to 7 days, and monitored for virus production. Cell cultures were monitored for Mg++-dependent reverse transcriptase activity using methods previously described [37,38]. Cultures were also monitored for expression of viral proteins via an indirect immunofluorescence assay utilizing murine monoclonal antibodies to the p24 core protein of HTLV-I, (a gift of Dr. K. Nagashima, Sapporo, Japan), to the p19,p24gag protein and p41 of HIV1, and a third monoclonal antibody to p24 of HTLV-II (kindly provided by Dr. Zaki Salahuddin). Cultures expressing both HIV-l and HTLV-II were co-cultivated onto different cell lines in an attempt to separate HIV-l from HTLV-II. Subcultures were performed on cell line BJAB, an EBV (Epstein-Barr virus)-free B cell line that we found can be selectively infected with HTLV-II, producing giant syncytial cells. Human herpes virus 6 was identified as described in the original isolation of this novel virus by Salahuddin et al [39]. T-cell subsets were determined by methods previously described [40]. Lymphocyte surface markers were determined using monoclonal antibodies to CD4 (T4), CD8 (T8), CD3 (T3), CD11 (Tll), Bl, B4, and interleukin-2 receptor (TAC) using the Coulter Epics-C cell analyzer. Virus Identification by Southern Hybridization Cell lines co-cultivated into the BJAB cell line could be rapidly expanded to produce sufficient virus for analysis for the presence of HTLV-II proviral DNA. DNA was extracted from unknown cell lines and from one control cell line known to be infected with HTLV-I (NS-I). Hybridization analysis was performed using a 3’ probe for the HTLV-II (MO) provirus genome. DNA was isolated from cells using standard phenol-chloroform extraction. Samples (15 pg) were digested with selected restriction enzymes as indicated in Figure 5, and then were run electrophoretically on 0.8% agarose gels. After electrophoresis, DNA was transferred to Gene-Screen Plus (DuPont) membranes by capillary transfer in 10 X SSC @SC: 0.15 mol/L sodium chloride, 0.015 mol/L tri-sodium citrate, pH 7.0).

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Flgure 1. Hand of Patient 1 showing extensive fissuring and swelling associated with pain and immobility. Generalized alopecia, hyperpigmentation, and skin edema were also present. Ultimately, global ulceration of the skin developed, resulting in fatal gram-negative sepsis.

Membranes were incubated in pre-hybridization Paraffin-embedded tissue biopsies were secbuffer (50% formamide, 10% dextran, 3 X SSC 1% tioned and stained with hematoxylin and eosin. SDS, 0.2 mg/mL salmon sperm DNA, 0.5% blotto powdered milk) for 4 hours at 42OC. Probes were RESULTS labeled with 32-labeled phosphorus using the ran- Case Reports dom primer method and added to the prehybridizaPATIENT 1: This 34year-old male IVDU developed a varicella zoster infection involving a right tion buffer. Hybridization was continued overnight at 42OC. Following hybridization, membranes were thoracic dermatome in June 1984. In October 1984, washed twice at room temperature with 2 X SSC a generalized pruritic dermatitis occurred. In Nocontaining 0.1% SDS (low stringency) and 0.1 X vember 1984, painful adenopathy developed in the SSC containing 0.1% SDS at room temperature and axilla and epitrochlear area. One month later, his hands became swollen, pruritic, and painful, necesat O°C for 45 minutes (high stringency). MemPhysical examination rebranes were covered in Saran Wrap and exposed to sitating hospitalization. X-Omat AR film with intensifying screens at vealed generalized lymphadenopathy associated with extensive lichenification and brawny skin. -70°C. Over the course of hospitalization, total body alopeFreshly obtained skin and lymph node biopsy samples were imbedded in Osyl media and snap cia occurred with the development of intense hyand progressive induration and frozen in methanol dry ice. Biopsy samples were perpigmentation stored at -7OOC prior to sectioning. Tissue was sec- fissuring of his hands and feet (Figure 1). Ulcertioned at -2OOC and fixed to 25 X 75mm glass ation developed over the pretibial area, elbows, and slides. Air-dried cryostat sections were fixed in cold buttocks. These ulcers became secondarily infected with Staphylococcus aureu8. In February 1985, he acetone for 10 minutes prior to staining. Sections were incubated with monoclonal antibodies to CD2 developed oral candidiasis, and in May, Pneumo(Tll), CD3 (Leu-4), CD4 (Leu-3), CD5 (Leu-1), cystis carinii pneumonia. By August, he was bedridden, experiencing continuous severe pain from CD8 (Leu-2), CD20 (Leu-16), K, A, and SlOO (Leu-6) [41]. After sections were washed with PBS, biotinythe multiple ulcers and fissures on his skin. On Seplated horse antimouse antibody was applied to the tember 51985, he developed septicemia with Pseusections. After a PBS wash, sections were incubated domonas aeruginosa and died:An autopsy was not with avidin-biotin peroxidase complex, followed by performed. LABORATORY STUDIES: His white blood cell count a substrate mixture of 3-amino-9-ethylcarbizole on admission was 6,300/mm3 with 30% polymorphoand hydrogen peroxide.

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Figure 2. Results (2A and PC) of lymph node biopsy of Patient 1 showing large numbers of epithelioid histiocytes within the paracortex, some filled with melanin pigment (2C). The number of lymphocytes is generally decreased, and no significant nuclear irregularities are evident (hematoxylin and eosin stain; original magnification X390, reduced by 50%). The axillary lymph node architecture in Patient 2 is shown (28). Note the dermatopathic changes. The paracortex is markedly expanded by an infiltrate of melanin-containing macrophages (20) demonstrated by Fontana Masson stain. Large numbers of epithelioid cells of presumed Langerhans cell lineage (S100 and T6+) are intermixed with the macrophages. Lymphocytes are depleted and show mild nuclear irregularities (hematoxylin-eosin stain; original magnification X390, reduced by 50%).

nuclear leukocytes, 5% band forms, 24% lymphocytes, 40% eosinophils (absolute count 2,520 cells/mm3), and 1% basophils. Throughout his hospital course, he had persistent eosinophilia ranging between 14% and 54%. Multiple stools for ova and parasites were negative. He had 70% T3 cells with 30% T4 cells and 40% T8 cells. Absolute T-cell subset counts were not calculated at this time. By July 1985, the percentage of T4 cells had decreased to 3.7% with 49% T3 cells and 35.5% T8 cells. In January 1985, left axillary lymph node biopsy was performed to ascertain the cause of his painful adenopathy. The paracortex contained large numbers of epithelioid histiocytes, some filled with melanin pigment as demonstrated with the Fontana Masson stain. The pathologic findings were most consistent with dermatopathic lymphadenopathy. Lymphocytes appeared depleted. No atypical lymphocytes were seen (Figures 2A and 2C). In March 1985, a skin biopsy was performed to determine the cause of his rapidly progressing dermatitis. Examination of the biopsy samples revealed a dense infiltrate in the upper dermis extending up to, but not involving, the epidermis. The infiltrate was composed of small lymphocytes without significant nuclear atypia, pigmented macrophages, and scattered numbers of multinucleated giant cells. Lymphocytes showed surface staining for T3. No B lymphocytes were identified. Special

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Figure 3. Skin biopsy results of Patient 1 demonstrating a dense cellular infiltrate within the dermis extending to the epidermis (3A and 3C). The infiltrate is composed of well-differentiated lymphocytes and scattered pigment-containing macrophages (hematoxylin and eosin stain; original magnification X155, reduced by 30%). Occasional multinucleated giant cells are also present (3C) (hematoxylin and eosin stain; original magnification X625; reduced by 30%). Skin biopsy results in Patient 2 showing a mild lymphocytic infiltrate within the dermis surrounding the elongated rete ridges and focally extending into the epidermis (38 and 3D). The lymphocytes show mild nuclear irregularities. Surface marker studies indicated that these lymphocytes were predominantly CD8 suppressor cells (hematoxylin and eosin stain; original magnification X155, reduced by 30%).

stains for T4 and T8 cells were not available at the time. Special stains for microorganisms yielded negative results. The histopathologic findings were interpreted as representing a “granulomatous dermatitis” of unknown etiology (Figures 3A and 3C). The patient’s serum contained antibodies to HIV-l by ELISA and Western blot and to HTLV I/II by ELISA. Western blot showed a weak p24 band on an HTLV-I viral lysate strip and reactivity to gp53, ~42, ~32, ~24, and weak p19 using an HTLV II-viral lysate strip (Figure 4, lanes B and a. LYMPHOCYTE CULTURE: Peripheral blood lymphocytes were placed in culture. After 4 months in culture, cells began to vigorously proliferate, but required the addition of TCGF. Cells were multinucleated and large with hairy projections. Surface phenotyping showed that they were T8 cells with a

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ori-

BylHl

I 5’

2.3-

BamH I

BamHi

1

’ 3.5kb’ t----F’

.

2,0-

1 --.

2 - ____

.3

4 I

I

I

Flgure 4. Results of Western blotting usrng HTLV-I and HTLVII strips. Lane A shows the reaction of a patient wrth HTLV-Iassociated myelopathy against HTLV-I (HUT 1028). Lanes B and D show the reactions of Patients 1 and 2 against the same HTLV-I viral lysates. Lanes C and E show the reactions of Patients 1 and 2 against HTLV-II viral lysates (MO). Note that sera react more strongly with HTLV-II than with HTLV-I.

Figure 5. Southern blots of DNA prepared nom rympnocyre cultures of Patrents 1 and 2. Hybridizatron was carried out under strrngent washing conditions. Lane 1 and 3 show the BarnHI digests of DNA from BJAB-infected cell lines of Patient 1 and 2, respectively. A 3.5-kb fragment IS apparent. Two fragments can be seen when BamHl fragments are digested with Bgl2. Hybrrdrzatron is carried out with a 3’ probe of HTLV-II (MO).

high expression of the TCGF receptor protein (TAC). The celI line was found to express Mg++dependent reverse transcriptase. Cells were found to also express characteristic antigens of HIV-1 (p19, ~24, and ~41). They also expressed the p24 antigen of HTLV-II. Cells were co-cultivated onto the BJAB line, and HTLV-II was purified free of HIV-l. These cells now expressed characteristic HTLV-II virions seen by electron microscopy. Southern blotting described below and in Figure 5 showed the virus to be HTLV-II. PATIENT 2: This male 40-year-old former IVDU developed P. carinii pneumonia in October 1984 and October 1985. In December 1985, he developed recurrent episodes of chills, anorexia, and the onset of a progressively painful, dry, and pruritic skin rash in association with increasing generalized painful adenopathy. In February 1986, he was hospitalized. Physical examination revealed oral thrush and diffusely dry, brawny, tender skin, with an unusual bronze cast to it. Painful nodules were present in the left and right upper arms. GeneraIized lymphadenopathy with 3- to 5-cm nodes was present with even larger axillary nodes. His left arm

became more indurated and S. aureus bacteremia occurred from the nodular subcutaneous abscesses in his arm. Despite prolonged treatment with antibiotic therapy, S. aureus bacteremia recurred from infected subcutaneous skin nodules. Over the next few months, his skin developed severe lichenification (Figure 6), becoming intensely pruritic and desquamating in large dry flakes. By September 1986, he was severely emaciated and had intractable pruritus. He refused further medical treatment and died at home. LABORATORY FINDINGS: The patient’s white blood cell count was 4,000 cells/mm” with 43% polymorphonuclear leukocytes, 7% band forms, 9% lymphocytes, 1% atypical lymphocytes, 13% mononuclear cells, and 27% eosinophils (absolute eosinophil count 1,080 cells/mm”). Significant eosinophilia of greater than 20% persisted throughout his hospitalization. Stools for ova and parasites were negative. He had a total of 208 T cells/mm”, with four helper cells/mm” and 55 suppressor cells/mms. PATHOLOGIC FINDINGS: Because of the new onset of generalized adenopathy, he underwent left axillary lymph node biopsy in February 1986 to rule out

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lymphoma. The lymph node showed expansion of the paracortex by large numbers of histiocytes, many containing melanin pigment. Residual lymphocytes appeared decreased in number, showed mild nuclear irregularities, and were admixed with plasma cells and a few eosinophils. Phenotyping of the lymph node showed moderate numbers of T8 suppressor cells and occasional T4 helper cells. A few B lymphocytes demonstrated polyclonal staining for K and X. Large numbers of cells showed staining for T6 and SlOO, indicative of Langerhans cell lineage (Figures 2B and 2D) [39]. The lymph node architecture was most consistent with dermatopathic lymphadenopathy. Because his skin lesions resembled early cutaneous T-cell lymphoma, skin biopsy was performed that showed mild hyperkeratosis with elongation of the rete ridges. There was a mild lymphocytic infiltrate within the upper dermis focally extending into the epidermis. Phenotyping indicated that the lymphocytic infiltrate consisted predominantly of T8 suppressor cells. Rare multinucleated giant cells were also seen within the infiltrate (Figures 3B and 3D). HIV-l antibody was present by ELISA and Western blot. HTLV I/II antibody was demonstrated by ELISA. Western blot analysis revealed weak ~53 and ~32, and strong p24 antibodies using an HTLV-I strip, and multiple bands using an HTLV-II strip (Figure 4, lanes D and E). LYMPH NODE CULTURE: Mononuclear cells were harvested from his lymph node and placed in culture. After 3 months in culture, cells began to vigorously proliferate, and a cell line was established that revealed numerous giant cells. The cells proved to be predominantly B cells marking with Bl and B4. The cells had a large ratio of cytoplasmic to nuclear cells. This cell line no longer needed TCGF and spontaneously proliferated. These cells showed the presence of HTLV-I p19 and p24 as well as HIV-l ~24. HTLV-I/II was separated from HIV-l by cocultivation of virus into the BJAB cell line that fails to support the growth of HIV-l allows but support the growth of HTLV-II and that produces giant syncytial cells. Electron microscopy showed the characteristic morphology of HTLV-II. Peripheral blood mononuclear cells also grew a novel herpes virus that was one of six isolates of herpes 6 described in 1986 [37]. IDENTIFICATIONOFHTLV-IIPROVIRALDNAUSING SOUTHERN HYBRIDIZATION: With the use ofstrin-

gent washing conditions, DNA preparations from both cell lines in BJAB culture were shown to be HTLV-II (Figure 5). With the HTLV-II 3’ probe, a 3.5kb fragment defined by the two known BamHI restriction sites in the 3’ half of the genome could be September

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Figure 6. The skin of Patient 2 showing and edema with marked scaling associated tus, crusting, and fissuring.

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lichenification intense pruri-

identified in both isolates (Figure 5, lanes 1 and 3). No signal was observed with BamHI digests of the control HTLV-I DNAs. Two fragments could be demonstrated when BanHI-digested fragments were further digested with Bgl 2 restriction enzymes (Figure 5, lanes 2 and 4). No hybridization was observed in the two isolates when the HTLV-I 3’ probe was employed.

COMMENTS In this article, we present two IVDUs dually infected with HIV-l and HTLV-II who developed a severe infiltrative dermatitis in association with dermatopathic lymphadenopathy and eosinophilia. As far as we know, this type of dermal and lymph node pathology has not been previously described in patients with HIV-l infection and may arise as a consequence of co-infection with HTLV-II. Dermatopathic lymphadenopathy is a common form of lymph node hyperplasia characterized by paracortical proliferation of histiocytic-like cells accompanied by the deposition of melanin pigment [42]. Dermatopathic lymphadenopathy can be associated with any chronic dermatosis and tends to be localized to the lymph node chain draining the involved cutaneous areas. Although the condition may look benign, clonal rearrangements of the T1991

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SEVERE SKIN DISEASE, EOSINOPHILIA IN PATIENTS WITH HTLV-II / KAPLAN ET AL TABLE I Pathologic Findings in Lymph Node Biopsy Specimensin HIV-l-Infected Patients Number

oi Biopsy Specimens

::

[451 I$ [481 [491 t::; [521 [531

Follicular Hyperplasia

ki

;i

“2’:

77 6 2

73

;;

43 18t

Mixed 6 3

Follicular Involution

Kaposi’s Sarcoma

Lymphoma

Angiofollicular Hyperplasia

MAIC

Other

1: 1

1

4 6

E*

1 KS

71

8

2 3 t KS

tz:i [561

2::

1::

16

52 2

tz;; I591

:II 37 20 8

[641 I651 Current report

98 121

;i t 2KS’ 36

15

2

4 t KS 1 4

1

8 : 31

:z

IiF 10

1,036

747

61

3 24

1

12

21

11

2

2

8

49

5

26

3

17 104

9

32

3

UC = mycobacterial infection includingMycobacterium tutwculosis and Mycobacterium avium-irttracellulare complex. lodehad associated aranulcma. ‘A!ssociakl MTB in t&ass

cell receptor can occur evenin the absenceof overt neoplastic cells [43]. This finding is particularly common in patients with mycosisfungoides[44-46] in whom the development of dermatopathic changesin the node is consideredan ominous sign [461. TG-expressingdendritic cells,a normal constituent of the lymph node paracortex, proliferate in largenumbers in dermatopathic lymphadenopathy [41].Thesecells arerelatedphenotypically to interdigitating cells of the skin and areprobably of Langerhanscell lineage.The dendritic cellsare thought to presentantigen to immunocompetent T cells. In dermatopathiclymphadenopathy,disruption of the skin by underlying skin diseaseis thought to result in the migration of the T6 cell from the skin to the lymph node, resulting in the depositionof melanin and in the proliferation of T6 cells laden with skin antigens within the node. Although dermatopathic lymphadenopathy is commonly found in benign lymph node biopsy specimensfrom patients who are not infected with HIV-l, particularly in patients with skin disease, this type of lymphadenopathy has not been described in HIV-l-infected patients. In the beginning of the HIV-l epidemic,whenlymph nodebiopsies were more frequently performed in patients with persistent generalizedlymphadenopathy, lesions characterizedby follicular hyperplasia predominated [47-64]. Follicular involution has also 306

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beendescribedpredominantly in patients with opportunistic infection and profound immune failure. Lymph node biopsies are now infrequently performed in HIV-l-infected patients unlessnodesare asymmetrically enlarged or appear to arise after lymph node collapse.These nodesgenerally show lymphoma, Kaposi’s sarcoma,or mycobacterial infection [65-67].In our personalexperiencewith 33 HIV-infected patients, lymph nodebiopsyrevealed lymphoma [ll], hyperplastic nodes [lo], mycobact&al infection [8], Kaposi’s sarcoma[2], Hodgkin’s disease[2], and other infection [2]. In a review of 1,036biopsy samplesfrom HIV-l-infected patients reported in the literature (Table I), only one node has been described as showing dermatopathic lymphadenopathy [55]. Numerousdescriptionsof the dermatologicmanifestations of HIV infection haveappeared,but the type of changesseenin our patients have not been reported [68]. There are somesimilarities between our casesand the caseof pseudo-S6zarysyndrome with the CD8 phenotype in a patient with AIDS reported by Janier et al [69]. Like Janier’s patient, both of our patients had diffuse erythroderma, which is often seen early in the courseof S6zary syndromeand mycosisfungoides.In addition, CD8 cells dominated the dermal infiltrate, particularly in Patient 2. In Patient 1,the predominant cell type infiltrating the skin was a T-cell bearingCD3. CD8 markers were not measuredat the time, but this

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patient’s CD4 cells were profoundly depleted, suggesting that the T cells in the skin may have been CD8 Unlike the patient of Janier et al, both of our patients showed giant cells in the skin, suggesting granulomatous dermatitis. The cells described in the skin of our patients did not have atypical features. Janier et al [69] did not describe the presence of dermatopathic lymphadenopathy, nor did their patient have antibody to HTLV-I/II. In HTLV-I infection with smoldering ATL, similar erythroderma and SBzary-like syndrome can be seen prior to the onset of full-blown leukemia [l,lO]. Granulomatous dermatitis had also been described years before the onset of ATL [70]. In ATL, however, the predominant cell type infiltrating the skin is the CD4 lymphocyte [1,10,71,72]. Our cases may represent a new form of CD8 mycosis-like illness caused by HTLV-II. Recently, Rosenblatt et al [11] showed that in a patient with a Tcell variant of hairy cell leukemia, the HTLV-II virus was present predominantly in the CD8 cells. The leukemic cells did not appear to have virus present in them. We have recently established cell lines from 10 patients dually infected with HTLVII and HIV-l; nine lines proved to be CD&positive cell lines expressing the receptor for TCGF (unpublished observation). These findings suggest that HTLV-II may preferentially infect CD8 lymphocytes, which is in contrast to HTLV-I, which usually infects CD4 cells. As in acute T-cell leukemia where HTLV-I-infected CD4 cells migrate into the skin, HTLV-II-infected CD8 cells may similarly aggregate in the skin, leading to the mycosis fungoideslike syndrome seen in our dually infected addicts. Both of our patients had impressive eosinophilia in the absence of drugs or overt parasitic infestation. This may simply reflect a reaction to injury to the skin. Alternatively, it is possible that HTLV-II infection of lymphocytes may result in the production of lymphokines or other factors such as eosinophilic chemotactic factor that could indirectly result in eosinophilia. The discovery of human herpes virus 6 in Patient 2 [39] was surprising, but we do not think it had a significant role in this patient’s illness. Herpes virus 6 infection is widespread in the general population, and we have found antibody to this herpes virus in almost all of our HIV-l-infected patients, including Patients 1 and 2 (unpublished observation). We still are uncertain as to the effect of human herpes virus 6 on the immunocompromised patient. Is HTLV-II a common cause of dermatitis in infected patients? We have now identified 36 dually infected patients. These patients are predominantly IVDUs aged 30 to 50. In addition to the dermatologic disease we describe, other skin diseases have been present, most notably ichthyosis and hyperSeptember

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pigmentation. We have not seen the skin disease that we describe in any of our 620 HIV-l-infected patients who do not have antibody to HTLV-I/II, although many other chronic dermatoses have occurred, including seborrheic dermatitis, psoriasis, and chronic erythroderma [68]. The presence of this type of skin disease in only two of 36 dually infected patients at first glance may argue against a role for HTLV-II as a cause of the dermatitis. However, low expression of disease is not unusual in retroviral infections. HTLV-IIinduced diseases, as in HTLV-I-induced diseases [1,10,71,72], may appear only after decades of infection and in only a small percentage of those infected. The presence of HIV-l infection may accelerate the appearance of disease produced by HTLV-II in dually infected patients. The dermatologic disease that we have described may represent one of the diseases produced by HTLV-II. Careful epidemiologic studies of these dually infected populations will be useful in providing information as to the full range of disease caused by HTLV-II when it infects patients in the absence of HIV-l.

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