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Molluscum contagiosum in patients with human immunodeficiency virus infection A review of twenty-seven patients Joseph J. Schwartz, MD, and Patricia L. Myskowski, MD New York, New York

Background: Molluscum contagiosum (MC) is a common and at times severely disfiguring cutaneous viral infection in patients with human immunodeficiency virus (HIV) infection. Objective: The purpose of this study was to describe the clinical course of MC in patients with HIV infection and to examine the relation between presentation of MC and the stage of HIV infection, as measured by T-cell subsets. Methods: This is a retrospective case study of 27 patients with MC and HIV infection who had T-cell subset determination within 60 days of diagnosis of MC. Results: The overall mean CD4 + count, CD4+ percentage, and CD4+/CD8 + ratio were 85.7/mm3, 5.9%, and 0.10, respectively. An inverse relation between CD4 + count and the number of MC lesions was observed (p = 0.0023). Fourteen patients (52%) had facial and neck lesions alone, and seven (26%) had lesions in areas associated with sexual transmission. Pneumocystis carinii pneumonia had occurred in 8 patients (31%) and Kaposi's sarcoma in 15 patients (56%). Conclusion: MC can occur as a late manifestation of HIV infection and is a cutaneous corre/ate of cellular immune deficiency. (J AM ACAD DERMATOL 1992;27:583-8.) Cutaneous viral infections are an important cause of morbidity in patients with human immunodeficiency virus (HIV) type 1 infection. 1 Molluscum contagiosum (MC) is caused by a double-stranded D N A virus of the family Poxviridae of which there are two strains, MCV-1 and MCV-2. 2 The disease is a common, and at times severely disfiguring, manifestation of HIV infection.3-13 The prevalence of M C in HIV-infected persons ranges from 5% to 18%.5, 6, 8,9 Although there have been a few case reports of severe CD4 + cell depletion in patients with HIV-associated MC, 14 there have been no large series of

patients with MC in whom associated immunologic findings and clinical characteristics have been analyzed. Immune status, as measured by the CD4 + count, can be used to predict the onset of acquired immunodeficiency syndrome (AIDS) in HIV-infected persons, 15 and certain infections are most likely to occur when CD4 + counts fall below a certain threshold (e.g., patients with CD4 + counts below 200 are at high risk for development of Pneumocystis carinii pneumonia [PCP], and cytomegalovirus infections usually occur at CD4 + counts below 5016). For these reasons, we decided to undertake this study. PATIENTS AND METHODS

From the Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center. Supported in part by grant 5-U01-AI27669-06 from the National Institutes of Health, Bethesda, Md. Presented in part as a poster presentation at the Fiftieth Annual Meeting of the American Academy of Dermatology, Dallas, Tex., Dec. 7-12, 1991. Accepted for publication April 8, 1992. Reprint requests: Patricia L. Myskowski, MD, Memorial SloanKettering Cancer Center, 1275 York Ave., New York, NY 10021. 16/1/38471

A retrospective case review was conducted of 35 consecutive patients with MC. In nine patients the diagnosis was confirmed by biopsy. The clinical setting was a tertiary care referral center. Most patients were involved in HIV-related treatment protocols. All patients were seen by at least one of us (P. M.) and most by both. The onset of MC was determined in most cases by serial physical examinations and in some cases by history. Twenty-seven patients were included in the study who had CD4 + counts within 60 days before or 30 days after the onset of MC.

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T a b l e I. C h a r a c t e r i s t i c s o f 27 p a t i e n t s w i t h H I V - a s s o c i a t e d m o l l u s c u m c o n t a g i o s u m Ol~rtunlstie Infections Patient No.

KS

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

+ + + + + + + + + + + + + + -

21 22 23 24 25 26 27

+ -

Pre-MC

PCP PCP -PCP/MAI --------CMV/PCP MiTB/CMV -q -----

-PCP PCP/CMV -PCP PCP --

Post-MC

--k PCP/CMV -PCP -PCP -----PCP/CrM -------

------k

Lemon location

Disease extent

Total CIM+

CD4 + %

CD4+/ CD8 +

Groin Limited Thigh Limited Face Limited Arm Limited Genitals/axillae Limited Face Limited Face Limited Chest/arms Limited Face Limited Genitals Limited Face Limited Face Limited Arm Limited Groin Limited Face Limited Face Limited Face Limited Face Limited Thigh Limited Face, chest Limited

45 177 77 31 107 94 18 286 294 172 6 381 97 42 15 22 83 14 30 208

2 7 9 5 ND 10 6 ND 12 14 1 17 7 4 2 3 21 3 5 8

0.02 0.09 0.14 0.07 N 0.14 0.08 0.2 0.16 0.23 0.03 0.25 0.1 0.08 0.03 0.09 0.41 0.04 0.06 0.1

Mean Median

110 80

7.4 6.5

0.12 0.09

Face/extremity Face Face/neck Face/neck Face/genitals Neck/chest Face

Extensive Extensive Extensive Extensive Extensive Extensive Extensive

20 15 5 5 10 48 13

5 2 1 1 2 2 1

0.15 0.04 0.02 0.02 0.04 0.03 0.02

Mean Median

17 13

2.0 2.0

0.05 0.03

Mean Median

86 42

5.9 5.0

0.10 0.08

Survival from D x of MC (as of 12/91)

17 m o 16 m o 38 m o 19 m o 70 m o 52 m o Died a t Died a t 39 m o 37 m o Died a t 37 m o 33 m o 9 mo 18 m o Died a t 9 mo Died a t 6 rno 10 m o

3 mo 22 m o

8 mo

10 m o 8 mo

35 m o 31 m o Died a t 19 m o Died a t 10 m o Died a t 21 m o 4 mo 4 mo

TOTAL 27

15

9 (35%)

4 (15%)

Limited, Fewer than 12 lesions; extensive,more than 12 lesions; CMV, cytomegalovirus; CrM, cryptocoocal meningitis; KS, Kaposi's sarcoma; MAI, myeobaeterium avium-intraeellulare; MiTB, miliary tuberculosis; ND, test not done; PCP,Pneumocystiscarinii pneumonia.

T h e occurrence of opportunistic infections, both before and after the development of M C , was recorded, as well as the general course of the M C infection. A l l patients were HIV-seropositive b y standard laboratory methods. Determination of the percentage of CD4 + lymphocytes was m a d e by conventional analysis; the absolute C D 4 + and CD8 + counts were calculated by multiplying the percentage of CD4 + or CD8 + lymphocytes b y the absolute lymphocyte count. RESULTS Twenty-six of the patients were homosexual men; t h e o n l y w o m a n h a d a h i s t o r y of i n t r a v e n o u s d r u g

use. T w e n t y o f t h e 27 p a t i e n t s h a d f e w e r t h a n 12 lesions, a n d seven h a d extensive d i s e a s e ( 1 2 l e s i o n s o r m o r e ) . T h e s e d a t a a r e s h o w n in T a b l e I. T h e o v e r a l l m e a n C D 4 + c o u n t was 86 a n d t h e m e d i a n w a s 42 ( n o r m a l 549 to 1481). T h e p e r c e n t a g e o f C D 4 + l y m p h o c y t e s w a s 6% ( n o r m a l 36% t o 5 9 % ) a n d t h e C D 4 + / C D 8 + r a t i o was 0.08 ( n o r m a l 1.00 t o 2 . 6 8 ) . N o n e of t h e p a t i e n t s h a d a C D 4 + p e r c e n t a g e m o r e t h a n 21% o r a C D 4 + / C D 8 + m o r e t h a n 0.5. T h e r e w a s an inverse r e l a t i o n b e t w e e n e x t e n t o f d i s e a s e a n d C D 4 + c o u n t (Fig. 1 ). T h e m e a n C D 4 + c o u n t a v a i l a b l e for t h e seven p a t i e n t s w i t h e x t e n s i v e

Volume 27 Number 4

October 1992

Molluscum contagiosum and H1V infection

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400-~

3502 300-4 O

+0 Q

0

250200"

D 00

150-

100-

50 0

o-o-

8 QQ

9

N I

!

12

Number of MC Lesions Fig. 1. Comparison of CD4 + counts among patients defined as having limited (--12 lesions). Open circles represent mean of the two groups. disease was 17, and the difference between the mean CD4 + count from this group and from patients with limited disease was statistically significant (p = 0.0023), using the log of CD4 + for equal variance. In addition, there was a significant difference (p = 0.0079) between the medians of the two groups by the Wilcoxon test. The clinical course of MC in our patients had atypical features. The disease was unremitting in all patients and in most cases increased in severity despite aggressive therapy. Fourteen patients (52%) had only facial and neck lesions (Fig. 2), and seven patients (26%) had lesions in areas associated with sexual transmission, such as the external genitalia and thigh. Except for local spread, in most cases the lesions remained at the initial location(s). Giant hyperkeratotic mollusca (> t cm) were observed in one patient. This case has been reported separately because of the unusual clinical presentation. 17 Giant mollusca developed in two other patients (Fig. 3). All three patients with giant MC had extremely low CD4 + counts (10 or fewer) and died shortly thereafter. Nine of the patients (35%) had an opportunistic infection before the diagnosis of MC infection, and four (15%) had an opportunistic infection after the diagnosis of MC. Kaposi's sarcoma was diagnosed

Fig. 2. Extensive molluscum contagiosum on beard area, a common site for MC in patients with HIV infection. Fig. 3. Giant molluscum contagiosum in patient with HIV infection. in 15 patients. Overall, 19 of the patients (73%) had one or more AIDS-defining conditions before the diagnosis of MC. Eight of the patients have died. DISCUSSION Various cutaneous disorders frequently accompany HIV infection. 51a These are more common in patients with later stages of HIV disease, compared with those with earlier or asymptomatic HIV infection.6.9, l0 Kaplan et al. l~ reported an increased prevalence of cutaneous disorders in 222 patients with AIDS. Of the 118 patients with T4 counts less than 100, 103 (87%) had at least one cutaneous disorder, whereas only 40 of [04 patients (38%) with T4 counts more than 100 were noted to have a skin disease. 1~ Sindrup et al., 7 in their study of t50 patients with mostly early HIV infection, found cutaneous viral infections in 10%. In addition, they found that seborrheic dermatitis was statistically associated with low CD4 + count.

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manifestation of advanced HIV infection, along with opportunistic infections such as PCP, cytomegalovirus, and atypical mycobacterial infections) 6 Furthermore, there was a statistically significant correlation between the CD4 + count and the extent of disease. This supports the association between an advancing stage of HIV infection and the extent of M C infection. 5' 8 In addition to a reduction in CD4 + lymphocytes, a decrease in Langerhans cells in AIDS 24 may also be a factor in the pathogenesis of MC because a lack of Langerhans cells is characteristic of lesional skin of M C in non-HIV-positive persons. 25

Fig. 4. Small moUuscum contagiosum on face. These lesions were first indication of H I V infection in this patient.

Several prospective studies have also examined the incidence of M C in various HIV-infected populations. 5"9 At least one such study suggests that MC accompanies progressive H I V disease.9 Goodman et al. 5 examined 117 consecutive patients with AIDS or AIDS-related complex (ARC) and found 9% with MC. In a similar study, Coldiron et al. 8 evaluated 100 consecutive patients with HIV infection (most with AIDS or A R C ) and discovered that, of the 92% of patients with cutaneous disorders overall, 8% had MC. In another study, Hira et aLe evaluated 1124 HIV-seropositive patients in Africa and found that 1.3% of patients with A R C and 5.2% of patients with AIDS had MC. In another study Matis et al. 9 noted an 18% incidence of M C in 34 patients with AIDS versus no M C in 25 patients who were only seropositive for HIV. This difference was statistically significant. The occurrence of M C in immunosuppressed persons was noted before the advent of AIDS. Extensive M C has been reported in patients receiving chemotherapy18 or corticosteroids, t 9 as well as those with congenital 2~and acquired immune deficiencies, particularly impaired cellular immunity. 2t Although the pathogenesis of M C is poorly understood, this study supports earlier evidence that the host cellular immune response is vital to the control of the disease. 22,23 This study quantifies these observations by using CD4 + cells as a measure of immunocompetence. The patients had a profound decrease in their total CD4 + count, CD4 + percentage, and C D 4 + / C D 8 + ratio at the onset of M C infection. The mean CD4 + count for the 27 patients was only 85. Therefore M C can be regarded as a

As expected from the low CD4 + counts, seven of our patients had episodes of PCP before the development of MC, and PCP developed in four patients after the onset of MC. In addition, there were four cases of cytomegalovirus infection and one case each of atypical mycobacterial infection and cryptococcal meningitis. Fifteen patients (55%) had Kaposi's sarcoma, but this most likely reflects the referral bias of our institution. In the setting of HIV infection, M C has an atypical clinical presentation and course. The infection is not self-limited and may be widespread. The lesions are frequently located on the face and upper body rather than the genital area. Extensive M C in the beard area was common (see Fig. 2), which suggest that the infection can probably be spread by shaving. The individual lesions often become large or atypical in appearance (see Fig. 3) and may be mistaken for basal cell carcinoma 26 or keratoacanthoma. 27 There have also been reports of disseminated cryptococcosis and histoplasmosis mimicking MC. 28-3~ For this reason, biopsies should be considered in patients in whom atypical M C lesions develop, especially with signs of systemic illness or rapid dissemination, even if the diagnosis appears obvious on clinical grounds. The low percentage of genital lesions in our patients brings to question sexual activity as the mode of transmission. The abundance of lesions on the face and neck is typical of the distribution seen in children in whom infection is believed to spread through fomites or casual contact. 31 For this reason, the mode of transmission of M C in HIV disease may not be solely by sexual contact but may rely on fomites or casual contact as well. Another possibility is reactivation of latent infection, as can be seen with other D N A viruses in immunocompromised persons. 32 Because routine serologic testing is not per-

Volume 27 Number 4 October 1992

formed, the incidence of previous or latent infection among the general population is not known. Furthermore, the presence of latent virus in nonlesional skin has not been examined by D N A hybridization or polymerase chain reaction techniques, and the MC virus cannot be grown in vitro. For these reasons, the possibility remains of a latent phase of infection with reactivation in the immunosuppressed HIV-infected host. The treatment of MC in the HIV-infected population remains a major challenge. Incision, curettage, cryotherapy with liquid nitrogen, electrodesiccation, and CO2 laser have been used. 33, .~4Topical tretinoin cream may control the spread of MC but frequently causes severe, treatment-limiting irritation. None of the locally destructive modalities is consistently effective in patients with HIV infection. The presence of MC virus in the epidermis adjacent to M C lesions in patients with AIDS may explain the recurrence of disease after the lesions are removed. 35

There is no effective systemic therapy for MC. A recent report described the use of systemic interferon-c~ without success.2~ It has been suggested that zidovudine (AZT) may influence the clinical course of M C in patients with HIV infection. One patient with a CD4 + lymphocyte count of 115 and extensive M C on his face and neck had a complete resolution of skin lesions after 1 month of zidovudine. 36 In our experience, patients receiving zidovudine have not improved. However, it is possible that zidovudine may be effective early in the course of HIV infection or possibly delay the onset of MC infection. M C may serve as a cutaneous marker of severe immunodeficiency. In adults whose HIV-antibody status is unknown, MC may be the first indication of HIV infection. For example, patient 17, an intravenous drug user who was in a high-risk group for HIV infection, had several small M C lesions on her face (Fig. 4) and was found to be seropositive for HIV infection. Patients with known HIV infection in whom MC develops may require reevaluation of their immune status. In this way, patients with previously unrecognized low CD4 + counts may be identified, and appropriate antiretroviral therapy and PCP prophylaxis begun. We have noted an increase in HIV-associated MC during the past 2 years. This may be explained by the increasing longevity of patients with low CD4 + counts because of improved antiretroviral therapy and prophylaxis and treatment of opportu-

Molluscum contagiosum and HIV itfection

587

nistic infections. We expect that the prevalence of this already common infection will continue to rise. REFERENCES

1. Nelson JA, GhaTal P, Wiley CA. Role of opportunistic viral infections in AIDS. AIDS 1990;4:1-10. 2. Scholz J, Rosen-Wolff A, Bugert J, et al. Molecular epidemiology of molluscum contagiosum. J Infect Dis 1988; 158:898-900. 3. Sarma DP, Weilbaecher TG. Molluscum contagiosum in the acquired immunodeficiency syndrome [Letter]. J AM ACAD DERMATOL1985;13:682-3. 4. Lombardo PC. Molluscum contagiosum and the acquired immunodeficiency syndrome. Arch Dermatol 1985;121: 834-5. 5. Goodman DS, Teplitz ED, Wishner A, et al. Prevalence of cutaneous disease in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. J AM ACAD DERMATOL1987;17:210-20. 6. Hira SK, Wadhawan D, Kamanga J, et al. Cutaneous manifestations of human immunodeficiency virus in Lusaka, Zambia. J AM ACAD DERMATOL1988;19:451-7. 7. Sindrup JH, Weismann K, Petersen CS, et al. Skin and oral mucosal changes in patients infected with human [mmunodeficiency virus. Acta Derm Venereol (Stock_h) 1988;68: 440-3. 8. Coldiron BM, Bergstresser PR. Prevalence and clinical spectrum of skin disease in patients infected with human immunodeficiency virus. Arch Dermato11989; 125:357-61. 9. Matis WL, Triana A, Shapiro R, et al. Dermatologic findings associated with human immunodeficiency virus infection. J AM ACAD DERMATOL1987;17:746-51. 10. Kaplan MH, Sadick N, McNutt NS, et at. Dermatologic fndings and manifestations of acquired immunodeficiency syndrome (AIDS). J AM ACAD D~RMATOL 1987;16:485506. 11. Alessi E, Cusini M, Zerboni R. Mucocutaneous manifestations in patients infected with human immunodeficiency virus. J AM ACADDERMATOL1988;19:290-7. 12. Penneys NS, Hicks B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J AM ACAD DERMATOL1985;13:845-52. 13. Fisher BK, Warner LC. Cutaneous manifestations of the acquired immanodeficiency syndrome--update 1987. Int J Dermatol 1987;26:615-29. 14. Katzman M, Carey JT, Elmets CA, et al. Molluseum contagiosum and the acquired immunodeficiency syndrome: clinical and immunologic details of two cases. Br J Dermatol 1987;116:131-8. 15. Goedert J J, Biggar R J, Melbye M, et al. Effect ofT4 count and cofactors on the incidence of AIDS in homosexual men infected with human immunodeficiency virus. JAMA 1987;257:331-4. 16. Masur H, Ognlbene FP, Yarchoan R, et al. CD4 + counts as predictors of opportunistic pneumonias in human immunodeficiency virus (HIV) infection. Ann Intern Med 1989;111:223-31. 17. Schwartz J J, Myskowski PL. HIV-reIated molluscum contagiosurn presenting as a cutaneous horn. Int J Dermatol 1992;31" 142-4. 18. Rosenberg EW, Yusk JW. Molluscum contagiosum: eruption following treatment with prednisone and methotrexate. Arch Dermato[ 1970;101:439-41. 19. Hellier FF. Profuse moUuscum contagiosa of the face induced by corticosteroids. Br J Dermatol 197 I;85:398.

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20. Mayuma H, Yamaoka K, Tsutsui T, et al. Selective immunoglobulin M deficiency associated with disseminated moLluscumcontagiosum. Eur J Pediatr 1986; 145:99103. 21. Cotton DWK, Cooper C, Barrett DF, et al. Severe atypical moUuscum contagiosum infection in an immunocomproraised host, Br J Dcrmatol 1987;116:871-6. 22. Heng MC, Steuer ME, Levy A, et al. Lack of host cellular immune response in eruptive molluscum contagiosum. Am J Dermatopatho[ 1989;11:248-54. 23. Steffen C, Markman J. Spontaneous disappearance of moUuscum contagiosum. Arch Dermatol 1980;116:923-4. 24. Belisto DV, Sanchez MR, Baer R, et al. Reduced Langerhans ceU Ia antigen and ATP-ase activity in patients with acquired immunodeficiency syndrome. N Engl J Med 1984;310:1279-82. 25. Bhawan J, Dayal Y, Bhan AK. Langerhans cells in molluscum contagiosum, verruca vulgaris, plantar wart, and condyloma acuminatum. J AM AChD DERMATOL 1986;15:645-9. 26. Fivenson DP, Weltman RE, Gibson SH. Giant molluscum contagiosum presenting as basal cell carcinoma in an acquired immunodeficiency syndrome patient [Letter]. J AM ACADDERMATOL1988;19:912-4. 27. Coekerdl CJ. Cutaneous manifestations of HIV infection other than Kaposi's sarcoma: clinical and histologic aspects. J AM ACADDERMATOL1990;22:1260-9. 28. Concus AP, Helfand RF, Imber M J, et al. Cutaneous

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cryptococcosis mimicking molluscum contagiosum in a patient with AIDS. J Infect Dis 1988;158:897-9. Miller SJ. Cutaneous cryptococcus resembling molluscum contagiosum in a patient with acquired immunodeficiency syndrome. Curls 1988;41:411-2. DeChavin MF, Revuz J, Deniau M. Histoplasmose ~t histoplasma duboisii: lesions cutan~s simulant des molluscum contagiosum. Ann Dermatol V6n~r~o~ 1993;i 13:715-6. Postlewaithe R. Mollttscum contagiosum: a review. Arch Environ Health 1970;21:432-52. Quinnan GV, Masur H, Rook A/t, et al. Herpesvirus infections in the acquired immune deficiency syndrome. JAMA 1984;252:72-7. Gonnering RS, Kronish JW. Treatment of periorbital molluscum contagiosum by incision and curettage. Ophthal Surg 1988;5:325-7. Friedman M, Gal D. Keloid scars as a result of CO2 laser for molluscum contagiosum. Obstet Gynecol 1987;70: 394-6. Smith K J, Skelton HG, Yeager J, et al. MoIluscum contagiosum--u[trastructural evidence for its presence in skin adjacent to clinical lesions in patients infected with human immunodeficieney virus type 1. Arch Dermatol 1992; 128:223-7. Betlloch I, Pinazo I, Mestre F, et al. Molluscum contagiosum in human immunodeficiency virus infection: response to zidovudine. Int J Dermatol 1989;28:351-2.