Spectrum of mucocutaneous manifestations in human immunodeficiency virus-infected patients and its correlation with CD4 lymphocyte count

Abstract

In this study, 100 HIV-positive cases (63 men, 37 women) with skin findings were included. The mean CD4 T cell count was 253 cells/mm³. A total of 235 dermatological manifestations were seen. The common infectious dermatoses were candidiasis (21%), Staphylococcal skin infections (20%), dermatophytoses (14%) and herpes zoster (6%). Among the non-infectious dermatoses were papular pruritic eruptions (20%), xerosis/ichthyosis (20%) and seborrhoeic dermatitis (16%). Statistically significant association (p < 0.05) with CD4 T cell count was seen in pyodermas, dermatophytoses and papular pruritic eruptions. Adverse drug reactions, diffuse hair loss, straightening of hairs and pigmentary changes were also noted. Although there was an absence of Kaposi’s sarcoma in our study, a case of verrucous carcinoma of penis was noted.

Keywords

HIV AIDS dermatology skin immunosuppression CD4 T cell count mucocutaneous manifestations

Introduction

Human immunodeficiency virus (HIV) infection is often associated with various skin disorders, some of which may be the presenting signs of the disease. They contribute significantly to patient morbidity in terms of quality of life and may also reflect the progress of HIV disease.

Cluster of Differentiation (CD4+) T lymphocyte count is one of the essential investigations and the best indicator of the current immunological competence of the HIV patient.¹ However, the standard test for CD4 T cell count requires sophisticated laboratory facilities, is expensive and is not readily available in resource poor settings.

Cutaneous manifestations are prominent affecting 86–96% of HIV-infected persons.^1–4 The skin lesions or combinations of skin conditions are so unique that the diagnosis of HIV/AIDS can often be suspected from the skin examination alone. The skin conditions often tend to appear at a specific stage in the progression of HIV, and like CD4 T cell count, may be an indicator of the development of AIDS and overall survival.^2,3

The present study was undertaken to note the different mucocutaneous lesions present in the HIV population and correlate their severity with the declining immunity as indicated by CD4 T cell count.

Material and methods

This prospective study included 100 HIV seropositive patients having skin findings, attending Dermatology outpatient department of Fr. Muller Medical College, Mangalore and Antiretroviral Treatment centre at Government Wenlock Hospital, Mangalore.

The study was started after prior approval by the institutional ethics committee. Informed consent was taken from each patient. In suspected patients and referred patients, after pretest counselling, blood samples were tested for anti-HIV antibodies as per strategy III of HIV testing by WHO. Patients underwent a thorough physical examination with emphasis on mucocutaneous manifestations. Findings were recorded on proforma. Relevant diagnostic tests were performed wherever required. CD4 count using flow cytometry was done in all patients.

The statistical analysis was done using Chi square test for non-parametrical data and a Student’s t-test for categorical variables as appropriate. Statistical Package for Social Sciences (SPSS Inc. Chicago, IL, version 16.0 for Windows) was used.

Results

One hundred HIV seropositive patients with a mean age of 32.9 years (range 5 to 56 years) were enrolled during the study period. Majority (72%) of patients were in the age group 21 to 40 years. Sixty-three patients were men and 37 were women. Majority of patients were married (58%), followed by 22% who were widowed, majority of whom were women.

The mean CD4 count was 253 cells/mm³. Patients were grouped based on their CD4 counts as <200 cells/mm³, 200–500 cells/mm³ and >500 cells/mm³. Only HIV-positive patients with mucocutaneous manifestations were included and hence incidence of these finding in the population could not be determined.

There were a total of 235 dermatological manifestations, with an average of 2.3 conditions per patient. The common infectious and non-infectious dermatoses according to the level of immunosuppression as well as their mean CD4 count and p-value have been shown in Tables 1 and 2, respectively. Fungal infections were the commonest among infectious dermatoses whereas papular pruritic dermatoses and xerosis/icthyosis were common among non-infectious dermatoses.

Table 1.

Distribution pattern of various infectious dermatoses in relation to CD4 count and their mean CD4 count.

Infections	Mean CD4 count (in cells/mm³)	CD4 count (in cells/mm³)			p *
Infections	Mean CD4 count (in cells/mm³)	<200	200–500	>500	p *
Pyodermas	250.2 ± 148.9	10	6	2	<0.05
Dermatophytoses	249.5 ± 99.76	6	9	0	<0.01
Candidiasis	144.2 ± 104.25	14	6	1	<0.09
Herpes zoster	263 ± 136.45	2	6	0	<0.12
HSV infection	193.2 ± 202.27	5	2	1	<0.25
HPV infection	182.4 ± 104.13	3	2	0	<0.14
Scabies	158.83 ± 90.75	7	3	0	<0.12
Molluscum contagiosum	311 ± 125.98	2	2	0	<0.20

*p < 0.05 statistically significant.

HSV: herpes simplex virus; HPV: human papilloma virus.

Table 2.

Distribution pattern of various non-infectious dermatoses in relation to CD4 count and their mean CD4 count.

Non-infectious dermatoses	Mean CD4 count (in cells/mm³)	CD4 count (in cells/mm³)			p *
Non-infectious dermatoses	Mean CD4 count (in cells/mm³)	<200	200–500	>500	p *
Seborrhoeic dermatitis	289.5 ± 179.37	8	5	3	<0.24
Xerosis/ichthyosis	249.8 ± 157.20	10	8	2	<0.11
Papular pruritic dermatoses	229.75 ± 229.37	13	5	2	<0.01
Adverse drug reactions	268.07 ± 167.25	8	4	2	<0.11
Diffuse hair loss	198.51 ± 161.42	5	1	1	<0.31
Nail changes	193.76 ± 141.89	21	10	1	<0.19
Oral manifestations	222.6 ± 159.12	4	1	0	<0.10

*p < 0.05 statistically significant.

Hair changes were seen in 11 patients which included diffuse alopecia in seven patients (63%), spontaneous straightening in three patients (27%) and alopecia areata in one patient (9%).

Nail changes were seen in 32 patients comprising 13.6% of all manifestations. Bluish discolouration of nails was observed in eight patients (25%), especially in those who were on antiretroviral therapy. Dystrophic nails were found in seven patients (21.8%), onychomycosis, koilonychia and longitudinal melanonychia in five patients (15.6%) each. Chronic paronychia and subungual hyperkeratosis in one patient (3.1%) each.

Oral manifestations were found in 29 patients. Oral candidiasis seen in 14 patients was most common (48%) of oral manifestations. Aphthae were seen in six patients (20%), pigmentation in five patients (17%), herpes labialis in two patients (7%), oral hairy leukoplakia and angular cheilitis in one patient each (3.4%) were some of the others noted.

There was one case of verrucous carcinoma of penis detected but no cases of Kaposi’s sarcoma were found.

Discussion

Our study conducted over one-year period included 100 HIV-positive patients having mucocutaneous manifestations. There were 63 men of whom majority (41%) belonged to the age group of 21 to 40 years. The male preponderance in the study indicates a greater involvement of male patients in the particular age group in ‘high-risk’ activities predisposing to HIV infections. Among women, 54% were widows and this may be attributed to heterosexual route of transmission of the infections from their husbands who had succumbed to it.

There were a total of 235 dermatological manifestations, with an average of 2.3 conditions per patient.

Fungal infections of the skin were the most common among the infectious dermatoses, accounting for 15.3% of the total skin disorders. Dermatophytic infections were seen in 14% patients, which was comparable with study conducted by Sud et al.⁴ (14.6%). They were found to be more common in those with moderate immunosuppression (CD4 count 200–500 cells/mm³) and this was statistically significant (p < 0.05). The mean CD4 count for dermatophytic infections was 249.5 ± 99.76 cells/mm³ and was consistent with the study by Sud et al.⁴ (212.8 ± 169.3 cells/mm³).

Candidiasis comprised 8% of all manifestations with a mean CD4 count of 144.2 ± 104.25 cells/mm³. We observed that when the CD4 count fell, the incidence of candidiasis increased greatly and was higher when CD4 counts were less than 200 cells/mm³. However in our study, it was not statistically significant (p < 0.09). In patients at high risk for AIDS, the presence of unexplained oral candidiasis heralds the development of serious opportunistic infections.

Herpes zoster was seen in eight patients, out of which six patients (75%) had CD4 count of 200–500 cells/mm³. The mean CD4 count was 263 ± 136.45 cells/mm³ which is similar to the study by Nnoruka et al.² (381.1 ± 181 cells/mm³). The lesions were morphologically bullous in two patients out of which in one patient the lesions turned haemorrhagic (Figure 1(a)). Ulcerative lesions were seen in two patients in whom it took longer time to crust and heal (Figure 1(b)). These lesions took almost four weeks to heal. The neuralgia associated was also more severe. Multidermatomal zoster with involvement of three dermatomes was seen in one patient.

Figure 1.

(a) The haemorrhagic lesions of herpes zoster and (b) haemorrhagic crusting with ulceration in another patient.

Herpes simplex virus (HSV) infection was seen in eight patients. Herpes genitalis (Figure 2) was seen in six (6%) patients and herpes labialis in two patients. Various Indian studies^5–8 reported an incidence of herpes genitalis ranging from 5 to 14%, that reflects a current trend for increased HSV infection in India. Incidence of HSV infection was 5.5 to 18% according to South East Asian studies.^3,9 It is considered the most common cause for genital ulcer disease in recent times. This, in presence of HIV, poses a greater risk of transmission of the disease and also greater morbidity as the disease is recurrent. Suppressive therapy adds to the financial burden of the patient. The majority (66%) of herpes genitalis patients had CD4 counts below 200 cells/mm³ as in other studies.^4–6,9

Figure 2.

Severe ulcerative lesions of herpes genitalis.

Bacterial infections were seen in 18% of patients. The incidence of pyodermas in Indian studies^4–8 was between 2% and 22%. Majority of pyodermas were seen in patients with CD4 counts <200 cells/mm³ and it was statistically significant (p < 0.05). Folliculitis was the most common presentation accounting for 4.3% of all skin findings and Staphylococcus aureus was the most common organism isolated from these lesions. The other pyodermas noted were ecthyma in 1.6%, impetigo in 0.8% and, abscess and cellulitis in 0.4% each. This low incidence of bacterial infection could be attributed to the indigenous use of antibiotics.

Scabies was seen in 10 patients (10%). Various Indian studies^4,7,8 report incidence of 3–10%. The high percentage of patients in our study may correspond to its higher prevalence in general population. Seven out of 10 patients had CD4 counts <200 cells/mm³. The lesions were extensive and with secondary bacterial infection requiring oral antibiotic therapy. Weekly applications of antiscabetic lotions for three weeks were needed to ensure no recurrences occurred. However no case of crusted scabies was found. The mean CD4 count was 158.8 ± 90.7 cells/mm³.

Among the non-infectious dermatoses, seborrhoeic dermatitis was present in 16% of patients in the present study with a mean CD4 count is 166.9 ± 123.7 cells/mm³. The commonest variety was generalised, followed by scalp alone and scalp and face. Fifty percent of patient had CD4 count <200 cells/mm³. The extent, severity and response to treatment were more difficult as the CD4 cell counts deteriorated. In various Indian studies,^5,7,8 its occurrence varied from 9% to 18%. The incidence in south-east Asia as reported by Goh et al.³ and Jing and Ismail⁹ was 18.7% and 28.8%, respectively. Malassezia species have been implicated in the causation of seborrhoeic dermatitis. The role of environmental factors that makes Indian patients less prone to seborrhoeic dermatitis or any difference in the type of organism found in India needs to be analysed by further studies.

Ichthyosis and xerosis may be the result of long standing illness, malnutrition, poor selfcare or immunological deficits. When the CD4+ cell count drops below 50 cells/mm³, generalised acquired ichthyosis with large fish scales may develop beginning on the legs.

Papular pruritic diseases were seen in 20% patients, comprising 8.5% of all skin disorders. Its prevalence varies between 8% and 45% according to the geographic area.^2,3,8,9 Papular pruritic eruptions were seen in 14 patients of which majority (57%) had CD4 counts <200 cells/mm³ and it was found to be statistically significant (p < 0.01). The mean CD4 count was 229.8 ± 229.4 cells/mm³. Higher mean CD4 counts in the current study may be due to the fact that 90% of papular pruritic eruptions patients were on highly active antiretroviral therapy. Eosinophilic folliculitis was seen in three patients in the present study. Mean CD4 count was 127 ± 108 cells/mm³.

Adverse drug reaction was present in 14% of patients in this study. Its incidence ranged between 2% and 17% in various studies.^3,4,7 Eight patients presented with maculopapular rash, majority due to nevirapine and two patients presented with Stevens Johnson Syndrome. The incidence of adverse drug reaction is high in HIV patients possibly due to impaired drug detoxification and viral modulation of immune response. Also generally, utility of drugs is more in HIV for prophylaxis and treatment of various concomitant illnesses.¹⁰

Diffuse hair loss was seen in seven patients. The incidence of diffuse alopecia in various studies ranges from 3% to 14%.^3,4,6 Chronic, diffuse hair loss in HIV-infected patients has been attributed to chronic HIV-1 infection itself and recurrent secondary infections, nutritional deficiencies, immunologic and endocrine dysregulation and exposure to multiple drugs. Many cytokines including IL-1, IL-6, TNF-α, and IL-10 increase in the mid to late stages of HIV-1 disease, and these may have an effect on the follicle. In addition, in HIV-1 disease, a constant state of oxidative stress is present. Oxidative stress is a common factor in immediate anagen release telogen effluvium.¹¹ Straightening of hairs was seen in three patients, where hair became thick, coarse and could not be combed properly. It was seen exclusively in men. Straightening of hairs has been seen in up to 6% patients.⁵

Nail changes were seen in 32 patients. Bluish discolouration of nails was observed in eight patients (25%), especially in those who were on antiretroviral therapy. Onychomycosis was also fairly common often involving multiple digits. Pattern of pigmentation seen are proximal bluish discolouration, diffuse pigmentation involving the whole nail, diffuse pigmentation over whole nail sparing the lunulae and transverse bands of pigmentation. Other nail changes included dystrophic nails, koilonychia, chronic paronychia and subungual hyperkeratosis.

Oral manifestations were found in 29 patients. Oral candidiasis was most common. Aphthae were seen in six patients, patchy hyperpigmentation involving buccal mucosa and lateral aspect of the tongue in five patients. Angular stomatitis was seen, which may be due to HIV infection, candidiasis or nutritional cause.

Increased pigmentation is commonly seen in HIV-infected persons. A study conducted by Smith et al.¹² on HIV patients, showed that immune dysregulation occurs which is supported by elevation of cytokines such as IL-1, IL-6 and TNF-α, increased levels of which induce a febrile response through the hypothalamus, and the neuropeptide α–MSH. IL-1 also upregulates α-MSH receptor expression by melanocytes as well as melanin production in the presence of MSH. α-MSH is a potent stimulant for melanocytic activation and pigmentation.

Verrucous carcinoma of penis was seen in one patient (Figure 3(a) and (b)) in our study and the CD4 count was 31 cells/mm³. The patient had a carcinoma in situ as confirmed by biopsy with no lymph node involvement and hence a partial amputation of the penis was done. However, in our patient human papilloma virus (HPV) isolation was not done due to financial constraints. There have been few reports of invasive squamous cell carcinoma of penis in association with HPV infection in HIV-infected individuals.¹³ But no case of Kaposi’s sarcoma was detected. There is a higher incidence of Kaposi’s sarcoma reported in western literature¹⁴ however there have been few reports from India.⁶

Figure 3.

(a) Verrucous carcinoma of penis and (b) full extent of lesion peri-operatively.

Conclusion

Thus, the present study reinforces the fact that skin is the mirror of the body and more so in HIV infection. It is the most common organ affected in HIV-infected persons and the skin findings are one of the important clinical prognostic markers and may even indicate a diagnosis of HIV infection.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Fauci

Lane

. HIV disease: AIDS and related disorders. Harrison's Principles of Internal Medicine 2012; Vol. 118th ed. New York: Mc Graw-Hill, pp. 1506–1587.

Nnoruka

Chukwuka

Anisuiba

. Correlation of mucocutaneous manifestations of HIV/AIDS infection with CD4 count and disease progression. Int J Dermatol 2007; 46(suppl. 2): 14–18.

Goh

Chan

RKW

Sen

. Spectrum of skin disorders in human immunodeficiency virus infected patients in Singapore and the relationship to CD4 lymphocyte counts. Int J Dermatol 2007; 46: 695–699.

Sud

Shanker

Sharma

. Mucocutaneous manifestations in 150 HIV-infected Indian patients and their relationship with CD4 lymphocyte count. Int J STD & AIDS 2009; 20: 771–774.

Shobhana

Guha

Neogi

. Mucocutaneous manifestations of HIV infection. Indian J Dermatol Venereol Leprol 2004; 70: 82–86.

Kumarasamy

Solomon

Madhivanan

. Dermatologic findings and manifestations among human immunodeficiency virus patients in South India. Int J Dermatol 2000; 39: 192–195.

Chopra

Arora

. Skin and mucocutaneous manifestations: useful clinical predictors of HIV/AIDS. J Clin Diagn Res 2012; 6: 1695–1698.

Jindal

Aggarwal

Kaur

. HIV seroprevalence and HIV associated dermatoses among patients presenting with skin and mucocutaneous disorders. Indian J Dermatol Venereol Leprol 2009; 75: 283–286.

Jing

Ismail

. Mucocutaneous manifestations of HIV infection: a retrospective analysis of 145 cases in a Chinese population in Malaysia. Int J Dermatol 1999; 38: 457–463.

10.

Smith

Skelton

Yeager

. Increased drug reactions in HIV-1 positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV-1 disease. Clin Exp Dermatol 1997; 22: 118–123.

11.

Smith

Skelton

DeRusso

. Clinical and histopathologic features of hair loss in patients with HIV-1 infection. J Am Acad Dermatol 1996; 34: 63–68.

12.

Smith

Skelton

Heimer

. Melanocytic activation in HIV-1 disease: HMB-45 staining in common acquired nevi. J Am Acad Dermatol 1993; 29: 539–544.

13.

Aboulafia

Gibbons

. Penile cancer and human papilloma virus (HPV) in a human immunodeficiency virus (HIV)-infected patient. Cancer Invest 2001; 19: 266–272.

14.

Engels

Biggar

Hall

. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 2008; 123: 187–194.