PREVALENCE OF DERMATOLOGICAL DISORDERS IN HIV/AIDS PATIENTS AND CORRELATION WITH IMMUNOSUPPRESSION IN LAGOS, NIGERIA
BY
NYOMUDIM EFFIONG ESSEN, MBBS (NIGERIA)
A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA IN PART FULFILMENT OF THE REQUIREMENTS FOR THE FELLOWSHIP OF THE COLLEGE IN INTERNAL MEDICINE (DERMATOLOGY/VENEREOLOGY)
NOVEMBER, 2006.
i DECLARATION
It is hereby declared that this work is original unless otherwise acknowledged.
The work has neither been presented to any other college for a fellowship nor submitted elsewhere for publication.
……………………
DR N. E. ESSEN
July 2006
ii CERTIFICATION
The study reported in this dissertation was done by Dr Nyomudim Effiong Essen under our supervision. We have also supervised the writing of the dissertation to our satisfaction.
Signature……………………………….. Prof Y M Olumide, MBBS (Ibadan), Dip Dermatol (Lond) FMCP, FWACP, MD (Ibadan), FAAD, FAS Consultant Physician/Dermatologist and Professor of Medicine, College of Medicine, University of Lagos, Lagos.
Signature……………………………….. Dr G C Okudo MBBS, FMCP, FAAD Consultant Physician/Dermatologist, Police Medical Services, Lagos, and Associate Lecturer, College of Medicine, University of Lagos, Lagos.
Signature……………………………….. Dr A S Akanmu, MBBS, FMCPath Consultant Haematologist and Senior Lecturer, Department of Pathology College of Medicine, University of Lagos, Lagos.
iii HEAD OF DEPARTMENT’S CERTIFICATION
I certify that this work was done by Dr N E Essen under the supervision of
Prof. Y. M. Olumide
Dr. G. C. Okudo and
Dr. A. S. Akanmu
Signature…………………………………
Prof. M. A. Danesi, MBBS, MRCPI, FMCP, FWACP
Head
Department of Medicine
Lagos University Teaching Hospital (LUTH)
Lagos.
iv
TABLE OF CONTENTS
Pages
Title i
Declaration ii
Certification iii
Table of Contents v
Dedication vi
Acknowledgement vii
List of Abbreviations x
List of Tables xi
List of Figures xiii
Summary xiv
Chapter One: Introduction 1
Chapter Two: Literature Review 3
Chapter Three: Aims and Objectives 28
Chapter Four: Materials and Methods 29
Chapter Five: Results 39
Chapter Six: Discussion 81
Chapter Seven: Conclusion and Recommendations 98
References 100
Appendices 114
v DEDICATION
To
The memory of
Hallel …………… a daughter who brought joy to me
Effiong ……………. a dear father with vision, who strove to ensure I am what I am today
Bassey ……………. a father-in-law who influenced my life.
vi
ACKNOWLEDGEMENT
This study would not have been possible without the help of God who opened doors and granted me favour and speed. To Him I am eternally grateful.
With all my love, I deeply appreciate my darling, Udy, and my wonderful daughters, Lala and Cutie, for their understanding and support. They sacrificed their comfort for this project to be accomplished.
I am especially thankful to Professor Olumide, my supervisor and ‘Mama’ for being a true mother. She not only made provision for my stay in Lagos to be comfortable, but urged me on when I was wont to relax, provided unfettered access to her books and journals (both hard copies and electronic) and took special interest in making the home front restful for me to be focused. The God that is uncommon will give you an uncommon blessing.
I am indeed indebted to my other supervisors. Dr. Okudo gave invaluable advice and was instrumental to getting approval for recruitment of patients from Nigeria
Institute of Medical Research (NIMR), Lagos. Dr. Akanmu was always there, even late at night, to provide valuable suggestions. He also helped in assaying the CD4 count for some of the control population free of charge.
I also appreciate my colleagues in the Dermatology unit; some of them have become consultants. They include Tahiru, Chinwe, Ngozi, Shola, Bolaji, Violet and Anaba. Anaba actually laid the foundation for this project before leaving for
Europe.
vii I thank the staff of NIMR, especially the Director-General, Dr Idigbe, for allowing this study, and Drs Ezechi, Akinbami, Njemanze, Somefun, Iloka and
Gbajabiamila for their help with this study.
I also thank Dr (Mrs) Banjo of Pathology department, LUTH, for help with histo- pathological analysis, and Messrs Linus, Ilori and Phillip of the Laboratory
Department for their help with laboratory analysis of the samples.
I thank the Head of Department of Medicine, LUTH, Prof Danesi, for the interest in this project, the Chairman MAC, Dr Oke, and other consultants for their help.
Dr Okubadejo provided valuable suggestions and proof-read the book. I also thank Prof Ekanem of Department of Community Health, Unilag, for assistance with data analysis.
I am grateful to the Head of Department of Internal Medicine, JUTH, Dr Ukoli, for her understanding and support, and to the management of JUTH for making my coming to Lagos possible. I also thank Prof Okehialam and Dr Agaba for proof- reading this work.
I indeed bless God for my beloved mother, Arit, and my mother-in-law, Eno, for their understanding and support. My siblings have been wonderful: Mfon with his wife Ima, ID, Big, Ima, Ifure and Kuyik. I cannot forget my in-laws Etuk, Bassey,
Gideon, Oborrt, Marie and Vicky for their prayers and support.
I also thank God for positioning men like Bishop Oyedepo, Pastors Adeyinka,
Agape and Haruna, Bro Joshua and Onuoha who have been of spiritual help to me. The Lord will multiply them and keep confirming the words of their mouths.
viii
To all other persons, who contributed in one way or the other, including all the doctors and nurses, medical students and other LUTH Staff, and the HIV/AIDS patients of LUTH and NIMR who were part of the study population, I am grateful.
The good Lord shall bless you beyond measure.
ix LIST OF ABBREVIATIONS ADC - AIDS dementia complex ARVs - Anti-retroviral drugs CDC - Centre for Disease Control and Prevention, Atlanta, USA CMV - Cytomegalovirus DM - Diabetes mellitus Eth - Ethambutol EV - Epidermodysplasia verruciformis FDE - Fixed drug eruption GUD - Genital ulcer disease HAART - Highly active anti-retroviral therapy IFN - Interferon IL - Interleukin IVDU - Intravenous drug use JUTH - Jos University Teaching Hospital KOH - Potassium hydroxide KS - Kaposi’s sarcoma LUTH - Lagos University Teaching Hospital MSM - Men having sex with men NIMR - Nigeria Institute of Medical Research PCP - Pneumocystis carinii pneumonia (now P. jiroveci) PPE - Pruritic papular eruption PZA - Pyrazinamide Rif - Rifampicin SD - Standard deviation SJS - Steven-Johnson’s syndrome STIs - Sexually transmitted infections TB - Tuberculosis TGF - Transforming growth factor TEN - Toxic epidermal necrolysis VDS - Vaginal discharge syndrome WB - Western blot
x
LIST OF TABLES Page
Table 1: Age and Sex distribution of patients and controls…………… 40
Table 2: Educational status of patients and controls………………….. 43
Table 3: Social classes of patients and controls……………………….. 45
Table 4: Income brackets of the patients and controls………………… 46
Table 5: Marital status of the patients and controls…………………….. 48
Table 6: HIV risk factors in patients and controls………………………. 50
Table 7a: More frequent skin disorders in HIV/AIDS patients
compared with controls...... 55
Table 7b: Less frequent skin disorders in HIV/AIDS patients
compared with controls…………………………………………. 56
Table 8: Prevalence of skin diseases in different
CDC stages of HIV/AIDS: ………………………………..…… 58
Table 9: Skin disease correlated with co-morbid illness
in HIV/AIDS patients……………………………………..…… 59
Table 10: Skin disease in relation to educational levels
in HIV/AIDS patients and controls………………………………60
Table 11: Skin disease in relation to income levels in
HIV/AIDS patients and controls………………………………….61
Table 12: Skin disease frequency compared with CD4 counts levels…..65
Table 13: Pattern of skin disease in HIV/AIDS patients with
CD4 counts <200 cells/µl……………………………………… 67
Table 14: Mean CD4 counts and viral loads in some
dermatological disorders in HIV/AIDS patients……….………. 69
xi Table 15: Mean CD4 counts and viral loads in relation to the
presence or absence of specific skin diseases………….…… 71
Table 16: Mean CD4 counts and viral loads in skin disease
categories in HIV/AIDS patients……………………………… 73
xii
LIST OF FIGURES Page
Figure 1: Sex distribution of the patients and controls…………………. 41 Figure 2: Educational levels of patients and controls…………………. 44 Figure 3: Income levels of HIV/AIDS patients and controls…………… 47 Figure 4: Number of past sexual partners in HIV/AIDS patients and controls……………………………………………. 51 Figure 5: Symptoms of skin disease in HIV/AIDS patients and controls……………………………………………………… 53 Figure 6: CD4 levels in HIV/AIDS patients based on CDC Classification……………………………………………………. 63 Figure 7: Prevalence of skin diseases at each level of CD4 count (CDC categories)……………………………………. 66 Figure 8: Skin disorders with frequency of ≥3 in HIV patients with AIDS-defining CD4 counts (<200cells/µl)……………… 68 Figure 9: Clinical photograph of multi-dermatomal herpes zoster in an HIV/AIDS patient…………………………………. 74 Figure 10: Clinical photograph of ano-genital warts in an HIV/AIDS patient…………………………………………………. 75 Figure 11: Clinical photograph of another HIV/AIDS patient with ano-genital warts…………………….…………………… 76 Figure 12: Clinical photograph of pruritic papular eruption of HIV/AIDS……………………………………………………… 77 Figure 13: Clinical photograph of sub-cutaneous nodules in an HIV/AIDS patient with granuloma annulare…………….… 78 Figure 14: Clinical photograph of same patient with sub-cutaneous nodules on the legs…………………………… 78 Figure 15: Clinical photograph of an HIV/AIDS patient with tinea cruris and post-bleaching syndrome………………….. 79 Figure 16: Clinical photograph of an HIV/AIDS patient with ecthyma gangrenosum………………………………..… 80
xiii
SUMMARY
Background: Skin manifestations are common presentations of HIV/AIDS and reflect the level of immunosuppression in the patient. The prevalence and pattern of skin disorders in HIV/AIDS patients varies from region to region. In Nigeria, the correlation of skin disorders with immunosuppression has not been determined.
Objective: To determine the prevalence of skin disorders in HIV/AIDS patients in
Lagos, Nigeria. To correlate skin diseases with the degree of immunosuppression.
Methods: A total of 401 HIV/AIDS patients from 2 HIV clinics (Lagos University
Teaching Hospital [LUTH] and Nigeria Institute of Medical Research [NIMR]) in
Lagos, Nigeria, were examined for skin diseases. The CD4 counts and viral loads of these patients were assayed. Also, 200 HIV-negative volunteers recruited from staff and students of LUTH were used as controls.
Results: The prevalence of dermatological disorders was significantly higher in
HIV/AIDS patients (72.8%) compared to HIV-negative controls (21.0%)
(p<0.001). The most prevalent disorders were pruritic papular eruption, xeroderma, dermatophytosis, seborrhoeic dermatitis and pyodermas. The prevalence of skin disorders was highest (93.6%) among patients with CD4 count
<200 cells/µl and lowest (39.5%) among those with CD4 count ≥500 cells/µl (χ2 for linear trend = 90.1, p<0.001). Pruritic papular eruption (PPE), chickenpox, epidermodysplasia verruciformis (EV), genital ulcer disease (GUD) and hair dystrophy (fluffy hair) were associated with profound immunosuppression (CD4 count <100 cells/µl). xiv
Conclusion: An inverse relationship was found between the prevalence of skin disorders in HIV/AIDS patients and the CD4 count. The presence of pruritic papular eruption, chickenpox, EV, GUD or hair dystrophy in HIV/AIDS patients in
Nigeria implies severe immunosuppression requiring institution of anti-retroviral drugs.
xv CHAPTER ONE
INTRODUCTION
In 1981, a new vista was opened into immunodeficiency with the diagnosis of acquired immunodeficiency syndrome (AIDS) in a group of homosexuals with
Kaposi’s sarcoma and Pneumocystis carinii pneumonia in USA.1 A novel virus, now known as human immunodeficiency virus (HIV) was found to be the aetiologic agent. It soon became clear that AIDS was only the end point of a chronic infection with this virus. The underlying basis for this infection is immunodeficiency.
The effector cells of the immune system include the macrophages, the B lymphocytes, and the T lymphocytes which are subdivided into CD4+ helper T cells and CD8+ T cells. The normal CD4 T cell count is about 800 (range 500-
1500) cells/µl.2 In healthy Nigerians, it is 823 (range 547-1327) cells/µl.3
Immunodeficiency results from continuous high-level HIV replication with destruction of CD4 T lymphocytes till the capacity of the body to replace them is exhausted. The progressive attrition in numbers and functional impairment of the
CD4 T cells leads to impairment of cell-mediated and humoral immunity with consequent susceptibility to opportunistic infections and malignancies.2
The CD4 T cell count and HIV RNA assay in plasma are used for monitoring patients with HIV infection. While the CD4 T cell count is the best indicator of the immediate state of the immunological competence of an HIV infected person, the
HIV RNA assay is the best predictor of what will happen to the CD4 count, and so predicts disease progression.1 These two methods of HIV monitoring are limited to a few externally funded centres in Nigeria because of the high cost of
xvi equipment and reagents, and lack of trained personnel to run these tests. There were only 8 centres in Nigeria where CD4 T cell counts and HIV viral load assays could be done as at late 2005. These included 3 in Lagos, 2 in Abuja and 1 each in Ibadan, Jos and Maiduguri.
Skin disease is a major problem in tropical countries like Nigeria where the weather is hot and humid.4 Persons with HIV have more skin diseases than the general population. Infact, up to 90-98% of HIV infected persons have skin disorders, and these may be atypical, more widespread, and/or resistant to regular medications.4,5 The skin is the largest organ in the body and is very readily accessible for inspection and biopsy. An inverse relationship between
CD4 T cells and the incidence and severity of skin disease in HIV/AIDS patients has been noted in previous studies.4,5,6 Since the per capita income in Nigeria is about $260 7 (N35,000) and it costs N750 for HIV screening, N3000 for a confirmatory test, N3000 for CD4 T cell count, and N5000 for HIV RNA assay, evaluation of skin disease may be an inexpensive, convenient and readily available means of monitoring patients with HIV/AIDS. If a significant correlation is established between the skin manifestations of HIV and the CD4 T cell count, then skin diseases can be used to stage patients, determine severity of immunodeficiency, and monitor treatment. This will lead to earlier intervention and initiation of anti-retroviral therapy, and reduction in the cost of managing these patients. Evaluation of the pattern of skin diseases will also help in planning an essential drug list for HIV patients. These and further documentation of the pattern of skin diseases in HIV/AIDS patients in Lagos, Nigeria were the goals of this study.
xvii CHAPTER TWO
LITERATURE REVIEW
2.1 THE BURDEN OF HIV
Infection by HIV is now a pandemic. Between 1999 and 2003, the number
of persons living with HIV/AIDS has risen from 33 to 40 million with a
global prevalence of 1.1%.8 In 2003 alone, an estimated 5 million new
infections and 3 million deaths from HIV/AIDS were recorded. Sub-
Saharan Africa harbours 60 to 70% of the world’s total HIV/AIDS cases
with a prevalence of 7.5-8.5% and about 28.5million cases as at
December 2003.8 In Nigeria, the first case of HIV/AIDS was reported in
1986 9; the prevalence has risen from 1.8% in1991 to 5.0% in 2003 10, but
slightly declined to 4.4% in 2005.11
Infection by HIV has wreaked havoc on Sub-Saharan Africa. It is the
leading cause of death, being responsible for 20% of all fatalities in this
region.12 It has reduced life expectancy from 62 to 47 years 13, and
overwhelmed the fragile health systems of poor sub-Saharan countries. It
has caused dislocations in the family, with loss of a parent leading to
income loss and declining school enrolment. Also, the disease has caused
a reduction in the productive sector of the economy, undermining food
security and increasing health-related costs for businesses.13
2.2 EPIDEMIOLOGY OF SKIN DISEASES IN HIV/AIDS
Skin disorders in HIV/AIDS patients include diseases that are unique to
HIV infection. Also included are diseases that are present in the general xviii population, but that in HIV/AIDS patients, are more frequent, may present in an atypical manner, pursue a more chronic or aggressive course, may not respond readily to conventional therapy, and may recur frequently.14
In poor tropical countries, especially sub-Saharan Africa, other factors facilitate the development of skin diseases. These include the hot/humid climate, poor living conditions without pipe-borne water or drainage, malnutrition, ignorance, and poor hygiene.4 This is typically what is found in certain areas of Lagos, Nigeria.
Sivayathorn et al 15 in Bangkok, Thailand found 95% of HIV infected patients to have one form of skin disease or another. Conditions with high prevalence included oral candidiasis, pruritic papular eruption, seborrheic dermatitis, herpes zoster, oral hairy leukoplakia, herpes simplex infection and dermatophytosis. Other South-East Asian studies equally found a high prevalence of skin diseases in HIV-infected patients.6 Also, penicilliosis was becoming a more frequent opportunistic infection in that region.6 Studies in India also found a prevalence of muco-cutaneous lesions to be 40% with oral candidiasis, dermatophytosis, gingivitis and herpes zoster being the most common lesions.16
In Spain, Munoz-Perez et al 17 found a lower prevalence of 69% of patients with skin diseases. This also correlates with the study in Finland by Valle et al 18 that found oral candidiasis and seborrheic dermatitis to be the most common dermatological manifestations. In Brazil, Rosatelli et al
19 found fungal infections to be the commonest dermatological manifestation of HIV/AIDS.
xix In sub Saharan Africa, the pattern of clinical presentation of AIDS patients is different. Common symptoms and signs at presentation are weight loss, fever, night sweats and diarrhoea.12 Skin disorders are frequent early manifestations. A study of dermatological disorders among HIV-positive police officers in Dar es Salaam found the pattern of skin diseases to be similar to what obtains in the Asian studies.20 However, Kaposi’s sarcoma and pruritic papular eruption were associated with severe immune deficiency with CD4 counts less than 75 cells/µl.20 In South Africa, the commonest manifestations are herpes zoster, seborrheic dermatitis and pruritic papular eruption.21 Mahe et al 22 in Mali found the commonest skin disorders in HIV patients to be herpes zoster, seborrheic dermatitis,
Kaposi’s sarcoma, prurigo, sexually transmitted diseases, and extensive dermatophytosis. Pitche et al 23 in Lome, Togo, found an increasing prevalence of skin diseases in HIV patients on follow-up. The prevalence increased from 60% at the start of the study to 100% over a 6-month period of follow-up. The pattern of skin diseases was similar to the Malian study, but pruritic papular eruption, oral candidiasis and herpes zoster were the top 3 disorders. In Ghana, Lartey 24 found the prevalence of skin disorders to be 14% with pruritic papular eruption, oral thrush, herpes zoster, tinea and Kaposi’s sarcoma constituting the top 5 cutaneous disorders. Another Ghanaian study corroborated the earlier study with herpes zoster, pruritic papular eruption, and Kaposi’s sarcoma being the major presentations of HIV-related dermatoses in a dermatology clinic in
Kumasi.25
xx Few studies have been done to assess dermatological manifestations of
HIV/AIDS in Nigeria. Olumide 26 found HIV/AIDS-related dermatoses to be among the top 10 diagnoses in a dermatology clinic, constituting about
4.37% of all consultations. In another study, Olumide et al 27 found the commonest skin disorders among HIV-positive patients presenting at a specialist dermatology clinic in Lagos to be pruritic papular eruption and eosinophilic folliculitis. Aderibigbe 28 found the commonest cutaneous disorders in HIV patients presenting in a dermatology clinic in Lagos to be herpes zoster, prurigo, dermatophytosis, human papilloma virus infections and exfoliative dermatitis. This is similar to what obtains in most other sub-
Saharan African countries. Onayemi et al 29 reported scabies, tinea cruris and pityriasis versicolor as other skin manifestations in Nigerian patients, and suggested that young adults with infective and parasitic dermatoses should be screened for HIV infection. Ahamefule 30 found a prevalence of skin diseases in HIV-positive subjects in a Lagos prison to be 66.7%.
Altraide 31, in a study of a dermatology clinic in Lagos, found seborrheic dermatitis to have a positive predictive value of 9.3% for HIV seropositivity, while pityriasis rosea was not associated with HIV. This same study found both conditions to have a low prevalence (less than 3% each) in that specialist dermatology clinic. Mohammed 32 and Omeife 33 found no relationship between HIV and leprosy in studies in Zaria and
Benin respectively.
Kaposi’s sarcoma is the commonest skin tumour in HIV patients.14 It was not reported in a study from South East Asia.6 In Nigerian patients, the prevalence of this tumour is low.14
xxi
2.3 PATHOGENESIS AND PATHOPHYSIOLOGY OF SKIN DISEASES IN
HIV/AIDS.
Skin diseases in HIV patients result from progressive depletion of CD4 T
cell lymphocytes.5 This is confirmed by the finding that cutaneous
manifestations that were noted to develop when CD4 T cell counts
declined to certain levels with advancing HIV infection, have been noted to
reappear at similar CD4 T cell counts when the immune system of the
host is being reconstituted as in highly active anti-retroviral therapy
(HAART).5, 34, 35
Furthermore, subsets of T helper cells (Th1 and Th2) have been found to
play significant roles in HIV-related skin diseases. Th1 lymphocytes
promote cellular immunity, produce interleukin (IL)-2, IL-12 and interferon-
γ (γ-IFN). They suppress Th2 response and their effects are aimed at
eradication of infection. Predominant Th1 is the normal state in
immunocompetent individuals. In contrast, Th2 lymphocytes promote
humoral immunity and produce IL-4, IL-5 and IL-10, suppress Th1, and
are associated with allergy.5
Patients infected with HIV initially have normal CD4 T cell numbers, a low
viral load and a Th1 dominant immunologic milieu. Later, with advancing
infection, patients have low CD4 cell numbers, high viral load and a Th2
dominant immune status. Many of the unusual cutaneous manifestations
of HIV infection are linked to the Th2 immunologic status. It is postulated
that the Th2 cytokines may act as or promote the activity of associated
angiogenetic factors both in circulation or locally.5,36 This may be important
xxii in the development of Kaposi’s sarcoma (KS). The HIV tat gene has been
found to be angiogenic and therefore important in development of KS.
Other cytokines with angiogenic effects include IL-1, IL-6 and transforming
growth factor (TGF) –β. Also, levels of IL-2 and γ-IFN were found to be
lower in HIV patients with pruritic papular eruption than those without this
condition. Increased IL-5 levels may also be responsible for oesinophilia
and hyper-IgE, poor prognostic factors, in HIV patients.37
2.4 CLASSIFICATION OF HIV RELATED SKIN DISEASES
Cutaneous manifestations related to HIV/AIDS can be classified into 3
categories viz cutaneous hypersensitivity reactions, infections/infestations,
and neoplasia.14 Cutaneous hypersensitivity reactions in HIV/AIDS
patients include the exanthem of HIV-1 seroconversion syndrome, HIV-
associated pruritus (AIDS prurigo), eosinophilic folliculitis, pruritic papular
eruption (PPE), lichenoid papular dermatosis (LPD), xeroderma (xerosis
and acquired icthyosis), seborrheic dermatitis, hypersensitivity vasculitis
(cutaneous necrotizing vasculitis), psoriasis, Reiter’s disease, granuloma
annulare, apthous stomatitis, disorders of hair growth including alopecia,
and adverse drug reactions.
Infection/infestations in HIV/AIDS patient could be viral (herpes simplex
virus, varicella-zoster virus, molluscum contagiosum, cytomegalovirus
infection, Epstein-Barr virus, human papilloma virus), bacterial
(staphylococcal, Pseudomonas infection, mycobacterial, Bartonella
infection, Hemophilus ducreyi infection and treponemal infections), fungal
(dermatophytosis, candidiasis, histoplasmosis, cryptococcosis,
penicilliosis, protothecosis), parasitic (scabies, Acanthamoeba and xxiii Naegleria infections) and other infections [like Pneumocystis jiroveci
(previously P. carinii ) infection].
Cutaneous neoplasia include Kaposi’s sarcoma, cutaneous lymphoma
(Hodgkin’s and non-Hodgkin’s lymphoma), squamous cell carcinoma,
metastatic basal cell carcinoma and anorectal or cloacogenic carcinoma.14
2.5 CLINICAL FEATURES OF DERMATOLOGICAL MANIFESTATIONS OF
HIV/AIDS
The skin is affected in virtually all patients with HIV/AIDS.5,38 Skin
diseases also tend to be more frequent as immune deficiency
progresses.38 Skin diseases may serve as the initial or only problem that
the patient suffers from for much of the course of the HIV infection.
Serious opportunistic infections may present for the first time in the skin so
that a skin lesion may be the harbinger of a life-threatening illness. Also,
skin lesions may appear unusual and may not be accurately diagnosed by
clinical inspection alone. Furthermore, response to treatment may be
poorer than expected. Skin diseases in HIV infected persons are important
and may be the most debilitating element of the patient’s condition.5 Many
cutaneous disorders appear when the CD4 T cell count falls below
100cells/µl. Indeed, cutaneous anergy is one of the diagnostic features of
AIDS.14
2.5.1 HYPERSENSITIVITY REACTIONS
The exanthem of HIV-1 seroconversion syndrome: The seroconversion
syndrome of HIV-1 is a clinical illness that may last about 3 to 21 days and
occurs after the estimated incubation period of 1 to 8 weeks.14 The xxiv syndrome is commonly passed off as malarial fever.43 The exanthem may be a non-pruritic macular erythematous eruption on the trunk, a widespread symmetrical maculopapular or papulovesicular eruption, or a roseola-like non-itchy, non-scaly exanthem affecting the face, neck and upper trunk.14, 43 The palms and soles may be involved, and in severe cases, the oral mucosa and genitalia. It is a self-limiting illness and the diagnosis of this exanthem is often done retrospectively.14
Seborrheic dermatitis: This presents as hypo-pigmented, erythematous, and/or follicular, scaling macules or plaques on the scalp, face, the upper
V-shaped area of the chest, the back, the axillae and the groin.5, 14, 39, 40 Its aetiology is linked to the yeast Pityrosporum ovale. It may present as exfoliative dermatitis in severe cases. It occurs early in HIV and is prognostic of HIV progression. In a specialist dermatology clinic in Lagos,
Nigeria, the positive predictive value of seborrheic dermatitis for HIV was found to be 9.3%.31
Psoriasis: This is a chronic inflammatory papulosquamous disorder that typically presents as erythematous papules and plaques covered by silvery adherent scales. Attempts to scrape off the scales leave minute bleeding points (Auspitz sign). In HIV patients, psoriasis may involve the flexural surfaces like the groin and axillae (psoriasis “inversus”), the lesions may be guttate or pustular, severe exfoliative dermatitis
(erythroderma) may ensue, and keratoderma blennorrhagicum (with keratotic papules and pustules on the palms and soles) may develop.5, 14,
39, 40 xxv
Reiter’s syndrome: This is made up of the triad of urethritis, conjunctivitis, and arthritis (especially sacroiliitis). Other manifestations include keratoderma blennorrhagicum and oral ulcers.
Pruritic papular eruption: Lesions appear as discrete, flesh-coloured or slightly erythematous papules typically on the exposed surfaces of the body, principally the extremities. The lesions are usually non-follicular, symmetrically distributed, and very pruritic. Excoriated papules heal leaving hypo-pigmented spots surrounded by a hyper-pigmented halo.
Post-inflammatory hyper-pigmented papules are another common mode of presentation. Pruritic papular eruption is thought to be a hypersensitivity reaction to arthropod bites.
Lichenoid papular dermatoses: These present as violaceous or ashy grey (on Negroid skin) shiny papules on the trunk and extremities.
Xeroderma: This includes a very dry skin (xerosis) as well as the association of hyperkeratosis with a fish scale appearance (ichthyosis).
There is also reduced sweating. The extensor surfaces of the arms and legs are the usual sites affected. It is thought to be precipitated by deficiency of vitamin A.14
Cutaneous drug eruptions: HIV patients have a higher tendency to adverse drug reactions. The common offenders include thiacetazone, a cheap anti-tuberculous agent and sulphonamides (present in cotrimoxazole and over-the-counter antimalarials such as Fansidar® and xxvi Metakelfin®). Drug reactions could present as exanthematous drug rash, fixed drug eruptions, Stevens-Johnson syndrome (SJS) or even toxic epidermal necrolysis (TEN). Exanthematous drug rash may present as macular and/or papular eruptions that may appear about 8 to 12 days after initiation of therapy, become widespread and desquamate, and disappear in about 3 to 5 days.5 Fixed drug eruptions appear as discrete, hyperpigmented or erythematous macules or patches that may slightly scale. The muco-cutaneous sites are frequently involved. SJS may present as fever and widespread blisters of the skin and mucosa of the mouth, eye or genitals. TEN is a more severe reaction with confluent bullae and widespread denudation of the skin. Zidovudine is noted for hyperpigmentation of the nails. Foscarnet causes mucosal ulcers due to direct toxicity of this agent.5, 14 It is excreted in urine and the peri-urethral site is commonly affected.5
Hair disorders: Alopecia, fluffy hair, premature greying (canities) and elongation of the eyelashes (trichomegaly) have been observed in HIV patients. Trichomegaly is associated with use of recombinant interferon A.
True telogen effluvium has been reported in HIV patients with high fevers.
Fluffy or woolly hair may be found in these patients and may be a sign of malnutrition.14
Nail disorders: Nail deformities and colour changes are also seen in HIV patients. Nail pigmentation may be seen in persons using “bleaching” creams, or drugs such as zidovudine, hydroxyurea, cyclophosphamide, phenytoin, lithium and sparfloxacin. Grey nails have been reported to have xxvii a positive predictive value of 81% for CD4 counts below 200 cells/µl.44
Leuconychia (white nails) may be found in patients with hypo- albuminaemic states like cirrhosis or nephrotic syndrome. Beau’s lines, which represent periods of arrested nail growth, may be seen in HIV patients. A yellow discolouration of the distal portion of the nails, similar to yellow nail syndrome, has been reported in HIV patients. Yellow nail syndrome may be secondary to metabolic abnormalities, lymphoedema, and hypoxia.
Nail plate thickening with subungual hyperkeratosis may result from infection by dermatophytes, Candida, Scytalidium, or other non- dermatophyte fungi. Fungal infection of the nail may produce distal and lateral subungual onychomycosis (DLSO), white superficial onychomycosis (WSO) or proximal subungual onychomycosis (PSO).
PSO is specific for HIV infection.45, 46
Granuloma annulare: It is an inflammatory disease characterized by necrobiotic dermal papules. Lesions typically appear as skin coloured, erythematous or violaceous, well-defined dome-shaped papules that are arranged in a complete or half circle.14, 47 The centre of the lesions may be hyperpigmented and may have a scalloped appearance. The commonly favoured sites are the dorsal aspects of the hands and feet. Other presentations include subcutaneous nodules, perforating lesions, annular or circinate erythematous types.13, 47
Vascular lesions: Hypersensitivity vasculitis (cutaneous necrotizing vasculitis) may occur in HIV patients. It commonly affects the post- xxviii capillary venules, and presents mainly as palpable purpura, but also as
erythematous macules, wheals, papules, vesicles, nodules, ecchymosis,
ulcers, and livedo reticularis (a net-like pattern on the skin).13
Histologically, leukocytoclastic vasculitis is commoner than the
lymphomonocytic form. Thrombocytopenia in HIV patients may present as
non-palpable purpura or petechiae. The aetiology includes idiopathic
thrombocytopenic purpura, use of recreational drugs, and viral infections
such as cytomegalovirus (CMV).
Urticaria/allergy: Patients may present with urticaria, allergic symptoms
like rhinitis, dermatitis, and pruritus.2,5
2.5.2 INFECTIONS
2.5.2.1 VIRAL INFECTIONS
Chickenpox: The primary infection with the varicella-zoster virus (VZV)
leads to chicken-pox (primary varicella). This presents as crops of vesicles
at various stages of development. The lesions are usually pruritic and may
be secondarily infected by bacteria. The crusted lesions may heal with
scarring.
Herpes zoster: This is a reactivation of varicella-zoster infection and
presents as vesicular eruptions following a dermatome with a burning
sensation. In HIV patients, more than one dermatome may be involved.
The lesions soon become crusted when the vesicles rupture and
secondary bacterial infection may ensue. Lesions heal by secondary
intention leaving scars. Motor nerve involvement, neuralgia, persistent
xxix ulcerations and chronic verrucous lesions are complications. Recurrent herpes zoster may occur in HIV patients.
Herpes simplex virus (HSV): This virus causes painful vesicles that may ulcerate. In immunocompromised individuals, muco-cutaneous (oro-labial, genital and anal areas) ulcers and verrucous erosions may occur. Lesions in HIV patients may last for several months.
Cytomegalovirus (CMV): Infection by CMV in HIV patients may present as chronic, non-healing perianal ulcers. There is a lack of response to acyclovir, unlike herpes simplex ulcers. Other presentations include verrucous lesions, palpable purpuric papules, vesico-bullous eruptions, and hyperpigmented, indurated plaques.2,5,14 Skin disease by CMV is said to be relatively infrequent despite the high frequency of CMV viraemia.5
Viral warts: The human papilloma virus is the aetiologic agent of viral warts. The lesions usually have a rough, verrucous surface. Lesions could appear on the face, scalp, limbs, and almost any part of the body. Genital lesions in adults may reflect sexual transmission, and peri-anal lesions may suggest homosexual behaviour. Extensive perianal warts may cause difficulty with defecation and cause secondary constipation.
Molluscum contagiosum virus (MCV): This is a large pox virus that is transmitted by direct contact. The lesions are dome-shaped, umbilicated papules on any part of the body, especially the genitalia and face. Multiple lesions of molluscum may mimic cutaneous cryptococcosis or pneumocystosis, and if solitary, pyogenic granuloma, keratoacanthoma, or basal cell carcinoma.5,14 xxx
2.5.2.2 BACTERIAL INFECTIONS
Pyodermas: These are bacterial infections caused mainly by
Staphylococcus aureus, Streptococcus pyogenes, Haemophilus
influenzae, Pseudomonas aeruginosa or P. cepacia with formation of pus
or ulcers. They include folliculitis, carbuncles, impetigo, and ecthyma.
Folliculitis presents as widely distributed acneiform papules and pustules
over the skin. Lesions may be pruritic and excoriated. Botryomycosis is an
extension of staphylococcal or Pseudomonas folliculitis with formation of
bacterial colonies into the dermis. It is a chronic, suppurating,
granulomatous lesion that may present as an inflammatory nodule,
discharging ulcer, sinus, or fistula.5,14 Impetigo presents as localized or
widespread oedematous crusted areas of skin with yellowish surface
crusts. It commonly affects the axillary, inguinal, and other intertriginous
sites in HIV patients. Deeply seated bacterial skin infections like
pyomyositis, deep abscesses, and necrotizing fascitis, may present as
diffuse, red, warm, tender areas in the skin. Swelling and induration may
occur.
Bacillary angiomatosis: The causative organisms are Bartonella
quintana and B. henselae. The lesions are vascular and appear as small,
pinpoint reddish to purple papules that may mimic pyogenic granuloma.
Bacillary angiomatosis could also present as subcutaneous nodules that
may be located deep enough to involve soft tissue and bone.5 In a
xxxi minority of cases, it could present as nondescript crusted ulcerations, plaques, and cellulitis.14
Syphilis: Syphilis may present in HIV patients as the typical solitary painless chancre in primary, or papulosquamous lesions with involvement of palms, soles and mucosa in secondary disease. The lesions may be coppery red with slight scaling. However, atypical presentations may defy diagnosis. These atypical presentations include rapid progression (within months) from primary chancre to tertiary syphilis, syphilitic vasculitis (lues maligna), sclerodermiform lesions, verrucous plaques, extensive oral ulcerations, keratoderma, deep cutaneous nodules, and widespread gumma.14
Chancroid: This is caused by the fastidious organism, Haemophilus ducreyi. The clinical presentation of chancroid in HIV patients is similar to that in immunocompetent individuals. However, atypical presentations with greater numbers of deep punched-out ulcers that may be phagedenic, may occur. The incubation period may be longer, and response to treatment poorer.48
Mycobacterial infections: Mycobacterial skin lesions can be caused by any of the species. Scrofuloderma has been reported in HIV patients.
Other presentations include small papules and pustules that resemble folliculitis, atopic dermatitis-like eruptions, localized cutaneous abscess, non-specific ulcerations, palmar and plantar hyperkeratosis, and sporotrichoid nodules. M. marinum, which causes swimming pool xxxii granuloma, may present as painful erythematous papules and nodules on
the limbs or ears.14
2.5.2.3 FUNGAL INFECTIONS
Candidiasis: This is caused most frequently by Candida albicans. Other
species like C. tropicalis are increasingly being isolated in HIV patients.
The oral cavity is most frequently affected. Other common sites are the
vulva, nails and intertriginous areas. Oral lesions could present as white
patches on the tongue or buccal mucosa (pseudo-membranous), a
hypertrophic layer on the dorsum of the tongue (hyperplastic variant), an
erythematous atrophic type, or angular cheilitis.
Vaginal candidiasis presents as very pruritic, erythematous vulvo-vaginitis
with a creamy vaginal discharge. Intertriginous lesions usually appear as
satellite or erythematous lesions on body folds. Folliculitis may also be a
presentation of candidal infection.
Dermatophytosis: These are fungal diseases caused by dermatophytes.
The species Epidermophyton, Microsporum and Trichophyton are the
causative agents. The lesions appear as keratotic, scaly or erythematous
plaque lesions with active edges and central clearing. In patients that use
steroid creams, the lesions may appear atypically (tinea incognito).
Proximal white onychomycosis is specific for HIV infection.14, 49
Histoplasmosis: Among the deep mycoses, histoplasmosis is the one
most frequently encountered in HIV patients in Nigeria.14 Histoplasmosis
has non-specific cutaneous manifestations and these include nodules,
macules, ulcers, folliculitis, vegetative plaques, as well as acneiform, xxxiii herpetiform, or umbilicated papules.14 Muco-cutaneous areas are predominantly affected, and ulcerated or nodular lesions on the palate, gingiva and tongue may be found.50
Cryptococcosis: Cutaneous manifestations occur only in about 5% of
AIDS patients with cryptococcosis and these include molluscum contagiosum-like lesions, subcutaneous nodules, ulcers, papules, pustules, draining sinuses, cellulitis, herpetiform lesions and pyoderma gangrenosum-like lesions.14
Penicilliosis: Penicilliosis is an opportunistic infection that is increasingly being reported in South East Asia. The causative organism is Penicillium marneffei, a dimorphic fungus. Cutaneous manifestations include skin- coloured or pigmented umbilicated papules, necrotic papules, vesicles, pustules, acneiform lesions, and abscesses. Papular lesions have been reported on the mucosal surfaces (mouth, eyes and genitalia). It has been reported to mimic oral thrush, the diagnosis being made only after mycological culture.51
Sporotrichosis: Until the HIV epidemic, sporotrichosis was seen in patients with haematological malignancies, alcohol abuse, diabetes mellitus, or other form of immunosuppression. The causative agent is
Sporothrix schenckii. The disease could present as lymphocutaneous, fixed cutaneous, disseminated cutaneous or systemic forms.14,52
Cutaneous lesions may be ulcers, papules, nodules, plaques and pustules. There may be internal organ involvement that is fatal. xxxiv
2.5.2.4 PARASITIC INFECTIONS
Scabies: The mite, Sarcoptes scabiei, is the aetiologic agent for scabies.
HIV patients with CD4 counts beyond 200cells/µl may present with typical
features like intense pruritus, excoriated papules and the characteristic
burrows. Atypical presentations occur in more profoundly
immunocompromised patients. The “anergeic form” is a disseminated
papular form with each papule being a burrow.14 Norwegian scabies is a
crusted hyperkeratotic type that mimics palmo-plantar hyperkeratotic
disorders like psoriasis. In this form of scabies, the lesions are teeming
with mites. Scabies may also involve the scalp and simulate seborrheic
dermatitis. Diffuse scabies may appear like atopic dermatitis. Nodular
scabies may simulate lymphomatoid papulosis or a reaction to insect
bites.
Pneumocystosis: Pneumocystis jiroveci (previously P. carinii) skin
disease may present as friable reddish papules or nodules in the ear canal
or the nares, small translucent molluscum contagiosum-like papules,
bluish cellulitic plaques, and deep-seated abscesses.
Strongyloidiasis: Strongyloides stercoralis presents as larva currens, an
urticarial serpeginous eruption due to migration of the larvae in the skin. It
may cause cutaneous lesions that mimic urticaria, figurate erythema, and
livedo reticularis in HIV patients.5,39
Amoebiasis: Amoebiasis cutis (caused by Entamoeba histolytica), a rare
form of amoebiasis with cutaneous lesions, may present on the peri-anal xxxv region as multiple painful ulcers and sinuses with purulent discharge.53
The protozoan, Acanthamoeba castellani, may cause necrotic nodules or
painful ulcerations of the skin, especially the extremeties.14
2.5.3 NEOPLASIA
Kaposi’s sarcoma (KS): KS is a vascular neoplasm that has assumed
more importance with the advent of HIV. It presents as hyperpigmented or
violaceous macules, papules, plaques or nodules on the limbs, trunk or
buccal mucosa. Lesions tend to develop rapidly in a bilateral symmetric
pattern along the lines of skin cleavage (Langer’s line).14,41,42 The lesions
may coalesce to form large confluent plaques or aggregates of nodules
and tumours. Pain and ulceration may occur if pressure-bearing areas like
the soles are affected. Widespread involvement of internal organs does
occur. It is said that one internal lesion develops for every five skin
lesions.5 Differential diagnoses include haemangiomas, bacillary
angiomatosis, pyogenic granuloma, dermatofibroma, a flat naevus,
mycosis fungoides, malignant melanoma, molluscum contagiosum,
ecchymosis, pityriasis rosea, secondary syphilis, or a patch/papule of
lichen planus.5,40 Nnoruka reported epidemic KS in Enugu, Nigeria, to be
aggressive in women.54
Cutaneous lymphoma: Cutaneous T cell lymphoma (Sézary syndrome)
and less commonly B cell lymphomas may be present in HIV patients.14,55
Skin lesions could be papules, nodules, or plaques. B cell lymphomas
could present initially as skin lesions, but most commonly, as secondary
(metastatic) skin disease.
xxxvi
2.6 LABORATORY DIAGNOSIS OF HIV
The diagnosis of HIV depends on the demonstration of antibodies to HIV
and/or the direct detection of HIV or one of its components. Commercial
tests for HIV screening became available in 1985.56 Enzyme linked
immunosorbent assay (ELISA) is the standard screening test for HIV.
Most tests utilize HIV antigens to bind IgG antibodies in the patient’s
sample. Bound HIV antibodies are then complexed with enzyme-labelled
anti-human IgG and are then detected in a colorimetric reaction. First
generation tests utilized viral lysates, but the third generation tests use
recombinant viral proteins and peptides with increased sensitivity and
specificity approaching 99%.56 Current recommendations for the serologic
diagnosis of HIV infection include a repeatedly reactive ELISA that is
confirmed by a second assay, usually the Western Blot.1,56 WHO
recommends the use of 2 ELISA tests that contain different antigens and
rely on different test principles for confirmation of HIV sero-positivity in
developing countries as a cost-effective alternative.56
The Western Blot involves the incubation of patient’s serum with a nitro-
cellulose strip on which have been blotted viral proteins that have been
electrophoretically separated. Human anti-bodies directed against specific
HIV proteins can be identified by binding to enzyme-linked anti-human
IgG. The CDC and the Association of State and Territorial Public Health
Laboratory Directors (ASTPHLD) criteria for a positive test is one that
demonstrates the presence of 2 of p24, gp41 and gp120/160. A negative
xxxvii result has no bands to any of the antibodies. An indeterminate result is
one with a positive band to only one antibody; in such cases, the test
should be repeated after 1 month.1,56
Methods for direct detection of HIV or its components include the p24
antigen capture assay and the polymerase chain reaction (PCR). The p24
antigen capture assay is an ELISA type assay that detects the viral protein
p24 in the blood of HIV patients where it exists either as a free antigen or
complexed to anti-p24 antibodies. The levels of p24 are highest during the
first few weeks of infection. Levels fall after production of anti-p24
antibody. It is most useful in testing HIV patients with suspected acute HIV
syndrome.1
The PCR, which can also be used to detect virus, is of 2 types: RT-PCR
(Amplicor™) and the bDNA (Quantiplex™). The RNA tests have a
sensitivity of 40 to 50 copies of HIV RNA/ml of plasma and the DNA PCR
tests detect pro-viral DNA at one copy per 10,000–100,000 cells. This
extreme sensitivity has a consequence, loss of specificity and therefore
false positivity.1
2.7 LABORATORY MONITORING OF HIV
Two tests are helpful in providing information on the prognosis and
ultimately, response to therapy in HIV patients. These are the CD4 T cell
lymphocyte count (CD4 count) and plasma HIV RNA assay.
The CD4 T cell count is the best indicator of the immediate state of
immunologic competence of the HIV patient.1 It correlates very well with
the level of immunologic competence. In normal Nigerians, the count is xxxviii 547-1327 cells/µl.3 Patients whose CD4 T cell counts fall below 200 cells/µl are categorized as having AIDS and are at risk of opportunistic infections.1,2 A decline in CD4 T cell numbers of 25% is an indication for considering change of therapy in patients who are on HAART.1
Plasma HIV RNA assay predicts what will happen to the CD4 count in the near future and hence provides prognostic information.
Methods of assessing CD4 count include fluorescence-activated cell sorter (FACS) count, Cytosphere, Dynabead, immuno-alkaline phosphatase, TRAX and flow cytometry. Flow cytometry is the gold standard for determining CD4 count.57 Using this method, the total lymphocyte count is determined by haematological testing. The total lymphocyte count is the product of the total white cell count and the lymphocyte percentage on differential leucocyte count. The proportion of
CD4 T cell count is determined by labelling the lymphocytes with monoclonal antibodies to CD4 antigen and detecting them on the Cyflow machine by flow cytometry57. Causes of low CD4 counts include acute viral infections, tuberculosis, sarcoidosis, corticosteroid therapy, systemic lupus erythematosus, and defects of purine metabolism.58 Pregnant
Nigerian women were found to have lower counts than non-pregnant persons.3
HIV viral assay is done by 3 methods; two are based on enzymatic amplification of target nucleic acids and include Amplicor monitor assay
(Roche molecular system) and NASBA (Organon Technika). The third
xxxix utilizes branched-chain DNA hybridization signal amplification (branched-
chain DNA, Chiron).56
2.8 CORRELATION OF CD4 T CELL COUNT WITH SKIN DISEASE
Some skin disorders have been shown to have a positive correlation with
the severity of immunosuppression measured as the level of CD4 T cell
count.15,17,18,59 Schaub et al 60 have even gone as far as using skin
disease to determine the stage of HIV/AIDS. Goldstein et al 61 found
herpes zoster, drug eruption, condylomata acuminata, Kaposi’s sarcoma,
eosinophilic folliculitis, pruritic papular eruption, herpes simplex virus
infection, molluscum contagiosum and seborrheic dermatitis as conditions
that correlated significantly with mean CD4 T cell counts with a standard
deviation of less than 10%. Skin conditions that correlated with CD4
counts >300cells/µl include herpes zoster and drug reactions. Those that
correlate positively with low CD4 counts <100 cells/µl include condylomata
acuminata, Kaposi’s sarcoma, eosinophilic folliculitis, pruritic papular
eruption, herpes simplex virus infections, molluscum contagiosum, and
seborrheic dermatitis.22,61 This supports the findings of Schwartz et al 62
that molluscum contagiosum is associated with CD4 levels <50 cells/µl
and that the number of lesions is inversely related to CD4 counts.
Generalised papular, crusted, or eczematous lesions of scabies are
associated with CD4 counts <200 cells/µl.63
xl
CHAPTER THREE
AIM AND OBJECTIVES
3.I AIM
To determine the prevalence of skin disorders in HIV/AIDS patients in
Lagos, Nigeria, and correlate this to the degree of immunosuppression.
3.2 OBJECTIVES
1. To determine the frequency and spectrum of skin diseases in
HIV/AIDS patients in Lagos.
2. To correlate the frequency and spectrum of skin diseases with the
degree of immunosuppression specifically the CD4+ T cell count
and HIV plasma viral load.
xli
CHAPTER FOUR
MATERIALS AND METHODS
4.0 This was a cross-sectional analytical study carried out over a 9-month
period from November 2005 to July 2006.
4.1 STUDY AREA
This study was carried out in Lagos, Nigeria. Lagos is the economic nerve
centre of Nigeria and a fast growing city with an estimated population of
over 9 million persons 64. It is a cosmopolitan city that accommodates
people from virtually every ethnic group in Nigeria, the West African sub-
region, and beyond, with diverse socio-cultural affiliations.
4.2 STUDY SITES
This study was done in 2 centres in Lagos: Lagos University Teaching
Hospital (LUTH) at Idi-Araba and Nigeria Institute of Medical Research
(NIMR) at Yaba. LUTH is a foremost 800-bed tertiary health care facility
that receives patients from all over Nigeria. NIMR is a research institute
that has an out-patient clinical department solely for the care of HIV/AIDS
patients. At NIMR, patients requiring hospitalization are referred to LUTH
or other health care facilities. Data from the clinic registers show that each
of these centres handles about 2000 new HIV/AIDS patients annually. Up
xlii till late 2005, HIV/AIDS patients paid N1000 monthly for anti-retroviral
drugs with free laboratory monitoring. However, currently, ARVs are free.
4.3 STUDY POPULATION
The study population comprised all new HIV/AIDS patients that attended
the HIV clinics of Lagos University Teaching Hospital (LUTH), Idi-Araba
and Nigeria Institute of Medical Research (NIMR), Yaba, Lagos during the
study period.
4.3.1 INCLUSION CRITERIA
(i) Patients that had been confirmed HIV positive by at least 2 positive
ELISA tests or a positive ELISA test with a positive Western Blot
(ii) Patients who were old enough to give informed consent (≥18 years
of age).
4.3.2 EXCLUSION CRITERIA
(i) Patients that were already on anti-retroviral drugs
(ii) Patients that did not give informed consent.
4.4 ETHICAL CONSIDERATION
Ethical clearance for the study was obtained from the Research and
Ethical Committee of the Lagos University Teaching Hospital (Appendix
1). Approval for the study was obtained from Nigeria Institute of Medical
Research.
4.5 SAMPLE SIZE
The sample size was determined using the formula
N = (Zi-a)2pq xliii d2
Where N = minimum sample size
Zi-a = the standard deviation set at1.96 which
corresponds to 95% confidence level
p = prevalence of skin disease; for this study, a
prevalence of 80% was used
q = 1-p
d = absolute precision = 0.05
The required sample size N = 1.962 x 0.8 x (1-0.8)
0.052
= 246
Therefore, 246 HIV/AIDS patients and 246 controls were needed for the study. The high number of controls needed for this study made it desirable to reduce this population to less than 200. This necessitated a re- calculation of the minimum sample size using three formulae 65 viz
N1 = fn
N2 = cfn and
f = (c+1)/(2c)
Where N1 = sample size of the smaller group
N2 = sample size of the larger group
f = the adjustment factor; 4/5 was chosen to bring N1
to less than 200
n = the initial calculated sample size
c = ratio of larger to smaller group xliv
The sample size of the smaller group (the control population)
N1 = fn
= 246 x 4/5
= 197
The ratio of the larger to the smaller group, c, is calculated as
f = (c+1)/(2c)
4/5 = (c+1)/(2c)
4(2c) = 5(c+1)
8c = 5c + 5
8c – 5c = 5
c = 5/3
Therefore, the sample size of the larger group (HIV/AIDS group)
N2 = cfn
= (5/3) x fn
= (5/3) x 197
= 328
The minimum adjusted sample size would therefore be 197 for the control
population and 328 for HIV/AIDS patients.
4.6 METHODOLOGY
A total of 435 consenting HIV/AIDS patients that met the inclusion criteria
were recruited. Two hundred and ten (210) patients from LUTH and 225
from NIMR were recruited by systematic random sampling. The study
protocol was explained to the patients by the investigator and interviews xlv were conducted using a structured questionnaire (Appendix II) designed to provide information on socio-demographic characteristics, HIV risk factors and sexual behaviour, pre-morbid states, opportunistic infections, drug history and symptoms of skin disease such as rash, pruritus, discolouration, swelling, pain, ulcer or other symptoms. Occupations of subjects were used to group them into 5 classes according to the
Registrar General’s social class classification. 66 These classes are class I
(professionals and businessmen/women), class II (lesser professions and trade), class III (skilled non-manual and skilled manual), class IV (semi- skilled manual) and class V (unskilled manual to unemployed) (see
Appendix V). The subjects’ average monthly incomes were also used to categorize patients into low, medium and high income groups. Subjects with an estimated monthly income of less than thirty thousand naira
(
Co-morbidity was evaluated by seeking a history of renal disease, diabetes mellitus, cancer, hepatitis B and C infection, psychiatric illness, significant alcohol intake, chronic diarrhoea, wasting syndrome, tuberculosis (pulmonary and extra-pulmonary), cryptococcal meningitis,
AIDS dementia complex, peripheral neuropathy, CMV retinitis, toxoplasmosis and Pneumocystis carinii pneumonia. Where available, information on subjects’ co-morbidity was retrieved from subjects’ case- notes. Many of these subjects had liver function tests, fasting/random xlvi blood sugar, urea, electrolytes and creatinine assays, and serological tests for Hepatitis B and C done routinely in the clinics. HIV wasting syndrome is defined as weight loss of at least 10% in the presence of diarrhoea or chronic weakness and documented fever for at least 30 days that is not attributable to a concurrent condition other than HIV infection itself.67 In clinical practice, and therefore in this study, any involuntary weight loss of that magnitude is typically considered wasting.68 Diarrhoea was defined as 2 or more loose or watery stools daily occurring continuously or intermittently for one month. Additionally, available information in the patients’ case-records was retrieved to further document co-morbid states. Patients were then grouped into co-morbid factors
“present”, “absent” or “unknown”. Significant alcohol consumption was investigated by means of the CAGE questionnaire 69,70.71 (Appendix VII).
Significant alcohol consumption has dermatological manifestations (like digital clubbing, fluffy hair, reversal of pubic hair pattern, gynaecomastia, spider angiomas, palmar erythema, etc).
Physical examination structured to document all cutaneous and muco- cutaneous lesions was done on each patient. A magnifying lens was used to better characterize some skin lesions like papules or suspected verrucous lesions. Diagnosis of skin lesions was clinical. The syndromic approach to diagnosis and treatment was used for some sexually transmitted infections (STI) of dermatological importance such as genital ulcer disease (GUD).72 However, relevant diagnostic laboratory investigations were performed where the diagnosis was uncertain or might influence therapy. xlvii
4.7 LABORATORY DIAGNOSIS OF SKIN DISEASE
1) Skin scraping from the edge of a suspected fungal lesion: The
material scraped off onto plain white paper was neatly wrapped and
transported to Central Public Health Laboratory, Yaba for 30% KOH
mount and direct examination as well as fungal culture on
Saboraud’s agar.73
2) Skin biopsy for suspected deep mycoses, malignant lesions, and
lesions in which the diagnosis was unclear by clinical examination:
The biopsies were fixed in 10% buffered formalin 74 and sent for
histology. Histology slides were read in conjunction with a
pathologist at the Histopathology department of LUTH, Lagos.
Where deep mycosis was suspected, the biopsy was divided in two
for histology and fungal culture.
Skin disorders were classified as infective and non-infective dermatoses.
The infective dermatoses were further classified as viral, bacterial, fungal
and parasitic diseases. The non-infective dermatoses were sub-classified
as cutaneous hypersensitivity disorders and neoplasia.
4.8 ASSESSMENT OF IMMUNE AND VIROLOGICAL STATUS
The subjects of this study were patients attending the retroviral clinics of
LUTH and NIMR. At these centres, all patients have pre-enrolment CD4
counts and viral load tests carried out routinely. Assay methods for both
CD4 count and viral load are the same in both institutions. CD4 T cell
count was assayed by semi-automation using the Cyflow machine made
by Partec® GmbH, Otto-Hahn Str 32, Münster, Germany, as
xlviii recommended by the manufacturers (see Appendix VII). HIV viral load was assayed by the Roche Amplicor® technique (see Appendix VIII).
Subjects’ results were retrieved from their clinical records.
Patients were then classified by the revised CDC staging system 75 (see
Appendix III). Patients that were asymptomatic, had acute sero-conversion illness, or had persistent generalized lymphadenopathy (PGL) belong to category A. PGL is defined as lymphadenopathy (>1cm) at 2 or more extrainguinal sites for more than 3 months in the absence of causes other than HIV. Since this was a cross-sectional study, PGL could not be used.
Also, patients that had no symptoms of skin diseases, but on examination had skin lesions that were not HIV-related (such as keloids, acne vulgaris, lipoma, seborrheic keratosis, etc) were also classified as asymptomatic.
Patients that had any of the AIDS-defining disorders listed in Appendix IV were classified as category C. Any patient that was neither A nor C was regarded as B category.
The CD4 count levels were also used to classify subjects into category 1
(CD4 count above 499 cells/µl), category 2 (CD4 count 200-499 cells/µl) and category 3 (CD4 count below 200 cells/µl).
Patients were counselled on their skin disorders and where appropriate, secondary preventive measures were advised. Prescriptions were given for some skin disorders while those that required long-term follow-up were referred for further care at LUTH Skin Clinic, Harvey Road, Yaba, Lagos.
Some of the patients were seen on follow up visits. Also, patients that were not eligible for the study had the benefit of a dermatological consult during this study at the study sites. xlix
4.9 CONTROL POPULATION
Two hundred (200) age and sex matched controls were recruited from
volunteers among the medical and nursing staff population of LUTH, the
final year medical student population of College of Medicine, University of
Lagos, and subjects that came for voluntary counselling and testing for
HIV. All the controls had 5ml of blood drawn from an ante-cubital vein
which was used for HIV screening using the Capillus® HIV double ELISA
screening kit, and for determination of CD4 count by flow cytometry using
the Cyflow® machine and Partec® CD4 easy count kit (see Appendix VII).
4.10 DATA ANALYSIS
The data was analyzed using EPI-info 2002. Data obtained were
presented in form of frequency distributions for categorical variables, and
means and standard deviations for continuous variables. The prevalence
of each dermatological disorder was calculated and presented as a
percentage. The mean CD4 T cell count and viral load were calculated for
each dermatological diagnosis with a frequency of 3 or more occurrences.
The mean CD4+ T cell count and viral load determined for each
dermatological diagnosis were compared using analysis of variance
(ANOVA). Chi-square (χ2) test was used for group comparison to
determine the significance of observed differences. The t test was used to
compare means. A p value that was <0.05 was accepted as statistically
significant.
l
CHAPTER FIVE
RESULTS
5.0 RESULTS
A total of 435 HIV/AIDS patients and 200 HIV-negative controls who
met the inclusion criteria were recruited for this study. The data for
34 HIV/AIDS patients were incomplete and were therefore not used
for analysis. Data for 401 HIV/AIDS patients and 200 HIV-negative
controls were therefore used for analysis. All the subjects in the
HIV/AIDS population in this study were confirmed HIV-1 positive. No
case of HIV-2 was seen.
li
5.1 DEMOGRAPHICS
5.1.1 STUDY POPULATION
The study population comprised 401 subjects aged 20 to 74 years with a
mean age of 36.0 ± 7.1 years. About 68% of the study population was
aged less than 40 years. The males were significantly older with mean
age of 39.6 ± 7.6 years compared to the females with 33.8 ± 8.9 years
(z=6.69, p=<0.001). The age and sex distribution of the patients are
shown in Table 1 and Figure 1.
Table 1: Age and Sex distribution of Patients and Controls
Age HIV/AIDS PATIENTS CONTROL POPULATION (Group) Males Females Total Males Females Total No(%) No(%) No(%) No(%) No(%) No(%) 20-24 - 25 (6.2) 25 (6.2) 8 (4.0) 16(8.0) 24(12.0) 25-29 12 (3.0) 66 (16.5) 78 (19.5) 14(7.0) 40(20.0) 54(27.0) 30-34 30 (7.5) 64 (16.0) 94 (23.4) 24(12.0) 38(19.0) 62(31.0) 35-39 35 (8.7) 41 (10.2) 76 (19.0) 24(12.0) 12(6.0) 36(18.0) 40-44 36 (9.0) 23 (5.7) 59 (14.7) 2(1.0) 6(3.0) 8(4.0) 45-49 24 (6.0) 18 (5.0) 42 (10.5) 4(2.0) 6(3.0) 10(5.0) 50-54 8 (2.0) 5(1.3) 13 (3.2) - 4(2.0) 4(2.0) 55-59 5 (1.2) 3(0.8) 8 (2.0) 2(1.0) - 2(1.0)
lii ≥60 1 (0.2) 5 (1.2) 6 (1.5) - - - Total 151(37.7) 250(62.3) 401 (100) 78(39.0) 122(61.0) 200 (100)
Mean ages:
HIV/AIDS patients CONTROLS z statistic p value
36.0 ± 7.1yrs 32.1 ± 4.0yrs 4.04 <0.001
70
60
50
40
MALES FEMALES
30
FREQUENCY(%)
20
10
0 HIV/AIDS CONTROLS
liii
Figure 1: Sex distribution of HIV/AIDS patients and controls
5.1.2 CONTROL POPULATION
The control population was aged 20 to 59 years with 78 males and 122
females. The mean age of the control population was 32.1 ± 4.0 years.
There was no statistically significant difference in the mean age of males
compared to females (z=1.10, p=>0.27). However, there was a significant
difference in the mean age of the control population compared to the
HIV/AIDS population (z=4.04, p=<0.001).
5.2 SOCIO-ECONOMIC CHARACTERISTICS
5.2.1 EDUCATION
About 74% of the HIV/AIDS patients had completed secondary education
or had higher education. Only 4.5% had no formal education. The control
population was statistically more learned with 97% having had education liv up to or above secondary level. The educational levels of the patients and
control are shown in Table 2.
Table 2: Educational level of HIV/AIDS patients and controls
Educational HIV/AIDS PATIENTS CONTROL POPULATION
level Males Females Total Males Females Total
No (%) No (%) No(%) No (%) No (%) No(%)
None 6(1.5) 12(3.0) 18(4.5) - - -
Primary 36(8.8) 51(12.7) 87(21.7) 3(1.5) 3(1.5) 6(3.0)
Secondary 70(17.5) 127(31.7) 197(49.1) 9(4.5) 17(8.5) 26(13.0)
Tertiary 39(9.7) 60(15.0) 99(24.7) 66(33.0) 102(51.0) 168(84.0)
Total 151(37.7) 250(62.3) 401(100) 78(39.0) 122(61.0) 200(100)
lv HIV/AIDS CONTROLS
90
80
70
60
50
40
FREQUENCY(%)
30
20
10
0 None Primary Secondary Tertiary HIGHEST EDUCATIONAL LEVEL
Figure 2: Educational levels of HIV/AIDS patients and controls
5.2.2. OCCUPATION lvi About 70% of the study population was belonged to either social class IV
or V compared to 35% of the control population. These comprised
unemployed persons, students, or persons involved in unskilled or semi-
skilled occupations. There is a statistically significant difference between
the HIV/AIDS patients and the control population that had 34% in these
classes (χ2=205.58, p=<0.001). This is represented in Table 3.
Table 3: Social Classes of Patients and Controls
SOCIAL CLASS HIV/AIDS CONTROL PATIENTS POPULATION No (%) No (%) I 18(44.9) 106(53.0)
II 24(6.0) 9(4.5)
III 77(19.2) 17(8.5)
IV 120(29.9) 10(5.0)
V 162(40.4) 58(29.0)
Total 401 (100) 200(100)
Χ2 =205.58 (4 degrees of freedom), p = <0.001
5.2.3. INCOME BRACKET
Up to 70% of the study population belonged to the low income group
compared to 32% of controls. This is shown in Table 4. lvii
Table 4: Income Bracket of Patients and Controls
Income HIV/AIDS PATIENTS CONTROL POPULATION
bracket Males Females Total Males Females Total
No(%) No(%) No(%) No(%) No(%) No(%)
High 8(2.0) 4(1.0) 12(3.0) 5(2.5) 7(3.5) 12(6.0)
Medium 59(14.7) 47(11.7) 106(26.4) 45(22.5) 79(39.5) 124(62.0)
Low 84(21.0) 199(49.6) 283(70.6) 28(14.0) 36(18.0) 64(32.0)
Total 151(37.7) 250(62.3) 401(100) 78(39.0) 122(61.0) 200(100)
Χ2 = 81.52, degrees of freedom = 2, p =<0.001
lviii HIV/AIDS patients
12 3%
106 26%
high medium low
283 71%
Control population
12 6%
64 32%
high medium low
124 62%
Figure 3: Income levels of HIV/AIDS patients and controls
lix 5.2.4. MARITAL STATUS
Significantly more persons (18.2%) in the HIV/AIDS population were
separated, divorced or widowed compared to 2% in the control population
(p<0.05). This is shown in Table 5.
Table 5: Marital Status of Patients and Controls
MARITAL STATUS HIV/AIDS CONTROL
PATIENTS POPULATION
No (%) No (%)
Single 129(32.2) 105(52.5)
Married 199(49.6) 91(45.5)
Separated 7(1.7) -
Divorced 14(3.5) -
Widowed 52(13.0) 4(2.0)
Total 401(100) 200(100)
lx 5.3 HIV RISK FACTORS AND SEXUAL HISTORY
Many subjects had multiple risk factors for HIV/AIDS. The predominant
risk factor for HIV acquisition in this study was heterosexual intercourse in
100% of cases. Homosexuality and intravenous drug abuse (IVDU) were
not reported. Blood transfusion was reported in 18(4.5%) of the HIV/AIDS
patients compared to 2(1%) in the control (p = 0.08). Scarification was
significantly more common in the HIV/AIDS group 33(8%) than in the
control group 3(1.5%) (p = <0.01). Occupational exposure to HIV was
significantly more common in the control population [48(24%)] compared
to the HIV/AIDS patients [6(1.5%)] (p = <0.001).
Oral sex was reported in 83(20.7%) of the HIV/AIDS population and in
42(21%) of the control population (p = 0.95). HIV/AIDS patients were more
likely to have multiple sexual partners (56.6%) compared to controls
(10.5%) (p = <0.001). None of the HIV/AIDS patients denied ever having
sexual intercourse compared to 26% of the control population that had
never had coitus. The number of past sexual partners (over the last 10
years) in HIV/AIDS patients compared to controls is shown in Figure 4.
HIV risk factors and their frequency are shown in table 6.
Table 6: HIV Risk Factors in HIV/AIDS Patients and Controls
lxi
HIV RISK FACTOR HIV/AIDS PATIENTS CONTROLS p
YES NO Yes NO value
No(%) No(%) No(%) No(%)
Heterosexual coitus 401(100) - 148(74) 52(26) <0.001
Multiple sexual partners 227(56.6) 174(43.4) 21(10.5) 179(89.5) <0.001
Homosexuality - 401(100) - 200(100) -
Oral sex 83(20.7) 318(79.4) 42(21) 158(79) 0.95
Blood transfusion 18(4.5) 383(95.5) 2(1) 198(99) 0.08
Scarification 33(8.2) 368(91.8) 3(1.5) 197(98.5) <0.01
IVDU - 401(100) - 200(100) -
Occupational exposure 6(1.5) 395(98.5) 48(24) 152(76) <0.001
lxii HIV/AIDS CONTROLS
70
60
50
40
30
FREQUENCY(%)
20
10
0 0 1 to 2 3 to 5 >5 NUMBER OF SEXUAL PARTNERS (PAST 10 YRS)
Figure 4: Number of past sexual partners in HIV/AIDS patients and controls
lxiii 5.4 DRUG HISTORY
The most frequently used drug by the HIV/AIDS patients were anti-
tuberculous agents in 15.5% of the patients. Other drugs were
Immunace® (a selenium preparation) in 37(9.2%), antibiotics 18(4.5%),
anti-diarrhoeal agents 12(3.0%), anti-histamines 7(1.7%), native
medications 30(7.5%), oral hypoglycaemic agents 5(1.2%) and unknown
drugs 50(12.5%).
5.5 SKIN DISEASE
The most common complaints by the HIV/AIDS patients were rash in
195(48.6%) and pruritus in 141(35.2%). Dyschromia was reported in
29(7.2%), pain in 20(5%) and swelling in 6(1.5%) of the patients. The
commonest sites of dyschromia reported were the limbs and the face.
Patients who presented with pruritic papular eruption or had used
bleaching creams most frequently reported this symptom. Pain and
swelling were frequent complaints in HIV/AIDS patients with bacterial skin
infections, and also in one patient with Kaposi’s sarcoma. The commonly
affected sites were the limbs and trunk.
The symptoms reported by the control population were rash in 25(12.5%)
and pruritus in 11(5.5%). This is shown in Figure 5.
The mean duration of symptoms was significantly shorter in HIV/AIDS
patients (42.3 ± 110.1 weeks) than in the control population (140.9 ± 205.4
weeks) (t=3.3, p=0.001).
lxiv
HIV/AIDS CONTROLS
60
50
40
30
FREQUENCY(%) 20
10
0 rash pruritus dyschromia pain swelling SYMPTOMS OF SKIN DISEASE
Figure 5: Symptoms of skin disease in HIV/AIDS patients and controls
lxv Skin disorders were present in 292(72.8%) of the HIV/AIDS patients compared to
42(21.0%) of the controls (χ2=145.13, p=<0.001). The most prevalent skin disorders were pruritic papular eruption 105(26.2%), xeroderma
(xerosis/ichthyosis) 46(11.5%), dermatophytosis 23(5.7%), seborrheic dermatitis
19(5.0%) and pyoderma 19(5.0%) The frequencies of the different skin disorders in these patients are shown in Tables 7a and 7b.
Among HIV patients with skin diseases, 50%(147) had only one while the rest
50%(149) had more than one type of skin disease. Among those with more than one skin disease, 110(37%) had two while 39(13%) had three different diagnoses. The most frequent combination of skin diseases pruritic papular eruption and xeroderma in 41(13.9%) of the patients.
Figures 9-16 are clinical photographs of some of the dermatological disorders encountered in the HIV/AIDS population in this study.
lxvi Table 7a: More frequent skin disorders in HIV/AIDS patients compared with controls
SKIN DISORDERS HIV/AIDS CONTROL
PATIENTS POPULATION
No(%) No(%)
Pruritic papular eruption 105(26.2%) -
Xeroderma (xerosis/ichthyosis) 40(11.5%) -
Dermatophytosis 23(5.7%) 3(1.5%)
Seborrheic dermatitis 19(5.0%) 3(1.5%)
Pyodermas 19(5.0%) -
Post-bleaching syndrome 17(4.2%) 4(2.0%)
Herpes zoster 17(4.2%) -
Acneiform eruptions 15(3.7%) 15(7.5%)
Genital ulcer disease 14(3.5%) -
Nail changes 6(1.5%) -
Pityriasis versicolor 4(1.0%) 4(2.0%)
Epidermodysplasia verruciformis 4(1.0%) -
Drug eruption 3(0.7%) -
Kaposi’s sarcoma 3(0.7%) -
Lichenoid eruptions 3(0.7%) -
Intertrigo 3(0.7%) -
Fluffy hair 3(0.7%) -
Table 7b: Less frequent skin disorders in HIV/AIDS patients compared with controls lxvii
SKIN DISORDER HIV/AIDS CONTROLS
PATIENTS
No(%) No(%)
Anogenital warts 2(0.5%) -
Eosinophilic folliculitis 2(0.5%) -
Chickenpox 2(0.5%) -
Urticaria 2(0.5%) -
Seborrheic keratosis 2(0.5%) 1(1%)
Granuloma annulare 2(0.5%) -
Alopecia areata 1(0.25%) -
Atopic dermatitis 1(0.25%) 5(2.5%)
Nickel dermatitis 1(0.25%) -
Keloid 1(0.25%) 1(0.5%)
Vitiligo 1(0.25%) -
Scrofula 1(0.25%) -
Psoriasis 1(0.25%) -
Pityriasis rosea 1(0.25%) -
Sézary syndrome 1(0.25%) -
Miliaria 1(0.25%) 2(1.0%)
Lipoma 1(0.25%)
Foot ulcer - 1(0.5%)
Callosity - 1(0.5%)
Dermatophytosis was seen in 23(5.3%) of the HIV/AIDS patients. The most common modes of presentation were as tinea unguium [9(39%)] and corporis
lxviii [7(30%)]. Tinea cruris was seen in 3(13%) patients and tinea incognito in
2(8.7%). Tinea involving more than one body site was the presentation in
4(17.4%) patients. Most [16(69.6%)] of the patients with tinea had actually used bleaching creams and also had the post-bleaching syndrome. One of such patients with extensive tinea cruris and post-bleaching syndrome is shown on
Figure 15.
Majority of the patients (41.6%) had an AIDS-defining illness, most commonly tuberculosis or wasting syndrome, and were therefore classed as category C. Up to 27.2% of the patients were asymptomatic. These asymptomatic patients had spouses or consorts that were known to be HIV positive in 66 (60.6%) cases.
The HIV status of these asymptomatic patients only became known on voluntary counselling and testing (including pre-marital and pre-employment screening).
These patients all presented to the clinics in anticipation of starting anti-retroviral therapy. Category B patients comprised 31.2%. This is shown in Table 8.
Skin diseases were more frequently seen in patients with CDC category B and C illness than in category A. The prevalence of skin disease increased significantly from 21.1% in asymptomatic patients (category A) to 89.6% and 94.0% in categories B and C respectively (χ2 for linear trend = 233.43, p = <0.001). This is shown in table 8.
Table 8: Prevalence of skin disease in CDC stages in HIV/AIDS patients
lxix CDC class SKIN DISEASE Total Prevalence
Present Absent
A 23(5.7%) 86(21.5%) 109(27.2%) 21.1%
B 112(27.9%) 13(3.2%) 125(31.2%) 89.6%
C 157(39.2%) 10(2.5%) 167(41.6%) 94.0%
Total 292(72.8%) 109(27.2%) 401(100%) 72.8%
Χ2 for linear trend = 233.43, p=<0.001
The effect of co-morbid factors on the presence of skin diseases in HIV patients is shown in Table 10. Co-morbid factors that were statistically significant were the presence of tuberculosis (any site) (p<0.001), wasting syndrome (p<0.001), chronic diarrhoea (p<0.001), and psychiatric illness (p=0.01). Renal disease, diabetes mellitus, and hepatitis B or C seropositivity were not statistically associated with an increased prevalence of skin diseases in HIV patients
(p>0.05).
Table 9: Skin disease correlated with co-morbid illness in HIV/AIDS patients
Variable Skin Variable Variable Variable Total Χ2 p
lxx disease positive negative unknown value value
Renal Present 17(77%) 129(72%) 146 292 0.19 0.66 disease Absent 5(23%) 48(27%) 56 109
Diabetes Present 10(62.5%) 142(74%) 140 292 0.91 0.34
Mellitus Absent 6(37.5%) 51(26%) 52 109
Tuberculosis Present 94(91%) 192(67%) 6 292 23.0 <0.001
Absent 9(9%) 95(33%) 5 109
Hepatitis B Present 11(85%) 61(81%) 309 292 Fisher 1.0
Absent 2(15%) 14(19%) 93 109 exact
Hepatitis C Present 2(100%) 66(79.5%) 224 292 Fisher 1.0
Absent - 17(20.5%) 92 109 exact
Psychiatric Present 3(100%) 289(72.6%) - 292 Fisher 0.33 illness Absent - 109(27%) - 109 exact
Peripheral Present 38(86.4%) 253(71.1%) 1 292 6.9 0.01 neuropathy Absent 6(13.6%) 103(28.9%) - 109
Wasting Present 138(92%) 154(61.4%) - 292 47.2 <0.001 syndrome Absent 12(8%) 97(38.6%) - 109
Diarrhoea Present 104(92%) 188(65.3%) - 292 32.5 <0.001
Absent 9(8%) 100(34.7%) - 109
Skin disease was significantly more common in HIV/AIDS patients than the control population across the educational levels of primary and tertiary levels (p
<0.05). This is shown in Table 10. This difference was also observed across all income levels (p <0.05) as shown in Table 11.
lxxi
Table 10: Skin disease in relation to educational levels in HIV/AIDS patients and controls
Educational Skin disease in HIV/AIDS Skin disease in controls P
level Present Absent Total Present Absent Total value
No(%) No(%) No(%) No(%) No(%) No(%)
None 9(2.2) 9(2.2) 18(4.5) - - - -
Primary 70(17.5) 17(4.2) 87(21.7) 2(1.0) 4(2.0) 6(3.0) 0.02
Secondary 148(36.9) 49(12.2) 197(49.1) 14(7.0) 12(6.0) 26(13.0) 0.48
Tertiary 65(16.2) 34(8.5) 99(24.7) 26(13.0) 142(71.0) 168(84.0) <0.001
TOTAL 292(72.8) 109(27.2) 401(100) 42(21.0) 158(79.0) 200(100)
Table 11: Skin disease in relation to income levels in HIV/AIDS patients and controls
lxxii Income Skin disease in HIV/AIDS Skin disease in controls P bracket Present Absent Total Present Absent Total value
No(%) No(%) No(%) No(%) No(%) No(%)
High 7(1.7) 5(1.3) 12(3.0) 4(2.0) 8(4.0) 12(6.0) 0.04
Medium 70(17.5) 36(9.0) 106(26.4) 9(4.5) 115(57.5) 124(62.0) <0.001
Low 215(53.6) 68(17.0) 283(70.6) 29(14.5) 35(17.5) 64(32.0) <0.001
TOTAL 292(72.8) 109(27.2) 401(100) 42(21.0) 158(79.0) 200(100)
5.6 LABORATORY MARKERS OF IMMUNOSUPPRESSION
The mean CD4 count of the HIV/AIDS patients was significantly lower at
223.6 ± 176.4 cells/µl compared to 774.9 ± 250.7cells/µl in the control
population (t = 25.5, p = <0.001).
There was a statistically significant sex difference in the CD4 count of the
control population with a value of 695.9 ± 181.3 cells/µl for males
lxxiii compared to 825.5 ± 276.2 cells/µl for females (t = 2.59, p = 0.01). This
difference was not statistically significant in the HIV/AIDS population with
values of 207.5 ± 162.2 cells/µl for males and 233.4 ± 184.0 cells/µl for
females (t = 1.42, p = 0.16).
The mean viral load of the HIV/AIDS patients was 4.7 ± 1.0 log RNA copies/ml.
lxxiv 38 9%
above 499 202 200-499 51% under 200 161 40%
Figure 6: CD4 levels in HIV/AIDS patients based on CDC classification
5.7 CORRELATION OF SKIN DISEASE WITH IMMUNOSUPPRESSION
lxxv The prevalence of skin disorders increased significantly with declining CD4 counts in HIV/AIDS patients (χ2 for linear trend = 90.1, p = <0.001). Skin disease prevalence was 39.5% in patients with CD4 counts ≥500cells/µl, increasing to 54.7% in patients with CD4 counts 200-499cells/µl, and finally reaching 93.6% in those with CD4 counts <200cells/µl. This is shown in
Table 12 and Figure 7.
The pattern of skin diseases in severely immunocompromised patients
(CD4 counts <200 cells/µL) is depicted in Table 13 and Figure 8. Pruritic papular eruption, xeroderma and dermatophytosis were still the most prevalent disorders.
The mean CD4 count was significantly lower in HIV/AIDS patients with skin diseases (170.2 ± 148.4 cells/µl) compared to those without skin diseases
(374.3±161.6 cells/µl) (t = 11.83, p = <0.001).
The mean viral load was also higher in HIV/AIDS patients with skin disease
(4.9±0.9 log RNA copies/ml) compared to HIV/AIDS patients without skin disease (4.1±1.0 log copies/ml) (t = 5.5, p = <0.001).
The mean CD4 count and viral loads of the frequent skin disorders are shown in table 14.
lxxvi
Table 12: Skin disease frequency compared with CD4 count levels
CD4 Count Skin Disease Prevalence
Level Present Absent Total
≥500 15(3.7%) 23(5.7%) 38(9.5%) 39.5%
200-499 88(21.9%) 73(18.2%) 161(40.1%) 54.7%
<200 189(47.1%) 13(3.2%) 202(50.4%) 93.6%
Total 292(72.8%) 109(27.2%) 401(100%) 72.8%
Χ2 for linear trend = 90.1, p = <0.001
lxxvii 100 93.6
90
80
70
60 54.7
50
39.5 40
30
SKIN DISEASE PREVALENCEDISEASESKIN(%)
20
10
0 >499 200-499 <200 CD4 LEVELS
Figure 7: Prevalence of skin diseases at each level of CD4 count
(CDC categories)
Table 13: Pattern of skin disease in HIV/AIDS patients with CD4 counts
<200 cells/μl
lxxviii Type of skin disease Frequency Percentage (%) Pruritic papular eruption 99 49 Xeroderma 35 17.3 Dermatophytosis 16 7.9 Genital ulcer disease 14 7 Herpes zoster 10 5 Post-bleaching syndrome 10 5 Seborrheic dermatitis 6 3 Acneiform eruptions 5 2.5 Pyoderma 4 2 Hair dystrophy 3 1.5 Epidermodysplasia verruciformis 3 1.5 Kaposi’s sarcoma 3 1.5 Chickenpox 2 1 Anogenital warts 2 1 Lichenoid eruptions 2 1 Nail pigmentation 2 1 Eosinophilic folliculitis 1 0.5 Intertrigo 1 0.5 Alopecia areata 1 0.5 Vitiligo 1 0.5 Pityriasis rosea 1 0.5 Stevens-Johnson syndrome 1 0.5 Lipoma 1 0.5 Keloid 1 0.5 Sèzary syndrome 1 0.5
lxxix 120
99 100
pruritic papular eruption xeroderma 80 dermatophytosis genital ulcer disease herpes zoster post bleaching syndrome 60 seborrhoeic dermatitis acneiform eruptions
FREQUENCY pyoderma hair dystrophy 40 35 epidermodysplasia verruciformis Kaposi's sarcoma
20 16 13 10 10 6 5 4 3 3 3 0 TYPE OF SKIN DISEASE
Figure 8: Skin disorders in HIV patients with AIDS-defining CD4 counts (<200cells/µl)
lxxx Table 14: Mean CD4 counts and viral loads in some dermatological disorders in HIV/AIDS patients
Skin disorder Frequency Mean CD4 count Mean viral load (cells/µl) (log copies/ml) Pruritic papular eruption 105 74.9 ± 53.5 5.11 ± 0.88 Xeroderma 40 125.9 ± 112.1 4.26 ± 1.42 Dermatophytosis 23 172.4 ± 155.7 5.18 ± 0.48 Seborrheic dermatitis 19 240.7 ± 165.0 3.10 ± 0.39 Pyoderma 19 275.6 ± 144.9 4.41 ± 0.79 Post-bleaching syndrome 17 178.7 ± 169.5 5.03 ± 0.61 Herpes zoster 17 210.9 ± 173.2 5.19 ± 0.69 Acneiform eruptions 15 283.5 ± 169.8 4.35 ± 1.00 Genital ulcer disease 14 91.5 ± 72.4 5.20 ± 1.00 Pityriasis versicolor 4 260.0 ± 280.0 4.65±1.07 Epidermodysplasia verruciformis 4 98.0 ± 84.6 5.27 ± 0.33 Kaposi’s sarcoma 3 112.3 ± 5.77±0.49 Lichenoid eruptions 3 260.0 ± 53.9 5.79 ± 0.35 Intertrigo 3 253.3 ± 126.2 5 .20 ± 0.39 Hair dystrophy 3 90.0 ± 69.5 5.04±0.81 Chicken pox 2 50.0 ± 42.4 5.20 ± 0.40
Table 14 shows the mean CD4 counts and viral loads for some of the
dermatological disorders in this study. Low mean CD4 counts were seen in lxxxi genital ulcer disease (91.5 ± 72.4 cells/µl), epidermodysplasia verruciformis (98 ±
84.6 cells/µl), hair dystrophy (fluffy hair) (90 ± 69.5 cells/µl), pruritic papular eruptions (74.9 ± 53.5 cells/µl) and chicken pox (50 ± 42.4 cells/µl).
Higher mean CD4 counts were seen in acneiform eruptions (283.5 ± 169.8 cells/µl), pityriasis versicolor (260 ± 280 cells/µl), lichenoid eruptions (260 ± 53.9 cells/µl), pyodermas (275.6 ± 144.9 cells/µl), intertrigo (253.3 ± 126.2 cells/µl), seborrheic dermatitis (240.7 ± 165.0 cells/µl) and herpes zoster (210.9 ± 173.2 cells/µl).
Mean viral loads were lowest for seborrheic dermatitis (3.10 ± 0.39 log copies/ml), pyodermas (4.41 ± 0.79 log copies/ml), and acneiform eruptions (4.35
± 1.0). Higher mean viral loads were found in lichenoid eruptions (5.79 ± 0.35 log copies/ml).
Table 15: Mean CD4 count and viral loads in relation to presence or absence of specific skin disorders in HIV/AIDS patients.
lxxxii
Skin disease Present Absent
Variables P-value
Pruritic papular CD4 count 74.9±53.5 276.4±174.6 <0.001 eruption Viral load 5.11±0.88 4.55±1.01 <0.001
Xeroderma CD4 count 125.9±112.1 234.2±178.9 <0.001
Viral load 4.26±1.42 4.63±1.02 0.08
Seborrhoeic CD4 count 240.7±165.0 228.9±177.0 0.68 dermatitis Viral load 3.10±0.39 4.54±1.02 <0.001
Herpes zoster CD4 count 210.9±173.2 226±177.7 0.22
Viral load 5.19±0.69 4.65±1.02 0.10
Kaposi’s sarcoma CD4 count 112.3±65.6 224.5±176.7 0.15
Viral load 5.77±0.49 4.59±1.05 <0.001
Genital ulcer CD4 count 91.5±72.4 209.8±188.2 0.03 disease Viral load 5.20±1.00 4.56±1.07 0.41
When skin diseases were categorized in HIV/AIDS patients, those with
hypersensitivity reactions had significantly lower mean CD4 count (146 ± 142
cells/µl) compared to those without such skin disease (298 ± 175 cells/µl,)(t = lxxxiii 9.54, p = <0.001). These patients also had significantly higher viral loads (4.97
±0.95 log RNA copies/ml) compared to those without cutaneous hypersensitivity disorders (4.44 ±1.00 log RNA copies/ml) (p = <0.001).
There was no statistically significant difference in the mean CD4 counts and viral loads of the patients with or without viral and bacterial infections (see table 16).
There was a statistically significant difference in the mean CD4 count of patients with fungal infections (154.6 ± 134.1 cells/µl) compared to those without fungal infections (259.1 ± 185 cells/µl)(t = 5.84, p = <0.001). There was also a significant difference in the mean viral load in the patients with (4.09 ± 0.89 log copies/ml) and without (4.57 ± 1.05 log copies/ml) fungal infections (t = 2.16, p =
0.03). This is shown in table 16.
lxxxiv Table 16: Mean CD4 counts and viral loads in disease categories in HIV/AIDS patients
Skin disease class Variable Present Absent p value
Hypersensitivity CD4 count 146±142 298±175 <0.001
Reactions viral load 4.97±0.95 4.44±1.00 <0.001
Viral infections CD4 count 177±158 227±177 0.12
Viral load 5.04±0.65 4.65±1.02 0.19
Bacterial infections CD4 count 221±152 224±178 0.93
Viral load 4.70±0.82 4.68±1.02 0.95
Fungal infections CD4 count 155±134 259±185 <0.001
Viral load 4.09±0.89 4.57±1.05 0.03
Malignancies CD4 count 112±65.6 224.5±176.7 0.15
Viral load 5.77±0.49 4.59±1.05 <0.01
Present = particular class of skin disease present
Absent = particular class of skin disease absent
lxxxv
Figure 9: Clinical photograph of multi-dermatomal herpes zoster in an HIV/AIDS patient.
lxxxvi
Figure 10: Clinical photograph of ano-genital warts in an
HIV/AIDS patient
lxxxvii
Figure 11: Clinical photograph of another HIV/AIDS patient with anogenital warts
lxxxviii
Figure 12: Clinical photograph of pruritic papular eruption of
HIV/AIDS. The patient had used skin-lightening creams to
“bleach” the hyperpigmented papules.
lxxxix
Figure 13: Clinical photograph of subcutaneous nodules in an HIV/AIDS patient with sub-cutaneous granuloma annulare
Figure 14: Clinical photograph of same patient with sub-cutaneous nodules on the legs
xc
Figure 15: Clinical photograph of an HIV/AIDS patient with tinea cruris and post-bleaching syndrome.
xci
Figure 16: Clinical photograph of an HIV/AIDS patient with ecthyma gangrenosum.
CHAPTER SIX
DISCUSSION
xcii
6.1 DEMOGRAPHICS AND HIV RISK FACTORS
The population most at risk of HIV/AIDS is the young, adventurous,
sexually active and productive age group of 20-40 years.76 This study
showed that 68% (273) of the HIV/AIDS patients were less than 40 years
and 82.8% (332) less than 45 years of age, thus corroborating this fact.
This also correlates with the age specific HIV prevalence rates in Nigeria
with the age groups 20-24, 25-29 and 30-34years having the highest rates
of 5.7%, 5.6% and 4.2% respectively.10
Over 1% of the HIV/AIDS population was over 60 years of age. This
shows a changing trend as earlier studies in Lagos University Teaching
Hospital (LUTH) showed no single HIV positive case in subjects above 60
years of age.77 More recent Nigerian studies have shown an increasing
age of HIV infection with age 76 years recorded in Ibadan which is
comparable to the highest age of 74 years in this study.78 The increasing
numbers of the elderly population with HIV is a source of worry to
clinicians, and may change the face of AIDS to a wrinkled one.79 Improved
healthcare from better access to evidence based medicine via the internet
in recent years, as well as the training of more specialist doctors in the
country, may have translated to an increase in the ageing population. In
addition, elderly men are more likely to be widowed and remarry other
women and so increasing their risk of acquiring HIV. Also, the vaginal
epithelium in elderly women undergoes atrophic changes with decreased
vaginal lubrication and a greater tendency to micro-abrasions on coitus
predisposing to a more efficient transmission of HIV 79,80.
xciii The reversal of the male: female (M:F) ratio of HIV/AIDS patients is another new trend. Earlier studies showed the M:F ratio to be 2:1 in
Nigeria.77 This study revealed a M:F ratio of 3:5 with the females comprising 62.3% of the HIV/AIDS population. A similar trend was also noted in a recent study of HIV/AIDS patients in Yaoundé, Cameroon.81
This raises a number of questions. Is there truly a reversal of the M:F ratio or there has always been a higher female preponderance? In developing countries like Nigeria, where women are largely not economically independent, they are unlikely to seek medical attention early. Men may have better access to health-care facilities and data available would always include them. It is only when treatment is made free, as anti- retrovirals are now, and medical care more accessible and affordable, that females are brought or self-present for medical care, and this would reflect in the data. Furthermore, women are more at risk of HIV because of their vulnerability to sexual assault.82 Also, biological factors in women increase the risk of male to female transmission of HIV. These biological factors include the large surface area of the vaginal epithelium, the prolonged exposure to infected seminal fluid in women, the greater quantity of fluids transferred from men to women, the higher viral content of male sexual fluids, the micro tears that can occur in vaginal tissue from sexual penetration, and the greater probability of genital ulcer disease being unapparent in women.80,83,84
The younger mean age of the females (33.8 ± 8.9 years compared to
39.6 ± 7.6 years for males) and the fact that no male was seen in the 20-
24 years age bracket could be explained by the fact that females generally mature earlier than males and are initiated into sexual relationships by xciv older men and much earlier than males of the same age. A study of secondary school students between the ages of 13 to19 years in South
West Nigeria showed that 50% of female students were sexually active with most of them having their first sexual intercourse between 15 and
19years of age.85 Also, the low socio-economic status of the females in this study with 70% of them belonging to social classes IV and V
(students, unemployed, or involved in semi skilled or unskilled occupations such as petty trading) puts them at a disadvantage. This is corroborated by a study in Ibadan that showed 40% of HIV/AIDS patients to be traders.78 In such a setting, women are more likely to engage in sex for commercial reasons.
Though the HIV/AIDS patients were significantly more likely than the controls to be separated, divorced or widowed, the differences in social classes (income levels and education) may have accounted for this. The significant age difference between the two groups may also be a factor in this difference. However, being separated, divorced or widowed is a risk factor for HIV. Certainly, such patients are more likely to have a plurality of sexual partners. Furthermore, an illiterate of the lower social class is less likely to be aware of the disease and its preventive measures.
Heterosexual intercourse was the most important risk factor for HIV acquisition in this study. This is in keeping with previous African studies.8,21,81 Up to 26% of the control population claimed they had never had coitus unlike the HIV/AIDS group where there was no claim of virginity. The study protocol, which provided no anonymity (the
xcv investigator had to interview the subjects, examine their skins, and take samples for HIV screening and CD4 count assay), may have contributed to non-disclosure of sexual practices. Furthermore, control subjects that had multiple sexual partners may have declined to take part in the study for fear of HIV testing. However, the findings are close to those of Oladapo et al 86 who reported 32.5% of medical students in Sagamu, Southwest
Nigeria, as denying ever having had sexual intercourse.
The risk of having multiple sexual partners had been highlighted by an earlier Nigerian study.76 In this study, up to 57% of the HIV/AIDS patients admitted to having had more than 2 sexual partners (past or present) compared to 11% of the control population. It is instructive to note that up to 26% of the HIV/AIDS patients (about 50% of the unmarried population) reported having no sexual partner in the past one year. This could be explained by either remorse and increasing religiosity observed in these patients, the effect of repeated counselling on lifestyle modification, the effect of stigma on relationships, or deliberate falsehood considering the socio-cultural circumstances in Nigeria where sexual matters are not to be discussed in public. Furthermore, sexual intercourse is unlikely to appeal to a very ill patient with AIDS.
Up to 20% of the individuals in both the HIVAIDS and control population admitted to oral sex. Oro-genital transmission is difficult to prove or quantify as oro-genital contact generally accompanies other sexual activities.20,87,88,89.
xcvi Other risk factors reported among the HIV patients in this study, in combination with heterosexual intercourse, include multiple sexual partners (57%), blood transfusion (4.5%) and scarification (8.2%).
Scarifications for tribal identification and medicinal purposes are usually undertaken with unsterilized instruments. The importance of scarifications as HIV risk factor cannot be quantified because of the difference in socio- economic statuses of the study population and controls.
Intravenous drug use (IVDU) and homosexuality were not reported. This may reflect a low prevalence rate or under-disclosure for fear of stigmatization. It is in contrast to European and Asian studies where homosexual behaviour and intravenous drug use are major risk factors.17,18,59,60,56
Up to 24% of the control population compared to 1.5% of the HIV/AIDS patients reported an occupational risk of HIV. These were doctors, nurses, laboratory scientists, or final year medical students. However, despite the risk, only one (a laboratory scientist), was HIV positive. This corroborates the rarity of occupational acquisition of HIV, the risk of infection per exposure being estimated at 0.5%.90 It is also in keeping with the fact that hospital staff are very well informed about HIV preventive measures for
HIV.
All the patients in this study were positive for HIV-1. No single case of
HIV-2 was seen. Although HIV-1 is the predominant virus type worldwide,
HIV-2 is found predominantly in West Africa. The complete absence of any case of HIV-2 is not altogether unexpected.91,92 Epidemiological data xcvii from the National Sentinel Surveys in Nigeria have shown an increase in
HIV-1 infection from 89% to 98% between 1999 and 2001 and a decline in
HIV-2 infections from 4% to 2% during the same period.92 Mixed infections
by the 2 viruses had also declined from 7% to less than 1% within the
same period.92 This corroborates earlier projections looking at the
concomitant transmission of the two viruses within the same sexually
active population which indicated a positive association between
pathogenicity and reproductive success, and suggested that HIV-1 would
competitively displace HIV-2 in the longer term.93 Other factors that may
account for low HIV-2 seroprevalence rates (such as widespread use of
rapid testing procedures without follow-up confirmatory Western blotting
and inadequately trained personnel for HIV testing) were not operational in
this study.
6.2 SKIN DISEASE
The prevalence of skin diseases in the HIV/AIDS patients in this study is
72.8% compared to 21% in the control population. It agrees with previous
international studies.16,18,23,81,94,95 It is also close to the 66.7% recorded by
Ahamefule in a study of a Lagos prison.30 It is, however, higher than the
14% from Ghana 24 and 41.7% from Tanzania 20, but lower than the 80-
95% in Thailand.6,15 The different prevalence rates from Tanzania and
Thailand may reflect regional variation in skin disease prevalence from
environmental or even cultural practices. The use of a non-dermatologist,
who was not interested in HIV skin diseases, as a second investigator xcviii may have accounted for the very low prevalence reported by Lartey in
Ghana.
About one half of all HIV/AIDS patients with skin diseases presented with two or more dermatological diagnoses. This agrees with Rosatelli et al 19 who found the average number of dermatological diagnoses in Brazilian
AIDS patients to be 2.45. The plurality of dermatological disorders is a function of worsening immunosuppression.
The most frequent skin disorders encountered in HIV/AIDS patients in this study were pruritic papular eruption 105 (26.2%), xeroderma
(xerosis/ichthyosis) 46 (115%) and dermatophytosis 23 (5.7%). Previous studies all showed pruritic papular eruption and xeroderma to be amongst the most frequent skin disorders.6,16,20,23,61,81,95
Pruritic papular eruption (PPE) of HIV/AIDS was the commonest skin disorder. It is more prevalent in Africa, South East Asia and the Florida area of USA.61,96,97 The symmetry, plurality and distribution of lesions on exposed body areas may possibly reflect the frequency of arthropod bites or a systemic response to these bites as IL-2 and γ-IFN levels have been found to be low in PPE.36,37 It has been reported in all parts of the globe and together with eosinophilic folliculitis, is referred to as itchy red bump disease. An earlier study in Lagos 27 had found PPE and eosinophilic folliculitis to be the most common skin disorders in HIV patients.
Xeroderma characterized by xerosis or ichthyosis was the third most frequent skin disorder. Most of the patients did not complain of their xcix xerotic or ichthyotic skins, perhaps because they were more concerned with having treatment for HIV than appearance. Some of these patients had other stigmata of malnutrition such as fluffy hair, and presented with co-morbid disorders like chronic diarrhoea, wasting syndrome and oro- pharyngeal candidiasis.
Dermatophytosis has remained among the common HIV-associated dermatoses in Lagos and Africa in general.22,24,29,49,81 Onychomycosis, the most frequent presentation of dermatophytosis in this study (39%), has been noted to have psycho-social impact on HIV patients.46 Tinea incognito and tinea involving more than one body site were the presentation in 6(26%) patients. Most of these patients had used
“bleaching” creams and also presented with the post-bleaching syndrome.
The use of hydroquinone or steroid-containing skin-lightening creams is quite common in Nigeria and among other dark-skinned individuals in sub-
Saharan Africa and Europe.98,99 Several reasons, ranging from the inexpensive nature of these products to aggressive advertising where these creams are depicted to be the reason for the fair, flawless skins of models, make them appealing to not only young women, but also the elderly women and males. Chronic use of these creams results in a post- bleaching syndrome which comprises of exogenous ochronosis (abnormal hyperpigmentation of the knuckles, face, skin of extensor surfaces of joints), striae, telangiectasis leading to a red-man appearance (l’hômme rouge), steroid-induced acne, hypertrichosis, friable skin, and plucked chicken skin.99,100,101,102 Although the use of skin lightening creams cuts across all socioeconomic strata, persons involved in certain occupations c are more likely to use them than others.98,99 These include commercial sex workers and entertainment practitioners. These occupations are associated with multiple sexual partners and therefore an increased risk of
HIV transmission.
Seborrheic dermatitis was found in 19(5%) of the HIV patients. A previous dermatology clinic-based Lagos study had reported the prevalence of seborrheic dermatitis to be 2.87%.31 The positive predictive value of this condition for HIV seropositivity was reported as 9.3%.31 The commonest presentation was as scaly hypopigmented macules or patches on the naso-labial folds, and response to anti-fungal agents such as ketoconazole was poor.
Genital ulcer disease (GUD) was seen in 12(3.0%) patients. It is a reflection of the reciprocal relationship (epidemiological synergy) between
HIV infection and GUD whereby each may alter the transmission and manifestations of the other, resulting in a potentially explosive mutually reinforcing spiral of infection.103,104,105 Although VDRL, Tzanck smear and
Gram stain were done for these patients with GUD, the syndromic approach was used in diagnosis and management. In HIV patients, clinical diagnosis is usually not reliable, the primary chancre of syphilis is rarely seen, and multiple pathogens may be incriminated in STIs.16,104
Furthermore, there are limitations to aetiological diagnosis by laboratory investigations. Tzanck smears for HSV and Gram stain for H. ducreyi are neither sensitive nor specific, and VDRL may not be positive at the stage of the chancre.104,105,106 Diagnosis of chancroid is limited by the stringent ci growth requirements of this fastidious organism, with isolation rates of 53 to 88%.104
Genital warts were seen in 2 patients and these were profuse. In one case it was recalcitrant to treatment with podophyllin paint and imiquimod cream.
This pattern of top skin disorders in HIV/AIDS patients in Lagos is slightly different from an earlier study by Aderibigbe 28 where herpes zoster, prurigo, dermatophytosis, Kaposi’s sarcoma, human papilloma virus infections, exfoliative dermatitis and drug eruptions were the skin disorders seen in 15 HIV/AIDS patients. This earlier study was done in a specialist dermatology clinic and this would be influenced by the bias of referral of patients by self or primary physician. Moreover, only patients with unusual or extensive disease were recruited. It may, however, reflect a changing pattern over the past 13 years.
Acneiform eruptions and atopic dermatitis were the only disorders that were significantly more common in the control population than the
HIV/AIDS patients. Acneiform eruptions were seen in 15(2.7%) of the
HIV/AIDS patients compared to 15(7.5%) in the control population. The difference in prevalence of acne in the two groups can be explained by the younger population of the control group. Furthermore, acne has been known to have an inverse/paradoxical relationship to immunosuppression.
Patients whose acne lesions cleared when their CD4 counts became very low after immunosuppression by HIV were noted to have a flare after their cii CD4 counts rose with anti-retroviral drugs.35 Acneiform eruptions may also follow the use of bleaching creams. Exogenous ochronosis was more prevalent in the HIV/AIDS patients (4.2%) compared with the control population (2%). However, this difference was not statistically significant
(p = 0.16)
The greater prevalence of atopic dermatitis in the control population can also be explained by differences in the social classes of the two groups.
Atopic dermatitis is commoner in the higher social class presumably because of fewer infections and greater exposure to foods (such as dairy products) that may influence the differentiation of the T helper cells towards Th2 route.5,36
Scabies and pityriasis versicolor were not frequently seen in this study.
This could be explained by the frequent prescription of benzyl benzoate to most patients with itchy dermatoses, a trend noted amongst some of the doctors caring for HIV/AIDS patients. Pityriasis versicolor was noted to occur with about the same frequency in both the control and HIV/AIDS populations. Other studies from South Africa 21 and Cameroon 81 reported a low prevalence.
A notable finding in this study was the rarity of Kaposi’s sarcoma. This is similar to studies in South East Asia.6,103 It is however different from the high prevalence in other African countries,20,23,24,81 USA (Florida)96 and
Europe.17,18 The incidence of Kaposi’s sarcoma is highest in those areas with the highest sero-prevalence of human herpes virus-8 (HHV-8).41,42
The prevalence of HHV-8 in Lagos is 26.5%, a figure much lower than the ciii average of >50% in East and Central Africa.107,108,109 The prevalence of
HHV-8 in the rest of Nigeria is not known. The differences in prevalence of
Kaposi’s sarcoma can represent geographic and/ethnic distribution of the virus. This may explain the more frequent reports of Kaposi’s sarcoma in northern Nigeria.110,111
Epidermodysplasia verruciformis was seen in 4 (1%) of the HIV/AIDS patients. The commonest sites of involvement were the hair-margins and the upper chest. It has not been previously reported in African HIV/AIDS patients. Definite diagnosis in these patients was by histology of punch skin biopsy.
Chickenpox was infrequently seen in HIV/AIDS patients. The 2 patients with this infection had disseminated disease with pulmonary involvement necessitating in-patient management. This was the first infection in both patients. The severity of this infection in HIV/AIDS patients makes preventive measures (such as immunization of young adults who have never had chickenpox) desirable.
Nail changes were seen in 6(1.5%) of the HIV/AIDS patients.
Hyperpigmentation of the nails was seen in 4 patients while half and half nails were seen in 2 patients. The aetiology of half and half nails in these patients was HIV-associated nephropathy; one of the patients eventually had haemo-dialysis. Nail hyperpigmentation is usually related to drugs especially Zidovudine. Other incriminated drugs include phenytoin, lithium, sparfloxacin and cyclophosphamide. The patients in this study were not on civ anti-retroviral drugs. However, sparfloxacin is increasingly being used in
Nigeria especially for respiratory infections, and its contribution to
pigmentation in these patients is uncertain. Although nail pigmentation
may be found in Blacks, the role of HIV infection may not easily be
discountenanced. A recent study from Malawi reports grey pigmentation of
the nails to have a positive predictive value of 81% for severe
immunosuppression.44
Pityriasis rosea (PR) was seen in 1 (0.25%) patient. The lesions were
typical for PR and had been present for over 2 months. A previous study
in Lagos, Nigeria, found no relationship between PR and HIV.31
An HIV positive woman with subcutaneous granuloma annulare was seen.
She presented with painless subcutaneous nodules on the extensor
surfaces of the limbs (Figures 12 & 13). Histology of one of the nodules
revealed collagen sclerosis with palisading histiocytes. She was
scheduled for intralesional triamcinolone injection but was lost to follow up.
Skin disorders that have no direct relationship with HIV were also seen
though infrequently. These include seborrhoeic keratosis, keloid, nickel
dermatitis, lipoma and miliaria. These may just reflect the prevalence of
these disorders in the general population.
6.3 CORRELATION WITH IMMUNOSUPPRESSION
Skin diseases were more prevalent as immunosuppression increased.
The increase in prevalence from 39% in HIV/AIDS patients with CD4 cv count ≥500cell/ml to 94% in those with CD4 count <200cells/ml is in keeping with results from previous studies.6,15,23,81
The mean CD4 count was significantly lower in HIV/AIDS patients with skin disease (170.2 ± 148.4 cells/µl) compared to HIV/AIDS patients without skin disease (374 ± 148.4 cells/µl) (p = <0.001). This is explained by immune degradation with progressive decline in CD4 numbers. The greater prevalence of skin disorders in HIV/AIDS patients with normal CD4 counts (≥500 cells/µl) compared to controls could be explained not just by a decline in CD4 cell numbers but a qualitative decline in CD4 cell function.
Viral loads typically predict the rate of decline of CD4 numbers and therefore indirectly, skin disease. The mean viral loads were higher in
HIV/AIDS patients with skin disease (4.91 ± 0.92 log copies/ml) compared to those without skin disease (4.11 ±1.01 log copies/ml).
Skin diseases associated with relatively higher CD4 counts include pyodermas (275.6 ± 144.9 cells/µl), lichenoid eruptions (260 ± 53.9 cells/µl), pityriasis versicolor (260 ± 280 cells/µl), intertrigo (253.3 ± 126 cells/µl), seborrhoeic dermatitis (240.7 ± 165 cells/µl), nail changes (250 ±
60.8 cells/µl) and herpes zoster (210.9 ± 173.2 cells/µl). This is consistent with previous studies where cutaneous hypersensitivity reactions and herpes zoster have all been documented to occur earlier in HIV/AIDS when the CD4 count is still relatively high.6,15,61,81
Skin diseases associated with profound immunosuppression (CD4 counts
<100 cells/µl) include chickenpox (50 ± 42.4 cells/µl), pruritic papular cvi eruption (74.9 ± 53.5 cells/µl), hair dystrophy (fluffy hair) (90 ± 69.5 cells/µl), and epidermodysplasia verruciformis (98 ± 84.6 cells/µl). Several studies have reported the increasing prevalence of viral infections and pruritic papular eruption as immunosuppression worsens.61,62,81 Unlike in
Europe and the US where chickenpox (primary varicella) is a childhood disease, many children in tropical and sub-tropical regions of the world escape this infection.39 This may explain the relatively lower prevalence of herpes zoster in this study compared to some European studies where it ranked first or second.17,18,60 It also explains the chickenpox (primary varicella) cases seen in the adult population in this study. Varicella patients had the lowest mean CD4 counts in this study and it would be appropriate to state that varicella is a marker of advanced immunosuppression in Lagos, Nigeria. Both cases of varicella had severe disease necessitating in-patient care.
Pruritic papular eruption has been recognized as another marker of advanced immunosuppression.23,58,81,112 This was corroborated in this study. It was observed that quite a number of these patients try to “bleach” out the hyperpigmented papules using skin-lightening agents (see Figure
10).
The absence of molluscum contagiosum in this study cannot be explained.
Molluscum contagiosum is not uncommonly seen in immunocompetent subjects in Lagos, especially children, where a prevalence of 1% is noted.113
cvii The mean viral loads were highest in drug eruptions (fixed drug eruptions,
Steven-Johnson’s syndrome, toxic epidermal necrolysis) (6.29 ± 0.47 log
copies/ml), Kaposi’s sarcoma (5.77 ± 0.49 log copies/ml), and herpes
simplex virus (HSV) infections (5.70 ± 0.25 log copies/ml). This agrees
with Mbuagbaw et al.81 The higher viral loads in drug eruptions can be
explained by the fact that these conditions occur early in HIV infection
when the CD4 count is still high. The occurrence of these skin disorders
may predict a faster progression to AIDS. The high viral loads in HSV
infections may be explained by the evidence of direct activation of HIV
replication by HSV-2.114
Viral loads were lowest in seborrheic dermatitis (3.10 ± 0.39 log
copies/ml), xeroderma (4.26 ± 1.42 log copies/ml), pyodermas (4.41 ±
0.79 log copies/ml) and acneiform eruptions (4.35 ± 1.0 log copies/ml).
6.4 LIMITATION OF THE STUDY
Diagnosis of sexually transmitted infections was syndromic. Fluorescent
antibody test, Treponema pallidum haemagglutination test, and chlamydial
serology were not carried out for these patients; therefore, specific
aetiological diagnosis of STIs could not be made. However, these patients
had VDRL and Gram stain of swabs from ulcers and endocervical/high
vaginal swabs where indicated.
The control population used for this study was not an exact match for the
HIV/AIDS patients. A community within Lagos would have provided a
better match. However, the stigma associated with HIV seropositivity in cviii Nigeria would have made it almost impossible to recruit enough controls
within a limited time. Even with a more enlightened population like the one
used as controls in this study, there was still a lot of resistance to
participation in the study.
CHAPTER SEVEN
CONCLUSION AND RECOMMENDATIONS
7.1 CONCLUSION
The prevalence rate of skin disease in HIV/AIDS patients in Lagos,
Nigeria, is 72.8%. Skin disorders are three times more prevalent in
HIV/AIDS patients than in HIV-negative subjects (χ2 = 86.0760, p =
<0.001).
A significant inverse relationship between the CD4 counts and frequency
of skin disease in HIV/AIDS patients was also established. There was a
2.4 times increase in skin disease prevalence in patients with CD4 counts
<200 cells/µl compared to those with CD4 counts ≥500 cells/µl (χ2 for
linear trend = 90.1, p = <0.001).
The most prevalent skin disorders in HIV/AIDS patients in Lagos are
pruritic papular eruption 105(26.2%), xeroderma 40(11.5%),
dermatophytosis 23(5.7%), seborrhoeic dermatitis 19(5.0%) and
pyodermas 19(5.0%). There was an apparent rarity of Kaposi’s sarcoma
(3 cases, 0.7%) compared to other African studies.
cix Chickenpox, pruritic papular eruption, epidermodysplasia verruciformis,
genital ulcer disease and hair dystrophy (fluffy hair) are associated with
advanced immunosuppression.
7.2 RECOMMENDATIONS
Skin diseases can be used to predict immune status where CD4 count
assays are not available. In such cases, patients with chickenpox, pruritic
papular eruption, epidermodysplasia verruciformis, genital ulcer disease,
and hair dystrophy should be regarded as profoundly immunosuppressed
and anti-retroviral therapy offered.
A broader dermatological knowledge may be needed to make the
diagnosis of some of the skin diseases like epidermodysplasia
verruciformis. Medical students may need to spend longer than the current
2 weeks (in most medical schools in Nigeria) in Dermatology postings to
be better acquainted with skin lesions. More dermatologists would also
need to be trained to offer care to HIV/AIDS patients even where
laboratory facilities are not available. The vast majority of patients are
seen at the primary and secondary health care facilities. Therefore,
continuing medical education is recommended.
The relatively high prevalence of genital ulcer disease (GUD) in HIV/AIDS
patients in this study calls for improved case detection strategies of STIs
in asymptomatic patients at primary level health care facilities. This would
lead to early diagnosis and treatment of GUD and reduce spread of HIV. cx
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APPENDIX I cxxiii ETHICAL CLEARANCE FOR THE STUDY
APPENDIX II
QUESTIONNAIRE cxxiv
Prevalence of dermatological disorders in HIV/AIDS patients and correlation with immunosuppression in Lagos, Nigeria
Study No
Pt’s initials/Hosp No
Age [yrs]
Sex M F
Religion Xtianity Islam Others
Level of education None 10 20 30
Occupation
Income bracket Low Medium High
Marital status Single Married Divorced Widowed
HIV risk factors Heterosexual IVDU MSM
Blood Scarification Others
No of present sexual partners 0 1 2-3 >4
No of past sexual partners 0 1-2 3-5 >6
[Past 10 yrs]
Type of sexual activity vaginal oral anal
Medical History Present Absent Unknown
cxxv Renal disease
DM
Cancer
Hepatitis B infection
Hepatitis C infection
Psychiatric illness
Alcohol [significant]
Other HIV-related disease Present Absent Unknown
Diarrhoea >1month
Wasting syndrome
TB
Cryptococcal meningitis
ADC
Peripheral neuropathy
CMV retinitis
Toxoplasmosis
PCP
Drug history
Anti-TB Rif INH PZA Eth
cxxvi Strept Diateben B6 Others
Septrin prophylaxis Yes No
Others [specify]……………………………………………………….
Dermatological manifestations
Symptoms Rash Pruritus Dyschromia
Swelling Pain Ulcer
Others [specify]……………………………..
Duration of symptoms……………………………………….
No of episodes…………………………….
Physical examination [describe lesions]……………………………
Scalp …………………………………………………
Face …………………………………………………
Mouth …………………………………………………
Neck …………………………………………………...
Arm/forearm …………………………………………
Hands ………………………………………………….
Trunk …………………………………………………..
Genitalia …………………………………………………
Anus……..……………………………………………
Intertriginous areas …………………………………
Legs …………………………………………………….
Feet ……………………………………………………..
Provisional diagnosis ………………………………………..
Weight………………………………………………..kg
cxxvii Laboratory results
HIV sero-positivity HIV I HIV 2 Date
Confirmatory test ELISA WB Date
Lab investigation(s) performed ……………………………………..
…………………………………………………… … … …… …… … …
Final diagnosis …………………………………………………
Classification of skin disease…………………………..
FBC result…………………………………………..…………………….
CD4 T cell count …………………………. cells/µl
HIV viral load ………………………….. log RNA copies/ml
CDC class……………………
APPENDIX III
CDC REVISED CLASSIFICATION SYSTEM FOR HIV/AIDS 75
cxxviii
1993 Revised classification system for HIV infection and expanded AIDS surveillance case definition for adolescents and adults.
A B C
CD4 Count Asymptomatic, acute Symptomatic AIDS defining
(cells/µl) HIV or not A or C disorders
PGL* condition
≥500 A1 B1 C1
200-499 A2 B2 C2
<200 A3 B3 C3
Any patient in the C category or with CD4 count <200 cells/µl has AIDS.
PGL* = persistent generalized lymphadenopathy
APPENDIX IV
AIDS-DEFINING DISORDERS 115
▪Candidiasis of bronchi, trachea or lungs cxxix ▪Candidiasis, oesophageal
▪Cervical carcinoma, invasive
▪Coccidioidomycosis, disseminated or extrapulmonary
▪Cryptococcosis, extrapulmonary
▪Cryptosporidiosis, chronic intestinal (1-month duration)
▪Cytomegalovirus (CMV) disease (other than liver, spleen or nodes)
▪CMV retinitis (with loss of vision)
▪Encephalopathy, HIV-related
▪Herpes simplex, chronic ulcers (1-month duration); or bronchitis, pneumonitis or oesophagitis
▪Histoplasmosis, disseminated or extrapulmonary
▪Isosporiasis, chronic intestinal (1-month duration)
▪Kaposi’s sarcoma
▪Lymphoma, Burkitt’s
▪Lymphoma, immunoblastic (or equivalent term)
▪Lymphoma (primary) of brain
▪Mycobacterium avium-intracellulare complex or M. kansasii, disseminated or extrapulmonary
▪Mycobacterium tuberculosis, any site
▪Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
▪Pneumocystis carinii pneumonia
▪Pneumonia, recurrent
▪Progressive multifocal leucoencephalopathy
▪Salmonella septicaemia, recurrent
▪Toxoplasmosis of brain cxxx ▪Wasting syndrome, due to HIV
APPENDIX V
OCCUPATIONAL CLASSIFICATION OF PATIENTS 66
The Registrar General’s (Britain) Social Class Classification
Subjects are classified into 5 classes as follows:
cxxxi
SOCIAL CLASS DESCRIPTION EXAMPLES
I Professionals Lawyers, doctors Businessmen/women Large employers
II Lesser professions Teachers Trade Shop-keepers
III N Skilled non-manual Clerical workers M Skilled manual Electricians, lorry-drivers
IV Semi-skilled manual Machine operators, masons
V Unskilled manual to Farm workers, labourers Unemployed
APPENDIX VI
INCOME GROUP CLASSIFICATION OF PATIENTS 30
Subjects classified into 3 income groups viz:
Low - cxxxii Medium - N30-200,000 monthly income High - > N200,000 monthly income APPENDIX VII CAGE QUESTIONNAIRE FOR DIAGNOSIS OF SIGNIFICANT ALCOHOL CONSUMPTION 70,71 Significant alcohol was investigated by means of the CAGE questionnaire. C – Have you ever felt you ought to Cut down on your drinking? cxxxiii A - Have people Annoyed you by criticizing your drinking? G - Have you ever felt Guilty or bad about your drinking? E - Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (Eye-opener)? More than one “Yes” answer to these questions was taken as significant alcohol or an indication of alcohol abuse or dependence. APPENDIX VIII METHODOLOGY OF LABORATORY TESTS PERFORMED HIV SCREENING The control population was screened for HIV using the Capillus™ HIV-1/HIV-2 screening kit supplied by Trinity Biotech. This test is a direct latex agglutination cxxxiv test for the detection of antibodies to HIV-1 and/or HIV-2 in human whole blood, serum or plasma. It does not require sophisticated equipment and can be done in the side laboratory. It has a sensitivity of 99.3% for serum and 100% for whole blood, and a specificity of 99.7%.116 The steps in the test are: 1. A capillary slide (supplied by manufacturer) is placed on the interpretation station (a card with a black background). 2. The latex reagent was then mixed to ensure a homogenous suspension by: (i) gently rocking the bottle (ii) drawing the latex reagent up and down a few times with the graduated dropper 3. Then 120µl of the latex reagent is drawn into the graduated dropper and deposited on the slide at the edge of the mixing well furthest away from the capillary channel 4. A fresh disposable pipette tip is then attached to the pre-calibrated pipette and 10µl of test sample (whole blood) drawn and dispensed into the latex solution. 5. Using the pipette, the sample and the latex were mixed by pumping the mixture in and out of the tip 3 times, and stirring in a circular motion for 5 times. 6. The pipette tip is used to move the well-mixed sample and latex solution to the opening of the channel until the capillary flow begins. 7. The latex mixture was then allowed to flow through the entire capillary channel and into the viewing window. This may take 3-7 minutes. cxxxv 8. The viewing window is then observed. Any latex agglutination represents a positive test. Samples showing no aggregation are considered non- reactive. CD4 COUNT ASSAY This was done by flow cytometry using the Partec® CD4 easy count kit manufactured by PartecGmbH and the Cyflow machine. The steps in this test are: 1. Using an Eppendorf® pipette, 50µl of whole blood was drawn and placed in a Cytecs® test-tube. 2. Then 10µl of CD4 Partec® easy count reagent was added and mixed gently. 3. This was incubated for 15 minutes at room temperature and protected from light. 4. Then 0.8ml of dilution buffer was added and shaken/vortexed gently. 5. The tube with its content was placed in the Cyflow machine and an automated CD4 value was recorded by the machine and printed out. VIRAL LOAD ASSAY This was done using the Roche Amplicor® HIV-1 Monitor test, version 1.5. The steps in the test are: Amplification 1. Program the TC9600 or TC2400. Refer to package insert. 2. Place Micro Amp tray in the TC9600 or TC2400 cxxxvi 3. Start thermal cycle Detection 1. Remove the tray from the thermal cycler during the final hold and place into the tray base. Carefully remove caps from the tubes 2. Add 100µl of HIV Monitor Denaturation Solution to the tubes using Amplicor® electronic impact pipette (program 1). The impact pipette automatically performs mixing by pipetting up and down 5 times. 3. Prepare working wash solution in a graduated cylinder by adding 1 volume of 10x-wash concentrate to 9 volumes of distilled or deionized water. Transfer working wash solution to Wash Buffer as reserve. 4. Allow HIV-1 Monitor Microwell Plate® (MWP) to warm to room temperature before removing from the foil pouch. 5. Using the Impact® pipette (program 2), pipette 100µl of HIV-1 Monitor Hybridization solution into each MVP well 6. Add 25µl of denatured amplicon from the amplification tray into row A of the HIV-1 Monitor MWP using the impact pipette (program 3). The impact pipette automatically performs mixing by pipetting up and down 5 times and then retains 25µl for the next dilution. 7. Transfer 25µl of amplicon solution from row A to row B. Repeat this procedure 5 more times making dilutions of 1:5, 1:25, 1:125, 1:625, 1:3125. Discard the 25µl from row F after mixing. 8. Add 25µl of denatured amplicon from the same position on the amplification tray as used in step 6 into row G of the MWP QS wells using the impact pipette (program 3) cxxxvii 9. Transfer 25µl from row G to row H. This creates dilution (neat x 1:5). Discard 25µl from row F after mixing. 10. Cover the MWP and incubate for 1 hour at 37ºC 11. Wash the MWP 5 times with Working wash solution using an automated plate washer. Refer to package insert. 12. Using the Impact® pipette (program 2), pipette 100µl of AVP-HRP conjugate to each well 13. Cover the MWP and incubate for 15 minutes at 37ºC. 14. Prepare Working Substrate by mixing 12.0ml of Substrate A and 3.0ml of Substrate B for each MWP. Protect from light. 15. Wash the MWP 5 times with working wash solution using the automated plate washer 16. Using the Impact® pipette (program 2), pipette 100µl of working substrate to each well. Allow colour to develop for 10 minutes at room temperature in the dark 17. Using the Impact® pipette (program 2), pipette 100µl of Stop Reagent to each well. 18. Measure the optical density at 450nm within 10 minutes of adding the Stop solution. Record the absorbance value for each patient’s specimen and control tested. Using these absorbance values, perform appropriate calculations. cxxxviii