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Print version ISSN 0365-0596
On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.77 no.6 Rio de Janeiro Nov./Dec. 2002
CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
Dermatoses in HIV-infected patients with different degrees of immunosuppression*
Fernando CardosoI; Heloísa RamosII; Márcio LoboIII
Degree, "Universidade Federal de Pernambuco". Dermatologist, "Universidade de
São Paulo-Ribeirão Preto". Head of Teaching Dept., Sanitary Dermatology,
"Hospital de Infectologia Giselda Trigueiro", Natal/Rio Grande do Norte State
IIMaster Degree, "Universidade de São Paulo". PhD, "Universidade de São Paulo". Adjunct-Professor, "Universidade Federal de Pernambuco". Head of the Infirmary of the Medical Clinic at the "Hospital das Clínicas"
IIILecturer, "Universidade Federal de Pernambuco". Titular Professor of Dermatology, Tropical Medicine Department of the "Universidade Federal de Pernambuco". Coordinator of Post-graduate Studies in Tropical Medicine at the "Universidade Federal de Pernambuco"
The T-helper CD4+ lymphocyte blood count and number of viral RNA
copies are laboratory markers tracing the progression of HIV-induced immunodeficiency.
OBJECTIVES: Relate the markers indicating the varying degree of imunity in HIV-infected patients to the clinical aspects of the dermatoses present.
METHODS: The sample consists of 172 patients, who were submitted to quantifications of T CD4+ and CD8 lymphocytes by the cytometric flow technique as well as quantifications of viral RNA by the nucleic acid amplification technique (NucliSens). They were classified in patients with or without accentuated immunosuppression, based on the CDC-1992 clinic and laboratory classification of HIV infection.
RESULTS: The average percentage of skin afflicted by dermatoses was 12.5% and the average number of dermatoses per patient was 2.08. Neoplasic dermatoses and dermatoses of the miscellaneous group predominated in individuals with CD4+ T 200 cells/mm3 lymphocyte values, whereas CD4+ T >200 cells/mm3 lymphocyte values predominated in patients infected by arthropods.
CONCLUSION: The number of dermatoses per patient proved to be a marker for the course of immunosuppression (p=0,003). The percentage of skin extension affected by dermatoses did not lend itself to measuring the severity of dermatoses in HIV-infected patients (p=0,6058). The CD4+ T and CD8+ T and viral load lymphocyte count were efficient measurers of the degree of immunosuppression in dermatosis-infected patients (p=0.003).
Key words: allergy and immunology; skin diseases; Acquired Immunodeficiency Syndrome.
There is a general agreement on the high frequency of dermatoses in patients infected by the HIV virus. Mucocutaneous manifestations are made present from the onset of the disorder and continue appearing throughout the course of immunodeficiency and triggered by retrovirus.1-8 There are descriptions of increased severity of dermatoses with the progression of immunosuppression.9
The T Helper CD4+ lymphocyte count is used as a marker of the progression of immunodeficiency induced by retrovirus.7,10,11 It is believed that concentration of the HIV-virus RNA in plasma reflects the quantity of viruses present in the organism. Viral load is proportional to the number of infected CD4+ T lymphocytes present in blood circulation, which maintains the relation with the number of infected cells in ganglions and tissues (approximately 2% of the CD4+ T lymphocytes found in the circulation and 98% in ganglions and tissues).3,7
The utilization of HAART, i.e. "Highly Active AntiRetroviral Therapy", since 1995 has brought about changes in the presentation and evolution of dermatoses in HIV-infected patients. It is able to trigger the disappearance of cutaneous lesions or prevent more severe opportunistic diseases, resulting in the partial recuperation of the immune system.13
In Brazilian scientific work, there has been no case registered of average viral load values in HIV-infected patients with dermatoses. The relation between immunosuppression (T CD4+ and viral load) indicators and more frequent dermatoses in these patients has yet to be analyzed in Brazil, as also their relations with antiretroviral medication.
The Hospital Giselda Trigueiro (HGT), in Natal (Rio Grande de Norte State (RN)), is the reference center in the state capital for infectocontagious diseases. The hospital promotes descriptive studies representative of the epidemiological situation found in the state of HIV infection and its association with dermatoses. As such, clinical epidemiological findings of dermatoses in Natal may be contrasted with what is currently known nationally and internationally.
This paper documents the frequency of dermatoses and percentage of body surface afflicted by these dermatoses in HIV carriers, identified according to the HIV-infection classification system (CDC, 1992) at the moment of the first dermatologic consultation. It relates these clinical findings to laboratory findings, like CD4+ T lymphocyte count and viral load, and describes the existing relation between the dermatosis characteristics and the use of antiretroviral medications.
SAMPLING AND METHODS
This study was approved by the Comissão de Ética Médica do Hospital Giselda Trigueiro (Hospital Giserlda Trigueiro Medical Ethics Commission) in Natal, Rio Grande de Norte State (RN). Consent was obtained in writing from the participants.
A total of 381 HIV-infected patients above the age of 13 were evaluated as to the presence of dermatoses. They were attended to in medical check-ups from September 1, 1999 to February 29, 2000, after having sought care at an outpatient's clinic specialized in AIDS. For operational reasons, only interned patients were included in the first five even-numbered beds at the AIDS infirmary of the Hospital Giselda Trigueiro (Natal/RN) during this same period of time.
One-hundred-and-seventy-two patients were included in this study. 159 were in outpatient's care and 13 committed to hospital.
The total number of dermatoses present in each patient was registered during the physical examination. They were clinically identified through a laboratorial confirmation at a later date. The dermatoses were registered once only at the time of the first dermatologic consultation.
The study includes all dermatosis patients, those infected by HIV (who show two positive anti-HIV serologies by third-generation Elisa method and a positive confirmatory serology, and indirect or Western-Blot immunofluorescence); as well as symptomatic or asymptomatic patients who showed laboratory exams with T CD4+ lymphocyte count and viral load documented, with up to a four-month interval between the data collection and the dermatologic exam.
The dermatoses were diagnosed clinically, and classified clinically and laboratorially into seven items, according to Zalla et al14 and Ray.,15 These were: 1) bacterial infections; 2) viral infections; 3) fungus infections; 4) arthropod infections; 5) infections by protozoans; 6) cutaneous neoplasias; and 7) non-infectious, non-parasitic and non-neoplasic dermatoses, or those with badly-defined etiology (miscellaneous). The severity of these dermatoses was later evaluated in accordance with the extension of corporal affliction (rule of nine to calculate the percentage of burnt body surface): cephalic segment and throat, 9%; upper limbs, 9% each segment; hemitrunk and lower limbs, 18% each segment.16
At the first dermatologic consultation, patients were classified as individuals without accentuated immunosuppression, i.e. those pertaining to categories A1, A2, B1 and B2 of the HIV-infection classification system (CDC, 1992), and as individuals with accentuated immunosuppression, i.e. those pertaining to categories A3, B3, C1, C2, and C3 of this classification system. See chart 1, below.
The lymphocyte count in patients' peripheral blood was performed by the FACScount machine, a cytometric flow technique.17
The technique utilized for quantification of viral RNA was NucliSens, licensed by Organon Teknika Inc., by means of the NucliSens Reader, a computerized quantification instrument with a 80 cps/ml detection limit.
Results were submitted to statistical analysis. For data comparison, the T-student test, Fisher and Snedecor F (Anova), and Duncan and chi-square tests were used. A 5% level of minimal significance was adopted.
On average, 12.5% of the 172 patients had skin affected by dermatoses, a 2.08% average of dermatoses per patient, the average duration of seropositivity being equal to 525.6 + 71.2 days. The average viral load was 109,114.05 cps/ml, that of CD4+ T lymphocytes was 383.15 cells/mm3, and the average CD4+/CD8 T lymphocyte relation was 0.33.
The most frequent dermatoses were classified as: miscellaneous (seborrheic dermatitis, pruritic papular eruption of HIV or EPP, acquired ichthyosis, psoriasis, xerodermia, non-specific eczema, photoallergic contact dermatitis), fungals and viruses, representing 38%, 34.4% and 15.1% of the sampling, respectively. There were no protozoan infections. The eight most frequent diagnoses (74.6% of dermatoses) were: dermatophytoses, seborrheic dermatitis, EPP of HIV, verruca vulgaris, mucocutaneous candidiases, versicolor pityriases, acquired ichthyosis, and herpes simplex.
There was no statistically significant difference in mean percentages of body surface afflicted by dermatoses between different immunity groups at the time of the dermatologic examination (t=0.52, with 356 degrees of release and p=0.6058).
The less frequent dermatoses proved to have a significant difference of occurrence among patients with distinct degrees of immunosuppression (Table 1).
There was a statistically significant difference between the averages of CD4+ and CD8+ T lymphocytes and viral load among groups of patients with different degrees of immunosuppression (Table 2).
There was an inversely proportional exponential relation, (r=0.21, t=2.80, with 171 degrees of release and p=0.006) between the CD4+ T lymphocyte and viral load values.
There was a statistically significant difference between the number of dermatoses per individual in patients with different degrees of immunosuppression. In the accentuated immunosuppression group, the average viral load increased as did the number of dermatoses per individual (Table 3).
As for average CD4+ T lymphocyte values in cells/mm3, dermatoses per arbovirus predominated in patients with CD4+> 200; neoplasias and dermatoses classified as miscellaneous had higher occurrence in the CD4+< 200 group, in accordance with Table 4.
For viral load values, a statistically significant difference was obtained by comparing only patients showing dermatoses with fungal etiology (Table 5).
There was no statistically significant difference detected among the averages of body surface afflicted by dermatosis in antiretrovirus user groups and non-user groups (t=0.93, with 356 degrees of release and p=0.3539).
No significant statistical difference was observed in dermatosis frequency in patients receiving anti-retrovirus therapy as opposed to those who were not (chi-square M-L=1.61, with 3 degrees of release and p=0.656), a similar finding in dermatosis groups distributed between antiretrovirus users and non-users (Table 6).
The classification of patients with varying degrees of immunosuppression was adapted to the purpose of the study, reflecting the laboratorial situation of the immunologic competence markers of the patients with dermatoses while these lasted.
Categorizations of viral load and number of CD4+ T lymphocytes are reflected in the therapeutic guide of seropositive individuals with HIV,18,19,20 and the publications evaluating the presence of dermatoses at varying levels of measurement of the CD4+ T lymphocyte.9,13,14,21,22,23,25,26
While there were reports of resemblance between the viral quantification methods regarding reproducibility and sensitivity, and differences regarding value ranges subject to quantification,28,29 the NucliSens method is the only one available at the hospital in question, as is the cytometric flow technique used for CD4+ T lymphocyte quantification in these patients, both described as high-sensitivity.29
Norms do not exist for classifying HIV-infected patients in terms of severity, according to viral load levels, though it is known that values above the 30,000-50,000 cps/ml range are associated with the highest risk of progression from AIDS to death, and that undetectable values, or even in the 5,000 to 10,000 cps/ml range, are associated to a more favorable clinical course.7,20,30
There are no descriptive studies available on dermatoses and their relations to viral load. Neither norms nor consensus exist for classifying the increasing levels of severity in viral load categories. Viral loads are interpreted as low or acceptable when up to 10,000 cps/ml; value intervals are median or of concern when from 10,001 cps/ml up to 50,000 cps/ml; and, above 50,000 cps/ml, values are high or intolerable.
There are descriptions of high individual variability in CD4+ T lymphocyte number, mainly at levels above 2000 cells/mm3.25,29 Variability also occurs with viral load values.11 Values without a normal distribution obtain standard deviation for values higher than the averages for the diverse categories of viral load values found (Table 3).
The subcategorization of individuals into ranges of up to 200 cells/mm3 and greater than 200 cells/mm3 was the option chosen for CD4+ T lymphocytes, a division applied to the CDC/1992 HIV-infection classification system for identifying AIDS patients and merely infected patients.Values less than or equal to 50,000 cps/ml and greater than 50,000 cps/ml of viral load were used to identify patients without and with accentuated immunosupression, respectively.
The epidemiological characteristics of the sample correspond to descriptions in epidemiological bulletins in Brazil, mainly in relation to characteristics of age, anatomical sex (2:1 man-to-woman ratio), and sexual conduct (higher occurrence of infected heterosexuals, followed by bisexuals and homosexuals).31
The finding according to which there is no statistically significant difference between the average percentage of skin extension affected by dermatoses among patients with and without accentuated immunosuppression, does not correspond to the expectative logic by which there would be greater extension of dermatoses among severe immunosuppressed patients.
Nonetheless, the skin extension afflicted by dermatoses does not prove to be a measure of the degree of immunosuppression, independent of the use of antiretroviral medication, just as it was not a measure of the severity of dermatoses in HIV-infected patients.
The encounter of the higher number of scaly erythematous dermatoses included in the miscellaneous group (seborrheic dermatitis, EPP of HIV, acquired ichthyosis, non-specific eczema, psoriasis, xerodermia, erythrodermia, granuloma annular, ungual hyperchromia, photodermatitis, chronic cutaneous LE, LE induced by medication and vitiligo), followed by dermatoses of fungal and viral etiology, coinciding with world and national reports, according to which these three categories of dermatoses include the most frequent skin diseases in patients infected by retrovirus.2,13,32,33,34
While the high occurrence of dermatoses included in the miscellaneous group require more detailed analysis, no scientific classification has been recognized which would allow a subdivision of this category containing badly-defined etiologies of dermatoses.
The fact that patients with AIDS show a tendency to immune response conversion from Th1-to-Th2 pattern has been described in papers by Ramos12 in patients with EPP of HIV, a disease included in the miscellaneous group.
The predominance of Th2-like CD8+ lymphocyte clones triggered hypergamaglobulinemia E via production of IL-4 and IL-13, and eosinophilia via production of IL-5.36
Symptoms and clinical signs resulting from immunology mediated by Th2 lymphocytes in HIV-infected patients include eosinophilia, high levels of IgE in the blood, allergic manifestations, eczematous recurrences and infections of the respiratory tract.12,34,35,36
Peripheral blood eosinophilia was found to be frequent, mainly in patients with eczematous syndromes and EPP of HIV, while not statistically analyzed.
Three cases of Kaposi's sarcoma were obtained, though only in men, and five registered cases of oral hairy leukoplasia in men and one case registered in women.
There are differences in the prevalence of dermatoses among HIV-infected men and women, who show a lower frequency of Kaposi's sarcoma and oral hairy leukoplasia.26,35
The most frequent CD4+ T lymphocyte averages in this paper, in number of cells/mm3 and viral load in copies/ml, in decreasing order of values for CD4+ lymphocytes per dermatoses, were: pityriasis versicolor (537.5; 20,445.0); condyloma accuminadum (431.6; 22,000.0); herpes simplex (410.1; 72,608.3); oral hairy leukoplasia (377.3; 299,530.0); dermatophytoses (371.5; 159,198.2); seborrheic dermatitis (358.2; 122,942.4); verruca vulgaris (337.0; 18,846.9); acquired ichthyosis (283.4; 21,777.7); molusco contagiosum (277.0; 124,666.7); EPP of HIV (276.3; 193,922.6); and mucocutaneous candidiasis (248.8; 284,141.4).
Some findings coincided with previous papers, like the occurrence of condyloma accuminatum, verruca vulgaris and dermatophytosis in seropositivity stages asymptomatic to the HIV virus,24,25 though values obtained differed from those described by Reynaud-Mendel et al,25 i.e. from 450-to-550 cells/mm3 for dermatophytoses, and the high levels of CD4+ lymphocytes in patients showing verruca vulgaris.
Higher levels of CD4+ T lymphocyte were found in relation to the literature, in individuals with condyloma accuminadum, pityriasis versicolor and Herpes simplex, all above 400 cells/mm3; the verruca vulgaris finding, in addition to dermatophytosis, affected patients with lower levels of CD4+ T lymphocytes (i.e. below 380 cells/mm3).
There are descriptions of folliculitis flare-ups at initial and intermediary stages of HIV-infection; average value of CD4+ T lymphocytes of 250cells/mm3 in diagnoses of impetigo bullous with a risk in dissemination of the S. aureus and S. pyogenes bacterial agents, causing septicemia, in patients showing CD4+ T lymphocyte levels lower than 200 cells/mm.3 CD4+ T lymphocyte averages were obtained in number of cells/mm3 for cases of folliculitis, furuncle and ecthyma of 503.9, 529.0 and 645.5, respectively.
For Reynaud-Mendel et al.,25 the seborrheic dermatitis dermatoses, impetigo bullous, oral hairy leukoplasia, molusco contagiosum, xerodermia and eosinophilic folliculitis showed the following average CD4+ T lymphocyte in number of cells/mm3:450,250,200,150,100 and 50, respectively. The average values found for the same dermatoses were: 358.2; 386.0; 377.3; 277.0; 70.5; and 276.3 cells/ mm3respectively.
Comparative difficulties were observed in the values expressed in absolute numbers due to their great individual variability, though findings of very low CD4+ T lymphocytes values were described for dermatoses like pruritic papular eruption of HIV, 50 to 100 cells/mm3 (Johnson13) ;xerodermia, 246 cells/mm3 (Reynaud-Mendel et al.;25 oral hairy leukoplasia, 316 cells/mm3 and from 200 to 500 cells/mm3 (Johnson,13 Reynaud-Mendel et al.,25 respectively); oral candidiasis, 200 to 500 cells/mm3 and 316 cells/mm3 (Bartlett4 AND Reynaud-Mendel et al.,25 respectively).
It is important to consider that the present study alludes to the frequency of dermatoses in HIV-infected patients receiving highly active anti-retroviral therapy (HAART), and that the sample studied showed the average of CD4+ T lymphocyte values to be above 200 cells/mm3.
While the effectiveness of the use of these high potential medications is known in the control of viral replication and, consequently, changes in the immunologic response pattern are recognized in user-patients, but scientific descriptions are necessary to understand and locate the paradigm used by HAART and the effect on the dermatoses.
Studying the behavior of these dermatoses in individuals with different degrees of immunosuppression may be used to identify risk markers in HIV-infected patient, once they are present in all of the clinical stages of the infection, thereby allowing the dermatologist to give an early diagnosis of infection by retrovirus and of severe opportunistic infections of the extracutaneous disturbance.
The most common dermatoses (miscellaneous, fungal and viral) occur at statistically similar frequencies among patients with different degrees of immunosupressoin; those of bacterial etiology (p=0.0091) and by arthropods (p=0.0255) predominate in individuals without accentuated immunosuppression, while the neoplasias predominate in individuals with accentuated immunosuppression (p=0.0009).
The percent of skin extension affected by dermatoses does not prove to be a marker of immunosuppression degree (p=0.6058), independent from the use of antiretroviral medications (p=0.03539); yet, it does not lend itself to measure dermatoses in HIV-infected patients.
The growing number of dermatoses per patient proved to be a marker of the course of immunosuppression (p<0.02), measured by the increase in viral load values in individuals with accentuated immunosuppression.
The fact of using antiretrovirals or not did not modify the frequency of dermatoses in patients infected by retrovirus (p=0.656).
The number of CD4+ and CD8+ T lymphocytes, aside from viral load, was demonstrated as a parameter measuring the degree of immunodeficiency in the patients studied (p<0.003).
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Av. Rui Barbosa, 1122, Edifício Dorian Gray, Bl. B, Apto. 802
Lagoa Nova Natal/RN 59075-300
Phone/Fax: (84) 211-9643 / 232 7909
Received in September,
20th of 2001.
Approved by the Consultive Council and accepted for publication in May, 22nd of 2002.
* Work done at "Hospital Giselda Trigueiro - Natal/RN".