On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.78 no.6 Rio de Janeiro Nov./Dec. 2003
CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
Dermatologic alterations in children with Aids and their relation to clinical-immunological categories and viral load*
Vânia Oliveira de CarvalhoI; Leide Parolin MarinoniII; Luzilma Terezinha Flenick MartinsIII; Suzana GiraldiIV; Kerstin TaniguchiV ; Jeanine BertognaVI
Degree in Pediatry. Pediatric Dermatology Service, Department of Pediatry, Federal
University of Parana
IIAdjunct Professor. Head of the Pediatric Dermatology Service, Department of Pediatry, Federal University of Parana
IIIMaster's Degree in Pediatry. Assistant Professor of Pediatric Infectology, Department of Pediatry, Federal University of Parana
IVMaster's Degree in Pediatry. Substitute Professor, Pediatric Dermatology Service, Department of Pediatry, Federal University of Parana
VMaster's Degree in Pediatry, Assistant Professor, Pediatric Dermatology Service, Department of Pediatry, Federal University of Parana
VIPediatrician, Pediatric Dermatology Service, Department of Pediatry, Federal University of Parana
Ever since the beginning of the Acquired Immunodeficiency Syndrome (Aids) epidemic,
a number of dermatoses have been frequently described in patients with this
disease. In the literature, case reports and studies in series of adult patients
with atypical lesions are frequent found. By contrast, there are few reports
on cutaneous alterations in pediatric patients with Aids.
OBJECTIVE: The purpose of the following prospective survey is to evaluate the presence of dermatoses in 40 pediatric patients with Aids.
METHOD: Forty patients diagnosed with Aids and less than 13 years of age were seen for six months. The following features were evaluated: number of dermatoses, clinical characteristics, distribution in accordance with the clinical-immunological categories in relation to CD4 T-lymphocyte and viral load values.
RESULTS: The prevalence of dermatoses in the first evaluation was 82.4%. In a longitudinal follow-up, 92.5% of the patients developed some kind of skin problem. Children belonging to the worst clinical-immunological category, with a viral load higher than 100,000 copies/ml showed a higher number of dermatoses when compared to the mildest categories. The number of dermatologic alterations per patient was 6.8 in clinical category C and 3.6 in A. In the immunological severe category, it was 7.0, while in the mild one, it was 3.7. For viral load > 100,000, the number was 7.3, and for < 100,000, it was 4,2 (all with statistical significance).
CONCLUSION: Dermatological alterations were frequent and directly related to advanced stages of Aids in pediatric patients. Higher frequencies of skin alterations in pediatric patients with Aids indicate that it is necessary to perform careful and frequent dermatological examinations of these patients.
Key words: skin diseases; HIV; immunosuppression; skin manifestations; Acquired Immunodeficiency Syndrome.
The Acquired Immunodeficiency Syndrome (Aids) has become a worldwide epidemic.1 Various systems in the organism are affected by the Human Immunodeficiency Virus (HIV). Skin lesions have been observed ever since the first descriptions of the disease,2 first manifestations of illness or evidence of the deterioration of the immunological system.3,4
Several authors refer to the greater number of skin diseases in adults with Aids2,5,6,7 as well as to their direct relation with the deteriorating immunological system. Some publications have demonstrated the same situation in children, with atypical and recurrent dermatoses.3,8,9
Viral load represents the number of RNA copies of HIV, and its increase precedes the drop of CD4 T-lymphocyte numbers. Viral load count also assesses the response to anti-retroviral treatment.10 High HIV RNA levels that are equivalent per milliliter of plasma indicates the worst prognosis.11,12
The relation of viral load with dermatological alterations in Aids patients is not well established. But it is generally believed that HIV may occasion alterations in Langerhans and keratinocyte cells, which may increase the skin's susceptibility to various diseases.13,14
HIV has already been detected as infecting Langerhans cells in the epidermis.15 Furthermore, this cell may be present in lower numbers in the skin lesions of Aids patients.16,17 The immune deregulation provoked by HIV causes abnormal stimulation of the keratinocyte.13 Nevertheless, the likely functional alterations of these cells have not yet been established.13,16,18
This prospective study assesses the skin diseases in 40 Aids children and their relation to the clinical categories, and CD4 T-lymphocyte and viral load values.
MATERIAL AND METHODS
From March 1997 to February 1998, 40 children with Aids were subject to a prospective evaluation at the Pediatric Dermatology ambulatory clinic of the Federal University of Parana Hospital de Clinicas. The 40 Aids children were undergoing follow-up treatment at the Pediatric Infectology Service. The study received the approval of the Ethics and Research Committee on Human Beings, and the consent of all persons responsible for the patients.
At the first visit, the medical history was taken in accordance with the specially delineated protocol for this type of research, i.e. physical examination and classification of the Aids into clinical-immunological categories and determination of the viral load. Each patient was accompanied for six months with bimonthly evaluations, or at shorter intervals if necessary.
The classification system for the degree of immunosuppression of Aids was based on criteria established by the Centers for Disease Control and Prevention (CDC). According to the latter, immunological categories are determined in accordance with CD4 T-lymphocyte values and the child's age into: Category 1 - mild; Category 2 - moderate; and Category 3 - severe. The clinical categories vary as a function of the symptoms present in: Category N - asymptomatic children; Category A - mildly symptomatic infection; Category B - moderately symptomatic infection, and category C-severely symptomatic infection.19 As such, children classified as C3 show more HIV-infection symptoms and low CD4 T-lymphocyte values (Table 1).
In accordance with the number of viral HIV copies, the patients were divided into two groups. The first one contained those with a viral load below 100,000 copies/ml, while the other grouped together those above 100,000. Due to the scarce amount of studies on the subject and since values have yet to be established for the pediatric age group, the same values were used as those suggested for the disease progression in adults.11,20
A high viral load level indicates the worst prognosis.11 In children, the death rate for viral load below 100,000 is 15%. From 10,000 to 100,000, it is 40%. And for values above 1,000,000, it is 71%.21 In the evaluation of 37 children with Aids, those with a viral load below 100,000 copies belonged to the severe clinical-immunological categories.22 As such, the authors opted for separating the two groups by using the viral load value of 100,000 copies as the watershed.
When necessary, laboratory tests, direct mycologic bacterioscopy, cultures for fungi and bacteria, cytologic and histopathologic examination were carried out.
The data were evaluated in an Excel spreadsheet. And the statistical analysis includes the c 2 and exact Fisher tests obtained by Epi Info software.
The average age of the 40 patients was 46.9 months within a range varying from three to 119 months. Among them, 22 (55%) were female and 18 (45%) were male. The viral transmission was vertical in 39 patients (97.5%), and by blood transfusion in one case. Fifteen children (37.5%) were living in two orphanages. Twelve (30%) were under their biological parents' tutelage, and 13 (32.5%) under other relatives'.
Six patients satisfied the CDC criteria for clinical category A, 19 for B and 15 for C. Patients were distributed according to CD4 T-lymphocyte values, with 17 children belonging to category 1, 13 to category 2 and 10 to category 3. The determination of viral load was under 100,000 copies/ml in 30 patients, and above 100,000 copies/ml in 10 children.
During the survey's term, all patients were taking anti-retroviral medication: 22 received two reverse transcriptase inhibitors; 15, two reverse transcriptase inhibitors in association with a protease inhibitor; and three, a reverse transcriptase inhibitor in association with a protease inhibitor. The prophylaxis against infection by Pneumocystis carinii, i.e. sulfamethoxazole-trimethoprim, was used in 34 patients.
In the first evaluation, all patients had dermatological alterations in each of the 81 diagnoses, with seven of them showing only residual dyschromias. As such, the prevalence of patients with skin diseases was 82.5%.
In the sixth-month evaluation, the incidence of patients with dermatological alterations was 92.5%. One-hundred and ninety-five consultations were done. This amount was higher in patients belonging to the severe clinical-immunological categories (Graph 1). Patients with viral load below 100,000 copies/ml had a rate of 4.6 consultations per patient (c/p). Those above 100,000 copies/ml had a rate of 5.5. c/p (c2=6.77; P=0.0095 significant).
For six months, 198 dermatological alterations were observed at a rate of five diagnoses per patient. Patient numbers and episodes of different dermatological alterations can be found in table 2.
The distribution of the proportion of dermatological diagnoses per patient in the clinical-immunological and viral load categories shows a statistically significant relation with the severe Aids categories. The ratio of diagnoses per patient in clinical category A was 3.6 and in C, 6.8 (p<0.0001). For mild immunology, it was 3.7, while for severe, 7 (p<0.0001). The viral load had 4.2 <100,000 copies/ml, and 7.3 > 100,000 copies/ml (p<0.0001). The other data can be found in Graph 2.
There were 45 skin diseases of infectious etiology (viral, bacterial and fungal). As such, they were the most frequent kinds, with 29 patients (72.5%) having a dermatological disease of infectious etiology (p<0.0001). It must be pointed out that given the aim of comparing these skin diseases with the frequency of others, the patients were included only once (even when showing infectious diseases from different agents during the survey period).
Twenty patients had fungal infections (17 by Candida). Viral infections occurred in 15 patients (nine by Herpes group viruses). Bacterial infections afflicted 10 patients (six by Staphylococcus aureus). Here the infectious skin diseases amounted to 45 cases, because some patients had skin infections caused by different agents during the six months of follow-up.
Candidiasis occurred in 17 patients, making for a total of 26 infection episodes. Pityriasis versicolor appeared in five patients and dermatophytosis in one.
Herpes simplex was present in three patients, thus adding up to six episodes. One patient had two episodes of herpes zoster. Five patients had varicella with clinical characteristics similar to those observed in children with Aids, with more numerous lesions in three cases. Five children had measles, three presented with viral exanthema, and there was only one case of molluscum contagiosum.
Xeroderma occurred in 67.5% of patients and was identically distributed in the clinical-immunological and viral load categories.
Strofulus prurigo occurred in 52.5% of patients (21 cases). The occurrence was higher in those from the mild clinical-immunological categories and viral load under 100,000 copies/ml.
Contact dermatitis occurred in 15 patients (37.5%). The type of reaction involved was mainly from primary irritants in 11 cases (nine from diaper dermatitis, and two from perioral dermatitis caused by saliva).
Four patients (10%) had six episodes of drug eruption (known as pharmacodermia in Brazil). The clinical presentation varied from maculous exanthema and/or disseminated papulosa to localized papulous lesions. It was characterized by a sudden onset four to six days after the introduction of the remedy (sulfamethoxazole-trimethoprim in three, amoxacillin, ritonavir and vancomycin in one of each case). The histological study that was carried out on three patients confirmed drug eruption.
Residual dyschromias occurred in 13 patients (32.5%), with hypochromic and/or hyperchromic lesions after varicella, strofulus prurigo, herpes zoster and others.
To analyze the distribution of the dermatological alterations in the clinical-immunological and viral load categories, only skin disease percentages were used, and not the absolute number, since there were different patient numbers in each group. This analysis could be performed on skin diseases when the rate was higher than 10 cases (fungal, viral and bacterial infections, pruritus from insect stings, xeroderma, contact dermatitis and residual dyschromias). Its distribution is demonstrated in table 3.
For the immulogical categories, the following statistically significant differences were observed. Category 1: prurigo by insect stings at 64.7% (p=0.0078); Category 2: fungal infections at 76.9% (p<0.0001); Category 3: viral infections at 80% (p<0.0001); residual dyschromias at 60.0% (p<0.001); and bacterial infections at 50% (p<0.0001).
In the clinical categories, statistically significant differences were observed for: Category A: prurigo by insect stings, 66.7% (p=0.0095); Category C: fungal infections, 66.7% (p=0.0081); bacterial infections, 53.3% (p<0.001); viral infections, 66.7% (p<0.0001); contact dermatitis, 60% (p<0.001) and residual dyschromias, 66.7% (p<0.0001).
There were no statistically significant differences for Category B, in which xeroderma was the most observed disorder (68.4%), followed by prurigo by insect stings (63.2%) and fungal infections (42.1%).
Regarding viral load, prurigo by insect stings was identically distributed in both groups. For patients having a viral load above 100,000 copies/ml, the highest statistically significant percentage was verified for fungal infections: 90% (p<0.0001); bacterial infections: 50% (p<0.001); viral infections: 70% (p<0.001); residual dyschromias: 60% (p<0.001).
The subject of dermatological manifestations in Aids patients constitutes a new chapter in dermatology due to their atypical clinical characteristics, frequency of relapses and therapeutic difficulty. The pediatric population with Aids involves a growing group mainly in developing countries. This survey characterizes the dermatoses present in a group of patients with the disease who live in such characteristically specific countries.
The survey population was made up of 40 patients identically distributed with respect to sex, the average age of which was 47 months. Similar data were registered in Brazil by the Ministry of Health in 1998, with 133 cases in male and 115 in female children below the age of 13 years, 79% of them less than 48 months.23
The high prevalence of dermatoses (82.5%) observed in the present study was also reported in Romania (90%) in two transversal surveys that included 62 and 400 children, respectively.24,25
The number of evaluations stipulated in six months of observation was 160. But due to dermatological crossovers there was a total of 195 evaluations, with a higher proportion in patients belonging to the severe clinical-immunological categories and viral load above 100,000 copies/ml. Owing to the higher degree of immunosuppression, the latter had dermatological manifestations over shorter time intervals and required monthly evaluations.
The percentage of patients with dermatological alterations was 92.5%, with 198 diagnoses and a rate of five different dermatoses per patient over six months. Other authors who undertook longitudinal studies on Aids children found similar data, such as Léauté-Labréze9 in France who found 94.2%, and El Hachem8 in Italy who referred to 89%. Adult surveys also demonstrate a high incidence of dermatoses: Muñhoz-Pérez26 in Spain found 69% of patients with cutaneous affections. In the United States the proportion of diagnoses per patient was 4.7%,27 demonstrating that skin diseases have high prevalence and incidence in Aids adults and children alike.
The distribution of the rate of diagnoses per patient in accordance with CD4 T-lymphocyte values shows that patients classified in immunological category 3 had a higher rate of dermatoses. Similar data were observed in the United States in a longitudinal study of 21 children in which patients with CD4 T-lymphocyte values below 200/mm3 showed a rate of four dermatological diseases per patient.3
Similarly, the distribution of dermatological diagnoses was greater for patients in the severe clinical categories, with 3.6 in A and 6.9 in C. El Hachem,8 surveying 85 pediatric patients in Italy refers to skin diseases in 54% of those from Category N, 90% of those from A and B, and in 97% of patients from Category C.
In the present survey, there was a higher proportion of dermatological diseases in patients with viral load above 100,000 copies/ml (p<0.0001). It was not possible to make comparisons, because there were no studies found in the literature evaluating dermatoses in relation to viral load in the pediatric population.
In the longitudinal evaluation, patients classified in clinical categories C, immunological 3 and with viral load above 100,000 copies/ml had a higher rate of dermatoses. These data may be explained by the immunological and nutritional alterations caused by Aids, which are more pronounced in patients with advanced-stage disease.28-32
Dermatoses caused by infectious agents were the most frequent (72.5%). The authors who carried out similar longitudinal surveys also observed the higher frequency of infectious diseases, which varied from 52.4%3 to 73%.8,9 The highest number of infectious dermatoses results most likely from the alteration of skin barrier functions resulting from the disease; Stingl33 cites the reduction of Langerhans cells responsible for presenting antigens that reach the skin through the immunological system. According to Smith,34 the increase in colonization by staphylococcus would be responsible for the higher number of infections in patients with reduced CD4 T-lymphocytes.
In adults, Spira35 and Rosatelli6 found a higher number of patients with infectious skin diseases. Furthermore, other authors verified a higher number of eczematous dermatoses.13,26
In this survey, candidiasis was the fungal infection of highest incidence (42.5%). It was observed by the authors who evaluated the incidence of dermatoses in children3,8,9,36 and adults with Aids.5,7 Repetitive episodes were frequent, similar in that respect to what is described in the literature.3,8 The lesions were only slightly extensive and restricted to the oral cavity and perineum. This was different to what El Hachem8 observed when he referred to extensive candidiasis lesions and esophagal affection. The therapeutic scheme, in association with anti-retrovirals, which the children were receiving in the present study, had not been recommended beforehand. It may have been a determinant factor for the change in clinical aspect of the lesions.
The literature shows that the new combined anti-retroviral therapies are beneficial and assist in improving the clinical condition. Its effect may also be observed in the dermatological manifestations.37 Over the past few years, the use of protease inhibitors in combination with reverse transcriptase inhibitors under different schemes has constituted a highly effective anti-retroviral therapy causing the suppression of viral replication, and thereby improving patients' survival rates.38
The systematic evaluation of the oral cavity in Aids patients is fundamental for early detection of infection by Candida and of repetitive episodes. Subsequently, treatment may be instituted with the aim of avoiding extensive lesions, which may accentuate a nutrition disorder.4,39
The average age of children with candidiasis in this survey was 51 months. This age differs from what has been observed in children without Aids, the majority of which are less than 12 months old.40 In children over the age of one, who show no other immunosuppression causes, the presence of candidiasis may be a sign that should lead the practitioner to suspect Aids.
Studies in vitro demonstrate the synergy between the herpes virus and HIV.41 The incidence of herpes simplex in the pediatric age range with Aids varies from 7.5%3,9 to 25%.8 In the present survey, herpes simplex occurs in 7.5% of patients with frequent relapses and residual hypochromia, which are clinical characteristics also observed by Lim.3 Extensive, chronic and resistant lesions to acyclovir were described in Aids patients.8,42,43
Studies in series of Aids children have demonstrated variable incidence of herpes zoster, from 4%3 to 20%,8,9 with extensive lesions that are difficult to manage therapeutically.8,9 In this study, the disease occurred in one patient who presented with few clustered vessels that were linearly disposed, intermixed with areas of normal skin, and with a relapse 60 days later. The diagnosis was confirmed by the Tzanck test.
Herpes zoster may manifest itself either exuberantly and chronically, or discreetly. This is why the Tzanck-technique cytological test must be carried out on all vessiculous lesions in Aids patients, and, when necessary, on biopsies showing giant multinucleated cells.
Varicella occurred in five patients and showed similar clinical characteristics to those observed in children without Aids. But the lesions were more numerous and disseminated in three cases. One patient was diagnosed with varicella prior to being included in the survey (the patient was diagnosed by the pediatric infectology service) and showed new episodes in the course of the survey. Another case, evolving for 30 years, showed vessiculous lesions. Relapse of varicella was already described by Pitche.44,45 Yet the previous diagnosis of varicella did not exclude the possibility of its diagnosis in Aids patients. When a repetition of varicella does occur or its course is prolonged (for longer than 2 weeks), then the infection must be investigated for HIV.44
Five children had measles, with positive serology in four cases and one with typical exanthema, nosocomial infection and an unspecific histopathologic study. There were no complications, which differs from what Palumbo46 observed. He described a 50% death rate in a study of six measles cases. Currently, the associated use of anti-retroviral drugs and the resulting improvement in patients' nutrition are factors that may have contributed to a favorable course for the patients of the present survey.
Three patients had viral exanthemas. One patient had lacy-aspect maculoerythematous lesions on the limbs, which is typical for infectious erythema. In the other two patients, disseminated maculopapulous exanthema was observed. It was accompanied by hyperthermia, hemogram with lymphocytosis, a histopathologic study releasing a drug eruption and negative serology for measles. Resulting from the unavailability of viral identification methods for a virus series, the diagnosis was presumptive and based on the clinical, evolutive and laboratory characteristics.
Molluscum contagiosum is a frequent viral infection in Aids patients.38 In studies in series of pediatric patients, Forsea24 in Romania observed 34.6%. Lim3 in the United States refers to only two cases in an evaluation of 21 patients that lasted three years. In the present study there was only one case of molluscum contagiosum. However, the authors believe that in an evaluation spanning a longer period of time this incidence might have been greater.
Bacterial infections occur in 25% of patients. Staphylococcus aureus was the main agent identified. Léauté-Labréze9 report three cases in 35 children, this low rate being attributed to adequate follow up. El Hachem,8 who found 6% of bacterial infections, attributed this low rate to the use of gammaglobulin. The skin of Aids patients is colonized by Staphylococcus aureus. Furthermore, the decrease of CD4 T-lymphocytes facilitates infection by this agent.34
The authors of the present study believe that the population's socioeconomic situation and difficulties in maintaining good hygiene, in association with the immunosuppression provoked by Aids and colonization by Staphylococcus aureus, are the conditioning factors for the largest number of bacterial infections when compared to what is found in the literature.
Xeroderma or acquired ichtyosis, which is frequent in diverse studies on skin diseases in Aids,24,35 occurred in 67.5% of the patients surveyed in this study. It was identically distributed in clinical-immunological and viral load categories.
Smith27 found xeroderma in 75% of the 912 adult patients observed in the longitudinal studies and did not show a relation with the degree of immunosuppression. The author suggests that xerosis results from the reduction of interleukins 1 and 6, and of HIV-provoked interferon alpha. These reduced substances in the plasma altered the lipid metabolism, increasing the epidermal loss of water and provoking xeroderma. Another possible cause of xeroderma would be nutritional disorders in Aids patients. The latter are manifested by skin scaling similar to what can be observed in patients without the disease but with severe nutritional disorders.4,47
Strofulus prurigo is most frequent in regions where the climate is hot and humid.48 The reactivation of hypersensitivity manifestations to insect stings is described in adults with Aids. It results from the loss of desensitization acquired during infancy due to the alteration of T cell receptors produced by the syndrome.46
In longitudinal studies of pediatric patients, some authors did not observe cases of strofulus prurigo.3,8 By contrast, Léauté-Labrezé9 in France referred to 12 cases in 35 Aids patients, and Forsea24 in Romania cited 17.5% in 62 children.
In the present study strofulus prurigo occurred in 52.5% of patients (21 cases), but in patients of the mild clinical-immunological categories and with viral load below 100,000 copies/ml. This indicates that the partially intact immune system is necessary for hypersensitivity to occur with insect stings.
Contact dermatitis occurred in 15 patients (37.5%). The type of reaction involved was by primary irritant in 11 cases (nine cases of diaper dermatitis, and two of perioral dermatitis by the saliva). In the study carried out in Brazil on adults with Aids, contact dermatitis occurred in 10.8% of Aids patients.49 In the present study, the high frequency of contact dermatitis resulted from the large number of diaper dermatitis cases occurring in children lacking sphincter control or because they were less than two years of age. Or the contact dermatitis even occurred from neurological alterations resulting from Aids (four cases). Inadequate hygiene habits may also have contributed to this high incidence.
Drug eruptions occurred in 10% of patients, similar to what was described in other studies set in this age range, in 12%8 and 11%9 of patients. Rosatelli6 in Brazil refers to 14.8% of drug eruptions in adults with Aids, and sulfamethoxazole-trimethoprim was the causative drug in most cases. Patients with an advanced stage of the disease took a high number of drugs with therapeutic and prophylactic ends. They are therefore most prone to drug eruptions.47,50
Post-inflammatory residual dyschromias may emerge consequently to any process of an inflammatory nature.51 They may be transitory or definitive and yet represent dermatological sequelae of the disease in Aids patients.52 This occurred in 32.5% of patients and was directly related to the severe immunosuppression categories.
Dermatological alterations have a high prevalence and incidence in pediatric patients with Aids. They are directly related to the severe clinical and immunological categories with viral load above 100,000 copies/ml. The evaluation of Aids children who belong to severe categories must be performed on a monthly basis. The laboratory investigation of skin lesions is important for an early diagnosis of dermatological diseases and for treating them adequately. Such an approach may proportionately diminish mortality in children with Aids.
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Received in November,
29th of 2001
Approved by the Consultive Council and accepted for publication in August, 15th of 2003
* Work done at "Hospital de Clínicas da Universidade Federal do Paraná".