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AIDS and the pediatric ENT specialist
INTERNATIONAl JOURNAL OF
Pediatric
Oto
ELSEVIER
International Journal of Pediatric Otorhinolaryngology 32 (Suppl.) (1995) S7-S12
,&.cUI .,.!!I!!!l u6UJ.Ogy
Special lecture I
AIDS and the pediatric ENT specialist Nicola Principi Clinica Pediatrica 4, UniversitiI di Milano, Via GB Grassi 74, 20157 Milan, Italy
1. Introduction
Although most HIV seropositive individuals live in Africa and South America, HIV infection and its more important clinical manifestation, AIDS, is also found in people living in industrialized Western Countries. To date in North America and Western Europe several hundred thousand AIDS cases have been described. Among children, the incidence of AIDS varies between 1 and 3% of the total number of cases registered in the general population. With the exception of Romania, where the particular socioeconomic situation has produced a relatively high number of AIDS cases due to needle exchanges, in Europe the highest figures are present in those countries, like Italy, where the most important cause of HIV infection is drug abuse with a high incidence among women of childbearing age who are drug abusers. Vertical transmission is by far' the most important mode of acquisition of infection for children. In Italy, as of June 30, 1994, 427 cases of AIDS in patients under 13 years of age had been registered, and among them more than 90% had acquired the infection ftom the mother [4]. However, children with AIDS form only part of the patients in the pediatric age group with HIV infection, in fact there are two other groups of children: that of HIV infected patients who are asymptomatic or only mildly symptomatic and consequently do not meet the AIDS definition; and that of seroreverters, i.e., the subjects who, even if born to HIV infected mothers, are not infected and loose passively acquired maternal anti-HIV antibodies during the first months of life. The exact numbers of subjects belonging to these two groups are not definite because the notification of HIV antibody seropositivity is not mandatory in most countries. However, it has been calculated that the group of children with asymptomatic or mildly symptomatic HIV infection is at least equal to the group of AIDS pediatric patients, while it is well known that the group of seroreverters is approximately four times bigger than that of HIV infected children [7]. So the total number of children involved in HIV problems in all the Western World is of the order of some tens of thousands. 0165-5876/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-5876(94)01137-Z
S8
N. Principi / Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
Table I Sensitivity of early diagnostic tests for HIV in infants according to age 2-4
30-50 30-50 10-25 < 10 NA
3-6
>6
> 95 > 95
> 95 > 95 20-40 70-90 > 95
(months)
(weeks) Culture PCR p24 IgA IVAP
1-2
50 50 20-50 10-30 NA
70-90 70-90 30-60 20-50 NA
30-50 50-80 > 95
2. Peculiarity of HIV infection in pediatrics Because vertical transmission of HIV is the main mode of acquisition of infection in pediatrics and because only 15-20% of children born to HIV infected mothers are infected, the first problem with which pediatricians are faced with is the differentiation between really infected children and simple carriers of maternal antibodies. At the beginning of the AIDS era this differentiation was based only on the disappearance of maternal antibodies during a period of time which can last from birth to the 15th month. However, this system, used to prepare the CDC classification for children born to HIV infected mothers (PO for children in the indeterminate period, PI for those with clinically asymptomatic infection and P2 for those with HIV related symptoms) [3] had several limitations, the most important of which is the late evaluation of the infectious status, thus delaying the needed prophylaxis and the possible therapy in children with rapidly evolving infection. Today, several tests can diagnose HIV infection in children during the first weeks of life (Table 1), thus permitting a valuable identification of those subjects for whom particular medical attention is needed [5]. The second characteristic of HIV infection in pediatrics is the natural history of the disease. In adults the asymptomatic period is usually very long and when symptomatology appears it is especially related to superimposed infections. However, in pediatrics two different groups of children can be demonstrated: firstly, that of patients who tend to have a very rapid progression towards death, and secondly, those children with a history of long term survival. The analysis of the follow-up of 624 children with perinatal HIV infection collected by the Italian Register for HIV infection in children demonstrates that about 25% of children die before 5 years of age while the remainder live much longer [8]. The differentiation between short-term and long-term survivors may be performed both with laboratory tests and with clinical examination. Among laboratory tests biological properties of HIV together with a decline of CD4 cell count and an increase of immunoglobulins A,M,G and E are the most useful and the easiest to perform [6,13,15].
N. Principi I Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
S9
Table 2 Clinical markers of prognosis in HIV infected children Long-term survivors (n = 154) Lymphadenopathy Parotitis Failure to thrive Fever Diarrhoea Lymphoid interstitial pneumonitis Neurologic disorders Secondary infections
140 48 76 64 47 26 17 25
(91°;(,) (31'/"0) (49%) (42%) (31%) (17%) (11%) (16%)
Short-term survivors (n 70 10 93 85 60 24 69 84
= 120)
(58'/'(,) (8%) (78%) (71%) (50%) (20%) (58%) (70%)
Italian Register for HIV infection in children, Lancet 1994.
As far as clinical examination is concerned the analysis of the frequency with which signs and symptoms appear (Table 2) demonstrates that some of them are more common in subjects with a relatively good prognosis, while others are typical of a rapid progression of infection [8]. In many cases symptomatology involves the neck, head and lungs and thus the pediatric ENT specialist may be one of the first doctors to be faced with symptomatic infection. 3. ENT specialist involvement in HIV infected children
All the authors who have studied this problem agree that acute otitis media (AOM) is much more common in HIV infected children than in normal subjects of the same age [1,12]. However, the studies which consider not only the number of episodes of AOM, but also the proportion of children who suffer from AOM in each group, demonstrate that HIV infection does not seem to favor the occurrence of AOM per se but on the contrary predisposes to recurrences. Moreover, the analysis of recurrences according to the classification of HIV infected children in asymptomatic (PI) or symptomatic (P2) children demonstrates that the tendency to recur is significantly evident only in P2 children, probably as a consequence of the much more severe immunodeficiency of these subjects. Bacteriology of AOM in HIV infected children is not different from that demonstrated in normal children [12]. Moreover the in vitro sensitivity of these bacteria is similar to that expected. These data suggest that antibiotics usually employed against AOM in normal children might be prescribed also against AOM in HIV infected patients. However, the efficacy of the treatment seems to be strictly related to the degree of evolution of the HIV infection, being quite similar to that of normal patients in PI children but much more reduced in P2 ones [12]. Moreover, in some cases treatment failure may be followed by a poorly responding chronic suppurative disease and by a complete breakdown of the tympanic membrane. All these data indicate that further studies are needed to establish which is
SIO
N. Principi / Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
the best drug and the optimal duration of treatment for AOM in P2 children, and if there is a real need for a systematic prophylaxis. Cervical lymphadenopathy is very common in HIV infected children [11]. The differential etiological diagnosis must be made among viral, bacterial, opportunistic infections and malignancies, even if the latter are much more common in adults than in children. However, the most common forms of lymphoadenopathy seen in HIV infected children is generalized and can actually be considered to be a direct expression of HIV infection itself. In this case the nodes are usually no greater than 2 cm in diameter, rubbery, well defined and mobile, without tenderness or signs of inflammation. The enlargment is chronic, lasting for months to years, and over time tends 'to reduce as a consequence of the depletion of the patient's lymphoid tissue as the HIV infection progresses. In most of the cases it is associated with other evidence of lymphoproliferation such as that involving parotid, lung, liver and spleen. This complex disease is defined as the diffuse infiltrative lymphocytosis syndrome and is considered benign because it is generally associated with long-term survival. No specific treatment is required. Parotitis may be another of the symptoms of HIV infection [2]. At least two different aspects of parotid involvement are described: acute bacterial recurrent parotitis and chronic enlargement. In the first case individual episodes respond to proper antibiotic treatment, directed toward the most commonly responsible bacteria (Staphylococcus aureus, Streptococcus pneumoniae and other streptococcal species). In the case of chronic enlargement children present with a bilaterally symmetric swelling of the entire gland that is usually soft and non-nodular without signs of acute inflammation. The enlargment is due to a hyperplasia of the lymph nodes situated on the lateral surface or within the substance of the parotid gland as can be easily demonstrated by ultrasonography. No specific treatment is required unless the gland becomes so enlarged as to cause severe psychological problems which can be solved only by surgical excision. Among oropharyngeal lesions the most common are recurrent aphtous ulcers, gingivostomatitis and candidiasis [9]. Oropharyngeal candidiasis occurs in 15-40% of cases and may be severe enough to impair alimentation and lead to nutritional deficiencies and failure to thrive. Moreover, it may be complicated by an extension of the infection to other sites and typically has a high recurrence rate, unless antifungal therapy is continued. Pulmonary involvement is very common in HIV infected children and more than 80% of them develop lung diseases at some time during the course of their illness. Bacterial pneumonias, lymphoid interstitial pneumonitis and opportunistic infections, particularly Pneumocystis carinii pneumonia are the most frequent diseases of the lower respiratory tract. The differential diagnosis between them is not always easy to perform on a clinical and radiological basis; moreover, in children the sputum examination is quite rare, the lung biopsy remains a too invasive procedure and, until recently, bronchoscopy could not be used because of the lack of a proper apparatus. The recent development of much smaller flexible bronchoscopes permits bronchoscopy even in very young children and this method has rapidly become the best alternative to more invasive procedures when associated with bronchoalveolar
N. Principi / Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
SII
lavage [14]. In fact the recovered fluid can be used both for cytological and bacteriological studies, thus allowing an accurate diagnosis and a specific therapy. As regards lymphoid interstitial pneumonitis, recent studies have demonstrated that in the lavage fluid an increase in lymphocytosis with a significant reduction of the CD4:CD8 ratio without any presence of viral antigens or bacteria are characteristic of this disease. The recovery of a specific virus or bacterium is indicative of a specific disease. In our experience [10] bronchoalveolar lavage permitted a precise definition of the etiology of lung disease in 86% of the cases and an effective treatment with a complete resolution or at least improvement of the same high percentage. This supports the conclusion that bronchoscopy and bronchoalveolar lavage should be performed on HIV infected symptomatic children with respiratory problems as early in the course of the disease as possible, preferably before the onset of respiratory failure. From this simple and not exhaustive review it is however clear that the role of the ENT specialist in reducing clinical problems of HIV infected children may be particularly important. We all have to try to do our best in order to improve the quality of life of these particularly unhappy children. References [I] Barnett, E.D., Klein, J.P., Pelton, S.l. and Luginbuhl, L.M. (1992) Otitis media in children born to human immunodeficiency virus infected mothers. Pediatr. Infect. Dis. J. II, 360-364. [2] Brady, M.T. and Van Dyke, R.B. (1992) Involvement of the ear, sinuses, oropharynx, parotid, cervical lymph nodes and eye. In: Yogev, R. and Connor, E. (Eds.), Management of HIV Infection in Infants and Children. Mosby Year Book, pp. 287-323. [3] Centers for Disease Control (1987) Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 36, 225-236. [4] Commissione Nazionale per la lotta contro I' AIDS (National Committee against AIDS) (1994) Aggiornamento dei casi di AIDS notificati in Italia al 30/6/1994, p. 18. [51 Consensus Workshop (1992) Early diagnosis of HIV infection in infants. J. Acquir. Imm. Def. Synd. 5,1169-1178. [6] de Martino, M., Tovo, P.A., Galii, L. et al. (1991) Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiency virus. J. Pediatr. 119, 702-709. [7] European Collaborative Study (1991) Children born to women with HIV-I infection: natural history and risk of transmission. Lancet 337, 253-260. [8] Italian Register for HIV infection in children (1994) Features of children perinatally infected with HIV -I surviving longer than 5 years. Lancet 343, 191- 195. [9] Marchisio, P. and Principi, N. (1994) Treatment of oropharyngeal candidiasis in HIV infected children. Eur. J. Clin. Microbiol. Infect. Dis. 13, 338-340. [10] Onorato, J., Marchisio, P., Picco, P., Morandi, B., Zocchi, C, Monti, C and Principi, N. (1993) Value of bronchoalveolar lavage (BAL) in HIV + children. Pediatr. AIDS HIV Infection 4, 327. [II] Oxtoby, M.J. (1994) Vertical acquired HIV infection in the United States. In: Pizzo, P.A. and Wilfert, CM. (Eds.), Pediatric AIDS: The Challenge of HIV Infection in Infants, Children and Adolescents, 2nd Edn. Williams and Wilkins, pp. 3-21. [12] Principi, N., Marchisio, P., Tornaghi, R., Onorato, 1., Massironi, E. and Picco, P. (1991) Acute otitis media in human immunodeficiency virus infected children. Pediatrics 88, 566-571. [13] Principi, N., Marchisio, P., De Pasquale, M.P., Massironi, E., Tornaghi, R. and Vago, T. (1994) HIV-I reverse transcriptase codon 215 mutation and clinical outcome in children treated with zidovudine. AIDS Res. Human Retrovir. 10, 721-726.
SI2
N. Principi lInt. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (/995) S7-S12
[14] Sculerati, N., Ambrosino, M.M., Avni-Singer, A.J., Horwitz, D.A. and Lawrence, R.M. (1989) Diagnostic flexible bronchoscopy in human immunodeficiency virus (HIV)-positive children. Intern. J. Pediatr. Otorhinolaryngol. 18, 119-127. [15] Vigano, A., Principi, N., Crupi, L. et al. (1995) Elevation of IgE in HlV infected children and its correlation with the progression of the disease. 1. Allergy Clin. Immunol. in press.
Pediatric
Oto
ELSEVIER
International Journal of Pediatric Otorhinolaryngology 32 (Suppl.) (1995) S7-S12
,&.cUI .,.!!I!!!l u6UJ.Ogy
Special lecture I
AIDS and the pediatric ENT specialist Nicola Principi Clinica Pediatrica 4, UniversitiI di Milano, Via GB Grassi 74, 20157 Milan, Italy
1. Introduction
Although most HIV seropositive individuals live in Africa and South America, HIV infection and its more important clinical manifestation, AIDS, is also found in people living in industrialized Western Countries. To date in North America and Western Europe several hundred thousand AIDS cases have been described. Among children, the incidence of AIDS varies between 1 and 3% of the total number of cases registered in the general population. With the exception of Romania, where the particular socioeconomic situation has produced a relatively high number of AIDS cases due to needle exchanges, in Europe the highest figures are present in those countries, like Italy, where the most important cause of HIV infection is drug abuse with a high incidence among women of childbearing age who are drug abusers. Vertical transmission is by far' the most important mode of acquisition of infection for children. In Italy, as of June 30, 1994, 427 cases of AIDS in patients under 13 years of age had been registered, and among them more than 90% had acquired the infection ftom the mother [4]. However, children with AIDS form only part of the patients in the pediatric age group with HIV infection, in fact there are two other groups of children: that of HIV infected patients who are asymptomatic or only mildly symptomatic and consequently do not meet the AIDS definition; and that of seroreverters, i.e., the subjects who, even if born to HIV infected mothers, are not infected and loose passively acquired maternal anti-HIV antibodies during the first months of life. The exact numbers of subjects belonging to these two groups are not definite because the notification of HIV antibody seropositivity is not mandatory in most countries. However, it has been calculated that the group of children with asymptomatic or mildly symptomatic HIV infection is at least equal to the group of AIDS pediatric patients, while it is well known that the group of seroreverters is approximately four times bigger than that of HIV infected children [7]. So the total number of children involved in HIV problems in all the Western World is of the order of some tens of thousands. 0165-5876/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-5876(94)01137-Z
S8
N. Principi / Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
Table I Sensitivity of early diagnostic tests for HIV in infants according to age 2-4
30-50 30-50 10-25 < 10 NA
3-6
>6
> 95 > 95
> 95 > 95 20-40 70-90 > 95
(months)
(weeks) Culture PCR p24 IgA IVAP
1-2
50 50 20-50 10-30 NA
70-90 70-90 30-60 20-50 NA
30-50 50-80 > 95
2. Peculiarity of HIV infection in pediatrics Because vertical transmission of HIV is the main mode of acquisition of infection in pediatrics and because only 15-20% of children born to HIV infected mothers are infected, the first problem with which pediatricians are faced with is the differentiation between really infected children and simple carriers of maternal antibodies. At the beginning of the AIDS era this differentiation was based only on the disappearance of maternal antibodies during a period of time which can last from birth to the 15th month. However, this system, used to prepare the CDC classification for children born to HIV infected mothers (PO for children in the indeterminate period, PI for those with clinically asymptomatic infection and P2 for those with HIV related symptoms) [3] had several limitations, the most important of which is the late evaluation of the infectious status, thus delaying the needed prophylaxis and the possible therapy in children with rapidly evolving infection. Today, several tests can diagnose HIV infection in children during the first weeks of life (Table 1), thus permitting a valuable identification of those subjects for whom particular medical attention is needed [5]. The second characteristic of HIV infection in pediatrics is the natural history of the disease. In adults the asymptomatic period is usually very long and when symptomatology appears it is especially related to superimposed infections. However, in pediatrics two different groups of children can be demonstrated: firstly, that of patients who tend to have a very rapid progression towards death, and secondly, those children with a history of long term survival. The analysis of the follow-up of 624 children with perinatal HIV infection collected by the Italian Register for HIV infection in children demonstrates that about 25% of children die before 5 years of age while the remainder live much longer [8]. The differentiation between short-term and long-term survivors may be performed both with laboratory tests and with clinical examination. Among laboratory tests biological properties of HIV together with a decline of CD4 cell count and an increase of immunoglobulins A,M,G and E are the most useful and the easiest to perform [6,13,15].
N. Principi I Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
S9
Table 2 Clinical markers of prognosis in HIV infected children Long-term survivors (n = 154) Lymphadenopathy Parotitis Failure to thrive Fever Diarrhoea Lymphoid interstitial pneumonitis Neurologic disorders Secondary infections
140 48 76 64 47 26 17 25
(91°;(,) (31'/"0) (49%) (42%) (31%) (17%) (11%) (16%)
Short-term survivors (n 70 10 93 85 60 24 69 84
= 120)
(58'/'(,) (8%) (78%) (71%) (50%) (20%) (58%) (70%)
Italian Register for HIV infection in children, Lancet 1994.
As far as clinical examination is concerned the analysis of the frequency with which signs and symptoms appear (Table 2) demonstrates that some of them are more common in subjects with a relatively good prognosis, while others are typical of a rapid progression of infection [8]. In many cases symptomatology involves the neck, head and lungs and thus the pediatric ENT specialist may be one of the first doctors to be faced with symptomatic infection. 3. ENT specialist involvement in HIV infected children
All the authors who have studied this problem agree that acute otitis media (AOM) is much more common in HIV infected children than in normal subjects of the same age [1,12]. However, the studies which consider not only the number of episodes of AOM, but also the proportion of children who suffer from AOM in each group, demonstrate that HIV infection does not seem to favor the occurrence of AOM per se but on the contrary predisposes to recurrences. Moreover, the analysis of recurrences according to the classification of HIV infected children in asymptomatic (PI) or symptomatic (P2) children demonstrates that the tendency to recur is significantly evident only in P2 children, probably as a consequence of the much more severe immunodeficiency of these subjects. Bacteriology of AOM in HIV infected children is not different from that demonstrated in normal children [12]. Moreover the in vitro sensitivity of these bacteria is similar to that expected. These data suggest that antibiotics usually employed against AOM in normal children might be prescribed also against AOM in HIV infected patients. However, the efficacy of the treatment seems to be strictly related to the degree of evolution of the HIV infection, being quite similar to that of normal patients in PI children but much more reduced in P2 ones [12]. Moreover, in some cases treatment failure may be followed by a poorly responding chronic suppurative disease and by a complete breakdown of the tympanic membrane. All these data indicate that further studies are needed to establish which is
SIO
N. Principi / Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
the best drug and the optimal duration of treatment for AOM in P2 children, and if there is a real need for a systematic prophylaxis. Cervical lymphadenopathy is very common in HIV infected children [11]. The differential etiological diagnosis must be made among viral, bacterial, opportunistic infections and malignancies, even if the latter are much more common in adults than in children. However, the most common forms of lymphoadenopathy seen in HIV infected children is generalized and can actually be considered to be a direct expression of HIV infection itself. In this case the nodes are usually no greater than 2 cm in diameter, rubbery, well defined and mobile, without tenderness or signs of inflammation. The enlargment is chronic, lasting for months to years, and over time tends 'to reduce as a consequence of the depletion of the patient's lymphoid tissue as the HIV infection progresses. In most of the cases it is associated with other evidence of lymphoproliferation such as that involving parotid, lung, liver and spleen. This complex disease is defined as the diffuse infiltrative lymphocytosis syndrome and is considered benign because it is generally associated with long-term survival. No specific treatment is required. Parotitis may be another of the symptoms of HIV infection [2]. At least two different aspects of parotid involvement are described: acute bacterial recurrent parotitis and chronic enlargement. In the first case individual episodes respond to proper antibiotic treatment, directed toward the most commonly responsible bacteria (Staphylococcus aureus, Streptococcus pneumoniae and other streptococcal species). In the case of chronic enlargement children present with a bilaterally symmetric swelling of the entire gland that is usually soft and non-nodular without signs of acute inflammation. The enlargment is due to a hyperplasia of the lymph nodes situated on the lateral surface or within the substance of the parotid gland as can be easily demonstrated by ultrasonography. No specific treatment is required unless the gland becomes so enlarged as to cause severe psychological problems which can be solved only by surgical excision. Among oropharyngeal lesions the most common are recurrent aphtous ulcers, gingivostomatitis and candidiasis [9]. Oropharyngeal candidiasis occurs in 15-40% of cases and may be severe enough to impair alimentation and lead to nutritional deficiencies and failure to thrive. Moreover, it may be complicated by an extension of the infection to other sites and typically has a high recurrence rate, unless antifungal therapy is continued. Pulmonary involvement is very common in HIV infected children and more than 80% of them develop lung diseases at some time during the course of their illness. Bacterial pneumonias, lymphoid interstitial pneumonitis and opportunistic infections, particularly Pneumocystis carinii pneumonia are the most frequent diseases of the lower respiratory tract. The differential diagnosis between them is not always easy to perform on a clinical and radiological basis; moreover, in children the sputum examination is quite rare, the lung biopsy remains a too invasive procedure and, until recently, bronchoscopy could not be used because of the lack of a proper apparatus. The recent development of much smaller flexible bronchoscopes permits bronchoscopy even in very young children and this method has rapidly become the best alternative to more invasive procedures when associated with bronchoalveolar
N. Principi / Int. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (1995) S7-S12
SII
lavage [14]. In fact the recovered fluid can be used both for cytological and bacteriological studies, thus allowing an accurate diagnosis and a specific therapy. As regards lymphoid interstitial pneumonitis, recent studies have demonstrated that in the lavage fluid an increase in lymphocytosis with a significant reduction of the CD4:CD8 ratio without any presence of viral antigens or bacteria are characteristic of this disease. The recovery of a specific virus or bacterium is indicative of a specific disease. In our experience [10] bronchoalveolar lavage permitted a precise definition of the etiology of lung disease in 86% of the cases and an effective treatment with a complete resolution or at least improvement of the same high percentage. This supports the conclusion that bronchoscopy and bronchoalveolar lavage should be performed on HIV infected symptomatic children with respiratory problems as early in the course of the disease as possible, preferably before the onset of respiratory failure. From this simple and not exhaustive review it is however clear that the role of the ENT specialist in reducing clinical problems of HIV infected children may be particularly important. We all have to try to do our best in order to improve the quality of life of these particularly unhappy children. References [I] Barnett, E.D., Klein, J.P., Pelton, S.l. and Luginbuhl, L.M. (1992) Otitis media in children born to human immunodeficiency virus infected mothers. Pediatr. Infect. Dis. J. II, 360-364. [2] Brady, M.T. and Van Dyke, R.B. (1992) Involvement of the ear, sinuses, oropharynx, parotid, cervical lymph nodes and eye. In: Yogev, R. and Connor, E. (Eds.), Management of HIV Infection in Infants and Children. Mosby Year Book, pp. 287-323. [3] Centers for Disease Control (1987) Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 36, 225-236. [4] Commissione Nazionale per la lotta contro I' AIDS (National Committee against AIDS) (1994) Aggiornamento dei casi di AIDS notificati in Italia al 30/6/1994, p. 18. [51 Consensus Workshop (1992) Early diagnosis of HIV infection in infants. J. Acquir. Imm. Def. Synd. 5,1169-1178. [6] de Martino, M., Tovo, P.A., Galii, L. et al. (1991) Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiency virus. J. Pediatr. 119, 702-709. [7] European Collaborative Study (1991) Children born to women with HIV-I infection: natural history and risk of transmission. Lancet 337, 253-260. [8] Italian Register for HIV infection in children (1994) Features of children perinatally infected with HIV -I surviving longer than 5 years. Lancet 343, 191- 195. [9] Marchisio, P. and Principi, N. (1994) Treatment of oropharyngeal candidiasis in HIV infected children. Eur. J. Clin. Microbiol. Infect. Dis. 13, 338-340. [10] Onorato, J., Marchisio, P., Picco, P., Morandi, B., Zocchi, C, Monti, C and Principi, N. (1993) Value of bronchoalveolar lavage (BAL) in HIV + children. Pediatr. AIDS HIV Infection 4, 327. [II] Oxtoby, M.J. (1994) Vertical acquired HIV infection in the United States. In: Pizzo, P.A. and Wilfert, CM. (Eds.), Pediatric AIDS: The Challenge of HIV Infection in Infants, Children and Adolescents, 2nd Edn. Williams and Wilkins, pp. 3-21. [12] Principi, N., Marchisio, P., Tornaghi, R., Onorato, 1., Massironi, E. and Picco, P. (1991) Acute otitis media in human immunodeficiency virus infected children. Pediatrics 88, 566-571. [13] Principi, N., Marchisio, P., De Pasquale, M.P., Massironi, E., Tornaghi, R. and Vago, T. (1994) HIV-I reverse transcriptase codon 215 mutation and clinical outcome in children treated with zidovudine. AIDS Res. Human Retrovir. 10, 721-726.
SI2
N. Principi lInt. J. Pediatr. Otorhinolaryngol. 32 (Suppl.) (/995) S7-S12
[14] Sculerati, N., Ambrosino, M.M., Avni-Singer, A.J., Horwitz, D.A. and Lawrence, R.M. (1989) Diagnostic flexible bronchoscopy in human immunodeficiency virus (HIV)-positive children. Intern. J. Pediatr. Otorhinolaryngol. 18, 119-127. [15] Vigano, A., Principi, N., Crupi, L. et al. (1995) Elevation of IgE in HlV infected children and its correlation with the progression of the disease. 1. Allergy Clin. Immunol. in press.