Pediatric HIV infection
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《美国医学杂志》
1 Department of Pediatrics, VMMC and Safdarjang Hospital,Delhi, India
2 National Institute of Communicable Diseases, Delhi, India
3 Department of Pediatrics, Kalawati Saran Children Hospital,Delhi, India
Abstract
Objective: The present cross sectional study was undertaken to study clinical profile of HIV infection in children in Northern India. Methods: 64 children from newborn to eighteen years, presenting for confirmation of diagnosis of HIV infection or monitoring of CD4-CD8 counts in confirmed cases, were evaluated. Children were categorized as per CDC classification of Pediatric HIV. The diagnosis was confirmed by serological tests or PCR assay. CD4-CD8 counts were done by FACS Count. Results: Majority of the children were between 18 months to 5 years. Adolescents comprised 24% of the case. 51.5% children were infected through the mode of mother to child transmission. 39% of the case was transfusion-mediated. Unsafe medical injections probably contributed to 6.2% and heterosexual promiscuity led to 3.1% cases. Clubbing, not described in Indian studies so far, was seen in 9.3% cases. Conclusions: HIV infection is a chronic childhood disease extending into adolescence, and contaminated blood and unsafe medical injections are still important routes of HIV transmission in India.
Keywords: Pediatric HIV; Contaminated blood; Unsafe medical injections; Clubbing
HIV and AIDS have made a huge global impact permeating the social, cultural and economic fabric of almost all nations. In India too, ever since the diagnosis of the first case of the HIV infection in 1986, this problem has been growing at an exponential rate. As per the data collected during the annual round of HIV sentinel surveillance 2003 by NACO, the estimated number of HIV infected individuals in India is 5.1 million. This includes 55,145 children. Despite the magnitude of the problem, there is paucity of data on clinical profile of HIV infected children in India. The differences in presentation of infection in perinatally infected, transfusion acquired and parenterally infected children have not been studied properly. Also, there are no Indian studies addressing the clinical spectrum of HIV infection in an adolescent. The older children and their families have needs for specific services and support different from those required by younger children. Moreover, this article also attempts to draw attention to the presumed modes of transmission that are at variance with the published information.
In fact, despite the introduction of mandatory screening of blood products for more than 10 years, transfusion acquired HIV remains a significant problem.[1] The detection of HIV in children with a possible parenteral route of transmission due to unsafe medical injections also raises a serious concern about the standard of work precautions followed by health care workers. Changing lifestyles and risk taking behavior also expose the adolescents to HIV infection. Hence, the present project was undertaken with the objectives to study: (1) the clinical manifestation of HIV-1 infected children in relation to routes of transmission and (2) the clinical profile of HIV-1 infected adolescents.
Materials and Methods
An observational cross-sectional study of all HIV seropositive children, presenting to the AIDS division of the National Institute of Communicable Diseases (NICD), New Delhi, for confirmation of diagnosis or monitoring of CD4-CD8 counts was performed. An informed consent was taken from parents/patients. A total of sixty-four such children, newborn to eighteen years, who presented during January 2002 to December 2002, were enrolled. All patients were analyzed with special emphasis on demographic details, nutritional status, presenting symptoms, past history of illnesses, categorization of disease at presentation and at the time of gravest illness as per 1994 CDC classification for Pediatric HIV infection,[2] possible routes of transmission, type of therapy being instituted and spectrum of opportunistic infections. Probable tuberculosis was considered with symptoms of persistent cough/fever and/or weight loss and no response to routine antibiotics along with supportive radiological findings, positive Mantoux (induration over 5mm) and/or history of contact with tuberculosis. Confirmed pulmonary tuberculosis was considered if smear or culture of M. tuberculosis was positive from sputum or gastric aspirate.
The following criteria were considered for diagnosis of lymphoid interstitial pneumonitis (LIP)[3]; chest X-ray with diffuse reticulonodular infiltration with at least two of the following:
(i) Bilateral parotid swelling
(ii) Generalised lymphadenopathy
(iii) Digital clubbing
(iv) Treatment response to corticosteroids
Recurrent lower respiratory tract infection (LRTI) was defined as 2 episodes of infection in one year or three episodes over any period of time, while persistent LRTI was defined as persistence of radiographic abnormality for more than 3 months.[4]
The presumed mode of transmission was deduced after a confidential interview with the parents regarding sexual behavior, history of blood transfusion in parents, in child and HIV serology status of parents was taken. The transmission was attributed to blood transfusion in those children who had history of transfusion more than 3 months ago and whose parents were seronegative. In other children with seronegative parents and no history of blood transfusion but prior history of hospitalization and medical injections, the mode of transmission was deduced to be parenteral. History of tattooing, ear piercing and prior surgery was also taken. Since the NICD is a diagnostic referral center, the line of treatment being received by children at different centers was not interfered with. Supportive and/or antiretroviral therapies (ART) were, however, instituted in the newly diagnosed children with clinical symptoms of HIV or evidence of immune suppression as per the guidelines.[5]
The diagnosis was confirmed by positive serology in children over 18 months of age (58 children), a positive polymerase chain reaction (PCR) for HIV RNA repeated twice (2 patients) and/or positive serology in children below 18 months of age, but with clinical features strongly suggestive of pediatric AIDS (4 infants) as per revised World Health Organisation (WHO) clinical case definition for Pediatric AIDS.[6],[7] Because of high prevalence of infection and malnutrition in developing countries, this definition has been evaluated to have moderate sensitivity (35-68%) but good specificity (86-93%).[8] Recently, the same definition was used in Ugandan children less than 18 months with high specificity of 98% and a positive predictive value of 93%.[9]
Serology was performed by three positive ELISA (Enzyme Linked Immunosorbent Assay) or rapid tests using different antigens or different principles according to WHO strategy III.[10] The different ELISA/Rapid kits used were DETECT-HIV (Biochem Immunosystems, Montreal), HIV-SPOT (Genelabs Diagnostics, Singapore) and HIV-EIA (labsystems, Hel Sinki). PCR to detect HIV infection was done on peripheral blood mononuclear cells and was based on amplification of gag gene. CD4-CD8 counts were done by Flow cytometry using FACS Count machine (Beckton and Dickinson, San Jose, USA) in thirty-six patients.
Results
A total of 64 children in the age group of 20 days to 17 years were evaluated. table1 summarizes the age and sex distribution of children. Six children were below 18 months of age while fifteen were aged 10 years or more at the time of evaluation. Fifty-one children were residents of Delhi while the rest thirteen were from the states of Uttar Pradesh, Rajasthan, Punjab and Haryana.
Perinatal HIV Infection
The age of 33 children who acquired HIV infection through their mothers ranged from 20 days to 13 years table2. Majority of these children were in the age group of 18 months to 5 years. Twenty-eight out of these thirty- three children were symptomatic. Fourteen children had only category A symptoms as per 1994 CDC classification and five were asymptomatic. Overall nineteen children (57.5%) were asymptomatic to mildly symptomatic.
The clinical spectrum in these symptomatic children is shown in table4. The commonest presentations were failure to thrive, lymphadenopathy, tuberculosis and recurrent LRTI.
Nine children (27.2%) were on antiretroviral therapy with the age range of 3 to 12 years. Mean age at the onset of ART was 6.6 years and average duration of ART was 1.07 years (range 1 month to 4 years).
Transfusion Acquired HIV Infection
In the present study, 25 (39.1%) of 64 children had HIV acquisition through contaminated blood transfusions. Amongst these, 19 were thalassemics. In the remaining six, two had received blood transfusion preoperatively and four were transfused blood for anemia or weakness as per the medical records. The median age of thalassemic children at presentation was 8 years (range 3 to 17 years). Also, the median duration of known HIV infection in these children was of 2 years (range 1-4 years). Most thalassemics had manifestations like hepatosplenomegaly arising out of their disease or its complications like recurrent LRTIs in 2 splenectomised thalassemics. Otherwise, the majority of these patients were asymptomatic of HIV infection. The clinical profile of symptomatic children is enlisted in table4. No child in this group was on antiretroviral therapy.
Six children within the age range of 3 to 16 years in the present study had acquired HIV infection through single blood transfusion. One of them had candida esophagitis, detected endoscopically two years back at the time of diagnosis of HIV infection when ART was started. He was asymptomatic thereafter. Two others in this group had variable combination of recurrent LRTI, hepatosplenomegaly, parotid enlargement, oral candidiasis, ENT infection and tuberculosis. They were also on ART for one year each. The remaining three were asymptomatic at the time of evaluation and were not on ART.
HIV Infection through Presumably Parenteral Route
In 4 children with HIV seronegative parents and no history of previous blood transfusion but with a history of hospitalization and injectable medications presumably parenteral transmission was considered. One child of 8 months had presented with persistent LRTI since birth, chronic diarrhea, oral candidiasis, hepatosplenomegaly and failure to thrive with past history of admission in NICu 0 for neonatal sepsis. The remaining three were between 18 months to 5 years of age and their signs and symptoms are also mentioned in table4.
HIV Infection through Heterosexual Promiscuity
Two adolescents, a 15-year-old male and 17-year-old female gave a history of high-risk unprotected sexual behavior proceeding HIV infection. They were asymptomatic at the time of study.
Interestingly, most of the children (thirty-four) were asymptomatic at the time of evaluation. Twenty-two children had not developed any feature of HIV infection so far and the manifestations of HIV infection had subsided in the remaining twelve table3.
The most common clinical features table4 were failure to thrive, tuberculosis, oral manifestations, lymphadenopathy and recurrent or persistent lower respiratory tract infection (LRTI). Oral manifestations were in the form of oral candidiasis, tooth abscess, oral ecchymoses in a child with pancytopenia, parotid enlargement and recurrent aphthous ulcers. Dermatologic conditions included anogenital warts, chickenpox, seborrhoeic dermatitis, papular urticaria, maculopapular skin rash, molluscum contagiosum and disseminated scabies. ENT infections were in the form of mastoid abscess, CSOM and otomycosis. CNS manifestations included delayed milestones and distal paraesthesia .
Fourteen children were taking anti-tubercular treatment based on clinical criteria, radiological findings and response to treatment. Clubbing was seen in six children. Two of them had taken irregular antitubercular therapy. Although four had history of recurrent episodes of dyspnoea on exertion, but at the time of evaluation their chest was clinically clear except for mild tachypnoea and normal cardiovascular examination. Also, there was no radiological evidence of interstitial pneumonia or bronchiectasis.
Older Children and Adolescents with HIV Infection
Out of 15 children above 10 years of age with HIV infection, majority[10] had transfusion-acquired infection. Of these children, 8 were multi-transfused thalassemics, while two had past history of having received single blood transfusion. Five of the thalassemics were asymptomatic of HIV infection. Amongst the remaining three, all were in CDC category A (dermatitis), B (chronic diarrhoea), and C (disseminated tuberculosis) respectively. They were mostly in immune category 1[3] or 2.[4] None of them was on antiretroviral therapy (ART). In the remaining two transfusions-mediated HIV infected children, one child had past history of candida esophagitis, the second one had history of recurrent pyomeningitis and had growth retardation, lymphadenopathy, pancytopenia and sensorineural deafness. He did not receive ART because of financial constraints.
All the three survivors of perinatal infection were on ART. One of these three was asymptomatic (CDC category N), while two were mildly symptomatic (Category A) at presentation. Two of these had past history of severe category C symptoms (disseminated tuberculosis and delayed milestones respectively) and one had past history of category B symptoms (chronic diarrhoea). Each child was in immune category 1, 2 and 3 respectively. They were on ART for 1, 2 and 5 years respectively,
Both adolescents with sexual promiscuity were asymptomatic, immune category 1 and not on treatment. No child with possibly parenteral transmission was in this group.
Out of the sixty-four children, only fourteen were on antiretroviral therapy. All children received nutritional rehabilitation and anti-infection prophylaxis to prevent occurrence of opportunistic infections.[11]
Discussion
The present study highlights the increasing prevalence of children with HIV infection in and around Delhi. Sixty-four children were evaluated in one-year period, whereas a similar earlier study from a national referral center has documented 27 HIV positive children over a period of 4 years in Northern India.[12]
22 children (34.3%) did not have any symptoms of HIV infection till the time of evaluation and were diagnosed either during routine screening of multi-transfused children or of children born to HIV positive mothers. Overall, forty-five (70.3%) children were either asymptomatic or had mild symptoms like lymphadenopathy at presentation. European collaborative study has also documented similar trends.[13] Moreover, there were 15 children above 10 years of age, with five children on antiretroviral therapy and the remaining only on supportive therapy. Hence, with the growing number of older children surviving with HIV with only intermittent symptoms, it can now be considered a chronic illness akin to asthma and diabetes.
In this age group of more than ten years, all three survivors of perinatally acquired HIV infection were on antiretroviral therapy. In a prospective European collaborative study which also describes characteristics of thirty-four children infected with HIV surviving 10 years or more, three quarters of patients were on combination therapy with three or more drugs. Thus, with the advent of Highly active antiretroviral therapy (HAART) and increased survival, there is a need to address issues such as disclosure of HIV status, institution, adherence and monitoring of HAART. In the same European collaborative study, three children had never received ART. In the present study too, the average age at institution of ART in these three children was 7 years. The prevalence of such long-term slow progressors needs to be seen in a larger study in India.
Two cases of HIV infection due to heterosexual promiscuity highlight changing values and lifestyle in Indian adolescents. The need for health education for HIV infected adolescents regarding pregnancy, contraception, safe sex, and mother to child transmission of HIV has been emphasized by reports of even vertically infected girls becoming pregnant and continuing their pregnancies.[14]
The presumed modes of transmission also raise a cause for concern. In the present study, only 33 children (51.5%) were infected through mother to child transmission (MTCT). However, in Africa and Western countries, more than 90% of HIV infection in children is acquired perinatally.[9] Also, in this study, twenty-five (39%) children acquired HIV consequent to transfusion of contaminated blood. This is despite the fact that mandatory screening of donated blood for HIV antibodies has been in force since 1993.[1]
Presuming adequate screening for anti-HIV I and anti-HIV II antibodies, transmission of HIV may still be possible during window period. This calls for more prudent usage of blood or blood products. Feasibility of antigen assays or PCR assays to screen blood products for checking acquisition of transfusion mediated HIV also needs to be studied. Stringent quality control practices need to be instituted in HIV testing laboratories.
The possible parenteral transmission in four (3.1%) children also draws attention towards defective infection- control practices of health care professionals. A prevalence study for HIV seropositivity studied the risk factors for HIV infection among children of one to 24 months old in Kinshasa, Zaire.[15] Among HIV seropositive children who had previously not been transfused and had seronegative mothers, the seropositives had received more medical injections than seronegatives (median 34.5 vs 14.5; p=0.006). The authors concluded that one of the risk factors for HIV acquisition was increased lifetime number of medical injections. Conventionally, transmission efficiency of HIV through percutaneous exposure was assumed to be 0.3-0.5%.[16] But recent case-control studies by CDC suggest transmission efficiency through unsafe injections that resemble deep injuries without post exposure prophylaxis (PEP) may well be over 2%.[17] Probability to acquire HIV from an infected injectee increases with unsafe medical practices e.g., through multidose vials, rinsing pans, syringe use without sterilization, introduction and maintenance of intravenous catheters. In countries with generalized epidemics, unsafe medical injection may contribute to 10-20% or more of HIV infection in children and adults not explained by vertical or sexual transmission.[18] This is compounded by the fact that HIV-1 can remain viable in a syringe for four weeks.[19] With growing prevalence of HIV in India, it is imperative that significant cuts in iatrogenic transmission may be achieved by ensuring safe work practices, both by private and public health care providers.
The clinical features are similar to those reported earlier from developed and developing countries, including India.[9],[12],[20] However, clubbing, in relation to HIV infection not described well in Indian studies, was noticed in 6 patients with underlying tuberculosis and recurrent LRTI. Pulmonary tuberculosis has been described as a cause of clubbing in adults.[21] Dhurat et al have also noticed clubbing in 25% children with HIV infection, with tuberculosis in an earlier study.[22] Clubbing has also been described in association with lymphoid interstitial pneumonitis (LIP) in HIV infected children. As the typical radiological findings of reticulonodular infiltration and adenopathy might not be present,[23] it is possible that LIP was under-diagnosed in our study. In an earlier case report from India too, a case of LIP in a multitransfused thalassemic child was diagnosed late due to inexperience with this entity.[24] Bronchiectasis, occurring as sequelae of LIP, recurrent pneumonia or unresolved pneumonia in HIV-infected children can also produce clubbing.[25] Owing to resource constraints, we could not perform CT scans or lung biopsies in our patients to confirm the diagnosis. The association of clubbing with HIV infection needs to be explored in further studies to find out whether, in areas of high HIV seroprevalence, a child with history of progressive or recurrent dyspnoea and clubbing without any obvious cause may be considered for HIV testing.
Conclusion
HIV infection is now a chronic disease with a substantial number of surviving adolescents. Safe blood and safe work practices can reduce the burden of HIV infection in India. In areas of high HIV seroprevalence, a child with progressive or recurrent dyspnoea and clubbing may be considered for HIV testing.
References
1. The Gazette of India: Extra ordinary. Part-II, Sec 3(i) Drugs and Cosmetics Act, 22nd January, 1993; 13.
2. CDC. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994; 43: 1-10.
3. Kiwanuka J, Graham SM, Coulter JBS, Gondwe JS, Chilewani N, Carty H, Hart CA. Diagnosis of pulmonary tuberculosis in children in an HIV-endemic area, Malawi. Ann Trop Pediatr 2001; 21: 5-14.
4. Wald ER. Recurrent and nonresolving pneumonia in children. Semin Respir Infect 1993 Mar; 8: 46-58.
5. CDC. Guidelines for the use of antiretroviral agents in Pediatric HIV infection. MMWR 1998; 47(4): 1-38. Update Dec 2001 at http: www.hivatis.org
6. World Health Organisation. Acquired immunodeficiency syndrome (AIDS): WHO/CDC case definition for AIDS. Wkly Epidemiol Rec 1986; 61:69-73.
7. World Health Organisation. Report on the meeting of the technical working group on HIV/AIDS in childhood. WHO/GPA/SFI/892. World Health Organisation, Geneva; 1989.
8. Lepage P, van de Perre P, Dabis F, Commenges D, Orbinski J, Hitimana DG, Bazubagira A, nvan Goethem C, Allen S, Butzler JP et al. Evaluation and simplification of the World Health Organization clinical case definition for paediatric AIDS. AIDS 1989; 3: 221-225.
9. Bakaki P, Kayita J, Moura Machedo JE, Coulter JB, Tindyeba D, Ndugwa CM, Hart CA. Epidemiologic and clinical features of HIV-infected and HIV-uninfected Ugandan children younger than18 months. J Acquir Defic Syndr 2001; 28: 35-42.
10. Laboratory diagnosis of HIV/AIDS and national HIV testing strategies. In Baveja UK, Sokhey J, eds. Manual on laboratory diagnosis of common opportunistic infections associated with HIV/AIDS. 1st edn. Delhi; NICD, 2000: 8-15.
11. CDC. Guidelines for preventing opportunistic infection among HIV-infected persons. MMWR 2002; 51:1-52.
12. Lodha R, Singhal T, Jain Y, Kabra SK, Seth P, Seth V. Pediatric HIV infection in a tertiary care center in North India: Early impressions. Indian Pediatr 2000; 37: 982-986.
13. European Collaborative study group. Fluctuations in symptoms in human immunodeficiency virus infected children: The first 10 year of life. Pediatrics 2001; 108: 116-122.
14. Crane S, Sullivan M, Feingold M, Kaufman GE. Successful pregnancy in an adolescent with perinatally acquired human immunodeficiency virus. Obstet Gynecol 1998; 92(4 Pt 2):711.
15. Mann JM, Francis H, Davachi F, Baudoux P, Quinn TC, Nzilmabi N, Bosenge N, Colebunders RC, Piot P, Kabote N, Asila PK, Malonga M, Curran JW. Risk factors for Human Immunodeficiency Virus seropositivity among children 1-24 months old in Kinshasa, Zaire. Lancet 1986; 654-6.
16. Prevention of HIV transmission in health care settings. In Training module on HIV infection & AIDS for medical officers . National AIDS control organization, Ministry of Health and Family Welfare, 2000; 59-66.
17. CDC. A case control study of HIV seroconversion in health care workers after percutaneous exposure to HIV-infected blood.France, United Kingdom and United States, January 1988-August 1994; MMWR 1995; 44: 929-933.
18. Gisselquist DP. Estimating HIV-1 transmission efficiency through unsafe medical injection. Int J STD & AIDS 2002; 13: 152-159.
19. Bowden S, Druce J, Kelly H. Stability of blood-borne viruses in the environment and risk of infection. Victorian Inf Dis Bult 1999; 2: 71-72.
20. Lambert HJ, Friesen H. Clinical features of paediatric AIDS in Uganda. Ann Trop Paediatr 1989; 9: 1-5.
21. Reeve PA, Harries AD, Nkhoma WA, Nyangulu DS, Wirima JJ. Clubbing in African patients with pulmonary tuberculosis. Thorax 1987; 42: 986-987.
22. 0 Dhurat R, Manglani M, Sharma R, Shah NK. Clinical Spectrum of HIV infection. Indian Pediatr 2000; 37: 831-836.
23. 0 Marquis JR, Berman CZ, Dicarlo F, Oleske JM. Radiographic patterns of PLH/LIP in HIV positive children. Pediatr Radiol 1993; 23: 328-330.
24. 0 Sen S, Goyal RS, Kumar A, Pande I, Khare SD, Chattopadhya D, Malviya AN. Acquired immunodeficiency syndrome (AIDS) with Lymphocytic Interstitial Pneumonitis (LIP) in a multitransfused child with thalassemia major. Indian Pediatr 1992; 29: 1413-1417.
25. Sheikh S, Madiraju SK, Steiner P, Rao M. Bronchiectasis in pediatric AIDS. Chest 1997; 112: 1202-1207.(Sehgal R, Baveja UK, Chat)
2 National Institute of Communicable Diseases, Delhi, India
3 Department of Pediatrics, Kalawati Saran Children Hospital,Delhi, India
Abstract
Objective: The present cross sectional study was undertaken to study clinical profile of HIV infection in children in Northern India. Methods: 64 children from newborn to eighteen years, presenting for confirmation of diagnosis of HIV infection or monitoring of CD4-CD8 counts in confirmed cases, were evaluated. Children were categorized as per CDC classification of Pediatric HIV. The diagnosis was confirmed by serological tests or PCR assay. CD4-CD8 counts were done by FACS Count. Results: Majority of the children were between 18 months to 5 years. Adolescents comprised 24% of the case. 51.5% children were infected through the mode of mother to child transmission. 39% of the case was transfusion-mediated. Unsafe medical injections probably contributed to 6.2% and heterosexual promiscuity led to 3.1% cases. Clubbing, not described in Indian studies so far, was seen in 9.3% cases. Conclusions: HIV infection is a chronic childhood disease extending into adolescence, and contaminated blood and unsafe medical injections are still important routes of HIV transmission in India.
Keywords: Pediatric HIV; Contaminated blood; Unsafe medical injections; Clubbing
HIV and AIDS have made a huge global impact permeating the social, cultural and economic fabric of almost all nations. In India too, ever since the diagnosis of the first case of the HIV infection in 1986, this problem has been growing at an exponential rate. As per the data collected during the annual round of HIV sentinel surveillance 2003 by NACO, the estimated number of HIV infected individuals in India is 5.1 million. This includes 55,145 children. Despite the magnitude of the problem, there is paucity of data on clinical profile of HIV infected children in India. The differences in presentation of infection in perinatally infected, transfusion acquired and parenterally infected children have not been studied properly. Also, there are no Indian studies addressing the clinical spectrum of HIV infection in an adolescent. The older children and their families have needs for specific services and support different from those required by younger children. Moreover, this article also attempts to draw attention to the presumed modes of transmission that are at variance with the published information.
In fact, despite the introduction of mandatory screening of blood products for more than 10 years, transfusion acquired HIV remains a significant problem.[1] The detection of HIV in children with a possible parenteral route of transmission due to unsafe medical injections also raises a serious concern about the standard of work precautions followed by health care workers. Changing lifestyles and risk taking behavior also expose the adolescents to HIV infection. Hence, the present project was undertaken with the objectives to study: (1) the clinical manifestation of HIV-1 infected children in relation to routes of transmission and (2) the clinical profile of HIV-1 infected adolescents.
Materials and Methods
An observational cross-sectional study of all HIV seropositive children, presenting to the AIDS division of the National Institute of Communicable Diseases (NICD), New Delhi, for confirmation of diagnosis or monitoring of CD4-CD8 counts was performed. An informed consent was taken from parents/patients. A total of sixty-four such children, newborn to eighteen years, who presented during January 2002 to December 2002, were enrolled. All patients were analyzed with special emphasis on demographic details, nutritional status, presenting symptoms, past history of illnesses, categorization of disease at presentation and at the time of gravest illness as per 1994 CDC classification for Pediatric HIV infection,[2] possible routes of transmission, type of therapy being instituted and spectrum of opportunistic infections. Probable tuberculosis was considered with symptoms of persistent cough/fever and/or weight loss and no response to routine antibiotics along with supportive radiological findings, positive Mantoux (induration over 5mm) and/or history of contact with tuberculosis. Confirmed pulmonary tuberculosis was considered if smear or culture of M. tuberculosis was positive from sputum or gastric aspirate.
The following criteria were considered for diagnosis of lymphoid interstitial pneumonitis (LIP)[3]; chest X-ray with diffuse reticulonodular infiltration with at least two of the following:
(i) Bilateral parotid swelling
(ii) Generalised lymphadenopathy
(iii) Digital clubbing
(iv) Treatment response to corticosteroids
Recurrent lower respiratory tract infection (LRTI) was defined as 2 episodes of infection in one year or three episodes over any period of time, while persistent LRTI was defined as persistence of radiographic abnormality for more than 3 months.[4]
The presumed mode of transmission was deduced after a confidential interview with the parents regarding sexual behavior, history of blood transfusion in parents, in child and HIV serology status of parents was taken. The transmission was attributed to blood transfusion in those children who had history of transfusion more than 3 months ago and whose parents were seronegative. In other children with seronegative parents and no history of blood transfusion but prior history of hospitalization and medical injections, the mode of transmission was deduced to be parenteral. History of tattooing, ear piercing and prior surgery was also taken. Since the NICD is a diagnostic referral center, the line of treatment being received by children at different centers was not interfered with. Supportive and/or antiretroviral therapies (ART) were, however, instituted in the newly diagnosed children with clinical symptoms of HIV or evidence of immune suppression as per the guidelines.[5]
The diagnosis was confirmed by positive serology in children over 18 months of age (58 children), a positive polymerase chain reaction (PCR) for HIV RNA repeated twice (2 patients) and/or positive serology in children below 18 months of age, but with clinical features strongly suggestive of pediatric AIDS (4 infants) as per revised World Health Organisation (WHO) clinical case definition for Pediatric AIDS.[6],[7] Because of high prevalence of infection and malnutrition in developing countries, this definition has been evaluated to have moderate sensitivity (35-68%) but good specificity (86-93%).[8] Recently, the same definition was used in Ugandan children less than 18 months with high specificity of 98% and a positive predictive value of 93%.[9]
Serology was performed by three positive ELISA (Enzyme Linked Immunosorbent Assay) or rapid tests using different antigens or different principles according to WHO strategy III.[10] The different ELISA/Rapid kits used were DETECT-HIV (Biochem Immunosystems, Montreal), HIV-SPOT (Genelabs Diagnostics, Singapore) and HIV-EIA (labsystems, Hel Sinki). PCR to detect HIV infection was done on peripheral blood mononuclear cells and was based on amplification of gag gene. CD4-CD8 counts were done by Flow cytometry using FACS Count machine (Beckton and Dickinson, San Jose, USA) in thirty-six patients.
Results
A total of 64 children in the age group of 20 days to 17 years were evaluated. table1 summarizes the age and sex distribution of children. Six children were below 18 months of age while fifteen were aged 10 years or more at the time of evaluation. Fifty-one children were residents of Delhi while the rest thirteen were from the states of Uttar Pradesh, Rajasthan, Punjab and Haryana.
Perinatal HIV Infection
The age of 33 children who acquired HIV infection through their mothers ranged from 20 days to 13 years table2. Majority of these children were in the age group of 18 months to 5 years. Twenty-eight out of these thirty- three children were symptomatic. Fourteen children had only category A symptoms as per 1994 CDC classification and five were asymptomatic. Overall nineteen children (57.5%) were asymptomatic to mildly symptomatic.
The clinical spectrum in these symptomatic children is shown in table4. The commonest presentations were failure to thrive, lymphadenopathy, tuberculosis and recurrent LRTI.
Nine children (27.2%) were on antiretroviral therapy with the age range of 3 to 12 years. Mean age at the onset of ART was 6.6 years and average duration of ART was 1.07 years (range 1 month to 4 years).
Transfusion Acquired HIV Infection
In the present study, 25 (39.1%) of 64 children had HIV acquisition through contaminated blood transfusions. Amongst these, 19 were thalassemics. In the remaining six, two had received blood transfusion preoperatively and four were transfused blood for anemia or weakness as per the medical records. The median age of thalassemic children at presentation was 8 years (range 3 to 17 years). Also, the median duration of known HIV infection in these children was of 2 years (range 1-4 years). Most thalassemics had manifestations like hepatosplenomegaly arising out of their disease or its complications like recurrent LRTIs in 2 splenectomised thalassemics. Otherwise, the majority of these patients were asymptomatic of HIV infection. The clinical profile of symptomatic children is enlisted in table4. No child in this group was on antiretroviral therapy.
Six children within the age range of 3 to 16 years in the present study had acquired HIV infection through single blood transfusion. One of them had candida esophagitis, detected endoscopically two years back at the time of diagnosis of HIV infection when ART was started. He was asymptomatic thereafter. Two others in this group had variable combination of recurrent LRTI, hepatosplenomegaly, parotid enlargement, oral candidiasis, ENT infection and tuberculosis. They were also on ART for one year each. The remaining three were asymptomatic at the time of evaluation and were not on ART.
HIV Infection through Presumably Parenteral Route
In 4 children with HIV seronegative parents and no history of previous blood transfusion but with a history of hospitalization and injectable medications presumably parenteral transmission was considered. One child of 8 months had presented with persistent LRTI since birth, chronic diarrhea, oral candidiasis, hepatosplenomegaly and failure to thrive with past history of admission in NICu 0 for neonatal sepsis. The remaining three were between 18 months to 5 years of age and their signs and symptoms are also mentioned in table4.
HIV Infection through Heterosexual Promiscuity
Two adolescents, a 15-year-old male and 17-year-old female gave a history of high-risk unprotected sexual behavior proceeding HIV infection. They were asymptomatic at the time of study.
Interestingly, most of the children (thirty-four) were asymptomatic at the time of evaluation. Twenty-two children had not developed any feature of HIV infection so far and the manifestations of HIV infection had subsided in the remaining twelve table3.
The most common clinical features table4 were failure to thrive, tuberculosis, oral manifestations, lymphadenopathy and recurrent or persistent lower respiratory tract infection (LRTI). Oral manifestations were in the form of oral candidiasis, tooth abscess, oral ecchymoses in a child with pancytopenia, parotid enlargement and recurrent aphthous ulcers. Dermatologic conditions included anogenital warts, chickenpox, seborrhoeic dermatitis, papular urticaria, maculopapular skin rash, molluscum contagiosum and disseminated scabies. ENT infections were in the form of mastoid abscess, CSOM and otomycosis. CNS manifestations included delayed milestones and distal paraesthesia .
Fourteen children were taking anti-tubercular treatment based on clinical criteria, radiological findings and response to treatment. Clubbing was seen in six children. Two of them had taken irregular antitubercular therapy. Although four had history of recurrent episodes of dyspnoea on exertion, but at the time of evaluation their chest was clinically clear except for mild tachypnoea and normal cardiovascular examination. Also, there was no radiological evidence of interstitial pneumonia or bronchiectasis.
Older Children and Adolescents with HIV Infection
Out of 15 children above 10 years of age with HIV infection, majority[10] had transfusion-acquired infection. Of these children, 8 were multi-transfused thalassemics, while two had past history of having received single blood transfusion. Five of the thalassemics were asymptomatic of HIV infection. Amongst the remaining three, all were in CDC category A (dermatitis), B (chronic diarrhoea), and C (disseminated tuberculosis) respectively. They were mostly in immune category 1[3] or 2.[4] None of them was on antiretroviral therapy (ART). In the remaining two transfusions-mediated HIV infected children, one child had past history of candida esophagitis, the second one had history of recurrent pyomeningitis and had growth retardation, lymphadenopathy, pancytopenia and sensorineural deafness. He did not receive ART because of financial constraints.
All the three survivors of perinatal infection were on ART. One of these three was asymptomatic (CDC category N), while two were mildly symptomatic (Category A) at presentation. Two of these had past history of severe category C symptoms (disseminated tuberculosis and delayed milestones respectively) and one had past history of category B symptoms (chronic diarrhoea). Each child was in immune category 1, 2 and 3 respectively. They were on ART for 1, 2 and 5 years respectively,
Both adolescents with sexual promiscuity were asymptomatic, immune category 1 and not on treatment. No child with possibly parenteral transmission was in this group.
Out of the sixty-four children, only fourteen were on antiretroviral therapy. All children received nutritional rehabilitation and anti-infection prophylaxis to prevent occurrence of opportunistic infections.[11]
Discussion
The present study highlights the increasing prevalence of children with HIV infection in and around Delhi. Sixty-four children were evaluated in one-year period, whereas a similar earlier study from a national referral center has documented 27 HIV positive children over a period of 4 years in Northern India.[12]
22 children (34.3%) did not have any symptoms of HIV infection till the time of evaluation and were diagnosed either during routine screening of multi-transfused children or of children born to HIV positive mothers. Overall, forty-five (70.3%) children were either asymptomatic or had mild symptoms like lymphadenopathy at presentation. European collaborative study has also documented similar trends.[13] Moreover, there were 15 children above 10 years of age, with five children on antiretroviral therapy and the remaining only on supportive therapy. Hence, with the growing number of older children surviving with HIV with only intermittent symptoms, it can now be considered a chronic illness akin to asthma and diabetes.
In this age group of more than ten years, all three survivors of perinatally acquired HIV infection were on antiretroviral therapy. In a prospective European collaborative study which also describes characteristics of thirty-four children infected with HIV surviving 10 years or more, three quarters of patients were on combination therapy with three or more drugs. Thus, with the advent of Highly active antiretroviral therapy (HAART) and increased survival, there is a need to address issues such as disclosure of HIV status, institution, adherence and monitoring of HAART. In the same European collaborative study, three children had never received ART. In the present study too, the average age at institution of ART in these three children was 7 years. The prevalence of such long-term slow progressors needs to be seen in a larger study in India.
Two cases of HIV infection due to heterosexual promiscuity highlight changing values and lifestyle in Indian adolescents. The need for health education for HIV infected adolescents regarding pregnancy, contraception, safe sex, and mother to child transmission of HIV has been emphasized by reports of even vertically infected girls becoming pregnant and continuing their pregnancies.[14]
The presumed modes of transmission also raise a cause for concern. In the present study, only 33 children (51.5%) were infected through mother to child transmission (MTCT). However, in Africa and Western countries, more than 90% of HIV infection in children is acquired perinatally.[9] Also, in this study, twenty-five (39%) children acquired HIV consequent to transfusion of contaminated blood. This is despite the fact that mandatory screening of donated blood for HIV antibodies has been in force since 1993.[1]
Presuming adequate screening for anti-HIV I and anti-HIV II antibodies, transmission of HIV may still be possible during window period. This calls for more prudent usage of blood or blood products. Feasibility of antigen assays or PCR assays to screen blood products for checking acquisition of transfusion mediated HIV also needs to be studied. Stringent quality control practices need to be instituted in HIV testing laboratories.
The possible parenteral transmission in four (3.1%) children also draws attention towards defective infection- control practices of health care professionals. A prevalence study for HIV seropositivity studied the risk factors for HIV infection among children of one to 24 months old in Kinshasa, Zaire.[15] Among HIV seropositive children who had previously not been transfused and had seronegative mothers, the seropositives had received more medical injections than seronegatives (median 34.5 vs 14.5; p=0.006). The authors concluded that one of the risk factors for HIV acquisition was increased lifetime number of medical injections. Conventionally, transmission efficiency of HIV through percutaneous exposure was assumed to be 0.3-0.5%.[16] But recent case-control studies by CDC suggest transmission efficiency through unsafe injections that resemble deep injuries without post exposure prophylaxis (PEP) may well be over 2%.[17] Probability to acquire HIV from an infected injectee increases with unsafe medical practices e.g., through multidose vials, rinsing pans, syringe use without sterilization, introduction and maintenance of intravenous catheters. In countries with generalized epidemics, unsafe medical injection may contribute to 10-20% or more of HIV infection in children and adults not explained by vertical or sexual transmission.[18] This is compounded by the fact that HIV-1 can remain viable in a syringe for four weeks.[19] With growing prevalence of HIV in India, it is imperative that significant cuts in iatrogenic transmission may be achieved by ensuring safe work practices, both by private and public health care providers.
The clinical features are similar to those reported earlier from developed and developing countries, including India.[9],[12],[20] However, clubbing, in relation to HIV infection not described well in Indian studies, was noticed in 6 patients with underlying tuberculosis and recurrent LRTI. Pulmonary tuberculosis has been described as a cause of clubbing in adults.[21] Dhurat et al have also noticed clubbing in 25% children with HIV infection, with tuberculosis in an earlier study.[22] Clubbing has also been described in association with lymphoid interstitial pneumonitis (LIP) in HIV infected children. As the typical radiological findings of reticulonodular infiltration and adenopathy might not be present,[23] it is possible that LIP was under-diagnosed in our study. In an earlier case report from India too, a case of LIP in a multitransfused thalassemic child was diagnosed late due to inexperience with this entity.[24] Bronchiectasis, occurring as sequelae of LIP, recurrent pneumonia or unresolved pneumonia in HIV-infected children can also produce clubbing.[25] Owing to resource constraints, we could not perform CT scans or lung biopsies in our patients to confirm the diagnosis. The association of clubbing with HIV infection needs to be explored in further studies to find out whether, in areas of high HIV seroprevalence, a child with history of progressive or recurrent dyspnoea and clubbing without any obvious cause may be considered for HIV testing.
Conclusion
HIV infection is now a chronic disease with a substantial number of surviving adolescents. Safe blood and safe work practices can reduce the burden of HIV infection in India. In areas of high HIV seroprevalence, a child with progressive or recurrent dyspnoea and clubbing may be considered for HIV testing.
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