Age Related Clinical Manifestations of HIV Infection in Indian Children by Ira Shah Department of Pediatric HIV Clinic, B. J. Wadia Hospital for Children, Mumbai, India
Summary Aim: To determine the various clinical manifestations of HIV infection in children as per the age. Setting: Pediatric and Perinatal HIV clinic in a tertiary pediatric hospital over a period of 7 years. Study design: Retrospective and prospective analysis. Methods and Materials: Clinical manifestations of 317 HIV infected children were noted and commonest clinical symptoms were determined. The various clinical manifestations as per age were analysed. Results: The mean age of presentation of HIV infection was 4.5 2.9 years. Predominant mode of transmission was vertical (83 per cent). Most of the children (75 per cent) were in Class B or C on presentation. There was no significant difference in the clinical symptoms and mode of transmission of HIV. The predominant clinical features seen were hepato-splenomegaly (51.1 per cent), lymphadenopathy (48.6 per cent) and tuberculosis (43.4 per cent). Patients with vertical transmission presented at an early mean age of 4.1 2.7 years as compared to those who acquired it by other means, which was statistically significant. PCP pneumonia was the earliest manifestation in toddlers and hepatosplenomegaly, lymphadenopathy, chronic diarrhea was seen in pre-schoolers. Systemic organ dysfunction due to HIV was seen in older children. Conclusions: Hepatosplenomegaly, lymphadenopathy and opportunistic infections together in a child may be suggestive of HIV infection. High suspicion and early diagnosis will lead to early management and decrease in the incidence of HIV related morbidity.
Introduction HIV is an epidemic of global proportions. With the reporting of first cases in the early eighties, the scenario is of a world-wide menace in a span of 20 years. As per UNAIDS 2003, 40 million individuals around the globe are HIV infected of which 2.5 million (6.3 per cent) are children.1 Maximum cases of newly diagnosed HIV infection in children is reported from South East Asia and Africa while countries like USA and western European countries report less than 1 per cent of newly infected HIV positive children.1 In developing countries, pediatric AIDS comprises as much as 15–20 per cent of all AIDS cases.1 5 000 000 children are already estimated to have died due to HIV and AIDS in 2003. With advent of antiretroviral therapy, the natural course Acknowledgement The authors thank Dr Dod, CSE of B. J. Wadia Hospital for Children for giving permission to publish this article. Correspondence: Dr Ira Shah, 240 D. Walkeshwar Road, Malabar Hill, Mumbai 400 006, India. E-mail
[email protected].
of the HIV epidemic is altered with HIV becoming a more chronic disease. To determine the natural history of the HIV epidemic is then going to be difficult to predict. This study follows the clinical manifestations of HIV infection in children and its correlation with age to aid in early diagnosis of the disease so that adequate management can be initiated as soon as possible. Methods and Materials This retrospective and prospective analysis was conducted in Pediatric & Perinatal HIV clinic at B.J. Wadia Hospital for children, Mumbai, India. 317 HIV positive children who presented to the HIV clinic from December 1996 to December 2003 were included in the study. After verbal informed consent from the parents/guardians all the referred patients above 15 months of age were retested for their HIV test by two different ELISA tests on at least two subsequent visits – DETECT – HIVMC (v.2.) and HIV-CheX and were considered HIV infected if positive by both the kits. Western blot was used for confirmation of HIV status in those who could afford the test and was considered positive
ß The Author [2005]. Published by Oxford University Press. All rights reserved. For Permissions, please email:
[email protected] doi: 10.1093/tropej/fmi018 Advance Access Published on 24 June 2005
Downloaded from https://academic.oup.com/tropej/article-abstract/51/5/300/1690177 by guest on 11 August 2018
300
IRA SHAH
if it showed the presence of at least two of the envelope (gp 120 and gp 160/gp 41) and any of the gag (p24, p27, p55) or pol (p31, p51, p66) bands. In patients below 15 months of age, DNA PCR test using the Roche Amplicor technique was done to confirm infectivity. All children with positive HIV DNA PCR tests were retested at 18 months with ELISA tests to reconfirm their HIV status. All the children were monitored periodically for clinical evaluation and management. Each child had a through history and physical examination. All patients were subjected to a complete hemogram, Mantoux test, X-Ray chest and urine and stool examination. Other relevant investigations were done as when required. All the clinical data was recorded in a preset Performa. Tuberculosis was presumptively diagnosed on the basis of symptomatology, history of adult contact with open kochs, radiological deterioration, Mantoux test, sputum or gastric lavage for acid fast bacilli, lymph node biopsy and response to antituberculous treatment. Failure to thrive was determined when weight was less than 80 per cent of expected for age and weight for height was less than 90 per cent of the expected. Chronic diarrhea was diagnosed if the child had diarrhea lasting for more than 14 days. Persistent generalized lymphadenopathy (PGL) was diagnosed as presence of enlarged lymphnodes (41 cm) in 2 or more sites for more than 3 months after excluding other causes.2 Pneumocystis carinii pneumonia (PCP) was diagnosed on the basis of clinical findings of dysnea, fever, X-Ray evidence of bilateral diffuse alveolar infiltrates and confirmed by bronchoalveolar lavage or gastric lavage. Lymphoid interstitial pneumonia (LIP) was diagnosed on basis of respiratory symptoms, hypoxia, X-Ray chest showing interstitial pulmonary infiltration which responded poorly to antibiotic therapy. HIV encephalopathy was confirmed by neuroimaging. HIV nephropathy was determined by presence of hematuria and/or proteinuria with other deranged renal function tests. HIV cardiomyopathy was diagnosed by presence of echocardiographic abnormalities. ITP was diagnosed on the basis of thrombocytopenia with presence of giant megakaryocytes on bone marrow examination excluding other causes of thrombocytopenia. Chronic hypertrophic parotitis was diagnosed by clinical examination. Chronic fever was diagnosed as fever lasting more than 14 days excluding other causes of fever. Candida albicans was diagnosed by clinical, microscopic and culture study. All patients were classified into CDC Class N, A, B, C as per revised CDC classification of HIV in children.3 The mode of transmission of HIV was determined by establishing maternal HIV status (vertical), evaluating history of blood/blood product transfusion (transfusion related) and sexual abuse in children. Journal of Tropical Pediatrics
The various clinical manifestations were correlated with age. The data was analyzed by -square test and ANOVA-1 test using the Analyse–It software (v. 1.7). Results A total 317 patients tested positive for HIV infection of which 182 were boys and 135 were girls with male to female ratio being 1.35:1. The age group of these patients ranged from 4 months to 12 years with mean age of presentation being 4.5 years 2.9 years (median age ¼ 4 years). The predominant mode of transmission was vertical as depicted in Table 1. Unknown transmission was when the route of infection could not be ascertained. The patients who had acquired HIV through blood/blood component transfusion were patients with thalassemia (95 per cent) and leukemia (5 per cent). As per revised CDC classification, 24 patients (7.6 per cent) were in Class N, 55 patients (17.4 per cent) were in Class A, 167 patients (52.7 per cent) were in Class B, and 71 patients (22.3 per cent) were in Class C at the time of presentation. There was no significant difference in the clinical class depending on the mode of transmission ( p ¼ 0.1153) with patients with vertical transmission or blood transfusion acquired HIV being distributed fairly equally in all classes. The predominant clinical features seen were hepatosplenomegaly, lymphadenopathy and tuberculosis. The clinical features are listed in Table 2. Of the patients with tuberculosis, the commonest presentation was pulmonary kochs in 109 (75.7 per cent) patients followed by Miliary TB in 11 (7.6 per cent) patients, tuberculous meningitis (diagnosed by CSF examination and CT brain) in 8 (5.5 per cent) patients and tuberculous lymphadenopathy (proven by biopsy) in 8 (5.5 per cent) patients. 6 patients (4.3) had disseminated TB and 2 patients (1.4 per cent) had only a positive Mantoux test (45 mm was considered positive) without other clinical symptoms. Of the skin lesions noted, the commonest was chronic non-specific dermatitis in 55 (59.1 per cent) patients, herpes zoster in 21 (22.6 per cent), scabies in 11 (11.8 per cent) patients and molluscum contagiosum in 5 (5.4 per cent) patients. Measles was seen in one (1.1 per cent) patient. two patients (3.3 per cent) with chronic diarrhea had isospora positive and five patients (8.3 per cent) had giardiasis. Table 1 Mode of transmission of HIV infection Mode of transmission Vertical Transfusion Unknown
Vol. 51, No. 5
Downloaded from https://academic.oup.com/tropej/article-abstract/51/5/300/1690177 by guest on 11 August 2018
No. of patients (per cent) 263 (83) 20 (6.3) 34 (10.7)
301
IRA SHAH
Table 2 Clinical manifestations of HIV and correlation with age Clinical manifestations Hepatosplenomegaly Lymphadenopathy Tuberculosis Failure to thrive Skin disorders PUO Chronic diarrhea Recurrent respiratory infection Parotitis Candidial infection Chronic otitis media LIP HIV encephalopathy PCP HIV cardiomyopathy ITP HIV nephropathy Lymphoma
No. of patients (per cent) 162 154 144 113 94 69 60 55 54 48 36 11 11 7 6 4 3 2
(51.1) (48.6) (45.4) (35.6) (29.3) (21.8) (18.9) (17.4) (17) (15.1) (11.3) (3.5) (3.5) (2.2) (1.9) (1.3) (0.9) (0.6)
Candidial infection presented as oral thrush in 45 (93.8 per cent) patients, esophageal candidiasis in 2 (4.2 per cent) patients and systemic candidiasis in 1 (2 per cent) of patients. When the various clinical manifestations were correlated with age it was found that patients who acquired HIV infection vertically would present much earlier (4.10 2.69 years) as compared to patients who acquired HIV infection through unknown mode of transmission (6.71 2.93 years) and through blood or blood component transfusion (7.14 3.83 years) which was statistically significant ( p50.0001). There was no difference in age of presentation between boys and girls (4.61 2.99 years vs. 4.51 2.96 years) ( p ¼ 0.7). Patients with HIV infection would present with hepatosplenomegaly, lymphadenopathy, chronic diarrhea, oral thrush between 3 and 4 years of age whereas PCP pneumonia was seen predominantly up to 2 years of age and HIV cardiomyopathy. HIV encephalopathy and ITP would present beyond 6 years of age which was statistically significant (Table 2). The predominant patients with lymphadenopathy were males (103 patients) as compared to females (51 patients) which was statistically significant ( p ¼ 0.0014). 17 patients (5.4 per cent) died during the study, 28 patients (8.8 per cent) were lost to follow up while remaining 272 patients (85.8) are on regular follow up. Discussion HIV infection in children in India is increasing. As reported in other studies, and also found in our
Mean age of presentation s.d. in years
p value
3.72.4 4.0 2.6 4.4 2.8 4.2 2.9 4.8 2.5 4.6 2.9 3.8 2.8 4.9 2.8 4.4 2.5 3.6 2.9 4.0 2.2 5.0 2.2 6.3 3.8 1.7 0.5 8.0 2.9 8.2 4.4 3.0 3.4 5.2 1.7
50.0001 0.002 0.342 0.10 0.25 0.93 0.04 0.25 0.68 0.009 0.24 0.62 0.05 0.008 0.005 0.01 0.15 0.74
study, pediatric HIV primarily is a vertically transmitted infection4,5 83 per cent of the patients in our study had acquired HIV through this route. Thus prevention of mother to child transmission of HIV programmes would play a major role in decreasing the incidence of HIV infection in children. Even though vertical transmission of HIV was the predominant mode of infection in children, most of the patients presented to the HIV clinic at a mean age of 4.5 years and by that time over 75 per cent of the patients were already in CDC Class B and C signifying that early diagnosis of HIV in children is difficult because the symptoms of bacterial infections, failure to thrive, diarrhea overlap with other common childhood conditions seen in non-HIV infected children. Thus, it is important to determine the most common clinical manifestations of HIV infection in children so that one can test for HIV early in suspected infected children. Systemic and pulmonary findings were common in the first HIV infected children who presented in the USA and in Europe; whereas chronic diarrhea, wasting and severe malnutrition are predominant presentations in Africa.6,7 In our study, the predominant clinical presentations seen were hepatosplenomegaly, lymphadenopathy, tuberculosis, failure to thrive, skin problems, pyrexia of unknown origin, recurrent respiratory tract infections, chronic otitis media and chronic diarrhea thus having a mixed presentation of both European and African studies. Other Indian studies have also reported increased incidence of tuberculosis, generalized lymphadenopathy, hepatosplenomegaly4,5 with HIV infection. In our study incidence of HIV
302
Downloaded from https://academic.oup.com/tropej/article-abstract/51/5/300/1690177 by guest on 11 August 2018
Journal of Tropical Pediatrics
Vol. 51, No. 5
IRA SHAH
encephalopathy, pneumocystis carinii pneumonia and lymphoid interstitial pneumonia was relatively less as against those report in the USA and Europe.8,9 However similar low incidences of PCP and HIV encephalopathy have been reported in Indian children.4,10 Among the early manifestations of HIV in children reported are HIV encephalopathy and opportunistic infections;8,9 lymphadenopathy, splenomegaly and hepatomegaly often are seen in the 1st year of life. Failure to thrive, fever, diarrhea and secondary infections are seen at a later age.11 In our study, we found that Pneumocystis carinii pneumonia would occur much early in life (more in infancy) and hepatosplenomegaly, lymphadenopathy, chronic diarrhea, Candidial infection were seen in older children usually by 4 years of age. However, HIV encephalopathy was seen in the latter half of the 1st decade and systemic manifestations such as HIV cardiomyopathy and Idiopathic thrombocytopenic purpura would be seen much later. Thus it appears that clinical manifestations of HIV in children vary in developed compared to developing countries. Though most of the patients were vertically infected, 5.4 per cent of our patients have died and other 8.8 per cent have been lost to follow up suggesting that survival with vertically acquired HIV may be longer than previously estimated. In fact, it has been reported that mean survival time of vertically infected children ranges from 75 to 90 months and approximately 70 per cent of them reach the age of 6 years.12 Understanding the epidemiology of pediatric HIV infection and progression of the disease may reveal opportunities to identify infected children early so that appropriate treatment can be offered to improve the quality of life. Conclusions The commonest early manifestations of HIV in Indian children are hepatosplenomegaly, lymphadenopathy, opportunistic infections, and chronic diarrhea. PCP occurs most commonly in infancy. However incidence is low in Indian population. HIV encephalopathy and systemic manifestations of the
Journal of Tropical Pediatrics
disease occur in older children who survive for a longer time. Vertical transmission if controlled can drastically decrease the HIV related problems in children.
References 1. AIDS Epidemic Update December 2003 – Global summary of the HIV/AIDS. 2. Fauci AS, Lane HC. Human immunodeficiency virus disease: AIDS and related disorders. In: Harrison’s Principles of Internal Medicine, 14th edn. Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martini JB, Kasper DL, et al. (eds), McGraw-Hill, New York. 1998; p. 1819. 3. 1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of Age. 1994. Morbidity and Mortality Weekly Report (MMWR) 43 (RR-12); 1–10. 4. Madhivanan P, Mothi SN, Kumaraswamy N, Yepthomi T, Venkatesan C, Lambert IS, Solomon S – Clinical manifestations of HIV infected children. Indian J Pediatr 2003; 70: 615–20. 5. Dhurat R, Manglani M, Sharma R, Shah NK. Clinical spectrum of HIV infection. Indian Pediatrics 2000; 37: 831–36. 6. Daga SR, Verma B, Gosavi DV, et al. HIV infection in children: Indian experience. Indian Pediatr 1999; 36: 1250–52. 7. WHO/UNAIDS. HIV in Pregnancy. A Review. 1999 Geneva: Joint United Nations Programme on HIV/ AIDS. 8. Muller BU, Pizzo PA. Pediatric human immunodeficiency virus infection. In: AIDS: Biology, Diagnosis, Treatment and Prevention, 4th edn. Denita VT, Hellman S, Rosenberg SA (eds), Lippincott-Raven, Philadelphia, 1997; 443–46. 9. European Collaborative study. Neurological signs in young children with human immunodeficiency virus infection. Pediatric Infect Dis J 1990; 9: 402–06. 10. Cherian T, Ramakrishna B, Babu PG, John TJ, Raghupathy P. Pneumocystic carinii pneumonia in pediatric acquired immunodeficiency syndrome. Indian Pediatr 1997; 34: 530–54. 11. Scarlatti G, Pediatric HIV infection. Lancet 1996; 348: 863–68. 12. Ruiz Contreras J. National history of HIV infection in the child. Allergologia et Immunopathologia, 1998; 26: 135–39.
Vol. 51, No. 5
Downloaded from https://academic.oup.com/tropej/article-abstract/51/5/300/1690177 by guest on 11 August 2018
303
