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Original Articles Indian Pediatrics 2001; 38: 239-246 |
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Clinical profile of HIV infection |
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From the Bai Jerbai Wadia Hospital for Children, Acharya Dhonde Marg, Parel, Mumbai 400 012, India. Correspondence to: Dr.
Rashid H. Merchant, Dean & Professor of Pediatrics, Director,
THE global impact of the Human Immunodeficiency Virus (HIV) epidemic has been so dramatic and devastating that it has been described as the "epidemic of our century". In developed countries, acquired immunodeficiency syndrome (AIDS) in children constitutes only 2% of all HIV infections whereas in Asia and Africa, it comprises 15-20% of all cases, due to greater affliction of women in the childbearing age group(1). Thus, for the developing world, having not yet conquered malnutrition, diarrhea and infections, the dilemma continues. In India, the disease threatens to assume alarming proportions with estimates that the current level of infection will soon double(2), earning it the dubious distinction of being the "World’s AIDS Capital". Although, there is no dearth of literature on HIV disease in adults, the full spectrum of the disease in children has not been studied, particularly in the Indian context. This study details the clinical mani-festations seen in HIV infected children and highlights our clinical experience.
This prospective study was conducted at the HIV clinic at a tertiary pediatric care center in an urban metropolis. From August 94 onwards, 285 HIV positive patients have been referred to the clinic. These included: (a) patients born to HIV positive women at a sister institute, the maternity hospital and who tested positive twice for HIV one at 9 months and second between 15-18 months of age; (b) those referred with a positive ELISA test from other hospitals, medical practitioners and orphan-ages; and (c) transfusion dependant patients including thalassemia and hemophilia who tested positive on a routine HIV screening. Efforts were made to establish the source of infection by establishing maternal HIV status and evaluating history of blood/blood product transfusion, accidental needle-stick injury and sexual abuse in the children. After informed consent from either parent, all the referred patients were re-tested for their HIV status at our center by two different ELISA tests on atleast two subsequent visits. The HIV-1 and HIV-2 serology in all children was performed using two different ELISA kits, DETECT-HIVMC(v.2) (Biochem Immuno Systems Inc. Montreal, Quebec, Canada H3M 3 A2) and HIV-CheX (Xcyton Diagnostics Pvt. Ltd. Jyothi Industrial Estate, Bangalore) having a sensitivity of over 99.5%. Western blot test was performed in patients who could afford the test and considered positive if it showed the presence of atleast two of the envelop (gp120 and gp 160/gp41) and any of gag (p24, p27, p55) or pol (p31, p51, p66) bands (Immunoblot Assay, Speciality Ranbaxy Limited, Clinical Reference Laboratory, Mumbai). In patients below 15 months of age, DNA Polymerase chain reaction (PCR) tests were performed using the Roche Amplicore technique for confirming the infectivity. All testing was done in accordance with the manufacturer’s instructions. All the clinical data was recorded on a proforma and cases were scheduled for follow-up at 3 monthly interval. Protein energy malnutrition was graded as per IAP classi-fication(3). Tuberculosis was diagnosed on the basis of symptomology, history of adult contact with tuberculosis, radiology, Mantoux test, sputum and gastric lavage for acid fast bacilli, lymphnode biopsy and response to anti-tuberculosis treatment. Persistent generalized lymphadenopathy (PGL) was diagnosed as presence of enlarged lymphnode (>1 cm) in two or more sites for more than 3 months after excluding other causes(4). Chronic lung disease (CLD) was defined as presence of reticulonodular pattern with or without hilar adenopathy that persisted on chest X-ray for 2 month or more and that was unresponsive to anti-microbial including antitubercular therapy. Chronic hypertrophic parotitis (CHP) was diagnosed by clinical examination. Neuro-imaging was done for diagnosis of encephalo-pathy. Candida albicans was diagnosed by clinical, microscopic and culture study. Pneumocystis carinii pneumonia (PCP) was diagnosed by X-ray evidence of bilateral diffuse alveolar disease and confirmed on bronchoalveolar lavage. All patients were subjected to a complete blood count, erythrocyte sedimentation rate (ESR), routine urine, Mantoux test and chest X-ray. Other relevant investigations were done as and when required. The siblings and parents of all patients were also screened for HIV by ELISA test after a verbal informed consent. Our social counselor offered pre and post-test counseling to parents. Total confidentiality of all results was maintained.
A total of 285 patients tested HIV positive of which 48 (16.84) have remained asymptomatic so far while 30 (10.52%) died during the study period and 39 (13.68%) were lost to follow up after their first clinic visit. Two hundred and thirteen patients (74.73%) were below the age of five years as shown in Table I. Various modes of transmission are shown in Table II. In 247 (86.66%) the infection was perinatally acquired while 33 (11.57%) children were infected through blood/blood products. These included 26 with thalassemia, 2 with hemophilia, 1 with leuke-mia, 1 was dependant on regular hemodialysis, 2 infants who had undergone exchange transfusion for hyperbilirubinemia during the neonatal period and 1 had received plasma transfusion. The route of infection could not be ascertained in 5 (1.75%).
The clinical manifestations noted at initial presentation or on follow up are shown in Table III. Protein energy malnutrition was the commonest manifestation, noted in 127 (44.56%) cases. Of these 51 had Grade III PEM and 76 had Grade IV PEM. No case of kwashiorkar was seen. Eighty-four patients (29.47%) had tuberculosis. These included 48 with isolated pulmonary lesions, 21 with disseminated tuberculosis, 8 with biopsy proven cervical tubercular lymphadenopathy and 7 with neurotuberculosis (diagnosed by a positive CSF TB antigen and CT scan brain). Hepatosplenomegaly was a common present-ing feature seen in 82 (28.77%) cases. PGL was seen in 67 (23.50%) cases. Skin lesions noted in 63 (22.10%) included herpes zoster in 19, chronic non-specific dermatitis in 20, scabies in 18, pyoderma in 15, molluscum contagiosum in 3 and chronic paronychia in 2 patients. Forty three (15.08%) children developed chronic diarrhea. The pathogens isolated were Escherechia coli in 12, Kleb-siella in 5, Candida albicans in 8, Giardia lamblia in 3 and Cryptosporidium in 2 patients. Candida albicans was isolated from 42 (14.73%) cases that developed oral thrush. CLD was diagnosed in 32 (11.22%), out of these 10 patients had grade 4 clubbing. Twenty seven (9.47%) children had CHP. Twenty six (9.12%) patients developed chronic otorrhea during the study. Twenty four (8.42%) children suffered from recurrent lower respiratory tract infections. PCP was diagnosed in 11 (3.88%) including two infants who underwent exchange transfusion in the new-born period. Eleven (4.56%) developed non-tuberculous CNS manifestations in the form of HIV encephalopathy. Their presenting features included delayed milestones in 5, neuro-regression in 2, neuropsychiatric disorders in 2, status epilepticus in 1 and a case of vacuolar myelopathy manifesting as an upper motor neuron paraplegia. Routine CSF examination revealed elevated protein levels and CSF Western blot was positive in all these cases. Neuroimaging in these cases revealed cerebral atrophy in 5, white matter demyelination in 4, basal ganglia calcification in 2, ventricular dilatation in 2 and cerebellar atrophy in 1. Although reported in literature, no case of HIV associated nephropathy, cardiac or ocular involvement, autoimmune disease or malig-nancy were noted in our study.
Symptomatic patients were noted to have a mean hemoglobin of 8.2 g/dl (range of 6-9 g/dl) and a mean ESR of 102 mm/1st hour (range of 88-120 mm/1st hour). We did not observe a single case with clinical or labo-ratory evidence of thrombocytopenia. Thirty (10.52) cases died during the study which included 7 cases of encephalopathy, 5 cases of disseminated TB, 4 with severe pneumonia and sepsis, 3 cases of neuro-tuberculosis and 2 cases each of Grade IV PEM, infant with PCP, and fungal sepsis. Autopsies were not done in any of above.
There is little information available on the clinical profile of HIV infection in children in India with few published reports including a small cohort reported from Mumbai(5). Mother-to-child transmission (MTCT) still remains the primary route of infection in the pediatric population(6) and accounted for 86.66% of cases in our study. A combination of immunologic naivete and immunologic dysfunction contributes to quicker progression of disease in children as compared to adults. It has been reported that children who acquire the infection pertinatally become symptomatic substantially earlier than those infected by other route(7). The mean survival time of vertically infected children ranges from 75 to 90 months and approximately 70% of them reach the age of 6 years(8). This is illustrated by the fact that around 75% of children in this study presented below the age of five years. MTCT has been shown to be reduced with peripartum therapeutic intervention using Zidovudine (AZT)(9,10). The second most common source of infection is through blood or its products, emphasizing the importance of regular HIV screening of transfusion dependant patients. Screening blood does not prevent transmission from an infected donor in the "window period"(11). Infants who acquire HIV perinatally have birth weight and height percentiles comparable to uninfected ones(12) but may develop postnatal growth retardation. Chronic diarrhea, opportunistic infections or HIV infection per se may be responsible for protein energy malnutrition. This was the commonest clinical feature of immunodeficiency noted by us; therefore nutritional intervention should be instituted early in the care plan of thse children. Tuberculosis was the most common infection encountered in our study, with about 30% showing evidence of pulmonary or extra-pulmonary involvement, which was high as compared to the other studies(6,11). Tuber-culosis in HIV infected patients is often disseminated caused by atypical mycobacteria and is multidrug resistant(14). We could not document the presence of atypical myco-bacteria, or the multi-drug resistant tuber-culosis because of the lack of culture facilities. Considering the high seroprevalence of HIV infection in tuberculosis in children as reported from Mumbai(15) and Zambia(6), tuberculosis should be regarded as a sentinel illness for HIV infection and screening for the disease in all cases of disseminated tuberculosis is recom-mended. Other common clinical presentations noted were hepatosplenomegaly and PGL, which are due to lymphoproliferation and indicate better immunity. Amongst skin infections, herpes zoster was the common opportunistic infection seen as a recurrent infection and is often the first clinical indicator of AIDS. Non-specific dermatitis was another common skin lesion, however we could not do skin biopsies. Atypical crusted form of scabies seen in these cases was highly contagious and resistant to treatment. A syndrome of chronic diarrhea with weight loss (Slim disease) is one of the major manifestations of AIDS(16). Two important explanations for this are infection by oppor-tunistic organisms or HIV enteropathy, which results in alteration of immunity(17) with per-sistent infection leading to prolonged diarrhea, malabsorption and subsequent malnutrition. In an earlier study conducted in Bombay, a HIV seroprevalence of 24% in cases of chronic diarrhea was reported(15). Candida albicans, a fungal pathogen is another common opportunistic infection. The clinical presentation varied from oral thrush to disseminated fungal infection. CLD was an important distinguishing feature of this study, seen in the age group of 4-8 years. Grade 4 clubbing was seen in 10 of them. Lymphoid interstitial pneumonia (LIP) a form of chronic lung disease is an important distinctive marker of pediatric HIV infec-tion(18). Although chronic in nature, LIP may be complicated by acute exacerbations with intercurrent bacterial or viral infections. LIP is commonly associated with parotid enlarge-ment and PGL, and is usually associated with good prognosis(19). Definitive diagnosis is by lung biopsy, which was not performed in any of our cases(20). A distinguishing clinical finding in this study, not seen in such a large number in a study from Nigeria(11), was the presence of a painless unilateral or bilateral chronic parotid enlargement (Fig. 1). This was seen in older patients between 4-8 years of age. Many of these patients were diagnosed and treated as mumps before referring to us. The enlarge-ment of the parotids is due to lymphocytic infiltration of the gland. Ultrasound shows dialatation of acini and cyst formation due to lymphoreticular proliferation (Fig. 2). Parotitis occurs at a stage of HIV infection when the immunity is still intact(21).
PCP presents as an acute, diffuse and life threatening pneumonitis, most commonly seen below 1 year of age. Nine patients with PCP responded to a twenty-one day course of 20 mg/kg/day per oral of Trimethoprim-Sulfa-methoxazole (TMP-SMX). Interestingly, both the infants who were infected following ex-change transfusion died in the first year of life with symptomatology of severe immuno-deficiency and in both Pneumocystis carinii was isolated on bronchoalveolar lavage. In both these infants a diagnosis of HIV infection was confirmed by a positive DNA PCR. The early onset of symptoms in these two infants who had been infected through blood rather than perinatally, could be attributed to the very high viral load transmitted during the process of exchange transfusion. In the setting of developing countries, it is very difficult to reach a definitive diagnosis of PCP using bacteriological techniques, as bronchoalveolar lavage and lung biopsy though ideal to retrieve the organism(22), being invasive, are seldom performed. In infants and young children where PCP is common, and often a fatal illness, on a high index of suspicion, early therapy should be instituted(22,23). The CNS is a sanctuary site for HIV(24). True incidence of CNS disease is unknown. Clinically two forms of encephalopathy have been described: a more severe, rapidly prog-ressive form (delayed or regression of mile-stones, spinal cord involvement, dementia, psychiatric disturbances, motor and behavio- ral disturbances) and a static encephalopathy (development of skills and abilities below the normal expected rate). Basal ganglia calci-fication is an important marker of HIV-1 related CNS disease(25). Seven of eleven patients in this study with progressive encephalopathy died within a period of 4-6 months after diagnosis. We were unable to correlate the clinical features with the immunological or virological status of our patients, as they could not afford the CD4/CD8 and viral load testing. Twenty five patients are currently undergoing anti-retroviral therapy (ART) and will form the basis of a detailed report in future. Pediatric HIV infection is already showing a major impact on infection rates and child mortality in the developing world, and is threatening to wipe out gains achieved in child survival for the last few years. There are difficulties in making an early diagnosis due to overlap in symptomology with common childhood illnesses. We therefore recommend that any child presenting with malnutrition, chronic diarrhea, or recurrent respiratory tract infection, or disseminated tuberculosis, be screened for HIV infection in order to ensure early diagnosis and a management plan for not only the patient but also for the entire family. This study highlights the clinical presentations that we noted and the difficulties we have in settings similar to ours in making precise diagnosis. Contributors: RHM co-ordinated the study and drafted the paper; he will act as the guarantor for the paper. JSO and RVB participated in the data collection, and also helped in drafting the paper. JK helped in counselling and data collection. Funding:
Nil.
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