| Abstract|| |
Background: Human immunodeficiency virus (HIV) infection in India has now been prevalent over three decades, and an increasing number of children are being affected with HIV. The spectrum of pathologic lesions in children with acquired immunodeficiency syndrome (AIDS) in India has not been well described. Materials and Methods: A review of systematically conducted autopsies of 11 (10 boys and 1 girl) children with AIDS is presented. Results: The mode of HIV transmission in 6 children was vertical; in one it was blood transfusion and in 4 children route was presumably vertical as these were children of orphanage. The clinical manifestations were failure to thrive; 9 children, persistent gastroenteritis; 8, recurrent fever; 5, bacterial infections; 5, hepatosplenomegaly; 5, candidiasis; 1, scabies; 1, skin rash; 2, tuberculous (TB) meningitis; 1 and paraplegia; in 1 child. The spectrum of pathologic lesions observed were precocious involution in thymus in 3 and dysinvolution in 2 cases. Infectious diseases comprised of TB; 4 cases, cytomegalovirus infection (CMV) 4; bacterial pneumonia and meningitis; 7, and esophageal candidiasis in 2 cases. Dual or multiple infections were observed in 9 (82%) cases; these comprised of two lesions in 2, three lesions in 2, four lesions in 4, and five lesions in 1 case. TB, bacterial pneumonia, meningitis, and CMV infection are the most frequent causes of death in children with AIDS. Vascular lesions showing features of arteriopathy were observed in 5 cases and brain in one case showed non-Hodgkin's lymphoma. Conclusions: This study provides a better insight into the spectrum of pathologic lesions in children with AIDS in India. TB and CMV infection has been found to be the most prevalent infection in our children.
Keywords: Acquired immunodeficiency syndrome, autopsy, cytomegalovirus, India, lymphoma, pediatric, tuberculosis
|How to cite this article:|
Lanjewar DN, Bhatia VO, Lanjewar SD. Pathologic lesions in children with acquired immunodeficiency syndrome an autopsy study of 11 cases from Mumbai, India. Indian J Pathol Microbiol 2016;59:166-71
|How to cite this URL:|
Lanjewar DN, Bhatia VO, Lanjewar SD. Pathologic lesions in children with acquired immunodeficiency syndrome an autopsy study of 11 cases from Mumbai, India. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Dec 11];59:166-71. Available from: http://www.ijpmonline.org/text.asp?2016/59/2/166/182028
| Introduction|| |
Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV). The pediatric AIDS follows adult HIV infection, and the majority of pediatric infection is acquired perinatally. After South Africa and Nigeria, India is estimated to have the highest number of people living with HIV. According to Department of AIDS Control, New Delhi, Government of India; around 1.37 lacks, children are living with HIV in India. Despite large number of cases of pediatric AIDS in India, very few clinical studies and only two autopsy reports have been described in the literature., The status and natural history of HIV infection in children and the spectrum of pathologic lesions in children with AIDS in our epidemiological situation are also not very well described. Therefore, a review of systematically conducted autopsies on 11 cases of pediatric AIDS is presented.
| Materials and Methods|| |
Between 1991 and 2003; 11 autopsies in children with AIDS were studied at Sir J.J. Hospital and Grant Medical College, Mumbai. These children were hospitalized and sera from clinically suspected cases of pediatric AIDS were tested using DETECT-HIV enzyme-linked immunosorbent assay (Biochem immune system Inc., Montreal, Canada) for HIV-1 and-2 antibodies. All the sera reactive by the above test kits were further tested using immunocomb HIV-1 and -2 Bispot test kit (Organics, Yavne, Israel). The sera that were reactive by both test systems were labeled as HIV reactive sera, and the children were determined to be HIV-positive. The methodology of performing autopsies in infants, described by Letulle was followed. At autopsy deep parallel incisions were given 1 cm apart through the organs; afterward organs were fixed in plastic drum containing 10% formalin; further dissection of the organs was carried out 48 hrs after formalin fixation and irrespective of presence or absence of grossly visible lesions, tissue sections obtained from all the organs were studied with H and E, Periodic acid-Schiff, Mucicarmine, Ziehl–Neelsen, Verhoff's Von Gieson, and Gomori's Methanamine silver stain.
| Results|| |
The clinical data, risk factors and clinical diagnosis of 11 cases are presented in [Table 1]. All the cases were seroreactive for HIV-1 antibodies. The gender composition comprised of 10 boys (88%) and 1 girl (12%). The risk factors were vertical transmission in 6 children and blood transfusion in one child while risk factors in four orphan children are presumed to be vertical. The predominant clinical presentation was failure to thrive in 9 children and gastroenteritis in 8 children. The other clinical manifestations included recurrent bacterial infections (5 patient), recurrent fever (5 patients), hepatosplenomegaly (5 patients), candidiasis (1 patient), skin rash (2 patients), scabies (1 patient), and central nervous system (CNS) manifestation (2 patients).
|Table 1: Demographic data and clinical presentation in children with acquired immune deficiency syndrome (n=11 cases)|
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The autopsy findings in these cases revealed several AIDS-defining illness [Table 2] as per the CDC case definition. Thymus was available for study in five patients; precocious involution of thymus characterized by marked depletion of lymphocytes, loss of corticomedullary differentiation, and microcystic dilatation of Hassall's corpuscles was seen in three patients while dysinvolution of thymus characterized by absence of Hassall's corpuscles was noted in the remaining two patients [Figure 1]a. Hilar lymph nodes were enlarged in 6 patients and showed follicular hyperplasia in 4 patients while lymph node in two cases showed tuberculosis (TB). The spleen was examined in all the 11 patients; in 5 patients it showed lymphoid hyperplasia while in one case spleen showed TB granuloma; in remaining five patients spleen showed depletion of lymphocytes; In five patients hyperplasia of Peyers' patches was identified. Bone marrow was not studied in any of the patients.
|Table 2: Clinical diagnosis and pathological findings in pediatric acquired immune deficiency syndrome (n=11 cases)|
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|Figure 1: (a) Microscopy shows dysinvolution of thymus with loss of corticomedullary differentiation and occasional calcified Hassall's corpuscle (H and E, ×100). (b) Microscopy of lymph node shows nongranulomatous necrotizing tuberculosis lesion (H and E, ×100). (c) Microscopy of lung shows characteristic intranuclear inclusions of cytomegalovirus in alveolar lining cells (H and E, ×200). (d) Microscopy of esophagus shows periodic acid-Schiff positive pseudohyphal and yeast forms of fungi (PAS, ×200)|
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Infectious diseases were seen in 10 patients while lymphoma of the brain was identified in one patient. TB of the lung was identified in 4/11 (36%) patients, the other organs involved by TB were liver (3 patients), lymph nodes (2 patients), spleen (1 patient), and TB meningitis (3 patients). The TB lesions were characterized by nongranulomatous inflammation with areas of necrosis infiltrated by polymorphs and macrophages [Figure 1]b. These lesions showed tubercle bacilli with Ziehl–Neelsen stain. Bacterial infections leading to bronchopneumonia and bacterial meningitis were observed in 4 patients. Cytomegalovirus (CMV) infection was observed in 4/11 (36%) patients. The CMV infection was seen in adrenals (4 patients), gastrointestinal tract (GIT) (3 patients), lungs (2 patients), kidney (1 patient) and thyroid (1 patient). The infected cells were large and showed the characteristic intranuclear and intracytoplasmic inclusions of CMV [Figure 1]c. Esophageal candidiasis was diagnosed in 2 patients by the presence of pseudohyphae and budding yeast forms [Figure 1]d. Simultaneous, dual or multiple infections were observed in 9/11 (82%) patients; these comprised of two lesions in 2 patients (C4 - TB lung and TB meningitis and C7 - CMV and arteriopathy); three lesions in 2 patients (C2 - Bacterial Bronchopneumonia, Bacterial meningitis and arteriopathy, C11 - TB lung, TB meningitis, aspergillosis of lung); four lesions in 4 patients (C1 - bronchopneumonia, bacterial meningitis, esophageal candidiasis, precocious involution of thymus, C5 - TB, microglial nodule, dysinvolution of thymus, arteriopathy, C6 - bronchopneumonia, bacterial meningitis, CMV, precocious involution of thymus, C8 - CMV, esophageal candidiasis, dysinvolution of thymus, arteriopathy) and five lesions in one patient (C3 - TB, CMV, precocious involution of thymus, arteriopathy, microglial nodule). Arteriopathy was noted in 5 patients; it was characterized by thickening of the vessel wall, intimal fibrosis, narrowing of lumina and fragmentation of elastic fibers [Figure 2]a and [Figure 2]b. These changes were seen in small and medium-sized arteries of lungs (5 patients), kidneys (2 patients), GIT (2 patients) pancreas (1 patient) and spleen (1 patient). One patient of arteriopathy showed infarct in lung and spleen. Microglial nodules characterized by clustering of microglia, astrocytes, and mononuclear cells were observed in 2 cases. Multinucleated giant cells considered to be the hallmark of HIV encephalopathy were not identified in any of our patients. Lymphoma was found in the brain of a 5-year-old boy whose parents were HIV reactive. This boy initially presented with weakness in both lower limbs that subsequently progressed to paraplegia. Magnetic resonance imaging (MRI) of spine showed a diffuse intramedullary lesion while MRI brain did not reveal any specific findings. The gross examination of the brain showed marked edema along with thickening of the optic, olfactory and abducent nerves [Figure 2]c. The coronal sections through brain did not show any tumor. Microscopic examination of the brain showed diffuse large B-cell non-Hodgkin's Lymphoma involving subarachnoid space, lining of ventricles, Virchow Robin's spaces, and brain parenchyma. The optic, oculomotor and abducent nerves also showed infiltration by lymphoma [Figure 2]d. The immunohistochemistry of this tumor showed positivity for leukocyte common antigen, CD 34 and CD 68 and negativity for CD 3, p53, and bcl2.
|Figure 2: (a) Microscopy of lung shows thickening of arterial wall due to intimal and medial fibrosis (H and E, ×200). (b) Microscopy of lung shows fibrosis of arterial wall and fragmentation of internal elastic lamina (VVG, ×400). (c) Basal surface of the brain shows thickening of the optic, oculomotor and abducent nerve in a case of central nervous system lymphoma. (d) Microscopy shows large round cells having large hyperchromatic nuclei infiltrating into the abducent nerve (H and E, ×400)|
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| Discussion|| |
Sir J.J. Hospital in Mumbai is a public hospital run by State Government that provides free services to HIV-infected patients. Autopsies on adults and children with AIDS are routinely performed in our institute. Mumbai city was the only one in India where Coroner's Act was in place; hence, Coroner gave permission for postmortem examination in 9 patients. After abolition of Coroner's Act; in July 2000, consent for postmortem examination was obtained from next of kin in two patients. Thus in all 11 cases in the present study consent for postmortem examination was obtained. After 2003, we could not perform any postmortem in a HIV-infected child. In India, even today, giving birth to a neonate by an unmarried female is a social stigma; therefore, neonates born to unmarried females are abandoned into garbage, or near railway or bus station. When an abandoned neonate/infant is identified by someone; information is given to police, and the police brings them to the orphanages. It is also observed that neonates born to HIV-infected mothers or to commercial sex workers are also brought in orphanages. Four children in the present study were from orphanage that is located near our Hospital. In this study; 6 (54%) children had acquired HIV perinatally (mother HIV reactive), and the risk factors in 4 (36%) children from the orphanages was unknown. It is possible that the children from orphanages were abandoned by their HIV infective mother/commercial sex workers, and hence it is assumed that 10 (90%) children in the present study have acquired HIV through vertical transmission.
HIV-infected children in developed countries have a mean age at diagnosis of 17 months and median of 9 months, and their clinical symptoms may not manifest until the age of 7 years. 4 children in the present study had presented before 1 year of age. The usual clinical features seen in children with AIDS are lymphadenopathy, hepatosplenomegaly, oral candidiasis, failure to thrive, chronic diarrhea, weight loss, fever, and recurrent bacterial infections.,, In the present study, 8 (73%) children presented with persistent diarrhea. In African, children with AIDS diarrhea was observed in 78% patients. The Indian data of HIV-infected children presenting with diarrhea have shown the prevalence of cryptosporidium in 6–10% patients.,
The criteria laid down by the CDC, Atlanta, suggests that a positive serology in a child more than 18 months of age is taken as a case of proven HIV infection. A definitive diagnosis of AIDS in children <18 months of age can be made by demonstration of HIV antigen by polymerase chain reaction or viral culture. During our study period, these tests were not available in our institute. The criteria lay down by CDC; Atlanta for confirming HIV infection in children below 18 months indicates that HIV reactive children above 1 month of age showing the presence of diseases such as CMV infection (excluding lymph nodes, spleen, and liver) and candidiasis indicates AIDS in the children. Four children (C3, C6, C7, C8) in the present study had age range from 2 months to 11 months showed CMV infection in lung, adrenal, kidney, GIT and thyroid indicates that these are children with AIDS. Another four children (C3, C4, C5, and C11) showed widespread TB; therefore, they are also categorized as cases of AIDS. One child (C1) had esophageal candidiasis and showed precocious involution of thymus; hence, this case is also categorized as AIDS. Bacterial infections manifesting as otitis media, sinusitis, pneumonia or sepsis are the first clinical findings in children with AIDS., Three of our children (C1, C2, C6) showed bronchopneumonia along with bacterial meningitis and one another child (9C) showed bacterial meningitis; therefore, all patients of bacterial infection are categorized as AIDS. One child (C10) in the present study showed CNS lymphoma; thus, all 11 children in the present study are categorized as AIDS.
The various opportunistic pathogens implicated in children with AIDS; include Candida species, Pneumocystis jirovecii (PCJ), histoplasma capsulatum, aspergillus species, cryptococcus, CMV, toxoplasma gondii, Mycobacterium tuberculosis and Mycobacterium avium-intracellulare.,,,, In the present study, infections were identified in 10 children which comprised of CMV, TB, pneumonias, meningitis, aspergillosis, and candidiasis. The prevalence of CMV infection in children with AIDS has been variedly described as 26–39%.,,, CMV infection was observed in 4 (36%) patients in our study. The World Health Organization estimates that HIV prevalence among children with TB, in countries with moderate to high prevalence, ranges from 10% to 60%., With increasing coverage of antiretroviral treatment, the incidence of TB has been decreasing but remains substantially higher in HIV-positive children than in the general pediatric population. PCJ is frequently detected in children with AIDS in both developed and African countries., We have not found any patient of PCJ in our study. Cryptococcosis appears to be less frequent in HIV-infected children, and only few cases of cryptococcosis complicating pediatric AIDS have been reported in the literature. Bacterial infections are frequently seen in children with AIDS and prevalence of repeated bacterial infections has been reported in 17% of HIV-infected children. Pulmonary lymphoid hyperplasia/lymphoid interstitial pneumonia complex (PLH/LIP) is one of the AIDS-defining criteria in children. PLH is characterized by the presence of lymphoid follicles with germinal centers around bronchioles and LIP is characterized by diffuse alveolar septal infiltration by admixture of lymphocytes, plasma cells, plasmacytoid lymphocytes, and few immunoblasts. PLH/LIP is considered to be result of atypical response to Epstein–Barr virus. We did not find PLH/LIP complex in any of our children. The changes of precocious involution and dysinvolution of thymus are considered to be irreversible lesions, in the present study lesions in thymus were identified in 5 children. The pathogenesis of arteriopathy is not clear however it is suggested that elastic tissue damage occurs due to increased exposure to the endogenous and exogenous elastases secondary to repeated bacterial infections; in this study arteriopathy was identified in 5 children. In developed countries, arteriopathy is reported to be seen only in children with long-term survival. Non-Hodgkin's lymphoma is one of the most fatal complications of the AIDS and approximately, 75% cases are of diffuse large B-cell lymphoma., In this study, one child had CNS lymphoma. It is essential that primary congenital immunodeficiency disorders such as severe combined immunodeficiency syndrome, Nezelof's syndrome, DiGeroge's syndrome, Wiskott-Aldrich syndrome, and ataxia telangiectasia should be excluded before making a diagnosis of AIDS in children [Table 3]. In the present study, primary immunodeficiency syndrome was ruled out on clinical as well as on the basis of postmortem findings. In summary, a thorough knowledge of pediatric HIV infection, the prevalence of opportunistic infections and the survival patterns of these children are needed to establish baseline information in our scenario. The present autopsy study showed marked discrepancies between antemortem and postmortem diagnosis. At autopsy, clinically unsuspected diagnosis was documented in 90% cases. This study provides a better insight into the spectrum of pathologic lesions in children with AIDS in India. TB and CMV infection has been found to be the most prevalent infection in our children. TB, owing to its endemicity in India will emerge as the most prevalent disease, contributing to increased mortality and morbidity in HIV-infected children.
|Table 3: Differences between congenital immunodeficiency and acquired immune deficiency syndrome|
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Dr. Vijay V. Joshi (USA).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Dhanesheshwar N Lanjewar
Grant Government Medical College, Mumbai - 400 008, Maharashtra
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]