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Clinical Presentation, Treatment Outcome and Survival Among the HIV Infected Children with Culture Confirmed Tuberculosis Alok Kumar*,1, Sanjay Upadhyay2 and Geeta Kumari2 1
School of Clinical Medicine and Research, University of the West Indies, West Indies; 2The Naz Foundation, New Delhi, India Abstract: Background: We studied the clinical presentation, diagnosis, treatment outcome and survival in children with HIV and Tuberculosis (TB) co-infection. Methods: All HIV infected children with symptoms or signs consistent with tuberculosis were screened. We studied 24 cases of culture confirmed TB from among a cohort of 213 HIV infected children. All these children were on HAART for their HIV infection. Information on TB was collected by retrospective chart review of these children. Results: In a cohort of 213 children with vertically transmitted HIV infection, a total of 76 (36%) children suspected to have tuberculosis based on their clinical presentation together with either a positive Mantoux test or AFB positivity or mycobacterium culture positivity were treated for TB and 24 children had culture positive TB. The median age at diagnosis of TB was 16 months. Over half of these children had some immunodeficiency. Common presentations were fever (87%), history of contact with an open case of TB (79%), cough for more than 2 weeks (75%), malnutrition (71%), hepatosplenomegaly (71%), chronic diarrhea (67%) and generalized lymphadenopathy (58%). Mantoux test result was positive in 12 (50%) patients. Chest roentgenograms were abnormal in all the children, with hilar and/or Para tracheal node (62%) and lobar or segmental opacification (57%). Twenty one (87%) children had pulmonary TB at the time of their diagnosis. One or more sites of Extrapulmonary TB were confirmed in 10 (41%) patients. After six months of ATT, the cure rate was 64%. Three patients had documented drug-resistant. Five children (20%) died. Conclusion: TB is a common co-infection in HIV infected children and children often present with un-resolving pneumonia. It carries significant mortality despite the HAART and adequate anti-tuberculosis treatment in these children.
Keywords: Tuberculosis, HIV infection, treatment outcome, children. INTRODUCTION Countries where Tuberculosis (TB) is still endemic, a significant proportion of HIV infected individuals acquire Tuberculosis [24]. In India, as in many developing countries, Tuberculosis is still a significant public health problem in both the adult and the pediatric population. Countries where Tuberculosis was rare, there is a resurgence of this illness fueled by the increased susceptibility of the HIV infected population to this infection [8, 25]. The Indian National AIDS Control Organization (NACO) estimates that 5.21 million people were living with HIV in India in 2005, giving an adult prevalence of 0.91% [13]. Delhi is one of the low prevalence states in India with a prevalence of 0.25% [13]. The survey findings by Indian Council for Medical Research revealed the national prevalence of sputum positive pulmonary TB in India is about 4 per 1000 population [3]. The deleterious influence of HIV infection and AIDS on the susceptibility to and the course of the TB among adults are well-documented [2, 5, 11, 12]. Adults with HIV disease have an increased incidence of pulmonary and extra pulmonary TB and also present with atypical pulmonary TB, less frequently being sputum smear-positive, and have a higher mortality rate [2, 5, 11, 12]. A number of reports are avail*Address correspondence to this author at the School of Clinical Medicine & Research, University of the West Indies (Cave Hill Campus) & The Queen Elizabeth Hospital, Martindales Road, St. Michael, Barbados, West Indies; Fax: (246) 429 5374; E-mail:
[email protected] 1570-162X/07 $50.00+.00
able on the clinical manifestations and the outcome in small numbers of pediatric patients with HIV infection and TB [6, 16, 17, 21]. In the most studies on HIV infection and TB in children from the developing countries, TB is not confirmed by culture. This could lead to the over diagnosis of pulmonary TB, because the nonspecific clinical and radiological pictures could be confused with numerous other HIVassociated lung conditions. However, a few of reports include culture-positive TB cases, these studies are mostly from developed countries and there are none from India [10]. The aim of this study was to evaluate our experience with HIV-infected children who were culture-positive for Mycobacterium tuberculosis with specific reference to the clinical picture, diagnosis, response to treatment and the survival. This study provides a useful opportunity of reviewing a fairly large cohort of HIV and TB co infected children with adequate work up and attending the HIV treatment center at major hospitals in New Delhi, India and to gain valuable experience in the management of children with HIV and TB co-infection. METHODS This is a retrospective descriptive study. All the children diagnosed with HIV infection and enrolled at the Naz Foundation in New Delhi for their care and treatment from January 2000 through December 2005 were included in this study. There were 213 children enrolled into this care and treatment program. All these children were attending one of the specialized HIV treatment centers attached to the major © 2007 Bentham Science Publishers Ltd.
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hospitals in New Delhi, India. All HIV infected children are routinely screened for tuberculosis at the time of their HIV diagnosis and have repeated screening when they present with symptoms or signs consistent with tuberculosis. Tuberculosis screening includes chest x-ray, Mantoux test and AFB (Acid Fast Bacilli) staining, Mycobacterium culture on gastric lavage or other specimens such as cerebrospinal fluids, joint aspirate, lymph node aspirates. All the HIV infected children who were culture positive for tuberculosis were included in this study.
treatment. Routine susceptibility testing (Isoniazid only or Isoniazid and Rifampin) was done after the first six months of treatment if there were evidence of treatment failure. Treatment, clinical course and the results of follow-up mycobacterium cultures were recorded. Outcome of all patients up to the time of this report was established by follow-up and by contacting the local authority primary health clinic staff.
In children older than 18 months the diagnosis of HIV infection was established by a positive serology to HIV by 2 different enzyme-linked immuno-sorbent assay (ELISA) tests (Murex Diagnostics, Kent, UK; Organon Teknika, Boxtel, the Netherlands; and Abbott, Chicago, IL). In patients younger than 18 months with the clinical picture of HIV infection, the diagnosis was confirmed by DNA PCR testing using the ultra sensitive kits with sensitivity to detect up to 50copies/ml. Culture for M. Tuberculosis was by a radiometric method (Bactec®). When a positive growth was obtained, it was sub cultured on to Lowenstein Jensen medium and a niacin test was done to identify M. Tuberculosis.
There were 213 children with vertically transmitted HIV infection who were enrolled at the Naz Foundation during the 2000-05. Their age ranged between 9 months to 11 years at the time of their enrolment at this center. All these children were screened for the tuberculosis and a total of 76 (36%) children suspected to have tuberculosis based on their clinical presentation together with either a positive Mantoux test or AFB positivity or Mycobacterium culture positivity were treated for TB. Forty-one children had a documented AFB smear result in their case notes and the same number of children had a documented culture results. Of the 41 children who had AFB staining and culture of their gastric aspirate or other suitable specimen, 18(44%) had AFB smear positive and 24 (54.5%) were culture positive. Of the 22 samples of gastric lavage, 10(45%) were smear positive and 12 (54%) culture positive, where as from the 7 CSF samples, 4(57%) were smear positive and 5 (71%) were culture positive and from 9 lymph node sample 7(77%) were smear positive and the same number were culture positive. There was only one child who was AFB smear positive but culture negative. Of the remaining 52 children, out of the 76 children who were treated for tuberculosis, who were culture negative or had no documented culture results 40 had pulmonary TB and 12 had Extrapulmonary TB including Tuberculoma (4), Tuberculous meningitis (3), Tuberculous lymphadenitis (2), Tuberculous arthritis (1), Potts spine (1) and Tuberculous otitis (1).
The clinical records of all these dually infected patients were reviewed for the purpose of this study. Their nutritional status was also recorded based on the Wellcome classification [1]. The WHO staging for children was used to categorize these children based on their clinical presentations [23]. All these children were either on HAART at the time of diagnosis of their TB or were placed on HAART shortly after the diagnosis of their HIV infection. Combination of Zidovudine and Lamivudine with Nevirapine is the routine first line treatment for HIV in children and all but 4 children were on this regimen. Four children were on their second regimen consisting of Zidovudine plus Lamivudine plus a Protease inhibitor – Nelfinavir in 2 children and Ritonavir in 2 children. The clinical features at the time of the diagnosis of Tuberculosis were noted. A history of contact with an adult with pulmonary TB (source case) was obtained by parental recall and from the local authority health clinics. A Bacillus Calmette-Guerin (BCG) immunization is routinely given at birth with reported uptake of over 90% [18]. Results of tuberculin skin testing, full blood count, liver function test, cerebrospinal fluid results and lymphocyte markers (CD4 helper cells) were noted where available. Chest radiographs were read by a radiologist. Intermittent short course Anti-Tuberculosis Therapy (ATT) was given under direct observation, as advocated in the Revised National TB Control Program (RNTCP), was used in all the children. Patients were treated according to the RNTCP; and for the uncomplicated TB they received Isoniazid- Rifampin- Pyrazinamide- Ethambutol (HRZE) 3 days a week for 2 months (intensive phase) and IsoniazidRifampin (HR) 3 days a week for 4 months (continuation phase). In patients with TBM, the four drugs used during the intensive phase were HRZS (instead of HRZE). Continuation phase of treatment in TBM and spinal TB with neurological complications were given for 6 - 7 months, extending the total duration of treatment to 8 - 9 months. Steroids were used initially in hospitalized cases of Tuberculous Meningitis (TBM) and reduced gradually over 6-8 weeks. Children were re-cultured after the sixth month of their anti-tubercular
RESULTS
There were 24 (11.3%) culture-confirmed cases of TB including 15 males and 9 females with a median follow up for 28 months (Range, 9 - 62 months). Their baseline clinical characteristics are summarized in Table 1. The median age at the diagnosis of their HIV infection was 11 months (Interquartile Range, 9-14 months) and TB was 16 months (Interquartile Range, 6-14 months). Both TB and HIV infection were diagnosed at the same time in 14(58.3%) patients, and in all but 4 cases, these children presented with sign and symptoms of TB and there was history of the mother being positive for the HIV where as in the remaining 4 cases HIV was suspected because of the presence of the AIDS defining features at the outset. Additional 4 children were diagnosed with TB with in 6 months of the HIV diagnosis. In 2 patient HIV infections was not suspected until 7 months after the diagnosis of TB, the mother being unaware of her own HIV status. A history of contacts (an adult with open case of pulmonary TB in the family) was present in 79% of the cases. The clinical features leading to the diagnosis of TB, Types of TB and the tuberculin test results are summarized in Table 2. History of fever was present in 21(87%) of cases and in 16 (75%) of them it was of the duration more than 2 weeks. Chronic cough (defined as cough for duration of over 2 weeks) was present in four-fifths of cases. Two-thirds were
HIV and Tuberculosis Co-Infection in Children
Table 1.
Current HIV Research, 2007, Vol. 5, No. 5
Some Baseline Clinical Characteristics of the HIV Infected Children who were Culture Positive for Tuberculosis
Table 2.
Presentation of the Tuberculosis in the HIV Infected Children Features
Baseline characteristics
501
No. (%)
No. (%) Clinical features at the time of TB diagnosis
Age at diagnosis of HIV infection < 1 Year
14(58.3)
1 – 5 Years
8 (33.3)
6 – 10 Years
2 (8.3)
Age at diagnosis of Tuberculosis < 1 Year
11(45.8)
1 – 5 Years
11 (45.8)
6 – 10 Years
2 (8.3)
Mean age at the time of diagnosis of TB (months)
21
Median age at the time of diagnosis of TB (months)
16
CD4 cell counts at the time of diagnosis of Tuberculosis < 15%
3(12.5)
15 – 24%
8(33.3)
> 25%
9(37.5)
Not available
4(16.7)
WHO Clinical Staging for HIV infected children Stage I
0(0.0)
Stage II
0(0.0)
Stage III
11(45.8)
Stage IV
13(54.2)
malnourished at the time of diagnosis of their TB, their weight being less than 80% of the standard for their age and sex (Wellcome Classification). Of the six children who did not have a history of chronic cough, three had TB meningitis and asymptomatic pneumonia and two had intracranial Tuberculoma and presented with seizures while one had TB arthritis of right knee joint with out any pulmonary involvement. Twenty one (87%) children had pulmonary TB at the time of diagnosis of their TB infection. Three children, who did not have pulmonary TB, had presented with Tuberculoma (2) and Arthritis (1) of right knee. Of the children who had pulmonary TB and had presented with pneumonia, 13 had pneumonia which was resistant to the usual antibiotics treatment and had persisted for over two weeks while two had presented with short duration symptoms of less than a week and features of impending respiratory failure and died with in a week of presentation, where as there were as six children who were diagnosed pneumonia on chest radiogram but had no symptoms suggestive of pneumonia. One or more sites of Extrapulmonary TB were confirmed in 10 (41%) patients, all of whom had some evidence of pulmonary involvement as well. Six children had TB meningitis; two of them had disseminated TB. Among the other pathological diagnosis, two (both were infants) had disseminated TB and two had persistent right ear otorrhea, where as one each had hydrocephalus without any evidence of meningitis at that time, pot spine and arthritis of right knee.
Fever
21(87)
Chronic Cough (> 2 weeks duration)
18(75)
Hepato-Spleenomegaly
17(71)
Chronic Diarrhea
17(71)
Malnutrition (< 80% of standard for age and sex)
16(67)
Generalized Lymphadenopathy
14(58)
Anemia ( 10 mm) in 12 (50%) patients (Table 2). Resistance testing was done in 6 children who failed therapy at 6 months. Drug resistance to one or more anti-tuberculous drug was found in 3 of the 6 specimens sent for resistance testing. One child was found to have resistant to INH and another was resistant to both INH and Rifampicin while one had multi drug resistance (resistant to Isoniazid, Rifampin and Streptomycin). Resistance testing on the adult source cases of the children with Drug resistance was negative. These testing were done after these children were identified to be resistant. Table 3 shows the findings from the chest radiographs of the 21 children with HIV disease and TB. None of the chest radiographs from the 21 children that had documented re-
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ports showed pleural effusion. Also, none of these children had normal radiograph. Table 3.
Findings from the Chest Radiographs of the 21 Children with HIV Disease and TB Findings
No. (%)
Hilar and/or Para tracheal nodes
13(62)
Lobar or segmental opacification
12(57)
Bronchopneumonia
7 (33)
Peri-hilar opacification
4 (19)
Lobar or segmental collapse
4 (19)
Calcification
4 (19)
Military opacification
3 (14)
Cavitations
3 (14)
Of the 21 patients who completed 6 months of ATT, results for repeat culture was available for 17 patients and 6 (35.3%) of them were still positive for Mycobacterium TB. Of these patients 3 (2 cases of Pulmonary TB and 1 case of arthritis) had documented drug-sensitive TB and were eventually culture negative after 8 months, 9 months and 13 months (in case of the TB arthritis) of therapy respectively. The remaining 3 patients (one with isolated pulmonary TB, one with TB meningitis and pulmonary TB and one with disseminated TB) had documented drug-resistant TB. Two children were still receiving treatment with Isoniazid, Rifampin, Ethionamide, Ethambutol and Ofloxacin (14 and 16 months of therapy) when M. Tuberculosis was re-cultured from an ear swab and gastric aspirate. The third patient (who had disseminated TB) died shortly after he completed a 6month course of Isoniazid, Rifampin, Pyrazinamide and Streptomycin. Five (20%) children (age – 9, 10, 10, 12 and 26 months) died, the cause of death was recorded as TB meningitis in two case, disseminated TB in one case, pulmonary TB with HIV encephalopathy and PCP in one case and Nevirapine induced acute hepatic failure in one case. One child (age 12 months) who had the disseminated TB and who died had multi drug resistance (resistant to Isoniazid, Rifampin and Streptomycin). Sixteen were surviving and three patients were lost to follow-up, all three were migrants from other states and they went back to their home state before completion of their therapy. The median survival time after the TB diagnosis for the 21 children for whom the complete data was available, was 10 months (mean, 15 months) with a range of 3 to 46 months. The median survival time after the diagnosis of TB for those who died was 10 months (Range 9-26 months) as compared with the median survival time of 12 months (Range 3 -46 months) for those who survived. One child had deranged liver function test 6 weeks after starting the ATT, his therapy was discontinued for 4 weeks and then restarted once his liver function test were normal and he was able to complete his therapy. Another patient had to discontinue ATT due to liver failure. This child was on ARV comprising Zidovudine, Lamivudine and Nevirapine along with ATT when he developed jaundice and deranged
liver function. His ATT was discontinued but his liver function continued to deteriorate despite being off ATT for week when the decision to change his ARV was made but he deteriorated rapidly and died after 2 days. Given the clinical scenario, his death was attributed to the acute liver failure from Nevirapine toxicity. DISCUSSION Infection with Mycobacterium tuberculosis is common in developing countries and is usually pulmonary [6, 10, 16, 17, 21]. In a study of the Ethiopian children with TB, authors reported a six fold increased mortality among the HIV infected children as compared to the HIV negative children [17]. Similarly poor outcome of the TB co-infection in HIV infected children have been reported in other studies [10,16, 21]. However, in all these studies there were no antiretroviral (ARV) used to treat these HIV infected children. Accurate information on TB in children with HIV infection is scanty both in terms of prevalence as well as disease spectrum because of difficulties in diagnosis. Few studies have examined the prevalence, presentation and outcome of the culturally proven TB in HIV infected children [10, 14, 20]. The prevalence of TB among children infected with HIV in this study is similar to those reported from other developing countries with mid to high prevalence of HIV and where TB is still endemic [10,14]. However, it is much higher as compared to the prevalence reported from developed countries where TB was almost non-existent [23]. Over two-fifths of our HIV infected children were younger than 12 months at the time of their TB diagnosis with the median age being 16 months. Over half of these children had some immunodeficiency based on their CD4 cell count and two-thirds had WHO stage IV of the HIV infection. Majority of the HIV positive children infected with the Mycobacterium Tuberculosis presented with pulmonary TB and chronic cough along with weight loss in association with a diagnosis of pneumonia that was resistant to treatment was the common presentation leading to the investigation and diagnosis of TB. Similar observations have been made in other reports from the developing countries [10, 17, 20, 21]. Nearly half of these HIV positive children co-infected with TB, had extra-pulmonary TB with nearly one third having severe form of TB in the form of disseminated TB, NeuroTuberculosis and TB arthritis. All these children with extra pulmonary TB, with the exception of three also had pulmonary involvement. Higher proportion of these HIV positive children having extra-pulmonary involvement particularly the severe forms of TB may partly have been due to the young age the time of infection with the TB. A similar increased incidence of extra-pulmonary TB was found in previous studies on culture-confirmed TB cases in HIV-infected children [4, 10, 15, 20, 23]. This is higher than the expected 16% extra-pulmonary TB among the Indian children without HIV infection [22]. CNS involvement has been a common finding in HIV and TB co-infected children with the reported incidence being very close our own [4, 15]. Interestingly we found that half of our HIV infected children with the TB co-infection had a positive (> 10 mm) Mantoux test. False-negative Tuberculin skin tests may occur in individuals with a compromised immune system, including those with HIV infection. CDC recommends that the
HIV and Tuberculosis Co-Infection in Children
HIV-positives persons with tuberculin test reaction of 5mm or more are at greater risk of developing TB and hence they should be administered prophylactic treatment [9]. However, in countries like India where both the diseases are endemic, TB may develop early in the HIV disease, when the body’s immunity is still largely unimpaired and TST showed > 10mm results in almost 45% of such cases [19]. Our findings strongly support the earlier report by Sawhney et al. from the Indian subcontinent [19]. A significantly larger number of HIV positive cases with tuberculin test result of 10mm or more are likely to have TB in the Indian setting as is the case with HIV-seronegatives. Hence, in countries endemic for TB, the infection is likely to occur early, when the body immunity is still intact, giving rise to a strongly positive tuberculin reaction. On chest radiography Para tracheal and or hilar lymph nodes were more common in these HIV/TB-co infected children with nearly two-thirds having this finding. Lobar or segmental opacification was also found in over half of these children with involvement of the upper lobe in over twothirds of these cases. Of note pleural effusion was a rare finding. Except for the absence of pleural effusion and upper lobe involvement in these children, other chest radiograph findings were similar to that found in a previous study [16, 20]. Over a third of the children who were co-infected with TB and HIV and had completed six months of treatment and had a repeat culture, were still positive for the Mycobacterium Tuberculosis. This failure rate was lower as compared to reports HIV infected children from other developing countries where HAART was not used [10, 17, 20]. In a similar study among HIV and TB co-infected children from Dominican Republic in the Caribbean where some children received ARV treatment and by using six months ATT therapy, reported rate of failure was similar to our own and the authors wondered whether a longer duration of therapy was necessary for these children [7]. Therefore, findings from our study support these observations by Espinal et al. [7] and agues for a longer duration of therapy extending up to 9 months in children with HIV and TB co infection. In only half of these cases failure could be attributed to the drug resistance. Poor absorption of the ATT may have been another possible reason for failure of therapy given that a high proportion of these children had malnutrition and/or chronic diarrhea. Drug resistance was seen in three patients out of the six patients who had failed therapy and had resistance testing done from among a total of 17 patients who had completed six months of therapy and had a repeat culture. This would translate to 17.6% resistance of which two-thirds were multidrug resistant, presuming that those who responded to the therapy and were culture negative at 6 month were not resistant to any of the anti-tuberculous drugs used in their treatment. This figure was lower as compared to some other reports [4, 15]. Findings form this study and some other studies where directly observed therapy was used [20] supports the recommendation for directly observed therapy for TB in these children in order to minimize the incidence of drug resistance. Over all a fifth of these children with HIV and Tuberculosis co-infection died during treatment of their Tu-
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berculosis and only one of these cases had infection with documented drug resistance Mycobacterium Tuberculosis. In conclusion, Tuberculosis is a common infection among the HIV infected children and occurs at a young age in the context of the Indian subcontinent perhaps due to endemic nature of Tuberculosis in this part of the world with increased exposure to infective cases of Tuberculosis at a younger age. Non-resolving pneumonia, progressive malnutrition despite adequate ARV and contact with an adult case of pulmonary TB should alert clinician to investigate for TB in these children. After the directly observed standard six months treatment regimen, one third these children remained culture positive for M. Tuberculosis. One fifth of these HIV and TB co-infected children died despite adequate treatment for both the HIV and TB in this setting. ACKNOWLEDGEMENTS We sincerely thank Miss Anjali Gopalan, the Director of the Naz Foundation, New Delhi for her permission to undertake this useful and enriching exercise. We also thank all the staff at the Naz Foundation, New Delhi. Our thanks is also due to Dr. T Pensi, Pediatrics HIV Consultant, AIDS treatment Center at the Ram Manohar Lohia Hospital, New Delhi for her support in carrying out this project. We also disclose that this project was carried out using the funds provided through the Study and Travel Grant from The University of the West Indies. REFERENCES [1] [2]
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Received: May 16, 2007
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Accepted: July 2, 2007
