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R.H. Merchant
R.C. Shroff
From the Bai Jerbai Wadia Hospital for Children, Acharya Donde Marg, Parel,
Mumbai 400 012, India.
Reprint requests: Dr. R.H. Merchant, Professor of Pediatrics and Chief Division of Neonatology, B.J. Wadia Hospital for Children, Acharya Donde Marg, PareI, Mumbai 400 012, India.
Manuscript received: June 25, 1997;
Initial review completed: August 4,1997;
Revision accepted: April 16, 1998.
The association of human immuno-deficiency virus (HIV) and tuberculosis has two important facets: (a) high incidence of atypical mycobacterial infection, especially that caused by Mycobacterium avium and Mycobacterium intracellulare
complex(1); and (b) emergence of multidrug resistant (MDR) strains which makes TB once again an 'incurable' disease(2).
A syndrome of chronic diarrhea and significant weight loss (Slim's disease)(3) is one of the major manifestations of acquired immune deficiency syndrome (AIDS). There are two important explanations. for this complication: (a) Opportunistic enteric infection(3,4) for which the common organ~ isms include candida, cryptosporidium, cytomegalovirus, giardia, isospora belle and salmonella; and (b) HIV enteropathy which results in dysfunctional immunity at the lamina propria
of the gut with a resultant decreased secretory IgA(5), the principle protective intestinal immunoglobulin.
Although prevalence of HIV seropositivity has been documented in many states and population groups in India, most of the samples screened and data available have been from the high risk group, especially adults. As data on HIV seropositivity in children is scanty, we determined the prevalence of HIV in children with chronic diarrhea and disseminated TB admitted to a pediatric hospital. The results of the study are presented in this communication.
Subjects and Methods
A prospective study of 100 patients admitted in one of three pediatric units of a large university affiliated pediatric hospital, which is not situated near the 'red light area', was carried out over a period of two years, from July 1994 to June 1996. Patients belonged to low socio-economic strata and were recruited after proving the diagnosis of disseminated TB or chronic diarrhea as outlined below. Fifty children with disseminated TB (defined for study purpose as miliary or CNS TB) and 50 with chronic diarrhea (the passage of three or more watery stools daily for a period of at least 14 days), in whom disaccharide intolerance was ruled out, were tested for HIV seropositivity. Their ages ranged from 1 month to 11 years. Both sexes were equally represented. CNS tuberculosis was diagnosed on the basis of CT Scan and cerebrospinal fluid examination along with supportive evidence of TB. Miliary TB was diagnosed clinically on the basis of miliary mottling on chest skiagram. In the clinical setting of chronic diarrhea where in. sugar intolerance was ruled out, a routine stool
examination, and stool culture as well as special staining for cryptosporidium was done.
All children in the study were subjected to ELISA testing using the NOVOPATH
HIV I and II EIA kit of Biorad Labs. If a patient tested HIV positive, the ELISA test was repeated using a solid phase EIA HIV test kit for HIV I and II of Biochem Immunosystens Inc., Canada. Both these HIV kits utilize third generation ELISA technique. The patient was declared HIV seropositive only after confirming seropositivity using these two different ELISA techniques. For all patients who tested HIV seropositive
by ELISA technique the Western Blot was also performed. For Western Blot testing, the New Lav Blot 1, New Lav Blot 2 and Biorad Methods were used.
All patients less than 15 months of age who tested seropositive by ELISA or Western Blot had their infectivity confirmed by polymerase chain reaction for HIV DNA. In every child who tested HIV positive, the mothers HIV status was also checked using the same ELISA kit. In two patients with CNS TB, cerebrospinal fluid was tested for HIV antibodies by Western Blot technique. Clinical and laboratory data were recorded on a preformated proforma and complete confidentiality was maintained.
Results
Nine children (18%) with disseminated TB and twelve children (24%) with chronic diarrhea tested HIV seropositive, giving a total seropositivity of 21% (Table I). A 3-month-old infant with miliary TB, born to a HIV positive mother whose ELISA test was positive, tested negative by PCR
for HIV Viral DNA, thus indicating only a passive transfer of
antibodies. This patient was excluded from the study.
In the present study, the commonest
mode of transmission (71%) was perinatal. Three children had acquired the infection following transfusion of unscreened blood, while 1 case, an 11 year old street child, had a definite history of unprotected sexual
encounter
(Table
II). He also suffered from
veneral warts but tested negative for syphilis. In 2 children, the exact mode of transmission could not be ascertained.
In 2 cases with CNS affection, the. CSF Western Blot test was done and both tested positive, confirming the diagnosis of HIV encephalopathy. In both these patients, CT scan of brain showed basal ganglia calcification.
Of the cases with chronic diarrhea, 40% (20/50) had asscociated oral candidiasis and another 10% (5/50) had both oral and perianal candidiasis.
Stool testing in patients with chronic diarrhea revealed giardiasis in 4 (8%), cryptosporidiosis in 3 (6%) and candidiasis in 10 (20%). Twelve patients (24%) had pathogenic strains of E. coli grown in stool culture, while three cases each (6%) had Klebsiella and Pseudomonas aeruginosa species grown on stool culture.
Patients who had candidiasis on stool culture were treated with fluconazole in the dose of 10-15 mg/kg/day for a period of 3-4 weeks. However, unlike other immunocompetent patients, these children did not respond to therapy or relapsed within 1-2 weeks after stopping treatment. Ketoconazole was used in 1 patient for the treatment of esophageal candidiasis. Patients with disseminated TB were initially treated with the first line bactericidal antituberculous drugs, but 5 of the HIV positive children required second line drugs. The incidence of atypical or MDR-TB could not be evaluated in this study.
Out of the 21 children who were HIV positive, 3 children with extensive TB and 3
with chronic diarrhea expired during the study period of 2 years. Post mortem was not performed in any of these children. Long term outcome could not be studied due to poor follow up.
TABLE
I
HIV Seropositivity in Cases of Disseminated Tuberculosis and Chronic Diarrhea
|
|
Disseminated tuberculosis |
Chronic diarrhea
|
|
Age group |
No. tested |
No. +ve |
%+ve |
No. tested |
No. +ve |
%+ve |
|
1 - 15 mo |
9 |
3 |
33.3 |
23 |
6 |
26.1 |
|
16 mo - 3 yr |
18 |
3 |
16.7 |
20 |
4 |
20.0 |
|
4-7yr |
10 |
2 |
20.0 |
6 |
2 |
33.3 |
|
≥8yr |
13 |
1 |
7.7 |
1 |
0 |
0 |
|
Total |
50 |
9 |
18.0 |
50 |
12 |
24.0 |
All the 9 seropositive children below 15 months of age were confirmed
positive by PCR technique.
TABLE II
Mode of Transmission in HIV
Seropositive Children (N
= 21)
Mode of
transmission |
No.
seropositive |
Percentage
seropositive |
|
Perinatal |
15 |
71.4 |
|
Blood transfusion |
3 |
14.3 |
|
Sexual route |
1 |
4.8 |
|
Unknown |
2 |
9.5 |
Discussion
children are caught in the HIV epidemic as innocent bystanders. The HIV pandemic is spreading rapidly at a global level and it is estimated that the 2-3 million
I
deaths due to TB that have occured in 1995 are attributable to HIV infections(6). It has been projected that death due to HIV and TB will continue to rise and will constitute
14% all TB deaths by the year 2000 AD(7).
Similarly with diarrheal infections rampant in the tropical countries, HIV has become a common cause of persistent, recurrent and
recalcitrant diarrhea(5).
.
The prevalence of HIV infection in the
!
adult population of TB victims in Bombay
city has been documented to be around 23% (unpublished data). The present study showed an equally high HIV seropositivity rate among children with disseminated tuberculosis. The seroprevalence
of HIV in a population of pregnant women studied in Bombay is
approximately 1%(8), accounting for the high incidence of perinatally transmitted HIV infection as was found in this study.
Most infants who get HIV through their mothers succumb to their
illness in the first few years of life. Statistical analysis shows
that 15-25% of HIV infected children. in the western countries
progress to AIDS in the first year and, 10-12% annually
thereafter(9). In sub-Saharan Africa, 44% of HIV infected newborns died within the first few
years of life(10).
The severity of HIV associated disease and the length of survival are also deter- mined by the exposure to different infections
prevalent in an area as well as the availability of health care
services. Tuberculosis is one of the most common life threatening opportunistic infections among children infected with HIV, and it occurs at higher CD4 cell counts when immune deficiency is comparatively less advanced(11). Studies from Zambia show that the HIV seroprevalence rate is 37% amongst children with tuberculosis, as compared to 11%
amongst those without TB; HIV seropositivity was 53% in the 12-18 month age group and 14% in 10-14 year olds(10). Unfortunately, similar studies from India are lacking; however as the disease pattern and socio-economic conditions are similar to those in Africa, the alarmingly high HIV seroprevalance
in this study can be explained. Although formal studies could not be performed, the need for second line anti-tuberculous drugs in 5 of the HIV positive children, shows that MDR-TB has added greatly to the difficulties in combating this disease. Indeed, as the mortality from MDR-TB approaches that of untreated TB infection, this disease may once again come to be known as "captain of all men of death".
Under-diagnosis and under-reporting make HIV-associated chronic diarrhea in children an even lesser known identity, the cause of diarrhea being obscure and often involving a complex interaction between infections by well-defined enteric pathogens and intestinal immune deficiencies. Diarrhea is a complication of HIV infection
in
30-60% of adult patients with AIDS in industrialized countries and in 60-90% of such patients from Africa(10).
The reduced T-helper cells function results in alteration in the
mucosal immune system (MIS) in the gut; resulting in a persistence of infection by mycobacteria and protozoa(12). The antigen induced mast cell activation results in immediate hyper-sensitivity mediated secretory diarrhea, while alterations in the neuro-endocrine immune networks can cause autonomic dysfunction(13). Candidiasis is the most common opportunistic infection in these cases and usually tends to become disseminated, first spreading to the esophagus. Odynophagia with oral thrush is a definite marker for HIV.
As AIDS spreads, the achievements
made in the sphere of child survival and primary health care can be severely under- mined. According to WHO, in areas where 20% of women are HIV-infected, the child mortality rates increase by over one third. The most important approach in controlling pediatric AIDS is by reducing perinatal transmission of HIV; As sexual transmission accounts for 80-90% of HIV infection in Asia, efforts to promote safer sexual practises as well as prevention of mother to infant transmission using anti-retroviral therapy(4) should be taken up as priority issues.
Given the high incidence of HIV seropositivity in this study, it may be advisable to confirm these findings on the basis of larger community based data before recommending mandatory HIV testing in all children with disseminated tuberculosis and chronic diarrhea. There is hence a need to collect more data on this subject and take appropriate preventive and therapeutic measures before the dual infection of TB and HIV spread to epidemic uncontrollable proportions.
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