Introduction

Many relate the steep curve of TB epidemics worldwide and in Ukraine to a sweeping pace of HIV pandemics [5, 8, 9].

Data with numbers of HIV-infected provided by MPH of Ukraine and the Ukrainian Centre for AIDS Prevention reveal that, as of 01.01.2011, some 14 thousand (30.8 per 100 thousand) out of more than 110 thousand on dispensary observation (242.0 per 100 thousand) were diagnosed with AIDS [4].

In 2010, 20.5 thousand (44.7 per 100 thousand) new HIV cases, almost a fifth of them (19.8%) being children born to HIV-infected mothers, were registered in the country [4].

The progression of HIV infection in children is different from that in adults: in 20% children with perinatal HIV transmission path clinical implications emerge and swiftly progress already during their first year of life. Fatalities related to AIDS or AIDS-related conditions can happen even before the HIV status of an infant is confirmed with lab testing. The disease progresses slowly in 80% HIV-infected children, many of them showing AIDS symptoms not before school or adolescence age [11].

Severe immune deficit caused by a progressive reduction of CD4+lymphocyte count and their functional insufficiency is characteristic for HIV infection. It is a well-established fact that CD4+lymphocyte count reduction at HIV infection increases risk of opportunistic infections of which TB is the most serious one [2, 3, 11].

HIV in combination with immune deficit leads to progression from TB mycobacteria infection phase to that of disease; TB in active form, in its turn, spurs further replication [3].

One particular feature of the child's body is that children until five years old demonstrate considerably higher total CD4+lymphocyte count than adults; however, the count gradually decreases to that of adults by age six. Unlike the absolute count, the CD4+lymphocyte rate is unrelated with age and identical for children of all age groups. This is why the CD4+lymphocyte rate is the most objective indicator to evaluate immunosuppression level. Patients with low CD4+lymphocyte counts have poorer prognosis. Parallel tests of CD4+lymphocyte rate and viral load index dynamics allows determining the disease forecast in HIV-infected children [6, 7, 10, 12].

The clinical progression of the diseases and its prognosis in HIV/TB co-infected children depend on many factors and first of all, of the mode of infection with HIV. More than 90% HIV infection cases found in practical paediatrics are related to perinatal infection occurring either before the child birth or intrapartum. They relate some (3–5 %) HIV contraction cases to breast-feeding of infants. Intrauterine infection leads to rapid HIV infection progression, causes spontaneous abortions, congenital defects and stillbirths [1, 2].

Observation of infants with perinatal contact with HIV infection has become a daily practice for primary care paediatricians. The number of HIV-infected infants who have also contracted TB is also on the rise, which only underscores the need for further investigation into HIV/TB concurrent infections in children.

The study objective has been to study into TB development particularities in HIV-infected children.


Research Material and Techniques

The study involved 55 HIV-infected children aged between 0 and 14 first diagnosed with TB, of those 32 (58.2%) boys and 23 (41.8%) girls. They were predominantly — 41 (74.5%) — town-dwellers, with 14 more children (25.5%) permanently residing in rural area. Epidemiological, clinical and lab testing methods were
used throughout the study.

The works were performed for budget money.


Research Results and Their Discussion

The analysis of TB epidemiological situation indicators' dynamics in HIV-infected children under 14 y. o. in 2005–2009 in Ukraine revealed a 2.3 times increase in all TB types (from 0.3 to 0.71 per 100 thousand children of respective age). For the same period, the ratio of first-diagnosed TB cases in HIV-infected children to that of first-diagnosed TB cases in children population increased from 4.6% to 8.2%. In the past five years, the TB morbidity rate among HIV-infected children aged between 0 and 14 fluctuated from 1,640 to 1,900 cases per 100 thousand HIV-infected children. According to 2009 data, the above index exceeded the one for the population more than 200 times (with all active TB forms morbidity rate among children in population at
8.9 per 100 thousand children population).

According to our observations, some 61.9% of affected children were from socially vulnerable families. Seven children 7 (12.7%) were considered to hail from non-needy families. The proportion of children orphans living in boarding houses made 25.4% (14 children). It should be noted that 27 (49.1%) children were raised in incomplete families. Eight (14.5%) children were from families with alcohol-addicted parents. There was information on substance abuse by parents in 11 (20.0%) cases. The real facts may be far more critical, though; in other words, adverse factors do play a serious role in families of HIV-infected children. The age distribution of children first diagnosed with TB in active phase was, as follows: five (9.1В±3.9) % before one year old; 24 (43.6В±6.7)% children from one to four; 19 (34.5В±6.4)% of those from five to nine; and seven (12,7В±4,5)%, from ten to 14.

In the majority of children 47 (85.5±4.8)% cases — TB was diagnosed at medical care referral to general practitioners in relation to health complaints; only in eight (14.5±4.8)% cases the process was discovered based on results of tuberculin diagnostics. Meanwhile, organ-specific tuberculosis has been diagnosed in population based on tuberculin diagnostics in more than 50% cases.

During the studying of life histories of the children, attention was paid to information related to birth weight, neonatological diagnosis, nature and number of intercurrent diseases, and allergic reactions before specific process identification.

Information on birth weight was excerpted from growth charts of 37 children; of those, nine (24.3%) had birth weight not exceeding 2,500 g; two (5.4%), up to 1,000 g; 13 (35.1%) had birth weight of up to 3,000 g; nine (24.3%) were in the range between 3,000 and 3,500 g; and six (16.2%), in excess of 3,500 g.

It was possible to track down neonatological pathology in only 13 children, of whom three (23.1%) had hypotrophy, another three (23.1%), intrauterine hypoxia, four (30.8%) had CNS affliction, and three (23.1%) more with timely delivery were diagnosed with immaturity. 34 children (61.8В±6.6%) did not receive BCG vaccination because of medical contraindications. This can be explained with the fact that BCG vaccination is not envisaged in Ukraine for children born to HIV-infected mothers (or those who have developed AIDS); such vaccination is only allowed for children cleared of HIV status according to lab tests carried out at of the age of 18 months. Nevertheless, a certain proportion of children did receive BCG in maternity clinics because of their mothers' HIV status unknown by the time of delivery.

Of 55 children studied, 21 (38.2В±6.6)% received BCG vaccination at birth. The BCG mark failed to appear in four persons and reached 4 mm in another four; that is, BCG vaccination of HIV-infected children had no effect in (19.0В±8.6)% cases and only little effect, (19.0В±8.6)% cases. The remainder of children (13) had BCG marks from 5 mm to 10 mm in size. No cases of complicated BCG vaccinacion were registered.

Almost a half of the children (26) had information about intercurrent diseases in their anamnesis prior to TB process diagnosis. The children were most frequent (almost 100%) to have acute respiratory diseases; 19 (73.1%) had recurrent bronchitis and 17 (65.4%), pneumonia. There were also individual cases of ORL pathologies (otitis, sinusitis, quinsy), also anaemia, hepatitis b, nonspecific lymphadenitis, skin and mucous membrane diseases (stomatitis, conjunctivitis, streptococcal impetigo), parasitic diseases, intestinal infections, and dysbacteriosis. The discovered opportunistic infections included Seborrhoeic dermatitis (16.4%), fungal skin and mucous membrane diseases (16.4%), chronic diarrhoea (3.6%), and recurrent parotitis (1.8%). Burdened anamnesis was pertinent for 14 (25.5%) children of whom three (21.4%) had multivalent allergy, four (28.6%) were mono-allergic to medications, and seven (50.0%), to foodstuffs.

Epidemiological factor is seen as one of the most important ones of effect on TB infection progression in children. 44 children (80.0В±5.4)% were conclusively established to have contact with TB patients, of these, 38 (86.4%) had it inside their families and six (13,6%) had long-time household contacts. There were 35 (63.6%) children who contacted patients with lab test-confirmed Koch's bacillus release; of these, contacts with resistant TB forms were registered in seven (20.0%) cases.

We were able to ascertain the duration of contact with TB patients in 27 children under survey; the majority of them (17, or 62.9В±8.4%) were in permanent contact one to twelve months until diagnosed with a local TB form, 10 (37.1В±6.8%) children were in permanent contact from 18 to 24 months and longer. It should be noted that chemoprophylaxis was administered to just 17 (30.9В±6.2%) of those children who were first diagnosed with tuberculosis and lived in disease hotbeds. Tolerance to chemoprophylaxis in these children was unsatisfactory in 40% cases. During the course of TB examination, children were administered tuberculin diagnostics. The assessment of intensity of skin reactions to Mantoux test with 2 TU PPD proved negative in 34.6% patients, doubtful (with infiltrate up to 5 mm in size) in just 3.6%, positive in 41.8%, and hyperergic (17 mm and more), in 20.0% children. A comparison with TB-affected, HIV-negative children shows a trend towards a greater frequency of negative and doubtful reactions (СЂ>0.05) that can be explained with complications in delayed hypersensitivity reaction development in children with immune system irregularities (immune deficit).

Concomitant diseases are known to belong to TB development risk factors in children. Owing to comprehensive examination of the mentioned group of children, a concomitant pathology was found as of the
moment of TB diagnosis in 33 children (60.0В±6.6)%.

One and two concomitant diagnoses were found in nine children (16.4%) each; three concomitant diagnoses were found in seven (12.7%); four and more, in eight (14.5%) children.

Concomitant pathologies in HIV-infected children with TB were represented by the following diseases and conditions: candidoses (29.1%), recurrent bacterial infections (20.0%), psychophysiological development retardation (18.2%), skin diseases (16.4%), anaemias (16.4%), congenital abnormalities (9.1%), herpes dermatitis (5.5%), cytomegalovirus infection (5.5%), thrombocytopaenia (3.6%), responsive pancreatitis (3.6%), palsy and paralysis (3.6%), dysbacteriosis and chronic diarrhoea (3.6%), helminthoses (3.6%), pneumocystic pneumonia (1.8%), relapsing parotitis (1.8%), condylomas (1.8%), papillomatous prolifera_ tions (1.8%), adenoid vegetations (1.8%), hearing loss (1.8%), and hairy leukoplakia (1.8%).

Tuberculosis often debuts under the guise of various therapeutic 'masks'. Based on the data of 32 children on their latest disease before TB diagnosis it was established that the children had some acute condition that immediately preceded the TB diagnosis in more than 90% cases. HIV-infected children had verifiably higher (compared with HIV-negative) rates of pneumonia (11 cases, or 34.4В±8.4%), acute bronchitis (nine cases, or 28.1В±8.0%), ARD (four cases, or 12.5В±5.9%), otitis (three cases, or 9.4В±5.2%). That is, it is necessary to thoroughly check HIV-infected children with high cold-related and viral diseases at general medical care network facilities or AIDS Prevention Centres with mandatory Mantoux tests with 2 РўU PPD.

The onset of TB disease was sub-acute in 23 (41.8 %) HIV-infected children and acute, in 11 (20.0%).

The progressive form of onset in absence of complaints was noted in 21 (38.2%) children. Before the beginning of specific treatment, 36 children from that group complained about their health status: 50.9% had coughs, 5.5% complained of shortness of breath, and 45.5% had febrile course. Manifestations of intoxication syndrome characterised with weakness, fatigability, loss of appetite, sweating, body mass reduction were observed in 49.1% children. There were no health complaints from 34.5% patients.

The analysis of the structure of clinical TB forms showed 27 (34.2%) had tuberculosis primary complex that progressed with complications in eight (33.3%) children. Disseminated tuberculosis was the second most frequent: 22 (27.8%) children. Tuberculosis of intrasternal lymphatic nodes was observed in 20 (25.3%) children; almost a half of the patients (10 children) with that type of tuberculosis had complications in the form of infiltration, lung tissue collapse and lesion of the bronchi. Generalised tuberculosis with damage to lungs, intrasternal lymphatic nodes and the nervous system was found in four (5.1%) children.

At admission, 45.5% had unsatisfactory general health condition, 18.2% had sleep disturbances, and 52.7%, loss of appetite. Excessive sweating at night was observed in 34.5% children, and 7.3% patients complained of pains in the chest. Objective observation data showed skin pallor (70.9%); periorbital cyanosis in 32.7% children, oropharyngeal changes- in a quarter of the patients (25.5%). Short breathing was discovered
during the objective observation in 21.8% despite initial complaints of that from only 5.5% children.

Productive cough was twice as frequent as dry cough and predominantly with mucous expectoration. That way, the majority of HIV-infected children had complaints and clinical implications also proper to non-specific respiratory system diseases at the time of being diagnosed with TB.

All of the HIV/TB-infected children had changes in their lymphatic nodes at the time of specific process identification. The majority of them (83.6%) had enlarged peripheral lymphatic nodes in groups of five to six and more. The lymphatic nodes predominantly had elastic body with the size of up to 10 mm. The lymphatic nodes of the cervical group were the most frequent to enlarge while the axillary ones were found to be twice as less frequent (63.3% and 29.1%, respectively). Other groups of lymphatic nodes (submandibular, submental, supraclavicular, inguinal) were enlarged in considerably smaller number of cases (from 20.0% to 3.6%). Generalised lymphadenopathy was observed in 27.3% children. 65.5% children were found to have enlarged liver and 38.2%, enlarged spleen.

According to our data, the majority (60.0%) of children had 3rd, and 40.0% — 4th clinical stage of HIV infection. In other words, almost all of the children had certain specific HIV manifestations.

CD4+lymphocyte counts, both in absolute terms and percentagewise, showed grave immunosuppression in 17 (34.0%) children with almost the same 16 (32.0%) number of patients having insubstantial immunosuppression. The number of children with light and medium immunosuppression was almost identical: eight and nine (16.0% and 19.0%), respectively. That is, immunosuppression manifestations took place in more than 90% cases and took a grave form in every third child.

The observation carried out by specialist physicians resulted in the following deviations from the norm observed in HIV/TB-infected children: 7.3% in cardiovascular, 12.7% in central nervous and 9.1% in digestion systems. Deviations in locomotorium (5.5%) and sensory organs (3.6%) were found in a slightly lesser
number of cases. At analysing FBC lab test results, reduced haemoglobin and RBC counts were found in 61.8% cases, leukopenia, in 67.3%, high lymphocyte count, in 36.4%, and lymphopenia, in 43.6% cases. That is, insufficient cellular immune response was found in 80.0% children with HIV/TB. Increased levels of alanine aminotransferase were noted in 36.4% and of asparagine aminotransferase, in 38.9% children; reduced total protein serum levels were found in 29.1% children first diagnosed with tuberculosis.

Mycobacterium tuberculosis were found in 18.6% observed HIV/TB-infected children, which is higher than the relevant bacterioexcretion index for children in population in 2006–2009 (10.2%–15.8%).


Conclusions

The study results confirmed that close contact with TB patient, the lacking or inefficient BCG vaccination, concomitant diseases and living in socially vulnerable, low living standard families are factors contributing to
TB development in HIV-infected children.

90% children with HIV/TB had acute conditions (pneumonia being the verifiably most frequent one) and addressed general-purpose medical institutions for medical help immediately before diagnosed with TB. 61.8% children born to HIV-infected mothers received no BCG vaccination because of medical contraindications. Among BCG-vaccinated children, 38.0% had either low-grade mark or no mark at all, which speaks for low efficiency of such vaccination.

Immunosuppression symptoms in HIV-infected children were discovered in more than 90% cases; every third child had them in grave form.

61.8% children with HIV/TB demonstrated positive reaction to subcutaneous tuberculin injectinon; a fifth of the children had hyperergic reaction to Mantoux test with 2 TU PPD.
TB is diagnosed in HIV/TB-infected children upon referral in 85% cases while in population more than 50% diagnoses result from tuberculin diagnostic tests.
There is no strict correlation between Mantoux results and immunosuppression level; that is, tuberculin test may be positive even with immunosuppression symptoms available which fact speaks of diagnostic value of the test.


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