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Extra-pulmonary tuberculosis in children

H C Maltezou, P Spyridis, D A Kafetzis

AbstractMethodsThe clinical and epidemiologi-cal features of 102 children with extra-

pulmonary tuberculosis, diagnosedbetween 1982 and 1998 at P & A KyriakouChildrens Hospital were reviewed.ResultsDuring the past decade, a 50%

increase of admissions for extra-pulmonary tuberculosis was observed.The source of infection was disclosed in 48

patients. Diagnoses included superficiallymphadenitis (n = 48), pleural eVusion(n = 27), meningitis (n = 16), skeletal tu-

berculosis (n = 5), miliary tuberculosis(n = 3), abdominal tuberculosis (n = 2),and pericarditis (n = 1). Miliary tubercu-

losis developed in infants, lymphadenitis

and meningitis in preschool children, andpleural eVusion and skeletal tuberculosis

in older children. None of the patientswith extra-pulmonary tuberculosis died;however, six patients with meningitis

developed permanent neurological defi-cits. In these patients, antituberculoustreatment was introduced at a median of

six days following admission as comparedwith one day in patients with no complica-tions. Poverty, immigration, and limited

access to medical services were commonamong patients with meningitis.(Arch Dis Child2000;83:342346)

Keywords: M tuberculosis; extra-pulmonary

tuberculosis

Tuberculosis constitutes the main infectiouscause of death worldwide. An estimated 1.3million cases of tuberculosis and 450 000 asso-ciated deaths occur annually in children.1

Extra-pulmonary tuberculosis accounts for upto one third of all cases.2 3 Children show ahigher predisposition to the development ofextra-pulmonary tuberculosis.4 5 The impact ofextra-pulmonary tuberculosis is greatestamong infants and young children who tend todevelop more severe extra-pulmonary disease,especially mening itis and miliar y

tuberculosis.

4 5

A significant increase in the number of chil-dren with tuberculosis has been noticed inGreece recently, which is mainly attributed tothe immigration shift from Eastern Europeduring the past decade. In particular, theannual incidence of childhood tuberculosis inthe area of Athens has increased from 7.8 casesper 100 000 children during the 19871990period to 14 cases per 100 000 children duringthe 19951998 period, of which 4.5% (19871990) and 31% (19951998) occurred in chil-dren of immigrants.6 In 1999, the incidence inthe general population in Greece was 22 cases

per 100 000, of which 43% were immigrants(Infectious Diseases Confirmation and Inter-vention Center, Ministry of Health, Athens,Greece; personal communication).

In the current study we present our 17 yearsexperience with extra-pulmonary tuberculosisin children, with emphasis on epidemiologicaland clinical features, and outcome.

Patients and methodsP & A Kyriakou Childrens Hospital is a 510bed university tertiary care hospital in Athens,Greece. It provides medical services to ap-proximately 800 000 paediatric residents, inassociation with the only other 800 bed paedi-

atric hospital in this area. Medical services areprovided to all children irrespective of countryof origin,status of insurance, or other socioeco-nomic parameters. All children 0 to 14 yearsold who were admitted with tuberculosisbetween January 1982 and December 1998were identified through a computerised data-base system. Only patients with an extra-pulmonary site of infection were included inthe study.

Extra-pulmonary tuberculosis was definedas identification of Mycobacterium tuberculosisthrough ZiehlNeelsen acid fast stain and cul-ture in LoewensteinJensen or BACTECmedia in a tissue or specimen from a site otherthan lung parenchyma, in association with

clinical and/or imaging findings compatiblewith infection locally. In case of negativecultures, extra-pulmonary tuberculosis wasdefined as clinical, laboratory, imaging, and/orhistopathological evidence of mycobacterialinfection in a site other than hilar lymph nodesor lung parenchyma, in association with a posi-tive tuberculin skin test reaction and/or historyof exposure to tuberculosis, and exclusion ofother diseases. Tuberculin skin test was inter-preted at 4872 hours following intracutane-ous injection of 5 tuberculin units of purifiedprotein derivative, and was considered positiveor negative when the local induration was atleast 10 mm or less than 10 mm, respectively,

regardless of erythema. The RT23-SSI and the5780A PasteurMerieux tuberculin lots wereused before and after 1995, respectively.

Access to medical services was determinedby the completeness of the routine vaccinationschedule (diphtheria and tetanus toxoids,pertussis vaccine, and poliovirus vaccine)according to the patients age. BCG vaccine isadministered to all children at the time ofschool entry (6 years of age) or at any age inchildren at high risk for tuberculous infection,following a negative tuberculin skin test.

DiVerences between continuous variableswith non-normal distribution were estimated

Arch D is C hild2000;83:342346342

University of AthensSecond Department ofPediatrics, P & AKyriakou Childrens

Hospital, Athens,11527, GreeceH C MaltezouP SpyridisD A Kafetzis

Correspondence to:Dr Kafetzisemail:[email protected]

Accepted 24 May 2000

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with the MannWhitney test. All statisticalanalyses were two tailed.

ResultsDuring the study period, 102 children wereadmitted with extra-pulmonary tuberculosis in

our hospital.Between the 1980s and the 1990s,a 50% increase of admissions for extra-pulmonary tuberculosis was noted. The corre-sponding increase of admissions for pulmonarytuberculosis was 106% (fig 1). Overall, extra-pulmonary tuberculosis accounted for 9% ofthe total 1161 cases of tuberculosis admitted inour hospital during the study period. Table 1lists the characteristics of patients with extra-pulmonary tuberculosis. Table 2 shows the siteof infection and the corresponding ages of thechildren. Forty per cent of the cases ofextra-pulmonary tuberculosis were cultureconfirmed (table 3). One multiple drug resist-ant M tuberculosis strain was detected amongthe cases studied; all other isolates weresusceptible to antituberculous agents.

LYMPHADENITIS

A total of 48 patients were admitted withtuberculous lymphadenitis. Lymph node en-largement was the only sign of infection in 47of them, preceding their admission by a medianof 35 days (range: two days to one year). Theremaining patient was admitted with highgrade fever; he developed lymph node enlarge-ment three days post-admission. The sub-mandibular and anterior cervical lymph nodeswere the most frequently involved nodes.

Twenty four of the 48 patients had a concur-rent site of infection, including hilar lymphad-enitis (23 patients) and adenoid tonsils andnasal tubercle (one patient). Chest radiographsdisclosed a primary focus of infection andenlarged hilar lymph nodes in 21 patients, andcalcified nodules in two others; the remaining25 patients had normal chest radiographs.Tuberculin skin test in 47 patients had amedian induration of 15 mm (range 1030mm). One patient noted a 5 mm induration.

Treatment consisted of a nine month courseof isoniazid and rifampicin (35 patients) or asix month course of isoniazid and rifampicin in

association with pyrazinamide during the firsttwo months (13 patients). Thirty three of the48 patients underwent surgery for diagnosticand/or therapeutic reasons at a median of 60days (range: two days to one year) following theonset of lymphadenitis, including total excision(27 patients), incision and drainage (fivepatients), and wide debridement (one patient).Lymph node examination in 29 patientsrevealed histopathological features compatiblewith tuberculosis in all and M tuberculosisdetection in 11. In addition, histopathologyand cultures revealed tuberculosis in theexcised nasal granuloma and adenoid tonsils.Two patients had a second operation; one

because of the development of axillary tubercu-lous lymphadenitis 75 days following totalremoval of collateral epitrochlear lymphadeni-tis, and another for aesthetic reasons. Gastricfluid cultures were performed in 15 patientsand were positive in eight. Overall, 19 cases oftuberculous lymphadenitis were culture con-firmed. In the remaining 29 cases, distinctionfrom non-tuberculous mycobacterial lymphad-enitis was based on a positive tuberculin skintest reaction, in association with chest radio-graphic findings compatible with tuberculosisand/or a history of exposure to tuberculosis.

Figure 1 Distribution of patients with pul monary tuberculosis and extra-pulmonarytuberculosis according to year of admission.

140

120

80

100

60

40

0

20

Pulmonary tuberculosis

1982 1984 1986 1988 1990 1992 1994 1996 1998

Extra-pulmonary tuberculosis

Table 1 Characteristics of 102 children withextra-pulmonary tuberculosis (%)

Sex (male/female) 63/39Median age (range), years 4.5 (0.5 to 14)Immigrants 12 (12)Very low income or unemployed family 13 (13)Completely unvaccinated* 20 (23)Immunodeficiency 0 (0)I de nt ifi ed s ou rc e o f i nf ec ti on 4 8 ( 47 )

*Against diphtheria, tetanus, pertussis, poliovirus, measles,mumps and rubella, according to the patients age.Of 87 children with recorded vaccination status.Close family member or friend in all cases.

Table 2 Distribution of 102 children withextra-pulmonary tuberculosis with reference to site ofinfection and age

Site of infectionNo.of children(%)

Median age(range)

Lymphadenitis* 48 (47) 3 (112)Pleural eVusion 27 (26.5) 10 (214)Meningitis 16 (15.5) 4 (0.510)Skel eta l tuberculosis 5 (5) 6 (614)Miliar y tuberculosis 3 (3) 0.5 (0.51)A bd om ina l t ub er cu lo si s 2 ( 2) 6 .5 ( 3. 5 9. 5)

Pericarditis 1 (1) 9

*One patient had also adenoid tonsils and nasal tubercle.One patient had also tuberculous otitis and mastoiditis.

Table 3 Culture confirmed cases of extra-pulmonarytuberculosis (%)

Type of infectionNo.of culture confirmedcases

Lymphadenitis 19 (39.5%)Pleural eVusion 9 (33%)Meningitis 8 (50%)Skeletal tuberculosis 1 (20%)Miliar y tuberculosis 3 (100%)Abdominal tubercul osis 0 (0%)Pericarditis 1 (100%)Total 41 (40%)

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PLEURAL EFFUSION

Of the 27 patients with tuberculous pleuraleVusion, 24 had symptoms including fever (22patients), cough (10 patients), chest pain(seven patients), weakness (five patients),weight loss (four patients), and respiratory dis-tress (two patients). Fever persisted for amedian of 10 days (range 130 days). In theremaining three asymptomatic patients, pleuraleVusion was detected through contact investi-

gation of a family member recently diagnosedwith tuberculosis. The median tuberculin skintest induration for 26 patients was 20 mm(range 1030 mm); one patient had noreaction. In addition to pleural eVusion, chestradiographs showed enlarged hilar lymphnodes and nodular infiltrates in nine patients,interstitial markings in two, and atelectases inanother. Seventeen patients had gastric fluidcultures, nine of which were positive. Fifteenpatients received isoniazid plus rifampicin fornine months, and 12 received isoniazid andrifampicin for six months in association withpyrazinamide during the first two months.Adjunctive steroid treatment was administered

for six weeks in 13 patients. All 27 patientsnoted clinical and radiographic response; how-ever, three of them had recurrence of pleuraleVusion within one month of steroid discon-tinuation. Residual lesions (parenchymal orlymph node calcifications, or small pleuraladhesions) were present at treatment comple-tion in six patients; all others noted completeradiographic resolution.

MENINGITIS

Of the 16 patients with tuberculous meningitis,six were completely unvaccinated, very lowincome immigrants. Overall, patients withmeningitis accounted for 46% of very lowincome patients, 42% of immigrants, and 25%

of completely unvaccinated patients with extra-pulmonary tuberculosis.

All patients with meningitis presented withhigh grade fever preceding their admission by amedian of seven days (range 017 days). Feverpersisted for a median of 19 days (range 550days). Additional signs and symptoms includednuchal rigidity (12 patients), vomiting (11patients), headache (nine patients), drowsiness(seven patients), refusal to feed (four patients),weakness (three patients), status epilepticus(one patient), and irritability (one patient).Overall, tuberculous meningitis cases wereclassified as grades I and II with eight patientsin each group.

The median tuberculin skin test indurationin 14 patients was 15 mm (range 1022 mm);two patients had no reaction. Chest radio-graphs showed nodular infiltrates and enlargedhilar lymph nodes in seven patients andcalcified nodules in two. Seven patients hadnormal radiographs. Computed tomographyand/or magnetic resonance examinations wereperformed in 11 patients and were abnormal insix. Findings included hydrocephalus in all sixpatients in association with basal gangliavascular infarcts in one patient, tuberclelocated at hypophysis in another, and spinalleptomeninges involvement in a third. Micro-

biological confirmation was established in eightpatients. Overall, cerebrospinal fluid (CSF)cultures were performed in 16 patients andwere positive in six; gastric fluid cultures wereattempted in 11 patients and were positive infour.

Patients with meningitis remained hospital-ised for a median of 33 days (range 16125days). Antituberculous treatment was insti-tuted in all patients at a median of two days

(range 08 days) following admission. From1982 to 1988, treatment for tuberculous men-ingitis consisted of isoniazid and rifampicin for12 months in association with streptomycinduring the first two months. Beginning in1989, pyrazinamide for two months was addedto the aforementioned regimen. Adjunctivesteroid treatment was administered to allpatients for a four week period followed bygradual dosage tapering. Five patients devel-oped generalised seizures followed by apnoea,including two who required mechanical venti-lation; two underwent shunt surgery for CSFflow relief; two had 7th cranial nerve palsy; andone developed transient diabetes insipidus.

None of the patients died. However, twopatients noted recurrence of meningitis as aresult of non-compliance with treatment. Closesupervision of treatment administration en-sured their compliance. Regarding long termcomplications, six of the 16 patients developedpermanent neurological deficits including bal-ance impairment and urinary incontinence(two patients), blindness (one patient), quadri-plegia, severe mental retardation, and seizures(one patient), fine movements impairment(one patient), and learning disabilities (onepatient). Both patients with meningitis recur-rence had neurological deficits. The medianinterval from admission to treatment introduc-tion was six days (range 38 days) for patients

with long term complications, and one day(range 03 days) for patients with no long termcomplications (p = 0.21). A further compari-son between patients with and without longterm complications showed that the formerpatients were younger (median age 3 v 5 years;p = 0.97), had smaller skin test reactions(median induration 7 v 15 mm; p = 0.45) andmore pronounced CSF abnormalities (table 4).In particular, increased white blood andneutrophil counts were associated with thedevelopment of complications (p < 0.10). NodiVerence was observed regarding the medianinterval from the onset of symptoms to time ofadmission and the addition of pyrazinamide to

treatment.

SKELETAL TUBERCULOSIS

Five patients developed skeletal tuberculosis.The following sites were aVected: hipfemoraljoint (two patients), knee joint (two), and tho-racic spine (one). Findings included localisedinflammation (four patients), fever (threepatients), limping as a result of pain (threepatients), and restricted movements (twopatients). Isotope scanning showed increasedradionuclide uptake from the involved sites.Patients had a median tuberculin skin testinduration of 20 mm (range 1420 mm).

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Enlarged hilar lymph nodes were shown inthree patients; the other two had normal chestradiographs. Surgery was performed in bothpatients with hipfemoral joint tuberculosisand revealed granulomatous tissue; however,bone cultures were negative. Synovial fluid cul-tures were performed in one patient with kneetuberculosis and were negative. Treatmentconsisted of isoniazid, rifampicin, pyrazina-mide, and streptomycin for two months,followed by isoniazid and rifampicin for a totalof 12 months. Complete clinical and imaging

restoration was achieved in all patients withinfive months of treatment introduction. How-ever, one patient developed chronic painlessotorrhoea three months following treatmentintroduction. Computed tomography showedmastoiditis, and otomicroscopy disclosed whitecaseous material and granulomatous tissue inthe inner ear. Cultures grew a multiple drugresistant M tuberculosis strain. Moderate unilat-eral high frequency sensorineural hearing losswas manifested. Ethambutol and cycloserinwere added to treatment for a total of sixmonths with complete clinical response.

MILIARY TUBERCULOSIS

Three patients developed miliary tuberculosis.

The following symptoms were present: fever(three patients), cough (two patients), failure tothrive (two patients), tachypnoea, expiratorywheezing, and prolonged expiration (onepatient), and night sweats (one patient). Chestradiographs showed bilateral, diVuse micron-odules and lobular consodilation (three pa-tients), atelectases (two patient), and enlargedhilar lymph nodes (one patient). The mediantuberculin skin test induration was 10 mm(range 1015 mm). All patients had positivegastric fluid cultures. Bronchiolitis was initiallydiagnosed in one infant; steroids were adminis-tered followed by clinical deterioration. At thattime, the patients positive tuberculin skin test

reaction and its family history of tuberculosisbecame known and the diagnosis was estab-lished. All three patients were successfullytreated with a nine month course of isoniazidplus rifampicin, in association with pyrazina-mide and streptomycin during the first twomonths. Steroids were also administered for sixweeks. No complications or relapse occurredamong the three infants with miliary tubercu-losis.

ABDOMINAL TUBERCULOSIS

Two patients developed abdominal tuberculo-sis; both presented with abdominal distension

and fever for two weeks. One patient reportedanorexia, fatigue, and low grade fever duringthe past three months, whereas constipationand dilated superficial abdominal veins wereencountered in the other. Both patients hadanaemia, positive skin test reactions (16 and 11mm), and normal chest radiographs. Abdomi-nal imaging revealed enlarged mesentericlymph nodes and a large amount of peritonealfluid in both patients, and an enteric

peritoneal fistula in one. No signs of intestinalobstruction were present. Patients received a12 month course of isoniazid plus rifampicin inassociation with pyrazinamid for two months.Excellent response was noted. Both patientsare free of active infection approximately 10years following diagnosis.

PERICARDITIS

One child was admitted with fever, chest pain,and respiratory distress of three days duration.Weight loss was noted during the last month.Tuberculin skin test reaction was 20 mm.Chest imaging findings included miliary tuber-culosis, accumulation of pericardial fluid, and

adhesions within the pericardial space. Para-centesis yielded 300 ml of fluid. Pericardial andgastric fluid cultures grew M tuberculosis. Thepatient was successfully treated with isoniazidand rifampicin for 12 months in associationwith streptomycin, pyrazinamide, and steroidsduring the first two months. No complicationsor relapse of tuberculosis occurred.

Discussion

Before the availability of agents with activityagainst M tuberculosis, the development oftuberculosis was associated with a progressivecourse and fatal outcome in up to 50% ofpatients.1 The introduction of antituberculousagents has become the cornerstone of manage-

ment of such infections. In the current study allchildren with extra-pulmonary tuberculosiswere successfully treated. No deaths occurred.

Tuberculous meningitis remains the mostserious form of extra-pulmonary tuberculosis.In the present study, long term complicationsonly occurred in patients with meningitis, per-manent neurological deficits developing inmore than one third. Younger age and delay inthe introduction of appropriate therapeuticagents rendered these children vulnerabletargets for the development of serious compli-cations. Similar findings have been reportedfrom other studies.4 5 79 In addition, in thepresent study, patients with neurological com-

plications tended to manifest smaller tubercu-lin skin test reactions and more pronouncedCSF abnormalities compared to patients with-out neurological complications. However, withthe small number of cases, these observationsdid not reach statistical significance.

In the present series, tuberculous meningitismanifested as a febrile illness with a medianduration of seven days prior to admission inassociation with a variety of signs and symp-toms. A more indolent course has beenobserved in other series and may postpone theestablishment of clinical suspicion fortuberculosis.8 9 Considering the resurgence of

Table 4 CSF findings in 16 children with tuberculous meningitis

ParameterPatients with long termcomplications (n=6)

Patients without longterm complications(n=10) p value*

WBC count (cells/l) 470 (3501240) 202 (80950) 0.10ALC count (cells/l) 433 (315930) 193 (64855) 0.27ANC count (cells/l) 77 (35310) 14 (095) 0.08Protein level (mg/l) 383 (82685) 92 (6168) 0.53Glucose level (mg/l) 16 (1070) 29 (1456) 1.00Glucose level ratio 0.08 (0. 080.65) 0.33 (0.240.41) 0.50

Results expressed as median (range).*Estimated by the MannWhitney test.CSF to serum glucose level ratio.WBC, white blood cell; ALC, absolute lymphocyte count; ANC, absolute neutrophil count.

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tuberculosis in children, tuberculous meningi-tis should not be forgotten in the diVerentialdiagnosis of meningitis. In such patients,individual risk factors, abnormal chest radio-graphs, and positive tuberculin skin testreactions may contribute to the diagnosis.10

As expected, superficial lymphadenitis con-stituted the predominant manifestation ofextra-pulmonary tuberculosis among the pa-tients studied.2 However, infants are more sus-

ceptible to severe forms of tuberculosis,5 11 andin the present study, miliary tuberculosispredominated in infants, superficial lymphad-enitis and meningitis in preschool children,andpleural eVusion and skeletal tuberculosis inolder children, confirming age dependentchanges in hostpathogen interactions, de-scribed by others.2 4 1 1

Increases in the numbers of children admit-ted with both pulmonary and extra-pulmonarytuberculosis were observed in our hospital dur-ing the past decade. These emerging trendsreflect the worldwide increasing incidence ofpaediatric tuberculosis.1 4 However, thenumber of children admitted with extra-

pulmonary tuberculosis fell from 1996 to1998.Beginning in 1993,yearly tuberculin skintest screening of all children up to 6 years of ageand then every two years up to 14 years of agewas introduced nationwide. The recent fall ofadmissions for extra-pulmonary tuberculosismay be a result of the early detection of asymp-tomatic tuberculous infection in Greece.

Several factors have been implicated in thecurrent resurgence of tuberculosis, includingthe acquired immunodeficiency syndrome(AIDS) epidemic, the emergence of multipledrug resistant M tuberculosis strains, poverty,immigration, homelessness, and inadequatetuberculosis control programmes.1 4 1 2 The sig-nificance of these factors is further intensified

during early childhood, not only because of theimmature immune responses of infants andyoung children, but also as a result of the eco-nomic and social dependence of this group ofpatients. However, in the current study, therewere no cases of AIDS, only one multiple drugresistant M tuberculosis strain was detected, andthere were excellent clinical responses to thestandard antituberculous regimens observed inall other patients. Despite this, drug resistanttuberculosis is emerging in Greece. In 1998,9.7% of M tuberculosis isolates from adultpatients were resistant to isoniazid, 3.9% torifampicin, and 4.1% to both agents; 55% ofthese strains came from immigrants (National

Reference Center for Mycobacteria, Hospitalfor Thoracic Diseases, Athens, Greece; per-sonal communication). In the light of a rise inincidence of resistant strains, treatment with

only two agents is no longer recommended asconventional sensitivity testing is not availablefor several weeks.

Immigrants accounted for only 12% of thestudy population. The current study extendedover a 17 year period. The fact that immigra-tion from Eastern Europe to Greece wasgreatly intensified during 19921997 and thatthe usual practice of new immigrants is eitherto immigrate alone or only with their older

children may explain this small proportion.Overall, immigration, poverty, unemployment,and restricted access to medical services asindicated by a deficient routine vaccinationstatus, were associated with up to 25% of thecases of extra-pulmonary tuberculosis. How-ever, the source of infection remained uniden-tified in up to 50% of our patients, so that therelative contribution of each parameter re-mains uncertain. Of note, approximately 50%of cases in immigrant, very low income, orunemployed families were patients with tuber-culous meningitis. Delays in identification andcontact tracing of infected adults are commonin such groups and render young children at

increased risk of developing tuberculosis.4

Childhood tuberculosis reflects the inad-equacy of the public health system in control-ling transmission of infection in thecommunity.4 7 Prompt and eYcient identifica-tion of the source of transmission and applica-tion of eVective environmental measures areintimately linked to the control of childhoodtuberculosis.

1 Raviglione MC, Snider DE, Jr, Kochi A. Global epidemiol-ogyof tuberculosis. Morbidity andmortalityof a worldwideepidemic. JAMA 1995;273:220-6.

2 Rieder HL, Snider DE Jr, Cauthen GM. Extra-pulmonarytuberculosis in the United States. Am Rev Respir Dis 1990;141:347-51.

3 Weir MR, Thornton GF. Extra-pulmonary tuberculosis.

Experience of a community hospital and review of theliterature. Am J Med1985;79:467-78.4 Starke JR. Resurgence of tuberculosis in children. Pediatr

Pulmonol1995;11(suppl):16-17.5 Smith S, Jacobs RF, Wilson CB. Immunobiology of

childhood tuberculosis: a window on the ontogeny of cellu-lar immunity. J Pediatr1997;131:16-26.

6 Spyridis P, Sinaniotis C, Tsolia M, Gelesme A, Mathiou-dakis J, Karpathios Th. Epidemiology of tuberculosis inchildren in the area of Athens (19871998). Abstract 268-PC. 29th World Conference of the International Union AgainstTuberculosis and Lung Disease. Bangkok, Thailand, 2326November 1998.

7 Snider DE Jr, Rieder HL, Combs D, et al. Tuberculosis inchildren. Pediatr Infect Dis J 1988;7:271-8.

8 Doerr CA, Starke JR, Ong LT. Clinical and public healthaspects of tuberculous meningitis in children. J Pediatr1995;127:27-33.

9 Newton RW. Tuberculous meningitis. Arch Dis Child 1994;70:364-6.

10 Kumar R, Singh SN, Kohli N. A diagnostic rule fortuberculous meningitis. Arch Dis Child 1999;81:221-4.

11 Kampmann B, Young D. Childhood tuberculosis: advances

in immunopathogenesis, treatment and prevention. CurrOpin Infect Dis 1998;11:331-5.

12 Cantwell MF, McKenna MT, McCray E, Onorato IM.Tuberculosis and race/ethnicity in the United States. Am JRespir Crit Care Med 1998;157:1016-20.

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