tuberculosis in neonates and infants · tuberculosis in neonates and infants epidemiology,...

THERAPY IN PRACTICEPedlotr Drugs 2005; 7 (4): 219.2341174.6e78/05/0004O219/S34.95/0

© 200S Adis Data Intormatloo BV. All rlgtits reserved.

Tuberculosis in Neonates and InfantsEpidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, andManagement Issues

Chrysanthi L. Skevaki and Dimitrios A. Kafetzis

Second Department of Pediatrics, 'P. and A. Kiriakou' Children's Hospital, University of Athens, Athens, Greece

Contents

Abstract 220

1. Epidemiologic Features 220

1.1 Incidence/Prevalence 2201.2 Transmission 221

1.3 iVlorbidity and iVlortaiity 2212. Pathogenesis 221

3. Cilnicai Manifestations 2224. Diagnosis 223

4.1 Tubercuiin Skin Tests 2234.2 Chest Radiography 223

4.3 Other imaging Studies 2244.4 Smears/Cuitures 2244.5 Poiymerase Chain Reaction 2244.6 Examination of the Cerebrospinai Fluid 2244.7 Aiternative Tests 224

5. Antitubercuious IVledications 2245.1 isoniazid 2245.2 Rifampin (Rifampicin) 226

5.3 Pyrazinamide 2275.4 Ethambutoi 2275.5 Streptomycin 227

5.6 Other Drugs 227

6. Future Therapeutic iVlodailties 2277. Therapeutic Drug Monitoring 227

8. Management Issues 2288.1 Perinatai Tubercuiosis 228

8.1.1 Pregnant Women with Positive Mantoux Skin Test But Normal Chest X-Ray 228

8.1.2 Pregnant Women with Positive Mantoux Skin Test and Abnormai Chest X-Ray 2298.2 Treatment of Latent Tubercuious infection 2308.3 Treatment of Tubercuiosis Disease in infants 230

8.3.1 Drug-Susceptibie intrathoracic Tubercuiosis 2308.3.2 Extrapuimonary Tubercuiosis 2318.3.3 Drug-Resistant Tubercuiosis 2318.3.4 Indications for the Use of Corticosteroids 2318.3.5 Co-Infection with HiV 232

9. Prevention 23210. Conciusions 232

220 Skevaki & Kafetzis

AbStrOCt Tuberculosis is one of the leading infectious causes of death and as such represents a major global health

problem. Infants may develop congenital tuberculosis from an infectious mother or, most commonly, they may

acquire postnatal disease by contact with an infectious adult source. Important epidemiologic, pathogenetic, and

clinical data regarding the management of infantile disease are reviewed.

Diagnostic evaluation includes tuberculin skin tests, chest radiography and other imaging studies, smears and

cultures, examination of the cerebrospinai fluid, and polymerase chain reaction, as well as the more recent

interferon-y assay.

Pregnant women with a positive Mantoux skin test but normal chest x-ray should either start chemoprophy-

laxis during gestation or after delivery depending on the likelihood of being recently infected, their risk of

progression to disease, as well as their clinical evidence of disease. Pregnant women with a positive Mantoux

skin test and chest x-ray or symptoms indicative of active disease should be treated with non-teratogenic agents

during gestation; all household contacts should also be screened. When tuberculosis is suspected around

delivery, the mother should be assessed by chest x-ray and sputum smear; separation of mother and offspring is

indicated only if the mother is non-adherent to medical treatment, needs to be hospitalized, or when drug-resis-

tant tuberculosis is involved.

According to the American Academy of Pediatrics, treatment of latent infection is highly effective with

isoniazid administration for 9 months. This regimen may be extended to 12 months for immunocompromised

patients. When drug resistance is suspected, combination therapies, which usually consist of isoniazid with

rifampin (rifampicin), are administered until the results of susceptibility tests become available. Organisms

resistant to isoniazid only may be treated with rifampin alone for a total of 6-9 months.

All infants with tuberculosis disease should be started on four agents (isoniazid, rifampin, pyrazinamide, and

ethambutoi or streptomycin) until drug susceptibility is assessed. For susceptible intrathoracic tuberculosis,

isoniazid, rifampin, and pyrazinamide are administered for a total of 2 months, at which point pyrazinamide is

withdrawn and the other two agents are continued for another 4-10 months depending on the severity of the

disease. The same regimen may be applied in extrapuimonary tuberculosis with the exception of skeletal,

miliary, and CNS disease, which require daily administration of isoniazid, rifampin, pyrazinamide, and

streptomycin for 1-2 months, followed by isoniazid and rifampin daily or twice weekly for another 10 months.

When drug-resistant tuberculosis is suspected, a regimen of isoniazid, rifampin, and pyrazinamide plus either

streptomycin or ethambutoi should be initially prescribed, until the results of susceptibility tests become

available. HIV-seropositive infants with pulmonary tuberculosis should receive isoniazid, rifampin,

pyrazinamide, and ethambutoi or an aminoglycoside for 2 months, followed by isoniazid and rifampin for a total

of at least 12 months.

Apart from conventional antimycobacterial agents, novel therapeutic modalities, which stimulate the host

immune system such as interleukin-2 (IL-2), IL-12, interferon-y, and tumor necrosis factor antagonists have been

tested with promising results.

The infectious agents responsible for tuberculosis are Myco- insight into current guidelines and recommendations for this sus-

bacterium tuberculosis, M. bovis, and M. africanum, which are all ceptible group of patients,

acid-fast microorganisms. Tubercle bacilli are located intracellu-

larly, grow only intermittently or assume a dormant form under 1. Epidemiologic Features

unfavorable conditions and may reactivate into a rapidly dividing

form. Although tuberculosis infection and disease affects all age ^-j incidence/Prevalence

groups, most published data regarding available antitubercuious

medication and alternative treatment regimens focus on the adult There is no doubt that tuberculosis continues to have a major

population. Information regarding the management of neonates impact on morbidity and mortality in both developing and devel-

and infants is reviewed in this article in an attempt to provide oped countries. According to the WHO, in 2003 there were 8.8

© 2005 Adis Data Informatian BV. All rights reserved. Pediatr Drugs 2005; 7 (4)

Tuberculosis in Infants: Management Issues 221

million new cases of tuberculosis worldwide, compared with 8.4million in 1999 and 8.0 million in 1997."'̂ l Approximately 2million deaths due to tuberculosis occur annually, which rendersthe disease the second most common infectious cause of deathnext to HIV infection.'•'I Currently, based on tuberculin sensitivity,more than one-third of the world's population is infected withM. tuberculosis.^'*^

Furthermore, it has been estimated that 1.3 million new casesand 450 000 deaths annually affect children under the age of 15years;'^' developing countries seem to bear the vast majority of theglobal disease burden. Epidemiologic data regarding congenitaland postnatally acquired infantile tuberculosis are quite limited.However, perinatal tuberculosis seems to be rare,'*" '̂ with fewerthan 300 cases reported in the English-language literature (39 newcases have been reported since the last major review in1980),i*'""' in contrast with the incidence of postnatal disease ininfants, which shows an escalating trend as a reflection of theglobal increase in tuberculosis over the last decade.''^' Infants athigh risk for tuberculous infection are shown in table I.

1.2 Transmission

Postnatal acquisition is the result of airborne inoculation ofM. tuberculosis bacilli through intimate contact with an adult withactive pulmonary tuberculosis. Hematogenous dissemination oftubercle bacilli during pregnancy may result in seeding of thegenitalia, endometrium, or placenta.''^' Congenital tuberculosismay occur hematogenously from the placenta and through theumbilical vein, by aspiration or ingestion of infected amnioticfluid or by direct contact with an infected birth canal duringdelivery.

Transmission of the organism from infected infants to theircontacts is considered unlikely to occur since in this age group the

Table I. Infants at high risk of acquiring tubercuiosis infection

Contacts of aduits with infectious tuberculosis

Contacts of aduits in one of the following contexts:

HIV infection or other immunosuppressive condition

healthcare workers dealing with high-risk patients

intravenous drug user

homelessness, low socioeconomic status in certain areas

residents of correctionai institutions or nursing homes

migrant workers

Parents or infant from high prevalence countries

HIV infection or other immunosuppressive condition (malnutrition, organ

failure, neoplastic disease etc.)

bacillary load of endobronchial secretions is low, cavitary diseaseis not common, and the ability to expectorate sputum is limit-ed [14-16] Nonetheless, purified protein derivative skin test conver-sion in healthcare workers after exposure to infants with dissemi-nated tuberculous infection and extensive lung disease has beenreported.''^' According to the Centers for Disease Control, anypatient with known or suspected M. tuberculosis infection shouldbe regarded as infectious and isolated."^'

1.3 Morbidity and Mortality

Tuberculosis during infancy is associated with great morbidityand mortality for a number of reasons. First, disseminated forms ofthe disease such as miliary and meningeal tuberculosis occur quitefrequently compared with other age groups.'"-^"' Second, associat-ed symptoms and signs are often non-specific, which results in asometimes disastrous diagnostic delay.""•̂ ""̂ l̂ Third, the propor-tion of diseased newboms and infants with a negative skin test(especially if they have disseminated forms of tuberculosis) ismuch higher than that for older children, which further impedesdiagnosis.l̂ "*' Furthermore, up to 40% of infected untreated infantsaged <1 year develop tuberculosis disease within 1-2 years,''^"'compared with approximately 25% of children aged 1-5 years,approximately 15% of adolescents,'̂ ^1 and approximately 5-10%of infected adults.

According to certain reports,t̂ '̂̂ '̂ the increased susceptibilityof newborns and infants to tuberculous disease can be attributed tothe relative immaturity of their immune system. More specifically,infants up to 12 months of age are said to have lower delayed-typehypersensitivity and cell-mediated immunity with a resultant in-ferior capacity to contain mycobacteria and to encapsulate them bygranuloma formation.'^^' Therefore, infection may progress todisease quickly and disseminate before treatment is started.'^^'Furthermore, infants are immunologically naive due to the lack ofprevious infection, which results in delay of containment; thisslower response seems to contribute to active disease.

Due to the anatomical underdevelopment of cranial arteries andcerebrospinal passages in small infants, cerebral infarction andhydrocephalus are common sequelae following inflammation ofthe meninges,'^'' with accompanying high rates of mortality andneurologic complications.

2. Pathogenesis

In order for postnatal tuberculosis to occur, an infant must befirst significantly exposed to a contagious adult. Airborne trans-mission of infective droplets is the most common mode of inocula-

© 2005 Adis Data Information BV. Aii rights reserved. Pediatr Drugs 2005: 7 (4)


tion. In this 'exposure' stage the child has a negative tuberculin

skin test, a normal chest radiograph, and no related symptoms or

signs. Following inhalation of the bacilli, a primary complex is

formed consisting of a peripheral lohar lesion and involvement of

the regional lymph nodes (usually the hilar nodes) through the

lymphatic system. In the vast majority of cases, the initial lesion

heals and calcifies, producing a Ghon lesion on chest radiography.

During primary complex formation, tuhercle bacilli may dissemi-

nate lymphohematogenously to pulmonary as well as extrapulmo-

nary sites such as the pleura, pericardium, lymph nodes, CNS,

bones and joints, skin, and gastrointestinal and genitourinary

systems. As a rule, this metastatic seeding becomes constrained

but in some cases it may lead to the development of extrapulmo-

nary disease: either primary tuberculosis (months to years later) or

reactivation of tuberculosis (several years later). Infants develop

only primary tuberculosis (absence of any pre-existing immunity)

in contrast with adults who can develop post-primary disease,

which occurs when individuals have pre-existing immunity to

mycobacterial antigens. Tuberculosis 'infection' is present if a

symptom-free infant has conversion of skin test reactivity from

negative to positive and either a normal chest roentgenogram or

one with granuloma or calcification in the lung parenchyma or

regional lymph nodes. Finally, tuberculosis 'disease' is the devel-

opment of associated symptoms or signs or of a characteristic

radiographic picture, which, in the case of neonates, may occur

within months from the primary infection.f^"'

Hematogenous spread from mother to fetus during pregnancy

leads to the formation of one or more primary complexes in the

liver, with involvement of the periportal lymph nodes, or in the

lungs."^' The bacilli sometimes remain dormant in the lungs and

start to multiply right after birth when oxygenation and circulation

are greatly enhanced, leading to active disease.'''' Aspiration or

ingestion of contaminated amniotic fluid creates multiple primary

complexes in the lung, gut, or middle ear.t^ '̂

To date, two distinct sets of criteria have been proposed in an

attempt to define true congenital tuberculosis. According to the

first, established by Beitzke'^'^ in 1935, the infant must have

proved tuberculous lesions and one of the following should apply:

lesions in the first few days of life, a primary hepatic complex, or

the exclusion of the possibility of postnatal transmission by the

separation of the infant at birth from the mother and other sources

of infection. Subsequently, Cantwell et al.'̂ l projected revised

diagnostic criteria, which apply more easily in current practice

(see table II).

Table II. Revised diagnostic criteria for congenital tuberculosis!^'

Proved tuberculous lesions and at least one of the following:

lesions in the first week of life

a primary hepatic complex or caseating hepatic granulomas

tuberculous infection of the placenta or the maternal genital tract

exclusion of the possibility of postnatal transmission by a thorough

investigation of contacts, including the infant's hospital attendants,

and by adherence to existing recommendations for treating infants

exposed to tuberculosis

3. Clinical Manifestations

Symptoms of congenital tuberculosis disease begin sometimefrom birth up to 4 months of age, most commonly around thesecond or third week of life.'̂ '̂ "' Often the clinical features ofinfantile tuberculosis are atypical mimicking other conditions suchas congenital viral infections and sepsis;'^'"'^' therefore, a highindex of suspicion is required in order to reach the diagnosis. Themost frequent symptoms and signs of congenital tuberculosis uponpresentation are: hepatosplenomegaly, respiratory distress, fever,lymphadenopathy, abdominal distension, lethargy, irritability, eardischarge, and papular skin lesions.'^' Less frequent symptomsappear to be vomiting, apnea, cyanosis, jaundice, seizures, andpetechiae, which occur in <10% of patients.'*' Similar symptoma-tology has been reported for infants with disease acquired afterbirth."^' Respiratory signs include tachypnoea, stridor, wheeze,crepitations, and bronchial breathing.'^"'

Specific clinical manifestations of either pre- or postnatallyacquired tuberculosis naturally depend on the site and severity oftuberculous lesions as well as on the time since infection. Allpossible forms encountered in adults, both pulmonary and extra-pulmonary, may occur, although with different frequencies com-pared with those in older age groups. As mentioned in section 1.3,disseminated and meningeal forms of the disease occur morefrequently in infants, which may be, at least partially, attributed tothe intrinsic immaturity of their immune system.

Mediastinal lymph node tuberculosis may easily result in com-pression of the infants' small airways with subsequent signs sug-gestive of bronchial obstruction and air entrapment such as wheez-ing and decreased respiratory sounds.'• '̂'• '̂'' Superficial tuberculouslymphadenitis most commonly affects the submandibular andanterior cervical nodes with fever and associated lymph nodeenlargement upon presentation. Tuberculous involvement of theCNS may present as meningoencephalitis, basal arachnoiditis, orintracranial tuberculomas.'^'" Meningitis usually manifests withfever, cough, nuchal rigidity, vomiting, alteration of conscious-

® 2005 Adis Data Informatian BV. All rights reserved. Pediatr Drugs 2006; 7 (4)


ness, and refusal to feed. Less common manifestations are abulging anterior fontanel and generalized seizures. As for miliarytuberculosis, common signs and symptoms include fever, cough,failure to thrive, hepatosplenomegaly, and respiratory distress.

4. Diagnosis

Diagnostic evaluation of an infant with tuberculosis disease israther challenging if one considers the non-specific nature of theassociated symptoms and signs. A high index of suspicion must betherefore maintained in particular contexts (see table I). In the caseof congenital disease, failure to respond to antibiotic therapy aswell as exclusion of other congenital infections are further indica-tions for tuberculosis evaluation.

Moreover, assessment of patients for tuberculosis differs be-tween developed and developing countries as the latter lack theresources for advanced laboratory-based diagnosis and sophisti-cated imaging techniques. Diagnosis in these areas depends prima-rily upon history, skin testing, and conventional chest x-ray.Nevertheless, India's tuberculosis control program, which wasintroduced in 1993 and improved the quality of diagnosis apartfrom other new policies implemented, may serve as a paradigm ofwise allocation of funds in a country with low economic develop-ment.'-''! This program had a tremendous impact on morbidity andmortality due to tuberculosis and indirectly produced significantcost savings."^'

4.1 Tuberculin Skin Tests

There are two major techniques for tuberculin skin testing: theMantoux test and the multiple puncture tests. However, the latterare associated with several disadvantages such as non-standardiza-tion of the amount of antigen introduced, the need for a subsequentMantoux test in the case of positivity (which is further complicatedby the 'booster phenomenon'), and high rates of false-positive andfalse-negative results.̂ ^^^ Furthermore, their widespread use led tothe practice of allowing non-professionals such as parents tointerpret the skin test results and report them to the physician,which is often misleading.'̂ ^^ Therefore, the Centers for DiseaseControl and the American Thoracic Society have suggested thatthe use of multiple puncture tests should be restricted or evencompletely abandoned.

A positive Mantoux test at 72 hours indicates infection withM. tuberculosis; tuberculin sensitivity develops 3 weeks to3 months after inhalation of the bacilli and remains for the child'slifetime. Following bacillus Calmette-Guerin (BCG) vaccination,an infant may or may not develop tuberculin reactivity. For those

who convert, the induration size is usually <10mm and wanes afterapproximately 3 years.''^' Recently, an in vitro assay of wholeblood for cell-mediated immunity has appeared quite promisingfor distinguishing between tuberculous infection and BCG reactiv-ity psi Yhis assay is based on the release of interferon-y (IFNy)from T lymphocytes in response to stimulation with the secretedantigen ESAT-6, which is absent in the BCG vaccine.

In general, a Mantoux skin test reaction of >10mm in childrenaged <4 years (this age group is regarded to be at increased risk fordissemination) is considered positive, independent of immuniza-tion status'̂ '̂̂ '̂ (table III). The respective cutoff value for infantsin close contact with a known or suspected infectious case oftuberculosis, for those clinically or radiographically suspected tohave tuberculous disease, and for immunosuppressed infants is5mm. A variety of factors including young age and severe forms oftuberculosis may diminish reactivity to tuberculin,'''°l whichmeans that a negative Mantoux result in infants does not in anycase exclude the possibility of tuberculosis.

4.2 Chest Radiography

A chest x-ray is an invaluable diagnostic tool in tuberculosisdisease as abnormal features are almost always exhibited. Com-mon manifestations among infants include: (i) hilar or paratrachealadenopathy; (ii) infiltrate; (iii) hilar or paratracheal adenopathyplus infiltrate; (iv) miliary pattern; (v) miliary pattern plus pleuraleffusion; (vi) pleural effusion; and (vii) mediastinal adenopa-thy.'""' Compression of the trachea, bronchi, or both with resultantatelectases is also quite frequent.''̂ -̂ "-'* '̂ Tuberculous lesions maybe located in any lung segment, although a recent study''* '̂ sug-gests that upper lobes and posterior segments are the most com-mon sites for tuberculosis in infants aged <1 year. In general,individuals who are standing at the time of infection develop aprimary focus in the right lower lobe of the lung, whereas thosewho are recumbent develop a primary focus in the posterior

Table III. Definition of a positive Mantoux skin test (5 TU-PPD) In infants

Reaction >5mm

Infants in close contact with a known or suspected infectious case oftuberculosis

Infants with abnormal chest x-ray

Infants with ciinicai evidence of tuberculosis

Immunosuppressed infants (HIV infection or other immunosuppressivecondition)

Reaction >10mm

AH infants without any risk factors

TU-PPD = tubercuiin units of purified protein derivative.

© 2005 Adis Data Information BV. Aii rights reserved. Pediatr Drugs 2005: 7 (4)


segments of the upper lobes. Nevertheless, it should be empha-sized that a normal chest radiograph does not necessarily rule outthe presence of tuberculosis or even miliary disease, which maydevelop within the subsequent days.''"''^'

4.3 Other imaging Studies

Plain radiography, ultrasound, CT, and magnetic resonanceimaging (MRI) are all important components of the diagnosticarmamentarium for tuberculosis in infants.'''̂ •'''•'" '̂ These imagingtechniques were reported to be indispensable in the early assess-ment and guided aspiration of a rare case of perinatal/congenitalspine tuberculosis accompanied by paravertebral abscess.'"*'' Thor-acic CT is especially helpful in infants because of better visualiza-tion of adenopathies compared with chest x-ray. Abdominal so-nography has been used in guided biopsy of hepatic foci; thistechnique has revealed caseating granulomas with tubercle bacilliand led to the diagnosis of congenital tuberculosis.'"'^''*' Ultra-sound, CT, and MRI have also been used in the diagnosis oftuberculosis of the CNS.

4.4 Smears/Cuitures

Specimens for smear or culture can be obtained from earlymorning gastric aspirate, (induced) sputum, cerebrospinai fluid(CSF), tracheal/bronchial aspirate, ear discharge, urine, peritonealfiuid, and biopsy of skin, liver, bone marrow, or lymph node,depending on the location of the lesion.'*'^°' Cultures take about6-12 weeks for results to be obtained, which limits the speed ofreaching a definitive diagnosis and thus impedes timely initiationof appropriate therapy. Moreover, microbiologic confirmation ofinfection is established in only a relatively small proportion ofpatients (larger though in infants when compared with older chil-dren) with gastric fluid being the most common biologic fiuidtested. Despite the low sensitivity associated with cultures, speci-ficity reaches 100% once positive.

4.5 Poiymerase Chain Reaction

Polymerase chain reaction (PCR) assays are both sensitive andspecific for the detection of M. tuberculosis in adults and theyprovide results within 1-3 days.'''^' However, the available assayshave limited applicability with gastric aspirates'^"' and a loweryield in infants in whom the bacillary burden is low; thus, the needfor culture is of highest priority in this age group. Furthermore,due to the extreme sensitivity of PCR, strictly sterile conditionsshould be maintained throughout collection, transportation, and

testing in order to avoid crossover contamination and false-posi-

tive reactions.

4.6 Examination of the Cerebrospinai Fiuid

Tuberculosis of the CNS in infants is associated with character-istic findings in the CSF, which may contribute to the diagnosis.More specifically, lymphocytic pleocytosis, increased proteinlevels, and decreased CSF/serum glucose ratio are the most typicalfeatures.'^"

4.7 Alternative Tests

Neopterin is a product of human macrophages that is releasedupon stimulation by IFNy and indicates cellular immune activa-tion. According to a study,'^^' infants with uncomplicated primarytuberculosis disease and a good response to therapy demonstratedno or slightly elevated neopterin levels compared with excessiveneopterin levels exhibited in infants with progressive primarytuberculosis.

According to a number of articles,'̂ -'"^ '̂ measurement of adeno-sine deaminase activity and IFNy levels in pleural fiuid improvesthe diagnosis of tuberculous pleurisy, with the latter alone havingthe highest sensitivity and specificity when compared with otherbiologic markers.f'^'

5. Antitubercuious Medications

Commonly used antituberculosis drugs are presented in tableIV and agents used in the treatment of drug-resistant tuberculosisare presented in table V.

5.1 Isoniazid

Isoniazid, a hydrazide of isonicotinic acid available in both oraland parenteral (intramuscular) formulations, is highly bactericidalfor M. tuberculosis. It inhibits the enzyme mycolase synthetase,which produces mycolic acid, and results in the disruption of themycobacterial cell wall.'^^' It has also been suggested that isonia-zid affects alterations in lipid levels, synthesis of nucleic acids, andproduction of adenosine triphosphate.''*'

Isoniazid is inexpensive, readily absorbed from the gastrointes-tinal tract when given on an empty stomach, and diffuses exten-sively into all body tissues and fiuids. Metabolism occurs throughacetylation in the liver and the rate of this process shows geneticpolymorphism. Neither drug efficacy nor adverse reactions such ashepatotoxicity seem to correlate with the acetylation status of achild.'^''*°' However, full maturity of the enzymatic pathways

© 2005 Adis Data information BV. Ali rights reserved. Pediatr Drugs 2005; 7 (4)


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© 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (4)


Table V. Agents used in the treatment of drug-resistant tuberculosis'"'

Drug Route of Dose (mg/kg/day)

administration

Maximum

dose (g)

Major adverse effects Comments

Ethionamide

Rifabutin

Kanamycin/capreomycin

Amikaoin

Cycloserine

Ciprofloxacin

Ofloxacin

PO

PO

IM

IV

PO

PO, IV

PO

Para-aminosalicylic PO

acid

15-20 (two or three divided 1

doses)

5-50 0.3

15-30

15-30

10-20 (two divided doses)

PO: 20-30 (two divided doses) PO: 1.5

IV: 15-20 (two divided doses) IV: 0.8

400-800 (two divided doses) 0.8

200-300 (three or four divided 10

doses)

Gl disturbance, hepatotoxicity

Gl disturbance, elevation of

aminotransferase levels,

discoloration of body secretions,

hematologic abnormalities

Renal toxicity, ototoxiclty

Renal toxicity, ototoxicity

Neuropsychiatric disturbances

Destruction of growing cartilage

in animals

Destruction of growing cartilage

in animals, Gl disturbance

Gl disturbance, hepatotoxicity

Bacteriostatic, penetratesblood-brain barrier

Interacts less with proteaseinhibitors compared withrifampin

Bactericidal, no cross-resistance with streptomycin

Bactericidal, no cross-resistance with streptomycin

Requires pyridoxine

supplementation and

monitoring of serum drug

concentrations

Gl = gastrointestinal; IM = intramuscular; IV = intravenous; PO = oral.

responsible for isoniazid metabolism is not reached until 4 years of

age; therefore, the incidence of the fast acetylator phenotype

increases with age.'^'' The route of elimination of metabolites of

isoniazid is primarily renal.

Because isoniazid is a competitive inhibitor of pyridoxine

metabolism, this drug may cause peripheral neuritis or convul-

sions. Therefore, infants who are breastfeeding, as well as those

who are malnourished, predisposed to neuropathy (those with

diabetes mellitus, uremia), or have symptomatic HIV infection

should receive pyridoxine supplements at a dosage of 0.5-1 mg/

Three to ten percent of children receiving isoniazid treatment

exhibit an asymptomatic transient elevation of serum transaminase

levels (not necessarily attributable to the administration of isonia-

zid). Clinically manifested hepatotoxicity is quite rare and occurs

more frequently with dosages exceeding 10 mg/kg/day,'^'^'' co-

administration of rifampin (rifampicin), pre-existing underlying

hepatic disease, and also with severe forms of tuberculous disease.

In children, monitoring of biochemical parameters during treat-

ment is indicated only when aggressive high-dose or concurrent

hepatotoxic therapy is being administered. Routine monitoring of

symptoms and signs of hepatotoxicity is recommended in all cases

and isoniazid should be discontinued immediately if they develop.

In addition, withdrawal, at least temporarily, should be considered

if liver enzyme levels exceed three to five times their upper limit of

normal.'^^'

5.2 Rifampin (Rifampicin)

Rifampin is available in oral and intravenous forms and acts bybinding to and thus inhibiting the (i-subunit of the bacterial DNA-dependent RNA polymerase.'^*l It is bactericidal against bothintra- and extracellular mycobacterial populations. Rifampin is alipid-soluble agent that is readily absorbed via the oral route anddistributes extensively in tissues and body fluids. Rifampin isavailable in 150mg and 300mg capsules, which are doses notappropriate for infants. Suspensions of 10 mg/mL have variablepotency; the most accurate is the one produced from the intra-venous form whereas the suspension produced from the capsuledoes not achieve 90% of the labeled potency until 7-14 days afterpreparation.'̂ ^^ Excretion occurs primarily through the biliary tractand secondarily through the urinary tract.



5.3 Pyrazinamide

Pyrazinamide, a synthetic analog of nicotinamide, is character-ized by potent sterilizing activity in the acidic intracellular pH.This drug is rapidly absorbed and distributed. The available tabletsof 500mg are unsuitable for young infants since the recommendeddosage is 35 mg/kg/day. Suspensions of 100 mg/mL have beenshown to be stable for 2 months.'^'" Elimination of pyrazinamidetakes place through glomerular filtration.

5.4 Ethambutol

Ethambutol is bacteriostatic at a dosage of 15 mg/kg/day andbactericidal at 25 mg/kg/day. Its main use is as a companion drugin various treatment regimens for tuberculosis, in order to preventthe emergence of resistant strains to other drugs. Ethambutol actsby interfering with cell metabolism and ultimately with mycobac-terial RNA synthesis.I*'! It may also play a role in the productionof the cell wall glycolipid arabinogalactan.'^*' In adults, ethambu-tol is well absorbed through the gastrointestinal tract, penetratesthe blood-brain barrier, undergoes extensive distribution, and isfinally excreted, partly unchanged, in the urine and feces.

The most serious adverse effect of this drug is optic neuritiswith resultant decreased visual acuity, central scotoma, and red/green color blindness (unilateral or bilateral). The risk of opticneuritis is both dose and duration dependent. This effect, althoughrarely reported in children,'®' has raised particular concern regard-ing the use of ethambutol in infants, since vision cannot beadequately examined in this population and early visual changescannot be detected in a timely manner. On the other hand,ethambutol is usually administered for only 2 months until resultsof susceptibility tests are available; the possibility of developmentof optic neuritis is very small during such a limited period.Therefore, it has been suggested that ethambutol may be usedsafely in cases of life-threatening forms of tuberculosis or drug-resistant tuberculosis.'™!

5.5 Streptomycin

Streptomycin is bactericidal for extracellular mycobacteria butit has little activity on bacilli located inside macrophages wherethe pH is low. Streptomycin is only available in a parenteral form;this is associated with some inconvenience, discomfort, as well asthe extra treatment-associated costs. The recommended startingpediatric dosage is 2 0 ^ 0 mg/kg/day but it should be determinedby peak and trough blood interactions.'^^' As with ethambutol, theuse of streptomycin is limited to initial treatment regimens when

drug-resistant tuberculosis is suspected or severe forms of thedisease are present.

5.6 Ofher Drugs

Several other drugs have antituberculous activities but areconsidered second-line agents because of their greater toxicity orlesser efficacy compared with the drugs mentioned in sections5.1-5.5. The most important characteristics of these medicationsare summarized in table V.

6. Future Therapeutic Modalities

As the prevalence of multidrug-resistant tuberculosis is increas-ing worldwide, the need for new therapeutic strategies and agentsis becoming imperative. In the last few years, a significant amountof research has focused on methods that stimulate the host immunesystem and enhance its capacity to eradicate mycobacteria. Inter-leukin-2 (IL-2),"" IL-12, IFNY,'^^! ^^^J ^^J^^^^ necrosis factor(TNF) antagonists'''^"' have all been used in the treatment ofadults with tuberculosis, with promising results. The role of TNFin the pathogenesis of active disease has not been fully elucidated.TNF levels are high in the early stages of the disease and thendecrease as the patient recovers,'^*' and may thus contribute to theprotective host immunity against M. tuberculosis. However, at thesame time, high levels of TNF have been implicated in thepathogenesis of the fever, cachexia, and weakness associated withtuberculosis.'"' Further studies are required to establish the effica-cy of these immunotherapeutic approaches and to determine theirrole in the treatment of tuberculosis in adults and children.

Apart from strategies that aim to stimulate the host responseagainst tubercle bacilli, another promising approach, yet largelyunexplored, appears to be one that will enable delivery of highconcentrations of antituberculous agents directly to the lungsthereby avoiding systemic toxicity.'^^'

7. Therapeutic Drug Monitoring

Therapeutic drug monitoring allows the physician to adjustdrug dosages early in the course of treatment, in order to achievetherapeutic serum drug concentrations and prevent the emergenceof drug resistance as well as the development of serious toxicity.Therapeutic drug monitoring is indicated for patients who are slowresponders to antituberculous regimens, receive additional drugsfor other medical reasons and are therefore at risk of drug-druginteractions, have drug-resistant disease and are receiving second-line antituberculous agents, and also for patients with coexisting

© 2005 Adis Data Informatian BV. Ail rights reserved. Pediatr Drugs 2005; 7 (4)


diseases that interfere with the absorption or elimination of admin-

istered drugs.''*'Since the pharmacokinetics of most antituberculous drugs in

infants are essentially unknown, and most of the relevant data areextrapolated from studies in adults and older children, therapeuticdrug monitoring is an invaluable ally in the treatment of tuberculo-sis in this specific subpopulation of patients.

8. Management Issues

8.1 Perinatal Tuberculosis

An evaluation algorithm for pregnant women at high risk fortuberculosis is presented in figure 1 while a management algo-rithm for the mother and newborn when tuberculosis is suspectedat delivery is presented in figure 2. In order to prevent perinataltuberculosis, high-risk pregnant women should undergo tuberculinskin testing. In the case of a positive result, chest radiography withappropriate abdominal shielding must be performed (see also table

8.1.1 Pregnant Women with Positive Mantoux S/c/n Test But

Normai Chest X-Ray

If infected pregnant women (positive Mantoux skin test) have

no clinical or radiographic evidence of tuberculosis disease, the

infant does not need to be separated from her after delivery and

does not require any special evaluation or treatment if the infant

remains asymptomatic. Suitable chemoprophylaxis for the mother

(commonly Isoniazid alone), along with vigilant monitoring for

the development of symptoms or radiographic findings suggestive

of active disease, should be initiated during pregnancy if recent

infection is likely or if she is considered to be at increased risk for

progression to disease (i.e. malnourished, HIV infected, immuno-

compromised or undergoing immunosuppressive therapy). Recent

infection is probable if the mother has conversion of skin reactivity

from negative to positive within the past 2 years or has recently

been in contact with an infectious source. If recent infection is not

probable and the mother is not at increased risk for progression to

disease, treatment for latent tuberculosis infection may be started

after delivery under the condition that chest radiographs remain

normal. Other members of the family should be tested and evalu-

ated thoroughly. If disease is suspected or verified within the

High-risk pregnant women

Mantoux skin test during pregnancy

Positive resuit

CXR with abdominal shielding

Normai CXR

Increased risk ofprogression to disease

Recentinfection likely

Abnormal GXR

No symptomsand CXR compatibiewith inactive disease

No ciinicalevidence of disease

• Start treatment after deiivery» No separation of mother and infant indicated• Evaluation of all family members and contacts

Start chemoprophyiaxisduring gestation

and monitor

• Start chemoprophyiaxis after deiivery• No separation of mother and infant indicated> No further evaluation/treatment of infant

necessary if asymptomatic and all otherfamiiy members and contacts test negative

Fig. 1. Evaluation algorithm for pregnant women at high risk for tuberculosis.!'^' CXR = chest x-ray.

© 2005 Adis Data Information BV, Ali rights reserved.

Symptoms orCXR showingactive disease

Sputum smearsand cultures

Treatment withnon-teratogenic agents

and screening of aiihousehold contacts

Pediatr Drugs 2005; 7 C4)


I Suspicion of tuberculosis around deiivery

• Separation of mother and newborn« Evaiuation of ail household contacts' Sputum smear of mother> CXR of mother

• CXR consistent with inactive disease> No symptoms

> Sputum smear negative• Negative history

CXR consistent with active disease

and/or associated symptomsand/or positive smear

• Infant at low risk

(no further evaluation necessary)• No further separation required• Mother is treated according to

history of previous therapy

• Ciinicai and radiographic assessmentof the infant for congenital tuberculosis

• Chemoprophyiaxis or therapyfor active disease accordingiy

• Treatment of mother for active disease• HIV serology for both mother and infant• No separation needed if mother is

not hospitalized, if drug adherencecan be maintained and no drugresistance is involved

Fig. 2. Management algorithm for the mother and newborn when tuberculosis is suspected at delivery. CXR = chest x-ray.

infant's environment, skin testing will be required for the infant aswell.

8.1.2 Pregnant Women with Positive Mantoux Skin Test and

Abnormal Chest X-Ray

If infected pregnant women (positive Mantoux skin test) aresymptom free and have an abnormal chest radiograph, which iscompatible with inactive tuberculosis (calcified or fibrotic le-sions), treatment should be postponed until after delivery. Noseparation of the mother and newborn is required but all familymembers and contacts should be evaluated.

A positive Mantoux test along with the presence of relatedsymptoms or a radiograph consistent with active disease in apregnant woman demands further evaluation with sputum smearsand cultures and initiation of appropriate therapy with non-terato-genic agents. Screening of household members should never beomitted.

When tuberculous disease is suspected in a pregnant woman atdelivery, the neonate must be separated from the mother until achest radiograph of the mother becomes available. If the radio-graph is abnormal, the infant should remain separated from themother until she is meticulously evaluated. The next essential stepfor evaluation of the mother is sputum examination for detectionof acid-fast bacilli. At the same time, all members of the familyand contacts should be investigated for tuberculosis infection ordisease.

If the mother has an abnormal roentgenogram but no radio-

graphic evidence of active disease, and this is also supported by

the history, physical examination, and sputum smear, the infant is

considered to be at low risk for infection, does not need to be

isolated from the infected mother, and does not require treatment

with antituberculous agents. The mother should be asked whether

she has received previous antituberculous chemotherapy and

should be given appropriate therapy (if she has not been previously

treated) in order to prevent exposure of the infant to reactivation

disease of the mother.

On the other hand, if the mother is thought to be contagious

based on clinical, radiographic, and sputum evidence, the infant

should be, in addition to being isolated from the mother, evaluated

for congenital tuberculosis by means of clinical assessment and

radiography. HIV serology should be also performed for the

mother and neonate. If the newborn has no evidence of tuberculo-

sis, isoniazid therapy (a single dose of 10 mg/kg daily) should be

immediately initiated for the infant while the mother is being

treated for active disease. Once therapy is started, further separa-

tion of the mother and infant (until the mother is proved to be non-

infectious) is only indicated if the mother requires hospitalization,

if non-adherence to the treatment regimen is suspected, or if drug-

resistant strains of M. tuberculosis are implicated. Isoniazid ther-

apy of the newborn should be sustained until the mother is sputum

and culture negative for 3 months. Before discontinuation, a

© 2005 Adis Data information BV. Ali rights reserved. Pediatr Drugs 2005; 7 (4)


tuberculin skin test should be performed on the infant; if it ispositive, therapy should be continued for a total of 9-12 months. Ifthe test is negative, isoniazid treatment may be discontinued with aMantoux test repeated after 6-12 months.

It is permissible for mothers who receive therapy for tuberculo-sis infection or disease to breastfeed their infants (unless, as notedpreviously, separation between them is indicated). Therefore,agents compatible with breastfeeding should be used. The onlydrugs considered to be safe in this particular situation are isonia-zid, rifampin, ethambutol, and streptomycin for first-line therapy,and kanamycin and cycloserine for second-line therapy. Thesedrugs are excreted in breast milk at small concentrations; theseconcentrations are not adequate for effective treatment or preven-tion in infants requiring antituberculous chemotherapy.'^''•*" How-ever, medications should be prescribed at the lower end of thetherapeutic range for these infants, in order to minimize the risk oftoxicity.'*°'

8.2 Treatment of Latent Tuberculous Intection

Latent tuberculosis infection is designated by a positiveMantoux skin test in the absence of symptoms and radiographicfeatures suggestive of active disease. Treatment of this condition isindicated to prevent progression to tuberculosis disease. Further-more, preventive therapy is indicated in infants who have beenrecently exposed to adults with contagious tuberculosis even in theabsence of a positive tuberculin skin test, as in the case of infantsbom to mothers with tuberculous disease. Infants may developtuberculin reactivity simultaneously with tuberculosis disease,which may often be quite severe. For this reason, in exposedinfants, preventive chemotherapy should start immediately andskin testing should be repeated 3 months later. If the infants remainnon-reactive to tuberculin, treatment may be discontinued; if thetest is positive, the full course of therapy should be administered.Evidently, it is very important, based on the child's history ofcontacts, to distinguish between a positive tuberculin responsereflecting 'latent' disease and tuberculin sensitivity coexistentwith primary tuberculosis. If a child who has active disease istreated with isoniazid chemoprophylaxis, the child might laterdevelop more serious progressive primary tuberculosis and treat-ment could then be problematic if isoniazid resistance has devel-oped.

The treatment of choice for latent tuberculous infection orrecent exposure in infants who have not been previously treated ismonotherapy with isoniazid.'*^' According to current recommen-dations isoniazid should be administered for 9 months. This regi-

men has been shown to reduce the incidence of tuberculousdisease by 90% during the first year after treatment, and theprotective effect has been reported to last for at least 30 years.'*^'Isoniazid is administered daily as a single dose of 10 mg/kg (300mg/kg is the maximum dose). However, when adherence to dailytherapy is suspected to be poor, isoniazid may be given twiceweekly under direct observation after 1 month of daily treatment.In this case, each dose should be 20-40 mg/kg (maximum dose900 mg/kg). Directly observed therapy (direct observation of apatient by a healthcare worker while the patient ingests the medi-cation) prevents the consequences of poor adherence (i.e. treat-ment failure, relapse, and secondary drug resistance). For infantswith HIV coinfection or any immunosuppressive condition, treat-ment should be continued for a minimum of 12 months.'^''

When latent infection with drug-resistant strains of M. tubercu-

losis is suspected, an initial regimen of isoniazid together withrifampin is recommended until the results of susceptibility tests ofisolates from either the infant or the adult contact are available.'^^'Drug resistance is suspected when the patient lives or was bom in acountry with a high prevalence of resistant strains, and when theadult source has documented drug-resistant tuberculosis or posi-tive smears/cultures after 2 months of antituberculous therapy or ahistory of previously under-treated disease. If the results of sus-ceptibility testing prove that the responsible organism is isoniazidresistant only (or if the drug eannot be tolerated by the patient),isoniazid should be discontinued and rifampin should be adminis-tered for a total of 6-9 months.l^ '̂ Rifampin can also be given on adaily or a twice-weekly basis. Regarding isolates resistant to bothisoniazid and rifampin, optimal therapy has not yet been estab-lished. Suggested regimens include the combination of a fluoro-quinolone with pyrazinamide or high-dose pyrazinamide andethambutol for 6-9 months. Finally, for bacilli resistant to multipledmgs an expert in pediatric tuberculosis should be advocated;'^^'the most common strategy is to prescribe two drugs to which theorganism is susceptible.

8.3 Treatment of Tuberculosis Diseose in Infants

8.3.1 Drug-Susceptible Intrattioracic Tubercutosis

The optimal management of tuberculosis requires treatmentregimens that combine the shortest possible duration with thehighest efficacy. Short-course regimens decrease the emergence ofsecondary drug resistance, reduce the total cost of treatment, andimprove patients' adherence. Congenital and acquired tuberculosisdisease in infants should be treated

® 2005 Adis Data Informatian BV. Aii rights reserved. Pediatr Drugs 2005; 7 C4)

Tuberculosis in Infants: Management Issues231

Upon suspicion of active disease, infants should be started onfour antituberculous medications (isoniazid, rifampin, pyrazi-namide, plus either ethambutol or streptomycin) until the organ-ism is known to be fully susceptible to all agents used."^' Currentrecommendations for drug-susceptible pulmonary tuberculosiswith or without intrathoracic adenopathy and for hilar adenopathyalone in infants suggest the use of isoniazid (10-15 mg/kg/day),rifampin (10-20 mg/kg/day), and pyrazinamide (15-30 mg/kg/day) for 2 months, followed by at least 4 months of isoniazid andrifampin.l''20,24,57,86-93i j ^ g continuation phase of the therapeuticregimen may be extended to 10 months depending on the severityof the disease." '̂̂ '*'*^! With the aforementioned regimen, treatmentmay be administered twice weekly right from the beginning'̂ "-^ '̂or after a phase of half a month,'^'l 1 or 2 months-long dailytherapy, preferably under direct observation; the success rate ofthis regimen approaehes 100%.

A study'"'] using isoniazid (10-15 mg/kg/day) and rifampin(10-15 mg/kg/day) with or without streptomycin (30 mg/kg/day)daily for 15 days followed by similar doses of isoniazid andrifampin twice a week for another 8.5 months suggested thisregimen was safe and effective for treating tuberculosis in younginfants aged <6 months. Some centers prefer to administer isonia-zid and rifampin without streptomycin for a total of 9 monthswhen drug resistance is considered rather unlikely."^i Again, thiscourse can be given daily initially, and then twice

8.3.2 Extraputmonary Tubercutosis

Antituberculous agents have excellent tissue penetration; more-over, only small numbers of mycobacteria are usually present atextrapulmonary sites of infection.'^'l Therefore, the regimens de-scribed in section 8.3.1 may also be used in patients with extra-pulmonary tuberculosis, with some exceptions. Treatment of skel-etal, miliary, and CNS tuberculosis requires daily administrationof isoniazid, rifampin, pyrazinamide, and streptomycin for 1-2months, followed by isoniazid and rifampin daily or twice weeklyfor another 10 months.l^^.se.'Wi T^g reason for the longer durationof treatment in the aforementioned cases is the limited number ofcontrolled trials and hence experience with these agents in patientswith extrapulmonary disease.'^''

Diagnostic and/or therapeutic surgery (including total excision,incision and drainage, and wide debridement) may be indicated forextrathoracic tuberculous lymphadenitis.'''^' Ventriculoperitonealshunting for CSF relief in tuberculous meningitis has also beenreported.'̂ '*'̂ '! In the case of bone and joint disease, evacuation oflarge abscesses'"^*' or even radical surgical reconstmction is some-times required.'^^'

© 2005 Adis Data infarmation BV. Aii rights reserved.

8.3.3 Drug-tlesistant Tubercutosis

Primary drug resistance arises when a patient is infected with astrain of M tuberculosis that is already resistant to a specific drug.Secondary resistance is the result of non-adherence of the patientto therapy or of the prescription of an inadequate treatment regi-men by the doctor, either of which may lead to predominance ofdrug-resistant organisms within a given population of bacilli. If theadult source of an infected infant has been previously treated fortuberculosis, is seropositive for HIV infection, or lives in a com-munity with high rates of primary dmg resistance or HIV preva-lence, it is very possible that the child will have dmg-resistanttuberculosis.

According to the Working Group On Anti-Tuberculosis DrugResistance Surveillance,"™' between 1994 and 1997, median re-sistance to any single drug, isoniazid, rifampin, ethambutol, andmultiple drugs was present in 9.9%, 7.3%, 1.8%, 1%, and 1.4% ofpatients, respectively, among patients from 35 countries with noprior treatment. Among patients who had received therapy in thepast for <1 month, resistance to any of these drugs occurred in36%, while multidrug resistance occurred in a median of 13%(range 0-54%). The highest rates of multidmg resistance werepresent in the former Soviet Union, Asia, the Dominican Republic,and Argentina. The impact of these data on childhood tuberculosisis obvious when one considers that contagious adults represent theonly source for transmitting the disease to children.

When dmg-resistant strains of M. tuberculosis are suspected, aregimen of isoniazid, rifampin, and pyrazinamide plus either strep-tomycin or ethambutol should be initially prescribed, pending theresults of susceptibility tests. When the latter become available,treatment should include at least two bactericidal drugs to whichthe isolate is susceptible. Additionally, therapy should usually becontinued for 12-18 months under directly observed therapy, inorder to be effective and prevent further emergence of resistance.

8.3.4 tr)dicafions tor the Use ot Corticosteroids

Corticosteroids are indicated in select forms of tuberculousdisease. Infants with serositis (pleural, pericardial effusion) expe-rience significant symptomatic relief upon administration of corti-costeroids.''''' Patients with endobronchial tuberculosis with ac-companying obstmction, emphysema, or atelectasis may also ben-efit from adjuvant cortieosteroids.'"' Tuberculous meningitis is aform of the disease with severe consequences and long-termneurologic sequelae, which may be partly alleviated by the use ofcorticosteroids."^'''' These dmgs act by minimizing local infiam-mation and thus decreasing intracranial pressure. Corticosteroidsare also indicated for miliary disease with alveolocapillary

Pediatr Drugs 2005; 7 (4)


block.l"l Prednisotie 1-2 mg/kg/day for 4-8 weeks with gradualtapering is the recommended regimeti.'̂ ^l Alternatively, dexa-methasone 0.5 mg/kg/day may be prescribed.

8.3.5 Co-lntecfion wifh HIV

All children with tuberculous disease should be tested for HIVinfection. HIV-seropositive infants with pulmonary tuberculosisshould receive isoniazid, rifampin, pyrazinamide, and ethambutoior an aminoglycoside for 2 months, followed by isoniazid andrifampin for a total of at least 12 months. The fourth drug duringthe initial phase of treatment may be withdrawn if the isolatedstrain proves to be fully susceptible and disseminated forms of thedisease are excluded. Meticulous monitoring is required in thissubgroup of patients because of the increased frequency of drugresistance and adverse drug reactions as well as interactions withantiretroviral agents.

9. Prevention

Contacts of infectious adults with tuberculosis should be skintested and appropriately managed. Infants in particular shouldreceive the highest priority during investigation of contacts sincetheir risk of progression to active disease once infected is veryhigh.

BCG is the only vaccine available, to date, for the prevention oftuberculosis. According to WHO recommendations, BCG vac-cines should be administered as a single dose during infancy,usually while the baby is in the maternity hospital. However,different countries have adopted diverse strategies regarding tu-berculosis control. In most countries, BCG vaccination is adminis-tered as recommended by the WHO. However, in some countries itis recommended as a single dose administered at other ages (inGreece it is recommended at the age of 5-6 years), in the US BCGis not recommended in the routine vaccination schedule, and inother regions of the world it is recommended that the vaccine beadministered twice.

Regarding the efficacy of the BCG vaccine in infants, variousstudies have been conducted with different results pro-duced.l""""''*' Protection seems to be higher for disseminatedforms of the disease than for pulmonary tuberculosis, and theeffect is probably time limited since vaccination during infancydoes not decrease the incidence of tuberculosis in adults. Howev-er, the BCG vaccination is recommended for Mantoux skin test-negative infants and young children who are inevitably exposed tounder-treated infectious adults or sources with multidrug-resistantdisease.""^! The BCG vaccine is considered extremely safe withthe most common adverse effects consisting of a local ulceration

and regional suppurative adenitis; osteitis and systemic complaints

(fever, irritability etc.) occur with a much lower frequency.

It is worth mentioning, as a reflection of the magnitude of

ongoing research regarding tuberculosis prevention, that as of June

2001, more than 190 candidate vaccines had been screened in

animal '̂ '̂

10. Conclusions

Tuberculosis in infants, whether congenital or postnatally ac-quired, necessitates timely diagnosis and appropriate managementof both the patient and contacts. The disease process is rapidlyevolving in this immunologically immature age group and theoutcome may be fatal if a high index of suspicion is not main-tained. As shorter and more effective therapeutic regimens aredesigned and clinically established, physicians should be able toencompass latest guidelines and recommendations in their every-day practice. Finally, further studies focused on the infantilepatient are needed, in order to achieve optimal conventional oralternative therapy for the prevention and treatment of tubercu-losis.

Acknowledgments

No sources of funding were used to assist in the preparation of this review.

The authors have no conflicts of interest that are direetly relevant to the

content of this review.

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Correspondence and offprints: Dr Dimitrios A. Kafetzis, Second Departmentof Pediatrics, 'P. and A. Kiriakou' Children's Hospital, University of Ath-ens, Thevon and Livadias St., Athens, GR-11527, Greece.E-mail: [email protected]

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