Tuberculosis in Neonates and Infants Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, and Management Issues

Pedlotr Drugs 2005; 7 (4): 219.234 THERAPY IN PRACTICE 1174.6e78/05/0004O219/S34.95/0

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 220 1.2 Transmission 221 1.3 iVlorbidity and iVlortaiity 221 2. Pathogenesis 221 3. Cilnicai Manifestations 222 4. Diagnosis 223 4.1 Tubercuiin Skin Tests 223 4.2 Chest Radiography 223 4.3 Other imaging Studies 224 4.4 Smears/Cuitures 224 4.5 Poiymerase Chain Reaction 224 4.6 Examination of the Cerebrospinai Fluid 224 4.7 Aiternative Tests 224 5. Antitubercuious IVledications 224 5.1 isoniazid 224 5.2 Rifampin (Rifampicin) 226 5.3 Pyrazinamide 227 5.4 Ethambutoi 227 5.5 Streptomycin 227 5.6 Other Drugs 227 6. Future Therapeutic iVlodailties 227 7. Therapeutic Drug Monitoring 227 8. Management Issues 228 8.1 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 229 8.2 Treatment of Latent Tubercuious infection 230 8.3 Treatment of Tubercuiosis Disease in infants 230 8.3.1 Drug-Susceptibie intrathoracic Tubercuiosis 230 8.3.2 Extrapuimonary Tubercuiosis 231 8.3.3 Drug-Resistant Tubercuiosis 231 8.3.4 Indications for the Use of Corticosteroids 231 8.3.5 Co-Infection with HiV 232 9. Prevention 232 10. 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 chemoprophylaxis 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-resistant 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

million new cases of tuberculosis worldwide, compared with 8.4 bacillary load of endobronchial secretions is low, cavitary disease million in 1999 and 8.0 million in 1997."'^l Approximately 2 is not common, and the ability to expectorate sputum is limit- million deaths due to tuberculosis occur annually, which renders ed [14-16] Nonetheless, purified protein derivative skin test conver- the disease the second most common infectious cause of death sion in healthcare workers after exposure to infants with dissemi- next to HIV infection.'•'I Currently, based on tuberculin sensitivity, nated tuberculous infection and extensive lung disease has been more than one-third of the world's population is infected with reported.''^' According to the Centers for Disease Control, any M. tuberculosis.^'*^ patient with known or suspected M. tuberculosis infection should Furthermore, it has been estimated that 1.3 million new cases be regarded as infectious and isolated."^' and 450 000 deaths annually affect children under the age of 15 years;'^' developing countries seem to bear the vast majority of the 1.3 Morbidity and Mortality global disease burden. Epidemiologic data regarding congenital Tuberculosis during infancy is associated with great morbidity and postnatally acquired infantile tuberculosis are quite limited. and mortality for a number of reasons. First, disseminated forms of However, perinatal tuberculosis seems to be rare,'*"^' with fewer the disease such as miliary and meningeal tuberculosis occur quite than 300 cases reported in the English-language literature (39 new frequently compared with other age groups.'"-^"' Second, associat- cases have been reported since the last major review in ed symptoms and signs are often non-specific, which results in a 1980),i*'""' in contrast with the incidence of postnatal disease in sometimes disastrous diagnostic delay.""•^""^^l Third, the propor- infants, which shows an escalating trend as a reflection of the tion of diseased newboms and infants with a negative skin test global increase in tuberculosis over the last decade.''^' Infants at (especially if they have disseminated forms of tuberculosis) is high risk for tuberculous infection are shown in table I. much higher than that for older children, which further impedes diagnosis.l^"*' Furthermore, up to 40% of infected untreated infants 1.2 Transmission aged <1 year develop tuberculosis disease within 1-2 years,''^"' compared with approximately 25% of children aged 1-5 years, Postnatal acquisition is the result of airborne inoculation of approximately 15% of adolescents,'^^1 and approximately 5-10% M. tuberculosis bacilli through intimate contact with an adult with of infected adults. active pulmonary tuberculosis. Hematogenous dissemination of According to certain reports,t^^'^^' the increased susceptibility tubercle bacilli during pregnancy may result in seeding of the of newborns and infants to tuberculous disease can be attributed to genitalia, endometrium, or placenta.''^' Congenital tuberculosis the relative immaturity of their immune system. More specifically, may occur hematogenously from the placenta and through the infants up to 12 months of age are said to have lower delayed-type umbilical vein, by aspiration or ingestion of infected amniotic hypersensitivity and cell-mediated immunity with a resultant in- fluid or by direct contact with an infected birth canal during ferior capacity to contain mycobacteria and to encapsulate them by delivery. granuloma formation.'^^' Therefore, infection may progress to Transmission of the organism from infected infants to their disease quickly and disseminate before treatment is started.'^^' contacts is considered unlikely to occur since in this age group the Furthermore, infants are immunologically naive due to the lack of previous infection, which results in delay of containment; this Table I. Infants at high risk of acquiring tubercuiosis infection slower response seems to contribute to active disease. Contacts of aduits with infectious tuberculosis Due to the anatomical underdevelopment of cranial arteries and Contacts of aduits in one of the following contexts: cerebrospinal passages in small infants, cerebral infarction and HIV infection or other immunosuppressive condition hydrocephalus are common sequelae following inflammation of healthcare workers dealing with high-risk patients the meninges,'^'' with accompanying high rates of mortality and intravenous drug user neurologic complications. homelessness, low socioeconomic status in certain areas residents of correctionai institutions or nursing homes 2. Pathogenesis migrant workers Parents or infant from high prevalence countries In order for postnatal tuberculosis to occur, an infant must be HIV infection or other immunosuppressive condition (malnutrition, organ first significantly exposed to a contagious adult. Airborne trans- failure, neoplastic disease etc.) mission of infective droplets is the most common mode of inocula-

tion. In this 'exposure' stage the child has a negative tuberculin Table II. Revised diagnostic criteria for congenital tuberculosis!^' skin test, a normal chest radiograph, and no related symptoms or Proved tuberculous lesions and at least one of the following: signs. Following inhalation of the bacilli, a primary complex is lesions in the first week of life formed consisting of a peripheral lohar lesion and involvement of a primary hepatic complex or caseating hepatic granulomas the regional lymph nodes (usually the hilar nodes) through the tuberculous infection of the placenta or the maternal genital tract lymphatic system. In the vast majority of cases, the initial lesion exclusion of the possibility of postnatal transmission by a thorough investigation of contacts, including the infant's hospital attendants, heals and calcifies, producing a Ghon lesion on chest radiography. and by adherence to existing recommendations for treating infants During primary complex formation, tuhercle bacilli may dissemi- exposed to tuberculosis nate lymphohematogenously to pulmonary as well as extrapulmonary sites such as the pleura, pericardium, lymph nodes, CNS, 3. Clinical Manifestations bones and joints, skin, and gastrointestinal and genitourinary systems. As a rule, this metastatic seeding becomes constrained Symptoms of congenital tuberculosis disease begin sometime but in some cases it may lead to the development of extrapulmo- from birth up to 4 months of age, most commonly around the nary disease: either primary tuberculosis (months to years later) or second or third week of life.'^'^"' Often the clinical features of reactivation of tuberculosis (several years later). Infants develop infantile tuberculosis are atypical mimicking other conditions such only primary tuberculosis (absence of any pre-existing immunity) as congenital viral infections and sepsis;'^'"'^' therefore, a high in contrast with adults who can develop post-primary disease, index of suspicion is required in order to reach the diagnosis. The which occurs when individuals have pre-existing immunity to most frequent symptoms and signs of congenital tuberculosis upon mycobacterial antigens. Tuberculosis 'infection' is present if a presentation are: hepatosplenomegaly, respiratory distress, fever, symptom-free infant has conversion of skin test reactivity from lymphadenopathy, abdominal distension, lethargy, irritability, ear negative to positive and either a normal chest roentgenogram or discharge, and papular skin lesions.'^' Less frequent symptoms one with granuloma or calcification in the lung parenchyma or appear to be vomiting, apnea, cyanosis, jaundice, seizures, and regional lymph nodes. Finally, tuberculosis 'disease' is the devel- petechiae, which occur in <10% of patients.'*' Similar symptoma- opment of associated symptoms or signs or of a characteristic tology has been reported for infants with disease acquired after radiographic picture, which, in the case of neonates, may occur birth."^' Respiratory signs include tachypnoea, stridor, wheeze, within months from the primary infection.f^"' crepitations, and bronchial breathing.'^"'

Hematogenous spread from mother to fetus during pregnancy Specific clinical manifestations of either pre- or postnatally leads to the formation of one or more primary complexes in the acquired tuberculosis naturally depend on the site and severity of liver, with involvement of the periportal lymph nodes, or in the tuberculous lesions as well as on the time since infection. All possible forms encountered in adults, both pulmonary and extra- lungs."^' The bacilli sometimes remain dormant in the lungs and pulmonary, may occur, although with different frequencies com- start to multiply right after birth when oxygenation and circulation pared with those in older age groups. As mentioned in section 1.3, are greatly enhanced, leading to active disease.'''' Aspiration or disseminated and meningeal forms of the disease occur more ingestion of contaminated amniotic fluid creates multiple primary frequently in infants, which may be, at least partially, attributed to complexes in the lung, gut, or middle ear.t^^' the intrinsic immaturity of their immune system. To date, two distinct sets of criteria have been proposed in an Mediastinal lymph node tuberculosis may easily result in com- attempt to define true congenital tuberculosis. According to the pression of the infants' small airways with subsequent signs sug- first, established by Beitzke'^'^ in 1935, the infant must have gestive of bronchial obstruction and air entrapment such as wheez- proved tuberculous lesions and one of the following should apply: ing and decreased respiratory sounds.'•^''•^''' Superficial tuberculous lesions in the first few days of life, a primary hepatic complex, or lymphadenitis most commonly affects the submandibular and the exclusion of the possibility of postnatal transmission by the anterior cervical nodes with fever and associated lymph node separation of the infant at birth from the mother and other sources enlargement upon presentation. Tuberculous involvement of the of infection. Subsequently, Cantwell et al.'^l projected revised CNS may present as meningoencephalitis, basal arachnoiditis, or diagnostic criteria, which apply more easily in current practice intracranial tuberculomas.'^'" Meningitis usually manifests with (see table II). fever, cough, nuchal rigidity, vomiting, alteration of conscious-

ness, and refusal to feed. Less common manifestations are a who convert, the induration size is usually <10mm and wanes after bulging anterior fontanel and generalized seizures. As for miliary approximately 3 years.''^' Recently, an in vitro assay of whole tuberculosis, common signs and symptoms include fever, cough, blood for cell-mediated immunity has appeared quite promising failure to thrive, hepatosplenomegaly, and respiratory distress. for distinguishing between tuberculous infection and BCG reactivity psi Yhis assay is based on the release of interferon-y (IFNy) 4. Diagnosis from T lymphocytes in response to stimulation with the secreted antigen ESAT-6, which is absent in the BCG vaccine. Diagnostic evaluation of an infant with tuberculosis disease is In general, a Mantoux skin test reaction of >10mm in children rather challenging if one considers the non-specific nature of the aged <4 years (this age group is regarded to be at increased risk for associated symptoms and signs. A high index of suspicion must be dissemination) is considered positive, independent of immuniza- therefore maintained in particular contexts (see table I). In the case tion status'^^'^^' (table III). The respective cutoff value for infants of congenital disease, failure to respond to antibiotic therapy as in close contact with a known or suspected infectious case of well as exclusion of other congenital infections are further indica- tuberculosis, for those clinically or radiographically suspected to tions for tuberculosis evaluation. have tuberculous disease, and for immunosuppressed infants is Moreover, assessment of patients for tuberculosis differs be- 5mm. A variety of factors including young age and severe forms of tween developed and developing countries as the latter lack the tuberculosis may diminish reactivity to tuberculin,'''°l which resources for advanced laboratory-based diagnosis and sophisti- means that a negative Mantoux result in infants does not in any cated imaging techniques. Diagnosis in these areas depends prima- case exclude the possibility of tuberculosis. rily upon history, skin testing, and conventional chest x-ray. Nevertheless, India's tuberculosis control program, which was 4.2 Chest Radiography introduced in 1993 and improved the quality of diagnosis apart from other new policies implemented, may serve as a paradigm of A chest x-ray is an invaluable diagnostic tool in tuberculosis wise allocation of funds in a country with low economic develop- disease as abnormal features are almost always exhibited. Com- ment.'-''! This program had a tremendous impact on morbidity and mon manifestations among infants include: (i) hilar or paratracheal mortality due to tuberculosis and indirectly produced significant adenopathy; (ii) infiltrate; (iii) hilar or paratracheal adenopathy cost savings."^' plus infiltrate; (iv) miliary pattern; (v) miliary pattern plus pleural effusion; (vi) pleural effusion; and (vii) mediastinal adenopa- 4.1 Tuberculin Skin Tests thy.'""' Compression of the trachea, bronchi, or both with resultant atelectases is also quite frequent.''^-^"-'*^' Tuberculous lesions may There are two major techniques for tuberculin skin testing: the be located in any lung segment, although a recent study''*^' sug- Mantoux test and the multiple puncture tests. However, the latter gests that upper lobes and posterior segments are the most com- are associated with several disadvantages such as non-standardiza- mon sites for tuberculosis in infants aged <1 year. In general, tion of the amount of antigen introduced, the need for a subsequent individuals who are standing at the time of infection develop a Mantoux test in the case of positivity (which is further complicated primary focus in the right lower lobe of the lung, whereas those by the 'booster phenomenon'), and high rates of false-positive and who are recumbent develop a primary focus in the posterior false-negative results.^^^^ Furthermore, their widespread use led to the practice of allowing non-professionals such as parents to Table III. Definition of a positive Mantoux skin test (5 TU-PPD) In infants interpret the skin test results and report them to the physician, Reaction >5mm which is often misleading.'^^^ Therefore, the Centers for Disease Infants in close contact with a known or suspected infectious case of Control and the American Thoracic Society have suggested that tuberculosis the use of multiple puncture tests should be restricted or even Infants with abnormal chest x-ray completely abandoned. Infants with ciinicai evidence of tuberculosis A positive Mantoux test at 72 hours indicates infection with Immunosuppressed infants (HIV infection or other immunosuppressive M. tuberculosis; tuberculin sensitivity develops 3 weeks to condition) 3 months after inhalation of the bacilli and remains for the child's Reaction >10mm lifetime. Following bacillus Calmette-Guerin (BCG) vaccination, AH infants without any risk factors an infant may or may not develop tuberculin reactivity. For those TU-PPD = tubercuiin units of purified protein derivative.

segments of the upper lobes. Nevertheless, it should be empha- testing in order to avoid crossover contamination and false-posi- sized that a normal chest radiograph does not necessarily rule out tive reactions. the presence of tuberculosis or even miliary disease, which may develop within the subsequent days.''"''^' 4.6 Examination of the Cerebrospinai Fiuid

Tuberculosis of the CNS in infants is associated with character- 4.3 Other imaging Studies istic findings in the CSF, which may contribute to the diagnosis. Plain radiography, ultrasound, CT, and magnetic resonance More specifically, lymphocytic pleocytosis, increased protein imaging (MRI) are all important components of the diagnostic levels, and decreased CSF/serum glucose ratio are the most typical armamentarium for tuberculosis in infants.'''^•'''•'"^' These imaging features.'^" techniques were reported to be indispensable in the early assessment and guided aspiration of a rare case of perinatal/congenital 4.7 Alternative Tests spine tuberculosis accompanied by paravertebral abscess.'"*'' Thor- Neopterin is a product of human macrophages that is released acic CT is especially helpful in infants because of better visualiza- upon stimulation by IFNy and indicates cellular immune activa- tion of adenopathies compared with chest x-ray. Abdominal so- tion. According to a study,'^^' infants with uncomplicated primary nography has been used in guided biopsy of hepatic foci; this tuberculosis disease and a good response to therapy demonstrated technique has revealed caseating granulomas with tubercle bacilli no or slightly elevated neopterin levels compared with excessive and led to the diagnosis of congenital tuberculosis.'"'^''*' Ultra- neopterin levels exhibited in infants with progressive primary sound, CT, and MRI have also been used in the diagnosis of tuberculosis. tuberculosis of the CNS. According to a number of articles,'^-'"^^' measurement of adenosine deaminase activity and IFNy levels in pleural fiuid improves 4.4 Smears/Cuitures the diagnosis of tuberculous pleurisy, with the latter alone having Specimens for smear or culture can be obtained from early the highest sensitivity and specificity when compared with other morning gastric aspirate, (induced) sputum, cerebrospinai fluid biologic markers.f'^' (CSF), tracheal/bronchial aspirate, ear discharge, urine, peritoneal 5. Antitubercuious Medications fiuid, and biopsy of skin, liver, bone marrow, or lymph node, depending on the location of the lesion.'*'^°' Cultures take about Commonly used antituberculosis drugs are presented in table 6-12 weeks for results to be obtained, which limits the speed of IV and agents used in the treatment of drug-resistant tuberculosis reaching a definitive diagnosis and thus impedes timely initiation are presented in table V. of appropriate therapy. Moreover, microbiologic confirmation of infection is established in only a relatively small proportion of 5.1 Isoniazid patients (larger though in infants when compared with older children) with gastric fluid being the most common biologic fiuid Isoniazid, a hydrazide of isonicotinic acid available in both oral tested. Despite the low sensitivity associated with cultures, speci- and parenteral (intramuscular) formulations, is highly bactericidal ficity reaches 100% once positive. for M. tuberculosis. It inhibits the enzyme mycolase synthetase, which produces mycolic acid, and results in the disruption of the 4.5 Poiymerase Chain Reaction mycobacterial cell wall.'^^' It has also been suggested that isoniazid affects alterations in lipid levels, synthesis of nucleic acids, and Polymerase chain reaction (PCR) assays are both sensitive and production of adenosine triphosphate.''*' specific for the detection of M. tuberculosis in adults and they Isoniazid is inexpensive, readily absorbed from the gastrointes- provide results within 1-3 days.'''^' However, the available assays tinal tract when given on an empty stomach, and diffuses exten- have limited applicability with gastric aspirates'^"' and a lower sively into all body tissues and fiuids. Metabolism occurs through yield in infants in whom the bacillary burden is low; thus, the need acetylation in the liver and the rate of this process shows genetic for culture is of highest priority in this age group. Furthermore, polymorphism. Neither drug efficacy nor adverse reactions such as due to the extreme sensitivity of PCR, strictly sterile conditions hepatotoxicity seem to correlate with the acetylation status of a should be maintained throughout collection, transportation, and child.'^''*°' However, full maturity of the enzymatic pathways

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Table V. Agents used in the treatment of drug-resistant tuberculosis'"' Drug Route of Dose (mg/kg/day) Maximum Major adverse effects Comments administration dose (g) Ethionamide PO 15-20 (two or three divided 1 Gl disturbance, hepatotoxicity Bacteriostatic, penetrates doses) blood-brain barrier Rifabutin PO 5-50 0.3 Gl disturbance, elevation of Interacts less with protease aminotransferase levels, inhibitors compared with discoloration of body secretions, rifampin hematologic abnormalities Kanamycin/ IM 15-30 Renal toxicity, ototoxiclty Bactericidal, no cross- capreomycin resistance with streptomycin Amikaoin IV 15-30 Renal toxicity, ototoxicity Bactericidal, no cross- resistance with streptomycin Cycloserine PO 10-20 (two divided doses) Neuropsychiatric disturbances Requires pyridoxine supplementation and monitoring of serum drug concentrations Ciprofloxacin PO, IV PO: 20-30 (two divided doses) PO: 1.5 Destruction of growing cartilage in animals IV: 15-20 (two divided doses) IV: 0.8 Ofloxacin PO 400-800 (two divided doses) 0.8 Destruction of growing cartilage in animals, Gl disturbance Para-aminosalicylic PO 200-300 (three or four divided 10 Gl disturbance, hepatotoxicity acid doses) Gl = gastrointestinal; IM = intramuscular; IV = intravenous; PO = oral. responsible for isoniazid metabolism is not reached until 4 years of symptoms and signs of hepatotoxicity is recommended in all cases age; therefore, the incidence of the fast acetylator phenotype and isoniazid should be discontinued immediately if they develop. increases with age.'^'' The route of elimination of metabolites of In addition, withdrawal, at least temporarily, should be considered isoniazid is primarily renal. if liver enzyme levels exceed three to five times their upper limit of normal.'^^' 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 5.2 Rifampin (Rifampicin) who are malnourished, predisposed to neuropathy (those with diabetes mellitus, uremia), or have symptomatic HIV infection Rifampin is available in oral and intravenous forms and acts by should receive pyridoxine supplements at a dosage of 0.5-1 mg/ binding to and thus inhibiting the (i-subunit of the bacterial DNA- dependent RNA polymerase.'^*l It is bactericidal against both Three to ten percent of children receiving isoniazid treatment intra- and extracellular mycobacterial populations. Rifampin is a exhibit an asymptomatic transient elevation of serum transaminase lipid-soluble agent that is readily absorbed via the oral route and levels (not necessarily attributable to the administration of isonia- distributes extensively in tissues and body fluids. Rifampin is zid). Clinically manifested hepatotoxicity is quite rare and occurs available in 150mg and 300mg capsules, which are doses not more frequently with dosages exceeding 10 mg/kg/day,'^'^'' co- appropriate for infants. Suspensions of 10 mg/mL have variable administration of rifampin (rifampicin), pre-existing underlying potency; the most accurate is the one produced from the intra- hepatic disease, and also with severe forms of tuberculous disease. venous form whereas the suspension produced from the capsule In children, monitoring of biochemical parameters during treat- does not achieve 90% of the labeled potency until 7-14 days after ment is indicated only when aggressive high-dose or concurrent preparation.'^^^ Excretion occurs primarily through the biliary tract hepatotoxic therapy is being administered. Routine monitoring of and secondarily through the urinary tract.

5.3 Pyrazinamide drug-resistant tuberculosis is suspected or severe forms of the disease are present. Pyrazinamide, a synthetic analog of nicotinamide, is character- ized by potent sterilizing activity in the acidic intracellular pH. 5.6 Ofher Drugs This drug is rapidly absorbed and distributed. The available tablets of 500mg are unsuitable for young infants since the recommended Several other drugs have antituberculous activities but are dosage is 35 mg/kg/day. Suspensions of 100 mg/mL have been considered second-line agents because of their greater toxicity or shown to be stable for 2 months.'^'" Elimination of pyrazinamide lesser efficacy compared with the drugs mentioned in sections takes place through glomerular filtration. 5.1-5.5. The most important characteristics of these medications are summarized in table V. 5.4 Ethambutol 6. Future Therapeutic Modalities Ethambutol is bacteriostatic at a dosage of 15 mg/kg/day and bactericidal at 25 mg/kg/day. Its main use is as a companion drug As the prevalence of multidrug-resistant tuberculosis is increas- in various treatment regimens for tuberculosis, in order to prevent ing worldwide, the need for new therapeutic strategies and agents the emergence of resistant strains to other drugs. Ethambutol acts is becoming imperative. In the last few years, a significant amount by interfering with cell metabolism and ultimately with mycobac- of research has focused on methods that stimulate the host immune terial RNA synthesis.I*'! It may also play a role in the production system and enhance its capacity to eradicate mycobacteria. Inter- of the cell wall glycolipid arabinogalactan.'^*' In adults, ethambu- leukin-2 (IL-2),"" IL-12, IFNY,'^^! ^^^J ^^J^^^^ necrosis factor tol is well absorbed through the gastrointestinal tract, penetrates (TNF) antagonists'''^"' have all been used in the treatment of the blood-brain barrier, undergoes extensive distribution, and is adults with tuberculosis, with promising results. The role of TNF finally excreted, partly unchanged, in the urine and feces. in the pathogenesis of active disease has not been fully elucidated. The most serious adverse effect of this drug is optic neuritis TNF levels are high in the early stages of the disease and then with resultant decreased visual acuity, central scotoma, and red/ decrease as the patient recovers,'^*' and may thus contribute to the green color blindness (unilateral or bilateral). The risk of optic protective host immunity against M. tuberculosis. However, at the neuritis is both dose and duration dependent. This effect, although same time, high levels of TNF have been implicated in the rarely reported in children,'®' has raised particular concern regard- pathogenesis of the fever, cachexia, and weakness associated with ing the use of ethambutol in infants, since vision cannot be tuberculosis.'"' Further studies are required to establish the effica- adequately examined in this population and early visual changes cy of these immunotherapeutic approaches and to determine their cannot be detected in a timely manner. On the other hand, role in the treatment of tuberculosis in adults and children. ethambutol is usually administered for only 2 months until results Apart from strategies that aim to stimulate the host response of susceptibility tests are available; the possibility of development against tubercle bacilli, another promising approach, yet largely of optic neuritis is very small during such a limited period. unexplored, appears to be one that will enable delivery of high Therefore, it has been suggested that ethambutol may be used concentrations of antituberculous agents directly to the lungs safely in cases of life-threatening forms of tuberculosis or drug- thereby avoiding systemic toxicity.'^^' resistant tuberculosis.'™! 7. Therapeutic Drug Monitoring 5.5 Streptomycin Therapeutic drug monitoring allows the physician to adjust Streptomycin is bactericidal for extracellular mycobacteria but drug dosages early in the course of treatment, in order to achieve it has little activity on bacilli located inside macrophages where therapeutic serum drug concentrations and prevent the emergence the pH is low. Streptomycin is only available in a parenteral form; of drug resistance as well as the development of serious toxicity. this is associated with some inconvenience, discomfort, as well as Therapeutic drug monitoring is indicated for patients who are slow the extra treatment-associated costs. The recommended starting responders to antituberculous regimens, receive additional drugs pediatric dosage is 20^0 mg/kg/day but it should be determined for other medical reasons and are therefore at risk of drug-drug by peak and trough blood interactions.'^^' As with ethambutol, the interactions, have drug-resistant disease and are receiving second- use of streptomycin is limited to initial treatment regimens when line antituberculous agents, and also for patients with coexisting

diseases that interfere with the absorption or elimination of admin- 8.1.1 Pregnant Women with Positive Mantoux S/c/n Test But Normai Chest X-Ray istered drugs.''*' Since the pharmacokinetics of most antituberculous drugs in If infected pregnant women (positive Mantoux skin test) have infants are essentially unknown, and most of the relevant data are no clinical or radiographic evidence of tuberculosis disease, the extrapolated from studies in adults and older children, therapeutic infant does not need to be separated from her after delivery and drug monitoring is an invaluable ally in the treatment of tuberculo- does not require any special evaluation or treatment if the infant sis in this specific subpopulation of patients. remains asymptomatic. Suitable chemoprophylaxis for the mother (commonly Isoniazid alone), along with vigilant monitoring for 8. Management Issues 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 8.1 Perinatal Tuberculosis progression to disease (i.e. malnourished, HIV infected, immunocompromised or undergoing immunosuppressive therapy). Recent infection is probable if the mother has conversion of skin reactivity An evaluation algorithm for pregnant women at high risk for from negative to positive within the past 2 years or has recently tuberculosis is presented in figure 1 while a management algorithm for the mother and newborn when tuberculosis is suspected been in contact with an infectious source. If recent infection is not at delivery is presented in figure 2. In order to prevent perinatal probable and the mother is not at increased risk for progression to tuberculosis, high-risk pregnant women should undergo tuberculin disease, treatment for latent tuberculosis infection may be started skin testing. In the case of a positive result, chest radiography with after delivery under the condition that chest radiographs remain appropriate abdominal shielding must be performed (see also table normal. Other members of the family should be tested and evaluated 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 Abnormal GXR

Increased risk of No symptoms progression to disease and CXR compatibie with inactive disease

Recent No ciinical • Start treatment after deiivery Symptoms or infection likely evidence of disease » No separation of mother and infant indicated CXR showing • Evaluation of all family members and contacts active disease

Sputum smears Start chemoprophyiaxis • Start chemoprophyiaxis after deiivery and cultures during gestation • No separation of mother and infant indicated and monitor > No further evaluation/treatment of infant necessary if asymptomatic and all other famiiy members and contacts test negative Treatment with non-teratogenic agents and screening of aii household contacts

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

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 CXR consistent with active disease > No symptoms and/or associated symptoms > Sputum smear negative and/or positive smear • Negative history

• Infant at low risk • Ciinicai and radiographic assessment (no further evaluation necessary) of the infant for congenital tuberculosis • No further separation required • Chemoprophyiaxis or therapy • Mother is treated according to for active disease accordingiy history of previous therapy • Treatment of mother for active disease • HIV serology for both mother and infant • No separation needed if mother is not hospitalized, if drug adherence can be maintained and no drug resistance 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 as If the mother has an abnormal roentgenogram but no radio- well. graphic evidence of active disease, and this is also supported by the history, physical examination, and sputum smear, the infant is 8.1.2 Pregnant Women with Positive Mantoux Skin Test and considered to be at low risk for infection, does not need to be Abnormal Chest X-Ray isolated from the infected mother, and does not require treatment If infected pregnant women (positive Mantoux skin test) are with antituberculous agents. The mother should be asked whether symptom free and have an abnormal chest radiograph, which is she has received previous antituberculous chemotherapy and compatible with inactive tuberculosis (calcified or fibrotic le- should be given appropriate therapy (if she has not been previously sions), treatment should be postponed until after delivery. No treated) in order to prevent exposure of the infant to reactivation separation of the mother and newborn is required but all family disease of the mother. members and contacts should be evaluated. A positive Mantoux test along with the presence of related On the other hand, if the mother is thought to be contagious symptoms or a radiograph consistent with active disease in a based on clinical, radiographic, and sputum evidence, the infant pregnant woman demands further evaluation with sputum smears should be, in addition to being isolated from the mother, evaluated and cultures and initiation of appropriate therapy with non-terato- for congenital tuberculosis by means of clinical assessment and genic agents. Screening of household members should never be radiography. HIV serology should be also performed for the omitted. mother and neonate. If the newborn has no evidence of tuberculo- When tuberculous disease is suspected in a pregnant woman at sis, isoniazid therapy (a single dose of 10 mg/kg daily) should be delivery, the neonate must be separated from the mother until a immediately initiated for the infant while the mother is being chest radiograph of the mother becomes available. If the radio- treated for active disease. Once therapy is started, further separa- graph is abnormal, the infant should remain separated from the tion of the mother and infant (until the mother is proved to be non- mother until she is meticulously evaluated. The next essential step infectious) is only indicated if the mother requires hospitalization, for evaluation of the mother is sputum examination for detection if non-adherence to the treatment regimen is suspected, or if drug- of acid-fast bacilli. At the same time, all members of the family resistant strains of M. tuberculosis are implicated. Isoniazid ther- and contacts should be investigated for tuberculosis infection or apy of the newborn should be sustained until the mother is sputum disease. and culture negative for 3 months. Before discontinuation, a

tuberculin skin test should be performed on the infant; if it is men has been shown to reduce the incidence of tuberculous positive, therapy should be continued for a total of 9-12 months. If disease by 90% during the first year after treatment, and the the test is negative, isoniazid treatment may be discontinued with a protective effect has been reported to last for at least 30 years.'*^' Mantoux test repeated after 6-12 months. Isoniazid is administered daily as a single dose of 10 mg/kg (300 It is permissible for mothers who receive therapy for tuberculo- mg/kg is the maximum dose). However, when adherence to daily sis infection or disease to breastfeed their infants (unless, as noted therapy is suspected to be poor, isoniazid may be given twice previously, separation between them is indicated). Therefore, weekly under direct observation after 1 month of daily treatment. agents compatible with breastfeeding should be used. The only In this case, each dose should be 20-40 mg/kg (maximum dose drugs considered to be safe in this particular situation are isonia- 900 mg/kg). Directly observed therapy (direct observation of a zid, rifampin, ethambutol, and streptomycin for first-line therapy, patient by a healthcare worker while the patient ingests the medi- and kanamycin and cycloserine for second-line therapy. These cation) prevents the consequences of poor adherence (i.e. treat- drugs are excreted in breast milk at small concentrations; these ment failure, relapse, and secondary drug resistance). For infants concentrations are not adequate for effective treatment or preven- with HIV coinfection or any immunosuppressive condition, treat- tion in infants requiring antituberculous chemotherapy.'^''•*" How- ment should be continued for a minimum of 12 months.'^'' ever, medications should be prescribed at the lower end of the When latent infection with drug-resistant strains of M. tubercu- therapeutic range for these infants, in order to minimize the risk of losis is suspected, an initial regimen of isoniazid together with toxicity.'*°' rifampin is recommended until the results of susceptibility tests of isolates from either the infant or the adult contact are available.'^^' 8.2 Treatment of Latent Tuberculous Intection Drug resistance is suspected when the patient lives or was bom in a country with a high prevalence of resistant strains, and when the Latent tuberculosis infection is designated by a positive adult source has documented drug-resistant tuberculosis or posi- Mantoux skin test in the absence of symptoms and radiographic tive smears/cultures after 2 months of antituberculous therapy or a features suggestive of active disease. Treatment of this condition is history of previously under-treated disease. If the results of sus- indicated to prevent progression to tuberculosis disease. Further- ceptibility testing prove that the responsible organism is isoniazid more, preventive therapy is indicated in infants who have been resistant only (or if the drug eannot be tolerated by the patient), recently exposed to adults with contagious tuberculosis even in the isoniazid should be discontinued and rifampin should be adminis- absence of a positive tuberculin skin test, as in the case of infants tered for a total of 6-9 months.l^^' Rifampin can also be given on a bom to mothers with tuberculous disease. Infants may develop daily or a twice-weekly basis. Regarding isolates resistant to both tuberculin reactivity simultaneously with tuberculosis disease, isoniazid and rifampin, optimal therapy has not yet been estab- which may often be quite severe. For this reason, in exposed lished. Suggested regimens include the combination of a fluoro- infants, preventive chemotherapy should start immediately and quinolone with pyrazinamide or high-dose pyrazinamide and skin testing should be repeated 3 months later. If the infants remain ethambutol for 6-9 months. Finally, for bacilli resistant to multiple non-reactive to tuberculin, treatment may be discontinued; if the dmgs an expert in pediatric tuberculosis should be advocated;'^^' test is positive, the full course of therapy should be administered. the most common strategy is to prescribe two drugs to which the Evidently, it is very important, based on the child's history of organism is susceptible. contacts, to distinguish between a positive tuberculin response reflecting 'latent' disease and tuberculin sensitivity coexistent 8.3 Treatment of Tuberculosis Diseose in Infants with primary tuberculosis. If a child who has active disease is treated with isoniazid chemoprophylaxis, the child might later develop more serious progressive primary tuberculosis and treat- 8.3.1 Drug-Susceptible Intrattioracic Tubercutosis ment could then be problematic if isoniazid resistance has devel- The optimal management of tuberculosis requires treatment oped. regimens that combine the shortest possible duration with the The treatment of choice for latent tuberculous infection or highest efficacy. Short-course regimens decrease the emergence of recent exposure in infants who have not been previously treated is secondary drug resistance, reduce the total cost of treatment, and monotherapy with isoniazid.'*^' According to current recommen- improve patients' adherence. Congenital and acquired tuberculosis dations isoniazid should be administered for 9 months. This regi- disease in infants should be treated

® 2005 Adis Data Informatian BV. Aii rights reserved. Pediatr Drugs 2005; 7 C4) Tuberculosis in Infants: Management Issues 231

Upon suspicion of active disease, infants should be started on 8.3.3 Drug-tlesistant Tubercutosis four antituberculous medications (isoniazid, rifampin, pyrazi- Primary drug resistance arises when a patient is infected with a namide, plus either ethambutol or streptomycin) until the organ- strain of M tuberculosis that is already resistant to a specific drug. ism is known to be fully susceptible to all agents used."^' Current Secondary resistance is the result of non-adherence of the patient recommendations for drug-susceptible pulmonary tuberculosis to therapy or of the prescription of an inadequate treatment regi- with or without intrathoracic adenopathy and for hilar adenopathy men by the doctor, either of which may lead to predominance of alone in infants suggest the use of isoniazid (10-15 mg/kg/day), drug-resistant organisms within a given population of bacilli. If the rifampin (10-20 mg/kg/day), and pyrazinamide (15-30 mg/kg/ adult source of an infected infant has been previously treated for day) for 2 months, followed by at least 4 months of isoniazid and tuberculosis, is seropositive for HIV infection, or lives in a com- rifampin.l''20,24,57,86-93i j^g continuation phase of the therapeutic munity with high rates of primary dmg resistance or HIV preva- regimen may be extended to 10 months depending on the severity lence, it is very possible that the child will have dmg-resistant of the disease."^'^'*'*^! With the aforementioned regimen, treatment tuberculosis. may be administered twice weekly right from the beginning'^"-^^' According to the Working Group On Anti-Tuberculosis Drug or after a phase of half a month,'^'l 1 or 2 months-long daily Resistance Surveillance,"™' between 1994 and 1997, median re- therapy, preferably under direct observation; the success rate of sistance to any single drug, isoniazid, rifampin, ethambutol, and this regimen approaehes 100%. multiple drugs was present in 9.9%, 7.3%, 1.8%, 1%, and 1.4% of A study'"'] using isoniazid (10-15 mg/kg/day) and rifampin patients, respectively, among patients from 35 countries with no (10-15 mg/kg/day) with or without streptomycin (30 mg/kg/day) prior treatment. Among patients who had received therapy in the daily for 15 days followed by similar doses of isoniazid and past for <1 month, resistance to any of these drugs occurred in rifampin twice a week for another 8.5 months suggested this 36%, while multidrug resistance occurred in a median of 13% regimen was safe and effective for treating tuberculosis in young (range 0-54%). The highest rates of multidmg resistance were infants aged <6 months. Some centers prefer to administer isonia- present in the former Soviet Union, Asia, the Dominican Republic, zid and rifampin without streptomycin for a total of 9 months and Argentina. The impact of these data on childhood tuberculosis when drug resistance is considered rather unlikely."^i Again, this is obvious when one considers that contagious adults represent the course can be given daily initially, and then twice only source for transmitting the disease to children. When dmg-resistant strains of M. tuberculosis are suspected, a 8.3.2 Extraputmonary Tubercutosis regimen of isoniazid, rifampin, and pyrazinamide plus either strep- Antituberculous agents have excellent tissue penetration; more- tomycin or ethambutol should be initially prescribed, pending the over, only small numbers of mycobacteria are usually present at results of susceptibility tests. When the latter become available, extrapulmonary sites of infection.'^'l Therefore, the regimens de- treatment should include at least two bactericidal drugs to which scribed in section 8.3.1 may also be used in patients with extra- the isolate is susceptible. Additionally, therapy should usually be pulmonary tuberculosis, with some exceptions. Treatment of skel- continued for 12-18 months under directly observed therapy, in etal, miliary, and CNS tuberculosis requires daily administration order to be effective and prevent further emergence of resistance. of isoniazid, rifampin, pyrazinamide, and streptomycin for 1-2

months, followed by isoniazid and rifampin daily or twice weekly 8.3.4 tr)dicafions tor the Use ot Corticosteroids for another 10 months.l^^.se.'Wi T^g reason for the longer duration Corticosteroids are indicated in select forms of tuberculous of treatment in the aforementioned cases is the limited number of disease. Infants with serositis (pleural, pericardial effusion) expe- controlled trials and hence experience with these agents in patients rience significant symptomatic relief upon administration of corti- with extrapulmonary disease.'^'' costeroids.''''' Patients with endobronchial tuberculosis with ac- Diagnostic and/or therapeutic surgery (including total excision, companying obstmction, emphysema, or atelectasis may also ben- incision and drainage, and wide debridement) may be indicated for efit from adjuvant cortieosteroids.'"' Tuberculous meningitis is a extrathoracic tuberculous lymphadenitis.'''^' Ventriculoperitoneal form of the disease with severe consequences and long-term shunting for CSF relief in tuberculous meningitis has also been neurologic sequelae, which may be partly alleviated by the use of reported.'^'*'^'! In the case of bone and joint disease, evacuation of corticosteroids."^'''' These dmgs act by minimizing local infiam- large abscesses'"^*' or even radical surgical reconstmction is some- mation and thus decreasing intracranial pressure. Corticosteroids times required.'^^' are also indicated for miliary disease with alveolocapillary

block.l"l Prednisotie 1-2 mg/kg/day for 4-8 weeks with gradual and regional suppurative adenitis; osteitis and systemic complaints tapering is the recommended regimeti.'^^l Alternatively, dexa- (fever, irritability etc.) occur with a much lower frequency. methasone 0.5 mg/kg/day may be prescribed. It is worth mentioning, as a reflection of the magnitude of ongoing research regarding tuberculosis prevention, that as of June 8.3.5 Co-lntecfion wifh HIV 2001, more than 190 candidate vaccines had been screened in All children with tuberculous disease should be tested for HIV animal '^^' infection. HIV-seropositive infants with pulmonary tuberculosis should receive isoniazid, rifampin, pyrazinamide, and ethambutoi 10. Conclusions or an aminoglycoside for 2 months, followed by isoniazid and rifampin for a total of at least 12 months. The fourth drug during Tuberculosis in infants, whether congenital or postnatally ac- the initial phase of treatment may be withdrawn if the isolated quired, necessitates timely diagnosis and appropriate management strain proves to be fully susceptible and disseminated forms of the of both the patient and contacts. The disease process is rapidly disease are excluded. Meticulous monitoring is required in this evolving in this immunologically immature age group and the subgroup of patients because of the increased frequency of drug outcome may be fatal if a high index of suspicion is not main- resistance and adverse drug reactions as well as interactions with tained. As shorter and more effective therapeutic regimens are antiretroviral agents. designed and clinically established, physicians should be able to encompass latest guidelines and recommendations in their every- 9. Prevention day practice. Finally, further studies focused on the infantile patient are needed, in order to achieve optimal conventional or Contacts of infectious adults with tuberculosis should be skin alternative therapy for the prevention and treatment of tubercu- tested and appropriately managed. Infants in particular should losis. receive the highest priority during investigation of contacts since their risk of progression to active disease once infected is very Acknowledgments high. BCG is the only vaccine available, to date, for the prevention of No sources of funding were used to assist in the preparation of this review. tuberculosis. According to WHO recommendations, BCG vac- The authors have no conflicts of interest that are direetly relevant to the cines should be administered as a single dose during infancy, content of this review. usually while the baby is in the maternity hospital. However, different countries have adopted diverse strategies regarding tu- References berculosis control. In most countries, BCG vaccination is adminis- t. World Health Organisation. Global tuberculosis control: WHO report 2001. Gene- va: World Health Organization. 2001 tered as recommended by the WHO. However, in some countries it 2. World Health Organisation. Tuberculosis: infection and transmission [online]. is recommended as a single dose administered at other ages (in Available from URL: http://www.who.int/mediacentre/factsheets/fsl04/en/ Greece it is recommended at the age of 5-6 years), in the US BCG [Accessed 2005 Jun 29] 3. Dye C. Scheele S, Dolin P, et al. Global burden of tuberculosis: estimated is not recommended in the routine vaccination schedule, and in incidence, prevalence, and mortality by country: WHO Global Surveillance and other regions of the world it is recommended that the vaccine be Monitoring Project. JAMA 1999; 282: 677-86 4. Dolin PJ. Raviglione MC, Kochi A. Global tuberculosis incidence and mortality administered twice. during 1990-2000. 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