- Email: [email protected]
Perinatal tuberculosis
Early Human Development 84 (2008) 795–799
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Early Human Development j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Perinatal tuberculosis New challenges in the diagnosis and treatment of tuberculosis in infants and the newborn Elizabeth Whittaker a,⁎, Beate Kampmann a,b,c,d,1 a
Academic Department of Paediatrics, Imperial College London, United Kingdom Wellcome Centre for Clinical Tropical Medicine, Imperial College London, United Kingdom c Institute for Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, South Africa d Centre for Respiratory Infections, Imperial College London, United Kingdom b
a r t i c l e Keywords: Perinatal Tuberculosis Neonatal
i n f o
a b s t r a c t With increasing rates of tuberculosis (TB) infection and disease worldwide, the rate of perinatal TB is also affected. A high index of suspicion by health professionals, in both the developed and developing world, is required to detect and manage tuberculosis in pregnancy and the early newborn period. Differences in immune responses in the fetus and neonate add to the diagnostic difficulties already recognised in young children. Although specific guidelines for the treatment of this potentially devastating disease are lacking due to paucity of experience, outcome is favourable, if the condition is recognised and treated according to existing TB protocols. HIV co-infection, multi- and extensively-drug resistant (MDR/XDR) TB contribute to the challenges. New diagnostic and vaccine developments hold future promise, but much work is needed to completely understand the complex immune responses to tuberculosis and control this disease. Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved.
1. Background
2. Pregnancy and tuberculosis
Worldwide, tuberculosis has increased rapidly over the past three decades, particularly in HIV endemic and impoverished areas in Africa and Asia. This trend has been mirrored in the UK and other resourcerich countries, mainly in the ethnic minority and immigrant communities. The classic age distribution of tuberculosis has also changed, moving from a peak in over 50s to a median age of under 30 years [1]. The change in epidemiology has already resulted in an increase in the proportion of women of child bearing age contracting tuberculosis (40% increase in the US between 1985 and 1992, prevalence 143.3/ 100,000 deliveries in London in 1998) [2,3] and subsequently is likely to impact on the incidence of perinatal tuberculosis (TB). Co-infection with HIV, drug resistant tuberculosis and infection control issues are some of the newer challenges facing physicians caring for vulnerable infants born to TB-infected mothers in both the developing and the developed world.
Over time, opinions as to whether pregnancy and tuberculosis have an impact on each other have varied. Hippocrates believed that pregnancy was beneficial and protected against tuberculosis. This view persisted until the 19th century, when Grisolle reported that the course of the disease was less favourable in pregnancy [4]. Such was the estimated devastating effect of tuberculosis in pregnancy that until recently abortion was recommended. In some parts of the world this practice persists, especially in cases of multi- and extensively-drug resistant (MDR/XDR) TB [5]. Recent studies support the view that TB, and in particular extrapulmonary TB are associated with increased antenatal hospitalisation, premature delivery, maternal mortality, perinatal infant mortality and intra-uterine growth restriction compared with healthy pregnant women (3, 6, 7). This is seen in both HIV positive and negative cohorts and is more marked in incompletely treated disease and women who are diagnosed later in pregnancy. 2.1. TB in the pregnant woman: diagnosis and management
⁎ Corresponding author. Tel.: +44 20 7594 3717; fax: +44 20 7594 3894. E-mail addresses: [email protected] (E. Whittaker), [email protected] (B. Kampmann). 1 Tel.: +44 20 7594 3915; fax: +44 20 7594 3894.
The presentation of tuberculosis in pregnancy varies: some women are symptom free, but a large number present with very non-specific symptoms common in pregnancy like malaise and lethargy, or more typical severe symptoms of TB. Although pulmonary TB is the commonest manifestation, extrapulmonary TB features more commonly
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than in a non-pregnant population (5–10%) (1, 8). Of note is that the tuberculin skin test (TST) is frequently found to be anergic, most likely due to altered immunological responses to Mycobacterium tuberculosis in pregnant women [6]. A delay between onset of symptoms and diagnosis occurs regularly, due to the non-specific nature of symptoms at presentation, reluctance to perform radiography and low index of suspicion, most likely also related to limited resources in the settings where this is more common [1,7]. Treatment response and time to clearance of bacilli from sputum are equivalent to non-pregnant women, and prognosis, if treated early, can also be similar. In the event of TB exposure, women with a positive TST, but clinically well with a normal chest X-ray, should be given chemoprophylaxis in accordance with national guidelines. Previous concerns about the use of isoniazid in pregnancy for chemoprophylaxis are unfounded, with an isoniazid-associated death rate of 0.001% [8]. If active tuberculous disease is found, anti-tuberculous treatment (ATT) should be commenced. Some groups recommend delaying start of treatment to the second trimester if the mother is well, but all agree that the benefit of treating the mother, preventing maternal morbidity and mortality and avoiding perinatal transmission, outweigh the risk of teratogenicity. A number of studies assessing rates of congenital malformations in infants exposed to ATT in utero have not demonstrated an appreciable difference [9–11]. A group in Peru have followed up children after in utero exposure to second line agents used for treatment of multidrug-resistant TB and performed a review of the literature showing that a low incidence of ototoxicity secondary to the aminoglycosides is the main concern [10]. Table 1 demonstrates the safety profile of ATT in pregnancy, lactation and the newborn baby.
Table 1 Anti-tuberculous drugs in pregnancy, lactation and in the newborn Use of anti-tuberculosis drugs in pregnancy, lactation and in the newborn baby Drug
Pregnancy
Rifampicin
Safe
Lactation
0.5% of adult dose detected Rifabutin Congenital defects in 0.5% of adult animal studies dose detected Rifapentine Rarely causes bleeding 0.5% of adult in mother if administered dose detected in last few weeks of pregnancy Isoniazid Safe, supplement with 0.75–2.3% of pyridoxine adult dose detected Pyrazinamide Limited data but 0.75–2.3% of recommended adult dose detected Ethambutol Safe in human beings, Yes in minute cleft palate, skull and amounts spine defects Yes in minute Ethionamide Premature labour, amounts congenital abnormalities Aminoglycosides Ototoxicity in fetus, 0.05–0.5% of renal damage adult dose detected Amikacin Likely ototoxicity Yes, concentration not known Kanamycin Ototoxicity, hearing 0.95–1.8 % of loss 2.3% adult dose Capreomycin Unknown, bronzing?? Not known Streptomycin Ototoxicity, greatest 1st 0.95–22.5% trimester, hearing loss in 8–11% children Quinolones Bone developmental 0.05–0.5% of abnormalities in adult dose animals detected
Newborn Safe 10–20 mg/kg/day Use not established Use not established
Safe 5–10 mg/kg/day
3. Perinatal TB 3.1. Prevention Perinatal TB is extremely rare if the mother is effectively treated in pregnancy. According to WHO, a mother is no longer considered infectious after treatment for 2–3 weeks [12]. If she is breastfeeding it is recommended that 6 months isoniazid is given to the baby, or alternatively 3 months isoniazid followed by a TST. If negative, BCG vaccine should be administered and treatment stopped; if positive, treatment should continue for 6 months, followed by the BCG at the end. If a diagnosis is made close to delivery, the baby and placenta should be carefully evaluated for evidence of perinatal TB infection and the infant treated empirically if there are any concerns or doubt. All of these infants should be carefully followed for 2 years. 3.2. Definition and presentation of perinatal TB in the infant Controversy has always surrounded the definition of congenital tuberculosis with criteria first described by Beitzke in 1935 [13], followed by revised criteria by Cantwell in 2002 which stated: the infant must have proved tuberculous lesions and at least one of a) lesions in the first week of life; b) a primary hepatic complex or caseating hepatic granulomata; c) tuberculous infection of the placenta or the maternal genital tract; d) exclusion of the possibility of postnatal transmission by a thorough investigation of contacts, including hospital staff [2]. Transmission is believed to be either in utero by haematogenous spread through the umbilical vein or ingestion of infected amniotic fluid; intrapartum aspiration or ingestion of amniotic fluid or direct contact with infected cervix/endometrium; or postpartum by inhalation or ingestion from an infectious source [2]. Because of the difficulties in ascertaining the exact time and circumstances of infection, more recently, perinatal tuberculosis is the preferred description encompassing TB acquired in utero, intrapartum or during the early newborn period and has replaced the term congenital tuberculosis. Distinguishing between the time frames is not crucial, as the presentation, diagnosis, management and prognosis are similar. Although unusual, (about 300 cases of perinatal TB have been described in the literature, in case reports, case series and reviews [2]) perinatal tuberculosis is believed to be increasing alongside a rise in TB incidence. Prompt treatment is required for the survival of these infants. Mortality is high, varying between 2 and 60% depending on delay to presentation and other factors, such as prematurity and coinfection with HIV [2,14]. Complications include a high rate of miliary tuberculosis and meningitis, resulting in seizures, deafness and death.
Safe 20–30 mg/kg/day
4. Tuberculosis in the neonate—immunological considerations
Retrobulbar neuritis; not recommended
The observation that young children, particularly under the age of 2, are the most vulnerable to tuberculosis, opens a window to our understanding of the immunopathogenesis of tuberculosis. The neonatal period should also be considered as a particularly vulnerable time for the following reasons: the fetal and neonatal immune system are subjected to multiple demands, such as protection against infection, avoidance of potentially harmful pro-inflammatory cytokine responses that can induce alloimmune reactions between mother and fetus and the transition from the “sterile” intra-uterine environment to the antigen-exposed “outside world”. It is increasingly recognised that CD4+CD25+ regulatory T-cells are abundant and potent at birth and inhibit Th1 cell immunity [15]. In the absence of acquired immune responses and immunological memory, the first line of defence lies with the innate immune response of the neonate. Flow cytometry has demonstrated reduced levels of MHC class II molecules between neonates and adults [16], which potentially contribute to impaired activity of antigen-presenting cells (APC) and result in qualitative differences in monocytes. Blood derived DCs are functionally
Safe
Use with caution, not absorbed orally Poorly absorbed by GI tract Poorly absorbed Minimal GI absorption Safe
Use with caution, shown to be safe for 5– 10 days
E. Whittaker, B. Kampmann / Early Human Development 84 (2008) 795–799
immature at birth relative to adult DCs and continue to express a less differentiated phenotype throughout early childhood [17]. It can be postulated that the bias against Th1-cell polarizing cytokines makes young infants more susceptible to tuberculosis, especially since the perinatal infection might have occurred via haematogenous spread rather than via primary lung infection. Some studies also suggest that neonatal APCs lack the capacity to deliver important Th1 polarizing signals to T-cells. Their capacity to synthesise interleukin (IL)-12, a key APC-derived cytokine, matures slowly during childhood [18] and neonatal, monocyte-derived DCs have a specific defect in IL-12p35 expression [19]. IL-12 is critical for the initial phases of Th1 polarization and also for maintaining the efficiency of the interferon (IFN)-γ transcription machinery in Th1 effector cells [19]. In cases of primary lung infection, the alveolar macrophage is the first line of defence in the innate immune response to TB and plays a critical role in amplifying the response to infection. Studies in the animal and human host have consistently demonstrated reduced microbial killing [20,21] and diminished monocyte recruitment to the site of infection in infants compared to adults [22]. Neonatal CD4 cells appear intrinsically deficient in their capacity to express Th1 effector function, partially attributed to hypermethylation of the proximal promoter of the IFN-γ gene [23], resulting in a highly restricted pattern of IFN-γ response to a variety of stimuli [24,25]. CD154 (CD40 ligand) expression is also significantly reduced compared with adult cells [26]. Impairment of innate pulmonary defences in the neonate and infant may allow mycobacteria to overwhelm the effects of the innate immune system prior to the initiation of an antigen-specific immune responses. The finding of generally impaired cell-mediated immune responses in the neonate and young children raise the question of whether antigen-specific immune responses to mycobacteria are equally affected. Delayed type hypersensitivity to purified protein derivative may be absent in up to 40% of HIV negative children presenting with extrapulmonary TB [27], compounding the difficulties of diagnosis in young children. However, studies measuring responses to neonatal vaccination with M. bovis BCG demonstrate potent Th1 responses, possibly related to the potent APC-activating properties of BCG vaccine. Much more needs to be learned from innate and antigen-specific studies of immunity in the newborn, and further research in this area is required, which will benefit not just our understanding of tuberculosis but other infections in this particularly vulnerable period of life.
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Many mothers are only found to have TB following diagnosis in the infant. As mentioned, the TST is typically unresponsive, but a repeat after 3 months is frequently found to be positive [2]. Interferon gamma release assays are an alternative immunological diagnostic option for these infants, but there are some concerns about the validity of these assays in newborns and infants, as depressed IFN-γ production in response to antigenic stimuli has been described in this age group [31]. However, positive responses to both the QFG-IT whole blood and Elispot assays have been described in cases of perinatal TB and in a contact tracing study [32,33]. Further investigations in this area are required and a negative IGRA should not deter empirical antituberculosis treatment pending microbiological confirmation. 4.2. Treatment and outcome of the infant Perinatal TB is usually fatal if untreated. Following appropriate investigation, the infants should be empirically commenced on treatment as per national guidelines. Since this is not a common disease, no therapeutic trials have determined the optimal treatment regimen and length. Complete recovery has been described following a standard treatment course of 2 months of 4 drugs (isoniazid, rifampicin, pyrazinamide and streptomycin), followed by 4 months of 2 drugs (isoniazid and rifampicin) [34]. However other regimens for up to 18 months have been described and clinicians should seek expert advice. Treatment length should be determined by clinical condition and response to treatment. Infants should receive regular monthly review following discharge until treatment is complete and follow up should then continue for up to 2 years. These infants are often very unwell and supportive therapy such as oxygen or respiratory support with ventilation may be required. Steroids are recommended in cases of TB meningitis or airway obstruction due to large lymphadenopathy. A case series of 17 infants less than 6 months ventilated secondary to respiratory failure caused by Mycobacterium tuberculosis revealed a favourable outcome for all [35]. All infants were HIV seronegative, median duration of stay in intensive care was 7 days (range 2–37 days), steroids were used in all children with large airway obstruction (n = 10), only one infant was TST positive and all responded to standard ATT. This contrasts with previous reports of high mortality in infants with tuberculosis. Improved outcome could be due to the fact that none of these infants had TB meningitis or HIV, but with aggressive management of TB in the very young, including intensive care, a good outcome can be achieved. 4.3. MDR/XDR TB in mothers and infants
4.1. Diagnosis of perinatal TB The diagnosis of perinatal TB is difficult without doubt—a high index of suspicion is required as TST is often negative (78% of the time in two case series [2,28]) and symptoms are often non-specific. These infants typically present at 2–4 weeks of age with fever, respiratory distress, lethargy +/− hepatomegaly and tend to be commenced on broad spectrum antibiotics for presumed sepsis. Unless there is a suggestive history in the mother, TB is often not suspected until deterioration/lack of response to antibiotics is noted. Diagnosis in the infant is based on TST, which is often negative, CXR and other radiology if symptoms suggest. Microbiological specimens such as gastric aspirates, ascitic fluid, lymph node biopsy, endotracheal aspirate, bone marrow and cerebro-spinal fluid should be obtained and stained and cultured for AFB. Gastric aspirates in neonates have a higher microbiological yield than in older infants (70%) and are well tolerated [29]. The chest X-ray is nearly always abnormal, with 50% showing a military TB pattern [30]. Newer modalities such as polymerase chain reaction (PCR) and restriction fragment length polymorphisms can be useful for diagnosis and identification of the index case. Ideally, placental and maternal vaginal or endometrial samples should be obtained, but this is frequently difficult given the later presentations.
One of the greatest challenges facing physicians caring for patients with tuberculosis is drug resistance. Rates of multidrug-resistant (MDR) strains (resistant to both isoniazid and rifampicin) including extensively drug resistant (XDR) strains (also resistant to fluoroquinolones and at least one second line injectable agent such as amikacin, kanamycin and/or capreomycin) are rising in many parts of the world. A case series of 7 infants born to mothers receiving treatment for MDR-TB in pregnancy demonstrated good outcomes for both mother and infant with no evidence of significant late-presentation toxicity in the infants [10,11]. All expecting mothers received treatment in the first or second trimester with smear and culture conversion in 6 of 7 patients. Each patient was managed with an aggressive individualised treatment regimen during and after pregnancy with very close monitoring. Use of chemoprophylaxis was not discussed in this paper, however in other reports, chemoprophylaxis was only given to the infant if the mother remained smear or culture positive at delivery [36]. In 2 cases, ethambutol and pyrazinamide were used for 3 months as chemoprophylaxis [33]. Klaus-Dieter et al. recommended screening the newborn infant for infection (TST/gastric washings/CXR) and recommended BCG, careful observation and repeat TST at 3 months if there was no evidence of infection in association with smear-negative
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maternal disease. WHO guidelines currently recommend the avoidance of chemoprophylaxis in the case of exposure to MDR-TB and observation for 2 years provided they are clinically well. 5. Infection control on the NICU In the context of late diagnosis of perinatal tuberculosis, a number of publications have discussed the risk of exposures to other neonates in the setting of the neonatal intensive care unit. Laartz et al. reviewed literature concerning congenital tuberculosis with particular attention to infection control, following a case in their unit [37]. Summarising 6 different publications with around 2814 infants exposed to perinatally infected infants, infected staff and infected parents in NICU and nursery settings, only 2 infants developed active tuberculosis. They concluded that aggressive follow up with a TST and isoniazid prophylaxis for those at risk was warranted. All infants at high risk were evaluated clinically and with radiography. Due to previously described anergy to the TST, the TST was repeated at 3 months. The use of an oscillatory ventilator with no expiratory filter was described as posing a theoretical risk of aerosolized respiratory secretions, but no secondary cases were found. Despite the low transmission rate in the NICU, careful consideration of air handling and use of isolation rooms where available are advised. 6. Neonatal TB and HIV—special considerations As mentioned above, the increasing rate of tuberculosis globally is driven by the HIV pandemic. The relationship between HIV and TB has been well described in the literature and a number of groups have investigated the effect of HIV co-infection on incidence and outcome of perinatal TB. Adhikari et al. described the investigation of 77 neonates with suspected TB in KwaZulu Natal, South Africa [38]. 11 infants had culture confirmed perinatal TB, of whom 6 were born to mothers with HIV/TB co-infection (55%, compared with a local antenatal prevalence rate of HIV infection of 23%). These neonates presented similarly to those described in the literature without HIV exposure and although there were no significant differences between the HIV exposed and unexposed groups, there was a trend towards more severe disease in the mothers and infants, in particular a greater incidence of prematurity and IUGR—which is known to be associated with HIV disease. Three of the 6 infants born to HIV seropositive mothers were HIV infected, reflecting a higher transmission rate than the 34% normally found in KwaZulu Natal. A further prospective case series of 107 pregnant women with TB, found a HIV infection rate of 77% and a mother to infant transmission rate for TB of 16%, with similar disease patterns in both mothers and infants to HIV uninfected controls. The VTRTB (vertical transfer of Mycobacterium tuberculosis) was not influenced by CD4 count or perinatal maternal viral load. The only risk factor of significance was untreated tuberculosis or default from treatment (p = 0.04) [39]. HIV transmission rate was 11%. Less than half of the mothers who transmitted TB to their neonates were sputum smear or culture positive, highlighting the significant problem of smear-negative transmission of TB previously reported. In this study, it was noted that some mothers transmitted TB despite long durations of ATT, emphasising the importance of investigation and comprehensive observation of these exposed infants for up to 2 years. It is essential that a high index of suspicion for perinatal TB is adopted by health care workers in areas where TB and/or HIV are prevalent, or in mothers recently immigrating from TB/HIV endemic areas [40,41]. Latent TB was found in 49% of 400 pregnant women in a study in Johannesburg. Although there is no evidence that there is an increased reactivation rate in pregnancy, given how deadly TB in pregnancy can be for both mother and infant, active screening and isoniazid preventative treatment of latent TB should be considered in areas of high TB endemicity. In summary, perinatal TB is a potentially devastating disease, but with a high index of suspicion and aggressive management can have a good outcome. Neonatalogists and paediatricians need to be aware of TB
and potentially HIV-co-infection in women of childbearing age presenting to our healthcare services, particularly from TB/HIV endemic countries. The care for the infant with perinatal TB starts with careful screening and treatment of pregnant women with TB to prevent this condition from occurring in the first place. References [1] Ormerod P. Tuberculosis in pregnancy and the puerperium. Thorax 2001;56: 494–9. [2] Cantwell MF, Shehab ZM, Costello AM, et al. Brief report: congenital tuberculosis. N Engl J Med 1994;330:1051–4. [3] Llewelyn M, Cropley I, Wilkinson RJ, Davidson RN. Tuberculosis diagnosed during pregnancy: a prospective study from London. Thorax 2000;55:129–32. [4] Grisolle A. De 1' influence que la grossesse et la phthisie pulmonaire exercant reciproquement l' une sur l'autre. Arch Gen Med 1850;22:41. [5] Good Jr JT, Iseman MD, Davidson PT, Lakshminarayan S, Sahn SA. Tuberculosis in association with pregnancy. Am J Obstet Gynecol 1981;140:492–8. 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Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFNgamma gene expression between human neonatal and adult CD45RO-T cells. J Immunol 2002;168:2820–7. [24] Rowe J, Macaubas C, Monger TM, et al. Antigen-specific responses to diphtheriatetanus-acellular pertussis vaccine in human infants are initially Th2 polarized. Infect Immun 2000;68:3873–7. [25] Kampmann B, Tena-Coki G, Anderson S. Blood tests for diagnosis of tuberculosis. Lancet 2006;368:282 author reply 282–3. [26] Nonoyama S, Penix LA, Edwards CP, et al. Diminished expression of CD40 ligand by activated neonatal T cells. J Clin Invest 1995;95:66–75. [27] van der Weert EM, Hartgers NM, Schaaf HS, et al. Comparison of diagnostic criteria of tuberculous meningitis in human immunodeficiency virus-infected and uninfected children. Pediatr Infect Dis J 2006;25:65–9. [28] Hageman J, Shulman S, Schreiber M, Luck S, Yogev R. 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Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Perinatal tuberculosis New challenges in the diagnosis and treatment of tuberculosis in infants and the newborn Elizabeth Whittaker a,⁎, Beate Kampmann a,b,c,d,1 a
Academic Department of Paediatrics, Imperial College London, United Kingdom Wellcome Centre for Clinical Tropical Medicine, Imperial College London, United Kingdom c Institute for Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, South Africa d Centre for Respiratory Infections, Imperial College London, United Kingdom b
a r t i c l e Keywords: Perinatal Tuberculosis Neonatal
i n f o
a b s t r a c t With increasing rates of tuberculosis (TB) infection and disease worldwide, the rate of perinatal TB is also affected. A high index of suspicion by health professionals, in both the developed and developing world, is required to detect and manage tuberculosis in pregnancy and the early newborn period. Differences in immune responses in the fetus and neonate add to the diagnostic difficulties already recognised in young children. Although specific guidelines for the treatment of this potentially devastating disease are lacking due to paucity of experience, outcome is favourable, if the condition is recognised and treated according to existing TB protocols. HIV co-infection, multi- and extensively-drug resistant (MDR/XDR) TB contribute to the challenges. New diagnostic and vaccine developments hold future promise, but much work is needed to completely understand the complex immune responses to tuberculosis and control this disease. Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved.
1. Background
2. Pregnancy and tuberculosis
Worldwide, tuberculosis has increased rapidly over the past three decades, particularly in HIV endemic and impoverished areas in Africa and Asia. This trend has been mirrored in the UK and other resourcerich countries, mainly in the ethnic minority and immigrant communities. The classic age distribution of tuberculosis has also changed, moving from a peak in over 50s to a median age of under 30 years [1]. The change in epidemiology has already resulted in an increase in the proportion of women of child bearing age contracting tuberculosis (40% increase in the US between 1985 and 1992, prevalence 143.3/ 100,000 deliveries in London in 1998) [2,3] and subsequently is likely to impact on the incidence of perinatal tuberculosis (TB). Co-infection with HIV, drug resistant tuberculosis and infection control issues are some of the newer challenges facing physicians caring for vulnerable infants born to TB-infected mothers in both the developing and the developed world.
Over time, opinions as to whether pregnancy and tuberculosis have an impact on each other have varied. Hippocrates believed that pregnancy was beneficial and protected against tuberculosis. This view persisted until the 19th century, when Grisolle reported that the course of the disease was less favourable in pregnancy [4]. Such was the estimated devastating effect of tuberculosis in pregnancy that until recently abortion was recommended. In some parts of the world this practice persists, especially in cases of multi- and extensively-drug resistant (MDR/XDR) TB [5]. Recent studies support the view that TB, and in particular extrapulmonary TB are associated with increased antenatal hospitalisation, premature delivery, maternal mortality, perinatal infant mortality and intra-uterine growth restriction compared with healthy pregnant women (3, 6, 7). This is seen in both HIV positive and negative cohorts and is more marked in incompletely treated disease and women who are diagnosed later in pregnancy. 2.1. TB in the pregnant woman: diagnosis and management
⁎ Corresponding author. Tel.: +44 20 7594 3717; fax: +44 20 7594 3894. E-mail addresses: [email protected] (E. Whittaker), [email protected] (B. Kampmann). 1 Tel.: +44 20 7594 3915; fax: +44 20 7594 3894.
The presentation of tuberculosis in pregnancy varies: some women are symptom free, but a large number present with very non-specific symptoms common in pregnancy like malaise and lethargy, or more typical severe symptoms of TB. Although pulmonary TB is the commonest manifestation, extrapulmonary TB features more commonly
0378-3782/$ – see front matter. Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.09.005
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than in a non-pregnant population (5–10%) (1, 8). Of note is that the tuberculin skin test (TST) is frequently found to be anergic, most likely due to altered immunological responses to Mycobacterium tuberculosis in pregnant women [6]. A delay between onset of symptoms and diagnosis occurs regularly, due to the non-specific nature of symptoms at presentation, reluctance to perform radiography and low index of suspicion, most likely also related to limited resources in the settings where this is more common [1,7]. Treatment response and time to clearance of bacilli from sputum are equivalent to non-pregnant women, and prognosis, if treated early, can also be similar. In the event of TB exposure, women with a positive TST, but clinically well with a normal chest X-ray, should be given chemoprophylaxis in accordance with national guidelines. Previous concerns about the use of isoniazid in pregnancy for chemoprophylaxis are unfounded, with an isoniazid-associated death rate of 0.001% [8]. If active tuberculous disease is found, anti-tuberculous treatment (ATT) should be commenced. Some groups recommend delaying start of treatment to the second trimester if the mother is well, but all agree that the benefit of treating the mother, preventing maternal morbidity and mortality and avoiding perinatal transmission, outweigh the risk of teratogenicity. A number of studies assessing rates of congenital malformations in infants exposed to ATT in utero have not demonstrated an appreciable difference [9–11]. A group in Peru have followed up children after in utero exposure to second line agents used for treatment of multidrug-resistant TB and performed a review of the literature showing that a low incidence of ototoxicity secondary to the aminoglycosides is the main concern [10]. Table 1 demonstrates the safety profile of ATT in pregnancy, lactation and the newborn baby.
Table 1 Anti-tuberculous drugs in pregnancy, lactation and in the newborn Use of anti-tuberculosis drugs in pregnancy, lactation and in the newborn baby Drug
Pregnancy
Rifampicin
Safe
Lactation
0.5% of adult dose detected Rifabutin Congenital defects in 0.5% of adult animal studies dose detected Rifapentine Rarely causes bleeding 0.5% of adult in mother if administered dose detected in last few weeks of pregnancy Isoniazid Safe, supplement with 0.75–2.3% of pyridoxine adult dose detected Pyrazinamide Limited data but 0.75–2.3% of recommended adult dose detected Ethambutol Safe in human beings, Yes in minute cleft palate, skull and amounts spine defects Yes in minute Ethionamide Premature labour, amounts congenital abnormalities Aminoglycosides Ototoxicity in fetus, 0.05–0.5% of renal damage adult dose detected Amikacin Likely ototoxicity Yes, concentration not known Kanamycin Ototoxicity, hearing 0.95–1.8 % of loss 2.3% adult dose Capreomycin Unknown, bronzing?? Not known Streptomycin Ototoxicity, greatest 1st 0.95–22.5% trimester, hearing loss in 8–11% children Quinolones Bone developmental 0.05–0.5% of abnormalities in adult dose animals detected
Newborn Safe 10–20 mg/kg/day Use not established Use not established
Safe 5–10 mg/kg/day
3. Perinatal TB 3.1. Prevention Perinatal TB is extremely rare if the mother is effectively treated in pregnancy. According to WHO, a mother is no longer considered infectious after treatment for 2–3 weeks [12]. If she is breastfeeding it is recommended that 6 months isoniazid is given to the baby, or alternatively 3 months isoniazid followed by a TST. If negative, BCG vaccine should be administered and treatment stopped; if positive, treatment should continue for 6 months, followed by the BCG at the end. If a diagnosis is made close to delivery, the baby and placenta should be carefully evaluated for evidence of perinatal TB infection and the infant treated empirically if there are any concerns or doubt. All of these infants should be carefully followed for 2 years. 3.2. Definition and presentation of perinatal TB in the infant Controversy has always surrounded the definition of congenital tuberculosis with criteria first described by Beitzke in 1935 [13], followed by revised criteria by Cantwell in 2002 which stated: the infant must have proved tuberculous lesions and at least one of a) lesions in the first week of life; b) a primary hepatic complex or caseating hepatic granulomata; c) tuberculous infection of the placenta or the maternal genital tract; d) exclusion of the possibility of postnatal transmission by a thorough investigation of contacts, including hospital staff [2]. Transmission is believed to be either in utero by haematogenous spread through the umbilical vein or ingestion of infected amniotic fluid; intrapartum aspiration or ingestion of amniotic fluid or direct contact with infected cervix/endometrium; or postpartum by inhalation or ingestion from an infectious source [2]. Because of the difficulties in ascertaining the exact time and circumstances of infection, more recently, perinatal tuberculosis is the preferred description encompassing TB acquired in utero, intrapartum or during the early newborn period and has replaced the term congenital tuberculosis. Distinguishing between the time frames is not crucial, as the presentation, diagnosis, management and prognosis are similar. Although unusual, (about 300 cases of perinatal TB have been described in the literature, in case reports, case series and reviews [2]) perinatal tuberculosis is believed to be increasing alongside a rise in TB incidence. Prompt treatment is required for the survival of these infants. Mortality is high, varying between 2 and 60% depending on delay to presentation and other factors, such as prematurity and coinfection with HIV [2,14]. Complications include a high rate of miliary tuberculosis and meningitis, resulting in seizures, deafness and death.
Safe 20–30 mg/kg/day
4. Tuberculosis in the neonate—immunological considerations
Retrobulbar neuritis; not recommended
The observation that young children, particularly under the age of 2, are the most vulnerable to tuberculosis, opens a window to our understanding of the immunopathogenesis of tuberculosis. The neonatal period should also be considered as a particularly vulnerable time for the following reasons: the fetal and neonatal immune system are subjected to multiple demands, such as protection against infection, avoidance of potentially harmful pro-inflammatory cytokine responses that can induce alloimmune reactions between mother and fetus and the transition from the “sterile” intra-uterine environment to the antigen-exposed “outside world”. It is increasingly recognised that CD4+CD25+ regulatory T-cells are abundant and potent at birth and inhibit Th1 cell immunity [15]. In the absence of acquired immune responses and immunological memory, the first line of defence lies with the innate immune response of the neonate. Flow cytometry has demonstrated reduced levels of MHC class II molecules between neonates and adults [16], which potentially contribute to impaired activity of antigen-presenting cells (APC) and result in qualitative differences in monocytes. Blood derived DCs are functionally
Safe
Use with caution, not absorbed orally Poorly absorbed by GI tract Poorly absorbed Minimal GI absorption Safe
Use with caution, shown to be safe for 5– 10 days
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immature at birth relative to adult DCs and continue to express a less differentiated phenotype throughout early childhood [17]. It can be postulated that the bias against Th1-cell polarizing cytokines makes young infants more susceptible to tuberculosis, especially since the perinatal infection might have occurred via haematogenous spread rather than via primary lung infection. Some studies also suggest that neonatal APCs lack the capacity to deliver important Th1 polarizing signals to T-cells. Their capacity to synthesise interleukin (IL)-12, a key APC-derived cytokine, matures slowly during childhood [18] and neonatal, monocyte-derived DCs have a specific defect in IL-12p35 expression [19]. IL-12 is critical for the initial phases of Th1 polarization and also for maintaining the efficiency of the interferon (IFN)-γ transcription machinery in Th1 effector cells [19]. In cases of primary lung infection, the alveolar macrophage is the first line of defence in the innate immune response to TB and plays a critical role in amplifying the response to infection. Studies in the animal and human host have consistently demonstrated reduced microbial killing [20,21] and diminished monocyte recruitment to the site of infection in infants compared to adults [22]. Neonatal CD4 cells appear intrinsically deficient in their capacity to express Th1 effector function, partially attributed to hypermethylation of the proximal promoter of the IFN-γ gene [23], resulting in a highly restricted pattern of IFN-γ response to a variety of stimuli [24,25]. CD154 (CD40 ligand) expression is also significantly reduced compared with adult cells [26]. Impairment of innate pulmonary defences in the neonate and infant may allow mycobacteria to overwhelm the effects of the innate immune system prior to the initiation of an antigen-specific immune responses. The finding of generally impaired cell-mediated immune responses in the neonate and young children raise the question of whether antigen-specific immune responses to mycobacteria are equally affected. Delayed type hypersensitivity to purified protein derivative may be absent in up to 40% of HIV negative children presenting with extrapulmonary TB [27], compounding the difficulties of diagnosis in young children. However, studies measuring responses to neonatal vaccination with M. bovis BCG demonstrate potent Th1 responses, possibly related to the potent APC-activating properties of BCG vaccine. Much more needs to be learned from innate and antigen-specific studies of immunity in the newborn, and further research in this area is required, which will benefit not just our understanding of tuberculosis but other infections in this particularly vulnerable period of life.
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Many mothers are only found to have TB following diagnosis in the infant. As mentioned, the TST is typically unresponsive, but a repeat after 3 months is frequently found to be positive [2]. Interferon gamma release assays are an alternative immunological diagnostic option for these infants, but there are some concerns about the validity of these assays in newborns and infants, as depressed IFN-γ production in response to antigenic stimuli has been described in this age group [31]. However, positive responses to both the QFG-IT whole blood and Elispot assays have been described in cases of perinatal TB and in a contact tracing study [32,33]. Further investigations in this area are required and a negative IGRA should not deter empirical antituberculosis treatment pending microbiological confirmation. 4.2. Treatment and outcome of the infant Perinatal TB is usually fatal if untreated. Following appropriate investigation, the infants should be empirically commenced on treatment as per national guidelines. Since this is not a common disease, no therapeutic trials have determined the optimal treatment regimen and length. Complete recovery has been described following a standard treatment course of 2 months of 4 drugs (isoniazid, rifampicin, pyrazinamide and streptomycin), followed by 4 months of 2 drugs (isoniazid and rifampicin) [34]. However other regimens for up to 18 months have been described and clinicians should seek expert advice. Treatment length should be determined by clinical condition and response to treatment. Infants should receive regular monthly review following discharge until treatment is complete and follow up should then continue for up to 2 years. These infants are often very unwell and supportive therapy such as oxygen or respiratory support with ventilation may be required. Steroids are recommended in cases of TB meningitis or airway obstruction due to large lymphadenopathy. A case series of 17 infants less than 6 months ventilated secondary to respiratory failure caused by Mycobacterium tuberculosis revealed a favourable outcome for all [35]. All infants were HIV seronegative, median duration of stay in intensive care was 7 days (range 2–37 days), steroids were used in all children with large airway obstruction (n = 10), only one infant was TST positive and all responded to standard ATT. This contrasts with previous reports of high mortality in infants with tuberculosis. Improved outcome could be due to the fact that none of these infants had TB meningitis or HIV, but with aggressive management of TB in the very young, including intensive care, a good outcome can be achieved. 4.3. MDR/XDR TB in mothers and infants
4.1. Diagnosis of perinatal TB The diagnosis of perinatal TB is difficult without doubt—a high index of suspicion is required as TST is often negative (78% of the time in two case series [2,28]) and symptoms are often non-specific. These infants typically present at 2–4 weeks of age with fever, respiratory distress, lethargy +/− hepatomegaly and tend to be commenced on broad spectrum antibiotics for presumed sepsis. Unless there is a suggestive history in the mother, TB is often not suspected until deterioration/lack of response to antibiotics is noted. Diagnosis in the infant is based on TST, which is often negative, CXR and other radiology if symptoms suggest. Microbiological specimens such as gastric aspirates, ascitic fluid, lymph node biopsy, endotracheal aspirate, bone marrow and cerebro-spinal fluid should be obtained and stained and cultured for AFB. Gastric aspirates in neonates have a higher microbiological yield than in older infants (70%) and are well tolerated [29]. The chest X-ray is nearly always abnormal, with 50% showing a military TB pattern [30]. Newer modalities such as polymerase chain reaction (PCR) and restriction fragment length polymorphisms can be useful for diagnosis and identification of the index case. Ideally, placental and maternal vaginal or endometrial samples should be obtained, but this is frequently difficult given the later presentations.
One of the greatest challenges facing physicians caring for patients with tuberculosis is drug resistance. Rates of multidrug-resistant (MDR) strains (resistant to both isoniazid and rifampicin) including extensively drug resistant (XDR) strains (also resistant to fluoroquinolones and at least one second line injectable agent such as amikacin, kanamycin and/or capreomycin) are rising in many parts of the world. A case series of 7 infants born to mothers receiving treatment for MDR-TB in pregnancy demonstrated good outcomes for both mother and infant with no evidence of significant late-presentation toxicity in the infants [10,11]. All expecting mothers received treatment in the first or second trimester with smear and culture conversion in 6 of 7 patients. Each patient was managed with an aggressive individualised treatment regimen during and after pregnancy with very close monitoring. Use of chemoprophylaxis was not discussed in this paper, however in other reports, chemoprophylaxis was only given to the infant if the mother remained smear or culture positive at delivery [36]. In 2 cases, ethambutol and pyrazinamide were used for 3 months as chemoprophylaxis [33]. Klaus-Dieter et al. recommended screening the newborn infant for infection (TST/gastric washings/CXR) and recommended BCG, careful observation and repeat TST at 3 months if there was no evidence of infection in association with smear-negative
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maternal disease. WHO guidelines currently recommend the avoidance of chemoprophylaxis in the case of exposure to MDR-TB and observation for 2 years provided they are clinically well. 5. Infection control on the NICU In the context of late diagnosis of perinatal tuberculosis, a number of publications have discussed the risk of exposures to other neonates in the setting of the neonatal intensive care unit. Laartz et al. reviewed literature concerning congenital tuberculosis with particular attention to infection control, following a case in their unit [37]. Summarising 6 different publications with around 2814 infants exposed to perinatally infected infants, infected staff and infected parents in NICU and nursery settings, only 2 infants developed active tuberculosis. They concluded that aggressive follow up with a TST and isoniazid prophylaxis for those at risk was warranted. All infants at high risk were evaluated clinically and with radiography. Due to previously described anergy to the TST, the TST was repeated at 3 months. The use of an oscillatory ventilator with no expiratory filter was described as posing a theoretical risk of aerosolized respiratory secretions, but no secondary cases were found. Despite the low transmission rate in the NICU, careful consideration of air handling and use of isolation rooms where available are advised. 6. Neonatal TB and HIV—special considerations As mentioned above, the increasing rate of tuberculosis globally is driven by the HIV pandemic. The relationship between HIV and TB has been well described in the literature and a number of groups have investigated the effect of HIV co-infection on incidence and outcome of perinatal TB. Adhikari et al. described the investigation of 77 neonates with suspected TB in KwaZulu Natal, South Africa [38]. 11 infants had culture confirmed perinatal TB, of whom 6 were born to mothers with HIV/TB co-infection (55%, compared with a local antenatal prevalence rate of HIV infection of 23%). These neonates presented similarly to those described in the literature without HIV exposure and although there were no significant differences between the HIV exposed and unexposed groups, there was a trend towards more severe disease in the mothers and infants, in particular a greater incidence of prematurity and IUGR—which is known to be associated with HIV disease. Three of the 6 infants born to HIV seropositive mothers were HIV infected, reflecting a higher transmission rate than the 34% normally found in KwaZulu Natal. A further prospective case series of 107 pregnant women with TB, found a HIV infection rate of 77% and a mother to infant transmission rate for TB of 16%, with similar disease patterns in both mothers and infants to HIV uninfected controls. The VTRTB (vertical transfer of Mycobacterium tuberculosis) was not influenced by CD4 count or perinatal maternal viral load. The only risk factor of significance was untreated tuberculosis or default from treatment (p = 0.04) [39]. HIV transmission rate was 11%. Less than half of the mothers who transmitted TB to their neonates were sputum smear or culture positive, highlighting the significant problem of smear-negative transmission of TB previously reported. In this study, it was noted that some mothers transmitted TB despite long durations of ATT, emphasising the importance of investigation and comprehensive observation of these exposed infants for up to 2 years. It is essential that a high index of suspicion for perinatal TB is adopted by health care workers in areas where TB and/or HIV are prevalent, or in mothers recently immigrating from TB/HIV endemic areas [40,41]. Latent TB was found in 49% of 400 pregnant women in a study in Johannesburg. Although there is no evidence that there is an increased reactivation rate in pregnancy, given how deadly TB in pregnancy can be for both mother and infant, active screening and isoniazid preventative treatment of latent TB should be considered in areas of high TB endemicity. In summary, perinatal TB is a potentially devastating disease, but with a high index of suspicion and aggressive management can have a good outcome. Neonatalogists and paediatricians need to be aware of TB
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