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Article

Extrapulmonary and Drug-Resistant Childhood Tuberculosis: Unveiling the Disease to Adopt the Optimal Treatment Strategy

Infectious Disease Unit, Department of Health Sciences, Meyer Children’s Hospital IRCCS, University of Florence, 50121 Florence, Italy
*
Author to whom correspondence should be addressed.
Pathogens 2023, 12(12), 1439; https://doi.org/10.3390/pathogens12121439
Submission received: 2 November 2023 / Revised: 1 December 2023 / Accepted: 8 December 2023 / Published: 12 December 2023
(This article belongs to the Special Issue Neglected Mycobacterial Diseases)

Abstract

:
Paediatric tuberculosis (TB) is a substantial threat among infectious diseases, particularly considering the high risk of extrapulmonary tuberculosis (EPTB), severe forms of the disease, and the spreading of drug-resistant strains. Describing the characteristics of children with EPTB and those with drug-resistant tuberculosis (DR-TB) and analysing the role of second-line drugs could facilitate the management of these cases. This retrospective study was conducted on 271 children diagnosed with active TB disease (44 EPTB cases, 9 DR-TB cases), originating from diverse geographic areas, who were referred to the infectious disease unit at Meyer Children’s Hospital, Florence, Italy, from 2006 to 2022. In most patients, the management of therapies was complicated by the impossibility to obtain drug susceptibility testing (DST) results, which improved over the years: 17/154 (11.04%) children had DST results between 2006 and 2013, and 50/117 (42.73%, p < 0.001) between 2014 and 2022. Second-line drugs were not exclusively administered to DR-TB cases, but also to EPTB cases (20/44, 45.45%). Drugs were generally well tolerated; adverse events occurred in 13 children (13/271, 4.80%) and were generally mild and reversable. Therapies were successful in 267 children (98.52%) considered cured, while 4 (1.48%) presented sequelae. Both univariate and multivariate logistic regression analyses were conducted to investigate factors associated with EPTB, DR-TB, and second-line drugs administration. Originating from Asia emerged as a risk factor associated with both EPTB and DR-TB (p = 0.013 and p = 0.045, respectively). The introduction of GeneXpert tests has significantly improved TB diagnosis and the obtaining of DST results. The administration of second-line therapies should be limited primarily to DR-TB cases, but it is possible that these drugs may also be beneficial in selected EPTB cases.

1. Introduction

Historically, tuberculosis (TB) is considered one of the most significant threats in the field of infectious diseases [1]. Even though the introduction of anti-TB drugs in the mid-20th century marked a crucial moment in the management of the disease [1], TB remains a global threat today: paediatric TB accounted for 1.2 million cases and 220,000 deaths in 2021 [2].
Infected children present a higher risk of developing TB disease compared to adults. However, diagnosing paediatric TB can be challenging since most children exhibit non-specific signs and symptoms [3]. Moreover, the majority of cases present with paucibacillary disease, reducing the sensitivity of microbiological investigations [4].
Compared to the adult population, a higher proportion of children present with extrapulmonary TB (EPTB), probably resulting from the immaturity of the immune system [5]. EPTB prevalence among children remains significant, even with the availability of the Bacillus Calmette–Guerin (BCG) vaccine [2]. Moreover, EPTB is often associated with origins in Sub-Saharan Africa or Asia [6,7], and poverty stands out among major factors influencing its prevalence [8]. Severe forms such as tuberculous meningitis (TBM) and miliary TB can develop rapidly and need to be diagnosed and treated without delay, given the high risk of sequelae and death [3,9].
Drug-resistant TB is a common concern, favoured by incorrect treatment and weak medical systems [10], making the evaluation of drug susceptibility testing (DST) of each patient and contact case necessary [4] to ensure the prescription of the appropriate therapy [8]. Notably, this is difficult to obtain in children, since paucibacillary disease is associated with low sensitivity of DST [4].
TB treatment requires the administration of multiple drugs [11]. First-line drugs, including isoniazid, rifampicin, pyrazinamide, and ethambutol, exhibit significant antitubercular activity [12,13,14,15]. These drugs are administered in the treatment of drug-susceptible (DS-TB) pulmonary cases [4,9], and they are mostly associated with favourable outcomes in these patients (88% of treated children in 2020) [2]. Drug-resistant TB (DR-TB) treatment requires the administration of second-line drugs, such as levofloxacin, moxifloxacin, linezolid, clofazimine, cycloserine, amikacin and the recently approved bedaquiline, and delamanid [4,16,17]. DST results must be considered when treating DR-TB cases, and children may undergo longer individualised regimens or the shorter all-oral bedaquiline-containing regimen (if they meet criteria outlined in guidelines) [4,16,17]. Second-line drugs are combined with first-line drugs, especially in isoniazid-resistant TB treatment and in the shorter all-oral bedaquiline-containing regimen. For the administration of any first-line drug to these patients, DST results must confirm susceptibility to them [4,16,17]. The role of these drugs has been demonstrated both in vitro [18] and in vivo [19].
The treatment regimens for drug-susceptible EPTB cases depend on the affected site. Tubercular lymphadenitis cases are treated following the same regimens adopted for PTB [4]. However, managing EPTB cases is more challenging when specific sites are affected, such as the central nervous system (CNS) and osteoarticular system, or in generalised forms of the disease (miliary TB). Considering the risk of sequelae and the suboptimal distribution of drugs in these sites, guidelines suggest longer regimens for these children [4]. Despite the administration of therapies, these forms exhibit a high rate of unfavourable outcomes: TBM is associated to a mortality rate of 19.3% of cases, and only 36.7% of children survive without neurological sequelae [20].
Studies focussing on paediatric management of EPTB and DR-TB cases are not as numerous as studies on adult cases. Moreover, most studies evaluate children in low-resource countries. Considering this and the challenges that paediatric TB presents, this study intends to analyse the characteristics and the management (including diagnosis, DST evaluation, administered drugs, adherence to treatment regimens, adverse events issues, and therapies outcome) of children diagnosed with active TB originating from diverse geographic areas and admitted to the infectious disease unit (IDU) at Anna Meyer Children’s University Hospital in Florence, Italy, a tertiary referral hospital, over a period of 17 years (2006–2022). The aim of the study is to evaluate risk factors associated with DR-TB and EPTB, and to evaluate retrospectively the management and outcome of active TB in these children.

2. Materials and Methods

2.1. Definitions

Children were classified into three categories, based on the guidelines of the American Academy of Pediatrics (AAP): uninfected children, children with tuberculosis infection (TBI), and children with TB disease [16]. The study analysed children with TB disease.
TB disease was diagnosed in children with symptoms, signs, or radiographic manifestations consistent with TB disease. Diagnosis was microbiologically confirmed through laboratory detection of M. tuberculosis using culture, microscopy, or molecular methods from specimens of sputum, gastric aspirate, bronchial washing, pleural fluid, cerebrospinal fluid (CSF), urine, other bodily fluid, or tissue biopsy [4,16]. Children were diagnosed with TBI if they had a positive TST or IGRA result, no symptoms or signs of disease, and normal chest radiograph findings or evidence of healed infection [16].
Disease was considered DR-TB if resistant to any drug used to treat DS-TB, multidrug-resistant TB (MDR-TB) if resistant to rifampicin and isoniazid, pre-extensively drug-resistant TB (pre-XDR-TB) if resistant to rifampicin and isoniazid and to any fluoroquinolone, extensively drug-resistant TB (XDR-TB) if concomitantly resistant to rifampicin, isoniazid, at least one fluoroquinolone, and at least one of the following parenteral drugs: amikacin, kanamycin, or capreomycin [16,17,21]. Cases without drug susceptibility testing results were categorised as neither susceptible nor resistant.

2.2. Study Design and Population

This single-centre study included children (aged 0–18 years) diagnosed with active TB, admitted to the IDU at Anna Meyer Children’s University Hospital in Florence, Italy, between January 2006 and October 2022.
Patient data were collected from clinical records and entered into an electronic database, including the following information: personal information (gender, date of birth, country of birth, and parents’ nationality); medical history [Bacillus Calmette–Guerin (BCG) vaccination status, HIV infection diagnosis, reason for TB investigation, symptoms, nationality, treatment, and resistance profile of the contact case]; patient management and tests conducted [dates of first and last observation, results of tuberculin skin test (TST) and IGRAs (Elispot, QuantiFERON in tube, QuantiFERON TB gold); results of microbiological investigations (microscopic examination, cultures, PCR GeneXpert, PCR GeneXpert Ultra), resistance profile, and imaging results]; treatment information (regimen and duration, adverse events, date and reason for discontinuation of drugs, and treatment outcome).
Patients and their families were asked about adverse reactions to antitubercular drugs. Considering the children’s conditions at the end of the follow-up (its duration was not standardised), cases were classified into the following outcome groups: treatment success (if cured and if the treatment was completed), treatment failure, death, lost to follow-up [22].

2.3. Laboratory and Microbiological Investigations

Trained nurses performed the TST using Mantoux’s procedure, which involves injecting 5 tuberculin units (in 0.1 mL) of purified protein derivative (Statens Serum Institute, Copenhagen, Denmark) into the volar surface of the forearm. After 48–72 h, a paediatrician from the IDU measured the resulting dermal induration. Following AAP guidelines, an induration greater than 5 mm was considered positive in children in close contact with known or suspected contagious individuals with TB disease, and in children suspected of having TB disease (with clinical or radiographic evidence). An induration greater than 10 mm was considered positive in children younger than 4 years of age, children with other medical conditions, those born in high-prevalence regions, and those frequently exposed to adults who were living with HIV infection, experiencing homelessness, incarcerated, injecting drugs, or having alcohol use disorders. All other cases were considered positive if the induration was greater than 15 mm [16].
All laboratory tests were conducted in the same laboratories at the University of Florence, following routinely performed procedures and the manufacturer’s instructions. The QuantiFERON Gold-In-Tube (QFT G-IT, Cellestis, Chadstone, VIC, Australia) was used for the IGRA testing. The QFT assays were conducted following the manufacturer’s instructions. The test result was interpreted by subtracting the value from the negative control and was considered positive if the antigen-dependent response was equal to or greater than 0.35 IU/mL, and negative if the mitogen-induced response was equal to or greater than 0.5 IU/mL, and the antigen-dependent response was less than 0.35 IU/mL. It was considered indeterminate if both the mitogen-induced and antigen-dependent responses were below the cut-off or if the mitogen-induced response exceeded 8 IU/mL [23].
Microscopic examination for acid-alcohol-resistant bacilli was performed using fluorescence microscopy, where the specimen is stained with auramine–rhodamine. The research of M. tuberculosis complex DNA was conducted using GeneXpert Ultra. During the period examined, different commercial methods were employed (Cobas–Roche, Artus Quiagen, GeneXpert MTB/RIF Ultra-Cepheid). Cultural examination was carried out on solid medium (Lowenstein Jensen), with an incubation period of 60 days, and on the liquid medium Mycobacteria Growth Indicator Tube (MGIT) (Becton, Dickinson, and Company), with an incubation period of 42 days. Strain identification was performed using Line Probe Assay (Hain), and DST was conducted using the BD MGIT™ TBc Identification Test. Resistance of M. tuberculosis was studied through DST on clinical samples, or through molecular investigation for genotypic resistance (GeneXpert Ultra). Clinical samples were collected on three consecutive days and analysed through microscopic examination, culture, and GeneXpert Ultra analysis.

2.4. Treatment

Patients were treated according to treatment regimens recommended by international guidelines, in particular referring to the AAP guidelines outlined in the “Red Book: 2021 Report of the Committee on the Infectious Diseases” [16].

2.5. Statistical Methods

Median and interquartile ranges (IQRs) were calculated for continuous variables (i.e., age and duration of treatment). Categorical data were compared using χ2 tests, or the Fisher exact test, as appropriate. Univariate logistic regression analysis was performed to investigate possible risk factors for confirmed DR-TB, and ORs with 95% confidence intervals (CIs) were calculated. Univariate and multivariate logistic regression analyses were used to investigate possible risk factors for EPTB, and to investigate factors associated with second-line drugs administration. Factors were included in the multivariate analysis if they were significant (p < 0.05) in the univariate analysis. Stata Software, version 14.0 (StataLLC, College Station, TX, USA) for Windows was used to perform the analyses.

3. Results

The study conducted an evaluation of 271 children diagnosed with TB disease (median age 6 years, IQR 3–11). Their characteristics are summarised in Table 1, Table A1 and Table A2.

3.1. Characteristics of the Study Population

The characteristics of patients aged ≤5 years and >5 years were similar (Table 1). Moreover, when evaluating male and female children, significant differences were not detected.
The majority of patients were of foreign origins (Figure 1). In fact, 63 cases (23.25%) were Italian, while 208 (76.75%) were either born abroad or born in Italy to foreign parents. Among the latter group, 45 (16.60%) originated from Asia, 48 (17.71%) from Eastern Europe, 2 (0.73%) from Western Europe, 72 (26.57%) from Africa, and 36 (13.28%) from South-Central America.
These patients underwent TB disease assessment for various reasons: 144 children (53.14%) had come into contact with a diagnosed or suspected case; 99 cases (36.53%) presented with symptoms indicative of TB-disease; and 25 patients (9.22%) were identified through a screening programme directed at immigrated and adopted children. Notably, children aged ≤5 years old were mainly evaluated for TB after coming into contact with a case (86/131; 65.65%; p < 0.001), while children aged >5 years old primarily presented with symptoms (68/140; 48.57%; p = 0.001). Furthermore, there is a correlation between the reason for investigation and the type of TB-disease: PTB cases were predominantly diagnosed after coming into contact with a case (138/227; 60.79%; p < 0.001), while EPTB patients were more often identified after presenting with symptoms (36/44; 81.82%; p < 0.001).

3.2. Clinical Characteristics

The predominant form of TB disease was pulmonary TB (PTB), accounting for 227 cases (83.76%). In 24 cases (8.86%), the disease exhibited involvement in both pulmonary and extrapulmonary sites, while only extrapulmonary sites were affected in 20 cases (7.38%). Among extrapulmonary TB (EPTB) cases, tubercular lymphadenitis was the most common, manifesting in 15 cases (15/44, 34.09%). Other sites involved included the pleura in 9 cases (9/44, 20.45%), the osteoarticular system in 7 cases (7/44, 15.91%), the central nervous system (CNS) in 5 cases (5/44, 11.36%), and abdominal organs in 4 cases (4/44, 9.09%). Notably, children presenting with tubercular meningitis were mostly aged ≤5 years old (4/5, 80.00%). The extrapulmonary sites affected in children ≤5 years old and >5 years old are described in Figure 2. Children from Asia had a higher proportion of EPTB cases (14/45; 31.11%; p = 0.013), compared to the rest of the geographical areas (Figure 1).
Within the study population, 58 children (58/271, 21.40%) exhibited drug susceptibility in drug-susceptibility testing (DST), while 9 cases (9/271, 3.32%) were found to be affected by drug-resistant strains. The drug-susceptibility pattern remained unidentified in 204 cases (204/271, 75.28%). Notably, among children diagnosed between 2006 and 2013, 17/154 (11.04%) had DST results, while between 2014 and 2022, they were 50/117 (42.73%, p < 0.001).
The resistant cases included 2 MDR-TB cases (22.22%), 1 preXDR-TB case (11.11%), and 1 XDR-TB case (11.11%). The drugs to which they exhibited resistance, and the number of cases resistant to each single drug are detailed in Figure 3. Notably, a higher proportion of resistant cases originated from Asia (4/9; 44.44%; p = 0.045), as depicted in Table A3, detailing the distribution of resistant and non-resistant cases. Furthermore, the proportion of resistant cases was evenly distributed between PTB and EPTB cases, as well as among children aged ≤5 years and >5 years.

3.3. Diagnosis

Diagnosis of TB infection was conducted using TST and/or IGRA testing. Children with a diagnosis of infection numbered 249 (91.88%). Specifically, 209 (77.12%) were found to be positive to TST, and 224 (82.66%) to IGRAs.
The diagnosis of disease was microbiologically confirmed in 123 cases (45.39%), using culture, microscopy, and PCR or GeneXpert tests. Various specimens were collected:
  • Gastric aspirate: collected in 182 cases (67.16%) and associated with positive results in 81 cases (81/182, 44.50%).
  • Stool: collected in 81 cases (29.89%) and associated with positive results in 17 cases (17/81, 20.99%).
  • Sputum: collected in 70 cases (25.83%) and associated with positive results in 32 cases (32/70, 45.71%).
  • Biopsy: collected in 11 cases (4.06%) and associated with positive results in 9 cases (9/11, 81.82%).
  • Broncho-alveolar lavage fluid: collected in 11 cases (4.06%) and associated with positive results in 5 cases (5/11, 45.45%).
  • Cerebrospinal fluid: collected in 9 cases (3.32%) and associated with positive results in 1 case (1/9, 11.11%).
  • Pleural fluid: collected in 7 cases (2.58%) and associated with positive results in 1 case (1/7, 14.29%).
Globally, culture resulted positive in 105 cases (38.74%), microscopy in 36 cases (13.28%), PCR in 32 cases (11.81%), and GeneXpert tests in 42 cases (15.50%).
Children were diagnosed with TBM in 5 cases, determined by clinical examination and neuroimaging. The diagnosis was microbiologically confirmed in 4 cases (80.00%): specimens associated with positive results were cerebrospinal fluid in 1 case, sputum in 1 case, and gastric aspirate in 2 cases. Neuroimaging and microbiological tests were performed within 3 days of hospitalisation.

3.4. Treatment

The treatment regimens only comprised first-line drugs for the majority of patients (204/271; 75.28%). However, 53 cases (19.56%) were also administered second-line drugs. Second-line drugs were more prominently utilised in cases exhibiting drug resistance (7/9; 77.78%), compared to non-resistant cases (46/262; 17.56%). The second-line drugs used in resistant patients (Table 2 and Table A4) included amikacin (5/9, 55.56%, p = 0.002), cycloserine (6/9, 66.67%, p < 0.001), linezolid (5/9, 55.56%, p < 0.001), moxifloxacin (4/9, 44.44%, p = 0.020), levofloxacin (2/9, 22.22%, p = 0.014), and para-aminosalicylic acid (2/9, 22.22%, p = 0.009).
Two children with DR-TB did not receive second-line drugs: both the patients tested resistant only to pyrazinamide and were treated with the three first-line drugs: isoniazid, rifampicin, and ethambutol.
Children without DST results were infected by a DR-TB contact-case in 14 cases. These patients were treated with first-line drugs in 5 cases (35.71%), and with second-line drugs in 9 cases (64.29%). Moxifloxacin was administered in 9 cases (64.29%), amikacin in 7 cases (50.00%) linezolid in 6 cases (42.86%), cycloserine in 5 cases (35.71%), and para-aminosalicylic acid (PAS) in 3 cases (21.43%).
Similarly, within the population diagnosed with EPTB, second-line drugs were employed in 20 out of 44 cases (45.45%), compared to the population diagnosed with PTB, where second-line drugs were used in 33 out of 227 cases (14.54%). Moxifloxacin (13/44; 29.55%, p = 0.001) and cycloserine (8/44, 18.18%, p = 0.004) emerged as the drugs that statistically were the most administered in EPTB cases. Other second-line drugs prescribed included amikacin, linezolid, levofloxacin, ciprofloxacin, clarithromycin, and streptomycin (Table 3). Among these patients (Table 4), 3 were DR-TB cases (1 ocular TB, 1 cardiac TB, 1 tubercular lymphadenitis), 5 were DS-TB cases (2 TBM, 1 osteoarticular TB, 1 tubercular lymphadenitis, 1 pleural TB), and 9 did not have DST results (3 TBM, 3 pleural TB, 2 osteoarticular TB, 2 tubercular lymphadenitis, 1 cardiac TB, 1 abdominal TB).
Children with TBM were treated with second-line drugs: moxifloxacin in 4 cases (80.00%), cycloserine in 3 cases (60.00%), amikacin in 3 cases (60.00%).
Finally, 20 non-DR PTB cases were treated with second-line drugs.
A total of 971 drugs were prescribed. Among these, 890 (91.66%) were administered for the entire recommended duration of the regimen. In the other cases, drugs were suspended for various reasons: 42 drugs (4.33%) due to adverse events; 9 (0.93%) after the DST results became available, due to patient resistance or index case resistance; and 3 (0.31%) due to treatment adherence issues. Additionally, 2 drugs (0.21%) were suspended due to difficulties in intravenous administration in one patient. Linezolid was suspended in 1 case after DST showed complete susceptibility to first-line drugs.
Adverse events presented in 13 children (Figure 4). Hypertransaminasemia was associated with the suspension of 26 drugs (26/42; 65.00%) in children who were administered isoniazid, rifampicin, pyrazinamide, and ethambutol. Notably, these drugs were administered simultaneously in the majority of these cases; in fact, this adverse event presented in 10 children. Isoniazid, rifampicin, pyrazinamide, and ethambutol were suspended a total of 5 times (5/42, 12.5%) in 2 children, due to vomiting and epigastric pain. One child had rifampicin, pyrazinamide, and ethambutol (3/42, 7.50%) suspended due to thrombocytopenia, and another patient suspended isoniazid, rifampicin, and pyrazinamide (3/42, 7.50%) due to the emergence of neutropenia. Ethambutol was suspended in 1 case (1/42, 2.50%) due to hyperuricemia. One patient suffered acute kidney injury after the administration of therapy; consequently, rifampicin and levofloxacin (2/42, 5.00%) were suspended.
After these children experienced adverse events, 9 cases (69.23%) re-initiated therapies (after a median discontinuation period of 4 weeks) and completed the treatment regimen; 2 cases (15.38%) re-initiated therapies (after a median discontinuation period of 3 weeks) and experienced adverse events again; 1 case (7.69%) suspended ethambutol and completed the treatment regimen with rifampicin, isoniazid, and pyrazinamide; 1 case (7.69%) experienced acute kidney injury but managed to complete therapy through a reduction in the dosages of rifampicin and levofloxacin.

3.5. Outcome

All children included in the study survived; 267 cases were considered cured (267/271, 98.52%) and 4 cured with sequelae (4/271, 1.48%). Among these cases, one child had EPTB and MDR-TB (1/4, 25.00%): this case was the only one that affected eye, resulting in monocular blindness. The other 3 cases had PTB (3/4, 75.00%), associated with sequelae affecting the lungs and respiratory function.

3.6. Factors Associated with Drug-Resistant Tuberculosis

Univariate analysis (Table 5) was used to evaluate factors associated with DR-TB.
Notably, the origin of children and/or parents was significantly associated with DR-TB, particularly Asia (OR: 10.927, p = 0.035) and South-Central America (OR: 10.182, p = 0.048). Factors that were found to be irrelevant included the sex and age of children, the localisation of the disease, and the calendar period.

3.7. Factors Associated with Extrapulmonary Tuberculosis

Evaluating data with univariate analysis, factors associated with EPTB (Table 6) included the origin of children and/or parents from Asia (OR: 2.710, p = 0.039), the presence of symptoms (OR: 13.143, p < 0.001), and the calendar period 2016–2020 (OR: 4.767, p = 0.003). The gender and age of children and drug susceptibility of the disease were found to be irrelevant. Multivariate analysis (Table 6) was conducted, focussing on the risk factors for EPTB emerging from the univariate analysis, considering origin from Asia (OR: 2.758, p = 0.041) and the calendar period 2016–2020 (OR: 5.088, p = 0.003), which were confirmed as factors associated with EPTB.

3.8. Factors Associated with Use of Second-Line Drugs

Finally, treatment management was evaluated with univariate analysis (Table 7). Factors significantly associated with the administration of second-line drugs included the presence of symptoms (OR: 2.961, p = 0.001), having EPTB (OR: 4.899, p < 0.001), having the diagnosis confirmed with microbiological testing (OR: 2.472, p = 0.010), and the calendar period 2011–2015 (OR: 5.268, p < 0.001). However, the gender and age of children and the country of origin did not influence the administration of second-line drugs. These factors, found to be relevant in the univariate analysis, were evaluated in multivariate analysis (Table 7), confirming that having EPTB (OR: 4.104, p = 0.002), having the diagnosis confirmed by microbiological testing (OR: 2.484, p = 0.021), and the calendar period 2011–2015 (OR: 4.737, p = 0.002) were associated with the use of second-line drugs. However, the presence of symptoms was not confirmed as a significant factor in the multivariate analysis (OR: 1.749, p = 0.153).

4. Discussion

Children with active TB were evaluated for their characteristics (focussing on cases of EPTB and DR-TB) and the administrated therapies. Originating from Asia was associated with a higher risk of presenting with EPTB or DR-TB, while other characteristics, including age and gender, did not influence the distribution of these cases. The management of second-line drugs was mainly influenced by disease characteristics, such as the presence of EPTB or DR-TB. Results of DST were not available for the majority of children, and therapies had to be managed empirically, but the proportion of children with DST results increased over the years. Adverse events were primarily associated with the administration of first-line drugs, while second-line drugs were suspended in one patient only. All children were considered cured, and only a minority had sequelae despite the treatment.
Age did not appear to influence the distribution of cases, although other studies have reported a higher incidence rate in younger children [24]. However, younger age was associated with tuberculous meningitis; a similar result was found in a German study, where children under 5 years of age presented a higher percentage of tuberculous meningitis cases [25], and in a 2009 retrospective cohort study conducted in South Africa, where the median age of meningitis cases was between 2 and 4 years of age [26]. The fact that tuberculous meningitis mostly affects younger children, associated with the severity of the condition, makes its management challenging, even though it represents only a minority of TB cases.
Originating from Asia emerged as a risk factor for DR-TB, consistent with the WHO list of high-burden countries for RR/MDR-TB, where 15 out of 29 countries are Asian [2]. This finding is also supported by publications, including Liu et al. and White et al., who evaluated TB characteristics in immigrants, and mentioned China, Vietnam, India, and the Philippines as the main countries of origin for cases presenting with DR-TB [27,28]. The higher risk of presenting with EPTB among Asian people was similarly found in other studies, in Italy by Scotto et al., in which EPTB in patients from Asia were 34/60 [29], and in Spain by Luque et al., in which EPTB in patients from Asia were 134/347 [30].
The diagnosis was mainly accomplished after screening in children ≤ 5 years of age, while it was due to the presence of symptoms in children > 5 years of age. This could be related to the fact that PTB is associated with non-specific or absent symptoms in younger children, while older children may develop a more typical clinical pattern.
The difficulty in obtaining DST results in the paediatric population is a well-known problem [4], and it complicated TB management in this study as well. For this reason, the majority of children were managed with empirical treatment. It should be noted that DST results were increasingly obtained over the years, so that the proportion of children without DST results to children with results improved from 2006–2013 to 2014–2022. This is probably due to the introduction of new laboratory tests, such as GeneXpert MTB/RIF and GeneXpert Ultra. Even though variable in different studies, the sensitivity was generally high, from 67.6% to 97.5%, with pooled value of 90.0% [31].
Children with drug-resistant TB constituted a minority of cases. Excluding first-line drugs, streptomycin showed the highest resistance rate. Although the limited number of cases does not allow a definitive conclusion to be drawn, the high proportion of streptomycin-resistant strains is well documented in other studies [32,33]. The use of streptomycin in first-line regimens during the past century has led to the development of streptomycin resistance [34]. Even though it is no longer included in first-line regimens in current guidelines, streptomycin resistance continues to be detected frequently, complicating TB management [35].
Predictably, resistant cases were treated using second-line drugs. Amikacin, cycloserine, linezolid, moxifloxacin, levofloxacin, and PAS were found to be the most administered drugs in these cases. This is consistent with recommendations [4], and with DST results for the children in the study. Second-line drugs were also administered in children with non-resistant TB. This could be a consequence of the fact that most children could not be evaluated with DST and that during empirical treatment, second-line drugs could have been used because of an unsatisfactory response to first-line drugs.
Second-line drugs administration was also associated with EPTB diagnosis, even though guidelines state that drug-susceptible cases should be treated with regimens containing first-line drugs [4]. These drugs were mainly used when TB affected challenging and difficult-to-treat localisations, including the CNS, bone, abdominal organs, the heart, and eye. Unsatisfactory results from first-line regimens and the concern of sequelae probably led to this result. Considering the site of disease, second-line drugs that were significantly associated with EPTB diagnosis were moxifloxacin and cycloserine, both also showing good penetration in sites such as CNS and bone [4]. Guidelines recommend first-line drugs for EPTB treatment [4], but the benefit to associate them with second-line drugs when treating sites that are difficult to penetrate, such as the CNS, is supported by other studies [36]. It is to be noted that second-line drugs administration should be as limited as possible to confirmed and probable DR-TB cases, as recommended by guidelines [4,16].
The use of second-line drugs was also influenced by the year in which these patients were treated, in particular in the period 2011–2015. This is probably associated with an increasingly conservative administration of second-line drugs in subsequent years.
The minority of children presented adverse events. Among these, hypertransaminasemia, vomiting, and epigastric pain were the most frequent, and were attributable to hepatotoxicity. Other adverse events were mostly observed in isolated cases. The association between anti-TB drugs and hepatotoxicity is known and has been analysed in numerous studies [37,38], but the fact that few children experienced it is consistent with Tersigni et al., who observed a lower incidence rate of hypertransaminasemia in the paediatric population [39] compared to the incidence rate in the general population [38]. Although the majority of studies associate second-line drugs with adverse events [40,41], only one second-line drug was suspended due to acute kidney injury, suggesting that second-line drugs were well tolerated by the children in the study.
New antitubercular drugs bedaquiline and delamanid are recommended for DR-TB treatment in the most recent guidelines [4,16]. They are associated with favourable outcomes [42], but this study could not evaluate their efficacy and association with adverse events, because bedaquiline and delamanid were not used in our population.
Limitations of our study included the absence of a long-term follow-up, which might have led to an overestimation of positive outcomes due to the potential missed detection of relapses and sequelae. There may also have been under-reporting of adverse events by patients and their families. Additionally, not all cases had a confirmed diagnosis. Considering the 17-year length of the study period, the number of cases is rather small (consistent with the incidence of TB in the geographical area where Meyer Hospital is located). Moreover, the low prevalence of drug-resistant cases limited the possibility of conducting strong statistical analyses. The study does not evaluate the recently approved drugs bedaquiline and delamanid. Finally, some missing data did not allow for an understanding of the reasons for all the choices that were made.

5. Conclusions

Paediatric TB presents several challenges, particularly in the diagnosis of the disease and obtaining DST results. The introduction of GeneXpert tests has significantly improved these issues. The geographic origin was confirmed a relevant factor: children from Asia had a higher risk of EPTB and DR-TB. In our population, anti-tubercular treatments are associated with favourable outcomes in almost all patients. Study children with EPTB were more likely to receive second-line drugs. While the administration of second-line drugs should be limited primarily to documented or suspected DR-TB cases, it is possible that these drugs may also be beneficial in selected EPTB cases that do not respond satisfactorily to recommended first-line treatments.

Author Contributions

Conceptualisation, E.C.; methodology, E.C., D.P., and F.C.; software, C.L.; validation, L.G. and E.C.; formal analysis, C.L.; investigation, D.P. and F.C.; resources, E.C. and L.G.; data curation, C.L.; writing—original draft preparation, D.P. and F.C.; writing—review and editing, E.C. and L.G.; visualisation, D.P.; supervision, E.C.; project administration, E.C. and L.G.; funding acquisition, E.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was approved by the Ethics Committee of the Meyer Children’s Hospital (20/12/2018-188/2018). All parents or guardians gave written informed consent for the participation of each child before the beginning of the study, according to the Italian legislation.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study at the first visit.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table A1. Characteristics of the study population (n = 271), classified by disease localisation.
Table A1. Characteristics of the study population (n = 271), classified by disease localisation.
Characteristics of Children in the StudyChildren with PTB 1
N = 227 (%)
Children with EPTB 2
N = 44 (%)
p
Male115 (50.66)27 (61.36)0.256
Female112 (49.34)17 (38.64)
[0–1) years5 (2.20)1 (1.72)1.000
[1–3) years23 (10.13)6 (13.64)0.673
[3–5) years69 (30.40)14 (31.82)0.993
[5–13) years91 (40.09)14 (31.82)0.389
≥13 years39 (17.18)10 (22.73)0.509
Born in Italy to Italian Parents54 (23.79)9 (20.45)0.776
Born in Italy to Foreign Parents84 (37.00)14 (31.82)0.628
Born Abroad89 (39.21)21 (47.73)0.376
Diagnosis after Contact with a Case138 (60.79)6 (13.64)<0.001
Diagnosis during Screening 323 (10.13)2 (4.55)0.393
Diagnosis in Children with Symptoms63 (27.75)36 (81.82)<0.001
Unknown3 (1.32)0 (0.00)-
BCG 4 Vaccinated36 (15.86)7 (15.91)0.828
Not BCG Vaccinated191 (84.14)37 (84.09)
Positive TST 5/QuantiFERON209 (92.07)40 (90.91)0.479
Negative TST/QuantiFERON14 (6.17)1 (2.27)
Unknown/Absent Result4 (1.76)3 (6.82)-
Microbiologically 6 Confirmed98 (43.17)25 (56.82)0.084
Not Microbiologically Confirmed90 (39.65)11 (25.00)
Unknown/Absent Result39 (17.18)8 (18.18)-
Positive PCR 758 (25.55)19 (43.18)0.015
Negative PCR128 (56.39)16 (36.36)
Unknown/Absent Result41 (18.06)9 (20.45)-
Positive Microscopy28 (12.33)8 (18.18)0.412
Negative Microscopy158 (69.60)28 (63.64)
Unknown/Absent Result41 (18.06)8 (18.18)-
Positive Culture84 (37.00)22 (50.00)0.104
Negative Culture104 (45.81)14 (31.82)
Unknown/Absent Result39 (17.18)8 (18.18)-
Drug-Resistant Tuberculosis6 (2.64)3 (6.82)0.165
Drug-Susceptible Tuberculosis42 (18.51)16 (36.36)0.015
Unknown Drug-Susceptibility Pattern179 (78.85)25 (56.82)0.003
Treated with First-Line Drugs182 (80.18)22 (50.00)<0.001
Treated with Second-Line Drugs33 (14.54)20 (45.45)
Unknown Therapy12 (5.28)2 (4.55)-
Children Cured224 (98.68)43 (97.72)0.510
Children with Sequelae3 (1.32)1 (2.28)
1 PTB: pulmonary tuberculosis. 2 EPTB: extrapulmonary tuberculosis. 3 Screening for immigrated/adopted children. 4 BCG: Bacillus Calmette–Guerin. 5 TST: tuberculin skin test. 6 Diagnosis achieved through PCR/microscopy/culture. 7 Polymerase chain reaction.
Table A2. Characteristics of the study population (n = 271), classified by drug-susceptibility pattern.
Table A2. Characteristics of the study population (n = 271), classified by drug-susceptibility pattern.
Characteristics of Children in the StudyDrug-Resistant TB 1 Cases
n = 9 (%)
Drug-Susceptible TB Cases
n = 58 (%)
Children without DST 2 Results
n = 204 (%)
p *
Male3 (33.33)38 (65.52)101 (49.51)0.317
Female6 (66.67)20 (34.48)103 (50.49)
[0–1) years0 (0.00)1 (1.72)4 (1.96)1.000
[1–3) years1 (11.11)8 (13.79)20 (9.80)1.000
[3–5) years2 (22.22)16 (27.59)65 (31.86)0.726
[5–13) years4 (44.44)20 (34.68)81 (39.71)0.738
≥13 years2 (22.22)13 (22.41)34 (16.67)0.668
Born in Italy to Italian Parents1 (11.11)14 (24.14)48 (23.53)0.690
Born in Italy to Foreign Parents5 (55.56)20 (34.48)73 (35.78)0.289
Born Abroad3 (33.33)24 (41.38)83 (40.69)0.743
Diagnosis after Contact with a Case5 (55.56)27 (46.55)112 (54.90)1.000
Diagnosis during Screening 30 (0.00)2 (3.45)23 (11.27)1.000
Diagnosis in Children with Symptoms4 (44.44)28 (48.28)67 (32.84)0.730
Unknown0 (0.00)1 (1.72)2 (0.98)-
BCG 4 Vaccinated1 (11.11)4 (6.90)38 (18.63)1.000
Not BCG Vaccinated8 (88.89)54 (93.10)166 (81.37)
Pulmonary Tuberculosis6 (66.67)42 (72.41)179 (87.75)0.165
Extrapulmonary Tuberculosis 53 (33.33)16 (25.79)25 (12.25)
Positive TST 6/QuantiFERON9 (100.00)54 (93.10)186 (91.18)1.000
Negative TST/QuantiFERON0 (0.00)2 (3.45)13 (6.37)
Unknown/Absent Result0 (0.00)2 (3.45)5 (2.45)-
Microbiologically 7 Confirmed9 (100.00)58 (100.00)56 (27.45)0.005
Not Microbiologically Confirmed0 (0.00)0 (0.00)101 (49.51)
Unknown/Absent Result0 (0.00)0(0.00)47 (23.04)-
Positive PCR5 (55.56)46 (79.31)26 (12.75)0.281
Negative PCR4 (44.44)12 (20.69)128 (62.75)
Unknown/Absent Result0 (0.00)0 (0.00)50 (24.51)-
Positive Microscopy2 (22.22)17 (29.31)17(8.33)0.642
Negative Microscopy7 (77.78)41 (70.69)137 (67.16)
Unknown/Absent Result0 (0.00)0 (0.00)49 (24.02)-
Positive Culture9 (100.00)48 (82.76)49 (24.02)0.001
Negative Culture0 (0.00)10 (17.24)108 (52.94)
Unknown/Absent Result0 (0.00)0 (0.00)47 (23.04)-
Treated with First-Line Drugs2 (22.22)45 (77.59)157 (76.96)<0.001
Treated with Second-Line Drugs7 (77.78)13 (22.41)33 (16.18)
Unknown Therapy0 (0.00)0 (0.00)14 (6.86)-
Children Cured8 (88.89)56 (96.55)203 (99.51)0.127
Children with Sequelae1 (1.11)2 (3.45)1 (0.49)
1 TB: tuberculosis. 2 DST: drug-susceptibility testing. 3 Screening for immigrated/adopted children. 4 BCG: Bacillus Calmette–Guerin. 5 Cases exclusively affecting extrapulmonary sites and cases affecting both lungs and extrapulmonary sites were included in this group. 6 TST: tuberculin skin test. 7 Diagnosis achieved through PCR/microscopy/culture. * Calculating p-value, “Drug-susceptible TB cases” and “Children without DST results” were considered as a single group and compared with “Drug-resistant TB cases”.
Table A3. Drug-resistant tuberculosis cases and non-drug-resistant tuberculosis cases, classified by origin.
Table A3. Drug-resistant tuberculosis cases and non-drug-resistant tuberculosis cases, classified by origin.
Origin of Children in the StudyDrug-Resistant TB 1 Cases
n = 9 (%)
Drug-Susceptible TB Cases and Children without DST 2 Results n = 262 (%)p
Italy0 (0.00)63 (23.75)0.123
Western Europe0 (0.00)2 (0.77)1.000
Eastern Europe1 (11.11)47 (18.01)1.000
Africa1 (11.11)71 (27.20)0.453
Asia4 (44.44)41 (15.71)0.045
South-Central America3 (33.33)33 (12.64)0.103
Unknown0 (0.00)5 (1.92)1.000
1 TB: tuberculosis. 2 DST: drug-susceptibility testing.
Table A4. Second-line drugs administered to drug-resistant cases, and drug-susceptible cases.
Table A4. Second-line drugs administered to drug-resistant cases, and drug-susceptible cases.
Second-Line DrugsDrug-Resistant TB 1
n = 9 (%)
Drug-Susceptible TB
n = 58 (%)
p
Amikacin5 (55.56)9 (15.52)0.015
Cycloserine6 (66.67)2 (3.45)0.000
Linezolid5 (55.56)2 (3.45)<0.001
Moxifloxacin4 (44.44)8 (13.79)0.047
Levofloxacin2 (22.22)3 (5.17)0.130
Para-aminosalicylic acid2 (22.22)0 (0.00)0.016
1 TB: tuberculosis.

References

  1. Daniel, T.M. The history of tuberculosis. Respir. Med. 2006, 100, 1862–1870. [Google Scholar] [CrossRef]
  2. World Health Organization. Global Tuberculosis Report 2022. Available online: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022 (accessed on 13 July 2023).
  3. Carvalho, A.C.C.; Cardoso, C.A.A.; Martire, T.M.; Migliori, G.B.; Sant’Anna, C.C. Epidemiological aspects, clinical manifestations, and prevention of pediatric tuberculosis from the perspective of the End TB Strategy. J. Bras. Pneumol. 2018, 44, 134–144. [Google Scholar] [CrossRef]
  4. World Health Organization. WHO Operational Handbook on Tuberculosis: Module 5: Management of Tuberculosis in Children and Adolescents. Available online: https://www.who.int/publications/i/item/9789240046832 (accessed on 13 July 2023).
  5. Dubois, M.M.; Brooks, M.B.; Malik, A.A.; Siddiqui, S.; Ahmed, J.F.; Jaswal, M.; Amanullah, F.; Becerra, M.C.; Hussain, H. Age-specific Clinical Presentation and Risk Factors for Extrapulmonary Tuberculosis Disease in Children. Pediatr. Infect. Dis. J. 2022, 41, 620–625. [Google Scholar] [CrossRef]
  6. Hayward, S.E.; Rustage, K.; Nellums, L.B.; van der Werf, M.J.; Noori, T.; Boccia, D.; Friedland, J.S.; Hargreaves, S. Extrapulmonary tuberculosis among migrants in Europe, 1995 to 2017. Clin. Microbiol. Infect. 2021, 27, 1347.e1–1347.e7. [Google Scholar] [CrossRef]
  7. Di Nuzzo, M.; Trentini, A.; Grilli, A.; Massoli, L.; Biagi, E.; Maritati, M.; Contini, C. Extrapulmonary tuberculosis among immigrants in a low-TB burden and high immigrant receiving city of northern Italy. J. Infect. Dev. Ctries. 2018, 12, 73–79. [Google Scholar] [CrossRef]
  8. Ben Ayed, H.; Koubaa, M.; Marrakchi, C.; Rekik, K.; Hammami, F.; Smaoui, F.; Ben, H.; Sourour, Y.; Imed, M.; Damak, J.; et al. Extrapulmonary Tuberculosis: Update on the Epidemiology, Risk Factors and Prevention Strategies. Int. J. Trop. Dis. 2018, 1, 1–6. [Google Scholar]
  9. Lamb, G.S.; Starke, J.R. Tuberculosis in Infants and Children. Microbiol. Spectr. 2017, 5, 541–569. [Google Scholar] [CrossRef]
  10. Seung, K.J.; Keshavjee, S.; Rich, M.L. Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis. Cold Spring Harb. Perspect. Med. 2015, 5, a017863. [Google Scholar] [CrossRef]
  11. World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 5: Management of Tuberculosis in Children and Adolescents. Available online: https://www.who.int/publications/i/item/9789240046764 (accessed on 13 July 2023).
  12. Pyrazinamide. Tuberculosis 2008, 88, 141–144. [CrossRef]
  13. Ethambutol. Tuberculosis 2008, 88, 102–105. [CrossRef]
  14. Isoniazid. Tuberculosis 2008, 88, 112–116. [CrossRef]
  15. Rifampin. Tuberculosis 2008, 88, 151–154. [CrossRef]
  16. American Academy of Pediatrics. Tuberculosis. In Red Book: 2021 Report of the Committee on Infectious Diseases, 32nd ed.; Kimberlin, D.W., Barnett, E.D., Lynfield, R., Sawyer, M.H., Eds.; American Academy of Pediatrics: Itasca, IL, USA, 2021; pp. 786–814. [Google Scholar]
  17. World Health Organization. WHO Operational Handbook on Tuberculosis: Module 4: Treatment: Drug-Resistant Tuberculosis Treatment. Available online: https://www.who.int/publications/i/item/9789240006997 (accessed on 13 July 2023).
  18. Rodríguez-Beltrán, É.; López, G.D.; Anzola, J.M.; Rodríguez-Castillo, J.G.; Carazzone, C.; Murcia, M.I. Heterogeneous fitness landscape cues, pknG low expression, and phthiocerol dimycocerosate low production of Mycobacterium tuberculosis ATCC25618 rpoB S450L in enriched broth. Tuberculosis 2022, 132, 102156. [Google Scholar] [CrossRef]
  19. Fregonese, F.; Ahuja, S.D.; Akkerman, O.W.; Arakaki-Sanchez, D.; Ayakaka, I.; Baghaei, P.; Bang, D.; Bastos, M.; Benedetti, A.; Bonnet, M.; et al. Comparison of different treatments for isoniazid-resistant tuberculosis: An individual patient data meta-analysis. Lancet Respir. Med. 2018, 6, 265–275. [Google Scholar] [CrossRef]
  20. Chiang, S.S.; Khan, F.A.; Milstein, M.B.; Tolman, A.W.; Benedetti, A.; Starke, J.R.; Becerra, M.C. Treatment outcomes of childhood tuberculous meningitis: A systematic review and meta-analysis. Lancet Infect. Dis. 2014, 14, 947–957. [Google Scholar] [CrossRef]
  21. Viney, K.; Linh, N.N.; Gegia, M.; Zignol, M.; Glaziou, P.; Ismail, N.; Kasaeva, T.; Mirzayev, F. New definitions of pre-extensively and extensively drug-resistant tuberculosis: Update from the World Health Organization. Eur. Respir. J. 2021, 57, 2100361. [Google Scholar] [CrossRef]
  22. World Health Organization. Definitions and Reporting Framework for Tuberculosis—2013 Revision: Updated December 2014 and January 2020. Available online: https://www.who.int/publications/i/item/9789241505345 (accessed on 13 July 2023).
  23. Cellestis/Qiagen. QuantiFERON(R)-TB Gold (In-Tube Method) Package Insert. Available online: www.quantiferon.com/wp-content/uploads/2017/04/English_QFTPlus_ELISA_R04_022016.pdf/ (accessed on 13 July 2023).
  24. Cowger, T.L.; Wortham, J.M.; Burton, D.C. Epidemiology of tuberculosis among children and adolescents in the USA, 2007–2017: An analysis of national surveillance data. Lancet Public Health 2019, 4, e506–e516. [Google Scholar] [CrossRef]
  25. Ducomble, T.; Tolksdorf, K.; Karagiannis, I.; Hauer, B.; Brodhun, B.; Haas, W.; Fiebig, L. The burden of extrapulmonary and meningitis tuberculosis: An investigation of national surveillance data, Germany, 2002 to 2009. Eurosurveillance 2013, 18, 20436. [Google Scholar] [CrossRef]
  26. Van Well, G.T.; Paes, B.F.; Terwee, C.B.; Springer, P.; Roord, J.J.; Donald, P.R.; van Furth, A.M.; Schoeman, J.F. Twenty years of pediatric tuberculous meningitis: A retrospective cohort study in the western cape of South Africa. Pediatrics 2009, 123, e1–e8. [Google Scholar] [CrossRef]
  27. Liu, Y.; Posey, D.L.; Yang, Q.; Weinberg, M.S.; Maloney, S.A.; Lambert, L.A.; Ortega, L.S.; Marano, N.; Cetron, M.S.; Phares, C.R. Multidrug-Resistant Tuberculosis in U.S.-Bound Immigrants and Refugees. Ann. Am. Thorac. Soc. 2022, 19, 943–951. [Google Scholar] [CrossRef] [PubMed]
  28. White, Z.; Painter, J.; Douglas, P.; Abubakar, I.; Njoo, H.; Archibald, C.; Halverson, J.; Robson, J.; Posey, D.L. Immigrant Arrival and Tuberculosis among Large Immigrant- and Refugee-Receiving Countries, 2005–2009. Tuberc. Res. Treat. 2017, 2017, 8567893. [Google Scholar] [CrossRef]
  29. Scotto, G.; Fornabaio, C.; Prato, R.; Saracino, A.; Tartaglia, A.; Di Tullio, R.; Carbonara, S.; Angarano, G.; Italian Study Group for Infectious Diseases in Immigrants. Tuberculosis and immigrants: A SIMIT (Italian Society of Infectious Diseases) clinical, epidemiological multicentric research investigation. New Microbiol. 2009, 32, 39–47. [Google Scholar]
  30. Luque, L.; Rodrigo, T.; Garcia-Garcia, J.M.; Casals, M.; Millet, J.P.; Cayla, J.; Oreau, A. Factors Associated with Extrapulmonary Tuberculosis in Spain and Its Distribution in Immigrant Population. Open Respir. Arch. 2020, 2, 119–126. [Google Scholar] [CrossRef]
  31. Kay, A.W.; González Fernández, L.; Takwoingi, Y.; Eisenhut, M.; Detjen, A.K.; Steingart, K.R.; Mandalakas, A.M. Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for active tuberculosis and rifampicin resistance in children. Cochrane Database Syst. Rev. 2020, 8, CD013359. [Google Scholar] [CrossRef]
  32. Guo, Q.; Pan, Y.; Yang, Z.; Liu, R.; Xing, L.; Peng, Z.; Zhu, C. Epidemiology and Clinical Characteristics of Pediatric Drug-Resistant Tuberculosis in Chongqing, China. PLoS ONE 2016, 11, e0151303. [Google Scholar] [CrossRef]
  33. Cakir, E.; Erdem, E.; Ozlu, N.; Seber, E.; Gencer, S.; Kilicaslan, Z. Demographic and microbial characteristics and drug resistance of childhood tuberculosis in Istanbul: Analysis of 1,541 cases. J. Infect. Dev. Ctries. 2014, 8, 304–309. [Google Scholar] [CrossRef]
  34. Murray, J.F.; Schraufnagel, D.E.; Hopewell, P.C. Treatment of Tuberculosis. A Historical Perspective. Ann. Am. Thorac. Soc. 2015, 12, 1749–1759. [Google Scholar] [CrossRef]
  35. Rocha, D.M.G.C.; Viveiros, M.; Saraiva, M.; Osório, N.S. The Neglected Contribution of Streptomycin to the Tuberculosis Drug Resistance Problem. Genes 2021, 12, 2003. [Google Scholar] [CrossRef]
  36. Cresswell, F.V.; Te Brake, L.; Atherton, R.; Ruslami, R.; Dooley, K.E.; Aarnoutse, R.; Van Crevel, R. Intensified antibiotic treatment of tuberculosis meningitis. Expert. Rev. Clin. Pharmacol. 2019, 12, 267–288. [Google Scholar] [CrossRef]
  37. Saukkonen, J.J.; Cohn, D.L.; Jasmer, R.M.; Schenker, S.; Jereb, J.A.; Nolan, C.M.; Peloquin, C.A.; Gordin, F.M.; Nunes, D.; Strader, D.B.; et al. An official ATS statement: Hepatotoxicity of antituberculosis therapy. Am. J. Respir. Crit. Care Med. 2006, 174, 935–952. [Google Scholar] [CrossRef] [PubMed]
  38. Tostmann, A.; Boeree, M.J.; Aarnoutse, R.E.; de Lange, W.C.; van der Ven, A.J.; Dekhuijzen, R. Antituberculosis drug-induced hepatotoxicity: Concise up-to-date review. J. Gastroenterol. Hepatol. 2008, 23, 192–202. [Google Scholar] [CrossRef] [PubMed]
  39. Tersigni, C.; Venturini, E.; Cordola, C.; Piccini, P.; Bianchi, L.; Montagnani, C.; Sollai, S.; Chiappini, E.; de Martino, M.; Galli, L. Latent tuberculosis in childhood: Tolerability of two different therapeutic approaches. Expert. Rev. Anti Infect. Ther. 2018, 16, 359–365. [Google Scholar] [CrossRef] [PubMed]
  40. Merid, M.W.; Gezie, L.D.; Kassa, G.M.; Muluneh, A.G.; Akalu, T.Y.; Yenit, M.K. Incidence and predictors of major adverse drug events among drug-resistant tuberculosis patients on second-line anti-tuberculosis treatment in Amhara regional state public hospitals; Ethiopia: A retrospective cohort study. BMC Infect. Dis. 2019, 19, 286. [Google Scholar] [CrossRef] [PubMed]
  41. Carroll, M.W.; Lee, M.; Cai, Y.; Hallahan, C.W.; Shaw, P.A.; Min, J.H.; Goldfeder, L.C.; Alekseyev, V.; Grinkrug, S.; Kang, H.S.; et al. Frequency of adverse reactions to first- and second-line anti-tuberculosis chemotherapy in a Korean cohort. Int. J. Tuberc. Lung Dis. 2012, 16, 961–966. [Google Scholar] [CrossRef]
  42. Pecora, F.; Dal Canto, G.; Veronese, P.; Esposito, S. Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid. Microorganisms 2021, 9, 1074. [Google Scholar] [CrossRef]
Figure 1. Distribution of cases (n = 271) by origin. For each continent, the number of total cases, extrapulmonary tuberculosis (EPTB) cases, and drug-resistant tuberculosis (DR-TB) cases are indicated. Created with mapchart.net.
Figure 1. Distribution of cases (n = 271) by origin. For each continent, the number of total cases, extrapulmonary tuberculosis (EPTB) cases, and drug-resistant tuberculosis (DR-TB) cases are indicated. Created with mapchart.net.
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Figure 2. Extrapulmonary sites affected: (a) sites affected in children aged ≤5 years old (20/131 extrapulmonary tuberculosis cases); (b) sites affected in children aged >5 years old (24/140 extrapulmonary tuberculosis cases). Created with Biorender.com.
Figure 2. Extrapulmonary sites affected: (a) sites affected in children aged ≤5 years old (20/131 extrapulmonary tuberculosis cases); (b) sites affected in children aged >5 years old (24/140 extrapulmonary tuberculosis cases). Created with Biorender.com.
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Figure 3. Drugs to which the study cases were found to be resistant. The number of cases found to be resistant is indicated for each drug. Blue columns correspond to drugs administered in first-line regimens. Orange columns correspond to second-line drugs.
Figure 3. Drugs to which the study cases were found to be resistant. The number of cases found to be resistant is indicated for each drug. Blue columns correspond to drugs administered in first-line regimens. Orange columns correspond to second-line drugs.
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Figure 4. Adverse events associated with administered drugs, and number of children presenting adverse events.
Figure 4. Adverse events associated with administered drugs, and number of children presenting adverse events.
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Table 1. Characteristics of the study population (n = 271), classified by age.
Table 1. Characteristics of the study population (n = 271), classified by age.
Characteristics of Children in the StudyChildren ≤ 5 Years OldChildren > 5 Years OldTotalp
n = 131 (%)n = 140 (%)n = 271 (%)
Male68 (51.91)74 (52.86)142 (52.40)0.972
Female63 (48.09)66 (47.14)129 (47.60)
Born in Italy to Italian Parents37 (28.24)26 (18.57)63 (23.25)0.082
Born in Italy to Foreign Parents65 (49.62)33 (23.57)98 (36.16)<0.001
Born Abroad29 (22.14)81 (57.86)110 (40.59)<0.001
Diagnosis after Contact with a Case86 (65.65)58 (41.43)144 (53.14)<0.001
Diagnosis during Screening 112 (9.16)13 (9.29)25 (9.22)0.845
Diagnosis in Children with Symptoms31 (23.66)68 (48.57)99 (36.53)<0.001
Unknown 2 (1.53)1 (0.71)3 (1.11)-
BCG 2 Vaccinated17 (12.98)26 (18.57)43 (15.87)0.274
Not BCG Vaccinated114 (87.02)114 (81.43)228 (84.13)
Pulmonary Tuberculosis111 (84.73)116 (82.86)227 (83.76)0.800
Extrapulmonary Tuberculosis 320 (15.27)24 (17.14)44 (16.24)
Positive TST 4/QuantiFERON118 (90.08)131 (93.57)249 (91.88)0.494
Negative TST/QuantiFERON9 (6.87)6 (4.29)15 (5.53)
Unknown4 (3.05)3 (2.14)7 (2.59)-
Microbiologically 5 Confirmed60 (45.80)63 (45.00)123 (45.39)0.677
Not Microbiologically Confirmed53 (40.46)48 (34.29)101 (37.27)
Unknown/Absent Result18 (13.74)29 (20.71)47 (17.34)-
Positive PCR 633 (25.19)44 (31.42)77 (28.41)0.144
Negative PCR78 (59.54)66 (47.14)144 (53.14)
Unknown/Absent Result20 (15.27)30 (21.43)50 (18.45)-
Positive Microscopy13 (9.92)23 (16.43)36 (13.28)0.089
Negative Microscopy99 (75.57)87 (62.14)186 (68.63)
Unknown/Absent Result19 (14.50)30 (21.43)49 (18.08)-
Positive Culture50 (38.17)56 (40.00)106 (39.11)0.426
Negative Culture63 (48.09)55 (39.29)118 (43.54)
Unknown/Absent Result18 (38.17)29 (28.71)47 (17.34)-
Drug-Resistant Tuberculosis4 (3.05)5 (3.57)9 (3.32)1.000
Drug-Susceptible Tuberculosis27 (20.61)31 (22.14)58 (21.40)0.874
Unknown Drug-Susceptibility Pattern100 (76.34)104 (74.29)204 (75.28)0.802
Treated with First-Line Drugs95 (72.52)109 (77.86)204 (75.28)0.164
Treated with Second-Line Drugs31 (23.66)22 (15.71)53 (19.56)
Unknown Therapy5 (3.82)9 (6.43)14 (5.2)-
Children Cured129 (98.47)138 (98.57)267 (98.52)1.000
Children with Sequelae2 (1.53)2 (1.43)4 (1.48)
1 Screening for immigrated/adopted children. 2 BCG: Bacillus Calmette–Guerin. 3 Cases exclusively affecting extrapulmonary sites and cases affecting both lungs and extrapulmonary sites were included in this group. 4 TST: Tuberculin Skin Test. 5 Diagnosis achieved through PCR/microscopy/culture. 6 Polymerase chain reaction.
Table 2. Second-line drugs administered to drug-resistant cases, drug-susceptible cases, and children without drug susceptibility testing results.
Table 2. Second-line drugs administered to drug-resistant cases, drug-susceptible cases, and children without drug susceptibility testing results.
Second-Line DrugsDrug-Resistant TB 1
n = 9 (%)
Drug-Susceptible TB
n = 58 (%)
Children without DST 2 Results
n = 204 (%)
p 3
Amikacin5 (55.56)9 (15.52)19 (9.31)0.002
Cycloserine6 (66.67)2 (3.45)11 (5.39)<0.001
Linezolid5 (55.56)2 (3.45)8 (3.92)<0.001
Moxifloxacin4 (44.44)8 (13.79)24 (11.76)0.020
Levofloxacin2 (22.22)3 (5.17)1 (0.49)0.014
Ciprofloxacin0 (0.00)0 (0.00)1 (0.49)1.000
Clarithromycin0 (0.00)0 (0.00)1 (0.49)1.000
Streptomycin0 (0.00)0 (0.00)1 (0.49)1.000
Para-aminosalicylic acid2 (22.22)0 (0.00)3 (1.47)0.009
1 TB: tuberculosis. 2 DST: drug-susceptibility testing. 3 Calculating P-value, “drug-susceptible TB” and “children without DST results” were considered as a single group and compared to “drug-resistant TB”.
Table 3. Second-line drugs administered to pulmonary tuberculosis cases and extrapulmonary tuberculosis cases.
Table 3. Second-line drugs administered to pulmonary tuberculosis cases and extrapulmonary tuberculosis cases.
Second-Line DrugsPulmonary Tuberculosis Cases
n = 227 (%)
Extrapulmonary Tuberculosis Cases
n = 44 (%)
p
Amikacin25 (11.01)8 (18.18)0.281
Cycloserine11 (4.85)8 (18.18)0.004
Linezolid12 (5.29)3 (6.82)0.717
Moxifloxacin23 (10.13)13 (29.55)0.001
Levofloxacin4 (1.76)2 (4.55)0.252
Ciprofloxacin0 (0.00)1 (2.27)1.000
Clarithromycin0 (0.00)1 (2.27)1.000
Streptomycin0 (0.00)1 (2.27)1.000
Para-aminosalicylic acid5 (2.20)0 (0.00)1.000
Table 4. Drug susceptibility of pulmonary and extrapulmonary tuberculosis cases.
Table 4. Drug susceptibility of pulmonary and extrapulmonary tuberculosis cases.
Drug SusceptibilityPulmonary Tuberculosis Cases
n = 227 (%)
Extrapulmonary Tuberculosis Cases
n = 44 (%)
p
Drug-resistant tuberculosis6 (2.65)3 (6.82)0.165
Drug-susceptible tuberculosis42 (18.50)16 (36.36)0.015
Children without DST 1 results179 (78.85)25 (56.82)0.004
1 DST: drug-susceptibility testing.
Table 5. Univariate analysis for factors associated with drug-resistant tuberculosis.
Table 5. Univariate analysis for factors associated with drug-resistant tuberculosis.
Univariate Analysis
Study Population Characteristicsn/N *OR 195% CI 2p
Male3/1421.000
Female6/1292.2600.553–9.2300.256
≤5 years 4/1310.8500.223–3.2380.812
>5 years5/1401.000
Europe1/1131.000
Africa1/721.5770.097–25.6240.749
Asia4/4410.9271.186–100.6390.035
South-Central America3/3610.1821.025–101.1730.048
Pulmonary tuberculosis6/2270.3710.089–1.5430.173
Extrapulmonary tuberculosis3/441.000
Diagnosed in 2006–20154/1781.000
Diagnosed in 2016–20225/932.4720.647–9.4350.186
1 OR: odds ratio. 2 CI: confidence interval; * n/N: number of drug-resistant cases/number of total cases.
Table 6. Univariate and multivariate analysis for factors associated with extrapulmonary tuberculosis.
Table 6. Univariate and multivariate analysis for factors associated with extrapulmonary tuberculosis.
Univariate Analysis Multivariate Analysis
Study Population Characteristicsn/N *OR 195% CI 2pOR95% CIp
Male27/1421.000
Female17/1290.6460.334–1.2510.195
≤5 years 20/1310.8710.456–1.6650.676
>5 years24/1401.000
Italy 9/631.000
Eastern Europe5/480.6980.218–2.2350.5440.6750.204–2.2310.520
Africa11/721.0820.417–2.8090.8711.0640.401–2.8240.900
Asia14/452.7101.051–6.9830.0392.7581.041–7.3050.041
South-Central America5/360.9680.298–3.1460.9571.1500.341–3.8750.822
Diagnosis after contact6/1441.000
Diagnosis during screening 32/252.0000.380–10.5190.413
Diagnosed with symptoms36/9913.1435.268–32.788<0.001
DR-TB 4 cases3/92.6950.648–11.2110.173
Non DR-TB cases41/2621.000
Diagnosed in 2006–20105/741.000
Diagnosed in 2011–201517/1042.6970.947–7.6750.0632.6700.920–7.7480.071
Diagnosed in 2016–202019/744.7671.673–13.5810.0035.0881.750–14.7950.003
Diagnosed in 2021–20223/192.5870.029–0.1800.2242.4380.510–11.6530.264
1 OR: odds ratio. 2 CI: confidence interval. 3 Screening for immigrated/adopted children. 4 DR-TB: drug-resistant tuberculosis. * n/N: number of extrapulmonary cases/number of total cases.
Table 7. Univariate and multivariate analyses for factors associated with second-line drugs administration.
Table 7. Univariate and multivariate analyses for factors associated with second-line drugs administration.
Study Population Characteristicsn/N *OR 195% CI 2pOR95% CIp
Male29/1421.000
Female24/1290.8910.487–1.6270.706
≤5 years 31/1311.6630.905–3.0540.101
>5 years22/1401.000
Italy 10/631.000
Eastern Europe10/481.3950.528–3.6810.502
Africa11/720.9560.376–2.4270.924
Asia13/452.1530.846–5.4780.108
South-Central America7/361.2790.440–3.7170.651
Diagnosis after contact20/1441.000
Diagnosis during screening 30/25
Diagnosed with symptoms32/992.9611.573–5.5750.0011.7490.813–3.7610.153
Pulmonary tuberculosis33/2271.000
Extrapulmonary tuberculosis 420/444.8992.436–9.854<0.0014.1041.691–9.9620.002
Microbiologically confirmed 535/1232.4721.243–4.9130.0102.4841.146–5.3840.021
Not microbiologically confirmed14/1011.000
Diagnosed in 2006–20106/741.000
Diagnosed in 2011–201533/1045.2682.076–13.368<0.0014.7371.764–12.7150.002
Diagnosed in 2016–202010/741.7710.608–5.1530.2940.9090.282–2.9310.874
Diagnosed in 2021–20224/193.0220.758–12.0510.1171.7170.387–7.6110.477
1 OR: odds ratio. 2 CI: confidence interval. 3 Screening for immigrated/adopted children. 4 Cases exclusively affecting extrapulmonary sites and cases affecting both lungs and extrapulmonary sites were included in this group. 5 Diagnosis achieved through PCR/microscopy/culture. * n/N: number of cases associated with second-line drugs administration/number of total cases.
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Pace, D.; Corvaglia, F.; Lisi, C.; Galli, L.; Chiappini, E. Extrapulmonary and Drug-Resistant Childhood Tuberculosis: Unveiling the Disease to Adopt the Optimal Treatment Strategy. Pathogens 2023, 12, 1439. https://doi.org/10.3390/pathogens12121439

AMA Style

Pace D, Corvaglia F, Lisi C, Galli L, Chiappini E. Extrapulmonary and Drug-Resistant Childhood Tuberculosis: Unveiling the Disease to Adopt the Optimal Treatment Strategy. Pathogens. 2023; 12(12):1439. https://doi.org/10.3390/pathogens12121439

Chicago/Turabian Style

Pace, Domenico, Francesca Corvaglia, Catiuscia Lisi, Luisa Galli, and Elena Chiappini. 2023. "Extrapulmonary and Drug-Resistant Childhood Tuberculosis: Unveiling the Disease to Adopt the Optimal Treatment Strategy" Pathogens 12, no. 12: 1439. https://doi.org/10.3390/pathogens12121439

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