**1. Introduction**

Globally, about one million children are diagnosed with tuberculosis (TB) each year, and 210,000 die because of TB-related complications [1]. The accurate estimation of the global burden of childhood tuberculosis is difficult, mainly due to the problems associated with the detection, diagnosis, and insufficient surveillance of the disease, especially in countries with high TB-incidence rates [2]. According to WHO estimates, children younger than 15 years account for 15–20% of the global TB burden, but the number of reported cases varies greatly between regions and ranges from 3 to 25% [3,4].

In Poland, childhood tuberculosis is not an epidemiologically significant problem, possibly due to low TB incidence in the general population. In 2018 and 2019, children accounted for 0.9% and 1.5% of all reported TB cases, respectively. The number of notified cases was 20 (38%) vs. 26 (32%) for the age group 0–4 years, and 32 (62%) vs. 55 (68%) for the age group 5–14 years, in 2018 and 2019, respectively [5].

**Citation:** Kozi ´nska, M.; Bogucka, K.; K ˛edziora, K.; Szpak-Szpakowska, J.; P ˛edzierska-Olizarowicz, W.; Pustkowski, A.; Augustynowicz-Kope´c, E. XDR-TB Transmitted from Mother to 10-Month-Old Infant: Diagnostic and Therapeutic Problems. *Diagnostics* **2022**, *12*, 438. https://doi.org/10.3390/ diagnostics12020438

Academic Editor: João Perdig<sup>ã</sup>o

Received: 4 January 2022 Accepted: 6 February 2022 Published: 8 February 2022

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Drug-resistant TB (DR-TB) in children is a special epidemiological, clinical, and diagnostic problem, and its global incidence remains unknown. The latest data indicate that around 25,000 to 32,000 children worldwide develop DR-TB annually, which accounts for 3% of all childhood tuberculosis cases [6].

DR-TB in children is usually of a primary nature and is most often transmitted to the child from a household contact, so these cases reflect the prevalence of DR-TB in the population of adult patients [7].

TB in children is often paucibacillary and therefore difficult to confirm using microbiological methods. Therefore, the diagnosis is often presumptive and based on a medical interview. It is believed that a child diagnosed based on clinical symptoms, who recently had close contact with an MDR-TB (resistant to at least isoniazid and rifampin) patient, should be treated according to the drug-susceptibility test performed for the patient identified as the likely source of infection. It was confirmed that the concordance of the drug-resistance profile of strains isolated from children aged <15 years and the source patient may reach the level of 96% [8].

The risk of infection with *Mycobacterium tuberculosis* complex (MTBC) in children depends on the age, duration of exposure, proximity of contact with the infected person, and the level of source virulence. Most cases of TB in children, especially in infants, are caused by household contacts, where the main sources of infection are parents, grandparents or older siblings. However, there are many documented cases of TB transmission outside the family, such as kindergartens, schools, family nursing homes, churches, school buses, and shops [9,10]. The most common source of infection is an adult who is profusely positive for *Mycobacterium tuberculosis*, diagnosed too late, and inadequately treated. It has been estimated that a sputum-positive patient might infect 30–50% of their household members. For this reason, active epidemiological investigation and contact tracing in the environment of sputum-positive patients are the most appropriate methods of identifying infected family members [11].

The present paper presents a case of transmission of extensively drug-resistant TB (XDR-TB, resistant to isoniazid and rifampin, plus any fluoroquinolone, and at least one of three injectable second-line drugs), Beijing 265 genotype, from a mother to her 10-monthold daughter. It is the first case in Poland and one of very few described in the world where treatment was effective in the mother and the infant recovered spontaneously.

#### **2. Case Study**

#### *2.1. Mother, Age 27 Years*

In January 2020, a 27-year-old woman with symptoms of tuberculosis visited a pulmonology clinic. For 2 months, she had a cough with mild haemoptysis and fever. A sputum smear was positive for mycobacteria (Acid Fast Bacilli, AFB+++), and the treatment was initiated according to the following regimen: rifampicin, isoniazid, ethambutol, and pyrazinamide. No improvement was achieved after 2 months of therapy, and an X-ray of the lungs on 24 March 2020 revealed patchy and nodular infiltrations localized in the right lung. The strain isolated from the sputum was identified as XDR-MTB, spoligotype Beijing 265. All molecular and biochemical tests were performed in the National Tuberculosis and Lung Diseases Research Institute in Warsaw, Poland. According to the drug-resistance phenotype determined on the liquid medium, treatment was introduced for drugs to which the strain was sensitive: linezolid, cycloserine, ethambutol, levofloxacin and ethionamide. The patient was still profusely positive for mycobacteria (AFB++). A bronchial secretion was collected on 1 April 2020 and the XDR strain, Beijing 265 genotype, was cultured again. Treatment was continued, but levofloxacin was substituted with moxifloxacin. A chest CT performed on 3 June 2020 revealed the presence of diffuse nodular lesions localized in the right lung (Figure 1A). Therapy with ethambutol was discontinued due to ophthalmic problems, while linezolid and ethionamide were discontinued because of sensory polyneuropathy. Follow-up tests for AFB (culture in solid and liquid media and detection of DNA directly in the clinical specimen) were negative in June 2020. After 6 months of antibiotic

treatment, a CT scan revealed the partial regression of lesions (Figure 1B). The patient's clinical status improved and treatment with bedaquiline, moxifloxacin, and cycloserine was finally sustained.

#### *2.2. Daughter, Age 10 Months*

The infant was first examined at the pulmonology outpatient clinic at the beginning of February 2020 when the mother tested positive for mycobacteria in the sputum (AFB+++), and antimycobacterial treatment was initiated, with continued microbiological tests for TB (inoculation on solid and liquid media and an antibiogram). A chest X-ray of the infant did not reveal any lesions in the lungs, and the IGRA (interferon-gamma release assay) was negative. A 3-month prophylactic treatment with isoniazid was initiated. In May 2020, the IGRA was repeated, and the result was positive. The infant was in good health without clinical symptoms. Gastric lavage specimens were sampled three times for microbiological tests. In June 2020, a chest X-ray and CT scan were performed again. Ground-glass opacities were identified in the lungs as well as enlarged lymph nodes in the lung hila and mediastinum (Figure 1C). A bronchoscopy was also performed, and the mucous secretion was aspirated and sent for microbiological tests. Because the infant was in good physical health and had no clinical symptoms, and the fact that the strain isolated from the mother was multi-drug resistant (no guidelines for prophylaxis in children having contact with XDR-TB), treatment was not initiated, and a decision was made to conduct weekly follow-up tests at the pulmonology outpatient clinic.

In July 2020, an MTBC strain was cultured from gastric lavage specimens sampled in May. The cultured strain was identical to the one cultured from the mother: XDR-TB, spoligotype Beijing 265 with MIRU-VNTR code 333654444432658 (Table 1). In October 2020, after a 3-month observation, gastric lavage specimens were collected three times again. Microbiological tests were negative. A CT was also repeated. Compared to the image acquired in June 2020, regression of the lesions was observed (Figure 1D), the lymph nodes decreased in size, and numerous minor calcifications appeared.

**Table 1.** Results of microbiological and genetic assays for MTBC strains cultured from the mother and infant.


Because the infant still had no clinical symptoms, antimycobacterial treatment was not initiated, and follow-up in the outpatient setting was continued. The girl remains in good health to this day, and her mental and physical development is normal.

In the reported household, there were also two other children, aged two and four years, in whom latent infection with *Mycobacterium tuberculosis* was confirmed using QuantiFERON-TB Gold Plus (QFT-Plus; Qiagen, Hilden, Germany).
