Congenital TB is defined as infection that develops as a result of an encounter between a TB-infected mother and her infant during the intrauterine period or during birth. Maternal TB can be transmitted to the fetus either transplacental or through the aspiration of infected amniotic fluid . To our best knowledge, our study is the first that includes the complete clinical information of 10 congenital TB infants in China, including treatment and follow-up information. Our study provides valuable insights into congenital TB infection.
Since female genital tuberculosis and tuberculous endometritis are associated with infertility, congenital TB is rare. Our data showed that 20% of the mothers were diagnosed with TB before pregnancy and received IVF. This suggests that the increasing availability of assisted reproductive technologies has a potential to increase the prevalence of congenital TB .
The mothers who transmit TB infection to their fetus during pregnancy are difficult to diagnose. A delay between the onset of symptoms and diagnosis occurs frequently, due to the non-specific symptoms at presentation, reluctance to perform radiography, and low index of suspicion . It was not surprising that the diagnosis of some maternal TB cases was made only after the infants’ exhibited symptoms of TB and were subsequently diagnosed. One study reviewed 170 cases of congenital TB and reported that 121 (71%) mothers were diagnosed at postpartum, of which 39 cases were completely asymptomatic . In our study, 70% of the mothers were diagnosed after delivery, among which two mothers were individually diagnosed by chest X-ray and T-Spot test after their babies were suspected for congenital TB. Thus, according to our study, if there is a strong suspicion of TB in the infant and the mother is not currently diagnosed with TB, then they should both be tested.
According to WHO guidelines for BCG vaccination, a single dose of the BCG vaccine should be given to all healthy infants as close to the time of birth as possible . However in our study, five out of ten patients had not received BCG when they were admitted to the hospital. One explanation is that the BCG vaccination is not given to preterm newborns, according to Chinese national protocol. Patients 1, 4, and 8 were preterm newborns that did not receive the BCG vaccine immediately after birth. Patient 10 presented with symptoms of TB on DOL 1, and as such, the BCG vaccination was delayed due to the uncertain TB status. The mother of patient 3 was diagnosed with TB during pregnancy, and as a result, the BCG vaccination was held for the newborn.
The symptoms of postnatal TB infection are usually exhibited 4 to 8 weeks after infection . Therefore, the symptoms of congenial TB could theoretically be present within two months after birth. However, Cantwell et al. analyzed 29 patients with congenital TB and reported that the onset age of TB ranged from 1 to 84 days; whereas Sonal et al. reviewed 21 congenital TB cases and reported the onset age as 1 to 90 days [3, 8]. Congenital TB symptoms commonly present in the first 2 to 3 weeks of life . In our study, the onset age varied from 1 to 50 days. Clinical manifestations of congenital TB can be diverse, nonspecific, and difficult to differentiate from neonatal bacterial or viral sepsis. In our study, fever was the most frequent symptom. Nonspecific markers found in patients with congenital TB included neutrophilia, thrombocytopenia, and elevated CRP levels . In our study, all of the patients presented with neutrophilia and elevated levels of CRP. Moreover, 70% of the patients with congenital TB had complications with thrombocytopenia.
The imaging results of our study showed that (1) the most frequent patterns of chest CT scans were multiple pulmonary nodules and mediastinal adenopathy, and (2) abdominal US showed hypoechoic nodules in the liver and spleen in 40% of the patients. Liver and spleen nodules were similarly found in adult TB patients, but the lung TB nodule features are quite different from other lung diseases and could lead to the suspicion of congenital TB when analyzed by an experienced radiologist or TB specialist. Recently, multiple pulmonary nodules have been described as a new radiographical finding in some published studies . Multiple pulmonary nodules on chest CT scans were considered as the progressive deterioration of miliary tuberculosis, consistent with caseating necrosis in a biopsy specimen . Several pediatric TB specialists and radiologists in China reported that both patterns of military TB and pulmonary nodules were specific image characteristics of congenital TB [11, 12]. TB-specific investigations should be performed when there are suspicions of TB based on imaging results.
The confirmation of TB infection is often challenging in newborns because markers specific to TB have poor sensitivity. For neonates, serial gastric fluid appears to be the most common specimen for TB pathogen identification. Lower sensitivity and a longer time before confirmation of culture-positive results frequently occurs in children because of decreased bacterial loads. In our study, the positive rate of AFB smear was 50% with the results available within 24 hours. Furthermore, only 20% of the cases showed a positive culture result by 13.5 to 16 days. Because of the limitation of the laboratory environment, our hospital was unable to perform drug susceptibility testing for TB. The GeneXpert assay is a hemi-nested real-time PCR test that simultaneously identifies Mtb/RIF resistance. Its diagnostic accuracy is comparable to culture in sputum samples and provides results within 24 to 48 hours . The WHO recommends GeneXpert for rapid diagnosis in communities with a high burden of TB . Our study results showed that GeneXpert is the most sensitive test, with an 80% positive rate. Furthermore, the result could be obtained within 24 hours. The tuberculin skin test is mostly negative in newborns since the test takes at least four weeks to be positive. In our study, two cases showed a positive tuberculin skin test result at two to three months of age. Currently, there are two types of commercially available IFN-γ release assays-the QuantiFeron TB Gold (Cellestis) and T-Spot TB (Oxford Immunotec) . The latter is an enzyme-linked immunospot (ELISPOT) assay used in our hospital. Though there are concerns about the applicability of these assays to newborns due to the decreased IFN-γ production in newborns, in our study the T-Spot assay demonstrated a relatively high sensitivity and was one of the best results for initial evidence of TB in our cases.
Compared to the previous congenital TB case report , our patients demonstrated a much better outcome with a 100% survival rate. Based on literature analysis, we theorize that the better outcomes in our study were a result of the new clinical diagnosis criteria for congenial TB and the introduction of LZD in the treatment regimen during the intensive phase of anti-TB treatment.
It is understandable that maternal history and typical imaging findings might be the only basis for diagnosis of congenital TB. The clinical diagnosis criteria of congenital TB in our center was: (1) if an infant has fever, respiratory distress, hepatosplenomegaly, or other nonspecific symptoms within two months after birth, (2) if the infant’s mother was diagnosed with active TB infection perinatally, and (3) if the infant’s imaging showed miliary tuberculosis or multiple pulmonary nodules in chest CT scans or multiple focal lesions in the liver/spleen by abdominal US. Infants that meet the criteria were put into isolation, further TB investigation was started, and anti-TB treatments were initiated. This might partially explain the fairly good prognosis of the ten congenital TB patients in our study.
The standard regimen for congenital TB includes INH, RIF, PZA, and ethambutol during the intensive phase for two months, followed by INH and RIF for seven to ten months during the continuation phase. Chest X-rays at the end of treatment is recommended [8, 15].
Linezolid (LZD) is a member of the oxazolidinone class of antibiotics, which exhibits bacteriostatic activity against Mtb, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains . Clinical trials in adults have revealed that LZD is an important component for the treatment of MDR and XDR TB [17, 18]. As a newer anti-Gram positive antibiotic, LZD has excellent penetration to the central nervous system. Furthermore, published studies support its effectiveness and safety in treating infections caused by resistant pathogens, including staphylococcal bacteremias and cerebrospinal fluid infections, for term and preterm newborns in neonatal intensive care units [19, 20]. Li et al. reported clinical data, which demonstrated that LZD improved the early outcomes of childhood TB meningitis for 36 cases . Since China has a serious epidemic of drug-resistant TB  and the immune system of neonates is not fully developed, our center has used LZD as a supplementary drug for congenital TB patients since 2015. In our study, LZD was administrated to seven patients, ranging in age from 4 to 70 days, for a duration of 2 to 6 months. This is most likely the first report of the long-term use of LZD for neonatal and infant congenital TB. The adverse events and side effects of LZD in our patients were monitored and evaluated by clinical symptoms, periodical whole blood counts, and serum liver/renal function analysis every one or two weeks. One patient presented with thrombocytopenia while receiving LZD, but recovered spontaneously without LZD withdrawal. Another two patients presented with hepatotoxicity during the intensive phase of treatment with INH, RIF, PZA, and LZD. However, it is difficult to differentiate the side effects induced by each drug. The low frequency of LZD-associated adverse side effects highlights the promising prospects of its use for the treatment of congenital TB. A LZD regimen during the intensive phase of anti-TB treatment might contribute to the improvement of outcomes of congenital TB.
It was reported that the overall mortality for infants with congenital TB is 100% if undiagnosed, and delayed infant diagnosis carries a 5-fold higher mortality rate in comparison with prompt diagnosis and treatment . In our study, responses to anti-TB drugs were good in all patients who finished the treatment, with chest X-rays revealing no infection at the end of treatment. However, only 33% of the patients in our study are currently thriving and have achieved normal developmental milestones.
This study has several limitations. First, this retrospective study was conducted in a single medical center, which makes applying the study results to the general population difficult. Second, the sample size was too small to demonstrate the effectiveness of new clinical diagnosis criteria and Linezolid in reducing the mortality of congenital TB. This issue may require further cooperation from multiple centers in the future for a comprehensive study. Furthermore, the clinical decisions of LZD administration was made according to the experience from neonatologists and TB specialists, which may result in practice variability. A clinical guide for the standard treatment of congenital TB is urgently needed.
In summary, congenital TB is a potentially fatal disease, but with a high index of suspicion and aggressive management, it can have a good outcome. Early diagnosis based on maternal history, typical imaging findings, and timely treatments are crucial. Multi-drug anti-TB treatment, including LZD, is safe and might be effective for infants and reduces mortality.