Severe Bleomycin‐Induced Pneumonitis Following Localized Injection in a Child With a TERT Variant and Short Telomeres

A previosuly healthy 4-year-old male was diagnosed with a progressive lymphatic-venous malformation which presented as a slowly enlarging right-sided buccal mass. He underwent sclerotherapy with localized injection of 15 mg bleomycin. Three days post-procedure, he developed mild symptoms including vomiting, facial swelling, and sore throat, which resolved with supportive care within 1–2 days Eighteen days post-procedure, he developed a dry cough and wheeze, associated with grunting, and sustained desaturations into the 70 s which prompted urgent evaluation. Chest radiograph revealed bilateral infiltrates, and the viral panel was positive for rhinovirus He tested negative for Chlamydia, coronaviruses, human metapneumovirus, influenza viruses, parainfluenza viruses, respiratory syncytial virus, and Mycoplasma pneumoniae. He was admitted for oxygen support and empirically started on azithromycin and amoxicillin/clavulanic acid. Despite initial treatments, his respiratory distress progressed and required transfer to the intensive care unit on day 3 of admission. Computed tomography (CT) of the chest showed diffuse ground-glass opacities with septal thickening, raising concern for interstitial lung disease, drug-induced pneumonitis, or organizing pneumonia (Figure 1a). Bleomycin-induced pneumonitis (BIP) via inadvertent systemic exposure was most likely given the onset following bleomycin exposure and the interstitial pattern on imaging. While rhinovirus was detected, the absence of fever, elevated inflammatory markers, and the distinctive interstitial pattern on imaging made viral pneumonia a less likely primary cause, though viral co-infection as a contributory factor to BIP cannot be excluded. The time of onset supports this conclusion, as BIP typically presents 1 week to 6 months following exposure [1]. Due to worsening respiratory status, he was treated with 5 days of pulsed steroids followed by a prolonged taper, along with montelukast and azithromycin (three times weekly) for their anti-inflammatory effects. The patient showed marked clinical improvement with complete resolution of respiratory distress and hypoxemia following the initiation of steroid therapy. He was subsequently discharged with outpatient follow-up planned with the pulmonary and genetics teams. Bleomycin is commonly used in pediatric patients as part of combination chemotherapy regimens for conditions such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, germ cell tumors, and certain sarcomas. It is also used as a sclerotherapy agent for treating vascular anomalies, particularly lymphatic and low-flow venous malformations, via intralesional injection. Despite its widespread use across these indications, most pediatric patients do not develop BIP, a rare but serious complication that can progress to pulmonary fibrosis. We present a previously healthy 4-year-old who developed severe BIP following localized bleomycin injection into a facial venous malformation prompting investigation into potential predisposing factors. IRB review was waived per institutional policy (MassGeneral Brigham). This report does not require approval by the ethics committee or written consent from the family. The severity of the patient's presentation, and absence of known risk factors, warranted further workup. Clinical next-generation sequencing of exons and adjacent intronic regions in genes associated with interstitial lung disease (ILD) such as surfactant disorders and telomere biology disorders, was performed using the Invitae Surfactant Metabolism Panel. Genetic analysis revealed a heterozygous variant of uncertain significance in TERT (c.2368 G > A, p.Val790Ile) (Figure 1b). This missense variant, which substitutes the amino acid valine with an isoleucine, is located within the reverse transcriptase domain, a region critical to telomerase function and known to be a hotspot for pathogenic variants (Figure 1c). The p.Val790Ile variant has an overall minor allele frequency of 0.0032% in gnomAD v4 but a specific ancestral frequency of up to 0.014% [2]. The affected valine residue shows moderate evolutionary conservation, being preserved in most mammalian species, though isoleucine is also occasionally observed (Figure 1c). After identification of this variant, telomere length was measured using the RepeatDx flow-FISH assay, a clinically validated method with high reproducibility (inter-assay CV as low as 3.3%) and strong correlation with the gold standard terminal restriction fragment analysis (R² ≥ 0.99), which is supported by age-matched normative data from over 800 healthy individuals [3]. Results showed markedly shortened telomeres, below the 1st percentile for age in all cell types, with lymphocyte telomeres measuring 6.6 kb (Figure 1d). Population frequency data from the gnomAD database indicate that no individuals have been reported as homozygous for the TERT: c.2368 G > A (p.Val790Ile) variant, which may suggest that homozygosity for this variant is uncommon in the general adult population and suggest potential clinical relevance, as truly benign variants are typically observed in the homozygous state in large population cohorts. Moreover, telomerase gene variants and borderline-short telomere lengths (1st–10th percentile) are collectively found in a notable proportion of the general population and may increase susceptibility to drug-induced toxicity under certain conditions, including bleomycin exposure [4-6]. This variant is more prevalent than those linked to classical monogenic telomere disorders; however, the telomere lengths in this patient are markedly shorter than expected, suggesting reduced telomerase complex function and impaired maintenance of telomere length. The panel included many of the most common genes for telomere biology disorders such as dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome, and patient did not have other syndromic features. We cannot rule out the possibility of other polygenic TERT variants or variants not detected by focused panel testing, as broader approaches such as whole exome sequencing (WES) or whole genome sequencing (WGS) were not pursued due to cost and insurance coverage limitations. Familial testing for sequence variant and telomere length were recommended to assess clinical significance, but the family deferred. Family history is notable for premature greying in one parent, however there is no family history of pulmonary fibrosis, aplastic anemia, or other features associated with telomere biology disorders. BIP is a recognized complication of bleomycin [7]. Free radical generation underlies the pathological mechanism of BIP, causing DNA strand breaks and cell death [8]. This toxicity is rarely seen in children, raising suspicion for an underlying predisposition in this patient. Telomere length is seen as central to ILD in adults, where short telomere length is a marker of poor prognosis [9]. Telomerases, particularly the catalytic subunit encoded by the TERT gene, are critical for maintaining this telomere length and ensuring adequate cellular repair [10]. Experimental models show that increased telomerase activity mitigates bleomycin-induced damage [10], whereas TERT-deficient models do not exhibit an increased degree of fibrosis [11]. Additionally, pediatric patients are known to have increased sensitivity to bleomycin toxicity compared to adults. Significant differences exist in toxicity thresholds, with adult risk increasing after cumulative systemic doses > 400 mg, whereas pediatric pulmonary abnormalities have been reported at doses as low as 60–120 units/m² [12]. In this case, the patient's weight was 13 kg and received 15 mg of intralesional bleomycin which is a relatively low dose, yet bleomycin likely contributed to toxicity in the presence of additional risk modifiers. Although the patient's telomere length was abnormal, it did not reach levels diagnostic for telomere biology disorders. When exposed to bleomycin, DNA repair capacity may have been impaired by this missense TERT. We hypothesize that this “second hit” unmasked a subclinical susceptibility, resulting in the development of BIP. Thus, the TERT variant and short telomeres may have acted as risk modifiers rather than primary disease driver. Treatment options for BIP remain limited, with high-dose corticosteroids considered the primary therapy and only sparse evidence supporting alternative approaches [13]. This patient underwent a 5-day course of pulsed steroids with a subsequent extended taper over 7 months and was also started on montelukast and thrice-weekly azithromycin. Currently, the patient is doing well, with resolution of cough, appropriate weight gain and good activity levels. Follow-up CT imaging obtained 5 months after the initial study demonstrated decreased multifocal diffuse ground-glass opacities throughout both lungs, with residual areas of patchy ground-glass opacities consistent with resolving BIP (Figure 1e). In summary, we report a pediatric patient who developed severe BIP following localized bleomycin therapy and was found to have shortened telomeres and a TERT variant of uncertain significance which may have contributed to impaired DNA repair capacity. While causality cannot be established, the temporal relationship and presence of potential genetic susceptibility raise the possibility that impaired telomerase capacity may have contributed to the patient's presentation. These findings underscore the need for further research into genetic risk factors for bleomycin toxicity in pediatric patients and the establishment of an international registry dedicated to bleomycin-induced pneumonitis. Yanki Okuducu: conceptualization, investigation, writing – original draft, methodology, visualization, writing – review and editing, resources. Anna Verwillow: conceptualization, investigation, writing original draft, methodology, visualization, writing – review and editing and resources. Mary Shannon Fracchia: conceptualization, writing – review and editing. Adila Abulhamail: writing – review and editing. Lael Yonker: conceptualization, writing – review and editing. Benjamin A. Nelson: writing – review and editing. T. Bernard Kinane: conceptualization, investigation, writing original draft, methodology, visualization, writing – review and editing and resources. The authors received no specific funding for this work. IRB review was waived per institutional policy (MassGeneral Brigham IRB). This report does not require approval by the ethics committee or written consent from the family. Both parents provided verbal consent for the study. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.