G Bilgin, ZR Onay, DM Tortop, S Giritk

Abstract

This case report presents an important case of tuberculosis and chylothorax complicated with immunodeficiency, highlighting its rarity and significance, particularly as the second case reported in the literature with a young age of 6 months. And secondary immunodeficiency was detected in this HIV negative patient. Underlying immune deficiency should be investigated in children with chylothorax and tuberculosis associations.

Introduction

Tuberculosis (TB) is an infectious disease that ranks among the top ten causes of mortality worldwide. Tuberculosis stands as the foremost cause of death resulting from a single infectious agent, with approximately one-fourth of the global population infected with Mycobacterium tuberculosis.¹ Chylothorax, a condition characterised by the accumulation of chyle in the pleural cavity due to thoracic duct injury or obstruction.² However, the association between TB and chylothorax is exceedingly rare but has been documented.³ The most relevant pathogenesis underlying TB chylothorax involves the blockage caused by tuberculous lymph nodes or the rupture of the thoracic duct, leading to heightened pressure in the adjacent lymphatic system and subsequent leakage of chyle into the pleural space.^3,4 Hence, our aim is to underscore the infrequent nature of the association between tuberculous chylothorax and highlight the importance of considering potential underlying immunodeficiency that may be contributing to its occurrence.

Case History

A 6-month-old male patient was admitted to the intensive care unit with prolonged history of fever, cough, and acute respiratory failure. He had a family history of consanguineous marriage and TB contacts. On physical examination, he had bilateral crackles on auscultation with a partial oxygen saturation of 91% in room air, hepatosplenomegaly, and developmental delay. The patient had anaemia, lymphopenia (1200 cell/µL), slight neutropenia (1400 cell/µL) and also elevated liver enzymes with ALT: 100 U/L and AST: 47 U/L. The patient, showing a miliary pattern on both chest X-ray and chest computed tomography (CT), tested positive for Tuberculin Skin Test. Acid-Resistant-Bacille (ARB) results were negative for 3 consecutive days. High-flow nasal cannula oxygen support and anti-TB treatment (rifampicin, isoniazid, ethambutol, pyrazinamide) were initiated. The examinations were revealed involvement in the cranial, ocular, and abdominal regions, along with pericardial effusion, confirming the diagnosis of disseminated TB. However, by day five of the therapy, anti-TB treatment was discontinued due to ten-fold increase in liver enzyme levels. After a week, with liver enzyme levels decreasing and confirmation that the index case was not drug-resistant, the anti-TB regimen was reintroduced with the addition of streptomycin and levofloxacin, along with steroid therapy due to meningitis, pericarditis, and persistent respiratory distress. The patient experienced significant improvement from those treatments, leading to the resolution of respiratory distress. By day 21, he developed a recurrence of respiratory distress requiring oxygen supplementation, prompting the need for repeat radiological imaging. Thoracic ultrasonography revealed a left-sided anechoic pleural effusion, subsequently confirmed with thoracentesis as chylothorax [glucose 6.38 mmol/L (concomitant serum glucose level was 5.99 mmol/L), protein level of 112.4 gr/L, cholesterol level of 1.34 mmol/L, triglyceride (TG) level of 10.72 mmol/L, leucocyte count of 3504/mm³ (96% lymphocytes)]. Concomitant serum total protein level was 55 g/L, and serum albumin level was 37 g/L. Conservative management, including chest tube placement, medium-chain triglyceride (MCT) diets, and total parenteral nutrition (TPN), were implemented. In regards of the aetiology of chylothorax chest CT was performed and there were multiple lymph nodes on the subcarinal, paratracheal, and left hilus locations with a maximum size of 24x13 mm, which were thought to be cause of obstruction of the thoracic duct (Figure 1). With conservative treatment, the chylothorax was resolved in 20 days, and did not recur. Steroid dosage was gradually reduced with the regression of pericardial effusion and respiratory insufficiency. Oral nutrition with MCT support was continued until the patient's condition stabilised. Gastric lavage, cerebrospinal fluid, and pleural fluid examinations yielded negative results for TB Polymerase Chain Reaction (PCR), ARB, and culture. Immunology consultations were sought to evaluate the possibility of immunodeficiency. Due to the course with lymphopenia (380-2300 cell/µL) and prolonged chylous drainage with associated malnutrition, immunology consultations were conducted to evaluate the possibility of immunodeficiency. Tests such as immunoglobulin profiling (IgG: 4.63 g/L, normal 3.0-9.0; IgA: 0.55 g/L, normal 0.15-0.70; IgM: 0.64 g/L, normal 0.40-1.60), lymphocyte subgroup panel (CD3+T: 66.2%, normal 46-76%; CD3+CD4+T: 25.48%, normal 31-54%; CD3+CD8+T: 36.64%, normal 10-31%; CD19+B: 4.92%, normal 14-44%; CD-CD16+56+(NK cells): 22.13%, normal 5-23%; CD4/CD8 ratio: 0.69, normal 1.34-3.04), dihydrorhodamine (DHR) test, and HIV-RNA were performed. Besides HIV-RNA and DHR tests being negative, combined immunodeficiency was suspected based on the results, leading to recommendations for HLA tissue typing, fluconazole, and co-trimoxazole prophylaxis. After 25 days of follow-up with high-flow nasal cannula oxygen support, the patient remained free of respiratory problems. Steroid treatment was completed over 60 days using a tapering scheme. Following two months of treatment with the condense anti-TB regimen, the patient was discharged, with plans to continue isoniazid and ethambutol for a total of 10 months, and the other antibiotic prophylaxis for bacterial and fungal microorganisms. During follow-up, secondary immunodeficiency was confirmed upon improvement of lymphopenia and lymphocyte subpopulations, and antibiotic prophylaxis was discontinued at the end of the first year of follow-up. Informed consent was obtained from the patient's parents for the publication of this case report.

Figure 1 On the 21st day of treatment, the left pleural effusion was detected on chest X-ray, and multiple lymph nodes on the subcarinal, paratracheal, and left hilus locations with a maximum size of 24x13 mm were detected on chest computed tomography.

Discussion

Chylothorax, due to tuberculosis, is a rare disease in children especially in infancy. It may occur as a result of thoracic duct obstruction, with the leakage of chyle into the pleural cavity, or as a chylous ascite transferring the pleural space through the diaphragm.^5,6 Depending on the severity of the thoracic duct lesion, it might occur unilaterally or bilaterally.⁷ The diagnosis of chylothorax is typically made based on pleural fluid analysis indicating elevated TG levels (>1.24 mmol/L), an absolute white cell count >1000 cells/mm³ with a lymphocyte fraction >80%, a pleural fluid cholesterol/serum cholesterol ratio <1.0, and presence of chylomicrons in paediatric patients.² In our case, elevated pleural fluid TG, lymphocytosis, and increased total protein levels were observed. Chylothorax may be caused by cardiac surgery, trauma, congenital malformation, infections etc.⁷ In the systematic review published in 2023, totally 10 cases of TB-chylothorax were identified in paediatric population.³ In the other review, 27.8% of the patients were developed chylothorax subsequent to the diagnosis of TB.⁴ The median time to development of chylothorax observed was 6.75 weeks (IQR 4-9w). Our patient, the chylothorax developed at the third week of anti-TB treatment with the age of six months (the second youngest case), provides significant contribution to the literature by demonstrating an extraordinarily early onset in comparison to previously documented cases.

The pathogenesis of TB-chylothorax is most commonly related to blockage or rupture of thoracic duct by mediastinal lymph nodes resulting with chylous leakage.³ In addition, abdominal lymphadenopathy obstructing the cisterna chyli, the opening of lymphatic-venous anastomosis, constrictive pericarditis, the thoracic duct damage due to immune reconstitution inflammatory syndrome (IRIS) are other mechanisms of chylothorax.⁴ In our patient, chylothorax developed possibly due to enlarged mediastinal lymph nodes, possibly as a result of IRIS, obstructing the thoracic duct. Subcarinal lymphadenopathy is the most prevalent site for TB lymphadenopathy in the chest, followed by the hila.8 Additionally, in our patient's CT scan, we observed multiple lymph nodes located in the subcarinal, paratracheal, and left hilar regions.

Chylothorax in the context of immunodeficiency is often associated with lymphatic dysfunction, which may arise from impaired lymphatic vessel development or secondary damage due to infections or inflammation. The loss of lymphocytes and immunoglobulins through the chyle can further compromise immune function, creating a vicious cycle that exacerbates both the immunodeficiency and the chylothorax.^5,7,8 In our patient, prolonged chylous drainage and lymphopenia, likely contributing to the immunodeficiency, may have delayed the healing process. HIV testing was included in the immunological evaluation due to its potential to exacerbate immunodeficiency through a reduced CD4/CD8 ratio and its known association with opportunistic infections such as tuberculosis, making it a critical differential diagnosis in this case.

In the treatment of TB-chylothorax, conservative management is applied with anti-TB regimen, and drainage of chyle causing respiratory compromise. In conservative management, low-fat or fat-free dietary modification and supplementation with MCT or TPN is also recommended to reduce chyle production.³ Since MCT is absorbed directly into the portal system, it allows the healing of the thoracic duct by decreasing the chyle circulation.⁹ Somatostatin analogues and surgical interventions are considered if conservative management fails to reduce chyle flow.^7,9 In our patient, chylothorax was successfully treated using conservative measures, including steroid regimen, antibiotic prophylaxis and anti-TB treatment, without the need for surgical interventions, despite the presence of immunodeficiency. Prolonged steroid therapy, as used in our patient, serves as an adjunctive treatment for TB meningitis and pericarditis by reducing inflammation and preventing fibrosis. Other indications for steroid therapy in similar cases include controlling severe systemic inflammation, alleviating immune-mediated complications, and modulating excessive cytokine responses. However, its prolonged use poses significant risks, including increased susceptibility to secondary infections, delayed wound healing, and potential suppression of the hypothalamic-pituitary-adrenal axis. In paediatric populations, additional concerns such as growth suppression and potential impacts on bone density must also be considered. To mitigate these risks, careful tapering of the steroid dose, as implemented in this case, helps to minimise adverse effects while maintaining therapeutic efficacy.

It is important to note that chylothorax not only leads to nutritional deficiencies but can also contribute to immunological deficiencies due to the loss of immune structures.⁹ In the presence of underlying immune deficiency, management of chylothorax may be more challenging. Therefore, it is crucial to recognise the presence of immunodeficiency and provide the necessary support to facilitate effective management. Considering the patient's clinical course, genetic evaluation for primary immunodeficiency may be warranted in similar cases to rule out underlying congenital immune disorders. Close follow-up remains essential for identifying any additional clinical findings that may indicate the need for further investigations.

In conclusion, the presence of chylothorax, though rare, warrants consideration during ongoing TB treatment. Particularly in infancy, clinicians should remain vigilant for pleural effusion development in TB patients, as it may signify the onset of chylothorax. Prompt recognition and careful management of chylothorax are crucial for improving patient prognosis. Through sharing our case involving various complexities during follow-up, we aim to enhance awareness regarding TB and its associated comorbidities.

Conflict of Interest Disclosures

The authors declare no conflict of interest.

Acknowledgement

We would like to express our gratitude to Sinem Can Oksay for their valuable contributions.

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