A rare case of isoniazid mono-resistant tuberculosis presenting as cardiac tamponade along with an anterior mediastinal mass in a 15-year-old immunocompetent patient

ABSTRACT

A 15-year-old boy presented with a sudden onset of breathlessness for 7 days, gradual loss of weight of 17.6 lbs over the last month and progressive hoarseness of voice for 7 months. The contrast-enhanced computed tomography (CECT) scan revealed a heterogeneously enhancing lesion in the anterior mediastinum with multiple discrete lymph nodes in the cervical and mediastinal locations. The GeneXpert MTB/RIF assay performed on the CT-guided biopsy of the mass was negative, but the culture for Mycobacterium tuberculosis was positive at 7 weeks of incubation. There was a suboptimal radiological response after 6 months of treatment. First-line drug susceptibility testing (DST) performed by line probe assay (LPA) on the positive culture detected high-level resistance to isoniazid. The treatment was modified as per DST results to which the patient responded well.

INTRODUCTION

Anterior mediastinal masses often pose a diagnostic challenge for clinicians.[1] Common aetiologies include thymoma, lymphoma, benign teratomas and germ cell tumours. Age and gender, combined with specific radiographic or clinical features that are often present, allow the identification of these lesions with a high degree of confidence in most cases. In a small proportion of patients, however, histology and culture are necessary to arrive at a definitive diagnosis and initiate appropriate treatment.[2]

We report a rare case in the world literature of isoniazid mono-resistant tuberculosis (TB) presenting with massive cardiac tamponade and hoarseness of voice along with an anterior mediastinal mass in a young immunocompetent man

CASE

A 15-year-old boy presented to the cardiology outpatient department of our institution with a sudden onset of breathlessness for 7 days. His medical history was significant for a gradual loss of weight of 17.6 lbs over the last month and progressive hoarseness of voice for 7 months. He had been diagnosed with hyperthyroidism in 2018 for which he had been taking non-allopathic treatment for the last 2 years. There was an absence of any history of syncope, palpitation or orthopnoea. The patient was non-diabetic, non-hypertensive and did not have any significant family medical illness. A thorough history taking revealed that the patient had been seeking treatment at an outside facility since November 2021, and a chest computed tomography (CT) scan had revealed an anterior mediastinal mass. However, one week before the current hospitalisation, he was evaluated for abdominal pain at an outside facility, and a whole abdomen ultrasonographic (USG) examination, as well as contrast-enhanced CT scan (CECT), was performed. The USG revealed mild hepatomegaly with ascites and abdominal lymphadenopathy. The contrast-enhanced CT scan (CECT) again revealed a heterogeneously enhancing lesion in the anterior mediastinum in the left pre-vascular space with multiple discrete lymph nodes in the lower cervical and mediastinal locations [Figures 1a-d and 2]. In addition, there were gross pericardial effusion and bilateral pleural effusion. The radiologist advised a histopathologic correlation, and the boy was referred to our centre for further evaluation, where he was admitted as a case of an anterior mediastinal mass under evaluation.

Figure 1.

Contrast-enhanced CT chest. (a) Axial image showing left cervical lymphadenopathy (arrows) at the level of the thoracic inlet. (b) Section at the level of the aortic arch showing a large heterogeneous anterior mediastinal mass with necrotic areas (arrow). (c) Lower section showing gross pericardial effusion (arrow) and right pleural effusion. (d) Coronal reconstruction showing mediastinal mass with pericardial effusion (arrow)

Figure 2.

HRCT scan of the chest showing patchy consolidation areas in the left upper lobe with multiple centrilobular nodules (arrow) in both lungs presenting as a ‘tree in bud configuration’

On admission, the vital signs of the patient were as follows: temperature, 40.6°C; weight, 77.1 lbs; blood pressure (BP), 100/60 mm Hg; heart rate, 76 beats/min; and peripheral capillary oxygen saturation by pulse oximetry, 95% on ambient air; jugular venous pressure (JVP) was raised, and heart sounds were muffled. Physical examination revealed decreased breath sounds at the anterior left lower lung fields. There was an absence of any palpable lymph nodes, and he had normal abdominal, neurological and skin examinations. Urgent echocardiography (ECHO) performed upon admission revealed gross pericardial effusion with impending tamponade but normal left ventricular function. The electrocardiogram (ECG) of the patient was in normal sinus rhythm, normal axis at 45° with a heart rate of 80 bpm and a normal PR interval of 0.15s. A prolonged QT interval and T-wave abnormalities were observed in V2 and V4 leads, respectively. There was an absence of a pathological Q wave. A chest X-ray revealed a large mediastinal mass with a widening on the left side [Figure 3]. A pericardiocentesis was performed on priority, which led to an improvement in the patient’s dyspnoea. The pericardial fluid was sent for biochemical analysis and adenosine deaminase (ADA) level determination. The cytospin smears from pericardial fluid were cellular and showed mature small lymphocytes with few macrophages, polymorphs and eosinophils on a haemorrhagic background. The pericardial fluid cytology was negative for malignant cells or atypical lymphoid cells. Mycobacterium tuberculosis complex was not detected by GeneXpert MTB/RIF assay performed on pericardial fluid. The value of ADA in the fluid was 84.5 IU/L.

Figure 3.

Chest X-ray showing large mediastinal mass with mediastinal widening and prominent broncho-vascular markings

A complete blood count (CBC) revealed normocytic hypochromic anaemia (8.9 gm/dl), but the differential counts were within the normal range. The erythrocyte sedimentation rate (ESR) was 32/h (normal, male <15 mm/h and female <20 mm/h). Microbiological diagnostic testing for bacterial and fungal pathogens did not yield any positive results. A CT-guided biopsy was performed for further evaluation of the mass, and samples were sent for histopathological examination as well as microscopy, culture and GeneXpert MTB/RIF assay for TB. Histopathological examination of the CT-guided biopsy of the mass revealed cores of fibro-collagenous tissue with suppurative necrosis and granuloma formation without any evidence of malignancy. Aggregates of lymphocytes, epithelioid histiocytes and Langhans giant cells were seen. The culture for Mycobacterium tuberculosis from the CT-guided biopsy sample was positive at 7 weeks of incubation. Both first- and second-line drug susceptibility testing (DST) [Figure 4a and b], performed by line probe assays (LPAs) (GenoType® MTBDRplus VER 2.0 and Genotype® MTBDRsl VER 2.0, Hain Life Science GmbH, Nehren, Germany), on the positive culture detected high-level resistance to isoniazid, but the isolate was sensitive to fluoroquinolones (FQs) and second-line injectable drugs (SLIDs).

Figure 4.

(a) First-line line probe assay (FL-LPA) showing the presence of Mycobacterium tuberculosis complex with high-level mono-isoniazid resistance (absence of wild-type band, katG WT for isoniazid and presence of mutation band, Kat G MUT1; black arrows). (b) Second-line line probe assay (SL-LPA) showing the presence of Mycobacterium tuberculosis complex without detectable drug resistance to second-line anti-tubercular drugs (presence of all wild-type bands and absence of mutation bands)

DISCUSSION

Anterior mediastinal masses represent a challenging and urgent diagnostic problem because the differential diagnoses range from benign to highly malignant conditions.[2] Patients with these lesions are typically asymptomatic until they develop mass effects, such as chest pain, dyspnoea or cough, due to compression of local structures. Our case presented with impending cardiac tamponade, where the pericardium was seeded from the infection in mediastinal lymph nodes.[3] In a review article by G Cherian, for the diagnosis of tuberculous aetiology in pericardial effusions (TPE), most often the spread is from the breakdown of infection in mediastinal nodes directly into the pericardium and the lymphatic drainage of the pericardium is mainly to the anterior mediastinal, tracheobronchial, lateral pericardial and posterior mediastinal lymph nodes. This has an important bearing on the groups of mediastinal lymph nodes that are enlarged in TPE.

Age and gender are the two most important initial features to consider in the evaluation of patients with an anterior mediastinal mass, as specific lesions tend to be more common in certain demographic groups.[4] Thymoma is the most common primary tumour in the Western population older than 30 years, while in individuals between 10 and 20 years, lymphomas or germ cell tumours are more likely. The causes of an anterior mediastinal mass in males can be broadly classified into two groups by decades of age, as shown in Figure 5. An assessment of the rapidity of the onset of symptoms is very helpful in narrowing the differential diagnosis.

Figure 5.

The proportion of tumour types by decades of age in males: HD/MLC-NHL, Hodgkin’s disease/mediastinal large cell non-Hodgkin’s lymphoma; LB-NHL, lymphoblastic non-Hodgkin’s lymphoma; NSGCT, non-seminomatous germ cell tumour

Our case presented with low-grade fever and sudden onset of breathlessness without any characteristic clinical symptoms or localisation on physical examination. The hoarseness of voice could have been due to the compression of the recurrent laryngeal nerve by the anterior mediastinal mass. There was an absence of any family history of TB. Radiology revealed an anterior mediastinal mass with massive pericardial effusion, and the final diagnosis could only be confirmed after histopathologic examination and positive culture.

The suspicion of a non-seminomatous germ cell tumour (NSGCT) or lymphoblastic non-Hodgkin’s lymphoma (LB-NHL) in our case was very strong, considering the age and gender of the patient and the insidious onset of symptoms. A LB-NHL exhibits characteristic cytology, and simple aspiration of fluid or bone marrow is highly successful in clinching the diagnosis. Ninety per cent of patients with NSGCT have markedly elevated serum alpha-fetoprotein (AFP) or β-HCG levels and are pathognomonic. In those clinical conditions where histology is necessary for diagnosis and/or treatment, a CT-guided transthoracic needle biopsy is the recommended imaging modality for the evaluation of most anterior mediastinal masses. Other techniques that may be employed in the biopsy of an anterior mediastinal mass include video-assisted thoracoscopic surgery (VATS), mediastinotomy and open surgical biopsy.[2]

The lack of overt infectious symptoms in our patient, combined with imaging abnormalities on CECT and non-conclusive cardiology investigations, prompted us to perform a CT-guided biopsy of the mass. TB can mimic malignancy both radiologically and clinically.[5]

Although the differential diagnosis of lymphoma was high on the list, the absence of atypical cells and the presence of suppurative necrosis went in favour of TB and we therefore did not proceed with immunohistochemistry (IHC). In addition, the culture grew Mycobacterium tuberculosis complex at 7 weeks of incubation.

The cartridge-based nucleic acid amplification assay (CB-NAAT) performed on the CT-guided biopsy of the mass was negative. The GeneXpert MTB/RIF assay can aid in the rapid diagnosis of TB but has poor sensitivity in extra-pulmonary samples. In a study conducted by Zeka et al.,[6] the sensitivity of this test was only 47.7% for smear-negative extra-pulmonary specimens while that for culture was 64.6%.

The LPAs recommended by the World Health Organization (WHO) use polymerase chain reaction (PCR) and reverse hybridisation methods for the detection of mutations associated with drug resistance.[7] The first-line LPA (FL-LPA) detects mutations in the rpoB gene for rifampicin resistance, in the KatG gene and in the InhA promoter region for isoniazid (INH) and ethionamide (Eto) resistance. The second-line LPA (SL–LPA) detects mutations in the gyrA and gyrB genes for FQ resistance and rrs and eis (low-level kanamycin resistance) for SLID resistance. However, the diagnosis of isoniazid resistance (Hr-TB) in India is the biggest challenge affecting its control because, under the universal DST (UDST) mandate, the CB-NAAT used in India’s national programme does not identify isoniazid resistance.[8] Globally, India has the largest burden of TB in the world. As per the WHO Global TB Report, 2022, India is one of the three countries that accounts for two-thirds of the global MDR/RR-TB cases in 2021.[9,10] In addition, the first national anti-TB drug resistance survey in India (2014–16) documented the incidence of Hr-TB in 11% of new TB cases and 25% in previously treated cases.[11] Treatment of Hr-TB is associated with worse outcomes than the treatment of fully sensitive TB.[12]

We got a CT-guided biopsy performed in our patient to achieve a rapid diagnosis considering the differential diagnosis of lymphoma in this age group. As soon as the histopathology report was available, our patient was initiated on conventional first-line anti-tubercular treatment with a fixed-dose combination of rifampicin and isoniazid (450 mg/300 mg), ethambutol (600 mg) and pyrazinamide (1000 mg). As the follow-up CT scans [Figure 6a-d] showed partial response even after 6 months of conventional treatment and FL-LPA testing revealed Hr-TB, the treatment of the patient was revised for 9 months to rifampicin (450 mg), ethambutol (800 mg), levofloxacin (750 mg) and pyrazinamide (1250 mg), after excluding resistance to FQs by the SL-LPA. The WHO consolidated guidelines on the treatment of drug-resistant TB recommend the addition of levofloxacin instead of streptomycin or other injectables in cases of rifampicin-susceptible, isoniazid-resistant TB.[13] The patient responded very well to the treatment and gained 8 kg weight after one month of the modified anti-tubercular treatment (ATT).

Figure 6.

Follow-up contrast-enhanced chest CT scan (axial sections) after 6 months. (a) Significant reduction in mediastinal mass size with a small residual para-aortic soft tissue mass (arrow). Adjacent segmental collapse also noted. (b, c) Complete resolution of pericardial effusion as compared to baseline CT. (d) The parenchymal window image at the level of the left upper lobe shows residual parenchymal nodules

To the best of our knowledge, we are reporting a rare case in the world literature of isoniazid mono-resistant TB along with an anterior mediastinal mass in a young immunocompetent man. We have also not come across any case on review of literature that has presented with cardiac tamponade along with hoarseness of voice.

In conclusion, our patient was a case of TB with pulmonary, mediastinal and pericardial involvement as well. A thorough history taking from the patient revealed that he had been seeking alternative treatment at a private facility since November 2021. He had been diagnosed with an anterior mediastinal mass for nearly 6 months before being referred to our facility. Probably, the lack of overt infectious symptoms caused a delay in getting definitive treatment. Even when he was referred to our centre, he was having abdominal pain and a USG with CECT revealed the mediastinal mass along with abdominal lymphadenopathy. All this reflects the lack of awareness of disease in Indian settings. In addition, the patient was a 15-year-old schoolboy, who was also worried about the interruption of his studies. He was also dependent on his parents for seeking treatment and was accompanied only by his mother after travelling for about 30 km. All this highlights the patient and societal factors associated with TB in India.

In an anterior mediastinal mass, with an unusual presentation, a thorough and logical scheme of investigations, including tissue diagnosis, should be performed to fully characterise the lesion and define optimal treatment. A high index of clinical suspicion for TB in an endemic country like India is important. The GeneXpert MTB/RIF assay has poor sensitivity for extra-pulmonary samples, and culture should always be performed for a definitive diagnosis. The value of culture is especially emphasised in smear-negative extra-pulmonary cases for the diagnosis of drug resistance, which in our case was performed by a rapid molecular assay. The UDST mandate in a high TB burden country like India should include the development of rapid molecular assays that test not only for rifampicin resistance but detect mutations coding for resistance to isoniazid as well. The main limitation of our case is the absence of a therapeutic drug monitoring (TDM) facility at our institute.

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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patient understands that their names and initials will not be published and that due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.