Cardiac Tuberculosis: A Case Series from Ethiopia, Italy, and Uganda and a Literature Review

ABSTRACT.

Extrapulmonary tuberculosis (TB) is estimated to account for up to 20% of active cases of TB disease, but its prevalence is difficult to ascertain because of the difficulty of diagnosis. Involvement of the heart is uncommon, with constrictive pericarditis being the most common cardiac manifestation. Diagnostic research for cardiac disease is frequently lacking, resulting in a high mortality rate. In addition to direct cardiac involvement, instances of cardiac events during antitubercular therapy are described. This case series describes five cases of TB affecting the heart (cardiac TB) from Italy and high-burden, low-income countries (Ethiopia and Uganda), including a case of Loeffler syndrome manifesting as myocarditis in a patient receiving antitubercular therapy. Our study emphasizes how cardiac TB, rare but important in high-burden areas, is a leading cause of pericardial effusion or pericarditis. Timely diagnosis and a comprehensive approach, including imaging and microbiological tools, are crucial. Implementing high-sensitivity methods and investigating alternative samples, such as detection of tuberculosis lipoarabinomannan or use of the GeneXpert assay with stool, is recommended in TB control programs.

INTRODUCTION

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis complex (MTBC), which manifests most commonly as a respiratory infectious disease and has a deep impact on the social and economic life of affected people worldwide. Nonetheless, it is estimated that up to 20% of active cases of tuberculosis disease have an extrapulmonary localization (extrapulmonary tuberculosis [EPTB]), with or without lung involvement, with a higher incidence in immunocompromised populations.¹

Risk factors for EPTB include socioeconomic status, host genetics, ethnic origin,² HIV status, and elder age, while vaccination with bacillus Calmette-Guérin (BCG) is associated with a lower incidence of both EPTB and miliary tuberculosis in children living in high-burden countries, although it is not protective in adolescents and adults.³ Given the difficulty in detection, prevalence estimates of EPTB are challenging, often resulting in a diagnosis of exclusion of any other reasons.⁴

Extrapulmonary TB involves lymph nodes, pleurae, and bones more frequently, but it can also affect every other organ or tissue. Moreover, heart involvement is rare and generally does not represent more than 5% of the total cases of TB, mostly in a constrictive pericardial presentation. In fact, 2–5% of EPTB is represented by constrictive pericarditis, with bacilli spreading directly from the lung and pleura in immunocompetent subjects and through dissemination in immunocompromised subjects.⁵ Myocarditis occurs in 0.14–2% of EPTB cases via hematogenous spread,⁵ while aortitis occurs in 0.3% of cases.⁶ Endocarditis and pancarditis have been anecdotally reported.⁷ Despite the paucity of available evidence, tuberculous pericarditis is a condition with high mortality, reaching rates as high as 40% in patients with AIDS and tuberculous pericarditis,⁸ therefore requiring timely detection.

In this study, we report five cases of cardiac TB, from Italy and from high-burden, low-income countries such as Ethiopia and Uganda.

CASE PRESENTATION 1

In November 2021, a 29-year-old man born in Mali and living in Italy for 7 years was admitted to the cardiology unit of Policlinico of Bari, Italy, for heart palpitations and chest pain. He was diagnosed with wide QRS tachycardia (heart rate, 250 bpm), which led to pharmacological cardioversion and placement of an implantable cardioverter defibrillator. Interferon-gamma release assays (IGRAs) performed at admission delivered undetermined results. HIV test was negative. A transthoracic echocardiogram (TTE) showed mildly reduced global kinetics (ejection fraction [EF], 50%), mild to moderate mitral and tricuspid valve insufficiency, and free wall thickness of the right ventricle. A pacemaker was implanted for the recurrent tachyarrhythmia. A positron emission tomography scan with 2-deoxy-2-[fluorine-18]fluoro-d-glucose (F18-FDG PET) confirmed heart inflammation and found mediastinal lymph node, D7 and L1 vertebral, and psoas muscle involvement. Magnetic resonance imaging (MRI) with contrast medium assessed medullary compression risk, and cardiac lymphoma or mesothelioma was initially suspected. Biopsy of vertebra D12 with histological examination showed histiocytic and lymphoid inflammation patterns and was negative for microbiological tests (bacteria, fungi, and mycobacteria). A cardiac biopsy revealed adipose tissue and fibrin, neither of which were diagnostic of cardiac neoplasia, and was negative for microbiological tests (bacteria, fungi, and mycobacteria). Microscopic, molecular, and cultural tests were used to search for MTBC in the samples mentioned above. In consideration of the radiological and clinical patterns, the patient underwent wide-spectrum antimicrobial treatment for 2 months with piperacillin/tazobactam at 18 g per day plus teicoplanin at 800 mg per day, followed by amikacin at 1 g per day plus daptomycin at 700 mg per day, and finally amoxicillin/clavulanic acid at 7.2 g per day plus vancomycin at 2 g per day for 2 months with neither clinical nor radiological benefit. After antimicrobial washout, a new bone biopsy was performed, which still resulted in no bacterial, mycotic, or mycobacterial isolation. The IGRA test, repeated more than 30 days after admission, was positive. The patient was then admitted to the infectious and tropical disease ward at the beginning of March 2022. As no benefits were obtained from long and wide-spectrum antimicrobial treatment, the standard four-drug antitubercular regimen (rifampin, ethambutol, isoniazid, and pyrazinamide) was initiated for presumptive TB (clinical and radiological criteria).

At the beginning of antitubercular treatment (ATT), a computed tomography (CT)-guided aspiration of the psoas muscle abscess was performed. This procedure aimed to provide clinical samples for microbiological confirmation and to perform source control. The aspiration liquid resulted in positive results for MTBC in microscopic, molecular, and culture tests. The GeneXpert test did not detect mutations associated with rifampin resistance. However, pyrazinamide was switched to moxifloxacin after 1 month because pyrazinamide resistance was detected by phenotypic antibiogram and subsequently confirmed by molecular test. Three weeks after the beginning of ATT, in consideration of slow clinical improvement and because of a suspected bacterial superinfection, linezolid at 1,200 mg per day and meropenem at 3 g per day were added for about 2 months. After 4 months, the patient was switched to maintenance treatment with Rifampicin and Isoniazid. Repetitive CT scans and CT-guided aspiration were done at weeks 1, 4, 8, and 11 after ATT initiation. Microscopic conversion of drainage collected from psoas muscle was documented after 24 days of ATT, and culture conversion was documented at 60 days. The MRI was repeated 2 months after ATT initiation with no significant changes. At month 11, an X-ray of the spine showed no evidence of bone involvement but revealed a residual discopathy. A transthoracic echocardiogram was performed at the start of treatment and at months 1, 2, and 4, with signs of improvement evident since month 1. A cardiac MRI was repeated at month 3, documenting partial resolution of the infiltration and the absence of pericardial effusion. The ejection fraction persisted at around 50–55% since the beginning of the condition. At month 13, the MRI pattern was stationary. Throughout the entire follow-up, serial electrocardiograms revealed no changes related to quinolones.

CASE PRESENTATION 2

A 42-year-old woman from Ethiopia, who was HIV negative and without other comorbidities, accessed the Medical Ward of St. Luke Catholic Hospital of Woliso, Ethiopia, for acute relapse of aortic steno-insufficiency and acute heart failure. An electrocardiogram showed sinus rhythm with incomplete left bundle branch block and signs of hypertrophic ventricle and overload. A chest X-ray showed enlargement of the cardiac silhouette and pleural effusion without signs of pulmonary compromise. Anemia with no alteration of white cells or platelets was found by blood cell count. In the echocardiogram, pericardial effusion of 2 cm was detected with initial signs of tamponade (diastolic collapse of right atrium), and therefore inotropic and diuretic treatments were started together with an angiotensin-converting enzyme inhibitor and oxygen support. Pericardiocentesis evacuated a yellowish liquid. The GeneXpert test of the pericardial effusion was negative. The patient was negative for TB symptom screening, but she reported a history of previous pulmonary TB, for which she had undergone 6 months of treatment (no medication anamnesis available) 3 years earlier. In consideration of the patient’s history and epidemiological background, a standard four-drug regimen for MTBC was initiated for pericardial TB (clinical and radiological criteria), together with steroid and nonsteroidal anti-inflammatory drug (NSAID) treatment of pericardial effusion. During hospitalization, the patient showed good tolerance to ATT treatment. After 4 weeks of ATT, the echocardiogram was repeated, with detection of reduced pericardial effusion but the presence of a fibrinous component and improvement of right atrial diastolic collapse. In consideration of clinical and imaging improvements, the patient was discharged after 4 weeks and referred to the outpatient clinic for follow-up.

CASE PRESENTATION 3

A 30-year-old man from Gambia, who was HIV negative and had been in Italy for 8 years, accessed the Emergency Unit of General Hospital in Palermo, Italy, for chronic abdominal pain, weight loss, and malaise. A CT scan documented pleural effusion, ascites, and para-aortic lymphadenopathy. Microscopic and molecular tests for MTBC and a bacterial germ culture of pleural drainage were negative. A bronchoalveolar lavage was performed, with negative results for microscopic and molecular tests for MTBC, negative results for other bacterial culture, and a positive result for Aspergillus antigen (unclear significance). A colonoscopy was performed, with no notable findings. The test for Helicobacter pylori was positive by esophagogastroduodenoscopy, so amoxicillin and levofloxacin therapy was prescribed. The screening for schistosomiasis in urine was negative. A hematologic evaluation was performed after microscopic examination of a blood smear, with the finding of anisopoikilocytosis and exclusion of the JAK2 mutation. The IGRA test was positive. As the patient presented with a diffuse state of xerosis, a cutaneous biopsy was performed, which showed epithelioid cells and gigantocellular granulomatous inflammation.

A month after discharge, the patient underwent a new total body CT scan for the persistence of symptoms. As multiple diffuse peritoneal nodules were found, an exploratory laparotomy and a biopsy were performed, with the detection of gigantocellular granulomatous inflammation. After this finding, 1 month later, the patient underwent a new hospitalization for anemia, cachexia, melena, and hematemesis, and abdominal pain. A further CT scan detected consolidative pneumonia with multiple solid formations, bilateral pleural effusion, mild pericardial effusion, ascitic effusion, and multiple colliquative mesenteric lymphadenopathies and nodulations, which were osteoblastic at the level of the anterior column of the L1 soma. As the suspicion of disseminated tuberculosis was still high, a new search for MTBC was performed by bronchoalveolar lavage: the microscopic examination was positive, as was the GeneXpert polymerase chain reaction (PCR) test, with any detection of mutations associated with rifampin resistance.

The patient was then transferred to the Infectious Disease Unit in Bari with a diagnosis of microbiologically confirmed disseminated tuberculosis (pulmonary, supra- and subdiaphragmatic lymph node, and skin involvement), and the standard four-drug ATT was started.

Two weeks after the initiation of ATT, the patient developed marked eosinophilia, and up to 2 months later, the patient showed signs of severe acute reduction of ejection fraction with cardiac failure. Therefore, a heart MRI was performed, which showed reduced ventricle contractility (EF, 20%) and right atrial dilatation. A myocardial biopsy found a marked presence of granulocytes and eosinophils at the endocapillary site, intermixed with fibrin and blood material. Identifications of parasites in whole blood (malaria, filaria, Schistosoma, and Trichinella), serological examinations of intestinal parasites (Trichinella, Strongyloides, Toxocara canis, Schistosoma, Onchocerca, and filariae) and parasitological investigations using faeces and urine were conducted to differentiate eosinophilia associated with the initiation of antitubercular treatment (Loeffler syndrome) from parasitic etiopathologies. All of these analyses yielded negative results.

During treatment, heart function was monitored by echocardiography, and an almost total recovery of EF (52%) was observed at the end of the treatment. Eosinophil counts decreased to a normal value. After 12 months, the patient reported no cardiac symptoms, the nutrition status was normal with full recuperation of body weight, and the ATT was completed.

CASE PRESENTATION 4

A 21-year-old man from Uganda, previously healthy, was admitted to the Emergency Department of St. John XXIII Hospital of Aber, Uganda, with fatigue, tachypnea, tachycardia, low blood pressure, and oxygen saturation of 93% on room air. Upon physical examination, he presented with signs of increased external jugular vein pressure, muffled heart sounds, moderate lower limb swelling, and tender hepatomegaly and complained of diffuse discomfort during palpation. After hospital admission, an abdominal ultrasound (US) scan revealed congestive hepatopathy, mild ascites, gross right pleural effusion, and massive pericardial effusion, which was confirmed by a chest X-ray. Therefore, he received a percutaneous pericardiocentesis with aspiration of serosanguineous fluid negative both for Gram staining and the real-time PCR test Xpert MTB/RIF. Tests for HIV and hepatitis B surface antigen were negative, so therapy with intravenous furosemide and oral prednisolone at 1 mg/kg was started. The next day, a urine lateral flow lipoarabinomannan (LF-LAM) test (Abbott Determine™ TB LAM Ag test) was positive, and antitubercular therapy with isoniazid, rifampin, pyrazinamide, and ethambutol was added. Once stabilized, with difficulty in breathing solved, the patient was discharged on day 5. During successive follow-up visits, the patient remained stable and asymptomatic and reported general well-being and good compliance with therapy.

CASE PRESENTATION 5

A 32-year-old woman from Liberia, in Italy for 1 year, was admitted to the General Medicine Unit of Policlinico of Bari, Italy, for an incidental finding of severe anemia. Here, she underwent a total body CT scan with contrast medium which detected pericardial effusion, a congestive liver, and an atrophic kidney. Blood transfusion and treatment with acetylsalicylic acid and colchicine were started. An HIV screening test was positive, with a viral load of 27 copies/mL and a CD4⁺ cell count of 630 cells/µL (30%). For this reason, the patient was transferred to the Infectious Disease Department, where a regimen of bictegravir/emtricitabine/tenofovir alafenamide was begun. A PCR assay of blood samples for Epstein-Barr virus, cytomegalovirus, human herpesvirus 1, 2, 6, 7, and 8, Toxoplasma gondii, and JC virus, serology investigations of blood samples for adenovirus, parvovirus 19, influenza virus A and B, enterovirus, Herpesviridae, and Mycoplasma, and autoimmunity investigations for antinuclear antibodies, anti-neutrophil cytoplasm antibodies, and anti-extractable nuclear antigens showed negative results. Venereal Disease Research Laboratory (VDRL) and hepatitis C virus (HCV) screening were negative, with hepatitis B virus (HBV) markers showing seroconversion. The pericardial effusion was monitored by US to confirm ongoing resolution. In consideration of the epidemiological background of the patient’s country of origin and given the absence of other evident causes of pericardial effusion, the standard four-drug regimen for MTBC was initiated for pericardial TB (clinical and radiological criteria) to limit the risk of development of constrictive pericarditis in the case of misdiagnosis. Treatment with NSAID was switched to steroids. At the same time, antiretroviral treatment was switched to tenofovir disoproxil/emtricitabine and dolutegravir twice per day. As the pericardial effusion showed a decreasing trend and no anemia was observed, the patient was discharged after 1 month with indication for follow-up.

Considerations and comparisons

These cases show the complexity of the cardiac TB condition. Cases 1, 3, and 5 have a more complete diagnostic process due to the availability of resources in Italy, even if just cases 1 and 3 stress the critical condition which can be encountered in a TB heart involvement. Still, case 5 is the only one describing the experience of a people living with HIV (PLWH). Cases 2 and 4 are perfect examples of the approach to TB in countries of high endemicity and low resources, where TB is one of the first concerns of a clinic in a pericardial effusion presentation. For this reason, it can be observed that the diagnostic delay for these two cases was much shorter than the one for cases 1 and 3, despite the shared critical presentation.

Finally, it must be highlighted that case 3 has been included in the article even though the cardiac involvement does not directly refer to M. tuberculosis but to a drug-related reaction.

In Table 1, we provide a detailed presentation of a single characteristic of each case, to facilitate the comparison between them.

Table 1.

Demographic and clinical features of patients with a diagnosis of cardiac TB

Sex	Age (years)	Country Of origin	Diagnostic Country	HIV Status	Clinical Presentation	Diagnostic Criteria	Treatment	Outcome	Diagnostic Delay (days) (patient related + health system related)
M	21	Mali	Italy	Negative	Heart palpitations and chest pain	Microbiological	HRZ Mfx (meropenem + linezolid as implementation treatment)	Treated	330 (240 + 90)
F	42	Ethiopia	Ethiopia	Negative	Cardiac tamponade	Clinical-radiological	HRZE	Ongoing follow-up	9 (2 + 7)
M	30	Gambia	Italy	Negative	Wasting syndrome from disseminated TB + acute heart failure after 2 months of ATT	Microbiological	HRZE	Treated	730 (30 + 700)
M	21	Uganda	Uganda	Negative	Fatigue, tachypnea, tachycardia, low blood pressure	Microbiological	HRZE	Treated	16 (15 + 1)
F	32	Liberia	Italy	Positive	Pericardial effusion without cardiac tamponade	Clinical-radiological	HRZE	In treatment	17 (0 + 17)

ATT = antituberculosis treatment; F = female; HRZE = isoniazid, rifampin, pyrazinamide, ethambutol; HRZ Mfx = isoniazid, rifampin, pyrazinamide, moxifloxacin; M = male; TB = tuberculosis.

Cardiac involvement of Mycobacterium

The heart presentation of TB can be divided according to the three involved anatomical districts (pericardial, myocardial, and vascular). The following sections examine these conditions separately to help reveal the differences in multidisciplinary management between the specific presentations.

Myocarditis and pericarditis.

Along with cancer, tuberculosis is one of the most common etiologies of pericarditis, especially in low-resource settings. About 1–2% of patients with tuberculosis have associated pericarditis,⁹ with the first cases reported as far back as the 17th century.⁹ On the other hand, isolated tuberculous myocarditis is extremely rare.¹⁰ Epidemiological studies show a predominance of tuberculous myocarditis in patients younger than 45 years of age, and it is twice as common in males.¹¹

Pericardial insemination with MTBC occurs in a retrograde fashion, by the lymphatic route, by hematologic dissemination, or, in rare cases, by direct damage to surrounding structures such as the lungs, pleura, or spine.¹² Isolated myocardial tuberculosis develops by the hematogenous or lymphatic route, as in the case of pericarditis; if associated with pericarditis, however, it is generally caused by direct invasion from the pericardium or by hematogenous or retrograde lymphatic dissemination from mediastinal lymph nodes.¹³

Tuberculous pericarditis can develop in several forms. The most common presentation is the effusive form (in about 80% of cases) with lymphocytic exudate, macrophages, and foamy cells. Clinical manifestations consist of heart failure, cardiac tamponade, and evolution to constrictive pericarditis with pericardial fibrosis. The dry form is the least common and presents with chest pain and ST segment supra-elevation evident on electrocardiography (ECG), in the absence of effusion on echocardiography, with fibrinous exudate, infiltrating macrophages, and T cells and granuloma formation at the histological examination.¹⁴ Atypical clinical presentations often lead to diagnostic delays and a poor prognosis.

On the other hand, tuberculous myocarditis includes the nodular form with myocardial damage and central caseation, miliary forms, or diffuse giant cell forms.¹⁵ The clinical manifestations are variable, ranging from no symptoms to sudden cardiac death, intractable ventricular arrhythmias, long QT syndrome, heart block, or congestive heart failure.^10,16 In this regard, clinical studies report that 80% of fatal cases occur in female patients with associated left ventricular systolic dysfunction.¹¹

In the diagnosis of tuberculous pericarditis, the cardiac CT scan is the gold standard for the detection of calcifications. The use of contrast medium reduces the artefacts and assesses the extent of pericardial effusion. Regarding this method, it can be observed that a CT scan of the chest district performed for other reasons was the starting point of the diagnostic process for case 5, which otherwise would have been neglected. Pericardial thickening is highly likely when nodular areas with increased attenuation, calcification of the anterior pericardium, a lack of changes in decubitus position, and increased pericardial contrast concentration are observed.^17,18 Transthoracic echocardiography could be diagnostic, but transesophageal echocardiography is recommended when the suspicion of cardiac tamponade is still high. In the case of thoracic involvement, chest ultrasonography allows detection of tuberculosis, dynamic follow-up of pleural effusions after evacuation, biopsy, or evaluation of nodular involvement. In many cases where there is a high suspicion of tuberculous pericarditis, in addition to pericardial fluid analysis, pericardial biopsy and histopathologic examination are recommended to identify pathognomonic granulomas.¹⁹ Finally, (18)F-FDG PET/CT has shown promising results in meeting the challenge in countries where TB is not endemic, such as by differentiating tubercular effusive pericarditis from idiopathic pericarditis.²⁰

The diagnostic criteria for myocarditis, such as cardiac enzyme elevation and left ventricular dysfunction on US, persist as clinical references for diagnosis. Typically, echocardiography may show an immobile echogenic mass in the ventricular myocardium in the case of a calcified myocardial tuberculoma. Cardiac MRI is a recent tool and shows characteristic T2 shortening in tubercular involvement, similar to that seen in intracranial tuberculomas. The characteristic appearance on T2 weighted images includes an isointense central core, corresponding to the central caseation, a hypointense border, representing the fibrous capsule, and a thin hyperintense line, which correlates with an inflammatory cellular infiltrate. Tuberculous cardiac mass shows no specific feature on echocardiography or MRI.²¹

Pharmacological treatment of tuberculous pericarditis is complex, based on combinations of therapeutic agents over long periods of time, which carry the risk of treatment resistance. Five main therapeutic agents are currently used: ethambutol, isoniazid, rifapentine, rifampin, and pyrazinamide.²² Surgery is recommended for patients in whom constrictive pericarditis persists²³ or in the case of those without constriction in the context of a lack of improvement in the clinical picture after 6–8 weeks of antitubercular treatment.²⁴ Once again, surgery can play a role in TB management, as sometimes also observed in pulmonary TB, where a surgical approach is sometimes recommended but not always easy to perform.^25,26 Clinical trials to date have shown persistently high rates of morbidity and mortality in patients with tuberculous pericarditis despite specific therapy. Pericardiectomy leads to improved mortality rates in patients with tuberculosis and improves patients’ symptoms, with Yadav et al. showing improvement in the New York Heart Association (NYHA) class after 1 year.²⁷ The use of steroids is a key element of pericardial TB management to prevent constrictive sequelae. Thus, in the context of TB-related pericardial effusion, the switch from NSAIDs or colchicine to steroids is recommended and reduces mortality. Neither pericardial surgery nor steroids are contraindicated in HIV-positive patients, who by contrast seem to benefit from steroids in terms of mortality more than HIV-negative individuals and to present no increase in postoperative risk.^5,23

There are few data reported in the literature on the treatment of patients with tuberculous myocarditis, with clinical trials recommending the initiation of etiologic treatment. Improvement in symptoms does not eliminate the associated risk of sudden death, so these patients require regular monitoring, most often by multidisciplinary teams.^28,29

In the terms of treatment and cooperative management of surgical and medical experience, our cases show that the initiation of ATT can reduce the need for surgical intervention and its related risk. In cases 1, 4, and 5, the patient’s prompt improvement made the surgical approach unnecessary. Unfortunately, the patient in case 2 could not undergo any surgical evaluation even if the condition could have benefited from it. This last consideration highlights the difference of management in different settings, which will be further discussed in a constrictive pericarditis.

Coronary artery disease and aortic involvement.

The aortic presentation of TB consists mainly of mycotic aneurysms and pseudoaneurysms, which can be a consequence of contiguous spread from surrounding districts or can be primary localizations. In the first case, the major source site is the vertebral bone and mediastinal lymph nodes. In the second case, the aorta is part of a disseminated pattern, even though a primary aortic presentation has been described.^30–33 Although very rare, intravesical BCG therapy-related tuberculous aortic aneurysms (TBAA) have been widely reported in the literature.^34,35 The clinical presentation includes both typical TB disease aspects (such as weight loss, night sweats, and fever) and typical arteritis symptoms (such as heart failure, asymmetric arterial hypertension, weak pulse at lower limbs, chest or abdominal pain, pulse mass, and claudication).³¹ Seemingly, being male and being between 61 and 80 years old are major risk factors for TB aortic aneurysm, and the distal arch and descending aorta are often involved.³³

In consideration of the difficult-to-reach site, the diagnosis is often presumptive. The imaging and laboratory diagnoses of TB-related aortic disease do not differ from those of other mycotic aneurysms: TTE, CT-angiography, MRI, and PET are involved in the morphological assessment as well as the laboratory findings of infection.³⁶ The risk of hemorrhagic rupture, stenosis, and real aneurysm formation represent the main concern of TBAA, as well as the major causes of death.^30,31,37

The management of TBAA is both medical and surgical. Since treatment guidelines do not indicate specific timing of ATT other than the 6-month regimen of PTB, several durations as well as specific treatment of cardiovascular comorbidities and steroids have been reported in the literature.^31,33 However, as mortality seems to be very low and mainly related to aorta damage, the surgical approach plays a pivotal role.³⁰ Both open surgery and endovascular aortic repair (EVAR) are valid approaches.³⁸ However, in a meta-analysis conducted by Yi et al., mortality in the open surgery group was related mainly to the emergent condition and perioperative complications, whereas EVAR showed worse long-term mortality, particularly when TB symptoms were consistent and patients had more comorbidities.³⁷ The meta-analysis also underlines the importance and timing of ATT initiation to prevent aneurysm recurrence. It seems that open surgery provides better debridement, which allows postponement of ATT, while ATT should be initiated perioperatively in cases when EVAR is performed. Still, preoperative ATT improves general outcomes, and a 6- to 24-month regimen has been reported in the literature regardless of the surgical technique.^33,37

Concerning TB-related coronary disease, further consideration can be given. Tuberculosis disease itself increased the risk of death due to coronary involvement as a chronic inflammatory systemic condition.^39,40 This correlation is also described for TB infection (previous latent TB).⁴¹ Nevertheless, cases of TB coronary arteritis have been described in reports showing that the tissue modification can result in both stenosis (for atheroma formation) and aneurysm, with clinical manifestations and a diagnostic approach similar to those described for common ischemic cardiopathy.^40,42 The presence of an aneurysmatic presentation can be challenging to distinguish from other vasculitis conditions of rheumatological significance. It is crucial to emphasize that the overall clinical manifestations of vasculitis and TB may be similar and that no actual indication can guide the clinician in a differential diagnosis, but epidemiological considerations may do so. For this reason, it is evident that the diagnosis is either presumptive or postmortem. Furthermore, research indicates a link between Takayasu’s arteritis and TB infection.⁴²

Cardiologic adverse events during TB treatment

Cardiologic adverse effects during TB treatment are related mostly to the frailty of the heart due to tubercular involvement. To describe these adverse effects, it is convenient to approach them alongside the three major manifestations of heart tuberculosis.

Constrictive pericarditis.

The most common consequence of tuberculous pericarditis is constrictive pericarditis, occurring in up to 60% of cases. It is a common complication in Africa, where the incidence of coinfections of TB pericarditis with HIV/AIDS is high, and diagnosis is often delayed.⁴³ Corticosteroid therapy can prevent constrictive pericarditis, and cases receiving corticosteroid treatment have been described.⁴⁴ As we reported for case 1, atrial fibrillation (AF) is common among patients with chronic constrictive pericarditis, so AF in young people should raise the suspicion for TB pericarditis.⁴⁵ Tuberculous constrictive pericarditis is also one of the main indications for surgical pericardiectomy, as chronic inflammation may result in heart failure. Usually, pericardiectomy is required when symptoms and signs do not improve or deteriorate after 4–8 weeks of antitubercular therapy or in cases of recurrence of cardiac tamponade.⁴⁶

Cardiac tamponade.

As reported for clinical cases 2 and 4, although rare, cardiac tamponade can occur.⁴⁷ Tuberculosis remains the most common cause of pericarditis in low- and middle-income countries (LMICs); therefore, besides being rare, cardiac tamponade must be excluded, as it remains a medical emergency that requires pericardiocentesis.⁴⁸ In this scenario, we cannot forget the risk of immune reconstitution inflammatory syndrome in pericarditis with ongoing antitubercular treatment, with worsening of pericardial effusion and therefore a higher risk for constrictive forms or cardiac tamponade.⁴⁹ A diagnosis of cardiac tamponade requires clinical signs such as increased jugular vein pressure, dyspnea, low blood pressure, and high heart rate, with less common signs being colder and cyanotic skin, and it needs instrumental evidence of pericardial effusion at the echocardiographic examination.⁵⁰

Other adverse effects.

In tuberculous myocarditis, one must discriminate between adverse effects in acute forms, involving mostly arrhythmic disturbances such as QT prolongation and ventricular fibrillation, and those in chronic forms, responsible for gradual heart failure. With this condition, more than with pericarditis, the risk of sudden cardiac death is not reduced by treatment.¹¹ Myocarditis is probably underdiagnosed, as it is often a postmortem finding in cases of sudden cardiac deaths.⁵¹ QT prolongation must be closely monitored in the case of administration of those antitubercular treatments causing QT prolongation, such as fluoroquinolones and bedaquiline.

Sudden death from exsanguination and cardiac tamponade is also frequent in tuberculous aortitis, manifesting with pseudoaneurysm or mycotic aneurysm.⁵² Since tuberculous aneurysms grow slowly, an outbreak of the disease could be abrupt, and diagnosis is often based on postmortem evidence.

Finally, besides the fact that diagnostics are becoming more sensitive for tuberculous involvement in the heart, with echocardiography and cardiac resonance playing a big role, tuberculosis of the heart remains underdiagnosed (Table 2).

Table 2.

Cardiologic AEs of antitubercular treatment

Treatment	Group	Cardiologic AEs	Other Evidence
Rifampin	I Line	No common AEs	Decrease in level of losartan and enalapril
Isoniazid	I Line	None	In vitro evidence of deficiency in heart development in embryos*
Ethambutol	I Line	None	None
Pyrazinamide	I Line	None	None
Fluoroquinolones	II Line, group A	QTc interval prolongation, particularly associated with moxifloxacin	None
Bedaquiline	II Line, group A	QTc interval prolongation	Low rate of cardiotoxicity
Linezolid	II Line, group A	None	None
Clofazimine	II Line, group B	QTc interval prolongation, especially if together with other drugs with the same AE	None
Cycloserine	II Line, group B	None	None
Terizidone	II Line, group B	None	None
Pretomanid	II Line, group C	QTc interval prolongation, more frequent if hypoalbuminemia is present	None
Delamanid	II Line, group C	QTc interval prolongation, more frequent if hypoalbuminemia is present	None
Meropenem	II Line, group C	None	None
Imipenem/cilastatin	II Line, group C	None	None
Amoxicillin/clavulanic acid	II Line, group C	None	None
Amikacin/streptomycin	II Line, group C	None	None
Ethionamide	II Line, group C	None	None
Prothionamide	II Line, group C	None	None
PAS	II Line, group C	No common AEs	Cardiac hypersensitivity†

AEs = adverse effects; I Line = first line; II Line = second line; QTc = corrected QT interval; PAS = para-aminosalicylic acid.

^*See reference 53.

^†See reference 54.

Cardiac presentation other than direct organ involvement.

Drug-related adverse events.

As mentioned above, we must consider the adverse effects of some antitubercular treatments on cardiac activity. Pretomanid, delamanid, fluoroquinolones, bedaquiline, and, to a lesser extent, clofazimine are frequently associated with QT prolongation syndrome. Usually, these drugs have a favorable risk profile,⁵⁵ but it is essential, when an antitubercular regimen is begun, to analyze and rule out other conditions or therapies that could contribute to QT prolongation, such as hypothyroidism or electrolyte imbalances. Excessive QT prolongation may lead to polymorphic tachycardia (torsade de pointes) and consequently a higher risk of sudden death. Nevertheless, the finding of QT prolongation often has a poor clinical effect, and it is just an ECG observation. However, a regular electrocardiographic follow-up during the anti-TB regimen is recommended, especially for PLWH, elderly patients, and those who present with low potassium levels and are receiving quinolones or bedaquiline.⁵⁵

A recent study of drug-resistant tuberculosis in Uganda has found a high prevalence of cardiovascular disease risk factors in patients with a new diagnosis of multidrug-resistant TB,⁵⁶ with a higher prevalence of central obesity, elevated diastolic blood pressure,⁵⁴ and diabetes.⁵⁷ This could be a result of BCG vaccine characteristics,⁵⁸ since with its limited duration, vaccination has delayed the outbreak of tuberculous disease in endemic countries, and the disease occurs much more often in older populations, who have more cardiovascular risk factors.

In the literature, some case reports of isoniazid-induced myocarditis with eosinophilia have been described as a cardiac manifestation of DRESS (drug reaction with eosinophilia and systemic symptoms).^59,60 It is not known if only isoniazid is responsible for this syndrome or if the syndrome is due to a combination of isoniazid and other antitubercular drugs, as DRESS is probably underdiagnosed and mostly an anecdotal finding. In case 3, the diagnosis of DRESS/Loeffler condition was made based on the exclusion of all other causes and on the timing of eosinophilia presentation after 2 weeks of ATT (Table 2).

Pulmonary arterial hypertension heart disease.

Pulmonary arterial hypertension (PAH) with right heart compromise is a common consequence of chronic lung diseases where hypoxia and vasoconstriction subvert lung vascularization.⁶¹ As for other chronic lung diseases like chronic obstructive pulmonary disease, pulmonary tuberculosis could be responsible for patterns of PAH, especially when it presents with severe and long-term damage in the lung parenchyma.⁶²

Right heart failure can show itself in acute form, when it is due to adult respiratory distress syndrome, and it can escalate into dyspnea with pulmonary edema and cardiogenic shock.⁶³ When tuberculosis causes long-term damage to the lung, as said, vascular changes may lead to pulmonary hypertension and consequently chronic right heart failure, manifesting itself with nonspecific symptoms such as peripheral edema, dyspnea, and chest pain.⁶⁴

Thromboembolic complications.

The inflammatory pattern triggered by tuberculosis is associated with a higher thromboembolic risk, as in every other acute inflammation characterized by an unregulated response.^65,66 The activation and increase of platelets in TB immunopathology are growing evidence in literature⁶⁷; the rise of platelets interacting with the already known neutrophil activation in TB and with the endothelium may be responsible for the formation of venous thromboembolism. As a result, thromboembolism must be considered in TB patients. Of note, anticoagulant therapy with warfarin needs to be closely monitored for its known interaction with antitubercular treatment.⁶⁸

Pericardial TB: LMIC perspectives.

Although most cases of pericarditis are generally considered idiopathic, M. tuberculosis is the primary cause in countries where TB is highly endemic, with an average prevalence of about 70% and even higher among the HIV population.⁶⁹ In these studies, the diagnosis of TB is composite, and different criteria and methods are used to determine the etiology of TB; molecular tests, culture, histology, and the response to ATT, together with anamnestic data, are all needed to reach the final diagnosis.^70,71 A confirmed diagnosis of pericardial TB always represents a challenging process, because neither the microbiological test nor the indirect test using a pericardial sample is completely accurate and a combination of several diagnostic tools is desirable,^72,73 which complicates the diagnostic process in a context where medical practice is already difficult in general. Nevertheless, LMICs can sometimes present a greater capacity to respond to TB in consideration of the high burden. As we observed in the case report from Uganda, the availability of urine LF-LAM helps the diagnostic workup. The same procedure is still not routine in high- and upper-middle-income countries (HMIC), such as Italy. In concert with this observation, the enormous effort of the WHO and other institutions to promote implementation of the GeneXpert test throughout LMICs is another sign of the attempts of the scientific community to fill the diagnostic gap for a pathology whose diagnosis is more difficult where the burden is higher.⁷⁴ Either way, the difficulty in performing more accurate diagnoses for specific conditions, such as cardiac disease, in LMICs is a focal issue: what has been previously discussed concerning imaging in cases of cardiac TB is still almost impossible to perform in such a context. For this reason, a recent project in South Africa has been started to improve cardiac disease diagnosis and registration.⁷⁵ Furthermore, in consideration of the important role of cardiac US in pericardial TB, it is interesting to stress that building capacity for US might be a new frontier of international cooperation: a training program to spread minimal cardiac echographic knowledge in a context where no specialized doctors work might favor a better outcome for cases of pericardial TB.^76–78

On the other hand, although pericardial TB is generally considered an obvious and severe clinical condition, several disease stages must be taken into consideration. Pericardial tamponades with TB-like symptoms or constrictive heart failure is not the only pericardial TB presentation, as the recurrence or absence of other symptoms can also be part of tuberculous pericarditis. For this reason, the background of a high TB burden represents in itself a “red flag” that can help the clinician not to underestimate a condition with a high risk of serious complications.^79–81 In consideration of the long-term expertise in managing ATT toxicity, starting preemptive treatment provides a more advantageous benefit-risk ratio than missing a pericardial TB diagnosis. For this reason, the initiation of ATT in a patient from a sub-Saharan country has been considered the best choice to avoid further complications: although theoretically an HMIC like Italy could have offered a stricter follow-up with prompt intervention in cases of recurrence, the epidemiological factor plays a pivotal role in the choice.⁸² In addition, it is important to note that HIV-positive patients are at greater risk of developing extrapulmonary TB,⁸³ which represented a further incentive to start preemptive ATT in the patient in case 5. Furthermore, the patient, as a recently arrived immigrant, presented the risk of being lost to follow-up due to social determinants.

CONCLUSION

Cardiac TB is a rare condition, but it still deserves consideration, especially in high-burden countries. In this setting, it represents the first etiology in cases of pericardial effusion or pericarditis. To miss or delay the identification of cardiac involvement in TB is associated with a high risk of death from cardiac complications. The diagnostic workup is challenging, and for this reason, a comprehensive approach should consider both imaging and microbiological tools. If cardiac MRI is the gold standard for heart investigations, cardiac US can provide enough information to suspect and follow up cardiac TB. In consideration of the affordability and safety of US, clinicians can be trained to implement this imaging tool, especially in resource-poor settings. On the other hand, since the microscopic and culture tests using pericardial liquid can be difficult to perform, the use of high-sensitivity methods and the implementation of investigations on alternative samples, such as TB-LAM or stool GeneXpert, should be included in the program to fight against TB.