A Systemic Review of TB with HIV Coinfection in Children

Table of Contents

Abstract

The epidemiology of tuberculosis is adversely impacted by the human immunodeficiency virus (HIV) coinfection. HIV-infected patients are more prone to opportunistic infections, most commonly tuberculosis, and the risk of death in coinfected patients is higher than in those without HIV. Due to the impaired cellular immunity and reduced immunological response in HIV-infected patients, the classic imaging features of tuberculosis usually seen in patients without HIV may present differently. The aim of this review article is to highlight the imaging features that may assist in the diagnosis of tuberculosis in patients with HIV coinfection.

Introduction

The combination of the human immunodeficiency virus (HIV) and tuberculosis in children has become a significant challenge to diagnose and manage globally. HIV infection increases the susceptibility to reactivation of latent Mycobacterium tuberculosis and speeds the progression of tuberculous infection. This has resulted in significant mortality among HIV-infected children [1, 2].

In 2014, according to the World Health Organization epi- demic update, an estimated 1 million children became ill with tuberculosis and, in 2015, 1 in 3 HIV deaths were due to tuberculosis [3]. This article reviews the imaging manifestations of tuberculosis with HIV coinfection in the chest, abdomen, musculoskeletal system and central nervous system.

Pulmonary tuberculosis and HIV coinfection

HIV-infected children have an increased risk of developing pulmonary tuberculosis with dissemination [4]. Subclinical pulmonary tuberculosis may be missed in severely immunosuppressed HIV-infected children [5]. Due to nonspecific clinical symptoms and signs, limited use of the tuberculin skin test and the difficulty in obtaining microbiological confirmation, the diagnosis of pulmonary tuberculosis in HIV-infected children is challenging [4–7]. Hence, the diagnosis of pulmonary tuberculosis often relies on a combination of clinical and radiologic findings [8, 9].

Chest radiographs are the imaging modality of choice for the diagnoses of pulmonary tuberculosis in children in developing countries, due to the high HIV and tuberculosis disease burden and limited availability of CT and MRI [4, 6, 10, 11]. Guidelines recommend that chest radiographs are routinely performed before the initiation of antiretroviral therapy in HIV-infected children in order to provide a radiologic base- line, to diagnose or exclude pulmonary tuberculosis and bacterial pneumonia as well as to evaluate for chronic lung dis- ease [10, 12, 13].

Mediastinal and hilar lymphadenopathy are the radiologic hallmarks of pulmonary tuberculosis on chest radiograph [5, 9, 14, 15]. The typical features of lymphadenopathy on the frontal chest radiograph include oval masses in the region of the hilar and the doughnut sign, which is represented on the lateral radiograph, superoanteriorly by the posterior aspect of the aortic arch and the right and left main pulmonary arteries and inferiorly by hilar and subcarinal nodes. The central lucency of the doughnut sign is formed by the bronchus intermedius (Fig. 1) [16]. However, a significant limitation of lymphadenopathy detection on chest radiograph is the poor inter-reader agreement reported in the literature in several studies [6–8, 17, 18]. The sensitivity and specificity for detecting lymphadenopathy on chest radiograph are low (67% and 59%, respectively) [5].

Fig 1 - Tuberculous mediastinal and hilar lymphadenopathy in a 2-year- old male child with HIV infection who presented with a chronic cough, fever and loss of weight. a Anteroposterior radiograph demonstrates hilar and superimposed subcarinal lymphadenopathy as evidenced by lobulated, dense masses (arrows) filling the hilar points bilaterally. b Lateral radiograph demonstrates the doughnut sign (arrows), which is formed by the normal right and left main pulmonary arteries and the aortic arch anteriorly and superiorly, and the hilar and subcarinal lymphadenopathy inferiorly. The radiolucent centre is formed by the trachea and upper lobe bronchi
Fig 2 - Cavitary pulmonary lesions in a 2-year-old male child with known tuberculosis. Anteroposterior (a) and lateral (b) radiographs demonstrate multiple right upper lobe cavities (arrows)

Important chest radiography findings associated with pulmonary tuberculosis include miliary nodules (<2 mm) and pulmonary cavitation (Fig. 2) [8, 19, 20]. Air space consolidation is a very nonspecific finding in primary pulmonary tuberculosis, but in combination with hilar or mediastinal lymphadenopathy is associated with pulmonary tuberculosis. Pleural effusions are uncommon in infants and young children with pulmonary tuberculosis, and more common in children >5 years of age. Pleural effusions are usually isolated, though 20% to 40% of children may present with associated parenchymal infiltrate or hilar or mediastinal lymphadenopathy [15].

US of the mediastinum is an alternative to chest radiograph in identifying lymph nodes and diagnosing pulmonary tuberculosis, especially in a resource-limited setting where sonography may be the only imaging modality. Furthermore, US has no radiation risk to children [21]. Bosch-Marcet et al. [22] found that 67% of children with pulmonary tuberculosis who had normal chest radiographs had lymphadenopathy on mediastinal US. Moseme et al. [21] used US to find lymph- adenopathy in 40% of children up to 13 years of age with proven or suspected pulmonary tuberculosis.

Abdominal tuberculosis and HIV coinfection

In contrast to adults, abdominal tuberculosis is uncommon in children with a reported incidence of 10% in those younger than 10 years of age and concomitant pulmonary tuberculosis in 1–5% of cases [23]. The scant paediatric literature on extrapulmonary tuberculosis does not indicate differences in frequency (with the exception of central nervous system tuberculosis) or location in HIV seropositive versus seronegative patients [24]. Therefore, overlap in the imaging findings in both these populations exist. Tuberculosis and HIV coinfection, however, results in more rapid disease evolution and higher mortality. The insidious onset of tuberculosis and its variable clinical features confounds or delays diagnosis with unnecessary laparotomy in some instances or fatality. The clinical presentation may mimic other infectious, inflammatory diseases or malignancy compounding the diagnostic dilemma [18].

Abdominal tuberculosis is purported to result from haematogenous seeding from primarily pulmonary or other sites or via lymphatic spread from involved lymph nodes or solid viscera [23]. Abdominal tuberculosis may involve single or multiple sites within the bowel, peritoneum, omentum, lymph nodes and solid organs [18].

US and CT are the main diagnostic modalities [18]. The most common US findings include ascites and mesenteric lymphadenopathy. Portal and peripancreatic lymphadenopathy may be present [18]. CT better demonstrates high density, loculated or free ascites, lymph node conglomerates and central hypoattenuation of nodes. Whilst peripheral rim enhancement of lymph nodes is highly suggestive of tuberculosis infection, this is not pathognomonic [18]. Tuberculosis lymph- adenopathy may be calcified initially or progressively [25]. Para-aortic lymphadenopathy is more likely in lymphoma compared to mesenteric lymphadenopathy in tuberculosis [26]; however, these conditions may be difficult to distinguish radiologically and coexist in HIV patients.

Inflammatory masses consisting of bowel, omentum and lymphadenopathy (“omental cakes”) can be demonstrated on cross-sectional imaging [25]. A combination of the above features, particularly with rim-enhancing or calcified nodes, is highly suggestive of tuberculosis [18].

Gastrointestinal tuberculosis commonly involves the terminal ileum and caecum indicated by bowel wall thickening on imaging [18]. This may occasionally be demonstrated on CT, as gastrointestinal contrast studies are not routinely performed in children in this scenario [25].

Organomegaly and calcified granulomas are frequently the only findings in abdominal tuberculosis. Visceral tuberculosis in the form of splenic microabscesses and hepatic granulomas are frequently part of disseminated (miliary) tuberculosis or as larger abscesses [18], manifesting as multifocal hypoechogenicities (Fig. 3) or hypodensities (Fig. 4).

Genitourinary tuberculosis is less common with cases of renal cavitation and papillary necrosis described [18]. The kidneys are involved by haematogenous spread.

A high index of suspicion for abdominal tuberculosis in HIV coinfection is warranted in the appropriate clinical setting given the nonspecific clinical presentation and that imaging findings are not pathognomonic.

Fig 3 - Abdominal tuberculosis in a 14-year-old female child who presented with hepatosplenomegaly and abdominal pain. The child had known HIV infection and proven pulmonary tuberculosis. a-b Abdominal US. Transverse sonogram of the spleen (a) demonstrates multiple subcentimeter scattered hypoechoic granulomas. Transverse sonogram of the liver (b) demonstrates multiple hypoechoic granulomas. The arrows indicate the hypoechoic granulomas in the spleen

Central nervous system tuberculosis and HIV coinfection

Infection of the central nervous system is due to the haematogenous dissemination from a primary focus usually in the lungs and is the most severe extrapulmonary manifestation of tuberculosis. Central nervous system tuberculosis is associated with a high mortality rate with severe neurological consequences [1]. Compared with HIV-negative individuals, HIV-positive individuals with tuberculosis are five times more likely to have central nervous system involvement [2]. In the study by Nelson [1], tuberculosis was found to be the AIDS defining condition in their cohort of patients [1].

Fig 4 - A 10-year-old male child with HIV infection and proven pulmonary tuberculosis with abdominal involvement. Coronal reconstruction of a chest and abdominal CT demonstrates multiple mediastinal nodes with hypodense centres and rim enhancement (black arrows). In the abdomen, there are hypodensities in the spleen (white arrow) and in the liver consistent with granulomas consistent with tuberculosis
Fig 5 - Tuberculous meningitis in a 3-year-old male child with HIV infection who presented with fever and a loss of consciousness. Axial contrast-enhanced T1-weighted MRI shows florid meningeal enhancement (arrows) that is most pronounced within the middle cerebral artery cisterns in an asymmetrical pattern

In HIV-infected patients, the central nervous system manifestations of tuberculosis are more likely to result in meningitis. The cause is usually basal leptomeningitis with the com- mon sequelae of communicating hydrocephalus, which is thought to be due to the obstruction of the basal cisterns by this thick inflammatory exudate [27, 28]. HIV infection im- pairs the cell-mediated immunity and, therefore, the immuno- logical response to the tubercule bacilli is insufficient to produce the intense, florid basal leptomeningitis that we often see in patients without HIV. HIV-infected patients with tuberculous meningitis tend to produce a more asymmetrical, nodular enhancement pattern (Fig. 5) [27–29].

Tuberculomas are granulomas that may result either from haematogenous dissemination or from extension of the central nervous system infection into the adjacent parenchyma. These tuberculomas may occur with or without pre-existing meningitis. They may be solitary or multiple and they usually have nodular or ring enhancement (Fig. 6). On MRI, early tuberculomas may appear hypointense on T2-weighted im- ages due to the caseous necrosis and paramagnetic effects (Fig. 6) [30, 31]. This feature on MRI may help to distinguish these lesions from tuberculous abscesses, which are often hyperintense on T2-weighted MRI.

Fig 6 - Brain MR angiography in a 5-year-old male child who presented to the casualty with right hemiplegia. a Axial T2-weighted image demonstrates a tuberculoma (arrow) with the characteristic central low signal and marked surrounding oedema. b Coronal contrast-enhanced image shows enhancement of the lesion (arrows). c Sagittal contrast- enhanced T1-weighted image demonstrates multiple rim-enhancing leptomeningeal tuberculomas (arrows)
Fig 7 - A 10-year-old male child presented to the casualty with headaches and focal neurology. The patient was diagnosed with central nervous system tuberculosis. a-c MRI demonstrates features of tuberculosis meningitis with a moyamoya pattern of infarctions. Axial T2-weighted image (a) demonstrates multiple watershed infarcts bilaterally (arrows). Axial diffusion-weighted image (b) confirms acute ischemic infarcts (arrows) in both posterior parietal lobes. Three-dimensional time-of- flight image (c) shows narrowing of the right and left posterior cerebral artery branches (arrows), compatible with vasculitis. There are multiple collateral vessels, which are features of moyamoya

Tuberculous abscesses in the central nervous system, al- though rarely seen in patients without HIV, are more common in HIV-infected patients [32]. They are usually larger and solitary compared to tuberculomas [1]. In HIV-infected patients, one needs to consider other differential diagnoses for a mass lesion such as toxoplasmosis, fungal granulomas and primary central nervous system lymphoma.

MR spectroscopy may assist in differentiating tuberculous and non-tuberculous brain lesions as the tuberculous lesions demonstrate a characteristic lipid peak [33, 34].

Cerebral infarction is a common complication of tuberculosis meningitis and the infarcted lesions are often located in the periventricular regions of the brain (basal ganglia, thalamus and internal capsule). The vessels most commonly in- volved are the perforating vessels at the base of the brain [34, 35]. HIV-infected patients are more likely to present with cortical cerebral infarcts, which are most likely related to HIV vasculopathy involving medium and large vessels (Fig. 7) [34].

MRI, particularly diffusion-weighted MRI, is sensitive in detecting these infarcts. Advanced MRI techniques, such as perfusion-weighted MRI, may provide additional information about the cerebral circulation and may be used to monitor response to anti-tuberculous treatment in central nervous system tuberculosis [34, 36]. Transcranial Doppler US is useful for assessing the vessels of the circle of Willis in children and can be used to identify the vasculopathies associated with tuberculous meningitis [37].

HIV-infected children also develop cerebral atrophy and ventriculomegaly as a result of volume loss. In HIV encephalopathy, the degree of atrophy correlates with the viral load and disease severity [30, 38].

Musculoskeletal tuberculosis and HIV coinfection

Although only 3% of all tuberculosis infections involve the musculoskeletal system [39], musculoskeletal tuberculosis is far more common in HIV-positive patients: 60% versus 3–5% of immunocompetent patients [40]. Half of these infections occur in the spine (particularly the thoracic spine in children) [41]. Less common forms include tuberculous arthritis and osteitis. Isolated tuberculosis of the soft tissue is extremely rare [39]. There is significant overlap in the imaging features of musculoskeletal tuberculosis in both patients with and with- out HIV.

Tuberculosis and immune reconstitution inflammatory syndrome

Immune reconstitution inflammatory syndrome is defined as clinical deterioration weeks or months after initiation of anti- retroviral therapy, resulting from immune system recovery [4, 42, 43]. Paradoxical immune reconstitution inflammatory syndrome is an excessive inflammatory response to a pre-existing, partially treated condition, while unmasking immune reconstitution inflammatory syndrome refers to progression of a previously asymptomatic, unrecognized or occult condition. Non-infectious forms of immune reconstitution inflammatory syndrome include malignancies and autoimmune processes [5, 43, 44]. Half of all variants are associated with Mycobacterium tuberculosis [44].

Bacille Calmette-Guérin (BCG)-associated immune reconstitution inflammatory syndrome is well recognized [43] and in some settings is the most frequent cause of that syndrome [45]. It usually manifests with inflammatory changes at the injection site and/or within the ipsilateral draining lymph nodes [45]. Children with lower CD4 counts and higher HIV viral loads are at greater risk for BCG-associated immune reconstitution inflammatory syndrome, as is initiation of anti- retroviral therapy at a young age [46].

There is limited literature on tuberculosis-associated immune reconstitution inflammatory syndrome in children [47]. Van Rie et al. [44] reported that the burden of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in sub-Saharan African children initiating antiretroviral therapy is low, with 5/104 (4.8%) of children younger than 8 years fulfilling the International Network for the Study of HIV-associated Immune Reconstitution Inflammatory Syndrome criteria for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. In a case series of 11 children with probable or culture-confirmed tuberculosis, four had paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome [5]. The lower incidence of tuberculosis-associated immune reconstitution inflammatory syndrome in children may relate to the paucibacillary nature of tuberculosis in children, where a lower pathogen burden results in less immune stimulation; however, since tuberculosis is often not microbiologically confirmed, some children initiated on tuberculosis treatment may not have tuberculous disease and so would not be at risk for paradoxical tuberculosis- associated immune reconstitution inflammatory syndrome [44].

It is important, but radiologically difficult, to distinguish tuberculosis-associated immune reconstitution inflammatory syndrome from drug-resistant tuberculosis or other opportunistic infections, including non-tuberculous mycobacteria and cytomegalovirus [5, 42]. The most common manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome are pulmonary, where radiologic features of tuberculosis-associated immune reconstitution inflammatory syndrome include worsening or new hilar or mediastinal lymphadenopathy with or without tracheobronchial compression, worsening or new reticular/nodular infiltrates, worsening or new air space consolidation or pleural effusions (Fig. 8) [5, 42–44]. The most common abdominal finding of tuberculosis-associated immune reconstitution inflammatory syndrome is enlarging lymphadenopathy with central low density [48]. Other abdominal manifestations include ascites and splenic microabscesses.

Fig 8 - A 4-year-old boy presented with pulmonary tuberculosis after 6 months of noncompliance with antiretroviral therapy. a Anteroposterior chest radiograph demonstrates right upper lobe dense consolidation, bilateral reticular infiltrates and lymphadenopathy. He was initiated on antiretroviral therapy and tuberculosis treatment simultaneously then presented 3 weeks later with clinically worsening symptoms. b-c Contrast-enhanced chest CT. Axial image (b) demonstrates mediastinal and hilar nodes (arrows) encasing the carini with lingular consolidation and right pleural effusion. Coronal reconstruction (c) demonstrates superior mediastinal nodal mass with central low density and bilateral axillary nodes (arrows)
Fig 9 - A 6-year-old HIV-positive patient with intracranial tuberculosis and immune reconstitution inflammatory syndrome. a Axial contrast- enhanced CT of the brain 1 month after initiation of antiretroviral therapy demonstrates a cluster of enhancing tuberculomas (arrows) in the pre-pontine cistern. b-c Axial MRI 2 months following the CT in (a). T1-weighted contrast-enhanced image (b) shows increased number and size of the tuberculomas (arrows). T2-weighted image (c) demonstrates worsening hydrocephalus (arrows)

Tuberculosis-associated immune reconstitution inflammatory syndrome is a potentially life-threatening complication in HIV-infected children with associated tuberculosis of the central nervous system. Tuberculosis-associated immune reconstitution inflammatory syndrome should be suspected when new neurological signs develop, usually in the first 3 months after the initiation of antiretroviral therapy in children with central nervous system tuberculosis [30, 31]. Marais et al. [49] reported worsening radiologic findings including tuberculous abscesses, tuberculomata, meningitis and hydrocephalus (Fig. 9). The tuberculomas in tuberculosis-associated immune reconstitution inflammatory syndrome are noted to have increased perilesional oedema compared to those in patients not receiving antiretroviral therapy [1, 49]. The risk factors that may increase the likelihood of paradoxical tuberculosis- associated immune reconstitution inflammatory syndrome are disseminated tuberculosis, a shorter time from tuberculosis treatment to antiretroviral therapy initiation and low CD4 count (<50 cells/μl) [50, 51].

Acknowledgements

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The final publication is available at: https://doi.org/10.1007/s00247-017-3895-9

Conclusion

Due to the impaired cellular immunity in HIV infection, there is increased susceptibility to opportunistic infections, tuberculosis being the most common. This presents a challenge in diagnosis as the radiologic manifestations of tuberculosis may present differently and often with multisystem involvement. Clinical presentation is nonspecific, and imaging findings in abdominal and pulmonary tuberculosis do not differ significantly with HIV coinfection. Hence, a high index of suspicion is warranted. HIV-infected individuals with tuberculosis are more likely to have central nervous system involvement, which again is more likely to manifest as meningitis. Tuberculous meningitis in these patients often presents as an asymmetrical nodular enhancement pattern on imaging. Tuberculous abscesses are also more common in HIV-infected patients. As the availability of antiretroviral therapy increases in resource-poor countries with a significant tuberculosis burden, the incidence of tuberculosis-associated immune re- constitution inflammatory syndrome is likely to increase. The most common manifestation of tuberculosis-associated immune reconstitution inflammatory syndrome is in the lungs with radiologic features of worsening or new air space consolidation or pleural effusion. Prompt diagnosis of tuberculosis in HIV-infected patients may result in earlier treatment, thereby the recognition of the imaging manifestations and complications on CT and MRI by the radiologist can play a critical role in the management of these patients.

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