Keywords

FormalPara Key Points

  • Susceptibility to Tuberculosis depends on the host’s immune response; any dysfunction leads to the progression of the disease.

  • Human immunodeficiency virus infection, chronic kidney disease, chronic liver disease, malnutrition, use of immunosuppressants, and elderly age are risk factors for progression of latent Tuberculosis to disease or increased susceptibility to Tuberculosis.

  • Management of Tuberculosis in patients of HIV would be to administer an appropriate regimen with minimal interaction of drugs in the proper time to prevent immune reconstitution.

  • Screening for latent Tuberculosis before starting antiretroviral therapy or other immunosuppressants would help in minimizing the complications; Rifamycin based regimens can be used when tested positive for Latent Tuberculosis.

1 Introduction

Tuberculosis is an opportunistic infection in humans and can be divided into active and latent tuberculosis. The global prevalence of tuberculosis infection is about 32%, out of which the majority are asymptomatic. The host’s active immune response makes the host asymptomatic, although the organisms persist within. Any compromise of the immune system would predispose for reactivation of underlying latent disease. Susceptibility to tuberculosis is determined by the host’s immune function irrespective of the active or latent phase. Control of infection requires a balance between immune-mediated eradication and limitation of inflammation. Dysfunction in immune regulatory mechanisms shifts the balance towards disease progression. Risk factors for immune dysregulation are human immunodeficiency virus (HIV) infection, malnutrition, chronic diseases like chronic liver disease, chronic kidney disease, substance abuse, elderly age, and use of immunosuppressive therapy. These risk factors are not mutually exclusive and can exacerbate each other.

Tuberculosis is known to be associated with increased morbidity and mortality among immunocompromised hosts. In this chapter, we give a brief description of various immunocompromised condition precipitating Tuberculosis.

2 Immunity to Tuberculosis

Mycobacterium tuberculosis enters the human body through droplet nuclei containing viable bacilli. These bacilli are usually trapped in the upper airways and propelled out by ciliated mucosal cells. Approximately 10% of these reach the alveoli. Alveolar macrophages phagocytize these bacilli, and this enhances the complement activation leading to opsonization of bacilli. Tuberculosis inhibits the lysis of phagosome by various mechanisms and prevents its self-destruction. In the initial stage, the bacilli disseminate widely through the lymph vessels to lung parenchyma and other organs and undergo growth inside the inactivated macrophages resulting in early granuloma formation.

In the next 2–4 weeks, host responds with a macrophage-activating cell-mediated response and tissue-damaging response. In most infected individuals, activated local macrophages stimulate T lymphocytes and release various lymphokines and effectively neutralize the bacilli. The central part of these lesions has necrotic material, and healing takes place gradually with fibrosis. The viable bacilli can be present in the necrotic tissue or stay dormant within the macrophage. In a minority of them, the above response is weak. It results in a delayed hypersensitivity reaction, leading to the destruction of the lesion and draining the necrotic debris to the environment through coughing. This debris contains lots of bacilli. Abdominal involvement is primarily due to Hematogenous spread from the primary focus.

Abdominal Tuberculosis is uncommon, making it approximately 5 per cent of all tuberculosis cases [1]. The mechanism of abdominal involvement can be by (a) swallowing of sputum causing direct seeding, (b) hematogenous spread, or (c) rarely due to consuming milk from cows affected with bovine TB.

3 Tuberculosis in Immunocompromised

Tuberculosis usually presents with localized involvement, commonly in the lungs. Still, it can sometimes present with dissemination to various organs like the brain, abdomen, and bones. Disseminated Tuberculosis is more common among immunocompromised individuals. Table 25.1 lists the different immunocompromised states associated with a high risk of developing tuberculosis infection. Tuberculosis in immunocompromised is associated with atypical manifestations, more extrapulmonary involvement, and rapid disease progression. Table 25.2 compares the differences and similarities between Tuberculosis in immunocompromised and immunocompetent individuals.

Table 25.1 High-risk tuberculosis groups
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Table 25.2 Characteristic features of Tuberculosis in immunocompromised and immunocompetent
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4 Tuberculosis and HIV

4.1 Epidemiology

In 2018, an estimated 36.8 million adults and children lived with HIV or acquired immune deficiency syndrome (AIDS), out of which 1.3 million were newly infected with tuberculosis [2, 3]. It is estimated that HIV patients are at a 20-fold increased risk of developing Tuberculosis compared to the non-HIV population. Also, approximately one-third of all AIDS-related deaths were attributable to Tuberculosis.

4.2 Pathophysiology and Pathogenesis

CD4+ T lymphocytes are the main target of HIV, and macrophages act as sanctuaries for HIV-1. Both these cells also play a crucial role in the immunity against tuberculosis infection. Hence, patients with HIV are at increased risk of infection with Tuberculosis and are prone to disseminated tuberculosis. This results from impaired phagocytosis by macrophages infected with HIV and downregulation of classical Th1 cellular responses against tuberculosis bacilli [4, 5]. Biopsies taken from the tuberculin skin test site revealed decreased T lymphocyte recruitment among patients with HIV-tuberculosis coinfection compared to non-HIV tuberculosis patients [3] (Fig. 25.1).

4.3 Clinical Manifestations

Tuberculosis and HIV coinfected patients present with variable clinical features, and it largely depends on the phase of the illness. Even though pulmonary involvement is the most common manifestation of Tuberculosis in HIV positive patients, atypical radiographic features like lower lobe involvement and less cavitation are more common in patients with advanced HIV infection. Extrapulmonary Tuberculosis is also seen in a higher number of patients with HIV infection. Among the extrapulmonary organs, lymphadenopathy, commonly the cervical and axillary lymph nodes, is the most commonly involved organ [6]. Abdominal Tuberculosis usually presents non-specific symptoms, including fever, night sweats, weight loss, pain abdomen, and diarrhea. On examination, they can have abdominal tenderness, ascites, and rarely lump abdomen. However, ascites were less common in HIV-tuberculosis coinfected patients than HIV seronegative patients [7]. Hence, a high index of suspicion should be kept for recognizing abdominal Tuberculosis.

4.4 Diagnosis

Screening for Tuberculosis is mandatory at the time of diagnosis of HIV [4]. Although there is no universally accepted screening tool for diagnosis among people living with HIV, various studies recommend historical questions like cough, fever, night sweats, or weight loss. In that case, a thorough examination and investigations should be performed to search for Tuberculosis focus [8].

The investigations to diagnose abdominal Tuberculosis in HIV infected patients are essentially the same as in non-HIV patients. Previous studies noted that abdominal Tuberculosis’s radiological features among early HIV infection were similar to those noted in non-HIV patients [9]. But patients with advanced HIV infection had higher rates of splenomegaly, hepatomegaly, lymphadenopathy, biliary tract abnormalities, bowel wall edema, and ascites [10].

4.5 Treatment

The main aim of managing tuberculosis in patients of HIV would be to administer an appropriate regimen with minimal interaction of drugs with antiretroviral drugs. In most of the patients, the regimen and duration of ATT will be the same as that in non-HIV infected patients. For patients who are not started on antiretroviral therapy (ART), antitubercular therapy (ATT) should be imitated first. Subsequently, ART is to be initiated. National AIDS Control Organisation (NACO) technical guidelines on ART initiation state that ART is to be started between 2 weeks to 2 months of beginning ATT in ART naïve patients (Table 25.3). In patients with CD4 count less than 50 cells/microL, ART can be initiated within 2 weeks of starting ATT. Among patients who develop tuberculosis while on ART, certain modifications to ART or ATT regimens need to be made to maintain the drugs’ efficacy and reduce the drug interactions. If the patient is receiving a nevirapine based ART regimen, it has to be changed to Efavirenz. In patients who are receiving protease inhibitor-based ART, rifampicin should be substituted with Rifabutin. In patients receiving raltegravir, an integrase inhibitor, based ART, either rifampicin should be substituted with Rifabutin, or raltegravir’s dose should be increased from 400 mg twice a day to 800 mg twice a day. Table 25.4 lists the various drug interactions between drugs of ART and ATT regimens.

Table 25.3 Treatment of HIV-TB coinfection as per NACO recommendations
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Table 25.4 Drug interactions between Antitubercular and Antiretroviral therapy
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4.6 Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS describes a collection of inflammatory disorders associated with paradoxical worsening of the preexisting infectious process following ART initiation in HIV affected individuals [5, 6, 11]. The frequency of IRIS is between 10–25%. Mycobacterium tuberculosis is the most frequent infection implicated in IRIS. Still, it can also be found with Cryptococcus neoformans, cytomegalovirus, hepatitis C and B viruses. IRIS is more frequent among patients with CD4 count <50 cells/microL at ART initiation. It usually occurs within the first eight weeks, may occur as early as one week after therapy initiation or as late as 12 months after initiation. At the onset of IRIS, there is a significant decrease in HIV viral load and a more substantial increase in CD4 count [7, 12].

IRIS with Tuberculosis may present with clinical manifestations of lymphadenitis, pneumonitis, acute respiratory distress syndrome, hepatitis, CNS tuberculosis, gut perforation, new-onset serositis, renal failure, or epididymitis [6, 8]. Temporal correlation with the onset of ART and onset of symptoms can yield a clue. IRIS is usually self-limiting, and treatment depends on the severity of manifestations. Milder forms are managed with close observation without interrupting ART. In the localized form, minor surgical procedures like drainage from the local site are adequate. Antimicrobial therapy targeting the inciting pathogen would be required. Short-term corticosteroids or non-steroidal anti-inflammatory drugs can be given to decrease inflammation when it is secondary to non-replicating antigens. The usual prednisolone dose would be 1.5 mg/kg for two weeks, followed by 0.75 mg/kg for the next two weeks, followed by a taper. In severe and life-threatening IRIS manifestations, ART needs to be stopped.

5 Tuberculosis after Other Forms of Immunosuppression

5.1 Steroid Therapy

Corticosteroid therapy is a known risk factor for Tuberculosis’s reactivation; however, the exact risk effect is not known [13, 14]. The risk is higher in patients receiving higher dose and long duration of corticosteroids. Studies on tuberculin skin test showed that corticosteroids at an amount of >15 mg/day for more than 2–4 weeks duration resulted in reduced reactivity to tuberculin antigen [15, 16]. The risk of tuberculosis reactivation is higher with systemic use of corticosteroids; Dong et al. have shown that the risk of tuberculosis reactivation was increased even with inhaled corticosteroid use [17]. Since the exact cutoff dose and duration of corticosteroids for tuberculosis reactivation are unknown, the decision on initiation of corticosteroid therapy and screening for latent tuberculosis before corticosteroid initiation needs to be individualized.

Fig. 25.1
figure 1

Risk of Tuberculosis in the time frame of HIV. In the early phase of the disease, CD4 count falls drastically, and HIV viral load increases; once the patient starts recovering, Tuberculosis’s risk increases gradually till Antiretroviral therapy is initiated; as ART is initiated, CD4 count increases and the risk of Tuberculosis decreases

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5.2 Tuberculosis after Biologics

Biologicals have changed the scenario in the management of rheumatological and some other autoimmune diseases. The main concern with them is the activation of latent Tuberculosis or contracting the fresh disease. TNF alpha inhibitors were commonly implicated, but sporadic cases of Tuberculosis were also reported with other biologicals like interleukin-6 inhibitors and anti-CD20 drugs.

5.2.1 Tumor Necrosis Factor-Alpha Inhibitor

TNF alpha is a proinflammatory cytokine produced by the macrophages, dendritic cells, and Th1 like cells when stimulated by M. tuberculosis bacilli. It has a vital role in macrophage activation, immune regulation, and formation of granulomatous inflammation [9, 10]. The use of TNF alpha inhibitors leads to an increased risk of serious infections, mainly intracellular opportunistic infections. All TNF alpha inhibitors have the risk for the development of Tuberculosis. Still, the highest risk is with infliximab and adalimumab [18]. The majority of these studies derive the conclusion from patients with rheumatoid arthritis where the disease perse imparts risk for Tuberculosis development. Tuberculosis onset is usually within the first six months after initiation of therapy. In the majority of the cases, it is due to the reactivation of latent infection [19,20,21]. Hence, it is essential to screen all patients for latent Tuberculosis before initiating TNF alpha inhibitors. As in all immunosuppressed conditions, there is a predisposition for extrapulmonary involvement with TNF alpha inhibitors.

5.3 Tuberculosis after Solid Organ Transplant/HSCT

Patients receiving solid organ transplantation or hematopoietic stem cell therapy are at increased risk of developing Tuberculosis due to the use of various immunosuppressive drugs. In recipients of solid organ transplant, the risk of developing Tuberculosis was estimated to be 20–74 fold compared with the general population [22]. The risk is present with all organ transplant types, but the highest risk was noted in lung transplant recipients. The risk of developing Tuberculosis is highest in the first year after transplant. Most of the infections occur within six months of transplant. Lungs are the most typical tuberculosis infection site among transplant recipients. Still, extrapulmonary and disseminated forms were reported in 16% and 23% of transplant recipients.

5.4 Tuberculosis and Autoimmune Diseases

Autoimmune conditions like rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and systemic vasculitis are associated with immune dysregulation. Hence, all autoimmune diseases are associated with an increased risk of developing infections, including tuberculosis. Also, therapy for autoimmune diseases mainly consists of corticosteroids, cytotoxic agents, and other immunosuppressants. The use of these immunosuppressant drugs also increases the risk of developing tuberculosis in patients with autoimmune disease.

6 Other Specific Immunological Factors

6.1 Chronic Disease

6.1.1 Diabetes Mellitus

Multiple studies have shown that there is an association between uncontrolled diabetes mellitus and Tuberculosis [23]. Individuals with diabetes mellitus have three times more risk of developing Tuberculosis compared to non-diabetic patients [24]. Also, diabetes mellitus was associated with poor outcomes after treatment of Tuberculosis. In a systematic review, Baker et al. have shown diabetes increased the risk of secondary transmission, tuberculosis relapse and death during treatment. Although there is no literature regarding screening for diabetes in individuals developing Tuberculosis, screening may be warranted given the recent epidemic of diabetes mellitus.

6.2 Malignancy

There is an increased risk of the development of tuberculosis among persons suffering from malignancy. It is more commonly seen among individuals with hematological malignancies and with head and neck cancer [13, 25].

6.2.1 Chronic Kidney Disease

Chronic Kidney disease (CKD) is a significant risk factor for Tuberculosis. The increased risk is multifactorial, including uremia induced cellular immune dysfunction, CKD induced malnutrition, and vitamin D deficiency. In a study, tubercular peritonitis was shown to affect one-third of the patients on continuous ambulatory peritoneal dialysis. Apart from the increased risk, certain ATT drug dose modifications are required in patients with CKD. Ethambutol and fluoroquinolones dose needs to be reduced by 50% in patients with CKD, and streptomycin should be avoided in CKD patients.

7 Chronic Obstructive Lung Disease

Chronic Obstructive Lung disease is an established risk factor for pulmonary Tuberculosis, but it is unknown for abdominal tuberculosis. Nevertheless, the risk factors and therapy for COPD can interfere with antitubercular treatment.

7.1 Chronic Liver Disease

It is known that chronic liver disease is an immunosuppressed condition and theoretically associated with an increased risk of tuberculosis infection. However, limited data is documenting this increased risk. Only a few studies have shown that underlying cirrhosis was a risk factor for Tuberculosis. It is important to note that patients included in these studies were also consuming alcohol, which is a risk factor on its own. Cirrhosis is well recognized as a risk factor for peritoneal tuberculosis.

8 Substance Abuse

8.1 Smoking

Worldwide, approximately 1.3 billion people currently smoke cigarettes or use other tobacco products, with more than 900 million tobacco users living in developing countries [15]. Tobacco is the second major cause of death in the world. Multiple studies have shown that smoking is a risk factor for tuberculosis infection and disease. Still, its effect on abdominal tuberculosis is unknown [14, 16, 17]. Smoking impairs the response to antitubercular drugs and results in poor treatment outcome [26].

8.1.1 Alcohol

Alcohol consumption is a significant risk factor for the development of tuberculosis [27]. Alcohol impairs the immune system and increases susceptibility to both reactivations of preexisting disease and contracting a new infection [18]. It can impart a collateral insult by malnutrition, liver disease, and reduced utilization of medical facilities. A daily intake of alcohol >40 gm/day increases risk, and the risk rises linearly with every 10–20 gm of additional intake [28].

8.2 Malnutrition

Tuberculosis and undernutrition interact with each other. Persons with a low body mass index (<18.5 kg/m2) have an increased risk of developing Tuberculosis [29]. Vitamin D plays a vital role in macrophage activation and mycobacterial growth restriction; hence, lower serum vitamin D levels appear to increase tuberculosis risk [30, 31].

8.3 Aging

Elderly age is a risk factor for developing Tuberculosis owing to the impaired immunity with aging. However, in developing countries, Tuberculosis is seen more in young adults. The reason for this difference is not known. Still, factors like Malnutrition, substance abuse might contribute to the increased incidence in young adults.

8.4 Primary Immunodeficiency/Congenital Disorders

Primary immunodeficiency disorders (PIDs) associated with phagocyte and cell-mediated immune dysfunction commonly predispose to mycobacterial infections. Common PIDs associated with increased tuberculosis infection include severe combined immunodeficiency disease (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial diseases (MSMD). Other than PIDs, congenital disorders like cystic fibrosis are also associated with an increased risk of tuberculosis infection in children.

9 Latent Tuberculosis and its Implications

The host defenses contain mycobacterium tuberculosis; it is either cleared from the individual or remains in the latent phase. During this phase, the individual is noninfectious and asymptomatic. This can be active at any time and more prone to activation during impaired immunity, as already described above. Hence, it is essential to rule out latent Tuberculosis before encountering any of the following conditions: HIV infection, patients waiting for a transplant, patients receiving chemotherapy, and those who need to be initiated on anti-TNF alpha therapy.

There are two main tests for diagnosis of Latent Tuberculosis (LTB), the Tuberculin skin test (TST) and the interferon-gamma release assay (IGRA) blood test. Tuberculin skin test interpretation—this test consists of an intradermal injection of tuberculin material (PPD—0.1 ml-5 tuberculin units) over the forearm, which stimulates a delayed type of hypersensitivity and causes an induration within 48–72 hours. The test is read by measuring the transverse diameter of the induration. Induration of 5 mm, 10 mm, 15 mm has a sensitivity of 98, 90, 50–60, respectively, and specificity increases as the cutoff increases.

The test is considered positive when the induration is

>15 mm in healthy individuals

>10 mm silicosis, CKD, Diabetes mellitus, malignancy

>5 mm HIV, Close contact of the contagious case, Immunosuppressed patients—TNF alpha inhibitors, chemotherapy, post-transplant, high dose steroid therapy

The test can be false negative either because of technical causes (improper storage of tuberculin material, improper administration, or wrong reading) or biological causes (active infection, HIV, recent vaccination, immunosuppressive drugs, immunosuppressive conditions, elderly individuals). Tests can be falsely positive because of infection by non-tubercular mycobacteria or BCG vaccination. When suspicion is strong and the test is negative, a test can be repeated or get IGRA.

IGRAs are blood tests that measure the T cell release of interferon-gamma following stimulation by Mycobacterium tuberculosis antigen. In the IGRA test, the blood sample is incubated with antigens and controls. The test is conducted at a specific temperature, and results are available in 24 to 48 hours. Although there is no clear advantage of IGRA over TST, they can be used in individuals who have already received BCG vaccination. A positive IGRA test detects one or more specific antigens of mycobacterium tuberculosis which includes ESAT-6 and CFP-10. IGRAs have specificity >95% and sensitivity between 70–90% depends on the type of IGRAs. Tests are reported as positive, negative, or uninterpretable. Uninterpretable warrants repeat testing.

Patients with a positive test for LTB should be treated with either Rifamycin based regimens or isoniazid-based therapies in Table 25.5 [20, 32].

Table 25.5 Treatment of latent tuberculosis
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10 Conclusion

There is an increased risk of developing Tuberculosis in patients with underlying immunocompromise. The list of immunocompromised states are enormous, but common conditions associated with increased risk of tuberculosis reactivation include HIV, immunosuppressive drug use, uncontrolled diabetes, substance use like alcohol, and chronic diseases like renal failure, liver disease, transplant recipients, malignancy, and autoimmune diseases. Even though Tuberculosis’s typical manifestations are common in patients with an underlying immunocompromised state, more patients present with atypical radiological features, extrapulmonary involvement, and disseminated Tuberculosis. Because of the atypical manifestations, a high suspicion is required for early diagnosis and treatment initiation. Tuberculosis treatment regimens grossly remain the same as in non-immunocompromised individuals. Some modifications to the ATT regimen or drugs dose and therapy duration may be needed in certain conditions.