Keywords

HIV/AIDS; CD4+; Pulmonary TB; Generalized TB; ART; Mortality

Abbreviations

AIDS: Acquired Immune Deficiency Syndrome; ART: Antiretroviral Therapy; HIV: Human Immunodeficiency Virus; LTBI: Latent TB Infection; TB: Tuberculosis

Introduction

HIV infection has a profound impact on the global tuberculosis (TB) problem. Due to its ability to destroy the immune system, HIV has emerged as the most significant risk factor for progression of dormant TB infection to clinical disease [1-4].

Progression from TB infection to TB disease is accelereted from different factors that reduced eficacity of body defence, like malnutrition, Diabetes, HIV immune deficencies, and treated patientes for a long time with immunosuppressors and corticosteroids therapy. The impact that HIV has on the pathogenesis of TB is clear. From above factors HIV infection plays the main role in increasing probbability of developing from infection to TB disease, and raise the risk of reactivation of the tuberculosis (post primary TB). It is one of the most important risk factors associated with an increased risk of latent TB infection (LTBI) progressing to active TB disease. HIV-infected people have an annual risk of 5% to 15% of developing active TB once infected [5]. TB is the most common opportunistic infection in people living with HIV worldwide. TB also occurs earlier in the course of HIV infection than many other opportunistic infections.

When someone has both HIV and TB each disease speeds up the progress of the other. In addition to HIV infection speeding up the progression from latent to active TB, TB bacteria also accelerate the progress of HIV infection [6].

The risk of progressing from latent to active TB is estimated to be between 12 and 20 times greater in people living with HIV than among those without HIV infection [7]. Overall it is considered that the lifetime risk for HIV negative people of progressing from latent to active TB is about 5-10%, whereas for HIV positive people this same figure is the annual risk [8,9].

In 2015 there were an estimated 10.4 million new cases of active TB worldwide. Globally 11% of the incident TB cases in 2015 are estimated to have been among people living with HIV [10].

It is also the most common cause of death in HIV-positive adults living in developing countries, despite being a preventable and treatable disease [11]. Around one third of the deaths in the AIDS subjects came from tuberculosis. Approximately 12-15 million people around the world are co-infected with HIV and TB. Tuberculosis can lead to 15% deaths in AIDS patients worldwide [12-15].

The risk of death in co-infected individuals is also twice that of HIV infected individuals without TB, even when CD4 cell count and antiretroviral therapy are taken into account [8,16,17].

By the world literature TB is second cause of the deaths in HIV positive patients. HIV positive patients have 30 times more risk, to have tuberculosis, than HIV negative. TB is the cause for 40% of deaths in AIDS patients in Africa and Asia [18]. Also TB is the largest single cause of death in the setting of AIDS [11], accounting for about 26% of AIDS-related deaths [15], 99% of which occur in developing countries [19].

In 2015 400,000 people who had both TB and HIV are estimated to have died, in addition to the 1.4 million people who died from TB alone [10]. Those people who have HIV and TB co-infection when they die are internationally reported as having died of HIV infection [20].

The annual number of new HIV diagnoses in Albania, 1993-2014 [21] are presented in Figure 1.

Figure 1: Tannery effluents discharged in open land.

In Albania the number of people with both TB and HIV is small, from January 2004 to December 2015, approximately 5.6 % of the 751 HIV positive people in Albania are co-infected with TB (from 751 HIV positive cases, 42 cases have TB and HIV coinfection) (Figure 2), however, it is a category that should not be neglected [22].

Figure 2: The distribution of HIV positive TB cases/100,000 populations, by years, 2004-2015 [22].

More than 60% of tuberculosis cases in HIV patients are pulmonary disease. Clinical manifestation depend from the HIV disease stage. In early stage when the celluary immunity is quasy perserved, pulmonary tuberculosis resembles with postprimary TB in adults, with cavernes and infiltrates in the superior lobes of the lungs.Tuberculine test are usually positive, also positive in sputum smear microscopy. In HIV advanced disease with damaged cellular immunity, TB presentation is non-specific: fever, weight loss, fatigue, with or without cough.

Patients with low CD4+ count, may have extrapulmonary disease in bone narrow, lymphatic nodes, CNS, liver ect. HIV positive people with pulmonary TB may have the classic symptoms of TB, but many people with both TB and HIV infection have few symptoms of TB or even less specific ones. In addition, up to a fifth of people with both pulmonary TB and HIV have normal chest X-rays. HIV positive people with TB may indeed frequently have so called “sub clinical” TB, which often is not recognized as TB and subsequently there are delays in both TB diagnosis and TB treatment. HIV infected people are also more likely than people who are not infected with HIV to have extra pulmonary TB. Forty to eighty percent of HIV infected people with TB have extra pulmonary disease, compared with 10-20% of people without HIV [23].

Starting with the issues above it is important knowing the situation of tuberculosis in HIV/AIDS patients in our country. We tried to have a comprehensive insight about the occurrence of pulmonary manifestations in HIV/AIDS patients, and especially coexistence with TB. Design study is to answer questions concerning sociocultural factors in patients living with HIV/AIDS and TB, clinical characteristics, impact of several factors and behavioral in the course of the disease, predictive role of CD4 count.

Materials and Methods

This was a retrospective observational cohort study. It was conducted at the Outpatient service for HIV/AIDS, part of Infectious Department, University Hospital Center, “Mother Teresa”, Tirana, Albania. From January 2004 to December 2015 among 77 adult HIV/AIDS patients with pulmonary complications, there were 27 cases of TB, from them 23(85.2%) cases as pulmonary tuberculosis and 4 (14.2%) cases as generalized tuberculosis. The diagnosis of tuberculosis was based on clinical symptomatology, radiological and/or microbiological evidence of tubercular infection or with histology confirmation.

Based on a protocol, demographic data, clinical-radiological characteristics, and CD4 count were collected. CD4 count was determined by flow cytometry. The CD4 count were obtained at clinical presentation. They were used to assess the magnitude of injury to the host immune system.

The main outcome variable was TB diagnosis. CD4 count, age, gender, smoking habits, residing in urban/rural areas, period of knowing HIV infection, clinical manifestation, chest radiograph presentation, death were the main independent variables.

The study was approved by the ethics committee of Medical University of Tirana, Albania.

Data Analysis

All data collected was dropped in the Microsoft Excel program, from which they were exported to Statistical Package for Social Sciences (SPSS) 20.0 and Medstat, with which statistical data analysis was performed. For all categoric variables (nominal, including binary/dichotomous and ordinal), the absolute numbers and percentages were calculated. For all numeric variables, where data were subject to normal distribution, arithmetic averages ± standard deviations were computed. Differences between discrete group variables was carried out using Hi-square test. Data was compiled by simple and composite tables as well as graphs. Significant values of p ≤ 0.05 were considered.

Results

In the serie of 77 HIV/AIDS patients with pulmonary complications, tuberculosis has been diagnosed in 27 (32.2%) patients, 23 (27.4%) –pulmonary TB and 4 (4.8%) generalized TB. According to all 27 TB patients, with pulmonary TB were 23 (85.2%) and with generalized TB - 4 (14.8%). PCP was concomitant in 3 patient and COPD in one patients with HIV/AIDS and pulmonary TB.

The average age of the subjects with pulmonary TB and generalized TB was respectively 48.1 ± 9.8 (32 to 67 years) and 47.8 ± 10.2 (42-63 years) years (Figure 3), males – 22 (95.7%) and 2 (50%) (Pearson Chi-Square Asymptotic Significance (2-sided) 0.007), smokers – 21 (91.3%) and 4 (100%) (Pearson's R 0.558, Spearman Correlation 0.558), urban residents 16 (69.6%) and 3 (75%), low educations – 11 (47.8%) and 4(100%), unemployed – 9(39.1%) and 1(25%),workers - 6 (26.1%) and 2 (50%).

Figure 3: TB patients according to the group-age (Pearson's R - 0.697, Spearman Correlation - 0.860).

For pulmonary TB and generalized TB, respectively, time of knowing HIV infection was 6.2 ± 2.2 (2 to 10 years) and 4 ± 2.2 (1 to 6 years) years, the average period treated with antiretroviral therapy - 5.3 ± 2.8 (1 to 10 years) and 2.9 ± 3 (0.2 to 6 years).

The pulmonary TB patients have been known living with HIV <3 years in 2 (8.7%) cases, 3-5 years in 7 (30.4%), 6-8 years in 9 (39.1%) and 9-12 years in 5 (21.7%) cases. The period of treatment with antiretroviral therapy in the pulmonary TB cases were ≤ 1 year in 2 (8.7%) cases, 2-4 years in 8 (34.8%) cases, 5-7 years in 7 (30.4%) cases and 8-10 years in 6 (26.1%) cases.

The generalized TB patients have been known living with HIV <3 years in 1 (25%) cases, 3-5 years in 2 (50%) and 6-8 years in 1 (25%). The period of treatment with antiretroviral therapy in the pulmonary TB cases were ≤ 1 year in 2 (50%) cases and 5-7 years in 2 (50%) cases.

CD4 counts in pulmonary TB patients resulted 200-299 cells/ml in 6 (26.1%) patients, 100-199 cells/ml in 8 (34.8%) patients and in 9 (39.1%) patients in level <100 cells/ml, while in all patients with generalized TB was <100 cells/ml. (Pearson's R 0.571, Spearman Correlation 0.602).

Clinically, pulmonary tuberculosis has acute onset in 9 (39.1%) patients, sub-acute in 12 (52.2%) patients, and chronic in 2 (8.7%) patients. In Table 1 are presented clinical manifestations and frequencies in relation to the all 77 patients with pulmonary complications, 23 cases with pulmonary TB and 4 cases with generalized TB.

Table 1: Respiratory symptoms among HIV/AIDS patients with pulmonary manifestations.

Pulmonary TB lesions are localised on the right lung in 5 (21.7%) cases, on the left - 8 (34.8%), and bilateral –10 (43.5%); generalized TB – 1 (25%) case on the right, 2 (50%) on the left and 1 (25%) bilateral; from all cases - 6 (22.2%) case on the right, 10 (37%) on the left and 11 (40.8%) bilateral (Figure 4). Pulmonary Tb lesions are localized in upper zones in 13 (56.5%) cases, middle zone – 7(30.4%) and lower zone – 3(13%): generalized TB - in upper zones in 2 (50%) cases, middle zone – 1 (25%), and lower zone – 1 (25 %); from all cases - in upper zones in 15 (55.6%) cases, middle zone – 8 (29.6%) and lower zone – 4 (14.8%) (Figure 5). More common was seen bilateral pulmonary lesions (Figure 4). Of the 27 patients, 12 (44.4%) presented with atypical patterns, with parenchymal opacities at middle and lower zones. Chest radiograph showing evidence of adenopathy in 5 (21.7%) cases, while with CT in 7 (30.4%) cases.

Figure 4: Nr of patients according to TB pulmonary localization.

Figure 5: Patients according to lung zones of TB localization.

Of all patients with HIV/AIDS and TB were reported 7 (26%) deaths (Figure 6): 4 (17.4%) of pulmonary TB and 3 (75%) of generalized TB. Deaths in the patients of pulmonary TB were grouped in level of CD4<199 cells/ml, while in generalized TB in CD4<100 cells/ ml. (Pearson Chi-Square 5.888, Asymptotic Significance (2-sided) 0.015).

Figure 6: Death outcome of patients with HIV/AIDS and TB.

Discussion

While TB and HIV co-infection remains a major public health problem in many parts of the world, the number is still lower in Albania [24]. When someone has both HIV and TB each disease speeds up the progress of the other [25]. TB is the most common opportunistic infection in people living with HIV worldwide [26]. TB also occurs earlier in the course of HIV infection than many other opportunistic infections [27].

With regard to the gender structure, TB - HIV patients have been predominated in males - 88.8%, comparewith 50-69% in males TB in HIV seronegative [25,26]. This is in accordance with another study in Albania [22], where 88% of TB and HIV patients were males. In Albania, more men than women are diagnosed with HIV and TB and die from it like in most of the world. This gender ratio is reported almost the same from decades in our country, suspecting under-diagnosis in women. It may be supposed that women with tuberculosis are not declared for a lot of sociocultural causes or various issue related with access in healthcare system and health services [22,27-29].

Therefore, notwithstanding the biological explanations, there are strong arguments in favor of a link between female undernotification rates in the context of specific cultural factors which play an important role in developing and transitional societies [30]. Similar situation may well apply in transitional Albania. However, not all researchers have found such a gender discrepancy [31,32].

The average age of the subjects with pulmonary TB was 48.1 ± 9.8 (32 to 67 years), with most affected 45-54 years (47.8%). In other studies the most affected age was 36-45 years old (35%) [22], under 33-40 years were at a higher risk for TB [32], 38-47 years and 28-37 years age groups (both 40%) [33] and 25-44 years [34] that may reflect behavioral differences in terms of exposure and various socio-economic factors [35].

HIV/AIDS with pulmonary TB and generalized TB, respectively, were smokers in 21 (91.3%) and 4 (100%) patients, this probably, among others, with the negative impact of tobacco related to the progression of both diseases. Although both smoking and HIV infection may be associated through their common associations with poverty and high-risk behavior, tobacco smoking appears to be an independent and important risk factor for contracting HIV [36,37]. Other studies have demonstrated rate of progression of HIV infection to AIDS in smokers [38,39], but this association has not been observed in all studies [40,41]. Smoking further raises the risk of contracting TB in HIV-positive persons [42]. HIV infected smokers also have higher respiratory symptoms and risk of mortality, when compared to non-smokers [43].

Many patients in our study had low educations, and unemployed. Education level is a risk factor for active TB among HIV/AIDS persons [44,45]. More than 70% of the patients with tuberculosis in our country had 0-8 years of education, a level which is significantly higher than in the overall Albanian population of the same age-group [46]. With regard to the structure of occupations, TB-HIV patients have been predominated in the unemployed and workers group, because of poor social economic factors and lack of heath care adherence.

The clinical presentation of pulmonary TB can vary widely in both immunocompetent and immunocompromised hosts. In general, the presentation in HIV-infected patients is similar to that seen in HIV-uninfected patients. Symptoms usually are present for weeks to months, and an acute onset of fever and cough is more suggestive of a non-mycobacterial pulmonary process. This is in accordance with our results of sub-acute onset of TB in most cases. In HIV-infected patients, clinical manifestations of pulmonary TB reflect different levels of immunosuppression. Earlier in the course of HIV disease, TB is more likely to present as classic reactivation-type disease, whereas patients with advanced immunosuppression are more likely to present with findings consistent with primary TB.

According to the respiratory symptoms we could not find significant difference in the patient with pulmonary complication vs. tuberculosis. Assessments of respiratory symptoms in HIV subject can be very difficult for many reasons. Respiratory symptoms are common in HIV patients, but may come from a wide spectrum of diseases. The spectrum of lung diseases in HIV-infected patients includes those linked to HIV and those not related to HIV.

Of the 27 patients, 12 (44.4%) presented with atypical patterns, with parenchymal opacities at middle and lower zones. Chest radiograph showing evidence of adenopathy in 5 (21.7%) cases, while with CT in 7 (30.4%) cases. CT scan, resulted a useful tool for assessing patients with intrathoracic adenopathy, especially in the suspicious of adenopathy in radiographic examination.

The chest radiograph is important examination of diagnosis for pulmonary TB. In tuberculosis patients with relatively intact immune system, the radiographic findings are similar to those met with in non-HIV population [47]. In patients with severe immunodeficiency, there are atypical manifestations like diffuse or lower lobe bilateral reticulo-nodular infiltrates [48]. Upper-lobe infiltrates and cavities are the typical findings in reactivation TB, whereas intrathoracic lymphadenopathy and lower-lobe disease are seen in primary TB. In HIV-infected persons with higher CD4 counts (>200 cells/ml), the radiographic pattern tends to be one of reactivation disease with upper-lobe infiltrates with or without cavities [49]. In HIV-infected persons who have a greater degree of immunosuppression (CD4<200 cells/ml), a pattern of primary disease with intrathoracic lymphadenopathy and lower-lobe infiltrates is seen. As chest radiographs may appear normal in up to 21% of those with culture-positive TB and CD4 of <50 cells/ml [50] a high index of suspicion must be maintained in evaluating an HIV-infected patient with symptoms suggestive of TB [51,52].

Every opportunistic infections and neoplastic disease have the specific clinical and radiographical presentations. However, there may be considerable variations and overlapping in these presentations. There is not a standard constellation signs, symptoms and imagery features for diagnosis of Tuberculosis in HIV patients. Therefore, when it is possible, it is preferable to have a definitive microbiological diagnosis or pathological diagnosis.

Several studies have used the patients' CD4 cell counts to assess immune suppression and found that a lower CD4 cell count was associated with a higher risk of TB infection [32,53- 57]. These studies are consistent with our findings where CD4 counts in pulmonary TB patients resulted 200-299 cells/ml in 6 (26.1%) patients, 100-199 cells/ml in 8 (34.8%) patients and in 9 (39.1%) patients in level <100 cells/ml, while in all patients with generalized TB was <100 cells/ml. (Pearson's R 0.571, Spearman Correlation 0.602) The depletion of CD4 cells, which is a main feature of AIDS, is certainly an important contributor to the increased risk of reactivation of latent TB and susceptibility to new M. tuberculosis infection. From the data of the study, results a strong correlation between CD4 count cells and TB severity, being the lowest in generalised forms, associated with high deaths rates (75% cases). The CD4 determine the immunosuppression degree in HIV positive patients. There is an inverse relationship between CD4 count and immunosuppression degree. Some of the relevant studies have concluded that CD4 is a strong predictor of the HIV disease progress and patients survival [58].

Of all patients with HIV/AIDS and TB were reported 7 (26%) deaths: 4 (17.4%) of pulmonary TB and 3 (75%) of generalized TB. Deaths in the patients of pulmonary TB were grouped in level of CD4<199 cells/ml, while in generalized TB in CD4<100 cells/ ml. (Pearson Chi-Square 5.888, Asymptotic Significance (2-sided) 0.015). We conclude, according with the literature data, that the CD4 cell count is a strong predictor of the risk of death in HIV patients with pulmonary complications [59]. In another study in our country the specific weight of mortality was 45.2% [22]. Death tuberculosis rates in HIV patients are reduced in 32% since 2004 year [60,61]. Patients with HIV and tuberculosis in Eastern Europe have a risk of death nearly four-times higher than that in patients from Western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in Eastern Europe [62].

Conclusion

TB is a common respiratory complication with high mortality rate in HIV/AIDS patients. The level of CD4+ count is predictive factor for severity of clinical manifestation and prognosis. Co-infection TB-HIV is more prevalent in males, smokers, low educations and unemployed. TB is often presented with atypical radiological patterns.

Acknowledgement

The authors wish to thank all subjects who participated in this study for their help in collecting the data and care health for patients living with HIV/AIDS.

Conflict of Interest

No competing financial interests exist.

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