Tuberculosis (TB) Co-infection with HIV/AIDS: Clinical Presentation at Lacor Hospital, a Post-conflict Northern Uganda

Aims: To characterize the various clinical presentations of TB diagnosed in HIV/AIDS patients in the post-conflict Northern Uganda. Study Design and Setting: A prospective cohort study was conducted on 320 TB/HIV/AIDS co-infected patients at St. Mary’s Hospital, Lacor which is a specialist hospital in Gulu, Northern Uganda from July 2009 to July 2010. Methodology: Clinical features of confirmed 320 HIV sero-positive patients with confirmed TB co-infection (170 males and 150 females) recruited consecutively were studied and followed up for three months, their clinical presentations analyzed using SPSS version13.0. Ethics and Review Committee approved the study and those who did not meet the inclusion criteria were excluded. All patients gave an informed consent/Assent for the study. Results: The commonest clinical presentations were fever 316(98.8%), productive cough 268(83.7%), evening/night sweats 267(83.4%), general malaise 277(86.6%), wasting 228(71.3%), anaemia 220(68.8%) and lymphadenopathy 100(31.3%). The clinical features which were associated statistically and significantly with TB/HIV/AIDS co-infection were: Low grade fever (p=0.006); haemoptysis (p=0.001); Night sweats and evening fevers (p=0.043); Chest pain (p=0.041); General malaise (p=0.037) and wasting (p=0.047). Most patients 262(81.9%) improved and were discharged on Directly Observed Therapy Short-course (DOTS) while 58(18.1%) died. Conclusion: Clinical assessment is a very important adjuvant in TB/HIV/AIDS co-epidemic diagnosis. Early diagnosis and prompt management of TB co-infection ensured longer life and reduced morbidity and mortality.


INTRODUCTION
Tuberculosis (TB) and Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) constitute the main burden of infectious diseases in resource-limited countries [1,2]. Estimates by the World Health Organization (WHO) indicate that there are more than 9 million new active cases of TB and close to 2 million deaths occur every year, and that 2.6 million new cases of HIV infection and 1.8 million AIDS-related deaths occur every year [1,2]. Mycobacterium tuberculosis-HIV/AIDS coinfections pose particular diagnostic and therapeutic challenges and exert immense pressure on health care systems in African and Asian countries with large populations of coinfected individuals [1,2].
In the most heavily affected countries, HIV/AIDS infection has reduced the life expectancy of the population by more than 20 years; slowed economic growth; and deepened household poverty [1,2]. The natural age distribution in many national populations in sub-Saharan Africa has been dramatically skewed by HIV/AIDS, with potentially perilous consequences for transfer of knowledge and values from one generation to the next [3,4,5,6].
Previous studies have indicated that Mycobacterium tuberculosis (MTB) continues to be one of the world's most prevalent and deadliest infectious microbe, killing about three million people every year [3,6,7,8]. The past two decades has witnessed an unprecedented resurgence of tuberculosis in both developed and developing countries and HIV/AIDS is the major culprit contributing to the increased incidence and prevalence of tuberculosis [9]. Previous studies also indicated that early diagnosis and prompt management of TB among HIV/AIDS patients ensured longer life and reduced morbidity [9,10,11,12,13]. The pattern of clinical presentations of tuberculosis has remarkably changed over the years especially with the emergence of multi-drug resistant bacilli on the one hand, and the rapid spread of HIV/AIDS which have posed newer threats and added a new dimension to the control of tuberculosis [14,15,16,17,18,19].
In Northern Uganda with a population of about 6-7 million, HIV/AIDS prevalence is high, fluctuating between 8-12% and this is perhaps because of the two decades of prolonged civil war between the Government of Uganda and the Lord's Resistance Army (LRA) [12]. The TB prevalence is equally high at about 8% and TB co-infection amongst people living with HIV/AIDS is estimated between 45-50% [12]. This increase in Tuberculosis/HIV/AIDS co-epidemic is a double tragedy to the fragile health care system in Northern Uganda and this has made case detection and management of Tuberculosis worrisome [12]. There are more cases of atypical presentation of TB/HIV/AIDS co-infection with more extra-pulmonary TB perhaps as a result of lowered immunity in HIV/AIDS patients.
This study provides basic information regarding the condition of TB/HIV/AIDS patients at St. Mary's Hospital Lacor and considered the state of TB patients with HIV/AIDS co-infection in general.
Knowledge about the clinical presentation from this study is hoped to help clinicians to implement changes that would further improve case detection, management and planning of prevention programs in rural Hospitals.

Setting
This study was conducted at St. Mary's Hospital -Lacor in Northern Uganda. The hospital is one of the Regional Referral hospitals and it is a Teaching Hospital for Gulu University Medical School. It is a 550 bed hospital and has a catchment area extending from South Sudan, Democratic Republic of Congo and the population of northern, eastern and western Uganda. The hospital is located in Gulu district which is 340 km from the capital, Kampala. The population that obtains services at Lacor hospital are mainly rural and have been affected by the 20 year old civil war in which nearly 90% of the population were displaced into the Internally Displaced Peoples Camps (IDPCs) for security and kept in congested environment and lacked the basic health services and amenities [12].

Design
A prospective cohort study was conducted over a period of one year (July 2009 to July 2010). A sample size of 320 participants was found sufficient to evaluate the clinical presentation in TB/HIV/AIDS co-infection with a power of 80% at a confidence interval of 95%.

Participants' Selection
TB participants were consecutively selected from serologically confirmed cases of HIV/AIDS; age above 12 years; patients who have been in Northern Uganda in the last one year; confirmed TB cases and informed consent/assent formed the inclusion criteria. Those that did not meet these inclusion criteria were excluded.

Data Collection
An evaluation of clinical presentation in TB/HIV/AIDS co-infection was conducted by specialist physicians, radiologists and surgeons who were in the hospital as members of the research team. Socio-demographic features (Age, sex, district, social/physical surrounding, occupation, marital status and educational levels) were elicited and documented in coded questionnaires.
Clinical symptoms and signs (fever, cough, chest pain, difficulty in breathing, abdominal pain/tenderness, general malaise, cervical/axillary/inguinal adenopathy, oral thrush, wasting, back pain /spine and joint pain/swelling) were evaluated and the findings were documented in the coded questionnaires, the imaging results, histological investigations and laboratory findings were recorded on the performa designed for the recruitment and followup of the participants.

Procedures
The Principal investigator and co-investigators took concise and detailed history and conducted physical examinations of all participants who were HIV positive and with suspected TB coinfection and performed all the plain radiography (PA-CXR, AP/Lateral spinal x-ray and joint x-ray) and did all the echocardiography (transabdominal ultra-sonography, chest, transthoracic echocardiography and joint ultrasonography) and ultrasound to confirm diagnosis of the various types of TB. The clinical, radiographic, ultra-sonographic and histological findings were synthesized and documented on coded questionnaires. For those patients that were coughing, sputum was taken for test for Alcohol Acid Fast Bacilli (AAFBs) on the ZN stains.
Pulmonary tuberculosis (PTB) was defined as being smear positive in at least two microscopic examinations or sputum smear positive in one microscopic examination plus an abnormal chest X-ray (CXR) consistent with TB. PTB was also defined as being sputum smear negative but with an abnormal CXR consistent with TB and or sputum smear negative with persistent or worsening abnormal CXRs taken at interval of one month apart despite adequate treatment with broad spectrum antibiotics for at least two weeks.
Extra-pulmonary TB was defined as TB of any organ other than the lungs such as (pleura, meninges, abdominal system, urinary system, bones, joints and skin).
Disseminated TB was defined as the presence of TB in the lungs (smear positive or smear negative with abnormal CXRs) and in at least one other body site (abdomen, lymph-node), miliary TB/presence of TB in liver or spleen biopsy samples.

Data Analysis
SPSS software package of version 13.0 was used to analyze the data. Univariate statistical analysis was conducted to generate frequencies and proportions and secondly bivariate analysis was used for determining associations between dependent and independent variables.

Ethical Consideration
The study was approved by the Ethics Committee of Gulu University Medical School and Uganda National Council of Science and Technology (UNCS&T). Informed consent/assent was obtained from each participant before any procedure was conducted.

Socio-Demographic Characteristics of the Participants
One hundred seventy males (53.1%) and One hundred and fifty females (46.9%) were enrolled into the study with a male to female ratio of 1.1:1.
The age range was 14-69 years with a mean of (34.3±9.6) years and median of 34 years.

Night sweats and evening fevers
Majority of the participants diagnosed with TB/HIV/AIDS co-infection presented with night sweats and evening fevers and the association was statistically significant (χ 2 =6.314; df=1; p=0.043) ( Table 2).

Chest pain
The majority of the participants diagnosed with TB/HIV/AIDS co-infection presented with chronic chest pain and this association was statistically significant at bivariate analysis (χ 2 =4.456; df=1; p=0.041) ( Table 2).

General malaise
The majority of the participants diagnosed with TB/HIV/AIDS co-infection presented with general malaise and this was statistically significant at bivariate analysis (χ 2 =6.458; df=1; p=0.037) ( Table 2).

The CD 4 Counts for the Participants
Two hundred and eight participants (65%) had CD 4 counts between 10-200 cells per ml; 80(25%) had between 201-500 cells per ml and 32(10%) between 501-800 cells per ml. None of the participants were already enrolled on HAART but about 30% were on Co-trimoxazole prophylaxis.

DISCUSSION
TB is one of the most important HIV/AIDS opportunistic infection world-wide and it has become one of the leading causes of death among people living with HIV/AIDS (PLWHA) [6,7,8]. Although patients with HIV/AIDS associated TB mostly have the typical clinical pictures, the frequency of atypical manifestations is increased in status of advanced immunesuppression therefore, making the diagnosis more difficult [8,9].
In the present study, the male to female ratio was 1.1:1; which showed a near unity in sex distribution of TB/HIV/AIDS co-epidemic in northern Uganda. However, the reason for slight male predominance could perhaps be because, males were more involved in risky social behavior, with multiple heterosexual partners and poor health seeking behavior leading to delay in HIV diagnosis and delayed initiation on Highly Active Antiretroviral Therapy (HAART) which increased the chances of TB opportunistic infection. This is in agreement with other findings of other researchers in other part of the world [20,21,22,23,24].
However, this finding differs from that of Nigeria which had a male to female ratio of 1:3; which indicated a female predominance [14,17]; this was perhaps because of polygamous marriages; early female marriages; freedom to remarry after divorce or death of a spouse which was practiced in that part of Nigeria and may have contributed to this disparity.
The mean age of the patients in this study was (34.3±9.6) years, similar to the observations of other researches elsewhere [24,25]. This substantiated the fact that HIV/AIDS was more common in people in their productive and sexually active age groups (Fig. 1).
Clinically, productive cough for 2 weeks or more and with haemoptysis attributed much higher frequency of smear positive pulmonary TB ( Table  2). Most participants presented with a low grade fever and followed by high grade fever ( Table 1). The presence of fever among these participants could be explained by TNF-α; a cytokine produced during the immune response to TB-HIV/AIDS co-infection [26,27,28]. Previous studies also reported presence of fever on initial presentation [27,28]. Lymphadenopathy was also a common finding: its frequent occurrence was noted by many researchers and was probably due to the pathological process of clearance of infected macrophages [7,27,28].
Haematological abnormalities such as anaemia, pancytopaenia and leucopenia were present in more of the participants; a finding that was similar to those previous studies, and might signify bone morrow involvement, especially in disseminated forms of TB infection [13,29].
This study produced evidence that disseminated TB existed in almost half of all the patients (Table 1) as similarly observed in previous studies [13,15,17,18]. A possible explanation was that extensive CD 4 T-cell depletion in HIV/AIDS infection resulted in impaired immunity against TB, leading to the development and dissemination of active TB.
Extra-pulmonary TB was found in less than ten percent of the total study population similar to previous studies (Table 1). This may be caused by the easier spread of the bacilli when the body's defenses were unable to amount an efficient immunological challenge to the bacilli [15,17].
Pulmonary TB was found in more than fifty percent of the participants studied. The fact was that pulmonary TB among HIV/AIDS participants had been reported as having variable prevalence and its frequency depended upon study location for example western countries tended to see this form of TB more often (70 to 90%) than all other  cases. Previous studies in Thailand seemed to indicate that fewer than half of all cases were purely pulmonary [13]. These differences may be attributed to many factors including the fact that western patients were less likely to be significantly immune-compromised and were more likely to have access to antiretroviral therapy in these circumstances; and therefore a more typical picture of TB would be expected while in northern Uganda the reverse was true; because these participants were more significantly immune-compromised with more than sixty percent of the participants with CD 4 + cells ranging from less than 10 cells per ml to 200 cells per ml; with various degrees of malnutrition and overwhelming secondary infections (malaria, pneumonia, gastroenteritis and bacteriaemia and septicaemia). These were probably aggravated by poor living conditions especially in this post-war environment and further compromised by poor health seeking behavior among the population.

Age of the patient
It was important to note that a third of TB/HIV/AIDS co-infected patients in this high HIV and high tuberculosis prevalent population presented with chest radiographs typical of postprimary TB (Chronic or reactivation tuberculosis). Fibro-cavitations were also noted in other previous studies in Asia, Africa and Uganda [13,19]. Therefore, significant burden of HIVrelated tuberculosis was probably due to reactivation of the latent infection and progression of chronic disease as a result of immunodeficiency.
In Northern Uganda, as it is true to Uganda and Africa at large, tuberculosis control efforts focuses on the effective treatment of smear positive patients. From this present study, the majority of HIV/AID participants with TB coinfection were smear negative, with 42.2% with disseminated TB and 4.4% with Extra-pulmonary TB. Active case finding was not undertaken nor was chemoprophylaxis of infected but nondiseased individuals being conducted in Northern Uganda. Whilst this approach may decrease the transmission of infection, it was not likely to prevent reactivation and progression of preexisting tuberculosis in relation to HIV infection.
In order to increase the case detection in Northern Uganda, this present study has highlighted the practical and optimal diagnostic pathway that can be utilized by the clinicians in this era of TB/HIV/AIDS co-epidemic by looking at the clinical features of the disease and subjecting the suspected cases to further diagnostic analysis.
The study has shown that TB can occur at any time during the course of HIV infection and Pulmonary TB was the commonest form of TB in HIV/AIDS participants, followed by disseminated TB and then extra pulmonary TB and the clinical presentation of TB depended mainly upon the degree of immune-suppression in these patients. The clinical presentation of TB in early stages of HIV infection was similar to that in HIV negative patients often resembling post-primary pulmonary TB with upper lobe reticulo-nodular infiltrates and fibro-cavitations lesion and sputum smear results were often positive. During the later stage of HIV infection the presentation of TB resembled primary disease with diffuse reticulonodularities involving predominantly the middle and lower lung zones; miliary pattern; hilar and mediastinal lymphadenopathy; pleural effusion and the sputum smear were often negative. Cases of smear negative TB were also noted to be on the increase following the TB/HIV/AIDS coepidemic.
For the disseminated TB and Extra-pulmonary TB; ultrasonography played an extraordinarily important diagnostic role. The commonest sites involved and those that were easily accessed by echography were the abdomen, chest and lymph-nodes (Table 1). In TB/HIV/AIDS coinfection; intra-abdominal lymphadenopathy was the most common, followed by Ascitis, pericardial effusion, splenitis and nephritis/peri-renal abscess which was detected at clinical examinations and imaging investigations.
It is important to note that there was a markedly low prevalence of oral thrush and oral Kaposi's sarcoma among the TB/HIV/AIDS co-infected participants; a factor which may be attributable to the changing epidemiology of HIV/AIDS in this post conflict environment. Furthermore, TB remains a major public health problem in Uganda with an annual incidence of 330 cases of all forms and 136 new smear positive cases per 100,000 people per year [1,4]. Uganda like most of Sub-Saharan Africa is still battling with the dual TB and HIV/AIDS epidemic and the HIV prevalence in the general population of Uganda is 7.4% and is estimated that about 60% of the TB patients are co-infected with HIV/AIDS [12]. This dual epidemic has resulted in a fourfold increase in the notification numbers of TB cases in the region and it stands as the number one killer of HIV/AIDS patients [4]. The clinical presentation of TB among the dually infected persons has changed and this has a bearing on the clinical management and design of public health interventions to respond to the dual epidemic [12].

CONCLUSION
Clinical assessment is a very important adjuvant in TB/HIV/AIDS co-epidemic diagnosis. The clinical features which were associated statistically and significantly with TB/HIV/AIDS co-infection were: Mild grade fever; haemoptysis; Night sweats and evening fevers; chronic chest pain; general malaise and wasting. Early diagnosis and prompt management of TB/HIV/AIDS co-infection ensured longer life and reduced morbidity and mortality.

CONSENT
All authors declare that written informed consent was obtained from the participants for publication of this information.

ETHICAL APPROVAL
All authors hereby declare that all experiments have been examined and approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki [30].