Hematologic Characteristics of Patients with Active Pulmonary, Extra-Pulmonary and Disseminated Tuberculosis: A Study of over Six Hundred Patients

Background: Many inflammatory cells, cytokines, acute phase reactants as well as platelets are recruited in the battle against the invading mycobacterium. As a result, alterations in the hematologic profile of infected patients are an-ticipated. Objectives: The primary objective was to investigate the various hematologic characteristics of patients with active tuberculosis. The secondary objective was to study the correlation between such hematologic characteristics and the type of tuberculosis including pulmonary, extra-pulmonary, and disseminated. Methods: This was a retrospective, descriptive study investigating the hematological findings in adult patients (aged 18 years or older) with active, bacteriologically-confirmed tuberculosis infection. Results: Among the 605 confirmed active tuberculosis cases, 465 (78.8%) were pulmonary, 104 (17.6%) extra-pulmonary, and 21 (3.6%) disseminated type. The mean age at diagnosis was 33.4 ± 11.4 years and males constituted 80.2% of cases. Peripheral leukocytosis was observed in 177 (30.1%) and leukopenia in 7 (1.2%) (Pulmonary type of tuberculosis was significantly associated with leukocytosis (P = 0.000)). Neutrophilia, lymphocytosis, patients with active tuberculosis. Leukocytosis can be seen in one-third of patients with pulmonary tuberculosis. Anemia of chronic diseases is the most common type of anemia observed in tuberculosis patients. Erythrocyte sedimentation rate and C-reactive protein are elevated in the majority of patients with active tuberculosis. Levels of the sedimentation rate can be useful indices to determine the extent of the disease.


Introduction
Tuberculosis (TB) remains a major global health problem. It is one of the top ten causes of death worldwide and the leading cause of death from a single infectious agent [1]. In the year 2010, an estimated ten million people fell ill with TB [1]. The diagnosis of TB remains a significant challenge despite the recent advent of molecular technologies. This diagnostic hurdle comes from the paucibacillary nature of the disease, the long time required to culture the bacteria, the low sensitivity of the new technologies, and the wide variety of clinical manifestations caused by the disease.
Inflammation is critical for TB pathogenesis. Many inflammatory cells are recruited in the battle against the invading Mycobacterium tuberculosis (MTB) bacilli including macrophages, monocytes, neutrophils, and primed T cells and B cells. Several pro-and anti-inflammatory cytokines, chemokines, and proteins are also produced by these cells with the most common outcome being lifetime control of the infection [2]. Besides these inflammatory cells, markers of platelet activity are also increased in plasma of patients with pulmonary TB compared with healthy control subjects. This platelet activity can alter the pro-inflammatory response and normalizes with anti-mycobacterial treatment [3] [4] [5]. Consequently, different studies have reported the presence of thrombocytosis in patients with TB. This increase in the platelet count has been correlated with the severity of TB and acute phase reactants [4] [6] [7]. Based on these facts, it is anticipated that TB infection can produce a range of alterations in the hematologic profiles of infected patients.
TB remains a common health problem in the state of Qatar with an incidence of 40/100,000 populations per year. About 97% of TB patients are expatriates (mostly from Asian countries with high TB prevalence). Qatar has a highly effective National TB Program with a case detection rate exceeding 70% [8]. All medications, laboratory, and radiological investigations for the diagnosis of TB are provided free-of-charge to all patients. To the best of our knowledge, hematologic characteristics in a large cohort of subjects with various types of active TB have seldom been reported in the literature.

Study settings and subjects
This was a retrospective, descriptive study investigating the hematological findings in adult patients (aged 18 years or older) with active, bacteriologically-confirmed TB infection who were admitted to Hamad General Hospital (HGH) (a university-affiliated and the largest tertiary referral hospital) during the period from 1 st January 2010 till 31 st August 2016. Because of the anticipated effects of anti-tuberculous medications on different hematologic values, only results of hematologic tests at initial presentation and before the initiation of anti-tuberculous medications were included in the analysis.
Study definitions Bacteriologically-confirmed TB case was defined in this study as a patient who received the diagnosis of active TB infection based on a positive acid-fast bacilli (AFB) smear in body fluids, and/or a positive MTB culture, and/or a positive MTB Polymerase Chain Reaction (PCR). The National Reference TB Laboratory in the State of Qatar performs a full range of TB work-up on any sample of suspected TB including MTB culture (using BACTEC MGIT 960 media-both solid and liquid media), PCR (GeneXpert MTB/RIF assay), fluorescence microscopy and Ziehl-Neelsen staining technique. Sputum for AFB is collected at HGH according to the Hamad Medical Corporation guidelines and the international standards [9].
Pulmonary TB was defined as TB that is confined to the lungs and diagnosed based on bacteriologically-positive sputum, Broncho-alveolar lavage (BAL), or lung biopsy. Extra-pulmonary TB was defined as an extra-pulmonary involvement in the absence of any evidence of lung infection and is bacteriologically confirmed by a positive biopsy or fluid analysis. Disseminated TB was defined as concomitant pulmonary and extra-pulmonary involvement.
Data collection Two investigators (LA & MA) independently performed an extensive review of the electronic medical records related to the enrolled patients. Using a standardized electronic form, each of the two investigators independently collected data regarding the demographic characteristics of the study subjects, the type of TB, the bacteriologic results, and the various hematologic parameters at the time of TB diagnosis. For quality assurance, three senior investigators (WI, AK & FK) further reviewed the collected data to confirm the accuracy of the information obtained.
Statistical analysis Qualitative and quantitative data values were expressed as frequency along with percentage and mean ± standard deviation with the median. Descriptive

Results
Among

Discussion
Some of the disease manifestations in the human body such as fever and cachexia along with alterations in the hematologic parameters are attributed to cytokine excess [10] [11]. Sedimentation of red cells is affected by forces both for and against sedimentation and the ESR is one of the acute-phase reactants that react to acute conditions in the body, such as infection, burns, surgery, or trauma [12].
The plasma concentration CRP increases during inflammatory states, a characteristic that has long been employed for clinical purposes. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is a part of the innate immune response [13]. The current study has shown that TB, in the State of Qatar, is a predominantly disease of young Asian men. This finding has also been demonstrated in previous studies by Ibrahim et al. and is expected in a country that relies heavily on the labor force from Asia for its economic and industrial projects [14] [15]. We have also demonstrated variable abnormalities in the leukocyte and differential leukocyte count with the most common being leukocytosis (30.1%), lymphopenia (24.1%), and neutrophilia (15.3%). Variability in leukocyte count seems a common finding in TB and has been previously reported in multiple studies. Bozoky et al. [16] in 1997 investigated the hematologic abnormalities in 380 patients with pulmonary TB. Leukocytosis with neutrophilia occurred in 18%. Leucopenia with neutropenia and lymphopenia was observed in 16% of patients with very severe clinical TB. Singh KJ et al. [17] prospectively examined the hematologic manife- been reported in other studies [16]. Nevertheless, few other studies reported higher anemia prevalence among TB patients. In the prospective study by Singh KJ et al. [17], normocytic normochromic anemia was observed in 84% of the disseminated/miliary cases and 86% of the pulmonary TB cases. More recent evidence supports the role of platelets in the host inflammatory and immune responses.
Furthermore, recent studies have also suggested the importance of mean platelet volume (MPV) as an inflammation marker in some chronic inflammatory disorders, such as rheumatoid arthritis, ulcerative colitis, and psoriasis [19] [20].

Conclusion
There is a wide range of variability in the leukocyte and differential leukocyte abnormalities observed in patients with active TB. Leukocytosis can be seen in one-third of patients with pulmonary TB. Anemia of chronic diseases is the most common type of anemia observed in TB patients. ESR and CRP are elevated in the majority of patients with active TB. Levels of ESR can be useful indices to determine the extent of the disease.