Sysmex Europe


Pathogen:Bacteria →Gram-positive rods →Mycobacterium tuberculosis
Geographical range:Worldwide
Incidence:9 million infections per year

Case history

A 23-year old man from Southeast Asia with an intermittent fever visited his physician four days after the initial fever onset. The man reported the following symptoms: shortness of breath, productive cough, abdominal pain, diarrhoea, night sweats and malaise. Considering the man’s symptoms, a complete blood count with WBC differential analysis was performed to investigate a possible tuberculosis infection.

Tuberculosis pathophysiology and diagnosis

Tuberculosis (TB) is a widespread infectious disease caused by various strains of mycobacteria (mainly Mycobacterium tuberculosis). Tuberculosis may infect any part of the body, but generally affects the lungs (pulmonary tuberculosis). The bacteria are spread through the air when people who have an active tuberculosis infection cough or sneeze and thus transmit respiratory fluids through the air. Most TB infections do not have symptoms, known as latent tuberculosis. About 10% of latent infections eventually progresses to active disease which untreated, can results in deaths (1). Tuberculosis of the lungs may also occur via infection from the blood stream. The hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones (2).

The mycobacterial infection begins in the pulmonary alveoli, where bacteria invade and replicate within endosomes of alveolar macrophages (1,3). Under normal conditions the macrophages identify the bacterium as foreign and attempt to eliminate it by phagocytosis and use of reactive oxygen species and acid. However, M. tuberculosis has a thick, waxy mycolic acid capsule that protects it. M. tuberculosis is able to reproduce inside the macrophage phagolysosome and will eventually kill the macrophage. Tuberculosis is classified as one of the granulomatous inflammatory diseases (such as Crohn’s disease and leprosy). Granulomas form when the immune system attempts to wall off substances it perceives as foreign but is unable to eliminate. Macrophages, T and B lymphocytes and fibroblasts aggregate to form granulomas surrounding the infected macrophages. The bacteria use the granulomas to avoid destruction by the host's immune system. Macrophages and dendritic cells in the granulomas are unable to present antigen to lymphocytes and thus the immune response is suppressed (4). Bacteria inside the granuloma can become dormant, resulting in latent infection.

Diagnosing active tuberculosis based merely on signs and symptoms is difficult. A diagnosis of TB should be considered in patients with signs of lung disease or constitutional symptoms lasting longer than two weeks. A chest X-ray and multiple sputum cultures are usually part of the initial differential diagnostic evaluation.

As representing an intracellular pathogen an active M. tuberculosis infection has a typical profile in blood WBC differential compared to extracellular bacterial and viral infections: activated monocytes, high neutrophil to lymphocyte ratio and high activation of neutrophils.

Screening and treatment for latent TB infection are indicated for groups in which the prevalence of latent infection is high and for patients with a high risk of reactivated disease (e.g. patients with HIV or diabetes or patients starting immunosuppressive therapy) (5). Latent infection can be diagnosed with a tuberculin skin test or an interferon-gamma assay.

Laboratory results


Case interpretation

The XN analyser results of the young man with fever and clinical focus on the lungs revealed a leukopenia with a relative increase in neutrophils (NEUT/LYMPH = 8.5). In the WDF channel the neutrophils showed an increased activation - NEUT-RI = 60.7 FI (increased fluorescence intensity) and combined with the increased activation of monocytes - MONO-SFL = 133.7 FI (increased fluorescence intensity) and a slightly increased parameter AS-LYMPH = 0.6% (antibody synthesising lymphocytes) the results could indicate active infection by intracellularly located bacteria.

The RET channel revealed a pathology in erythropoiesis represented by mild microcytic anemia, with 8.3% microcytes, 1.6% hypochromic cells and a normal Delta-He value, which could be interpreted as a functional iron deficiency due to an ongoing chronic inflammatory disease. The PLT-F channel revealed normal thrombopoiesis - no abnormality in total platelet count and normal IPF value.

The differential diagnosis in such pneumonia cases aim to distinguish the underlining cause, which can be either extracellular or intracellular bacteria, a viral infection or non-infectious inflammation process. The presented XN results showed an absolute decrease in neutrophil count. The activated neutrophils and a relative as well as absolute decreased lymphocyte count exclude a viral infection from differential diagnosis. In most cases pneumonia caused by extracellular bacteria would cause an increased absolute neutrophil count (together with an increased IG count), a decreased monocyte population and a negative Delta-He value. This description characterises an acute phase infection situation and would be usually also accompanied with thrombocytopenia. A non-infectious inflammation would result in neutrophilia and activation of neutrophils and monocytes would not be observed.

The slightly increased AS-LYMP parameter in the differential leukocyte count depict what are known as T-cell independent plasma cells, which are circulating unspecific antibody-producing cells activated directly by lipopolysaccharides released from the M. tuberculosis cell wall and binding to the B-cell receptor.

The overall results exclude an extracellular bacterial infection, non-infectious inflammation as well as viral infection. The final diagnosis of suspected tuberculosis was made by positive chest X-ray. Four weeks after the initial blood count and start of the antibiotic treatment the final TB diagnosis was confirmed by positive Ziehl-Neelsen stain sputum culture for acid-fast bacilli.


  1. World Health Organization (2015): Tuberculosis.
  2.  Kumar V, Abbas AK, Fausto N, Mitchell RN (2007): Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 516–522.
  3. Houben E, Nguyen L, Pieters J (2006): Interaction of pathogenic mycobacteria with the host immune system. Curr Opin Microbiol 9 (1): 76–85.
  4. Bozzano F (2014): Immunology of tuberculosis. Mediterr J Hematol Infect Dis 6 (1): e2014027.
  5. Ferrara G, Murray M, Winthrop K (2012): Risk factors associated with pulmonary tuberculosis: smoking, diabetes and anti-TNFα drugs. Curr Opin Pulm Med: 18:233-40.

Advanced clinical parameters

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