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T. Sehgal etal.
4.1 Introduction
Tuberculosis (TB) is a multi-organ disease and can inuence biochemical and haematological changes. These parameters are the routine investigations carried out to
rule out the type of infections in patients. The haematological parameters provide
important information about the types and numbers of blood cells in the blood,
mainly white blood cells (WBCs), red blood cells (RBCs), platelets erythrocyte
sedimentation rate (ESR) and haemoglobin [1]. Biochemical changes such as adenosine deaminase (ADA) and serum albumin often helps in diagnosis [2].
Tuberculosis remains a global health issue with high morbidity and mortality rates,
especially in Asian and African countries, with estimated cases of 10.6 million
annually and 1.6 million deaths globally [3]. TB is an infectious disease caused by
the bacilli Mycobacterium tuberculosis (Mtb). It primarily affects the lungs but can
also affect the meninges, bones, joints, intestines, lymph nodes, skin, endometrium,
and other tissues of the body. Tuberculosis transmission is still a problem due to a
variety of factors, such as social, economic and environmental. When TB patients
cough or sneeze, aerosols are formed and spread to other persons, whose immunity
is weakened. The World Health Organization (WHO) and National Tuberculosis
Elimination Programme (NTEP) recommended a directly observed treatment shortcourse (DOTS) strategy standard therapy for tuberculosis treatment [4–6].
Combinational drug therapy was used for the treatment of tuberculosis and has
been associated with increased incidences of variousside effects. These side effects
may be minor to lethal. The major side effects are hepatotoxicity, nephrotoxicity,
hypercalcaemia, neuropsychiatric manifestations, hyperuricaemia, ototoxicity and
hypokalaemia. Several other biochemical and haematological changes may occur in
the level of electrolytes, magnesium, phosphorus, lipid prole, platelet count, haemoglobin and hematocrit of TB patients, respectively [1, 2, 7, 8].
Although tuberculosis is a common illness, atypical and various spectra of clinical presentations pose a diagnostic and therapeutic challenge to physicians. To monitor the diagnostics and progress of tuberculosis therapeutics, haematological and
biochemical parameters are very important. On the basis of the current literature
and knowledge available, this chapter aims to study the changes in various haematological and biochemical parameters in all forms of tuberculosis patients.
4.2 Haematological Parameters
The diagnosis of tuberculosis mainly relies on the detection of tuberculosis by
microscopy, culture and the most advanced Nucleic Acid Amplication Test
(NAAT)-based diagnostics. Active tuberculosis produces clinical symptoms and
signs, including abnormalities in haematological and biochemical parameters.
Changes in haematological parameters are seen during the infection. Complete
blood count (CBC) is recommended for all patients as a routine investigation,
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irrespective of infection type, providing essential information in deciding treatment.
In tuberculosis, changes in various haematological parameters are seen, includinganemia, lymphopenia, monocytopenia, thrombocytopenia and alsothrombocytosis, neutrophilia and monocytosis. Reversible peripheral blood abnormalities
usually are associated with PTB [9]. The haematological changes sometimes act as
helpful factors, providing supporting diagnostic modalities and helping clinicians
make a holistic decision regarding the diagnosis, prognosis and treatment of the
disease. Due to signicant variability in the clinical presentationof tuberculosis, it
poses challenges for diagnostics and therapeutics to the physicians. In the literature,
numerous haematological abnormalities in association with tuberculosis have been
described, and these changes in haematological parameters may act as biomarker
for diagnosis, prognosis and response to antituberculosis therapy.
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4.2.1 Anaemia
Anaemia is a commoncondition associated with the diagnosis of tuberculosis. The
prevalence of anaemia in tuberculosis patients is much higherthan in healthy individuals. The hemoglobin (Hb) level tends to decrease as acid-fast bacilli (AFB)
smear positivity increases [10], and the presence of anaemia during the course
ofTB delays smear negativity. Anaemia is also associated with unfavourable TB
outcomes [10], and has ahigher risk of mortalityamong TB patients. Again,the
prevalence of anaemia is signicantly higher in HIV-TB (TB associated with Human
Immunodeciency virus infection)than in HIV-negative TB patients. Normochromic
normocytic anaemia is the most common type, followed by microcytic anaemia.
Anaemia in tuberculosis patients occurs as a consequence of chronic inammation
and without loss of blood or bone marrow suppression [11]. The blunted response
of erythropoietin due to the release of tumour necrosis factor (TNF) or other cytokines has been reported. In anaemic patients, cell-mediated immune response and
bactericidal capacity of leucocytes are signicantly suppressed. Recent metaanalysis shows that anaemia is a risk factor of TB, and the risk is increased depending on the severity of the anaemia [12]. Anaemia has been associated with severe
forms of TB, including meningeal and disseminated forms, suggesting that it may
serve to understanddisease severityin TB.
TB induces a systemic inammatory response that stimulates the synthesis of
hepcidin from hepatocytes and macrophages, the primary iron metabolism regulator [13]. Hepcidin modulates cellular iron export to plasma via ferroportin.
Ferroportin is both the receptor for hepcidin and the only known iron exporterin
vertebrates [13]. Ferroportin is expressed on cells that manage iron professionally
in the body, including duodenal enterocytes that absorb dietary iron, macrophages
in the liver and spleen that recycle old erythrocytes, hepatocytes that store iron and
placental trophoblasts that transfer iron to the foetus during pregnancy [14]. The
internalisation of ferroportin is triggered by the binding of hepcidin to ferroportin;
once internalised, the hepcidin-ferroportin complex is degraded in lysosomes and
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cellular iron export ceases [14]. Anaemia caused by a deciency in folic acid or
vitamin B12, although uncommon, has also been described in patients with TB.It
is primarily associated with malnutrition, an increase in folate consumption due to
the disease and intestinal malabsorption syndrome due to the localization of disease in the ileocecal region [15]. Anaemia can also occur in the early stages of
tuberculosis treatment. As treatment reduces inammation, iron becomes available
for haematopoiesis, causing an increase in reticulocytesand normal hematopoiesis
is gradually restored.
T. Sehgal etal.
4.2.2 Leucocyte Abnormalities
TB affects the white blood cells (WBC). Both leukopenia and leucocytosis are
abnormalities associated with tuberculosis [16]. In some instances, a leukamoid
reaction may be seen as resembling a neoplastic process [16]. Neutropenia or neutrophilia, lymphocytopenia or lymphocytosis and monocytopenia or monocytosis
may all be revealed in TB [16]. Lin F.-S etal. demonstrated that the prevalence of
leukopenia in TB patients was 10.4%, whereas it was 9.1% in previously treated TB
patients [17]. Neutrophils may also be affected, with neutrophilia being more common than neutropenia. Neutrophils are seen to revert to normal after successful
treatment [16]. Neutropenia is multifactorial and may be caused by the suppression
of bone marrow granulopoiesis by activated T cells, a deciency in folate and vitamin B12, bone marrow brosis or splenic sequestration [16]. Gelaw Y etal. demonstrated that female gender, elderly age group, more than 6 months of anti-TB
treatment and antibiotics were risk factors for low white blood cell count or leukopenia [15].
4.2.3 Platelet
Thrombocytosis and thrombocytopenia are both associated with TB [18].
Thrombocytopenia is seen in severe forms, such as miliary and disseminated TB,
whereas thrombocytosis is more prevalent in pulmonary TB (PTB) [18]. In the
majority of patients with disseminated/miliary TB, normal haematopoietic elements
in the bone marrow are severely suppressed. TB granulomas cause anaemia, monocytopenia and an increase in histiocytosis of the bone marrow [19]. Thrombocytosis
is associated with the severity of inammation and elevated interleukin 6 levels
[19]. Thrombocytosis could be the cause of hypercoagulability and may precipitate
thromboembolism and deep vein thrombosis (DVT) [19]. Rarely has TB-related
immune thrombocytopenia (ITP) been described in the medical literature [15].
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4.2.4 Erythrocyte sedimentation rate (ESR)
ESR is a blood test that measures the rate of fall of red blood cells in a column of
anticoagulated blood in 1h in millimetres per hour (mm/h) [20]. ESR is a low-cost
and easily accessible examination, particularly in resource-limited regions where
tuberculosis is prevalent. ESR is a general indicator of inammation [20]. Anaemia,
kidney failure, obesity, ageing and female gender are non-inammatory conditions
that can induce an elevated ESR.ESR is also elevated during menstruation and
pregnancy in women [20]. In addition, ESR is elevated in autoimmune diseases
such as rheumatoid arthritis and lupus, infections, certain renal diseases and neoplasms, including lymphoma and plasma cell disorders [20]. The determination of
the rise in ESR in pulmonary tuberculosis is related to an increase in brinogen and
plasma globulin levels associated with acute phase responses. If the patient was on
anti-tuberculosis therapy, the non-specic ESR value can also be used to assess the
disease’s response [20].
4.2.5 Rare Manifestations ofTB
See Table4.1.
Table 4.1 Rare manifestations of tuberculosis, description and clinical features
Manifestation Description Clinical features Other characteristics
Henoch–Schönlein
purpura (HSP)
Pancytopenia Haematological
It is a vasculitic
syndrome
characterised by
diffuse urticarial
lesions and palpable
purpura primarily
affecting the lower
extremities
abnormality due to
bone marrow
localisation of TB
It is associated with joint
pain, abdominal pain and
renal impairment
It is usually characterised
by fever, fatigue, loss of
weight and massive
splenomegaly. Diagnosis is
made on bone marrow
biopsy
Seen in patients with
pulmonary TB
Factors leading to
pancytopenia include
hypersplenism,
histiocytic hyperplasia,
maturation arrest of
haematopoietic cells
and inltration of the
marrow by granulomas
and subsequent
brosis of the bone
marrow
(continued)
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Table 4.1 (continued)
Manifestation Description Clinical features Other characteristics
Hemolytic anaemia Autoimmune
Myelobrosis It is a rare disorder
Hemophagocytic
lymphohistiocytosis
(HLH)
Leukemoid reaction It is dened as an
Disseminated
intravascular
coagulation (DIC)
Thromboembolism It is more common
hemolytic anaemia
(AIHA)
characterised by
extensive brosis of
the bone marrow
and a marked
decrease in normal
haematopoiesis
Occurs rarely in
TB.It is an
uncommon and
potentially fatal
disorder associated
with cytokine storm
and inammation
increased WBC
count (>50,000cells/
μL), which is a
physiological
response to stress or
infection. It is often
associated with the
presence of
immature precursors
of white cells and
red blood cells
It is a rare and
potentially fatal
manifestation of TB
in patients with TB
than in the general
population
It is characterised by high
reticulocyte count, raised
unconjugated bilirubin,
reduced haptoglobin and
blood smear showing
normocytic to macrocytic
anaemia with polychromasia
and other ndings of
spherocytes or agglutination
It may present as
pancytopenia secondary to
the myelosuppressive
effects of TB
It is characterised by fever,
cytopenias, organomegaly
and deranged laboratory
parameters, like
hypertriglyceridemia,
transaminitis, elevated
ferritin and coagulopathy
High leukocyte count in
blood lms with immature
precursors of white cells
and red blood cells, may
resemble a leukaemic
process
Occurs probably due to
mycobacterial endo- or
exo-toxins, capable of
initiating the clotting
cascade, or protein release
into circulation during
bacteraemia
TB can be responsible for
hypercoagulability as a
result of chronic
inammation
Seen in patients with
severe forms, such as
disseminated TB
TB may stimulate a
brotic reaction or may
develop in patients with
pre-existing
myeloproliferative
disorders
HLH is associated with
high mortality
It may rarely occur in
patients with extrapulmonary or
disseminated TB and is
common in older males
Has a high mortality
and is seen in patients
with miliary TB
There is an increase in
the plasma level of
factor VIII, brinogen
and the plasminogen
activator inhibitor as
well as a reduction in
natural anticoagulants
such as protein C and
antithrombin
T. Sehgal etal.
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4.2.6 Drug-Induced Changes
Many abnormalities seen in TB can also be induced by anti-tubercular therapy
(ATT), and it makes the diagnosis problematic in a patient who has started therapy.
Autoimmune haemolytic anaemia may developdue to the adverse effect of rifampicin, PAS and INH or may have been an underlying condition in these patients.
Megalobasltic anaemia may happendue to PAS (malabsorption of vit B12), sideroblastic anaemia due to INH, cycloserine, PZA,pure red cell aplasia due to INH
(immune mediated), agranulocytosis due to thioacatazone, PAS and streptomycin,
autoimmune thrombocytopenia due to INH and PAS, aplastic anaemia due to streptomycin, PAS; disseminated intravascular coagulation (DIC) due to INH (factor
XIII deciency), rifampicin (induction of cyto P-450), PAS (hypothrombinemia)
etc. [21–24] (Table4.2).
4.3 Biochemical Parameters
Tuberculosis is a systemic disease affecting multipleorgan-systems and thus,can
impact biochemical parameters.
4.3.1 Sodium
According to a number of studies, patients with newly diagnosed tuberculosis
have lower serum sodium levels than patients receiving treatment and healthy
controls [2]. Hyponatraemia i.e. low serum sodium levels may be caused by local
invasion of the hypothalamus, pituitary gland and adrenals or by the syndrome of
inappropriate anti-diuretic hormone secretion in the presence of TB meningitis
[2]. In one study involving 200 cases of tuberculosis, Jonaidi etal. found that
new cases of TB had lower serum sodium levels than those on treatment and
controls. In contrast, a study conducted by Olalekan etal. in southwestern Nigeria
on electrolyte imbalance among tuberculosis (TB) patients on medication found
that serum sodium was considerably lower among those on treatment compared
to new cases [25]. The inclusion of patients with chronic kidney disease or other
comorbidities such as HIV, etc. in their study group may account for the
difference [25].
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Table 4.2 Drug-induced changes in tuberculosis patients
Drug Blood ndings/other disorders
Rifampicin RBC-hemolysis
WBC-leukopenia, agranulocytosis
Platelets-thrombocytopenia, thrombocytopenic purpura
Clotting abnormalities-DIC
Isoniazid RBC—Sideroblastic anaemia, red cell aplasia WBC-agranulocytosis
Platelet—Thrombocytopenia
Ethambutol RBC—Hemolytic anemia
WBC—Neutropenia, eosinophilia
Platelet—Thrombocytopenia
Pyrazinamide RBC—Megaloblastic anemia, sideroblastic anaemia
Platelet—Thrombocytopenia
Rifapentine RBC—Aplastic anemia, AIHA
WBC—Agranulocytosis, leukemoid reaction, leukopenia
Platelet—Thrombocytopenia
Others—TTP, acute porphyria
Rifabutin WBC—Leucopenia
Cycloserine RBC—Megaloblastic anemia, sideroblastic anaemia
Para -aminosalicylic acid
(PAS)
Streptomycin WBC—Eosinophilia, leukopenia
Amikacin Causes drug rash with eosinophilia and systemic symptoms known
Levooxacin RBC—Hemolytic anemia
Moxioxacin WBC—Neutropenia
Clofazimine RBC—Hemolytic anemia, macrocytosis, elevated reticulocyte count
RBC—Hemolytic anemia, methemoglobinemia
WBC—Agranulocytosis
Platelet—Thrombocytopenia
Platelet—Thrombocytopenic purpura
as DRESS syndrome
WBC—Leukopenia
Platelet—Thrombocytopenia
T. Sehgal etal.
Ethionamide
prothionamide
Meropenem/imipenem RBC—Hemolytic anemia
Linezolid RBC—Anemia
4.3.2 Potassium
Potassium levels in newly diagnosed TB patients may be low or elevated. Ufoaroh,
etal. found that patients with newly diagnosed TB had substantially higher serum
WBC—Agranulocytosis, neutropenia
WBC—Neutropenia
Platelet—Thrombocytopenia
WBC—Neutropenia
Platelet—Thrombocytopenia
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potassium levels than the control group and those receiving treatment [2]. In contrast to the cases and the non-TB control group, patients on follow-up treatment had
a signicantly lower serum potassium concentration in their study. Olalekan etal.
found that the serum potassium levels of TB patients on treatment were lower than
those of newly diagnosed TB patients [25]. Similarly, Bhagyamma etal. found in
their study that patients with a new TB infection had decreased potassium serum
levels [26]. Salina etal. demonstrated that potassium-decient solid media inhibited
the growth of Mycobacterium tuberculosis, whereas potassium-rich solid media and
liquid media promoted its growth, indicating that mycobacteria may require a
potassium- rich environment to proliferate [27].
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4.3.3 Calcium
Low serum calcium levels have been observed in newly diagnosed TB patients.
Similar to the results of Ali-Gombe etal. and Rohini etal., Ufoaroh CU etal. found
that patients with newly diagnosed TB had substantially lower serum calcium levels
than those in the follow-up and non-TB control groups in their study on TB patients
[2, 28, 29]. The granulomatous disease tuberculosis is associated with alterations in
calcium metabolism, including hypercalcaemia and hypocalcaemia. Hypocalcaemia
can be attributed to malnutrition, impaired absorption and vitamin D deciency in
patients with pulmonary tuberculosis [2].
4.3.4 Albumin
Serum albumin levels are also substantially low in newly diagnosed TB patients
who had not yet begun treatment as compared to the non-TB control group [2, 30].
4.3.5 Liver Function Test(LFT)
TB is typically treated with a combination of isoniazid, rifampicin, pyrazinamide
and ethambutol, according to standard recommendations [31]. Drug-induced liver
injury (DILI) is a signicant adverse event of anti-TB treatment, leading to nonadherence, treatment failure, or drug resistance development [31]. Anti-TB DILI is
reported in 2–28% of patients worldwide [32]. Clinical manifestations of anti-TB
DILI can range from asymptomatic tomoderate elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to acute hepatitis and even liver
failure [31]. Hence regular monitoring ofLFT during the course of the management
is essential.Mycobacterium tuberculosis (Mtb) is the most prevalent opportunistic
infection among those with HIV [33]. There is an antiretroviral therapy (ART) for
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HIV infection that has resulted in a substantial decrease in AIDS-related deaths, but
it has also elevated the DILI associated with ART [34]. The reported incidence of
severe DILI associated with ART is approximately 10% [35]. Three of the four
standard ATT medications, namely rifampicin, pyrazinamide and isonicotinic acid
hydrazide (INH), as well as the majority of ART medications, are associated with
DILI [33]. Rifampicin can inhibit bilirubin absorption, resulting in hyperbilirubinaemia without conjugation. Both hepatocellular damage and granulomatous hepatitis may be caused by pyrazinamide. Hepatocytes are toxic to mono-acetyl
hydrazine, one of the primary metabolites of isoniazid. Co-trimoxazole prescribed
for Pneumocystis jirovecii or toxoplasmosis prophylaxis or treatment is associated
with both cholestatic jaundice and hepatic necrosis [33].
T. Sehgal etal.
4.3.6 Adenosine Deaminase (ADA)
ADA is an enzyme that catalyses the hydrolytic deamination of adenosine to inosine
and deoxyadenosine to deoxyinosine as part of purine metabolism [36]. ADA is
crucial for the proliferation and differentiation of lymphocytes, specically T lymphocytes [37]. Serum ADA is elevated in diseases associated with cellular stimulation, such as typhoid fever, infectious mononucleosis, liver disease, sarcoidosis,
leukaemia, brucellosis, acute pneumonia, rheumatoid arthritis, cancer and tuberculosis [38]. Although serum ADA levels are higher in patients with pulmonary tuberculosis than in healthy individuals, ADA should not be used to distinguish between
pulmonary TB and other pulmonary infections [39]. The serum ADA test has low
sensitivity (range, 12–44%) and high specicity range (96–100%) [36]. Therefore,
this test is not very usefulfor screening for tuberculosis. This test is benecial for
excluding tuberculosis in suspected cases with negative microbiological results
based on the high specicity of the serum ADA level [36]. Tarhan and colleagues
suggested that serum ADA levels can be used as a supplementary laboratory test in
conjunction with clinical and laboratory ndings to diagnose tuberculosis [40].
4.4 Conclusion
Various studies have shown that tuberculosis is associated with haematological and
biochemical changes [2, 41, 42]. The diagnosis of tuberculosis (TB) is not always
easy; thus, clinicians often need to rely on several parameters to diagnose
TB.Biochemical and haematological paramets play important role in the diagnosis
of tuberculosis as well as prognostication and monitoring treatment progression.
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