Mycobacterium Tuberculosis Clinical Aspects

Tuberculosis (TB) represents a major public health problem, especially in low-resource countries where the burden of the disease is more important. According to estimates of the World Health Organization (WHO), two billion people, roughly one third of the world’s population is latently infected with Mycobacterium tuberculosis the causative agent of the disease. In 2005 there were 8.9 million new cases of TB and 1.6 million deaths were attributed to the diseas. This scenario is aggravated by the human immunodeficiency virus (HIV) pandemic with roughly one third of the 40 million people currently infected with HIV also coinfected with TB.

The world can be divided into two parts based on the extent of tuberculosis epidemics. One part is the low-prevalence areas. They are composed of countries that experienced serious tuberculosis epidemics after the 18th century but have gradually overcome them and have finally reduced the incidence rate to 100 per 100 000 or less. The other part is the high-prevalence areas comprising countries with an incidence rate exceeding 100 per 100 000 that have suffered tuberculosis epidemics after the turn of the 20th century. The low-prevalence countries are industrialized countries, while the high-prevalence countries are mostly developing counties or areas. The latter accounts for two-thirds of the world population, but as much as 95% of the estimated number of newly occurring tuberculosis patients (of all forms) globally. Furthermore, 98% of tuberculosis deaths occur in these high-prevalence areas.¹ Tuberculosis accounts for 2.7% of the total disability-adjusted life-years in low- and middle-income countries.⁴ In addition to the difference in its level, there are clear differences in characteristics of tuberculosis disease. In high-prevalence countries, most tuberculosis patients are in their 20s to 40s, resulting in tremendous socioeconomic loss as this is the most productive generation. In contrast, among low-prevalence countries, tuberculosis is drifting to involve the elderly, socioeconomically marginalized people, medical high-risk groups (e.g. diabetics⁵ and those treated with immunosuppressive agents, such as TNF-alpha blockers⁶), which presents a challenge to both medical and welfare services.

As a consequence of the global efforts in tuberculosis control under the Directly Observed Treatment Short-course strategy since the 1990s, the incidence of tuberculosis is estimated to have started to decline for the first time around 2003, although very slowly.¹ At the same time, issues that had been given only lower priority in the developing world have emerged as unavoidable challenges. One of these issues is multi-drug resistant (MDR) tuberculosis that strikes a half million people annually and is a malignant burden to the patients and community, as well as to national tuberculosis programmes with its poor treatment outcome.⁷ In line with this problem, extensively drug resistant (XDR) strains of M. tuberculosis are emerging recently.⁸ The use of effective secondary drugs based on the result of high-performance drug sensitivity tests is necessary in order to address these issues, which requires technical innovation.⁷

A second newly emerging issue is co-infection of the HIV and M. tuberculosis. Currently, 15% of the new tuberculosis patients are infected with HIV, and in some areas or countries this proportion exceeds 50%. One quarter of the global tuberculosis deaths are due to HIV, and this is equal to one-third of new HIV-positive tuberculosis cases and to 23% of the estimated two million HIV-related deaths in 2007.¹ Diagnosing tuberculosis in these subjects with sputum smear examination alone cannot prevent their infectiousness and save their lives; more aggressive case-finding and treatment of smear-negative cases are required. Another issue is tuberculosis in children for whom Mycobacterium bovis Bacille Calmette Guerin (BCG) vaccination has been virtually the only control measure in developing countries. This also requires accurate diagnosis in the early stage of tuberculosis.⁹

As seen above, tuberculosis appears as a typical south-north problem of health, but currently in many developed countries over half of the new tuberculosis cases are foreign-born, that is, immigrants from high-prevalence areas, or spill-over of tuberculosis.^10,11 It is actually argued that to further reduce tuberculosis in the low-prevalence countries it is necessary to strengthen control efforts in the high-prevalence, developing countries.¹²

Clinical Manifestation of Mycobacterium tuberculosis

In general, clinical manifestations of illness are the first clue to the diagnosis of tuberculosis. However, they are often non-specific and misleading, and therefore the diagnosis is not always easy. This is especially the case for tuberculosis in children and in elderly subjects, as seen below. Further, extrapulmonary tuberculosis often poses a challenge to early diagnosis, especially pertaining to its variety of presentations. Clinical signs and symptoms of tuberculosis of the organs other than the lungs are summarized in ^134,302

Pleuricy

Primary infection cases have generally an acute course of symptoms than reactivation-type TB. Cough (non-productive) and chest pain (pleuritic—sharp, stabbing, associated with respiration). Feverishness, dyspnea, chills, sweats, weight loss in more advanced cases. TB pleural effusions are generally exudates.

Lymphadenopathy

Most often in the neck and head region, rare in the axillary & inguinal region. Right predominates but 1/4 have biliateral & 78% have multiple lesions. 41% have pulmonary TB. In superficial LN, lesion starts as a painless enlargement, with no inflammation over the skin, then may undergo pustulation and fistulation over several weeks or months. In a case with limited lesion, general symptoms are rare

Bone & Joint

Commonest in vertebral column, followed by hip and knee. Fever and wasting may appear in large inflammatory collections, but the local manifestation predominates. Pain is commonest. Soft tissue collection (cold abscess) at/near the bone or joint focus. Neurological signs (weakness or numbness from compression of the spinal cord).

Disseminated or miliary TB

Diverse depending on the organs involved. Feverishness, weakness or debility, anorexia, weight loss, headache (meningeal complication), abdominal pain/swelling (peritoneal involvement), cough.^39,40

Central nervous system

The presentation depends on the size and location of the tuberculoma and the pressure it produces.Early symptoms (feverishness, malaise, anorexia, irritability, headache) followed by neurological symptoms (progressive headache, lethargy, personality changes, memory disturbance, impaired cognition, confusion), and then stupor-coma with or without neurological deficit.

Cerebrospinal fluid for pressure, cellularity, protein, glucose,⁴⁶ MTB (microscopy, culture^47,48 and PCR^49,50), immunology (ELISA, IgG immune complex, antibody assays and IGRA^51–56), and ADA. Radiography, CT, MRI.^57–61 Meningeal biopsy (histology, MTB).

Other infections (fungal, viral, trypanosomal, bacterial), vascular (multiple emboli, SBE, thrombosis of sagittal vein), collagen vascular (SLE, polyarteritis, and others).

Abdominal

Frequency: peritonitis, followed by ileocaecal, anorectal and mesenteric lymph node infection.In peritoneal TB, abdominal swelling, fever, ascites, pain, anorexia/weight loss are common.^62,63

Peritonitis: ultrasound,^64–66 laparoscopy (with guided biopsy),^67–70 paracentesis of ascites for culture and IGRA^71,72 and ADA.⁷³

Malignant ascites, cirrhosis with spontaneous bacterial peritonitis, starch peritonitis, sarcoidosis, NTM peritonitis.

Pericarditis

Dyspnoea, tachycardia, neck vein distension, oedema, hepatomegaly, paradoxical pulse, pericardial rub, fever.^74,75

Pericardial tissue/fluid for bacteriology, histology,^76,77 IGRA,^78,79 and ADA.^80–82 Echocardiography,^83–85 CT and MRI (pericardial effusion and thickening),⁸⁶ ECG (low voltage, inversion of T).⁸⁷

Bacterial (e.g. Pneumococcus), viral (e.g. CMV, HSV, Coxsackievirus) or fungal (e.g. Aspergillus) infections; collagen vascular diseases; uremia; post-myocardial infarction or post-pericardiotomie; malignancy; trauma.

Genitourinary

Dysuria, frequency, nocturia, urgency, pain in the back, flank or abdomen, tenderness/swelling of the testis or epididymis, haematuria. Superimposed urinary tract infection with other bacteria in urinary stasis cases.^88–93

Tuberculosis in children

Because of its paucibacillary nature, tuberculosis of children is difficult to diagnose. Bacteriological confirmation seldom exceeds 30–40% among children in developed as well as developing countries.^106,107 Consequently, the diagnosis of tuberculosis in children in resource-poor settings is largely dependent on a combination of a history of contact with a known tuberculosis patient, clinical signs and symptoms, and special examinations, such as chest radiography and the TST when available. Edwards and colleagues observed a total of 91 tuberculosis cases younger than 15 years, of whom about half were HIV-infected, and found the following frequency of symptoms and signs in the HIV-seronegative children: weight loss 69%, fever 100%, cough 83%, night sweat 43%, fatigue 21%, tuberculosis contact 60%, malnutrition 57%, lymphadenopathy 88%, organomegaly 31%, positive TST 89%, elevated erythrocyte sedimentation rate 79%, and chest X-ray infiltration 100%.¹⁰⁸ Based on these observations, several point-scoring systems, diagnostic classifications and diagnostic algorithms have been developed to support an objective diagnostic judgment. Marais et al. tested such an approach and found that combining a persistent non-remitting cough lasting over 2 weeks, documented deterioration of health (in the preceding 3 months) and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity 62.6%; specificity 89.8%; positive predictive value 83.6%). The performance was poorer in HIV-infected children than in the low-risk group, which offers a serious challenge in resource-poor settings with high HIV epidemics.¹⁰⁹ However, given this set of sensitivity and specificity, the positive predictive value is calculated as only 24% in a patient population with a prevalence of tuberculosis of as high as 5%.

Tuberculosis in old ages

In low-prevalence situations, tuberculosis is a problem predominantly of the aged population and includes many more cases of clinical development in immunologically compromised subjects. This is why there are many tuberculosis cases with ‘atypical’ clinical presentation(s) in older persons.^110,111 Elderly patients are more likely to have extrapulmonary tuberculosis, including miliary disease.¹¹¹ The proportion of bacteriologically confirmed pulmonary tuberculosis patients was higher in the elderly than in the younger patients as reported in a meta-analysis.¹¹²

Fever, sweating and haemoptysis are less frequent in older patients, but dyspnoea is more frequent.¹¹² Laboratory findings, such as the TST-positive rate, serum total protein level and white blood cell counts, were lower in elderly patients. Also, cavity formation was less common in elderly patients, while lesions in the upper lung were similar for both age groups.¹¹² The most common chest X-ray findings in the elderly or immunocompromized tuberculosis patients are lesion in the lower zone accompanied by basal effusion or thickening.¹¹⁰ Such atypical clinical presentation of tuberculosis in the elderly can often cause delay in diagnosis, which can be further complicated due to underlying illnesses.

One of the basic indicators of quality in diagnosing tuberculosis is the delay in diagnosis (‘doctor's delay’, or ‘health system's delay’), that is, the time from the first visit of a patient until the establishment of tuberculosis diagnosis. Figure 2 depicts the delay separately for high-, intermediate- and low-prevalence settings, together with the patient's delay, that is, the time from the onset of clinical symptoms until the first visit to a health facility, based on published studies (T. Mori, pers. comm.). It is remarkable that these delays in the low-prevalence settings are always longer than those in the high-prevalence settings.

Sasaki et al. reviewed the diagnostic process of private practitioners with Japanese patients and concluded that insufficient medical work-ups, including AFB examinations of sputa and chest X-rays of subjects with a high suspicion for tuberculosis, was the principal cause of delayed diagnoses.^113,114 In Hong Kong, general practitioners' practice was reviewed, and it became clear that they depend too much on X-rays rather than sputum examinations, and that they were slow in referring tuberculosis patients to the government tuberculosis service.¹¹⁵ Rozovsky-Weinberger et al. compared the management of suspect tuberculosis cases at three public hospitals and seven not-for-profit private hospitals in the USA in terms of their rates of ordering acid-fast smears and isolations, and urged private hospitals to be more alert to tuberculosis.¹¹⁶ Similar reviews of hospital management were reported by several other studies,^117–119 the results of which illustrate the need for improved education of doctors. All of these studies urge a higher index of suspicion for tuberculosis in medical staff in low-prevalence countries.

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