TUBERCULOSIS Introduction - Is an important infectious disease globally.

Epidemiology - About 30% of the worlds population are infected - 8 10 million people develop the disease annually, out of which 3 million are in SubSaharan Africa. - There was a recent resurgence in pulmonary tuberculosis and the reasons for this are highlighted below i. ii. iii. iv. v. Worsening economic situations Multi-drug resistance HIV pandemic Decline of National Tuberculosis Control Programmes Large number of displaced persons from conflicts and wars are now living in poor conditions.

Predisposing Factors 1. Age is common in children < 5 years, those without immunization are more susceptible. 2. Sex - No sexual difference, except around the adolescent age, in which it is commoner among girls because of the increased pressure of menstruation which is associated with reduced immunity. 3. Malnutrition 4. Concurrent infections e.g measles, pneumonia 5. Overcrowding & Poor living conditions Pathology & Pathogenesis - It is a chronic infectious disease which has 2 very important characteristics: Association with vague symptoms especially in children Has a protracted course The infectious agents are Mycobaterium tuberculosis M . bovis M . Africanus - The Special characteristics of the organisms are as follows

They are non-motile, non-spore forming Are acid fast bacilli i.e not decolourised by acid after taking up ZN stain. Are slow-growing Can remain dormant and still be alive for years, they can manifest if there is immune suppression About the atypical organisms i. About 40 have been described ii. cause similar symptoms like M. tuberculosis iii. their treatment is usually different iv. they are not of public health significance

The Source of infection is SPUTUM of persons with open tuberculosis The Mode of Spread is by: i. Inhalation via the droplets nuclei. ii. Ingestion of contaminated cows or unpasteurised milk or contaminated food. iii. penetration of skin and mucous membranes.

PRIMARY INFECTION - Is infection in those who have been exposed to the organisms before. - 98% of it occurs in the lungs Primary Focus + Regional lymph node/Lymphatics = PRIMARY COMPLEX/GHONs COMPLEX Primary Focus - is the small area of inflammation where the organism lies after inhalation. - the organism is carried to the regional lymph nodes by histiocytes to form caseous necrosis. - can be one or multiple - its size varies from few mm to 2 cm in diameter. - the usual site is sub-pleural region. Symptoms & Signs i. May be symptomless ii. iii. May be associatedwith minor symptoms like malaise, fever (mimicking malaria) Mucocutaneous manifestations of primary tubeculosis: - are due to allergic reaction in the presence of tuberculin protein Erythema nodosum - reddish nodules seen in the forehead, inner side of forearm - can be missed in Blacks, but easily picked up in

Caucasians Phlyctenular conjunctivitis numerous yellowish nodules usually in the lateral aspect of the eye. it is engorged by vessels is commoner in this environment Natural Course - the primary complex heals in 85% of population - the risk of primary infection developing into active disease is about 5 15% in the first 10 years after infection. Ways of Progression of Primary Infection to Active Disease 1. Primary focus can spread to the contiguous part of the lung giving rise to tuberculous pneumonia. 2. Primary focus & the regional lymph nodes may merge and give rise to an area of consolidation 3. Extensive caseation & liquefaction can develop giving rise to cavity formation. 4. The inflamed nodes may compress the neighbouring bronchi giving rise to atelectasis or emphysema if it is total or partial obstruction respectively. 5. Node may erode through the bronchial wall, causing endobronchial tuberculosis (Note, there is no rupture of the bronchial walls here) 6. There may be discharge of the tubercle bacilli into the bronchial lumen leading to bronchogenic dissemination to other areas of the lungs 7. Nodes may erode into the blood vessels giving rise to haematogenous spread to other tissue 8. The affected nodes may develop fibrosis & encapsulation with viable tubercle bacilli persisting within the node for many years & may be the source of re-activation tuberculosis, called Postprimary infection. Periods Between the Primary Infection & Appearance of Clinical Evidence of various Forms of Tuberculosis Duration from Primary Infection Few months

1. Pulmonary tuberculosis

2. Miliary & Meningeal Tb 3. Tb Adenitis 4. Bones & Joints 5. Renal & Genital Tb 6. Post-primay infection (Reactivation)

2 6 months 3 9 months Several years except Tb spine which is earlier Decade A number of years

Section I. PULMONARY TUBERCULOSIS Introduction - Is the commonest form of Tb - It constitutes about 70% when it occurs alone and in combination with other forms - In children, it consists mainly of primary complex and its direct progression. Pathology Hilar enlargement may lead to bronchial compression with resulting hyperinflation or atelectasis Consolidation, patchy or lobar with or without pneuomothorax & pleural effusion. Cavitation is now common in children, though the incidence is still higher in adults. Clinical Presentation Symptoms i. Chronic cough is cough > 3 weeks therefore when clerking, ask the following: - Duration of the cough - Which time of the day is it worse? Night points to asthma - Does it prevent the child from sleeping? - Relieving or worsening factors - History of immunization ii. iii. iv. v. vi. vii. viii. Signs i. ii. Fever is usually high grade Anorexia Vomiting Weight loss or Not gaining weight Haemoptysis Night sweats Overcrowding Chest examination may reveal no abnormality Dyspneoa

iii. iv. v. vi. vii. N.B

Tachypnoea Localised wheezing Reduced breath sounds Crepitations Bronchial sounds

Clinical features of re-activation tuberculosis in older children are similar to those of the primary infection, but its cough is usually productive and there may be chest pain from pleural effusion. Differential diagnosis 1. Pneumonia Bacterial, Viral, Mycoplasma especially if the pneumonia is not responding to usual treatment 2. Lung abscess - can also be a complication of Tb 3. Bronchiectasis - can also be a complication of Tb 4. Pulmonary Fungal infection Do bronchial washout to examine for hyphae 5. Pulmonary neoplasm - though primary ones are not common, but secondaries do occur. Diagnosis Made from Detailed history of current illness cough, precipitating factors Past Medical history Family and Social History - for predisposing factors - 24 hour dietary report History of contact - in the childs immediate environment : nuclear family, type of apartment, school. Investigations 1. Tuberculin skin test - there are many forms, but 2 are of importance a. Heaf test - is a multiple puncture test - usually used for screening i.e for a large number of people - is less sensitive - Procedure Put the heaf gun on a slit lamp to sterilize. Put the old tuberculin, which is a clear fluid, on the skin on the flexor aspect of the forearm Place the plunger (has 6 needles) on the fluid over the skin and

plunge into the area Mark the the area with a pen and inform the person not to wash it

- It is read after 48 72 hours Grades 0 1 2 3 4 6 Un-indurated separate needle parts 6 Indurated, but separate An indurated circle with unraised centre The center is raised Ulceration of the area

Reading Grade 3 and 4 are regarded as POSITIVE. Though this does not indicate that the person has the disease, but has come in contact with the organism b. Mantoux test - Is for clinical diagnosis. It is very useful - The solution used is Purified Protein Derivative (PPD). - It is given intradermally using small needle and syringe - The dose is 0.1 ml of PPD, this contains 10 tuberculin units - A transparent ruler is used to read the diameter of the indurated area.

Grades Diameter, mm 04 59 10 Negative Doubtful positive, repeat the test with more concentrated solution of PPD, which contains 15-20 tuberculin units Positive

Positive Mantoux test - It only indicates that the person has actually come in contact with Mycobacterial organisms and may not necessarily have the disease. - It is not an indication to start treatment - But, it calls for further investigation Causes of False Negative Result 1. Severe overwhelming tuberculosis which is associated with a high degree of immune depression 2. Severe malnutrition 3. Measles or Pertussis in the immediate past 4. Steroid therapy 5. Cytotoxic therapy 6. HIV/AIDS 7. Poor technique 8. Impotent/Expired reagent N.B - the last 2 reasons are not medical Causes of False Positive Result 1. Poor technique if given intramuscularly, instead of intradermal 2. Cross reaction with other atypical mycobacteria. 2. Chest radiograph - Is indicated in all forms of Tb, but very important in chest Tb - The features that may be seen are Hilar/Paratracheal adenopathy shown by widening of the mediastinum Parenchymal lesions : i. Patchy infiltrates ii. Consolidation iii. Atelectasis iv. Pleural effusion v. Cavities probably show more severe disease vi. Pneumothorax 3. Bacteriological investigation i. Sputum is difficult to obtain in younger children ii. Gastric washout done because the patients swallow sputum especially in the morning before waking up.

The specimen is stained with ZN stain & cultured in LowensteinJensen medium. Note, the organism is not easy to culture, even in good laboratories, it is only 50% sensitive in children ( 80% in adult) 4. Erythrocyte Sedimentation Rate - Is not diagnostic of Tb - Is usually high ( seen also in other chronic conditions) - It is very useful to monitor treatment. 5. Full blood count Leucocytosis with predominance of lymphocytes

Section II. PLEURAL EFFUSION IN TUBERCULOSIS Introduction Pleural effusion occurs when i. sub-pleural primary focus ruptures into the pleural cavity ii. caseous node ruptures into the pleural cavity iii. there is haematogenous spread iv. and as a result of allergic response to tuberculin protein (just like in mucocutaneous reactions : erythema nodosum & phlyctenular conjunctivitis).

Clinical Features Symptoms Fever Cough Chest pain on deep inspiration Signs Dullness to percussion Diminished or absent breath sounds Investigation 1. Pleural tap - yields serofibrinous fluid, sometimes it is blood-stained - the protein content is high, 2- 4g/dl. - High white cell count with predominance of lymphocytes 2. Full blood count

leucocytosis with predominance of lymphocytes

3. Culture of the specimen yields tubercle bacilli in < 20%

Section III. MILIARY TUBERCULOSIS Introduction - Is the most severe form of disseminated tuberculosis because of the immature immunity. (Disseminated Tb is when the disease is found in at least 2 distinct parts/systems e.g Respiratory, GIT). Epidemiology common in 6 months 4 years Pathogensis - It occurs 2 6 months after primary infection - It occurs when there is haematogenous spread to different parts of the lungs & the body (i.e seeding) Clinical Manifestations - Is variable, it depends on i. Load of organisms ii. Organs affected iii. Immune status of the child - The onset of symptoms may be explosive or insidious Symptoms i. Fever ii. Anorexia iii. Weight loss iv. Cough v. Wheezing Signs - Depends on organs invloved i. Generalised lymphadenopathy ii. Hepato-splenomenogaly iii. Respiratory distress iv. Signs of meningitis seen in 20 40% patients v. Signs of peritonitis vi. Choroidal tubercles on fundoscopy

Investigations 1. Tuberculin skin test 2. Chest x-ray done because at least 70% of cases involve the lung it is diagnostic it shows multiple small rounded white reticulo-nodular opacities scattered all over the two lungs 3. Cerebrospinal fluid tap 4. Histological examination should be considered last, you only do this if others failed. a. Lymph node biopsy b. Liver biopsy c. Bone Marrow Aspiration / biopsy Differential diagnosis of Miliary Picture on Chest X-ray 1. Sarcoidosis is also a chronic granulomatous disease which tends to occur in adults 2. Eosinophilic pneumonia 3. Pulmonary fungal infection e.g Aspergillosis 4. Chicken pox pneumonia 5. Childhood histiocytosis syndrome Section IV. TUBERCULOSIS OF THE CNS It comprises of a. Tuberculous meningitis b. Tuberculoma a. TUBERCULOUS MENINGITIS

Incidence - Most common in children aged 6 months - 4 years Pathogenesis - Occurs about 2 6 months after the primary infection - Arises as a result of haematoganous spread of tubercle bacilli to the cerebral cortex and meninges.The caseous lesions rupture into subarachnoid space to cause meningitis. Clinical Manifestation - Can be divided into 3 stages

Stage I : Non-specific symptoms like o Fever o Headache o Weight loss o Irritability o Drowsiness Stage II : Evidence of Meningeal Irritation o Lethargy o Vomiting o Nuchal rigidity o Seizures o Positive Kernigs sign o Signs of brainstem involvement i.e Palsies of cranial nerves II, III, VI, VII, VIII o Other focal neurological signs Stage III o o o o o Hemiplegia or paraplegia Coma Decerebrate rigidity Opisthotonus Papilloedema & presence of choroidal tubercles on fundoscopy

Investigation 1. Tuberculin skin test 2. Chest X-ray 3. Examination of CSF most diagnostic CSF Picture In Tuberculous Meningitis i. The fluid is straw-coloured, or clear & colourless ii. White blood cell count : 10 500cells/mm with predominance of lymphocytes iii. Protein is very high, may be over 1g/dl (Normal is 10 40 mg/dl). Note, in partially-treated bacterial meningitis, there is combination of lymphocytes & polymorphs) iv. The glucose level is low, i.e < 40 mg/dl v. ZN staining may yield acid fast bacilli vi. Culture may be positive.

Prognosis - Depends on the stage of the disease at commencement of therapy Stage I - Good Stage III Mortality is high, even a high percentage of those who survive develop complications listed below

Complications 1. Blindness 2. Deafness 3. Paraplegia 4. mental retardation 5. Speech disturbance 6. Cranial Nerve Palsies 7. Seizures 8. Hydrocephalus

b. TUBERCULOMA of the CNS Epidemiology - Is less common than tuberculous meningitis. Pathology & Pathogenesis - Occurs from haematogenous spread - Is usually infra-tentorial - May be single or multiple Clinical Manifestations - It presents as an intracranial space-occupying lesion (it grows instead of rupturing). It is difficult to differentiate from intracranial tumours. - The features include i. Headache ii. Fever iii. Convulsion iv. Sutural diathesis v. Lateralising signs Investigations 1. Tuberculin skin test 2. Skull x-ray 3. Chest x-ray 4. CT scan shows discrete masses with surrounding oedema Diagnosis - Is mostly made during surgical exploration for intracranial tumour. Note, excision of tuberculoma is contra-indicated because it will result into fulminant meningitis.

Section V. TUBERCULOSIS OF SUPERFICIAL LYMPH NODES

Pathology & Pathogenesis - Occurs within 3 9 months of primary infection - Can affect any group of lymph nodes - May be unilateral or bilateral - The glands are initially discrete, mobile, firm and non-tender, but later become matted together if there is periadentis (inflammation of the surrounding tissue). - May form a discharging sinus Locations 1. Neck Anterior triangle - Posterior triangle - Supraclavicular nodes Clinical Presentation i. Constitutional symptoms may or may not be present ii. Swellings Examination of Glandular Enlargement iii. The site iv. The size - 2cm, it is pathological except for supraclavicular gland, in which even 0.5cm size is important. It is a pointer to lung & abdominal pathology. Investigations 1. Tuberculin skin test 2. Chest x-ray 3. Fine Needle Aspiration Biopsy (FNAB) - Using big bore needle - it is sensitive & diagnostic. It is conclusive in about 80% cases 4. Excisional biopsy of nodes for histological examination. - Used for the remaining 20% Differential diagnosis 1. Pyogenic lymphadenitis - Is common around the neck - Usually develops from URTI (infections of tonsils, fauces) or infections around the neck - It is tender & warm 2. Hodgkins lymphoma - The glands are firmer - Clinically, it is difficult to differentiate from TB adenitis - Is diagnosed by FNAC

3. Acute Lymphocytic Leukaemia - The patient is toxic, febrile & pale - There is leucocytosis - Blood film shows abnormal white cells 4. Fungal infection of lymph node - The nodes are usually hard (not firm) - Diagnosed by FNAB 5. Infection with Atypical Mycobacteria - Diagnosed by FNAB with special staining 6. HIV/AIDS In children, there is usually generalized lymphadenopathy Do retroviral screening

Section VI. ABDOMINAL TUBERCULOSIS Introduction It comprises of 1. Tb of the Intestine 2. Tb of the Abdominal Lymph nodes 3. Tb of the Peritoneum Clinically, it is difficult to differentiate all these. a. TUBERCULOUS ENTERITIS Pathology & Pathogenesis - Occurs as a result of haematogenous spread from a primary focus or by swallowing tubercle bacilli coughed out.

The most common sites are the jejunum & ileum, near the patches They form shallow ulcers

Clinical Features i. Abdominal pain ii. Diarrhoea alternating with constipation iii. Weight loss iv. Fever Mortality Is very high b. TUBERCULOUS MESENTERIC ADENITIS Pathology & Pathogenesis - arises from tuberculous enteritis (since the mesenteric nodes drain the intestinal tract) - the lymph node, omentum & peritoneum may become matted together, this is palpated as a firm mass, called Doughy Abdomen Clinical Features i. Diarrhoea alternating with constipation ii. Weight loss iii. Abdominal mass Subacute intestinal obstruction iv. features of Subacute intestinal obstruction c. TUBERCULOUS PERITONITIS Pathogenesis May arise from haematogenous spread or direct extension from an abdominal lymph node infection or intestinal focus

Clinical Features i. Fever ii. Abdominal swelling, due to ascites iii. Mild abdominal tenderness (due to stretching of peritoneum), a feature of subacute peritonitis Investigation of Abdominal Tuberculosis 1. Tuberculin skin test 2. Chest x-ray 3. Plain abdominal x-ray : shows

- relative gaslessness in the GIT - calcified glands 4. Abdominl ultrasound preferred to abdominal x-ray 5. Ascitic tap for bacteriological studies Differential Diagnosis 1. Abdominal Malignancies

Section VII. TUBERCULOUS OF THE SPINE (Tuberculous Spondylitis/Potts disease) Introduction - Commonest and most important bones affected by tuberculosis in children. Pathology & Pathogenesis Occurs 2 years after primary infection The sites are i. Thoracic vertebrae is the commonest ii. Lumbar is the second commonest iii. Cervical - May arise from a. Lymphatic spread from an adjacent area b. Haematogenous spread from a primary focus - The infection usually starts in the body of the vertebrae, then spread to other parts. - It may follow this course Infection Collapse Cold abscess Cord compression Clinical Features i. Back pain ii. iii. iv. Spinal rigidity & limitation of spinal movement Diffilculty in walking (short steps ) to avoid stretching the nerves Reduced muscle power which may progress to paralysis

v. vi. vii. viii. ix. x. xi. xii. xiii. Investigation

Kyphosis (is exaggerated antero-posterior curvature of spine) Scoliosis (lateral flexion) gibbus Gibbus is sharp angulation Kyphoscoliosis Loss of voluntary bladder control Increased muscle tone (hypertonia) Hyper-reflexia Spastic quadriplegia it the cervical vertebrae are involved Spastic paraplegia if the other vertebrae are affected Sustained ankle clonus

1. Tuberculin skin test 2. Chest x-ray 3. X-ray of the Spine Specify the region. To do this, Locate T12 or palpate anterior superior iliac spine or end of scapula Findings : - Widening of intervertebral space - Distortion of the body of vertebrae - Vertebral collapse - Paraspinal abscess Complications 1. Paraspinal abscess 2. Psoas abscess Note that Psoas muscle arise from T12 L4 Patient presents with inability to walk or fixed flexion deformity while walking 3. Retropharygeal abscess (from cervical spine Tb) - There is hyperextension of the neck - Is diagnosed by x-ray of neck Differential Diagnosis 1. Idiopathic scoliosis or kyphosis 2. Acute non-tuberculous osteomyelitis of the spine Patient is acutely ill, febrile The site is tender & warm The duration is usually short

3. Rickets - Look for stigmata of it 4. Secondary Malignancies Affecting the CNS - e.g Burkitt Lymphoma, the child presents with inability to walk. It is diagnosed by CSF tap

5. Histoplasmosis duboisii of the spine - Is difficult to differentiate - CSF cytology for fungi (hyphae) - Is not very common

Section VIII. TREATMENT OF TUBERCULOSIS The mainstay of treatment is Combination chemotherapy. The duration of therapy is 8 months It is divided into 2 phases a. Intensive phase involves giving 4 drugs for the first 2 months b. Continuation phase 2 drugs are given for next 6 months Currently Used Regimen a. Intensive phase i. Streptomycin or Ethambutol ii. Pyrazinamide iii. Isoniazid iv. Rifamipcin N.B Streptomycin vs Ethambutol Streptomycin children < 3 years Ethambutol children > 3 years S/E Optic neuritis (blindness),

therefore, do visual acuity which is difficult to do for those < 3 yrs b. Continuation Phase i. Isoniazid ii. Thiacetazone use rifampicin to replace it in patients with HIV/AIDS because of the Stevens-Johnsons syndrome, though rifampicin is expensive. Dosages & Side effects of Anti-Tuberculosis Drugs Drugs 1. Streptomycin Dosages 20 40 mg/kg/day ( IM ) 2. Isoniazid 15 20mg/kg/day ( oral ) 3. Rifampicin 1 0 20 mg/kg/day ( oral ) 6. Ethambutol 15 20 mg/kg/day ( oral ) Side effects Toxicity to Cranial nerve 8 Rashes Renal damage Peripheral Neuritis Psychosis Hepatotoxity Orange discolouration of urine & tears GI disturbance Thrombocytopaenia Hepatoxicity Hyperuricaemia Skin rash Hepatoxicity Skin rash Haemolytic anaemia Stevens-Johnsons syndrome in HIV/AIDS patients Hepatotoxicity Optic neuritis blindness Hepatotoxicity

4. Pyrazinamide

25 30 mg/kg/day ( oral )

5. Thiacetazone

3 5 mg/kg/day ( oral )

Note, -

Only streptomycin is not hepatotoxic. If the patient develops jaundice, to identify the drug that causes this, stop all the drugs and start introducing them one by one.

To improve drug compliance, the administration can be done in 2 ways: a. Admit the patient b. Use Directly Observed Therapy (DOT) where patient comes to the clinic to take the drugs. It is being given by the nurses.

Indications for Corticosteroid As an Adjunct 1. Large pleural effusion - normally, you dont drain the effusion in Tb. 2. Endobronchial tuberculosis 3. Pericardial effusion 4. Tuberculous meningitis Supportive therapy 1. Improved nutrition 2. Screening of immediate family members 3. Surgical intervention where necessary e.g in Spine or Psoas or Retropharyngeal abscess Prevention of Tuberculosis in a Community 1. Case-finding and effective treatment 2. Contact tracing and INH prophylaxis Patient +ve tuberculin test Chest x-ray 3. BCG vaccination 4. Improvement in the general standard of living. Management of Newborn infant of a Mother with Tuberculosis 1. Mothers treatment should be commenced or continued if she has already started 2. INH prophylaxis should be started in baby soon after delivery and continued till mothers sputum has been negative thrice. 3. After this, the infant should have Mantoux test If ve, INH should be discontinued and the child vaccinated with BCG for long term protection If +ve, the infant should have Chest x-ray. If it is normal, continue the INH for 12 months, but if it is abnormal, treat as tuberculosis with Combination therapy. N.B - BCG vaccination takes 6 weeks for it become effective. - The use of INH-resistant BCG has been stopped since the company manufacturing it stopped the production.