Tuberculosis
Definition:
Tuberculosis is a systemic disease caused by Mycobacterium tuberculosis. The most frequent clinical presentation is pulmonary disease. Extrapulmonary disease may present as lymphatic involvement, genitourinary disease, osteomyelitis, miliary dissemination, meningitis, peritonitis, or pericarditis. Most cases are a result of reactivation of prior infection. Patient has highest risk are those with HIV, diabetes, chronic renal insufficiency, malignancy.
Epidemiology
-Thought to cause ¼ of preventable adult deaths in developing countries
-Causes 2-3 million deaths worldwide per year
-Risk factors (environment): close quarters, low light, crowded, low ventilation
-Risk factors (host): T-cell deficiency, steroid use, malnutrition
Microbiology
Mycobacteria are slender, curved, aerobic bacilli whose cell wall components make them acid-fast on Ziehl-Neelson staining. Mycobacterium tuberculosis multiplies slowly so that up to 6 weeks are required for culture. Disease due to M. tuberculosis tends to progress slowly, and responds slowly to treatment.
-Cell wall with high lipid content that stains red (“acid-fast”)
-Replication time=15-20 hours (compared with <1hour for other bacteria), so visible growth of colonies in culture takes 4-12 weeks
Transmission
M. tuberculosis is acquired by inhalation of microscopic droplets produced by individuals with active pulmonary TB during coughing, sneezing, or speaking. Overcrowded, poorly ventilated conditions increase the risk of transmission as does duration of exposure.
Disease Pathogenesis
TB infection: aerosolized droplets containing M. tuberculosis enter alveoli and initiate a non-specific response. The bacilli are ingested by macrophages and transported to regional lymph nodes. The may either be contained there or spread via the lymphatics or bloodstream to other organs. With the development of cell-mediated immunity, cytokines secreted by lymphocytes recruit and active macrophages, which organize into the granulomas characteristic of TB. Granulomas heal in the immunocompetant. Patients with granulomas are susceptible to reactivation at another point in time.
Active TB disease: on average, about 5-10% of adults infected with M. tuberculosis ultimately develop active TB, usually occurring within 1-2 years after infection. HIV is an important risk factor for developing active TB, as is recent infection, diabetes, poverty. These patients may develop systemic disease directly from primary infection.
Reactivation TB: Immune reaction (delayed-type hypersensitivity) leads to tissue destruction at site of replicationà cavitating caseated lesions (large numbers of multiplying bacilli encircled by rim of giant cells and granulomas). Most often forms in apex of lung (most highly oxygenated). Cavitations grow into airways, allowing bacilli now to be aerosolized in droplets and to be spread to outside world. Reactivation patients are the main cause of the spread of TB
Symptoms and signs:
-Pulmonary TB: persistent cough, mucopurulent sputum, hemoptysis (only 10%)
-Systemic symptoms: fever, night sweats, weight loss, malaise
-Extrapulmonary TB: nonspecific aside from unilateral cervical lymphadenitis
Clinical Features: Pulmonary TB and Extra-pulmonary TB
Primary TB: symptomatic primary TB is mainly a disease of children and the immunosuppressed. Signs of fever, malaise, cough, particularly in setting of recent TB exposure. A positive smear or culture is uncommon. CXR may show enlarged hilar or paratracheal lymph nodes with or without lung consolidation.
Reactivation TB: one or more non-specific systemic symptoms are usually present including weight loss, anorexia, fever, night sweats, or malaise.
In HIV negative adults, pulmonary TB is the most common presentation. It is also the most important type of TB epidemiologically since it accounts for the most transmission. TB may affect any organ in the body resulting in organ specific signs and symptoms. Extrapulmonary TB is more common in children and HIV positive patients.
Pulmonary TB: involves the lung parenchyma. History of cough is present in most cases. A cough of long durations > 2 weeks is indication for sputum smear for AFB. Cough may be productive or nonproductive, hemoptysis, chest pain, shortness of breath all possible symptoms. A patient may present looking ill and wasted with fever and tachycardia or look well. Chest exam may reveal localized crackles or pleural effusion. Sputum smear is usually positive in HIV negative patients but often negative in HIV positive patients. Complications include bronchiectasis and lung fibrosis.
TB lymphadenitis: The second most common manifestation of TB. Usually unilateral and involves cervical lymph nodes. Nodes may initially be rubbery and nontender, become fluctuant and can sometimes progress to chronic draining abscesses.
Pleural TB: an effusion can be detected on physical examination and confirmed by xray or diagnostic aspiration. TB is the most common cause of perstistent effusion in Africa in the absence of some other obvious cause. TB effusions are exudates and stained smear shows lymphocytes, but not usually acid fast positive. Pleural biopsy can confirm the diagnosis.
Bone TB: most commonly affects the spine (Pott’s disease). Vertebral collapse may ultimately produce a characteristic angular deformity and gibbus. Spinal TB responds well to anti TB treatment alone without surgery.
Miliary TB: most commonly affects HIV patients. History of fever, weight loss and malaise. Physical findings often non specific, can find hepatomegaly, splenomegaly, tachypnea. Chest xray will show tiny nodular opacities. Sputum smear is usually negative. Diagnosis is by clinical suspicion.
*TB meningitis: is commonly seen in children or HIV patients. Clinical presentation includes headache, irritability, vomiting, lethargy, or unexplained neurological decline. History is less acute than bacterial meningitis, meningismus may be mild at first. Cranial nerve palsies can occur as well as seizures. Diagnosis rests on CSF examination with lymphocytosis, raised protein and decreased glucose.
Abdominal TB: gastrointestinal TB may present as partial bowel obstruction with a history of fever. It can occur at any site in the GI tract, common in terminal ileum. Peritoneal TB may also be suspected on basis of exudative ascites without another cause. Adrenal TBoccurs when the adrenal glands are infected and eventually destroyed. This is the most common cause of adrenal insufficiency in our settings and should be treated with steroid replacement.
*Pericardial TB: often first suspected on the basis of globular enlargement of the cardiac silhouette on chest xray in patients with cariorespiratory symptoms. Seen more often in HIV positive patients. A pericardial rub or clinical features of cardiac tamponade (elevated JVP, pulsus parodoxus, hypotension) may be present. If untreated, patients can also develop constrictive pericarditis. Constrictive pericarditis risk can be reduced by adding steroids for the first 6-12 weeks of anti TB treatment.
Genitourinary TB: can involve any part of the male or female genitourinary tract. Presentation is subacute and diagnosis requires TB culture or biopsies. Renal TB presents with pain on urination, hematuria, flank pain or mass. The urine contains pus cells but the culture is negative for common bacteria. Genital tract TB in women presents with infertility, pelvic pain, mass or bleeding. Epididymal swelling is most common presentation of genital TB in men.
*Larngeal TB: TB infection at the level of the larynx causes airway obstruction. Treatment is intubation, steroids (to decrease the swelling), and anti-TB.
Tuberculosis (Pulmonary and Extra-pulmonary TB) Clinical Cases
Case 1
40 yo male with no past medical history is admitted to the hospital with 3 weeks of cough and shortness of breath. Patient tells you that his cough is mostly nonproductive and he sometimes produces a little sputum. He has not seen any blood in his sputum.
1. What is your differential diagnosis?
He does complain of intermittent fevers, but no nightsweats. No nausea or vomiting, no headaches or neck stiffness. The shortness of breath has become a little worse in the past 2 days.
On exam, blood pressure is 128/70 and heart rate 106. His temperature is 38.2 degrees.
In general, he is breathing normally with no difficulty. He does seem mildly wasted. No cervical lymphadenopathy. You do hear crackles on the right, anteriorly on your chest exam and heart rate is regular with no murmurs.
A rapid test is negative.
2. Do you want to initiate any treatment?
3. What other investigations do you want to order?
A CXR shows a right upper lobe cavitation. Sputum smear is positive for acid fast bacilli.
4. What is the diagnosis (exactly)? Which category?
5. What treatment will you initiate? How are the other categories of TB treated?
6. What are the possible long term complications of this particular diagnosis if the TB is not treated appropriately?
7. This case represents a typical case of TB in a non-IDS patient. How has HIV changed the epidemiology of TB?
8. Why is the presentation of TB different in HIV positive patients?
9. Why is the diagnosis of TB more difficult in HIV positive patients?
10. What can be done to prevent the spread of TB?
One month later the patient’s symptoms have not improved and the patients CXR is not changed.
11. Why might this patient not be responding to treatment?
12. What is the definition of MDR and XDR TB?
Case 2
30 yo female with HIV positive (last CD4 50 1 month ago, started on D4T/3TC/Nevirapine at that time) presents to hospital with complaints of headache and neck stiffness for 2 weeks. Her aunt tells you that for the past 7 days, the patients has been more confused, not making any sense when she talks. She also has been sleeping more and more. The patient has been more irritable and had 2 episodes of vomiting. On examination the patient is febrile and has oral thrush. There is neck stiffness and the Kernig’s sign is positive. The patient has a left 6th nerve palsy by examination.
1. What is your differential diagnosis?
2. What test do you want to perform and what are you looking for?
3. What treatments will you initiate?
You perform a lumbar puncture with shows mostly lymphocytes. The results also show increased protein and decreased glucose. The CSF gram stain is negative. A serum cryptococcal antigen is negative.
1. What is your impression?
2. What about the clinical history makes this more likely?
3. What will you see by examination with a left 3rd nerve palsy?
4. Why do cranial nerve abnormalities occur with TB meningitis?
5. Other than anti-TB, are there any other treatments that you would want to initiate? In what other TB diseases do we use steroids?
6. What stage is the patient’s IDS?
7. What other forms of EPTB are more common with IDS?
8. How is the treatment of TB different in patients with IDS?
