Essential respiratory medicine. Shanthi Paramothayan

Chapter 8. Respiratory infections

Learning objectives

 To understand the common types of respiratory infections

 To appreciate the risk factors for developing respiratory infections

 To understand the aetiology and pathogenesis of community acquired pneumonia (CAP)

 To understand the presenting symptoms and signs of CAP

 To understand the investigations used to make a diagnosis of CAP

 To understand the management of CAP

 To understand the prognostic scores used in CAP

 To understand the aetiology and pathogenesis of hospital acquired pneumonia (HAP)

 To learn the management of HAP

 To recognise the prognosis in HAP

 To appreciate the diagnosis, management, and prognosis of ventilator-associated pneumonia

 To understand respiratory infections in the immune- incompetent host

 To understand the management of aspiration pneumonia

 To recognise the presentation, diagnosis, and management of Mycobacterium tuberculosis

 To understand the diagnosis and management of latent tuberculosis

 To learn the management of opportunistic mycobacterial infections

Abbreviations

AAFB acid-alcohol-fast bacilli

ADA adenosine deaminase

ALT alanine transaminase

aMB atypical mycobacterium

AST aspartate aminotransferase

BAL bronchoalveolar lavage

BCG Bacille Calmette-Guérin

BOOP bronchiolitis obliterans organising pneumonia

BTS British Thoracic Society

CAP community acquired pneumonia

CF cystic fibrosis

CFT complement fixation test

CMV cytomegalovirus

CNS central nervous system

CO2 carbon dioxide

COPD  chronic obstructive pulmonary disease

CPAP  continuous positive airway pressure

CRPC C-reactive protein

CT computed tomography

DOT directly observed therapy

GCS Glasgow Coma Scale

GP General Practitioner

HAP hospital acquired pneumonia

Hib Haemophilus influenza B

HIV human immunodeficiency virus

HRCT high-resolution computed tomography

ICU intensive care unit

IGRA interferon gamma release assay

INH isoniazid

kPA kilopascals

LFT liver function test

LIP lymphoid interstitial pneumonia

MAC Mycobacterium avium complex

MAI Mycobacterium avium intracellulare

MDRTB multi-drug resistant tuberculosis

MRSA  methicillin-resistant Staphylococcus aureus

MTB Mycobacterium tuberculosis

NICE National Institute of Health and Care Excellence

NSIP non-specific interstitial pneumonia

PCR polymerase chain reaction

PCT pro-calcitonin

PEG percutaneous enterogastrostomy

PPD purified protein derivative

PSI pneumonia severity index

PYR pyrazinamide

RIF rifampicin

RSV respiratory syncytial virus

SALT speech and language therapy

SIADH syndrome of inappropriate anti-diuretic hormone

SOL space-occupying lesion

TB tuberculosis

VAP ventilator-associated pneumonia

WHO World Health Organisation

Introduction

The respiratory tract communicates with the environment, allowing micro-organisms to directly enter the respiratory tract and lungs. Therefore, infections of the upper and lower respiratory tract are very common. The majority of these are self-limiting and do not require any treatment. These infections are more prevalent in the very young, the elderly, and in those who do not have a competent immune system.

Respiratory tract infections

The diagnosis of a respiratory tract infection is made on clinical grounds. Viruses are a common cause of respiratory tract infections. Individuals with viral infections of the respiratory tract will develop a cough, a sore throat, headaches, nasal symptoms, fever, and myalgia. Investigations are rarely required except during epidemics, for example, an influenza epidemic, or when the patient’s symptoms are concerning. Most viral infections are self-limiting and those affected will recover without any treatment within a few days. They should be advised to rest, ensure adequate hydration, and take analgesia as required. Many will take over-the- counter cough medications to ease their symptoms. Box 8.1 lists the viruses that cause respiratory infections.

The common cold, caused by Rhinovirus, affects most of the population at least once every year. It does not require any treatment but is responsible for many days off work. Most adults would have had asymptomatic cytomegalovirus (CMV) infection during childhood. Only individuals who are immunosuppressed, especially those with HIV and those who have had solid organ transplants, develop symptoms when infected with CMV. Respiratory syncytial virus (RSV) infection results in seasonal outbreaks of respiratory illness, usually in the winter months and can cause complications in those with chronic lung and heart disease. RSV is the commonest cause of lower respiratory tract infection in infants and can be severe in premature babies who present with wheezing and apnoea; there is a risk of sudden death. Many of these viruses can cause pneumonia which will be discussed later in this chapter.

Box 8.1 Viruses affecting the respiratory tract.

 Adenovirus

 Coronavirus

 Cytomegalovirus (CMV)

 Influenza

 Parainfluenza

 Respiratory syncytial virus (RSV)

 Rhinovirus

_____

Sinusitis can occur due to a viral or bacterial infection of the maxillary sinus or, less commonly, the frontal and paranasal sinuses. Symptoms of sinusitis include headaches, periorbital and per nasal pain, fever, cough productive of purulent sputum, purulent nasal discharge, and post nasal drip. A CT scan of the sinus will show opacification of the maxillary sinus and mucosal oedema. Treatment of sinusitis is with antibiotics, nasal decongestants, and hydration. Rarely, surgical drainage may be required if medical therapy has failed.

Epiglottitis is a severe and potentially life- threatening infection of the epiglottis. It is common in young children and caused by haemophilus influenza type B (Hib) infection. Children will present with fever, sore throat, and cough, and the diagnosis must be made without delay. The treatment is with third generation cephalosporins, for example, cefotaxime. Epiglottitis can rapidly progress to respiratory distress and stridor caused by oedema of the epiglottis which can cause obstruction of the larynx. Children may require intubation and ventilation or an emergency tracheostomy. Children who are immunised with the Hib vaccine as protection against meningitis may also be protected against epiglottitis.

Laryngotracheobronchitis (croup) is most commonly caused by parainfluenza virus and is common in children in the winter months. It presents with a characteristic barking cough and fever, and can progress to respiratory distress and stridor.

Treatment is with nebulised bronchodilators, nebulised steroids, and steam inhalation.

Acute bronchitis affects the lower respiratory tract and results in cough, breathlessness, pleuritic chest pain, and fever.

Pneumonia

Pneumonia is an infection of the lung parenchyma which can be viral or bacterial. Immunocompromised patients are also at risk of ‘opportunistic’ infections which do not normally affect healthy individuals. These opportunistic infections, which include fungal and protozoal infections, will be discussed in a later section. Aspiration of gastric content and lipoid material can also result in a chemical pneumonia.

Viral pneumonia

Common causes of a viral pneumonia include influenza, adenovirus, parainfluenza, respiratory syncytial virus (RSV) and human metapneumovirus. H1N1 and Avian influenza A (HSN1) occur in pandemics and result in significant morbidity and mortality, with patients often requiring admission to the intensive care unit (ICU).

Patients with a viral pneumonia present with symptoms of dry cough, breathlessness, fever, headache, and myalgia. Diagnosis is made on clinical history, examination, culture of appropriate respiratory samples (such as nasal secretions and bronchial lavage), and serological tests. Polymerase chain reaction (PCR)-based diagnostic panels are available that can detect several respiratory viruses simultaneously. Viral cultures can take several days to process and are less sensitive than PCR analysis of respiratory secretions.

Patients with viral pneumonia can develop a secondary bacterial infection. This should be suspected if there is clinical deterioration, increase in the volume of sputum, which may be purulent, worsening breathlessness, and systemic symptoms. Blood tests will show an elevated white cell count with a neutrophilia, a rise in CRP and infiltrates or consolidation on the chest X-ray (CXR). Secondary Staphylococcus aureus pneumonia can occur after an influenza infection.

Sputum samples are rarely recommended with a viral pneumonia as these can be difficult to analyse because many non-pathogenic micro-organisms colonise the respiratory tract. Therefore, any positive sputum culture result must be interpreted with the clinical presentation in mind. Certain organisms, such as coagulase-negative Staphylococci and Candida species, are rarely pathogens.

Bacterial pneumonia

Bacterial pneumonia is a common cause of morbidity in the community and a common presentation to hospital. It is important to distinguish community acquired pneumonia (CAP) from hospital acquired pneumonia (HAP) as the latter is associated with a higher morbidity and mortality. Box 8.2 lists the common symptoms and signs of pneumonia.

Community acquired pneumonia (CAP)

Community acquired pneumonia (CAP) is a common acute lung infection that affects individuals living in the community. The annual incidence of CAP is 5—11/1000 of the adult population, with a higher incidence in children and the elderly. Every year between 0.5 and 1% of adults are diagnosed with a CAP. Risk factors include chronic lung disease, chronic renal disease, diabetes, abnormal immune system, and a preceding viral infection, such as influenza.

In a young and otherwise fit patient, CAP has a good prognosis and can be managed with oral antibiotics in the community. However, the morbidity and mortality can be high in the elderly and in the immunocompromised individual. Overall, 22—42% will require hospital admission and 1—10% will require admission to the ICU. Mortality ranges from 5% in the ambulatory setting to 35% in those admitted to ICU. Most pneumonia-associated deaths occur in people over the age of 84 years.

Pathophysiology

Bacterial infection of the lung parenchyma results in an inflammatory response from the host, with an outpouring of neutrophils and exudate into the alveolar spaces, resulting in consolidation. This compromises the oxygen exchange because of the ventilation-perfusion mismatch and results in type 1 respiratory failure. Inflammation of the pleura results in pleuritic chest pain and the development of a parapneumonic pleural effusion in a third of those with CAP. An empyema may develop in a certain percentage as discussed in Chapters 10 and 12. Table 8.1 lists the causes, typical clinical and radiological features, and the treatment of the common pneumonias.

Box 8.2 Symptoms and signs of pneumonia in the young and the elderly.

Patient demographics

Symptoms

Signs

Young and immunocompetent

Productive cough (green/rusty brown)

Fever (86%)

Rigors (15%)

Pleuritic chest pain (30%)

Dyspnoea

Haemoptysis

Night sweats

Headache

Myalgia

Nausea

Vomiting

Diarrhoea

Lethargy

Coughing

Temperature (86%)

Tachypnoea

Tachycardia

Consolidation: decreased breath sounds, dullness on percussion, increased vocal resonance and tactile focal fremitus, coarse crackles, bronchial breathing

Elderly or immunocompro

Symptoms above may be present

As above

mised

or absent

New confusion

Anorexia

Lethargy

Reduced mini mental test score (AMTS <8)

Table 8.1 Causes of pneumonia.

(Continued )

(Continued)

As described in Box 8.2, CAP has a variety of presentations. Immunocompetent young adults present with a cough productive of green or rusty sputum, breathlessness, pleuritic chest pain, small volume haemoptysis, fever, rigors, night sweats, and myalgia. Patients with mycoplasma, chlamydia, and legionella pneumonias usually present with more systemic symptoms, for example, nausea, vomiting, diarrhoea, headaches, and myalgia. The elderly and the immunocompromised may not have these classic symptoms as they cannot mount an inflammatory response. They are more likely to present with anorexia, feeling generally unwell, with a new confusion, and a reduced mini-mental test score.

Diagnosis of CAP

The diagnosis of pneumonia is made on the clinical symptoms and signs, and a chest X-ray (CXR) confirming new parenchymal shadowing. Those presenting with symptoms suggestive of a CAP should have a comprehensive history, examination, and investigations to confirm the diagnosis of CAP and to determine the severity. Investigations should include blood tests, CXR, urinary pneumococcal and legionella antigens and sputum for microbiological analysis. A CURB-65 score should be calculated in every patient presenting with a CAP; this guides management and has prognostic implications. Box 8.3 describes how the CURB-65 score is calculated.

A full blood count will usually show an elevated white cell count, with a raised neutrophil count. Leukopenia, with a white cell count <4 x 109 l-1, is associated with a poorer outcome. Mycoplasma pneumonia can be associated with cold agglutinins and a haemolytic anaemia. An elevated eosinophil count should raise the possibility of an eosinophilic pneumonia and will warrant further investigations, such as a bronchoalveolar lavage (BAL), a lung biopsy, and a HRCT. Eosinophilic pneumonias are discussed in Chapter 7.

Box 8.3 CURB-65 score.

The CURB-65 score is calculated by giving one point for each of the following prognostic features:

1. Confusion (abbreviated Mental Test Score 8 or less, or new disorientation in person, place, or time)

2. Urea >7 mmol/L

3. Raised respiratory rate (30 breaths per minute or more)

4. Blood pressure low; diastolic of 60 mmHg or less, or systolic of 90 mmHg or less

5. Age over 65 years

____

A raised urea signifies a worse prognosis. Hyponatraemia secondary to the syndrome of inappropriate anti-diuretic hormone (SIADH) can be associated with CAP, particularly legionella pneumonia. The CRP is always elevated in bacterial CAP, with a sensitivity of 73% and a specificity of 65%, although there is usually a lag, so it may not be raised at the onset of symptoms. Serial CRP measurements can be useful in monitoring response to treatment. Pro-calcitonin (PCT), a peptide precursor of calcitonin that is released by cells in response to bacterial toxins, can also be used to distinguish between bacterial and non-bacterial causes of pneumonia. PCT levels may also correlate with the severity of pneumonia.

Abnormal liver function tests (LFT), particularly a raised alanine transaminase (ALT) level, can occur with legionella or mycoplasma pneumonia. Deranged LFTs can also occur after treatment with intravenous antibiotics, particularly macrolides.

Microbiological diagnosis of CAP

Patients with a low-severity CAP do not routinely require sputum analysis. However, sputum should be sent in those presenting with moderate or severe CAP and when there is cavitation on the CXR. If the patient has a productive cough, then a deep cough sputum sample should be sent for Gram staining, culture, and sensitivity prior to starting antibiotics. There is huge variation in getting a positive sputum result, ranging from 10-80%. Some infections, such as Streptococcus aureus, are easily cultured, whereas Streptococcus pneumonia and Haemophilus influenzae are more difficult to culture, so false negative results can occur. Culture results are reported according to the amount of growth, with moderate or heavy growth indicating a true pathogen, whereas a light growth may indicate colonisation.

Bronchoscopy and bronchoalveolar lavage (BAL) samples are not routinely required, but should be considered in the immunocompromised

patient, those who have an abnormal CXR suggestive of malignancy, and in those not improving on empirical antibiotic therapy. BAL samples should have Gram staining, Ziehl-Neelsen staining for acid-fast bacilli (AFB), silver staining for pneumocystis jerovici, and stains for fungi. Cultures can take several days to weeks.

Blood cultures should be taken in those presenting with fever and other symptoms of sepsis, even in the absence of fever. Blood cultures are positive in 12% of hospitalised patients, with two-thirds growing Streptococcus pneumonia. Care should be taken when collecting blood for culture as there is a 10% rate of contamination with MRSA from the skin.

If Streptococcus pneumonia or legionella pneumophila infections are suspected, then urinary antigen testing is more sensitive and specific than blood cultures or sputum cultures, and gives a result more rapidly than cultures of sputum or blood. Urinary antigen testing has the advantage that the antigen will remain positive even after starting antibiotics, but as no pathogens are available, it is not possible to determine sensitivities. Therefore, it is recommended that sputum or BAL samples are also sent for microscopy, culture, and sensitivity.

Polymerase chain reaction (PCR) diagnostic kits are available to use on sputum samples which can give a result within a few hours for chlamydophila pneumoniae and mycoplasma pneumonia, although care must be taken to limit contamination from upper airway flora. If no sputum is available, then a throat swab for mycoplasma pneumonia PCR is recommended.

Complement fixation test (CFT), or paired serological test, can be used to diagnose legionella and mycoplasma infections, especially during outbreaks, and will show a fourfold rise in antibody titres. CFT is also recommended in any patient under 40 years presenting with pneumococcal pneumonia. The consultant microbiologist and public health consultant will usually be able to give advice about outbreaks and put in place public health safety measures, such as closure of infected hotels.

CMV serology can be requested if CMV pneumonia is suspected. Human immunodeficiency virus (HIV) test is recommended in any patient with an atypical presentation and an abnormal CXR.

Microbiological diagnosis is made in less than 40% of patients presenting with CAP. However, empiric antibiotic treatment results in outcomes as good as if the pathogen were detected, with only 1% treated in the community for CAP requiring hospitalisation because of treatment failure. The choice of initial antibiotic therapy is therefore made on the likelihood of the infecting organism.

Radiological diagnosis of CAP

The chest X-ray (CXR) is an essential investigation in making the diagnosis of CAP. NICE and British Thoracic Society (BTS) guidelines recommend that a CXR should be done in a timely way so that antibiotics can be prescribed within 4 hours of the patient presenting to hospital. The CXR may appear normal very early on or show interstitial infiltrates which are better seen on HRCT (Figure 8.1). In established CAP, the CXR will show consolidation in one or more lobes or show patchy consolidation of bronchopneumonia (Figure 8.2, Figure 8.3). Radiographic changes do not correlate with the pathogen, although Streptococcus aureus pneumonia and Klebsiella pneumonia present with cavitating lesions, the differential diagnoses for which include Mycobacterium tuberculosis infection, lung cancer, and vasculitis.

Figure 8.1 CXR showing left upper zone infiltration suggestive of early infection.

Figure 8.2 CXR showing right lower lobe consolidation.

Figure 8.3 CXR showing right middle and right lower lobe consolidation.

The differential diagnosis of CAP includes an exacerbation of COPD, exacerbation of asthma, acute bronchitis, pulmonary oedema, pulmonary embolus, adenocarcinoma in situ, eosinophilic pneumonia, hypersensitivity pneumonia, cryptogenic organising pneumonia or diffuse parenchymal lung disease. If there is no clinical improvement with appropriate antibiotics, then further investigations will be required.

Management of CAP

Patients presenting to their General Practitioner (GP) with symptoms and signs of a CAP should have a CXR and blood tests, including CRP measurement, to guide management. Pulse oximetry may be helpful in determining whether a patient needs to be admitted to hospital.

NICE Guidelines recommend that a five-day course of a single antibiotic should be given to those with a CRP of greater than 100 mg l-1 but with a CURB-65 score of less than 2. The choice of antibiotic will depend on local antibiotic prescribing guidelines and any antibiotic allergy that the patient may have. NICE recommends amoxicillin or tetracycline, and a macrolide or tetracycline for those with penicillin allergy. If symptoms do not resolve within three days, then the duration of antibiotic therapy should be increased. For those with a CRP between 20 and 100 mg l-1, a delayed antibiotic prescription should be considered, and the patient should be instructed to take the antibiotic if symptoms worsen. Patients with a non-severe CAP should expect clinical improvement within a week and complete resolution of symptoms by 6 weeks, although many report feeling fatigued for up to three months.

Radiological resolution usually takes up to six weeks after antibiotic treatment is completed. It is recommended that a CXR is done after 6 weeks to ensure complete resolution of changes.

Patients seen in hospital with a CURB-65 score of 2 or less and with no other adverse prognostic features should be started on oral dual antibiotic therapy with amoxicillin and a macrolide for 7—10 days. Those who are allergic to penicillin should be given either a macrolide alone or a tetracycline. If there are no adverse features, they could be discharged home with follow-up by the GP. The patient should be advised to rest, have adequate hydration, and seek medical help if their symptoms do not improve.

Patients with a diagnosis of CAP who have a CURB-65 score > 2 and those who have adverse prognostic features should be hospitalised and receive intravenous antibiotics, intravenous fluids, oxygen, and thromboprophylaxis to prevent pulmonary emboli. Adverse features include fever, respiratory rate > 24 breaths per minute, tachycardia, systolic blood pressure < 90 mmHg, oxygen saturation < 90% on room air, and confusion.

The aim should be to maintain oxygen saturation in the range of 94—98%, ensuring that there is no evidence of CO2 retention. Empirical intravenous antibiotic therapy should be started without delay once appropriate samples have been sent for microbiological analysis. These patients should be given nutritional support, a mucolytic agent, and physiotherapy for sputum clearance. Patients with COPD and asthma may benefit from regular nebulised bronchodilators.

The choice of empiric antibiotic therapy for CAP is based on the likelihood of a specific pathogen, and the local antibiotic prescribing guidelines which are based on resistance patterns. Microbiological classification prior to treatment is not practical as the organism is not always identified and waiting for identification may result in treatment delay.

As Streptococcus pneumonia is the commonest cause of CAP, it is recommended that intravenous amoxicillin or benzylpenicillin, together with a macrolide, is given. This combination has been shown to decrease mortality and length of hospital stay.

Patients who are allergic to penicillin should be commenced on a macrolide. Macrolides can cause prolongation of the QT interval and can interact with other drugs (discussed in Chapter 3). The prevalence of macrolide-resistant Streptococcus pneumonia is on the increase. Fluoroquinolones, such a levofloxacin and moxifloxacin, are also active against Streptococcus pneumonia so could be used as monotherapy. However, these drugs can also cause prolongation of the QT interval and ventricular arrhythmias in the elderly. Vancomycin and Teicoplanin are reasonable options in those who have travelled abroad where penicillin and macrolide resistance are high.

The antibiotic regime should be reviewed after 48 hours. If the patient is improving clinically, the fever has settled, and the CRP is coming down, then the intravenous antibiotics should be changed to oral antibiotics. There is no trial evidence regarding the optimal duration of antibiotic therapy, but treatment for 5—10 days is usually given as this results in improvement while minimising the risk of antibiotic-associated clostridium difficile infection.

Patients with a CURB-65 score of 3 or 4 with evidence of sepsis may develop hypotension and severe hypoxaemia requiring inotropic support, intubation, and ventilation on ICU.

A parapneumonic effusion occurs in 30—50% of patients with a CAP and will usually resolve without any intervention (Figure 8.4). In some cases, the effusion can progress to an empyema, the diagnosis and management of which are discussed in Chapter 12. Certain organisms, such as Staphylococcus aureus and Klebsiella pneumonia, can predispose to the development of a lung abscess, which is discussed in Chapter 12.

Figure 8.4 CXR showing right lower lobe consolidation with cavitation and a parapneumonic effusion.

Prognosis with CAP

Predictors of mortality include the CURB-65 score and the Pneumonia Severity Index (PSI) which is based on the patient’s gender, age, co-morbidities (diabetes, cardiac failure, renal failure), results of clinical examination, blood test results, and CXR findings. Additional adverse features include hypoxaemia (SaO2 <92% or PaO2 <8 kPA), white cell count >20 x 10 9 l-1 or <4 x 10 9 l-1, multilobe involvement and positive blood culture. Leukopenia, thrombocytopenia, and a raised serum glucose concentration in a non-diabetic patient, are also predictors of mortality.

A CT thorax should be considered when the CXR shows no improvement in the radiological changes, when there is a cavitating lesion, possible adenopathy, or clinical features of malignancy. These patients may also require a bronchoscopy to see if there is an obstructing lesion.

Mortality from CAP ranges from 5.1-13.6% (for all CURB-65 scores) in the community, but increases to 36% in patients who require admission to ICU. Young patients with a CURB-65 score of 0 have a good prognosis with a mortality of <1%. The majority will return to full health within a few weeks. The morbidity and mortality are greater in those over the age of 65 and those with co-morbidities, such as diabetes and COPD. Patients with a CURB-65 of 2 have a ninefold increase in risk of death. Those who survive complain of persistent fatigue, cough, and breathlessness. There is an increased risk of death in survivors over the next three years, with a one-year mortality of 27%, as hypoxia and the acute inflammatory response due to CAP are associated with death due to acute cardiac events. Box 8.4 lists the mortality associated with CURB-65 score.

Annual influenza vaccination is offered to the elderly and those with co-morbidities as this reduces the risk of ICU admission and the risk of death by 30%. Vaccination against pneumonia also offers protection against Streptococcus pneumonia.

Box 8.4 CURB-65 score and mortality.

CURB-65 score

Mortality (%)

Management

0

0.7

Oral antibiotics in community

1

2.1

Oral antibiotics in the community

2

9.2

Admit to hospital for intravenous antibiotics and close monitoring

3

14.5

Admit to hospital for intravenous antibiotics and close monitoring. May require ICU

4

40

Admit to ICU

Hospital acquired pneumonia (HAP)

Hospital acquired (nosocomial) pneumonia (HAP) is defined as a pneumonia that develops more than 48 hours after admission to hospital in a patient who did not have any symptoms or signs of pneumonia on admission. HAP accounts for 1.5% of all infections acquired in hospital and for most infection-associated deaths in hospitals. HAP increases the length of hospital stay by eight days and has a mortality of between 30 and 70%. HAP has a worse prognosis than CAP because the patient is older, has co-morbidities, and is infected with more virulent organisms. Elderly patients, those with diabetes, heart failure, and those who are immunocompromised are more likely to succumb to a HAP. The highest mortality is associated with Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli (41%) and methicillin-resistant Staphylococcus aureus (MRSA) at 32%. Anaerobic organisms are rarely implicated in a HAP.

Patients who develop HAP may not always have the usual symptoms and signs of pneumonia, such as fever and cough. They may appear nonspecifically unwell, become confused, refuse to eat and drink, become hypoxic, and develop signs of consolidation. Doctors looking after hospitalised patients should be alert to the possibility of HAP, and ensure that appropriate samples (sputum and blood cultures) are taken from these patients. A CXR may show a new area of consolidation, and blood tests may reveal a rising CRP and neutrophilia. Empirical intravenous antibiotic therapy, in accordance with local hospital policy, should be commenced while waiting for the results of cultures and sensitivities. As multi-drug resistance is common in this group of patients, a combination of antibiotics is often given with careful monitoring of the patient’s clinical state and the inflammatory markers. Usual antibiotics include Tazocin or Meropenem together with a macrolide.

Patients with HAP are likely to require intravenous fluids, nutritional supplements, and oxygen. Patients with a severe HAP often develop type 1 respiratory failure requiring continuous positive airways pressure (CPAP) or intubation and ventilation in the ICU. Deep vein thrombosis prophylaxis is essential.

Outpatients who have extensive contact with hospitals, including those on renal dialysis and those receiving chemotherapy, have an increased risk of developing multi-drug resistant infections, including MRSA. Other groups at risk include residents of nursing homes and other institutes. Healthcare workers are also more susceptible to developing these infections.

Ventilator-associated pneumonia

Ventilator-associated pneumonia (VAP) is a type of HAP that develops after a patient is intubated and ventilated on the ICU. Some 50% of those who are intubated and ventilated in the ICU will develop pneumonia, either through micro-aspiration or through contamination of the ventilator equipment. The routine use of proton pump inhibitors increases gastric pH, allowing bacteria to flourish. The organisms that cause VAP are the same as those causing HAP. Other organisms include Acinetobacter species and Stenotrophomonas maltophilia.

VAP is managed according to local antibiotic policies and the advice of the consultant microbiologist. Risk factors for developing multidrug resistance include hospitalisation for more than 48 hours, antibiotic therapy in the past 6 months, immunosuppression, and significant other co-morbidities.

Aspiration pneumonia

Aspiration pneumonia is common in patients with impaired swallowing which includes elderly patients, those with dementia, after a stroke, and those with neurological disease, for example, Parkinson’s disease and multiple sclerosis. Aspiration of gastric contents can also occur after a seizure when the airway is not protected and is commoner in alcoholics. Gastric contents are aspirated into the respiratory tract, resulting in a chemical pneumonia and anaerobic bacterial infection with organisms such as Bacteroides species. CXR will often show a right middle lobe consolidation as the right main bronchus leads directly from the trachea.

Management includes antibiotics with anaerobic cover, such as metronidazole, chest physiotherapy, and oxygen therapy. Any patient suspected of an aspiration pneumonia should be kept ‘nil by mouth’ until a speech and language therapy (SALT) assessment is made. If it is not safe for the patient to swallow, then nasogastric tube feeding may be necessary until the patient recovers. Recurrent aspiration pneumonia may warrant a percutaneous enterogastrostomy (PEG) tube in selected cases.

Micro-aspiration is also prevalent in hospitalised patients, especially in intubated and ventilated patients. Common organisms include gramnegative bacilli, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Entero- bacter spp. Gram-positive cocci include Staphylococcus aureus, MRSA, and Streptococcus species.

Lipoid pneumonia

Lipoid pneumonia is caused by the aspiration of exogenous lipid material into the lungs. This can occur in those taking laxatives and those taking nasal decongestants.

Pulmonary infections in the immunocompromised

Patients with an abnormal immune system are predisposed to developing viral, bacterial, fungal, and parasitic respiratory infections that rarely affect those with a normal immune system. Box 8.5 lists some conditions that increase the risk of opportunistic infections. Opportunistic viral infections include cytomegalovirus (CMV), varicella zoster, and herpes simplex infections. These patients are

Box 8.5 Patients at increased risk of respiratory infections.

Infection

Opportunistic infection

HIV infection

See Box 8.6

Immunosuppressive drugs

Bacterial, viral, fungal

Cytotoxic drugs for cancer

Bacterial, viral, fungal

Post bone marrow transplant

Invasive aspergillosis

Lymphoma

Bacterial, viral, fungal

Myeloma

Bacterial, viral, fungal

Splenectomy

Streptococcus pneumonia

Sickle cell disease

Streptococcus pneumonia

Renal transplant

CMV pneumonia

also more likely to develop bacterial pneumonia, often with more virulent organisms. Immunocompromised patients also succumb to fungal infection, such as pneumocystis jiroveci (previously known as pneumocystis carinii and still referred to as PCP), Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus niger, Histoplasmosis, and Candida albicans. Immunocompromised patients can be infected with parasites, such as toxoplasma, cryptosporidium, microsporidium and Strongyloides stercoralis. Immunocompromised hosts are more likely to be infected with Mycobacterium tuberculosis (MTB) and atypical mycobacteria, especially Mycobacterium avium intracellulare (MAI).

The immunocompromised host, when infected, may not present with the symptoms associated with infection, such as fever, as they are unable to mount an inflammatory response: they present with vague, non-specific symptoms.

Patients with lymphoma or myeloma have an immune paresis so that their white blood cells do no function properly. Patients who have had a splenectomy are at an increased risk of Gram positive cocci, for example, Streptococcus pneumonia, as are individuals with sickle cell disease. These individuals should be vaccinated against this organism and take penicillin V prophylaxis. Invasive pulmonary aspergillosis can occur after bone marrow transplant or in patients with lymphoma and has an extremely high mortality, even with intravenous antifungal treatment.

Patients with T-cell suppression, for example, after renal transplant, are at an increased risk of developing cytomegalovirus (CMV) pneumonia. The risk of this is increased if a seronegative patient receives an organ from a seropositive donor. The patients will develop non-specific symptoms, including cough, and the radiological features are also non-specific. A BAL or lung biopsy will reveal the characteristic ‘owl eye’ intranuclear inclusion bodies. Blood tests will show an increase in CMV IgM. Treatment is with Ganciclovir, foscarnet, or ribavarin.

Patients with HIV and a low CD4 count are at risk of being infected with a variety of opportunistic pathogens which are listed in Box 8.6.

Pneumocystis jiroveci infection can affect patients with HIV and a CD 4 count of <200 mm-3. The affected individual will present with a cough, severe breathlessness, and hypoxia. CXR will show bilateral, interstitial ground glass shadowing in a bat’s wing appearance (Figure 8.5, Figure 8.6).

Box 8.6 Pulmonary infections associated with HIV.

 Bacteria: Mycobacterium tuberculosis, Streptococcus pneumonia, Staphylococcus aureus, Cryptosporidium neoformans, Histoplasma capsulatum, Mycobacterium avium intracellulare (MAI).

 Virus: Pneumocystis jiroveci (PCP), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster (HVZ).

 Fungi: Aspergillus fumigatus, Candida albicans.

 Parasites: Toxoplasma gondii, Cryptosporidium, Microsporidium, Strongyloides stercoralis

Figure 8.5 CXR showing ground-glass shadowing of pneumocystic jiroveci.

Figure 8.6 HR CT thorax showing ground-glass shadowing of pneumocystis jiroveci.

Bronchial washings or a transbronchial biopsy will show organisms that stain positive with silver stains. Treatment for pneumocystis jiroveci is with high dose co-trimoxazole. Patients with HIV and a low CD 4 count should have prophylaxis with oral co-trimoxazole or nebulised pentamidine.

HIV can also result in a lymphoid interstitial pneumonia (LIP), non-specific interstitial pneumonia (NSIP) and bronchiolitis obliterans organising pneumonia (BOOP). HIV also predisposes to the development of pulmonary hypertension, Kaposis’s sarcoma, non-Hodgkin’s lymphoma, and Hodgkin’s lymphoma.

Mycobacterium tuberculosis

Tuberculosis (TB) is caused by the organism Mycobacterium tuberculosis (MTB). Mycobacterium bovis, which was endemic in cattle, was a cause of tuberculosis in humans in the past when milk was not pasteurised.

Epidemiology

Incidence: Worldwide, there are approximately nine million new cases of MTB every year, most occurring in the developing world, particularly Africa and Asia. Three million deaths/year are attributed to this infection worldwide. The World Health Organisation (WHO) has declared TB to be a global emergency.

In the UK, 12/100 000 of the population is affected. Immigrants from the Indian subcontinent are 40 times more likely to develop MTB than the Caucasian population (120/100 000) and those from Africa are 50 times more likely to develop MTB (211/100 000). Most new cases in the UK occur in inner cities, particularly London. There are approximately 8500 new cases in England and Wales every year and 73% of these occur in those born outside the UK.

Prevalence: A third of the world’s population, approximately 2 billion, are infected with latent TB and 15—20 million people have active TB.

Pathogenesis of primary pulmonary tuberculosis

Active pulmonary tuberculosis accounts for 52% of TB cases in the UK. MTB is spread from one individual to another through the respiratory tract by inhalation of a droplet containing the organism, and the formation of a Ghon focus in the upper lobes of the lung. MTB is an obligate aerobe and therefore has a predilection for the periphery of the upper lobes of the lungs which are relatively poorly perfused but well ventilated. The Ghon focus, together with mediastinal or hilar lymph node enlargement, is called the Primary Complex which forms within eight weeks of inhalation of the organism (Figure 8.7). In 90% of immunocompetent individuals the organism is contained, remains dormant, and does not cause clinical disease other than a mild febrile illness and in some cases erythema nodosum.

Over time, fibrosis of the upper zones can occur with calcification of the Ghon focus, resulting in the characteristic granuloma (Figure 8.8, Figure 8.9). Before it is calcified, it can be suspicious of an early lung cancer and, if in doubt, should be treated as a solitary pulmonary nodule (see Chapter 9).

Factors that predispose to the development of MTB include poor and overcrowded housing, overcrowded institutions, such as prisons, homelessness, poor nutrition, vitamin D deficiency (< 50 nmol l-1 of 25 hydroxycholecalciferol), alcoholism, and social deprivation. Individuals who are immunocompromised, the elderly, and those with chronic diseases, such as diabetes mellitus and chronic kidney disease, are also more susceptible to developing active TB.

Figure 8.7 CXR showing primary Mycobacterium tuberculosis infection.

Figure 8.8 CXR showing granulomas in the right lung.

Figure 8.9 CT thorax showing a calcified granuloma in the right lung.

In the UK, almost half of new cases are due to reactivation of MTB, which can occur decades after the original asymptomatic infection. Those with HIV with a CD4 count of less than 200 mm-3 are at risk of reactivation of MTB infection. Once reactivated, the organism can spread from the lungs to other parts of the body through the bloodstream.

Post-primary tuberculosis

In fewer than 10% of cases, the individual will develop the active disease after exposure, presenting with fever, malaise, poor appetite, and weight loss. This is called post-primary pulmonary TB and occurs in those who have some immune dysfunction, for example, HIV. The infection will spread through the lungs and present with radiological changes. The organism can spread to other organs and cause active disease, or lie dormant until it is reactivated. Tuberculin testing will be strongly positive in those who have a normal immune system.

Immunology

The host’s defence system recognises mycobacterial infections through toll-like receptors and destroys these organisms through the release of cytokines, including interferon-gamma. The formation of a granuloma by the human host ‘contains’ the organism in its dormant state. The lipids in the cell wall play an important role in the way the organism interacts with the host’s immune response.

Diagnosis

A diagnosis of MTB is made with careful clinical evaluation, a high level of suspicion and the appropriate investigations. Most of the symptoms are non-specific and in 25% of cases, they are absent. Box 8.7 lists the common clinical symptoms and signs of pulmonary tuberculosis.

Delay in making the diagnosis is common, resulting in transmission of the infection to others.

The median time between the onset of symptoms and diagnosis is 10 weeks, although in 42% of cases it takes more than three months for the diagnosis to be made. Many of these patients are treated with multiple courses of antibiotics without sputum samples being sent for culture. Individuals with HIV may present with atypical symptoms and signs, and all patients diagnosed with MTB should have an HIV test. MTB is a notifiable disease and information should be sent to Public Health England.

Radiological diagnosis

Patients who present with symptoms suggestive of TB should have a CXR. In acute pulmonary TB this may show as an area of consolidation, as a cavitating lesion in the upper lobes of the lung (Figure 8.10) and lymph node enlargement in any of the lymph nodes in the mediastinum. Rarely, widespread disease affecting the lung parenchyma can result in what is called miliary TB as the nodules, measuring less than 5 mm in size, resemble millet seeds (Figure 8.11). Chickenpox pneumonia resembles miliary tuberculosis (Figure 8.12).

Figure 8.10 CXR showing right upper lobe consolidation in active mycobacterium infection.

Figure 8.11 CT thorax showing miliary tuberculosis.

Figure 8.12 CXR of previous chickenpox pneumonia.

A unilateral pleural effusion is a common presentation. Some 5% of patients with pulmonary TB will have a normal CXR. Chronic lung changes from previous MTB infection include upper zone fibrosis, traction bronchiectasis, and signs of volume loss (Figure 8.13, Figure 8.14).

Microbiological and histological diagnosis

It is important to culture samples from the area that is affected to make a definite diagnosis of MTB and to find out the sensitivities to anti-tuberculous medication. Samples that could be sent include sputum, bronchial lavage, pleural fluid, pleural biopsy, or lymph node biopsy. It is recommended that samples are taken before starting treatment, but treatment should be initiated while waiting for cultures if the patient is symptomatic.

Figure 8.13 CXR showing changes of chronic mycobacterium tuberculosis infection.

Figure 8.14 CT thorax showing changes of chronic tuberculosis.

Sputum, if possible three early morning samples, should be sent for microbiological analysis and culture as the bacterial load is greater in these early samples. If the patient is unable to produce a sputum sample, then an induced sputum sample or bronchoalveolar lavage can be taken. In children, gastric washings can be helpful.

If viable mycobacteria are seen in the sputum, then it is called a ‘smear-positive case. Sputum microscopy will detect acid-fast bacilli (smearpositive result) within 24 hours but will not differentiate between different strains of mycobacteria or whether the organism is alive or dead. Cultures are required for that which takes several weeks as the organism is a slowly growing one.

Samples of urine, cerebrospinal fluid (CSF), or tissue from any affected site can be cultured if extra-pulmonary MTB is suspected. Samples for histology should be stained using the Ziehl-Neelsen stain which uses the Carbol-fuschin red dye which is acid and alcohol fast; the report will say ‘acid- alcohol-fast bacilli (AAFB).

The characteristic histological appearance of TB is a caseating granuloma. This is composed of an area of central necrosis surrounded by epithelioid giant cells, macrophages, and lymphocytes.

Specimens should not only be stained but should be cultured in a Lowenstein-Jensen medium which takes six weeks. There are newer culture techniques which can give the result of drug sensitivities within three weeks, although these are not in routine use yet.

Polymerase chain reaction (PCR) techniques can be useful when clinical suspicion is high but only small amount of material is available. DNA probes can be used for detecting certain multidrug-resistant strains of TB which can also help trace the spread of the drug-resistant TB. Adenosine deaminase levels >50 U l -1 in pleural fluid are strongly suggestive of pleural TB, even if organisms themselves are not cultured from the pleural fluid, with a sensitivity of 90% and specificity of 89%.

Immunological diagnosis

The host responds to MTB infection by a delayed Type 1V hypersensitivity reaction to the tubercle bacilli. Diagnostic tools that are based on this cellular immunity have been developed.

The cutaneous immune response to an intradermal injection of purified protein derivative (PPD) from the bacterium is used to determine whether there is an active infection, especially when it is not possible to culture the organism.

Figure 8.15 Preparation for a Mantoux test.

Figure 8.16 Forearm with purified protein derivative instilled intra-dermally.

In the Mantoux Test, 10 units (0.1 ml) of PPD is injected intra-dermally and the size of the induration is measured after 48—72 hours (Figure 8.15, Figure 8.16). In the HeafTest, a fixed amount of the PPD is injected intra-dermally using a spring-loaded gun and the size of the induration is measured.

The size of the reaction from either of these methods is read after 48—72 hours and graded according to the size of the induration as 1—4. Skin induration greater than 5 mm is considered positive and induration greater than 15 mm strongly positive. The response will be affected by the BCG vaccination status of the individual, as those who have had the BCG vaccine will show a mild response, even when they are not infected with MTB. This delayed Type 1V hypersensitivity test is not useful in individuals over the age of 35, those who have previously had active TB, in those who are immunocompromised, and those with miliary tuberculosis. Supplementary material demonstrates how a Mantoux test is carried out (www.wiley. com/go/Paramothayan/Essential_Respiratory_ Medicine). A strongly positive tuberculin response (Grade 3 or 4) should be investigated further with clinical assessment, chest X ray, and samples for culture as appropriate.

The interferon gamma release assay (IGRA) is an in vitro test that measures T-cell activation by MTB antigens. The Quantiferon Gold assay and the T- spot TB assay are available in the UK. Blood taken must be analysed within a few hours. The results of these investigations must be interpreted carefully together with all the other information available as a positive test on its own does not necessarily mean that the patient has MTB (Figure 8.17).

The differential diagnosis of MTB always includes sarcoidosis. Sarcoidosis (discussed in Chapter 7) presents with similar clinical symptoms and signs, similar radiological appearances, for example, hilar lymphadenopathy, and granuloma on biopsy samples. However, caseation is not seen with sarcoidosis and the immunological tests will be negative.

Management of MTB

Prior to the availability of anti-tuberculous drugs, patients with mycobacterium tuberculosis infection were treated with a variety of procedures which were aimed at containing the infection by preventing ventilation of the lung. This included plombage whereby several plastic balls were placed in the pleural space to prevent ventilation (Figure 8.18) or by thoracoplasty and rib resection (Figure 8.19) to remove the infected lung. Patients were also given an artificial pneumothorax.

Figure 8.17 Quantiferon testing kit.

Figure 8.18 CXR showing plombage left lung.

Figure 8.19 CXR showing right-sided thoracoplasty.

The standard treatment regime is a combination of Isoniazid (INH), Rifampicin (RIF), Pyrazi- namide (PYR), and ethambutol for two months, followed by rifampicin and isoniazid for a further four months. If the organism is sensitive to these drugs and the drugs are taken as advised, this regime is very effective with a <3% risk of relapse. The dose is calculated according to the weight of the patient and given once a day on an empty stomach. Combinations of drugs, for example, Rifinah, which contains rifampicin and isoniazid and Rifater which contains rifampicin, isoniazid, and pyrazinamide, reduce the number of tablets that the individual needs to take, making compliance easier. Pyridoxine, 10 mg, is always given to prevent INH-induced peripheral neuropathy.

Although the standard treatment is with four drugs, three drugs (RIF, INH, and PYR) can be used if the patient is a close contact of an index case who has a fully sensitive organism.

MTB is usually managed in secondary care by respiratory physicians and TB nurses. To ensure compliance, some patients may need directly observed therapy (DOT), when a healthcare professional observes the patient swallowing the tablets. DOT is recommended in immigrants with poor language skills, those in whom compliance is suspect and those with possible MDRTB. The WHO recommends DOT as a standard procedure for eradicating MTB worldwide as it has a success rate of around 95%.

Compliance can also be checked by looking at a urine sample which will turn an orange/red color if the patient is taking rifampicin.

In most cases (85%) of smear-positive TB which is fully sensitive, the sputum sample will be clear after two weeks of treatment. In cases where there is extensive cavitation on the CXR and a large burden of disease, several weeks or months of treatment may be required before the sputum is smear-negative.

These drugs are safe to take during pregnancy and while breast feeding. Standard treatment is for six months. The recommended regime should be continued even if the culture results are subsequently negative.

Box 8.8 lists the main side effects of the first line anti-tuberculous drugs. All of them can cause nausea, especially if taken on an empty stomach. Approximately 9% of patients on these drugs develop significant side-effects requiring all medication to be stopped and then reintroduced carefully, one at a time, to see which one has caused the problem. Patients who are older, female, and HIV positive are more likely to develop serious side effects to anti-tuberculous drugs. Patients with liver disease are at increased risk of hepatotoxicity, so should be monitored more closely. These patients may require second-line drugs. Patients with chronic renal failure will require a lower dose of ethambutol.

Hepatitis is the commonest side-effect, resulting in the medications having to be stopped. The liver function tests should be checked before

Box 8.8 Common side effects of anti-tuberculous drugs.

Drug

Dose and duration

Prior testing and monitoring

Common side effects

Isoniazid (INH)

300 mg for 6 months

Liver function test

Hepatitis

Peripheral sensory neuropathy

Rash

Fever

Rifampicin (RIF)

450 mg if <50 kg 600 mg if >50 kg for 6 months

Liver function tests

Hepatitis

Thrombocytopaenia

Itching

Fever

Red urine and secretions Enzyme inducer of cytochrome P450 so interaction with many drugs

Pyrazinamide

1.5 g if <50 kg 2.0 g if >50 kg for initial 2 months

Liver function tests

Hepatitis

Rash

Elevated uric acid level Rash

Ethambutol

15 mg kg-1 for initial 2 months

Visual acuity

Optic neuritis

commencing treatment, two weeks after starting treatment, and then at two months. Rifampicin blocks the excretion of bilirubin and results in an isolated increase in bilirubin which is not of concern. This will usually return to normal after two weeks. A rise in alanine transaminase (ALT) and aspartate transaminase (AST) are common in the first two to three months of treatment. It is only of concern if the levels rise to greater than four times the baseline and if the patient becomes symptomatic.

Although there is in vitro evidence that vitamin D enables monocytes and macrophages to kill MTB, there is no clinical trial evidence that treating vitamin D deficiency prevents infection with MTB or that giving vitamin D to patients with TB is beneficial.

A paradoxical reaction can occur in 6—30% of patients approximately 60 days after starting anti-tuberculous treatment when it appears that there is clinical and/or radiological worsening of the condition in a patient who initially appears to be improving.

HIV and MTB

Approximately 10% of patients with HIV are coinfected with MTB, therefore a high index of suspicion is required in this group, especially as these patients may not manifest the usual symptoms. Tuberculin testing will be negative because they are unable to mount an immunological reaction as their T lymphocytes are not functioning. These patients may present with lower lobe disease or disseminated disease if their CD4 count is less than 200 mm-3. Anti-retroviral treatment may worsen the condition, so anti-tuberculous treatment should be initiated before commencing antiretroviral treatment, so long as the CD4 count is >200 mm-3. For patients with HIV with a CD4 count of between 100 and 200 mm-3 and MTB, there is conflicting guidance as to when to start the TB treatment and anti-retroviral treatment, so specialist input from the genitourinary physician will be required.

Information to patients with TB

An individual who has been diagnosed with MTB should be given clear, written information about the disease, the medication required and the fact that six months of treatment is required to cure them of the disease. The side effects of the

medication should be explained, and they should be advised to stop the medication if they develop symptoms, such as fever, vomiting, or severe rash. If they are on medication that may interact with rifampicin, for example, anticoagulants, anticonvulsants, steroids, or oestrogens, including the oral contraceptive pill, they need to understand the consequences. It is essential that they understand that the tablets must be taken daily to prevent relapse and the development of MDRTB. Contracting TB is still a stigma in many societies and this will need to be addressed.

Infectivity of tuberculosis

Active TB will, if untreated, infect 10—15 people every year, so is a major public health concern. Those with pulmonary tuberculosis who are found to have AAFB in their sputum or BAL are considered infectious and called ‘smear-positive. These patients are usually admitted to a negative pressure isolation room on the ward, commenced on antituberculous treatment and kept in isolation for two weeks. After this time, in most cases, they will no longer be considered infectious, although when the bacterial load is large, a longer period of isolation may be required. If there is any doubt about multi-drug resistance, then the individual should be kept in isolation until the sensitivities are confirmed. Healthcare workers should wear a proper protective mask as should the patient if he or she were to go outside the room for any reason. Extrapulmonary tuberculosis cannot be caught, even by close contacts.

Contact tracing

Approximately 1—3% of close contacts of a smearpositive patient will be found to have the active disease. It is important, therefore, to assess the close contacts of the index case to see if they might have contracted tuberculosis. This includes close family members and work colleagues. This is important because contacts who might have been infected may not show any clinical symptoms which may later become activated. These individuals are considered to have latent tuberculosis. Contact tracing involves clinical assessment of symptoms, CXR, tuberculin testing, Quanteferon testing, and BCG status.

MTB is a notifiable disease and should be reported to Public Health England. The Public

Health consultant will be involved in any case of outbreak in the community. The Occupational Health Department will be involved in identifying and managing healthcare workers in any setting, for example, hospital or nursing home.

Screening of immigrants

All individuals arriving in the UK from areas of high prevalence of MTB are screened with a health status interview, evidence of BCG vaccination and a CXR, usually done at their country of origin. A tuberculin test is carried out in those younger than 35 years.

Latent tuberculosis

Individuals who are exposed to the organism but do not develop active disease are considered to have latent tuberculosis. The organism lies dormant because the host’s immune system contains it. These individuals are asymptomatic, are not infectious and will have a normal CXR, but will have a strongly positive tuberculin reaction.

These individuals are at risk of reactivation of tuberculosis at a later stage, for example, when they are older or become immunocompromised. Identifying and treating individuals with latent TB infection reduces the risk of reactivation which is 5—10%. The risk is greatest within the first two years of acquiring the infection.

Individuals with latent tuberculosis should be offered chemoprophylaxis, usually with INH for six months or INH and RIF for three months. As discussed earlier, there is a risk of a rise in liver enzymes, therefore liver function tests should be checked prior to starting treatment and one week later. Individuals who are candidates for biological therapy, such as anti-TNF-a treatment, which is commonly given for a variety of rheumatological, dermatological, and gastroenterological conditions, or those who are going to have chemotherapy or organ transplant, should also receive chemoprophylaxis.

In London, the ‘Find and Treat’ initiative screens patients at high risk of developing TB by CXR and symptom enquiry as there is evidence that reactivation of latent disease accounts for more new cases than new infections from transmission.

Prevention of Mycobacterium tuberculosis (MTB)

The BCG vaccination, containing a live attenuated strain of mycobacterium bovis, is offered to the children of high risk groups, such as immigrants, ethnic minorities, and healthcare workers who may be exposed to TB. Neonates and infants up to the age of three months can be given the BCG vaccination without tuberculin testing. Older children need Heaf testing to demonstrate a negative response before immunisation. The BCG provides 75% protection against the disease for a period of 15 years. The protective effect is stronger for TB meningitis than for pulmonary disease. There is little evidence that BCG offers protection when given to adults.

Treatment of multi-drug-resistant tuberculosis (MDRTB)

Multi-drug-resistant TB (MDRTB) occurs in those who have had a failure of treatment with anti-tuberculous drugs, usually in those who did not complete the treatment regime. The majority of these are from Africa or the Indian sub-continent, and rates of MDRTB have doubled in the UK in the past decade due to immigration. The rate of resistance is 8% for isoniazid, 1.7% for rifampicin and 1.2% for both. MDRTB causes approximately 10% of all TB deaths worldwide.

Patients with MDRTB must be isolated as they pose a huge public health risk. Outbreaks occurring in hospitals and prisons result in high mortality. MDRTB is managed in centres with expertise and experience. A prolonged course of second line drugs, for up to 24 months, may be required. Box 8.9 lists the second and third line drugs used for MDRTB. There is less evidence for the efficacy of the third line drugs.

In cases of MDRTB where drugs appear ineffective or when there are serious side effects from drug therapy, a lobectomy or pneumonectomy could be considered to remove the infected lung.

Box 8.9 Drugs used to treat MDRTB.

Second line drugs

 Aminoglycosides: amikacin, kanamycin

 Polypeptides: Capreomycin, viomycin, enviomycin

 Fluroquinolones: ciprofloxacin, levofloxacin, moxifloxacin

 Thioamides: ethionamide, prothionamide

 Cycloserine

 Terizidone

Third line drugs

 Rifabutin

 Macrolides

 Linezolid

 Thioacetazone

 Thionidazine

 Arginine

 Bedaquiline

____

Pulmonary complications of mycobacterium tuberculosis

Box 8.10 lists some of the pulmonary complications of MTB.

Box 8.10 Pulmonary complications of MTB.

1. Cavities

2. Aspergillus fumigatus or Aspergillus niger

3. Pneumothorax

4. Lobar collapse

5. Pleural effusion

____

Extra-pulmonary tuberculosis

MTB can disseminate and spread haematogenously to other organs. Approximately 20% of patients with pulmonary TB will have extra-pulmonary disease in an additional site. The very young, the elderly, and those who are malnourished and immunocompromised are most likely to develop extra-pulmonary TB. Extrapulmonary TB is more common in those from high prevalence nations.

Table 8.2 lists the other organs involved, the frequency of this involvement, the clinical presentation and what kind of specimen is used to make the diagnosis.

The diagnosis is confirmed by observing the acid-fast bacilli and culturing the organism from the samples. PCR analysis can be diagnostic if only a small amount of sample is available. Samples from pleura, the liver, the lymph nodes, and bone marrow generally have a good yield but CSF and pleural fluid less so. Samples should be sent to the laboratory in a sterile pot with no additives. Histopathology will show granuloma containing epithelioid macrophages, Langerhans giant cells and lymphocytes, with caseation in the centre.

Some 25% of patients with TB lymphadenitis may develop pain and increased swelling of the lymph nodes with treatment. This is a well-recognised phenomenon and does not indicate treatment failure. Oral corticosteroids are often given in this situation. The lymph nodes will start to shrink two to three months after treatment is started. Surgical removal of very large lymph nodes could be considered.

TB can affect the central nervous system (CNS) resulting in TB meningitis or a tuberculoma, which can present as a space-occupying lesion. In TB meningitis, cerebrospinal fluid (CSF) will have a high protein level, high lymphocyte count, and a low glucose level, and become culture positive in 50% of cases. CNS TB will require 12 months of treatment. Dexamethasone, 8—12 mg daily, reducing over six weeks, is usually given for TB meningitis. There is some evidence that thalidomide may be of benefit in TB meningitis.

TB of the spinal cord can result in TB myelitis and progress to involve the spinal cord with cord compression. Surgical decompression may be required. Surgery may also be required for the drainage of any tuberculous abscess.

Miliary tuberculosis results from the haema- togenous dissemination of mycobacterium tuberculosis to many organs. The CXR will show multiple, small nodules throughout the lung fields which is more obvious on a CT scan of the thorax. In patients who present with miliary tuberculosis, evidence of involvement of other organs should be actively sought. A CT head and lumbar puncture for analysis of CSF should be done urgently.

Table 8.2 Non-pulmonary tuberculosis.

Opportunistic (atypical) mycobacterium

Opportunistic mycobacteria, often called atypical mycobacteria, are saprophytes that are found in the environment; in soil and water. These organisms only cause disease in those who are immunocompromised or those with chronic lung disease. Mycobacterium avium complex (MAC) is a common cause of pulmonary disease worldwide.

Box 8.11 lists some of the opportunistic mycobacteria. Box 8.12 lists some of the common conditions that predispose to infection with these organisms.

Individuals with opportunistic mycobacteria infections present with cough, haemoptysis, malaise, and weight loss, but generally with less systemic symptoms than MTB. These organisms are not infectious and therefore cannot be caught by close contacts. These infections do not require contact tracing and are not notifiable. Disseminated MAI infections can occur in HIV patients, especially those with a low CD count of less than 200 mm-3.

Diagnosis of opportunistic mycobacteria is made with a history of respiratory symptoms, CXR, and HRCT thorax showing the characteristic ‘tree in bud’ appearance (Figure 8.20). Sputum and BAL samples will stain positive with Ziehl-Neelsen stain, raising the possibility of MTB. Cultures will exclude MTB and identify the correct species.

Treatment is required if the patient is systemically unwell. Treatment is with a combination of macrolides (clarithromycin or azithromycin), rifamycins (rifampicin or rifabutin) and ethambutol for 18—24 months. Other drugs that are used include fluroquinolones and aminoglycosides. Complete eradication is difficult, especially in those with chronic lung disease. Surgery in the form of lobectomy or pneumonectomy may be an option in those with heterogeneous disease, who are fit for major surgery.

Box 8.11 Opportunistic mycobacteria.

1. Mycobacterium kansasii

2. Mycobacterium avium intracellular intracellulare (MAI): also called Mycobacterium avium intracellular complex (MAC)

3. Mycobacterium xenopii

4. Mycobacterium malmoense

5. Mycobacterium chelonae

6. Mycobacterium marinarum

7. Mycobacterium gordonae

8. Mycobacterium abscessus

____

Box 8.12 Conditions that predispose to opportunistic mycobacterial infection.

1. Bronchiectasis

2. Pulmonary fibrosis

3. Cavitating lung diseases

4. Human immunodeficiency virus (HIV) infection

____

Figure 8.20 CT thorax showing ‘tree in bud’ appearance of atypical mycobacterial infection.

 Infections of the respiratory tract are very common and are mostly self-limiting.

 Viral infections of the upper respiratory tract are responsible for the common cold, laryngitis, and tracheobronchitis; these can be troublesome in infants and young children.

 Community acquired pneumonia is a common presentation to general practice and to hospitals and is caused by a variety of bacteria.

 The management and prognosis of CAP depend on whether the individual is immunocompetent, the CURB-65 score, and the causative organism.

 Patients with a CURB-65 score of 0 or 1 can be managed in the community with oral antibiotics and their prognosis is excellent.

 Patients with a CURB-65 score of 2 or more should be managed in hospital with intravenous antibiotics and supportive treatment, such as intravenous fluids, oxygen, and mucolytics.

 Investigations for CAP include CXR, blood cultures, sputum cultures, and urinary antigens for legionella and pneumococcus.

 The mortality of patients with a CURB-65 score of 3 or 4 is significant, and is greater in those who are over 85 years of age.

 The commonest organism causing CAP is Streptococcus pneumonia.

 The differential diagnosis for a cavitating lesion on CXR includes Staphycoccus aureus, Klebsiella pneumonia, Mycobacterium tuberculosis, vasculitic lesions, and lung cancer.

 HAP is a new infection which occurs in an individual who has been in hospital for at least 48 hours. The infecting organisms include Gram negative organisms such as Pseudomonas, Klebsiella and MRSA. HAP has a worse prognosis than CAP.

 VAP occurs in 50% of patients who are ventilated on the ICU. The risk of multidrug-resistant organisms is high and VAP has a high morbidity and mortality.

 Immunocompromised individuals are at high risk of respiratory infections with opportunistic organisms: CMV, bacteria, fungi, and parasites.

 Patients with HIV and a CD4 count of less than 200 cells mm-3 are at risk of contracting a variety of infections, і ncluding CMV, HSV, HVZ, PCP, MTB, aspergillosis, cryptosporidium, and MAI.

 MTB is an enormous health problem worldwide; 15-20 million with active TB, 9 million new cases every year and 3 million TB-related deaths every year.

 Factors that predispose to the development of MTB include malnutrition, deprivation, poverty, and overcrowding.

 Most patients who develop MTB in the UK are individuals from the African and Indian sub-continents.

 MTB is a notifiable disease. Contact tracing of the index case is required.

 The diagnosis of MTB is made based on clinical history, suspicious radiology and organisms being detected in appropriate samples; sputum, BAL, urine, pleural fluid.

 All those with a diagnosis of MTB should have an HIV test as the prevalence of HIV is 10% in this group.

 Treatment of pulmonary TB is usually with four drugs for 6 months. It is essential for individuals to complete treatment as otherwise there is a risk of multi-drug resistance and poorer outcomes.

 The WHO advocates DOT for individuals at risk and those who may not be compliant.

 Anti-tuberculous medications have side- effects, including hepatitis, so monitoring is required.

 Anti-tuberculous medications interact with many other drugs through the cytochrome P450 enzyme system.

 Patients who are immunosuppressed and those who are eligible for biological therapy (TNF-a) are at a risk of reactivation of latent TB and should have chemoprophylaxis.

 The results of the Mantoux test and Quanteferon should be interpreted carefully and will be affected by the age, ethnicity, and the BCG status of the individual.

 Extra-pulmonary TB can affect the lymph nodes, CNS, bone, the genitourinary system, the gastrointestinal system, and skin.

 Tuberculous meningitis has significant morbidity and mortality. Diagnosis must be made promptly and treatment may be required for 9-12 months.

■ Atypical mycobacteria are only pathogenic in immunocompromised individuals and those with chronic lung diseases. Treatment may be required for 18-24 months.

MULTIPLE CHOICE QUESTIONS

8.1 Which of the following statements about CAP is true?

A Antibiotic treatment should be delayed until positive cultures and sensitivities are available

B CAP should always be managed in hospital

C CAP should be suspected in a patient who becomes unwell after several days in hospital

D CURB-65 score is of prognostic value and should be always calculated

E Diagnosis of a CAP is made from the presenting symptoms

Answer: D

The diagnosis of CAP is made after assessing the clinical symptoms, signs, and radiological changes on a CXR in a patient who presents from the community. Once confirmed, antibiotic treatment should be started without delay. Patients who are young, have no serious comorbidities, and a CURB-65 score of 0 or 1 should be managed in the community with oral antibiotics. If a patient who has been in hospital for more than 48 hours develops pneumonia, then that is called a HAP.

8.2 Which of the following statements about CAP is true?

A Annual incidence of CAP is 50/1000 of adult population

B The commonest pathogen causing CAP is Staphylococcus aureus

C Mortality from severe CAP with a CURB-65 of 4 is 10%

D Patients with CAP always present with productive cough and fever

E Urinary antigens for pneumococcus have a high sensitivity and specificity

Answer: E

The annual incidence of CAP is 5—11/1000 of the adult population. The commonest pathogen is Streptococcus pneumonia. Mortality of severe CAP with a CURB-65 score of 4 is very high at 40%. These patients should be admitted to the ICU. Elderly and immunocompromised patients may not present with cough and fever as they are unable to mount an immune response. They often present with generalised malaise, confusion, and reduced appetite. Urinary pneumococcal antigen has a high sensitivity and specificity.

8.3 Which of the following statements about HAP is true?

A It accounts for 10% of all infections in hospital

B Mortality from HAP is 10%

C Pseudomonas aeruginosa is a common organism in HAP

D It is less common in ventilated patients on ICU

E Patients with HAP always present with fever and cough

Answer: C

Pseudomonas aeruginosa and other Gramnegative bacteria are common causes of a HAP which is more likely to occur in those who are immunocompromised, have comorbidities, and chronic lung disease. HAP accounts for 1.5% of all infections in

hospital and mortality is 30—70%. HAP (or VAP) is more common in intubated patients due to micro-aspiration. Patients who are immunocompromised do not always present with the classic symptoms of an infection.

8.4 Which of the following statements about respiratory infections in the immunocompromised host is true?

A Pneumocystis jiroveci pneumonia only occurs in those with HIV

B Patients with HIV and MTB should not have anti-tuberculous treatment until they receive anti-retroviral drugs first

C Patients who have sickle cell disease are likely to develop fungal infections

D Patients with T cell suppression are at risk of developing CMV pneumonia E Aspergilloma occurs in patients with HIV

Answer: D

PCP can occur in any patient who is immunocompromised, those with bone marrow or solid organ transplant, on chemotherapy, or immunosuppressed with drugs. Patients with HIV who develop TB should have treatment for TB. Patients with sickle cell disease are at risk of developing Streptococcus pneumonia infection so should have the vaccine against this organism and take prophylactic penicillin V.

8.5 Which of the following statements about MTB is true?

A Worldwide more people have active TB than latent TB

B 10% of individuals with HIV get TB C 90% of individuals exposed to MTB will develop the active disease

D 25% of new cases of TB occur in those born outside the UK

E A granuloma is highly infectious

Answer: B

Approximately one-third of the world’s population has latent TB and 15—20 million have active TB. Fewer than 10% of those exposed to the organism develop the active disease. Some 73% of the new cases in the UK develop in those born outside the UK, predominantly from Africa and the Indian subcontinent. A granuloma is a calcified Ghon focus seen on a CXR and is not infectious.

8.6 Which of the following statements about MTB is true?

A Patients with TB and a cough are always infectious to others and should be kept in isolation

B Negative sputum samples rules out TB

C A Mantoux test is a specific and sensitive test in diagnosing TB

D Patients with CNS TB should be treated for 12 months

E Tuberculous pleural effusion is neutrophilic

Answer: D

Only patients with live mycobacterium in their sputum (smear-positive) are infectious and should be kept away from others at least until two weeks of treatment is complete. Negative sputum samples do not rule out TB which is made with a combination of clinical, radiological, microbiological, and immunological tests. A Mantoux test is not sensitive or specific as it is affected by previous BCG, the age of the patient, and conditions that affect the T-lymphocytes, such as HIV, when it will be negative. CNS TB requires 12 months of treatment with anti-tuberculous drugs and often dexametha- sone. Tuberculous pleural effusions are lymphocytic.

8.7 Which of the following statements about anti tuberculous therapy is true?

A Pyrazinamide is the drug which is most likely to cause hepatitis

B The drugs should be stopped if there is any rise in liver enzymes

C Visual acuity should be checked before starting ethambutol

D Multi-drug-resistant TB is responsible for 50% of TB deaths.

E Fast acetylators are more likely to develop hepatitis than slow acetylators

Answer: C

Isoniazid is the drug most likely to cause hepatitis but adding in rifampicin increases the risk. Liver enzymes should be measured before starting the drugs and again two weeks after starting treatment. A small rise in the levels should be noted and monitored, but the drug should only be stopped if the patient becomes unwell and the enzymes (ALT and AST) rise four times greater than baseline. MDRTB is responsible for 10% of deaths worldwide. Genetic polymorphism means that low acetylators are more likely to develop liver failure than fast acetylators.

8.8 Which one of the following statements is true?

A 1—3% of close contacts of smear-positive patients will develop the active disease

B Latent TB is diagnosed with positive organisms on culture

C Those with latent TB will require four anti-tuberculous drugs for six months

D Risk of reactivation of latent TB is 25%

E The BCG vaccination should be offered to all university students

Answer: A

Latent TB implies that there are no organisms as there is no active disease and so treatment is with isoniazid for six months or isoniazid and rifampicin for three months. The risk of reactivation is 5—10% and is greatest in the first two years after infection. The BCG vaccination is usually given to babies and young children at high risk, such as immigrants and ethnic minorities. Although there is little evidence that it offers protection to adults, it is often offered to healthcare workers.

8.9 Which of the statements regarding opportunistic mycobacteria is true?

A Infections with opportunistic mycobacteria always need treating

B Treatment may be required for up to five years

C The characteristic radiological appearance is ‘tree in bud’

D Opportunistic mycobacteria are highly infectious

E Opportunistic mycobacteria infections should be notified

Answer: C

Opportunistic or atypical mycobacteria affect those with chronic lung disease and those who are immunocompromised and only need to be treated if the patient is symptomatic. Up to two years of treatment may be required. These saprophytes are not infectious and cannot be ‘caught’ and therefore not notifiable.

8.10 Which of the following statements regarding pneumocystis jiroveci (PCP) is true?

A Pneumocystis jiroveci is a parasite

B Pneumocystis jiroveci may be asymptomatic in the immunocompromised patient

C Diagnosis is made after culture of the organism for eight weeks

D Treatment is with macrolide antibiotics for six months

E CXR will show bilateral pleural effusions

Answer: B

PCP is a fungus which affects those who are immunocompromised. Patients can be asymptomatic in the early stages. Diagnosis is made on silver staining or florescent staining but it cannot be cultured. CXR usually shows bilateral ground glass infiltrates. Treatment is with co-trimoxazole or pentamidine.

FURTHER READING

American Thoracic Society (2005). Guidelines for the management of adults with hospital- acquired, ventilator-associated, and healthcare- associated pneumonia. American Journal of Respiratory and Critical Care Medicine 171 (4): 388-416.

American Thoracic Society and Centers for Disease Control and Prevention of Infectious Diseases (CDC) (2000). Targeted tuberculin testing and treatment of latent tuberculosis infection.

American Thoracic Society, American Journal of Respiratory and Critical Care Medicine 161: S221-S223.

Fine, M.J., Smith, M.A., Carson, C.A. et al. (1996). Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis.

Journal of the American Medical Association 275 (2): 134-141.

Fine, M.J., Stone, R.A., Singer, D.E. et al. (1999). Processes and outcomes of care for patients with community-acquired pneumonia results from the Pneumonia Patient Outcomes Research Team (PORT) cohort Study. Archives of Internal Medicine 159 (9): 970-980.

Lim, W., Baudouin, S., George, R.C. et al. (2009). BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 64 (Suppl 3): Ш1-Ш55.

Lim, WS., van der Eerden, M.M., Laing, R. et al. (2003). Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58 (5): 377-382.

Menéndez, R., Torres, A., Zalacain, R. et al. (2005). Guidelines for the treatment of community- acquired pneumonia: predictors of adherence and outcome. American Journal of Respiratory and Critical Care Medicine 172 (6): 757-762.

National Institute for Health and Care Excellence (2011). Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. NICE Guidelines (CG117). Available at: www.nice.org.uk/

National Institute for Health and Care Excellence (2014) Pneumonia in adults: diagnosis and management management. NICE \guidelines (CG191), (December). Available at: www.nice.org.uk/

National Institute for Health and Care Excellence (2016) Tuberculosis. NICE Guideline (NG33). [online] Available at: www.nice.org.uk/ guidance/ng33/resources/tuberculosis- 1837390683589.

Stagg, H.R., Zenner, D., Harris, R.J. et al. (2014). Treatment of latent tuberculosis infection a network meta-analysis. Annals of Internal Medicine 161 (6): 419^28.


If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!