18.4.4 Mycobacteria 4026 Hannah Jarvis and Onn Min

18.4.4 Mycobacteria 4026 Hannah Jarvis and Onn Min Kon

section 18  Respiratory disorders 4026 Colonization and aspiration Secretions in the upper airways of intubated patients often pool above the endotracheal tube. Efforts to reduce the aspiration of these secretions into the lower airways include continuous suc- tion of subglottic secretions through the use of specially designed endotracheal tubes. A meta-​analysis of 13 randomized controlled trials including 2442 patients found that subglottic suctioning was associated with lower rates of VAP but with no reduction in mortality. Aspiration of gastric contents occurs more commonly in patients nursed supine compared to patients nursed in a semi-​recumbent position. In intubated patients, some evidence indicates that eleva- tion of the head of the bed to 45 degrees significantly reduces rates of VAP compared to the supine position, but achieving constant head elevation above 30 degrees is practically challenging. Silver-​coated endotracheal tubes have been shown to reduce rates of VAP but are expensive. Other coating materials such as chlorhexidine are also being evaluated. Decolonisation of the digestive tract Selective digestive tract decontamination and selective oropharyn- geal decontamination are approaches in which antibiotic therapy is used to eradicate potentially pathogenic microorganisms in the oropharynx and gastric tract. In a large study involving 13 ICUs in the Netherlands, 28-​day mortality was reduced by 3.5% with the former and 2.9% with the latter. However, a follow-​up study reported that bacterial resistance had increased in the ICUs that used decontamination. Hence any strategy that embraces wide- spread use of antibiotics must also consider the potential harms from increasing antibiotic resistance rates. Oral decontamination with chlorhexidine is associated with reduced rates of VAP in patients undergoing cardiac surgery; 2% chlorhexidine is more effective than 0.2% or 0.12%. A reduction in mortality as a con- sequence of oral decontamination strategies has not been confirmed. Controversies/​future developments Hospital-​acquired pneumonia occurring in the non-​ICU setting re- mains a vastly understudied subject. Extrapolating treatment strat- egies from data derived from VAP may not be acceptable in future as concerns regarding antibiotic stewardship increase. Hurdles related to the diagnosis of VAP remain significant. The incorporation of bio- markers into diagnostic and prognostic algorithms is being actively pursued and holds promise. FURTHER READING Endimiani A, et al. (2011). Are we ready for novel detection methods to treat respiratory pathogens in hospital-​acquired pneumonia? Clin Infect Dis, 52 Suppl 4, S373–​83. Roquilly A, et al. (2015). Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and meta-​analysis. Clin Infect Dis, 60, 64–​75. Rosenthal VD, et  al. (2012). International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004–​2009. Am J Infect Control, 40, 396–​407. Kalil AC, et al. (2016). Executive Summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis, 63(5), 575-82. doi: 10.1093/cid/ciw504. Erratum in: Clin Infect Dis, (2017) 64(9), 1298. Clin Infect Dis, (2017) 65(7), 1251. Torres A, et al. (2017). International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J, 50(3), pii: 1700582. doi: 10.1183/13993003.00582-2017. Trotter AJ, et al. (2019). Recent and emerging technologies for the rapid diagnosis of infection and antimicrobial resistance. Curr Opin Microbiol, 51, 39–45. Yu VL (2011). Guidelines for hospital-​acquired pneumonia and health-​care-​associated pneumonia: a vulnerability, a pitfall, and a fatal flaw. Lancet Infect Dis, 11, 248–​52. Zilberberg MD, Shorr AF (2010). Ventilator-​associated pneu- monia:  the clinical pulmonary infection score as a surrogate for diagnostics and outcome. Clin Infect Dis, 51 Suppl 1, S131–​5. 18.4.4  Mycobacteria Hannah Jarvis and Onn Min Kon ESSENTIALS Mycobacteria are gram-​negative, rod-​shaped bacilli comprising the Mycobacterium tuberculosis complex (TB) and nontuberculous mycobacteria. Tuberculosis Infection, usually via inhalation, is often asymptomatic but can lead to primary TB or to latent TB infection which can subsequently de- velop into ‘reactivation’ or ‘post-​primary’ active disease. Pulmonary TB is the commonest manifestation, but extrapulmonary disease can affect almost any organ. Definitive diagnosis is by culture. Standard chemotherapy involves the use of rifampicin, isoniazid, pyrazinamide, and ethambutol. Drug resistance is an increasing problem. Around 1.3 million people die from TB each year. Nontuberculous mycobacteria Infection tends to present with a worsening of chronic re- spiratory symptoms in patients with underlying lung diseases. Diagnosis is difficult because these organisms are common in the environment. A long course of treatment with several drugs is required.

18.4.4  Mycobacteria 4027 Introduction The mycobacteria genus are gram-​negative, rod-​shaped bacilli which comprise the Mycobacterium tuberculosis complex (M. tuber­ culosis, M.  africanum, M.  bovis, M.  microti) and nontuberculous mycobacterium species, the most important of which for human disease include M. avium complex, M. kansasii, M. xenopi, M. fortu­ itum, M. abscessus, and M. malmoense. Tuberculosis (TB), the airborne condition caused by infection with the Mycobacterium tuberculosis complex, is responsible for more deaths worldwide than any other airborne respiratory infec- tion, with an estimated 10  million incident cases of tuberculosis worldwide and an estimated 1.3 million deaths in 2017. Most of these cases were found in India, China, and South-East Asia, yet TB remains a global disease with just under 6000 cases diagnosed in England in 2017. It also causes significant extrapulmonary disease. The nontuberculous mycobacteria (or ‘atypical’ mycobacteria) are generally less pathogenic and highly prevalent in the environment, but can cause significant pulmonary, as well as bone or soft tissue disease, in those who are immunocompromised or with existing structural pulmonary conditions. The emergence of drug-​resistant tuberculosis is an increasing concern. Multidrug resistant TB (MDR-​TB) is defined as resistance to rifampicin and isoniazid, whereas extensively drug-​resistant TB (XDR-​TB) is MDR-​TB with additional resistance to a fluoroquino- lone and at least one of three injectable second-​line drugs. Natural history Infection is usually via inhalation of aerosolized droplets containing bacilli to the middle or lower lobes. Here activation of the innate immune system results in either complete clearance of the bacilli or primary infection within the lung and associated mediastinal nodes (the Ghon complex). Primary infection is often asymptom- atic. Possible outcomes following exposure to Mycobacterium tuber­ culosis complex are shown in Fig. 18.4.4.1. Latent TB is a term denoting infection which has been con- tained in a state whereby the bacilli persist in a dormant form, not causing symptoms/​disease, but maintaining the potential to reacti- vate, replicate, and cause pathology at a later stage. Approximately 10–​15% of individuals with latent infection go on to develop ac- tive TB disease. Individuals that develop disease within 2 years of the initial infection have ‘primary’ disease, and those who develop disease later (possibly many decades later) have ‘post-​primary’ or ‘reactivation’ disease. Factors that increase the risk of progression to disease include HIV and immunosuppressive states, including treatments used in transplantation and inflammatory conditions (Table 18.4.4.1). Clinical features Pulmonary tuberculosis The manifestation of primary disease in the chest normally consists of mediastinal lymphadenopathy or effusions, although there may be consolidation or collapse secondary to bronchial compression from nodes. Post-​primary pulmonary disease classically causes cavi- tation and ‘fluffy’ upper zone disease. TB is generally ‘subacute’ and can cause prolonged symptoms of cough, fever, night sweats, weight loss, and fatigue. Although the cough is initially nonproductive, this generally progresses to sputum production and occasionally Exposure to Mtb No infection Primary TB infection established Latent TB infection Development of primary TB disease (within 2 years of infection) Active disease develops: ‘reactivation’ or ‘post- primary’ TB Active disease never develops Fig. 18.4.4.1  Outcomes following Mycobacterium tuberculosis complex (Mtb) exposure. Table 18.4.4.1  Individuals at high risk for the development of active tuberculosis disease from latent infection (based on NICE guidance) High-​risk groups for development of active TB disease HIV positive Injecting drug users Solid organ transplant recipients Patients with a haematological malignancy Patients with chronic renal failure or on haemodialysis Patients with a previous gastrectomy Patients receiving antitumour necrosis factor-α streatment Patients with silicosis

section 18  Respiratory disorders 4028 haemoptysis. There can also be immune-​mediated manifestations including erythema nodosum and uveitis in the absence of obvious clinical disease. Extrapulmonary tuberculosis The symptoms and signs of extrapulmonary disease reflect the site of disease as well as the systemic features of general malaise seen in classical pulmonary disease. Common extrapulmonary TB sites are as follows: • Lymph nodes: The commonest extrapulmonary site is cervical, presenting as fluctuant, tender swellings, often in the supraclavi­ cular or anterior cervical chain. Other common sites include the mediastinum, abdomen, axillary, and inguinal areas. • Bone: The spine is the commonest site of bony infection (Pott’s disease) and destruction at the site of disease can result in pain, deformity, and nerve impingement. • Gastrointestinal: This classically affects the terminal ileum and can be confused with inflammatory bowel disease. Advanced dis- ease involving the peritoneum can present with ascites. • Genitourinary tract: This should be considered in patients with a persistent sterile pyuria. Untreated, there is the potential for fi- brosis, calcification, and stricture formation. • Central nervous system:  Meningeal or cerebral involvement is rare but should be considered in individuals presenting with head- aches, fever, cranial nerve abnormalities, seizures, or behavioural changes. Cerebrospinal fluid obtained from a lumbar puncture may be lymphocytic with high protein and low glucose. • Miliary tuberculosis: This is a state of disseminated disease with multiorgan involvement that results from haematogenous spread, often in in the young and those with immunocompromise. Without treatment there is rapid progression and a significant risk of death. Pulmonary involvement is common with diffuse, small ‘millet-​sized’ tubercles present throughout the lung fields, but other commonly affected organs can include the brain, bone marrow, abdomen, liver, spleen, and renal tract. Nontuberculous (‘atypical’) mycobacteria Infection tends to present with a worsening of chronic respiratory symptoms in patients with underlying lung diseases such as chronic obstructive pulmonary disease or bronchiectasis. It is also an im- portant pathogen in patients with immunocompromise, particu- larly HIV. Patients may have systemic features such as weight loss or night sweats, or a worsening of cough and breathlessness. The respiratory radiology of nontuberculous mycobacteria can include cavities, bronchiectasis, small airway inflammation, nodules, and mediastinal nodes Diagnosis Mycobacterium tuberculosis complex The gold standard for diagnosis remains culture of the organism, allowing not only for certainty of diagnosis but also the identifica- tion of drug susceptibility. Unfortunately, due to the difficulty of accessing tissue or fluid samples in some instances, as well as the fas- tidious nature of the pathogen, this is only achieved in approximately 60% of cases. A diagnosis may therefore have to rely on recognition of a combination of clinical features. Microbiology A range of samples can be sent for microbiological examination. In pulmonary disease at least three sputum samples should be obtained, using hypertonic saline to induce sputum, if needed. In some patients bronchoscopy may be required to obtain re- spiratory samples. Samples should be assessed by an auramine or Ziehl–​Neelsen stain (‘smear’), looking for the presence of acid and alcohol fast bacilli, and also cultured for a minimum of 6 weeks. Molecular techniques such as the polymerase chain reaction are increasingly being used as they can provide a rapid and specific diagnosis. In respiratory samples there is a higher sensitivity than the smear, and molecular testing also allows for the rapid identifi- cation of drug resistance. In extrapulmonary disease samples such as lymph node aspirates, pleural fluid/​biopsies, ascites, and cerebrospinal fluid should be sent as appropriate. Radiology The classical features of TB are upper zone consolidation with cavi- tation (Fig. 18.4.4.2), but a range of appearances can be seen on plain imaging, including consolidation, mediastinal lymphaden- opathy, and effusions, and in some cases no abnormalities are pre- sent. Atypical features are particularly common in older people or immunocompromised and there should be a low threshold for the consideration of CT imaging of the appropriate system in suspected cases. CT allows the identification of intrathoracic abnormalities such as cavities, mediastinal nodes, effusions, and small airway in- flammation (Fig. 18.4.4.3), but also importantly in extrapulmonary Fig. 18.4.4.2  Chest X-​ray showing right upper zone cavitation and consolidation.

18.4.4  Mycobacteria 4029 disease, can help target subsequent investigations to increase the likelihood of successful microbiological sampling. MRI is particu- larly useful in central nervous system disease. PET/​CT scanning may also have a role in identifying occult sites of disease. Histology/​cytology When tissue has been collected operatively or endoscopically, histo- logical or cytological examination may reveal granulomas. The pres- ence of granulomas, while not specific to mycobacteria, can add significant support to a diagnosis and is useful in excluding other conditions such as malignancy (Fig. 18.4.4.4). Tuberculin skin test The intradermal injection of tuberculin, an extract from the filtrate of attenuated Mycobacterium tuberculosis complex, causes a de- layed hypersensitivity reaction in individuals previously exposed to mycobacteria. This reaction has been used as a surrogate marker for TB infection (latent or active) for over 100 years. A measure- ment of skin induration is made at 48–​72 hours (Fig. 18.4.4.5), but it must be recognized that the skin test can be affected by immunosuppression and patients with advanced disease can even be anergic. Interferon-γ release assays Interferon-γ release assays (IGRAs) are peripheral blood assays of prior TB exposure and measure ex-​vivo interferon-γ release on stimulation by two specific Mycobacterium tuberculosis complex antigens (ESAT-​6 and CFP-​10). These are relatively specific for Mycobacterium tuberculosis complex and avoid any cross reaction with Bacille Calmette–​Guérin (BCG) vaccinated individuals (as can be seen in the tuberculin skin test). Although they are likely to be more sensitive than the skin test in immunocompromised indi- viduals, they can still be attenuated in these circumstances. They have the additional advantage of requiring only one patient attend- ance compared to the two needed for the skin test. Nontuberculous (‘atypical’) mycobacterial infection The diagnosis of clinically significant nontuberculous mycobacterial infection is complex. The environmental prevalence of these patho- gens means that repeated culture or a single culture from a sterile site alongside appropriate symptomatology and radiological find- ings is necessary to make a diagnosis. This is particularly an issue in individuals with chronic lung disease, although in immunocom- promised individuals mycobacteria avium complex can also cause significant extrapulmonary disease. The decision to initiate complex and prolonged therapy is often complicated by patient frailty and comorbidities and can have a poor outcome. Latent tuberculosis The diagnosis of latent infection (versus active disease) relies on the presence of a positive IGRA or skin test, in the absence of clinical and radiological evidence of active disease. Fig. 18.4.4.3  CT chest showing consolidation with cavitation and bronchiolar (‘tree-​in-​bud’) changes. Fig. 18.4.4.4  Granuloma in a lung biopsy specimen. Fig. 18.4.4.5  Positive tuberculin skin test with blistering reaction.

section 18  Respiratory disorders 4030 Management/​treatment General management Those with significant pulmonary disease who are productive of sputum, and especially those with confirmed smear positive pul- monary tuberculosis, pose an infectivity risk. These patients should be nursed in respiratory isolation if admitted to hospital, or alterna- tively self-​isolate at home. Repeated sputum smears can guide clin- icians in assessing infectivity and response to treatment. As HIV is a major risk factor for progression from latent infec- tion to disease, and given that treatment of known HIV disease is an important factor in response to treatment, it is important to test for HIV in all cases of active TB. An assessment should be made of the ability of each patient to comply with their medication regime and directly observed therapy offered for those who may find this difficult (e.g. those who are homeless or engage in substance abuse). The medication regimen can be adjusted so treatment is given on an intermittent basis to as- sist with this but is not recommended for pulmonary disease as as- sociated with poorer outcomes. Identification and screening of close contacts should also be undertaken, and preventative treatment offered where appropriate. Drug treatment Tuberculosis Standard antituberculosis chemotherapy involves the use of rifam- picin, isoniazid, pyrazinamide, and ethambutol for 2 months, fol- lowed by rifampicin and isoniazid for a further four months. The use of multiple agents aims to prevent drug resistance. By two months most cultures should be complete and drug susceptibility available to guide ongoing therapy. Extrapulmonary tuberculosis is treated with the same regime, al- though CNS disease requires more prolonged treatment. The use of adjuvant corticosteroids should be considered when starting treat- ment for CNS or pericardial disease. Second-​ and third-​line drugs are reserved for cases of drug resist- ance or intolerance due to their reduced potency and increased tox- icity. These drugs include fluoroquinolones such as moxifloxacin or levofloxacin, linezolid, clofazimine and injectable drugs (amikacin/​ kanamycin or capreomycin). Novel agents such as bedaquiline and delamanid are now available for and notably bedaquiline is recom- mended as an integral part of the first line therapy in MDR TB. Latent TB preventative treatment (Table 18.4.4.2) is generally offered to individuals with history of recent exposure and to those who are immunosuppressed, including people about to start treat- ment with biological agents such as anti-​TNF therapy or transplant- ation candidates. Atypical mycobacteria These require treatment with at least two to three agents for 12–​24 months depending on the species and clinical presentation (Table 18.4.4.3). Monitoring Careful monitoring of patients receiving treatment for TB or atyp- ical mycobacteria is needed to identify the development of poten- tial side effects. The most common of these is drug induced liver damage, which can be severe and, in rare cases, life-​threatening. In addition, visual acuity and colour vision testing should be per- formed due to the potential of ocular complications with eth- ambutol. Neuropathy from isoniazid can be prevented with the concomitant use of pyridoxine. Drug interactions are common with rifampicin. Table 18.4.4.2  Treatment regimen for latent TB Drug Dose and frequency Duration Comment Isoniazid 300 mg OD (5 mg/​kg for adults or 10 mg/​kg for children) 6 months NICE WHO Isoniazid 300 mg OD (5 mg/​kg for adults or 10 mg/​kg for children) or 900 mg twice weekly (DOT) 9 months WHO ATS/​CDC Rifampicin 600 mg OD (10 mg/​kg) 3–​4 months ATS/​CDC WHO Rifampicin + Isoniazid 600 mg (10 mg/​kg) + 300 mg (5 mg/​kg adults and 10 mg/​kg children) OD 3 months NICE WHO Rifapentine + Isoniazid By body weight + 900 mg (15 mg/​kg) once weekly 3 months ATS/​CDC WHO Not in pregnancy or children <2 years ATS, American Thoracic Society; CDC, Centers for Communicable Disease (USA); DOT, directly observed therapy; WHO, World Health Organization; NICE, National Institute for Clinical Excellence (UK). Table 18.4.4.3  Suggested treatment regimen for atypical mycobacterial pulmonary infections in HIV negative patients
(based on American and British Thoracic Societies’ guidance) Pathogen Drug regime Duration M. avium complex Clarithromycin or azithromycin + rifampicin + ethambutol
(+/​-​ streptomycin/​amikacin if advanced disease or cavities) Until 12 months of negative sputa M. kansasii Rifampicin + ethambutol + isoniazid or a macrolide (clarithromycin/azithromycin) Until 12 months of negative sputa M. xenopi Clarithromycin or azithromycin + rifampicin + ethambutol + either a quinolone or isoniazid Until 12 months of negative sputa M. abscessus A multidrug regime involving and induction and continuation phase with combinations of injectable, oral and nebulised antibiotics Variable