Tuberculosis (ED)

The tuberculosis is the infection by the Mycobacterium tuberculosis. The emergency-department role is the suspect, the isolate, the sputum, the notify — the recognition and the airborne precautions before the confirmation, then the referral for the definitive diagnosis and the long therapy. The Fellowship candidate must know the presentation, the investigations, the RIPE therapy and its toxicity, and the public-health obligation.[1][2]

The pathogen and the transmission

The Mycobacterium tuberculosis is a slow-growing, obligate-aerobic, non-motile, intracellular, rod-shaped bacillus of the genus Mycobacterium. It is neither Gram-positive nor Gram-negative in the routine sense: its cell wall is rich in mycolic acid, arabinogalactan and lipoarabinomannan, which resist the decolourisation by the acid-alcohol after the carbol-fuchsin stain — the basis of the acid-fast (the Ziehl–Neelsen) property and of the auramine-rhodamine fluorescence stain. The waxy mycolic-acid wall also explains the slow growth (the colony on the Lowenstein-Jensen in 2 to 8 weeks), the resistance to the drying and the disinfectants, and the survival inside the macrophage.[1]

The transmission is by the airborne route — the aerosol of the droplet nuclei (1 to 5 micrometres) generated by the coughing, the sneezing, the singing or the forceful expiratory effort of the infectious case. The droplet nuclei remain suspended in the air for hours and travel on the air currents, which is the reason for the negative-pressure room and the N95 respirator (a surgical mask does NOT filter the droplet nuclei). The transmission requires a close, prolonged, indoor exposure; the brief ED contact is low-risk but the unrecognised infectious patient in the open ward or the waiting room is the classic outbreak seed. The infectiousness falls rapidly within 2 weeks of the effective therapy, which underlies the de-isolation criteria.[1][3]

The immunopathology — the granuloma and the latency

The inhaled bacillus reaches the alveolus and is taken up by the alveolar macrophage. The bacillus survives and replicates inside the macrophage by blocking the phagolysosome fusion (the lipoarabinomannan and the secretion system). The infected macrophage secretes the cytokines and recruits the monocytes, the T-cells and the epithelioid cells, forming the caseating granuloma — the organised structure that contains but does not always kill the bacillus. The central caseous necrosis (the cheese-like, the avascular) may liquefy and cavitate into the airway, releasing the bacilli and producing the contagious cavitary disease. [1]

The cell-mediated (the Th1) immunity develops over 2 to 10 weeks — the CD4+ T-cell, the interferon-gamma, the tumour-necrosis-factor-alpha and the macrophage activation. This is the basis of the tuberculin skin test (the Mantoux) conversion and the interferon-gamma release assay (the IGRA). The containment produces the latent tuberculosis infection (the LTBI) — a viable but dormant bacillus walled in the granuloma, infectious neither to the host nor to others, yet capable of the reactivation years to decades later. Any state that weakens the cell-mediated immunity — the HIV, the anti-TNF therapy, the transplant, the malnutrition, the diabetes, the chronic renal failure, the malignancy, the silicosis — raises the reactivation risk and is examined.[1]

The classification — the primary and the reactivation

The primary tuberculosis is the initial infection, often subclinical, producing the Ghon focus (the subpleural lower or middle-lobe lesion) and the hilar lymphadenopathy, which together calcify into the Ghon complex. The cell-mediated immunity contains it in the majority, but the latent infection persists.[1]

The reactivation (the secondary) tuberculosis is the reactivation of the latent infection years later, typically in the upper lobe (the high oxygen tension), with the cavitation, the fibrosis, and the caseating granulomata, and it is the contagious form. The risk factors are the HIV, the immunosuppression, the malnutrition, the diabetes, the chronic renal failure, the migrant or the travel from the endemic area, the alcohol, and the smoking.[1]

The risk factors — the conditions that weaken the cell-mediated immunity

The risk factors are examined because they raise the reactivation probability and they shape the index of suspicion. The strongest single risk factor is the HIV — the reactivation rate rises from 10 per cent over a lifetime to roughly 10 per cent per year, and the TB is the commonest opportunistic infection and a leading cause of the death in the HIV globally. The anti-TNF-alpha agents (the infliximab, the adalimumab), the transplant immunosuppression, the chronic steroids (the equivalent of the prednisolone 15 mg for a month) and the chemotherapy all weaken the granuloma. The silicosis damages the macrophage directly; the diabetes, the chronic renal failure, the malnutrition and the smoking impair the cell-mediated immunity. The migrant and the travel from the high-burden country (the sub-Saharan Africa, the South Asia, the South-East Asia, the Western Pacific) raise the prior exposure probability.[1]

[1]

The presentation

The pulmonary presentation is the chronic cough (more than 3 weeks), the haemoptysis, the night sweats, the weight loss, the fever, and the malaise. The extrapulmonary tuberculosis — the cervical lymphadenitis (the scrofula), the tuberculous meningitis (the chronic meningitis, the cranial-nerve palsy), the miliary (the disseminated, the millet-seed chest radiograph, the pancytopenia, the hepatosplenomegaly), the spinal (the Pott disease), and the pericardial and the gastrointestinal.[1]

[1]

The pleural TB presents as a unilateral pleural effusion in the young adult (the pleurisy of the primary infection); the pleural fluid is a lymphocytic exudate (the protein above 30 g/L, the lymphocyte predominance), and the biopsy with the caseating granulomata is more sensitive than the fluid culture. The pericardial TB presents with the pericardial effusion and the constriction; the TB meningitis presents with the subacute headache, the fever, the meningism and the cranial-nerve (the VI, the III) palsy, and the CSF shows the lymphocytic pleocytosis, the low glucose and the high protein, with the basilar exudate on the imaging. The abdominal TB mimics the Crohn disease, the obstruction or the ascites (the lymphocytic, the high-SAAG-equivalent exudate). The Pott disease (the spinal TB) affects the lower thoracic and the lumbar spine, erodes the disc and the adjacent vertebral bodies with the paraspinal cold abscess (the Pott abscess), and presents with the back pain and the neurological deficit. The scrofula (the cervical lymphadenitis) is the commonest extrapulmonary form, painless and matted, sometimes with the overlying skin discolouration and the sinus tract.

[1]

The investigations

The chest radiograph shows the upper-lobe cavitation, the fibrosis, the nodules, and the pleural effusion. The three sputum samples — the morning and the spot — for the acid-fast bacilli (the AFB) smear, the culture (the gold standard, the slow, the weeks), and the nucleic-acid amplification test (the NAAT, the GeneXpert, the rapid, the rifampicin-resistance). The interferon-gamma release assay (the IGRA, the QuantiFERON) supports the latent infection. The biopsy with the caseating granulomata and the AFB for the extrapulmonary. The bloods (the FBC, the liver function, the renal, the HIV).[1][3]

The sputum — the collection, the smear, the culture, the NAAT

The three sputum samples, at least one a morning specimen, are collected over at least 8 to 24 hours in the airborne-isolation room. A good specimen is the mucopurulent, not the saliva; the induced (hypertonic saline) or the bronchoscopic lavage specimen is taken if the patient cannot expectorate. Each is sent for the AFB smear (the Ziehl–Neelsen or the fluorescence — the rapid, the cheap, but a poor sensitivity at the low bacillary load and unable to distinguish the M. tuberculosis from the non-tuberculous mycobacteria), the culture (the Lowenstein-Jensen, the MGIT — the gold standard, the species confirmation, the sensitivity and the drug-susceptibility, but the 2 to 8 weeks), and the NAAT.[1][4]

The GeneXpert MTB/RIF (the Xpert) and the Xpert Ultra are the cartridge-based, closed, real-time PCR platforms that simultaneously detect the M. tuberculosis complex DNA and the rifampicin resistance (the rpoB gene) within 2 hours. The sensitivity exceeds the smear (especially in the smear-negative and the HIV-co-infected), approaches the culture, and is the WHO-recommended first test for the suspected TB. The Xpert Ultra adds the sensitivity for the low-bacillary-load and the paediatric disease. A single negative Xpert does NOT exclude the TB; the three-sputum protocol stands, and the smear-negative infectiousness, though lower, is not zero.[4]

The IGRA and the tuberculin skin test — for the latent infection

The tuberculin skin test (the Mantoux) injects the purified protein derivative intradermally and reads the induration at 48 to 72 hours; the cut-off is 5, 10 or 15 mm depending on the risk (the 5 mm for the HIV and the immunosuppressed, the 10 mm for the moderate risk, the 15 mm for the low risk). It is confounded by the prior BCG vaccination and by the non-tuberculous mycobacteria. The interferon-gamma release assay (the QuantiFERON-TB Gold, the T-SPOT.TB) measures the interferon-gamma released by the T-cells exposed to the TB-specific antigens (the ESAT-6 and the CFP-10); it is a single blood test, it does NOT cross-react with the BCG, and it does NOT distinguish the latent from the active disease. The reproducibility is imperfect, and neither test alone rules the TB in or out — the active TB is diagnosed by the microbiology, not by the IGRA.[7]

The ED role — the suspect, the isolate, the notify

The ED role is the recognition and the containment.[1][3]

1. The suspect — the chronic cough, the haemoptysis, the night sweats, the weight loss, the risk factor, the upper-lobe cavity on the radiograph.
2. The isolate — the airborne precautions, the negative-pressure room, the N95 mask for the staff, the applied at the suspicion and BEFORE the confirmation.
3. The sputum — the three samples for the AFB, the culture, and the NAAT.
4. The public-health notification — the TB is the notifiable disease; the contact tracing and the public-health team.
5. The disposition — the admission for the unwell, the immunocompromised, the MDR-suspected, the socially-unstable; the discharge with the follow-up for the well, with the isolation instruction and the public-health handover.

The airborne isolation — the engineering and the respirator

The airborne-infection isolation room (the AIIR) is a single-occupancy, negatively pressurised room (the air flows in, not out), with at least 6 to 12 air changes per hour, the high-efficiency particulate air (the HEPA) filtration, and the anteroom. The door stays closed. The N95 respirator (or the higher — the P2/P3, the FFP2/FFP3) is worn by every entrant; the surgical mask is for the patient on transport, NOT for the staff protection (the surgical mask does not filter the droplet nuclei and does not seal). The patient wears the surgical mask when outside the room (the CT, the transport), and the staff wear the N95 throughout.[3]

The de-isolation is considered after the patient is on the effective therapy for at least 2 weeks, is clinically improving (the reduced cough, the defervescence, the reduced sputum), AND has the three negative sputum smears (or the negative Xpert). The single negative Xpert in the low-risk, clinically improving patient is used in some protocols to shorten the isolation.[3]

The management — the RIPE therapy

The quadruple RIPE therapy is the first-line — the rifampicin, the isoniazid, the pyrazinamide, the ethambutol for the 2 months (the intensive phase), then the rifampicin and the isoniazid for the 4 months (the continuation). The total of the 6 months. The direct observation in the non-adherent. The drug toxicity:[1][2]

• The rifampicin — the liver-function derangement, the orange-red discoloration of the urine and the secretions (the benign, the warn the patient), the induction of the cytochrome P450 (the contraceptive and the warfarin failure).
• The isoniazid — the hepatitis, the peripheral neuropathy (the prevent with the pyridoxine or the vitamin B6).
• The pyrazinamide — the hepatitis, the hyperuricaemia and the gout.
• The ethambutol — the optic neuritis (the red-green colour blindness, the visual acuity — the baseline and the monitoring), especially at the higher dose and the renal impairment.

[1] [1] [1] [1]

The MDR-TB (the resistance to the rifampicin and the isoniazid) and the XDR-TB require the specialist regimen with the second-line drugs (the fluoroquinolone, the injectable, the newer agents) and the prolonged course.[2]

The drug resistance — the classification and the newer agents

The resistance is defined by the susceptibility pattern and it dictates the regimen, the duration and the public-health urgency. The isoniazid-monoresistant TB extends the rifampicin-ethambutol continuation. The rifampicin-monoresistant TB (the rr-TB, the rpoB mutation detected by the Xpert) is treated as the MDR-equivalent in much of the world. The MDR-TB (the rifampicin and the isoniazid resistance) and the pre-XDR (the MDR plus the resistance to a fluoroquinolone or an injectable) and the XDR (the MDR plus the resistance to a fluoroquinolone AND an injectable, and now a bedaquiline or a linezolid in the updated definition) need the prolonged, individualised, second-line regimen.[2][6]

The contemporary MDR regimen has shifted from the long injectable-based course toward the shorter, all-oral regimens built on the bedaquiline (the diarylquinoline, the ATP-synthase inhibitor), the delamanid and the pretomanid (the nitroimidazoles), the linezolid (the oxazolidinone) and a fluoroquinolone. The bedaquiline, validated in the phase-2 trial of Diacon and colleagues, transformed the MDR outcomes and the tolerability, and it is now the cornerstone of the WHO-recommended shorter MDR regimen.[6]

The latent tuberculosis infection (the LTBI)

The latent TB infection is the viable but dormant bacillus in the immune host — the positive TST or IGRA, the normal chest radiograph, the no symptoms and the no contagiousness. It is treated to prevent the future reactivation, and the treatment choice is graded by the reactivation risk. The 3HP (the rifapentine plus the isoniazid weekly for 3 months, the direct observation historically, now self-administered), the 4R (the rifampicin daily for 4 months) and the 6H to 9H (the isoniazid daily for 6 to 9 months, with the pyridoxine) are the principal regimens; the shorter rifamycin-based regimens are preferred for the completion and the lower hepatotoxicity, and the isoniazid is the historic but longer and more hepatotoxic option. The active TB is ALWAYS excluded (the chest radiograph, the symptom screen, the sputum if any feature) before the LTBI treatment, to avoid treating an active case with a single drug and breeding the resistance.[1][5]

The TB and the HIV — the special rules

The TB and the HIV co-infection is a two-way accelerator: the HIV drives the TB reactivation and the progression, and the TB accelerates the HIV. The presentation may be atypical — the smear-negative, the extrapulmonary, the miliary, the lower-lobe or the intrathoracic-lymph-node pattern, and the TB meningitis. The GeneXpert (the Xpert Ultra) is the first test (the higher yield than the smear in the paucibacillary disease). The timing of the antiretroviral therapy is critical — start early (within the first 2 weeks for the CD4 under 50) but watch for the immune reconstitution inflammatory syndrome (the IRIS, the TB-IRIS), the paradoxical worsening of the TB as the immunity recovers. The rifampicin interacts with the antiretrovirals (the protease inhibitors are the worst); coordinate with the HIV team. The MAC prophylaxis with the azithromycin does not treat the TB.[1][2]

The TB in the pregnancy, the child and the renal failure

In the pregnancy, the TB is treated with the standard RIPE — the rifampicin, the isoniazid (with the pyridoxine) and the ethambutol are safe; the pyrazinamide is traditionally avoided in the first trimester in some guidelines (the limited data) though the WHO includes it throughout. Untreated TB harms the mother and the foetus more than the treatment. In the child (under 5), the disease is often paucibacillary and the disseminated or the meningeal; the sputum is hard to obtain (the gastric aspirate, the induced sputum, the Xpert Ultra), and the disseminated and the meningeal TB are the indications for the LP and the high index of suspicion. The renal failure and the dialysis patient has a high reactivation risk and a delayed clearance of the ethambutol and the pyrazinamide — dose-adjust and monitor the LFT, the vision and the urate.[1]

The complications and the prognosis

The complications are the massive haemoptysis, the bronchiectasis, the chronic pulmonary aspergillosis (the fungal ball in the old cavity), the bronchopleural fistula, the Addison disease (the adrenal), and the death. The prognosis is the generally favourable with the completion of the therapy, but the MDR-TB carries the high mortality.[1][2]

[1]

The public health and the notifiable disease

The tuberculosis is a notifiable disease in virtually every jurisdiction, and the ED clinician has the statutory duty to notify the public-health unit within the local window (often within 1 working day for the suspected, and immediately for the MDR). The notification triggers the contact tracing (the household and the close contacts, the concentric-circle approach, with the TST/IGRA and the symptom screen, and the LTBI treatment of the infected contacts), the source-case investigation for the paediatric case, and the public-health oversight of the therapy (the directly-observed treatment in the non-adherent). The failure to notify is both a clinical and a legal failure.[1]

The prevention — the BCG and the infection control

The BCG vaccine (the live-attenuated Mycobacterium bovis) protects principally against the disseminated, the miliary and the meningeal TB of the childhood (around 80 per cent), with a variable and lower protection against the pulmonary disease; it is given at the birth in the high-burden countries and selectively (the high-risk neonate) in the low-burden countries.[8] The infection control — the early recognition, the prompt airborne isolation, the N95 respirator, the negative-pressure room, the rapid molecular diagnosis, and the adequate therapy of the infectious case — is the foundation of the TB control in the hospital. The latent-TB screening and treatment of the high-risk groups (the migrant, the HIV, the dialysis, the transplant, the anti-TNF) prevents the future reactivation. The high-burden countries pursue the active case-finding and the shorter regimens.

Common pitfalls

The recurring errors are: the failure to suspect (the chronic cough dismissed); the delay of the isolation (the staff and the patient exposure); the single sputum instead of the three; the omission of the HIV test; the under-recognition of the drug toxicity (the ethambutol optic neuritis, the isoniazid neuropathy, the rifampicin hepatitis); the failure to notify the public health; and the non-adherence with the prolonged therapy (the MDR). [1]

[1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1]

Red flags

The following features identify the TB or the dangerous situation, in which the isolation and the sputum and the notify are the priority: [1]

[1]

Exam pearls

• The ED mantra: suspect, isolate, sputum, notify — the isolation is the clinical decision made at the suspicion, before any test.
• The airborne precautions: the negative-pressure AIIR and the N95 respirator. The surgical mask is for the patient, NOT for the staff.
• The three sputum samples (at least one a morning, over 8–24 h) for the smear, the culture and the GeneXpert — never the single sputum.
• The GeneXpert MTB/RIF (the Xpert Ultra) detects the TB AND the rifampicin resistance in 2 hours — the WHO-recommended first test, replacing the smear.[4]
• The IGRA does NOT distinguish the latent from the active disease — the active TB is diagnosed by the microbiology. The IGRA/TST is for the LTBI and the prior exposure.[7]
• The upper-lobe cavity = the reactivation TB; the lower-lobe + the hilar node = the primary (the Ghon focus).
• The RIPE: rifampicin, isoniazid, pyrazinamide, ethambutol for 2 months, then the RH for 4 months — total 6 months. The pyrazinamide is dropped after the intensive phase.
• The pyridoxine (B6) 10–25 mg co-prescribed with the isoniazid to prevent the peripheral neuropathy — mandatory in the pregnant, the diabetic, the HIV, the alcoholic, the renal-failure.
• The rifampicin induces the CYP450 — the OCP fails, the warfarin dose rises, the protease-inhibitor antiretrovirals need adjustment.
• The ethambutol optic neuritis — the red-green colour blindness and the acuity; the baseline Ishihara and the acuity, the renal dose-adjust.
• The pyrazinamide — the hepatitis and the hyperuricaemia/gout; stopped after 2 months.
• The HIV test is mandatory in every suspected TB.
• The TB meningitis — the lymphocytic CSF, the low glucose, the high protein; treat empirically on the suspicion.
• The pleural TB — the lymphocytic exudate, the high ADA; the pleural biopsy (the Abrams) is more sensitive than the fluid culture.
• The miliary TB — the millet-seed CXR, the marrow pancytopenia, the choroidal tubercles; look for the co-existent meningitis.
• The LTBI — the positive IGRA/TST, the normal CXR, the no symptoms; treat with the 3HP, the 4R or the 6–9H to prevent the reactivation; exclude the active TB first.[5]
• The MDR-TB — the rifampicin + the isoniazid resistance; the bedaquiline-based all-oral shorter regimen.[6]
• The BCG protects the child against the miliary and the meningeal TB (around 80 per cent), not reliably against the pulmonary disease.[8]
• The notification is statutory — notify the public health for the contact tracing and the oversight.
• The de-isolation needs the effective therapy for at least 2 weeks, the clinical improvement, and the three negative smears (or the negative Xpert).[3]

References

1. [1]Furin J, Cox H, Pai M. Tuberculosis Lancet, 2019.PMID 30904262
2. [2]Lange C, Dheda K, Chesov D, Mandalakas AM, Udwadia Z. Management of drug-resistant tuberculosis Lancet, 2019.PMID 31526739
3. [3]Menon LJB, Feliciano CS, de Campos MR, Bollela VR. Decision making to discharge patients from airborne infection isolation rooms: The role of a single GeneXpert MTB/RIF strategy in Brazil Infect Control Hosp Epidemiol, 2020.PMID 32299529
4. [4]Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance N Engl J Med, 2010.PMID 20825313
5. [5]Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis N Engl J Med, 2021.PMID 33951360
6. [6]Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis N Engl J Med, 2009.PMID 19494215
7. [7]Tagmouti S, Slater M, Benedetti A, et al. Reproducibility of interferon gamma (IFN-γ) release Assays. A systematic review Ann Am Thorac Soc, 2014.PMID 25188809
8. [8]Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of bacillus Calmette-Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature Pediatrics, 1995.PMID 7596718