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Pathophysiology of pneumonia 

Pathophysiology of pneumonia
Chapter:
Pathophysiology of pneumonia
Author(s):

Jordi Rello

and Bárbara Borgatta

DOI:
10.1093/med/9780199600830.003.0115
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date: 30 November 2020

Key points

  • Hypoxaemia is a key element in pathogenesis, diagnosis, and prognosis of ventilator-associated pneumonia (VAP).

  • Aspiration of secretions from the airway is the main source of infection for VAP in mechanically-ventilated (MV) patients, and infection develops when bacteria overwhelms the host’s defences.

  • Prevention care bundles reduce the incidence of VAP, as well as MV duration and intensive care unit (ICU) length of stay.

  • Early antibiotic therapy is responsible for decrease in VAP incidence, but facilitates selection of multidrug-resistant organism.

  • Mortality is low, but VAP is an important cause of morbidity, with prolonged MV, ICU length of stay, and excessively high estimated costs.

Introduction

Hospital-acquired pneumonia (HAP) is defined as pneumonia developing 48 hours or more after hospital admission. Ventilator-associated pneumonia (VAP) is a type of HAP that occurs after 48–72 hours of endotracheal intubation and is responsible for approximately 80% of HAP, and so, is the most frequent form of infection in the intensive care unit (ICU). New definitions include worsening of oxygenation as a major criteria for differentiating VAP from other respiratory tract infections.

Epidemiology

VAP occurs with an incidence of 5–20 cases per 1000 ventilator days. Improving preventive measures have dramatically decreased its incidence over the last decade. Cumulative risk for developing VAP is 1–3% per day of MV, condensed within the first week following intubation. Rates are usually higher in surgical than medical ICUs. More than half of prescribed antibiotics in the ICU are for VAP treatment. It is an important cause of morbidity, with prolonged MV, ICU/hospital length of stay, and estimated costs as high as $40,000 per patient. ICU mortality ranges from 24 to 76%, with overall attributable mortality lower than 10%, focusing on surgical patients (in contrast with medical or trauma) [3]. Furthermore, infections caused by multiresistant pathogens, such as methillicin-resistant Staphyloccocus aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia, have substantially higher mortality. VAP is a prognostic marker in chronic obstructive pulmonary disease (COPD) patients who undergo cardiac surgery and are MV.

Pathogens

Bacteria are the almost exclusively responsible for HAP and VAP in immunocompetent patients, fungal and viral micro-organism are exceptionally isolated in this group of patients. Aetiological agents differ widely between populations since they are determined by the type of ICU, hospital or ICU length of stay, prior antimicrobial therapy, and diagnostic method used. Considering this, the most frequently isolated micro-organisms in VAP are Pseudomonas aeruginosa, Staphylococcus aureus, and Enterobacteriaceae. On the other hand, Candida and Enterococcus species should be considered as colonizers since there is not histological prove of them causing pneumonia.

Classification

Early-onset HAP or VAP is the one occurring during the first 4 days of hospitalization (ward or ICU respectively), whereas when it develops at the 5th day or afterwards is referred as late-onset HAP/VAP. Each one presents with a specific profile.

Early VAP

Usually due to aspiration of normal oropharynx flora in comatose patients or during intubation [1,2,3,4,5,6]. Caused by community-acquired pathogens (Streptococcus pneumoniae, Haemophilus influenza, or meticillin-susceptible S. aureus), where antimicrobial resistances are rare.

Late VAP

This is caused by micro-organisms that colonize the upper airway, biofilm, and respiratory tract [1,2,3,4,5,6], often by pathogens with strong intrinsic or acquired antimicrobial resistance. Risk factors for late-onset VAP include tracheobronchial colonization with enteric Gram negative bacilli (GNB) or P. aeruginosa, duration of MV, prolonged antibiotic treatment, and prior use of antibiotics within the preceding 30 days. Late VAP is independently associated with higher mortality. Caused mainly by GNB, 30–70% of cases are due to P. aeruginosa, Acinetobacter, or MRSA. Very late VAP in tracheostomized patients is associated with non-fermentative GNB.

Colonization of the lower respiratory tract

Patterns of colonization differ within ICU depending on infectious diseases protocols, hand hygiene, and airway management. Classically, four routes have been described; nevertheless, micro-aspiration of secretions from upper airways remains as the most important source, representing almost 90% of all cases. During hospitalization there’s a shift of flora colonizing the airway; initially, there’s a reduction of the normal flora, which facilitates the adhesion, and growth of enteric GNB and S. aureus. See Fig. 115.1 for the colonization’s evolution in MV patients.

Fig. 115.1 Organ colonization time-evolution during ICU stay.

Fig. 115.1 Organ colonization time-evolution during ICU stay.

* At 48 hours 80% of ETT are colonized, but heavy colonization occurs at 60–96 hours.

Endogenous

Oropharyngeal colonization

More than half of healthy patients can be chronically colonized by normal flora, with COPD patients being especially prone. In MV patient’s teeth, a composite of bacteria, mucus and detritus is formed—an adherent matrix called biofilm, which is a source for further bacterial colonization in addition to inflammation of periodontal tissue that can shed bacteria and inflammatory products into the lower respiratory tract.

Aspiration from the upper respiratory tract

  • The main route by which the bacteria invade lower respiratory tract: favoured by impaired or abolished cough reflex by sedatives and muscle paralysers.

  • Facilitated by the endotracheal tube (ETT) as a result of various mechanisms:

    • First, it keeps the vocal chords open.

    • Secondly, above ETT a pool of secretion is formed that by capillary leak goes down longitudinal channels formed by the folds of the cuff, even when correctly positioned and inflated at standard pressure. Subglottic secretion drainage reduces the risk for developing VAP.

    • Gross leakage occurs with tracheal suctioning, absence of positive end-expiratory pressure (PEEP), low pressure of the cuff, and disconnection from MV.

    • Furthermore, at the ETT’s inner surface biofilm forms, serving as a reservoir for infection and protection from antibiotic effects. This biofilm is reduced with a silver-coated ETT; on the other hand, it can be embolized into lung parenchyma with manipulation of the inner surface of the ETT.

Gastric: macro-aspiration

A nasogastric tube causes oesophageal sphincter incompetence resulting in oesophageal reflux [2,4,6,7] and the possibility of aspiration, especially in patients receiving enteral nutrition. Nonetheless, it is a secondary source of aspiration.

Contiguous and haematogenous spread

Both routes have been described, but are unusual sources of colonization.

Exogenous

Exogenous ways of colonization represent approximately <5% of all routs [2,4,6,7]. It refers to direct inoculation of the micro-organism through the ETT by health care workers that manipulates the patient’s airway. Inadequate hand washing may contribute to cross-infection with resistant species. The ventilator circuit is often highly colonized (80% of condensate after 24 hours by enteric gram-negative bacteria (EGNB); however, when it is routinely changed, there’s no impact on VAP incidence. Potential bacterial aerosolization can occur from precipitate of the condensate from warm humidifiers, which justifies the use of cascade humidifiers, which do not generate micro-aerosols.

Risk factors and prevention

Artificial airway is the most important risk factor for developing HAP, increasing the risk from 6 to 21-fold. Indeed, many authors use HAP and VAP interchangeably. Antibiotic exposure has a protective effect in early VAP, but increases risk for late VAP, since it selects multiresistant species. Risk factors for HAP are summarized in Box 115.1. Prevention [8,9] of VAP can be achieved with implementing care bundles, which include hand hygiene before airway manipulation, oral care with chlorhexidine, maintenance of intracuff pressure above 20 cmH2O to reduce leakage of oropharyngeal secretions to the lower airways tract, and sedation control protocols. Minimizing sedation is a strategy to be enhanced to prevent VAP. Furthermore, full bundles compliance reduces duration of MV and ICU length of stay.

Host response

VAP develops when micro-organisms present in distal lung tissue (alveoli) overwhelm host defences with its virulence and burden. Pneumonia in ventilated patients is a multifocal process disseminated within each pulmonary lobe. These foci of pneumonia are predominantly distributed in lower lobes and dependent zones of the lungs. Histological lesions are always located within large zones of altered lung parenchyma, which correspond to an inflammatory exudate with fibrin and some capillary congestion, ensuing at the 3rd to 7th day of pneumonia. Because of this multifocal and patchy distribution, quantitative biopsy cultures cannot reliably discriminate between patients with or without evidence of histological pneumonia [7].

In patients who develop VAP, altered innate and adaptive immune responses have been reported. Decreased T-helper lymphocytes (CD3+ and CD4+) due to accelerated apoptosis, increased monocyte apoptosis, and both peripheral and lung neutrophil dysfunction, all resulting in decreased clearing of pathogens.

Additionally, there is also a genetic component influencing the host’s response to the infection, polymorphism of the complement pathway (specifically C2 E318D) is associated with increased risk for VAP and higher mortality. Micro-arrays have demonstrated specific different immunological signatures for VAP and VAT.

References

1. Rello J, Lisboa T, and Koulenti D. (2014). Respiratory infections in patients undergoing mechanical ventilation. Lancet Respiratory Medicine, 2, 764–74.Find this resource:

2. Chastre J and Fagon JY. (2002). Ventilator-associated pneumonia. American Journal of Respiratory and Critical Care Medicine, 165, 867–903.Find this resource:

3. Rello J, Ollendorf DA, Oster G, et al. (2002). Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Chest, 122, 2115–21.Find this resource:

4. Rello J and Diaz E. (2003). Pneumonia in the intensive care unit. Critical Care Medicine, 31, 2544–51.Find this resource:

5. Vincent JL, Rello J, Marshall J, et al. (2009). International study of the prevalence and outcomes of infection in intensive care units. Journal of the American Medical Association, 302, 2323–9.Find this resource:

6. Diaz E, Lorente L, Valles J, et al. (2010). Mechanical ventilation associated pneumonia. Medicina Intensiva, 34, 318–24.Find this resource:

7. American Thoracic Society and Infectious Diseases Society of America. (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, 388–416.Find this resource:

8. Blot S, Rello J, and Vogelaers D. (2011). What is new in the prevention of ventilator-associated pneumonia? Current Opinions in Pulmonary Medicine, 17, 155–9.Find this resource:

9. Rello J, Afonso E, Lisboa T, et al. (2012). A care bundle approach for prevention of ventilator-associated pneumonia. Clinical Microbiology and Infection, 19(4), 363–9.Find this resource:

10. Gallego M and Rello J. (1999). Diagnostic testing for ventilator-associated pneumonia. Clinics in Chest Medicine, 20, 671–9.Find this resource:

11. Fàbregas N, Torres A, El-Ebiary M, et al. (1996). Histopathologic and microbiologic aspects of ventilator-associated pneumonia. Anesthesiology, 84, 760–71.Find this resource: