Pathogenesis of Staphylococcus aureus Necrotizing Pneumonia

The Role of PVL and an Influenza Coinfection

Bettina Löffler; Silke Niemann; Christina Ehrhardt; Dagmar Horn; Christian Lanckohr; Gerard Lina; Stephan Ludwig; Georg Peters

Disclosures

Expert Rev Anti Infect Ther. 2013;11(10):1041-1051. 

In This Article

Expert Commentary & Concept of the Pathogenesis for Necrotizing Pneumonia

Necrotizing pneumonia was defined as a separate disease entity based on the severe clinical symptoms that differ from the 'classical' pneumonia caused by PVL-negative S. aureus strains. Main characteristics and typical symptoms of necrotizing pneumonia are a preceding influenza infection, sudden onset and rapid worsening of the symptoms, leukopenia, airway hemorrhages, severe respiratory failure, a high mortality rate and necrotic destruction of wide areas of the lung.[2,3] Despite a large amount of epidemiological data that show a clear association between PVL and the clinical picture of necrotizing pneumonia, the role of PVL in disease development has been doubted, due to negative results from murine or simian experimental models.[9,11,27,28] As the inflammatory and cytotoxic actions of PVL are largely restricted to neutrophils, monocytes and macrophages isolated from humans and rabbits,[32] appropriate model systems are required to study the role of PVL in clinical disease development. Rabbit models and experiments based on human cells provide strong evidence that PVL exerts a destructive effect that causes necrotizing pneumonia.[25,35]

For experimental, clinical and epidemiological studies, a clear differentiation between PVL-induced necrotizing diseases and other S. aureus infections is crucial, as different S. aureus virulence factors are involved in disease developments. In a 'classical' S. aureus pneumonia, a large set of virulence factors, such as toxins, adhesins, enzymes and immunomodulators have been proposed to contribute to induce an infection.[53,54] By contrast, necrotizing infections are most likely toxin-mediated diseases caused by the cytotoxic action of PVL on immune cells (Figure 2). As PVL is a very potent activator and cytotoxic factor for human neutrophils, monocytes and macrophages, lung destruction can be explained by an indirect effect of dying immune cells on tissue structures. Neutrophils contain large amounts of serine proteases stored in vesicles that are released uncontrolled upon PVL-induced cell death in the surrounding tissue. Particularly in lung tissue this mechanism can cause massive tissue destruction, as there is insufficient activity of protease inhibitors in the alveolar spaces. Consequently, lung tissue is vulnerable to PVL-mediated diseases, whereas PVL and its action are rapidly inactivated within serum via the protease inhibitors and antibodies against PVL. The inactivation of PVL by serum antibodies might also account for the observation that a previous skin and soft-tissue infection is associated with improved prognosis in necrotizing pneumonia[3,55] and that preferentially young patients are affected by PVL-mediated diseases. The mean age in our reviewed cases was 24.7 years, ranging from newborn to 74 years (Table 1). The reason for this might be that young patients are less likely to have developed a protective antibody titer against PVL than older patients.[35]

Under the terms of this concept the detrimental effect of PVL is dependent on the number of sensitive immune cells that are affected. In case of a preceding influenza infection, the lung can be strongly infiltrated with activated inflammatory cells[49,50] that contain large amounts of proteases and additional active compounds.[56] As low doses of PVL are already sufficient to cause cell death, a superinfection with a PVL-producing strain can induce massive activation and destruction of infiltrated granulocytes, monocytes and macrophages that discharge their granular content and overrun the neutralizing capacity in the lung resulting in necrotizing pneumonia (Figure 2). An earlier influenza infection is documented or suspected in many cases of necrotizing pneumonia. In several clinical cases, it was reported that different types of viral infections, such as respiratory syncytial virus or parainfluenza virus, precede necrotizing pneumonia. Sometimes only unspecific symptoms, like nausea or vomiting, are reported that might be indicative of an undetected virus infection (Table 1). These observations support the hypothesis that a virus-induced influx of immune cells rather than a specific virulence factor of influenza virus contributes to necrotizing pneumonia.

Accordingly, necrotizing pneumonia is supposed to be a mainly toxin-mediated disease of the lung. As toxins exert their destructive action quickly and cannot be confined by antimicrobial treatments when released, therapy needs to be started early to prevent severe tissue damage. Therefore, necrotizing pneumonia should be diagnosed, before the disease enters into a septic and lung destructive stage. A young patient that presents with pulmonary or uncharacteristic symptoms, but rapidly worsens and develops dyspnea and leukopenia should be suspected of necrotizing pneumonia. Massive overgrowth of staphylococci in tracheal secretion can quickly support the diagnosis. After samples for microbiological analysis are taken, therapy should be started immediately with an anti-staphylococcal antibiotic in combination with clindamycin to decrease toxin release or even with additional toxin-suppressing agents. If therapy is started early, patients can fully recover without further signs of pulmonary disease.[13]

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