Pulmonary infarction (PI) is the consequence of the blockage of distal pulmonary arteries, which results in an ischemic insult that further leads to necrosis of the obstructed pulmonary tissue [1]. PI commonly occurs due to complications of another existing disease, such as pulmonary embolism (PE) in most cases, but it can also occur in the context of various infections and malignancy [1]. Very often misdiagnosis or delayed diagnosis of PE results in difficult identification of PI [2,3]. Furthermore, the short- and long-term consequences after PE that can lead to PI and a higher risk of death are still unclear [1,4,5].

This paper aims to provide available data on the prevalence of PI among individuals with PE, which is the most common cause of PI, the possible diagnostic strategies, and the clinical and prognostic impact of this disease.

Estimating the true prevalence of PI is difficult due to different definitions encountered in the literature [1]. Retrospective and prospective studies have assessed this knowledge gap [2,6,7,8]. For example, a retrospective study on 154 patients diagnosed with PE found that 29.2% had experienced PI, which was defined as a roughly homogenous region or a segment with “ground-glass opacity” on computed tomography (CT) examination [2]. Other studies also pointed out that PI is a possible complication of PE in more or less 30% of non-fatal cases [1,3]. However, PI should not be underestimated as its prevalence is much higher in postmortem examination of PE cases. A study by Mordeglia et al. that counted 560 autopsy examinations of patients with PE demonstrated that the prevalence of PI was 60%, which represent a very high number [9]. Therefore, when the death occurs unexpectedly or PE is suspected, an autopsy should be considered mandatory to investigate the PI [5].

Given the relevant incidence at forensic examinations, efforts have been made to identify predisposing factors for PI after PE. Trying to elucidate the predictors of PI in young patients with PE, Miniati et al. have reported that the odds ratio (OR) with a 95% confidence interval was 3.6 (1.88–6.91) for cigarette smoking, 1.16 (1.05–1.29) for age, and 1.04 (1.01–1.07) for body height [7]. Some observations indicate that individuals with other cardiopulmonary comorbidity have a higher risk of PI after acute PE [1]. Although consistent with the previous definition of PI, Kirchner et al. found no correlation between the risk of PI and heart failure, malignancy, clot burden, or preexisting pulmonary infections [2]. There is consensus that hemodynamic instability is a factor associated with adverse outcomes [10] but the assessment of the patient’s hemodynamic status in increasing PI incidence was beyond the scope of the Kirchner et al. study [2]. In particular, there are numerous findings indicating that the frequency of PI after PE is higher in patients who died from long-standing heart failure [7]. However, data on this field for young and healthy individuals are scarce and conflicting. From what has been described so far [2], efforts are needed for the stratification of patients who may develop PI.

Although not all cases of PE lead to PI, the relevant percentage of PI diagnosis on autopsy suggests the importance of understanding its pathogenesis as a first step toward a correct diagnosis.

In about 90% of cases, pulmonary artery occlusion is caused by thrombus formation in veins of the lower limb [11]. In absence of deep vein thrombosis, pulmonary artery occlusion could be explained by in situ thrombi formation [12]. When a pulmonary artery is occluded, the pressure in bronchial arteries increases to perfuse pulmonary capillaries [1]. Impaired blood flow and endothelial cell ischemia contribute to the increase in capillary permeability, which facilitates the extravasation of erythrocytes and causes alveolar hemorrhage [1]. Patients with impaired hemodynamics are more prone to PI since it interferes with the resolution of alveolar hemorrhage thus worsening necrosis [13]. This explains the increased risk of adverse outcomes in patients with hemodynamic instability [11]. These processes are reversible in some cases defined as incomplete infractions; the blood from the intra-alveoli can be reabsorbed within 2–4 days without causing necrosis of the surrounding tissue. On the other hand, in cases defined as true infarction when blood is not absorbed, tissue necrosis occurs within 1–2 days due to the destruction of erythrocytes to hemosiderin and alveolar bleeding [1,14]. After the insult, the formation of a fibrous scar occurs in the area affected by the infarct for a period of several weeks or even months [1].

PI is usually subpleural and wedge-shaped grossly and, on microscopic examination, appears as a region of dead alveolar walls. From a histological point of view, PI is defined as a well-defined area of coagulative necrosis of the lung parenchyma within a zone of hemorrhage, usually adjacent to the pleura [6]. Coagulative necrosis is a type of necrosis defined as a morphological feature in which protein denaturation is the main process coupled with minor enzymatic degradation, which consequently leads to longer preservation of tissue architecture after cell death. In the insulted area, there are usually present the metaplastic and alveolar atypical epithelial cells; and the surrounding pleural surface is commonly covered with fibrinous transude. Finally, thrombi are not always detectable histologically [1].

Localization of emboli on distal pulmonary arteries is a common characteristic of PI [8], which could occur even in young and healthy individuals [7]. Autopsy studies indicate that the diameter of vessels occluded by emboli could not be the major factor in determining PI. Specifically, the extension of the occlusion from arteries larger than three millimeters in diameter to smaller distal branches was not associated with PI. As opposed to emboli in pulmonary arteries of three or fewer millimeters in diameter, which are localized with PI [14]. Several studies have reported a trend in the localization of PI in the lower lobe but is not yet clear whether this is due to hemodynamic factors or not [2]. Furthermore, PI appears to be more likely when PE is determined by the occlusion of subsegmental pulmonary arteries [15].

The impact of PI following acute PE and the prognosis after specific management strategies are still not clear [1]. Thus, further studies to clarify these aspects are needed, to develop a patient-tailored protocol and to reassure the patients’ recovery. Indeed, studies on PI among PE patients concentrate on endpoints defined as the PI incidence, PE recurrence, cavitation, infectious complications, and death. Further research is needed to focus on the missing data such as the incidence of the post-PE syndrome and more importantly, novel therapeutic approaches [1]. Currently, there are no specific therapeutic strategies for PI, except for supportive measures and pain control with non-steroidal anti-inflammatory drugs or opioids [1,47]. Furthermore, PI can be complicated by lung infections that are difficult to control, leading to abscess formation and cavitation, which are related to various predisposing factors such as more extensive infarction, concomitant congestion, or atelectasis, and poor dental health [1]. For this reason, the initiation of empiric antibiotic therapy has been proposed as a reasonable therapeutic strategy in case of PI detection, to avoid further complications such as empyema or fistulae, which may require surgical therapy [48].

Due to the impact of PI on prognosis, its presence should be taken into account when stratifying the risk of patients with PE. This necessity is even more urgent in young patients and otherwise healthy individuals as misdiagnosis of PI in this group appears critical [4,10]. Since the infarcted area is ideal for the development of infections and inflammation, it could be responsible for adverse outcomes in young individuals [1,49].

Based on the evaluation of some clinical cases available in the literature, PI still represents a diagnostic challenge with a negative impact on the survival rate in case of misdetection [48,50]. In this section, we summarize how diagnostic progress can translate into a management strategy for patients with PI.

The Wells and Geneva scores are used to rank individuals based on the probability of acute PE and diagnostic tests are chosen based on these scores [51]. Therefore, patients with a high probability of thromboembolism are likely to be easily diagnosed with PI through the use of the same diagnostic techniques [50,51]. Although the CTPA remains the gold standard for the diagnosis of PI, in some cases this diagnostic method is not sufficient [10]. Therefore, other techniques have been proposed in this review. Improving diagnostic algorithm supporting CTPA with pulmonary US evaluation or MRI, especially in the emergency setting when patients cannot be easily transported, is not immediately feasible. However, there are prospects for improvement, as demonstrated by the current growing diffusion of pulmonary US in different clinical settings. A recent meta-analysis estimated that the US has a sensitivity of 91% and a specificity of 81% for the diagnosis of PE when compared with CTPA [33]. Pulmonary US and MRI exams should not replace the validated diagnostic tools for PE but represent additional imaging modalities when PI is suspected (Figure 3) [39]. The main problem in the diagnosis of PI is the high variability in the time of presentation after PE. Therefore, the absence of PI at the diagnosis of PE does not rule out later development. In this case, follow-up checks could be the keys to the timely diagnosis of PI.

Once PI is diagnosed, the therapeutic strategy should be aimed at treating the underlying cause and lowering the risk of its serious complications. In this regard, oxygen administration can be useful to prevent hypoxia [10] as well as antibiotic therapy should be considered to avoid infectious complications [48]. Whatever PE is the cause of PI, pharmacological treatment includes anticoagulant medication such as heparin followed by warfarin or other oral anticoagulants [10,16]. In case of coexistence of hemodynamic instability, the administration of systemic fibrinolytic or reperfusion treatments is approved [10,16].

Increasing our knowledge of the prevalence of PI among individuals with PE, especially young ones, together with the awareness of the most commonly associated risk factors could lead to a correct stratification of patients with PI, which emerges as a tremendous achievement. Moreover, new and highly sensitive diagnostic tools will have a major impact on our understanding of this pathology with further important implications for clinical practice and treatment.