In the last 20 years, lung transplantation has become an established practise for prolonging survival among patients with advanced-stage lung disease. According to the registry of the International Society for Heart and Lung Transplantation,1 a total of 3272 transplants were carried out in the year 2009, and during the first month mortality was fundamentally attributable to primary graft dysfunction (PGD) (27.1%), followed by infections (20.1%). In turn, almost 4% suffered acute rejection.

Thus, lung transplant recipients are at a high risk of developing many complications during the immediate postoperative period, including PGD, acute graft rejection of the development of infections, as commented above. The most frequent manifestation in all these clinical conditions is acute respiratory failure (ARF). For this reason, the differential diagnosis of these conditions can be very difficult to establish, and may have important consequences, since the treatment required in each case differs in certain aspects. Thus, in the presence of acute rejection, we need to increase the level of immunosuppression; in the case of PGD, immunosuppression must be lowered; and in patients with infections we must prescribe antibiotic treatment. In this context, although the diagnosis of PGD is fundamentally clinical, distinction between rejection and infection often requires histological evaluation of the samples obtained by fibrobronchoscopy with transbronchial biopsy. The use of this technique is limited, however, since it is invasive and has potential complications that can prove serious – particularly in patients with severe ARF.

Despite the existence of preventive measures against PGD,2 such as the optimization of lung preservation, the minimization of ischemia time, and the avoidance of barotrauma during lung donor maintenance, once the damage has been established, the treatment is similar to that applied in patients with respiratory distress syndrome. In any case, a survival rate of 80% in the first year after transplantation, and of 50% after 5 years of follow-up, is considered acceptable.

The fact that the lungs are in direct contact with the exterior, among other factors, contribute to the need for high levels of immunosuppression; despite such immunosuppression, however, the acute rejection rates remain high.3

Different biomarkers have been investigated with the aim of improving and anticipating the diagnosis of these disorders. A biomarker is defined as a parameter or characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathological conditions, or responses to drug treatment.4 An ideal biomarker is a parameter that can be recorded quickly from a sample obtained in a minimally invasive manner, and which is simple to preserve and handle. In addition, an ideal biomarker should be sensitive, reproducible, predictive and cost-effective. The lack of biological markers capable of predicting the early onset, progression and severity of disease has had a negative impact upon the identification and development of effective drug treatments for improving morbidity and mortality among critical patients.

Many biomarkers potentially useful for the differential diagnosis of post-transplantation ARF have been studied. However, their use in daily clinical practise is very limited, since the available supporting evidence is scarce. The present study offers a clinical review of the available evidence referred to the usefulness of the different biomarkers in application to the differential diagnosis of ARF in the immediate postoperative period of lung transplantation.

Primary graft dysfunction (PGD) is a form of acute lung injury occurring in the immediate post-transplantation period, and which has been defined by the consensus document of the International Society for Heart and Lung Transplantation as hypoxemia manifesting in the first 72h after lung transplantation, with pulmonary infiltrates evidenced on the chest X-rays.5 The prevalence of PGD ranges widely from 10–40%,6,7 and its appearance has prognostic implications, since it is associated with increased morbidity-mortality in the Intensive Care Unit (ICU).6,8,9 At clinical level, PGD has been almost exclusively associated with ischemic damage occurring during lung preservation and posterior reperfusion–though factors related to donor maintenance may also play an important role.10 The physiopathology of PGD is characterized by an increase in the concentration of inflammatory and endothelial and epithelial dysfunction biomarkers.11,12 For this reason, an analysis has been made of the usefulness of different biomarkers in the diagnosis of primary graft dysfunction, taking into account the degree of PGD (Table 1).

Acute rejection is also a frequent complication in the immediate postoperative period of lung transplantation. Its estimated incidence is 36% in the first year after transplantation, and compared with other organs, the lungs appear to be at an increased risk of rejection.39 On the other hand, the appearance of acute rejection can have important consequences for patient prognosis, since immunosuppressive treatment of acute rejection episodes increases the risk of infections.39 As has been commented above, the clinical characteristics of the disease are very similar to those of other complications that manifest during the same period, and this complicates the diagnosis. To date, bronchoscopy with the obtainment of a transbronchial biopsy has been the technique of choice for diagnosing acute rejection. Very few biomarkers have been investigated in application to the diagnosis of acute graft rejection (Table 2).

Despite the experience gained in the field of lung transplantation, supported by advances in the form of new surgical techniques and the introduction of new immunosuppressor drugs, the infections which transplant recipients may develop in the postoperative period are an important cause of morbidity and mortality. This problem is particularly manifest in the immediate postoperative period, since it is in this period when the risk of acute rejection is greater and higher levels of immune suppression are therefore needed.47 Moreover, the patient is in the hospital setting, with an increased risk of nosocomial infections. Table 3 shows the main biomarkers related to the development of the different infectious processes.

The studies carried out to date have a series of limitations that complicate interpretation of the results obtained. A first problem is the limited number of patients included in the different studies. Secondly, the included patients are very heterogeneous–a fact that makes it difficult to extrapolate the results obtained. Lastly, there are also differences in sample collection and processing, thus indicating the need to standardize such techniques. It is therefore important to emphasize that no ideal biomarker of help in the differential diagnosis of post-transplantation ARF has been defined to date.

New faster and more sensitive diagnostic techniques would allow us to establish a more effective diagnosis, based on the precise quantification of a concrete biomarker. In this sense, metabolomics allows the total assessment of metabolites in an organism, and represents a global evaluation of the biochemical and physiological condition of the patient. The detection of these markers can be made in different samples (fluids, cell types and tissues). Critically ill patients might benefit from these techniques, since they frequently suffer metabolic deregulations.55

Another aspect that may be of interest is research based on microRNA (miRNA), which has been shown to have many applications, such as for example in the early detection of lung cancer or rheumatoid arthritis.56–58 MicroRNA consists of small, non-coding molecules which nevertheless are important for the regulation of genic expression. These molecules are implicated in regulation of the development of the immune system and cell proliferation. For these reasons, research has recently focused on the relationship between the appearance of kidney and liver graft rejection and different types of microRNA. The results have revealed an association between certain types of microRNA and acute rejection.59 However, to date the studies in the field of transplantation include very few patients and have fundamentally focused on these kinds of transplantations.60,61

The success of lung transplantation is largely dependent upon its management in the immediate postoperative phase. Close monitoring of the evolution of the graft is therefore necessary from the immediate post-transplantation phase, in order to anticipate any problems capable of affecting the outcome. In this context, the analysis of the different biomarkers capable of contributing to the differential diagnosis of post-transplantation ARF is very important. Although some studies offer encouraging results, no ideal biomarker has yet been described capable of substantially improving the management and prognosis of these patients. The use of new techniques, such as the analysis of microRNA, could lead to further advances in this respect.

The authors declare that they have no conflicts of interest.