In this study, we showed that NT-proBNP, particularly when combined with PFTs, has the potential for use as a screening algorithm for PAH in patients with SSc, with "screen positive" patients then able to undergo further appropriate diagnostic testing. We also showed that NT-proBNP level correlates well with screening sPAPTTE
, which is currently regarded as the most useful noninvasive method of screening for PAH. However, a number of important limitations of TTE are related to the lack of sufficient tricuspid regurgitation to estimate sPAPTTE
, insufficient reliability in the context of coexistent lung disease, potential poor acoustic windows related to body habitus, the need for specific expertise in technique and interpretation, as well as issues related to cost and resource allocation [14
]. It is against these limitations of echocardiography that NT-proBNP and PFTs in combination offer an accurate and more convenient "first tier" of screening tests for SSc patients.
In Figure , we have proposed a screening algorithm for SSc-PAH based on the findings of this study. In this screening algorithm, TTE is replaced by PFTs and NT-proBNP as the first tier of screening investigations. Thus only patients who have either DLCOcorr < 70.3% with FVC/DLCOcorr ≥ 1.82, or NT-proBNP ≥ 209.8 pg/ml, or both, proceed to TTE, whereas those with DLCOcorr ≥ 70.3% and FVC/DLCO < 1.82 and NT-proBNP < 209.8 pg/ml are reassured and have repeated screening. If a patient is deemed to have a high clinical suggestion of PAH, then it would be appropriate to perform diagnostic tests to confirm or exclude PAH. The inclusion of PFTs (including FEV1, FVC, and DLCO) in the first tier of investigations also enables detection of patients with probable ILD who may require further investigation with HRCT.
Figure 3 A proposed screening algorithm for SSc-PAH. 6MWT, 6-minute walk test; DLCO, diffusion capacity of lungs to carbon monoxide, percentage predicted; FVC, forced vital capacity, percentage predicted; HRCT, high-resolution computed tomography of lung; NT-proBNP, (more ...)
Although we found that a sPAPTTE
cut point of > 42 mm Hg had a 100% sensitivity and specificity for PAH, we are unable to recommend this diagnostic cut point, as the control group in our study were selected on the basis of a sPAPTTE
< 30 mm Hg. In other studies, a lower cut-off point of sPAPTTE
> 30 mm Hg had a sensitivity of 90%, whereas a higher cut-off point of sPAPTTE
> 47 mm Hg had a specificity of 96% for PAH [15
In this study, we demonstrated a correlation of NT-proBNP with key diagnostic and prognostic RHC parameters, including mPAP, mRAP, and PVR [20
]. As RHC is the current gold-standard confirmatory investigation for PAH, these positive correlations again support the usefulness of NT-proBNP as a biomarker in SSc-PAH.
In the present study, we found a low or "normal" NT-proBNP level in all controls, but one patient with PAH had an NT-proBNP level below the cut point of 209.8 pg/ml. Such "false negatives" also were seen in a study from the Royal Free Hospital in the UK, which showed an NT-proBNP cut-point value of 395 pg/ml to have a sensitivity of 69% for PAH in a pilot study; this cut-point value was then separately tested in a larger prospective case-control study that produced a sensitivity of only 55.9% [20
]. The reasons for these false negatives are unknown, but may include the interference of glycosylation with the NT-proBNP assay [26
]. In our study, the patient with PAH and a low NT-proBNP had poor glycemic control. To overcome the potential problem of false negatives with NT-proBNP, we combined this biomarker with PFT. When combined with PFT, the NT-proBNP cut point of 209.8 pg/ml offered the excellent sensitivity (100%) for PAH that is desirable in a screening initiative. In the study by Mukerjee et al
], in which a higher NT-proBNP level of 395 pg/ml was determined as the cut point for PAH than in our study, 11 of 26 controls were undergoing the investigation for breathlessness, the cause of which may have led to a higher cut-point NT-proBNP level. In the subsequent validation study by Williams et al
], it is possible that the NT-proBNP cut point of 395 pg/ml was partly due to at least 20% of controls having ILD, which is in line with the findings from our study that suggest a higher NT-proBNP cut point (≥ 360.5 pg/ml) is required to separate PAH from ILD groups.
Our study has a number of strengths. The first is that all sera were assayed for NT-proBNP before the commencement of advanced therapies in a population newly diagnosed with PAH. Second, the inclusion of an ILD group offers a challenging and real-life complexity. Together, PAH and ILD account for more than 60% of SSc-related deaths, and the poorer prognosis of patients with ILD who also develop PAH is increasingly recognized [1
]. Although a significantly higher mean NT-proBNP level was seen in the PAH group compared with the ILD group, a higher NT-proBNP cut point was required to separate the PAH group from the ILD group. This implies that ILD alone may result in modest elevation of NT-proBNP. These findings are consistent with those reported in studies of BNP that included SSc-ILD patients, suggesting modestly increased BNP in ILD patients without PAH [28
]. Further, increased BNP levels are associated with greater mortality in ILD patients with coexistent PAH [28
]. Alternatively, the higher cut point in the PAH-versus-ILD groups may reflect a degree of undiagnosed pulmonary hypertension and right ventricular compromise in the ILD group. For the purposes of screening, the addition of an FVC/DLCO cut point to the lower threshold value of NT-proBNP (209.8 pg/ml) incorporates an easy-to-calculate, inexpensive, and potentially useful clinical tool that can suggest the presence of pulmonary vascular disease.
The application of the screening model to the subgroup of at-risk patients with "borderline" pulmonary hypertension (that is, mPAP, 20 to 24 mm Hg, and PCWP, ≤ 15 mm Hg) who do not currently satisfy Dana Point criteria for PAH, revealed that a high proportion of these patients (77.7%) would have screened positive. Although the natural history of this group requires further longitudinal study, the high sensitivity of the algorithm in a group of patients that would be regarded as having abnormal pulmonary pressures, and possibly evolving PAH, is encouraging and is required of a screening tool [30
Potential limitations of this pilot study may affect the generalizability of the findings. We have not included patients with left ventricular (LV) dysfunction, a factor that can increase the level of NT-proBNP. However, it is important to note that in our proposed screening algorithm, all patients with a positive NT-proBNP would progress to TTE to evaluate further for LV dysfunction and valvular heart disease. The goal of this screening algorithm is not to distinguish between PAH and left ventricular dysfunction but to select patients who may be developing cardiopulmonary complications for further investigations.
In this study, we also excluded patients with an eGFR < 30 ml/min, given the reduced renal excretion of NT-proBNP at these levels. However, with significant renal impairment, one would expect an increase in NT-proBNP, meaning a possible increase in false-positive screens but not an increase in false-negative screens. Further, this degree of renal compromise is not frequently seen in SSc patients.
Last, the study is limited by the relatively small size in each group and its observational case-control design. The prospective evaluation of this algorithm in a cohort of SSc patients is required to refine screening cut points, validate the model, assess predictive values, and determine the frequency of screening.
The cost-effectiveness of our proposed screening algorithm also merits evaluation. At present, the cost of TTE combined with PFT in Australia is approximately $A367, whereas the cost of the PFT combined with NT-proBNP assay is $A195. Therefore, potentially, our proposed screening algorithm may lead to a cost saving in screening for SSc-PAH, compared with the existing screening algorithm. Furthermore, NT-proBNP assays have become more clinically available with the widespread use of NT-proBNP in the diagnosis, prognosis, and risk stratification of patients with congestive cardiac failure.