The symptoms of SAA are caused by pancytopenia. Patients with severe anemia may have life-threatening conditions due to failure of the cardiac or circulatory system, especially if they have not received transfusions [11
]. Although bleeding due to thrombocytopenia was a major cause of death in the past, it is gradually declining due to the use of transfusions. Currently, infection leads to the highest percentage of death [13
]. Recovery from anemia and thrombocytopenia by immediate transfusions is temporary, but patients can achieve tolerable states. Moreover, transfusions allow patients for whom IST or SCT are not indicated to maintain life. In contrast, despite empirical antibiotic therapy, uncontrolled infections caused by neutropenia end in septic shock and deprive patients of an opportunity to receive treatment for SAA (SCT or IST). Therefore, neutropenia seems to have the worst survival compared with the other 2 components of Camitta's criteria.
In the past, several predictive models have been proposed to predict survival in SAA patients. However, none gained wide acceptance because they were impractical (some models included complex formulas) or relied on subjective indices (such as bone marrow morphologies and differential counts) [14
]. In 1976, Camitta et al. proposed more accurate criteria for SAA in a prospective randomized trial [17
]. Patients who met the SAA criteria had better survival because they received earlier allo-SCT. After this study, the SAA criteria by Camitta et al. became the most widely accepted standard for the diagnosis of AA [18
]. However, it is difficult to understand the process or reason why Camitta chose ANC, PLT, and CRC for the diagnosis of SAA, and why he set the standard values as ANC <0.5×109
/L, PLT <20×109
/L, and CRC <1%, and stated that 2 out of these 3 components must be satisfied. Until now, no studies have reviewed or validated Camitta's criteria.
The importance of ANC for predicting the prognosis of AA has been emphasized in other studies. Bacigalupo et al. subclassified SAA by ANC: very SAA (<0.2×109
/L neutrophils) and moderately SAA (0.2-0.5×109
/L neutrophils) [20
], and then patients were randomly assigned to receive IST or SCT. Patients with more severe AA showed better survival when treated with SCT than with IST. Another retrospective analysis of SAA patients treated with horse anti-thymocyte globulin (ATG)-based IST showed that baseline ANC was the most significant contributor to short-term survival [21
]. Most patients with low ANC counts present to the clinic with septic conditions; therefore, they are not able to undergo aggressive treatment or receive SCT or IST. Since patients with low ANC tend to have shorter survival times or poor responses to therapy, these patients have not been included in prospective studies.
In our study, patients with low ANC also had significantly poor OS. ANC <0.5×109/L and age significantly affected OS in multivariate analysis. A patient with low ANC might have a high rate of infection and short OS. ANC was the only statistically significant component of Camitta's 3 criteria to have an effect on OS. Based on our analysis, we believe that ANC <0.5×109/L should be an essential component of SAA diagnosis. Age was another significant prognostic factor for OS. Older patients tolerate severe infections less well than younger patients, and this might have influenced their poor OS. As this study was retrospective in nature, there was little information on the performance status of the patients; therefore, we could not analyze survival by performance status.
Few studies have verified the prognostic impact of CRC or PLT on SAA. Furthermore, in our study, these 2 components did not have a significant impact on OS. However, there was only 1 patient with a CRC ≥1% among the analyzed patients. Of the 92 analyzed patients, 17 (18.5%) who satisfied Camitta's criteria for ANC and PLT were not tested for CRC. Therefore, we excluded CRC as a continuous variable in the univariate and multivariate analyses.
Our study is limited by its retrospective nature. However, it is difficult to perform a prospective study that randomizes patients into supportive care only or the appropriate treatment groups, because SAA is fatal if not treated. Since this study population only included those who were not able to receive more intensive treatments such as allogeneic SCT or IST, it is possible that this analysis is only valid for patients who are excluded from intensive treatment. Therefore, this analysis may be biased due to the inequality of the study population. If the conclusion is the same for all severe AA patients regardless of treatment type, then the conclusion that ANC is an essential component for the diagnosis of SAA will be more solid. However, to ensure that the response to IST or SCT significantly influenced OS, and to more properly determine the natural course of SAA in patients, we excluded patients who responded to treatment. Few studies have analyzed the optimal diagnostic criteria for SAA or reported the survival rate of untreated SAA. This study is the first report arguing for a change in the diagnostic criteria of SAA.
In conclusion, ANC should be an essential and not an optional criterion for diagnosing SAA. This study suggests the need for a modified Camitta's criteria. Further studies in large populations are required to verify whether each of the 3 components of Camitta's criteria has the same statistical power in SAA diagnosis.