Although thrombocytopenia had been recognized as a significant risk factor for PH in SM respiratory infection, in the present study, the degree of thrombocytopenia by platelet deficit at a single time point and over a certain time period was evaluated to identify the optimal cut-off value in predicting PH. Also, results of the present study demonstrated the clinical heterogeneity of thrombocytopenia as the cause and its association with PH, which may explain the conflicting findings of previous observational studies and address the need for more precise and individualized risk classification based on comorbidities. Different measurement tools should be used in distinct subpopulations to predict PH; for example, platelet counts at the test date should be sufficient in patients with hematological and liver diseases, while d-index using serial platelet measurements performs more reliably for those with sepsis and other causes.
Mortality associated with PH was overwhelmingly high in the present study, especially in patients with hematologic malignancy. Recently, increasing numbers of cases have been successfully treated, which may be due to refinement of preventive measures of transmission, rising awareness of SM infections, and timely use of empirical antimicrobial therapy [18,19]. The mortality rate in the present study was highest within the first week of diagnosis (50%), demonstrating the potential fulminant behavior of SM infections. Notably, only one patient with hematological disease survived through hemorrhagic SM respiratory infection, and none of the neutropenic patients survived. In a previous study conducted by Bao et al, patients with severe prolonged neutropenia and thrombopenia due to hematological disorders were shown to have 100% mortality when encountering SM bacteremia . The present study echoes their findings, indicating that hematological abnormalities complicate the clinical course of SM respiratory infection and worsen the disease outcome. Although neutrophil counts may have been a decisive factor in infection control and hematopoiesis ability, it was also shown to be a significant risk factor for PH in previous studies . After multivariate analysis, we found that neutropenia was not an independent risk factor for PH or associated mortality, implying that neutropenia is probably a collateral finding along with underlying disease and thrombocytopenia.
Patients in the “Sepsis-Rx” and “Others” groups with SM-associated PH had higher proportions of pulmonary structural abnormalities and mechanical use. Because these patients are likely to receive mechanical ventilation due to pulmonary structure anomaly, they acquired SM infection through ventilator use. Until now, the attributable factors causing SM-related VAP remain unclear [1, 16]. A recent study found that exposure to ureido/carboxypenicillin or carbapenem during the week before VAP, and the severity of disease leading to respiratory and hematological failures, were independent risk factors for SM-VAP . Moreover, SM-VAP mortality remains high even in patients receiving adequate treatment, either monotherapy or combinations of antimicrobials.
Platelet counts at a single time point or over a given time period were significantly lower in patients with hematological and liver diseases than in those with sepsis or other diseases, but risk for PH did not differ significantly between these patients. Although thrombocytopenia is an independent determining factor for PH, patients experiencing long-term thrombocytopenia may develop a certain mechanism by which to compensate for the bleeding tendency. A previous study identified that an increased number of larger-sized platelets may compensate for the impaired platelet function in patients with chronic idiopathic thrombocytopenia . In acute myeloid leukemia patients who have thrombocytopenia, platelet aggregation and platelet activation predicted bleeding better than the platelet count alone . Overall, the bleeding risk is not only dependent on the platelet count but also on the platelet function, coagulopathy, and the underlying disease causing thrombocytopenia. Further mechanistic exploration of the cause of reduced platelet counts or function in different thrombocytopenic conditions is still needed to help develop and implement preventive strategies .
In the present study, thrombocytopenia due to hematological and liver diseases both had prolonged and profound low platelet levels and PH usually developed at the nadir of the platelet level. Meanwhile, the pattern of thrombocytopenia due to sepsis/medication or other causes were more alike and had higher average platelet count compared to those in hematological and liver disease. Traditionally, the pathophysiology of thrombocytopenia in chronic liver disease has long been attributed to hypersplenism, where pooling and sequestration of blood results in platelet consumption. Recently, other mechanisms, including bone marrow suppression by toxic substances such as alcohol or viral infection may also contribute to thrombocytopenia. In addition, the thrombopoietin, predominantly produced by the liver is markedly reduced in advanced-staged liver disease, which also contributes to reduced thrombopoiesis in the bone marrow . All mechanisms mentioned above can explain the thrombocytopenia caused by liver disease that may be secondary to bone marrow suppression, similar to those in hematological disorders.
The clinical consensus regarding the lowest platelet level needed to prevent bleeding in certain circumstances is that platelet counts must be above 20–50 x103 /uL for bronchoscopy exams and 50 x103 /µL for transbronchial lung biopsies . Statistical results from the present study show that platelet levels above 60–100 x103 /µL may plausibly prevent PH in patients with sepsis, liver disease and other causes, while lower platelet counts (above 17.5 x103 /µL) may be tolerated in patients with hematological diseases. In addition to certain cut-off levels for platelet counts, the accumulative platelet deficit over a given time period was found to be more reliable in predicting PH in patients with sepsis, medication-related, or other causes of thrombocytopenia. Although these groups of patients did not have thrombocytopenia as profound as in those with hematological disorders, they are more susceptible to developing PH in prolonged thrombocytopenia. Therefore, regular prophylactic platelet transfusion to maintain platelet levels above certain thresholds over unstable periods may be a potential strategy to prevent PH in this group of patients.
The present study used the largest database evaluating PH in patients with SM respiratory infections and is also the first study to extrapolate serial platelet measurements in predicting PH. Data in the present study provide clinicians with the optimal cutoff platelet level for transfusion therapy to prevent PH in thrombocytopenia of various causes. The concept of using d-index as a personalized measurement in evaluating the severity of thrombocytopenia can be implemented to prevent SM hemorrhagic pneumonia and bleeding disorders in various other diseases. Especially in the era of the COVID-19 pandemic, clinicians may also utilize the d-index to assess the risk of PH in sepsis due to COVID-19.
Regardless of the above strengths, the present study has several limitations. First is that we did not evaluate associations between PH, antibiotic use and corresponding antimicrobial susceptibility. Although in both clinical and animal studies, timely appropriate antibiotic use could reduce the risk of mortality in SM hemorrhagic pneumonia, systematic review demonstrated that even patients treated with appropriate antibiotics, including trimethoprim/sulfamethoxazole, fluoroquinolones, or both combined, the mortality remained high, even reaching 100% [11, 15]. Also, no prior antimicrobial therapy for SM bacteremia had shown a preventive effect for PH . Still, prompt administration of antibiotics is essential for control of infectious disease, but the use of antibiotics in preventing PH in SM respiratory infection does not appear to be an adequate measure.