Discussion
In this 10-year single-centre study of all hospitalised patients with newly diagnosed acute PE, we showed that presence of fever was associated with higher likelihood of underlying massive and submassive and DVT. The need for mechanical ventilation, hospital LOS and ICU admission was also higher in patients with acute PE and fever. Patients with acute PE and fever also had a higher mortality in a univariate analysis. To the extent of our knowledge, our study is probably the first to extensively study this clinical and prognostic correlation of PE and fever while accounting for underlying infections.
Fever has been reported as one of the key symptoms of PE along with cough, chest pain and dyspnoea with majority of the data emphasising its association with low grade fever.12 18 Presence of high-grade fever in the setting of thromboembolism is not supported by evidence and identification of another source has been suggested.18 In the recent data, low-grade fever in PE is detected in the range of 6%–33% and high-grade fever is reported variably from 3% to 14%.12–14 In our study, 24.5% population manifested fever with average peak temperature observed was 38.6°C (101.5°F) within 1 week of PE diagnosis. Comparably in a study by Murray et al, 18 out of 19 subjects with PE were afebrile after 1 week of diagnosis.14 The most common accompanying symptom, besides fever, manifested in our PE population was chest pain and shortness of breath which is a similar finding observed by Korkturk et al in a study of 39 patients with PE and fever.17 Identical description of symptoms including dyspnoea and restlessness was reported by Hodgosn et al in patients with PE and pulmonary infarction secondary to large or recurrent small emboli causing obstruction of pulmonary circulation.19
Fever that persisted beyond 1 week of initiation of anticoagulation was not attributed to PE itself and thus other causes should be evaluated.18 19 Several aetiologies have been proposed for persistent fever after 1 week of PE diagnosis including pulmonary infarct, superimposed infection, drug fever and Dressler like phenomenon.20–22 Stein et al
20 noted fever in 39 out of 267 patients with pulmonary infarction and haemorrhage and found more evidence of DVT in patients with PE and otherwise unexplained fever which was also observed in our study. Further, several patterns of PE-related fever were described based on duration including intermittent, sustained or hectic type,20–22 though intermittent and sustained type were noted more in our study group. In one of the studies on complicated PE,21 fever was observed in 26% of heparin and urokinase-treated patients (41 out of 158). In our study, we identified that fever was more likely in patients with massive and submassive PE compared with those with simple PE (55.9% vs 36.8%) and we did not find any statistical difference in terms of pulmonary infarcts between the two groups.
The pathophysiology of fever in PE has not been clearly understood.19 23 24 Several models for its mechanism have been mentioned in literature but none is supported by the evidence.25–27 The pyrogenic model described the production of inflammation cascade associated with tissue necrosis, vascular irritation and atelectasis that leads to rise in body temperature.15 16 This results in an elevated leucocyte count in the early part of disease course which was also observed in our study.17 Another mechanism explained by Jerjes and his colleagues22 is Dressler-like syndrome, caused by immune reactivity of serosa (pleura and pericardium) secondary to vascular remodelling, reported in 4% of patients with PE. This mechanism can result in pleural effusion, fever, anaemia and leucocytosis. Our study highlighted a noteworthy association of fever and higher incidence of massive/submassive PE and DVT in patients with acute PE.
In majority of the studies performed to identify the relationship of PE and fever, exclusion of other causes of fever was not well illustrated and thus its association with PE remained debatable.25–27 Our study is noteworthy in a way that we included microbiological data and clinical decision making to identify individuals in whom fever could be attributed to PE with more certainty and excluded those where we could not establish this relation with certainty. The antibiotic use was higher in patients with PE and fever. The common reasons recognised in the literature for initiation of antibiotics in patients with PE are leucocytosis, infiltrates on X-ray imaging or clinical symptoms that may suggest underlying pneumonia which are probably also true for our study cohort.17–19
The data regarding outcome of individuals with PE and fever are very limited. 25 26 28–33 Our study is striking in this regard that we investigated the morbidity and mortality data for this subset of population. Watanakunakorn25 reported that nearly half of the patients with PE with high-grade fever in his study died. This study was a series of seven patients with limited microbiological data evaluation. Additionally, outcome and patient characteristics were not well elaborated. Calvo-Romero et al
26 reported in hospital mortality of 7% in patients with PE and fever. Although the study included majority of the patients with PE diagnosed by various imaging modalities; however, it is limited by the fact that investigators favoured pneumonia as the cause of fever and had not considered other sources of infection into account. Furthermore, outcome data in this study including morbidity and mortality were similar in all groups. In a 4-year prospective study on predictive factors of PE, Bahloul et al
33 studied outcome data in patients with PE irrespective of occurrence of fever in patients who were critically ill. They reported mean length of hospital stay (LOS) of 25 days, mean ICU stay of 20.2 days and the in-hospital mortality rate of 52.9%. Even though the study included clinical characteristics, risk factors and outcomes in acute patients with PE, the authors did not signify association of fever in such patients and its clinical impact on patient outcomes. In our study, mean LOS for PE and fever was 14 days, with higher likelihood of ICU admission in fever group (69.5% vs 24.7%). We also found higher mortality in patients with PE and fever (22% vs 10.4%) along with higher need for mechanical ventilation (30% vs 6.6%).
There are several limitations of our study. First, we used a retrospective design where we were limited to the information obtained by the medical records and not direct patient contact. Second, we included patients from a single centre, which cares for an inner-city population with specific demographic characteristics. Third, our study group is relatively small compared with some large PE study which can affect study power. However, we believe that even with small patient population, our study was able to answer some interesting clinical questions. Fourth, we retrospectively reviewed all septic workup data in patients admitted with acute PE and fever and excluded all those patients with underlying infections. This could introduce selection bias. To address that bias, two study investigators (MS and MA) independently reviewed the patient charts and excluded patients where underlying cause of fever may be attributed to non-PE source. Fifth, we did not include any patients who had fever more than 1 week from diagnosis of PE. This was done in view of prior data that stated that fever beyond 1 week is less likely to be associated with PE.11 12 14 16 Sixth, since it is a 10-year study, advancement in medical practice might be a confounding factor which may have affected the study results. Finally, we did not include ICU severity scoring system (APACHE or SOFA scores) to estimate its contribution to mortality and LOS. Despite the limitations, our study highlights the potential association of fever with clot burden in acute PE that has both clinical and prognostic implications in care of these patients.