diffuse large b - cell lymphoma ( dlbcl ) is the most common subtype of lymphoma , and a curable disorder with systemic chemotherapy . since a phase iii study demonstrated the superior efficacy of the addition of rituximab , an anti - cd20 monoclonal antibody to chop ( cyclophosphamide , doxorubicin , vincristine , and prednisone ) regimen to chop alone in elderly patients with dlbcl , rituximab plus chop ( r - chop ) regimen has been the mainstay for treatment of dlbcl . however , treatment - related morbidity and mortality remain as an obstacle to overcome in dlbcl patients , particularly elderly patients because chop regimen induces myelosuppression with high probability of febrile neutropenia ( fn ) . thus , previous studies have shown that lymphoma was a tumor type at risk of fn [ 4 - 6 ] , and the occurrence of fn significantly reduced the dose - intensity of r - chop . a previous meta - analysis showed that the addition of rituximab to chemotherapy regimen did not increase the overall risk of severe infection as well as treatment related mortality ; however , rituximab - induced b - cell depletion might induce additional risk of infection . in clinical practice , we often experienced febrile complications in the  absence  of neutropenia in patients who received rchop . this non - neutropenic fever ( nnf ) might be related to various clinical situations , such as virus , drug hypersensitivity , or idiopathic cases . a recent retrospective study underscored the clinical significance of interstitial pneumonitis in hematologic malignancy including patients treated with r - chop . likewise , an increase in the occurrence of pneumocystis jiroveci pneumonia ( pjp ) was also reported in patients treated with r - chop [ 10 - 12 ] . however , all of these studies were retrospective and the study population was relatively small . therefore , we analyzed the frequency of nnf as well as its clinical and microbiological features in our patients registered in the prospective cohort study . in this study , we also compared clinical significance and risk factors of nnf with those of fn . the study population came from two prospective cohort studies of samsung medical center : samsung medical center lymphoma cohort study ( nct#00822731 , 2008 - 2011 ) and samsung medical center lymphoma cohort study - ii ( nct#01877109 , 2012-ongoing ) . these studies were approved by the institutional review board of the samsung medical center , and patients were registered prospectively and followed . their comprehensive baseline characteristics , including disease - related factors , including stage , extranodal involvement , serum lactate dehydrogenase ( ldh ) , and bone marrow involvement , and host - related factors , including age , sex , and performance status were recorded . treatment - related data including treatment response and toxicity were recorded during and after treatment . from the patients enrolled in the cohort study , we selected patients newly diagnosed with dlbcl who were treated with r - chop as a primary treatment r - chop chemotherapy was repeated every 21 days , and each cycle consisted of rituximab 375 mg / m , cyclophosphamide 750 mg / m , doxorubicin 50 mg / m , and vincristine 1.4 mg / m ( maximum dose , 2.0 mg / dose ) administered intravenously on day 1 , and oral prednisone 100 mg on days 1 through 5 . because of insurance issues in korea , g - csf could be administered when an absolute neutrophil count below 1,000/mmwas detected . patients were instructed to visit the emergency room if they felt febrile sense during the nadir period , and were started on initial empirical antibiotic therapy with cefepime or piperacillin / tazobactam according to institutional strategy for management of fn . all patients received intravenous administration of doxorubicin via central line : hickman catheter in almost all cases , but peripherally inserted central catheter as acceptable if the technical approach for hickman catheter insertion was difficult because of the tumor location . the primary objective of this study was to determine the incidence of nnf in patients receiving r - chop , and the secondary objective was to determine causes and identify clinical features of nnf . we also compared nnf with fn in terms of incidence , causes and clinical features , and risk factors . fever was defined as a single oral temperature measurement of  38.3c , or a temperature of  38c sustained over a 1-hour period . fever without evidence of grade 3 or 4 neutropenia was referred to as nnf whereas fn was defined as the occurrence of fever in a state of grade 3 or 4 neutropenia . fever associated with r - chop chemotherapy was defined as any febrile event occurring during repeated cycles of r - chop or up to 3 months after completion of r - chop chemotherapy . if anti - cancer treatment other than r - chop chemotherapy , such as radiotherapy or salvage chemotherapy was administered for progressive disease , any febrile episode after these other anti - cancer treatments was excluded from the r - chop chemotherapy - associated nnf or fn . the incidence and onset of nnf and fn were calculated according to the first episode of nnf and fn in each patient . however , given that occurrence of multiple episodes of fever was possible in a single patient , all febrile events were considered when describing the causes of nnf and fn . according to the identification of a causative microorganism , the terms  microbiologically defined infection  ( mdi ) ,  clinically - defined infection  ( cdi ) , and  unexplained fever  ( uf ) were used . infections were defined as mdi when a clinically significant pathogen was identified from a culture or a biopsy of an affected site . the definition of cdi was used if fever was accompanied by appropriate clinical findings ( for example , pulmonary infiltrates and respiratory symptom associated with fever ) . the incidence of febrile episode during courses of r - chop chemotherapy and the incidence of given type of infection and microbiologic etiology were described using frequency analysis . the cumulative probability of febrile events by cycle and overall survival ( os ) were calculated using the kaplan - meier method . the time to the first nnf or fn was defined as the time between the first day of r - chop and the date of the first nnf or fn . os was defined as the duration from the date of the first day of r - chop to the date of last follow - up or the date of death from any cause . the study population came from two prospective cohort studies of samsung medical center : samsung medical center lymphoma cohort study ( nct#00822731 , 2008 - 2011 ) and samsung medical center lymphoma cohort study - ii ( nct#01877109 , 2012-ongoing ) . these studies were approved by the institutional review board of the samsung medical center , and patients were registered prospectively and followed . their comprehensive baseline characteristics , including disease - related factors , including stage , extranodal involvement , serum lactate dehydrogenase ( ldh ) , and bone marrow involvement , and host - related factors , including age , sex , and performance status were recorded . treatment - related data including treatment response and toxicity were recorded during and after treatment . from the patients enrolled in the cohort study , we selected patients newly diagnosed with dlbcl who were treated with r - chop as a primary treatment r - chop chemotherapy was repeated every 21 days , and each cycle consisted of rituximab 375 mg / m , cyclophosphamide 750 mg / m , doxorubicin 50 mg / m , and vincristine 1.4 mg / m ( maximum dose , 2.0 mg / dose ) administered intravenously on day 1 , and oral prednisone 100 mg on days 1 through 5 . because of insurance issues in korea , g - csf could be administered when an absolute neutrophil count below 1,000/mmwas detected . patients were instructed to visit the emergency room if they felt febrile sense during the nadir period , and were started on initial empirical antibiotic therapy with cefepime or piperacillin / tazobactam according to institutional strategy for management of fn . all patients received intravenous administration of doxorubicin via central line : hickman catheter in almost all cases , but peripherally inserted central catheter as acceptable if the technical approach for hickman catheter insertion was difficult because of the tumor location . the primary objective of this study was to determine the incidence of nnf in patients receiving r - chop , and the secondary objective was to determine causes and identify clinical features of nnf . we also compared nnf with fn in terms of incidence , causes and clinical features , and risk factors . fever was defined as a single oral temperature measurement of  38.3c , or a temperature of  38c sustained over a 1-hour period . fever without evidence of grade 3 or 4 neutropenia was referred to as nnf whereas fn was defined as the occurrence of fever in a state of grade 3 or 4 neutropenia . fever associated with r - chop chemotherapy was defined as any febrile event occurring during repeated cycles of r - chop or up to 3 months after completion of r - chop chemotherapy . if anti - cancer treatment other than r - chop chemotherapy , such as radiotherapy or salvage chemotherapy was administered for progressive disease , any febrile episode after these other anti - cancer treatments was excluded from the r - chop chemotherapy - associated nnf or fn . the incidence and onset of nnf and fn were calculated according to the first episode of nnf and fn in each patient . however , given that occurrence of multiple episodes of fever was possible in a single patient , all febrile events were considered when describing the causes of nnf and fn . according to the identification of a causative microorganism , the terms  microbiologically defined infection  ( mdi ) ,  clinically - defined infection infections were defined as mdi when a clinically significant pathogen was identified from a culture or a biopsy of an affected site . the definition of cdi was used if fever was accompanied by appropriate clinical findings ( for example , pulmonary infiltrates and respiratory symptom associated with fever ) . the incidence of febrile episode during courses of r - chop chemotherapy and the incidence of given type of infection and microbiologic etiology were described using frequency analysis . the cumulative probability of febrile events by cycle and overall survival ( os ) were calculated using the kaplan - meier method . the time to the first nnf or fn was defined as the time between the first day of r - chop and the date of the first nnf or fn . os was defined as the duration from the date of the first day of r - chop to the date of last follow - up or the date of death from any cause . between september 2008 and january 2013 , a total of 1,142 lymphoma patients were registered in the two prospective cohort studies . among them , 435 patients were newly diagnosed with dlbcl and received at least one cycle of r - chop chemotherapy as a first - line treatment . finally , 397 patients with dlbcl were analyzed in this study , and their clinical characteristics at diagnosis are summarized ( table 1 ) . the median age was 55 years ( range , 16 to 86 years ) , and elderly patients aged 60 years or older accounted for approximately 36% of patients . approximately one half of patients ( n=189 , 47.6% ) presented as ann arbor stage iii or iv ; however , the international prognostic index ( ipi ) showed that 69% of patients belonged to low ( n=194 , 49% ) and low - intermediate risk groups ( n=79 , 20% ) , while 31% of patients belonged to high - intermediate ( n=60 , 15% ) and high ( n=64 , 16% ) risk groups . the median number of r - chop cycles was 6 ( range , 1 to 8) . among 397 patients , 39 ( 9.8% ) and 160 patients ( 40.3% ) experienced nnf and fn , respectively . the initial episode of nnf was most frequently observed around the fourth cycle of r - chop . thus , approximately 28% of the first visit for nnf occurred following the fourth cycle ( fig . by contrast , the initial fn event was commonly observed in earlier courses of cycle , and approximately 50% of the first hospital visits for fn occurred after the first chemotherapy cycle ( fig . 1b ) . the cumulative incidence of nnf after r - chop chemotherapy increased from 0.8% following the first cycle to 12.9% following the eighth cycle , whereas the cumulative incidence of fn increased from 20% following the first cycle to 47% following the eighth cycle . forty two episodes of nnf occurred in 39 patients with nnf ; three of these patients experienced multiple episodes of nnf . interstitial pneumonitis was the predominant clinical feature of nnf ( 23 out of 42 episodes , 54.8% ) ( table 2 ) . in all cases of atypical pneumonia , infectious bronchoalveolar lavage ( bal ) was performed for identification of causative pathogens ; 10 organisms were detected in nine patients . out of identified organisms causing interstitial pneumonitis , pjp was the most common pathogen ( n=4 ) . other pathogens included adenovirus ( n=2 ) , respiratory syncytial virus ( rsv ) ( n=2 ) , and cytomegalovirus ( cmv ) ( n=1 ) . for 14 patients in whom no pathogen was identified , trimethoprim - sulfamethoxazole was administered empirically under the impression of pjp . beside interstitial pneumonitis , catheter - related infection was the second most common form of nnf ( n=9 , 20.5% ) . among the identified pathogens causing bacterial infection , gram - positive organisms , including coagulase - negative staphylococcus and staphylococcus aureus were the most common ( 8/14 , 57.1% ) . grade iv febrile events were reported in four patients ( 4/39 , 10.3% ) , including three cases of interstitial pneumonitis , all of which were associated with mortality cases . two patients died due to adenoviral pneumonia and one due to interstitial pneumonitis of unknown pathogen . the remaining patient developed severe sepsis with candidemia even in the normal range of neutrophil count , and died despite receiving antifungal treatment with active supportive care . among other cases of nnf , two patients developed cmv esophagitis , which occurred after completion of the sixth cycle of r - chop , and was proven by endoscopic biopsy ; both patients recovered with antiviral treatment . among the 160 patients with fn , 65 patients ( 40.9% ) experienced at least two episodes of fn during their treatment period . of these 65 patients , 39 patients experienced two episodes of fn , whereas 26 patients experienced three or more : three episodes ( n=11 ) , four episodes ( n=8 ) , five episodes ( n=4 ) , and six episodes ( n=3 ) of fn during r - chop cycles . as a result there were 74 cases of cdi ( 26.8% ) , 70 cases of mdi ( 25.4% ) , and 132 cases of uf ( 47.8% ) . among the 144 cases with cdi and mdi , catheter - related infection ( 14.2% ) , gastroenteritis ( 10.7% ) , and lower respiratory tract infection ( 10.0% ) accounted for more than 35% of febrile events ( table 3 ) . bacteremia was detected in 46 cases , and coagulase - negative staphylococcus was the most common microorganism responsible for bacteremia ( 27.7% ) ; staphylococcus aureus ( 17.0% ) , enterococcus spp . ( 10.6% ) , and escherichia coli ( 10.6% ) were the next most prevalent organisms identified in blood ( table 3 ) . nine patients ( 9/160 , 5.6% ) experienced grade iv fn , two were mortality cases associated with fn , including septic shock with klebsiella bacteremia and fungal sinusitis with mucormycosis . univariate and multivariate analyses were performed to determine the risk factors associated with development of nnf as well as fn ( table 4 ) . the results of univariate analysis for risk factors of nnf showed that age older than 60 years increased the risk of nnf . other parameters were not related with the occurrence of nnf . as a result , in multivariate analysis , age was also demonstrated to be an independent risk factor for nnf . in univariate analysis , compared to nnf , the occurrence of fn showed significant association with all parameters of the ipi . however , multivariate analysis showed the same result as that of nnf , thus , advanced age was the only significant factor affecting development of fn ( p < 0.001 ; hazard ratio , 2.757 ) . over the median follow - up period of 34.4 months ( range , 3.7 to 63.0 months ) , the nnf - related mortality rate was 10.3% ( four deaths from 39 patients with nnf ) while the fn - related mortality rate was 1.3% ( two deaths from 160 patients with fn ) . at the time of analysis , the 4-year os was 77.3% . in comparison of os according to the presence of fn and/or nnf , patients who had experienced any febrile events showed worse survival compared to patients who did not have fn or nnf ( p=0.004 ) . separately , patients who experienced nnf showed significantly worse os ( p=0.04 ) ( fig . 2a ) , whereas os was not significantly different between patients with and without fn ( p=0.08 ) ( fig . between september 2008 and january 2013 , a total of 1,142 lymphoma patients were registered in the two prospective cohort studies . among them , 435 patients were newly diagnosed with dlbcl and received at least one cycle of r - chop chemotherapy as a first - line treatment . finally , 397 patients with dlbcl were analyzed in this study , and their clinical characteristics at diagnosis are summarized ( table 1 ) . the median age was 55 years ( range , 16 to 86 years ) , and elderly patients aged 60 years or older accounted for approximately 36% of patients . approximately one half of patients ( n=189 , 47.6% ) presented as ann arbor stage iii or iv ; however , the international prognostic index ( ipi ) showed that 69% of patients belonged to low ( n=194 , 49% ) and low - intermediate risk groups ( n=79 , 20% ) , while 31% of patients belonged to high - intermediate ( n=60 , 15% ) and high ( n=64 , 16% ) risk groups . the median number of r - chop cycles was 6 ( range , 1 to 8) . among 397 patients , 39 ( 9.8% ) and 160 patients ( 40.3% ) experienced nnf and fn , respectively . of those , 24 patients ( 6.0% ) experienced both febrile complications . the initial episode of nnf was most frequently observed around the fourth cycle of r - chop . thus , approximately 28% of the first visit for nnf occurred following the fourth cycle ( fig . by contrast , the initial fn event was commonly observed in earlier courses of cycle , and approximately 50% of the first hospital visits for fn occurred after the first chemotherapy cycle ( fig . 1b ) . the cumulative incidence of nnf after r - chop chemotherapy increased from 0.8% following the first cycle to 12.9% following the eighth cycle , whereas the cumulative incidence of fn increased from 20% following the first cycle to 47% following the eighth cycle forty two episodes of nnf occurred in 39 patients with nnf ; three of these patients experienced multiple episodes of nnf . interstitial pneumonitis was the predominant clinical feature of nnf ( 23 out of 42 episodes , 54.8% ) ( table 2 ) . in all cases of atypical pneumonia , infectious bronchoalveolar lavage ( bal ) was performed for identification of causative pathogens ; 10 organisms were detected in nine patients . out of identified organisms causing interstitial pneumonitis , pjp was the most common pathogen ( n=4 ) . other pathogens included adenovirus ( n=2 ) , respiratory syncytial virus ( rsv ) ( n=2 ) , and cytomegalovirus ( cmv ) ( n=1 ) . for 14 patients in whom no pathogen was identified , trimethoprim - sulfamethoxazole was administered empirically under the impression of pjp . beside interstitial pneumonitis , catheter - related infection was the second most common form of nnf ( n=9 , 20.5% ) . among the identified pathogens causing bacterial infection , gram - positive organisms , including coagulase - negative staphylococcus and staphylococcus aureus were the most common ( 8/14 , 57.1% ) . grade iv febrile events were reported in four patients ( 4/39 , 10.3% ) , including three cases of interstitial pneumonitis , all of which were associated with mortality cases . two patients died due to adenoviral pneumonia and one due to interstitial pneumonitis of unknown pathogen . the remaining patient developed severe sepsis with candidemia even in the normal range of neutrophil count , and died despite receiving antifungal treatment with active supportive care . among other cases of nnf , two patients developed cmv esophagitis , which occurred after completion of the sixth cycle of r - chop , and was proven by endoscopic biopsy ; both patients recovered with antiviral treatment . among the 160 patients with fn , 65 patients ( 40.9% ) experienced at least two episodes of fn during their treatment period . of these 65 patients , 39 patients experienced two episodes of fn , whereas 26 patients experienced three or more : three episodes ( n=11 ) , four episodes ( n=8 ) , five episodes ( n=4 ) , and six episodes ( n=3 ) of fn during r - chop cycles . as a result there were 74 cases of cdi ( 26.8% ) , 70 cases of mdi ( 25.4% ) , and 132 cases of uf ( 47.8% ) . among the 144 cases with cdi and mdi , catheter - related infection ( 14.2% ) , gastroenteritis ( 10.7% ) , and lower respiratory tract infection ( 10.0% ) accounted for more than 35% of febrile events ( table 3 ) . bacteremia was detected in 46 cases , and coagulase - negative staphylococcus was the most common microorganism responsible for bacteremia ( 27.7% ) ; staphylococcus aureus ( 17.0% ) , enterococcus spp . ( 10.6% ) , and escherichia coli ( 10.6% ) were the next most prevalent organisms identified in blood ( table 3 ) . nine patients ( 9/160 , 5.6% ) experienced grade iv fn , two were mortality cases associated with fn , including septic shock with klebsiella bacteremia and fungal sinusitis with mucormycosis . univariate and multivariate analyses were performed to determine the risk factors associated with development of nnf as well as fn ( table 4 ) . the results of univariate analysis for risk factors of nnf showed that age older than 60 years increased the risk of nnf . other parameters were not related with the occurrence of nnf . as a result , in multivariate analysis , age was also demonstrated to be an independent risk factor for nnf . in univariate analysis , compared to nnf , the occurrence of fn showed significant association with all parameters of the ipi . however , multivariate analysis showed the same result as that of nnf , thus , advanced age was the only significant factor affecting development of fn ( p < 0.001 ; hazard ratio , 2.757 ) . over the median follow - up period of 34.4 months ( range , 3.7 to 63.0 months ) , the nnf - related mortality rate was 10.3% ( four deaths from 39 patients with nnf ) while the fn - related mortality rate was 1.3% ( two deaths from 160 patients with fn ) . at the time of analysis , the 4-year os was 77.3% . in comparison of os according to the presence of fn and/or nnf , patients who had experienced any febrile events showed worse survival compared to patients who did not have fn or nnf ( p=0.004 ) . separately , patients who experienced nnf showed significantly worse os ( p=0.04 ) ( fig . 2a ) , whereas os was not significantly different between patients with and without fn ( p=0.08 ) ( fig . this study was a large - scale analysis focusing on the occurrence of nnf in dlbcl patients who were uniformly treated with r - chop and enrolled in prospective observation cohort studies . we found that approximately 10% of dlbcl patients experienced nnf whereas 40% of patients experienced at least one episode of fn during r - chop chemotherapy . besides the incidence , clinical features and causative microorganisms of nnf differed significantly from those of fn . thus , half of patients experienced fn after the first cycle of r - chop , consistent with previous studies reporting that hospital visits for fn were most likely to occur in early courses of treatment . however , the occurrence of nnf tended to increase with continuation of treatment and was most commonly observed around the fourth cycle . in addition , fn showed strong association with bacterial infection in which gram - positive organisms predominated , with a high incidence of catheter - related infection , and was usually controlled well with broad - spectrum antibiotics . in contrast , many cases of nnf showed interstitial pneumonitis without definite evidence of blood stream infection . we found that interstitial pneumonitis comprised approximately 55% of nnf cases ( n=23 , 54.8% ) . however , causative organisms were identified in only nine patients ( 39.1% ) in spite of active evaluation including bal , and pjp was the most common pathogen ( n=4 ) . although the rate of microbiologically proven pjp was extremely low , most cases with interstitial pneumonitis were treated with trimethoprim - sulfamethoxazole because they were diagnosed with probable pjp . given that most patients with probable pjp showed a response and recovered , the majority of our interstitial pneumonitis could be pjp , except for a few cases found to have adenovirus , rsv , and cmv . thus , in this study , the overall rate of pjp including definite and probable cases was 4.5% ( 18 cases from 397 patients ) . likewise , a recent survey regarding the prevalence of pjp in 713 patients receiving r - chop reported diagnosis of 14 and 18 patients with definite and probable pjp , respectively . thus , pjp incidence of 4.5% ( 32/713 ) , including definite and probable cases was reported , and the majority cases of pjp ( 22/32 , 68.7% ) developed after administration of the fourth r - chop cycle , similar to our results . given that opportunistic infection caused by virus or fungus is affected by impaired immunity , nnf might be associated with rituximab - induced impaired immunity . depletion of b cells after repeated doses of rituximab may have direct effects on antibody production . indeed , previous studies demonstrated impaired humoral immune response after rituximab treatment , which might be related to the risk of infection . however , altered t - cell  mediated immunity following rituximab has also been suggested , and cd4 + t - cell activation in response to pathogen was substantially impaired by b - cell depletion in an animal study . of note , the majority of interstitial pneumonitis ( 20/23 , 87% ) occurred after the third or fourth cycle of r - chop . we do not know exactly why this phenomenon appears to be more common at this period of time ; however , delayed recovery of cd4 + t cells after rituximab might be an explanation in part . in a japanese study , the number of cd4 + t cells in b - cell lymphoma patients showed a different time trend after r - chop  based chemo - immunotherapy when compared to the number of cd3 + , cd8 + , and cd56 + cells . in this study , six cycles of rchop like regimen followed by additional weekly rituximab two times was administered to the patients , and absolute numbers of peripheral blood t- and b - cells were determined . of the t cell subsets , the number of cd3 + , cd8 + , and cd56 + cells showed the lowest level after three cycles of treatment , and continued to increase until one year after therapy . regarding cd4 + t cells , the number of cells showed a constant decrease during treatment and the level was lowest after six courses of r - chop  based chemotherapy . thereafter it increased again ; however , the recovery was much slower and lasted for 2 years . and , importantly , the level of cd4 + count at 2 years after treatment was still lower compared to baseline level , whereas cd3 + , cd8 + , and cd56 + t cells showed slightly higher levels than observed at diagnosis . regarding the impact of rituximab on impaired cd4 + response , a previous randomized phase iii trial of chop with or without rituximab in patients with human immunodeficiency virus  associated non - hodgkin lymphoma reported a significant increase in infection - related mortality in patients with lowered cd4 + t - cell numbers . although many cases of infection - related mortality in these patients were directly related to uncontrolled bacterial infection , opportunistic infection was also more frequently observed in individuals randomized to rituximab . thus , opportunistic infections due to candida , pjp , cmv , and mycobacterium avium occurred in six of 99 r - chop  treated patients , whereas no opportunistic infections were observed in the 51 patients of the chop group . taken together , these results suggest that febrile events occurring in a non - neutropenic state , mainly interstitial pneumonitis might be related to rituximab - induced impaired cellular immunity . however , as quantitative assessment of lymphocyte subsets was not performed during treatment , it was impossible to determine the association of the occurrence of opportunistic infection with serial changes of the cd4 + t count . in addition , the probability of rituximab - induced interstitial pneumonitis also existed because several reports suggested the presentation of rituximab - induced lung injury as interstitial pneumonitis . however , rituximab - induced interstitial pneumonitis usually occurred after the first or second cycle of r - chop . thus , in our study , the majority of cases of interstitial pneumonitis might not be associated with rituximab - induced reactions . parameters reflecting advanced disease , such as elevated serum ldh , advanced stage , and extranodal involvement  2 were more likely to be associated with fn rather than nnf . this finding might be related to the fact that fn occurred mainly after the first or second cycle of r - chop because patients with higher tumor burden might be more susceptible to development of febrile complications owing to their poor performance status in relation to high tumor burden . on the other hand , the occurrence of nnf was mainly associated with old age , rather than tumor burden , which may be due to its relatively late occurrence compared to that of fn . the results of multivariate analysis showed that only age was an independent risk factor for fn as well as nnf . the incidence of both fn and nnf was significantly higher in elderly patients ( 31.0% in  60 years vs. 57.0% in > 60 years for fn , p < 0.001 ; 6.7% in  60 years vs. 15.5% in > 60 years for nnf , p=0.005 ) . this finding implies that much more attention is required and more effective infection prophylaxis is warranted in elderly patients . the inferior survival outcome of patients who had ever experienced fn or nnf implied a negative impact of febrile complications on survival outcomes . although the number of events was not large , relatively higher mortality rate in patients with nnf ( 10.3% , 4/39 ) compared with fn - related mortality ( 1.3% , 2/160 ) underscored the clinical significance of nnf , particularly interstitial pneumonitis . in conclusion , considering the negative impact of nnf on survival outcome and the higher vulnerability of elderly patients , effective preventive measures as well as close monitoring are warranted .
purposerituximab plus cyclophosphamide , doxorubicin , vincristine , and prednisone ( r - chop ) is the standard chemotherapy in diffuse large b - cell lymphoma ( dlbcl ) patients . although febrile neutropenia ( fn ) is the major toxicity of this regimen , non - neutropenic fever ( nnf ) becomes an emerging issue.materials and methodswe analyzed clinical features and outcomes of febrile complications from 397 patients with newly diagnosed dlbcl who were registered in the prospective cohort study . 
 they had completed r - chop between september 2008 and january 2013.resultsthirty-nine patients ( 9.8% ) had nnf whereas 160 patients ( 40.3% ) had fn . among them , 24 patients ( 6.0% ) had both during their treatment . compared to frequent occurrence of initial fn after the first cycle ( > 50% of total events ) , more than 80% of nnf cases occurred after the third cycle . 
 interstitial pneumonitis comprised the highest proportion of nnf cases ( 54.8% ) , although the causative organism was not identified in the majority of cases . 
 thus , pathogen was identified in a limited number of patients ( n=9 ) , and pneumocystis jiroveci pneumonia ( pjp ) was the most common . considering that interstitial pneumonitis without documented pathogen could be clinically diagnosed with pjp , the overall rate of pjp including probable cases was 4.5% ( 18 cases from 397 patients ) . 
 the nnf - related mortality rate was 10.3% ( four deaths from 39 patients with nnf ) while the fn - related mortality rate was only 1.3%.conclusionnnf was observed with incidence of 10% during r - chop treatment , and showed different clinical manifestations with respect to the time of initial episode and causes .