this prospective study was conducted in spain from july 2009 through march 2010 during the outbreak of pandemic ( h1n1 ) 2009 . all adult ( > 18 years of age ) patients with an influenza - like illness who sought medical attention and had > 1 risk factor for contracting influenza - related complications , according to centers for disease control and prevention recommendations ( www.cdc.gov/flu/about/disease/high_risk.htm ) or any other severity criteria , were sent to an outpatient infectious diseases clinic and were included in a protocol described below . the protocol included the collection of oropharyngeal and nasopharyngeal swab samples , tested as previously described ( 9 ) . a sputum sample was obtained if spontaneously expectorated , and 2 blood cultures were collected when low systolic blood pressure , hypo- or hyperthermia , signs of sepsis , or a score > 2 obtained by using the british thoracic society s curb-65 assessment tool ( 10 ) were present . patients had chest radiographs taken , c - reactive protein ( crp ) measured , and the severity of illness calculated by using the curb-65 score . the cdc real - time reverse transcription pcr ( rrt - pcr ) protocol for detection and characterization of the pandemic ( h1n1 ) the binaxnow s. pneumoniae urinary antigen test ( inverness medical diagnostics , princeton , nj , usa ) was performed and read as previously described ( 11 ) . criteria for diagnosis of s. pneumoniae infection required isolation of the microorganism from blood , isolation of the predominant organism from a qualified sputum sample ( 11 ) , or a positive urinary antigen test result . a total of 418 patients with an influenza - like illness were evaluated , of whom 179 were confirmed as having cases of pandemic ( h1n1 ) 2009 virus by rrt - pcr . of these , 99 ( 55.3% ) patients provided a urinary sample for pneumococcal antigen detection , 37 ( 20.7% ) a sputum sample , and 48 ( 26.8% ) blood cultures . there were no significant differences in demographic or clinical data among patients with or without a valid urinary sample for diagnostic testing , with the exception of pneumonia , which was more frequent among patients with an available sample ( 32.3% vs. 3.8% , p<0.001 ) . of 239 patients with rrt - pcr negative for influenza , pneumococcal infection was investigated in 171 , of whom 43 ( 25.1% ) had pneumococcal disease . of 100 patients who had influenza , a test available for pneumococcal detection , and no other bacterial pathogens identified , 14 had pneumococcal infection diagnosed ( 14% , 95% confidence interval 7.220.8 ; p = 0.03 , compared with patients without influenza ) . of these , 13 had a positive urinary antigen test result ; 8 ( 57.1% ) of the 14 had infection diagnosed only on the basis of this result . of the remaining 6 patients , s. pneumoniae was isolated from blood in 2 and in sputum from 4 . demographic characteristics did not differ between pneumococcal  co - infected and non  co - infected patients ( table ) . compared with patients with influenza infection only , those with pneumococcal co - infection more frequently had pneumonia ( p<0.001 ) , were more frequently admitted to hospital ( p<0.001 ) and to the intensive care unit ( p = 0.034 ) , had lower o2 saturation ( p = 0.006 ) and higher axillary temperature ( p = 0.009 ) , and more frequently had the following curb-65 score criteria : confusion ( p<0.001 ) , respiratory rate > 30 breaths / min ( p = 0.009 ) , and systolic blood pressure < 90 mm hg ( p = 0.03 ) ( table ) . curb-65 score was > 1 for 35.7% of patients with pneumococcal co - infection but only 3.5% of those with influenza infection only ( p<0.001 ) . levels of crp were significantly higher in patients with influenza plus pneumococcal disease ( 190.7 mg / l vs. 26.6 mg / l ; p < 0.001 ) . * all values are number ( % ) for categorical variables and median ( interquartile range ) for continuous variables . na , not applicable ; icu , intensive care unit ; curb-65 , confusion of new onset , urea greater than 7 mmol / l ( blood urea nitrogen [ bun ] > 19 ) , respiratory rate > 30 breaths / min , systolic blood pressure ( bp ) < 90 mm hg or diastolic blood pressure < 60 mm hg , age > 65 ( 10 ) . the  or fisher exact test was used for categorical variables and the mann - whitney test for continuous variables . asthma , chronic lung disease , heart disease , neurologic and neurodevelopmental conditions , blood disorders , endocrine disorders ( such as diabetes mellitus ) , kidney disorders , liver disorders , metabolic disorders , weakened immune system , people < 19 y of age who are receiving long - term aspirin therapy , people who are morbidly obese ( body mass index > 40 ) . measured in patients with signs of sepsis ; n values as shown . when only influenza cases with pneumonia were analyzed and those with pneumococcal co - infection ( n = 9 ) were compared with patients in whom only influenza was identified ( n = 15 ) , patients with pneumococcal co - infection more frequently had confusion ( p = 0.005 ) , a curb-65 score > 1 ( p = 0.007 ) , higher crp levels ( 255 mg / l vs. 89 mg / l , p = 0.008 ) , and a statistical trend to tachypnea > 30 ( p = 0.09 ) and to higher hospital admission ( p = 0.09 ) ( table ) . pneumococcal infection characteristics were also compared between patients with and without ( n = 43 ) pandemic ( h1n1 ) 2009 infection included in the study . confusion according to curb-65 criteria was more frequent among patients with both infections ( p = 0.003 ) , while other clinical data did not differ between groups . we found that the prevalence of concurrent pneumococcal infection was 14% in patients who had pandemic ( h1n1 ) 2009 virus infection with any risk factor for influenza - related complications or who met severity criteria . of note , infection more than half these patients would not have been diagnosed if a pneumococcal urinary antigen test had not been performed . we evaluated the frequency of pneumococcal disease in patients with the pandemic ( h1n1 ) 2009 virus through a systematic investigation by using validated diagnostic methods . although a recent study identified a high frequency of s. pneumoniae and haemophilus influenzae in nasopharyngeal swabs from patients with influenza a ( h1n1 ) tested by using molecular techniques ( 12 ) , their clinical significance and positive predictive value remain undetermined . moreover , the systematic calculation of the curb-65 score provided us a simple , objective , and useful tool for categorization of severity and comparison between patients . although the prevalence of pneumococcal infection in patients with influenza might have been overestimated by more frequent urinary sampling among those with pneumonia , we found that more than one third of the patients had nonpneumonic pneumococcal infections . compared with patients with influenza only , pneumococcal co - infected patients showed a higher severity of disease as defined by a higher frequency of curb-65 criteria , lower o2 saturation , and more frequent admission to the intensive care unit . furthermore , a curb-65 score > 1 was found to be a predictive factor of pneumococcal co - infection . although many co - infected patients also had pneumonia , a fact which might have explained the above - mentioned findings , the same predictive factors distinguished between influenza pneumonia and influenza plus pneumococcal pneumonia . this prevalence could be explained because , presumably , many of the noninfluenza patients met the influenza - like illness definition due to bacterial infection . however , it is unknown whether some of the influenza - attributable pneumococcal infection might have been underestimated , because s. pneumoniae might follow influenza after a lag period , and a delay in the request for medical attention might diminish the sensitivity of diagnostic tests for influenza . nonetheless , data from treated patients have shown a median duration of viral shedding of 5 to 9 days and slower viral clearance with delayed antiviral drug administration ( 13 ) . in summary , the prevalence of pneumococcal co - infection during the influenza a ( h1n1 ) 2009 pandemic was noteworthy , and it was associated with a higher severity of disease . in one third of the cases the clinical signs and symptoms did not indicate pneumonia , and more than one half could only be diagnosed with the urinary antigen test . a curb-65 score > 1 and crp levels proved to be useful tools to identify patients at higher risk for pneumococcal co - infection for whom physicians should adopt additional diagnostic and therapeutic measures .
we conducted a systematic investigation of pneumococcal co - infection in patients with a diagnosis of pandemic ( h1n1 ) 2009 and any risk factor for complications or with severity criteria . 
 we found 14% prevalence , with one third of patients having nonpneumonic infections . 
 a severity assessment score > 1 and high c - reactive protein levels were predictors of pneumococcal co - infection .