No single clinical feature or physical examination can reliably discriminate central nervous system (CNS) infections from other infectious diseases. Even among patients with bacterial meningitis, only about 44% of patients have all triad clinical features, namely fever, nuchal rigidity, and change in mental status [1]. In cases of aseptic meningitis, the clinical features are more indistinct than those in cases of bacterial meningitis, thus making aseptic meningitis much harder to differentially diagnose from other infectious diseases. Presently, cerebrospinal fluid (CSF) examination via lumbar puncture is the only diagnostic method available for diagnosing CNS infections.

Even though lumbar puncture is the standard procedure for diagnosing CNS infections, it is potentially an invasive procedure that may cause complications such as intramedullary hematoma, CSF leakage, headache exacerbation, and infections through the puncture site [2]. Not only can lumbar puncture result in complications but also may require procedural sedation if the patient is uncooperative. In addition, a lumbar puncture can be difficult or almost impossible if the patient has a narrow interspinal space. Moreover, a long postprocedural bed rest time means that the procedure should be performed only after careful consideration.

If a patient in the emergency department (ED) shows classical signs of CNS infection, such as nuchal rigidity or change in mental status, no room should be left for dissent in performing a prompt lumbar puncture. However, in mentally alert patients with complaints of acute-onset headache and fever without focal neurological deficits, physicians find it difficult to decide whether or not to perform a lumbar puncture.

When a neurologically intact patient complains of fever and headache, physicians usually carry out a thorough history taking and physical examination to infer the cause of the fever. If the cause of the fever (e.g., acute rhinitis, sinusitis, pharyngitis, laryngitis, pneumonia, cholecystitis or cholangitis, gastroenteritis, pyelonephritis, cellulitis, or tsutsugamushi) remains indeterminate after an initial history taking and physical examination, a lumbar puncture is usually considered to rule out the possibility of CNS infection. However, a considerable proportion of patients with fever and headache have negative results on CSF examination via lumbar puncture. This study aimed to identify blood test-related parameters that can aid in predicting CSF examination results among neurologically intact ED patients with complaints of acute-onset headache and fever.

A lumbar puncture was performed in 212 patients from October 2014 to September 2015 in our ED. Of these patients, 111 were excluded. Among the excluded patients, 16 had no evidence of fever, 44 had decreased or altered mental status (seizure 3, sedative drug overdose 3, metabolic encephalopathy 10, encephalitis 15, cerebral infarction 8, brain abscess 2, and unknown cause 3), 37 underwent CSF examination for purposes other than diagnosis of an acute CNS infection (demyelinating disease 17, myelitis 7, neuritis 4, hydrocephalus 3, brain syphilis 1, and metastatic malignant tumor 5), 5 had a hematologic disease, 1 had acquired immunodeficiency syndrome, and 8 had been transferred from another hospital to our hospital. Finally, 101 alert and oriented patients with fever and acute headache were included in this study. All the subjects underwent a lumbar puncture in the ED, of whom 45 had positive CSF test results (CSF pleocytosis) and 56 had negative results (no CSF pleocytosis) (Fig. 1).

In this study, we found that some of the initial ED blood tests among neurologically intact patients with fever and headache were significantly different between the negative and positive CSF examination result groups. Among the several hematologic parameters studied, only NLR and CRP level had an AUC of >0.7 in the ROC analysis. Although not sufficient as predictors, a NLR of ≥6 showed a diagnostic accuracy of 70.3% and a CRP level of ≥12.7 mg/L showed a diagnostic accuracy of 76.2% in predicting negative CSF examination results. These results suggest that some blood test parameters (NLR in WBCs and CRP level) might be able to help clinicians in their collaborative effort in pursuing the focus of fever. If blood test results show a NLR of ≥6 or a CRP level of ≥12.7 mg/L, clinicians may anticipate a negative CSF examination result and consider not only CNS infection but also other sources of fever.

Thirty-six (64%) of the 56 patients who had a negative CSF examination result after a lumbar puncture had a presumptive diagnosis on discharge from the ED or hospitalization. The most frequent presumptive diagnosis was gastrointestinal infection, followed by respiratory and urogenital infections. These patients, even though their fever was not from a CNS infection, only had fever and headache without any other prominent symptoms such as diarrhea, vomiting, sputum, or dysuria, probably making it difficult to decipher the cause of the fever initially. If an alert patient with fever and headache has no positive physical signs of CNS infection and blood test results show a NLR of ≥6 or CRP level of ≥12.7 mg/L, not only CNS infection but also other causes of fever should be considered. For such patients, it would be advisable to repeat a thorough medical history taking and physical examination for gastrointestinal infections, and to consider other tests such as chest or sinus radiography, urinalysis, and chest or abdominal computed tomography while judiciously considering a lumbar puncture.

Neutrophils are important cells in the immune defense system that control mast cells, epithelial cells, and macrophages, and play a major role in the inflammatory response. Changes in NLR have been reported in bacterial or viral infections, or inflammatory responses and have been helpful in the early diagnosis of various diseases [7-11]. Various cutoff NLRs have been proposed for the diagnosis of acute infection or inflammation. In this study, the proportion of neutrophils in WBCs and the NLR were significantly higher in the patients with negative CSF examination results than in those with CSF pleocytosis. According to the ROC analysis, the proportion of neutrophils in WBCs and NLR demonstrated AUC of 0.65 and 0.70, respectively. Although not sufficient as a predictor, NLR may help clinicians anticipate negative CSF examination results and investigate sources of fever other than CNS infection.

Serum CRP level remarkably differed between the two groups, being significantly higher in the negative than in the positive CSF examination group. The best cutoff CRP level was 12.7 mg/L, and CRP levels of ≥12.7 mg/L had an AUC of 0.77, with 71.4% sensitivity and 82.2% specificity in predicting negative CSF examination results. CRP levels of ≥44.5 mg/L had 91.1% specificity, and CRP levels of ≥147.2 mg/L had 100% specificity. Not a single alert patient with CRP levels higher than 147.2 mg/L had CSF pleocytosis. If an alert patient with fever and headache has a high CRP level, causes of infection other than CNS should also be suspected and investigated, even in neurologically intact patients.

In respiratory viral infections such as influenza, most of the patients have relative lymphocytopenia and monocytosis [12-16], and a LMR of <2 has been suggested as a reliable screening method instead of the rapid antigen test for the diagnosis of influenza [12,17]. Considering our study results and other previous research findings, we identified interesting facts about the lymphocyte and monocyte ratio in WBCs. Considering the fact that the final diagnosis of most patients with a positive CSF examination result was aseptic meningitis (40/45, 89%), in case of CNS viral infection, the proportion of lymphocytes in WBCs seems to increase and therefore result in an increased LMR. However, in cases of respiratory viral infections, the proportion of monocytes in WBCs increased and therefore resulted in a LMR of <2. We do not understand why no monocytosis was found in the CNS viral infections unlike in the respiratory viral infections, and it is beyond the scope of this study to delineate its immunologic mechanism.

The typical symptoms of CNS infections (headache, decreased or altered mental status, fever, photophobia, and nausea) are not pathognomonic symptoms that occur only in CNS infections [18,19]. In addition, according to the study by Nakao et al. [20], the Jolt accentuation test has a sensitivity of 21% and specificity of 82%, the Kernig test has a sensitivity of 2% and specificity of 97%, the Brudzinski sign has a sensitivity of 2% and specificity of 98%, and the nuchal rigidity has a sensitivity of 13% and specificity of 80% to detect CSF pleocytosis. When the authors performed a statistical analysis to test the ability of the hematologic parameters in predicting positive CSF examination results, none of the parameters had an AUC of >0.7 in the ROC analysis. However, the proportion of lymphocytes in WBCs of >14.3% had an accuracy of 70.3% (sensitivity 68.9%, specificity 71.4%, PPV 66.0%, NPV 74.1%, and AUC 0.69), and a LMR of >1.7 had an accuracy of 70.3% (sensitivity 84.4%, specificity 51.8%, PPV 58.5%, NPV 80.6%, and AUC 0.63) in predicting a positive CSF examination result. These results suggest that the proportion of lymphocytes in WBCs and LMR are not sufficient but are more reliable than clinical symptoms or physical examination in predicting the possibility of CSF infection. However, as no symptom or physical examination or blood test has sufficient sensitivity and NPV to predict a CNS infection [20], a CSF examination is always necessary whenever a clinician cannot exclude the possibility of a CNS infection.

Our study has several limitations. First, because we selected our patients through a retrospective review of the medical records for alert patients with fever and headache, an unintended selection bias might have existed. Second, sometimes physical examination was not performed or documented in the medical record, and we could not rely on the physical examinations performed by different physicians. Thus, we had to exclude physical examinations for CNS infections in this study. Third, in 36% of patients who had a fever, headache, and negative CSF examination result, we were not able to either presume or confirm a diagnosis, which meant that we were not able to fully analyze the negative CSF test group. Lastly, the actual infectious agents were not identified in the positive CSF examination group.

Among the neurologically intact adult patients who underwent a CSF examination on suspicion of CNS infection, those with negative CSF examination results had a significantly higher proportion of neutrophils in WBCs, lower proportion of lymphocytes in WBCs, higher NLR, lower LMR, and higher CRP level than the positive group. If this subset of patients has a NLR of ≥6 or CRP level of ≥12.7 mg/L in their blood test, not only CNS infection but also other sources of fever should be considered and investigated.