Etiology of central nervous system infections in the Philippines and the role of serum C-reactive protein in excluding acute bacterial meningitis

Objectives: The value of measurements of serum C-reactive protein (CRP) in differentiating central nervous system (CNS) infections of varying etiologies in the Philippines was investigated.Methods: A wide array of bacteriologic and virologic methods as well as computed tomography, typical clinical presentation, and autopsy were used for etiologic diagnosis.Results: Among 103 patients with CNS infection, etiology was identified in 60 (58%) cases. Bacteria were found in 19 (including 7 Streptococcus pneumoniae, 5 Haemophilus influenzae, 3 Neisseria meningitidis), tuberculosis in 4, viruses in 38 (including 20 coxsackievirus, 8 measles, 4 adenovirus, and 4 poliovirus infections), and brain abscess in 3 patients. C-reactive protein was elevated on admission in all 18 cases of bacterial meningitis tested, exceeding 50 mg/L in 17 (94%), and was not affected by prior antibacterial treatment. The mean CRP was significantly higher in the bacterial group than in the viral group (207 ± 111 mg/L vs. 39 ± 34 mg/L; P < 0.001). In the viral group one third had CRP above 50 mg/L. In patients with tuberculous meningitis, brain abscess, or cryptococcal meningitis, CRP was moderately to highly elevated.Conclusions: In the presence of a normal CRP concentration (below 10 mg/mL) acute bacterial meningitis is excluded even in a developing country setting and antimicrobial therapy is not warranted.     

Nosocomial bacterial meningitis, including central nervous system shunt infections.

Nosocomial bacterial meningitis and CSF shunt infections result in considerable morbidity and mortality, necessitating an organized and thoughtful approach to prevention, diagnosis, and management. Prophylactic antibiotics appear to reduce the rate of postcraniotomy meningitis often caused by S. aureus. On the other hand, prophylactic antibiotics do not appear to reduce the risk of developing a CSF shunt infection. CSF shunt infections usually require shunt removal and antimicrobial chemotherapy to effect a successful outcome.     

Creatine kinase in the serum of patients with acute infections of the central nervous system

Serum creatine kinase was assessed in 94 consecutive patients without convulsions admitted to hospital due to suspicion of infection of the central nervous system. No reliable discrimination between patients with aseptic and those with bacterial meningitis was obtained. Patients with bacterial meningitis and brain oedema, as well as patients with encephalitis, had significantly higher values (P less than 0.01) than patients with meningism, aseptic meningitis and bacterial meningitis without cerebral oedema. Very high values, above 2500 U/1, were encountered in only the most severe cases of bacterial meningitis. The highest serum CK value found in patients with encephalitis was 725 U/l. Reference values for control patients with meningism were 16-269 U/1. In a subset of 9 patients creatine kinase isoenzyme analysis was performed. In all cases only muscle type (MM) isoenzyme was found.     

The use of C-reactive protein from cerebrospinal fluid for differentiating meningitis from other central nervous system diseases

C-reactive protein (C-RP) determinations were performed by using the latex slide agglutination test on cerebrospinal fluid (CSF) from 235 patients. The patients were categorized into the following groups: bacterial meningitis (n = 74); viral meningitis (n = 10); fever without bacterial meningitis (n = 80); neurological symptoms without infection (n = 25); intracranial hemorrhage (n = 10); increased intracranial pressure that was secondary to pseudotumor cerebri or hydrocephalus (n = 16); and malignancies (n = 20). On the initial lumbar puncture, the C-RP was positive in 97% (72 of 74) of the patients in group 1, as compared with 0% (0 of 10), 6% (5 of 80), 20% (5 of 25), 50% (5 of 10), 6% (1 of 16), and 30% (6 of 20) in groups 2-7, respectively (P less than .0001). The C-RP test was able to detect bacterial meningitis with a sensitivity of 97% (72 of 74), a specificity of 86% (139 of 161), a positive predictive value of 77% (72 of 94), and a negative predictive value of 99% (139 of 141). These data indicate that C-RP determinations performed on CSF are useful and rapid clinical tests for the exclusion of the presence of bacterial meningitis in a patient.     

Laboratory diagnosis of central nervous system infections.

The laboratory diagnosis of CNS infection is essential for optimal therapy. Acute infection requires rapid turn-around testing with high predictive values, that is, the ability of a test to accurately identify those patients who do or do not have disease caused by a specific etiology. The Gram's stain, fungal stains of direct smears, antigen testing for C. neoformans, and culture of bacteria, fungi, mycobacteria, and some viruses are important tests for the diagnosis of acute infection. The laboratory diagnosis of chronic infection necessitates discussion between the clinician and laboratory technician to allow triaging of testing. Antigen tests for bacteria, fungi, and viruses; antibody tests for multiple microorganisms; and PCR testing for bacteria, M. tuberculosis, and many viruses are all important in limited clinical situations. All testing for acute or chronic disease depends on sufficient specimen that is transported to the laboratory in a manner that will not compromise viability or chemical integrity. Sterile containers that maintain moisture content, exclude oxygen for anaerobic requests, and are stored at proper temperatures (22 degrees C room, 4 degrees C refrigeration, or -20 degrees C freezer depending on pathogen and test) are mandatory. Many laboratory issues addressing the diagnosis of CNS infection are changing or evolving. Most important is the recognition that bacterial antigen testing for the diagnosis of acute bacterial meningitis rarely impacts patient management and is not routinely needed, CSF shunt infections differ from usual meningeal infections and require rapid diagnosis, and TB meningitis remains a difficult disease to diagnosis but may be confirmed first by PCR testing of CSF. In addition, Whipple's disease of the CNS can be confirmed using PCR with CSF; CJD has a marker protein, referred to as 14-3-3 antigen, that can be detected in CSF, and the diagnosis of fungal CNS disease requires careful interpretation of direct smears, antigen and antibody testing, and culture. Most difficult to diagnose among the CNS infections are viral meningitis and encephalitis. The appearance of new etiologies, such as West Nile virus, and the common use of PCR for the herpes viruses and enteroviruses represent important advances. Evolving methods for the laboratory diagnosis of CNS infection represent significant improvements over previous testing; however, the array of tests available demands more attention for appropriate selection, is significantly more expensive, and requires new skills for performance and interpretation. The responsibility for proper use of laboratory testing lies both with the clinician and laboratory technician.     

Herpesvirus infections of the central nervous system

In recent years, advances in the diagnosis and treatment of herpes simplex encephalitis (HSE) have been achieved due to the prevalence of antiviral drugs and the introduction of the polymerase chain reaction (PCR) to test the cerebrospinal fluid. The several clinical forms of herpes simplex virus type 1 (HSV-1) infections of the central nervous system (CNS), including acute disseminated encephalomyelitis and brainstem encephalitis, have been clarified. However, fatal, prolonged, or relapsed cases are still observed, and early detection and appropriate treatment is necessary to lead to a good prognosis for these intractable HSE cases. In adult HSV-2 infections, meningitis and myelitis associated with genital herpes are common. In the past, HSV-2 myelitis has been reported as a form of fatal necrotizing myelopathy; however, using PCR and magnetic resonance imaging studies, mild surviving cases are increasingly likely to be identified. Meanwhile, various CNS syndromes resulting from the herpes group viruses, including varicella-zoster virus and Epstein-Barr virus have also been reported. These herpesviruses have several characteristics in common, e.g., they exist in the latent state and they occur in both mucocutaneous and CNS infections. Adult HSV-1 and -2 infections of the CNS are discussed together with other herpes group virus infections of the CNS.     

Invasive bacterial infections of children in a rural province in the central Philippines

The etiology of invasive bacterial infections was studied among 956 Filipino children less than five years old who fulfilled the World Health Organization criteria for severe or very severe pneumonia or had suspected meningitis or sepsis. The most common invasive infections were due to Streptococcus pneumoniae (12 [1.3%]) and Haemophilus influenzae (12 [1.3%]); including four cases of pneumococcal meningitis and 11 cases of H. influenzae meningitis. Type 1 was the most common (six of the 12 isolates) of the pneumococcal serotypes. Serotypes/groups 1, 6, 14, and 23 accounted for 91.7% of the invasive isolates. The majority of the H. influenzae strains from blood (10 out of 10) and cerebrospinal fluid (6 out of 7) were type b. Almost all of the invasive S. pneumoniae (9 out of 12) and H. influenzae (11 out of 12) infections were seen before one year of age, which stresses the need to investigate early immunization of children for H. influenzae type b and S. pneumoniae, as well as maternal immunization to maximize the potential of immunoprophylaxis.     

C-reactive protein and serum amyloid A protein in neonatal infections

In this study, we examine C-reactive protein (CRP) and serum amyloid protein A (SAA). Although the former is the best known and most commonly used indicator of inflammation, certain considerations underline the inadequacy of CRP determination alone for the early diagnosis of infection. In fact symptoms often precede the CRP elevation. SAA protein comprises a family of polymorphic apolipoproteins produced mainly by the liver, and several studies have stressed its importance in the diagnosis and monitoring of various diseases. Pathological SAA values are often detected in association with normal CRP concentrations. SAA rises earlier and more sharply than CRP. Finally, contrary to CRP, SAA presents the same trend in viral as well as bacterial infections. Although the data available on SAA in neonates are currently very limited, it is possible to postulate a role of primary importance for SAA in the management of neonatal infections.     

The role of serum C-reactive protein in acute ischemicreperfusion injury of kidney

ObjectiveBlocking early C-reactive protein-mediated inflammatory reaction may have therapeutic implications in improving the prognosis of acute renal failure with severe ischemic-reperfusion injury. Therefore, the role of serum C-reactive protein in acute renal ischemic-reperfusion injury was investigated.MethodsFourteen New Zealand albino rabbits were selected and divided into a treated and a control group at random. An acute renal ischemia-reperfusion injury model was induced by clamping the right renal artery for 45 minutes with simultaneous contralateral nephrectomy, followed by right renal reperfusion. The treated group was injected with dexamethasone (1 mg/kg) 2 minutes before renal reperfusion. Serum C-reactive protein, blood urea nitrogen, creatinine, and urine volume were recorded at designed time phases in both groups. Data were expressed as mean ± standard deviation and analyzed using the Student's t test.ResultsIn the control group, there was a steady increase of serum C-reactive protein that reached its peak at 6-hour reperfusion, and a positive correlation between C-reactive protein and blood urea nitrogen and creatinine (r = 0.62 and 0.53, respectively); there was a negative correlation between C-reactive protein and urine volume (r = −0.52). Compared with the control group, C-reactive protein values in the treated group remained mainly in the baseline levels after reperfusion, with C-reactive protein peaking at 4-hour reperfusion (p<0.01), whereas urine volume increased significantly (p<0.01).ConclusionThis study indicates that C-reactive protein is involved in the pathogenesis of acute renal ischemic-reperfusion injury; blocking early C-reactive protein-mediated inflammatory reaction may have therapeutic implications in improving the prognosis of acute renal failure with severe ischemic-reperfusion injury.     

Antibacterial agents in infections of the central nervous system

Experimental animal models have provided information applicable to antimicrobial therapy of infections of the central nervous system. The efficacy of an antimicrobial agent in the therapy of bacterial meningitis depends on its ability to penetrate the blood-brain barrier, its activity in purulent cerebrospinal fluid, and a demonstration of rapid bactericidal activity against the offending pathogen. The recent emergence of resistant pathogens is challenging the therapy for bacterial meningitis. Various strategies for treating resistant pathogens have been evaluated in experimental animal models. Encouraging results have led to clinical trials to evaluate the efficacy of newer agents, alone or in combination with standard regimens.     

Epstein-Barr virus infections of the central nervous system

OBJECTIVE: Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. PATIENTS AND METHODS: For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. RESULTS: Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. CONCLUSION: Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.     

Cerebrospinal fluid levels of IL-6 in patients with acute infections of the central nervous system.

Interleukin-6 (IL-6) activity was measured in the cerebrospinal fluid (CSF) of patients with acute bacterial or viral meningitis and in AIDS patients with various cerebral disorders. Increased levels of IL-6 were detected in the CSF of patients with bacterial meningitis. On the contrary, most of the samples from patients with viral meningitis (predominantly caused by mumps virus) had no detectable IL-6 activity in CSF. A moderate increase of IL-6 levels was detected in the CSF of AIDS patients with AIDS dementia complex (ADC), progressive multifocal leukoencephalopathy and cerebral toxoplasmosis. Moreover, higher levels of IL-6 were detected in the CSF of patients with cryptococcal meningitis. We conclude that the initial events of CSF inflammation in patients with acute viral meningitis are different from those in patients with acute bacterial meningitis, and the role of IL-6 is less critical to the process.     

小胶质细胞在病毒性中枢神经系统感染中的作用

小胶质细胞是中枢神经系统中的免疫细胞,是中枢神经系统抵抗病原体入侵的第一道防线。当病原微生物进入脑组织后,小胶质细胞迅速做出反应,识别、吞噬病原微生物,呈递抗原和分泌多种生物活性物质。但是,小胶质细胞的过度活化又可诱发中枢神经系统免疫病理损伤或神经退行性病变。因而,具有生理和病理双重作用。本文就小胶质细胞在病毒感染性中枢神经系统疾病中的作用及其机制进行综述。     

C-reactive protein levels in HIV complicated by opportunistic infections and infections with common bacterial pathogens.

In order to determine the pattern of C-reactive protein (CRP) concentrations in HIV-infected patients with various other infections, we conducted a prospective study (for the period 1990-91) of all HIV-seropositive patients hospitalized with fever and a retrospective study (for the period 1990-95) of all patients infected with Mycobacterium avium complex (MAC) and Pneumocystis carinii pneumonia (PCP). Samples from blood, cerebrospinal fluid and sites with clinical signs of infection were obtained for bacteriological culture. Polymerase chain reaction (PCR) determination was performed for cytomegalovirus in blood and CSF. Patients with opportunistic infections had a significantly lower increase in CRP concentration than patients infected with common bacterial pathogens. Patients with PCP and mycobacterial infections had a distinct CRP response after the onset of therapy. Lack of CRP increase at diagnosis of MAC infection was associated with a shorter survival and normalization of CRP after MAC therapy with a significantly longer survival.     

Cerebrospinal fluid levels of lysozyme, IgM and C-reactive protein in the identification of bacterial meningitis.

Lysozyme (LZM), immunoglobulin M (IgM) and C-reactive protein (CRP) levels were determined in cerebrospinal fluid (CSF) from patients classified on the basis of clinical and laboratory findings into three groups: bacterial meningitis (n = 33), lymphocytic meningitis (n = 21) and controls (n = 54). IgM and CRP levels were determined by enzyme-linked immunosorbent assay (ELISA) and LZM by the lysoplate method. Discriminant analysis demonstrated that 93.94% (31/33) and 96.97% (32/33) of patients with bacterial meningitis were correctly classified on the basis of CSF determinations of IgM and LZM, respectively. However, the measurement of CRP levels in CSF correctly classified 100% of these patients (33/33), thus representing a useful additional marker for the screening of bacterial meningitis. Moreover, no more than 4% (3/75) of patients were incorrectly classified as belonging to the bacterial group on the basis of the CRP test. Thus, CRP titres less than or equal to 80 identify cases belonging to one of the non-bacterial groups, whereas titres greater than or equal to 640 classify the bacterial group, with a very low chance of misclassification. The authors recommend that CSF IgM or LZM levels be also measured for patients with CSF CRP titres of 160 and 320, for a more accurate diagnosis. The probability of these cases being of bacterial aetiology, as calculated from the combined results of these measurements, is presented.