CSF Cortisol in Meningitis

Motivation: This year, I have seen two patients with community acquired meningitis - both had viral meningitis.   When we stopped antibiotics on both, I had slight trepidation about what if we were wrong.  After all, microbiologic data on CSF can be misleading.  For example, in about 10% of patients, bacterial meningitis can present with lymphocytic predominance.  Low plasma glucose is present in only 50-60% of patients with bacterial meningitis.  Recently, I came across this article evaluating CSF cortisol as a specific marker of acute bacterial meningitis.

Paper:  Holub, M., Beran, O., Dzupova, O., et. al. "Cortisol levels in cerebrospinal fluid correlate with severity and bacterial origin of meningitis." Critical Care (2007) 11:R41

Methods: Study conducted in an academic hospital in Prague.  Inclusion criteria were symptoms of menigitis (fever, headache, meningismus) for less than 72 hours and lumbar puncture performed on admission prior to administration of steroids as part of meningitis treatment.  Bacterial meningitis was diagnosed by positive bacterial CSF culture or detection of bacterial DNA in CSF using PCR.  These patients were compared retrospectively to data from 37 patients with asceptic meningitis as well as data from CSF of 13 control patients who had received LP as part of headache workup.

Results:
Cohort: In total, 47 patients were diagnosed with bacterial meningitis (mean age of 42) with mean APACHE II score of 12.3.  At day 28, there was 15% mortality.  For the asceptic meningitis group, 37 patients were included with mean age of 38 and average APACHE II score of 3.  There were no deaths at 28 days. 

CSF Cortisol: Mean CSF cortisol level was 8.45 ug/dL (interquartile range: 2.14-10.08 ug/dL) in patients with bacterial meningitis compared to mean CSF cortisol level of 0.62 ug/dL (interquartile range: 0.47-1.02 ug/dL), p = 0.001.  Control patients had mean CSF cortisol level of 0.36 ug/dL (interquartile range: 0.29 - 0.44 ug/dL). 

Correlation: CSF cortisol level correlated with APACHE II score - a measure of severity of sickness ( r = 0.763, p < 0.001).  CSF cortisol also correlated with serum cortisol (r = 0.587, p < 0.001). 

Sensitivity/Specificity: After analyzing receptor operating curves, the best sensitivity/specificity for discriminating bacterial and asceptic meningitis are obtained by setting a threshold of 1.67 ug/dL, which resulted in sensitivity of 82% and specificity of 100%.  When comparing bacterial meningitis and control patients, a threshold value of 0.47 ug/dL results in sensitivity and specificity of 100%. 

Discussion: This paper adds cortisol to one of the panel of factors in CSF chemistry that can aid in discriminating bacterial and asceptic meningitis.  While neutrophilia has higher sensitivity than cortisol, the cortisol level is more sensitive than CSF glucose in detecting bacterial meningitis.  Perhaps, more importantly, the very high specificity makes elevated cortisol a very strong indicator of bacterial meningitis.  The etiology of elevated CSF cortisol appears to be directly related to the overall systemic inflammatory insult in bacterial infection (elevated APACHE II score and serum cortisol).  While this study is a good start, some of the weakness of the design itself are the retrospective nature and generally different clinical condition of bacterial and asceptic meningitis patients (vastly different APACHE scores and 28 day mortality).  If patients are very sick with viral meningitis, do they also have non-specific cortisol elevation?  This paper does not address and was not powered to evaluate this comparable subgroup of patients.  Nonetheless, next time, I do a lumbar puncture to evaluate for meningitis, I will add on a CSF cortisol.

Garlic for Hepatopulmonary Syndrome

Motivation: At some unfortunate moments, you see a person struggling to breathe, and there is not much you can do - even with a tank of oxygen.  Hepatopulmonary syndrome (HPS) falls into this category.  Short of a liver transplant, no effective medical therapies exist.  Multiple vasoconstrictive agents such as somatostatin analogues have been tried without success.  After meeting yet another patient with hepatopulmonary syndrome, I was searching for something out of the ordinary when I came across this paper testing the efficacy of garlic (Allium sativum).  Seems like it might work.

Paper: De, B.K., Dutta, D., Pal, S.K. et. al.  "The role of garlic in hepatopulmonary syndrome: A randomized controlled trial."  Can. J. Gastroenterol.  (2010), 24: 183-88.

Methods: Randomized controlled trial in a single center (Calcutta Medical College in Kolkata, India).  Patients were screened for enrollment if they had portal hypertension.  From this cohort, patients were screened for presence of intrapulmonary vascular dilation with elevated A-a gradient.  Exclusion criteria included intrinsic cardiopulmonary disease, massive ascites, sepsis, or other severe comorbid condions.  The selected patients  were randomized to placebo or garlic (at a dose between 1 to 2 g/m2/day based on multiples of 250 mg pills, mean dose 1.55 g/day).  Follow-up was 9-18 months.  Treatment of primary disease was continued during the trial (antivirals for HBV and HCV and abstinence from alcohol).

Results:
Cohort: Overall, 42 patients were randomized, and 21 patients received either garlic or placebo.  In followup, one patient in the placebo group was lost and not analyzed.  The mean age of the cohort was about 40 years of age, and majority had alcoholic liver disease followed by chronic Hepatitis B.  Majority (at least 85% in both groups) had clubbing on physical exam.  Mean PaO2 was 66 in the garlic group and 64 in the placebo group.  Mean MELD score was about 15 in both groups.

Efficacy:  After nine-months of follow-up, the mean arterial oxygen was higher in the garlic group compared to placebo (83.05 versus 68.75 mmHg, p<0.001).  The mean A-a gradient was lower in the garlic group compared to placebo (21.35 vs. 29.11 mmHg, p<0.001).  In the garlic group, there was a 24.7% increase in arterial oxygen levels compared to baseline (83.05 versus 66.62 mmHg, p<0.001).  Interestingly, in the placebo group, there was also a 7.37% increase in the A-a gradient (68.75 vs. 64.05 mmHg, p = 0.02).

Mortality:  In the garlic group, two patients died on follow-up (GI bleed and sepsis).  In the placebo group, there were seven deaths (mostly sepsis followed by GI bleed).  The mortality, while higher in placebo, did not reach significance (p = 0.052).

Adverse Effects: While no data were presented, authors mentioned that no complications occurred except for "occasional bad breath."

Discussion: This small single center randomized trial suggests that garlic may be efficacious in treating hepatopulmonary syndrome.  For a complex mixture like garlic, it is unclear how it acts, but garlic has been speculated to change vascular tone (particularly by NO signaling).  Since the patients continued to be treated for primary disease (such as by abstinence from alcohol or by antivirals for HBV or HCV), garlic may alternatively act by potentiating therapy for the primary conditions rather than by treating HPS.  In fact, even in the placebo group, the mean PaO2 increased over nine month follow-up indicating that patients getting effective treatment for primary liver condition also had mild subsequent improvement.  Given the surprising findings in this small trial (and some smaller previous trials), I was surprised that there has not been a larger trial yet.  Part of the difficulty likely lies in the fact that garlic is natural, cheap, and hence unlikely to generate large revenue for a drug manufacturer.  Still, a larger trial is very much needed since this current trial suffers from being small, single-center, and likely unblinded to the investigators.  For the next patient I meet with HPS, I will think about suggesting garlic!

Serial ANCA for Wegener

Motivation: Any time a  patient with Wegener's vasculitis (granulomatosis with polyangiitis) is admitted, the same question pops up on rounds.  Should an ANCA level be sent?  And, how does disease activity change with ANCA?  This question is a controversial one, and even briefly asking around, strong feelings abound about this topic among rheumatologists.  In 2007, one of the largest studies to examine this question was published.

Paper: Finkielman, J.D., Merkel, P.A., Schroeder, D., et. al. "Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis." Ann. Intern. Med. (2007), 147: 611-619.

Methods: This paper analyzes data from WGET trial, which was a radomized trial evaluating etanercept for maintenance of remission.  Patients who tested positive for antibodies against myeloperoxidase (p-ANCA) were excluded from further analysis both because of small number of patients and because of difference in disease course/phenotype in patients with p-ANCA Wegener's.  In this trial, quantitative measurement of anti-Proteinase 3 (anti-PR3) titers was used.  Serum samples were collected every 3 months.

Results:
Cohort: From the WGET trial, the paper analysed data from 156 patients with median age of 51 and median follow-up of 34 months.  The majority had history of disease activity in ear, nose, and throat (79%), kidneys (54%), and lungs (59%).  At baseline, 85.8% of the cohort had positive ANCA with antibodies against Proteinase 3.  Among the 156 patients, 76 received etanercept while 80 received placebo.

ANCA and Disease Severity: When evaluated across patients in cross-section, there was no statistically significant association between ANCA level titers (anti-PR3) and disease severity (measured by the Birmingham Vasculitis Activity Score), p = 0.07.  When measured longitudinally within the same patients, changes in ANCA levels explained less than 10% for variability in disease activity.

ANCA and Remission/Relapse:  In patients who were positive for ANCA at baseline, after adjusting for age, sex, disease severity, and treatment group, decrease in ANCA levels did not correlate with shorter time to remission (hazard ratio, 1.6 (0.97-2.49)).  Among patients who experienced relapse after remission (54 patients), increase in ANCA levels did not correlate with risk of relapse, adjusted hazard ratio of 1.0 (CI, 0.5-1.9).

Discussion:  Serial ANCA testing is unlikely to be helpful in predicting disease flare/remission or explaining disease activity.  Although ANCA titers taken longitudinally weakly correlated with disease activity, variance in ANCA levels explained less than 10% of disease activity hardly making it the first test to follow for diagnostic or prognostic purposes.  Also, while following patients, if ANCA turns positive, disease activity does not necessarily follow and may not require pre-emptive treatment.  Interestingly, decrease in ANCA was almost statistically significant in predicting shorter time to remission (CI: 0.97-2.49).  While this study may have been underpowered and may be hinting at a significant finding, the association is not strong enough to be visible even with a cohort above 100 patients making it likely a weak correlation.  In summary, while majority of patients with Wegener's have positive PR3 antibody or c-ANCA (about 85% in this group), serial follow-up of ANCA levels after diagnosis is unlikely to be helpful.