Procalcitonin: Nice to Know, Need to know, or Needs Further Research?

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Further Research?

J.-U. Jensen, J. Løken, and T. Mohr, on behalf of the Procalcitonin and Survival Study (PASS) Group (see Appendix)

Introduction

Sepsis remains a major cause of death in critically ill patients admitted to the intensive care unit (ICU) [1 – 2]. Infections increase the all-cause mortality during ICU admission from 12.1 % in non-infected patients to 43.9 % in infected patients [3].

Timely and effective antimicrobial treatment has crucial importance for prognosis.

Delayed correct antimicrobial treatment substantially increases mortality [4]. The Surviving Sepsis Campaign has optimized multifactorial sepsis treatment in an evidence-based manner, to the benefit of critically ill patients with sepsis [5].

In order to prevent complications from sepsis, we need to optimize the diagnostics of sepsis at a microbiological level as well as monitoring source control and the effects of antimicrobial chemotherapy.

For the majority of infectious conditions, the present microbiological laboratory does not offer sufficient sensitive and timely diagnostics in a sepsis setting (culture from possible foci). Comparing sepsis to a fast car with bad brakes on a mountain road, this can be compared to “looking out of the rear-window” to control the car – not a very comforting analogy.

Can Classical Methods of Diagnosing and Monitoring Infections be Used in the ICU?

Obviously, in an ICU setting, symptoms are seldom of any value. Classical signs of sepsis observed by the intensive care physician can often be blurred by the inflammatory response and the given treatment, e.g., temperature and dialysis treatment.

Specific bacterial infections, often linked to ICU-settings, such as ventilator associ- ated pneumonia (VAP), may be hard to interpret in terms of culture growth, radiol- ogy, and clinical findings.

Established inflammatory markers, like C-reactive protein (CRP) and leukocytes, suffer from several drawbacks, including rather slow kinetics in terms of both increase and decrease, and a far from perfect sensitivity and specificity for sepsis.

Regarding CRP, we know that nearly all conditions meriting ICU admission increase CRP to pathologic levels. Regarding leukocytes, we know that corticosteroid treatment increases the leukocyte count.

For the reasons listed above, there is a need for a better assessment of sepsis in the ICU. Procalcitonin (PCT) is a promising sepsis marker, which has been proposed as an aid for detecting and assessing bacterial infections. In this chapter, we will try to answer the following questions:

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1. What is the nature of the PCT molecule, and in which physiologic and patho- physiologic context should it be placed?

2. Which are the main (claimed) advantages of PCT compared to the already established methods of bacterial infection diagnosis and monitoring in the ICU?

3. How should we use PCT in the ICU? What quantity and frequency of measurements? And how do we interpret PCT levels?

4. Should PCT be implemented in all/any ICUs using the present evidence?

5. How should we expand our evidence base for the use (or non-use) of PCT in the ICU?

What is Procalcitonin?

Production of Calcitonin Precursors in Thyroid Tissue

PCT (' 12.6 kDa) is a 114 amino acid polypeptide prohormone of the calcium homeostasis hormone, calcitonin [6]. Calcitonin is produced in the neuro-endocrine medullary C-cells of the thyroid gland, which embryologically derive from the neu- ral crest. The initial investigational move, regarding calcitonin precursors, including PCT, was made when it was demonstrated that medullary thyroid cancer derives from the C-cells [7]. PCT produced in the C-cells undergoes posttranslational process- ing, leading to release of the mature, bioactive calcitonin hormone of 32 amino acids.

A study using a non-selective calcitonin assay, showed increased levels of immuno- reactive calcitonin in staphylococcal toxic shock syndrome. Gel-filtration studies showed a large molecule, now known to be approximately the size of PCT [8, 9].

Production of Calcitonin Precursors in Extra-thyroid Tissue

In animal studies, PCT and other precursors of calcitonin have been isolated in the following tissues: Adrenal, spleen, spinal cord, brain, liver, pancreas, colon, lung, fat tissue, testes, and stomach. In bacterial sepsis, the mRNA of the calcitonin (CALC)-1 gene is upregulated more uniformly than the mRNA of other inflammatory cytokines, such as tumor necrosis factor (TNF)-[ , interleukin (IL)-1 q and IL-6 [10].

The level of mature calcitonin does not increase significantly during sepsis. The explanation for this has been proposed as a ‘shift of pathway’, from a ‘specific pathway’ (where calcitonin precursors are released in secretory granules with enzyme activity to process the precursors to mature calcitonin hormone) to a more ‘general- ized pathway’ (where calcitonin precursors are ‘bulk released’ without secretory granules and thus without enzymatic activity to process peptides). Heat shock proteins (HSPs) may also bind to mature calcitonin under septic conditions, which may change the disposal of the mature calcitonin and/or augment the possibilities of detecting it immunologically [8].

Other calcitonin precursors are also upregulated under septic conditions; of these the mid-region, pro-adrenomedullin, seems to be a promising severity marker in sepsis [11].

Physiologic Role of Procalcitonin

Currently, the physiologic actions of PCT are not well understood at a molecular level, although some researchers claim an effect on intracellular cAMP production [12]. Monneret et al. [13] have shown that PCT modulates regulation of integrin CD

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Fig. 1. Daily increases and decreases in PCT after reaching a level of 1.0 ng/ml. Lines are medians, boxes show 25 %- and 75 % quartiles, and whiskers show 95 % CI. Increases are generally higher than decreases.

See text for discussion.

11b, and Wiedermann et al. have shown that PCT can modify chemotaxis in monocytes [14].

Interestingly, in light of the latest knowledge on the microcirculation, septic shock, and the growing understanding of the role of nitric oxide (NO) in these pro- cesses, the levels of NO increase and the expression of the NO synthase (NOS) gene is amplified when PCT is added to smooth muscle cells of rats, pre-treated with lipopolysaccharide (LPS), TNF-[ , and interferon (IFN) * [15].

Procalcitonin Toxicity and Potentials for Specific Therapy

In healthy hamsters, injection of PCT did not produce any adverse effects, and did not result in increased levels of TNF-[ or IL-1 q . However, when TNF- [ was injected into healthy animals, PCT levels increased many-fold [16]. PCT injection in septic hamsters increased mortality compared to septic hamsters that did not receive PCT injections [17]. Additionally, administration of PCT specific IgG to septic pigs resulted in an improved survival rate [18]. These findings indicate that PCT may itself have a toxic effect, and that immunoneutralization may prove to be a beneficial treatment for humans.

Increases In Procalcitonin Levels Compared to Speed of Elimination: Can we Count on Decreasing Procalcitonin Levels when Bacterial Infection is under Control?

Jensen et al. found that the rate of increase of PCT, when bacterial infection was not yet controlled, was generally much higher than the rate of elimination when infection was under control [19] (see Fig. 1). This is an important feature of PCT: If elimination matched production, we could risk seeing a decreasing level of PCT, when bacterial infection was still not under control.

Procalcitonin Elimination, Kidney Failure and Dialysis

A frequent and therapeutically challenging complication of sepsis is acute oliguric renal failure. This fact raises the question of how PCT is eliminated and, if it is par- tially or totally eliminated by the kidneys, how would this affect the use and inter- pretation of PCT in sepsis patients with acute renal failure?

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Is Procalcitonin Eliminated by the Kidney, and How is the Rate of Elimination Affected by Renal Dysfunction?

The elimination of PCT is presently not completely understood. Some degree of pro- teolysis is expected as with other plasma peptides/proteins. Additionally, some renal clearance has been claimed, primarily from the fact that the serum half-life of PCT seems to be increased in patients with renal failure [20]. In this study [20], PCT elimination was measured in 67 patients with a) normal creatinine clearance, b) moderately impaired creatinine clearance, and c) severely impaired creatinine clearance. The plasma half-life of PCT in the three groups was reported as a median of 30.0 hours (a), 35.4 hours (b), and 44.7 hours (c). These findings indicate that, although PCT elimination is probably in part renal, even patients with severe renal impairment eliminate PCT at a substantial rate. This suggests that even in patients with severe renal impairment, PCT elimination kinetics take over when the bacterial infectious condition is under control, although the decrease should be expected to be at a lower rate than in patients with normal renal function.

Procalcitonin Use During Continuous Veno-venous Hemofiltration and Hemodialysis

Level et al. [21] and Sitter et al. [22] have examined PCT levels in patients with and without bacterial infection, who are undergoing hemodialysis. Although both studies rely mainly on single measurements of PCT, the results show seemingly good dis- crimination among hemodialysis patients with and without bacterial infection. Both studies propose a higher PCT cut-off, of 1.0 ng/ml or 1.5 ng/ml, for bacterial infection in hemodialysis-patients.

Level et al. [23] investigated PCT clearance during continuous veno-venous hemofiltration (CVVH) in patients with septic shock and acute oliguric renal failure.

The sieving coefficient of PCT was 0.19 at 6 hours, which is close to the expected for a 13,000 Da polypeptide molecule (for comparison, the sieving coefficient of creatinine with a MW of 113 Da is 1.0; the sieving coefficient of myoglobin, MW of 17,000 Da, is 0.35; and the sieving coefficient of IL-1q , MW 17,000 Da, is 0.18). There was a non-significant tendency towards a decrease in the plasma levels of PCT in these patients. Although this was a small study (n = 13), it indicates that: 1) PCT is not cle- ared very fast by CVVH, and 2) there is some degree of clearance by CVVH, so PCT levels will decrease when bacterial infection is under control.

In support of these data, we found (unpublished data in an ICU population, described in [19]) that the chance of a decrease in PCT the first day after a limit of 1.0 ng/ml was reached, was similar in a group of patients with acute renal failure compared to patients with normal renal function (25/40 patients [62.5 %] vs. 150/233 patients [64.4 %]).

In conclusion the present evidence, although limited, suggests that PCT measurements can be used in patients with all degrees of renal failure and during treatment with hemodialysis or CVVH.

Procalcitonin, Trauma, and Surgery

Postoperative infective complications cause a high level of morbidity and mortality.

As in other cases of serious bacterial infections, prognosis is highly dependent on

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early diagnosis and treatment directed towards the etiologic agent, namely antimicrobial chemotherapy and source control. When treatment is initiated, monitoring the effect of the treatment is important to avoid a delay in change of therapy, when initial therapy is not adequate. Consecutive daily measurements of CRP are widely used for this purpose, but there are serious limitations of this marker in a postoperative setting.

A major disadvantage of CRP is that after surgery and trauma this marker generally increases for several days, reaching a plateau typically on day 2 – 4 following the event, and, therefore, in most cases not offering the needed guidance for early treatment of bacterial infection [24]. CRP increases consistently in nearly all patients after abdominal surgery and can predict bacterial infectious complications only at a late point in the post-operative course [24 – 26].

PCT has been proposed as an alternative marker for monitoring patients after surgery and trauma. Several groups have investigated the course of PCT and CRP following abdominal surgery. It has been consistently reported that PCT levels can increase even in surgery without postoperative bacterial infection. However, PCT levels decrease in the majority of patients without complications, as early as the first day after surgery. In contrast, PCT levels increase in the days after surgery in patients with postoperative bacterial infections. Likewise, in a baboon model of trauma, it was found that PCT levels increased shortly after trauma to moderately elevated levels, but decreased within 24 hours [27].

Procalcitonin and Antibiotic Usage in Patients Suspected of Having Lower Respiratory Tract Infection

In a randomized, controlled, single-blinded trial with PCT-guided treatment of patients suspected of having a lower respiratory tract infection admitted to a Swiss emergency department, Christ-Crain et al. demonstrated a relative risk of antibiotic exposure of 0.49 [95 % CI 0.44 – 0.55] in patients receiving PCT-guided treatment [28]. Clinical outcome parameters showed the same result, except for parameters related to antibiotic use, where the PCT-guided group had a significantly reduced use in all subgroups. This result has been reproduced recently [29], also in patients from the emergency department.

These studies demonstrate an advantage in the strategy of PCT-guided treatment compared to clinical judgment in the clinical action of withholding superfluous anti- biotics in the emergency department. The strategy of PCT-guided treatment has not yet been investigated in critically ill patients, but a randomized, controlled trial (RCT) is presently ongoing in Denmark.

Sepsis and Assessment of New Diagnostic Markers Against a Gold Standard

Traditionally new diagnostic tools, including new markers of inflammation, are tested against a gold standard for the condition under examination.

Sensitivity/Specificity Assessments and Limitations to this Strategy

Measurements of the percentage of positives in the new test (NEW TEST_positive) in a population designated positive by the gold standard (sensitivity) and percentage of

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negatives in the new test (NEW TEST_negative) in a population designated to be negative by the gold standard (specificity), are common and in effect, obligatory under the ruling paradigm:

Sensitivity = NEW TEST_positive/ GOLD STANDARD_positive Specificity = NEW TEST_negative/ GOLD STANDARD_negative

A major criticism of this scientific strategy is that very few conditions have a really true gold standard, making assessments of new diagnostic methods more difficult to interpret, when the quality of the gold standard is low. At the same time, the main motivation for assessing new diagnostic methods is often that the gold standard has some serious limitations. This is par excellence the situation when testing markers of inflammation and bacterial infection.

Many attempts to standardize diagnosis of infections have been made, and to some degree the latest consensus to standardize sepsis diagnostics [30] has been successful in increasing the number of patients who receive a specialized multifactor/multidisci- plinary sepsis treatment. Modern sepsis diagnostics may be very sensitive in finding a group of patients with an increased risk of serious bacterial, viral, parasitic, or fun- gal infection. However, the nature and pathophysiology of these different infections is, not surprisingly, very diverse. It may be unrealistic to find a single marker of inflammation/infection that increases uniformly (high sensitivity), no matter which microorganism is the cause of infection, and that does not increase when inflammation is caused by non-infectious conditions (high specificity). Finding such a marker would be very surprising, considering the present understanding of immunologic processes during infections with different microorganisms. Additionally, one might ask, what such a “universal marker” could actually contribute to the treatment of patients, since the treatment depends highly on which microorganism we want to treat.

To find several different inflammatory markers, that increase when one or two classes of microorganisms cause infection, may be more realistic from a pathophysiological point of view. This approach may even prove to be of greater clinical value, since specific antimicrobial treatment can be instituted as a consequence of abnor- mal values of the specific inflammatory marker.

So far, this pathophysiological viewpoint has been used remarkably little in testing inflammatory markers, as many studies have tested the sensitivity and specificity of these markers towards clinical terms like sepsis and infection, without differentiat- ing between the classes of microorganisms that cause the infection. Some thought should also be given to whether we really just want a marker of infection to find

‘clinical sepsis= SIRS + evidence of localized infection’. If we consider that ‘clinical sepsis’ is a good gold standard, there is no need for change, since this diagnosis is based on microbiological results and simple clinical measures.

Procalcitonin, C-reactive Protein, Leukocytes, and Sensitivity/

specificity for Sepsis: The Major Problems Gold Standard

Many studies have investigated the sensitivity and specificity of PCT measurements for clinical conditions, such as sepsis and infection. As mentioned above, there are some serious methodological limitations in this approach. Additionally, there are limits regarding: a) ‘locked bias’; b) the PCT assay used in the laboratory; and c) the chosen strategy of sampling (single vs. consecutive regimens)

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‘Locked bias’

When an investigation is made, a traditional and widely used method (e.g., CRP) is often tested against an alternative method (e.g., PCT). If a certain infection diagnosis is guided by a marker (e.g., CRP) AND the bacterial infection diagnosis is an endpoint, there will be a positive directed bias towards a coupling of this certain marker and the endpoint. If the new marker is not blinded, this will also be true for the new marker. However, blinding of the new marker is relatively easy: Results of the analyses can simply be concealed until they no longer have an acute relevance.

To even out conditions and to avoid an inert advantage of the traditional method, blinding of the analysis of the results of this marker is desirable, but unfortunately, impossible. When CRP is used as guidance for when to look for infection aggres- sively, infections will more often be found in patients with high CRP blood levels.

The direction of the bias is, however, in favor of conservatism, which to some degree is scientifically sound: If CRP is favored, PCT has to show an even better abil- ity to compete. This, in effect, makes results even more convincing, if they are positive; that is, finding PCT to be better in, for example, discriminating patients with and without bacterial infection. It does not seem reasonable to ‘change the world’

because of a very small diagnostic advantage.

Assays

The most commonly used assay until ' 2003 was the BRAHMS Lumitest®, a sand- wich immunoassay. The inter-assay variability for this assay in the measuring interval between 0.0 ng/ml – 1.0 ng/ml was 9 – 82 %. This makes the Lumitest ® assay of little use in this measuring interval [19]. Ironically, this is the interval of most inter- est regarding localized bacterial infections. Consequently, studies using this assay, and where a majority of the patients suffer from localized bacterial infections, should be interpreted very carefully, not necessarily because of the scientific qualities, but simply because of the quality of the assay. In contrast, the most commonly used assay presently, the KRYPTOR® PCT, has a functional assay sensitivity of 0.06 ng/ml, according to the manufacturer (BRAHMS Diagnostica, Henningsdorf, Ger- many), which makes this assay secure to use for localized bacterial infections.

Single versus consecutive procalcitonin measurements

Most of the comparisons between CRP and PCT in clinical conditions such as sepsis or infection have been performed with single measurements of both of these markers. It is well documented that trauma and surgery in itself cause an increase in CRP levels for 2 – 4 days. This makes tight monitoring of patients to discover emerging bacterial infection using CRP after trauma and surgery more or less impossible. PCT levels are increased by other factors than bacterial infection. Some examples are surgery, trauma, and acute left sided heart failure. One possible explanation for this is translocation of endotoxins from the intestine to the blood stream. However, when the initiating event has ended, PCT kinetics will nearly always be rapidly dominated by elimination, and although initial PCT levels may be increased, the level will thereafter decrease in the non-infected patient [24, 27].

By comparing single measurements of PCT (or any other marker) and CRP, one rules out the possibility that PCT may have an advantage in discriminating bacterial infection from non-bacterial conditions if consecutive measurements have been made.

The power of 20 different parameters has been tested in a multivariate Cox- regression model to predict mortality in critically ill patients, including: a) the ini-

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tial PCT value (PCT_initial); the maximum obtained PCT (PCT_max); and c) a dynamic parameter regarding if there is an increase in PCT the first day after reaching a cut off of 1.0 ng/ml (PCTincrease1.0) [19]. Similar parameters regarding CRP and leukocyte levels were investigated. The results were interesting in three aspects: 1) CRP and leukocytes did not show predictive power in any of these analyses; 2) PCT_max and PCTincrease1.0were both independent predictors of mortality; and 3) PCT_initialdid not predict mortality. These results support the idea that consecutive measurements of PCT may have a much greater value than single measurements. Hence this strategy should be more dominant in research comparisons.

In spite of the above mentioned limitations, the results from sensitivity/specificity studies are in favor of PCT, compared to CRP, as a sepsis marker (as comprehen- sively reviewed in the meta-analysis by Simon et al. [31]).

Procalcitonin and Mortality in the ICU: Prognostic Implications

In the attempt to deal with some of the above-mentioned problems and difficulties when comparing PCT with other inflammatory markers, we decided to look at the more solid endpoint, mortality. Additionally, we decided to make daily consecutive measurements of PCT in a mixed population of 472 ICU patients, to investigate if this strategy could increase the value of PCT measurements [19]. The main results are shown in Figure 2 and in Table 1.

These results confirm findings from other investigators that high PCT levels are closely linked to bacterial infection and complications of these infections and, additionally, they demonstrate that a PCT increase (PCTincrease1.0) is an independent predictor of mortality. The mortality rate was strongly dependent on how many days PCT had been increasing while the patient was in the ICU.

In conclusion, consecutive PCT measurements in the ICU can independently predict potential lethal infections. We believe this information could potentially be very valuable to the intensive care physician, because here we have a marker of inflammation that is better at discriminating bacterial infection from other causes of inflammation, better at monitoring this bacterial infection, and better on a daily basis at stratifying patients into different mortality risk groups, so that treatment can poten-

Fig. 2. Survival differences between patients with a decreasing vs. an increasing PCT after a limit of 1.0 ng/ml has been reached for the first time, i.e., PCT decreasing and increasing for just one day.

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Table 1. Mortality risks for patients with increasing and decreasing procalcitonin (PCT) levels [19]. p values are estimated with the Chi-square test for equal proportions. Patients with decreasing PCT levels after a limit of 1.0 ng/ml has been reached and patients with constantly low PCT values are counted as “Non-alert PCT”. Patients with increasing PCT after 1.0 ng/ml has been reached are “Alert PCT”. Patients can be included in several categories: e.g., patients with an increasing PCT trend for three days are also included in categories with increasing PCT trend at one and two days.

Days with delta-PCT after PCT

& 1.0 ng/ml

90-day mortality with PCT day-to-day change:

Relative risk PCT Increasing) (95 % CI)

p value for risk difference

Patients (n) Decreasing

(“Non-alert”)

Increasing (“Alert”)

1 30.7 % 56.1 % 1.8 (1.4 – 2.4) ‹ 0.0001 336

2 28.7 % 62.2 % 2.2 (1.6 – 3.0) ‹ 0.0001 261

3 26.0 % 72.4 % 2.8 (2.0 – 3.8) ‹ 0.0001 233

tially be adjusted according to severity of disease, thereby increasing the chances of effective and timely antibacterial treatment.

Is the Problem Solved?

Although consecutive PCT measurements may have the mentioned qualities compared to, e.g., CRP, whether this dynamic strategy can add something really beneficial to the treatment is still unknown. In other words, we do not know if daily consecutive PCT measurements are ‘nice to know’ or ‘need to know’. Are we merely confirming our (already chosen) clinical decisions, or can we actually change diagnostic and therapeutic strategy in a timely manner and thereby reduce complications of bacterial infection and/or reduce mortality in ICU patients?

We need more evidence at a higher level to show this. Therefore, we need RCTs that are statistically powered to investigate mortality differences between patients receiving PCT-guided treatment and the best standard of care.

In the following section we discuss why a lower level of evidence cannot be accepted for this issue.

Procalcitonin and Pulmonary Artery Catheters: A Comparison of the Implementation of Two Diagnostic Strategies in the ICU

The use of pulmonary artery catheters (PACs) in the seventies and eighties has taught us a valuable lesson on the level of evidence needed to introduce new diagnostic strategies in the ICU. Bearing this in mind, we can compare the process of introducing PCT as a diagnostic tool with the historic introduction of the PAC. The point is to determine whether widespread implementation of a new diagnostic method is actually or just seemingly of significant benefit to the critically ill patient.

Following the initial description by Swan et al. in 1970 [32], it became routine to place PACs in critically ill patients. More than 8000 papers on this technique have been published. In the beginning of the 1990s, it was questioned whether the systematic catheterization of a large part of the critically ill patients was of benefit or may even be harmful [33]. In 1996, Connors et al. [34] published an observational study suggesting a higher mortality in patients monitored with the catheter. The

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ICU-world was shaken – had patients been suffering lethal side-effects of this monitoring system? It became obvious that RCTs were needed. Several small-scale and a few large scale randomized trials were conducted, the most recent of which, in patients with acute lung injury (ALI) was published in May 2006 [35]. In this multi- center RCT, no benefit was found in the group monitored with a PAC compared to a central venous catheter. This indicated that PACs should not be inserted routinely.

The same kind of analysis should perhaps be conducted for sepsis markers.

The Need for RCTs in the ICU to Assess whether Procalcitonin- guided Treatment can Reduce Mortality in Critically Ill Patients?

To assess whether it is relevant to conduct a RCT regarding a treatment regime, two main criteria should be fulfilled:

1) The treatment regimen should be effective.

2) It should not be applied too late.

These conditions are presently fulfilled regarding PCT-guided antibiotic treatment, and an investigator initiated RCT, The Procalcitonin And Survival Study (PASS), is presently being conducted in Northern Europe (initiated in Denmark). The primary endpoint is a reduction of 28-day all-cause mortality. If the trial is positive, it will have demonstrated a way of reducing mortality in a broad population of ICU patients at a relatively low cost (approx. 10c for each analysis kit per day/patient), and worldwide implementation could be suggested, considering the almost absent adverse effects of the strategy. In contrast, if the result is negative regarding all measured primary and secondary endpoints, patients will be spared another useless test, like the PAC.

Conclusion

PCT, a 114 amino acid precursor of calcitonin, is a promising sepsis marker with an advantageous kinetic profile for use on a daily basis in the ICU. Clinical studies have shown a very close relation of this sepsis marker to bacterial infection, and it has been shown that an increasing level of procalcitonin for just one day after a cut-off is reached is an independent predictor of mortality in ICU patients.

The question of whether PCT-guided treatment can reduce mortality or morbidity in ICU patients remains to be answered. We await the results of an RCT to gain evidence either to encourage widespread implementation of PCT measurement in ICUs or alternatively, to stop implementation, if the results of such a trial are negative.

Appendix

The Procalcitonin And Survical Study Group Steering Committee: Dr. Klaus Thorn- berg, Gentofte ICU, Dr. Thomas Mohr, Glostrup ICU, Dr. Hamid Tousi, Herlev ICU, Dr. Peder Carl, Hvidovre ICU, Dr. Morten Bestle, Hilleroed ICU, Dr. Paul Fjeldborg, Skejby, Aarhus ICU, Dr. Kim Michael Larsen, Aarhus Sygehus ICU, Dr. Niels-Erik Drenck, Roskilde ICU, Dr. Christian Oestergaard Andersen, Dept. of Clinical Micro- biology, Herlev, Dr. Gitte Kronborg, Dept. of Infectious Disease, Hvidovre, Dr. Bet-

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tina Lundgren, Dept. of Clinical Microbiology, Hvidovre, Dr. Jens Ulrik Jensen, Dept. of Clinical Microbiology, Hvidovre, Professor Jens D. Lundgren, Copenhagen HIV Programme, Hvidovre. Principal Investigators (when not Steering Committee members): Dr. Lars Hein, Glostrup ICU, Dr. Jesper Loeken, Hvidovre ICU. All:

Copenhagen University Hospital, Denmark.

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