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Bi-monthly journal of the Dutch Society of Intensive Care

Netherlands Journal of Critical Care

Volume 17 - No 2 - May 2013

ReviewCurrent status of procalcitonin in the ICU

M. Meisner

Case reportCollapse due to acute aspiration of

a foreign body

H.F. de Kruif, G. Innemee, A. Giezeman,

A.M.E. Spoelstra- de Man

Clinical imageA traumatic aneurysm of the

pericallosal artery

A.C. van Dijk, W-J. van Rooij, A.M.F. Rutten

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Referenties:* Invasieve aspergillose bij volwassene patienten en kinderen die niet reageren op amfotericine B, toedieningsvormen van amfotericine B met lipiden en/of itraconazol of deze niet verdragen.1. D.W. Denning: Echinocandin antifungal drugs. The Lancet 362: 1142-51, 2003. 2. Bijlage 5 Beleidsregel BR/CU-2076

Raadpleeg de volledige productinformatie alvorens CANCIDAS voor te schrijven

M Merck Sharp & Dohme BV, Postbus 581, 2003 PC Haarlem, Tel. 0800-9999000, email [email protected], www.msd.nl, www.univadis.nl

Evidence. Experience. Confidence

Cancidas® Breed toepasbaar bij

• Invasieve candidiasis

• Invasieve aspergillose*

• Empirische antifungale therapie

Antifungale therapie zonder compromis

• Voor volwassenen én kinderen

• Voor neutropenen én niet-neutropenen

• Goed verdragen1

•

Eenvoudige dosering• Als add-on DBC volledig vergoed2

• 11 jaar klinische ervaring

(caspofungin, MSD)

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3/40

13_A_042nieuw, wordt door Ton geplaatst

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Ecalta® Als medicatieveiligheid telt

• Geen klinisch relevante geneesmiddelen interacties1-5

• Geen dosisaanpassing in verband met gewicht,

lever- en nierfunctiestoornissen1-5

Doeltreffend en gemakkelijk 1-5

8/17/2019 NJCC Mei 2013.pdf

5/401NETH J CRIT CARE VOLUME 17 NO 2 MAY 2013


E D ITO R IA L

3 A.B. Johan Groeneveld

R E V IE W S

4 Current status of procalcitonin in the ICU

M. Meisner

13 Acute viral lower respiratory tract infections in paediatric intensive

care patients

S.T.H. Bontemps, J.B. van Woensel, A.P. Bos

C A S E R E PO R TS

19 Sepsis and bleeding in an obstetric patient who is a Jehovah’s Witness

A case report with a brief review of the literature of severe septic shock

during pregnancy

V.C. van Dam, B.L. ten Tusscher, A.R.J. Girbes

23 Collapse due to acute aspiration of a foreign body

H.F. de Kruif, G. Innemee, A. Giezeman, A.M.E. Spoelstra-de Man

PR O C O N

27 Non Invasive Ventilation; PROs and CONs

A.F. van der Sluijs

CLINICAL IMAGE30 A traumatic aneurysm of the pericallosal artery

A.C. van Dijk, W-J. van Rooij, A.M.F. Rutten

32 Editorial Board

32 International Advisory Board

35 Information for authors

I N H O U DE X E C U T I V E E D I T O R I A L B O A R DA.B.J. Groeneveld, editor in chief Mw. drs. I. van Stijn, managing editorJ. Box, language editor

C O P Y R I G H TNetherlands Journal of Critical CareISSN: 1569 -3511

NVIC p/a Domus MedicaP.O. Box 2124, 3500 GC Utrecht T.: +31-(0)30- 6868761

© 2013 NVIC. All rights reserved. Except asoutlined below, no part of this publication maybe reproduced, stored in a retrieval systemor transmitted in any form or by any means,electronic, mechanical, photocopying, recordingor otherwise, without prior written permission ofthe publisher. Permission may be sought directlyfrom NVIC.

D E R I V A T I V E W O R K SSubscribers may reproduce tables of contentsor prepare lists of articles including abstractsfor internal circulation within their institutions.Permission of the publisher is required for resaleor distribution outside the institution. Permission

of the publisher is also required for all otherderivative works, including compilations andtranslations.

E L E C T R O N I C S T O R A G EPermission of the publisher is required to store oruse electronically any material contained in this journal, in cluding any ar ticle or par t of an article.

S U B S C R I P T I O N SAn annual subscription to The NetherlandsJournal of Critical Care consists of 6 issues. Issueswithin Europe are sent by standard mail andoutside Europe by air delivery. Cancellationsshould be made, in writing, at least two monthsbefore the end of the year. The annual su bscription fee for the Netherlan dsis 170 euro, for Europe 285 euro, for the rest of theworld 380 euro. Subscriptions are accepted on a

prepaid basis only and are entered on a calendaryear basis.Please make your cheque payable to Van ZuidenCommunications B.V., PO Box 2122, 2400 CCAlphen aan den Rijn, the Netherlands or you cantransfer the fee to ING Bank, account number67.87.10.872, Castellumstraat 1, Alphen aan denRijn, the Netherlands, swift-code: ING BNL 2A. Donot forget to mention the complete address fordelivery of the Journal.

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Van Zuiden Communications B.V.PO Box 21222400 CC Alphen aan den Rijn The Netherlands Tel.: +31 (0)172-47 61 91E-mail: [email protected]: www.njcc.nl

NETHERLANDS JOURNAL OF CRITICAL CARE

Netherlands Journal of Critical Care is indexed in:

EMBASE EMCare Scopus

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From February 2013 onwards, the Netherlands Journal of Critical Care (NJCC) will be published by

Van Zuiden Communications B.V. Te journal will have a slightly different cover and layout. Te

editorial board is grateful for this opportunity to change publishers, put forward by the Dutch Society

of Intensive Care, and hopes that it will represent a step forward in the professional growth of the

journal . Obviously, we would like to express our grat itude towards Interactie BV and the managing

editor Arthur van Zanten for their diligent help over the past ten years or so to raise the journal to

international standards. Te future is not without challenges, including the shaping of the website

and online submission system and balancing the costs of publishing. While the transition may have

resulted in some delays in handling manuscripts, the editorial staff is now fully prepared to receive

and rapidly process interesting national and international papers. We welcome all high quality

submissions.

Tis issue of the NJCC timely highlights important ICU issues such as ICU detection of severe

infection by biomarkers and how they fit in antibiotic stewardship programmes. Life-threatening viral

infections increasingly occur and necessitate mechanical ventilation in the ICU. In this respect, wecan learn from our pediatrician colleagues how to handle these infections. And maybe non-invasive

venti lation is not always appropriate after all. We have interesting case reports and a clinica l image

with unique findings.

Prof. dr. A.B. Johan Groeneveld

Editor in chief

E D I T O R I A L

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8/404 NETH J CRIT CARE VOLUME 17 NO 2 MAY 2013


Accepted April 2013

Abstract

Tis review outlines the main indications for the measurement

of procalcitonin (PC) on the intensive care unit (ICU):

diagnosis or exclusion of sepsis (severe sepsis, septic shock) andassessment of severity and course of sepsis-related systemic

inflammation, control of focus and response to antibiotic

therapy. Follow up measurements of PC are frequently done

on the ICU and recommended to individualize decisions

regarding the indication and duration of antibiotic therapy.

Studies related to this topic and also the practical experience

with the routine use of this marker as a guide to treatment are

summarized in this review. Furthermore, conditions, which

may increase PC independently from sepsis, are prevalent in

ICU patients and will also be discussed.

Use of PCT as a sepsis marker on the ICU

PC has been recognized as a marker of sepsis since 1993.1

Initially, PC was mainly used for the diagnosis of (bacterial)

sepsis and for the differential diagnosis of a bacterial versus

non-bacterial aetiology of systemic inflammation. In the

meantime, indications have been extended to a more dynamic

use, e.g. to follow up and guide sepsis-related therapy, including

antibiotic treatment and focus control – both in outpatients

and ICU patients. Te uniform induction during sepsis, the

correlation of concentrations with severity of inflammation

(high levels in patients with severe sepsis), the relative

specificity for bacteria-induced systemic inflammation and ashort half-life of induction and elimination fitting the needs of

daily routine diagnostics support the clinical use of PC as a

biomarker on the ICU.

Biochemistry and induction

PC is produced by the organism and therefore an indirect

or host-response related biomarker of systemic inflammation,

mainly induced by microbial infection (sepsis, severe sepsis,

septic shock). Te 114-116 amino acid protein and its shorter

calcitonin-N-ProC fragments are measured by the presently

Current status of procalcitonin in the ICU

available diagnostic tests. Te protein is induced within several

hours (3-6 hrs, peak 12-24 hours) after the respective stimulus

(e.g. endotoxinemia, sepsis, systemic inflammation and various

proinflammatory mediators). Peak levels decline with a 50%plasma disappearance rate of roughly 1,5 days and somewhat

more in patients with severe renal dysfunction. Te normal

range of PC in healthy individuals is quite low (< 0.1 ng/

ml), so that as the reference range for diagnosis of sepsis,

concentrations above 0.25 - 0.5 ng/ml are usually used. When

deciding on antibiotic therapy, the lower threshold with higher

sensitivity is usually used. Te protein has various biological

functions, e.g. chemotactic effects on monocytic cells and

modulation of expression of inducible nitric oxide synthase

(iNOS) in vascular smooth muscle cells. Tese functions are

partially time-dependent and they are different in native and

prestimulated cells. PC neutralisation affects survival and

organ dysfunction in animal septic shock models. PC can be

produced by adherent (not circulating) activated monocytes

and tissue cells, where induction is augmented by a crosstalk

of invading monocytic cells with adipocytes, as demonstrated

by ex vivo experiments.2 Also, the liver obviously plays a major

role in PC induction.3,4

PC can be induced by a variety of non-septic conditions as well,

e.g., during cardiogenic shock, in patients with severe renal or

hepatic dysfunction, after major surgery, in patients with severe

systemic inflammatory response syndrome (SIRS) and multiple

organ dysfunction syndrome (MODS), as well as in severepancreatitis or during release of proinflammatory cytokines.4

However, as compared to severe sepsis, induction in these cases

is often moderate (usually < 2 ng/ml) and – if related to a specific

event – for a short period of time only (1-2 days). However,

conditions inducing PC without sepsis are more frequent

in ICU patients and hence should be considered (table 1). In

addition, in patients with local infection or those with a weak

systemic inflammatory response, PC levels may remain low. In

patients with neutropenia or those under immunosuppression

(e.g. corticosteroids) suppression of PC is only moderate.

M. Meisner

Clinic of Anaesthesology and Intensive Care Medicine, Staedtisches Krankenhaus Dresden-Neustadt, Germany

Correspondence

M. Meisner – e-mail: [email protected]

Keywords - Sepsis, severe sepsis, procalcitonin, pneumonia, bacterial infections, mycoses

R E V I E W

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PCT and other presently used markers of sepsis

Te diagnosis of sepsis and monitoring of therapy could be

improved if PC measurements were added to the clinical

and conventional signs of sepsis.5 PC has different properties

when compared with CRP or lactate – markers which are often

recommended for diagnosing sepsis. CRP, for example, has a

low specificity for sepsis and concentrations do not indicate the

risk and severity of sepsis well.6-8

It responds late and plasmalevels may be affected by immunosuppression. A decline of

CRP towards the normal range may take from several days up

to one week. At the acute onset of sepsis or severe sepsis, some

patients may present with a moderate increase of CRP only (e.g.

50-100 mg/l) which may not reflect the progression or severity

of the disease. Such levels can also be observed in various other

ICU patients, e.g. post-surgical. In contrast, high CRP levels

(e.g. > 300 mg/l) are also induced after major surgery, especially

major abdominal or retroperitoneal surgery in patients without

sepsis.9 Tus, it is difficult to draw therapeutic conclusions from

CRP levels on the ICU. Tis may lead to under recognition of

sepsis by CRP in an acute situation.

Lactate is primarily a marker of cellular and oxidative

metabolism and perfusion and hence an epiphenomen of sepsis

only. Significantly increased or high levels of lactate mainly

occur in patients with severe or progressive stages of sepsis, e.g.

if severe organ dysfunction or septic shock are already present.

o significantly affect the outcome, sepsis must be recognizedand treated early – at best prior to the onset of shock or organ

dysfunction. Furthermore, lactate does not differentiate septic

from nonseptic shock.10

Other markers like fever, leukocytes, blood sedimentation rate,

coagulation parameters, thrombocytes, acute phase proteins

and pathogen-associated molecules like endotoxin and PCR

based methods may be useful for the diagnosis of sepsis

as well. First, as an early sign of sepsis suspected by routine

diagnostics measured for other indications (like thrombocytes

and coagulation parameters) or as a supplemental marker, but

Table 1. Conditions, which may induce PCT other than bacterial infection

Condition Expected Peak (approx.) Estimated range Reference

Postsurgical, posttraumaticNon-abdominal trauma or surgery: low orno PCT induction.Abdominal or retroperitoneal surgery/trauma, thoracic surgery

Peak levels on day 1, rapidly declining

If PCT is increased above the expected typicalrange, postoperative complications are morefrequently observed

< 1 ng/ml for peripheral, non-abdominaltrauma or minor abdominal surgery)< 2 ng/ml for abdominal surgery ortrauma, cardiac surgery.2 ng/ml is possible in patients withextended retroperitoneal or majorabdominal surgery, liver transplantation

9, 78-82

Cardiogenic shock Initially no increase.Increasing levels after 1-3 days, if high dosecatecholamines are required

May be intermediate to high (e.g.> 0.5 ng/ml to > 10 ng/ml)

83-85

MODS, severe SIRS Increasing slowly with severity > 0.5 ng/ml - > 10 ng/ml 17, 86, 87

Pancreatitis, severe Initially; normal PCT indicates mild oroedematous pancreatitis.Increasing levels related with severity, organdysfunction and necrosis

< 0.2 ng/ml: mild or oedematouspancreatitis.In patients with severe pancreatitis:0.5 ng/ml - > 10 ng/ml

53, 54, 58, 59

Autoimmune disorders Usually not elevated in:Rheumatoid arthritis, chronic arthritis, systemicsclerodermia, amyloidosis, thyreoiditis, psoriasis,inflammatory bowel disease, systemic lupuserythematosus.Can be elevated in Kawasaki Syndrome,Goodpasture´s Syndrome, Anti-neutrophilantibody-positive vasculitis, autoimmunehepatitis or primary sclerosing cholangitis, M. Still

In most autoimmune disorders no orminor induction of PCT only (0.1-1 ng/ml).

Some induce significant PCT levels of> 1 ng/ml -10 ng/ml (see left column)

88-94

Severe renal dysfunction If decompensated or end stage disease only, orhaemodialysis.

In the lower range, 0.1-2 ng/ml, constantelevation

27, 95-98

Severe liver dysfunction Chronic, Child C onlyIn some cases increased level in patients withacute liver failure

In chronic disease in the lower range,0.1-2 ng/ml, constant. In acute caseshigher levels reported

99

After prolonged resuscitation Peak day 1 In case of prolonged CPR, levels arerelated with prognosis

100, 101

Heat Shock Acute High concentrations reported 102, 103

New-born first days of life Peak day 1-2 Use adapted reference range 104-106

Paraneoplastic Very rare, except MCT 107

OKT-3, Anti Lymphocyte Antigens Acute Medium range, low if pre-treatment withcorticosteroids

108-110

End stage of tumour disease Chronic Low (0.5-2 ng/ml) 42

Rhabdomyolysis Acute May be very high Individual reports

Severe burns, inhalation trauma, aspiration. First days and during severe SIRS or infection Follow up recommended 111-114

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most of these markers lack specificity and their ability to assess

the risk, severity and course of the disease is often poor.

Due to the distinct profile of PC as compared to these

markers, PC is used in a number of ICUs as a biomarker of

sepsis – along with a variety of other signs of sepsis e.g. those

from routine measurements – and is often included in the daily

routine and clinical rounds, since diagnostic and therapeuticdecisions are influenced by this marker, e.g. the assessment of

efficacy of therapeutic measures.

Indications and measurement of PCT on the ICU

Indications for PC measurement on the ICU basically do not

differ from indications in other patients. However, different

from the emergency department, consecutive measurements

are most frequent on the ICU. Tis means that patients can be

monitored and any unnecessary antibiotic use can be limited.

Single or semi-quantitative measurements for differential

diagnosis are far less useful on the ICU. Indications are

summarized in table 2.

Confirmation or exclusion of the diagnosis of sepsis,

severe sepsis, septic shock

Te major strength of PC is its high positive predictive value

to rule in the diagnosis of sepsis, severe sepsis or septic shock

and its high negative predictive value (in case of normal or low

PC plasma concentrations) to exclude a severe SIRS, mainly

due to bacterial infection (table 3). Also, the probability for

bacteraemia is significantly increased in patients with higher

PC levels or reduced in case of normal PC.11-13Tis finding

has been confirmed by various publications and it has been

implemented in guidelines and the FDA-approval in the

USA.14-16 High PC levels are also related to a high risk of organdysfunction and mortality due to sepsis.17-21 However, local

bacterial infection or bacterial colonisation cannot be excluded

by PC. Fungal infection, when complicated by systemic

inflammation, may also induce PC. Tese patients frequently

have PC levels in a medium elevated range only (1-5 ng/ml)

or they do not respond to antibiotic therapy.22 ypically these

patients have a high risk profile. Terapy should be started

early if there is suspicion. A rapid decline after antifungal

therapy has been reported.22-24

Local infection

Local bacterial infection or bacterial colonisation usually do

not induce PC. Even in patients with acute appendicitis, acute

cholecystitis even with local peritonitis the PC response

may be weak. Tis should be known and hence diagnosis or

therapy should not be excluded by a low PC. Interestingly, a

conservative treatment of less severe appendicitis has recently

been discussed as well.25,26 On the contrary, high PC levels in

a patient with appendicitis or local peritonitis is undoubtedly a

sign for urgent intervention.

Te information of normal PC levels on the ICU has various

consequences: for example, microbial findings may be

interpreted as local infection or bacterial colonisation only andantibiotic treatment may not be necessary. Further, invasive or

non-invasive diagnostic or therapeutic interventions may not

be urgently needed, since the diagnosis of sepsis is unlikely and

the sepsis-related risk of organ dysfunction and mortality are

low.

PCT elevation in patients without sepsis

Moderately increased PC levels in patients without sepsis

have been observed at various conditions. Usually, PC levels

in these cases are not very high (< 2 ng/ml) and induction

Table 2. Indications for PCT-guided monitoring of treatment on the

ICU

• To confirm or exclude diagnosis of sepsis, severe sepsis, septic shock(including differential diagnosis)

• Assessment of severity of s ystemic inflammation, caused by sepsis(severe sepsis/septic shock), reflecting the risk of organ dysfunctionand mortality. The need of urgent interventions thus can be betterestimated

• Follow up of systemic inflammation after focus removal or focustherapy, to assess efficacy of treatment

• In patients with antibiotic treatment in order to better estimate theduration of therapy or to withhold or stop therapy, e.g. if there is nosepsis, if the focus has been cured. For related algorithm see below.

Exclusion criteria should be obeyed.• To determine and monitor patients, who do not need antibiotics on the

ICU, to exclude the risk of sepsis and life-threatening systemic infectionand bacterial infection. In case of persistent elevated PCT: diagnosisand therapy should be re- evaluated.

For specific indications:• In patient with pancreatitis: to early asses severity and infection• To support or exclude diagnosis of bacterial infection with high or low

probability, e.g. bacterial meningitis, bacteraemia, peritonitis, sepsisfrom urinary tract infection.

• If there is no response of PC T levels to antibiotic therapy: fungalinfection or other diagnosis may be present (PCT often 1-5 ng/ml)

• PCT can also be used in out-patients for indication and monitoring ofantibiotic therapy, mainly in patients with respiratory tract infections.

Table 3. PCT levels in patients with bacterial infection and variousseverity of systemic involvement

SIRSMedian (*), rangeMean (+), SD

Sepsis Severesepsis

Septicshock

Reference,number ofobservations

- - 2.4 ± 0.5 (+) 37 ± 16 45 ± 22 (69) n = 145

0.6 ± 2.2 (+) 6.6 ± 22.5 - - 35 ± 68 (70) n = 337

1.3 ± 0.2 (+) 2.0 ± 0 8.7 ± 2.5 39 ± 5.9 (71) n = 100

< 0.5 ng/ml (*) 0.8 ng/ml - - 4.3 ng/ml (7) n = 190

3.8 ± 6.9 (+) 1.3 ± 2.7 9.1 ± 18.2 38 ± 59 (72) n = 101

3.0 (0.7-29.5) (*) - - 19.1(2.8-351)

16.8 (0.9-351)„all septicpatients“

(73) n = 33

0.5 ± 0.2 (+)(approx.)

2 ± 2(approx.)

18 ± 10(approx.)

20 ± 10(approx.)

(74) n = 101

0.38 (*) (0.16-0.93quartiles)

3.0 (1.48-15) 5.58(1.84-33)

13.1 (6.1-42) (6) n = 101

0.6 (0 -5.3) (*) 3.5 (0.4-6.7) 6.2(2.2-85)

21.3 (1.2-654) (5) n = 78

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is short (1-2 days) and often related to a specific event. Such

conditions are more frequently seen on the ICU than in the

average population. Te ICU physician should know this

and interpret PC values accordingly (table 1). However,

decisions made on an increase of PC that are not related to

sepsis should be done by exclusion. Primarily, every increase

should be interpreted first as a possible sign of sepsis, until afollow up and further clinical examination have excluded this

diagnosis and levels can be explained otherwise. Undoubtedly,

this is a grey area, since at the acute onset of sepsis, in patients

without organ dysfunction and during early stages of sepsis or

in patients with respiratory tract infections or pneumonia even

a small increase of PC is important for the diagnosis of sepsis

(e.g. PC > 0.25 ng/ml).

Depending on the type of ICU, postsurgical and posttraumatic

induction of PC can frequently be observed, mainly following

abdominal surgery or abdominal trauma. Induction may

also relate to severe SIRS and MODS, e.g., in patients with

prolonged cardiogenic shock requiring catecholamines. Ten,the initial concentration may be low, but it may increase during

the following days sometimes even to high levels (>10 ng/ml).

In patients with severe renal or liver dysfunction, a moderate,

but constantly elevated basal level can be seen and, usually,

concentrations do not exceed 1-2 ng/ml. PC induced by heat

shock, rhabdomyolsis and some specific types of autoimmune

disorders as well (especially those where monocytic cells are

involved) and concentrations can be quite high. Endotoxinemia

or bacterial translocation may explain induction in some

patients with prolonged cardiogenic shock, abdominal trauma

or surgery, severe acute liver dysfunction or severe MODS. In

other patients, severe tissue trauma and invasion of monocytic

cells or exposure to proinflammatory cytokines may explain

induction of PC.

Usually, follow up of measurements in relation to a specific

event (e.g. surgery, trauma), or non-responsiveness to

therapeutic interventions (e.g. in cases of severe chronic renal

or liver dysfunction) point to induction of PC independently

of sepsis.

Severity and course assessment: inflammation

monitoring

Assessment and monitoring of the course and severity of theSIRS is a major indication for the measurement of PC on

the ICU. PC levels are a mirror of the activity of SIRS in

patients with sepsis (table 2). Te 50% plasma disappearance

rate of about 1,5 days for PC as previously mentioned allows

a daily follow up for monitoring of the patient.27 Even if the

correlation with disease severity is rather a qualitative than

a quantitative one and a gold standard is missing, high PC

levels (e.g. concentrations from 2-10 ng/ml) usually indicate

severe systemic inflammation with high probability of organ

dysfunction.

Very high peak levels (> 100 ng and even more than 1000

ng/ml) are mostly transient and last for only 1-2 days; they

are usually seen at the acute onset of inflammation only. If

immediate therapy is effective, such high concentrations may

not necessarily indicate a fatal prognosis. For example, in

patients with pyelonephritis and urosepsis, high concentrations

have often been observed, but patients most frequently havea good prognosis, if therapy starts immediately.28 Similarly,

a significant decline most often indicates resolution of the

disease.29,30 But on the contrary, if treatment is not effective

and PC levels remain elevated, then the mortality rate is

increased. 5,17,29,31,32

If the infection focus has been cured and the sepsis disappeared

(as confirmed by low PC), antibiotics can often be stopped

earlier than recommended by general guidelines, which do

not consider individual responses.33,34 If there is no decline of

the systemic inflammatory response, then re-evaluation of the

working hypothesis or therapy is recommended.

Antibiotic stewardship: PCT- guided antibiotic therapy

Increasing evidence has been compiled that PC can be used

to guide antibiotic therapy, leading to individualized or shorter

antibiotic treatment courses as compared to a fixed standard

regimen, also in patients on the ICU. On average, a 2-3 day

reduction of antibiotic therapy has been reported (table 4).

Most of the patients in these studies had acute respiratory tract

infections, although this approach has been used for other

infections and patients with sepsis and severe sepsis as well.

Various, albeit basically similar, algorithms have been used.

Some include both a fixed cut-off value and evaluation of the

kinetics. No negative side effects have been reported so far, but

there is on-going criticism that the statistical power to rule out

significant effects on mortality is low and that mainly patients

with lower respiratory tract infections have been investigated. 35

So far, 3691 patients have been investigated in randomized

clinical trials, of whom 166 died in control groups and 159 in

PC-guided groups, confirming non-inferiority of the latter

strategy by excluding an effect on mortality below 8-10%. 35

With a computer based model and analysis of retrospective

ICU data from 1312 patients, a virtual use of the PC-guided

algorithm resulted in substantial reduction of treatment costs,

based on the German diagnosis-related groups calculation.36

In the Netherlands, a prospective study using a PC-guided

algorithm for the management of antibiotic therapy is

underway.37

Effects on microbial resistance rate have also been postulated,

but this has not been confirmed yet. Usually, less antibiotic

treatment is related with less microbial resistance and less

antibiotic-related side effects. Tus, the beneficial effect of this

approach may surpass the reduction of antibiotic consumption.

All patients receiving antibiotics on the ICU should be

evaluated daily by PC. We nevertheless recommend that

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further information is documented and included into decision

making on treatment. Tis includes clinical data regarding the

success of treatment of the infection focus and related data

(physical, biochemical and clinical signs and symptoms). Also,

the general situation of the patient should be taken into account,

as for example the presence or absence of organ dysfunctionand sepsis. Te expertise of the treating subspecialty (e.g.

abdominal surgery) should also be taken into account. Te

decision to stop, change or continue antibiotics should thus be

done by the medical team in a consensus decision.

In our ICU we use a checklist with documentation of

both PC, microbiological data and a selection of further

focus-related and clinical data to increase patient safety. All

decisions are discussed with the medical team and the decision

is documented. PC-guided recommendations are based

on the algorithm of Bouadma ( figure 1).34 In the checklist,

source, signs and symptoms of infection and successful or

unsuccessful treatment of the focus, the presence or absence

of sepsis and organ dysfunction, PC values and the algorithm

based recommendation and possible exclusion criteria are

documented. All criteria are re-evaluated daily with regard to

three main issues. (i) Efficacy at the onset of therapy (on day1-3 of antibiotic treatment). If there is a response to therapy,

antibiotics are continued. (ii) After day 3, latest on day 7: the

recommendation to stop therapy (if there is no sepsis and

no acute organ dysfunction anymore and the focus has been

eliminated and PC is low according to the algorithm). Most

frequently this is possible between days 3-6 after onset of

therapy. (iii) Re-evaluation of therapy, if treatment has not

been effective according to these criteria. Lastly, on day 7 we

suggest a final stop and basic revaluation of antibiotic therapy.

If antibiotics are continued then the reasons must be discussed

Table 4. Randomized controlled trials using PCT-guided algorithms to guide antibiotic therapy report a shorter and patient-adapted, individualizedantibiotic treatment

Patients included PCT Algorithm Result Reference

Community acquiredpneumonia(CAP)

PCT 0,5 ng/ml: Bacterial infection requiring therapy is likely:antibiotic therapy is recommended (strong recommendation)For patients already taking antibiotics uponadmission: if PCT 1 ng/ml) if decrease after3 days to 25-35% of the baseline value.

Reduction of treatment1.7 days in thePCT group (6.6 ± 1.1 vs. 8.3 ± 0.7 days)

(77)n = 27

Patients in intensive carewith suspected infections,multicentre study

For algorithm, see figure 1. Antibiotic-free days:PCT: 14.3 ± 9.0 days, control: 11.6 ± 8.2days (23% relative reduction in antibioticexposure), no differenceIn mortality (28 days)

(34)n = 621

Ventilator-associatedPneumonia(VAP), 5 centres

PCT after 72 hours: < 0.25 ng/ml or PCT>0.25 ng/ml to 1 ng/ml: discontinuation of antibiotictherapy is not recommended (level of recommendation,less strong or strong, respectively).Daily re-evaluation after 72 hours.

Antibiotic-free days:13 days (PCT) vs. 9.5 days (control group),27% relative reduction in antibiotictreatment (study primaryend point). Secondary end points (riskassessment):

no differences between thegroups (mortality, treatmentdays with ventilationor in intensive care)

(65)n = 101

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and documented. Exclusion criteria for this approach must be

known (e.g. therapy for local infection, when necessary, e.g. in

case of local destructive infection like endocarditis, infection

of cerebral drainage, bone or cartilage, impaired immunologic

function e.g. in patients with severe SIRS or MODS or infectionwith specific and aggressive pathogens like tuberculosis and

other potentially harmful microbial species). Using team-based

decisions combined with clinical evaluation of the patient

rather than the PC-based algorithm alone, we did not observe

significantly negative side effects in individual patients despite

a significant number of patients not treated by antibiotics in

our ICU.

Specific indications

Bacteraemia

On average, in patients with bacteraemia, often higher PC

levels have been reported as compared to patients with negative

blood cultures. Also the negative predictive value of low PC

levels to exclude bacteraemia is high.11,12,38-42 If PC had been

used as a single decision tool, as reported in a group of patients

with urosepsis, for example, 40% fewer blood cultures would

have been taken, whereas 94-99% of patients with bacteraemia

would still be correctly diagnosed (with PC >0.25 ng/ml).13

However, some patients with positive blood cultures may have

low or normal PC values as well, since PC is a marker of the

individual immune response to infection which may be weak

even during bacteraemia.

Meningitis

In patients with acute bacterial meningitis, various studies

have reported high PC levels, most often higher than 0.5 ng/

ml. In patients with viral meningitis, PC levels were found

to be barely elevated.43-46 Tis information was used to reduce

antibiotic treatment during epidemic outbreaks.47-48 Although

the initial antibiotic therapy was given to all patients (since

there may be false negative results), duration of therapy could

be significantly reduced using serial measurements of PC. In

patients with sub acute or local infection, e.g. infection of an

internal or external ventricular drainage, PC levels do not

respond sufficiently.49 Infection monitoring of patients with

ventricular drainage by PC is thus not recommended. Also,

measurement of PC in the cerebral fluid is not indicative.

Endocarditis

In patients with bacterial endocarditis, PC levels are usually

elevated. Median values on admission were 3.5 ng/ml in a study

from Kocazeybek et a l. (50 patients) 50 and 6.5 ng/ml in another

study by Mueller et al.51 However, similarly as in patients

with bacteraemia, PC may be low in patients with bacterial

endocarditis, e.g. if the systemic inflammatory response is not

activated.52 Hence, echocardiography is still the gold standard.

However, also on the ICU, patients with elevated PC levels

may have endocarditis and this focus should also be excluded

in cases of increased PC. In our ICU, we have several case

reports of patients, primarily presenting with unspecific

symptoms, cardiogenic shock or fever but with increased PC,

where endocarditis was diagnosed early following an elevated

PC.

Pancreatitis

PC may indicate severity of acute pancreatitis: if initial PC

levels are low (< 0.2 ng/ml) this is more frequently due to

oedematous or mild pancreatitis only.53-56 Whether antibiotic

therapy is required in these patients has not yet finally been

decided upon, but it may not be necessary if there is no

sepsis and PC is low. During the course of the disease, highPC levels are more frequently seen in patients with severe

pancreatitis and infected necrosis.57-59 o assess severity,

PC seems to be equivalent to various scoring systems. 60

Discriminating infected versus non-infected necrosis, however,

is not possible by PC levels, since severe pancreatitis also

induces PC.61,62

Pneumonia

In patients with pneumonia, increased PC levels may be

expected as well, but plasma levels may not be very high in all

Figure 1. Example of an algorithm for an individual guide for antibiotic therapy according to ref. 34

Guidelines for initiating antibiotiocs according to PCT value.

Except any situation requiring immediate therapy …

PCT…

< 0.25 ng/ml 0.25 - 0.5 ng/ml 0.5 - < 1.0 ng/ml ≥ 1.0 ng/ml

Antibiotics strongly discouraged Antibiotics discouraged Antibiotics encouraged Antibiotics strongly encouraged

Guidelines for stopping, continuing or changing antibiotics according to daily measured PCT value.

PCT …

< 0.25 ng/ml Decline more than 80% or 80% of peak(maximum) value or ≥ 0. 25 to < 0. 5 ng/ml

Decline of PCT less than 80% ofpeak value and PCT ≥ 0.5 ng/ml

Increase of PCT above previous andPCT ≥ 0.5 ng/ml

Stopping antibiotics stronglydiscouraged

Stopping antibiotics encouraged Continuing antibiotics encouraged Changing antibiotics stronglyencouraged

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patients. Even in patients with bacterial pneumonia, depending

on the patients analysed, in up to one third of patients with

bacterial pneumonia, PC in the lower range has been

reported, whereas in approximately another third PC was

high. Normal or low PC values were also reported in patients

with viral or atypical pneumonia. Nevertheless, measurement

of PC in patients with pneumonia is recommended – not as aprimary diagnostic tool, but to follow up and assess efficacy of

treatment, both in patients with community-acquired (CAP)

and ventilator-associated pneumonia (VAP). Various studies

indicate that declining PC levels in patients with pneumonia

indicate a favourable prognosis, whereas persistently elevated

PC levels were more frequently observed in patients with

a fatal course.29,63 In other studies, the duration of antibiotic

treatment in patients with CAP and VAP was shorter when

PC-guided-algorithms were used instead of fixed treatment

courses.33,34,64,65 An individual approach to therapy in

patients with pneumonia is recommended, since pneumonia

is a very heterogeneous disease, with various aetiology,associated pathogens, severity and patients’ risk profile. Tis

recommendation to use a PC-guided approach is part of the

German guideline for the treatment of lower respiratory tract

infection and CAP.66 In various constellations, short treatment

courses with antibiotics are sufficient in some patients

without major risk factors and less severe disease.67,68 PC

measurement supported these individual decisions, if specific

PC-dependent algorithms were included in the therapeutic

approach in patients with CAP and lower respiratory tract

infections.33,34,64

In conclusion

Daily quantitative measurement of PC is recommended on

the ICU in all critically ill patients with a suspected diagnosis

of systemic inflammation, after focus removal and during

antibiotic therapy to monitor systemic inflammation and

success of therapy. Tis approach affects therapeutic and

diagnostic decisions, if plasma levels are interpreted together

with other clinical data. Further indications for measurement

of PC in the ICU are related to specific questions, e.g., the

diagnosis of bacterial sepsis, meningitis, diagnosis of a possible

focus of infection e.g. endocarditis, assessment of the presence

and severity of systemic inflammation e.g. in patients withpancreatitis or as an additional tool to exclude severe systemic

inflammation in patients with primary local infection or

bacterial colonisation. o guide antibiotic therapy, PC can be

used not only in patients with lower respiratory tract infections

and CAP but also in sepsis and severe sepsis of different

aetiology on the ICU, resulting in shorter treatment courses

without harming the patient, this in accordance with currently

available evidence.

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93. Moosig F, Csernok E, Reinhold -Keller E, Schmitt W, Gross WL. Elevated procalci-tonin levels in active Wegeners granulomatosis. J Rheumatol 1998;25:1531-1533.

94. Eberhard OK, Haubitz M, Brunkhorst FM, Kliem V, Koch KM, Brunkhorst R.Usefulness of procalcitonin for differentiation between activity of systemicautoimmune disease (systemic lupus erythematosus/systemic antineutrophilcytoplasmatic antibody-associated vasculitis) and invasive bacterial infection.Arthrit is Rheum 1997;40:1250-1256.

95. Dahaba AA, Rehak PH, List WF. Procalcitonin and C-reactive protein plasma con-centrations in nonseptic uremic patients undergoing hemodialysis. IntensiveCare Med 2003;29:579-583.

96. Steinbach G, Bölke E, Grünert A, Orth K, Störck M. Procalcitonin in patients withacute and chronic renal insufficiency. Wien Klin Wochenschr 2004;116(24):849-853.

97. Meisner M, Hüttemann E, Lohs T, Kasakov L, Reinhart K. Plasma concentrationsand clearance of procalcitonin during continuous veno-venous h emofiltrationin s eptic patients . Shock 2001;15:171-175.

98. Schmidt M, Burchardi C, Sitter T, Held E, Schiffl H. Procalcitonin in patientsundergoing chronic hemodialysis. Nephron 2000;84:187-188.

99. Elefsiniotis IS, Skounakis M, Vezali M, Pantazisa KD, Petrocheilou b A, PirounakiaM, et al. Clinical significance of serum procalcitonin levels in patients with acuteor chronic liver disease. Eur J Gastroenterol Hepatol 2005;18:525-530.

100. Fries M, Kunz D, Gressner AM, Roissant R, Kuhlen R. Procalcitonin serum levelsafter ouf-of-hospital cardiac arrest. Resuscitation 2003;59:105-109.

101. Oppert M, Reinicke A, Müller C, Barckow D, Frei U, Eckard KU. Elevations in pro-calcitonin but not C-reactive protein are associated with pneumonia after car-diopulmonary resuscitation. Resuscitation 2002;53:167-170.

102. Becker KL, Nylen ES, Arifi AA, Thompson KA, Snider RH, Alzeer A. Effekt of classicheatstroke on serum procalcitonin. Crit Care Med 1997;25:1362-1365.

103. Hausfater P, Hurtado M, Pease S, Juillien G, al. e. Is procalcitonin a marker ofcriticall illness in heatstroke? Intensive Care Med 2008;DOI10.2007/s00134 -008-1083y.

104. Chiesa C, Panero A, Rossi N, Stegagno M, De Giusti M, Osborn JF, et al. Reliabilityof procalcitonin concentrations for the diagnosis of sepsis in critically illneonates. Clinical Infectious Diseases 1998;26:664-672.

105. Turner D, Hammerman C, Rudensky B, Schlesinger Y, Goia C, Schimmel MS.Procalcitonin in preterm infants during the first few days of life: introducing anage related nomogram. Arch Dis Chiold Fetal Neonatal 2006;9:F283-286.

106. Stocker M, Fontana M, el Helou S, Wegscheider K, Berger TM. Effect of pro-calcitonin-guided decision making on duration of antibiotic therapy in sus-pected neonatal early-onset sepsis: prospective randomized intervention trial.Neonatology 2010;97:165-174.

107. Bihan H, Becker KL, Snider RH, Nylen E, Vittaz L, Lauret C, et al. Calcitonin precur-

sor levels in human medullary thyroid carcinoma. Thyroid 2003;13:819-822.

108. Kuse ER, Jaeger K. Procalcitonin increase after anti-CD3 monoclonal antibodytherapy does not indicate infectious disease. Transpl Int 2001;14:55.

109. Sabat R, Höflich C, Döcke WD, Oppert M, Kern F, Windrich B, et al. Massive ele-vation of procalcitonin plasma levels in the absence of infection in kidneytransplant patients treated with pan-T-cell antibodies. Intensive Care Med2001;27:987-991.

110. Abramowi cz D, Schandene L, Goldmann M. Release of tumor necrosis factor,interleukin-2, and gamma-interferon in serum after injection of OKT2 monoclo-nal antibody in kidney transplant recipients. Transplantation 1989;47:606-608.

111. von Heimburg D, Stieghorst W, Khorram-Sefat R, Pallua N. Procalcitonin – asepsis parameter in severe burn injuries. Burns 1998;24:745-750.

112. Lavrentieva A, Konta kiotis T, Lazaridis L, Tsotolis N, Koumis J, Kyriazis G, et al.Inflammatory markers in patients with severe burn injury. What is the best indi-cator of s epsis? Burns 200 6;33:189-194.

113. Ulrich D, Noah EM, Pallua N. Plasma-Endotoxin, Procalcitonin, C-reaktives

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Accepted April 2013

Abstract

Acute lower respiratory tract infection (LRI) is common in

children and in up to 15% of hospitalized cases subsequent

referral to a paediatric intensive care unit is necessary.Respiratory syncytial v irus, parainfluenza viruses, rhinoviruses

and newly emerging viruses like human metapneumovirus,

human bocavirus and coronaviruses are commonly isolated

pathogens from these patients. Developmental aspects of

respiratory anatomy and mechanics are of great importance

in the pathophysiology of LRI and explain why children with

the condition are more susceptible to respiratory insufficiency

compared to adults. Studies on histopathological changes

in viral LRI have identified both direct viral induced

cellular damage and immunopathology as playing roles in

the development of severe respiratory distress. Molecular

diagnostic tools, most importantly real time polymerase chain

reaction, have shown that mixed viral infections are common.

Clinical relevance is, however, uncertain. Host factors like

age, co-morbidity and possibly genetic factors are probably

more important in modulating disease severity. reatment

is limited to supportive measures. Consensus regarding the

optimal mode of invasive ventilatory support is lacking. A shift

from invasive ventilatory support to non-invasive ventilation

is occurring. Ribavirin, corticosteroids, immunoglobulines

and bronchodilators are ineffective in treating viral LRI.

Antibiotics are prescribed commonly, but their effect has not

been demonstrated in prospective randomised trials and abacterial pathogen is only found in half the cases. Surfactant

and small interfering RNAs may be promising treatment

options in the future. Prospective studies however are needed

to demonstrate their effect.

Introduction

Acute lower respiratory tract infection (LRI) is common in

children and is associated with high morbidity and mortality.

Pneumonia and bronchiolitis are the most common clinical

syndromes of acute LRI in children, however, specific

Acute viral lower respiratory tract infections in paediatricintensive care patients

definitions are lacking. In particular, in infants and young

children signs and symptoms of pneumonia and bronchiolitis

overlap to a great extent. Terefore, many studies use the

term acute lower respiratory tract infection, making nodifferentiation between pneumonia and bronchiolitis. LRI in

infants and children may be severe and necessitate admission

to a paediatric intensive care unit (PICU). Tis paper will

give an up-to-date review on epidemiology, pathophysiology

and treatment options of acute life-threatening viral LRI in

children. Te aim is to provide health care workers who are less

familiar with treating severely ill children with more insight

into this condition.

Epidemiology

LRI accounts for about 20% of all paediatric hospitalizations

in the US; of them up to 15% are admitted to a PICU.1 LRI

is one of the most frequent reasons for mechanical ventilator

support in the PICU. In children under the age of 1 year, viral

bronchiolitis is the predominant cause (44%), after the first year

pneumonia becomes more important (25%).2 In the first year of

life, hospital admission due to LRI is predominantly caused

by viral bronchiolitis. Hospital admittance rates for viral

bronchiolitis are approximately 20-30 per 1000 for children

younger than 1 year in the US and Europe.3 Up to 10% of these

patients may need PICU admission for supportive treatment

and monitoring.4

Causative agents

In up to two-thirds children aged 6 months to 15 years, LRI

is caused by a virus.5 At least 26 different viruses have been

described with respiratory syncytia l virus (RSV), parainfluenza

viruses and rhinoviruses as the most common agents.5 In

children under the age of 1 month, adenovirus (10%) and

herpes simplex virus (5.5%) are also important pathogens. In

addition, adenoviruses may also lead to severe, life-threatening

pneumonia in both older children and adults.6,7 Especially

serotypes 3, 7, and 14 are capable of inducing severe necrotising

S.T.H. Bontemps, J.B. van Woensel, A.P. Bos

Emma Children’s Hospital/Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

Correspondence

S.T.H. Bontemps – e-mail: [email protected]

Keywords - Lower respiratory tract infection, children, paediatric intensive care unit, virus

R E V I E W

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pneumonia.8 Among the more recently discovered viruses,

human metapneumovirus (2001), human bocavirus (2005)

and coronaviruses are recognised as a frequent cause of LRI

in children.5,8,9 Finally, influenza A or B viruses mainly cause

pneumonia in children under 2 years of age. Te importance

of viruses as a cause of life-threatening LRI was emphasised

by the emergence of severe acute respiratory syndrome (SARS)in 2002, avian Influenza A (H5N1) in 2003 and pandemic

Influenza A (H1N1) in 2009.

Differences between children and adults

Several developmental factors contribute to the relatively high

susceptibility of infants for developing respiratory insufficiency

over the course of a LRI.

In the first place, developmental aspects leading to differences

in pulmonary anatomy are of interest. Children have fewer

alveoli and far less alveolar surface area compared to adults.

Te number of alveoli grows from 20 million at birth to 300

million at the age of 8 years. Simultaneously, alveolar surfacearea increases from 2.8 m2 to 32 m2. In adulthood alveolar

surface comprises 75 m2. Collateral ventilation channels are

not developed in the first years of life, allowing no ventilation

distal to an obstructed airway. Interalveolar channels (pores

of Krohn) appear at 1 to 2 years of age and bronchiole-

alveolar channels (canals of Lambert) at 6 years. Terefore,

young children are more at risk of developing atelectasis and

consequently ventilation-perfusion mismatch.

Secondly, lung mechanics are different in children. Children

have reduced elastic recoil of their alveoli. More importantly

the chest wall of an infant is more compliant and the ribs are

aligned more horizontally compared to adults. Tis hampers

the generation of negative intra-pleural pressure in cases of

imminent respiratory distress. In contrast to the chest wall

compliance, lung compliance is reduced in infants, leading

to a greater tendency of the lung to collapse in the setting of

respiratory disease.

Tirdly, children have significantly narrower airways compared

to adults. Considering Poiseuille’s law, we can imagine how

resistance to airflow can rise dramatically with only a minor

decrease in diameter.

Fourthly, because of relatively weak cartilaginous support

of the airways, forced expiration and subsequent rise inintra-pleural pressure may easily cause dynamic compression

and airway obstruction. Finally, infants are more at risk of

serious respiratory infections compared to adults because

their immune system is still immature. As the child grows so

the lungs mature. Compliance of the lungs increases by 150%

during the first year of life and after the age of 6 years lung

recoil increases as well. Progressive ossification of the rib cage

and growing intercostal muscle tone decrease the compliance

of the chest wall. By the age of 10 years the ribs are oriented

downward.

Pathology and pathophysiology

Several biological processes occur during viral infection of

the lung. Viuff et al. found widespread apoptosis in respiratory

epithelial cells in bovine RSV infected calves.10 In addition, a

marked neutrophil infiltration was noted contributing to the

obstruction of airways and alveolar filling. Tese findings

suggest the importance of both direct viral induced cellulardamage, mainly by apoptosis, as well as immunopathology

in the development of severe respiratory distress during viral

LRI.10-12 Apoptosis and inflammation are probably important

mechanisms in the clearance of viral pathogens but when out of

balance may also lead to bystander injury and as such contribute

to the injurious effects in the lung. It has been shown that severe

clinical signs and pathological changes continue even after

clearance of the virus.10 Te abundant neutrophil influx as seen

during RSV LRI probably plays a key role in the development

of acute respiratory distress syndrome (ARDS) in many

children with severe RSV. A characteristic feature of RSV LRI

is the obstruction of small airways and air-trapping by plugs ofmucus, fibrin and debris of leucocytes and dead epithelial cells.

Because children have small airways, this can already cause

hypoventilation. Obstruction is further aggravated by oedema

and peribronchiolar cellular infiltrates. Severe progressing

disease with subsequent alveolar and interstitial involvement

is characterised by infection and cell death of alveolar epithelial

cells and alveolar filling. Inflammatory infiltrates and oedema

of alveoli and interstitial tissues cause severe difficulties in gas

exchange and may present clinically as ARDS.11,13

Clinical patterns

Both pneumonia and bronchiolitis can cause severe respiratory

distress. Bronchiolitis occurs mainly in young children under the

age of 1 year and is associated with widespread crackles, wheezing

and hyperinflation.3 Pneumonia may also occur in older children

and may be associated with consolidation, infiltration or pleural

effusion.14 Initial signs of LRI usually include cough, fever and

poor feeding. Because of the compliant chest wall and reduced

lung compliance, the work involved in breathing is higher in

children compared with adults. Clinically this presents as

marked tachypnoea, intercostal retractions, nasal flaring and

the use of respiratory accessory muscles. Obstructed narrow

airways may cause hyperinflation, wheezing and a prolongedexpiratory phase. Some infants will stop breathing from fatigue

when facing excessive respiratory demands. RSV is also able to

cause significant apnoea not induced by fatigue in which altered

sensitivity of laryngeal chemoreceptors may be involved.15 Despite

the increased work of breathing, hypoxemia and hypoventilation

may develop. Atelectasis is common and may worsen hypoxemia.

Diagnostics

Te aetiology of childhood LRI is often difficult to

establish. Clinical signs and symptoms of viral and bacterial

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Acute viral lower respiratory tract infections in paediatric intensive care patients

LRI highly overlap and the isolation of a causative agent

is hampered by the difficulty of collecting lung secretions

from the lower respiratory tract. However, sputum induction

through the inhalation of hypertonic saline can provide a

solution to this problem.16 Bronchoalveolar lavage (BAL) is an

invasive technique that involves endotracheal intubation or

bronchoscopy. Terefore, it is more common to obtain materia lfrom the upper respiratory tract by nasopharyngeal washes or

swabs. It is still controversial whether or not viruses isolated

from the upper respiratory tract truly reflect the causative

agents involved in lower respiratory disease. In particular,

rhinoviruses are notorious within this context. Tey are found

in up to 35% of asymptomatic children and remain detectable

for five weeks after infection.17,18

Molecular Diagnostic Tools

raditionally used methods for detecting respiratory

viruses include viral culture, immunofluorescense assays

and measuring antibodies in paired serum samples. Viralculture is unfit for guiding initial management strategy since

it takes days to weeks before the results are known. More

importantly, detecting viruses through cultures is not possible

for all viruses.19 Immunofluorescense assays improve patient

outcome by shortening hospitalization and reducing antibiotic

use.20 Furthermore, an important financial benefit has been

noted.20,21 Real time polymerase chain reaction (PCR) has

proved to surpass other methods for diagnosing viral LRI.

Besides its ability to present results readily, it is possible

to detect a much broader range of viral pathogens with this

technique.1,19,22-24 Multiplex PCR assays are very sensitive and

specific. Potential benefits lie in the prevention of nosocomial

infections, reduction of diagnostic procedures and possibly

antibiotic use.21

The antibiotic controversy

Differentiating between viral, bacterial or mixed infections

on clinical grounds is not usually possible and bacterial

co-infection is not uncommon in viral LRI.25-28 Furthermore,

some patients are suspected of concomitant sepsis. For these

reasons the majority (55-95%) of children admitted to the

PICU with viral LRI are still treated with antibiotics. Tis

poses considerable overtreatment because a bacterial pathogenis only isolated in 18-57% of cases.26-28 A number of studies,

performed in an emergency department or paediatric ward,

found a reduction in the prescription of antibiotics if the results

of fast viral testing by PCR were available. Only one study has

been performed in a PICU setting, showing that PCR had no

impact on antibiotic use in children ventilated for LRI. 29

Physicians seem more reluctant to withhold antibiotics when

treating severely ill patients with LRI. Clinical deterioration

may be the result of bacterial superinfection and results of

bacterial cultures are usually not available on admission. It has

been shown that mechanically ventilated patients with RSV

LRI with a positive culture of blood or endotracheal aspirate

require prolonged ventilator support, suggesting that in some

infants bacterial superinfection contributes to the development

of respiratory failure.27,30 Unrecognised bacterial co-infection

may aggravate the clinical course, especially in patients

with underlying diseases. In contrast, it is unlikely that allpatients needing PICU admission will benefit from antibiotics.

Prospective randomized trials are needed to show whether

patients with viral LRI admitted to the PICU benefit from

treatment with antibiotics. Performing a BAL on admission

may help in guiding antibiotic treatment, as previously shown

by Bonten et al. in adult ICU patients. 31

Mixed infections

Most children suffering from viral respiratory disease only

have mild symptoms. Determining why a small subgroup of

children will develop a severe, life-threatening syndrome

poses an intriguing scientific question. PCR has shown that viral co-infections in paediatric LRI occur in up to 35% of

cases.17,22,32,33 Te clinical relevance of the detection of multiple

viruses, however, is uncertain and there is much controversy on

this point.19,32-35 A cumulative pathogenic effect may result in

more severe disease during co-infections. Viral load in children

with RSV and hMPV infections has indeed been associated

with disease severity.36,37,38 Alternatively, there are reports that

rhinovirus mediates triggering of interferon stimulated genes

inducing an antiviral state, thereby protecting the child from

a severe course of disease after infection with a second virus.17

Clearly, a major role of multiple infections in the determination

of disease severity has not been demonstrated.

Host factors

Host factors are likely to be of greater importance in

determining disease severity. Well known risk groups for

severe disease include young infants under the age of 3 months,

premature infants and those with an underlying illness such

as chronic lung disease, congenital heart disease, neurological

disease or immunodeficiency.3,11 In addition, genetic factors

may be of importance. Polymorphisms in genes encoding for

LR4, chemokine receptors and interleukins and surfactant

proteins, all of which may modulate the inflammatoryresponse, have been associated with disease severity in RSV

LRI.39,40

Treatment

Antiviral drugs

Ribavirin has broad antiviral activity against both DNA and

RNA viruses. Tere has been much debate on the effectiveness

of Ribavirin in infections caused by adenovirus, human

metapneumovirus, parainfluenza virus and RSV.7,41-44 Apparent

clinical success is limited to case reports and small series and

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as far as we know there have been no prospective randomized

controlled trials.45 Ribavirin is therefore not recommended.

Varicella-Zoster or Herpes Simplex LRI may be treated with

Aciclovir. Influenza A and B infections can be treated with

neuraminidase inhibitors such as Oseltamivir and Zanamivir.

If started within 48 hours after the onset of symptoms, they

reduce median time to resolution of symptoms by 0.5-2.5days.46 According to WHO guidelines, Oseltamivir is also

the drug of choice in the treatment of pandemic influenza A

(H1N1) and avian influenza (H5N1).47,48

Antibiotics

Te British Toracic Society (BS) advises considering treating

every child with severe LRI with antibiotics since bacterial

and viral LRI cannot be reliably distinguished from each

other.49 Randomised controlled trials evaluating the effect of

antibiotics in mild to moderate RSV LRI, have shown that

antibiotics are not beneficial.50 However, no such data for

children admitted to a PICU are available. Consequently,a reduction in antibiotic use is unlikely until prospective

trials have shown whether these patients will benefit from

antibiotics. Performing a BAL on admission may be helpful in

guiding antibiotic treatment.

Corticosteroids and Intravenous immunoglobulines

Besides cytopathic effects on respiratory epithelial cells, the

host cellular immune response contributes to the pathogenesis

of RSV LRI. Terefore, patients may benefit from treatment

with immunosuppressive drugs such as corticosteroids or

intravenous immunoglobulin. Tere is abundant evidence,

however, that corticosteroids are not effective in the treatment

of RSV. In 2010 a Cochrane review found no clinical relevant

effect of systemic or inhaled glucocorticoids in the treatment of

acute viral bronchiolitis.51 Furthermore, no beneficial effect of

dexamethasone was found in children mechanically ventilated

for severe RSV LRI.52,53 Although not based on solid scientific

data, corticosteroids are not recommended for treatment

of coronaviruses (including SARS), seasonal influenza,

pandemic H1N1 and avian influenza H5N1.7,47,48 Intravenous

immunoglobulin with a high neutralizing activity against RSV

has showed to be ineffective and should not be used.54

Surfactant

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