Anda di halaman 1dari 5

CMJ1105-CME-Farrar.

qxd 9/5/11 3:55 PM Page 483

CME Tropical medicine Clinical Medicine 2011, Vol 11, No 5: 483–7

The most important feature of severe dence in support, argues that moderate
Dengue dengue is increased capillary perme- viraemia is controlled in asymptomatic
ability leading to dengue shock syn- dengue infection. The host immune
Jamie Whitehorn, Wellcome Trust clinical drome (DSS). When shock becomes system develops long-lasting immunity to
research fellow, Hospital for Tropical established, mortality rates of ⬎10% the serotype of the infecting strain and
Diseases, Ho Chi Minh City, Vietnam; have been reported, although they can be short-lived cross-protection against het-
Jeremy Farrar, director, Hospital for less than 1% when patients are looked erologous serotypes. The levels of cross-
Tropical Diseases, Oxford University after by experienced clinical teams. protective antibody directed against the
Clinical Research Unit and Wellcome Trust
The dengue virus is a single stranded, heterologous serotypes fall below neutral-
Major Overseas Programme, Ho Chi Minh
positive-sense RNA virus approximately ising levels after a few months. From this
City, Vietnam
11 kb in length. It is a member of the stage onward, infection with a second het-
Flavivirus genus, which also includes erologous strain may result in increased
Dengue is the most rapidly spreading yellow fever, Japanese encephalitis and viral uptake via FcÁ receptors into mono-
arboviral disease globally, occurring in West Nile virus. There is considerable cytes and enhanced viral replication.
over 100 countries. The burden of dengue genetic diversity in the dengue virus Severe disease has been reported during
has increased at least fourfold over the last family with four serotypes (Den I, II, III primary infections, however, and not all
three decades: it is estimated that there are and IV). secondary infections lead to severe dis-
50 million dengue infections and 616,000 The major global vector is Aedes ease, so other theories (viral and host
disability-adjusted life years annually. aegypti. The adult mosquito is strongly genetic factors) have been suggested to try
Approximately 500,000 severe dengue anthropophilic, prefers resting in shel- to explain the complex epidemiologic and
cases are reported annually, with 20,000 tered dark areas inside houses, with a immunopathogenetic features.
dengue related deaths in 2002. These fig- diurnal feeding pattern usually peaking
ures are inevitably a gross underestimate mid-morning and late afternoon. Clinical features
as many countries do not report their data.
Dengue fever is a mild, self-limited
The clinical management and outcome Pathophysiology
of patients with dengue still varies widely febrile episode, commonly associated
from country to country. This is particu- The most widely cited hypothesis to with a rash. It usually begins with fever,
larly true as dengue emerges in new areas explain the features of severe dengue is respiratory symptoms, anorexia, nausea,
of the world where the public health sys- increased viral replication due to vomiting and headache. Back pain, myal-
tems are not experienced in the preven- enhanced infection of monocytes in the gias, arthralgias and conjunctivitis may
tion of the disease, or the surge capacity presence of pre-existing antidengue anti- also occur. The initial fever usually
in clinics and hospitals is not available to bodies at subneutralising level (antibody- resolves within one week, and a few days
deal with the sudden increase in the dependent immune enhancement). later a generalised morbilliform or mac-
number of patients and the clinical expe- This observation, which has strong epi- ulopapular rash may develop. Fever may
rience is limited. In these settings, mor- demiologic and in vitro experimental evi- return with the rash (Figs 1 and 2).
tality and morbidity are often higher
than in other regions where dengue has dĂďůĞϭ͘tŽƌůĚ,ĞĂůƚŚKƌŐĂŶŝnjĂƚŝŽŶ;t,KͿĐĂƐĞĐůĂƐƐŝĨŝĐĂƚŝŽŶ͘
been endemic for decades. Dengue
Dengue cases have been seen more fre- ĐƵƚĞĨĞďƌŝůĞŝůůŶĞƐƐ͕ůŝǀĞŝŶŽƌƚƌĂǀĞůƚŽĞŶĚĞŵŝĐƌĞŐŝŽŶǁŝƚŚƚǁŽŽƌŵŽƌĞŽĨƚŚĞĨŽůůŽǁŝŶŐ͗
quently outside endemic areas in recent • ŚĞĂĚĂĐŚĞĂŶĚͬŽƌƌĞƚƌŽͲŽƌďŝƚĂůƉĂŝŶ
decades. This is due to the enormous • ŶĂƵƐĞĂĂŶĚͬŽƌǀŽŵŝƚŝŶŐ
shift to urban living, increase in tourism, • ƌĂƐŚ
business related travel and global deploy- • ĂĐŚĞƐĂŶĚƉĂŝŶƐ
ment of military and international non- • ƚŽƵƌŶŝƋƵĞƚƚĞƐƚƉŽƐŝƚŝǀĞ
governmental organisations. No vaccine • ůĞƵŬŽƉĞŶŝĂ
or prophylaxis is available. ŶLJǁĂƌŶŝŶŐƐŝŐŶƐ;ĂďĚŽŵŝŶĂůƉĂŝŶ͕ƉĞƌƐŝƐƚĞŶƚǀŽŵŝƚŝŶŐ͕ĨůƵŝĚĂĐĐƵŵƵůĂƚŝŽŶ͕ŵƵĐŽƐĂůďůĞĞĚŝŶŐ͕
ůĞƚŚĂƌŐLJ͕ůŝǀĞƌĞŶůĂƌŐĞŵĞŶƚ͕ŝŶĐƌĞĂƐĞŝŶ,d͕ĨĂůůŝŶŐƉůĂƚĞůĞƚĐŽƵŶƚͿǁŝƚŚůĂďŽƌĂƚŽƌLJĐŽŶĨŝƌŵĂƚŝŽŶ͘

Severe dengue including DSS


Epidemiology
^ĞǀĞƌĞƉůĂƐŵĂůĞĂŬĂŐĞůĞĂĚŝŶŐƚŽ^^
Dengue is now classified by the World &ůƵŝĚĂĐĐƵŵƵůĂƚŝŽŶĂŶĚƌĞƐƉŝƌĂƚŽƌLJĚŝƐƚƌĞƐƐ͗
Health Organization (WHO) into dengue • ƐĞǀĞƌĞďůĞĞĚŝŶŐ
fever and severe dengue (Table 1). Full
details of the 2009 WHO scheme can be
• ƐĞǀĞƌĞŽƌŐĂŶŝŶǀŽůǀĞŵĞŶƚ;ůŝǀĞƌ͕E^͕ŚĞĂƌƚ͕ŬŝĚŶĞLJƐĂŶĚŽƚŚĞƌƐͿ

CNS ⫽ central nervous system; DSS ⫽ dengue shock syndrome; HCT ⫽ haematocrit.
found online (see key references).

© Royal College of Physicians, 2011. All rights reserved. 483


CMJ1105-CME-Farrar.qxd 9/5/11 3:55 PM Page 484

CME Tropical medicine

The two groups of dengue (dengue seminated intravascular coagulation


fever and severe dengue) form part of a (DIC). Patients with DSS have significant
continuous spectrum of severity. The abnormalities in all the major pathways
most important clinical features of severe of the coagulation cascade.
dengue are capillary permeability leading
to DSS. Other complications include
severe mucosal bleeding (and, less com-
Diagnosis
monly, intracerebral and pulmonary Classic dengue illness can be an easy
haemorrhage), pleural effusions, diagnosis to make in endemic regions
encephalopathy, pneumonia and liver with experienced clinical staff and a high
dysfunction. prior probability that a febrile illness
Thrombocytopenia is a very common with rash and thrombocytopenia is
feature in dengue and there is abnormal caused by dengue. However, most symp-
platelet function. Mild prolongation of toms and signs accompanying dengue
prothrombin and partial thromboplastin infection are common to many febrile ill-
times with reduced fibrinogen levels is nesses, with few features that reliably dis-
common, but fibrin degradation prod- criminate dengue especially early on.
ucts have not been found to be elevated Proof of a dengue infection depends on
to a degree consistent with classic dis- confirmatory reverse transcriptase-poly-
merase chain reaction (RT-PCR), dengue
serology, specific dengue NS1 antigen
detection or viral isolation, if available.
Serologic confirmation of acute dengue
infection relies on the demonstration of
specific immunoglobulin (Ig) M and
IgG antibodies against dengue in
patients’ serum.
The differential diagnosis is extensive &ŝŐϮ͘ŚĂƌĂĐƚĞƌŝƐƚŝĐƐŬŝŶŵĂŶŝĨĞƐƚĂƚŝŽŶƐŝŶ
and varies depending on where the patient ĐŽŶǀĂůĞƐĐĞŶƚĚĞŶŐƵĞ͗;ĂͿĞĂƌůLJ
is seen, but would include malaria, ĐŽŶǀĂůĞƐĐĞŶƚŵĂĐƵůĂƌĚŝĨĨƵƐĞƌĂƐŚ
typhoid, leptospirosis, scrub and murine ŽĐĐƵƌƌŝŶŐŝŶƚŚĞĨŝƌƐƚǁĞĞŬĂĨƚĞƌƌĞĐŽǀĞƌLJ͖
typhus, septicaemia, other viral haemor- ;ďͿƚLJƉŝĐĂůĐŽŶǀĂůĞƐĐĞŶƚƌĂƐŚǁŝƚŚ͚ŝƐůĂŶĚƐ
ŽĨǁŚŝƚĞŝŶĂƐĞĂŽĨƌĞĚ͛͘
rhagic fevers (eg Ebola, Lassa fever),
chikungunya, and Rift Valley fever (usually pressure and peripheral perfusion are
without a rash). A pulse pressure of less essential. For patients with DSS, WHO
than 20 mmHg is one of the early mani- recommends immediate volume replace-
festations of shock, usually occurring ment with isotonic crystalloid solutions,
before the onset of systolic hypotension. followed by the use of plasma or colloid
solutions, specifically dextrans, for pro-
Management found or continuing shock.
Although there are currently no spe-
The mainstay of treatment is prompt, but
cific drugs for dengue, there is effective
careful, fluid resuscitation. If appropriate
treatment based primarily on careful
volume resuscitation is instituted at an
fluid management. Judicious restoration
early stage, shock is usually reversible. In
of circulating plasma volume is the cor-
some severe cases, and in patients inappro-
nerstone of therapy for patients with
priately resuscitated, patients may progress
DSS. For uncomplicated dengue fever,
to irreversible shock and death. Careful
less aggressive oral or parenteral fluid
clinical judgement is required throughout
therapy is frequently indicated.
the patient’s stay in hospital to maintain an
&ŝŐ ϭ͘ĐƵƚĞƐŬŝŶŵĂŶŝĨĞƐƚĂƚŝŽŶƐŽĨ effective circulation whilst assiduously
ĚĞŶŐƵĞ͗;ĂͿĐŚĂƌĂĐƚĞƌŝƐƚŝĐŵŝŶŽƌďůĞĞĚŝŶŐ Severe dengue and dengue shock
avoiding fluid overload.
ŶĞĂƌŝŶũĞĐƚŝŽŶƐŝƚĞƐ͖;ďͿƐĞǀĞƌĞďůĞĞĚŝŶŐ syndrome
ĐĂƵƐĞĚďLJƉƌĞƐƐƵƌĞĨƌŽŵďůŽŽĚƉƌĞƐƐƵƌĞ Close attention and regular review
ĐƵĨĨ͖;ĐͿƌĂƐŚŝŶĞƐƚĂďůŝƐŚĞĚĚĞŶŐƵĞƐŚŽĐŬ (every 15–30 minutes during episodes of This section focuses on the manage-
ƐLJŶĚƌŽŵĞ͘ shock) of haematocrit (HCT), pulse ment of DSS. Management of unusual

484 © Royal College of Physicians, 2011. All rights reserved.


CMJ1105-CME-Farrar.qxd 9/5/11 3:55 PM Page 485

CME Tropical medicine

complications, such as dengue the patient’s clinical condition has sta-


encephalopathy or fulminant hepatitis • marked elevation of (or rapidly
bilised after this time (wider pulse pres-
rising) HCT
is not addressed as it is similar to the sure, stable pulse rate, warm peripheries,
standard management. • pleural effusions or ascites at the time
stable HCT), the rate of fluid administra-
of presentation with shock. Large vol-
Patients admitted with established DSS umes of fluid must be present to be tion may be reduced to 10 ml/kg/hr for
should be cared for in an intensive care clinically detectable, implying either two hours, then gradually reduced to
or high dependency unit. Extreme care is recent onset of catastrophic leak or a maintenance levels over the next
needed to balance the requirement for steady loss of fluid over a longer time 6–8 hours. A suitable schedule might be
intravenous (iv) fluid to maintain plasma before the development of haemody- as follows:
volume against the risk of leakage of
administered fluid into the interstitial
namic compromise. • 10 ml/kg/hr for two hours
space. The leaked fluid may contribute to • 7.5 ml/kg/hr for two hours
the development of pleural effusions, Young patients • 5 ml/kg/hr for four hours, then
ascites, respiratory compromise and the • 2–3 ml/kg/hr for 24–36 hours.
potential downward spiral towards Severe dengue occurs infrequently in For most patients, iv therapy can then
multi-organ failure, DIC and death. As is infants, but special care must be taken be stopped, provided that the clinical
often the case in looking after the criti- with the fluid management in this age condition has been stable for 24 hours.
cally ill, patients with the severest capil- group. Fluid accounts for a greater pro- If there is evidence of ongoing cardio-
lary leak syndrome and most at risk of portion of body weight in infants and vascular compromise after the first hour
these complications are also those in the minimal daily requirements are corre- of treatment (no improvement in pulse
greatest need of the most aggressive cir- spondingly greater. Cardiovascular and pressure or pulse rate, persisting periph-
culatory support. Getting this balance of renal function are still developing and eral shutdown, a rising HCT), a colloid
fluid resuscitation and ongoing capillary there is less reserve to cope with distur- solution (6% dextran 70 or 6% starch
leak right is the most difficult issue in bance. Finally, capillary beds are intrin- solution) should be substituted for the
managing patients with DSS. sically more permeable than those of crystalloid solution at an initial rate of
older children or adults. All infants 10–20 ml/kg/hr. Hyperoncotic prepara-
must be treated as high risk patients and tions such as 10% dextran have been
Assessment warrant early intervention with very implicated in the development of renal
Rapid clinical assessment of pulse, blood careful resuscitation and intensive mon- failure when used in hypovolaemic
pressure (BP), peripheral perfusion, itoring. patients and should be avoided. If large
urine output and mental state deter- volumes of colloid are infused, regular
mines initial management. The results of assessment of the coagulation profile is
Resuscitation and management
basic laboratory investigations including required.
HCT (preferably available on the ward) Resuscitation with parenteral fluids Frequent observation of vital signs,
and platelet count are useful, but initia- should be started immediately after the mental state, urine output and serial HCT
tion of treatment must not be delayed initial rapid assessment. Reliable iv access measurements are used to assess the
pending their availability. Detailed exam- must be secured as soon as possible. response to treatment. After initial resus-
ination should be carried out once resus- Rarely, in patients with profound shock, citation, most patients can be managed
citation is in progress. a venous cutdown or insertion of an successfully with the reducing schedule of
intra-osseous line may be necessary. All isotonic crystalloid fluid until the reab-
patients with shock or respiratory com- sorptive phase of the illness begins
Features of severe disease promise should receive oxygen by face around day 6–7. If there are further
mask or nasal cannula. A regular episodes of cardiovascular decompensa-
The following features are commonly
schedule of clinical observations (pulse, tion after the initial episode, supplemen-
associated with severe disease and a com-
BP) at least every 30–60 minutes should tary treatment with small infusions of
plicated clinical course:
be instituted, with a detailed record of all 5–10 ml/kg of colloid may be required.
• poor peripheral perfusion fluid intake and output. The HCT should Patients with no recordable pulse or
• narrow pulse pressure (⬍10 mmHg) be measured every two hours for the BP must be managed more vigorously.
with poor peripheral perfusion first six hours and thereafter every Profoundly shocked patients require col-
• compromised cerebral perfusion 4–6 hours until the patient is stable. loid therapy (6% dextran 70 or 6% starch
(lethargy, irritability, drowsiness or For most patients with DSS, resuscita- solution) immediately. Despite initial
restlessness) tion should be started with an isotonic severity, most patients improve with
• presentation with shock early in the crystalloid solution (physiologic saline, aggressive volume replacement and can
course of the disease (before day 4 of Ringer’s lactate or Ringer’s acetate) at a be managed subsequently as outlined
fever) rate of 10–15 ml/kg over one hour. If above. Central venous pressure (CVP)

© Royal College of Physicians, 2011. All rights reserved. 485


CMJ1105-CME-Farrar.qxd 9/5/11 3:55 PM Page 486

CME Tropical medicine

monitoring provides useful information who fail to improve clinically after Careful attention to treatment guide-
to direct fluid therapy, but insertion of appropriate fluid resuscitation, particu- lines and frequent reassessment of the
lines should be carried out only by expe- larly if the HCT unexpectedly fall. patient by experienced personnel
rienced personnel and with careful atten- Platelet concentrates and fresh frozen should help to limit the occurrence of
tion to the coagulation state. Inotropic plasma can also be helpful, but are effec- iatrogenic fluid overload. Early identifi-
support may be required in addition to tive for only a few hours. Routine platelet cation of rare patients with catastrophic
volume support. Significant pleural effu- transfusions are not indicated. Steroids leak or severe underlying disease
sions and respiratory compromise are are not recommended in the manage- may allow pre-emptive intervention
likely to develop; pleural and ascitic ment of severe dengue. before there is significant respiratory
drainage and artificial ventilation may all compromise.
prove to be necessary. Metabolic and Early respiratory signs of severe fluid
electrolyte derangements are common in Fluid overload overload include tachypnoea and reces-
these critically ill patients and should be sion, and evidence of ascites and pleural
Clinically significant fluid overload
actively sought and treated. effusions. Pulmonary oedema, cyanosis
develops in several situations:
and respiratory failure are late manifesta-
Blood transfusion • Most commonly, it follows either tions. In addition, severe fluid overload
administration of iv fluid in excessive may compromise cardiac function,
Blood transfusion is indicated only for amounts or too rapidly in patients resulting in hypotension and circulatory
patients with major bleeding and should with moderate capillary leak, or con- failure. Measurement of CVP is helpful
be undertaken with extreme care because tinued parenteral fluid therapy when in differentiating between haemody-
of the problem of fluid overload. Major leak has resolved and the reabsorp- namic instability resulting from severe
bleeding in DSS is almost always associ- tive phase of the disease has begun. overload and instability caused by
ated with severe or prolonged shock, • Rarely, it may be seen in patients inadequate treatment of the underlying
usually from the gastrointestinal tract or with catastrophic leak, for whom hypovolaemia.
vagina. Underlying causes include pro- support of the circulation is not
found thrombocytopenia in combina- possible without administration of
tion with gastritis or stress ulceration. large volumes of fluid. Current research
Internal bleeding may not become • Fluid overload may occur in Vaccine
apparent for many hours until the first patients with underlying chronic
melaena stool is passed. Blood transfu- disease, particularly cardiac or renal A vaccine against dengue would be a
sion should be considered in all patients disorders. major advance in the control of the
disease. In view of the theoretical risks of
antibody-mediated enhancement, a suc-
cessful vaccine would have to offer lasting
Key points protection against all four serotypes. The
leading vaccine candidate at present is a
Dengue is the most widely distributed mosquito-borne viral infection of humans, affecting
chimeric vaccine – a recombinant clone
an estimated 100 million people worldwide each year, with 40% (2.5 billion) of the
world’s population estimated to be at risk for infection based on yellow fever vaccine strain, with
dengue virus membrane and envelope
Dengue should be considered in any patient with fever, particularly if there is a recent protein genes substituted into the con-
travel history to endemic regions struct. This chimeric vaccine has shown
Dengue severity exists as a continuous spectrum of dengue fever through to severe promise in phase II clinical trials and
dengue appears safe and immunogenic. It is antic-
ipated that phase III trials will start in the
The most important of the many clinical features associated with severe dengue, from the near future in multiple countries in Asia
standpoint of threat to life and guiding clinical intervention, is increased vascular
permeability leading to the dengue shock syndrome and Latin America.

During the critical phase of illness, regular review (every 15–30 minutes) of vital signs is
essential (pulse rate, blood pressure, peripheral temperature and haematocrit) Diagnostic aids

The mainstay of treatment is prompt, vigorous, but judicious fluid resuscitation. If it is Making a diagnosis early in the disease
appropriate to institute volume resuscitation at an early stage, shock is usually reversible and the ability to predict which patients
will progress to severe disease would sig-
Careful clinical judgement is required throughout the patient’s stay in hospital to nificantly aid clinical management.
maintain an effective circulation whilst assiduously avoiding fluid overload
Specific IgM against dengue can be used
KEY WORDS: aedes, arbovirus, dengue, dengue shock syndrome, flavivirus as a sensitive maker of dengue infection

486 © Royal College of Physicians, 2011. All rights reserved.


CMJ1105-CME-Farrar.qxd 9/5/11 3:55 PM Page 487

CME Tropical medicine

and commercially available diagnostic domains could be a target for protease particularly prone to the development
kits are available. The detection of the inhibitors and through inhibition of viral of shock, and adults are at increased
dengue protein NS1 also has proven use entry. The challenge is to bridge the gap risk of bleeding. Prompt, but judicious
in diagnosis and is of particular use in between findings in the laboratory and fluid resuscitation of fluid balance in
the first few days of illness. Real time effectiveness in patients. However, given DSS is the most important therapeutic
PCR is a highly sensitive diagnostic tool the progress in the understanding of intervention. Over-zealous resuscita-
in dengue diagnosis, but the cost of mol- dengue virus biology, the future of drug tion in the presence of ongoing capil-
ecular tests such as PCR makes it an development is encouraging. lary leak must be avoided.
impractical tool for use in many settings There are potential therapeutic devel-
where dengue is prevalent. opments for the treatment of other fla- Key references
A rapid sensitive test that combines viviruses such as hepatitis C. In view of 1 The 2009 World Health Organization
detection of NS1, IgG and IgM, allowing structural similarities between different scheme. http://whqlibdoc.who.int/
diagnosis of infection throughout the ill- flaviviruses, these developments could be publications/2009/9789241547871_eng.pdf
ness course, would be a major advance in used in the field of dengue treatment. As 2 Details of two double-blind, randomised
clinical trials to assess the potential of a
dengue diagnostics. The development of the severe manifestations of disease are
specific antiviral and to evaluate steroids in
appropriate clinical algorithms for use in in part due to the immune response, dengue. www.controlled-trials.com
resource limited settings in parallel with perhaps the development of an 3 Hales S, de Wet N, Maindonald J,
the development of molecular diagnostic immunomodulatory agent would be the Woodward A. Potential effect of population
tools is necessary if the burden of dengue best therapeutic strategy. Currently, two and climate changes on global distribution
of dengue fever: an empirical model.
is to be adequately dealt with. Detection of double-blind, randomised clinical trials
Lancet 2002;360:830–4.
plasma leakage through serial ultrasound are being conducted, one to assess the 4 Gubler DJ. Cities spawn epidemic dengue
and with echocardiography may be a potential of a specific antiviral and the viruses. Nat Med 2004;10:129–30.
useful adjunctive tool in the management other to evaluate steroids in dengue (see 5 Halstead SB. Pathogenesis of dengue: chal-
of patients with dengue diagnosis, partic- key references). lenges to molecular biology. Science
1988;239:476–81.
ularly identifying those patients at highest
6 Cummings DA, Iamsirithaworn S, Lessler
risk of developing severe disease. Conclusions JT et al. The impact of the demographic
transition on dengue in Thailand: insights
Over the past 40 years, the incidence of from a statistical analysis and mathematical
Antidengue drugs
dengue infections, particularly the modeling. PLoS Med 2009;6:e1000139.
A greater understanding of dengue virus more severe forms including DSS, has Epub 2009 Sep 1.
increased dramatically. Dengue is now 7 Wills BA, Nguyen MD, Ha TL et al.
biology has meant that drug targets have
Comparison of three fluid solutions for
been identified that could potentially be one of the most common reasons for
resuscitation in dengue shock syndrome.
the site of a therapeutic agent. The stag- hospital admission in Asia and the N Engl J Med 2005;353:877–89.
gering success in developing drugs Americas during the rainy seasons. The
against HIV is an example of how effi- mortality rate for patients admitted
cient and effective antivirals can be with established DSS is 1–5%, even Address for correspondence:
developed given appropriate funding. with the best available care, although it Professor J Farrar, Oxford University
Potential targets receiving research can be much higher (⬎10%). The most Clinical Research Unit, Hospital for
attention are the viral proteins NS3 and important clinical feature of dengue is Tropical Diseases, 190 Ben Ham Tu,
NS5, which play an integral role in increased vascular permeability leading District 5, Ho Chi Minh City, Vietnam.
genome replication. Their protease to DSS. Infants and younger people are Email: jfarrar@oucru.org

© Royal College of Physicians, 2011. All rights reserved. 487