Tropical Infections Symposium

Journal of Pediatric Critical Care
P - ISSN: 2349-6592 | E - ISSN: 2455-709

Year: 2017 | Volume: 4 | Issue: 3 | DOI-10.21304/2017.0403.00192
Symposium
Tropical infections: Topical relevance
Guest Editorial
M. Jayashree*, Sunit Singhi**
*Head , Pediatric Critical care division, Post Graduate Institute of Medical Education and
Research (PGIMER), Chandigarh.**Chairman, Pediatrics, Medanta, the Medicity, Gurugram,
NCR, Professor Emeritus, Department Of Pediatrics and Advanced Pediatrics Centre,Post graduate
Institute of Medical Education and Research, Chandigarh, India
Received: 30-Jun-17/Accepted: 5-Jul-17 /Published online: 20-Jul-17
Correspondence:
Prof Sunit Singhi, MBBS, MD, FIAP, FAMS, FISCCM, FICCM, FCCM,Chairman, Division
of Pediatrics, Medanta, The Medicity, Gurugram, NCR 122001. Phone: +91-81681886201,
01244141414 Ext 7316, Email: sunit.singhi@gmail.com
Infectious diseases are leading causes of morbidity and mortality in tropical

countries. Many of these are widely prevalent in or are unique to tropical and sub-tropical
regions and have been labelled as Tropical infections. The WHO reports that the common
infections namely, tuberculosis, malaria, diarrhoea and pneumonia, cause between 0.40- 1.05
million deaths per year in low income countries1; about 40% of these deaths are in the 0-14
years age group. In countries of Africa,Asia,Central America and South America, which
comprise 40% of world-population, tropical diseases like malaria 2,3 accounts for about 10 %
deaths. Though the overall under-five mortality rates has shown a 50% decrease between
years 1990- 2012 as per WHO-UNICEF report of 2013, still half of these deaths occur in 5
countries, of which India is one4.The key factor attributed to the decrease in under five
mortality rates has been the vaccine success story; better delivery of existing vaccines and
development of newer vaccines5.However, it has not been possible to replicate similar
success for tropical infectious diseases due to absence of effective vaccines against most of
them. The mortality related to these diseases has either remained unchanged or increased
4
.More importantly, tropical infections cause more Disability Adjusted Life Years (DALYs, a
metric of years lost due to premature deaths and disability)6, than HIV/AIDS7. All this
eventually translates into a potentially large socioeconomic burden for resource limited
countries due to enhanced hospital and healthcare costs further adding fuel to the fire of
poverty and continuing the vicious cycle of poverty and increased infections 4.
The Indian sub-continent by virtue of its location,forms a major part of tropical and sub-
tropical region and is home to a myriad of tropical infections. Most of these diseases are
vector borne and hence largely influenced by seasons which are conducive for vector
breeding. Some are perennial while some peak during pre-monsoon and monsoon seasons.
Despite being a major region for tropical diseases, there is paucity of epidemiological data
from India, with respect to aetiology, and surveillance8 of these diseases. Most of the
published data relating to tropical diseases, is mainly in the form of single centre case series
or reports 9,10,11.One such retrospective study from India among patients who had succumbed
to acute febrile illnesses,had reported, malaria (23%), leptospirosis (22%), and dengue (2 %).
The worrisome part was the huge chunk of undifferentiated fevers which contributed to about
54% 1.
In resource limited settings undifferentiated fever is by and large treated empirically owing to
overlapping clinical picture and limited access and slow turnaround time of diagnostic tests12.
Moreover, the diagnosis in most of these diseases is antibody based and hence a negative
result especially in the first week does not negate the diagnosis. The decision making for
clinicians can be also be difficult in setting of co-infections e.g. malaria and dengue occurring
in the same patient 10,11,13.
An important impediment to arriving at a specific clinical diagnosis is the propensity of these
infections to often present as acute physiological derangements like shock, respiratory
distress and failure, encephalopathy with raised intracranial pressure, or multiorgan
dysfunctions (MODS). The pathogenic mechanisms causing these derangements and
multisystem involvement are multifactorial viz infection associated vasculitis, capillary leak,
hypoxia, secondary bacterial infections and hemophagolymphohistiocytosis(HLH). The
cascade of DIC and thrombocytopenia, which often associated with these illnesses can further
compound the MODS. The physiological derangements and the differences in organ failure
across different aetiologies of tropical infections are very subtle further adding to the clinical
confusion especially in a critically ill child.
In view of the above concerns, the Indian Society of Critical Care Medicine (ISCCM) had
constituted an expert committee to formulate guidelines for management of critically ill
patients with tropical fevers. Based on the available epidemiological data from India and the
experience of the expert group 14, guidelines have been laid down for common tropical
infections viz. dengue, scrub typhus, malaria, typhoid, leptospirosis and bacterial sepsis 14.
Given the ambiguity of clinical features and paramount importance of timely management,
the ISCCM has recommended a “syndromic approach” for diagnosis and treatment rather
than an “individual disease approach”. The principles of early management are akin to that of
any other critical illness, immediate physiological stabilisation being the key. This should be
followed by use of ‘point-of-care” diagnostics and empiric antimicrobial therapy targeting
likely tropical infections based on the syndromic classification. Sometimes empiric therapy
for more than one tropical infection may be warranted as co-infections are common. This
approach seems most rational given the high morbidity and mortality associated with these
infections.
All the critically ill children with tropical infections need provision of organ support in a
Pediatric Intensive Care Unit (PICU). Their intensive care needs include ventilation,
hemodynamic and neurological stabilisation, renal replacement therapy, and blood or
component therapy. However, in a resource limited setting like ours, intensive care is a scarce
and expensive commodity and hence needs to be used judiciously. Hospitals treating these
children especially during epidemics need to put in place strict PICU admission guidelines
and PICU triaging so as to prioritise care to the most needy. Managing these children in
PICU can also be very challenging; over aggressive management with fluids, ventilation and
blood components can be counter-productive. For intensivists, it is therefore a tight rope
walk, balancing between under-treatment and over-treatment during the course of the illness.
While integrated preventive measures in the form of improved sanitation, vector
management, disease surveillance, and research on newer vaccines are the lasting solution to
the menace of tropical infections, the intensivists need to be prepared for managing the
monsoon surge of these infections. In this issue of Journal of Pediatric Critical Care, we are
presenting an evidenced based approach to management of the common tropical infections in
children(dengue, scrub typhus, enteric fever, leptospirosis, malaria and diphtheria) with
special reference to their epidemiology, clinical features, complications, and intensive care
needs. We hope that this issue of the journal serves to sensitize timely and effective
management of tropical infections in the coming season.
Conflict of Interest: None Source of Funding: None
References:
1. Abrahamsen SK, Haugen CN, Rupali P, Mathai D, Langeland N, Eide GE, et al. Fever
in the tropics: aetiology and case-fatality - a prospective observational study in a tertiary
care hospital in South India. BMC Infect Dis 2013 ;30(13):355.
2. WHO (2011). The 10 leading causes of death by broad income groups (2008) [Internet].
Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html
3. Istúriz RE, Torres J, Besso J. Global distribution of infectious diseases requiring

intensive care. Crit Care Clin 2006;22(3):469–488.
4. Hotez PJ. Pediatric Tropical Diseases and the World’s Children Living in Extreme
Poverty. Journal of Applied Research on Children: Informing Policy for Children at
Risk. 4(2).
5. United Nations Inter-agency Group for Child Mortality Estimation. Levels and Trends
in Child Mortality. [Internet]. Available from:
http://www.unicef.org/media/files/2013_IGME_child_mortality_Repo
6. Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-
adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a
systematic analysis for the Global Burden of Disease Study 2010. Lancet Lond Engl
2012;380(9859):2197–223.
7. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and
regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a
systematic analysis for the Global Burden of Disease Study 2010. Lancet Lond Engl
2012;380(9859):2095–128.
8. John TJ, Dandona L, Sharma VP, Kakkar M. Continuing challenge of infectious

diseases in India. Lancet Lond Engl 2011;377(9761):252–69.
9. Sankhyan N, Saptharishi LG, Sasidaran K, Kanga A, Singhi SC. Clinical profile of

scrub typhus in children and its association with hemophagocyticlymphohistiocytosis.
Indian Pediatr 2014;51(8):651–3.
10. Kaur H, John M. Mixed infection due to leptospira and dengue. Indian J Gastroenterol
Off J Indian Soc Gastroenterol 2002;21(5):206.
11. Bhalla A, Sharma N, Sharma A, Suri V. Concurrent infection with dengue and malaria.
Indian J Med Sci 2006;60(8):330–1.
12. Chaturvedi HK, Mahanta J, Pandey A. Treatment-seeking for febrile illness in north-
east India: an epidemiological study in the malaria endemic zone. Malar J 2009;8:301.
13. Magalhães BML, Alexandre MAA, Siqueira AM, Melo GC, Gimaque JBL, Bastos MS,
et al. Clinical Profile of Concurrent Dengue Fever and Plasmodium vivax Malaria in the
Brazilian Amazon: Case Series of 11 Hospitalized Patients. Am J Trop Med Hyg
2012;87(6):1119–24.
14. Singhi S, Chaudhary D, Varghese GM, Bhalla A, Karthi N, Kalantri S, et al. Tropical
fevers: Management guidelines. Indian J Crit Care Med Peer-Rev Off Publ Indian Soc
Crit Care Med 2014;18(2):62–9.
P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Dengue in children: Issues in critical care settings
Nitin Dhochak*, Rakesh Lodha**
*Resident, **Professor Department of Pediatrics, All India Institute of Medical Sciences,
New Delhi, India
Received: 10-Jun-17/Accepted: 5-Jul-17/Published online: 20-Jul-17
Correspondence:
Dr.Rakesh Lodha, Professor, Department of Pediatrics, All India Institute of Medical Sciences,
New Delhi. Phone: 9873019470 E-mail: rlodha1661@gmail.com
ABSTRACT
Dengue infection is an important tropical infection that can be responsible for serious illness and
intensive care admission in children. Dengue virus belongs to Flavivirus genus and is
transmitted by Aedes aegypti and Aedes albopictus mosquito. New World Health Organisation
classification for the disease into dengue with/ without warning signs and severe dengue better
identifies patients requiring in-hospital treatment and classifies atypical cases with severe end
organ system involvement (liver, brain, heart, etc.) without shock or bleeding diathesis. Point of
care tests for Non-Structural Protein 1 antigen and IgM based immuno-assay are important
adjuncts to early diagnosis in emergency wards. Capillary leak and bleeding are central
mechanism of manifestations of severe dengue. Severe capillary leakage creates intravascular
hypovolemia which needs correction with aggressive but not over-jealous fluid therapy with
timely tapering of high fluid rates, to maintain a fine balance of adequate resuscitation and
preventing fluid overload at the same time. Indication for use of colloids upfront especially in
patients with evidence of severe plasma leakage needs further evaluation. Transfusion of fresh
whole blood or fresh packed red cells is important in patients with suspected severe bleeding. In
view of recent evidence, prophylactic transfusion of platelets is going out of favour and platelets
should be transfused for severe bleeding irrespective of platelet counts. Echocardiography and
central venous pressure based fluid status evaluation act as precious adjuncts to for better
assessment of intravascular volume. Atypical manifestation like neurological manifestations,
renal failure, abdominal compartment syndrome, hemophagocytic lymphohistiocytosis need
further documentation for better management of critically ill patients. Outcomes worldwide are
improving with structured protocol based management.
Keywords: Dengue, Aedes aegypti ,Capillary leak, Shock

Introduction
Dengue fever manifests as a wide spectrum of clinical illness ranging from mild
undifferentiated fever to severe hemorrhagic illness requiring intensive care. Capillary
leakage leading to third space and clinical apparent and occult bleeding contribute to
hypoperfusion and shock. We will discuss issues specific to critical care settings and review
evidence for controversies in management.
Epidemiology
Worldwide, approximately 4 billion people are at risk for dengue infection, with 50-100
million apparent dengue infections estimated. There are close to 10000 deaths every year due
to dengue infections and temporal trends indicate increase in deaths over past two decades
primarily due to increased incidence of symptomatic dengue cases which has doubled every
decade since 1990 1. Almost 500000 cases are hospitalized in India with severe dengue 2.
Virus and the vector
Dengue is caused by dengue virus (DENV), which is an arthropod born single stranded RNA
virus from genus Flavivirus, family Flaviviridae. It has four distinct antigenically different
serotypes, DENV 1, 2, 3 and 4. Each serotype can have multiple phylogenetically different
genotypes, usually denoted from I to IV. Co-circulation of various serotypes has been
implicated in co-infections with multiple serotypes simultaneously which could affect disease
severity 3. Recently a new serotype of dengue, DENV 5, has been reported from Malaysia but
exact categorisation of the isolate is yet to be confirmed 4.
DENV is transmitted principally by Aedes aegypti, which is a day biting mosquito. The
mosquito takes multiple feeds from same or multiple individuals. Predominant dwelling sites
are household water collections and construction sites. Transmission is maintained through
subclinical human infection and trans-ovarian transmission. Aedes albopictus has been
expanding throughout the world and has been implicated in transmission of arboviruses
including dengue, though is not as efficient vector as Aedes aegypti 5. Extrinsic incubation
period of DENV is typically 8-12 days (time from feeding of mosquito on infected human to
ability to transmit to next human) and intrinsic incubation period is usually 4-10 days (human
bite by infected mosquito to appearance of symptoms).
Classification
Dengue illness manifest as wide range of severity from inapparent/asymptomatic cases to

severe dengue with hemorrhage and hemodynamic instability. Ratio of symptomatic to
inapparent cases in children has been described ranging from 1:1 to 1:18 6. World Health
Organisation (WHO) 1997 case definition used stringent criteria to classify dengue into
dengue fever and dengue hemorrhagic fever(DHF) where all four of the following should be
present to be classified as DHF: fever lasting 2-7 days, hemorrhagic tendencies,
thrombocytopenia (platelet counts <1,00,000/mm3) and hemoconcentration [20% or more
increase in hematocrit (HCT)]). Limitation of these classification included inadequate
sensitivity and severe cases were not being included in DHF criteria 7. Also atypical severe
manifestation involving various organ systems (renal, liver, neurological) didn’t find place in
WHO 1997 classification. To overcome these limitations, a new classification was release by
WHO in 2009, summarised in table 1 8. Clinical cases were classified to streamline treatment
guideline about need for admission and aggressive therapy and evaluation. Requirement of
hospitalisation with WHO 2009 classification was reported be increased from 17% to 51.3%
in a retrospective study 9. In 2011, WHO published revised and expanded edition of dengue
guidelines and included unusual and atypical manifestations of dengue under the term
“expanded dengue syndrome”.
Table 1. WHO 2009 classification of dengue case classification 8
Dengue ± warning signs Severe dengue

Probable Dengue Warning signs
Lives in/travel to dengue  Abdominal pain or Severe plasma leakage
endemic region. tenderness leading to
 Fever and 2 of  Persistent vomiting  Shock (dengue shock
following  Clinical fluid syndrome)
 Nausea and vomiting accumulation  Fluid accumulation
 Rash  Mucosal bleed with respiratory
 Aches and pains  Lethargy, restlessness distress
 Tourniquet test  Liver enlargement >2 Severe bleeding
positive cm Severe organ involvement
 Leukopenia  Laboratory: increase  Liver: AST or
 Any warning sign in hematocrit ALT≥1000 IU/L
Laboratory confirmed concurrent with rapid  Neurological:
dengue: important when no decrease in platelet impaired
signs of plasma leakage count consciousness
 Heart and other
organs
Pathogenesis
After bite by infected mosquito, virus replicated locally in regional lymph nodes and is
disseminated to lymphatic and reticulo-endothelial system. Then the virus is replicated in
reticulo-endothelial system, leading to viremia and host response. Both innate immunity and
cellular response act against the virus, mounting defence response with abundant cytokines
like interferon gamma (IFN-gamma), tumor necrosis factor (TNF), interleukin 2 (IL-2) etc.
Structural proteins like precursor membrane (pre-M) and envelope (E) and non structural
protein 1 (NS1) are primary targets of antibody formation. Anti pre-M and E protein
antibodies are implicated in antibody dependent enhancement during secondary infection by
enhancing internalisation of virus into cells without neutralising the virus and hence severe
infection in secondary cases and infants born to sero-positive mothers 10.
As the fever begins to decrease, critical phase starts. Capillary leakage is the hallmark of
critical phase. Capillary leakage leads to loss of intravascular water to serous cavities (pleural
effusion, ascites) and subcutaneous space which creates intravascular fluid depletion. If
inadequately treated, and often compounded with decreased oral intake by patient, it can
progress to shock leading to impaired end organ perfusion and multi-organ dysfunction.
Capillary leakage also produces symptoms secondary to inadvertent fluid collection like
respiratory failure due to massive pleural effusion, pulmonary edema, intra-abdominal
hypertension and abdominal compartment syndrome. Capillary leakage usually last 24-48
hours followed by resorption of leaked fluid which can present with fluid overload leading to
pulmonary edema. Mechanism of capillary leakage is endothelial dysfunction due to
cytokines storm which is proposed to be more of functional defect than structural defect. That
explains the transient nature and quick recovery of capillary leak and absence of
inflammatory infiltrates in capillaries 11.
Bleeding diathesis is another important feature of severe dengue illness. Increased bleeding
tendency is secondary thrombocytopenia as well as coagulation abnormalities due to
disseminated intravascular coagulation (DIC). Mechanisms described for thrombocytopenia
include immune mediated destruction due to molecular mimicry of NS1 antigen with human
platelet, DIC, bone marrow suppression due to viremia, peripheral sequestration of platelets
etc12. Severe overt and concealed hemorrhages can complicate shock.
Various end organ dysfunctions included in expanded dengue syndrome are explained partly
by hypovolemia and shock and partly due to cytopathic effects of virus. Recently
hemophagocytosis has been documented in severe dengue infections in children which may
be contributing partly to severity of dengue infection and needs further studies 13.
Clinical features
Classical dengue illness can be divided into three phase; febrile phase, critical phase and
recovery phase. Initial febrile phase lasts approximately 3-7 days is characterised by high
grade fever. Other common symptoms are conjunctival injection, coryza, myalagia,
headache, abdominal pain and retro-orbital pain. Body aches and joint pain are common and
severe, hence termed breakbone fever. Few patients may have upper respiratory tract
symptoms and diarrhea 14. Rash is seen in approximately one fourth of patients which is flat
generalised blanchable erythema appearing on day 2-4 of illness. Mild hemorrhagic
manifestations can be seen during this period including petechiae and epistaxis. Patients with
underlying predisposition may have more severe bleeding like children on aspirin, peptic
ulcer disease, malignancy on chemotherapy etc. Tourniquet test is usually positive during
this period. It is done by inflating blood pressure cuff between systolic and diastolic pressure
around the arm for 5 minutes. If there are ≥10 petechiae/square inch, test is considered
positive. In a meta-analysis, pooled sensitivity, specificity and area under curve of tourniquet
test for diagnosis of dengue was 58%, 71% and 0.70 respectively 15.
Capillary leakage heralds onset of critical phase which is usually associated with
improvement in fever. Other important feature of critical phase is abnormal hemostasis and
thrombocytopenia. Capillary leak manifests as pleural effusion and ascites. Severe pleural
effusion may lead to respiratory distress. Severe intravascular depletion manifests as cool
extremities, tachycardia, poor pulses which can progress to hypotensive shock if appropriate
volume resuscitation is not provided. Severe bleeding manifestation can include melena,
hematemesis, hematuria and occult bleeds like capsular hematoma of liver. Critical phase
lasts for approximately 48 hours. There can be epigastric tenderness and hepatomegaly on
examination.
Recovery phase is associated with absorption of leaked fluid which manifest as polyuria,
hypertension and sinus bradycardia. If there was excessive fluid leakage or overzealous fluid
resuscitation, patient may develop fluid overload leading to congestive cardiac failure and
pulmonary edema. Low grade fever may reappear during this phase. An erythematous
maculo-papular rash with small islands of hypo-pigmentation may appear during this phase
distributed over lower extremities and trunk, commonly called “islands of white in sea of
red”. Pruritis is common.
Atypical manifestations
Atypical manifestations of dengue are also known as “Expanded dengue syndrome”. This can
be due to organ dysfunction, co-infections (with malaria, leptospira, salmonella,
chikungunya) and serious manifestations of dengue in high risk groups (infants,
immunocompromised, underlying co-morbidity like hemoglobinopathy, hypertension etc)16.
Specific organ system manifestation can include brain, liver and gastrointestinal, heart,
kidney, etc.
In a study in children from south India, gastrointestinal symptoms were most common;
hepatitis was present in 11% cases while only 0.8% developed fulminant liver failure. Other
gastrointestinal manifestations include acalculous cholecystitis, parotiditis, pancreatitis.
Commonest neurological manifestations described were seizures (7%), encephalopathy, and
intracranial hemorrhage17. Other less common manifestations can include aseptic meningitis,
acute disseminated encephalomyelitis, Guillain Barre syndrome. Other described organ
involvement includes myocarditis, pericarditis, heart block (cardiovascular), hemoglobinuria,
renal failure, haemolytic uremic syndrome (renal) etc. 16
Common differential diagnoses are other hemorrhagic virus infection, chikungunya infection,
scrub typhus, severe bacterial sepsis, severe malaria etc.
Management in emergency department
Dengue illness should be suspected in children presenting with acute febrile illness in
endemic areas especially during rainy season. Management in emergency department will
include assessment of severity and triaging, stabilization and treatment of life-threatening
complications and evaluations to confirm diagnosis or differential diagnosis.
Initial stabilization
All children classified under dengue fever with danger signs and severe dengue illness should
be managed in patient with protocol driven approach as suggested in WHO guideline 2009 8.
Airway and breathing should be managed accordingly. Respiratory distress/ failure in dengue
patients is usually due to pleural effusion, acidosis, pulmonary hemorrhage and/or pulmonary
edema. Supportive therapy with supplemental oxygen and initial evaluation with a chest X-
ray should be done. Circulation should be classified as hemodynamically stable with warning
signs, compensated shock (hypoperfusion with normal blood pressure), and hypotensive
shock, which will decide further management.
Fluid resuscitation
Hemodynamically stable with danger signs: Children with danger signs are started with
intravenous crystalloid like normal saline (NS) or Ringer’s lactate (RL) at 5-7 ml/kg/hr for 1-
2 hours. Further fluid therapy will depend on clinical improvement and HCT change. If
improving clinically and HCT decreases, fluid rate should be decreased to 3-5 ml/hr for 2-4
hours and then 2-3 ml/hr. If worsening clinically and hematocrit increases, fluid rate should
be increased to 5-10 ml/hr and child should be rigorously monitored for hemodynamic
instability. If clinical worsening and falling hematocrit, suspect bleeding, this can be occult
gastrointestinal hemorrhage. Urgent blood product transfusion should be sought.
Compensated shock: Children should be started on fluid bolus (NS or RL) at 5-10 ml/kg over
one hour. If no improvement and static or increasing hematocrit, start with IV bolus of
RL/NS -10-20 ml/kg over 1 hour. If there is no improvement, give another bolus of
crystalloid or colloid. HCT should be followed and blood transfusion should be given if there
is fall in hematocrit without clinical improvement. Fluids should be tapered as soon as child
is clinically improving and shock is passive.
Hypotensive Shock: Hypotensive shock is life-threatening should be managed aggressively

with rapid bolus of crystalloid or colloid solution at 20 ml/kg over 15 minutes with rigorous
monitoring. If no improvement, give second bolus preferably colloid 10-20 ml/kg over 30
minutes to 1 hour which will be repeated if no improvement. Bleeding should be considered
and treated. Patients not improving even after that need to be admitted in intensive care units
and further management.
A more aggressive approach to managing dengue patients with shock for rapid reversal of
hemodynamic instability and prevention of further organ damage has been reported: a
protocol with rapid bolus up to 60 ml/kg over first hour for hypotensive shock was followed;
in non responders, inotropic support guided by serial HCT and CVP monitoring (target ≥6-8
mm Hg) and echocardiography findings for fluid assessment (left ventricular volume) and
cardiac dysfunction(diastolic or systolic). In a before and after protocol retrospective review,
they demonstrated reduction in mortality after starting proposed protocol based treatment
compared to WHO algorithm, 6.3% vs 16.6%, respectively (p<0.05) 18.
Choice of fluid
Isotonic crystalloid (NS, RL) as well as colloids (gelatin, hydroxyethylstarch, dextran, 5%

albumin) have been used in fluid resuscitation in dengue. Colloids tend to be limited to
intravascular space and increase intravascular volume by reabsorbing water form third
spacing, hence more effectively expanding intravascular volume. There have been three trials
in children comparing colloids against crystalloids which didn’t demonstrate any outcome
benefit but colloid group showed faster recovery of HCT, less use of rescue colloid, and
faster correction of hemodynamic state. One study showed longer fluid therapy in RL group
compared to colloids 19. These studies included dextran, gelatin and hydroxyethyl startch,
albumin was not studied (19–21). No difference in outcomes was noticed between
colloids(10% Haes steril vs 10% Dextran) 22.
In a case series of three patients with dengue shock syndrome, pulmonary edema was
documented with resuscitated with RL on WHO protocol. One of the patients succumbed to
respiratory failure, while two improved with positive pressure. Whether colloids should be
used as first in children with severe leakage at diagnosis is matter of debate 23.
In a single study, hypertonic sodium lactate (sodium 504 mmol/L, potassium 4.02 mmol/L,
calcium 1.36 mmol/L, chloride 6.74 mmol/L, lactate 504 mmol/L, total osmolarity – 1020
mosm/L) was compared with RL in resuscitation and maintenance fluid for first 12 hours for
dengue shock syndrome in children. Hypertonic sodium lactate provided energy by lactate
and acts by decreasing cellular edema due to its hyperosmolarity. They demonstrated less
soluble vascular cell adhesion molecule- 1 (marker of endothelial inflammation) and fluid
overload in hypertonic sodium lactate group. Most of the clinical end points were similar but
hypertonic sodium lactate group required higher rescue colloid infusion(hydroxyethyl starch)
24
. There are no studies evaluating role of balanced salt solutions in resuscitation of shock.
Recommendations: In view of the available evidence, the WHO guidelines for fluid
management of dengue appear appropriate. In a small subset of patients, especially those with
refractory shock/ late presentation with shock, there may be a role for individualised
treatment regimen, including infusion of colloids.
Role of blood products
Blood products are commonly used and often misused in the management of dengue. In a
study from Brazil, 35.2% of the blood product transfusions didn’t meet transfusion criteria
and hospitalization cost increased significantly in patients transfused blood products 25. As
per WHO guidelines, severe bleeding can be recognized by overt severe bleed with
hemodyamic instability, fall in hematocrit with hemodynamic instability, refractory shock
which fails to respond to 40-60 ml/kg fluid, hypotensive shock with low/normal HCT,
persistent or worsening metabolic acidosis especially with abdominal tenderness or
distension. Management includes 5-10 ml/kg of fresh packed red cells or 10-20 ml/kg of
fresh whole blood 8.
Bleeding in dengue patients has a multiple contributing factors including thrombocytopenia,

DIC, hepatic dysfunction, vascular dysfunction etc. Platelet transfusion is a common response
to bleeding manifestation in dengue fever. Some use specific platelet count cut-offs for
platelet transfusion (commonly < 20,000/mm3). Recent large trial in adult between supportive
care with prophylactic platelet transfusion (if platelet counts < 20,000/mm3) vs supportive
care demonstrated similar incidence of bleeding (21% vs 26%, p=0.16); while more
transfusion related adverse events were seen in prophylactic transfusion group(relative risk =
6.26, 1.43-27.34) with some patents demonstrating serious side-effects like anaphylaxis,
transfusion related acute lung injury, fluid overload, etc.26 Similarly in adults, prophylactic
platelet transfusion were associated with longer hospital stay and delayed achievement of
platelet counts >50000/mm3 which could partially be explained by blunting of
thrombopoietin response to thrombocytopenia by platelet transfusion27. Studies from children
didn’t reveal significant difference significant difference in bleeding episodes in various
platelet count groups28. Similarly among children with severe thrombocytopenia
(<20,000/mm3), platelet transfusion didn’t affect final clinical outcome or incidence of major
bleeding episodes29. Other contributors for bleeding should also be addressed and coagulation
studies and correction with fresh frozen plasma transfusion should be considered.
Recommendations: Blood transfusion should only be given in children with suspected/

severe bleeding. Current literature does not support prophylactic platelet transfusions for
thrombocytopenia; platelet transfusions may be considered for children with severe bleeding.
FFP may be considered in children with significant coagulopathy.
Supportive care and initial investigations
Apart from fluid management and blood products, supportive care is an important part of
dengue management. Initial investigations in a sick child should include hemogram with
HCT, coagulation studies, blood sugar, blood gas, serum electrolytes. Additional blood
sample should be sent to blood bank for blood grouping and cross-match. Chest X ray should
be done in children with respiratory distress. Hypoglycemia and hyperglycemia should be
quickly identified and treated accordingly. Metabolic derangement like dyselectrolytemia and
acidosis should be corrected and followed. Repeat HCT should be done following fluid
boluses to determine response. Clinical monitoring of vital signs, urine output and repeat
investigations should be done on case to case basis. Poorly responding or children with
complications should be shifted to intensive care units for further management.
Point of care tests for diagnosis of dengue include strip immunoassay for NS1 antigen and
IgM/IgG. These tests provide quick results within minutes and can be useful in difficult to
reach settings. The reported sensitivity and specificity of these tests range from 45-88% and
92-100%, respectively 30.
Definitive Diagnosis
Diagnostic tests can be divided into two types- detection of virus components or viral culture
and serological tests of host immunity. During acute infection, virus particles or antigens can
be detected up to first five days of illness, following which serological tests are used.
1. Virus detection: The methods available are virus culture, nucleic acid detection by
polymerase chain reaction(PCR) and NS1 antigen detection by enzyme linked
immunosorbent assay (ELISA). Dengue virus can be isolated from diagnostic samples in
mosquito or mammalian cell lines. This method is 100% specific but has poor sensitivity
(approximately 40%) and takes 1-2 weeks to provide report precluding its use in clinical
practice. But it is helpful in characterization of genotypes of various serotypes. PCR provide
result within 4 hours with good sensitivity (60-100%) and specificity (100%), but it’s costly
and not easily available usually at community level. NS1 ELISA provides results in 6 hours
with good sensitivity (67-98%) and specificity (100%). All these tests require special
laboratories. Point of care NS1 test strips are also being utilized with comparable sensitivity
and specificity to in house techniques 30. Due to heat labile nature of virus, these tests should
be conducted as soon as possible and transport and storage of sample should be at low
temperature (4oC).
2. Serological assay: IgM appears by day 3-5 in primary infection and results are positive in
93-99% sixth day onwards. IgM is measured using M antibody capture ELISA (MAC-
ELISA). IgG becomes positive on day 9 of illness which stays positive for months. During
secondary infection, IgM level are low but IgG response is very rapid and strong; titres of
IgG > 1:1280. Point of care IgM enzyme immunoassay kits are also available 31.
Issues in Intensive Care Unit
Refractory shock
In children with shock persistent despite initial fluid management, one should actively look
for occult severe bleeding, metabolic derangements (acidosis, hypoglycaemia,
hypocalcemia), myocarditis and cardiac dysfunction, abdominal compartment syndrome,
massive pleural/ pericardial effusion causing obstructive shock and coexistent bacterial
sepsis.
Occult bleeding should be suspected in all patients with non responsive dengue shock
syndrome. WHO guideline 2009 recommends blood transfusion in patients not responding to
fluids with normal or falling HCT. It also warns that the usual cut off of hemoglobin of 10
g/dl for blood transfusion in uncontrolled septic shock as advised in surviving sepsis
guidelines, could be misleading due intravascular volume contraction and lower threshold
should be kept in dengue patients. 8,32
Objective evaluation of cardiac function can be effectively used to guide inotropic therapy.
Some of the patients may have diastolic dysfunction in dengue patients who may benefit from
treatment with lusitropic agents like milrinone.33 Inotropic support should be guided as per
Surviving Sepsis Guidelines for septic shock and modulated with echocardiogram findings.
Myocarditis has been demonstrated in dengue illness. Blood troponins and creatine
phospokinase should be estimated for suspected myocarditis.
Fluid overload
Appropriate fluid administration is life saving intervention in management of dengue

patients. But dengue patients are also predisposed to fluid overload which is due to iatrogenic
excessive fluid administration, use of hypotonic fluids for resuscitation and resorption of
fluid from extravascular space to intravascular space at end of critical phase. Fluid overload
can manifest as hypertension, bradycardia, heart failure and pulmonary edema. Excessive
utilization of crystalloid in patients with already severe capillary leakage has been
demonstrated to cause pulmonary edema. 23
Judicious use of colloid during resuscitation could decrease overall fluid overload. Fluid rate
should be decreased timely once hemodynamic stability is established to prevent overload.
Treatment of established fluid overload includes fluid restriction, respiratory support in form
of continuous positive pressure and measure to remove excess fluids. Diuetics like
furosemide infusions have been shown to improve oxygenation parameters in children with
hypoxemia but one has to be very cautious to not give diuretics during active capillary
leakage as it will further worsen intravascular hypovolemia. 34 Refractory fluid overload may
require renal replacement therapies like continuous renal replacement therapy (CRRT),
hemodialysis (HD) or peritoneal dialysis. CRRT is preferred because it causes minimal
hemodynamic instability.
Neurological complications
Seizures and encephalopathy are commonest neurological manifestation of dengue illness. In

a study in adults, almost 60% patient with neurological manifestations didn’t have other
clinical features of dengue. Diagnosis was based on isolation of dengue IgM in serum and
CSF and few patients also demonstrated CSF dengue PCR positivity. 35 So dengue should be
suspected in suspected encephalitis patients in endemic regions. Other less common
manifestations include intracranial bleed, Guillain Barre syndrome, acute disseminated
myeloencephalitis, hepatic encephalopathy, etc.33 Treatment is primarily supportive with anti-
epileptic medicines and identification and management of raised intracranial pressure, if any.
Renal failure
Proposed mechanism for acute kidney injury in dengue are hypotension, direct viral damage,
hemoglobinuria, and myoglobinuria, glomerulonephritis, haemolytic uremic syndrome etc. 36
Renal failure further complicates the fluid overload, contributes to encephalopathy and
metabolic derangement like acidosis and dyselectrolytemia. Management is conservative.
Renal replacement therapy modes useful during acute infection are CRRT, PD and HD.
Bleeding diathesis complicate utilization of anticoagulation in CRRT and HD. Local
anticoagulation with citrate or prostacyclin is a useful alternative.
Abdominal compartment syndrome
Excessive third spacing, fluid overload, intra-abdominal bleed can contribute to intra
abdominal hypertension (more than 10 mm Hg in children). Abdominal compartment
syndrome (ACS) is intra-abdominal hypertension with new onset end-organ dysfunction.37
Increased intra abdominal pressure can lead to worsening of renal function due to impairment
of perfusion, hemodynamic instability by impairing preload and respiratory distress by
splinting of diaphragm. ACS has been documented in severe dengue infections in case reports
and series. 33,38 Management includes treatment of fluid overload with diuretics or renal
replacement, gastrointestinal decompression through nasogastric tube and flatus tube,
paralytic agents, etc. Persistent increased abdominal pressure will require peritoneal drainage.
Respiratory failure
During critical phase, respiratory distress is mainly due to pleural effusion which is secondary
to third spacing and fluid overload. Other causes of respiratory distress can be acute
pulmonary edema and metabolic acidosis. Management is providing respiratory support with
oxygen and positive pressure as needed, and correction of fluid overload as explained earlier.
Co-infections
Co-infection of dengue with other viruses (chikungunya, zika virus), malaria and bacterial
sepsis have been well described. Dengue chikungunya co-infection is well reported from
India. Mechanisms implicated in co-infection are simultaneous infection of mosquito with
both organisms or sequential infections. Clinical features are usually consisting of both the
infection with fever, headache, arthritis, rash, photophobia being common manifestations.39
Few reports showed severe neurological manifestations.40 Severity of co-infection to
individual infections is not well defined as only few case series are documented which also
show variable presentation from mild forms to severe life-threatening infections. Treatment is
directed towards both the infections.
Hemophagocytic Lymphohistiocytosis (HLH)
HLH has described in dengue which is due to uncontrolled activation of T cells and
macrophages leading to cytokine storm. Suspicion of HLH is kept in patients whose fever
lasts beyond 7 days with progressive and persistent cytopenias. Incidence of HLH is not clear
as it is not usually evaluated upfront in severe dengue illness. Diagnosis is based on HLH
2004 guidelines which recommend five out of these eight criteria- fever, splenomegaly,
bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, demonstration of
hemophagocytosis in tissues, slow/absent NK-cell-activity, hyperferritinemia, and high-
soluble interleukin-2-receptor levels.41 Recently two case series described patients of dengue
with HLH. Treatment included steroid pulse therapy and few patients received intravenous
human immunoglobulins with good response.13,42
Outcome
Clinical outcome are improving with better health care facilities and well defined protocols.
Overall mortality due to dengue among hospitalized patients have been reported up to 2.5% 2.
Among children, mortality rates are lower than in adults with recent studies from intensive
care units describing mortality <1%. This can partly be explained by less co-morbidities in
children and improving clinical care.43,44 Presence of more than 3 warning signs was
associated with prolonged hospital stay, higher incidence of shock and increased number of
blood product transfusions.45 Recent meta-analysis suggested an increased severity of
secondary infections compared to primary infections.46 Severity of illness in secondary
infections increased with increased time gap between primary and secondary infections.47

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P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Scrub typhus
M L Keshavamurthy* Karthi Nallasamy**
*Senior Resident, **Assistant Professor, Pediatric Critical Care Unit, Advanced

Pediatrics Centre, PGIMER, Chandigarh,India
Correspondence:
Dr Karthi Nallasamy, Assistant Professor, Pediatric Critical Care Unit, Advanced
Pediatrics Centre PGIMER, Chandigarh160012, Email: ny.karthi@gmail.com
ABSTRACT
Scrub typhus is an important emerging tropical infection that can have severe
manifestations in children leading to intensive care admission. It is caused by Orientia
tsutsugamushi, a gram negative bacterium transmitted to humans by the bite of larval
trombiculid mites. The organism is endemic in south-east Asia and the disease is reported
from virtually all parts of India. The hallmark of this infection is vasculitis and endothelial
injury with intense inflammatory response involving myocardium, pulmonary, nervous
and hematological systems. Children present often in post-monsoon season with
undifferentiated fever and various degrees of organ involvement that progress to fatal
multi organ failure if untreated. Presence of an eschar can be a vital diagnostic clue.
Common laboratory features include thrombocytopenia, elevated transaminases and
hypoalbuminemia. The diagnosis is confirmed by detection of IgM antibodies by IFA and
ELISA or by PCR based assays. Definitive treatment with doxycycline or azithromycin
and aggressive supportive care including ventilation, hemodynamic support, and
management of AKI and raised intracranial pressure are the mainstay. The mortality
ranges from 6-15%, which currently on the improving trend due to better case
identification and early initiation of antibiotics along with intensive care.
Key words: Scrub typhus, Tropical fever, Children, India, Intensive care
Introduction
Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi, an obligate
intracellular gram negative bacterium that differs from rickettsia in its cell wall structure
and genetic material. As the name suggests, scrub refers to the type of vegetation that
harbors the vector and ‘typhus’ meaning fever with stupor in Greek.1The infection is
transmitted by Trombiculid mites and humans are accidentally infected when exposed
during occupational and recreational activities in the habitat of mites such as grasses and
dirty home environments. The clinical features may vary from nonspecific febrile illness
to constitutional symptoms that can progress to widespread involvement of various
organ systems. Children often present with one or more organ failures requiring
Intensive Care Unit (ICU) admission. The issues specific to critical care and current
evidence based management are reviewed here.
Epidemiology
Globally scrub typhus is predominantly distributed in the ‘tsutsugamushi triangle’ which

stretches from Japan in the east through China, the Philippines, tropical Australia in the
south and west through India, Pakistan, possibly to Afghanistan and southern parts of
Russia in the north.2 Early reports of scrub typhus in Indian subcontinent emerged from
Assam region during world wars. 3 Since then, several papers have reported cases in
adults and children from various parts of India including Haryana, Jammu and Kashmir,
Himachal Pradesh, Uttaranchal, West Bengal, Assam, Maharashtra, Goa, Kerala and
Tamilnadu indicating that the disease is ubiquitous.4 Like other tropical infections, scrub
typhus has a seasonal pattern; most cases are reported during rain and post monsoon
months typically between July and November. The cases are seen from rural and urban
backward areas which are the natural habitat of the vector. However, there is increasing
serological evidence from metropolitan cities. 5-7 In an Indian multicentre survey, out of
all cases admitted in ICU with suspected diagnosis of tropical fevers, scrub typhus
formed >15% of cases.7
Pathogenesis
The larval stage of Trombiculid mite (infected chigger) bites humans while feeding and
inoculates the organism Orientia tsutsugamushi. The bite site progresses through papule
to ulcer and finally evolving into a necrotic eschar with regional lymphadenopathy. The
organism initially multiplies in the eschar and then gets disseminated through lymphatics
and within mononuclear white blood cells hematogenously to primarily affect the
endothelium of various organs like heart, lung, brain, liver kidney, pancreas, skin and
macrophages of liver and spleen. 8-10
The infection induces both humoral and cell mediated immunity. Increased
concentration of interferon-alpha, IL-8 and IL-15 is observed in infected patients.11
There is also evidence of direct invasion of infected host cells by the organism. Cytotoxic
lymphocyte activation during acute infection could play an important role in destroying
the infected host cells. Disseminated vasculitis with perivasculitis is the hallmark of
scrub typhus infection with predilection to endothelium of myocardium, nervous and
pulmonary system.
Clinical features
The incubation period from the time of exposure can range from 6-21 days. The illness
severity can vary from an undifferentiated febrile illness to severe systemic disease with
multi-organ failure. The initial manifestations include fever, cough, vomiting, headache
and myalgia. Skin rash, commonly maculopapular or petechial, may be seen over the
trunk and spreads to extremities to involve palms and soles. Examination findings would
include edema, hepatosplenomegaly, lymphadenopathy and typical eschar. Eschar is
seen in 4-68% in various studies reported from India.12-14 and if found is a clue to
diagnosis. It is 5–20 mm in diameter, formed at the bite site, progressing initially from
a papule to vesicle and finally an ulcer with a black necrosis. A typical eschar resembles
a cigarette burn though eschar formed in warm and damp areas of the body do not have
the necrotic surface. The clothing pattern, previous exposure to pathogen and variations
in cutaneous immunity may influence the development and distribution of eschar. In
dark skinned individuals small eschars can be easily missed. In one pediatric study, the
distribution of eschar was found to be more common in inguinal (35%), genitalia and
buttock (27%) regions as compared to axilla (18.9%), trunk (10.8%) face (2.7%) and
neck (5.4%). Lymphadenopathy was seen in 67.5% 15
Complications:
The diagnosis and therefore treatment of scrub typhus in the first week is often missed
due to lack of clinical suspicion and presentation as undifferentiated fever. Systemic
involvement is seen from the second week of illness particularly in untreated children.
The extent of organ involvement may vary but it is not uncommon to see children
presenting with more than one organ failures.
Respiratory distress/ Acute Respiratory Distress Syndrome (ARDS)
Respiratory distress and failure is one of the commonest complications. Most studies
report ARDS in 30-75% of hospitalized patients.16,17 Higher incidence is seen in ICU
cohorts. There may be development of interstitial pneumonia and non-cardiogenic
pulmonary edema owing to vasculitic process. Respiratory failure can also occur
secondary to pulmonary edema caused by myocardial dysfunction. Children most
commonly present with cough and rapid breathing and progress to ARDS. The
pathogenesis may follow the sequential exudative, fibroproliferative and fibrotic stages,
however, prompt treatment with appropriate antimicrobials usually lead to rapid
recovery. Various studies show that delayed treatment, Sequential Organ Failure
Assessment (SOFA) score, serum albumin, platelet count and Lactate Dehyrogenase
(LDH) are independent predictors for ARDS and need for mechanical ventilation.16, 17
Septic shock and myocarditis:
Circulatory and cardiovascular system involvement includes septic shock, myocarditis

and rhythm disturbances. It is seen that the time taken for O. tsutsugamushi infection to
progress to septic shock may be longer as compared to other gram negative bacterial
infections. Widespread endothelial injury results in distributive shock in the second
week of illness. However, a significant proportion of children (10-34%) may have
associated myocarditis that can complicate fluid management. 12 Ischemic injury due to
vasculitis and circulating inflammatory cytokines are attributed in the development of
myocardial injury. Myocarditis can be subclinical or fulminant presenting with elevated
CK-MB, ECG changes, reduced ejection fraction on echocardiography and cardiogenic
shock. Nevertheless, cardiac recovery is excellent if it is adequately treated in the acute
stage.
Meningitis and encephalitis:
The incidence of CNS manifestations in scrub typhus is largely under reported in India,
literature reports range from 11% to 41% 18,19 The organism gains access to brain via
infected monocytes and affects the endothelial cells resulting in leptomeningeal
infiltration. Aseptic meningitis and meningoencephalitis are increasingly reported while
uncommon manifestations include isolated cranial nerve palsies, ADEM and stroke.
Clinical features range from mild irritability to nuchal rigidity and seizures and altered
sensorium. These children generally show good response to therapy if started early
during the disease.
Acute Kidney injury
The incidence of AKI in scrub typhus ranges from 8-40%, with nearly 10% requiring
renal replacement therapy (20). A report from south India showed that among children
with AKI, 29% were found to be in stage 1, 42% in stage 2, and 29% were in stage 3. 21
The probable mechanism for renal injury is vasculitis; other contributing factors include
direct renal involvement by the organism, decreased blood flow and in some cases due
to panvascular coagulation and rhabdomyolysis.22, 23 Renal failure requiring dialysis was
associated with poor outcome.
Hepatitis
Increase in liver transaminases is seen in 64-100% patients, the elevation though tends
to be mild (2- 4 times of normal values). Hypoalbuminemia (<3.0g/dL) is reported in
54-100%children. There may be increased direct bilirubin and alkaline phosphatase in
some cases.21,24
Hematological dysfunction
Thrombocytopenia is a consistent feature and platelet count of 150x103/µL or lower is

reported in 60-100% of children.21,24 Petechiae were seen in 47% cases however
significant clinical bleeding is less common except in children with DIC and multi-organ
failure. Hemophagocytic lymphohistiocytosis (HLH) is a recognized complication
though no clinical or laboratory feature could reliably distinguish HLH from severe
scrub typhus. Serum ferritin and bone marrow examination may be performed in
suspected cases. It has been observed that children with scrub typhus associated HLH
frequently experience DIC and ARDS during hospitalization.25
Investigations:
Thrombocytopenia is the single most common hematological abnormality; severe

thrombocytopenia with platelet count less than 50x103 /µL is seen in up to half of
patients. Mild anemia and mild to moderate leukocytosis may be present. Biochemical
abnormalities include hyponatremia, elevated transaminases and hypoalbuminemia.
Abnormal urinalysis is not uncommon and elevation of serum creatinine (>1mg/dL) can
be seen in 20% of children. 24 Chest X-ray may be abnormal in 50-72% with unilateral
or bilateral non-homogenous opacities and reticulonodular shadows. Minimal pleural
effusion and hilar adenopathy may be seen. In scrub typhus with neurological
manifestations, early lumbar puncture may not be feasible in all cases due to severe
thrombocytopenia, but if done would show lymphocytic pleocytosis with elevated
protein and normal glucose. CT or MRI may show multiple low attenuation lesions at
corpus callosum, hyperintensities in periventricular white matter, cerebral hemorrhages
and infarcts.
Laboratory confirmation
Serological testing is still the most common method of diagnosis. Weil-Felix is a

nonspecific test which, although being done widely in resource limited settings due to
its easy availability and low cost, has poor sensitivity (50%). A high OXK titer (>1:320)
is reported to predict scrub typhus. Indirect immunofluorescent antibody (IFA) test,
which uses fluorescence-labeled anti-human immunoglobulin to detect antibodies in the
serum of the patient.26 Although considered as gold standard for diagnosis of scrub
typhus, it is limited by its need for expertise and equipment, hence may not be available
in most areas where the disease is prevalent. IgM Elisa is the most practical useful test
for confirmation being 97% sensitive and 99% specific. It can be done in any phase of
infection after initial 2-3days of illness onset(26).PCR based assays are available in
limited centers. Eschar and blood samples can be used for testing. It is highly specific
but sensitivity varies with the molecular target and PCR methods.
Differential diagnosis:
Acute undifferentiated febrile illness of three days or more with or without organ
involvement during typical tropical rainy season should be suspected as a case of scrub
typhus. Presence of eschar is pathognomonic and is a useful diagnostic clue. However,
at acute care settings, several other tropical infections such as dengue, malaria, typhoid,
leptospirosis and severe bacterial sepsis may present with overlapping clinical features
and may be confused with scrub typhus. The challenge lies in distinguishing them at the
time of presentation. Both dengue and scrub typhus present with thrombocytopenia,
signs of capillary leak and circulatory abnormalities, subtle laboratory features like
presence of hemoconcentration or leucopenia may help in discriminating dengue to a
certain extent. Dengue and malaria can be diagnosed at admission using point of care
rapid diagnostic tests. However, if a definitive diagnosis is not possible at the outset, it
is recommended to treat children empirically for scrub typhus till serological
confirmation is available.
Emergency room management:
Initial management in ER should focus on stabilization of airway, breathing and

circulation. Children who present with tachypnea and circulatory abnormalities should
receive oxygen. Most cases with respiratory distress and mild ARDS respond well to
positive pressure by non-invasive CPAP or NIV. Those with persistent hypoxemia
and/or severe encephalopathy with GCS ≤ 8 require endotracheal intubation and
mechanical ventilation. Management of septic shock follows standard guidelines using
fluids and vasoactive drugs. Myocardial dysfunction should be actively looked for in all
children who present with circulatory abnormalities. Children with encephalitic
presentation may require a neuroimaging and initial measures to control seizures and
raised intracranial pressure.
Specific therapy:
Early treatment with doxycycline (5mg/kg/day in 2 divided doses, i.v. or oral) shortens
the disease course and reduces mortality. Duration of therapy is variable; 5 days or 3
days after defervescence in uncomplicated cases. In severe scrub typhus with organ
failure it may be given for 7-14 days. Azithromycin (10mg/kg/day for 5 days) is an
effective alternative.
Doxycyline vs Azithromycin: In Thai adult patients with scrub typhus of any severity, a
3-day course of azithromycin was non-inferior to a 7-day course of doxycycline.27 A
recent randomized controlled trial in 57 children also showed azithromycin to be as
effective as doxycycline or chloramphenicol for uncomplicated scrub typhus.28 Fever
defervescence occur earlier with doxycycline whereas azithromycin is better tolerated
between the two drugs. Currently, doxycycline remains the first choice even for children
younger than 8 years. Several reports have shown that short course of doxycycline does
not result in dental adverse effects.
Intensive care needs
Indications for transfer to PICU
Children with scrub typhus who present with one or more organ failures at admission
require care in an Intensive Care Unit. The indications for PICU transfer include ARDS,
septic shock, myocarditis, and encephalopathy and raised intracranial pressure.
Mechanical ventilation
Acute respiratory failure is the most common reason for ICU admission in patients with
scrub typhus. Non-invasive ventilation (NIV) is used with reasonable success in adults
with early ARDS. In an Indian study, 17% patients were managed solely on NIV without
the need for invasive ventilation.29 Invasive mechanical ventilation (IMV) for ARDS
follows standard principles of lung-protective strategies. In a cohort of 16 patients with
respiratory failure, the mean (SD) PF ratio was 160 (120) and in those mechanical
ventilated, the mean (SD) peak airway pressure and positive end expiratory pressure
were 19.8±4.3 cmH2O and 7.6±5.1 cmH2O respectively.17 It is observed that the
improvement in oxygenation is generally prompt with antibiotic therapy. The duration
of ventilation was 7.2 (95% CI, 5.9-8.5) days in those needing IMV in one of the studies.
29
Hemodynamic management
Children with persistent circulatory abnormalities and fluid-refractory shock should be

evaluated for underlying myocarditis. In children with echocardiographic evidence of
myocardial dysfunction, addition of an inodilator such as dobutamine or milrinone may
be required to improve cardiac output. Continuous electrocardiographic monitoring is
desired to detect rhythm abnormalities.
Neurological monitoring
Children with acute encephalitis syndrome require supportive care including seizure
control, sedation and analgesia and management of raised intracranial pressure (ICP).
Invasive ICP monitoring could be useful in comatose children but may not be feasible
in the initial days due to accompanying thrombocytopenia. Most children recover with
early antibiotic therapy and the neurological outcome is generally better than patients
with viral encephalitis.
Renal replacement
Acute Kidney Injury (AKI) occurs in up to 40% of patients of which most remain non-
oliguric; only a small proportion requires dialysis. The modality of renal replacement
therapy (RRT) is based on patient’s age and clinical status. Oliguric AKI and
requirement of RRT are associated with unfavorable outcome.
Hematological support
Thrombocytopenia with clinical bleeding may require platelet transfusion. Platelet count
recovers with antibiotic treatment and defervescence. Management of HLH is primarily
supportive. Immunomodulatory agents (IVIG and steroids) are reserved for refractory
cases with progressive organ dysfunction.25
Multi organ dysfunction syndrome
Incidence of MODS in severe scrub typhus was 14.3% in a pediatric study. Most
frequently observed organ involvement are hematologic and respiratory dysfunction.
Skin rash, longer time to defervescence, anemia, thrombocytopenia, elevated AST and
bilirubin were associated with increased occurrence of MODS.30
Outcome
In ICU cohorts, mortality rate ranges from 6 to 15% 12,24,31 Prompt antibiotic treatment
shortens the clinical course and improves outcome. The time interval between initiation
of therapy and clinical improvement range from 1 to 7 days. Higher severity of illness
score at admission, failure to achieve defervescence and progression of multi-organ
failure are associated with poor outcome.
References:
1. Venkategowda PM, Rao SM, Mutkule DP, Rao MV, Taggu AN. Scrub typhus: Clinical
spectrum and outcome. Indian J Crit Care Med 2015;19(4):208–13.
2. Ecology and control of rodents of public health importance. Report of a WHO Scientific
Group. World Health Organ Tech Rep Ser 1974;(553):1–42.
3. Mackie TT. Observations on tsutsugamushi disease (scrub typhus) in Assam and Burma.
Trans R Soc Trop Med Hyg 1946;40:15–56
4. Rahi M, Gupte MD, Bhargava A, Varghese GM, Arora R. DHR-ICMR Guidelines for
diagnosis and management of Rickettsial diseases in India. Indian J Med Res
2015;141(4):417–22.
5. Narvencar KPS, Rodrigues S, Nevrekar RP, Dias L, Dias A, Vaz M, et al. Scrub typhus
in patients reporting with acute febrile illness at a tertiary health care institution in Goa.
Indian J Med Res 2012;136(6):1020–4.
6. Mittal V, Gupta N, Bhattacharya D, Kumar K, Ichhpujani RL, Singh S, et al. Serological

evidence of rickettsial infections in Delhi. Indian J Med Res 2012;135(4):538–41.
7. Rungta N. Scrub typhus: Emerging cause of multiorgan dysfunction. Indian J Crit Care
Med 2014;18(8):489–91.
8. Walsh DS, Myint KS, Kantipong P, Jongsakul K, Watt G. Orientia tsutsugamushi in

peripheral white blood cells of patients with acute scrub typhus. Am J Trop Med Hyg
2001;65(6):899–901.
9. Moron CG, Popov VL, Feng HM, Wear D, Walker DH. Identification of the target cells
of Orientia tsutsugamushi in human cases of scrub typhus. Mod Pathol Off J U S Can
Acad Pathol Inc 2001;14(8):752–9.
10. Rajapakse S, Rodrigo C, Fernando D. Scrub typhus: pathophysiology, clinical
manifestations and prognosis. Asian Pac J Trop Med 2012;5(4):261–4.
11. Paris DH, Jenjaroen K, Blacksell SD, Phetsouvanh R, Wuthiekanun V, Newton PN, et al.
Differential patterns of endothelial and leucocyte activation in “typhus-like” illnesses in
Laos and Thailand. Clin Exp Immunol 2008;153(1):63–7.
12. Palanivel S, Nedunchelian K, Poovazhagi V, Raghunadan R, Ramachandran P. Clinical

profile of scrub typhus in children. Indian J Pediatr 2012;79(11):1459–62.
13. Vivekanandan M, Mani A, Priya YS, Singh AP, Jayakumar S, Purty S. Outbreak of scrub
typhus in Pondicherry. J Assoc Physicians India 2010;58:24–8.
14. Mahajan SK, Rolain JM, Sankhyan N, Kaushal RK, Raoult D. Pediatric scrub typhus in
Indian Himalayas. Indian J Pediatr 2008;75(9):947–9.
15. Arun Babu T, Vijayadevagaran V, Ananthakrishnan S. Characteristics of Pediatric Scrub

Typhus Eschar in South Indian Children. Pediatr Dermatol 2017;34(2):124–7.
16. Wang C-C, Liu S-F, Liu J-W, Chung Y-H, Su M-C, Lin M-C. Acute respiratory distress
syndrome in scrub typhus. Am J Trop Med Hyg. 2007 Jun;76(6):1148–52.
17. Moon KM, Han MS, Rim CB, Lee JH, Kang MS, Kim JH, et al. Risk Factors for
Mechanical Ventilation in Patients with Scrub Typhus Admitted to Intensive Care Unit at
a University Hospital. Tuberc Respir Dis 2016;79(1):31.
18. Sood AK, Chauhan L, Gupta H. CNS Manifestations in Orientia tsutsugamushi Disease
(Scrub Typhus) in North India. Indian J Pediatr 2016;83(7):634–9.
19. ViswanathanS, MuthuV, Iqbal N, Remalayam B, GeorgeT. Scrub typhus meningitis in

South India - a retrospective study. PLoS ONE 2013;8:e66595
20. Attur RP, Kuppasamy S, Bairy M, Nagaraju SP, Pammidi NR, Kamath V, et al. Acute
kidney injury in scrub typhus. Clin Exp Nephrol 2013;17(5):725–9.
21. Kumar M, Krishnamurthy S, Delhikumar CG, Narayanan P, Biswal N, Srinivasan S. Scrub

typhus in children at a tertiary hospital in southern India: clinical profile and
complications. J Infect Public Health 2012;5(1):82–8.
22. Kim D-M, Kang DW, Kim JO, Chung JH, Kim HL, Park CY, et al. Acute renal failure due
to acute tubular necrosis caused by direct invasion of Orientia tsutsugamushi. J Clin
Microbiol. 2008 Apr;46(4):1548–50.
23. Hwang K, Jang HN, Lee TW, Cho HS, Bae E, Chang S-H, et al. Incidence, risk factors
and clinical outcomes of acute kidney injury associated with scrub typhus: a retrospective
study of 510 consecutive patients in South Korea (2001-2013). BMJ Open 2017
15;7(3):e013882.
24. Sankhyan N, Saptharishi LG, Sasidaran K, Kanga A, Singhi SC. Clinical profile of scrub
typhus in children and its association with hemophagocytic lymphohistiocytosis. Indian
Pediatr 2014;51(8):651–3.
25. Jin Y, Huang L, Fan H, Lu G, Xu Y, Wu Z. Scrub typhus associated with hemophagocytic

lymphohistiocytosis: A report of six pediatric patients. Exp Ther Med 2016 ;12(4):2729–
34.
26. Janardhanan J, Trowbridge P, Varghese GM. Diagnosis of scrub typhus. Expert Rev Anti
Infect Ther 2014;12(12):1533-40.
27. Phimda K, Hoontrakul S, Suttinont C, Chareonwat S, Losuwanaluk K, Chueasuwanchai S

et al. Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus.
Antimicrob Agents Chemother 2007;51(9):3259-63.
28. Chanta C, Phloenchaiwanit P. Randomized Controlled Trial of Azithromycin versus

Doxycycline or Chloramphenicol for Treatment of Uncomplicated Pediatric Scrub
Typhus. J Med Assoc Thai 2015;98(8):756-60.
29. Griffith M, Peter JV, Karthik G, Ramakrishna K, Prakash JAJ, Kalki RC, et al. Profile of
organ dysfunction and predictors of mortality in severe scrub typhus infection requiring
intensive care admission. Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care
Med 2014;18(8):497–502.
30. Zhao D, Zhang Y, Yin Z, Zhao J, Yang D, Zhou Q. Clinical Predictors of Multiple Organ
Dysfunction Syndromes in Pediatric patients with Scrub Typhus. J Trop Pediatr
2017;63(3):167–73.
31. Rathi N, Rathi A. Rickettsial infections: Indian perspective. Indian Pediatr 2010;47(2):157-
64.
P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Managing Malaria in the Pediatric Intensive Care Unit
Madhusudan Samprathi*, Suresh Angurana**
* Senior Resident, Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER,
** Assistant Professor, Department Of Pediatrics, Government Medical College And
Hospital (GMCH), Sector 32, Chandigarh, India
Correspondence:
Dr.Suresh Kumar Angurana, Assistant professor, Department of Pediatrics,
Government Medical College and Hospital (GMCH), Sector 32, Chandigarh,India-160032.
Phone: 9855373969 E mail : sureshangurana@gmail.com
ABSTRACT
Malaria in children is associated with high mortality and morbidity. High index of suspicion
is required for diagnosis. Clinical assessment should be supplemented by laboratory
investigations including peripheral blood smear examination and rapid diagnostic tests.
Common associated life-threatening problems include coma, seizures, raised intracranial
pressure (ICP), shock, respiratory failure, acute kidney injury, anemia and fluid and
electrolyte abnormalities. Aggressive supportive care in pediatric emergency and pediatric
intensive care unit includes control of airway, breathing and circulation; maintaining
adequate intravascular volume; management of raised ICP and status epilepticus; and close
monitoring for early detection of complications. Artesunate combination therapy should be
administered promptly. Clinical evaluation, laboratory workup, specific antimicrobial
therapy, supportive treatment and management of associated complications should go hand in
hand in a protocolized way for better outcome.
Key words: Malaria, Child, PICU, Artesunate
Introduction
Malaria is a protozoan disease that continues to affect millions of lives around the world
every year causing significant morbidity and mortality. Though developed countries have
virtually eliminated the disease, most of the developing world including India still grapples with
this deadly infection.1 Consequently, the world has witnessed varying phases of treatment
regimes and control programs to tackle malaria over time. Malaria affects all age groups and
presents with multisystem manifestations. It is one of the important tropical infections in the
‘tropical fever’ conundrum, easily treatable, if recognized early and managed appropriately.
Children with severe malaria often present with various complications that require admission to
pediatric intensive care unit (PICU) for monitoring, treatment of complications, and organ
support. Severe malaria commonly present as serious medical emergencies. Early, aggressive,
and appropriate intensive care is required to prevent morbidity and mortality. This review
focuses on management of malaria from the perspective of an intensivist.
Epidemiology
Latest WHO estimates reveal that there were 212 million cases of malaria with 429,000
deaths in 2015 alone, with the African region bearing the brunt of the disease with 90% of these
cases and 92% of deaths.2 More than 2/3rd of deaths occurred in under-5 children in high
transmission areas. Though under-5 malaria death rate fell by 29% between 2010 and 2015, it is
an important killer in this age group, claiming one child every 2 minutes. South-East Asia, the
Middle East and Latin America are also significantly affected. India accounts for 70% of the
burden of the South East Asian Region of WHO. Within India, about 91% of malaria cases and
99% of malarial deaths occur in the high disease burden states which are the Northeastern (NE)
states, Andhra Pradesh, Chhattisgarh, Gujarat, Jharkhand, Karnataka, Madhya Pradesh,
Maharashtra, Odisha, Rajasthan and West Bengal.3 It is an important cause of admission to
PICU, frequently progressing to multiorgan dysfunction syndrome (MODS) and having a high
mortality.4-7 Severe malaria once believed to be mainly caused by Plasmodium falciparum has
been increasingly attributed equally to P. vivax over the past few decades.8-10 In a Brazilian study
on P. vivax-associated admissions to PICU, male sex, age <5 years, parasitemia >500/mm3 and
presence of acute or chronic co-morbidity were independently associated with PICU admission.
11
Biology and transmission dynamics

There are 5 species of the genus Plasmodium which cause malaria in human beings: P.
falciparum, P. vivax, P. ovale, P. malariae, and in parts of Southeast Asia, P. knowlesi. Malaria
is transmitted to humans by bite of infected female Anopheles mosquito. Other modes of
transmission include transfusion of infected blood, use of contaminated needles and
transplacentally from an infected mother to fetus. Plasmodium undergoes an asexual cycle called
schizogony in man (vertebrate host) and a sexual cycle called sporogony in the vector, anopheles
(invertebrate host). Incubation period varies from 9-40 days, being shortest for P. falciparum
and longest for P. malariae. Knowledge of the life cycle (Figure 1) is essential in understanding
the phases of illness and natural course.
The clinical presentation of malaria is closely related to the dynamic relationships
between the causative agent (Plasmodium species), vector (Anopheles mosquito) and host (man)
characteristics in a area (Figure 2). The pattern and intensity of transmission of the parasite is
determined by density, longevity, biting habits and efficiency of mosquito vector and in turn
determines the background level of acquired protective immunity in the host and the clinical
picture.1
Transmission can be ‘stable’ or ‘unstable’. When it is constant, frequent and occurs all
through the year, it is called stable transmission. When it is low, erratic or focal it is called
unstable transmission. Geographical areas are classified into high and low transmission areas.
An area with >1 case/1000 population is a high transmission area and that with 0-1
case/thousand population is a low transmission area. Sub-Saharan Africa, where transmission is
stable, entomological inoculation rate (number of infectious bites/year) is high and P. falciparum
predominates is a high transmission area. High transmission areas have higher morbidity and
mortality in early childhood and asymptomatic infections in older age groups. Most of Asia has
low and seasonal transmission with roughly equal prevalence of P. falciparum and P. vivax
malaria and a lower entomological inoculation rate and is thus a low transmission area.
Protective immunity is not acquired and symptomatic disease can occur at any age. Changes in
environmental, economic or social conditions (heavy rains after drought, large population
movements) and breakdown in malaria control programs can precipitate epidemics.1 In India,
22% of the population lives in high transmission areas (parts of the North Eastern states, Odisha
and Rajasthan), 67% in low transmission areas and 11% in malaria free areas.12
Figure 1: Life cycle of the malarial parasite and its relation to phases of illness.
Clinical features
Uncomplicated malaria
Illness begins with a prodrome of nonspecific symptoms of fatigue, headache, arthralgia,
myalgia, abdominal and chest pain mimicking a viral illness that may last for 2-3 days. This is
followed by fever, which is the cardinal symptom of malaria. The classic malarial paroxysm
consists of fever with chills and rigors occurring at periodic intervals (24 hours for P.
falciparum, 48 hours for P. vivax and P. ovale and 72 hours for P. malariae) with abdominal
pain, nausea, vomiting, diarrhea, back pain, pallor and jaundice. These classic paroxysms,
though eloquently described, are uncommon in children and periodicity is least apparent with P.
falciparum. Splenomegaly, hepatomegaly and pallor are important examination findings. No
specific set of signs and symptoms reliably differentiates malaria from other tropical infections.
The clinical diagnosis of uncomplicated malaria is based on the following WHO
recommendations: in low risk areas - history of exposure to malaria, fever in last 3 days with no
features of severe disease; in high risk areas, history of fever in last 1 day, or in children,
presence of palmar pallor (Hb < 8 g/dl). Prompt and appropriate antimalarial therapy at this stage
when there is no organ dysfunction can ensure a rapid and complete recovery. If not, the
increasing parasite burden may lead to organ dysfunction which may become potentially life
threatening (severe malaria).
Severe malaria
Severe malaria is defined as the presence of ≥1 complications (Table 1) and P.

falciparum or P. vivax parasitemia and absence of an identified alternative cause.13 The
definition is same for P. vivax and P. falciparum malaria but no parasite density thresholds are
described for P. vivax. About 1% of symptomatic infections complicate into severe malaria. The
severity of malaria, like the clinical presentation, also depends on characteristics of the agent-
vector-host triad (Figure 2). Severe malaria, attributed mainly to P. falciparum has been
increasingly seen to be caused by P. vivax leading one to suspect if ‘benign tertian malaria’ is
benign.14,15 Multiple studies have shown that P. vivax is as capable as P. falciparum to cause
virtually any complication that defines severe malaria and has similar mortality rates.16-19
Atypical presentations ranging from viral hepatitis-like presentation, acute abdomen,
gastrointestinal bleed, generalized edema, hyperglycemia to rarely, subacute intestinal
obstruction, hemiplegia, severe headache and ptosis can be seen.20
Figure 2: Factors affecting the clinical presentation of malaria

Table 1: Features of severe P falciparum malaria13
Complications and organ system involvement
Cerebral malaria:
It is defined as coma lasting at least 1 hour after termination of a seizure or correction of
hypoglycemia with asexual forms of P. falciparum in blood with no other cause to explain the
coma.13 Cerebral malaria is a medical emergency which is rapidly reversible with few sequelae if
diagnosed and managed on time. Prompt diagnosis demands an accurate peripheral blood film
(PBF) assessment with reliable exclusion of other causes. Incidental parasitemia in endemic
areas may pose a problem interfering with the specificity of the diagnosis by PBF. In a post
mortem study of cerebral malaria in Malawi, 24% of patients had other causes.21 Mechanisms of
brain injury in cerebral malaria include parasite sequestration causing hypoxia-ischemia;
cytokines, chemokines and excitotoxicity; and endothelial activation, apoptosis, blood-brain
barrier dysfunction, and intracranial hypertension.22
Encephalopathy is the cardinal feature of severe malaria, and besides being caused by
Cerebral malaria per se and and co-infections like viral encephalitis, it is often caused by easy to
recognize and treat etiology such as hypoglycemia, seizures (postictal or non-convulsive status
epilepticus), electrolyte imbalances (hypo or hypernatremia) or metabolic acidosis. These
patients regain consciousness within a few hours after resuscitation and outcome depends on
timing of treatment. If encephalopathy is due to a prolonged post-ictal state, patients usually
regain consciousness within 6 hours and have a good neurological recovery. On the other hand,
if it is due to a covert status epilepticus, the neuro-cognitive outcome will be variable. If coma
lasts more than 24-48 hours, it is commonly associated with raised intracranial pressure (ICP)
and has a worse neurological outcome.
Studies have shown that up to 80% of patients with cerebral malaria are admitted with
seizures and seizures recur in 60% during admission. There may be raised ICP or brainstem signs
(abnormalities in posture, pupil size and reaction, ocular movements or abnormal respiratory
patterns). Retinopathy is seen in 2/3rd of children with clinically defined cerebral malaria.23,24 It
has 3 components: retinal whitening, vessel changes, and retinal hemorrhages. It is most readily
appreciated in fully dilated pupils with thorough direct ophthalmoscopic examination and may be
the only clinical feature to differentiate malarial and non-malarial coma. It has both diagnostic
and prognostic significance as mortality is highest in children with papilledema and retinopathy,
compared to those with retinopathy alone and those with normal fundus.25,26 Retinal signs
resolve over 1 to 4 weeks without sequelae.25
The commonest neurological sequelae in survivors of cerebral malaria are cognitive
sequelae in 14-25% of children. Predictors for the development of these sequelae include
hypoglycemia, seizures, depth and duration of coma and hyporeflexia. Other sequelae described
include speech and language impairment (11.8%), epilepsy (10%) and behavior and
neuropsychiatric disorders.22
Cardiovascular complications
A wide range of cardiovascular complications have been reported, including subclinical
electrocardiographic changes, raised cardiac markers, shock and fatal myocarditis.27-29 Shock can
be due to hypovolemia, microvascular changes or myocardial dysfunction. Though absolute or
relative hypovolemia is always a component of every child with shock, it is important to
remember that changes at a microvascular level (like sequestration, endothelial dysfunction and
changes in blood rheology) are more important in children with severe malaria and shock;30
hypovolemia is relatively mild and not commensurate with degree of end organ damage.31
Myocardial dysfunction is known in severe malaria.32 Increased pulmonary pressures and
myocardial wall stress that has been documented in severe malaria supposedly occur from the
pathophysiologic cascade from intravascular hemolysis, NO depletion and consequent
cardiopulmonary effects.33 A prospective study in Ghanaian children with severe malaria showed
increased cardiac index (CI) on day 0 compared to day 42 correlated negatively with hemoglobin
but not with impaired tissue perfusion parameters or metabolic acidosis.34 Parasite levels had a
significant influence on metabolic acidosis but not on CI. Changes in cardiac function,
hemoglobin levels and metabolic acidosis were most prominent in children below 2 years. There
are several case reports of peripheral gangrene in both P. vivax and P. falciparum malaria.
Pulmonary complications
Pulmonary complications presenting with respiratory distress are seen in up to 40% of
children with severe P. falciparum malaria.35 Causes ascribed include respiratory compensation
of metabolic acidosis, noncardiogenic pulmonary edema, concomitant pneumonia and severe
anemia. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are important
complications in severe P. falciparum malaria as well as in P. vivax and P. ovale malaria.36,37
ARDS can develop either at initial presentation or after initiation of treatment when the
parasitemia is falling and the patient is improving. Increased alveolar capillary permeability
resulting in intravascular fluid loss into the lungs appears to be the key pathophysiologic
mechanism. P. falciparum malaria with severe metabolic acidosis or acute pulmonary edema is
known to present with a clinical picture of ‘pneumonia’, hence a high index of suspicion in
endemic areas is essential.
Hyperparasitemia
Definition of hyperparasitemia is controversial, with lower cutoffs being suggested over
the years. The WHO defined hyperparasitemia as a parasite index of >2% in low transmission
areas and >5% in high transmission areas.38 As symptoms have been seen to develop with lower
parasite indices, studies have suggested cutoffs as low as 0.5% to define hyperparasitemia.39 A
higher parasite load accelerates the pathological process, increases the risk of severe malaria,
organ failure, and antimalarial drug resistance.40
Hypoglycemia
Hypoglycemia (blood sugar <2.2 mmol/l or <40 mg/dl) is a defining feature of severe
malaria and the most frequent metabolic complication.41 It indicates a poor prognosis,
predominantly when accompanied by acidemia (pH <7.3) or hyperlactatemia (lactate >5 mmol/l)
and is an independent risk factor for mortality. A random blood sugar estimation using a point-
of-care glucose device is mandatory at admission in all children with suspected malaria for
timely recognition and prevention.
Acute kidney injury(AKI)

Malaria is an important cause of AKI in the PICU.42,43 It has been seen mostly with P.
falciparum though P. vivax is increasingly noted to cause renal impairment. It is less common in
younger children as compared to non-immune adults and older children with P. falciparum
malaria. Several hypotheses have been proposed including mechanical obstruction by infected
erythrocytes, immune mediated glomerular and tubular pathology, fluid loss due to multiple
mechanisms and alterations in the renal microcirculation.44 Disseminated intravascular
coagulation (DIC), jaundice and parasite density (≥3+) were found to be significant factors
contributing to mortality in children with AKI.45
Anemia
Definitions for anemia in malaria are given in Table 1. Mechanisms leading to anemia
include direct and indirect destruction of parasitized and non-parasitized RBC, immune-complex
mediated hemolysis, suppression of erythropoiesis, dyserythropoiesis, and significant bleeding.
46
Pre-existing micronutrient deficiency prevalent in malaria endemic areas also contributes to
the anemia.
Diagnosis
Timely diagnosis and management of malaria is a continuing challenge. Differentiating
malaria from several other infections in malaria endemic areas which present at the same time of
the year and initiating initial, empirical management in such critically ill children in crowded
emergency rooms is a huge challenge. Overlapping clinical presentations adds to difficulties in
arriving at specific diagnoses. The ISCCM guidelines on management of tropical fevers classify
the clinical presentations of tropical fever into 5 categories viz. undifferentiated fever, fever with
rash/thrombocytopenia, fever with ARDS, febrile encephalopathy, and fever with multiorgan
dysfunction.47 Malaria with its protean manifestations figures among the common causes in each
of these categories.47 Hence a diagnosis of malaria based on clinical features alone can lead to
overtreatment. All suspected cases of malaria should undergo either a parasitological test (light
microscopy) or rapid diagnostic test (RDT) to confirm the diagnosis.13
Light microscopy
Light microscopic examination of a PBF is considered the gold standard test. Thick
smears are more sensitive for detecting the presence of malaria parasites, while thin smears are
useful for detecting the species. Sensitivity is about 75% for a single thick blood film; it is lower
in those with immunity, non-falciparum malaria, partially treated malaria or low-level
parasitemia. Smears are positive if about 50-100 parasites/ml are present, though experienced
technicians may be able to detect even 5 parasites/ml.48 Blood should be used as soon as possible
to minimize morphological changes in the parasites.
Rapid diagnostic tests
The advent of RDTs has dramatically improved patient management in the emergency
room (ER). RDTs are lateral flow immunochromatographic antigen-detection tests, which rely
on the capture of dye-labeled antibodies to produce a visible band on a strip of nitro-cellulose.
With malaria RDTs, the dye-labeled antibody first binds to a parasite antigen, and the resultant
complex is captured on the strip by a band of bound antibody, forming a visible test line (T). The
control line (C) gives information on the integrity of the antibody-dye conjugate. Parasite
antigens used here are pfHRP2 (P. falciparum histidine rich protein 2, specific for P.
falciparum), pLDH (Plasmodium lactate dehydrogenase - species specific LDH for P. falciparum
and P. vivax, and a pan malarial LDH), and pAldolase (pan malarial antigen). As we encounter
both P. falciparum and non-falciparum infections, combination RDTs that detect all species and
can distinguish P. falciparum from non-falciparum are preferred.
Advantages of RDTs are they are quick, easy, relatively inexpensive and reliable (overall
80-95% sensitivity and 85% specificity).48 Disadvantages are they do not provide information
about parasite density and continue to be positive 2-3 weeks after disappearance of the parasite.
Hence, they are not useful to detect a recrudescence or monitor resolution. Also, RDTs perform
better at high parasite concentrations and are variable with a low parasitemia. Evidence says that
algorithms incorporating RDTs can substantially reduce antimalarial prescribing if health
workers adhere to test results. Negative RDTs are equally important to improve overall health
outcomes in febrile children.49 A recent systematic review revealed that the two RDTs performed
satisfactorily for the diagnosis of P. falciparum, but the pLDH tests had higher specificity,
whereas the pfHRP2 tests had better sensitivity. A combination of both antigens might be a more
reliable approach for the diagnosis of malaria.50
Polymerase chain reaction
Polymerase chain reaction (PCR) is the most reliable method for detecting parasites (97%
sensitivity and 100% specificity) and is especially helpful in low-level infections with a limit of
detection of 0.5-5 parasites/μL.48 They are, however, more expensive, prone to contamination,
and require sophisticated equipment and hence primarily used in research.
Management
The main objectives of treatment of severe malaria are to prevent death, disabilities and
recrudescent infection.13 Management comprises clinical assessment of the patient, specific
antimalarial treatment, and supportive care. Here we discuss the specific treatment using
antimalarial drugs as well as supportive care of critically ill children with severe malaria in
PICU.
Specific treatment: Antimalarial drugs
Management of uncomplicated malaria mainly involves administration of antimalarial
drug/s and symptomatic treatment (Table 2). Management of severe malaria is a medical
emergency as it can lead to death within hours. Achieving therapeutic concentrations of a highly
effective antimalarial drug as soon as possible is the main goal. The core principles of anti-
malarial usage are early initiation, rational use, appropriate combination therapy, and appropriate
weight based dosing.
Two important groups of antimalarial drugs are available today- artemisinin derivatives
(artesunate, artemether), and cinchona alkaloids (quinine, quinidine, chloroquine). A Cochrane
systematic review in 2012 incorporating evidence from 8 randomized controlled trials (1664
adults, 5765 children) concluded that use of artesunate reduced mortality by 40% in adults and
25% in children.51 A small increase in neurological sequelae was observed, which were however
self-limited and no difference was notable by day 28. Artemisinin derivatives are more effective,
simpler, and safer than the cinchona alkaloids. Overall, artesunate is more effective than
artemether which is more effective than quinine. For pre-referral administration, intramuscular
(IM) artesunate is more effective than rectal artesunate which is more effective than IM
artemether, followed by IM quinine in children <6 years. In children > 6 years, rectal artesunate
is not recommended, otherwise the same comparison holds true.52
The combination drugs available in artemisinin combination therapy (ACT) are
artesunate+sulfadoxine-pyrimethamine, artesunate+amodiaquine, artemether+lumefantrine,
dihydroartemisinin+piperaquine, Artesunate+mefloquine (avoided in cerebral malaria), and
artesunate+doxycycline or clindamycin.13 The dose of artesunate is 3 mg/kg/day for children
weighing <20 kgs and 2.4 mg/kg/day for larger children. Younger children require a higher dose
due to larger volume of distribution. Route of ACT must be parenteral for atleast 24 hours and
later, once patient starts taking orally, can be converted to oral to complete a 3-day course.
Table 2: Table summarizing choice of antimalarial drugs in malaria based on species and clinical
presentation
Uncomplicated Severe
P. vivax Areas with chloroquine susceptibility: chloroquine or ACT ACT +Primaquine
Areas with chloroquine resistance: ACT
Primaquine: 0.25-0.5 mg/kg/d for 14d
Except in <6months and known G6PD deficiency
G6PD deficiency: 0.75 mg/kg/week for 8 weeks
G6PD status unknown and unavailable: individualize
P. falciparum ACT+single dose of primaquine in low transmission areas ACT+single dose of

(0.25 mg/kg) primaquine in low transmission
No G6PD testing required areas (0.25 mg/kg
No G6PD testing required)
Mixed ACT+Primaquine (as for P. vivax) ACT+Primaquine (as for P.
vivax)
Not known As for uncomplicated P. falciparum As for complicated P.
falciparum
Chloroquine resistance in P. vivax: current scenario
Artesunate plus sulfadoxine-pyrimethamine remains a safe and effective for
uncomplicated P. falciparum malaria. Chloroquine remains a safe and an effective for
uncomplicated P. vivax malaria. The epicentres of chloroquine-resistance are the eastern
provinces of Indonesia and in the past 5 years, convincing evidence has been reported from
South America and some Asian countries. Reports from the Indian subcontinent (India,
Afghanistan, and Pakistan) are mostly reassuring.53
Intensive care issues
As in any critically ill child, irrespective of the underlying diagnosis, initial assessment
and stabilization are paramount to ensure a good outcome. Stabilization starts with assessment
and management of airway, breathing, and circulation.
Airway and breathing:
Tachypnea may be due to pulmonary complications, shock or just ‘silent’ tachypnea
(acidotic breathing) due to acidosis, and severe anemia. Children with tachypnea, pallor, or
shock should be promptly started on oxygen through nasal prongs or face mask. Indications for
endotracheal intubation and ventilation in children with severe malaria are Glasgow Coma scale
score < 8, status epilepticus, ALI/ARDS, shock, pulmonary edema, and myocardial dysfunction.
Circulation:
Assessment and optimization of volume status is one of the foremost priorities in children
with severe malaria. It is well known that no single parameter from clinical examination, central
venous pressure, echocardiography to advanced thermodilution techniques can reliably assess
volume status irrespective of the underlying disease. Fluid resuscitation in critically ill children
has been an intense debate. The landmark ‘FEAST trial’ on more than 3000 African children
suffering from severe febrile illness (more than half of whom had malaria) showed that fluid
boluses significantly increased 48 hour mortality irrespective of type of fluid.54 Cardiovascular
collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid
resuscitation.55
Thus, in the absence of uniform recommendations, pediatric intensivists need to
remember following points in this regard. Each child must be assessed individually with a
combination of clinical, bedside, and laboratory parameters. Crystalloids are the fluids of choice
as evidence is lacking for colloids/balanced salt solutions. Fluid boluses should be given with
extreme caution only if there is hypotension. Presence of acute kidney injury or severe acidosis
unresponsive to fluids is an indication for renal replacement therapy. Urgent blood transfusion is
important if hemoglobin is <7 gm%. Children presenting with high grade fever and
hemodynamic instability should receive intravenous broad-spectrum antibiotics as coexistent
bacterial sepsis is always a consideration.13
Management of cerebral edema:
Management of cerebral edema remains largely supportive. Therapeutic measures include
stabilization of airway, breathing, and circulation; neutral neck position, head end elevation by
30°, adequate sedation and analgesia, minimal stimulation, and seizure control; and maintenance
of euthermia and euglycemia. Short-term hyperventilation to achieve PCO2 ~30 mm Hg using
bag ventilation can be done if signs of impending herniation are present. A Cochrane systematic
review to study the role of mannitol in children with cerebral malaria found only one randomized
trial and concluded that short of further trials mannitol cannot be recommended as a general
adjunct for treating cerebral malaria.56 Once the child is shifted to PICU, invasive ICP
monitoring would be valuable option in guiding therapy. Studies have shown that pediatric
intensivists can safely and successfully perform burr holes at bedside for establishing ICP
monitoring.57
Adequate control of seizure and status epilepticus is essential and use of antiepileptic
drugs is like other diseases. A detailed approach to treatment of SE can be found elsewhere.58 A
single IM dose of phenobarbitone at 20 mg/kg increased mortality; hence it should not be given
without respiratory support. There is no role for prophylactic anticonvulsants.13
Hyperparasitemia and role of exchange transfusion:
Exchange transfusion (ET) rapidly reduces the parasitic index (PI) and expected to cause
survival benefit. Whether it is more effective when compared to chemotherapy alone resulting in
any survival benefit is not clear. Evidence in children is scarce.59,60 The WHO guidelines thus do
not make any recommendation regarding exchange transfusion. In a few studies that
demonstrated the benefits of ET in children with hyperparasitemia.59,60 volume used has been
variable, from a partial ET at 40 ml/kg to double volume ET at 160 ml/kg. On an average around
4/5th of preexchange PI was reduced by ET irrespective of the preexchange PI. Reduction in PI
did not depend on percentage of blood volume exchanged or the chemotherapeutic agent used
(quinine or artisunate). All the children survived intact without and sequelae and required around
5-10 days to get a discharge. Adverse events reported during the procedure include
hypocalcemia, oozing from lines, and bradycardia. The procedure, being labor-intensive method
may be used in complicated malaria with hyperparasitemia or multiorgan dysfuction which fail
to respond to chemotherapy alone, preferably in an intensive care setting.
Treatment and prevention of hypoglycemia:

Rapid recognition and correction of hypoglycemia is extremely important. A bolus (5
ml/kg) of 10% dextrose solution should be given by a rapid intravenous push. RBS should be
rechecked after 30 minutes. It is important to give 10% dextrose in normal saline or Ringer´s
lactate for maintenance infusion to prevent hypoglycemia. Routine blood glucose measurement,
frequent monitoring, and early recognition are mandatory.
Acute kidney injury:
Loop diuretics can convert an oliguric renal failure to non-oliguric renal failure without
affecting outcome of the disease though the conversion reduces the risk of volume overload.
There is little evidence on beneficial effect of vasoactive drugs. Nephrotoxic drugs such as ACE
inhibitors, NSAIDs, aminoglycosides, cephalosporins should be avoided.
Early institution of renal RRT is beneficial. More than half of patients with malaria in different
series required RRT.61,62 Early RRT is often indicated to take care of hypercatabolic state.
Although peritoneal dialysis may be less effective because of the complicating circulatory
disturbances, practically it may be the only available dialysis modality in children. Beneficial
effects of continuous peritoneal dialysis have been observed in patients of malarial AKI. A
comparative study to evaluate efficacy of hemofiltration versus peritoneal dialysis showed
significant lower mortality with hemofiltration (15 vs. 47%).63 Rate of resolution of acidosis and
decline in the serum creatinine concentration with hemofiltration were more than twice than with
peritoneal dialysis. RRT was required for a significantly shorter period with hemofiltration.63 In
adults with AKI (of all causes) indicated intermittent hemodialysis and continuous RRT appear
to lead to similar clinical outcomes in ARF patients.64 Majority of antimalarial drugs are
metabolized in liver and excreted through kidneys. What happens to their metabolism and
excretion when both the organs are involved needs to be clearly understood for effective
management and prevention of adverse drug reactions.
Pulmonary complications:
Timely intubation and mechanical ventilation, hemodynamic stabilization, and
optimizing fluid balance along with chemotherapy are the cornerstones of management.
Coexistent bacterial sepsis is frequently present in patients with malarial ARDS though an
obvious focus may not be evident, necessitating broad spectrum antibiotics. As mortality is high,
timely intervention in PICU is life saving.
Anemia:
All children with hemoglobin <7 gm% should be urgently transfused.13
Outcome of severe malaria

A study on Gambian children showed that cold peripheries, deep coma, hypoglycemia,
elevated admission urea levels and multiple convulsions were the strongest predictors of
mortality.65 In a large prospective study on 1682 Indian children with confirmed malaria, 374
subjects had severe malaria. Case fatality rate was 12%. Multiple regression analysis showed that
respiratory distress, coma, multiple organ dysfunctions, and hyperparasitemia were the major
predictors of death.66 Another large study on 1320 patients with complicated malaria, 22% of
them children had an overall case fatality rate of 4.3%, being significantly higher in children
(12.3%) compared to adults (2%). Major causes of death were cerebral malaria (45.6%), malaria
with a respiratory infection (19.3%) and anemia (10.5%).67 Another study from South India on
922 adults showed that 21.8% had more than 7 days of hospitalization, 8.6% required intensive
care, and 1.2% died. More than 3 days history of fever, leukocytosis, severe thrombocytopenia,
and renal failure were predictors of prolonged hospitalization and/or intensive care.68
Conclusion
Severe malaria is associated with high mortality and morbidity in children. Management
of severe malaria is a medical emergency which requires high index suspicion, rapid diagnosis,
and aggressive management. The diagnosis should be prompt and investigations should include
peripheral blood smear and rapid diagnostic tests depending upon availability and expertise.
Antimalarial drugs should be administered promptly according to the weight of child. Artesunate
combination therapy is recommended in malaria. Supportive treatment is of utmost importance
and includes control of airway, breathing and circulation; management of cerebral edema, raised
ICP and status epilepticus, anemia, and acute kidney injury; maintaining adequate intravascular
volume; and vigilant monitoring of cardiovascular, respiratory, renal, neurological system, and
fluid and electrolyte status to detect complications and their treatment.

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P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Intensive care issues in Acute Encephalitis in Children
Mounika Reddy*, Arun Bansal**
*Senior Resident, **Professor, Pediatric Critical Care Unit, Advanced Pediatrics Centre,
PGIMER, Chandigarh,India
Correspondence:
Prof Arun Bansal, Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER,
Chandigarh 160012, Phone:0172-2755328, Email: drarunbansal@gmail.com
ABSTRACT
Encephalitis is a major cause of acute neurological dysfunction among children
and constitutes a medical emergency. Acute infectious encephalitis is usually viral in
etiology. However, immune-mediated encephalitis, which are eminently treatable also
forms asignificant proportion. The evaluation and management have evolved with the
advances in diagnostic studies, neuromonitoring techniques and antimicrobials. Early
recognition, systematic approach and institution of timely appropriate symptomatic and
specific therapy are essential to improve outcomes. Cerebrospinal fluid examination and
neuroimaging may point to a specific diagnosis. With few exceptions, no specific therapy
is available for most forms of viral encephalitis. Morbidity and mortality can be
significantly reduced in HSV encephalitis by adequate treatment with acyclovir while
delays in treatment can be devastating. Long term sequelae are common among survivors.
Key words: Encephalitis, children, intensive care, viral, Herpes
Introduction
Encephalitis is an important cause of morbidity and mortality in children. While on

one hand, the changing epidemiology and spread of arboviral encephalitis presents new
challenges to the pediatricians, the availability of newer imaging and viral diagnostic
techniques, advances in neurocritical care and availability of better antiviral and
immunomodulatory therapies is changing the management of children with suspected
encephalitis.1
Definitions
Encephalitis: Encephalitis is defined as inflammation of the brain parenchyma with
clinical evidence of neurological dysfunction. Though, strictly speaking, it is a pathological
diagnosis requiring tissue confirmation on brain biopsy or autopsy, there may be surrogate
markers of neuronal inflammation in cerebrospinal fluid (CSF) or on neuroimaging.2,3
Acute or sub-acute onset global cerebral dysfunction with fever may be due to an
infective encephalitis, non-infective encephalitis or encephalopathy. Non-infective
encephalitis may be immune mediated, as in, acute demyelinating encephalomyelitis
(ADEM) which usually follows infections and vaccinations. It is important to differentiate
this entity from infective encephalitis as the management differs. Often, encephalitis may co-
exist with concomitant inflammation of meninges (meningoencephalitis), spinal cord
(encephalomyelitis) or nerve roots (encephalomyeloradiculitis).
Encephalopathy: Encephalopathy is non-inflammatory diffuse brain dysfunction. It
may or may not be associated with fever and can occur secondary to various conditions like
systemic infections, metabolic disturbances, hypoxia, ischemia, critical illness, organ
dysfunction, trauma, vasculitis, drugs and intoxications. Non-infective causes of
encephalopathy are usually characterized by absence of fever, gradual onset, absence of CSF
pleocytosis and lack of focal changes on neuroimaging.4
Etiology
Encephalitis is usually caused by viruses and some small intracellular bacteria and
parasites which infect the brain parenchyma directly. A wide range of viruses cause viral
encephalitis in children in tropical countries, most common being herpes viruses,
enteroviruses and arboviruses (Table1).3 The various infectious and non-infectious conditions
that may mimic viral encephalitis are presented in table 2.2
Table 1: Causes of acute viral encephalitis

Sporadic (not geographically restricted):
 Herpes viruses: Herpes simplex virus (HSV) 1 and 2, Varicella Zoster virus (VZV),
Epstein Barr virus (EBV), Cytomegalovirus (CMV), Human herpes virus (HHV) 6
and 7
 Enteroviruses: Enterovirus 70 and 71, Coxsackie virus, Poliovirus, Echovirus,
Parechovirus
 Paramyxoviruses: Measles virus, Mumps virus
 Rabies virus
 Others (rare): Influenza virus, Adenovirus, Parvovirus B19, Rubella virus
Endemic and epidemic(geographically restricted):
 Arboviruses: Japanese encephalitis (JE) virus, Dengue virus, Chikungunya virus,
West Nile virus, Tick-borne encephalitis
Epidemiology
The epidemiology of viral encephalitis is changing due to spread of arboviruses to
new areas (e.g. Japanese encephalitis virus, West Nile virus across North America and
Europe), increasing number of immunocompromised patients who are at risk of encephalitis
due to various pathogens, and reduction in encephalitis due to vaccine preventable diseases
like measles, mumps, varicella, and rubella.
The incidence of encephalitis in children is not known exactly due to under-reporting, lack of
large prospective studies and use of different case definitions or diagnostic studies. The
annual incidence is 5-10/100,000 as per most studies with higher incidence in younger
children.The cause of encephalitis is diagnosed in less than one-third cases. Herpes simplex
virus (HSV) encephalitis remains the most commonly diagnosed sporadic viral encephalitis
the world over, though in Asia, Japanese encephalitis (JE) is the most common cause of
epidemic encephalitis.1,5
Table 2: Diseases that may mimic viral encephalitis
CNS infections:
 Bacterial meningitis
 Tuberculosis
 Brain abscess
 Mycoplasma pneumonia infection
 Enteric fever
 Leptospirosis
 Listeriosis
 Brucellosis
 Lyme disease
 Rickettsiae: Scrub typhus, Rocky mountain spotted fever (RMSF), Q fever,
Ehrlichiosis, Cat-scratch fever
 Parasites: Cerebral malaria, Cysticercosis, Toxoplasmosis, Amoebiasis
 Fungi: Candidiasis, Cryptococcosis, Histoplasmosis, Coccidiomycosis
Para/post-infectious causes:
 Guillian Barre syndrome (GBS)
 Acute demyelinating encephalomyelitis (ADEM)
Non-infectious causes:
 Vasculitis
 Intracranial bleed
 Ischemic stroke
 Primary brain tumour or metastasis
 Metabolic encephalopathy: Hypoglycemia, diabetic ketoacidosis, uremia, hepatic
failure, Reye syndrome, mitochondrial diseases,toxins or drugs
 Epilepsy
Pathogenesis
Several mechanisms have been proposed in the pathogenesis of encephalitis. It may
be due to direct viral cytopathology (destruction of cells by viruses) or it may be a para/post-
infectious inflammatory or immune mediated response (e.g. Measles). Other mechanisms
which may be operating include diffuse cerebral edema (e.g. influenza), vasculitis (e.g.
Varicella zoster virus) and demyelination.3 With a particular virus, a single mechanism may
predominate or multiple mechanisms may be involved.
Pathogens must cross the blood−brain barrier to cause encephalitis. It may be through
the re-activation of latent infection in the neural pathways (e.g. herpes viruses) or through
viremia and subsequent spread across the blood–brainbarrier (e.g. enteroviruses, arboviruses).
Some viruses may exhibit tropism for certain areas of the brain. HSV primarily targets the
parenchymal cells in temporal lobes, though it may also involve the frontal and parietal areas.
Japanese encephalitis virus has a predilection to involve the thalami and the basal ganglia.
Presentation
The clinical syndrome of acute infectious encephalitis is considered in any acutely
febrile child with altered consciousness and signs of diffuse cerebral dysfunction. Viral
encephalitis usually begins with an acute flu-like prodrome followed by high grade fever,
nausea, vomiting, headache, acute cognitive dysfunction and behavior changes, often
associated with new onset seizures and focal neurological signs. The irritability, somnolence
or abnormal behavior is greater than that usually seen in children with any febrile illness.
Meningeal signs may be present as encephalitis is invariably associated with some degree of
leptomeningeal inflammation.6,7
Table 3: Salient points on history and examination

History:
 Symptoms: onset, progression, severity (in chronology)
 History of similar illness in family/community
 Travel history
 Vaccination history
 Contact with insects or animals
 Occupation history and history of recreational activities
 Presence of an immunocompromised state: malnutrition, retroviral infection,
primary immunodeficiency, cancer chemotherapy, post-transplant patients etc.
General examination:
 Pallor, icterus, edema
 Rash: maculopapular, petechial, purpuric, vesicular
 Lymphadenopathy, hepatosplenomegaly
 Respiratory: crepitations
Neurological examination:
 Higher mental functions
 Cranial nerve involvement
 Tone abnormalities
 Focal neurological signs
 Abnormal/extrapyramidal movements
 Meningeal signs
 Signs of raised intracranial pressure (ICP) – altered pupillary responses, raised
blood pressure, bradycardia, altered respiratory pattern, abnormal posture
(decorticate or decerebrate), papilledema
Approach
A child with suspected acute infectious encephalitis constitutes a medical emergency.
Systematic approach with early recognition of the clinical syndrome, initial stabilization,
prompt empirical therapy and meticulous supportive care followed by appropriate diagnostic
evaluation and rapid institution of specific therapy when available is essential to prevent
ongoing brain damage and improve outcomes. Assessment and treatment have to proceed
simultaneously as it is associated with high mortality and morbidity with long-term sequelae
among survivors. The salient points to note on history and examination are given in table 3.
Certain clues may point to a specific etiology (table 4). One should also search for other
possible explanations of coma.6
Investigations
Evaluating a child with suspected viral encephalitis includes investigating for the
specific etiology, and presence and severity of organ dysfunction. Complete blood picture
may reveal anemia, leukocytosis or leucopenia, and/or thrombocytopenia. Atypical
lymphocytes may be seen in Epstein Barr virus (EBV) infection. Serum electrolytes,
coagulation studies, renal and hepatic function tests should be obtained. Elevated amylase
and lipase levels may be noted in mumps encephalitis. Blood cultures are important to
identify any bacterial or fungal etiology, though positive cultures may only point to
encephalopathy due to systemic infection rather than primary encephalitis.
Table 4: Epidemiological and clinical pointers to specific etiology
Season Late summer, early fall: enteroviral, arboviral
Winter: influenza
Geography Sporadic: HSV
Endemic to tropical areas: arboviral infections
Insect/animal contact Birds: JE, Cryptococcus neoformans
Dogs: Rabies
Swine: JE
Mosquitoes: malaria, dengue
Ticks: RMSF
Lymphadenopathy HIV, EBV, CMV, Measles, rubella, Mycobacterium tuberculosis
Parotitis, orchitis Mumps
Rash VZV, HHV6, Parvovirus, Rubella, enterovirus, mycoplasma,
measles, mumps
Respiratory symptoms Influenza, adenovirus, mycoplasma, Mycobacterium tuberculosis
Cerebellar ataxia VZV, EBV, Mumps
Cranial nerve HSV, EBV, Listeria, tuberculosis, cryptococcosis
abnormalities
Rhombencephalitis/basal HSV, Enterovirus, Listeria, tuberculosis
meningoencephalitis
Table 5: CSF characteristics in various CNS infections1

CSF Normal Viral Acute Tuberculous Fungal
characteristic meningo- bacterial meningitis meningitis
encephalitis meningitis
Opening 7-15 cm Normal-high High High High-very
pressure high
Gross Clear Clear or Cloudy Cloudy/ straw Clear/cloudy
appearance hemorrhagic coloured with
cobweb
formation
WBC/mm3 <5 Slightly High – very Slightly Normal-high
increased-high high increased 0-1000
(5-5000) (100-50,000) (25-500)
Differential All Mostly Mostly Mostly Mostly
cell count lymphocytes lymphocytes Neutrophils lymphocytes lymphocytes
CSF/plasma 66% Normal Low Low-very low Normal-low
glucose ratio (<30%)
Protein (g/l) <0.45 Normal-high High (>1) High-very Normal-very
(0.5-1) high high
1.0-5.0 0.2-5.0
Specific diagnostic investigations include cerebrospinal fluid (CSF) analysis,

neuroimaging, and viral studies guided by epidemiological and clinical clues. Identification
of etiological agent is essential for definitive treatment, potential prophylaxis, prognostication
and public health interventions. However, despite extensive testing, etiological diagnosis
often remains elusive.5
Lumbar puncture (LP) to obtain CSF is essential in patients of encephalitis to identify
the cause for tailored therapy and must be performed as early as possible. However, delay in
doing LP should not delay the administration of empirical antimicrobials. Contraindications
to performing a LP include presence of new onset seizures (focal/generalized), focal
neurological signs, deep coma, features of raised intracranial pressure (ICP). In such cases,
neuroimaging is warranted prior to doing a LP and findings of intracranial space occupying
lesion, cerebral edema or brain shift (herniation across midline or tentorium or foramen
magnum) on neuroimaging contraindicate LP. Findings on CSF analysis in various central
nervous system (CNS) infections are presented in table 5.
In viral encephalitis, CSF is usually clear with mildly raised opening pressure. There is
mild to moderate CSF pleocytosis, predominantly lymphocytic; however, early in the course,
it may be normal or neutrophilic. CSF red cell count is usually normal or slightly raised, but
it may be markedly raised in HSV encephalitis or acute necrotizing hemorrhagic
leukoencephalitis. CSF:blood glucose ratio is often normal but may be reduced in mumps or
enteroviral infections and CSF protein is usually slightly raised.6
Table 6: Characteristic neuroimaging patterns in viral encephalitis

Etiology Characteristic neuroimaging pattern
HSV encephalitis Temporal lobe edema and hemorrhage
Bilateral temporal lobe involvement is nearly pathognomonic but
is a late finding
Japanese B encephalitis Thalamus, basal ganglia
Enterovirus 71 encephalitis Mid brain, pons, medulla (brainstem encephalitis)
VZV encephalitis Cerebral cortex, basal ganglia, cortical white matter junction,
cerebellum
Dengue encephalitis Basal ganglia, thalami, temporal lobe. May present as acute
hemorrhagic or necrotizing encephalitis
Rabies encephalitis Basal ganglia, thalami, brainstem, limbic system, spinal cord as
well as frontal and parietal lobes
Influenza encephalitis Cortex and white matter
The definitive etiological diagnosis of encephalitis is through demonstration of the

pathogen in the CNSbyculture or polymerase chain reaction (PCR) of brain tissue/CSF or by
demonstrating specific antibody response in CSF. Detecting the pathogen elsewhere in the
body doesn’t necessarily indicate CNS infection. CSF viral culture is rarely done these days
as newer more sensitive PCR techniques are now available like ‘real time’ and ‘quantitative’
PCR for many organisms with improved yield.
The most commonly available CSF viral PCR is for HSV encephalitis. CSF HSV PCR is
>95% sensitive and specificand remains positive in 80% even a week after starting antiviral
therapy. However, it may be negative in first few days of illness. In case of strong clinical
suspicion of HSV encephalitis, it should be repeated after a couple of days. If two PCRs are
negative, then it is unlikely to be HSV infection. Further investigations may be guided by the
clinical picture and initial CSF or neuroimaging findings.
Newer enzyme immunoassays can detect specific IgM and IgG antibodies in serum and
CSF for most viruses and mycoplasma pneumonia though negative result in the acute phase
doesn’t rule out infection. Four-fold rise in antibody titers between the paired acute and
convalescent sera collected 2-4 weeks apart to document seroconversion doesn’t help in
immediate management but may be useful for retrospective etiological diagnosis. Presence of
virus specific IgM antibodies in higher titers in CSF as compared to serum implies CNS
infection, as IgM usually doesn’t cross blood brain barrier (BBB) unless inflamed.7
PCR or culture or antigen testing of a throat swab or nasopharyngeal aspirate may help in
identification of mycoplasma, chlamydia, adenovirus, influenza virus, mumps and measles.
Enterovirus may be identified in a throat swab or a rectal swab. Fluid from a vesicular lesion
can be sent for electron microscopy, immunofluorescence, antigen detection, PCR or culture
to identify herpes viruses or enterovirus. Brain biopsy for culture, electron microscopy, PCR
and immunohistochemistry has a very limited role and may be done in deteriorating
undiagnosed patients.
Neuroimaging plays an important role in the evaluation of a child with viral
encephalitis. In emergency settings, to identify focal lesions or cerebral edema, computed
tomography (CT) scan is preferred to magnetic resonance imaging (MRI) scan as it is
cheaper, more widely available and technically less difficultto acquire. However, MRI is has
better sensitivityto detect brain parenchymal changes and is important for prognostication
(Table 6). In the early stages, conventional MRI may be normal and special sequences like
diffusion-weighted imaging (DWI) may be useful in such conditionsto detect early changes.8-
10
Fig 1: MRI in Japanese encephalitis Fig 2: MRI in HSV encephalitis
Electroencephalogram (EEG) has a supportive role in the intensive management of

encephalitis. It helps in detecting non-convulsive status epilepticus (NCSE) and in
demonstrating burst suppression during treatment of refractory status epilepticus. EEG also
has a diagnostic role. In most cases of encephalitis, it may show non-specific diffuse high
amplitude slow waves of encephalopathy. Periodic lateralized epileptiform discharges are
usually seen in HSV encephalitis though they are not highly specific.
Treatment
In a child with suspected viral encephalitis, evaluation and treatment should proceed
together. The treatment includes initial stabilization, definitive therapy, management of
complications and supportive care.
Initial stabilization:
The priorities during management in emergency include:
 Assessment of airway and stabilization
 Hemodynamic assessment and resuscitation if needed
 Assessment of level of consciousness using a quantitative scale like GCS
 Management of complications like seizures and raised intracranial pressure (ICP)
Definitive therapy:
After initial stabilization, the treatment of viral encephalitis involves definitive antiviral or
immunomodulatory therapy to halt or reverse the disease progression. Presumptive treatment
pending neuroimaging and/or lumbar puncture includes administering antimicrobials to cover
for organisms causing both bacterial meningitis and viral encephalitis. As HSV is the most
common cause for sporadic encephalitis and currently one of the very few potentially
treatable causes of viral encephalitis, there should be a high index of suspicion and acyclovir
should be empirically started as early as possible. In proven cases of HSV encephalitis,
acyclovir is given for a total of 3 weeks duration because of the risk of relapse with shorter
therapies. CSF examination may be repeated at the end of treatment and acyclovir should be
continued if fever persists or CSF HSV-PCR is still positive.11 Other treatable causes of viral
encephalitis are varicella zoster encephalitis (acyclovir), cytomegalovirus (CMV)
encephalitis (ganciclovir, valaciclovir).12,13
Management of complications:
The most important neurological complications of encephalitis are raised ICP and status
epilepticus. Ideally, such children should be managed in an intensive care setting with
continuous neurocritical care monitoring.14
Presence of raised ICP should be anticipated in children with encephalitis and proactively
managed. When it is clinically suspected, an ICP monitoring catheter should be inserted for
objective measurement. First tier anti-raised ICP measures include head end elevation to 15-
300, keeping head in midline, minimal stimulation, control of fever and seizures.
Osmotherapy may be used to reduce the cerebral edema. Hypertonic saline is preferred over
mannitol for osmotherapy because of lesser side effects like hypotension or renal failure and
presence of additional rheological benefits. For raised ICP refractory to these measures,
barbiturate coma or Decompressive craniectomy may be considered.
Seizures are a common presentation in encephalitis and time-based protocolized
management of status epilepticus improves outcomes. First line anti-epileptics include
benzodiazepines, phenytoin, valproate and levetiracetam while barbiturate coma, ketamine,
lignocaine and general anesthesia may be tried in refractory status epilepticus. Non-
convulsive status epilepticus (NCSE) should be considered in all children with unexplained
persistent encephalopathy and continuous EEG monitoring should be done.
Supportive care:
Supportive care is paramount in management of children with encephalitis. Patient
positioning and prevention of bed sores, nutrition and physiotherapy should be meticulously
taken care off. Tracheostomy should be considered in those anticipated to require prolonged
airway or respiratory support.
Prognosis
Withthe recent advances in diagnosis and management, mortality due to encephalitis
in children has come down significantly, however, neurological sequelae are still common in
long term survivors. They include motor, sensory and cognitive impairments, epilepsy,
behavioral problems and psychiatric disorders. Long term follow-up and neurorehabilitation
are important to improve outcomes.
Conclusion
Encephalitis is a common problem in pediatrics, mostly caused by viruses. Early
diagnosis and meticulous management is critical for better outcomes. CSF examination and
neuroimaging are critical for diagnosis and management. Supportive care is the mainstay of
therapy and acyclovir is the drug of choice in those with clinical suspicion of herpes
encephalitis. Inspite of the best treatment, mortality is still significant and long-term sequelae
are common in those who survive.
References
1. Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, et al. Management of
suspected viral encephalitis in adults-Association of British Neurologists and British Infection
Association National Guidelines. J Infect 2012;64(4):347-73.
2. Thompson C, Kneen R, Riordan A, Kelly D, Pollard AJ. Encephalitis in children. Arch Dis
Child 2012;97(2):150-61.
3. Solomon T, Hart IJ, Beeching NJ. Viral encephalitis: a clinician's guide. Pract Neurol
2007;7(5):288-305.
4. Roos KL. Encephalitis. Handb Clin Neurol 2014;121:1377-81.
5. Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, et al. The management of
encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin
Infect Dis 2008;47(3):303-27.
6. Sharma S, Mishra D, Aneja S, Kumar R, Jain A, Vashishtha VM. Consensus guidelines on
evaluation and management of suspected acute viral encephalitis in children in India. Indian
Pediatr 2012;49(11):897-910.
7. Chaudhuri A, Kennedy PG. Diagnosis and treatment of viral encephalitis. Postgrad Med J
2002;78(924):575-83.
8. Lo CP, Chen CY. Neuroimaging of viral infections in infants and young children.
Neuroimaging Clin N Am 2008;18(1):119-32; viii.
9. Gupta RK, Soni N, Kumar S, Khandelwal N. Imaging of central nervous system viral
diseases. J Magn Reson Imaging 2012;35(3):477-91.
10. Bookstaver PB, Mohorn PL, Shah A, Tesh LD, Quidley AM, Kothari R, et al. Management of
Viral Central Nervous System Infections: A Primer for Clinicians. J Cent Nerv Syst Dis
2017;9:1179573517703342.
11. Gnann JW, Jr., Whitley RJ. Herpes Simplex Encephalitis: an Update. Curr Infect Dis Rep
2017;19(3):13.
12. Rozenberg F. Acute viral encephalitis. Handb Clin Neurol 2013;112:1171-81.
13. Kneen R, Michael BD, Menson E, Mehta B, Easton A, Hemingway C, et al. Management of
suspected viral encephalitis in children - Association of British Neurologists and British
Paediatric Allergy, Immunology and Infection Group national guidelines. J Infect
2012;64(5):449-77.
14. Kramer AH. Viral encephalitis in the ICU. Crit Care Clin 2013;29(3):621-49.
P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Enteric fever
Javed Ismail*, Sunit Singhi**

*Senior Resident, Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh
**Chairman, Division of Pediatrics, Medanta, the Medicity, Gurugram, NCR and
Professor Emeritus, Department Of Pediatrics, Advanced Pediatrics Centre,
Post graduate Institute of Medical Education and Research, Chandigarh, India
Correspondence
Prof. Sunit Singhi, Chairman, Division of Pediatrics, Medanta, The Medicity, Gurugram,
NCR 122001. Phone: +91-81681886201, 01244141414 Ext 7316,
Email:sunit.singhi@gmail.com
ABSTRACT
Enteric fever is a major public health problem especially for India due to poor sanitation,
lack of clean drinking water and poor food hygiene. It can affect all age groups, but recent
shift towards infants and young children is worrisome. The majority of patients improve
with ambulatory treatment, supportive care, and administration of appropriate antibiotics
early during course of the disease. Hospitalization is indicated in patients with persistent
vomiting, poor oral intake or severe diarrhea or any of the serious complications. Patients
with shock, encephalopathy, intestinal perforation or hemorrhage and toxemia should be
managed in the intensive care unit. Diagnosis is often based on serological tests but blood
culture remains the gold standard. Ceftriaxone is the drug of choice for complicated
enteric fever. A short course of dexamethasone for 2 days may decrease the mortality in
children with serious complications. Early surgical intervention is warranted in intestinal
perforation. The emergence of multidrug-resistant strains, is a serious concern thus
necessitating more focus on preventive measures. Integrated preventive approach like
improvement in sanitation, hygienic food practices and mass vaccination will go a long
way in decreasing the incidence of these infections.
Key Words: Children, Enteric fever,
Introduction
Enteric fever is a common public health problem in India and is becoming a challenge in the face
of increasing antimicrobial resistance. Children below the age of 5 years are the most affected
age group.1 Few of serious complications may require intensive care management in these
children.
Epidemiology
Enteric fever is widely prevalent worldwide, especially so in the Indian subcontinent with a
reported incidence of 6.3 million cases per year.2 The disease is mostly endemic with sporadic
cases occurring in persons who travel to endemic areas. South-central, South East Asia, and
southern Africa have the highest prevalence of disease of which Indian subcontinent having the
highest incidence of typhoid among travelers.3 Hospital-based studies from India analyzing
fevers presenting to hospitals, have reported a prevalence of 9.7% (95% CI 5.7 – 16%) for
enteric fever.4 The incidence among children has been reported to be 340/100000 and
493/100000 population-year among under five and 5- 15 years of age respectively. Though the
prevalence over time has shown an overall decreasing trend, the shift towards increased
incidence in younger children is worrisome.4,5 The risk factors identified for transmission of the
disease include poor sanitation, overcrowding, ingestion of unhygienic street foods,
contaminated water, and history of contact with a patient. The epidemics in India have been
caused mostly by fecal contamination of drinking water by the typhoid carriers.
Pathogenesis
The causative organism of enteric fever is Salmonella typhi (called as S. enterica serotype
Typhi), S. paratyphi A, B or C which are gram-negative bacilli of the Enterobacteriaceae family.
Humans are the only reservoir of infection. The transmission of the disease occurs through direct
contact or indirectly via contact with fecal contaminated food or water.
The ingested organisms survive the acidic pH of the stomach and pass down to infect the small
bowel mucosa. This is responsible for producing intestinal symptoms following which the
organism enters the circulation through lymphatics, to cause the systemic manifestations.
Chronic use of proton pump inhibitors, primary immunodeficiency disorders like chronic
granulomatous disease, neutropenia’s, organ transplant recipients are some factors that
predispose to severe infection. The incubation period ranges from 6 to 21 days (typically 2
weeks).
Clinical presentation
Children typically present with fever, anorexia, non-localized abdominal pain and a dry cough.
Fever is the presenting complaint in the majority (90%) of patients. Fever is usually of remittent
nature, without touching baseline, characteristically called “step ladder” pattern and the spikes
often reach 40oC by the end of first week of the illness. Vomiting, diarrhea and occasionally
constipation can occur during the first week of illness If untreated fever becomes unremitting and
the illness may progress with appearance of CNS symptoms like a headache, irritability and
meningeal signs. Clinical examination reveals a coated tongue, few scattered blanching
erythematous skin lesion (rose spots), hepatomegaly and a soft splenomegaly. Occasionally,
children may present as acute abdomen with hypotension pointing to intestinal perforation.
Neuropsychiatric manifestations like severe agitation, delirium or obtundation can also be seen.
Paratyphoid fever usually presents with similar clinical features, but with shorter incubation
period and milder manifestations. During the convalescent phase, the general well-being,
appetite improves and the systemic signs resolve. This may sometimes be followed by a
prolonged asymptomatic carrier state in about 10 – 15% of patients.
Multiorgan involvement /Complications
Ten to 15% of children may land up with serious complications usually in the second week of
illness; important among them being intestinal perforation or hemorrhage and typhoid
encephalopathy. Factors that determine the occurrence of complications and overall outcome are
duration of illness before seeking appropriate antibiotic therapy, age of the child, vaccination
status, virulence of the strain and the host nutritional and immune status. Infants and younger
children are at higher risk of systemic toxicity1; the initial illness tends to be very nonspecific in
this age group and progresses to systemic manifestations like anasarca, hepatomegaly, seizures,
thrombocytopenia, and bleeding making clinical suspicion difficult.6 The multidrug resistant
strains are highly virulent and result in intense bacteremia and a higher rate of complications.7
Intestinal complications
Intestinal perforation occurs in about 1-3% of hospitalized patients with enteric fever. Though
the published data on incidence of typhoid intestinal perforation is highly variable among the
community based and hospital based Indian studies, higher rates of perforation have been
reported from western Africa (10% to 33%).8,9 The presence of abdominal tenderness in a child
with suspected enteric fever should always alert the physician towards this complication though
younger children may manifest with milder symptoms like fever and vomiting at presentation.
Immunologically mediated release of cytokines like TNFα from the sensitized macrophages
causes necrosis of the bowel wall resulting in intestinal perforation.10 Perforation is common in
older children (>5 years) as the immune mechanisms are mature. The common site affected is the
terminal ileum (70-80%) followed by less commonly involved sites like jejunum, cecum, colon
or gall bladder. Unusual complications like appendicitis, appendicular perforation and toxic
megacolon have also been reported.11,12
Neurological complications
Children may present with neurological manifestations like headache, photophobia, vomiting,
and neck stiffness. Encephalopathy is a common presentation. In a cohort of 129 children from
single center observational study, about 30 children (23%) had neurological manifestations at
admission.13 Complications like meningitis, encephalomyelitis, and seizures are also described.
Benign intracranial hypertension, Guillain-Barre syndrome, acute cerebellar ataxia, cranial nerve
palsies and peripheral neuritis have been rarely reported.14–17
Renal involvement including cystitis, pyelitis, pyelonephritis and mild proteinuria have
been reported. Rare but serious manifestations like myocarditis, glomerulonephritis, acute
respiratory distress syndrome (ARDS) and hepatic manifestations like jaundice, hepatitis may
occur with highly virulent S. Typhi infection.18–20 Hematological complications include bone
marrow suppression, hemophagocytic lymphohistiocytosis (HLH) and disseminated
intravascular coagulation (DIC). Osteomyelitis, soft tissue abscesses, mycotic aneurysms have
also been reported commonly as a complication of paratyphoid infections.21 Case fatality has
been reported to be higher in young children and infants.22
Emergency Management
A comprehensive history and thorough clinical examination is needed to identify the
manifestations of enteric fever. Early clinical diagnosis is often difficult to establish as the
findings are nonspecific and may mimic other febrile illnesses like malaria, scrub typhus,
Epstein-Barr virus and brucellosis. For patients in non-endemic regions, the history of recent
travel to the endemic area is important.
Children with persistent vomiting, abdominal distention, and poor oral acceptance or severe
diarrhea or any complications must be hospitalized. Stabilization of airway, breathing and
circulation take precedence over other therapy in all critically ill children. Children presenting
with shock may require fluid resuscitation followed by vasoactive support and those presenting
with altered sensorium and a Glasgow Coma Scale of less than 8 may require airway
stabilization during emergency management.
The point of care tests like TUBEX TF (IDL, Sweden) and Typhidot (Malaysian Biodiagnostic
Research, Malaysia) may be useful in an emergency setting for diagnosis. The former is an
antibody-based test on the principle of inhibition reaction between host and in vitro antibodies
that compete for S. Typhi-specific lipopolysaccharide. A visible decolorization of serum in the
test reagent indicates a positive test. The latter is based on a qualitative Enzyme-Linked
Immunosorbent Assay (ELISA) that detects the presence of IgG and IgM antibodies against S.
Typhi outer membrane protein. These tests have been reported to have a sensitivity of 55 – 70%
and a specificity of more than 85%. 23
Specific therapy
The important factor correlated with poor outcome is the delay in initiating an effective antibiotic
therapy. Most patients with uncomplicated disease improve with home-based treatment
comprising appropriate oral antibiotics, hydration, and supportive care. Parenteral antibiotics are
indicated in children with persistent gastrointestinal symptoms, poor oral acceptance and those
with neurological manifestations. Most Salmonella spp are resistant to ampicillin,
chloramphenicol, and trimethoprim-sulfamethoxazole. This antibiotic resistance is transferable
through plasmids between organisms thus posing a significant risk factor for the development of
multidrug resistant Salmonella infection (resistant to ampicillin, chloramphenicol, and
trimethoprim-sulfamethoxazole). Fluoroquinolones resistant strains have been reported from
various countries. Currently, third generation cephalosporins are being widely used; though few
sporadic reports of resistance having been documented.24 Reassuringly there have been some
reports of increased susceptibility to previously used drugs like co-trimoxazole and
chloramphenicol.25
Therefore, while deciding empiric therapy local data on resistance pattern, should help in making
the right antibiotic choice. For uncomplicated quinolone sensitive strains, cefixime or
fluoroquinolones are the initial antibiotics of choice. In areas of prevalent fluoroquinolone
resistance, third-generation cephalosporins should be used as the first line of choice for
hospitalized patients and oral cefixime (20 mg/kg/d) for ambulatory patients.21,26 Parenteral
antibiotics should be given for a period of at least 5 days after defervescence or for a total
duration of 14 days. It has been observed that a total treatment duration of 14 days is associated
with zero relapse rate.27 Alternatively, azithromycin can be used in cases of strains resistant to
cephalosporins. Multidrug-resistant strains should be suspected in children presenting with short
duration of illness, serious complications, failure to respond to first-line antibiotics or a known
household contact or during an epidemic of MDR typhoid fever.7 Children with enteric fever
have severe anorexia along with spiking fever, necessitating adequate hydration, liberal use of
antipyretics and early resumption of nutrition.
Intensive Care Needs
Depending on the clinical condition and complications a hospitalized patient may need
admission to PICU for the following:
1. Hemodynamic monitoring for shock
2. Neurological monitoring for encephalopathy
3. Monitoring for abdominal complications
4. Fluid and electrolyte balance
5. Bleeding diathesis due to thrombocytopenia
5. Disseminated intravascular coagulation and multiorgan failure
Organ supportive therapies
Children presenting with shock or enteric encephalopathy should be treated with steroids
preferably dexamethasone as an initial dose of 3 mg/kg followed by 1mg/kg every 6 hours for
total 8 doses. In the Indonesian cohort, treatment with dexamethasone in patients with severe
typhoid decreased the mortality from 50% to 10%.28,29 Thus, high dose dexamethasone has been
recommended for children with severe complications like shock, delirium, and encephalopathy.
30
Acute transverse myelitis due to enteric fever may be treated with high-dose
methylprednisolone followed by oral steroids for one week along with specific antimicrobial
therapy.31
Intestinal hemorrhage requires intensive monitoring, volume resuscitation, and blood transfusion.
Patients with suspected intestinal perforation should be stabilized first followed by urgent
surgical intervention. Secondary peritonitis with gram-negative organisms like E. coli and
Klebsiella is common after perforation and may lead to secondary organ dysfunction.
Radiological evidence of perforation, pneumoperitoneum has been reported in 54 to 70% of
children suspected of perforation.32,33 Though pneumoperitoneum is a definitive radiological sign
of perforation, its absence should not delay surgical intervention as surgery is the only definitive
option. There is no role for conservative management; a delay in surgical intervention has been
associated with poor outcomes.32 The overall case fatality rate due to typhoid intestinal
perforation varies between 15% to 25% and the mean duration of hospital stay is about 18 to 23
days.33,34 The common postoperative complications are entero-cutaneous fistula and wound
infection. Majority of the children die with overwhelming sepsis rather than as a complication of
surgery. Delayed presentation to the hospital, presence of shock, fecal peritonitis, prolonged
duration of perforation, younger age at presentation are identified risk factors for mortality in
enteric fever.
Acute respiratory distress syndrome requires mechanical ventilatory support. Myocarditis
presenting as cardiogenic pulmonary edema and/or shock with ST segment, and T wave changes
requires35 supportive care which includes ventilation, fluid restriction and inotropic support
while cardiac function takes few days to improve. Other complications like hepatitis, cystitis,
cerebellar ataxia, cranial nerve palsies require only conservative management. As a rare
complication progressive thrombocytopenia and pancytopenia, can occur secondary to infection
induced hemophagocytic lymphohistiocytosis (HLH).36 Patients usually improve with
conservative management with appropriate antibiotics as in any other case of infection induced
HLH.
Diagnostic tests
Positive blood culture confirms the diagnosis. The yield of culture positivity in first week of
illness has been shown to be up to 90% but it decreases as time elapses. The blood culture yield
increases if amount of blood sample taken is as per recommendations of World Health
Organization --10 to 15mL from school children and 2 to 4 mL and from preschool children and
toddlers (WHO).37 Bone marrow culture has the highest yield, especially in partially treated
patients. In a systematic review of 529 patients with proven S. Typhi infection, 61% were
detected by blood culture and 96% were detected by bone marrow culture.38 Though the culture
positive yield from the stool and urine samples increase after the second week of illness, the
overall yield is low (about 10% and 35% respectively). Nonspecific laboratory findings like
normocytic, normochromic anemia, leukopenia, and a mild increase in transaminase levels may
occur frequently.
Serological tests
The widely used serological test in a community setting for diagnosis of enteric fever is Widal
Test. It detects the antibodies against the O and H antigens of S. Typhi the predictive value of
which is variable among geographic areas. A titer of 1:160 is considered positive if done during
the second week of illness and a fourfold rise in titers of paired sera is considered more specific.
False negative test occurs due to inadequate antibody response while a false positive test occurs
due to antigenic cross-reactivity with non-typhoid salmonella and vaccine strains.
Outcomes
The overall mortality rate has decreased over the period of time to about 1% irrespective of
emergence of resistant strains.39 Children with serious complications like intestinal perforation,
encephalopathy and those requiring intensive care admission have a higher mortality. The overall
risk of becoming a chronic carrier is less than 2% in children.40
Preventive strategies
Provision of safe drinking water and hygienic sanitary practices are the most effective public
health preventive strategies. Currently, two vaccines have been recommended by WHO, the oral
(Ty21a vaccine) and the injectable Vi capsular polysaccharide vaccine. The Vi capsular
polysaccharide vaccine is to be administered at 2 years and should be repeated every three years.
Ty21a is available as enteric-coated capsules to be administered on days 1, 3 and 5 and to be
repeated every three years for individuals living in or traveling to endemic regions. Those
children treated for enteric fever should be vaccinated after 4 weeks of recovery.
Conclusions
With the advent of effective antibiotics, vaccines and availability of intensive care the mortality
due to enteric fever is on the decreasing trend. The emerging threat of multidrug resistant strains
mandate a rational use of antibiotics, effective utilization of the available preventive strategies
like provision of safe drinking water, improving hygiene and sanitation, administration of mass
vaccination.
References
1. Sinha A, Sazawal S, Kumar R, et al. Typhoid fever in children aged less than 5 years. Lancet Lond
Engl 1999; 354:734-7.
2. Crump J, Mintz E. Global Trends in Typhoid and Paratyphoid Fever. Clin Infect Dis 2010; 50:241-
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3. Ochoa TJ, Cleary TG. Salmonella. In: Ralph D. Feigin, James D Cherry, Sheldon L. Kaplan, Gail J.
Demmler-Harrsion, editors. Feigin and Cherry’s textbook of pediatric infectious diseases. Seventh
edition. Philadelphia, PA: Elsevier/Saunders; 2014.
4. John J, Van Aart CJC, Grassly NC.The Burden of Typhoid and Paratyphoid in India: Systematic
Review and Meta-analysis. PLoS Negl Trop Dis 2016; 10:e0004616.
5. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, et al. A study of typhoid fever in five Asian
countries: disease burden and implications for controls. Bull World Health Organ 2008; 86:260-8.
6. Rajajee S, Anandi TB, Subha S, et al.Patterns of resistant Salmonella typhi infection in infants. J
Trop Pediatr 1995; 41:52-4.
7. Zaki SA, Karande S: Multidrug-resistant typhoid fever: a review. J Infect Dev Ctries 2011; 5:324–
337.
8. van Basten JP, Stockenbrügger R. Typhoid perforation. A review of the literature since 1960. Trop
Geogr Med 1994; 46:336-9.
9. Ameh EA. Typhoid ileal perforation in children: a scourge in developing countries. Ann Trop
Paediatr 1999; 19:267–272.
10. Everest P, Wain J, Roberts M, et al. The molecular mechanisms of severe typhoid fever. Trends
Microbiol 2001; 9:316–320.
11. Lau SKP, Woo PCY, Chan CYF, et al.Typhoid fever associated with acute appendicitis caused by
an H1-j strain of Salmonella enterica serotype Typhi. J Clin Microbiol 2005; 43:1470-2.
12. Arun Babu T, Ananthakrishnan S, Jayakumar P, et al. Unusual complication of toxic megacolon in
typhoid colitis. Indian J Pediatr 2014; 81:504-6.
13. Biswal N. Letters to the Editor. J Trop Pediatr 1994; 40:190-4
14. Bhatt GC, Dewan V, Dewan T, et al. Pseudotumour Cerebri with Multiple Cranial Nerve Palsies in
Enteric Fever. Indian J Pediatr 2014; 81:196-7.
15. Joshi N, Bhattacharya M, Yadav S, et al. Cranial nerve palsies in typhoid fever: report of three
cases. Ann Trop Paediatr 2011; 31:255-8.
16. Dewan P, Pooniya V, Kaushik JS, et al. Isolated cerebellar ataxia: an early neurological
complication of enteric fever. Ann Trop Paediatr 2009; 29:217-9.
17. Parakh A, Kumar D, Mishra K. Enteric fever presenting as acute ataxia. J Paediatr Child Health
2013; 49:E251.
18. Odetunde O, Ezenwosu O, Odetunde O, et al. Typhoid glomerulonephritis and intestinal perforation
in a Nigerian child. Niger J Clin Pract 2014; 17:655.
19. Ugas MB, Carroll T, Kovar L, et al. Salmonella Typhi–Induced Septic Shock and Acute Respiratory
Distress Syndrome in a Previously Healthy Teenage Patient Treated With High-Dose
Dexamethasone. J Investig Med High Impact Case Rep 2016; 4:232470961665264.
20. Shetty AK, Mital SR, Bahrainwala AH, et al. Typhoid hepatitis in children. J Trop Pediatr 1999;
45:287-90.
21. Bhan M, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. The Lancet 2005; 366:749–762.
22. Buckle GC, Walker CLF, Black RE. Typhoid fever and paratyphoid fever: Systematic review to
estimate global morbidity and mortality for 2010. J Glob Health 2012; 2:010401.
23. Thriemer K, Ley B, Menten J, et al. A systematic review and meta-analysis of the performance of
two point of care typhoid fever tests, Tubex TF and Typhidot, in endemic countries. PloS One 2013;
8:e81263
24. Qamar FN, Azmatullah A, Kazi AM, et al. A three-year review of antimicrobial resistance of
Salmonella enterica serovars Typhi and Paratyphi A in Pakistan [Internet]. J Infect Dev Ctries 2014;
8[cited 2017 May 26] Available from: http://www.jidc.org/index.php/journal/article/view/3817
25. Chand HJ, Rijal KR, Neupane B, et al. Re-emergence of susceptibility to conventional first line
drugs in Salmonella isolates from enteric fever patients in Nepal. J Infect Dev Ctries 2014; 8:1483-7
26. Kumar P, Kumar R. Enteric Fever. Indian J Pediatr 2017; 84:227–230.
27. Engels EA, Falagas ME, Lau J, et al. Typhoid fever vaccines: a meta-analysis of studies on efficacy
and toxicity. BMJ 1998; 316:110-6.
28. Punjabi NH, Hoffman SL, Edman DC, et al. Treatment of severe typhoid fever in children with high
dose dexamethasone. Pediatr Infect Dis J 1988; 7:598–600.
29. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of Mortality in Chloramphenicol-Treated
Severe Typhoid Fever by High-Dose Dexamethasone. N Engl J Med 1984; 310:82-8.
30. Pickering M, Larry K, Kimberlin M, David W, Long M, Sarah S, et al. Red Book: 2012
Report of the Committee on Infectious Diseases. [Internet]. Elk Grove Village; Chicago:
American Academy of Pediatrics Caldwell Letter Service [distributor; 2012. [cited 2017 Jul
6] Available from: http://online.statref.com/default.asp?grpalias=HKN
31. Mishra K, Kaur S, Basu S, et al. Acute transverse myelitis: an unusual complication of
typhoid fever. Paediatr Int Child Health 2012; 32:174-6.
32. van der Werf TS, Cameron FS. Typhoid perforations of the ileum. A review of 59 cases,
seen at Agogo Hospital, Ghana, between 1982 and 1987. Trop Geogr Med 1990; 42:330-6.
33. Rahman GA, Abubakar AM, Johnson A-WBR, et al. Typhoid ileal perforation in Nigerian
children: an analysis of 106 operative cases. Pediatr Surg Int 2001; 17:628-30.
34. Mogasale V, Desai SN, Mogasale VV, et al.Case Fatality Rate and Length of Hospital Stay
among Patients with Typhoid Intestinal Perforation in Developing Countries: A Systematic
Literature Review. PLoS ONE 2014; 9:e93784.
35. Childs L, Gupta S. Salmonella enteritidis induced myocarditis in a 16-year-old girl. Case
Rep 2012; 2012:bcr2012007628-bcr2012007628.
36. Patel R, Non LR, Despotovic V, et al. Typhoid Fever Complicated by Hemophagocytic
Lymphohistiocytosis and Rhabdomyolysis. Am J Trop Med Hyg 2015; 93:1068-9.
37. Organization WH, others: Background document: the diagnosis, treatment and prevention
of typhoid fever [Internet]. 2003; [cited 2017 Jul 6] Available from:
http://apps.who.int/iris/bitstream/10665/68122/1/WHO_V-B_03.07_eng.pdf.
38. Mogasale V, Ramani E, Mogasale VV. What proportion of Salmonella Typhi cases are
detected by blood culture? A systematic literature review [Internet]. Ann Clin Microbiol
Antimicrob 2016; 15[cited 2017 Jul 5] Available from: http://ann-
clinmicrob.biomedcentral.com/articles/10.1186/s12941-016-0147-z
39. Azmatullah A, Qamar FN, Thaver D, et al. Systematic review of the global epidemiology,
clinical and laboratory profile of enteric fever [Internet]. J Glob Health 2015; 5[cited 2017
Jul 6] Available from: http://www.jogh.org/documents/issue201502/jogh-05-020407.pdf.
40. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ 2006;
333:78–82.
P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Diphtheria: Relic or Relevant
Shalu Gupta*, M. Jayashree**

*Senior Resident, **Professor,Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER,
Chandigarh,India
Correspondence
Prof M Jayashree, Chief Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER,
Chandigarh 160012, Phone: 9815594343Office: 7087008311, Email: mjshree@hotmail.com,
mjshree64@gmail.com
ABSTRACT
Diphtheria is an acute localized infection of the throat associated with systemic
manifestations caused by the toxin producing Corynebacterium diphtheriae. Diphtheria
continues to remain a serious public health problem in children largely related to lack of
effective immunisation. The grey, brown, and dirty pseudo membrane is pathognomonic of
this disease. The exotoxin produced by the pathogen is responsible for systemic effects.
Severity of infection is determined by site of infection, immunization status of the patient,
and extent of systemic involvement. Airway obstruction, myocarditis, acute kidney injury,
thrombocytopenia and neuropathy are some of the serious complications associated with this
disease. Of these, myocarditis is the most dreaded complication and carries a very high
mortality. Diphtheria is a clinical diagnosis and specific antitoxin is the mainstay of therapy
and should be administered as early as possible. Antibiotics are used to eradicate residual
organisms, stop toxin production and decrease infectivity. The indications for PICU transfer
include severe pharyngo tonsillar disease, delayed presentation to hospital (> 5 days),
delayed antitoxin therapy, signs of airway obstruction and/ormyocarditis. Extremes of ages,
severe disease, unimmunized children, myocarditis and delayed administration of antitoxin
are all poor prognostic factors.
Key words: diphtheria, children, intensive care, myocarditis, antitoxin
Introduction
Diphtheria is an acute localized infection of the throat associated with systemic manifestations
caused by the toxin producing Corynebacterium diphtheriae. The pseudo membrane in the throat is
pathognomonic of this disease. The ability of C.diphtheriae to produce exotoxin results from the
acquisition of a lysogenic bacteriophage which encodes for the toxin gene and facilitates production
of the toxin.
The four biotypes of diphtheria (mitis, gravis, belfanti, and intermedius) can be differentiated by
their colony characteristics, degree of haemolysis and fermentation reactions. The other non-toxin
producing strains cause milder disease in humans. In the pre-vaccine era, diphtheria called the
"strangling angel of children “was the leading cause of death among them.
Diphtheria was first recognized as a specific disease by Brettoneau in 1826 and named “la
diphthérite” owing to its leather-like exudate in the oropharynx (Greek: leather = dipthera).1 Edwin
Klebs discovered the organism in 1884, followed a year later by Fredrick Loeffler who first
cultured the bacterium. In 1889, Emile Roux and Yersin purified the diphtheria toxin. A year later,
Von Behring demonstrated the use of serum therapy in diphtheria which won him the first Nobel
Prizein the year1901.
Epidemiology
C. diphtheriae is an exclusive inhabitant of human mucous membranes and skin. The spread of the
disease occurs via respiratory droplets, direct contact with respiratory secretions or infected skin
lesions. Asymptomatic respiratory tract carriage plays an important role in transmission.
With effective vaccine, the incidence of diphtheria has steadily declined throughout the United
States and Western Europe.1 However, resurgence and epidemic outbreaks have been reported from
different parts of the world mainly in adolescents and adults, rather than in children.2-5 Some of the
factors attributed to this resurgence were waning immunity in adults, lack of natural exposure to
toxigenic C diphtheriae, large population of under immunized adults, decreased childhood
immunization rates, population migration, and overcrowding. This possibly resulted in an
epidemiologic shift towards more adolescents and adults getting the disease.
The scenario in developing economies is different; diphtheria continues to remain a serious public
health problem in children largely related to lack of effective immunisation. In 2015 an outbreak of
respiratory diphtheria with a case fatality of 27% was reported from two health districts in the
province of KwaZulu-Natal in South Africa.6 More recently, Corynebacterium ulcerans from cats
and dogs is emerging as an important causative agent for diphtheria.7
Pathogenesis
Corynebacteria are aerobic, non-encapsulated, non–spore-forming, non-motile, pleomorphic, Gram-

positive bacilli. The upper respiratory tract mucosa is the most common site of infection, other sites
being, buccal mucosa, upper and lower lips, hard and soft palate, tongue and nasal cavity. Nasal
infection presents with whitish membrane on the nasal septum. Faucial diphtheria is characterised
by the pathognomonic grey, brown dirty pseudo membrane which is a dense necrotic coagulum of
organisms, epithelial cells, fibrin, leukocytes, and erythrocytes.8 The organisms multiply locally
but exotoxin produced is absorbed into the blood and is responsible for systemic manifestations like
acute tubular necrosis, thrombocytopenia, cardiomyopathy, and polyneuropathy or myelopathy.8
Severity of infection is determined by the site of infection, immunization status of the patient, and
the extent of dissemination of exotoxin. The exotoxin inhibits cellular protein synthesis by
inactivating protein synthesis elongation factor 2 (EF2). An alternative cytotoxic pathway
consisting of direct toxin mediated chromosomal DNA damage has also been proposed.9
Clinical presentation
C. diphtheriae causes localized mucosal infection and exotoxinemia. Tonsils or pharynx is the
primary site of infection followed by nose and larynx. The local signs and symptoms of
inflammation follow an incubation period of 2-5 days. Sore throat is the universal symptom in
tonsillar and pharyngeal diphtheria. Dysphagia, hoarseness, malaise, or headache may be reported.
Fever is usually low grade or absent unlike streptococcal sore throatwhich are characterised by high
grade fever.The membrane can be unilateral or bilateral extending up to uvula, soft palate, posterior
oropharynx, glottis, and larynx. The concurrent soft-tissue oedema and enlarged cervical lymph
nodes gives rise to the characteristic ‘bull-neck’ appearance.10
Nasal diphtheria presents as serosanguinous, purulent, and erosive rhinitis with shallow ulceration
of the external nares and upper lip.A membrane severity scoring has been proposed to grade the
extent of pseudo-membrane at time of presentation; ‘0’ membrane cleared before presentation; ‘1’
only nose or incomplete coverage of tonsils; ‘2’ confluent coverage of tonsils; ‘3’ as above plus
palate and/or pharyngeal wall; ‘4’ as above, plus nasal and/or larynx.11 Severe disease is associated
with extensive local spread, profound prostration, bull-neck, airway compromise and systemic
complications. Untreated patients, shed the bacterium in nasal and oropharyngeal secretions for two
to six weeks after inoculation.
Complications:
Airway obstruction
Upper airway obstruction presenting as stridor is the commonest complication seen in nearly three
fourths of patients, reasons being manifold; laryngeal membrane and edema, extensive pharyngo-
tonsillar disease, oedema of soft tissues in submental and anterior cervical areas, necrosis or
bleeding into the airways.
Myocarditis
It is the most dreaded complication of diphtheria as it is associated with very high mortality.
Diphtheric myocarditis is a late first week complication and seen in about two thirds of patients,
with respiratory symptoms. Incompletely immunized state, severity of the local disease and delayed
antitoxin therapy are associated with high risk of myocarditis.11,12 The combination of bull neck and
pseudo-membrane admission score of > 2 was found to be the best predictor for development of
diphtheritic myocarditis. The toxin has a predilection for the conduction system of the heart and
causes acute inflammation of sinoatrial and atrioventricular nodes. Carnitine a co transporter of
long chain fatty acids is depleted, resulting in fatty acid accumulation. Disproportionate tachycardia
may be the first sign of toxin-induced myocarditis. The other manifestations include conduction
disturbances, arrhythmias, congestive heart failure and circulatory collapse. ECG changes of
complete heart block and ischemia, were associated with high mortality compared.11
Neuropathy
Peripheral neuropathy, is a late complication and develops anywhere from 10 days to 3 months
after the onset of oropharyngeal disease. Like myocarditis, the incidence of polyneuropathy is also
directly proportional to the severity of local disease and exotoxinemia. Bulbar symptoms in the
form of nasal or hoarse voice along with dysphagia and palatal palsy begin 3–6 weeks after initial
infection and progress to polyneuropathy at around 8 weeks.13 The bulbar symptoms vary from
mild to severe but are seen in almost all patients with diphtheritic polyneuropathy.13,14 Dysphagia
may be accompanied by excessive salivation, nasal regurgitation and aspiration into the airways,
necessitating nasogastric feeding. Numbness of the tongue and face and dysphonia may also be
seen. The polyneuropathy is predominantly motor but can be associated with paraesthesia,
hypoesthesia, and hyperesthesia. Sensory ataxia may be seen in few patients. Autonomic
neuropathy manifests as tachycardia, arrhythmias, hypertension or hypotension; these are difficult
to distinguish from diphtheritic myocarditis. There is an inverse relationship between latency and
recovery of motor symptoms, longer latency is associated with early recovery. Respiratory muscles
are first to recover, followed by palatal and limb muscles.15
Acute kidney injury
Renal tubules are susceptible to the toxin mediated injury, leading to acute tubular necrosis.
Elevated serum creatinine at admission is predictive of a fatal outcome.11
Diagnosis
Diphtheria is a clinical diagnosis and requires a high degree of suspicion especially in an
unimmunised child.
Clinical criteria7
Any patient with at least one of the following :
 Respiratory diphtheria: An upper respiratory tract illness with fever and one of the
following two: croup or an adherent membrane in at least one of the following
three locations: tonsil, pharynx or nose.
 Nasal diphtheria: Uni- or bi-lateral nasal discharge initially clear and becoming
bloody.
 Cutaneous diphtheria: Skin lesion.
 Diphtheria of other sites: Lesion of conjunctiva or mucous membranes.
 Laboratory criteria: Isolation of toxin-producing C. diphtheriae or C. ulcerans from
a clinical specimen.
 Epidemiological criteria: An epidemiological link by human-to-human
transmission.
Case classification7
A: possible case: Any person meeting the clinical criteria for respiratory diphtheria.
B: probable case: Any person meeting the clinical criteria for diphtheria and with an
epidemiological link.
C: confirmed case: Any person meeting the clinical and the laboratory criteria.
Differential diagnosis
Other causes of membranous tonsillopharyngitis like infectious mononucleosis, Group A
streptococcal tonsillo-pharyngitis, oral candidiasis, Vincent’s angina, and agranulocytosis must be
considered in the differential diagnosis of respiratory diphtheria. Presence of high grade fever,
tonsillar exudates, tender anterior cervical adenopathy, white plaques on the buccal mucosa, painful
and bleeding gums, and atypical lymphocytosis suggests alternative diagnosis.
Laboratory Diagnosis
A throat or nasopharyngeal swab for Albert staining is the first diagnostic test for respiratory
diphtheria. The organism is gram positive, club shaped and pleomorphic bacilli with terminal
swelling (Chinese letter pattern) on the Albert’s stain. The diphtheroid which are normal throat
commensals can also stain positive on Albert’s stain. The tests for toxigenecity are required to
differentiate both.
Specimens must be transported immediately and rapidly inoculated into blood agar and selective
tellurite media. The latter inhibits the growth of normal oral flora; however, C. diphtheriae reduce
the tellurite salts, producing characteristic black colonies.
Test for Toxigenicity: The Elek test uses the principle of immunoprecipitation based on the
detection of characteristic precipitin lines formed when the exotoxin meets the diffusing antitoxin.
16
7 mm is taken as the best antitoxin to inoculum distance.17 The tests for toxigenicity is most
important and should be done without delay.
Recently, real time PCR with rapid turnaround time has been used for the detection of the
diphtheria toxin structural gene (tox).18 A negative toxPCR test on isolates excludes the diagnosis.
Another toxin assay method which includes rapid phenotypic enzyme immunoassay (EIA) using
equine polyclonal antitoxin is simple, rapid, accurate, and specific phenotypic method for the
detection of toxigenicity.19
Management
Emergency Room Management
The initial part of management should always focus on stabilisation of the Airway, Breathing
and Circulation. Airway compromise should be anticipated and treated promptly in children
with extensive local disease and bull neck. Intubation is risky as it can cause dislodgement of
pseudo membrane and other friable local tissue and bleeding.20 Tracheostomy on the other
hand provides a better conduit for tracheal toileting and is easier to maintain compared to
endotracheal tube.20
Strict hemodynamic monitoring including continuous 24-h electrocardiographic monitoring is
necessary for early detection and progression of myocarditis.
Indications for transfer to PICU
Patients with diphtheria require strict isolation. The indication for PICU transfer includes
severe pharyngo tonsillar disease, delayed presentation to the hospital (> 5 days), delayed
antitoxin therapy, signs of airway obstruction and/ormyocarditis.
Intensive Care Needs
1. Airway maintenance and care
2. Hemodynamic monitoring for shock, and arrhythmias
3. Fluid and electrolyte balance
4. Bleeding diathesis due to thrombocytopenia
5. Respiratory muscle weakness and need for ventilation
6. Disseminated intravascular coagulation and multiorgan failure
7. Acute kidney injury and need for renal replacement therapy
Specific therapy
The goals of specific therapy are: neutralization of circulating toxin, eradication of residual
bacteria, and establishment of active immunity to diphtheria toxin.
Antitoxin
Specific antitoxin is the mainstay of therapy and should be administered as early as possible
based on clinical diagnosis. Since antitoxin neutralizes only unbound toxin, its efficacy
diminishes if therapy is delayed. The dose of antitoxin is determined by site and size of the
membrane and duration of illness. Both intravenous and intramuscular route can be used; the
former is given as an infusion over 30-60 minutes. Equine diphtheritic antitoxin requires a test
dose of 50-100 units prior to full dose. Antitoxin is not useful for cutaneous diphtheria. The
recommended treatment dosages are as follows:
 Pharyngeal or laryngeal disease of 2 days duration: 20,000 – 40,000 units

 Nasopharyngeal disease: 40,000 – 60,000 units
 Extensive disease of 3 days or more or any patient with diffuse swelling of the neck:
80,000 – 120,000 units
Antibiotics:
Eradication of residual organisms to halt toxin production and reduce infectivity (prevent
transmission to others) is done with antibiotics. The drug of choice includes penicillin or
erythromycin for 14 days. The dosage regime is:
o Penicillin G:40,000 IU/Kg 4-6 hourly IM/IV till toxicity subsides; followed by
procaine penicillin 25 – 50,000 IU/Kg IM once daily for a total duration of 14 days.
o Erythromycin: 40-50 mg/kg/day in four divided doses for 14 days is an effective drug
for elimination of carriers. Patients treated with appropriate antimicrobials usually
become non-infective in less than four days.
Other Supportive therapy:
Carnitine: Carnitine replacement has been studied as a therapeutic option keeping in mind
that carnitine depletion occurs in diphtheritic myocarditis. In a case controlled study from
Brazil, patients who received carnitine showed a significant reduction in the incidence of
myocarditis, and mortality as compared to the controls.21 Despite this the current evidence
does not support the role of carnitine in Diphtheric myocarditis.
Cardiac Pacing: Conduction system disturbances in patients with diphtheria myocarditis are
markers of severe myocardial damage and poorly responsive to ventricular pacing.12 Though
the study from Vietnam, had reported a 27% survival rate in patients who underwent cardiac
pacing,22 insertion of a pacemaker in critically ill children and adolescents can be potentially
risky and life-threatening procedure. Also it has been shown that improving electrical activity
(pacemaker)failed to translate into good mechanical activity (cardiac output) due to severely
damaged myocardium. Pacemaker insertion can be associated with complications like
infection, thrombus and myocardial perforation.23 The role of immunosuppressive therapies
such as steroids and immunoglobulin is inconclusive.24,25
Isolation
Patients with suspected diphtheria should be strictly isolated until complete treatment and two
cultures obtained at least 24 hours apart are negative. Patients, whose initial cultures are negative,
should also be isolated till completion of antibiotic course.
Contact prophylaxis
All close contacts including household members, healthcare providers, exposed to oral or
respiratory secretions, require prophylaxis and toxoid immunization if immunization status is
incomplete. After cultures have been obtained, contacts should be treated with a single dose
of Benzathine penicillin (600,000 units intramuscularly [IM] for individuals <6 years of age and
1.2 million units IM for individuals ≥6 years of age) or oral erythromycin (500 mg four times daily
for 7 to 10 days.26 All traceable contacts of these patients should be advised throat swab cultures
and must be closely watched for symptoms.
Prognosis
The case fatality rate of diphtheria with treatment is 5–10%.10 Mortality is higher in extremes of
ages, severe disease, unimmunized children and delayed administration of antitoxin. Diphtheritic
myocarditis is associated with a mortality rate of 60-70%; cardiogenic shock, ventricular
arrhythmias, acute kidney injury are poor prognostic markers. Children with bull neck, mucosal,
skin, or nasal bleeding, severe airway obstruction requiring a tracheotomy, or a pseudomembrane
score of >2 are at risk of death.11
Protection
Clinical disease does not provide natural immunity. The only effective control measure against
diphtheria is universal immunization with diphtheria toxoid. Immunization does not prevent
respiratory or cutaneous carriage of toxigenic C diphtheriae, but decreases the severity of local
disease, systemic complications, transmission, and provides herd immunity. Serum antitoxin
concentration of 0.01 IU/mL is considered protective.
References:
1. Lai J, Fay KE, and Bocchini JA. Update on childhood and adolescent immunizations: selected
review of US recommendations and literature: Part 2. Curr Opin Pediatr 2011; 23:470-481.
2. Dittmann S, Wharton M, Vitek C. Successful control of epidemic diphtheria in the states of the
Former Union of Soviet Socialist Republics: lessons learned. J Infect Dis 2000; 181: S10-22.
3. Markina SS, Maksimova NM, Vitek CR, et. al. Diphtheria in the Russian Federation in the 1990s.
J. Infect. Dis 2000;181: S27–S34.
4. Wagner KS, White JM, Lucenko I. Diphtheria Surveillance Network. Diphtheria in the post
epidemic period, Europe, 2000-2009. Emerg Infect Dis 2012; 18:217-25.
5. Oyo-Ita A, Nwachukwu CE, Oringanje C. Interventions for improving coverage of child
immunization in low- and middle-income countries. Cochrane Database Syst Rev 2011;
7:CD008145.
6. Mahomed S, Archary M, Mutevedzi P. An isolated outbreak of diphtheria in South Africa, 2015.
Epidemiol Infect 2017; 145:2100-2108.
7. Zakikhany K and Efstratiou A. Diphtheria in Europe: current problems and new challenges. Future
Microbiol 2012;7: 595-607.
8. Hadfield TL, McEvoy P, Polotsky Y. The Pathology of Diphtheria. J Infect Dis 2000; 181:S116-
120.
9. Lessnick SL, Bruce C, Baldwin RL. Does diphtheria toxin have nuclease activity? Science 1990;
250:832–8.
10. Adler NR, Mahony A and Friedman ND. Diphtheria: forgotten, but not gone. Intern Med J. 2013;
43:206-210.
11. Kneen R, Nguyen MD, Solomon T. Clinical features and predictors of diphtheritic cardiomyopathy
in Vietnamese children. Clin Infect Dis2004; 39: 1591-8.
12. Varghese MJ, Ramakrishnan S, Kothari SS. Complete heart block due to diphtheritic myocarditis
in the present era. Ann Pediatr Card 2013; 6:34-8.
13. Sanghi V. Neurologic manifestations of diphtheria and pertussis. Handb Clin Neurol 2014;
121:1355-1359.
14. Piradov MA, Pirogov VN, Popova LM, et al. Diphtheritic polyneuropathy. Arch Neurol 2001; 58:
1438–1442.
15. Kanwal SK, Yadav D, Chhapola V. Post-diphtheritic neuropathy: a clinical study in paediatric
intensive care unit of a developing country. Tropical Doctor 2012; 42: 195-7.
16. Efstratiou A, Engler KH, Mazurova IK. Current Approaches to the Laboratory Diagnosis of
Diphtheria. J Infect Dis 2000; 181: S138–145.
17. Reinhardt DJ, Lee A, Popovic T. Antitoxin-in-membrane and antitoxin-in well assays for detection
of toxigenic Corynebacterium diphtheriae. J ClinMicrobiol1998; 36:207–210.
18. Mikhailovich VM, Melnikov MG, Mazurova IK. Application of PCR for detection of toxigenic
Corynebacterium diphtheriae strains isolated during the Russian diphtheria epidemic, 1990 through
1994. J Clin Microbiol 1995; 33:3061-3.
19. Engler KH, Efstratiou A. A rapid ELISA for confirmation of diphtheria caused by toxigenic
Corynebacterium spp. In: Abstracts of the 8th European Congress of Clinical Microbiology and
Infectious Diseases; 1997 May; Lausanne, Switzerland. Clin Microbiol Infect 1997; 3:14.
20. Jayashree M, Shruthi N and Singhi S. Predictors of Outcome in Patients with Diphtheria Receiving
Intensive Care. Ind Pediatr 2006; 43: 155- 160.
21. Ramos A, Barrucand L, Elias PRP. Carnitine supplementation in diphtheria. Indian Pediatr 1992;
29: 1501-5.
22. Dung N, Kneen R, Kiem N. Treatment of severe diphtheritic myocarditis by temporary insertion of
a cardiac pacemaker. Clin Infect Dis 2002; 35:1425‑9.
23. Washington CH, Ayuthaya I N S, Makonkawkeyoon K, et al. A 9-year-old boy with severe
diphtherial infection and cardiac complications. BMJ Case Rep 2014; doi: 10.1136/bcr-2014-
206085.
24. Mason JW, O’Connell JB, Herskowitz A. A clinical trial of immunosuppressive therapy for
myocarditis. The myocarditis treatment trial investigators. N Engl J Med 1995; 333:269‑75.
25. Thisyakorn U, Wongvanich J, Kumpeng V. Failure of corticosteroid therapy to prevent diphtheritic
myocarditis or neuritis. Pediatr Infect Dis 1984; 3:126‑8.
26. Farizo KM, Strebel PM, Chen RT. Fatal respiratory disease due to Corynebacterium diphtheriae:
case report and review of guidelines for management, investigation, and control. Clin Infect Dis
1993; 16:59-62.
P - ISSN: 2349-6592 | E - ISSN: 2455-709
Symposium Article
Leptospirosis
Abhijit Choudhary* Arun Baranwal**
*Senior Resident, **Professor, Division of Pediatric Critical Care, Advanced Pediatrics Center,
PGIMER, Chandigarh, India
Correspondence:
Dr. Arun Baranwal MD PG Diploma-Critical Care (UK), MAMS, FIAP, FRCPCH(UK)

Professor, Division of Pediatric Critical Care,Advanced Pediatrics Center, PGIMER,
Chandigarh, India. Phone: 7766908325.E mail: baranwal1970@gmail.com
ABSTRACT
Leptospirosis is a zoonotic infection with ubiquitous distribution caused by spirochete

leptospira, and humans are incidental hosts. Leptospirosis is mostly reported during rainy
season when there is freshwater flooding and water logging with poor sewage drainage.
Leptospira are transmitted to humans by exposure to a water environment contaminated by
urine of the infected animals. There are two distinct phases of leptospirosis, the initial
“septicemic phase” due to leptospira mediated injury is closely followed by “immune phase”.
Clinical symptoms include fever, headache, myalgia, vomiting, respiratory symptoms, and
thus it is difficult to differentiate from other viral illnesses. Leptospira have a predilection for
kidneys and causes acute tubular necrosis and interstitial nephritis. The sever form of
Leptospirosis is characterized by hepatic, respiratory and renal dysfunctions, hemorrhagic
manifestations, cardiovascular collapse and CNS dysfunction. Microscopic Agglutination
Test (MAT) is the gold standard for diagnosis, however ELISA is a pragmatic alternative to
MAT for confirming the diagnosis. Majority (90%) of leptospirosis cases are mild and can
resolve spontaneously. Early initiation of antimicrobials can lead to faster recovery and may
prevent from progression to severe leptospirosis. Penicillin, oral or intravenous, are the first
lines of therapy. Supportive care is of utmost importance for management of leptospirosis
and associated organ dysfunctions.
Key Words: Leptospirosis, Children, Critical Care.

Introduction:
Leptospirosis is a zoonotic infection with ubiquitous distribution caused by spirochete leptospira,

and humans are incidental hosts. Leptospirosis in children result in wide variety of clinical
manifestations ranging from subclinical infection resembling other viral illnesses to a more severe
form termed as “Weil Syndrome/Disease” or “Icteric Leptospirosis”. It is characterized by hepatic
and renal dysfunction, hemorrhagic manifestations, cardiovascular collapse, CNS dysfunction
with a high mortality.1
Epidemiology:
Leptospirosis is an occupational disease and is increasingly being reported with occupations

associated with outdoor activities in contaminated water.2-4 Leptospirosis is mostly reported during
rainy season when there is freshwater flooding and water logging with poor sewage drainage.
Annual incidence is estimated from 0.1-1 per 100,000 in temperate climates to 10-100 per 100,000
in the humid tropics. Incidence of more than 100 per 100,000 is encountered during outbreaks and
in high-exposure risk groups. High endemic regions are South Asia, Southeast Asia, Central and
South America, Caribbean and Pacific Islands. In India, cases are mostly reported from coastal
regions of Gujrat, Maharashtra, Karnataka, Kerala, Tamilnadu, Andhra Pradesh, Andaman and
Nicobar, and Orissa.5,15 It assumes epidemic potential during floods in these provinces.
Transmission to humans:
There are seven distinct species of pathogenic leptospira and more than 200 serological variants
(serovars), Leptospira interrogans being the most common species pathogenic to humans.1
Leptospira infect many mammals like rats, rodents, cats, dogs, cattle, pigs, foxes, jackals,
mongooses, raccoons, bandicoots etc., and humans represent the dead end in the chain of
transmission. Among these mammals, rats and rodents are the most important reservoirs
worldwide. Leptospira are transmitted to humans either by contact with blood, urine, tissues, or
organs of infected animals or by exposure to an environment that has been contaminated by them;
urine being the most important as Leptospira are excreted in the urine of infected animals for
prolonged time. And thus, freshwater / water-logged areas / waterbodies contaminated by urine of
rats is the most important vehicle of transmission.6-8
Pathogenesis:
Leptospira enter human body via lungs through aerosol droplets, skin breaks, mucous membranes
and conjunctival membranes causing sub-clinical infection or overt disease. Post entry, leptospira
invades lymphatic system and bloodstream and spreads rapidly throughout the body. Due to slow
growth of Leptospira, clinical manifestations appear after incubation period of 5-14 days (range,
2-30 days). There are two distinct phases of leptospirosis, the initial phase “septicemic phase” is
due to leptospira mediated injury and “immune phase” occurs due to activation of host immune
response. Leptospira cause widespread endotheliopathy and capillaritis possibly by endotoxin
release leading to capillary leaks and hemorrhagic diathesis. Bleeding in these patients is also
attributed to depletion of serum prothrombin, thrombocytopenia or both.9 Patients have widespread
hepatocellular injury leading to hepatic dysfunction. Jaundice is contributed by intravascular
hemolysis as well.10 Lung involvement is predominantly due to hemorrhage; severe cases may
have massive hemoptysis. Haemorrhagic pneumonitis with interstitial and intra-alveolar
haemorrhages surrounded by focal capillary injury are common pathologic changes.15 Leptospira
have a predilection for kidneys and cause acute tubular necrosis and interstitial nephritis.
Respiratory and Renal failure are the leading causes of death in these patients.11 Patients with
severe leptospirosis have evidence of a “cytokine storm” with higher levels of IL-6, TNF-alpha
and other cytokines compared to those with milder disease.12 Patients may develop meningitis
which is due to deposition of antigen-antibody complexes rather than due to leptospira directly.
Clinical Features:
Leptospirosis is systemic infection, characterized by extensive vasculitis with varied presentation.

The incubation period is generally 5-14 days (range, 2-30 days).1 Both anicteric and icteric
leptospirosis follow a biphasic course.
Anicteric Leptospirosis
Majority (~90%) of patients with leptospirosis are anicteric. During the first stage (septicemic
stage), patients have abrupt appearance of fever, chills, vomiting, headache, severe myalgia
restricting mobility; these symptoms may last for 4-7 days. This stage is difficult to differentiate
from a viral illness. Physical examination during this septicemic stage may reveal conjunctival
suffusion, erythematous macular / maculopapular rash, petechiae, purpura, generalized muscle
tenderness, generalized lymphadenopathy and hepatosplenomegaly. Chest radiograph may reveal
confluent infiltrates, consolidation or small patchy snowflake like lesions in the periphery of lung
fields. Patient may become asymptomatic for 1-3 days, and this symptomatic improvement
coincides with disappearance of leptospires from blood, CSF and other tissues. It is followed by
reappearance of fever heralding the onset of second stage (immune stage), which may last from 4-
30 days. This stage is characterized by rash, headache, meningitis and uveitis. Other manifestations
include disproportionate tachycardia with myocarditis, polyserositis, encephalitis. Lumbar
puncture during the immune stage may reveal CSF pleocytosis with or without meningeal
symptoms or signs.
Icteric Leptospirosis (Weil Syndrome)
Weil syndrome is severe form of leptospirosis which occurs in less than 10% of patients, and is
characterized by jaundice, severe encephalopathy, shock and renal failure. Jaundice is the hallmark
of Weil syndrome with conjugated hyperbilirubinemia with usual bilirubin concentration <20
mg/dL. There is minimal elevation of aspartate and alanine aminotransferases with values rarely
exceeding 100-200 IU/dL respectively. Widespread vasculitis causes third spacing of fluids;
patients may present with or develop hypovolemic shock later. Respiratory involvement is
characterized by cough, chest pain and blood-tinged sputum. Severe cases may present with
hemoptysis, rapidly progressive respiratory distress and respiratory failure. Patients initially have
basal crepts which may rapidly spread upwards. Chest radiograph shows basal and mid zone
opacity. It is the commonest cause of early death during first few days. Renal dysfunction usually
occurs during the first week, worsens until end of second week, starts improving thereafter with
complete recovery by the end of fourth week provided patient is maintained on renal replacement
therapy.15 Usually, there is no residual renal dysfunction. If left untreated, renal dysfunction is the
commonest cause of late mortalities.13 Patients may develop features of myocarditis, with cardiac
arrhythmias, supraventricular tachyarrhythmia and atrioventricular blocks being common.
Ventricular tachyarrhythmias are infrequent. Meningoencephalitis, radiculitis and peripheral
neuropathy have also been reported. Hyponatremia is a consistent finding in patients with severe
icteric leptospirosis. Other biochemical abnormalities that occur are hypokalemia,
thrombocytopenia and elevated prothrombin time.
Differential Diagnosis:
Tropical infections that closely resemble leptospirosis and are prevalent in the same regions where
leptospirosis is endemic are viral hepatitis, malaria, dengue fever / dengue hemorrhagic fever,
scrub typhus, enteric fever and acute encephalitis syndrome. Possibility of co-infections should
always be considered due to similar epidemiology of these diseases. Icteric leptospirosis should
be differentiated from fulminant hepatitis due to Hepatitis A and Hepatitis E viruses.
Differentiating features are mildly elevated liver enzymes, features of capillary leak,
thrombocytopenia and acute renal failure early in the course of illness in Leptospirosis as against
viral hepatitis. Also, creatinine phosphokinase levels may be elevated in the former unlike in viral
hepatitis patients.14
Case Definitions- National Centre for Disease Control (NCDC), India have given following case
definitions for management of leptospirosis.15
Suspected Leptospirosis: Acute febrile illness with headache, myalgia and prostration associated
with a history of exposure to infected animals or an environment contaminated with animal urine
with one or more of the following :
1. Calf muscle tenderness

2. Conjunctival suffusion
3. Jaundice
4. Anuria / oliguria, and/or proteinuria
5. Hemorrhagic manifestations (intestines, lung)
6. Meningeal Irritation
7. Nausea, Vomiting, Abdominal pain, Diarrhea
Probable Leptospirosis: Clinically suspected case with one of the following presumptive
laboratory tests being positive :
 A positive result in immune assay based rapid diagnostic tests, e.g., slide agglutination test
/ latex agglutination test / immunochromatographic test
 A Microscopic Agglutination Test (MAT) titer of 100/200/400 or above in single sample
based on endemicity
 Microscopic demonstration of leptospires directly or by staining methods in blood, CSF
and/or urine
Confirmed Leptospirosis: A suspect / probable case with one of the following confirmatory
laboratory tests being positive :
 Isolation of leptospires from clinical specimen on culture of blood, CSF and/or urine
 Four-fold or greater rise in the MAT titer between acute and convalescent phase serum.
 Positive rapid diagnostic test followed by positive ELISA.
 Positive PCR test.
Laboratory Diagnosis:
The initial investigations required in a suspected case of leptospirosis are complete blood count
with peripheral smear, ESR, electrolytes, renal function tests and urine routine examination.
Patient may have anemia, polymorphonuclear leucocytosis and thrombocytopenia. Peripheral
smear may reveal toxic granules. Icteric leptospirosis may have hyperbilirubinemia with mildly
elevated transaminases (usually in hundreds). Acute inflammatory markers like CRP and
procalcitonin may be elevated along with ESR. Patients may have markedly elevated creatine
phosphokinase suggesting presence of myositis. Urine routine may reveal hematuria, proteinuria
and casts.
Serological tests:
Leptospira can be cultured from blood, urine, CSF and most tissues during the septicemic stage of
illness which lasts for 4-7 days after which the circulating antibodies appear during the immune
phase. However, leptospirouria can last for few weeks.
The various serologic tests available for diagnosis of leptospira are microscopic agglutination test
(MAT), enzyme-linked immunosorbent assay (ELISA), indirect hemagglutination assay.
Microscopic agglutination test (MAT) is the gold standard for diagnosis in which live antigens are
used from common endemic leptospira serovars (>200 serovars). A single titer should be
interpreted in the background of degree of endemicity present in the region. Four-fold or greater
rise in the titer between acute and convalescent phase serum confirms the diagnosis.15 The test is
time consuming and potentially hazardous to laboratory workers, however it is an important
epidemiological tool for serovar identification.
ELISA IgM is pragmatic alternative to MAT for the presumptive diagnosis of leptospirosis due to
its simplicity, sensitivity and potential of standardization.16 It requires just one genus-specific
antigen which is shared by all serovars. However, it is less specific and weak cross reactions with
other diseases may occur. Slide agglutination test is equivalent to ELISA IgM, is inexpensive, can
easily and rapidly be performed at bedside.17 Indirect hemagglutination assays are less sensitive
and specific compared to ELISA. Some of these tests are made available at the primary and
secondary healthcare centers in the regions with high endemicity, and referral diagnostic
laboratories have been established at Delhi, Surat, Ahmedabad, Bengaluru, Madurai, Chennai, Port
Blair, Izatnagar (UP) and Gwaliar by the Government of India.15
Management
Majority of leptospirosis cases are mild and can resolve spontaneously. Early initiation of
antimicrobials can lead to faster recovery and may prevent progression to severe leptospirosis.1
Antimicrobials should be started as early as possible and before the invading organisms damage
endothelium as after day 10 of illness organism disappears from blood and CSF with appearance
of antibodies. However, antimicrobial therapy should not be denied even after 10 days.
Diagnosis of leptospirosis is suspected based on presenting symptoms and signs, risk factors and
exposure history. Rapid diagnostics tests can aid in diagnosis but negative result does not rule out
early infection.18 A suspected, probable or confirmed case of leptospirosis should be treated with
antimicrobials, Penicillins being the first line therapy. In a randomized double-blind trial,
intravenous crystalline penicillin (for 7 days) was shown to be effective in severe leptospirosis as
it significantly reduced duration of fever, length of hospitalization, improved renal functions and
prevented leptospiral shedding in urine. It was effective even when the therapy was initiated late
during illness.19 However, this positive effect of intravenous crystalline penicillin (5 days) was
negated by another placebo-controlled trial among patients with icteric leptospirosis.20
Suputtamongkol et al. in their open randomized controlled trial evaluated effect of three
antimicrobials (penicillin, cefotaxime and doxycycline) on leptospirosis, and they did not find any
significant difference in terms of time to deffervescence and length of hospitalization between the
three treatment groups.21 Azithromycin (for 3 days) was not found to be inferior to Doxycycline
(for 7 days) in the treatment of leptospirosis.22 Recommendations from National Center for Disease
Control (India) for the treatment of leptospirosis with organ dysfunction(s) are as follows :
1. Without organ Dysfunction

Children <8 years: Oral Amoxicillin/ Ampicillin for 7 days
Children >8 years: Oral Doxycyclne for 7 days (as in adults)
2. With organ Dysfunction
Inj. Crystalline penicillin, 2–4 lacs IU/Kg/ day for 7 days.
Alternative regimes for individuals sensitive to penicillin group of drugs:
Intravenous Ceftriaxone 50-75 IV mg/kg/day for 7 days OR
Intravenous Cefotaxime 50-100 IV mg/kg/day for 7 days OR
Intravenous Erythromycin 30-50mg/kg/day in divided dose for 7 days
Supportive Care
Supportive care is of utmost importance for management of leptospirosis, characterized by organ

support measures applicable to any critically ill patients with multi-organ dysfunction. Prompt and
specific treatment is required for dehydration, shock (hypovolemic, distributive, cardiogenic),
acute respiratory and renal failure. Maintaining euvolemia and normal electrolyte balance is
important. Renal failure can be prevented by ensuring optimal circulatory volume.23,24 Anecdotal
reports suggest role of corticosteroids in patients with profound shock. Leptospirosis causes a non-
oliguric and hypokalemic form of acute kidney injury; however, patients can develop oligo-anuric
acute kidney injury due to acute tubular necrosis. Peritoneal dialysis or hemodialysis may be
required for renal failure. Other renal replacement measures have also been tried successfully.25
High-dose corticosteroid has been used for treatment of immune-complex mediated renal failure,
but its role is not fully established. Liver failure should be managed with supportive care. Plasma
exchange with hemodiafiltration may have a role in patients with severe hyperbilirubinemia and
oligo-anuric acute kidney injury.25
Conclusions
Leptospirosis is a zoonotic disease common in the rainy season characterized by febrile illness,
myalgia, headache, conjunctival congestion, skin rashes, respiratory symptoms, and non-oliguric
kidney injury mimicking a viral illness. Its severe form is characterized by jaundice, respiratory
distress, oligo-anuric renal failure with multiorgan dysfunction syndrome. Early clinical suspicion
and early administration of antimicrobial are essential to prevent progression to sever form and
limiting complications of severe leptospirosis. The latter is recommended to be treated with
intravenous crystalline penicillin and supportive care in critical care setting.
References:
1. Shah I. Leptospirosis. Pediatr Infect Dis 2012 ;4:4-8.
2. Centers for Disease Control and Prevention (CDC). Update: outbreak of acute febrile illness
among athletes participating in Eco-Challenge-Sabah 2000--Borneo, Malaysia, 2000. MMWR
Morb Mortal Wkly Rep 2001;50:21-4.
3. Centers for Disease Control and Prevention (CDC). Outbreak of leptospirosis among white-
water rafters--Costa Rica, 1996. MMWR Morb Mortal Wkly Rep 1997;46:577–9.
4. Gaynor K, Katz AR, Park SY, Nakata M, Clark TA, Effler PV. Leptospirosis on Oahu: an
outbreak associated with flooding of a university campus. Am J Trop Med Hyg 2007;76:882–5.
5. World Health Organization. Report of the Brainstorming Meeting on Leptospirosis

Prevention and Control. Mumbai, 16-17 February 2006, WHO India and Regional Medical
Research Centre, WHO Collaborating Centre for Diagnosis, Research, Reference and Training in
Leptospirosis. Retrieved July 6, 2017, from:
http://www.searo.who.int/entity/emerging_diseases/topics/Communicable_Diseases_Surveillanc
e_and_response_SEA-CD-216.pdf.
6. Palaniappan Raghavan UM; Ramanujam Subbupoongothai; Chang Yung-Fu. Leptospirosis:

pathogenesis, immunity, and diagnosis. Curr Opin Infect Dis 2007; 6:284-92.
7. Gillespie RWH, Ryno J. Epidemiology of Leptospirosis. Am J Public Health Nations Health

1963;53:950–5.
8. Turner LH. Leptospirosis I. Trans R Soc Trop Med Hyg 1967;61:842–55.
9. Wagenaar JFP, Goris MGA, Partiningrum DL, Isbandrio B, Hartskeerl RA, Brandjes DPM, et
al. Coagulation disorders in patients with severe leptospirosis are associated with severe bleeding
and mortality. Trop Med Int Health 2010;15:152–9.
10. Avdeeva MG, Moĭsova DL, Gorodin VN, Kostomarov AM, Zotov SV, Cherniavskaia OV.
The role glucose-6-phosphate dehydrogenase in pathogenesis of anemia in leptospirosis. Klin
Med (Mosk) 2002;80:42-4.
11. Arean VM. The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil’s
disease). Am J Pathol 1962;40:393-423.
12. Felzemburgh RDM, Ribeiro GS, Costa F, Reis RB, Hagan JE, Melendez AXTO, et al.
Prospective study of leptospirosis transmission in an urban slum community: role of poor
environment in repeated exposures to the Leptospira agent. PLoS Negl Trop Dis 2014;8:e2927.
13. Katz AR, Buchholz AE, Hinson K, Park SY, Effler PV. Leptospirosis in Hawaii, USA, 1999-
2008. Emerg Infect Dis 2011;17:221-6.
14. Shah I, Warke S, Deshmukh CT, Kamat JR. Leptospirosis-an underdiagnosed clinical
condition. J Postgrad Med 1999;45:93–4.
15. National guidelines for Diagnosis, Case Management, Prevention and Control of
Leptospirosis. National Centre for Disease Control, 2015. Retrieved July 6, 2017, from:
http://www.ncdc.gov.in/writereaddata/mainlinkfile/File558.pdf
16. Vitale G, La Russa C, Galioto A, Chifari N, Mocciaro C, Caruso R, et al. Evaluation of an

IgM-ELISA test for the diagnosis of human leptospirosis. New Microbiol 2004;27:149–54.
17. Brandão AP, Camargo ED, da Silva ED, Silva MV, Abrão RV. Macroscopic agglutination
test for rapid diagnosis of human leptospirosis. J Clin Microbiol 1998;36:3138-42.
18. Haake DA, Levett PN. Leptospirosis in Humans. Curr Top Microbiol Immunol 2015;387:65–
97.
19. Watt G, Padre LP, Tuazon ML, Calubaquib C, Santiago E, Ranoa CP, et al. Placebo-
controlled trial of intravenous penicillin for severe and late leptospirosis. Lancet Lond Engl 1988
27;1:433-5.
20. Edwards CN, Nicholson GD, Hassell TA, Everard CO, Callender J. Penicillin therapy in
icteric leptospirosis. Am J Trop Med Hyg 1988;39:388–90.
21. Suputtamongkol Y, Niwattayakul K, Suttinont C, Losuwanaluk K, Limpaiboon R, Chierakul

W, et al. An open, randomized, controlled trial of penicillin, doxycycline, and cefotaxime for
patients with severe leptospirosis. Clin Infect Dis Off Publ Infect Dis Soc Am 2004 15;39:1417–
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al. Doxycycline versus Azithromycin for Treatment of Leptospirosis and Scrub Typhus.
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24. Barrett-Connor E, Child CM ,Carter M J. Renal failure in leptospirosis. South. Med. J
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multiple organ failure successfully treated by plasma exchange and high-volume hemofiltration.
Case Rep Nephrol 2011;817414.

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Journal of Pediatric Critical Care

P - ISSN: 2349-6592 | E - ISSN: 2455-709

Received: 30-Jun-17/Accepted: 5-Jul-17 /Published online: 20-Jul-17

Infectious diseases are leading causes of morbidity and mortality in tropical

3. Istúriz RE, Torres J, Besso J. Global distribution of infectious diseases requiring

8. John TJ, Dandona L, Sharma VP, Kakkar M. Continuing challenge of infectious

9. Sankhyan N, Saptharishi LG, Sasidaran K, Kanga A, Singhi SC. Clinical profile of

Keywords: Dengue, Aedes aegypti ,Capillary leak, Shock

Virus and the vector

Dengue illness manifest as wide range of severity from inapparent/asymptomatic cases to

Table 1. WHO 2009 classification of dengue case classification 8

Dengue ± warning signs Severe dengue

Management in emergency department

Hypotensive Shock: Hypotensive shock is life-threatening should be managed aggressively

Isotonic crystalloid (NS, RL) as well as colloids (gelatin, hydroxyethylstarch, dextran, 5%

Role of blood products

Bleeding in dengue patients has a multiple contributing factors including thrombocytopenia,

Recommendations: Blood transfusion should only be given in children with suspected/

Supportive care and initial investigations

Issues in Intensive Care Unit

Appropriate fluid administration is life saving intervention in management of dengue

Seizures and encephalopathy are commonest neurological manifestation of dengue illness. In

Abdominal compartment syndrome

Hemophagocytic Lymphohistiocytosis (HLH)

Conflict of Interest: None Source of Funding: None

14. Pothapregada S, Kamalakannan B, Thulasingham M, Sampath S. Clinically Profiling Pediatric

17. Pothapregada S, Kamalakannan B, Thulasingam M. Clinical profile of atypical manifestations of

23. Premaratna R, Liyanaarachchi E, Weerasinghe M, de Silva HJ. Should colloid boluses be

28. Pothapregada S, Kamalakannan B, Thulasingam M. Role of platelet transfusion in children with

*Senior Resident, **Assistant Professor, Pediatric Critical Care Unit, Advanced

Received: 13-Jun-17/Accepted: 4-Jul-17/Published online: 15-Jul-17

Globally scrub typhus is predominantly distributed in the ‘tsutsugamushi triangle’ which

Respiratory distress/ Acute Respiratory Distress Syndrome (ARDS)

Septic shock and myocarditis:

Circulatory and cardiovascular system involvement includes septic shock, myocarditis

Meningitis and encephalitis:

Acute Kidney injury

Thrombocytopenia is a consistent feature and platelet count of 150x103/µL or lower is

Thrombocytopenia is the single most common hematological abnormality; severe

Serological testing is still the most common method of diagnosis. Weil-Felix is a

Emergency room management:

Initial management in ER should focus on stabilization of airway, breathing and

Intensive care needs

Indications for transfer to PICU

Children with persistent circulatory abnormalities and fluid-refractory shock should be

Multi organ dysfunction syndrome

Conflict of Interest: None Source of Funding: None

6. Mittal V, Gupta N, Bhattacharya D, Kumar K, Ichhpujani RL, Singh S, et al. Serological

8. Walsh DS, Myint KS, Kantipong P, Jongsakul K, Watt G. Orientia tsutsugamushi in

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Madhusudan Samprathi*, Suresh Angurana**