2.2 Dengue, Chikungunya and Rickettsia Infections

Question 1

The dengue virus is a small ssRNA virus from the _______________ (others include Japanese encephalitis virus, Zika virus, yellow fever virus):
• 4 distinct dengue serotypes (1 to 4) exist and can cause the full spectrum of disease
• Infection confers lifelong immunity to that specific serotype and short-term (2 – 3 months) cross-immunity to other serotypes
• Transmission: human-to-human through the bite of infected ____________________________
• Unusual routes: donor organs/tissues, RBC transfusion, vertical transmission

Answer 1

Flaviviridae family;

Aedes aegypti and Aedes albopictus female mosquitoes

Question 2

Dengue is the most rapidly spreading mosquito-borne viral disease in the world (incidence has increased 30-fold with widening geographical expansion in the last 50 years):
• About 50 million dengue infections annually and about 2.5 billion people (40%) live in dengue-endemic countries (at risk of dengue)
• Aedes aegypti is found from 35°N to 35°S (corresponds to a ________________→ tropics and subtropics)
• Globalisation of trade and rapid
urbanisation (especially in Latin America and Asia) have fuelled the spread of dengue

Many factors have contributed to the re-emergence of dengue fever in the world:
• Population growth + poorly planned urbanisation → overcrowding
• Poor water distribution and sanitation
• Changing lifestyles (e.g. increased use of plastic containers and tyres where standing water can collect → breeding ground for Aedes mosquitoes)
• Modern transportation (increased movement of viruses, mosquitoes, humans)
• Lack of effective mosquito control + increased _______________ further geographical expansion of A. aegypti and dengue virus

Answer 2

winter isotherm of 10°C ;

global temperatures →

Question 3

Dengue haemorrhagic fever (DHF) has been a legally notifiable condition since 1972, and dengue fever (DF) since 1977 → all 4 serotypes circulate (with 1 main one predominating at any one time):
• MOH is notified via a faxed/electronic form no later than 24 hours from diagnosis (residential address and place of work helps identify any clusters)
• Usually occur throughout the year with a __________________ in number of cases

Answer 3

mid-year peak

Question 4

[Transmission of Dengue Virus]

Female Aedes aegypti mosquitoes are __________ which preferentially feed on humans and are well adapted to the urban environment:
• Dengue virus circulating in the blood of an infected person is ingested by a mosquito during feeding, and infects the mosquito’s midgut
• Extrinsic incubation period: virus then spreads systemically through the mosquito over ____________(influenced by environmental conditions like temperature)
o Mosquito remains infected for the rest of its life
o Virus can be transmitted to other humans after this incubation period
• Intrinsic incubation period: after infection of a new host, the symptoms occur after a period of __________ (may go up to 14 days)

Answer 4

day-biting urban mosquitoes;

8 – 12 days;

3 – 7 days

Question 5

[Pathogenesis of DHF/DSS]

Dengue virus target cells: mainly cells of the ________________

Infection of these cells → immune mediators → adaptive and cellular immune responses

PATHOGENESIS OF DHF/DSS
During secondary infection (by a different serotype), antibody-dependent enhancement causes more severe dengue (compared to the primary infection):
• ______________ antibodies (IgG) raised during primary infection bind to the surface of infecting virus, facilitating ____________
• Increases number of infected cells and viral burden (in vivo viral concentration) induces a robust host immune response (inflammatory cytokines and mediators) which causes ____________________

Collectively, the host immunologic response creates a physiological tissue environment which promotes capillary permeability when viral burden declines rapidly:
• Exact mechanisms unclear → plasma leakage thought to be associated with functional (not destructive) effects on endothelial cells
• Activation of infected monocytes and T cells, complement, and production of mediators, monokines, cytokines and soluble receptors may also be involved
• _______________ may be associated with altered megakaryocytopoiesis by infection of human haematopoietic cells and impaired progenitor cell growth:
o Causes platelet dysfunction (activation/aggregation), increased destruction or consumption (peripheral sequestration and consumption)

Answer 5

reticuloendothelial system (spleen, liver, bone marrow), monocytes, lymphocytes, Kupffer cells, alveolar macrophages

Non-neutralising/sub-neutralising cross-reactive;

entry into host cells;

short-lived capillary leakage;

Thrombocytopenia

Question 6

Dengue infection is a dynamic and systemic disease with a wide clinical spectrum from asymptomatic disease to severe and non-severe clinical manifestations:
• Most patients recover after a self-limiting nonsevere clinical course, but a minority progress to severe disease (typically children and young adults)
• After the intrinsic incubation period, the illness begins abruptly and is followed by the _________, __________ (24h around time of defervescence) and ___________ phases

Answer 6

febrile;

critical;

recovery

Question 7

[Dengue: WHO 1997 Classification]
Dengue fever had been classified by WHO in 1997 to dengue fever, dengue haemorrhagic fever and dengue shock syndrome.

A. Dengue Fever
• Fever: acute onset, 2-7 days plus
• Two or more of the following:
- Headache, backache, myalgia
- Rash: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
- Retro-orbital pain
- Bleeding 
- Leucopenia

B. Dengue Haemorrhagic Fever (DHF)
• Fever
• Bleeding manifestations
- Petechiae, ecchymosis, epistaxis, gum bleeding, GI bleed
• Platelet \_\_\_\_\_\_\_\_\_\_
•  Plasma leakage
- Haematocrit change \_\_\_\_\_\_\_\_
- Pleural effusion, ascites
- Hypoalbuminaemia

C. Dengue Shock Syndrome
• DHF plus
• Rapid weak pulse and pulse pressure ________ OR
• Systolic BP _________

Answer 7

maculopapular or flushing; petechial with islands of sparing;

<100x109/L;

> 20%;

<20mmHg;

<90mmHg

Question 8

In 2009, WHO revised the dengue classification scheme in response to studies indicating that the 1997 scheme may underestimate severe disease in adults compared to children. Using this scheme, dengue illness can be classified as: dengue, dengue with warning signs and severe.

• Dengue fever: fever and 2 of nausea/vomiting, rash, ache and pains, positive ___________, _________.
• Warning signs are: _________________, persistent vomitting, clinical fluid accumulation, mucosal bleed, lethargy, restlessness, liver enlargement >2cm, labrotary: increase in HCT concurrent with _________________
• Severe dengue is defined by one or more of the following: (i) _______________ that may lead to shock (dengue shock) and/or fluid accumulation, with or without respiratory distress, and/or (ii) severe bleeding, and/or (iii) severe organ impairment (liver: AST/ALT >=1000, CNS: impaired consciousness, heart and other orans)

Answer 8

tourniquet test;

leukopenia;

abdo pain and tenderness;

rapid decrease in platelet count;

plasma leakage

Question 9

[Dengue: Febrile phase]
Duration 2 to 7 days

Symptoms:

• Sudden onset fever
• Headache (________________ pain)
• Myalgia, arthralgia
• Gastrointestinal symptoms
• Haemorrhagic manifestations
• Rash: ______________
• Petechial with __________________

Differential diagnosis: viral (chikungunya, influenza, HIV seroconversion), bacterial (typhoid, leptospirosis, rickettsial), parasitic (malaria)

Answer 9

frontal or retro-orbital

Maculopapular or flushing;

islands of sparing

Question 10

[Dengue: Critical Phase]
Day 4 to 7 illness at time of defervescence, lasts ____________

Clinical Warning Signs:

• Plasma leakage (pleural effusion, ascites)
• Persistent vomiting
• Severe abdominal pain
• Tender hepatomegaly >2cm
• Mucosal bleeding
• Lethargy; restlessness

Laboratory Warning Signs:

• High or ↑ haematocrit
• Rapid ↓ platelet

Examination:
- Peripheral circulation
- Narrowed pulse pressure (SBP – DBP <20mmHg)
- Plasma leakage
Risk of shock, bleeding and organ impairment

Around the time of defervescence (subsidence of fever; temperature drops to ________________) usually at day 4 – 7 of illness, the critical phase (24 – 48 hours) occurs:
• Occurs with a risk of shock, bleeding and organ impairment

The period of clinically significant plasma leakage usually lasts 24 – 48 hours, and as dengue vascular permeability progresses, ______________ worsens and results in shock:
• Initial stage of shock: compensation mechanism maintains normal SBP, tachycardia and peripheral vasoconstriction with reduced skin perfusion (cold extremities and delayed capillary refill time) → DBP _______ and PP ________
• Patients in dengue shock remain conscious and lucid • Decompensation: both SBP and DBP drop rapidly → prolonged hypotensive shock and hypoxia causes multi-organ failure and extremely difficult clinical course
o Often complicated by major bleeding (contributed by coagulopathies)
o Massive bleeding may occur without prolonged shock when ______, ________, _______________ have been taken
o Most deaths from dengue are due to profound shock (especially if situation is complicated by fluid overload)
• Unusual manifestations: acute liver failure, encephalopathy (even in absence of severe plasma leakage or shock), cardiomyopathy, encephalitis

Answer 10

24 to 48hrs;

37.5 - 38°C or less;

hypovolaemia;

rises;

narrows;

aspirin, ibuprofen or corticosteroids

Question 11

[Dengue: Recovery Phase]
Afebrile 48 to 72 hours with rapid improvement of patient symptoms

Manifestations:

• Symptoms improve, appetite returns
• Reabsorption of fluid > _________ > haematocrit stabilizes
• Rapid recovery of _______________
• Biphasic fever

Following the 24-48hr critical phase, gradual reabsorption of __________________ takes place in following 48-72 hours. General well-being improves, appetite returns, gastrointestinal symptoms abate, haemodynamic status stabilizes. Some patients may have a rash of “isles of white in the sea of red”.

Answer 11

diuresis;

WBC and platelets;

extravascular compartment fluid;

Question 12

[Dengue: Laboratory Changes]

• Febrile phase: FBC initially normal then________________
• Critical phase: rapid ↓ PLT with ↑ __________________. LFTs show mild to moderate elevated transaminases usually _________.
• Recovery phase: WBC then PLT recovery. HCT ↓ from reabsorption of fluid

Answer 12

progressive decrease in WBC then PLT;

HCT during plasma leakage;

AST > ALT

Question 13

[Dengue: Potential Clinical Issues]

• Febrile phase: Anorexia, nausea, dehydration
• Critical phase: Maximal capillary leakage leading to ___, ____, ____
• Recovery phase: Reabsorption and __________

Answer 13

shock, bleeding, organ impairment;

fluid overload

Question 14

DENGUE: DIAGNOSTIC TESTING
Efficient and accurate diagnosis of dengue is of primary importance for clinical care:
• Early stages (viraemia): virus isolation, nucleic acid detection, antigen detection
• End of acute phase: ___________
• Direct methods of virus detection are specific, but must be balanced against cost and accessibility (choice of diagnostic method depends on purpose, time of sample collection, type of facilities, technical expertise)

[Direct virus detection]

Nucleic acid detection assays (e.g. dengue PCR):
• Used when the patient is __________ (before day 5 of illness):
• Most sensitive and expensive
• Results are specific and can identify _________
• Early appearance (pre-antibody) so opportunity to impact on patient treatment
• Potential false positive due to contamination
• Not possible to differentiate between primary and secondary infection
• Expensive and requires specific equipment and QC

Virus isolation:
• specific
• Possible to identify serotype by using __________
• Not possible to differentiate between primary and secondary infection
• Not commonly done in clinical settings (takes several days to weeks):
• Slow turnaround time and requires laboratory expertise, facilities for cell culture and fluorescent microscopy

NS1 antigen testing
• Commercially available, yields results within a few hours (can be used in field settings and provides results in < 1 hour)
• Not as sensitive as viral isolation or RNA detection

[Serological methods (used after day 5 when viruses and antigens disappear from blood)]

Serology
• Antibodies to the dengue virus appear in the blood after day 5 (sample obtained after the first week of illness at low cost):
• May not be as specific + may persist for several weeks
• Need 2 samples
• Can distinguish between primary and secondary infection
• least expensive
• useful for confirmation of acute infection
• May miss cases because IgM level is low or undetectable in some cases of infections

Answer 14

serology;

viraemic;

viirus serotype;

specific antibodies

Question 15

[Interpreting Dengue Tests: Primary vs Secondary Infections]
Primary dengue infection
- IgM antibodies detectable in 50% _______ then 80% by ________ and 99% by _______, persists up to 3 months
- IgG antibodies low titres at end 1st week, detectable for several months, probably even life

Secondary dengue infection

• IgG detectable at high levels even in acute phase, persists from 10 months to life
• IgM lower in 2o infection and may be undetectable in some cases

Answer 15

D3-5;

D5;

D10

Question 16

What are the indications for hospitalization for dengue?

Symptoms related to hypotension

• dehydrated, unable to __________
• giddiness or _________
• profuse perspiration, fainting, _____ during defervescence
• hypotension or cold extremities

Bleeding: spontaneous bleeding, independent of platelet count

Organ impairment

• enlarged, tender liver, although not yet in shock
• chest pain or respiratory distress, cyanosis

Findings through further investigation
- pleural effusion, ascites or asymptomatic; gall bladder thickening

Coexisting conditions

• pregnancy, DM, hypotension, OUDH, haemolytic anemias and others
• overweight or obese (________ difficult in emergency)
• infancy and age

social circumstances

• living alone, far from health facility
• wthout reliable means of transport

Answer 16

tolerate oral fluids;

postural hypotension;

hypotension;

rapid venous access

Question 17

[Dengue]

Investigations that must be done for a dengue patient include:
1. Daily FBC
• Haematocrit: look for ____________ (increased: ___________; decreased: __________-)
• Platelet: rapid decrease in platelets with rapid increase in haematocrit
• Haemoglobin: rapid drop
In DHF, FBC > once a day may be needed. Results are urgent as plasma leakage occurs in __________. Especially vital ________________________

2. LFT & urea and creatinine (if nausea, vomiting, abdominal pain)
   When assessing the patient, it is important to monitor for:
3. Blood pressure (hypotension: SBP ______________ narrowed PP ____________; postural hypotension)
4. Signs of plasma leakage
5. Strict fluid balance (input and output)

There is no specific antiviral for dengue fever, so management is mostly supportive:
• Adequate fluid assessment + monitoring for presence of warning signs
• Encourage intake of oral fluids + judicious IV fluids
• Avoid ___________________

Answer 17

20% change from baseline ;

plasma leakage;

occult bleed;

hours, not days;

24 hours before and after defervescence

< 90mmHg;;

< 20mmHg;

NSAIDs/IM injections

Question 18

Chikungunya
• _________ RNA virus
• Genus ____________
• Chikungunya in local language of Tanzania means “that which bends up” or “stooped walk” referring to the ____________ which is the hallmark of the disease
• Mosquito vectors ________________ (same as for Dengue)
•In endemic areas of Africa, chikungunya virus transmission occurs in a cycle involving humans and animals (non-human primates and perhaps other animals) (__________ cycle)
• In Asia and elsewhere, outbreaks are sustained by mosquito transmission among susceptible humans (_______ cycle)

Answer 18

Single-stranded;

Alphavirus;

severe arthralgia;

Aedes aegypti and Aedes albopictus;

sylvatic;

urban

Question 19

INCUBATION PERIODS The chikungunya virus has extrinsic and intrinsic incubation periods like dengue fever:
• Intrinsic incubation period: time between __________________________
• Extrinsic incubation period: time between ___________________ (virus must replicate and reach the mosquito salivary glands to be transmitted)
o Period varies depending on the temperature (the warmer the temperature, the shorter the extrinsic incubation period and the sooner transmission occurs)
• In cool temperatures and many temperate areas, mosquitoes may die before the extrinsic incubation period is complete

Answer 19

infection and development of viraemia;

mosquito blood meal from a viraemic host and transmission of virus to a new host

Question 20

Chikungunya: PATHOGENESIS
Following the bite of an infected mosquito, chikungunya virus replicates in the skin fibroblasts before disseminating to the liver, muscles, joints, lymphoid tissue:
• Disease onset coincides with rising viral titre (triggers innate immune response involving the production of ______________
• Patients successfully clear the infection about 1 week after (only at this point evidence of CHIKV-specific adaptive immunity occurs) → coincides with development of ________________

Answer 20

type I interferons);

viral-specific antibodies (IgG and IgM)

Question 21

[Chikungunya: Clinical Manifestations]

• Following the bite of a mosquito infected with CHIKV, symptomatic disease occurs after an incubation period of ________ (range 1-12 days).
• Acute infection is characterized by sudden onset of high fever of high fever, lasting several days.
• Joint symptoms are usually __________, occur most commonly in the ________________ but can affect more proximal joints. Pain, tenderness and swelling can be incapacitating to the patients.
• ________________ rash usually occurs 3 days or later after onset of illness and lasts 3 to 7 days.

Answer 21

3-7 days;

symmetric;

hands and feet;

Macular or maculopapular

Question 22

[Chikungunya: Diagnostic Testing]
Three main types of laboratory tests are used for diagnose CHIKV: PCR and serology can be used in the clinical setting whereas virus isolation is usually done in ________________.

• First week of illness: patient becomes symptomatic with high fever → viraemia
( ____________detectable by PCR in blood)
• By end of first week: patient recovers, and symptoms subside → viraemia decreases (CHIKV RNA becomes undetectable)
• Antibodies: develop during ________ and recovery (IgM first then IgG) → persist for weeks to months after recovery

Answer 22

reference laboratories;

CHIKV RNA;

acute phase

Question 23

[CLINICAL COURSE: Chikungunya]
After an incubation period of 2 to 6 days, patients develop acute onset of ___, _______, ______, ______ lasting approximately 1 week:
• After recovering from the acute illness, some patients develop persistent rheumatic symptoms (e.g. polyarthralgia) lasting for weeks to months
• During acute febrile phase, CHIKV PCR may detect ongoing viraemia, which decreases as the patient recovers and becomes undetectable after a week
• Serologies (IgM, IgG) become detectable by the end of the first week and remain in plasma for months after the acute infection

Answer 23

high fever, myalgia, polyarthralgia, and rash

Question 24

CHIKUNGUNYA & DENGUE
Chikungunya and dengue may present similarly and must be differentiated as dengue may cause much worse outcomes (e.g. death):
• CHIKV presents with _______________ fever and more frequent occurrence of maculopapular rash
• CHIV patients may complain of diffuse body pain but is more ____________________
• Less common to have __________________ , as well as shock or severe haemorrhage in CHIK

Answer 24

more acute and shorter duration;

frequently more pronounced and localised to joints and tendons;

marked thrombocytopenia, leukopenia and neutropenia;

Question 25

In the investigation of chikungunya, the exclusion of other conditions (e.g. malaria, dengue, bacterial infections) is important. There are no specific antivirals available for chikungunya, so treatment is largely supportive:

Symptomatic treatment
• Paracetamol: relieve fever
• NSAIDs: relieve arthritis (aspirin is not advisable due to risk of developing __________ in children under 12 years of age)

Vector control
• Environmental management: modifications (long-lasting transformations like ____________), manipulations (temporary changes to vector habitats like removal of discarded objects which collect water)
• Chemical control: larvicides, adulticides (complementary to environmental management), space spraying
• Biological control: natural vector predators (e.g. ____________), introduction of sterile male mosquitoes

Personal protection
• Insect repellent (DEET), household insecticides
• Mosquito bed nets and window screens, protective clothing

Collaborations
• Entomological and epidemiological surveillance
• Inter-agency coordination
• Government: administrative advocacy, legislative and regulatory framework
• Community: social mobilisation and media communication

Answer 25

Reye’s syndrome ;

piped water supply;

larvivorous fish

Question 26

Rickettsial infections

• _____________ gram-negative rods
• Vectors: _______________ such as fleas, mites

In Singapore:

Murine typhus (Rickettsia typhi)

• Bite of rat fleas (also cat and mice fleas)
• Contact with rats e.g. construction workers, garbage collectors

Scrub typhus (Orientia tsutsugamushi)

• Bite of grass mites
• Contact with mite habitats in long grass e.g. hikers, soldiers

Answer 26

Obligate intracellular;

ectoparasites

Question 27

Rickettsiae bacteria differ from most other bacteria in that they can live and multiply only inside the cells of another organism (host) and cannot survive on their own in the environment.

The rickettsial pathogens are transmitted by ectoparasites such as fleas, lice, mites, and ticks. Organisms can be transmitted by bites from these ectoparasites or by the __________________ .

The Rickettsial spp. are classically divided into the typhus and spotted fever group. R.typhi or murine typhus has been reported among travelers returning from Asia, Africa, and the Mediterranean. It is transmitted by _____________ which are present throughout the tropics and subtropics, in port cities and coastal regions. Humans exposed to flea-infested cats, dogs, and animals while traveling in endemic regions, or who enter or sleep in areas infested with rodents, are at most risk for these fleaborne rickettsioses.

Scrub typhus, which is transmitted by ________________, is endemic in northern Japan, Southeast Asia, the western Pacific Islands, eastern Australia, China, India, and Sri Lanka. More than 1million cases occur annually. Most travel-acquired cases of scrub typhus occur during visits to rural areas in endemic countries for activities such as camping, hiking, or rafting

Answer 27

inoculation of infectious fluids or feces from the ectoparasites into the skin;

rodent fleas ;

mites encountered in high grass and brush

Question 28

[Typhus]
- Incubation period: 1-3 weeks

• Clinical Presentation: Headache, fever, rash, myalgia, nausea, maculopapular rash, may have eschar
• Approximately half may develop rashes, typically non pruritic, macular or maculopapular rash which begin on the _________ and spreads to the __________.
• An eschar can occur at the site of the tick bite. This is a ____________ following a mite or flea bite, which will then develop ________________.
• Nausea, vomiting, diarrhoea, cough, lymphadenopathy, may also be present. .
• Lab tests: WBC usually normal (may be leucopenic), thrombocytopenia, raised transaminases
• Laboratory abnormalities that may be noted include leukopenia or leucocytosis, although most have normal WBC, thrombocytopenia in severe illness, elevations in hepatic enzymes, bilirubin and creatinine
• Diagnosis is usually based on clinical recognition and serology. An acute and convalescent serology done 14 days later demonstrating _____________ isconclusive, however this is usually helpful in retrospect. PCR and IHC are not routinely available in most laboratories and found only in specialized centres.
• Diagnosis: Acute and convalescent serology. PCR and immunohistochemistry also available.
• Treatment with ________________
• Antibiotics are not recommended for prophylaxis of rickettsial diseases.
• Travelers should be instructed to minimize exposure to infectious arthropods during travel (including lice, fleas, ticks, mites) and animal reservoirs (particularly dogs) when traveling in endemic areas. The proper use of insect or tick repellents, self-examination after visits to vector-infested areas, and wearing protective clothing are ways to reduce risk.

Answer 28

abdomen;

extremities;

painless papule; subsequent central and a black crust;

4 four fold rise in titre ;

doxycycline x5-10 days or for > 3days after defervescence