Approach to acute febrile illness

Approach to acute febrile illness

1. Acute Febrile Illness in
Indonesia
Fadel Muhammad Garishah, MD
Division of General Medicine

2. Acute Febrile Illness
• Leads to hospitaliza.on!
• The possible cause?
• Worrying parents: serious infec.on/life
threatening, febrile seizure
• Emerging infec.ous diseases(?)
• Co-infec.ons, comorbidi.es

3. n engl j med 376;6 nejm.org February 9, 2017550
The new england journal of medicine
Fever

in
a

Returning

Traveler
Fever

with
Respiratory
Symptoms
Suspected

Life-
Threatening
Tropical

Infection
Malaria Possible
Obtain thick and thin blood films
or RDT
P. vivax
,
P. ovale
,
P. malariae
, or
P. knowlesi
malaria
Treat with ACT or chloroquine, with or without
primaquine
Uncomplicated Nonfalciparum
Malaria
Treat with ACT Consider hospi-
talization for 24 hr
Uncomplicated
Falciparum
Malaria
Treat with parenteral artesunate, followed
by ACT
Severe

Falciparum
or

Knowlesi

Malaria
P. falciparum
malaria
If qSOFA score
≥
2, consider ICU
care
If highly transmissible disease
suspected, isolate patient as appropriate
Urgent
Hospital

Admission
History: travel, fever onset, symptoms, possible exposures Examination: rash, jaundice, altered mentation, neck stiffness, cellulitis,
abdominal tenderness, pulmonary consolidation, eschar, lymphadenopathy, genital sores, eye signs
Risk assessment:
Suspected life-threatening tropical infection? Suspected highly transmissible infection?
Isolate patient as appropriate
Investigations: CBC, biochemical studies (e.g., LFTs and creatinine),
C-reactive protein, blood cultures, chest film, urine microscopy and culture, baseline serologic tests, whole-blood EDTA sample for PCR, saving of serum for later testing, and specific investigations for focal disease; RDTs for diseases endemic in the visited areas (e.g., dengue, leptospirosis, and rickettsioses for Southeast Asia)
Uncomplicated

Disease

(qSOFA
Score

<2
and

No

Signs

of

Severe

Disease)
Assess qSOFA score (altered mentation, tachypnea, hypotension) Assess for signs of severe disease (cyanosis, meningism, peritonism, digital gangrene) Possible highly transmissible infection? If yes, isolate patient as appropriate
Initial

Risk

Assessment
Resuscitate if patient in shock Perform blood cultures Obtain malaria films or RDT, if appropriate; treat
severe malaria with parenteral artesunate, followed by ACT
Consider empirical antibiotic treatment, taking
into account possible pathogens and likely AMR patterns
History, examination, and investigations (as for
qSOFA score <2)
Consider causes of life-threatening tropical
infections, as well as cosmopolitan causes of sepsis
Assess risk of highly transmissible infection
Possible

Severe

Disease

(qSOFA
Score
≥
2
or
Other
Clinical

Concern)
If bacterial pneumonia suspected, treat as community-acquired pneumonia Consider highly transmissible infections (influenza, tuberculosis, MERS-CoV, measles) Consider unusual infections with pulmonary involvement (Q fever, psittacosis, leptospirosis,
Katayama fever, scrub typhus, melioidosis)
If eosinophilia consider filariasis, strongyloidiasis, fungal infections
Consolidation

(Clinically

or

on

Chest

Film)
Test for influenza with rapid test or PCR Treat with neuraminidase inhibitor Isolate at home (or in hospital, if avian influenza suspected)
Within

4

Days

after

Return

from

Country

Where

an
Outbreak

of

Influenza

or

a

Pandemic

Was

Occurring
Rule out possible life-threatening infections (lepto-
spirosis, severe malaria, viral hemorrhage fevers, yellow fever, severe dengue, Carrión’s disease)
Consider acute viral hepatitis (hepatitis A, B, C, E),
CMV, EBV (serologic tests)
Consider acute cholangitis — stones, liver flukes
(ultrasound, blood cultures, stool examination)
Fever

with

Jaundice
Common causes
Travelers’ diarrhea (ETEC, norovirus) Giardiasis Cryptosporidiosis Campylobacter
infection
Shigellosis Nontyphoidal salmonellosis Intestinal amebiasis
Diarrhea is usually self-limiting, though empirical anti-
biotics may reduce symptom duration
Investigate with stool microscopy and culture, blood
cultures, stool PCR or Ag detection; sigmoidoscopy with biopsy to rule out inflammatory bowel disease
Rehydration and empirical treatment with macrolides
or fluoroquinolones (tinidazole or metronidazole, if amebiasis or giardiasis suspected)
Consider:
Cosmopolitan causes (e.g., appendicitis, urinary
tract infection, cholecystitis, pancreatitis)
Enteric fever (blood culture) Giardiasis (stool microscopy, Ag detection, PCR);
treat with tinidazole or metronidazole
Acute cholangitis — stones, liver flukes (ultrasound,
blood cultures, stool examination)
Liver abscess — pyogenic or amebic (blood cultures,
ultrasound, serologic tests)Fever

with

Abdominal

Pain

or

Tenderness
(without

Diarrhea)
Fever

with

Diarrhea
Severe,

Prolonged

or

Bloody

Diarrhea
Consider:
Cosmopolitan causes (e.g.,
urinary tract infection, EBV, viral URTI, cellulitis, abscesses)
Common tropical or subtropical
causes (e.g., dengue, rickett- sial infections, leptospirosis, chikungunya, Zika virus [all diagnosed on serologic tests, Ag detection, or PCR] and enteric fever [blood cultures])
Consider empirical antibiotics
(doxycycline or azithromycin) to cover rickettsia and leptospirosis
Undifferentiated
Nonmalarial
Fever
Consider enteric fever (empirical
treatment with IV ceftriaxone), endocarditis (echocardiogram),
tuberculosis, brucellosis,
visceral leishmaniasis, Q fever,
abscess, noninfective causes Prolonged

Fever

(>7
Days)
Consider scrub typhus
or spotted fever group rickettsial infection
Diagnosis: serologic
tests or PCR
Empirical treatment:
doxycycline
Eschar

Present
Consider dengue,
chikungunya, Zika virus and rickettsial infections, acute HIV infection, measles, Katayama fever
Consider empirical
doxycycline for rickettsia, once dengue ruled out
Rash

Present
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4. Fever in the Tropics is Malaria
un<l it is ruled out

6. n engl j med 376;6 nejm.org February 9, 2017552
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Table
1.
Life-Threatening
Tropical
Infections
Characterized
by
Fever.*
Disease

(pathogen)
Incubation

Period
Geographic

Regions

Affected
Vector

or

Exposure
Diagnostic

Test
Treatment
Viral
infections
Avian influenza (H5N1 influen
-
za A virus)
2–8 days
East and Southeast Asia
Poultry
RT-PCR
Oseltamivir, peramivir, or
zanamivir
MERS-CoV
2–14 days
Arabian peninsula
Contact with infected humans or
camels
RT-PCR
Supportive
Ebola virus disease, Lassa fe
-
ver, and Marburg hemor
-
rhagic fever
<22 days
Africa
Contact with infected humans or
animals
RT-PCR
Supportive; also consider
ribavirin for Lassa fever
Crimean–Congo hemorrhagic
fever
1–9 days for tick bite,
3–13 days for infec
-
tive contact
Southern Europe, Middle
East, Africa, northwestern China
Ixodid (hard) ticks; contact with
infected humans or animals
RT-PCR
Supportive
Yellow fever
3–8 days
South America, Africa
Aedes mosquitoes; haemagogus
and sabethes mosquitoes in the jungle cycle
RT-PCR, IgM ELISA
Supportive
Severe dengue
4–7 days
Widespread, particularly
South and Southeast Asia, South and Central America, Caribbean, Africa
Aedes mosquitoes
NS1 or IgM rapid diagnostic
test, NS1 and IgM ELISAs, RT-PCR
Supportive
Japanese encephalitis
5–15 days
Asia, western Pacific
Culex mosquitoes
IgM ELISA
Supportive
Rift Valley fever
2–6 days
Africa, Arabian peninsula
Mosquitoes (species vary by re
-
gion); exposure to blood from infected animals
RT-PCR, IgM ELISA
Supportive
Rabies (rabies virus and

other lyssaviruses)
20–60 days (usually lon
-
ger than 4 weeks but can be shorter; occa
-
sionally months or years)
Widespread
Animal bite
Saliva: virus isolation and RT-
PCR; serum and spinal flu
-
id: RFFIT for antibody de
-
tection; skin biopsy: RT- PCR and immunofluores
-
cence assay
Wound cleaning, human ra
-
bies immune globulin, and vaccination if high- risk bite; supportive care if disease develops
Bacterial
infections
Anthrax (
Bacillus anthracis
)
1 day for cutaneous an
-
thrax, 1–7 days for pulmonary anthrax
Enzootic in Africa and Asia
Contact with infected animals or
animal products
Bacterial culture, RT-PCR
Prolonged combination an
-
timicrobial therapy, an
-
titoxin
Enteric fever (
Salmonella

enterica
serovar Typhi

and
S.
enterica
serovar
Paratyphi A and C)
6–30 days
South and Southeast Asia
Fecal–oral transmission
Bacterial culture
Antimicrobial therapy (mul
-
tidrug resistance is common)
Epidemic typhus (
Rickettsia
prowazekii
)
7–14 days
Central Africa; Asia; Central,
North, and South America; usually outbreak- associated
Human body lice (
Pediculus
humanus
), flying squirrel

ectoparasites, possibly some ticks
IgM and IgG ELISAs, PCR
Doxycycline
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7. n engl j med 376;6 nejm.org February 9, 2017 553
Approach to Fever in the Returning Traveler
Leptospirosis
2–29 days
Widespread, particularly
South and Southeast Asia and South America
Contact with urine from infected
animals (many domestic and wild animals, including rodents)
IgM and IgG ELISAs, PCR
Doxycycline or azithromycin
(for mild infection); par
-
enteral penicillin, doxy
-
cycline, or third-genera
-
tion cephalosporin (for severe infection)
Louseborne relapsing fever
(
Borrelia recurrentis
)
4–14 days
Ethiopia, Eritrea, and Sudan
Human body lice (
P. humanus
)
Microscopic examination of
blood smear, IgM and IgG ELISAs, PCR
Doxycycline (Jarisch–
Herxheimer reactions are common and may require ICU admission)
Melioidosis (
Burkholderia

pseudomallei
)
1–21 days (but can be
months or years)
South and Southeast Asia,
northern Australia; isolat
-
ed reports from Africa and South America
Contact with contaminated soil
or surface water
Bacterial culture
Ceftazidime or a carbapen
-
em, followed by pro
-
longed oral therapy with cotrimoxazole
Murine or endemic typhus

(
R. typhi
)
7–14 days
Widespread, particularly
Southeast Asia
Rodent fleas
IgM and IgG ELISAs, PCR
Doxycycline or chloram
-
phenicol
Oroya fever, or Carrión’s dis
-
ease (
Bartonella bacillifor
-
mis
,
B. rochalimae
, and

B. ancashensis
)
10–210 days
South America, particularly
Peru
Phlebotomine sandflies
Bacterial culture
Ciprofloxacin plus ceftriax
-
one, chloramphenicol
Scrub typhus (
Orientia tsutsu
-
gamushi
)
6–20 days
Asia and northern Australia
Larval mites (chiggers)
IgM and IgG ELISAs, PCR
Doxycycline, azithromycin
Spotted fever group rickettsioses
2–14 days
Widespread
Mostly ticks
IgM and IgG ELISAs, PCR
Doxycycline
Plague (
Yersinia pestis
)
2–6 days for bubonic
plague, 1–3 days for pneumonic plague
Remote areas of Africa, Asia,
and South America
Rodent fleas
Bacterial culture
Aminoglycosides (strepto
-
mycin or gentamicin), tetracyclines, or fluoro
-
quinolones
Protozoal
infections
East African sleeping sickness
(
Trypanosoma brucei rhode
-
siense
)
7–21 days
Eastern and southern Africa
Tsetse flies
Microscopic examination of
blood, lymph node fluid,

or chancre-tissue biopsy specimen
Suramin (for early stage),
eflornithine plus nifurti
-
mox (for late stage), melarsoprol (for late stage)
Falciparum malaria
(
Plasmodium falciparum
)
7–30 days (can be lon
-
ger)
Africa, Asia, South America;
highest risk of infection in sub-Saharan Africa
Anopheles mosquitoes
Microscopic examination of
thick and thin blood smears; rapid diagnostic tests (antigen detection)
Parenteral artesunate (for
severe malaria), ACT (for uncomplicated ma
-
laria)
Knowlesi malaria (
P. knowlesi
)
10–14 days
Southeast Asia, particularly
Borneo
Anopheles mosquitoes
Microscopic examination of
thick and thin blood smears
Same as treatment for falci
-
parum malaria
*

The listed diseases are those with an incubation period of less than 4 weeks and at least a 5% risk of death within 4 weeks aft
er symptom onset in the absence of treatment. Only dis
-
eases largely confined to tropical or subtropical regions are included. Data are from Jensenius et al.
11
ACT denotes artemisinin-based combination therapy, ELISA enzyme-linked immu
-
nosorbent assay, ICU intensive care unit, MERS-CoV Middle East respiratory syndrome coronavirus, RFFIT rapid fluorescent focus
inhibition test, and RT-PCR real-time polymerase
chain reaction.
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8. n engl j med 376;6 nejm.org February 9, 2017554
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Table
2.
Obtaining
a
History
of
the
Returning
Traveler
with
Fever.*
History
Implications

or

Associated

Diseases
Day-by-day itinerary
Provides geographic disease associations
Vaccinations and malaria prophylaxis
Narrow the differential diagnosis but do not rule out vaccine-preventable diseases or malaria
Other drugs taken while or since traveling
Partial treatment of infection may delay or alter disease presentation (e.g., malaria)
Immune status (diabetes, glucocorticoid treatment, renal failure, splenectomy,
diseases associated with immune deficit)
Melioidosis, listeriosis, tuberculosis, fungal infections, CMV infection
Consumption of unclean water, unpasteurized milk, or improperly cooked or
raw food
Travelers’ diarrhea, giardiasis, nontyphoidal salmonellosis, enteric fever, shigellosis, campylobacter

infection, hepatitis A and E, amebic dysentery, brucellosis, listeriosis
Exposure to fresh water (rafting, kayaking, swimming in rivers or lakes, floods)
Leptospirosis, acute schistosomiasis
Skin contact with soil (e.g., walking barefoot)
Strongyloidiasis, melioidosis
Tattoos, piercings, intravenous drug use, or medical procedures (e.g., injections
and blood-product transfusions)
Hepatitis B or C virus infection, acute HIV infection, CMV infection, malaria, babesiosis
Sexual contact, specifically unprotected sex with a new partner, commercial sex
workers, or multiple partners
Primary herpesvirus infection; acute HIV infection; hepatitis A, B, or C virus infection; syphilis; gonor
-
rhea; Zika virus infection; viral hemorrhagic fevers
Visits with relatives or friends while abroad (Was anyone ill?)
Tuberculosis, other infections transmitted by exposure to ill persons
Insect bites
Mosquitoes
Malaria, dengue fever, chikungunya, Zika virus infection, Japanese encephalitis, yellow fever, Rift Valley
fever, West Nile virus infection, filarial fever
Ticks
Rickettsioses, Q fever, tickborne relapsing fever, Lyme disease, tickborne encephalitis, babesiosis,
Crimean–Congo hemorrhagic fever, tularemia
Mites
Scrub typhus, rickettsialpox (
R. akari
)
Fleas
Murine typhus, plague
Lice
Louseborne relapsing fever (
B. recurrentis
), epidemic typhus (
R. prowazekii
), trench fever (
Bartonella
quintana
)
Flies
Leishmaniasis, African sleeping sickness, bartonellosis, phlebotomus (sandfly) fever
Triatomine bugs
Chagas’ disease
Animal bites
Rabies, cat-scratch fever (
B. henselae
), rat-bite fever (
Spirillum minus
or
Streptobacillus moniliformis

infection), simian herpesvirus B infection
Close contact with animals
Toxoplasmosis, anthrax, Q fever, hantavirus infection, Nipah virus, Hendra virus, plague, psittacosis,
diseases from animal ectoparasites
Close contact with wild or pet birds
Psittacosis, avian influenza
*
CMV denotes cytomegalovirus, and HIV human immunodeficiency virus.
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9. Early Treatment for Severe/Life-
Threatening Infec<ons
• Sepsis
– Early an.bio.c injec.on
• Malaria
– Artemisinin-Based Combina.on Therapy
• Other infec.ons
– Broad-spectrum an.bio.cs un.l diagnosis
established
– Doxycycline (?)
– Isola.on (?)

10. n engl j med 376;6 nejm.org February 9, 2017556
The new england journal of medicine
Table
3.
Serious
Transmissible
Infections
in
Febrile
Returning
Travelers.
Infection
Geographic

Regions

Affected
Mode

of

Transmission
Incubation

Period
Immediate

Precautions


for

Suspected

Infection*
Viral
hemorrhagic
fevers
Ebola virus disease
Guinea, Sierra Leone, Liberia, Ivory
Coast, Sudan, Uganda, Kenya, Democratic Republic of Congo, Republic of the Congo, Gabon, Angola, Zimbabwe
Direct contact with blood, secretions, or
-
gans, or other body fluids of infected persons; contact with objects (e.g., needles or clothing) contaminated with infected secretions
2–21 days
Isolate patient and use strict barrier
nursing techniques; hospital workers have frequently been infected in Ebola outbreaks
Marburg hemorrhagic fever
Ivory Coast, Sudan, Uganda, Kenya,
Democratic Republic of Congo, Republic of the Congo, Gabon, Angola, Zimbabwe
Initial infection through exposure in
mines or caves inhabited by rousettus bats; person-to-person transmission requires direct contact with blood or other body fluids from an infected person (feces, vomit, urine, saliva, or respiratory secretions)
3–10 days
Isolate patient and use strict barrier
nursing techniques
Lassa fever
Guinea, Sierra Leone, Liberia, Nigeria
Initial infection through direct or indirect
contact with infected rodent excreta on surfaces or in food or water; per
-
son-to-person transmission occurs through contact with infected body fluids (e.g., blood, saliva, urine, or se
-
men)
5–21 days
Isolate patient and use strict barrier
nursing techniques
Crimean–Congo hemorrhagic fever
Broad area of endemicity: Africa, Middle
East, Asia, Eastern Europe; outbreaks in Russia, Turkey, Iran, Kazakhstan, Mauritania, Kosovo, Albania, Pakistan
Tickborne transmission, but possible
transmission to humans through di
-
rect contact with body fluids of infect
-
ed humans or animals
1–9 days for tick
bite, 5–13 days for direct con
-
tact
Isolate patient and use strict barrier
nursing techniques
Severe
acute
respiratory
infections
Influenza A
Global distribution; outbreaks of avian
influenza in Southeast Asia and China
Direct or airborne transmission
1–4 days
Isolate patient and use strict barrier
nursing techniques; staff should wear FFP3 or N95 masks
MERS-CoV
Arabian Peninsula, particularly Saudi
Arabia
Direct contact with respiratory secretions
or airborne transmission of large droplets
2–14 days
Isolate patient and use strict barrier
nursing techniques; staff should wear FFP3 or N95 masks
Pneumonic plague
Remote areas of Africa, Asia, and South
America
Inhalation of infective droplets or hema
-
togenous spread to lungs in septice
-
mic or bubonic plague
1–3 days, if ac
-
quired through inhalation
Isolate patient and use strict barrier
nursing techniques; staff should wear FFP3 or N95 masks; prophylac
-
tic oral ciprofloxacin or doxycycline should be administered if a health care worker is exposed
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11. n engl j med 376;6 nejm.org February 9, 2017 557
Approach to Fever in the Returning Traveler
immediately if they might have a life-threatening
and potentially transmissible infection. Patients
transferred from a health care facility in another
country may also need to be isolated before it
has been established whether they are colonized
or infected with drug-resistant bacteria. Health
care workers in direct contact with patients at
high risk for a viral hemorrhagic fever or severe
airborne infections can reduce their risk of ex-
posure by increasing levels of personal protec-
tion, including meticulous hand hygiene, double
gloves, fluid-repellent disposable gowns and foot-
wear, a full face shield or goggles, and a fluid-
repellent respirator (FFP3 [filtering facepiece,
class 3] or N95) for splash and respiratory pro-
tection. Negative-pressure isolation reduces the
risk of airborne pathogen transmission to other
patients and staff. Finally, those responsible for
hospital infection control and public health must
be informed about all patients with a suspected
or confirmed life-threatening infection with the
potential for person-to-person transmission.
Approach to Lower-Risk Travelers with Fever
Once the life-threatening and transmissible causes
of fever in a returning traveler have been ruled out,
there is a long list of other possible causes of fever,
not all of which are related to travel in tropical
regions or to an infectious disease (Fig. 1, and
Table S2 in the Supplementary Appendix).
45
How-
ever, the number of possible travel-related infec-
tious causes can be reduced substantially by iden-
tifying possible exposures and applying knowledge
of the incubation periods for various infections.
A detailed travel and activity history is essential.
46

Different geographic regions are associated with
different presentations; systemic febrile illness
without localizing findings is common among
travelers returning from sub-Saharan Africa or
Southeast Asia, acute diarrhea is common among
those returning from South Asia and Central Asia,
and dermatologic problems are common among
those returning from the Caribbean, Central
America, or South America.
47
Travel in temperate
regions may also be associated with specific tick-
borne infections, such as Lyme disease, tulare-
mia, babesiosis, and spotted fevers in parts of the
United States and other diseases in eastern Eu-
rope and Russia. Each country visited, with dates,
must be determined and activity-based risks iden-
tified, including types of accommodation; food
eaten; exposure to animals, fresh water, and
Other
serious
infections
Measles
Global distribution with regional out
-
breaks
Direct or airborne transmission
7–21 days
Isolate patient; check status of vaccina
-
tions and previous infections in con
-
tacts in hospital (staff and other pa
-
tients)
Chickenpox
Global distribution
Direct or airborne transmission
10–21 days
Isolate patient; check status of vaccina
-
tions and previous infections in con
-
tacts in hospital (staff and other pa
-
tients)
Pulmonary tuberculosis
Global distribution; common in Africa
and Asia
Airborne transmission
Months to years
Isolate patient; for suspected case of
multidrug-resistant tuberculosis, isolate patient in negative-pressure room, if available
*

Strict barrier nursing techniques include the use of masks, gloves, and gowns. FFP3 denotes filtering facepiece, class 3.
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12. Ini<al Inves<ga<ons
• Complete blood count
• Rapid test: Malaria, Dengue
• Serology, ELISA, PCR
• Blood Smear, Sputum Smear
• Chest X-Ray
• Urine/Fecal Examina.on
• Liver Func.on, Kidney Func.on