An Approach to Fever without a Source in Infants and Children

Authors:

Dr. April Kam MD, DTMH, MScPH, FRCPC

Parnian Arjmand MSc, MD Candidate

Dr. David Goldfarb MD, FRCPC

Date Created: December 2012

Learning Objectives

Be able to define Fever Without a Source (FWS)

Develop an approach to categorizing and managing a child presenting with fever

Learn about some of the key red flags and special circumstances for children presenting with fever

Caveats…

Need to be aware of local epidemiology Prevalence of infections can vary dramatically based

on geography, season, context of epidemic

Fever Differential Diagnosis can be quite broad– we will only cover most commonly seen entities

Broaden your differential, particularly in immunocompromised children (e.g. HIV, severely malnourished, etc.)

Caveats…(cont’d)

In many countries the epidemiology is changing dramatically due to newly introduced vaccines (e.g. Hib, PCV) and the spread of HIV

Can often see co-infections e.g. Among < 5 yr olds in Nigeria with confirmed

malaria, 9% also had UTI (Okunola PO et al., 2012)

Caveats… (cont’d)

Very little published data on the management of fever without localizing signs in children in the developing world

Drug resistance rates climbing dramatically in the developing world…

Target Audience

Health care providers working at first level referral centre – primary care hospital

Basic laboratory facilities (e.g. microscopy) and medications available

Need to adapt to your facility based on epidemiology, testing, and antimicrobials available – know the local guidelines!

Main reference

Integrated Management of Childhood Illnesses – Management of a Child with Serious Infection or Severe Malnutrition

https://apps.who.int/chd/publications/referral_care/contents.htm

Definitions

Fever without a Source (FWS) or Fever without Localizing Signs (FWLS) or Fever without a Focus (FWF):

Rectal temperature > 38°C (> 101ºF) in an infant or child w/ a physical exam that does not suggest a focus of infection

Fever

An intrinsic adaptive response that activates the immune system

Is controlled by the hypothalamus Shortens the length of disease

Etiologies

Infection Infection Infection Other causes much less likely

Inflammation – e.g. Kawasaki disease CNS disorder – e.g. Hypothalamic dysfunction Metabolic Iatrogenic: drugs, immunizations

4 Major Categories for child presenting with fever

Fever due to infection without localized signs – i.e. FWLS (no rash) in > 2 mo

Fever due to infection with localized signs (no rash) in > 2 mo

Fever with rash in > 2 mo Special Situations/Red Flags

Young infant (7 days - 2 months) – high risk serious bacterial infection

HIV infection Severe Malnutrition

Differential Dx of FWLS (no rash)Diagnosis of fever In favour

Malaria (only in children exposed to malaria transmission)

• Blood film or rapid test positive• Severe anemia• Enlarged spleen• Jaundice

Septicemia • Seriously and obviously ill with no apparent cause• Purpura, petechiae• Shock or hypothermia in young infant

Typhoid • Seriously and obviously ill with no apparent cause• Abdominal tenderness• Shock• Confusion

Urinary tract infection • Incontinence in previously continent child• Vomiting with no diarrhea• Crying on passing urine or increased frequency• White blood cells, bacteria or nitrites on micro/UA

Fever associated with HIV infection

• Signs of HIV infection (see red flags)

Differential Dx of Fever with localizing signs (no rash)

Diagnosis of fever In favour

Meningitis • LP positive• Stiff neck• Bulging fontanelle• Meningococcal rash (petechial or purpuric)

Otitis media • Red immobile ear-drum on otoscopy• Pus draining from ear• Ear pain

Mastoiditis • Tender swelling above or behind ear

Osteomyelitis • Local tenderness• Refusal to move the affected limb• Refusal to bear weight on leg

Skin and soft tissue infection

• Cellulitis• Boils• Skin pustules• Pyomyositis (purulent infection of muscle)

Differential Dx of Fever with localizing signs (no rash) – cont’d

Diagnosis of fever In favour

Pneumonia • Cough with fast breathing• Lower chest wall indrawing• Fever• Coarse crackles• Nasal flaring• Grunting

Viral upper respiratory tract infection

• Symptoms of cough/cold (e.g. rhinorrhea)• No systemic upset

Throat abscess • Sore throat in older child• Difficulty in swallowing/drooling of saliva• Tender cervical nodes

Sinusitis • Facial tenderness on percussion over affected sinus• Foul nasal discharge

Differential Dx of Fever with rashDiagnosis of fever In favour

Measles • Typical rash• Cough, runny nose, red eyes• Mouth ulcers• Corneal clouding• Recent exposure to a measles case• No documented measles immunization

Viral infection • Mild systemic upset• Transient non-specific rash

Meningococcal infection • Petechial or purpuric rash• Bruising• Shock• Stiff neck (if meningitis)

Relapsing fever (borreliosis)

• Petechial rash/skin haemorrhages• Jaundice• Tender enlarged liver and spleen• History of relapsing fever• Positive blood smear for Borrelia

Typhus • Epidemic of typhus in region• Characteristic macular rash

Dengue Hemorrhagic Fever (or other HFs)

• Bleeding from nose or gums, or in vomitus• Bleeding in stools or black stools• Skin petechiae• Enlarged liver and spleen• Shock• Abdominal tenderness

Special Situations/Red Flags

Young infant – 7 days to 2 months

HIV infected child

Severely malnourished child

Young infant 7 days – 2 months

Presume Serious Bacterial Infection e.g. Pneumonia, sepsis, meningitis

Show less specific signs Can present with Fever or Hypothermia Irregular breathing, jaundice, apnea, grunting, seizure,

vomiting, abdominal distension, lethargy, anorexia

HIV infected or potentially infected

HIV infected children have higher risk of sepsis and opportunistic infections

Signs common to HIV infected infants: Recurrent infections, oral thrush, chronic parotitis,

generalized lymphadenopathy, hepatosplenomegaly, persistent/ recurrent fever lasting >7 days, neurological dysfunction, Herpes Zoster, HIV dermatitis

More specific signs: pneumocystic pneumonia, esophageal candidiasis, lymphoid interstitial pneumonia, shingles or Kapsosi sarcoma

Signs common to both HIV infected and non-infected infants: chronic otitis media, persistent diarrhea, failure to thrive

Severe Malnutrition

Definition - edema in both feet or severe wasting and weight for height < -3 SD or <70%

Assume that all severely malnourished children have an infection (regardless of presence of fever) and treat with antibiotics

On exam look for: dehydration, pallor, signs of HIV infection/ local infection, fever, ulcers, skin changes of kwashiorkor

HISTORY AND PHYSICAL

History Duration of fever Residence in or recent travel to an area with Plasmodium

falciparum (malaria) transmission Skin rash Stiff neck or neck pain Headache Pain on passing urine (generally child ≥ 3yr) Ear pain – e.g. pulling on pinna Immunizations

History (cont’d) What was the temperature and how was it measured? Level of activity prior and after onset of fever Infection(s) during pregnancy or at birth Ill contacts or recent travel history Oral intake Presence of lethargy/ irritability Presence of cough/ vomiting Urination frequency/ abdominal pain/ back pain/ new onset of

incontinence (e.g. UTI) Protection of the affected area in deep soft tissue/ bone infection Underlying medical conditions (e.g. sickle cell disease, urinary tract

reflux, etc.)

History (cont’d) - Immunizations It is particularly important to know if Hib, pneumococcal, meningococcal

and/or yellow fever vaccines have been given and are up to date

Nearly all low income countries have now rolled out Hib vaccine > 18 countries in developing world have also recently introduced

PCV 6 countries in sub-Saharan “meningitis belt” have just introduced

new meningococcal A conjugate vaccine Rapid increase in number of children vaccinated against yellow

fever with assistance GAVI

Vaccination with the above conjugate vaccines (i.e. Hib, PCV) dramatically reduces the risk of occult bacterial infection in children presenting with fever without localizing signs

Physical Examination Always fully undress child General appearance (alert, playful, irritable, consolable,

lethargic) Oxygen saturations (if available) Stiff neck Hemorrhagic skin rash - purpura, petechiae Skin infections - cellulitis or skin pustules Discharge from ear/red immobile ear-drum on otoscopy Severe palmar/conjunctival pallor Refusal to move joint or limb Local tenderness Fast breathing

Physical Examination Toxic-appearing:

Lethargic: decreased level of consciousness/ poor eye contact, failure to interact with environment or parents

Poor perfusion and cyanosis Hypo/ hyperventilation Purpura may be present Woods, CR.

Epiglottitis (supraglottitis): Clinical features and diagnosis. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012.

Physical Examination

Watch for signs of raised intracranial pressure: Bulging fontanelle Poor feeding, Vomiting Headache, Irritability Papilledema Lethargy, Seizures Cushing’s triad: hypertension, widened pulse

pressure, bradycardia

Management: Fever in 2 month – 3 year GROUP

Fever 2 months – 3 years

The first step is to determine if the child is toxic looking i.e. septic If the patient is septic, do septic work up and

start antibiotics, fluids, and provide oxygen

Fever 2 months – 3 years

In the non-septic child, the second step is to determine if the fever is due to an infection with or without localized signs by doing a detailed history and physical If a focus is found, treat accordingly If no focus is found, investigate as FWLS or

Fever without a source

Fever 2 months – 3 years

Example of an institutional algorithm for FWLS in the 2 m – 3 year age group developed for Botswana referral hospital (where there is very low/no malaria, no typhoid, no dengue) is provided on the next page

Child Appears Toxic• Lethargic (not interacting with caregivers/environment)•Poorly perfused (cap refill > 2sec)•Hypoventilating or tachypneic for age

No

Algorithm: Fever without a Source – Ages 2 months to 3 years

Definition: Child between 2 months and 3 years with an axillary temperature > 37.5 and no obvious source of infection after a thorough History and Physical

Yes

T > 38.5 axillaryNoYes

Sepsis evaluation•Blood Culture•Urinalysis and Culture•CBC•LP if indicated by symptoms•Consider malaria smear if indicatedAdmit to WardStart empiric antibiotics- Cefotaxime 50mg/kg/dose 6 hourly

•No diagnostic test•Paracetemol 15mg/kg/dose•Discharge home•Return if fever > 48 hrs or seems more sick•NO Antibiotics

Tests: Blood Cx or FBC and then Blood Cultures only if WBC > 15,000UA and Cx: if Male < 6 mo, Female < 2 yr or T > 40CXR: if dyspnea, cough/ralesLP: if < 15 mo, or associated with seizure and does not meet criteria for simple febrile seizure

Child is HIV positive, CD4 <25% or unknown or child is HIV Exposed and HIV status unknown

YesNo

Treatment:- If any diagnostic tests are suggestive of a source for infection treat according to protocol for that diagnosis . However, if no tests are indicated or all test are normal AND If FBC or WBC > 15,000 THEN -> Amox/Clav for 48 hours If FBC or WBC < 15,000 then do not give antibiotics ALL children regardless of whether they are given abx NEED: F/U in 48 hours if still febrile or at any time if they appear more sick & Paracetemol 15 mg/kg/dose

*Normal Rates

Age Respiratory Heart

2-12 months <50/min <160/min

1-2 years <40/min <120/min

2-5 years <40/min <110/min

6-8 years <30/min <110/min

Management – Presumed Septicemia

Treatment Give benzylpenicillin IV (50 000 units/kg every 6 hrs)

or ampicillin 50 mg/kg IM every 6 hrs) plus chloramphenicol (25 mg/kg every 8 hrs) for 7 days

If significant drug resistance to these antibiotics among Gram-negative bacteria, follow the local guidelines for management of septicaemia may be a third-generation cephalosporin such as ceftriaxone (80 mg/kg IV, once daily over 30-60 minutes) for 7 days

Management – Presumed Septicemia (cont’d)

Supportive care If a high fever of ≥ 39°C (≥ 102.2°F) is causing

the child distress or discomfort, give paracetamol (15mg/kg/dose every 4 hours, maximum 5 doses/day )

Fluid intake and nutritional management

Manage complications including seizures, hypoglycemia, electrolyte abnormalities

Investigations for FWLS – Depending on availability

Blood smear or rapid diagnostic test (RDT) for malaria (if endemic)

LP if signs suggest meningitis (with no signs of raised intracranial pressure, in stable patient)

Blood culture in suspected sepsis Full Blood Count Urinalysis/Microscopy CXR – if pneumonia is suspected

Management: FEVER in7 day – 2 month old GROUP

Management 7 day to 2 month old

Investigations: Check glucose Do Cultures – Urine and Blood Do an LP CXR if available

Management: Oxygen, Fluids, Antibiotics

Management 7 day to 2 month old

Ampicillin (50 mg/kg IM/IV every 6 hrs for 2 days) then oral amoxicillin (15 mg/kg every 8 hrs for 5 days) OR oral ampicillin (50mg/kg PO every 6 hrs on an empty stomach for 5 days)

plus IM gentamicin (7.5 mg/kg once daily) for a total of 7 days of therapy

You may continue IV Ampicillin beyond 2 days if child continues to appear unwell

Management 7 day to 2 month old (cont’d)

If S. aureus is known to be an important cause of neonatal sepsis locally, or signs suggestive of severe staphylococcal infection (e.g. skin pustules), give IM cloxacillin (50 mg/kg every 6-8 hrs depending on age) plus IM gentamicin (7.5 mg/kg once daily)

Management 7 day to 2 month old - Suspected or Confirmed Meningitis

Give IM ampicillin (50 mg/kg every 6-8 hrs depending on age) plus IM gentamicin (7.5 mg/kg once daily). An alternative regimen is IM ampicillin plus IM chloramphenicol (25 mg/kg every 6 hours).

Chloramphenicol should not be used in premature infants and should be avoided in infants in the first week of life

Some centres use third generation cephalosporins

MANAGEMENT: SEVERE MALNUTRITION

Investigations may include

Glucose (mandatory) Labs: Hb/ Htc if severe pallor Electrolytes (generally hypokalemic) Blood culture TB investigations HIV testing, etc.

Management of child admitted with severe malnutrition

Multidimensional management in two phases of stabilization and rehabilitation [see chapter 7 in the WHO manual]

Management of child admitted with severe malnutrition

All severely malnourished children receive A broad-spectrum antibiotic

Ampicillin (50 mg/ kg IM/IV 6-hourly for 2 days) then oral amoxicillin (15 mg/ kg 8-hourly for 5 days) OR oral ampicillin (50 mg/kg IM/IV for 5 days) over a total of 7 days

Gentamicin (7.5 mg/kg IM/IV) once daily for 7 days

If child fails to improve within 48 hours: add chloramphenicol (25 mg/kg IM/IV 8-hourly) for 5 days

Local antibiotic regimen may be different due to different resistance rates

Management of child admitted with severe malnutrition

Measles vaccine if child > 6 mo (not immunized) or > 9 month

Delay vaccination if in shock

MANAGEMENT: COMMON INFECTIONS

Diagnostic Criteria for Urinary Tract Infections

Clinical signs: Malodorous urine/ hematuria Abdominal tenderness/ suprapubic pain Vomiting, irritability, diarrhea Fever > 38 °C for over 24 hrs Dysuria, vaginitis/ vulvalitis

Labs: Urinalysis from suprapubic aspirate or transurethral catheter

Leukocyte esterase Nitrite WBC Culture

Treatment of Urinary Tract Infections

For Oral agents, be aware of local susceptibilities – treatment include: Amoxicillin/Clavulanate, First generation

cephalosporins, Quinolones

If <6months, or septic, require admission and IV Ampicillin & Gentamicin

Other Common Infections Malaria (see-

http://apps.who.int/medicinedocs/documents/s19105en/s19105en.pdf for details) Varies by severity, endemic species, and resistance patterns Antimalarial treatment:

IM/IV Artesunate first line for severe malaria due to P. falciparum in most regions (pre-referral rectal artesunate an option)

Measles Two doses of Vitamin A to all children; immediately on diagnosis

and within 24 hours

Other Common Infections Typhoid

Chloramphenicol (25 mg/ kg every 8 hours) for 14 days If systemic signs/ upset: benzylpenicillin (50 000 units/ kg every 6

hours) for 14 days in addition to chloramphenicol (dosed as above)

Ear infections Acute otitis media - Amoxicillin (50 mg/kg PO TID) X 7 days Chronic suppurative otitis media – wicking and topical antibiotic such as

chloramphenicol drops if available

Summary FWS: fever without a specific source in an acutely ill, temp (rectal)

> 38ºC (100.4ºF)

Infection is the most common etiology of FWS

There are four categories of infants presenting with fever: young infant with serious risk of bacterial infection, infectious fever without rash, fever due to infection with localized signs, and fever with rash

Management strategies vary depending on geographical area, access to resources, presentation, and infant age

Red flags to watch out for: severely malnourished infant, infant with signs of HIV and young infant (7 days to 2 months)

General References

MANAGEMENT OF THE CHILD WITH A SERIOUS INFECTION OR SEVERE MALNUTRITION Guidelines for care at the first-referral level in developing countries. WHO. 2000

IMCI UTI guidelines: Urinary Tract Infections in Infants and Children in Developing Countries in the Context of IMCI http://whqlibdoc.who.int/hq/2005/WHO_FCH_CAH_05.11.pdf

Credits

Dr. April Kam MD DTMH MScPH FRCPC

Assistant Professor, Pediatric Emergency Medicine

Department of Pediatrics, McMaster Children’s Hospital

Parnian Arjmand MSc MD Candidate

McMaster University

Dr. David Goldfarb MD FRCPC

Assistant Professor, Infectious Diseases

Department of Pediatrics, McMaster Children’s Hospital

Adjunct Senior Lecturer, University of Botswana