FEVER OF UNKNOWN ORIGIN

TEMPERATURE FEVER (FUO)

The hypothalamic thermoregulatory center an elevation of body temperature temperatures >38.3°C (>101°F) on two or more

FEVER AND RASH

balances excess heat production from metabolic (>37.2°C/98.9°F in the morning and occasions and an illness duration of ≥3 weeks,
activity in muscle and liver with heat dissipation >37.7°C/99.9°F in the evening) in conjunction with no known immunocompromised state and
from the skin and lungs to maintain a normal body with an increase in the hypothalamic set point unrevealing laboratory and radiologic
temperature of 36.8° ± 0.4°C (98.2° ± 0.7°F), with investigations into the cause
diurnal variation (lower in a.m., higher in p.m.).

GROUP 1 DEFINITION OF TERMS

Banzuela, Alvie Marie HYPERPYREXIA HYPERTHERMIA PYROGEN
Barba, Louie Andrew temperatures >41.5°C (>106.7°F) that can occur an uncontrolled increase in body temperature any fever-causing substance, including
Barce, Cathryn Marie with severe infections but more commonly that exceeds the body’s ability to lose heat exogenous pyrogens (e.g., microbial toxins,
Battung, Andrea Rose occur with CNS hemorrhages without a change in the hypothalamic set point. lipopolysaccharide, superantigens) and
Bejer, Kaye Diane Hyperthermia does not involve pyrogenic pyrogenic cytokines (e.g., IL-1, IL-6, TNF)
Gaminde, Evander molecules.
Llanza, Christine Sarah
Vibar, Angelo Carlo

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01 ❑ The hypothalamic set point

increases, causing peripheral
vasoconstriction (i.e., heat
conservation).

❑ The patient feels cold as a result

of blood shunting to the internal
organs.
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6

04
02 ❑ Mechanisms of heat production
(e.g., shivering, increased
hepatic thermogenesis) help to
raise the body temperature to
03
❑Increases in peripheral prostaglandin E2 account for the
the new set point. nonspecific myalgias and arthralgias that often
accompany fever. ❑ When the set point is lowered again by resolution or
treatment of fever, processes of heat loss (e.g., peripheral
vasodilation and sweating) commence.

ETIOLOGY Approach to
the Patient
• Most fevers are associated with self-limited infections
(usually viral) and have causes that are easily identified.

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 06 History of animal bites

01 The site of onset of the rash and its direction and rate of spread

07 Recent dietary exposures

HISTORY 02 Immune status

08 Existence of cardiac abnormalities

A meticulous history is essential,

with particular attention to the 03 Immunization status
HISTORY
chronology of events (e.g., in the
case of rash:
09 Recent exposure to ill individuals

04 Medications taken within the previous month

10 Sexual contacts

05 Exposure to domestic pets and other animals

11 Specific travel history

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PHYSICAL
12 Trauma
EXAMINATION
HISTORY
13 The presence of prosthetic materials

◼ A thorough physical examination should be performed. A consistent site

for taking temperatures should be used.

◼ Temperature–pulse dissociations (relative bradycardia) should be noted if

present (sometimes present, for example, with typhoid fever, brucellosis,
leptospirosis, factitious fever).

◼ Close attention should be paid to any rash, with precise definition of its
salient features.

11 12
 ▪ Describing a rash
number, size, shape, color borders, pattern location 1. LESION TYPE
CONFIGURATION
▪ Change of skin color,
configuration that may be due to:
texture,
ARRANGEMENT
• Colonization or infection of infective/pathogenic DISTRIBUTION
RASH
organisms
• Toxin production by infecting organisms on skin
structures ◼ Lesion type
• Immune-mediated/autoimmune destruction of the
- (e.g., macule, papule, nodule, vesicle, pustule,
skin’s architecture due to a response against an
purpura, ulcer;)
infecting organism
• Changes in vasculature (e.g. vaso-occlusion, necrosis, ◼ configuration
vasodilation) - (e.g., annular or target),

◼ arrangement, distribution

- (e.g., central or peripheral)

13 14

01
Centrally distributed
maculopapular eruptions
(e.g., viral exanthems, exanthematous drug-induced
eruptions)
02 Peripheral eruptions
(e.g., Rocky Mountain spotted fever, secondary syphilis,
bacterial endocarditis)
05 Urticaria-like eruptions
in the presence of fever, usually due to urticarial vasculitis
caused by serum sickness, connective tissue disease,
infection (hepatitis B virus, enteroviral, or parasitic infection),
06
Nodular eruptions
(e.g., disseminated
nodosum, Sweet’s syndrome)
fungal infection, erythema

or malignancy (particularly lymphoma)

2. CLASSIFICATION OF RASH 2. CLASSIFICATION OF RASH

03
Confluent desquamative
erythemas
(e.g., toxic shock syndrome)
04 Vesiculobullous eruptions
(e.g., varicella, primary HSV infection, ecthyma
gangrenosum)
07 Purpuric eruptions
(e.g., meningococcemia,
disseminated gonococcemia)
viral hemorrhagic fever,
08
Eruptions with ulcers or eschars
(e.g., rickettsial diseases, tularemia, anthrax)

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 Lesion type Configuration
• Annular - round or circular with central clearing
• macule • pustule • Circinate - round, circular > arciform: partial circle
• papule • purpura
• Iris or target -also known as target lesions and are a series of
• nodule • Ulcer
• Vesicle concentric rings. These have a dark or blistered center.
• Gyrate - connecting arcs
• Linear - straight

Features of Rash
Arrangement • Serpiginous – meandering; wander as though following the
track of a snake.
• Localized - grouped into specific areas • Margination – sharp, ill-defined
• Generalized - dispersed all over • Satellite Lesions - commonly used to describe a portion of
• Symmetric - no pattern the rash of cutaneous candidiasis in which a beefy red plaque

Lesion Type
• Asymmetric - pattern lacking randomness may be found surrounded by numerous, smaller red macules
• Discrete - separate
located adjacent to the body of the main lesions
• Grouped - clustered
• Zosteriform - dermatomal
• Confluent (coalescing) - smaller into larger
• Cleavage plane - arranged along lines of skin tension 17

Papules
Macules
• Circumscribed area of change in normal skin color
• raised, solid lesions <5 mm in diameter
without change in consistency, flat; may be any size;
non-palpable

• i.e., a blanchable erythema

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Plaques Nodules
• lesions >5 mm in diameter with a flat, plateau-like • are lesions >5 mm in diameter with a more rounded
surface configuration.

• Elevation of skin occupying a relatively large area in • Similar with papule but extends up to dermis or
relation to height; often formed by confluence of subcutaneous tissue; differentiated from papule by
papules palpability and depth rather than size

21 22

Wheals Vesicles
• (urticaria, hives) are papules or plaques that are pale • Circumscribed, elevated, fluid-containing lesion less
pink and may appear annular (ringlike) as they enlarge than 0.5 cm in greatest diameter; may be
intraepidermal or subepidermal in origin

• classic (nonvasculitic) wheals are transient, lasting

only 24 h in any defined area.

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Bulla Pustules
• Circumscribed elevation of skin containing purulent
• Similar with vesicle, except lesions are more than 0.5 fluid of variable character (i.e. fluid or exudates may
cm in greatest diameter be white, yellowish, greenish, or hemorrhagic)

• vesicular processes such as varicella or herpes

simplex may evolve to pustules.

25 26

Nonpalpable purpura Palpable purpura

• a flat lesion that is due to bleeding into the skin
• a raised lesion that is due to inflammation of the
• If <3 mm in diameter, the purpuric lesions are termed vessel wall (vasculitis) with subsequent hemorrhage.
petechiae;

• if >3 mm, they are termed ecchymoses.

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 Ulcer

• a defect in the skin extending at least into the upper

layer of the dermis, and an eschar (tâche noire) is a
necrotic lesion covered with a black crust.
Classification of Rash

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CENTRALLY
DISTRIBUTED
▪ Most common type

MACULOPAPULAR LESIONS ▪ Centrally Distributed

- lesions are primarily from the center/axis
(trunk, head, neck) to the periphery

➢ Still’s Disease is a diagnosis of exclusion

➢ Typhoid Fever: (+) rose spots
➢ Lyme Disease: (+) erythema migrans

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 Measles
▪ Aka First Disease, Rubeola
▪ First of the exanthems described/discovered
▪ Etiologic Agent: measles virus (Paramyxovirus)

▪ Rash
→ Starts from the hairlines 2-3 days into the illness and moves down the body
→ Typically sparing palms and soles
→ Begins as discrete erythematous lesions, which become confluent as the rash spreads
o Forehead → behind the ears → neck → trunk → extremities
→ Fade in order of appearance
Table 1. Centrally Distributed
Maculopapular Eruptions ▪ Fever + 3 C’s
→ Conjunctivitis
→ Cough
→ Coryza (Rhinitis)

▪ Koplik Spots
→ in the oropharynx – pathognomonic for measles
→ 1-2 mm white or bluish lesions with an erythematous halo on the buccal mucosa
→ Generally seen during the first 2 days of symptoms

▪ Transmission
→ Respiratory droplets (airborne)
→ Contagious several days before and up to 5 days after lesions appear

▪ Prodrome (10-15 days): fever, coryza, hacking bark-like cough, photophobia

▪ Complications: otitis media, pneumonia, diarrhea, subacute sclerosing panencephalitis (Dawson encephalitis)
33 34

Rubella
▪ Aka German Measles
▪ 3rd disease → ”3-day measles”
▪ Etiologic Agent: Rubella Virus
▪ Rash: pink macules and papules
→ From hairline downwards
→ Tends to clear from originally affected areas as it migrates
→ May be pruritic

✓ 1st Day: Forehead → face → trunk → extremities

✓ 2nd Day: Facial exanthema fades
✓ 3rd Day: Exanthem fades completely

▪ Forchheimer sign/spots: petechiae on the soft palate during prodrome

✓ Non-specific → develops in infectious mononucleosis and scarlet fever

Figure 1. (Left) Koplik Spots, (Right) Measles

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 Dengue
▪ Caused by Flavivirus PERIPHERALLY
DISTRIBUTED
▪ Vector-borne transmission: Aedes aegypti mosquito infected with dengue virus
▪ Incubation Period: 4-10 days
▪ Manifestations
→ Initially diffused flushing
→ Midway through illness, usually with lysis or relief of fever, then
maculopapular rash develops
→ Rash begins on trunk, extremities, and face (sparing palms and soles) and ◼ Peripherally Distributed – from the periphery to the center, centripetally

will eventually desquamate → Rickettsia tsutsugamushi is related to RMSF

• Herman’s Rash: characteristic rash seen in dengue → Secondary Syphilis
• Accompanied by pruritus (hyperesthesia in some cases)
- Palmar and plantar lesions

→ Hand-Foot-and-Mouth Disease
→ After defervescence, petechiae on extremities (in some cases)
→ Accompanied with chills, severe frontal headache, nausea, and vomiting - Also has palmar and plantar lesions

◼ Caused by Coxsackievirus infection

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01 Macular to petechial

02 Start on wrists and ankles, start centripetally, and

appear on palms and soles only later in the disease
Table 2. Peripherally Distributed
Rocky Mountain
03
Maculopapular Eruptions Lesion evolution from blanchable macules to
Spotted Fever petechiae

04 Tick vector

05 Clinical Syndrome: Headache, myalgia, abdominal pain

→ Mortality rate up to 40% if untreated

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 Hand – Foot – Mouth Disease

CONFLUENT DESQUAMATIVE
ERYTHEMAS
01 02 03
◼ Tender mixed papules and clear vesicles
-- Infectious or autoimmune disease beginning as diffuse or severe erythema followed by
◼ Etiologic Agent: Coxsackievirus A16 ◼ Sore throat, sore mouth
with surrounding zone of erythema
desquamation
(most common)
◼ Fever with vesicles in oral cavity → distributed peripherally and in the mouth.
◼ Affects primarily children < 10 years old
coalesce to form bullae → Tender vesicles, erosions in mouth,
→ Can spread to other family members 0.25-cm papules on hands and feet with rim
of erythema evolving into tender vesicles
→ Seen in summer and fall
◼ Extensor surfaces of hands and feet, also
found around the mouth
◼ Clinical Syndrome: Transient Fever

41

SCARLET FEVER
Kawasaki Disease
▪ Children 2–10 years old
▪ Usually follows Group A Streptococcal pharyngitis
→ Pyrogenic exotoxins A,B,C • Idiopathic • Children <8 years old

▪ Diffuse blanchable erythema beginning on face and

Figure 3. Scarlet Fever
spreading to trunk and extremities
• Rash similar to scarlet fever
→ Desquamation in 2nd week Clinical Presentation
(scarlatiniform)
▪ Circumoral pallor, sandpaper texture
• cervical adenopathy,
▪ Pastia’s lines – accentuation of linear erythema in skin fold pharyngitis, coronary
▪ Enanthem of white evolving into strawberry tongue • Fissuring of lips, (+) Strawberry artery vasculitis
tongue, conjunctivitis, edema
▪ Clinical presentation: fever, pharyngitis, headache of hands, feet
Figure 4. Pastia’s lines.
Accentuation of body lines.

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 Staphylococcal Scalded Skin Syndrome
STREPTOCOCCAL TOXIC SHOCK SYNDROME STAPHYLOCOCCAL TOXIC SHOCK SYNDROME

Group A Streptococcus
S. aureus
→ Associated with pyrogenic exotoxin A and/or B or • Classical example of a confluent desquamative erythema
certain M types → TSS Toxin 1, enterotoxin B • S. aureus
→ In setting of severe Group A Streptococcal infection Diffuse erythema involving palms → Toxin-induced (TS1 toxin of Staphylococcus on
Scarlatiniform rash Pronounced erythema of mucosal surfaces the dermal-epidermal junction)
Diffuse erythema involving palms; pronounced • Diffuse tender erythema
erythema of mucosal surfaces; conjunctivitis; Conjunctivitis
desquamation 7–10 days into illness • Often with bullae and desquamation
Desquamation 7–10 days into illness
• (+) Nikolsky’s sign
→ Clinical presentation: → Clinical Presentation:
• Children < 10 years old
- multiorgan failure - fever
- hypotension → Ritters Disease in neonates
- hypotension
• Clinical Presentation: irritability, nasal or conjunctival
- multiorgan dysfunction desquamation

45 46

STEVEN-JOHNSONS SYNDROME (SJS) AND Clinical Features

TOXIC EPIDERMAL NECROLYSIS (TEN)
→ Fever > 39 C
• SJS and TEN differs in body distribution → Tender and painful skin lesions
• Life-threatening conditions → DERMATOLOGIC EMERGENCY
→ Sore throat and conjunctivitis Figure 7. (Left) SJS, (Right) TEN
• Usually caused by reaction to drugs / medications
• Characterized by blisters and epidermal detachment caused by epidermal necrosis in → Erythematous and purpuric macules
the absence of significant dermal inflammation - Some present as target lesions
• Causes:
→ Diffuse erythema progressing to bullae, with epidermal
→ Drugs
sloughing and necrosis
Sulfonamides → Mucosal involvement (including genitalia)
→ Antimalarial drugs
→ Cotrimoxazole → (+) Nikolsky sign
Phenytoin → SJS involves <10% of epidermis
Lamotrigine
- Usually mucosal areas are spared
Allopurinol
Nevirapine → TEN involves >30%epidermal necrosis
Phenobarbital
Carbamazepine
NSAIDS (oxicams) Figure 8. SJS, TEN, and in between body
distribution of clinical presentation
47 48
 Varicella
• Incubation period 14-21 days
• Macules (2-3mm) evolving to papules,
then progressing to vesicles on

VESICULOBULLOUS ERUPTIONS erythematous base (dew drops on a

rose petal)

• Caused by Varicella Zoster virus

• Lesions appear as crops and pruritic
pustules and then crusting

50

Variola
▪ Small pox
▪ Prodrome of fever, headache, myalgia, and vomiting
differs from varicella in that

Primary Herpes Infection

(1) skin lesions in any given area are at same stage of
development and
(2) there is a prominent distribution of lesions on face
❑ Caused by Herpes simplex virus type 1 and 2 ❑ Sexually active young adults HSV2
and extremities (including palms, soles)
❑ Children and young adults for HSV1 ❑ Incubation period 1-26 days

Figure 11. Variola (small pox)

51 52
 Disseminated
Herpes
URTICARIA - LIKE ERUPTIONS
o Generalized vesicles that can evolve to pustules and ulcerations

o Usually occurs in immunocompromised patients

53

NODULAR ERUPTIONS
Urticaria-like eruptions

• Urticaria commonly referred as hives, characterized by pale, erythematous, raised, well

demarcated pruritic lesions of varying size
• Drug induced urticaria can be caused by:

→ IgE dependent mechanism - occurring within minutes to 36 hours after drug exposure
→ Circulating immune complexes (serum sickness) occurring 6-12 days after exposure
→ Direct mast cell degranulation

55
 Erythema Nodosum Sweet Syndrome
◼ Known as acute febrile neutrophilic dermatosis
◼ Inflammation of the fat cells under the skin caused by ◼ A reactive phenomenon and considered a cutaneous marker of
infection (e.g. streptococcal, fungal, mycobacterial), drugs systemic disease
(e.g. sulfa, penicillins, oral contraceptive hormones), or
◼ Causes: idiopathic, malignancy, hematologic, drug induced,
idiopathic
pregnancy, inflammatory bowel disease
◼ Type 4 hypersensitivity reaction ◼ Presentation: fever, leukocytosis, arthralgia, conjunctivitis /
◼ Large violaceous, non-ulcerative, tender, subcutaneous iridocyclitis
nodules ◼ Acute tender erythematous plaques, nodes, pseudovesicles that
occur on head, neck, legs, arms

◼ Lesions have dense infiltration of neutrophils

57 58

Bacterial
• Acute meningococcemia (Neisseria meningitides)
→ Difficult to identify due to few cases and classic features (hemorrhagic rash, meningismus (pseudomeningitis) and
impaired consciousness) appear late
→ Direct contact with respiratory droplet secretions through coughing, sneezing, kissing
→ Incubation period: 3-4 days

PURPURIC ERUPTIONS → First 4-6 hours: nonspecific symptoms

→ 8 hours: maculopapular rash – purpuric to petechiae commonly on the trunk and lower portions of the body –
coalesce - ecchymotic
• Chronic meningococcemia (Neisseria meningitides)
• Purpura fulminans (Severe DIC)
• Disseminated gonococcal infection (Neisseria gonorrheae)
• Thrombotic thrombocytopenic purpura
→ Idiopathic
→ Petechial rash
• Hemolytic Uremic Syndrome (Escherichia coli O157)
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Acute meningococcemia Disseminated gonococcal infection

Purpura fulminans

61 62

01 Viral hemorrhagic fever

(e.g. Dengue fever, Ebola, Lassa Fever, etc.)

02 Coxsackie virus A9

Viral 03 Echovirus 9

04 Epstein – Barr Virus

05 Cytomegalovirus

63 64
 Tularemia
◼ Cause: Francisella tularensis

ERUPTIONS ◼ Mode of Infection: Exposure to ticks, biting flies, infected

animals

with ULCERS and/or ESCHARS

Tularemia: necrotic ulcer
◼ Rash: ulceroglandular form; erythematous tender papule
evolving to necrotic, tender ulcer with raised borders.

→ Maculopapular rash may occur

◼ Clinical presentation:

→ fever,

→ headache

→ lymphadenopathy
Tularemia: lymphadenopathy

66

Anthrax

Cause: Bacillus anthracis Rash: pruritic papule evolving to painless ulcer

Mode of infection: exposure to animals surrounded by vesicles and then developing to
central eschar with edema
or animal products; exposure to anthrax spores
Clinical presentation: fever, headache,
lymphadenopathy

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Reference:

• Harrison’s Principle of Internal Medicine, 20th Edition

Thank you
for your attention

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