Abstract
The syndrome of fever and rash provokes anxiety in both the patient and the provider. The differential diagnosis for febrile patients with rash is extensive. The causes range from the trivial (e.g. a viral exanthema) to the life threatening (e.g. meningococcaemia). Causes may be infectious or non infectious (e.g. drug allergies). A systematic approach is important. The presenting lesions have to be broadly categorized into macular, petechial, diffusely erythematous, vesicular, pustular and nodular. A proper history and careful clinical examination is necessary, rather than relying on laboratory tests which may not be immediately available. An early clinical diagnosis is essential, since in some cases, empirical therapy has to be started as soon as possible.
This paper emphasizes the clinical approach to a patient with a skin rash, especially from the point of view of a non dermatologist.

Evaluating a febrile patient who has a skin rash is a challenging task. The causes are many and prompt diagnosis is important in quite a few cases. This article reviews, in brief, the common causes for this syndrome, based primarily on the morphology of the presenting rash.

In the initial evaluation of the febrile patient with rash certain factors must be given urgent priority:^1,2

1. Is the patient well enough to be evaluated on an outpatient basis or is admission required? Most cases of fever with rash warrant admission, though some (e.g. an urticarial drug rash or a viral exanthem) may be managed on an outpatient basis with a watchful approach.
2. If admission is required, can further time be spent eliciting a detailed history or is urgent cardio respiratory support required in an intensive care facility?
3. Does the nature of the rash warrant isolation procedures (as required for viral and bacterial diseases that can be spread through droplet infection)? Whether or not such are deemed necessary, the health care provider should be prudent to take all proper precautions in his interactions with the patient. Wearing gloves is a must during an examination.
4. In certain cases, immediate antimicrobial therapy has to be instituted without waiting for the results of a laboratory work up. This is most important in case of suspected meningococcal septicaemia, bacterial septic shock and toxic shock syndrome caused by staphylococci or streptococci, or overwhelming cutaneous bacterial infections like necrotizing fascitis. Immediate therapy can make a difference between life and death.
5. Does the disease require notification from the public health point of view? This may be of prime importance in a medical centre catering to densely populated areas. A single case of dengue fever may herald onset of an epidemic of menacing proportions.

In the history, some points may be of vital help. Thus, a recent exposure to other febrile patients should be asked for, so also drugs taken in the past few weeks, whether the patient has been travelling recently, occupational exposures, sexual exposures and risk factors of HIV infection, prior medical history including diabetes and allergies. All this information may turn out to be vital. Immune status is important since many of these diseases can present differently in immunocompromised persons.³

Though several types of fevers exist, in actual practice, it is probably easier to construct a diagnostic approach based on the morphology of the rash.4,5
The first type of skin rash that a physician is most likely to see in a febrile patient is an eruption composed of macules, papules or more commonly both (maculopapular rash). The common infections which can cause maculopapular eruptions are:

Secondary syphilis, early meningococcaemia, rickettsial infections and typhoid fever. A brief description of these conditions is given below:

Secondary syphilis : The eruption usually occurs 2-6 weeks after the primary ulcer of syphilis (chancre) develops. In 30% cases, the chancre may be present when the rash starts. The rash is often initially intense on the palms, soles, head and neck, but later on may be diffuse. Initial lesions are macular (roseolar) but new lesions come in crops and ultimately evolve to a polymorphous pattern, in which papules with scaling (papulosquamous lesions) are prominent. A peripheral collarette of scaling (Biett’s collar) is considered by some to be diagnostic. Oral and genital lesions (mucous patches and condylomata lata) are also common, as is generalized adenopathy. Fever, headache, arthralgias and malaise are frequent symptoms.

Early meningococcal infection, Rocky mountain spotted fever, murine typhus also begin with a macular eruption before becoming petechial. The first two characteristically begin acrally, while the last starts in the axilla.

Besides the classic manifestations of enteric fever, rose spots are a rare but important presentation. They are soft pink papules common on trunk, appearing in the first week of the illness.

Many viral infections like rubella, rubeola, parvovirus B-19, enterovirus and Human Immunodeficiency virus-1 produce a maculopapular rash.

Several non infectious conditions like serum sickness, autoimmune diseases like lupus and dermatomyositis, erythema multiforme can also cause maculopapular rashes. The latter shows pathognomonic “target lesions” on the distal extremities which are circular lesions with two or three colours arranged concentrically.

The second type of rash that is seen in febrile patients is Bullous and Pustular lesions. An important infectious cause is staphylococal bacteraemia, which can cause widespread pustular and bullous lesions. Gonococcaemia can cause a scanty eruption of pustules on a petechial base (“purpuric pustules”) mainly on the acral areas. The rash of varicella is characteristic (“dew drops on rose petal appearance”), polymorphous and truncal. Herpes simplex virus can cause disseminated vesicular eruptions in immunocompromised patients. The lesions can be grouped and umbilicated.

Vesiculobullous eruptions can also have non infectious causes. Bullous erythema multiforme, dermatitis due to allergy to plants (phytodermatitis) and autoimmune bullous diseases like pemphigus can give extensive vesiculobullous eruptions. Phytodermatitis is mainly on exposed areas. Pemphigus shows characteristic detachment of normal looking skin if a shearing force is applied (Nikolsky sign). Pustular psoriasis is also an important cause of pustular lesions with fever. In this condition, crops of superficial pustules arise in a known patient of psoriasis, who has been given systemic steroids or is being weaned off steroids.

The third type of rash seen in febrile patients is a diffusely erythematous (scarlatiniform) rash. Group A streptococci can cause scarlet fever, where there are sheets of erythema, exudative pharyngitis, strawberry tongue as well as petechiae in the skin folds (Pastia’s lines). Streptococcal and staphylococcal infections can also cause toxic shock syndrome with hypotension and multiorgan failure.

Two identical looking conditions, staphylococcal scalded skin syndrome (SSSS) and toxic epidermal necrolysis (TEN) have different aetiologies. The former is due to epidermolytic toxins of staphylococci, while the latter is usually due to a drug reaction. Both these conditions give rise to a diffusely erythematous rash which is tender. On giving tangential pressure on the skin (Nikolsky’s sign), the superficial skin tends to peel off. Later on there is spontaneous sloughing of the skin. In SSSS, the separation of the skin occurs at a higher level (granular layer); hence the course is shorter and healing is faster, while in TEN, the separation is at the dermo-epidermal junction and hence healing is slower, the course is protracted and the prognosis extremely guarded.

Kawasaki’s disease is mostly reported in children.6 The cause is unknown. The rash appears within 3 days of the onset of fever and is often scarlatiniform on the trunk and erythematous on the extremities. Mucous membrane involvement is very common and includes a strawberry tongue and conjunctival hyperaemia. Non suppurative cervical adenopathy is common, hence the synonym, mucocutaneous lymph node syndrome.

Dermatological causes of diffuse erythema with scaling that can sometimes cause fever are drug eruptions, eczema, generalized (erythrodermic) psoriasis and cutaneous lymphoma (Sezary’s syndrome).

The fourth type of eruption that can occur in a febrile patient is Petechial purpuric) eruptions. These are the most serious eruptions occurring in this scenario and warrant immediate evaluation to rule out life threatening illnesses.

Neisseria meningitides can cause a rapidly evolving illness which is a real medical emergency and may have to be treated on empirical grounds alone. Early skin lesions tend to be small irregular, petechial, raised and tender. The centre of the lesion is necrotic. The lesions can coalesce to form large necrotic patches, which if associated with hypotension, meningitis and multiorgran failure is referred to as purpura fulminans which is accompanied by disseminated intravascular coagulation.

Gonococcaemia can also produce fever, rash (pustules on a purpuric base) and polyarthritis.

Bacterial endocarditis can cause small petechiae to appear in crops on the extremities, conjunctiva and also in unusual locations like sublingually and on the tympanic membrane.

Many other bacterial infections can cause petechial eruptions, especially in neutropenic or immunocompromised patients.

Viral illnesses like dengue (break bone fever) can cause haemorrhagic lesions and also multisystem involvement which can be rapidly fatal, especially in children.

Certain important non infectious conditions also must be considered in evaluating petechial rashes. These include Henoch Schonlein purpura in children, hypersensitivity vasculitis in both children and adults, rheumatic fever, thrombocytopenic purpura, etc.

Another type of eruption that a febrile patient can present with is urticarial lesions. The most common cause here is angioneurotic oedema mostly due to drugs, which is accompanied by lip and periorbital swelling and may present as medical emergency due to laryngeal oedema. Other conditions like Lyme disease (not seen in India) or viral infections like hepatitis virus can present as urticarial eruptions.

The last type of eruptions occurring in a febrile patient are the nodular eruptions.

Two important conditions which occur are Erythema nodosum, which is a septal panniculitis,7 while the other is erythema nodosum leprosum which is a vasculitic process.8 The former is a reaction pattern due to one of several underlying conditions, where tender erythematous nodules occur more commonly on lower legs, knees and arms. The latter occurs in multibacillated types of leprosy and is seen in crops, all over the body, including the face. The lesions can ulcerate and even occur as a life thretening process (erythema necroticans).

Laboratory data, is not often available initially. However, a complete blood count with differential, blood chemistry, liver function tests, blood and urine cultures may help in identifying organisms responsible, and more importantly give a clue as to the prognosis of the patient.

Aspirates, scrapings and pus may be subjected to Gram staining and culture. Biopsy samples from nodular or purpuric lesions can be helpful. Biopsy may be useful to diagnose herpetic infections, autoimmune diseases like lupus, vasculitis, secondary syphilis, etc.

Serological tests may be useful in diagnosis of lupus, rheumatoid arthritis, syphilis, human immunodeficiency virus infections.

In conclusion, the syndrome of fever and rash can tax the diagnostic acumen of even the most astute and experienced clinician. A proper diagnostic approach, relying on the tripod of history, physical examination and properly targeted laboratory investigations can elicit a diagnosis in most cases.

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