Fever with rash clinical approach

Fever with rash is one of the most common problems encountered by practicing pediatricians. As the clinical features are shared by many conditions diagnosis may not be easy and management may be delayed in many cases. 
Few of these entities which are eminently manageable, progresses fast so that therapeutic window is crossed by the time of diagnosis is established. In these clinical scenarios diagnosis and decision should be made without delay with a rapid clinical examination and minimum investigations.

Before we proceed with clinical approach let us see what are the common causes

Once in a while we get purely dermatological conditions presenting with fever. Fever may be unrelated to the condition e.g. some super added complications like secondary infection. This article does not include these situations. Here we discuss situations when some manifestations on the skin during fever episodes help as a marker for the diagnosis of the systemic illness.

Major group of conditions (1)

1. Infectious diseases 
2. Connective tissue disorders
3. Drugs
4. Immune phenomena 
5. Malignancies

Practical approach is to narrow down the possibilities in to one of the above classes then try to pinpoint using clinical and basic lab investigations.

Infectious disorders constitute the main reason across ages, but the relative proportion of the other groups varies with age.
 Role of drugs directly or indirectly should be considered in all ages. 
Connective tissue  disorders are common in adolescence and middle ages, 
and dermatological manifestation of internal malignancies in the older age group.  Age and sex distribution is helpful to narrow down possibilities in conditions occurring in younger age groups too. E.g. Infections like Exanthem subitum,is more common below two years,(2) infectious mononucleosis mostly involve adolescent age. Among the connective tissue disorders most of the cases of Kawasaki and SOJIA presents below five years(3). Systemic lupus erythematosus is most common in adolescent age group especially in females.

Presentations in emergency departments

Majority of fever rash cases present in stable state. Small percent cases may come in unstable situation getting admitted in intensive care unit. Once in a while an infectious disease which may pose a threat to the health workers in the ICU, or rarely this may be an entity which has epidemiological and public health importance which has to be notified at the earliest (4). As the priority is to stabilize the patient health workers may not consider this aspect and are likely to get infected during this. This can be avoided only by keeping this point in mind in all cases getting admitted in ICU and by screening skin and mucosa especially areas which are likely to be missed unless specifically looking for that. 
In all cases check the back, buttocks nape of neck and perineum which are often missed. Small vesicles behind ear lobe may serve as a clue for herpes encephalitis in a case coming with seizures or altered sensorium. Presence of vesicles usually indicates herpes or varicella, but neurological complications like  aseptic meningitis     , brainstem encephalitis, encephalomyelitis acute cerebellar ataxia are reported following  hand foot mouth disease (5) . Similarly a miner skin bleed may indicate meningococcemia in a case of shock. An Eschar in an unusual situation may be the only indicator of scrub typhus. Generalized rash is unlikely to be missed(6).

Herpes labialis

SSSS

SSSS

Pattern of  vital signs derangement  serves as  diagnostic clue.

Shock if fluid loss excluded indicates either increased vascular permeability or cardiac involvement. Here again the pattern of cardiac involvement is different in different situations. 
Most of the viral infections involve either myocardium or pericardium. Apart from these  impulse -generation and conduction are also involved in cardiac involvement in Leptospirosis causing disturbance in rate and rhythm of heart. 
We are likely to miss these clinical findings in a casual examination of heart if we give less importance to heart sounds and rhythm. Unless intensity of heart sound, presence of third heart sound and rate and rhythm is not specifically looked for this situation is likely to be missed. 
Most of us give more importance to murmurs which is very rare in these situations. Murmurs indicate valvulitis which argues for few entities among these. Below five year kids Kawasaki is the most important condition followed by juvenile idiopathic arthritis. In an older child systemic lupus erythematosus or infective endocarditis can cause valvulitis. 
Murmurs at the apex should be given more importance than murmur at base of heart. Higher grades of intensity may argue for an already existing problem. Most of the murmurs due to cardiac involvement are of lower grades, which may be missed in a casual examination.(7) 
Muffled heart sounds occur in myocardial involvement and in pericardial effusion. Third heart sound argues for myocardial involvement.

Another common mistake is to over diagnose infections as a cause of hypo tension in a case with rash.

Kawasaki disease may occasionally present with shock. These cases may have thrombocytopenia and disturbed coagulation states. As these groups of findings strongly argue for an infection we are very likely to miss this atypical presentation. The blood picture with high ESR and CRP also may argue for an infection at this stage. 
This entity is all the more important as the involvement of coronary vessel is more in this type of presentation. Unless we keep this possibility in mind the valuable therapeutic window for administration of IVIG will be missed with dire consequences.(8)

Atypical presentation of other connective tissue disorders in adolescent age group also is likely to be mistaken for infection.

A patient presenting with jaundice,lymphadenopathy fever and rash may be a rare presentation of drug reaction e.g. Dapsone syndrome,  Dilantin sodium.(9)

A patient presenting with respiratory distress OR respiratory failure in PICU may be due to cardiac involvement, lung parenchyma and pleural involvement. 
First look at the depth of breathing. Deep inspiration makes respiratory or cardiovascular reason less likely. Deep inspiration with clear chest may be due to metabolic acidosis or CNS involvement. Severe distress with minimal chest findings may occur in viral pneumonias where interstitial involvement is more common.
 Distress due to cardiac failure also may also cause minimal ausculatatory findings .
If there is asymmetry in the clinical signs like disparity in chest movement or air entry between two sides an entity selectively involving parenchyma or pleura is likely.  E.g. Mycoplasma,Leptospira and Legionella involve parenchyma or pleura in this manner. 

Patients presenting with altered sensorium or seizures indicates involvement of brain directly or indirectly due to hepatic or renal involvement, provided common metabolic and electrolyte abnormalities are ruled out. Skin manifestation may give a clue in bacterial meningitis due to meningococi, many viruses and leptospira.

Rarely high blood pressure with encephalopathy may present with altered sensorium or seizures in few connective tissue disorders.

Diagnostic approach in stable patients

Patients presenting in the outpatient section with classical features may be disposed with symptomatic management or reassurance.eg many cases of hand foot mouth disease, rubella, exanthem subitum. Situations where diagnosis is doubtful get admitted in ward for detailed work up.

Points in the history(10)

1. History of contact with similar patients, chance of exposure to unusual infections, pets

2. Travel history

3. Immunisation history

4. Family history of connective tissue disorders

5. Drug history in detail

7. History suggestive of immunodeficiency disorders as this may lead to modified presentations of common disorders

In the evaluation of case proper main stress on three major aspects.

• 1. Details about fever, and the time relation with rash 
• 2. Details about rash
• 3. Findings in systems other than skin

Longer the duration of fever chances of infections as a reason is less. Most of these infections evolve and subside in days. Infectious mononucleosis, cytomegalovirus and toxoplasma may last for weeks. Hepatitis B can have peripheral rash lasting for weeks. If fever and rash last beyond weeks consider reasons other than infections. Eg drug rashes, underlying immune phenomena, connective tissue disorders are more likely in those cases

The time relation of rash with fever helps. Rash on day 1 in varicella, day 2 in scarlet fever, day 3 in smallpox, day 4 for measles ,day 5 typhus or 6 in dengue  and seventh day in  typhoid fevers. Early rashes and mucosal involvement in Kawasaki is unlikely in the first three days even though painful edema and erythema can have an onset.

Maculopapular rashes are the commonest and may be associated with all the above broad category of causes. Bulla/vesicles, cutaneous bleeds, urticaria, palpable purpura, redness can occur in isolation or combination. Pattern of onset and spread, areas of body parts involved and the manner of involution gives useful clues. Onset behind the ear and lateral side of face, spreading to the trunk and the limbs and the involution in the reverse manner is typical in measles. Whether flexural or extensor aspect is more involved, trunk or periphery more involved is it symmetrical or asymmetrical and whether palms and soles involved are helpful points. Palms and soles are spared in many except measles, Kawasaki, ricketsiels and drugs.

Even though Kawasaki disease was described in late sixties we were aware of this entity since late nineties. May be many cases of Kawasaki must have been managed as infections. Now we are aware of this entity, and may be over diagnosing. This is partly justified as classical features may take time and therapeutic window is too short. Coronary involvement comes down to 4% against 20 percent with treatment of IVIG if given early. If we have any clinical features which will help to exclude the closer differentials will help to avoid this over diagnosis. Scarlet fever, staphylococcal scalded skin syndrome and few other viral infections are the commonest entities creating confusion in a child below five years. 

KAWAZAKI DISEASE

Few points in the appearance and distribution helps 

• Vesicles and bullae practically rules out possibility of Kawasaki
• Lips and tongue is more involved than the fauci and posterior pharyngeal wall. Lips are always involved. Sparing of lips and tongue rules out Kawasaki.
• Congestion of throat common, but patch on tonsils unlikely in Kawasaki disease. If tonsillar patch is there consider entities like IMN or bacterial tonsillitis 
• Cutaneous bleeds are rare in Kawasaki in spite of the fact that thrombocytopenia and coagulation disturbance occur in severe cases during early phase. Painful swelling and erythema of feet and hands involving dorsum occur early preceding the rash. Rash is more common on the trunk and groin. In the periphery as against scarlet fever where the maculopapular rashes occur, painful swelling on dorsum predominates over rash in Kawasaki.

.Peeling can occur in viral and bacterial infections, but peeling starting from peri- ungual area is typical of Kawasaki disease. Peri- anal peeling may occur in infections also. So if peeling is not there in peri ungual areas consider other conditions than Kawasaki disease.

Pattern of involvement of mucosa also helps.

Conjunctival congestion non-purulent with predominant sclera involvement with limbal sparing is typical. Not much of edema of lids. There may be conjunctival bleed even though skin bleeds are rare. Slit lamp examination may show evidence of iridocyclitis which is uncommon in measles dengue mycoplasma and legionella. Periorbital edema without much involvement of eyes as such argues for IMN. Congestion of palpebral conjunctiva occur in leptospira, legionella mycoplasma infections

SSSS causes painful erythema around lips spreading to face and neck,spares the lips and tongue. Kawasaki involves the lips and tongue but not much of lesions on the face outside lips.

Fissuring and bleeding from lips occur in Kawasaki but Involvement of lips with charring occur more in drug induced rash.

scarlet fever later stages ,rarely few viral infections . 

SSSS (Staphylococcal scalded skin syndrome)

Anal mucosa involvement is more common with drug but Kawasaki spares mucosa but involve the peri-anal skin.

Target lesions argue for drug reaction but once in a while infections like mycoplasma, herpes may lead to Stevens Johnson syndrome. But these cases follow the episode of infection.

Viral infections usually cause small vesicles. Bacterial infections cause’s larger vesicles and bulla. Honey colored crusts and inflammation of base helps here. 
Appearance and distribution helps to differentiate varicella from HFMD.HFMD affects predominantly younger children even though more and more cases reported from older kids..Knees, elbows, buttocks, palms and soles and oral and fauci areas are predominantly involved in HFMD. Varicella predominantly affects the trunk. Involvement of palms and soles and oral mucosa less common. Varicella may affect the eyes but HFMD wont.

Hand foot mouth disease 

More than one type of skin lesions also helps to narrow down the possibilities.Maculopapular and cutaneous bleeds more common in dengue but other types of lesions like urticaria vesicles are unlikely. Maculopapular lesions target lesions vesicles urticaria in any combination with mucosal involvement argues for drug rash.But cutaneous bleeding is rare. Charring of lips more common with drug rash.

Urticarial rashes are less common with viral infections. They can occur with bacterial infections, notable one is staphylococcal. Urticaria is usual with vasculitis and other immune phenomena and drugs.

Erythema, generalized or local nature can occur in many infections, Kawasaki and drugs .

Other systems

Significant enlargement of lymph nodes palpable liver and spleen argue for infections, but may occur in connective tissue disorders and drugs. Drugs like dapsone may cause fever, rash generalised lymphadenopathy, hepatosplenomegaly and jaundice all of which are usually features of infection.

Muscle and joints. Dengue, Leptospira, Legionella affects muscles than joints. Chikun guinea, Rubella, Parvovirus predominantly affects joints. Muscle and joint involvement is one of the major features of connective tissue disorders ,which is predominant depends on the type.

Evidence and pattern of involvement of heart and lung may give clues. as different disorders may affect these systems in different manner.

Examination of eyes for type of congestion, jaundice, bleeding and evidence of iridocyclitis helps

Assessment of nervous system to decide the type of involvement may give a clue whether the basic entity involve the CNS directly or indirectly. It may range from aseptic meningitis to encephalitis with severe affection of vital areas in the brain parenchyma.

Basic investigations

Basic investigations like blood counts, ESR, CRP will help during this initial work up. WBC and platelet count on the lower side argue for viral infections with the exception of infectious mononucleosis. Low WBC and platelet count with high ESR is usual pattern in SLE. Quantitative CRP less than 15 ,ESR less than 40 practically rules out possibility of Kawasaki disease. Leptospirosis is always associated with high WBC count with predominant neutrophils and High ESR. WBC and platelet count not so high or low and normal ESR is the usual pattern in Rickettsial diseases.

	Associate signs	WBC Count	Neutrophil count	Lymphocyte	Platelet count	CRP	Possibility
Fever with rash Fever with rash	Cervical lymph nodes only	High	High	Normal	High	High	Kawasaki disease
	Congestion of eyes Generalized lymph node      Liver spleen jaundice Muscle tenderness	Low	Low	Low	Low	Low	Dengue/legionella/Mycoplasma
		High	Low	High	Low	Low	IMN
		High	High	normal	Low	High	Leptospirosos
	Neck stiffness	High	High	normal	normal	High	Meningococcemia
		Normal	Normal	High	Normal	Low	Viral meningitis
	Arthritis	Low	Low	Low	Low	High	SLE
		Low	Low	Normal	Normal	Normal	Parvo,Rubella,ECHO,Coxachie
	Cardiac involvement    a,Murmur	High	High	Normal	High	High	Kawasaki
		High	High	Normal	Normal	High	Juvenile rheumatoid arthritis
		Low	Low	Low	Low	High	SLE
	b.Myocarditis	High	High	Normal	Low	High	Leptospirosis
	c.Pericardial effusion	Low	Low	low	Low	High	SLE
	d.arrhythmia	High	High	Normal	Low	High	Leptospirosis
	Lung signs	High	High	Normal	Low	High	Leptospirosis
		Normal	Normal	Normal	Normal	Normal	Mycoplasma