Waterhouse-Friedrichsen Syndrome

Synonyms: Purpura fulminans, originally called adrenal apoplexy.

The Waterhouse-Friderichsen syndrome is a severe complication of meningococcal infection. Neisseria meningitides causes meningitis and septicaemia. The septicaemia has an even higher mortality than the meningitis although they often co-exist. Together they are devastating with a high mortality, even if diagnosis and treatment is prompt.

Some authors regard the Waterhouse-Friderichsen syndrome as the complications of meningococcal septicaemia but others are more specific that it is haemorrhage into the adrenal glands. Adrenal haemorrhage can occur with other causes of septicaemia and has been reported as a complication of severe, fatal Staphylococcus aureus infection in children.¹ It has also been reported with Streptococcus infections and the postmortem findings of adrenal haemorrhage cannot be assumed to be pathognomonic of meningococcal infection.²

Cortisol is required to maintain the vascular tone mediated by the adrenergic system and aldosterone maintains extracellular fluid volume. Hence sudden loss of the adrenals, especially at a time when they would normally be extremely active, causes a sudden Addisonian crisis with circulatory collapse.

This a feature of meningococcal infection that is discussed elsewhere. There are no available figures on how many of the total, or how many of the fatalities, suffered from the Waterhouse-Friderichsen syndrome but it does seem quite common in those who died suddenly.³

About 75% of meningococcal infection presents with the classical purpuric rash that spreads so rapidly that the spread is almost visible. The rash is not due to meningitis but septicaemia and so it is part of the Waterhouse-Friderichsen syndrome. Meningitis and septicaemia may co-exist.

Fulminant Meningococcal Septicaemia presents with:

• Extensive haemorrhage into the skin
• Hypotension
• Shock
• Confusion
• Coma
• Death within a few hours of the onset of symptoms.
• Disseminated intravascular coagulation due to activation of complement system can also occur.
• Haemorrhage into adrenal glands may or may not be present.

Without prompt treatment, mortality rate approaches 100 %.

Although meningococcal septicaemia is the classical cause of adrenal haemorrhage it can occur with other causes of septicaemia along with coagulopathies, diseases of pregnancy, shock and other stresses.

• Lumbar puncture.
• Blood culture.
• Check FBC, coagulation screen, U&E.
• It may be possible to detect adrenal haemorrhage by ultrasound whilst the child is still alive and hence to influence management.⁴

Transfer to hospital for intensive care is a matter of great urgency. Venous access should be established as soon as possible and life support mechanisms including assisted ventilation may be necessary.

Drugs

IM or IV benzyl penicillin should be given immediately,^{5 6} even if this reduces the chance of culturing an organism. The dose of benzyl penicillin is 300mg in babies under 1, 600mg between ages 1 and 9 and 1200mg over 9, including adults. This must be done as soon as possible and GPs should carry this drug in their bag to administer whilst awaiting an ambulance. Penicillin allergy is reported in around 14% of people but serious consequences occur in just over 1%.⁷ The Health Protection Agency recommends that no other drug need be carried for the purpose.⁸ The risk of fatal anaphylactic shock seems tiny,⁹ especially compared with the devastating consequences of not treating this disease.

If there is circulatory collapse or any other suggestion of Waterhouse-Friderichsen syndrome then 100mg of hydrocortisone should also be given. If possible give IV but if no vein is accessible IM will have to suffice.

Prophylactic Steroid Administration

Meningococcal infection carries a significant mortality and morbidity. Much may be due to the Waterhouse-Friderichsen syndrome although diagnosis of adrenal haemorrhage, other than at post-mortem examination when it is too late, is very difficult. Therefore it is fair to ask if prophylactic steroids, perhaps given with antibiotic, will save lives. A Cochrane review has shown benefit from steroids in treating severe sepsis and septic shock.¹⁰

The question has been addressed by "Clinical Evidence". They found no RCTs on the use of adding corticosteroids in children with meningococcal septicaemia. Two RCTs found no significant difference in mortality between adding corticosteroids and adding placebo in children with severe sepsis. One systematic review found that adding steroids to the hospital regime of adults with meningococcal meningitis reduced mortality.¹¹ This benefit was not reproduced in children. Two RCTs found no significant difference in mortality between adding corticosteroids and adding placebo in children with severe sepsis. None of the trials seemed adequately powered to detect a difference.

Immediate administration of penicillin is advocated on the grounds that in this unpredictable and possibly rapidly fatal disease it may give benefit and is unlikely to cause harm. If there is any suggestion of circulatory collapse the same may well be said of giving hydrocortisone.

Surgical

Sometimes the septicaemia can cause serious problems of skin or bone necrosis requiring surgical intervention. This may involve skin grafting or even amputation of affected limbs.¹²

Much of the damage would seem to be due to disseminated intravascular coagulation (DIC). Early treatment and appropriate management is important.¹³

Case mortality rates for meningococcal meningitis are around 3 to 6% under 15 years old, being slightly higher in those under one year old. It rises a little between 15 and 25 and over 25 the mortality rate is around 15%.¹⁴ It is not possible to say how much of the mortality is due to meningitis or septicaemia and how much is due to the Waterhouse-Friderichsen syndrome but the mortality with this condition is very high.

The Men C vaccine appears to be having benefit in terms of reducing the number of cases of meningococcal disease. Meningococcal disease is notifiable and the relevant authority will advise about antibiotic prophylaxis for close contacts. This usually means family members and "kissing contacts."

Rupert Waterhouse was born in Sheffield in 1873 and qualified at St Bartholomew's Hospital. After working in Rheumatology and then in the RAMC in the First World War, he practised as a pathologist. In 1911 he published A case of suprarenal apoplexy in The Lancet.¹⁵ He died in 1958.

Carl Friderichsen was a Danish pediatrician from Copenhagen who was born in 1886 and died in 1979. His publication was in 1918.¹⁶

There are other publications that predate those two. Little published in England in 1901¹⁷ and Marchand in Germany in 1880.¹⁸ The condition is occasionally referred to as the Marchand-Waterhouse-Friderichsen syndrome.