Waterhouse-Friderichsen Syndrome

Synonyms: Purpura fulminans, originally called adrenal apoplexy.

The Waterhouse-Friderichsen syndrome (WFS) is a severe complication of meningococcal infection.Neisseria meningitides causes both meningitis and septicaemia: the associated septicaemia has an even higher mortality than the meningitis, although they often co-exist. Together they are devastating, even where diagnosis and treatment is prompt.

Some authors regard the WFS as the complications of meningococcal septicaemia (i.e. purpuric rash, disseminated intravascular coagulation or DIC and shock) but others view it more specifically as haemorrhage into the adrenal glands. Adrenal hormones - cortisol and aldosterone - are required to maintain vascular tone and extracellular fluid volume. Hence acute adrenal failure, especially under the stress of acute illness when the adrenal glands would normally be extremely active, causes a sudden Addisonian crisis with catastrophic circulatory collapse.

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 streptococcal infections and the postmortem findings of adrenal haemorrhage are not pathognomonic of meningococcal infection.²

Approximately 10-17% children with septic shock associated with meningococcal infection show signs of adrenal insufficiency and these children also tended to have a more severe disease presentation than those without adrenal suppression.³ There are no available figures as to what proportion of fatalities suffered from the WFS, but it does appear to be quite common in those who die suddenly of the infection.⁴ Meningococcal infection is more commonly seen in children than adults and in those without a functional spleen.

Initial presenting complaints are diverse and nonspecific, including:

• Cough
• Dizziness
• Headache
• Sore throat
• Chills
• Rigors
• Weakness and malaise
• Restlessness and apprehension
• Myalgia and arthralgia
• Fever

About 50-75% of meningococcal infection presents with the classical purpuric rash that spreads very rapidly. The rash is not due to meningitis but to septicaemia and is part of the Waterhouse-Friderichsen syndrome.

• Extensive haemorrhage into the skin
• Hypotension
• Shock
• Confusion
• Coma
• Death (within a few hours of the onset of symptoms)
• DIC

These may occur with or without haemorrhage into adrenal glands. Without prompt treatment, the 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 (LP) - current guidelines⁶ advise a cautious approach to LP in children with meningococcal disease because of the risk of cardiovascular decompensation in shocked individuals, the possibility of DIC and of neurological deterioration in patients with severe meningococcal meningitis with unrecognised raised intracranial pressure.
  In those patients with a purpuric rash (rare except with meningococcus), the results of the LP are unlikely to significantly influence management.
• Microbiology - community-based doctors sometimes worry that giving antibiotics prior to LP or blood culture will reduce the rate of culture in equivocal cases. However, this pay-off is accepted as disease progression can be so rapid and early treatment so critical. Increasingly polymerase chain reaction-based tests will enable diagnosis irrespective of early treatment.
• Blood tests - FBC, inflammatory markers, coagulation screen, U&Es.
• Radiology - It may be possible to detect adrenal haemorrhage by ultrasound whilst the child is still alive and hence to influence management.⁷

• Where meningococcal septicaemia or WFS is suspected, arrange urgent transfer to hospital - this is the key priority in the community.
• Antibiotics should be given as soon as possible^9,10 usually while arranging transport to hospital (see below).
• Where a patient is unconscious, support their airway. Oxygen should be used, particularly when the respiratory rate is raised.
• Venous access should be established as soon as possible. Where hypovolaemia is suspected, give iv fluids but do not delay antibiotic therapy or transport to hospital doing so. 4.5% human albumin solution is the fluid recommended for volume resuscitation in meningococcal disease but is unlikely to be available rapidly in primary care and crystalloid or alternative colloid fluids may be used in its place.⁶

Acute hospital management usually consists of antibiotic administration, volume resuscitation, ventilatory and inotrope support in an intensive care setting.

Antibiotics

• Parenteral antibiotics should be given at the earliest opportunity.^9,10 The evidence on effectiveness of pre-hospital antibiotics is inconclusive - there has been no prospective trial of immediate pre-hospital or delayed treatment undertaken In retrospective studies, giving early antibiotic is actually associated with increased case fatality rates, possibly because disease severity is an important confounding factor,^11,12 but current guidance (SIGN,⁵ NICE¹³) is in line with this recommendation.
• Antibiotics can be administered iv, im or po. Give im antibiotics as proximally as possible, into a part of the limb that is still warm.
• Benzylpenicillin has been recommended since 1988 as first-line treatment and guidance continues to recommend that all GPs should carry it and inject it unless there is a history of immediate allergic reaction after previous penicillin exposure. GPs do not need to carry alternative antibiotics,¹⁴ but third generation cephalosporins (e.g. cefotaxime) and chloramphenicol are recommended alternatives. Penicillin allergy is reported in around 14% of people but serious consequences occur in just over 1%.¹⁵ The risk of fatal anaphylactic shock seems tiny,¹⁶ especially compared with the devastating consequences of not treating this disease.

Steroids

• Meningococcal infection carries a significant mortality and morbidity and much of this may be due to associated WFS. The diagnosis of adrenal haemorrhage is very difficult except at post-mortem. This has led to the suggestion that prophylactic steroid use is a rational treatment with the potential to save lives.³ Others resist, arguing these drugs have potential for significant harm as well as benefit.
• A Cochrane review has shown benefit from steroids in acute bacterial meningitis (all causes) in adults and children, reducing mortality rates, severe hearing loss and neurological sequelae.¹⁷
• For meningococcal meningitis there is more limited data but a trend towards a reduction in mortality for patients treated with steroids, similar to that seen with haemophilus and pneumococcal meningitis.
• Evidence for the use of corticosteroids in meningococcal septicaemia remains limited. High-dose steroids should be avoided in septic shock, but impaired adrenal gland responsiveness and diminished glucocorticoid production are often present in both adults and children with refractory septic shock and their condition may be improved by low-dose, replacement hydrocortisone and results of current trials are awaited.¹⁸

Surgical

• Full-thickness skin and soft-tissue necrosis can be extensive with purpura fulminans, requiring skin grafting and amputations in about 90% of affected patients. 25% of patients in one series required amputations of all extremities.¹⁹
• Fasciotomies performed early may limit the level of amputation in some patients.²⁰

Much of the damage would seem to be due to disseminated intravascular coagulation (DIC). Early treatment and appropriate management is important.²¹

Meningococcal disease may progress very rapidly and has a mortality of up to 50% in the most severely ill cases. Early recognition, aggressive resuscitation, specialist advice and transfer to ICU can reduce this mortality to less than 5%.⁸ Overall, case mortality rates for meningococcal meningitis are around 3-6% under 15 years old, being slightly higher in those under one year old. It rises a little between 15-25 and over 25, the mortality rate is around 15%.²²It 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 rate associated 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.²³ 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 1918.²⁴
• There are other publications that predate those two. Little published in England in 1901²⁵ and Marchand in Germany in 1880.²⁶ The condition is occasionally referred to as the Marchand-Waterhouse-Friderichsen syndrome.