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Waterhouse Friderichsen Syndrome

Waterhouse-Friderichsen Syndrome

Waterhouse-Friderichsen syndrome, also known as hemorrhagic adrenalitis, is a condition that describes acute adrenal failure, caused by hemorrhage within the adrenal glands after a severe bacterial infection, in particular meningococcal disease. The condition is most frequently seen in children younger than 10 years old.


Presentation

The onset of meningococcal Waterhouse-Friderichsen syndrome is characterized by non-specific signs and symptoms such as fatigue, tremor, fever, sweating, diarrhea, vomitingheadache, muscle pain and abdominal pain [9]. These symptoms ultimately progress into massive organ failure, coma, shock, low blood pressure and sepsis [10].

A characteristic macular rash develops early in the disease process and resembles the spots seen in typhoid fever. The rash later becomes petechial and purpuric and has a dusky gray color. Other distinguishing features include atrophy of the tongue, dysphagia and cracks around the corners of the mouth of the patient. Unlike other forms of meningococcal disease, meningitis is not a feature of WFS. 

As the patient deteriorates, heart rate increases and the development of low blood pressure signals the progression into septic shock. Peripheral cyanosis becomes prominent as the individual becomes confused and might fall into coma [11]. Metabolic abnormalities include hypoglycemia, hyperkalemia, hyponatremia and acidosis, alongside acute renal failure in cases of severe sepsis. Hematologic disturbances are characterized either by leukocytosis or leukopenia (a very negative prognostic factor), severe thrombocytopenia, as well as changes in prothrombin time and partial thromboplastin time, suggesting diffuse intravascular coagulation or DIC. C-reactive protein levels can be normal or elevated. Blood or CSF cultures may be positive for meningococci which can also be isolated from smears of cutaneous lesions. 

Fever
  • Tick-borne Rickettsia rickettsii Rocky Mountain spotted fever Rickettsia conorii Boutonneuse fever Rickettsia japonica Japanese spotted fever Rickettsia sibirica North Asian tick typhus Rickettsia australis Queensland tick typhus Rickettsia honei Flinders[en.wikipedia.org]
  • We describe a 20-year-old man who presented with a 1-day history of fever, chills, malaise, and vomiting. He collapsed in the emergency room, requiring mechanical ventilation and intravenous vasopressors for resuscitation.[ncbi.nlm.nih.gov]
  • The patient presented with neck pain and fevers of 2 days' duration. Computed tomography of the neck revealed a mass in the retropharyngeal space, suggesting an abscess.[ncbi.nlm.nih.gov]
  • Though the meningococci of cerebrospinal fever are the typical pathogens involved, other organisms, such as streptococci and pneumococci, may be involved.[britannica.com]
  • We underline that when a patient presents fever and petechiae (50-60% of patients), WFS must be considered, even when the patient has a non-toxic appearance.[ncbi.nlm.nih.gov]
Pleural Effusion
  • On evaluation, she had severe pneumonia with pleural effusion, hepatic dysfunction, thrombocytopenia, and coagulopathy. She died eight hours after arriving in the emergency department. Cultures of antemortem blood and pleural fluid yielded MSSA.[doi.org]
Painful Cough
  • They include headaches, chills, weakness, malaise, restlessness, fever, joint pain, muscle pain, cough, dizziness and rigors.[symptoma.com]
Epigastric Pain
  • The patient presented with a six hour history of sudden onset epigastric pain, vomiting, chills, and rigors. A presumptive diagnosis of cholangitis with septicaemic shock was made.[ncbi.nlm.nih.gov]
Liver Dysfunction
  • Abstract Pasteurella multocida is an opportunistic pathogen causing bacteraemia in patients with liver dysfunction.[ncbi.nlm.nih.gov]
Hypotension
  • Ratio Low Tissue Perfusion 267 Mitochondrial Antioxidant Activity and Disease Processes 278 A Possible Role for Iron Ions in Organ Injury 302 Optimizing Red Blood Cell Transfusion Practice 309 Augmented Acute Normovolemic Hemodilution 319 Permissive Hypotension[books.google.com]
  • A 59 year old women presented to the accident and emergency department with tachycardia and hypotension following a one day history of feeling unwell. She was peripherally shutdown, cyanosed, hypoxic, had a purpuric rash and numbness to her fingers.[endocrine-abstracts.org]
  • Upon arrival even with persistent hypotension despite double scheme amines (dopamine, norepinephrine) and fluid resuscitation, also high ventilatory requirements with data from acute lung injury, in frank anuria and acute renal injury, severe metabolic[omicsonline.org]
  • […] also H influenzae, S pneumoniae, staphylococci, less commonly, linked to hypoxia during a difficult L&D, acute adrenal insufficiency Epidemiology Most common in hot, dry climates, especially in West Africa Clinical Generalized purpuric rash, shock, hypotension[medical-dictionary.thefreedictionary.com]
  • All three had rapidly progressive clinical deterioration with leukopenia, neutropenia, severe metabolic acidosis, profound tachycardia, and secondary hypotension during their brief clinical illnesses.[doi.org]
Desquamating Rash
  • Panel A shows the petechial and desquamating rash in Patient 3, and Panel B the petechial rash in Patient 1. Panel C shows a cross-section of an adrenal gland in Patient 3 with gross hemorrhage throughout.[doi.org]
Neck Pain
  • The patient presented with neck pain and fevers of 2 days' duration. Computed tomography of the neck revealed a mass in the retropharyngeal space, suggesting an abscess.[ncbi.nlm.nih.gov]
Tremor
  • The onset of meningococcal Waterhouse-Friderichsen syndrome is characterized by non-specific signs and symptoms such as fatigue, tremor, fever, sweating, diarrhea, vomiting, headache, muscle pain and abdominal pain.[symptoma.com]

Workup

Diagnostic workup is broad, although the increasing incidence of the condition has prompted the establishment of more uniform criteria to assure proper diagnosis. The three cardinal criteria are defined by positive blood cultures for meningococci or the occasional isolation of the organisms from peripheral blood smears, specific gravity fixation on urinalysis and renal failure demonstrated by the elevation of creatinine serum levels and blood urea nitrogen [12]. Other important diagnostic markers are the following: severe shock, hypernatremia, significant oliguria, anuria for 24 to 36 hours, albuminuria, hypokalemia,  hematuria or cylindruria, significant leukocytosis, petechial rash developing into a purpuric rash and facial swelling.

Diagnosis of WFS is not limited to any particular factor of those mentioned above. In acute, rapidly progressing cases, clinical signs are sufficient to diagnose the disease. Suspected chronic cases necessitate the consideration of additional factors for conclusive diagnosis, such as lab studies and the culture or isolation of meningococcal organisms. 

Pleural Effusion
  • On evaluation, she had severe pneumonia with pleural effusion, hepatic dysfunction, thrombocytopenia, and coagulopathy. She died eight hours after arriving in the emergency department. Cultures of antemortem blood and pleural fluid yielded MSSA.[doi.org]

Treatment

WFS is an emergency condition and antibiotics need to be promptly administered. The most common antibiotic used today is ceftriaxone. Reversal of adrenal shock can sometimes be established with hydrocortisone, and widespread necrosis may necessitate plastic surgery or grafting [13].

Treatment of WFS is directed primarily to the resolution of shock, toxemia, bacteremia and adrenal insufficiency due to decreased adrenocortical hormone levels. The treatment of septic shock follows the usual process with cautious administration of 3000 to 4000 cc of parenteral fluids over a 24 hour period. Repeated administration of 500 cc of plasma every 12 hours is also recommended due to its osmotic effect and the subsequent elevation in blood pressure. 

Toxemia results from the bacterial products of invasion and is majorly responsible for the pathophysiologic changes associated with the disease. It is generally countered with serotherapy, defined as the injection of antitoxin or a serum containing antibodies. Current treatment guidelines recommend the administration of 60,000 to 120,000 units of antimeningococcal serum in the initial 24 hours, although there is no clear evidence for its beneficial effects.

Chemotherapy has proven very useful in the control of meningococcemia. Sulfadiazine, a sulfonamide drug, is particularly effective. High parentral and oral doses are required to combat the massive bacteremia present in the disease. Initial doses of sulfadiazine consist of 5 gm injected parenterally and 8 gm taken orally, followed by large doses so that a total of 25 to 30 gm are given in the first 24 hours. Blood levels of sulfadiazine need to be monitored to adjust the dosage, with the aim of maintaining a blood level of 15 to 20 gm per 100 cc.

Prognosis

Bilateral adrenal hemorrhage carries a case fatality rate of 15% and prognosis is dependent on the nature of the underlying disease and its severity. In particular, Waterhouse-Friderichsen syndrome displays a mortality rate of 55% - 60% and prognosis worsens with any delay in diagnosis or treatment. Death in WFS is generally result of sepsis and occurs even after therapeutic or supportive treatment with antibiotics and glucocorticoid administration. Patients who later suffer chronic adrenal failure due to hemorrhage can recover, although such instances remain rare [8].

Etiology

Waterhouse-Friderichsen syndrome (WFS) results from a severe bacterial infection and is most commonly associated with a Neisseria meningitidis blood infection, the organism usually related to the occurrence of meningitis in adults and elderly populations. Other known bacterial causative agents include Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, Mycobacterium tuberculosis and various gram-negative organisms such as Pasteurella spp., Klebsiella spp., Escherichia coli and Haeomophilus influenzae  [3] [4]. The variant associated with tuberculosis is caused by tubercular hemorrhagic destruction of the adrenal glands and is particularly characterized by mineralocorticoid deficiency. WFS, however, is not exclusively caused by bacterial pathogens and can sometimes result from the intake of medications that promote blood clotting, such as steroids. Other disturbances, such as low platelet counts, primary antiphospholipid syndrome and renal vein thrombosis [5] can also cause WFS.

Meningococcal WFS is highly contagious when close contact is established between an affected and a non-affected individual. Contamination usually occurs after kissing an affected individual or through inhalation of large respiratory droplets.

Epidemiology

Waterhouse-Friderichsen syndrome is a rare condition that targets mostly children younger than 10 years old. The overall prevalence of adrenal hemorrhage is much more elevated and has been estimated to be around 15% in individuals who die of shock.

Patients affected by WFS are at a high risk of death due to, either the bacterial septicemia itself, or the complications of the adrenal hemorrhage, even after treatment with high stress doses of glucocorticoids. Mortality rate amongst the patients with adrenal hemorrhage is estimated to be around 15% and is dependent on the underlying disease. It can amount to up to 55% - 60% in patients with WFS [6].

Sex distribution
Age distribution

Pathophysiology

The sequence of events responsible for non-traumatic adrenal bleeding is still poorly understood, although current knowledge involves several factors that include the anatomy of the venous drainage of the adrenals (limited to a single draining vein), adrenal vein spasm, thrombosis and adrenocorticotropic hormone (ACTH) secretion related to a stress reaction.

Stress plays a central role in the pathophysiological process and it is thought that increased stress levels associated with any cause, but particularly infection, lead to an increase in ACTH secretion. This ultimately results in elevated blood perfusion to the adrenals, overwhelming the limited drainage capacity of the gland and leading to extensive hemorrhage. Stress also causes a release of catecholamines that results in spasms of the adrenal vein and subsequent venous stasis and hemorrhage. Venous stasis is exacerbated by coagulopathies that lead to thrombosis and may be directly caused by sepsis, primary antiphospholipid syndrome, disseminated intravascular coagulation (DIC) or heparin-induced thrombocytopenia [7].

Bilateral adrenal hemorrhage, regardless of the underlying process, leads to acute adrenal failure which can cause an adrenal crisis if not recognized early and treated adequately.

Prevention

Vaccination against meningococcus is the primary preventive strategy against Waterhouse-Friderichsen syndrome. Recommendations from the Center for Disease Control include routine vaccinations for all children and adolescents between 11 and 18 years of age as well as for individuals with certain immunodeficiencies or poor spleen function.

Summary

Waterhouse-Friderichsen Syndrome (WFS) is a rare disease targeting mostly children younger than 10 years old and manifests with acute adrenal failure, following hemorrhage into the adrenals and bacterial infection. Meningococcal infection is the most common cause, but other bacterial organisms are also involved. Presentation is characterized initially by widespread non-specific symptoms, although an elevated pruritic rash is very characteristic of the disease. Progression may lead to an acute adrenal crisis, shock and death, if adequate treatment is not provided [1] [2]. Diagnosis can be established clinically in acute cases, while chronic cases may necessitate the performance of a range of laboratory tests that demonstrate metabolic and hematologic abnormalities, such as hypoglycemia, hyponatremia, hyperkalemia, negative ACTH stimulation test, thrombocytopenia and hematologic changes indicative of diffuse intravascular coagulation. Ceftriaxone is the antibiotic of choice and needs to be administered promptly along with fluids and osmotic solutions to combat shock. Prognosis is poor, with mortality rates of up to 60%.

Patient Information

Waterhouse-Friderichsen syndrome (WFS) is a condition invloving extensive bleeding into the adrenal glands, which results in their functional failure. Bacterial infections are primarily responsible, particularly Nisseria meningitidis, although other organisms such as Group B streptococci, Pseudomonas aeruginosa, Streptococcus pneumoniae and Staphylococcus aureus have also been incriminated. Rare causes of WFS by factors that promote or inhibit blood clotting include medications, steroid use, low platelets, renal vein thrombosis and primary antiphospholipid syndrome.

Initial symptoms of WFS are fluctuating and non-specific. They include headaches, chills, weakness, malaise, restlessness, fever, joint pain, muscle pain, cough, dizziness and rigors. The symptoms can be very mild and non-troublesome to the patient, leading to a delayed diagnosis and ultimately a higher risk of death. A very characteristic feature of the disease is the pruritic rash caused by septicemia, which occurs in 50 to 75% of the patients. The development of a full blown blood infection and organ failure results in extensive hemorrhage into the skin, shock, confusion, coma, hypotension and ultimately death. Death can occur very rapidly, in a few hours after the onset of septicemia and the resulting hemorrhage into the adrenal glands.

Diagnosis of WFS may be established clinically in case it is acute but chronic variants are also dependent on characteristic laboratory results. Metabolic abnormalities include hypoglycemia, hyponatremia, hyperkalemia, acidosis and acute renal failure in severe sepsis. An increased number of white blood cells or a very diminished number of those can be present, alongside decreased platelets. Meningococcal organisms can be cultured from blood samples or detected from skin lesions.

WFS is an emergency and prompt administration of antibiotics is critical. The antibiotic of choice is ceftriaxone. Administration of fluids and plasma are also important to combat shock. The Center for Disease Control recommends vaccination against meningoccoci as the primary method of prevention.

References

Article

  1. Rao RH. Bilateral massive adrenal hemorrhage. Med Clin North Am. 1995; 79(1):107-29.
  2. Vella A, Nippoldt TB, Morris JC 3rd. Adrenal hemorrhage: a 25-year experience at the Mayo Clinic. Mayo Clin Proc. 2001 Feb; 76(2):161-8.
  3. Piccioli A, Chini G, Mannelli M, et al. Bilateral massive adrenal hemorrhage due to sepsis: report of two cases. J Endochrinol Invest 1994; 17:821–4.
  4. Adem PV, Montgomery CP, Husain AN, et al. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children. The New England journal of medicine. 2005 Sep 22; 353(12):1245-51.
  5. Arnason JA, Graziano FM. Adrenal insufficiency in the antiphospholipid antibody syndrome. Semin Arthritis Rheum. 1995 Oct; 25(2):109-16.
  6. Tormos LM, Schandl CA. The Significance of Adrenal Hemorrhage: Undiagnosed Waterhouse-Friderichsen Syndrome, A Case Series. J Forensic Sci. 2013 Mar 4.
  7. Ketha S, Smithedajkul P, Vella A, Pruthi R, Wysokinski W, McBane R. Adrenal haemorrhage due to heparin-induced thrombocytopenia. Thromb Haemost. 2013 Feb 7; 109(4).
  8. Jahangir-Hekmat M, Taylor HC, Levin H, et al. Adrenal insufficiency attributable to adrenal hemorrhage: long-term follow-up with reference to glucocorticoid and mineralocorticoid function and replacement. Endocr Pract. 2004 Jan-Feb; 10(1):55-61.
  9. Ip M, Teo JG, Cheng AF. Waterhouse-Friderichsen syndrome complicating primary biliary sepsis due to Pasteurella multocida in a patient with cirrhosis. J Clin Pathol. 1995 Aug; 48(8):775-7.
  10. Carey T. Adrenal hemorrhage with purpura and specticemia (Waterhouse Friderichsen syndrome). Ann Intern Med. 1940; 13(9):1740-1744.
  11. Friderichsen C. Waterhouse–Friderichsen syndrome (W.–F. S.). Acta Endocrinol1955; 18:482–92.
  12. Rucks W, and Hobson J. Purpura fulminans (Waterhouse-Friderichsen syndrome): report of case with recovery. J Pediat. 1943; 22:226–232.
  13. Nelson J, Goldstein N. Nature of Waterhouse-Friderichsen syndrome; report of case with successful treatment with cortisone. J Am Med Assoc. 1951 Jul 28; 146(13):1193–1197.

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Last updated: 2018-06-21 18:15