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A 30-Year-Old Woman With Fever and a Rash

  • Authors: Andrea Bianchin, MD; Moreno Agostini, MD
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This activity is intended for clinicians in primary care, emergency care, and infectious diseases.

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  1. Describe the typical presentation and management of a commonly encountered medical condition in clinical practice.


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  • Andrea Bianchin, MD

    Andrea Bianchin, MD, Intensive Care Unit (Anestesia e Rianimazione), Presidio Ospedaliero di Montebelluna, Azienda U.LSS. n.8 di Asolo, Montebelluna (TV), Italy


    Disclosure: Andrea Bianchin, MD, has disclosed no relevant financial relationships.

  • Moreno Agostini, MD

    Moreno Agostini, MD, Director, Intensive Care Unit (Anestesia e Rianimazione), Presidio Ospedaliero di Montebelluna, Azienda U.LSS. n.8 di Asolo, Montebelluna (TV), Italy


    Disclosure: Moreno Agostini, MD, has disclosed no relevant financial relationships.


  • Laurie E. Scudder, MS, NP-C

    Nurse Planner, Medscape; Adjunct Assistant Professor, School of Health Sciences, George Washington University, Washington, DC;  Curriculum Coordinator, Nurse Practitioner Alternatives, Inc., Ellicott City; Nurse Practitioner,  Baltimore City School-Based Health Centers, Baltimore, Maryland


    Disclosure: Laurie E. Scudder, MS, NP-C, has disclosed that she has no relevant financial relationships.


  • Rick G. Kulkarni, MD, FACEP

    Rick G. Kulkarni, MD, FACEP, Assistant Professor, Yale School of Medicine, Section of Emergency Medicine, Department of Surgery, Attending Physician, Medical Director, Department of Emergency Services, Yale-New Haven Hospital, CT


    Disclosure: Rick G. Kulkarni, MD, FACEP, has disclosed no relevant financial relationships.

  • Erik D. Schraga, MD

    Erik D. Schraga, MD, Clinical Instructor of Emergency Medicine, Stanford/Kaiser Emergency Medicine Residency Program, Department of Emergency Medicine, Kaiser Permanente, Santa Clara Medical Center, Santa Clara, CA


    Disclosure: Erik D. Schraga, MD, has disclosed no relevant financial relationships.

  • Michael S. Bronze, MD

    Michael S. Bronze, MD, Stewart Wolf Professor, Chairman of the Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK


    Disclosure: Michael S. Bronze, MD, has disclosed no financial relationships.

  • Luis M. Soler, BA

    Luis M. Soler, BA, Associate Editor, eMedicine/WebMD, New York, NY


    Disclosure: Luis M. Soler, BA, has disclosed no relevant financial relationships.

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A 30-Year-Old Woman With Fever and a Rash



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Waterhouse-Friderichsen syndrome is a severe complication of Neisseria meningitidis infection. N meningitidis is a gram-negative aerobic diplococcus with a particular affinity for the bloodstream and meninges. Infection with N meningitidis may cause clinical conditions ranging from fever and bacteremia to life-threatening septic shock. It is a commensal bacterium in many humans that resides in the nasopharynx and colonizes up to 25% of healthy people, without causing illness. It is transmitted by aerosolized respiratory particles and secretions. It is not known why some people who carry invasive strains of the bacteria become ill while others do not. A particular virulence factor may be a cause, but is not fully understood. Crowded living conditions, such as college dormitories and military barracks, increase the risk of transmission. Other risk factors include smoking and upper respiratory tract infection, as well as systemic diseases such as multiple myeloma, nephrotic syndrome, or systemic lupus erythematosus. Immune defects, deficiency of humoral immunity or the complement-mediated immune system, and anatomic or functional asplenia predispose patients to N meningitidis infection, with a relative risk of 500 in asplenic patients. Outbreaks of N meningitidis infection appear to be seasonal, occurring most often in spring and winter. The yearly incidence of the disease is about 1 case per 100,000 people.[1,2,4,5]

N meningitidis spreads through the inhalation of respiratory secretions transmitted by a carrier. The onset of symptoms occurs approximately 3-4 days after inoculation. The patient typically begins having symptoms of a respiratory illness, followed by fever, headache, and vomiting; this rapidly progresses to the development of mental status changes (such as lethargy or confusion). Meningeal infection likely results from hematogenous spread, as N meningitidis can be isolated via blood cultures in approximately 75% of patients. Meningococcal sepsis with multisystem involvement, however, occurs in only one fifth of cases of meningitis caused by N meningitidis. The mortality rate of meningococcal sepsis is very high; it is even more lethal than isolated meningococcal meningitis. Waterhouse-Friderichsen syndrome is 1 of the most severe complications of meningococcal infection. Although often classified by the presence of multiorgan dysfunction in the presence of meningococcal infection, the syndrome is, typically, more specifically defined by the presence of hemorrhage into the adrenal glands.[2,3,4]

A typical purpuric rash may be seen as a result of septicemia. This usually first appears on the trunk and lower extremities and subsequently spreads throughout the body surface. The development of purpura fulminans (PF), a life-threatening hemorrhagic condition characterized by hypotension, disseminated intravascular coagulation (DIC), and purpura, indicates a poor prognosis. Although the presence of purpura fulminans is classic for meningococcal infection, multiple causes may be responsible and should also be considered. Three general categories of PF are recognized: acute infectious PF, idiopathic PF, and abnormalities of the coagulation system. In fact, the majority of PF cases are caused by coagulation abnormalities. Occasionally, meningococcal infection causes only focal disease, such as conjunctivitis, septic arthritis, urethritis, purulent pericarditis, or respiratory tract infection (eg, pneumonia, epiglottitis, and otitis media).[2]

The diagnosis of Waterhouse-Friderichsen syndrome (or of meningococcal sepsis in general) must be made early and should be based on the clinical features of fever, purpuric rash, altered mental status, meningeal signs, hypotension, and septic shock. Specific testing should be used for confirmation and for guiding subsequent treatment, but it should not delay the initiation of therapy. An effort should be made to obtain blood cultures before administering antibiotics to the patient. The results are not typically available for 12-24 hours; however, they may guide subsequent therapy. A lumbar puncture should be performed early in the course of treatment, but it should not delay the administration of antibiotics. Cerebrospinal fluid (CSF) analysis should include a cell count and differential, culture, Gram stain, and protein and glucose concentrations. The presence of meningitis is identified by leukocytosis with polymorphonuclear predominance, an elevated protein concentration, and a low glucose concentration. Gram stains are often negative in meningitis. Cultures may also be obtained from synovial, pleural, or pericardial fluid, if appropriate. Methods for identifying meningococcus other than culture are available, such as antigen detection from biological fluids. This method is rapid and can provide an exact identification of the serogroup, but it commonly produces false-negative results. A polymerase chain reaction (PCR) can also identify specific serogroups and does not require the presence of a live organism.[4]

Without prompt treatment, the mortality rate of Waterhouse-Friderichsen syndrome approaches 100%. Even with rapid and optimal medical therapy, approximately 40% of patients with meningococcal sepsis do not survive. When DIC is present, the mortality rate is as high as 90%. The overall mortality of meningococcal disease is 10-20%, with the same percentage of survivors having permanent neurologic sequelae (ie, neurologic disability, loss of a limb, and hearing impairment).[4,5]

The most important therapeutic point for meningococcal infection is early administration of appropriate antibiotics. Empiric antibiotics should be administered whenever there is any suspicion of meningococcal infection because delays in therapy expose patients to a risk of severe illness, permanent disability, or death. Common antimicrobial agents are active against Neisseria species. Penicillin G is usually the first-line antibiotic therapy, and it has a low prevalence of resistance. In areas where penicillin-resistant strains have been identified, such as the United Kingdom or Spain, a third-generation cephalosporin can be used instead. Initial treatment with broad-spectrum antibiotics is recommended in any septic patient, as antibiotic treatment can later be changed once a specific organism is identified. Early goal-directed therapy should be initiated, with a particular focus on fluid administration and maintenance of an adequate blood pressure. The efficacy of corticosteroid treatment is controversial, but it is typically recommended in cases of sepsis and meningitis. Debridement of skin and subcutaneous tissues, with subsequent skin grafting and/or limb amputation, may be necessary if septicemia results in peripheral hypoperfusion with skin and bone necrosis. In cases of fulminant meningococcemia, patients should be immediately transferred to an intensive care unit (ICU) for aggressive fluid therapy, vasopressor support, and intensive hemodynamic monitoring. Activated protein C may be of use in a very limited number of patients. Treatment of DIC includes the administration of fresh frozen plasma. Additional treatments currently under investigation include monoclonal antibodies to inflammatory mediators, such as endotoxins, tumor necrosis factor, interleukins, and interferon-gamma.[4,5]

All persons who have been in close contact with a patient with meningococcal infection are at an elevated risk for contracting the disease. The spread of meningococci occurs via respiratory secretions, and it is quite easily transmitted to close contacts. For this reason, all household members, classmates, medical staff, or anyone else recently associated with the patient must be considered at risk for acquiring the disease. The probability of transmission varies with the duration and closeness of exposure; it is highest during the first few days following the onset of disease. The risk of transmission is higher with actions that result in direct exposure of secretions to mucous membranes, including kissing; mouth-to-mouth resuscitation; and sharing of food, glasses, bottles, or cigarettes. People who have stayed more than 8 hours in close proximity to an infected patient or who have had direct contact with a patient's secretions within 1 week before the onset of symptoms should receive prophylactic treatment. Chemoprophylaxis should be given as soon as possible, as the efficacy of prophylaxis is very low if antibiotics are not started within 10-14 days after exposure. Cultures of oropharyngeal or nasopharyngeal tissue are not useful for determining whether or not antibiotics are necessary, and waiting for the results of these examinations can cause an inappropriate delay in the administration of prophylactic treatment. Rifampin, ciprofloxacin, or ceftriaxone are all effective choices. The duration of chemoprophylaxis should be 1-2 days, depending on the antibiotic used. Ciprofloxacin and ceftriaxone require a single dose treatment, and rifampin may be given twice daily for 4 doses.[1,3,5]

A vaccine is available for controlling outbreaks of N meningitidis. The quadrivalent polysaccharide vaccine is protective against all serogoups except B, and its administration is recommended in the presence of at least 3 cases during 3 months or less, or when 10 cases occur per 100,000 people in larger communities. Routine vaccination is not recommended and is not cost-effective.[3,5]

The patient in this case was admitted to the ICU after early initiation of intravenous ceftriaxone. The patient's blood cultures grew serogroup C N meningitidis. A few hours after admission, petechial lesions appeared and rapidly spread throughout her trunk, legs, back, and face. The lesions became progressively larger and hemorrhagic (see Figures 3 and 4). Aggressive fluid therapy, vasopressor support, fresh frozen plasma, and activated protein C therapy were given. She required mechanical ventilation after developing acute respiratory failure. Renal failure soon followed and dialysis was initiated. Her hands and feet became increasingly cyanotic (see Figure 5). Despite aggressive therapy, multiple organ dysfunction and DIC progressed; the patient died 4 days after admission. The post-mortem examination confirmed meningococcal sepsis and revealed acute purulent meningitis, adrenal apoplexy, thrombotic microangiopathy, purpura confluens, and epidermolysis bullosa; these findings are consistent with a diagnosis of Waterhouse-Friderichsen syndrome.