Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians, but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please email us at ccsuggestions@medscape.com with the subject line "Case Challenge Suggestion." We look forward to hearing from you.
Background
A 30-year-old woman presents to the emergency department with malaise, diffuse myalgia, and a diffuse rash. A rash similar to this patient's rash is shown in Figure 1.
Figure 1.
Her symptoms began the day before presentation and initially improved with ibuprofen before worsening today. Her boyfriend, who has accompanied her to the emergency department, adds that she has been vomiting and has had intermittent confusion during the night.
She also complains of a diffuse headache that worsens with movement, but she denies photophobia, fever, abdominal pain, hematemesis, or diarrhea. She has not had any urinary symptoms or low back pain. She also denies having a cough or shortness of breath.
The patient's medical history is remarkable only for a major trauma that occurred 3 months ago when she was hit by a car crossing the street. She suffered multiple rib fractures as well as intra-abdominal injuries requiring a laparotomy, but she does not know the specifics of her surgery. She does not have any chronic medical conditions and does not take any regular medications. She smokes cigarettes but denies heavy alcohol use or illicit drug use.
Physical Examination and Workup
Upon physical examination, the patient appears drowsy and uncomfortable. Her oral temperature is 100.9°F (38.3°C). She is tachycardic and hypotensive, with a heart rate of 120 beats/min and blood pressure of 80/60 mm Hg. Her respiratory rate and oxygen saturation are normal (16 breaths/min and 99% on room air, respectively). She grimaces in pain with movement of her joints — particularly with neck movement, which is limited. Her pupils are 3 mm and equally reactive. Her neurologic examination findings, including cranial nerves, are normal (examination somewhat limited by drowsy mental status).
The patient has a nonpainful purpuric rash on her arms, trunk, and face consisting of patchy macules and patches approximately 1-4 cm in diameter.
No cervical, axillary, or inguinal lymphadenopathy is noted. Her lungs are clear, and her heart sounds are normal, without any murmurs or gallops. She has a soft and nontender abdomen, with no splenomegaly. No midline spinal tenderness or costovertebral angle tenderness is detected. No evidence suggests a septic joint, and no extremity swelling is noted. The remainder of the examination is unremarkable.
Laboratory studies show an elevated WBC count of 17.6 × 103 cells/µL, hemoglobin level of 13.6 g/dL (reference range, 12-15.5 g/dL), and platelet count of 54 × 103 cells/µL (reference range, 15-40 × 103 cells/µL). Her creatinine level is 3.3 mg/dL (reference range, 0.74-1.35 mg/dL), and her blood urea nitrogen level is 57 mg/dL (reference range, 10-20 mg/dL). Electrolyte concentrations and hepatic studies are normal.
The patient's myoglobin and creatine kinase concentrations are elevated, at 332 µg/L and 149 U/L, respectively. The C-reactive protein level is high, at 22 mg/dL. The partial thromboplastin time is elevated at > 120 seconds, and the international normalized ratio is 2.14. The D-dimer value is markedly elevated, at > 10 µg/mL. A serum pregnancy test is negative.
Arterial blood gas analysis shows a pH of 7.3 (reference range, 7.35-7.45), lactate level of 64.9 mg/dL (reference range, 4.5-19.8 mg/dL), partial pressure of carbon dioxide of 35.4 mm Hg (reference range, 35-45 mm/Hg), partial pressure of oxygen of 318 mm Hg (reference range, 75-100 mm Hg), and oxygen saturation of 99.3% (reference range, ≥ 95%) while using an oxygen mask at 10 L/min. Blood is drawn for culture and sent to the laboratory.
Discussion
Waterhouse-Friderichsen syndrome is bilateral adrenal hemorrhage and disseminated intravascular coagulation (DIC), usually secondary to a severe case 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 a broad range of infections, from an asymptomatic carrier state to septic shock.
N meningitidis 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.
The reason why some people who carry invasive strains of the bacteria become ill whereas others do not is unclear. 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 for 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 anatomical or functional asplenia predispose patients to N meningitidis infection, with a relative risk of 500 in asplenic patients, which may be particularly relevant in this patient who had a laparotomy 3 months ago, which, in retrospect, likely included a splenectomy. 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.[1,2,3,4,5]
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 to have symptoms of a respiratory illness, followed by fever, headache, and vomiting; this may then rapidly progress to the development of mental status changes (such as lethargy or confusion).
Meningeal infection probably results from hematogenous spread; 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.
Waterhouse-Friderichsen syndrome is a severe complication of N meningitidis infection. N meningitidis is a gram-negative aerobic diplococcus with a particular affinity for the bloodstream and meninges. Infection may cause clinical conditions ranging from fever and malaise to life-threatening septic shock. N meningitidis 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. The reason why some people who carry invasive strains of the bacteria become ill whereas others do not is unclear. N meningitidis spreads through the inhalation of respiratory secretions transmitted by a carrier.
Manifestations
The mortality rate of meningococcal sepsis is very high; it is even more lethal than isolated meningococcal meningitis. Waterhouse-Friderichsen syndrome is one 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] There is often also a petechial to purpuric rash that usually first appears on the trunk and lower extremities and subsequently spreads. The development of purpura fulminans (PF) — a life-threatening hemorrhagic condition characterized by hypotension, DIC, and purpura — indicates an extremely poor prognosis (Figure 2).
Figure 2. Purpura fulminans illustration.
Although the presence of PF is classic for meningococcal infection, multiple other 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, most PF cases are caused by coagulation abnormalities.
Meningococcal infection can instead sometimes only cause focal disease, such as conjunctivitis, septic arthritis, urethritis, purulent pericarditis, or respiratory tract infection (eg, pneumonia, epiglottitis, and otitis media).[2]
Diagnostic Testing
In order to optimize the clinical outcome, 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/or sepsis. 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, although the results are not typically available for 12-24 hours. When meningitis is a consideration, a lumbar puncture should be performed early in the course of treatment, but it should not delay the administration of antibiotics.
The presence of meningitis is identified by CSF 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 meningococcal bacteria 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. Polymerase chain reaction 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]
Lumbar puncture should be performed early, but it should not delay the administration of antibiotics. Meningitis is identified by leukocytosis with polymorphonuclear predominance, an elevated protein concentration, and a low glucose concentration. Waterhouse-Friderichsen syndrome diagnosis is based on clinical features that include fever, purpuric rash, altered mental status, meningeal signs, hypotension, and septic shock.
Treatment
The most important therapeutic point for meningococcal infection is early administration of appropriate antibiotics. Empirical antibiotics should be administered whenever meningococcal infection is suspected because delays in therapy expose patients to risk for severe illness, permanent disability, or death.
Common antimicrobial agents are active against Neisseria species. Penicillin G is usually the first-line antibiotic therapy; 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 all sepsis cases because 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 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 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 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 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]
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 all sepsis cases because antibiotic treatment can later be changed once a specific organism is identified.
The most important therapeutic point for meningococcal infection is early administration of appropriate antibiotics. Empirical antibiotics should be administered whenever meningococcal infection is suspected because delays in therapy expose patients to a risk for severe illness, permanent disability, or death.
Close Contact Prophylaxis
All persons who have been in close contact with a patient with meningococcal infection are at elevated risk of contracting the disease. Meningococci are spread via respiratory secretions, and they are 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 after the onset of disease. The risk for 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, because 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 for prophylaxis.[6] Azithromycin can be used in areas with ciprofloxacin-resistant strains.[6] The duration of chemoprophylaxis should be 1-2 days, depending on the antibiotic used. Ciprofloxacin, ceftriaxone, and azithromycin require single-dose treatment, and rifampin may be given twice daily for four doses.[1,3,5,6]
Several vaccines are available for controlling outbreaks of N meningitidis infection. The quadrivalent polysaccharide vaccine (Menomune) was the first meningococcal vaccine approved by the US Food and Drug Administration for serogroups A, C, Y, and W-135; however, this vaccine has largely been replaced by two quadrivalent conjugate vaccines (Menactra, Menveo) for most populations. Two meningococcal vaccines for serogroup B are also available in the United States (Bexsero, Trumenba).
Routine vaccination with Menactra or Menveo is recommended for young adolescents beginning at age 11-12 years, with a booster dose at age 16-23 years.[6] Serogroup B vaccines are not recommended for routine vaccination by the US Centers for Disease Control and Prevention, but adolescents and young adults may receive Trumenba (three doses) or Bexsero (two doses) at age 16-23 years.[7,8]
For outbreak situations, meningococcal vaccines A/C/Y and W-135 plus serogroup B administration are recommended in the presence of at least three cases during 3 months or less, or when 10 cases occur per 100,000 people in larger communities. These vaccines are also recommended for high-risk individuals (eg, complement deficiencies, asplenia, microbiologists routinely exposed).[7,9,10]
Chemoprophylaxis should be given as soon as possible, owing to the significantly reduced effectiveness if not started within 10-14 days of exposure. Meningococci are easily transmitted to close contacts via respiratory secretions. Prophylactic treatment should be administered to all individuals who have been in close proximity to an infected patient for more than 8 hours or who have had direct contact with a patient's secretions within 1 week before the onset of symptoms. Rifampin, ciprofloxacin, or ceftriaxone are all effective for prophylaxis, along with azithromycin, which can be used in geographic areas of ciprofloxacin resistance. Depending on the agent chosen, the duration of chemoprophylaxis should be 1-2 days (ie, ciprofloxacin, ceftriaxone, and azithromycin: single dose; rifampin: twice daily for four doses). Waiting for the results of tissue cultures can cause an undue delay in prophylactic treatment; cultures of oropharyngeal or nasopharyngeal tissue are not useful for determining whether or not antibiotics are necessary.
Progression and Outcome
The patient in this case was admitted to the intensive care unit after early initiation of intravenous ceftriaxone. The patient's blood cultures grew N meningitidis serogroup C. 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. A hemorrhagic rash due to meningococcal septicemia similar to this patient's rash is shown in Figure 3.
Figure 3. Legs of a patient showing meningococcal septicemia, a rash associated with severe meningitis, or meningococcemia.
Aggressive fluid therapy, vasopressor support, fresh frozen plasma, and activated protein C therapy were given. The patient required mechanical ventilation after developing acute respiratory failure. Renal failure soon followed, and dialysis was initiated. Her hands and feet became increasingly cyanotic.
Despite aggressive therapy, multiple organ dysfunction and DIC progressed; the patient died 4 days after admission. The postmortem 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. It also revealed that the patient was asplenic, likely from her surgery 3 months earlier following major trauma.
