1. CLINICAL PRESENTATION
Dr. Juan Carlos Díaz Torre
DR. JCDT
Pediatra Neonatólogo
dr_diaz_torre@hotmail.com
( 779 ) 100 - 40 - 26
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2. Rash, Pain, and Dyspnea Progressing
to Respiratory Failure
A 68-year-old woman presents to the emergency
department (ED) complaining of progressive
shortness of breath, flank pain, fever, and
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weakness. A diffuse, pinkish rash that had started 6
hours before presentation is noted over her
extremities and trunk.
She has a history of diabetes and has been taking
glyburide irregularly, with poor glycemic control
documented by blood glucometer record. 2

3. About 10 days ago she noted a small ulcer on the
dorsum of her left foot that started to grow in
size, with associated low-grade fever and pain
along her left leg. Her primary doctor prescribed
her a course of amoxicillin, which she is currently
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taking.
She takes no other medications, does not smoke
tobacco, and does not use illicit drugs or alcohol.
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4. She reports no headache, neck
stiffness, nausea, vomiting, expectoration, chest
pain, cough, sore throat, abdominal
pain, changes in urine
color, melena, hematemesis, or bleeding.
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She has no medical allergies and has not
recently traveled outside her home country of
Cuba.
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5. On physical examination, the patient is a mildly
obese female who appears very ill and is in acute
distress. Pallor, mild cyanosis, poor capillary refill
(3-4 sec), and a weak, rapid radial pulse are noted.
She is conscious and is alert and oriented.
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She has a patent airway and her respiratory rate is
30 breaths/min with bilateral rales and diminished
air entry into both lung bases.
Normal S1 and S2 heart sounds are heard with no
discernible murmur.
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6. She is tachycardic with a heart rate of 122
beats/min. The pharyngeal examination shows no
erythema or exudate. The axillary temperature is
98.6°F (37°C). Her blood pressure is 85/50 mm Hg.
No jugular venous distension is noted.
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The abdominal examination is unremarkable;
examination of the stool is negative for occult
blood.
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7. Her skin appears plethoric and cool with a
diffuse, nonvesicular, nonpalpable, petechial, non-
blanching rash (see images).
A necrotic, crusted black eschar is observed on her
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left leg. The eschar is about 5 cm in diameter.
Neurologic examination is unremarkable and there
are no signs of meningismus.
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8. Laboratory studies are ordered; these include a
complete blood cell count with a hemoglobin of
14.4 g/dL (144 g/L); a hematocrit of 42% (0.42 L/L);
white cell count of 7 x 103 /µL (7 x 109 /L) with a
neutrophilic predominance of 79%; a platelet count
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of 250 × 103/µL (250 × 109/L); and a normal
peripheral smear.
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9. Her coagulation studies at admission are all
normal, but her creatinine is significantly elevated
at 3.2 mg/dL (285 µmol/L).
Arterial blood gas analysis (with supplemental
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oxygen) reveals a pH of 7.10, PaO2 of 80 mm
Hg, PaCO2 of 49 mm Hg, SaO2 of 90%, bicarbonate
of 13 mmol/L, and a base deficit of -15.2 mmol/L.
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10. A lumbar puncture is performed, which shows a
clear acellular cerebrospinal fluid with low
glucose 34.8 mg/dL (1.9 mmol/L) and a normal
protein level. The results of a urinalysis are
normal. She is hypoglycemic, with finger stick
glucose of 58.7 mg/dL (3.2 mmol/L).
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Electrolyte analysis demonstrates mild
hyperkalemia (5.7 mmol/L).
A chest radiograph shows changes consistent
with early adult respiratory distress syndrome
(ARDS). 10

11. The patient is treated in the ED with intravenous
(IV) crystalloid, IV steroids, vasopressor
support, and IV antibiotics.
Endotracheal intubation is performed due to
worsening hypoxic respiratory failure, and the
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patient is placed on a mechanical ventilator; the
patient is then transported to the intensive care
unit.
Gram stain and blood culture samples of the skin
lesions are obtained. 11

12. DR. JCDT
A purpuric petechial rash is seen
around the umbilical zone
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13. DR. JCDT
The rash is disseminated all over the
patient's skin, with a mild cyanotic tint.
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14. DR. JCDT
A closer view of the inguinal zone shows a
purpuric unblistered rash.
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15. What is the diagnosis?
.
Hint: Consider the patient's history, leg ulcer, and
described lesions.
- Henoch-Schönlein purpura
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- Anaphylactic shock secondary to amoxicillin
- Waterhouse-Friderichsen syndrome
- Toxic epidermal necrolysis
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16. Correct answer:
.
- Henoch-Schönlein purpura
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- Anaphylactic shock secondary to amoxicillin
- Waterhouse-Friderichsen syndrome ****
- Toxic epidermal necrolysis
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17. While in the ICU, the patient's shock progressed in
spite of high doses of vasopressors and stress
doses of glucocorticoids maintained through her
hospital course. Her blood coagulation profile was
compatible with disseminated intravascular
coagulation (DIC).
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Serum cortisol was not measured because
hydrocortisone was administered in the ED.
The Gram stain, skin lesion cultures, and
cerebrospinal fluid cultures were all negative.
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18. In this case, the diagnosis of Waterhouse-
Friderichsen syndrome (WFS) was made clinically
on the basis of the patient's history and
laboratory findings.
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Although hypoglycemia, hypotension, and
hyperkalemia could be associated with severe
sepsis, acidosis, and acute renal failure, some
clues suggested the WFS diagnosis, such as
hypotension that does not respond to
vasopressors (later confirmed in this case), skin
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rash, DIC, and the abrupt onset of shock.

19. The presence of shock, DIC, skin lesions, and
bilateral adrenal hemorrhage in the presence
of sepsis are specific criteria for WFS.
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Her history of poorly controlled diabetes, as
well as the leg ulcer, aroused suspicion for
bacterial infection through her skin ulcer.
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20. Blood cultures later revealed a widely susceptible
(gentamicin, amikacin, ciprofloxacin, norfloxacin,
meropenem, aztreonam, among others)
Pseudomonas aeruginosa infection.
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A CT scan of the abdomen was not performed
because of the progressive deterioration of the
patient's clinical condition.
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21. WFS was first described by the British physician
Rupert A. Waterhouse in 1911 as "a case of
suprarenal apoplexy" and by Carl Friderichsen, a
Danish pediatrician, in 1918, although previous
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cases had been reported in the few years
beforehand.
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22. WFS is generally associated with fulminant
meningococcemia (Neisseria
meningitides), although many other organisms have
been associated with WFS, including viruses such as
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cytomegalovirus and HIV, parvovirus B19, and
Epstein-Barr virus.
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23. Other organisms involved are bacteria such as
Staphylococcus aureus, Haemophilus
influenzae, Streptococcus
pneumoniae, Pseudomonas
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aeruginosa, Escherichia coli, and Mycobacterium
tuberculosis; and fungi such as Histoplasma
capsulatum (among others).
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24. Noninfectious etiologies include birth
trauma, pregnancy, idiopathic adrenal vein
thrombosis, bilateral metastatic adrenal
malignancies, seizures, anticoagulant
therapies, or following venography, trauma, and
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surgery.
Recently, antiphospholipid antibody syndrome
has been associated with adrenal hemorrhage
and infarction.
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25. Adrenal hemorrhage is a rare condition; only 10%
of patients with adrenal hemorrhage develop
glandular failure.
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More than 90% of both glands must be destroyed
before signs of adrenal insufficiency manifest;
however, adrenal failure that does develop from
adrenal hemorrhage is usually lethal.
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26. The fact that glucocorticoid replacement does not
always prevent death in patients with adrenal
hemorrhage or acute insufficiency suggests that
WFS is a consequence rather than a cause.
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Symptoms and signs may be diverse but are
typically sudden and unexpected, sometimes
without prior illness. Even with aggressive
therapy, many patients die in less than 24-36 hours.
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27. Early in the course of disease, the patient may
experience flank, epigastrium, and/or abdominal
pain.
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Complaints may include an acute onset of
symptoms commencing with chills, malaise, severe
headache, vertigo, vomiting, and prostration.
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28. Hours later, hypotension or collapse with
agitation, delusions, and extensive areas of
petechial-hemorrhagic rash appear in the
mucosae and skin that may become confluent and
form extensive purpuric areas ("flowers of
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death").
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29. Extensive subcutaneous confluent hemorrhage
known as "purpura fulminans" may also occur and
is caused by DIC.
This rash is present in more than 75% of patients
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and usually begins as a pink, maculopapular
eruption on the extremities; it also develops a
petechial component that becomes ecchymotic
and hemorrhagic.
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30. Petechiae often appear initially on the
ankles, wrists, and in the axillae and may spread to
any part of the body (including the conjunctiva);
however, it tends to spare the palms, soles, and
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head.
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31. Despite these rather impressive clinical
findings, the clinical diagnosis of WFS may be
extremely challenging.
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Patients who appear in the initial and nontoxic-
appearing stage without any skin lesions may be
difficult to distinguish from patients with benign
viral illness.
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32. The pathophysiology of this syndrome is not well
understood, but available evidence has implicated
adrenocorticotropic hormone (ACTH), adrenal vein
spasm and thrombosis, and the normally limited
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venous drainage of the adrenal gland.
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33. The adrenal gland has a rich arterial supply, in
contrast to its limited venous drainage, which is
critically dependent on a single vein.
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Furthermore, in stressful situations, ACTH secretion
increases, which stimulates adrenal arterial blood
flow that may exceed the limited venous drainage
capacity of the organ and lead to hemorrhage.
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34. In addition, adrenal vein spasm induced by high
catecholamine levels secreted in stressful situations
and by adrenal vein thrombosis induced by
coagulopathies may lead to venous stasis and
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hemorrhage.
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35. The adrenal cortex produces both cortisol (a
glucocorticoid) and aldosterone (a
mineralocorticoid).
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Cortisol maintains cardiac output, vascular
resistance, and hepatic glucose output. Shock and
death can occur without adequate glucocorticoids.
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36. Aldosterone modulates renal sodium reabsorption
in exchange for potassium excretion.
Hyperkalemia is caused by aldosterone deficiency
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and/or acidosis due to shock and poor perfusion.
Immunodeficiency seems to be a predisposing
condition to WFS resulting from infectious
processes.
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37. Patients with splenectomy or
asplenia, diabetes, organ transplantation, and
those receiving chemotherapy or chronic steroids
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are at higher risk for septic shock and death after
an infection.
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38. In WFS, a normal to slightly elevated leukocyte
count with a left shift is often seen. The chemistry
profile may demonstrate an elevated anion-gap
metabolic acidosis secondary to lactic acid
production.
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If there is bilateral adrenal
hemorrhage, hyponatremia, hyperkalemia, mild
azotemia, leukocytosis with
eosinophilia, and, occasionally, hypoglycemia may
be found.
38

39. The blood pressure may be abnormally low.
Coagulation abnormalities may be present and
may reflect ongoing DIC and consumptive
coagulopathy.
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40. These abnormalities include elevated
prothrombin time, partial thromboplastin
time, fibrin degradation products, and decreased
fibrinogen and platelets.
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Low serum cortisol levels indicate relative adrenal
insufficiency.
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41. A contrast-enhanced abdominal CT scan will
typically demonstrate enlargement of the adrenal
glands with bilateral hemorrhage.
Gram stain and cultures should be obtained from
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blood, cerebrospinal fluid, urine, and sputum. In
a large percentage of patients, no organisms will
be seen on Gram stain and cultures will not reveal
any organism for more than 24 hours.
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42. Other microbiologic testing, such as wound
cultures, should be directed by the clinical scenario.
Smears of petechial skin lesion scrapings should be
performed. These efforts may demonstrate the
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pathogen in about 70% of cases.
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43. Due to the fulminant course of WFS, therapy should
start as soon as the diagnosis is suspected. Initial
antibiotic coverage should be broad, consisting of a
third-generation cephalosporin
(eg, cefotaxime, ceftriaxone) in adults.
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In this case, a highly susceptible P aeruginosa strain
was isolated.
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44. Antibiotics with reported antipseudomonal effects
include penicillins
(ticarcillin, piperacillin, piperacillin/tazobactam), cep
halosporins (ceftazidime, cefepime), carbapenems
(imipenem/cilastatin, meropenem, doripenem), mo
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nobactamics (aztreonam), aminoglycosides
(tobramycin, gentamicin, amikacin, netilmicin), fluor
oquinolones (ciprofloxacin, levofloxacin), and
colimicin.
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45. However, decision making regarding specific
antipseudomonal therapies should be guided
by local resistance patterns.
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Supportive therapy includes intravenous
fluids, inotropic support, mechanical
ventilation, and correction of coagulopathy and
electrolyte abnormalities as needed.
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46. In adrenal crisis, the goal is to reverse the
hypovolemia with crystalloid, which may be
supplemented with 5% dextrose IV (given the
hypoglycemia often seen in these patients).
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Testing for cortisol should be obtained if adrenal
dysfunction or hemorrhage is suspected, and
glucocorticoids should be urgently administered.
46

47. Stress-dose glucocorticoids, either hydrocortisone
50 mg every 6 hours or dexamethasone 4 mg every
12 hours can be administered. Dexamethasone
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does not interfere with the cortisol assay, and
corticotrophin stimulation can be performed after
the patient receives dexamethasone.
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48. Mineralocorticoid replacement with fludrocortisone
may be indicated in patients with a history of
bilateral, extensive adrenal hemorrhage in order to
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replace mineralocorticoid hormone requirements
based on results of adrenal function testing or the
clinical picture.
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49. Therapy is unnecessary in (acutely ill)
patients receiving more than 100 mg of
hydrocortisone daily, as this dose is
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thought to provide adequate
mineralocorticoid replacement.
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50. In spite of adequate and aggressive treatment
with fluids, glucocorticoids, antibiotic
therapy, and ventilation, the patient in this case
continued to decompensate and died 12 hours
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later due to multiorgan failure thought to be
secondary to
P aeruginosa septic shock.
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51. Although the antibiotic selection on admission
was effective against P aeruginosa lately
isolated, the initial selection of amoxicillin (which
is not effective in the treatment of this bacteria)
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and the delay in recognizing the patient's severe
sepsis may be responsible for the final outcome
in this patient.
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52. The diagnosis of WFS was later confirmed via
autopsy, wherein massive bilateral suprarenal and
hemorrhagic effusion in other organs was
observed. The adrenal glands and renal medulla
had a macroscopically diffuse dark red color.
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No histologic signs of immunodeficiency were
found, but the liver and spleen were enlarged and
friable.
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53. There were no signs of meningitis.
Rapidly progressive vascular collapse and
acute respiratory failure caused by
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P aeruginosa septicemia (with lower
extremity cellulitis/ulcer being the portal of
entry) were considered responsible for the
patient's multiple organ failure and cause of
death.
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54. Review:
You are examining an adult patient who you
suspect may be manifesting WFS. Which of the
following organisms would most likely be seen in
this patient?
- H influenza
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- M tuberculosis
- N meningitidis
- Cytomegalovirus 54

55. Correct answer:
- H influenza
- M tuberculosis
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- N meningitidis ****
- Cytomegalovirus
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56. N meningitidis is the most frequent organism
reported as a cause of WFS, although massive
vaccination has decreased the incidence.
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The other organisms have also been identified
in cases of WFS.
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57. If you do in fact suspect a diagnosis of WFS in a
patient you are examining, which of the following
courses of action would be best?:
- Antibiotics should be prescribed but only after
bacterial susceptibility confirmation
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- Broad-spectrum antibiotics and supportive therapy
should be initiated as soon as WFS is suspected
- Treatment should focus on normalizing the cortisol
and aldosterone levels only
- The patient should be referred to radiography for 57
chest imaging

58. Correct answer:
- Antibiotics should be prescribed but only after
bacterial susceptibility confirmation
- Broad-spectrum antibiotics and supportive
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therapy should be initiated as soon as WFS is
suspected ****
- Treatment should focus on normalizing the
cortisol and aldosterone levels only
- The patient should be referred to radiography 58
for chest imaging

59. Due to the fulminant course of this
syndrome, therapy should be started as soon
as the diagnosis is suspected.
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Initial antibiotic coverage should be broad.
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60. Gracias por su atención
DR. JCDT
Dr. Juan Carlos Díaz Torre
Pediatra Neonatólogo
dr_diaz_torre@hotmail.com
(779) 100 - 40 - 26
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