Download A Case of Atypical Urticaria

Clinical Case Study
Clinical Chemistry 62:4
558–562 (2016)
A Case of Atypical Urticaria
Mariela Marinova,1* Mitja Nabergoj,2 Carlo Artusi,1 Martina M. Zaninotto,1 and Mario Plebani1
CASE DESCRIPTION
QUESTIONS TO CONSIDER
A 50-year-old woman presented with urticarial rash, fever, and pharyngitis. A week before, she had been examined in the emergency department for widespread pruritic erythematous-edematous plaques associated with
remittent fever (up to 38.5 °C) and sore throat. Laboratory results revealed neutrophilic leukocytosis and increased inflammatory markers. Thus, the woman was
diagnosed with urticaria and associated mild fever, which
was confirmed by a dermatologic examination. The patient had started antibiotic therapy with levofloxacin, antihistamines, and low-dose steroids. Because of the persistence of symptoms and the appearance of weakness
and widespread muscle pain despite therapy, she was admitted for further assessment. At the time of admission,
the patient was febrile (37.7 °C), and physical examination revealed laterocervical lymphadenopathy, hepatomegaly, and highly congested throat. Numerous confluent, erythematous, urticarial macules and papules that
coalesced into urticarial plaques were observed.
Laboratory results are shown in Table 1. Radiological
examinations revealed multiple, reactive abdominal and
neck lymphadenopathies of small size (maximum 15 mm).
Owing to the appearance of bilateral arthralgia of the
wrists, hands, and knees, broad-spectrum antibiotic therapy and low-dose methylprednisolone were started while
awaiting the results of more biochemical tests. Antinuclear antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies, anti-dsDNA antibodies, and
rheumatoid factor were negative. Complement C3 and
C4 were within reference intervals. Blood and urine cultures revealed no evidence of bacterial, viral, or fungal
infection.
Under the suspicion of a systemic inflammatory disease, plasma ferritin was measured and found to be
20920 ␮g/L (10 –120 ␮g/L), with glycosylated ferritin
(GF)3 14% (50%– 80%).
1. What are the causes of rash and fever in adult patients?
2. What are the common causes of extreme hyperferritinemia?
3. What does reduced glycosylated ferritin suggest?
DISCUSSION
Clinicians are often faced with diseases presenting with
fever and rash that have both infectious and noninfectious causes. The most common infectious causes are
viral diseases and toxic shock syndrome, whereas drug
reactions and connective tissue diseases are most common among the noninfectious causes. Hyperferritinemia
occurs in inflammatory processes such as acute phase response, liver failure, malignant and autoimmune diseases, hemochromatosis, hereditary hyperferritinemia
cataract syndrome, benign hyperferritinemia, and druginduced hypersensitivity syndrome.
Extreme hyperferritinemia with reduced glycosylation (⬍20%) can be found in rare clinical conditions
such as hemophagocytic lymphohistiocytosis (HLH) or
adult-onset Still disease (AOSD). The diagnosis of HLH
was ruled out, as the patient did not manifest some of the
main diagnostic criteria such as cytopenia, splenomegaly,
hypertriglyceridemia, and hypofibrinogenemia.
The decreased GF combined with the clinical symptoms suggested the diagnosis of AOSD. Antibiotic treatment was suspended immediately, the dose of steroids was
increased, and an immunosuppressive treatment (cyclosporine) was started. The patient’s clinical and biochemical status improved within 3 days. Eighteen months after admission, the patient is doing well, and the biochemical and
hematologic parameters are completely normalized with no
recurrence. The cyclosporine A was gradually reduced to
low doses, which she still takes today.
ADULT-ONSET STILL DISEASE
1
2
Departments of Laboratory Medicine and Hematology and Clinical Immunology,
University-Hospital, Padova, Italy.
* Address correspondence to this author at: Department of Laboratory Medicine,
University-Hospital of Padova, Via Giustiniani, 2, 1-35128 Padova, Italy. E-mail
[email protected].
Received May 8, 2015; accepted August 31, 2015.
DOI: 10.1373/clinchem.2015.243220
© 2015 American Association for Clinical Chemistry
3
Nonstandard abbreviations: GF, glycosylated ferritin; HLH, hemophagocytic lymphohistiocytosis; AOSD, adult-onset Still disease; PMN, polymorphonuclear neutrophil.
558
AOSD, a variant of rheumatoid arthritis in adults, was
first described by Bywaters in 1971 (1 ). It is a rare
inflammatory disease of unknown etiology that has
been recently classified as a polygenic autoinflammatory disorder. Incidence has been estimated at 0.16 –
0.4 per 100 000 people. AOSD is generally characterized by the classical triad of daily spiking fever
(ⱖ39 °C) persisting for ⬎1 week, arthritis, and a typ-
Clinical Case Study
Table 1. Results of laboratory testing performed at admission and relative age- and sex-dependent reference intervals.
Test
Patient values
9
Reference interval
Leukocytes, ×10 /L
20.8
Neutrophils, %
87.0
50–70
Erythrocyte sedimentation rate, mm/h
62
0.5–15
10.5
1.5–4.5
Fibrinogen, g/L
C reactive protein, mg/L
4.4–11.0
300
Albumin, g/dL
0–2.1
3.1
Alanine aminotransferase, U/L
Aspartate aminotransferase, U/L
3.8–4.4
62
7–35
44
10–35
␥-Glutamyltransferase, U/L
211
3–45
Lactate dehydrogenase, U/L
730
135–214
ical nonpruritic salmon-colored rash on the trunk
and limbs. Other features consistent with the clinical
presentation of AOSD include pharyngitis, lymphadenopathy or splenomegaly, myalgia, arthralgia, pericarditis, and pleuritis. Laboratory findings include increased leukocyte and polymorphonuclear neutrophil
(PMN) counts (⬎10 ⫻ 109/L, PMN ⬎80%) and
marked hyperferritinemia, both significant parameters
for diagnosis of AOSD (2, 3 ). AOSD remains difficult
to diagnose clinically because of the overlapping features with infectious, neoplastic, and rheumatologic
conditions. Thus, it is crucial that these other conditions be excluded before considering AOSD, as there is
still no specific marker for this disease. The most
widely used classification criteria for diagnosis of
AOSD are those of Yamaguchi et al. (4 ), which imply
an assessment of specific signs and symptoms as well as
laboratory findings (Table 2). They include 4 major
criteria and 5 minor criteria. To make a diagnosis of
AOSD, 5 criteria (at least 2 major) need to be fulfilled.
Their use yields 96.2% sensitivity and a 92.1% specificity (4 ).
Since the late 1980s, several authors have suggested
that an increased serum ferritin concentration may indicate AOSD. The exact mechanisms leading to the hyperferritinemia during AOSD are still not clear. Several isoforms of ferritin have been described, one of which is GF.
According to the literature, the percentage of GF in
AOSD is low and differs dramatically from the percentages in other systemic diseases. Interestingly, unlike serum ferritin concentrations, ferritin glycosylation remains low both during the active disease state and in
Table 2. AOSD classification criteria adapted from Yamaguchi et al. (4 ) and Fautrel et al. (5 ).
Reference
Major classification criteria
Minor classification criteria
Yamaguchi et al.
Fever >39°C, intermittent, >1 week
Sore throat
Leukocytosis >10000/mm3 with >80% PMNs
Lymph node enlargement
Typical salmon pink rash
Splenomegaly
Arthralgia >2 weeks
Liver dysfunction (high aspartate/alanine
aminotransferase)
Negative antinuclear antibodies,
rheumatoid factor
Fautrel et al.
Spiking fever ≥39°C
Maculopapular rash
Arthralgia
Leukocytes ≥10000/mm3
Transient erythema
PMNs ≥80%
Pharyngitis
Glycosylated ferritin ≤20%
Clinical Chemistry 62:4 (2016) 559
Clinical Case Study
remission. Fautrel et al. have proposed a new set of criteria that includes GF ⱕ20% (Table 2). Based on their
proposal, a diagnosis of AOSD requires the fulfillment of
4 major criteria, or 3 major and 2 minor criteria. When
using the Fautrel et al. criteria instead of those of Yamaguchi et al., sensitivity goes down to 80.6% but specificity goes up to 98.5% (5 ).
A few cases have been reported in the literature in
which AOSD manifested with atypical cutaneous features, causing a delay in diagnosis (6, 7 ). In some cases,
this led to serious complications such as HLH, disseminated intravascular coagulopathy, thrombotic thrombocytopenic purpura, diffuse alveolar hemorrhage, and pulmonary arterial hypertension (8 ).
In the current case, a few days before admission, the
patient’s clinical and laboratory findings were nonspecific
(pruritic erythematous-edematous plaques, neutrophilic
leukocytosis, and increased inflammatory markers) and suggestive of a pathological condition, which led the clinician to
an incorrect diagnosis (urticaria and mild fever).
It should be emphasized that on admission, the patient
had urticarial lesions and not the typical evanescent salmonpink rash. In addition, she never had fever peaks ⱖ39 °C for
more than a week. Therefore, it was not possible to make a
diagnosis of AOSD based on the most widely used Yamaguchi et al. criteria. The determination of the GF, a test that
is not commonly performed in routine laboratory practice,
was crucial to reach a correct diagnosis.
The method for determination of GF is complex; we
used the method of Worwood et al. (9 ) with minor modifications. Briefly, Con A Sepharose 4B and Sepharose 4B
gels (GE Healthcare Bio-Sciences) were washed twice
with 10 times the packed gel volume in sodium phosphate buffer (20 mmol/L, pH 7.25, containing 500
mmol/L NaCl) and suspended in 2 times the packed gel
volume. We placed 600 ␮L Con A Sepharose 4B suspension (or Sepharose 4B suspension as a control) and 100
␮L serum into a solid-phase extraction column (Chromsystems Chemicals). The columns were rotated at room
temperature for 90 min. Supernatant was collected after
centrifugation (1 min at 2080g). We measured the ferritin concentration in each supernatant with an electrochemiluminescence immunoassay (Cobas e601, Roche
Diagnostics). The patient sample was assayed in duplicate, and GF was obtained from the difference between
total ferritin (Sepharose 4B) and unbound ferritin (Con
A Sepharose 4B). The intraassay CVs (n ⫽ 10) were
⬍3% and ⬍5% for negative pool samples (concentration
close to 62%) and positive pool samples (concentration
close to 14%), respectively. The interassay CVs (n ⫽ 20)
were ⬍9% and ⬍15% with the same pools.
Given the complexity of the method and the rarity
of the disease involved, it is reasonable that this method
should be performed only in laboratories that have the
proper professional skills.
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Clinical Chemistry 62:4 (2016)
POINTS TO REMEMBER
• The most common causes of rash and fever in adults are
infections such as measles, chickenpox, rickettsial infection, and toxic shock syndrome, whereas drug reactions
and connective tissue diseases are the most common
noninfectious causes.
• Extreme hyperferritinemia of ⬎10 000 g/L could be observed in extrahepatic biliary obstruction, acute severe
hepatocellular damage including sepsis and drug toxicity, the presence of malignancy, inflammatory and infectious diseases, and iron-overload syndrome.
• Extreme hyperferritinemia with reduced glycosylation
(⬍20%) can be found in rare clinical conditions such as
HLH or AOSD.
• AOSD is a rare inflammatory disease of unknown etiology and is a variant of rheumatoid arthritis.
• AOSD is generally characterized by the classical triad of
daily spiking fever (ⱖ39 °C) persisting for ⬎1 week,
arthritis, and a typical nonpruritic salmon-colored rash
on the trunk and limbs.
• Hyperferritinemia with reduced glycosylation (⬍20%) is
a useful marker for diagnosis of Still disease.
Author Contributions: All authors confirmed they have contributed to the
intellectual content of this paper and have met the following 3 requirements: (a)
significant contributions to the conception and design, acquisition of data, or
analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
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