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Description of Case patient’s history, physical examination, cannot be ruled out and should be
and routine screening blood tests and investigated as an underlying disorder
A 46-year-old woman was hospitalized cultures. In this case the history gives no preceding a more common cause for
due to fever of up to 39uC of one week’s apparent clue; therefore the organomegaly prolonged fever.
duration. The patient complained of should be the basis for the assessment. The Multiple blood, urine, and stool cultures
weakness, night sweats, and weight loss massive splenomegaly narrows down the were negative. The patient’s laboratory
for two weeks prior to admission. The differential diagnosis, as only a few results revealed pancytopenia with 2,800
patient had no past medical history, and conditions generally cause this degree of leukocytes/mm3 (2,200 neutrophils, 400
did not take any medications, supple- splenic enlargement (Box 1). These include lymphocytes, 200 monocytes, and no
ments, or illicit drugs. She was born and infectious causes, such as bacterial (ty- eosinophils or basophils/mm3). The he-
lived all her life in a rural village. She was phoid fever, Mycobacterium tuberculosis, or moglobin level was 98 g/l, and the platelet
indirectly exposed to farm animals and AIDS with M. avium complex) and fungal count was 59,000/mm3. The reticulocyte
pets, yet had no close contact with these, agents (histoplasmosis), but more com- count was 1.5%. The erythrocyte sedi-
and her family was not engaged in monly splenomegaly results from parasitic mentation rate was elevated at 104 mm/h.
agricultural work. She denied having been diseases such as malaria and leishmaniasis. Her prothrombin time and partial throm-
bitten by ticks or fleas. There was no Viruses such as those causing infectious boplastin time were prolonged (41.5% and
history of recent foreign travel or eating mononucleosis, i.e., Epstein-Barr virus 46.6 seconds, respectively), and the fibrin-
raw meat or unpasteurized milk. She (EBV) and cytomegalovirus (CMV), or ogen level was low at 82 mg/dl. The
reported no rashes, arthralgia, dryness of hepatitis viruses rarely cause this degree of peripheral blood smear showed mature
eyes, mouth ulcers, or mucocutaneous organomegaly. Hematologic disorders white blood cells with a mild left shift, and
bleeding. such as myeloproliferative diseases, lym- a few red blood cell schistocytes. The
On examination she appeared pale and phoma, or chronic lymphocytic leukemia serum creatinine and urea levels and
sweaty. The cardiorespiratory examina- and hairy cell leukemia, as well as electrolytes were all normal. Liver function
tion was unremarkable. A markedly tender thalassemia intermedia and autoimmune tests (LFTs) were elevated at three to four
and enlarged liver and spleen, 3 cm and hemolytic anemia, should also be consid- times the normal values, with hyperbiliru-
10 cm below the costal margins, respec- ered. Infiltrative diseases such as Gaucher binemia of 27 mmol/l (0–17 mmol/l).
tively, were noted, with no palpable lymph disease, sarcoidosis, and amyloidosis may The lactate dehydrogenase was markedly
nodes. Periorbital and peripheral extrem- potentially cause massive splenomegaly. elevated at 4,245 U/l (300–620 U/l). An-
ity edema was also present. The previous history of complete health, ti-nuclear antibody, rheumatoid factor,
the tenderness of the spleen, and the anti-neutrophilic cytoplasmatic antibody,
What Are Likely Etiologies for abrupt onset of high fever all argue for anti-cardiolipin and circulating anticoagu-
This Patient’s High Fever and an acute rather than a chronic smoldering lants were all negative, as were direct
Organomegaly? disease (such as an infiltrative, autoim- Coombs tests. Serology for Mycoplasma,
mune, or a chronic hematologic neoplastic Brucella, Legionella, Q fever, spotted fever,
Physicians commonly see patients with disease). Nevertheless, a chronic disease murine typhus, HIV, EBV, CMV, hepa-
prolonged fever. There are many different
possible etiologies, most commonly infec- Citation: Levy L, Nasereddin A, Rav-Acha M, Kedmi M, Rund D, et al. (2009) Prolonged Fever,
tious, but neoplastic and inflammatory or Hepatosplenomegaly, and Pancytopenia in a 46-Year-Old Woman. PLoS Med 6(4): e1000053. doi:10.1371/
autoimmune disorders may also be a journal.pmed.1000053
possibility. Less common conditions in- Academic Editor: Ronald C. W. Ma, Chinese University of Hong Kong, China
clude drug-related fevers, factitious (i.e., Published April 14, 2009
self-induced) fevers, and other rare diseas-
Copyright: ß 2009 Levy et al. This is an open-access article distributed under the terms of the Creative
es. Some patients with prolonged fever will Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
remain undiagnosed despite an intensive provided the original author and source are credited.
diagnostic work-up. Funding: This manuscript had no specific funding, and no funding agent played a role in the article’s
The diagnostic approach should be preparation.
based on any potential clues in the Competing Interests: The authors have declared that no competing interests exist.
Abbreviations: CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus;
HLH, hemophagocytic lymphohistiocytosis; LFT, liver function test.
The Learning Forum discusses an important clinical
problem of relevance to a general medical audience. * E-mail: levyliran@hadassah.org.il
Provenance: Not commissioned; externally peer reviewed
that should be asked repeatedly is: what is N Cytopenia involving two or more cell lines
the primary process due to which this N Hypertriglyceridemia or hypofibrinogenemia
hemophagocytosis results? Primary hemo- N Hemophagocytosis ( with no evidence for malignancy )
phagocytosis is so rare at this age as to be
New Criteria
practically nonexistent. A continued
search for a malignancy or an infectious
organism should be performed, and sple-
N Low or absent natural killer cell activity.
be more properly termed hemophagocytic and secondary HLH. Primary HLH, liferation with hemophagocytosis. It also
lymphohistiocytosis (HLH). The most found most often in young children, is a develops as a consequence of strong
typical presenting signs and symptoms hereditary transmitted disorder, consid- immunological activation.
are fever, hepatosplenomegaly, and cyto- ered to be an autosomal recessive disease, This secondary form is encountered
penias. Less frequently observed clinical affecting immune regulation. Recently, most often with severe infection. The
findings are neurological symptoms, mutations in one of two genes have been viral-associated [8], most often EBV-
lymphadenopathy, edema, skin rash, and found to underlie 40%–50% of cases: the related form is also termed fatal or
jaundice [1,3,4]. Common laboratory gene encoding perforin, the major im- fulminant infectious mononucleosis, yet
findings include hypertriglyceridemia, a mune cytotoxic protein, and the gene other viruses have been implicated. At-
coagulopathy with hypofibrinogemia, and encoding MUNC 13-4, a protein involved tempts should be made to screen for an
elevated LFTs. in exocytosis of perforin-bearing cytotoxic infection with EBV, CMV, and parvovirus
The entity comprises two different granules during apoptosis [7]. Secondary B19, either through serologic testing or
conditions that may be difficult to distin- HLH, which is found in both children and PCR, in-situ hybridization, or (in the case
guish from each other [2,5,6]: primary adults, comprises a lymphohistiocytic pro- of CMV) immunofluorescent antigen test-
ing. Serologic testing for HIV and human
herpesvirus-6 infection should also be
considered [9]. Bacterial infections such
as brucellosis, salmonellosis, tuberculosis,
and rickettsiosis have been reported to
cause this rare syndrome. Parasitic diseas-
es such as malaria and leishmaniasis may
also induce secondary HLH [7]. The
presentation of visceral leishmaniasis with
hemophagocytic syndrome is rare in all
age groups, especially in adults [10,11,12].
Furthermore, the Leishmania serological
test and bone marrow examination in-
cluded in the work-up may be initially
negative, necessitating repeated bone mar-
row procedures for diagnosis [10]. Indeed,
diagnosing Leishmania in this patient on the
sixth bone marrow aspirate (after five
previous negative examinations) is an
extreme example. HLH may also develop
subsequent to other forms of immunolog-
ical stress and activation, as in the
macrophage activating disorder in rheu-
matic diseases, but is most often seen
accompanying malignancy [13]. It has
Figure 3. Bone marrow aspirate showing multiple parasites (black arrows) within and
been described during the course of active
released from the monocyte, consistent with the presence of Leishmania amastigotes. lymphoma, but also in patients in com-
(Giemsa stain.) plete remission [14]. Even if an infection
doi:10.1371/journal.pmed.1000053.g003 known to be associated with HLH has
References
1. Favara B (1992) Hemophagocytic lymphohistio- 9. Fisman DN (2000) Hemophagocytic syndromes 17. Weisser M, Khanlari B, Terracciano L, Arber C,
cytosis: A hemophagocytic syndrome. Semin and infection. Emerg Infect Dis 6: 601–608. Gratwohl A, et al. (2007) Visceral leishmaniasis: A
Diagn Pathol 9: 63–74. 10. Gagnaire MH, Galambrun C, Stephan JL (2000) threat to immunocompromised patients in non-
2. Henter JI, Aricò M, Egeler RM, Elinder G, Hemophagocytic syndrome: A misleading com- endemic areas? Clin Microbiol Infect 13:
Favara BE, et al. (1997) HLH-94: A treatment plication of visceral leishmaniasis in children—A 751–753.
protocol for hemophagocytic lymphohistiocytosis. series of 12 cases. Pediatrics 106: E58. 18. Castellino G, Govoni M, Lo Monaco A,
HLH study Group of the Histiocyte Society. Med 11. Matzner Y, Behar A, Beeri E, Gunders AE, Montecucco C, Colombo F, et al. (2004) Visceral
Pediatr Oncol 28: 342–347. Hershko C (1979) Systemic leishmaniasis mim- leishmaniasis complicating a connective tissue
3. Aricò M, Janka G, Fischer A, Henter JI, icking malignant histiocytosis. Cancer 43: disease: Three case reports from Italy. Lupus 13:
Blanche S, et al. (1983) Hemophagocytic lym- 398–402. 201–203.
phohistiocytosis: Diagnosis, treatment, and prog- 12. Bhutani V, Dutta U, Das R, Singh K (2002) 19. Adini I, Ephros M, Chen J, Jaffe CL (2003)
nostic factors. Report of 122 children from the Hemophagocytic syndrome as the presenting Asymptomatic visceral leishmaniasis, northern
international registry. Leukaemia 10: 197–203. manifestation of visceral leishmaniasis. J Assoc Israel. Emerg Infect Dis 9: 397–398.
4. Janka GE (1983) Familial hemophagocytic lym- Physicians India 50: 838–839. 20. Bain BJ (2006) Morbidity associated with bone
13. Kaito K, Kobayashi M, Katayama T, Otsubo H,
phohistiocytosis. Eur J Pediatr 140: 221–230. marrow aspiration and trephine biopsy—A re-
Ogasawara Y, et al. (1997) Prognostic factors of
5. [No authors listed] (1987) Histiocytosis syndromes view of UK data for 2004. Haematologica 91:
hemophagocytic syndrome in adults: Analysis of
in children. The Writing Group of the Histiocyte 1295–1296.
34 cases. Eur J Haematol 59: 247–253.
Society. Lancet 1: 208–209. 21. Goldschmidt N, Gural A, Kornberg A, Spectre G,
14. Goldschmidt N, Amir G, Krieger M, Gilead L,
6. Henter J-I, Elinder G, Ost Å (1991) Diagnostic Paltiel O (2003) Fatal hemophagocytic syndrome Shopen A, et al. (2004) Prolonged fever of
guidelines for hemophagocytic lymphohistiocyto- in a patient with panniculitis-like T-cell lympho- unknown origin and hemophagocytosis evolving
sis. The FHL Study Group of the Histiocyte ma and no clinical evidence of disease. Leuk into acute lymphoblastic leukemia. Am J Hematol
Society. Semin Oncol 18: 29–33. Lymphoma 44: 1803–1806. 76: 364–367.
7. Filipovich AH (2006) Hemophagocytic lympho- 15. Craig F, Clare N, Sklar J, Banks P (1991) T-cell 22. al (2007) HLH-2004: Diagnostic and therapeutic
histiocytosis and related disorders. Curr Opin lymphoma and the virus-associated hemophago- guidelines for hemophagocytic lymphohistiocyto-
Allerg Clin Immunol 6: 410–415. cytic syndrome. Am J Clin Pathol 97: 189–194. sis. Pediatr Blood Cancer 48: 124–131.
8. Imashuku S, Kuriyama K, Sakai R, Nakao Y, 16. Jiménez M, Ferrer-Dufol M, Cañavate C, Gu- 23. Histiocyte Society (2008) Current treatment
Masuda S, et al. (2003) Treatment of Epstein- tiérrez-Solar B, Molina R, et al. (1995) Variability protocols. Available: http://www.histio.org/site/
Barr virus-associated hemophagocytic lymphohis- of Leishmania (Leishmania) infantum among stocks c.kiKTL4PQLvF/b.1767369/k.AAF9/Current_
tiocytosis (EBV-HLH) in young adults: A report from immunocompromised, immunocompetent Treatment_Protocols.htm. Accessed 18 February
from the HLH study center. Med Pediatr Oncol patients and dogs in Spain. FEMS Microbiol Lett 2009.
41: 103–109. 131: 197–204.