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406
Brief Reports
CID 1998;27 (August)
massive production of infectious particles [7]. These cells become
activated early upon infection, indicated by a release of proinflammatory cytokines such as TNF-a [7]. Patients display increased cytokine levels, suggesting monocyte/macrophage activation in vivo as well [8]. Therefore, it seems reasonable to conclude
that monocytes/macrophages are an important source of shockinduced mediators during filovirus infections.
The main route of infection is person-to-person transmission by
intimate contact through the skin and secretions. Virus enters
through minute lesions of the skin and mucosae and might obtain
either direct access to the vascular system or indirect access via
the lymphatic system (figure 1). Common characteristics of primary target organs (lymph nodes, liver, and spleen) are large numbers of sessile macrophages, known to be primary sites for virus
replication [4–7]. After entry via the lymph capillaries, virus particles are transported to the lymph nodes, where macrophages are
bathed by lymphatic fluid in the sinuses. After primary infection,
replication continues in secondary and tertiary lymph nodes, resulting in the release of particles into the venous vascular system
(viremia) (figure 1). The subsequent step of infection seems to be
mediated by macrophages in the liver sinuses and spleen, where
macrophages are in close contact with circulating blood. This contact occurs in the spleen via open blood circulation, with sheathed
capillaries (macrophages) and sessile macrophages present along
the venous sinuses, and in the liver via Kupffer cells (sessile macrophages) located in the venous portal sinuses (figure 1). Thus, replication and activation may be initiated quickly in all these organs,
since macrophages can be infected without penetration of cellular
or tissue barriers.
Organ tropism may be determined further by specific structural
characteristics of the endothelium. The portal liver sinuses are
lined by a discontinuous endothelium that does not rest on a regular
basement membrane. This endothelium contains transcellular gaps,
allowing virus particles to directly enter the space of Disse from
the blood [4, 6] and to infect hepatocytes without passing any
barrier (figure 1). The endothelia of several other organs (e.g., the
kidneys and circumventricular organs) are also discontinuous, but
continuous basement membranes and the blood-liquor barrier may
prevent efficient infection. The pantropism in late stages of filovirus disease seems to be due to extravasation of infected circulating
monocytes/macrophages, resulting in spread of virus in extravasal
tissues. Endothelial cells are also targeted by filoviruses, and cytolytic replication may further contribute to viremia and the spread
of virus [4–6, 9, 10].
In conclusion, direct access of filoviruses to sessile macrophages
present in the lymph nodes, liver, and spleen seems to be an
important factor for replication and systemic release of shockinducing mediators. Macrophage-derived mediators act on multiple
organs, but mainly on the endothelium. The endothelium responds
by an increase in permeability, dysregulation of vascular tone,
expression of cell-adhesion molecules, and development of a procoagulatory phenotype that together substantially contribute to the
occurrence of shock.
Capnocytophaga Sepsis in a Patient with Waldenström’s
Macroglobulinemia
humans with or without periodontal disease [1]. Although these
organisms may cause a wide variety of infections in immunocompetent hosts, they have been increasingly recognized as a cause
of sepsis in immunocompromised individuals, notably those with
granulocytopenia [2]. We describe a case of capnocytophaga septicemia in a patient with Waldenström’s macrogobulinemia.
A 79-year-old man presented to the emergency department with
a 2-day history of fever, chills, shortness of breath, weakness,
and confusion. Four days before presentation he had undergone
plasmapheresis for Waldenström’s macroglobulinemia. In the past
he had been treated with melphalan and prednisone, which had
been discontinued several months earlier because there was no
evidence of hyperviscosity syndrome.
Capnocytophaga species are capnophilic, gram-negative, gliding bacilli that are commonly isolated from the oral cavity in
Reprints or correspondence: Dr. Eugenio Guzman, Department of Medicine,
Saint Vincents Hospital and Medical Center, 153 West 11th Street, New York,
New York 10011.
Clinical Infectious Diseases 1998;27:406–7
q 1998 by the Infectious Diseases Society of America. All rights reserved.
1058–4838/98/2702–0032$03.00
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Hans-Joachim Schnittler and Heinz Feldmann
Institute of Physiology, Westfälische-Wilhelms-Universität, Münster; and
Institute of Virology, Philipps-University,
Marburg, Germany
References
1. Peters CJ, Sanchez A, Rollin PE, Ksiazek TG, Murphy FA. Filoviridae:
Marburg and Ebola viruses. In: Fields BN, et al., eds. Virology. 3rd ed.
Philadelphia: Raven Press, 1996:1161 – 76.
2. Feldmann H, Klenk HD. Marburg and Ebola viruses. Adv Virus Res 1996;
47:1 – 52.
3. Brouckaert P, Fiers W. Tumor necrosis factor and the systemic inflammatory response syndrome. Berlin: Curr Top Microbiol Immunol 1996;
216:167 – 87.
4. Geisbert TW, Jahrling PB, Hanes MA, Zack PM. Association of Ebolarelated Reston virus particles and antigen with tissue lesions of monkeys
imported to the United States. J Comp Pathol 1992; 106:137 – 52.
5. Ryabchikova E, Kolesnikova L, Smolina M, et al. Ebola virus infection
in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. Arch Virol 1996; 141:909 – 21.
6. Zaki SR, Goldsmith CS. Pathology of Ebola virus haemorrhagic fever.
Curr Top Microbiol Immunol 1998 (in press).
7. Feldmann H, Bugany H, Mahner F, Klenk HD, Drenckhahn D, Schnittler
HJ. Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages. J Virol 1996; 70:2208 – 14.
8. Villinger F, Rollin PE, Brar SS, et al. Markedly elevated levels of IFNg/a, IL-2, IL-10, and TNF-a associated with fatal Ebola virus infection.
J Infect Dis 1998 (in press).
9. Schnittler HJ, Mahner F, Drenckhahn D, Klenk HD, Feldmann H. Replication of Marburg virus in human endothelial cells: a possible mechanism
for the development of viral haemorrhagic disease. J Clin Invest 1993;
91:1301 – 9.
10. Yang Z, Delgado R, Xu L, et al. Distinct cellular interactions of secreted
and transmembrane Ebola virus glycoproteins. Science 1998; 279:
1034 – 6.
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Brief Reports
Approximately 2 hours after arrival at the emergency department, the patient became increasingly confused, tachypneic (respirations, 38/min), and hypotensive (blood pressure, 85/35 mm Hg).
He had a temperature of 104.37F and an oxygen saturation of 68%
despite the administration of 1.0 FIO2 via a nonrebreather mask.
He was noted to have severe dextroscoliosis with decreased
breath sounds in the right lung base but no crackles or wheezes.
Cyanosis of the distal extremities and some purpuric lesions on
the legs and arms were observed. There were no meningeal signs
present, and the appearance of the oral cavity was unremarkable.
The remainder of the findings were within normal limits.
The WBC count was 4.5 1 109/L with a differential of 64%
neutrophils. The hemoglobin concentration was 13.4 g/L, and the
platelet count was 40 1 109/L. The rest of the hematologic profile
revealed disseminated intravascular coagulation (DIC), with a prothrombin time of 14.4 seconds (normal, 11.2–13.5 seconds), INR
(international normalized ratio) of 1.43, and a partial thromboplastin time of 56.5 seconds (normal, õ39 seconds). The fibrinogen
level was 3.1 g/L (normal, 1.5–4.5 g/L), and the fibrin degradation
products were increased (ú1.0 mg/mL). The serum creatinine level
was 265.2 mmol/L, the serum lactate level was 5.81 mmol/L, and
the lactate dehydrogenase level was 1,346 IU/L.
A presumptive diagnosis of gram-negative septicemia was
made. Blood for cultures was drawn, and empirical treatment with
gentamicin, vancomycin, and ceftazidime was begun. Tracheal
intubation was performed and the patient was mechanically ventilated for respiratory support. A pulmonary artery catheter was
inserted for hemodynamic monitoring. Norepinephrine, dopamine,
and dobutamine were administered. A gram-negative rod was identified in the blood culture Ç48 hours later. The patient’s condition
continued to deteriorate. The DIC worsened, requiring transfusions
of platelets, fresh frozen plasma, cryoprecipitate, and packed
RBCs. The patient became oliguric, and continuous veno-veno
hemodialysis was soon initiated. The patient continued to require
large amounts of norepinephrine to maintain a mean aortic pressure
of 60–65 mm Hg. On day 13, the gram-negative organism was
identified as Capnocytophaga species CDC (Centers for Disease
Control and Prevention) biogroup DF (dysgonic fermenter)-1. Although the species of the bacterium could not be further identified,
biochemical criteria indicated that it was of human origin. The
organism was susceptible to ceftriaxone, cefotaxime, ceftazidime,
ampicillin, piperacillin, ticarcillin, amoxicillin/clavulanic acid, aztreonam, and imipenem, and it was resistant to gentamicin, trimethoprim-sulfamethoxazole, and amikacin.
Because of wishes expressed by the patient before this episode,
a do-not-resuscitate order was instituted and, after 2 weeks, family
members asked that any further aggressive measures be withheld.
The patient died shortly thereafter. An autopsy was performed that
revealed infarction of the spleen and distal extremities, nephrosclerosis, and congestion and edema of the lungs. A postmortem blood
culture yielded Enterococcus faecalis, Enterococcus faecium, and
Acinetobacter anitratus.
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Capnocytophaga is a genus in the family Cytophagaceae. These
organisms are closely related to both Fusobacterium and Bacteroides species and can be divided into two main groups: those species
found in the human oral cavity— C. ochracea, C. gingivalis, and
C. sputigena (previously known as CDC biogroup DF-1)—and
those species found in the oral cavity of dogs and other animals—
C. canimorsus and C. cynodegmi (CDC biogroup DF-2) [1].
Capnocytophaga species can produce a wide variety of infections in immunocompetent hosts. Sites of infections that have been
described include the respiratory tract, eyes, and abdomen;
wounds; bones; blood; and even amniotic fluid [2, 3]. Capnocytophaga bacteremia has been well documented among immunocompromised hosts, mainly in those with hematologic malignancies
or those receiving immunosuppressive therapy. Such patients are
usually neutropenic, with or without oral pathology. Neither of
these conditions were observed in our patient. Multiple myeloma
and capnocytophaga bacteremia have been described in a patient
who was neutropenic secondary to chemotherapy [4].
It is unclear if our patient’s underlying disease could have contributed to the development of the septicemia, since cellular immunity appears to be preserved in most patients with Waldenström’s
macrogobulinemia [5]. No reports of neutrophil dysfunction have
been reported, although it has been noticed that Capnocytophaga
species produce factors that can inhibit neutrophil motility and
chemotaxis [6]. Plasmapheresis may have predisposed the patient
to infection; however, respiratory and phagocytic function of
phagocytes is usually not influenced by plasmapheresis [7].
Eugenio Guzman, David Coun, and Ira Wagner
Department of Medicine, Saint Vincents Hospital and Medical Center,
New York, New York
References
1. Gill VJ. Capnocytophaga. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s principles and practices of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995:2103 – 6.
2. Parenti DM, Snydman DR. Capnocytophaga species: infections in nonimmunocompromised and immunocompromised hosts. J Infect Dis 1985;
151:140 – 7.
3. Campbell JR, Edwards MS. Capnocytophaga species infections in children.
Pediatr Infect Dis J 1991; 10:944 – 8.
4. Gandola C, Butler T, Badger S, Cheng E, Beard S. Septicemia caused by
Capnocytophaga in a granulocytopenic patient with glossitis. Arch Intern
Med 1980; 140:851 – 2.
5. Dimopoulos MA, Alexanian R. Waldenstrom’s macroglobinemia. Blood
1994; 83:1452 – 9.
6. Wilson ME, Jonak-Urbanczyk JT, Bronson PM, Dudas KC, Apicella MA,
Genco RJ. Capnocytophaga species: increased resistance of clinical isolates to serum bactericidal action. J Infect Dis 1985; 156:99 – 106.
7. Jungi TW, Aeschbacher B, Nydegger UE. Preserved respiratory and phagocytic functions of phagocytes exposed to flat sheet plasmapheresis equipment. Int J Artif Organs 1987; 10:307 – 14.
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