Infectious Diseases, 2015; 47: 107–111
CASE REPORT
Severe Puumala virus infection in a patient with a lymphoproliferative disease treated with icatibant
OUTI LAINE1,2, ILONA LEPPÄNEN3, SIRPA KOSKELA1, JAAKKO ANTONEN1, SATU MÄKELÄ1, MARJATTA SINISALO1, ANTTI VAHERI4 & JUKKA MUSTONEN1,2 From the 1Department of Internal Medicine, Tampere University Hospital, 2School of Medicine, University of Tampere, 3Department of Anesthesiology and Intensive Care, Tampere University Hospital, Tampere, and 4Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland
Abstract Early identification of patients at risk of a severe course of hantaviral disease and lack of effective medication represent a global challenge in the treatment of this emerging infection. We describe a 67-year-old female patient with a history of chronic lymphoproliferative disease involving the spleen and an extremely severe acute Puumala hantavirus infection. She was treated with the bradykinin receptor antagonist icatibant and recovered. She is the second patient with a spleen abnormality and severe Puumala infection treated with icatibant in our hospital. We suggest that patients with spleen abnormalities may be more susceptible to severe hantavirus disease. The activation of the kinin-kallikrein system and the formation of bradykinin in hantavirus-infected endothelial cells indicate that the role of bradykinin receptor antagonist icatibant in the treatment of hantavirus disease is worth studying.
Keywords: Bradykinin receptor antagonist, hantavirus, icatibant, lymphoproliferative, spleen
Introduction The disease burden caused by hantaviruses is considerable. About 150 000 cases of hemorrhagic fever with renal syndrome (HFRS) are recorded annually in Eurasia and in the most severe forms the mortality rises up to 15% [1,2]. In Europe the most common cause of HFRS is Puumala virus (PUUV) and most reports come from Finland, where the mortality rate is low, ranging from 0.1% to 0.4% [3]. The clinical course of PUUV-HFRS is influenced by host-related characteristics; adult age [4,5], female sex [5,6], and HLA-B8-DR3 haplotype [7,8] being adverse prognostic factors. Biomarkers recently found to predict disease outcome include interleukin-6, pentraxin-3, indoleamine 2,3-dioxygenase, and soluble urokinase-type plasminogen activator receptor [3]. Early detection of potentially severe disease is of clinical value even though the treatment still consists of supportive measures with no specific therapy [3].
Antonen et al. recently reported a severe case of PUUV-HFRS in a 37-year-old Finnish man who had undergone a splenectomy 18 years previously because of congenital spherocytosis [9]. Now we report another patient with probably an even more severe PUUV-HFRS who had a malignant chronic lymphoproliferative disease affecting the spleen. Both patients were medicated with a bradykinin receptor antagonist, icatibant (Firazyr®; Shire Human Genetic Therapies AB, Lund, Sweden), and recovered.
Case report On 13 November 2013 we received a 67-year-old female patient with a history of chronic lymphoproliferative disease since the year 1999 and acute symptoms indicating a severe infection. Morphologically her blood disease was considered either atypical chronic lymphocytic leukemia (CLL) or splenic marginal zone lymphoma. Her CD5-negative lymphocyte
Correspondence: Outi Laine MD PhD, Department of Internal Medicine, Tampere University Hospital, PO Box 2000, FI-33521 Tampere, Finland. Tel: ⫹ 358 50 541 5205. Fax: ⫹ 358 3 311 64388. E-mail: [email protected] (Received 11 June 2014 ; accepted 17 September 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.969304
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O. Laine et al. were cold from the elbows and knees downwards. Her condition resembled severe sepsis and she was immediately transferred to the intensive care unit (ICU). Laboratory analyses revealed hemoconcentration, leukocytosis (85% neutrophils), thrombocytopenia, hypoalbuminemia, and increased plasma creatinine level (Table I). Plasma alanine aminotransferase rose to 154 U/l (range 10–45 U/l); other liver function tests remained normal. The length of the spleen was 13.3 cm (Table I). Blood cultures remained negative. An acute PUUV infection was serologically confirmed by a high IgM titer detected by μ-capture enzyme-immunoassay (EIA) based on baculovirus-expressed nucleocapsid protein [10]. The PUUV-specific IgG antibody was also positive but the titer was low. In the ICU a severe multi-organ failure was diagnosed. Anuria necessitated continuous renal replacement therapy (CRRT). The patient experienced respiratory failure and mechanical ventilation was started. Capillary leakage was severe and the patient remained hypotonic (mean arterial pressure 50 mmHg) despite the massive fluid replacement. High doses of vasoactive drugs, corticosteroids, albumin infusions, and even wide-spectrum antibiotics were used. No bleeding problems were noted. Despite all the supportive measures the patient’s condition deteriorated and became critical. After one day of treatment in the ICU a 30 mg dose of icatibant was administered subcutaneously. The dose was repeated 6 h later. During the next 48
immunophenotype was atypical for CLL and there were no chromosomal aberrations. The disease had manifested as a splenic enlargement, the maximum length of her spleen being 27 cm as measured by ultrasound in February 2007. She did not have lymphadenopathy, her lymphocyte count was only moderately elevated, and she had had a few episodes of mild autoimmune hemolytic anemia. She did not have hypogammaglobulinemia but she had suffered from pneumonia and several mild upper respiratory tract infections in 2002–2003 while working as a private childminder. Due to symptomatic splenomegaly she received intermittent pharmacotherapy between the years 2000 and 2007 with a good response. Since the cessation of R-CHOP (rituximab, cyclophosphamide, vincristine, and prednisolone) treatment in June 2007 the disease had been inactive and the patient had been asymptomatic. The latest abdominal ultrasound in August 2011 had revealed a normal spleen length of 11 cm. In August 2013 the blood count was normal; 39% of leukocytes were lymphocytes, the absolute value of lymphocytes was 1.9 ⫻ 109/l. Figure 1 illustrates the timescale of the clinical course of the infection. The patient presented with diarrhea and vomiting that had begun 7 days earlier and were followed a couple of days later with high fever. She also complained of blurred vision. She had been oliguric for a couple of days. On admission to the hospital the patient was hypotonic (systolic blood pressure 75–87 mmHg) and her extremities
Fever Hypotonia Anuria CRRT Mechanical ventilation Intensive care unit
Hematocrit max and min
0.59
Platelets min (10E9/l)
34
0.22
CRP max (mg/l)
89
Leukocytes max (10E9/l)
35.5
Creatinine max (µmol/l)
265
Albumin min (g/l)
12 0
2
4
6
8
10
12
14
16
18
20
Days (from the onset of fever) Figure 1. Timescale illustrating the clinical course of a severe case of acute Puumala virus (PUUV) infection. Icatibant 30 mg was administered subcutaneously twice with a 6-h interval on the second day of hospitalization (day 4). CRP, plasma C-reactive protein value; CRRT, continuous renal replacement therapy; max, maximum; min, minimum.
Puumala hantavirus infection, spleen, and icatibant Table I. Laboratory values and radiological findings of a patient with a severe Puumala hantavirus infection.
Variable Blood hematocrit minimum Blood hematocrit maximum Blood leukocytes maximum Blood platelets minimum Serum creatinine maximum Plasma C-reactive protein maximum Plasma albumin minimum Chest X-ray Abdominal ultrasound
Value (reference range) or finding 0.22 0.59 35.5 34 265 89
(0.35–0.46) (0.35–0.46) (3.4–8.2) ⫻ 109/l (150–360) ⫻ 109/l (50–90) μmol/l (0–10) mg/l
12 (36–45) g/l Bilateral pleural effusion and atelectasis An enlarged spleen, length 13.3 cm
h counting from the latter dose the patient’s condition remained critical. However, stabilization could be observed towards the end of the 48 h period and gradual improvement enabled the use of more moderate fluid replacement. Vasopressins could be totally withdrawn 7 days after the administration of icatibant. Due to the substantial amount of bilateral pleural transudate the weaning from mechanical ventilation was unhurried and the patient was extubated only 11 days later. Diuresis started 12 days later and CRRT treatment could be finished after 13 days of treatment. For this extremely severe PUUV-HFRS the patient needed 15 days of care in the ICU and altogether 30 days of care in the university hospital, after which she was transferred for further rehabilitation to a health care center. Two months later two of her toes had to be amputated because of the necrosis that developed during the critical phase of the disease. Five months after the acute phase of the disease she still needs a walker despite the intensive physiotherapy, and is medicated for neuropathic pain. Otherwise she has recovered very well. Her kidney function is normal. The blood count is normal and the CLL is stable without any therapy.
Discussion The spleen is critically engaged in innate and adaptive immune responses against bloodborne bacterial, viral, and fungal infections [11]. It acts as a filter, removing damaged blood cells and foreign particles by its large population of mononuclear phagocytes [12]. Macrophages recognize some bacteria directly, others need to be first opsonized by complement or spleen-derived molecules. The marginal zone of spleen either generates or provides an environment that supports the survival of a population of IgM memory B cells. They are responsible for the production of natural antibodies necessary for the spleen to
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remove the poorly opsonized organisms, such as encapsulated bacteria [13,14]. Our patient with an extremely severe PUUV infection had a malignant CLL-type lymphoproliferative disorder that resembled splenic marginal zone lymphoma. It seems plausible to assume that the disease affecting the spleen may have had an adverse impact on the clinical course of the disease. Spleen enlargement is reported to be associated with several acute viral infections including PUUV infection [15]. The spleen enlargement during acute PUUV infection does not associate with the two main manifestations of the disease, namely thrombocytopenia and acute kidney injury, and it does not seem to relate to the fluid accumulation either [15]. The enlargement, however, is known to associate inversely with the highest blood leukocyte count [15]. Consistently, our patient had a modest enlargement of the spleen compared with the latest preinfection measurement and a notable leukocytosis. The enlargement of the spleen could possibly be a consequence of the proliferation of mononuclear cells as an immune response directed by cytotoxic T lymphocytes, regulatory T cells, and proinflammatory cytokines [3,16,17]. On the other hand, a sizeable spleen may cause pooling of leukocytes thus decreasing the number of leukocytes measured in the blood. Assessment of spleen function in clinical practice is generally based on the morphological alterations of erythrocytes [13]. In the peripheral blood smear Howell-Jolly bodies were not found but some pitted erythrocytes were noted. Lymphoid malignancies are considered a possible cause of hyposplenism, i.e. derangement of the basic functions of the spleen [14]. In postsplenectomy cytomegalovirus mononucleosis the poor control of early viremia is attributed to the lack of splenic filtration and the absence of brisk IgM response [18]. In addition to the present patient with a lymphoproliferative disease affecting the spleen our group has reported a splenectomized patient with a severe PUUV infection, but neither of the patients had a lack of brisk IgM response [9]. In CLL, hypogammaglobulinemia is present in about 25% of patients and has been considered as a main cause for infections in the past. The pathogenesis of hypogammaglobulinemia in CLL is not completely understood, but it is somewhat related to a progressive decline in functional B cells and also to a suppression of residual normal B-cell function [19]. Patients with hypogammaglobulinemia have a higher risk for bacterial infections, particularly for those caused by encapsulated organisms [20]. However, hypogammaglobulinemia is not the only reason for infections, since CLL patients with normal serum immunoglobulin levels also have an increased risk for infections [21]. Blood T-cell levels are usually normal
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in untreated CLL patients but diverse functional defects are observed [22]. In particular, the T-cell dysfunction causes a high risk for viral infections. Our patient did not have hypogammaglobulinemia but she had suffered recurrent respiratory tract infections while working with young children. Due to the decreased amount of functional B cells, CLL patients also respond poorly to vaccines that are dependent on adaptive humoral immunity by secretion of highly specific serum IgG antibodies [23]. A low PUUVspecific IgG response has been shown to be associated with disease severity [24]. The PUUV-specific IgG titer of our splenectomized patient was clearly positive whereas the titer of the present patient was borderline positive. Increased capillary permeability and vascular leakage characterize all hantavirus infections but the mechanisms behind them are not yet fully resolved [3,16]. Endothelial cells infected by hantaviruses are found to have increased activation of the kininkallikrein system [25]. This results in the liberation of inflammatory peptide bradykinin, which is an inducer of vascular permeability, edema formation, and hypotension [25,26]. The conversion of prekallikrein to kallikrein may occur via autoactivation of coagulation factor XII (FXII) or independently of FXII [26–28]. Thus a compound that inhibits bradykinin binding or the activity of FXII or kallikrein may prevent vascular leakage encountered in hantavirus infection. The ability of synthetic polypeptide icatibant to act as a selective, competitive antagonist of bradykinin type 2 receptor may explain the beneficial effect observed in severe PUUV infection [9,25]. Interestingly, acquired angioedema mediated by mast cells or bradykinin treatable with icatibant has also been reported to highly associate with lymphoproliferative disorders [29]. The two patients with abnormalities of spleen were both treated with icatibant. They were among the most severely ill cases out of the nearly 600 patients that have been treated in our hospital for acute PUUV infection. Of them, the present case was probably even more critically ill. She had extreme fluid retention and treatment-resistant hypotonia, thus the pharmacokinetics of a drug given subcutaneously might be unpredictable. The uncertainty about the pharmacokinetics of icatibant might explain the long interval between the dosing of the drug and the clear improvement in the patient’s condition. The lymphoproliferative disease affecting especially the rapid clearance of pathogens by the spleen [30] may also have contributed to the slow beginning of the recovery. However, the 2 day delay between the dosing of the drug and the clinical improvement may also suggest that icatibant had no significant role in the recovery.
To conclude, we now have described another patient with an extremely severe PUUV infection and probably deficient spleen function. To predict a severe hantavirus disease, it may be wise to note the patients with spleen abnormalities. The bradykinin receptor antagonist icatibant is worth a further study in the treatment of severe hantavirus infection. Declaration of interest: The authors have no interests to declare. The study received no funding.
References [1] Vaheri A, Henttonen H, Voutilainen L, Mustonen J, Sironen T, Vapalahti O. Hantavirus infections in Europe and their impact on public health. Rev Med Virol 2013;23:35–49. [2] Kariwa H, Yoshimatsu K, Arikawa J. Hantavirus infection in East Asia. Comp Immunol Microbiol Infect Dis 2007; 30:341–56. [3] Mustonen J, Mäkelä S, Outinen T, Laine O, Jylhävä J, Arstila PT, et al. The pathogenesis of nephropathia epidemica: new knowledge and unanswered questions. Antivir Res 2013;100:589–604. [4] Huttunen NP, Mäkelä S, Pokka T, Mustonen J, Uhari M. Systematic literature review of symptoms, signs and severity of serologically confirmed nephropathia epidemica in paediatric and adult patients. Scand J Infect Dis 2011;43: 405–10. [5] Hjertqvist M, Klein SL, Ahlm C, Klingstrom J. Mortality rate patterns for hemorrhagic fever with renal syndrome caused by Puumala virus. Emerg Infect Dis 2010;16:1584–6. [6] Klein SL, Marks MA, Li W, Glass GE, Fang LQ, Ma JQ, et al. Sex differences in the incidence and case fatality rates from hemorrhagic fever with renal syndrome in China, 2004–2008. Clin Infect Dis 2011;52:1414–21. [7] Mustonen J, Partanen J, Kanerva M, Pietilä K, Vapalahti O, Pasternack A, et al. Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Kidney Int 1996;49:217–21. [8] Mäkelä S, Mustonen J, Ala-Houhala I, Hurme M, Partanen J, Vapalahti O, et al. Human leukocyte antigenB8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha (-308) G/A polymorphism. J Infect Dis 2002;186:843–6. [9] Antonen J, Leppänen I, Tenhunen J, Arvola P, Mäkelä S, Vaheri A, et al. A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant. Scand J Infect Dis 2013;45:494–6. [10] Vapalahti O, Lundkvist A, Kallio-Kokko H, Paukku K, Julkunen I, Lankinen H, et al. Antigenic properties and diagnostic potential of puumala virus nucleocapsid protein expressed in insect cells. J Clin Microbiol 1996;34:119–25. [11] Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity 2013;39:806–18. [12] Card J, Outschoorn U. Hypersplenism and hyposplenism. In: Kauhansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U, editors. Williams hematology. New York: McGraw-Hill; 2010 pp 815–17. [13] Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet 2011;378:86–97. [14] William BM, Corazza GR. Hyposplenism: a comprehensive review. Part I: basic concepts and causes. Hematology 2007;12:1–13.
Puumala hantavirus infection, spleen, and icatibant [15] Koskela SM, Laine OK, Paakkala AS, Mäkelä SM, Mustonen JT. Spleen enlargement is a common finding in acute Puumala hantavirus infection and it does not associate with thrombocytopenia. Scand J Infect Dis 2014; 46:723–6. [16] Vaheri A, Strandin T, Hepojoki J, Sironen T, Henttonen H, Mäkelä S, et al. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013;11:539–50. [17] Koivula TT, Tuulasvaara A, Hetemäki I, Mäkelä S, Mustonen J, Sironen T, et al. Regulatory T cell response correlates with the severity of human hantavirus infection. J Infect 2014;68:387–94. [18] Han XY, Hellerstedt BA, Koller CA. Postsplenectomy cytomegalovirus mononucleosis is a distinct clinicopathologic syndrome. Am J Med Sci 2010;339:395–9. [19] Hamblin AD, Hamblin TJ. The immunodeficiency of chronic lymphocytic leukaemia. Br Med Bull 2008;87: 49–62. [20] Travade P, Dusart JD, Cavaroc M, Beytout J, Rey M. [Severe infections associated with chronic lymphoid leukemia. 159 infectious episodes in 60 patients.] Presse Med 1986;15:1715–18 (in French). [21] Moreira J, Rabe KG, Cerhan JR, Kay NE, Wilson JW, Call TG, et al. Infectious complications among individuals with clinical monoclonal B-cell lymphocytosis (MBL): a cohort study of newly diagnosed cases compared to controls. Leukemia 2013;27:136–41. [22] Scrivener S, Goddard RV, Kaminski ER, Prentice AG. Abnormal T-cell function in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma 2003;44:383–9.
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[23] Sinisalo M, Aittoniemi J, Kayhty H, Vilpo J. Vaccination against infections in chronic lymphocytic leukemia. Leuk Lymphoma 2003;44:649–52. [24] Pettersson L, Thunberg T, Rocklov J, Klingstrom J, Evander M, Ahlm C. Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients–implications for treatment. Clin Microbiol Infect 2014;20:235–41. [25] Taylor SL, Wahl-Jensen V, Copeland AM, Jahrling PB, Schmaljohn CS. Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system. PLoS Pathog 2013;9:e1003470. [26] Golias C, Charalabopoulos A, Stagikas D, Charalabopoulos K, Batistatou A. The kinin system—bradykinin: biological effects and clinical implications. Multiple role of the kinin system—bradykinin. Hippokratia 2007;11:124–8. [27] Kaplan AP, Silverberg M. The coagulation-kinin pathway of human plasma. Blood 1987;70:1–15. [28] Joseph K, Tholanikunnel BG, Kaplan AP. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci U S A 2002;99:896–900. [29] Bygum A, Vestergaard H. Acquired angioedema–occurrence, clinical features and associated disorders in a Danish nationwide patient cohort. Int Arch Allergy Immunol 2013;162: 149–55. [30] Hosea SW, Brown EJ, Hamburger MI, Frank MM. Opsonic requirements for intravascular clearance after splenectomy. N Engl J Med 1981;304:245–50.
CASE REPORT
Severe Puumala virus infection in a patient with a lymphoproliferative disease treated with icatibant
OUTI LAINE1,2, ILONA LEPPÄNEN3, SIRPA KOSKELA1, JAAKKO ANTONEN1, SATU MÄKELÄ1, MARJATTA SINISALO1, ANTTI VAHERI4 & JUKKA MUSTONEN1,2 From the 1Department of Internal Medicine, Tampere University Hospital, 2School of Medicine, University of Tampere, 3Department of Anesthesiology and Intensive Care, Tampere University Hospital, Tampere, and 4Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland
Abstract Early identification of patients at risk of a severe course of hantaviral disease and lack of effective medication represent a global challenge in the treatment of this emerging infection. We describe a 67-year-old female patient with a history of chronic lymphoproliferative disease involving the spleen and an extremely severe acute Puumala hantavirus infection. She was treated with the bradykinin receptor antagonist icatibant and recovered. She is the second patient with a spleen abnormality and severe Puumala infection treated with icatibant in our hospital. We suggest that patients with spleen abnormalities may be more susceptible to severe hantavirus disease. The activation of the kinin-kallikrein system and the formation of bradykinin in hantavirus-infected endothelial cells indicate that the role of bradykinin receptor antagonist icatibant in the treatment of hantavirus disease is worth studying.
Keywords: Bradykinin receptor antagonist, hantavirus, icatibant, lymphoproliferative, spleen
Introduction The disease burden caused by hantaviruses is considerable. About 150 000 cases of hemorrhagic fever with renal syndrome (HFRS) are recorded annually in Eurasia and in the most severe forms the mortality rises up to 15% [1,2]. In Europe the most common cause of HFRS is Puumala virus (PUUV) and most reports come from Finland, where the mortality rate is low, ranging from 0.1% to 0.4% [3]. The clinical course of PUUV-HFRS is influenced by host-related characteristics; adult age [4,5], female sex [5,6], and HLA-B8-DR3 haplotype [7,8] being adverse prognostic factors. Biomarkers recently found to predict disease outcome include interleukin-6, pentraxin-3, indoleamine 2,3-dioxygenase, and soluble urokinase-type plasminogen activator receptor [3]. Early detection of potentially severe disease is of clinical value even though the treatment still consists of supportive measures with no specific therapy [3].
Antonen et al. recently reported a severe case of PUUV-HFRS in a 37-year-old Finnish man who had undergone a splenectomy 18 years previously because of congenital spherocytosis [9]. Now we report another patient with probably an even more severe PUUV-HFRS who had a malignant chronic lymphoproliferative disease affecting the spleen. Both patients were medicated with a bradykinin receptor antagonist, icatibant (Firazyr®; Shire Human Genetic Therapies AB, Lund, Sweden), and recovered.
Case report On 13 November 2013 we received a 67-year-old female patient with a history of chronic lymphoproliferative disease since the year 1999 and acute symptoms indicating a severe infection. Morphologically her blood disease was considered either atypical chronic lymphocytic leukemia (CLL) or splenic marginal zone lymphoma. Her CD5-negative lymphocyte
Correspondence: Outi Laine MD PhD, Department of Internal Medicine, Tampere University Hospital, PO Box 2000, FI-33521 Tampere, Finland. Tel: ⫹ 358 50 541 5205. Fax: ⫹ 358 3 311 64388. E-mail: [email protected] (Received 11 June 2014 ; accepted 17 September 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.969304
108
O. Laine et al. were cold from the elbows and knees downwards. Her condition resembled severe sepsis and she was immediately transferred to the intensive care unit (ICU). Laboratory analyses revealed hemoconcentration, leukocytosis (85% neutrophils), thrombocytopenia, hypoalbuminemia, and increased plasma creatinine level (Table I). Plasma alanine aminotransferase rose to 154 U/l (range 10–45 U/l); other liver function tests remained normal. The length of the spleen was 13.3 cm (Table I). Blood cultures remained negative. An acute PUUV infection was serologically confirmed by a high IgM titer detected by μ-capture enzyme-immunoassay (EIA) based on baculovirus-expressed nucleocapsid protein [10]. The PUUV-specific IgG antibody was also positive but the titer was low. In the ICU a severe multi-organ failure was diagnosed. Anuria necessitated continuous renal replacement therapy (CRRT). The patient experienced respiratory failure and mechanical ventilation was started. Capillary leakage was severe and the patient remained hypotonic (mean arterial pressure 50 mmHg) despite the massive fluid replacement. High doses of vasoactive drugs, corticosteroids, albumin infusions, and even wide-spectrum antibiotics were used. No bleeding problems were noted. Despite all the supportive measures the patient’s condition deteriorated and became critical. After one day of treatment in the ICU a 30 mg dose of icatibant was administered subcutaneously. The dose was repeated 6 h later. During the next 48
immunophenotype was atypical for CLL and there were no chromosomal aberrations. The disease had manifested as a splenic enlargement, the maximum length of her spleen being 27 cm as measured by ultrasound in February 2007. She did not have lymphadenopathy, her lymphocyte count was only moderately elevated, and she had had a few episodes of mild autoimmune hemolytic anemia. She did not have hypogammaglobulinemia but she had suffered from pneumonia and several mild upper respiratory tract infections in 2002–2003 while working as a private childminder. Due to symptomatic splenomegaly she received intermittent pharmacotherapy between the years 2000 and 2007 with a good response. Since the cessation of R-CHOP (rituximab, cyclophosphamide, vincristine, and prednisolone) treatment in June 2007 the disease had been inactive and the patient had been asymptomatic. The latest abdominal ultrasound in August 2011 had revealed a normal spleen length of 11 cm. In August 2013 the blood count was normal; 39% of leukocytes were lymphocytes, the absolute value of lymphocytes was 1.9 ⫻ 109/l. Figure 1 illustrates the timescale of the clinical course of the infection. The patient presented with diarrhea and vomiting that had begun 7 days earlier and were followed a couple of days later with high fever. She also complained of blurred vision. She had been oliguric for a couple of days. On admission to the hospital the patient was hypotonic (systolic blood pressure 75–87 mmHg) and her extremities
Fever Hypotonia Anuria CRRT Mechanical ventilation Intensive care unit
Hematocrit max and min
0.59
Platelets min (10E9/l)
34
0.22
CRP max (mg/l)
89
Leukocytes max (10E9/l)
35.5
Creatinine max (µmol/l)
265
Albumin min (g/l)
12 0
2
4
6
8
10
12
14
16
18
20
Days (from the onset of fever) Figure 1. Timescale illustrating the clinical course of a severe case of acute Puumala virus (PUUV) infection. Icatibant 30 mg was administered subcutaneously twice with a 6-h interval on the second day of hospitalization (day 4). CRP, plasma C-reactive protein value; CRRT, continuous renal replacement therapy; max, maximum; min, minimum.
Puumala hantavirus infection, spleen, and icatibant Table I. Laboratory values and radiological findings of a patient with a severe Puumala hantavirus infection.
Variable Blood hematocrit minimum Blood hematocrit maximum Blood leukocytes maximum Blood platelets minimum Serum creatinine maximum Plasma C-reactive protein maximum Plasma albumin minimum Chest X-ray Abdominal ultrasound
Value (reference range) or finding 0.22 0.59 35.5 34 265 89
(0.35–0.46) (0.35–0.46) (3.4–8.2) ⫻ 109/l (150–360) ⫻ 109/l (50–90) μmol/l (0–10) mg/l
12 (36–45) g/l Bilateral pleural effusion and atelectasis An enlarged spleen, length 13.3 cm
h counting from the latter dose the patient’s condition remained critical. However, stabilization could be observed towards the end of the 48 h period and gradual improvement enabled the use of more moderate fluid replacement. Vasopressins could be totally withdrawn 7 days after the administration of icatibant. Due to the substantial amount of bilateral pleural transudate the weaning from mechanical ventilation was unhurried and the patient was extubated only 11 days later. Diuresis started 12 days later and CRRT treatment could be finished after 13 days of treatment. For this extremely severe PUUV-HFRS the patient needed 15 days of care in the ICU and altogether 30 days of care in the university hospital, after which she was transferred for further rehabilitation to a health care center. Two months later two of her toes had to be amputated because of the necrosis that developed during the critical phase of the disease. Five months after the acute phase of the disease she still needs a walker despite the intensive physiotherapy, and is medicated for neuropathic pain. Otherwise she has recovered very well. Her kidney function is normal. The blood count is normal and the CLL is stable without any therapy.
Discussion The spleen is critically engaged in innate and adaptive immune responses against bloodborne bacterial, viral, and fungal infections [11]. It acts as a filter, removing damaged blood cells and foreign particles by its large population of mononuclear phagocytes [12]. Macrophages recognize some bacteria directly, others need to be first opsonized by complement or spleen-derived molecules. The marginal zone of spleen either generates or provides an environment that supports the survival of a population of IgM memory B cells. They are responsible for the production of natural antibodies necessary for the spleen to
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remove the poorly opsonized organisms, such as encapsulated bacteria [13,14]. Our patient with an extremely severe PUUV infection had a malignant CLL-type lymphoproliferative disorder that resembled splenic marginal zone lymphoma. It seems plausible to assume that the disease affecting the spleen may have had an adverse impact on the clinical course of the disease. Spleen enlargement is reported to be associated with several acute viral infections including PUUV infection [15]. The spleen enlargement during acute PUUV infection does not associate with the two main manifestations of the disease, namely thrombocytopenia and acute kidney injury, and it does not seem to relate to the fluid accumulation either [15]. The enlargement, however, is known to associate inversely with the highest blood leukocyte count [15]. Consistently, our patient had a modest enlargement of the spleen compared with the latest preinfection measurement and a notable leukocytosis. The enlargement of the spleen could possibly be a consequence of the proliferation of mononuclear cells as an immune response directed by cytotoxic T lymphocytes, regulatory T cells, and proinflammatory cytokines [3,16,17]. On the other hand, a sizeable spleen may cause pooling of leukocytes thus decreasing the number of leukocytes measured in the blood. Assessment of spleen function in clinical practice is generally based on the morphological alterations of erythrocytes [13]. In the peripheral blood smear Howell-Jolly bodies were not found but some pitted erythrocytes were noted. Lymphoid malignancies are considered a possible cause of hyposplenism, i.e. derangement of the basic functions of the spleen [14]. In postsplenectomy cytomegalovirus mononucleosis the poor control of early viremia is attributed to the lack of splenic filtration and the absence of brisk IgM response [18]. In addition to the present patient with a lymphoproliferative disease affecting the spleen our group has reported a splenectomized patient with a severe PUUV infection, but neither of the patients had a lack of brisk IgM response [9]. In CLL, hypogammaglobulinemia is present in about 25% of patients and has been considered as a main cause for infections in the past. The pathogenesis of hypogammaglobulinemia in CLL is not completely understood, but it is somewhat related to a progressive decline in functional B cells and also to a suppression of residual normal B-cell function [19]. Patients with hypogammaglobulinemia have a higher risk for bacterial infections, particularly for those caused by encapsulated organisms [20]. However, hypogammaglobulinemia is not the only reason for infections, since CLL patients with normal serum immunoglobulin levels also have an increased risk for infections [21]. Blood T-cell levels are usually normal
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in untreated CLL patients but diverse functional defects are observed [22]. In particular, the T-cell dysfunction causes a high risk for viral infections. Our patient did not have hypogammaglobulinemia but she had suffered recurrent respiratory tract infections while working with young children. Due to the decreased amount of functional B cells, CLL patients also respond poorly to vaccines that are dependent on adaptive humoral immunity by secretion of highly specific serum IgG antibodies [23]. A low PUUVspecific IgG response has been shown to be associated with disease severity [24]. The PUUV-specific IgG titer of our splenectomized patient was clearly positive whereas the titer of the present patient was borderline positive. Increased capillary permeability and vascular leakage characterize all hantavirus infections but the mechanisms behind them are not yet fully resolved [3,16]. Endothelial cells infected by hantaviruses are found to have increased activation of the kininkallikrein system [25]. This results in the liberation of inflammatory peptide bradykinin, which is an inducer of vascular permeability, edema formation, and hypotension [25,26]. The conversion of prekallikrein to kallikrein may occur via autoactivation of coagulation factor XII (FXII) or independently of FXII [26–28]. Thus a compound that inhibits bradykinin binding or the activity of FXII or kallikrein may prevent vascular leakage encountered in hantavirus infection. The ability of synthetic polypeptide icatibant to act as a selective, competitive antagonist of bradykinin type 2 receptor may explain the beneficial effect observed in severe PUUV infection [9,25]. Interestingly, acquired angioedema mediated by mast cells or bradykinin treatable with icatibant has also been reported to highly associate with lymphoproliferative disorders [29]. The two patients with abnormalities of spleen were both treated with icatibant. They were among the most severely ill cases out of the nearly 600 patients that have been treated in our hospital for acute PUUV infection. Of them, the present case was probably even more critically ill. She had extreme fluid retention and treatment-resistant hypotonia, thus the pharmacokinetics of a drug given subcutaneously might be unpredictable. The uncertainty about the pharmacokinetics of icatibant might explain the long interval between the dosing of the drug and the clear improvement in the patient’s condition. The lymphoproliferative disease affecting especially the rapid clearance of pathogens by the spleen [30] may also have contributed to the slow beginning of the recovery. However, the 2 day delay between the dosing of the drug and the clinical improvement may also suggest that icatibant had no significant role in the recovery.
To conclude, we now have described another patient with an extremely severe PUUV infection and probably deficient spleen function. To predict a severe hantavirus disease, it may be wise to note the patients with spleen abnormalities. The bradykinin receptor antagonist icatibant is worth a further study in the treatment of severe hantavirus infection. Declaration of interest: The authors have no interests to declare. The study received no funding.
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