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Severe Thrombocytopenia and Response to Corticosteroids in a Case
of Nephropathia Epidemica
Robert Dunst, MD, Thomas Mettang, MD, and Ulrich Kuhlmann, MD ● Nine days after working in the woods, a previously healthy 32-year-old man fell seriously ill. His symptoms
included high fever, chills, diffuse myalgia, severe headache, and back pain. On the fifth day of onset of symptoms,
blood tests showed creatinine levels of 5.4 mg/dL accompanied by marked proteinuria. After admission to the
hospital, a diagnosis of nephropathia epidemica (NE) caused by Puumala virus was made using solid-phase
enzyme-linked immunosorbent assay (ELISA). The patient gradually recovered renal function without requiring
dialysis. However, he surprisingly experienced a sharp decline in platelet count to a minimum of 2,000/
L with
concomitant occurrence of petechiae and conjunctival hemorrhage. Prednisolone was intitiated, resulting in a swift
rise in platelets. Six days later, when the medication was withdrawn, a sharp decrease in platelets recurred. The
steroids were then readministered for the next 3 months, thus reestablishing a stable platelet count. The immediate
rise of platelets after administration of prednisolone supports the pathophysiological view of hantavirus infection
as an immunologically mediated disease. Corticosteroids in the treatment of hantavirus-associated thrombocytope-
nia might need further systematic evaluation.
1998 by the National Kidney Foundation, Inc.
INDEX WORDS: Hantavirus; nephropathia epidemica; Puumala virus; thrombocytopenia; treatment; prednisolone.
UNTIL THE KOREAN War, the clinical umala virus infection can proceed with a highly
manifestation of hantavirus infection, hem- variable course, and sporadic fatal cases have orrhagic fever with renal syndrome (HFRS), did been described.7-11 What follows is the report of not attract much attention. In the following a case of a young man suffering from NE with years, similarities between the so-called Korean associated uncomplicated renal failure but life- hemorrhagic fever1 and other illnesses outside southeast Asia, particularly nephropathia epi-demica (NE) first encountered in Scandinavia,2were noted. Today, hantavirus infection has emerged as a worldwide zoonosis.3 Only re- cently another clinical manifestation of hantavi-rus infection, the hantavirus pulmonary syn- In October 1995, a 32-year-old white man suffering from proteinuria and rapidly deteriorating renal function was drome (HPS), has been described in the United referred to our department. His medical history was unre- markable except for the passage of a kidney stone in 1993.
NE is prevalent in northern and central Europe Five days before admission, the patient reported the and is caused by a specific hantavirus serotype, sudden onset of a high fever (40.5°C), chills, and devastating the so-called Puumala virus. Usually, NE is a muscle pain, particularly in the lower limbs. Two days later, benign disease with virtually no mortality and after being put on clarithromycin, a severe left-sided retrobul- mild hemorrhage at worst.5,6 Mild to moderate bar headache, nausea, and loin pain developed. For painrelief, the patient was prescribed a medication containing thrombocytopenia and acute renal failure are caffeine, acetaminophen, and acetylsalicylic acid; however, common, generally reversible complications not no nonsteroidal anti-inflammatory drugs had been adminis- requiring treatment or dialysis. However, cases tered. He had not been swimming in ponds or rivers but had published in recent years have shown that Pu- been woodcutting in the forest around Schorndorf, Baden-Wu¨rttemberg, on two separate occasions, one 14 days andthe other 6 days before admission. On admission, the patientstill felt weak but reported that his initial complaints had From the Department of Nephrology, Robert Bosch Hospi- disappeared. No reduction in urine volume had been ob- tal, Stuttgart, Federal Republic of Germany. Received November 5, 1996; accepted in revised form Address reprint requests to Robert Dunst, MD, Depart- ment of Nephrology, Robert Bosch Hospital, Auerbachstr. Electrocardiogram was normal. Ultrasound examination 110, D-70376 Stuttgart, Germany.
showed splenomegaly (15.2 ϫ 5.5 cm); kidneys were nor-mal in size but showed increased echogenicity and a gentle ௠ 1998 by the National Kidney Foundation, Inc. subcapsular fluid rim. A chest radiograph was unremarkable.
American Journal of Kidney Diseases, Vol 31, No 1 (January), 1998: pp 116-120 THROMBOCYTOPENIA AND CORTICOSTEROIDS IN NE White blood cell count was 10,900/µL (2% bands, 59% polymorphonuclear leukocytes, 27% lymphocytes, 1% eo-sinophils, 9% monocytes, 2% plasma cells); hemoglobin,149 g/L; platelet count, 62,000/µL; no fragmented red bloodcells were noted; blood urea nitrogen, 50.9 mg/dL; creati-nine, 4.9 mg/dL; uric acid, 9.7 mg/dL; sodium, 132 mmol/L;potassium, 3.8 mmol/L; total protein, 6.3 g/dL; ␥-GT, 111U/L; lactate dehydrogenase, 372 U/L; haptoglobin, 418mg/dL; C-reactive protein, 7.9 mg/dL. Antibodies againsthepatitis A, B, C, and E virus and the hepatitis B surfaceantigen were negative. Within normal limits were calcium,phosphate, transaminases, prothrombin time (PT), and acti-vated partial thromboplastin time (aPTT). Antistreptokinase,antinuclear, and antineutrophil cytoplasmic antibody titers Thrombocytopenia and steroids.
were negative. On urine analysis, protein was 500 mg/dL;leukocytes, 26,000/mL; erythrocytes, 24,000/mL; and phasecontrast microscopic examination showed 14% dysmorphicerythrocytes and 2% acanthocytes. No casts were detected.
2,000/µL), petechiae on the fore edge of the shin were noted.
Solid-phase enzyme immunoassay using recombinant Concomitantly the patient showed conjunctival hemorrhage nucleocapsid antigen of a Puumala serotype and a Hantaan of his right eye, which resolved within 3 days.
serotype strain (Progen Biotechnik GmbH, Heidelberg, At this point, on day 12, the patient received one unit of Germany) enabled the diagnosis of nephropathia epidemica packed thrombocytes, resulting in no increase in thrombo- caused by a Puumala serotype (Table 1). The results were cyte count (2,000/µL) after 6 hours. The same day, intrave- expressed as the ratio of the photometric extinction of nous administration of prednisolone (100 mg daily) was patient serum and a reference control.
The following day, the thrombocyte count rose to 4,000/ µL, and 6 days later (by day 18) had risen to 40,000/µL. Byway of trial, medication was then stopped, only to have the The patient never did show any uremic symptoms and did thrombocyte count drop to 9,000/µL by day 21. Predniso- not require dialysis. Creatinine had risen to its maximum lone was then reinitiated at a continuous dose of 100 mg per (5.8 mg/dL) on day 7 (days were counted beginning with the day, and by day 27, the day of discharge, thrombocytes had onset of symptoms) but had returned to normal (1.4 mg/dL) recovered to 88,000/µL. Renal studies were within normal on day 14. However, the thrombocyte count showed a limits, although slight proteinuria persisted.
dramatic decline from 62,000/µL on day 6 to 2,000/µL on In an outpatient setting, the patient was doing reasonably day 12 (Fig 1). Ethylenediaminetetraacetic acid–induced well except for the occurrence of prednisolone-induced thrombocytopenia was ruled out by evaluating thrombocytes Cushing’s disease and a slightly elevated blood pressure, in citrated blood. PT and aPTT were normal, as was the which was treated with hydrochlorothiazide. When platelets fibrinogen level (344 mg/dL), but fibrin D-dimers were reached a high of 126,000/µL on day 30, prednisolone was found to be increased to 8.0 mg/L (normal, Ͻ0.5 mg/L). A slowly tapered off over a period of 11 weeks. After bone marrow sample disclosed that thrombopoiesis was discontinuation of steroids on day 105, the patient’s platelet slightly increased, and megakaryocytes of all stages could counts remained normal (day 117; 206,000/µL; see Fig 1).
be observed. Granulopoiesis and erythropoiesis were nor- Twenty months after the initial episode, proteinuria had mal. Studies done by Mueller-Eckhardt of Gießen did not completely resolved. Platelets and renal function were detect any free antithrombocyte antibodies and showed normal. However, labile hypertension with blood pressure normal immunoglobulin (Ig) G covering of glycoprotein values up to 160/90 mm Hg required close follow-up. At this point HLA typing showed the patient being negative for On day 10 (thrombocytes, 3,000/µL), the patient devel- oped petechiae to his soft palate. On day 12 (thrombocytes, Table 1. Serological Data
NE is the European type of HFRS. However, hemorrhagic manifestations in NE are rare and mild if present. In general, they consist of petechiae (present in 2% to 12% of patients atrisk),5,12 conjunctival bleeding (6% to 12%),5,13 and epistaxis (1% to 28%).13,14 Moderate to severe gastrointestinal bleeding (melena, he- matemesis) was seen in 2% to 3% of infected *Values Ͼ1.5 are considered positive.
patients.5,13 Macroscopic hematuria, hemoptysis, Table 2. Association of Severe Complications in NE
typical clinical manifestation of Puumala virus With Thrombocytopenia
infection as meticulously delineated by La¨h-devirta.2 After the acute onset with fever, chills, myalgia, headache, back pain, and nausea, fi- nally renal failure developed. Remarkable, and very unusual, was the profound decrease of platelets (down to 2,000/µL) on the 12th day of the disease without clear-cut clinical evidence of Anticipating other disorders predisposing thrombocytopenia, a bone marrow sample of ourpatient ruled out diminished platelet production.
and ecchymoses occasionally occur. In the Asian In light of possible interstitial nephritis, drug- type of HFRS, hemorrhagic complications con- induced thrombocytopenia then had to be the tribute in a significant proportion of cases to the primary suspect explaining increased platelet consumption. Directly before admission, the NE has long been considered a benign disease patient was taking clarithromycin and a combina- normally associated with no mortality.5,13 How- tion of acetylsalicylic acid, acetaminophen, and ever, severe complications and sporadic fatal caffeine. The administration of all of these drugs cases have been reported in recent years (Table could be associated with thrombocytopenia; nev- 2). All of them were associated with severe ertheless, in absolute terms, the probability would thrombocytopenia (9,000 to 37,000/µL). Five of be extremely low. Some minor evidence against these six fatalities showed laboratory data sug- drug-induced thrombocytopenia was the absence gesting disseminated intravascular coagulation of the rise of platelets after discontinuation of the (DIC). In Belgium, a growing number of NE drugs. Other conditions were ruled out by labora- cases were complicated by pulmonary edema tory results or on clinical grounds.
cause of bleeding has been noted in 20% to 70% General causes of thrombocytopenia in a viral of European patients.2,5 Platelet counts below infection may include impaired platelet produc- 30,000/µL were very rare, with lowest values tion, vasculopathy, DIC, and a variety of immune ranging between 6,000 and 26,000/µL in some of the larger study populations (Table 3). In Asian Vascular dysfunction most likely attributed to studies, thrombocytopenia occurred in 69% to virus replication in the endothelium is the hall- mark of the pathophysiological derangements in At its outset, the case reported here reflects the HFRS.19 It not only accounts for hemorrhagiccomplications and renal failure; it can also Table 3. Thrombocytopenia in HFRS
The diagnosis of DIC can usually be made by careful consideration of both the clinical situa- tion and laboratory data. The best screening tests for DIC are measurements of the fibrin degrada-tion products (FDP), PT, fibrinogen level, and platelet count.20 The situation in our thrombope- nic patient first disclosed some contradictory aspects. As an indicator of reactive hyperfibri- nolysis in late-stage DIC, FDP (d-dimeric form) were elevated. The normal fibrinogen could not rule out DIC because fibrinogen is also an THROMBOCYTOPENIA AND CORTICOSTEROIDS IN NE acute-phase protein with the possibility of pseudo- developed normal platelet counts, which per- normal levels. However, the absence of major sisted after discontinuation of the drug 3 months bleeding, shock, and early-stage laboratory mark- later. Circulating immune complexes were in- ers such as prolonged PT or aPTT militated deed observed in some patients up to 8 months after onset of NE. Almost 2 years after the acute (d-dimeric form) have been described as being phase of the disease, the patient was asymptom- falsely positive in about 20% of patients.21 In atic except for labile arterial hypertension. In- renal failure, elevated levels of FDP are often deed, hantavirus infections might account for a primarily related to delayed clearance rather than certain percentage of chronic renal disease or A growing body of data support the view of The response to treatment with steroids is further evidence of the immunologically medi- ease.3,19 Specific immune mechanisms such as ated pathogenesis of the disease. Immune com- early IgE production, T cell activation, and plexes activate the classical complement path- activation of both the classical and alternative way. The action of corticosteroids does not complement pathways have been identified. Im- significantly decrease the concentration of circu- mune complexes were shown especially in se- lating antibodies; it rather interrupts cytokine- rum,15 and on renal tubules and glomeruli23 of affected patients. Of particular interest in our leukocytes.27 As one consequence, complement- setting was the demonstration of immune com- triggered phagocytosis of immune complex– plexes on platelets.24,25 By activating comple- loaded thrombocytes might be decreased.
ment, triggering mediator release, and inducing More systematic investigations on the action platelet aggregation, they could result in further of corticosteroids in HFRS seem to be warranted.
thrombocytopenia and vascular injury. However, some immunologic findings such as missingperivascular infiltrates of mononuclear cells and The authors thank Maurice Mareschal for reviewing the others differ from those seen in classic immune- Only recently an association of certain major 1. Lee JS: Clinical features of hemorrhagic fever with histocombatibility complex markers (HLA B8 renal syndrome in Korea. Kidney Int 40:S88-S93, 1991 2. La¨hdevirta J: Nephropathia epidemica in Finland: A DRB1*0301 haplotype is very strongly associ- clinical, histological and epidemiological study. Ann Clin ated with various autoimmune diseases.26 These 3. Papadimitriou M: Hantavirus nephropathy. Kidney Int results probably imply that the immune system of the host contributes to the damage seen in 4. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Puumala virus infection. A vigorous immune Ksiazek TG, Feldmann H, Sanchez A, Childs J, Zaki S, response can be considered a predisposing factor Peters CJ: Genetic identification of a hantavirus associatedwith an outbreak of acute respiratory illness. Science of more severe disease. However, our patient 5. Mustonen J, Brummer-Korvenkontio M, Hedman K, Considering platelet-associated immune com- Pasternack A, Pietila¨ K, Vaheri A: Nephropathia epidemica plexes as a possible cause of thrombocytopenia, in Finland: A retrospective study of 126 cases. Scand J Infect the patient was started on 100 mg prednisolone 6. Mettang T, Weber J, Kuhlmann U: Akutes Nierenversa- intravenously. After 6 days, an increase in plate- gen durch Hantavirus-Infektion. Dtsch Med Wochenschr lets from 2,000/µL to 40,000/µL was noted. The close relationship between corticosteroid therapy 7. Zeier M, Zo¨ller L, Weinreich T, Padberg-Wolf E, and thrombocyte count was shown when, 3 days Andrassy K, Ritz E: Severe hemorrhagic complications after discontinuation of the drug, the platelet from infection with nephropathia epidemica strain of Hanta-virus. Clin Nephrol 38:190-192, 1992 count fell sharply from 40,000/µL to 9,000/µL.
8. Pilaski J, Feldmann H, Morzunov S, Rollin PE, Ruo SL, Lauer B, Peters CJ, Nichol ST: Genetic identification of therapy at 100 mg each day orally, the patient a new Puumala virus strain causing severe hemorrhagic fever with renal syndrome in Germany. J Infect Dis 170:1456- thrombokinetics in Korean hemorrhagic fever. Seoul J Med 9. Linderholm M, Settergren Bo, Ahlm C, Burman L-A, 19. Cosgriff TM, Lewis RM: Mechanisms of disease in Tra¨ff S, Ba¨cklund U, Juto P: A Swedish fatal case of hemorrhagic fever with renal syndrome. Kidney Int 40:S72- nephropathia epidemica. Scand J Infect Dis 23:501-502, 20. Williams EC, Mosher DF: Disseminated intravascu- 10. Forslund T, Saltevo J, Anttinen J, Auvinen S, Brum- lar coagulation, in Hoffman R, Benz EJ, Shattil SJ, Furie B, mer-Korvenkontio M, Korhonen A, Poutiainen M: Compli- Cohen HJ, Silberstein LE (eds): Hematology. New York, cations of nephropathia epidemica: Three cases. J Intern NY, Churchill Livingstone, 1995, pp 1758-1769 21. Bick RL, Baker WF: Diagnostic efficacy of the 11. Valtonen M, Kauppila M, Kotilainen P, La¨hdevirta J, D-dimer assay in disseminated intravascular coagulation.
Svartba¨ck C-M, Kosunen O, Nurminen J, Sarkkinen H, Brummer-Korvenkontio M: Four fatal cases of nephropathia 22. Lane D, Ireland H, Knight I, Wolff S, Kyle P, Curtis epidemica. Scand J Infect Dis 27:515-517, 1995 JR: The significance of fibrinogen derivatives in plasma in 12. Pilaski J, Ellerich C, Kreutzer T, Lang A, Benik W, human renal failure. Br J Haematol 56:251-260, 1984 Pohl-Koppe A, Bode L, Vanek E, Autenrieth IB, Bigos K, 23. Hung T, Zhou J-Y, Tang Y-M, Zhao T-X, Baek LJ, Lee HW: Haemorrhagic fever with renal syndrome in Lee HW: Identification of Hantaan virus-related structures in kidneys of cadavers with hemorrhagic fever with renal 13. Settergren B, Juto P, Trollfors B, Wadell G, Norby SR: Hemorrhagic complications and other clinical findings 24. Yang P: Measurement of platelet function and detec- in nephropathia epidemica in Sweden: A study of 355 tion of specific immune complexes on platelet surfaces in serologically verified cases. J Infect Dis 157:380-382, 1988 epidemic hemorrhagic fever. Shanghai Med J 7:275-278, 14. Settergren B, Juto P, Trollfors B, Wadell G, Norrby SR: Clinical characteristics of nephropathia epidemica in 25. Yang P, Sun T, Wu C, Wang J, Xu Z, Chen B, Zhou G: Sweden: Prospective study of 74 cases. Rev Infect Dis A study on the pathogenesis of hemorrhage in epidemic hemorrhagic fever. Acta Academiae Medicinae Shanghai 15. Lee M, Kim BK, Kim S, Park S, Han JS, Kim ST, Lee JS: Coagulopathy in hemorrhagic fever with renal syndrome 26. Mustonen J, Partanen J, Kanerva M, Pietila¨ K, (Korean hemorrhagic fever). Rev Infect Dis 11:S877-S883, Vapalahti O, Pasternack A, Vaheri A: Genetic susceptibility to severe course of nephropathia epidemica caused by 16. Mustonen J, Vaheri A, Clement J: Third International Puumala hantavirus. Kidney Int 49:217-221, 1996 Conference on Haemorrhagic Fever With Renal Syndrome 27. Schimmer BP, Parker KL: Adrenocorticotropic hor- (HFRS) and Hantaviruses. Nephrol Dial Transplant 11:730- mone: Adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical 17. Becker C, Goubeaud G, Zeier M, Zo¨ller L: Hantavirus- hormones, in Hardman JG, Goodman Gilman A, Limbird Infektionen und chronische Niereninsuffizienz. Med Welt LE (eds): Goodman’s & Gilman’s The Pharmalogical Basis of Therapeutics. New York, NY, McGraw-Hill, 1996, pp 18. Park S, Kim BK, Lee JS, Lee M: A study on


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