Case Report
Acalculous cholecystitis associated with hemorrhagic fever with renal syndrome J. B. Nicolas Department of General Internal Medicine, CHU Dinant Godinne UCL Namur, Yvoir, Belgium Hantaviruses are responsible for various types of hemorrhagic fevers depending on the involved subtype. In Europe, Puumala virus is responsible for an epidemic nephropathy. This infection can be complicated by severe abdominal pain. A rarely reported cause of this presenting symptom is acalculous cholecystitis, which must be integrated in the clinicobiological spectrum and should not lead to a surgical sanction. Its presence seems to be correlated with the severity of the disease, whose main pathophysiological phenomenon is plasma leakage induced by a microvascular endothelial dysfunction. We report the case of a young male patient who presented with severe hantavirus infection complicated by acalculous cholecystitis. Keywords: Epidemic nephropathy, Hemorrhagic fever, Hantavirus pulmonary syndrome, Puumala, Acalculous cholecystitis, Plasma leakage, Endothelial dysfunction
Introduction Hantaviruses belong to the Bunyaviridae family. In Europe, the most prevalent subtype is Puumala virus (PUUV), which is mainly transmitted to humans by the red bank vole (Myodes glareolus) living in forests, copses and hedges. It causes a mild form of hemorrhagic fever with renal syndrome (HFRS), whose spectrum of severity is very wide, going from unapparent infection (in the vast majority of cases), over different grades of acute but transient kidney injury (AKI) and in exceptional cases, even up to death in multi-organ failure. Cardiopulmonary syndrome is less frequent with the PUUV subtype. PUUV infection, like any other form of hantavirus disease (HTVD), is often accompanied by severe abdominal pain as presenting symptom before AKI installs. A rarely reported cause of these is acalculous cholecystitis, which is defined by a thickening of the gallbladder wall over 4 mm without associated lithiasis and of spontaneous resolution.
Case Description An 18-year-old male patient presented to emergency room in October 2012, in a context of flu-like syndrome with fever, chills and frontal headache that began 6 days ago [ 5 day 0, corresponding to the onset of symptoms, the following clinical hallmarks and lab data will thus be expressed in days Correspondence to: Dr Jean-Baptiste Nicolas, Department of General Internal Medicine, CHU Dinant Godinne UCL Namur, Yvoir, Belgium. Email: [email protected].
ß Acta Clinica Belgica 2015
post-onset of symptoms (POS)]. On 3 days POS appeared disabling pain in the right upper quadrant. Systematic history found an anorexia without any other digestive complaint, disappearance of fever since the day before, a notion of transient and recent blurred vision without photo-phonophobia, absence of cardio-respiratory and urinary complaint, except of a darker urine colour, absence of recent abroad travel, animal bite or sting. We did not note any walk in the woods, no passage in a cellar, attic, stable, lodge or other poorly ventilated space. He, however, had a picnic in the park of a castle 6 days earlier, in the Belgian Condroz, near the city of Ciney. The patient had no remarkable medical or surgical history. He was neither taking any medication nor illicit drug. Physical examination on admission (6 days POS) found a blood pressure at 125/65 mmHg, heart rate at 98/min, temperature at 37.6uuC, pulse oxygen saturation in ambient air at 98% and weight at 84 kg. The patient presented signs of extracellular dehydration with dry mucous membranes and lazy skin fold. Cardiopulmonary auscultation was unremarkable. The abdomen was painful to deep palpation in the right upper quadrant with a positive Murphy’s sign without clinical signs of peritoneal irritation. Peristalsis was slowed. Lumbar percussion was painful on the right side. The admission blood sample objectified the following pathologic results: C-reactive protein increased to 43.5 mg/l, leukocytosis at 11 770/ml with 3190 lymphocytes and 2272 monocytes, platelets significantly
Nicolas
Acalculous cholecystitis associated with hantavirus infection
lowered to 48 000/ml, fibrinogen increased to 463 mg/ dl, mild hyponatremia at 136 mEq/l, impaired renal function with urea at 65 mg/dl and creatinine at 2.1 mg/dl (or a calculated estimation of glomerular filtration rate using MDRD at 43.94 ml/min/ 1.73 m2), total and direct bilirubin slightly increased to, respectively, 1.44 and 0.64 mg/dl, serum iron was lowered to 47 mg/dl and ferritin increased to 2914 mg/dl. A urine dipstick performed at admission showed an estimated proteinuria and haematuria at three z, confirmed by microscopic analysis (10–20 RC/field). The rest of the urinary sediment was unremarkable. A urinary sample performed by the GP on 4 days POS already showed pathologic proteinuria at 0.45 g/l (nlv0.1 g/l). A chest X-ray upon admission was unremarkable. An abdominal ultrasound performed in emergency room (Fig. 1) showed a thickened gallbladder wall measured at 5 mm and characterised by a discreetly laminated appearance, the so-called reticular pattern.1,2 No dilatation of intrahepatic or extrahepatic biliary ducts was noted. Millimetric hyperechogenic rounded structure was noted up to its front wall (cholesterol granuloma in the first hypothesis). Pancreas looked banal. There was no dilatation of the pyelocaliceal cavities. We noted a discreetly dedifferentiation of both kidneys, which were not swollen (bipolar axial echographic length measured at 12 cm for the right kidney and at 11 cm for the left one). A small liquid blade on the lower side of the right kidney was observed. The patient was then admitted to the general internal medicine service for further support. Differential diagnosis arose between hantavirus infection and leptospirosis. For acute and/or convalescent seroconfirmation of a recent PUUV hantavirus
infection, specific anti-PUUV IgM, and respectively IgG antibodies were scheduled in ELISA screening technique. A treatment with ceftriaxone 2 g/day and metronidazole 500 mg 3 times/day was started empirically pending serology and clinicobiological evolution. Further evolution has been marked by a rapid deterioration of renal function (creatininemia at 5.6 mg/dl on 7 days POS, 8.7 mg/dl on 8 days POS, 11.3 mg/dl on 9 days POS, nl v1.25 mg/dl), reaching a plateau of 11.8 mg/dl on 10 days POS (with urea at 156 mg/dl). At this time, the level of bicarbonate was 17 mEq/l. The patient did neither develop hypo- or hyperkaliemia nor clinical fluid overload. A blood gas analysis on 10 days POS showed arterial pH 7.30, paO2 90 mmHg, paCO2 38 mmHg and base excess – 7.1 mmol/l; this slight hypoxaemia implies an indeniable component of transient acute lung injury (ALI), often seen together with AKI, as in this case report.3–6 Creatinine level then decreased rapidly without the need for recourse to renal replacement therapy, falling to 1.1 mg/dl (urea 24 mg/dl) on 16 days POS, day of hospital discharge. In parallel, platelet count (initially 48 000/ml, nl 150 000–400 000/ml) gradually increased to correct on 10 days POS (170 000/ml). C-reactive protein reached a maximum of 106 mg/l on 9 days POS (nl v5 mg/l) and normalised on 16 days POS. Plasma sodium reached a minimum of 130 mEq/l on 8 days POS (nl 137–145 mEq/l) (due to diminished sodium reabsorption in the proximal tubule7) and a maximum of 146 mEq/l on 15 days POS (context of osmotic polyuria). Albuminaemia fell rapidly until 23.20 g/l on 9 days POS, in a context of nephrotic range proteinuria over 4 g/24 hours. Lactate dehydrogenase (LDH) levels also increased significantly until 1133 IU/l on 10 days POS (nl 313–618 IU/l)
Figure 1 Thickened gallbladder wall measured at 5 mm and characterised by a discreetly laminated appearance.
Nicolas
and were still high at 989 IU/l at discharge. Lipase level, normal at admission, increased until 886 IU/l on 16 days POS (nl 23–300 IU/l) and even remained high at 974 IU/l on a control sample made on 25 days POS, while the patient was asymptomatic. Urinary outflow measured by 24 hours found a minimum of 650 ml on 9 days POS, then increased rapidly to 4900 ml on 13 days POS, with an in–out balance at – 2200 ml over the 24 hours and a weight loss of 1.7 kg in 24 hours, occurring in a context of osmotic polyuria. Minimum blood pressure was measured at 120/ 70 mmHg on 6 days POS and maximum at 180/ 110 mmHg on 13 days POS, this last value justifying a short treatment with amlodipine 5 mg, given the concomitant appearance of headache without meningeal signs. Body weight found a maximum of 86.3 kg on 10 days POS and a minimum of 80.2 kg on 25 days POS. Maximum tympanic temperature was measured at 37.9uuC on 6 days POS. Comparative evolution of major biological and clinical parameters is summarised in Table 1. In terms of treatment, no renal replacement therapy was initiated. The patient benefitted from fluid restriction adapted to in–out balance (balance between 0 and z500 ml over the 24 hours) during the oliguric phase and from hyperhydration during the polyuric phase. Antibiotherapy by ceftriaxone and metronidazole was interrupted on 8 days POS due to lack of sufficient arguments to continue. Puumala virus serology returned positive for IgG (ratio 6.74, positive w1.50) and IgM (ratio 9.26, positive w2.00) on 11 days POS. Leptospirosis serology was cancelled.
Acalculous cholecystitis associated with hantavirus infection
Patient had invalidating pain in the right upper quadrant related to acalculous cholecystitis initially described. Pain was relieved by the administration of IV pethidine until 400 mg/24 h. Pethidine could be stopped on 13 days POS and pain persisted until 15 days POS. Administration of morphine derivatives led to multiple side effects like several episodes of urinary retention, nausea and obstinate constipation. There was no need for cholecystectomy, since no criterion was met. Patient was discharged on 16 days POS and reviewed in consultation 25 days POS. Clinical examination was quite normal at that time.
Discussion This case is remarkable from several points of view. First, it reports a case of acalculous cholecystitis associated with hantavirus infection, which is a rarely described entity. To the best of our knowledge, there are two case reports8,9 and a South Korean series10 relating the association misunderstood. These suggested that a gallblader wall thickening greater than or equal to 4 mm was significantly associated with more severe disease (platelet count and albumin significantly lower, significantly higher levels of aspartate aminotransferase (ASAT) and LDH, higher incidence of severe renal failure requiring haemodialysis), and that this thickening could therefore be useful in predicting the severity of HTVD. This is true in our patient, apart from the fact that the severe acute renal failure did not meet the criteria of renal replacement therapy. But, we know that only 5% of hospitalised PUUV-infected patients require dialysis and some prolonged intensive-care treatment.11
Table 1 Comparative evolution of biological and clinical parameters. Days POS
3
6
7
8
9
11
13
15
16
25
Creatinine (mg/dl) nl 0.66–1.25 Urea (mg/dl) nl 19–43 Cl Creat (mL/min) nl w90 Na (mEq/l) nl 137–145 K (mEq/l) nl 3.5–5.1 HCO{ 3 (mmol/l) nl 22–30 P (mg/dl) nl 2.5–4.5 Mg (mg/dl) nl 1.6–2.3 Platelets (|103/ml) nl 150–400 CRP (mg/l) nl v5.0 Albumin (g/l) nl 37.00–53.00 LDH (IU/l) nl 313–618 Lipases (IU/l) nl 23–300 Amylases (IU/l) nl 30–110 Urinary outflow (ml/24 hours) Weight (kg) Max BP (mmHg) 140/100 Max Tuu (uuC) Abdominal pain (max AVS)
0.81 35 126
2.1 65 68 136
263 16.4
220 8.4
1.0 26 143 141 4.6 28.0 4.2 1.8 256 v1.0
923 879 163
11.7 155 12 134 3.9 19.0 8.2 2.4 196 60.0 25.73 814
1.1 24 130 145 4.3 27.0 3.8 1.2 220 5.0
804 44 55
11.3 143 13 130 3.9 20.0 7.3 2.2 124 106.4 23.20 729 157 84
1.3 28 110 146 4.3 26.0
48 43.5
8.7 119 16 130 3.6 20.0 6.1 2.1 81 95.5 25.05 824 243 125 650
3.2 83 45 144 4.7 24.0
40
5.6 97 25 135 4.2 24.0 4.8 2.2 53 89.1
833
989 886
470 974
2750
3300
1700
37.4 0/10
84 120/70
130/80
170/120
150/110
145/85
180/110
5000 83 180/100
37.9 3/10
36.9 8/10
36.7 5/10
36.9 6/10
37.1 3/10
37.6 0/10
37.5 3/10
80.2 160/100
0/10
POS: post-onset of symptoms; nl: normal values; Cl Creat: estimated creatinine clearance by Cockroft–Gault formula; Na: sodium; K: potassium; HCO{ 3 : bicarbonates; P: phosphorus; Mg: magnesium; CRP: C-reactive protein; LDH: lactate dehydrogenase; Max BP: highest value of blood pressure over the 24 hours; Max Tuu: highest value of auricular body temperature over the 24 hours; Max AVS: highest value of visual analogue scale over the 24 hours.
Nicolas
Acalculous cholecystitis associated with hantavirus infection
These acalculous cholecystitis occurring in the context of viral infection usually resolve spontaneously and should not lead to unnecessary surgery. In terms of pathophysiology, the most likely and the most frequently cited mechanism is a phenomenon of plasma leakage, leading to oedematous swelling of various organs, especially the kidneys.8,12–15 Serositis is also possible in severe cases with pleural and/or peritoneal effusion. It is very likely that the thickening of the gallbladder wall is the consequence of the same mechanism. This hypothesis should be confirmed if possible on surgical or autopsy pieces, by identifying deposit of immune complexes, oedema, hantavirus perinuclear inclusions in endothelial cells, P-bodies, ... South American Andes virus (ANDV) infection of Syrian hamsters is currently the only animal model of hantavirus pathogenesis that closely mimics human disease, but it causes hantavirus pulmonary syndrome (HPS), and is not suitable for the study of HFRS. However, it should be interesting to observe the gallbladder of these infected hamsters.16 The plasma leakage is secondary to the occurrence of endothelial dysfunction predominant in microvascular beds of lungs and kidneys. This endothelial dysfunction seems to be the consequence of a particular tropism of hantavirus for endothelial cells, which internalise it, especially via a beta-3 integrin turned inactive, this one losing its ability to interact with the vascular endothelial growth factor receptor (VEGF receptor).13 This results in a powerful increase of the effect of VEGF on endothelial cell permeability. Indeed, several studies have shown internalisation of vascular endothelial-cadherins (VE-cadherins),13 essential molecules to the formation of the junction between endothelial cells, as a result of interaction between VEGF and receptor VEGFR2. The result is a disassembly of intercellular junctions and hyperpermeability of the endothelial barrier. This is really a dysfunction, most of the time reversible and not cell destruction. Several studies also suggest an increase in VEGF levels during the acute phase of the disease, with a peak corresponding to the peak serum creatinine, but also during the recovery phase, and especially in severely ill patients, suggesting also a protective role of VEGF, especially in kidney recovery.12 Several therapeutic interventions targetting endothelial protection have yet to be investigated, in particular, the way of microRNAs.13 Thrombocytopaenia, almost invariably described in the first phase of infection, should also come from the interaction of platelets with endothelial cells covered with hantavirus through inactivated beta-3 integrins.13 Another noteworthy element in our patient is the occurrence of a biological pancreatitis, with elevated
lipase more than three times the norm, with this elevation predominating on 25 days POS, or at a time when the patient became asymptomatic. Exactly the same unexplained phenomenon of so-called ‘‘late onset chemical, but not clinical pancreatitis’’ was already observed in 2/62 cases of the 1993 HFRS (PUUV) outbreak in South-Belgium.17 Real pancreatitis, i.e. also confirmed by typical changes on medical imaging, has only very rarely been documented so far. Zhu et al. reported two cases of severe, medical imaging-confirmed, pancreatitis, in which the striking particularity was that serum amylases started rising only after all other (including renal) parameters were normalising, as in our case report.18 It is possible that this results from the same mechanism of endothelial hyperpermeability, with plasma leakage causing transient slight oedematous pancreatitis.19 We therefore believe that the severity of HTVD is correlated with the intensity of the plasma leakage, which can, as we have seen, be apprehended by the clinical and some simple additional tests, i.e. biology, abdominal ultrasound and chest radiography. It would be interesting to elaborate a severity score that would take into account, e.g. platelet count at admission, presence or absence of serositis or thickened gallbladder wall, LDH level, possibly levels of albumin and lipases. This could be predictive of the severity of the disease, including the possible need of renal replacement therapy or intensive-care admission.
Conclusion This case relates the occurrence of acalculous cholecystitis and acute biological pancreatitis in a patient with HFRS, this association supporting the hypothesis of endothelial dysfunction with plasma leakage as the main pathophysiological mechanism of HTVD. The development of a severity score at admission, based, in particular, on the presence of a thickened gallbladder wall and biological parameters, could help in predicting the need and duration of hospitalisation and the possible need of renal replacement therapy.
Disclaimer Statements Funding None. Conflicts of interest None. Ethics approval None required.
References 1 Ziraman I, Celikbas A, Ergonul O, Degirmenci T, Uyanik SA, Koparal S, et al. Crimean-Congo hemorrhagic fever: aid of abdominal ultrasonography in prediction of severity. Vector Borne Zoonotic Dis. 2014;14(11):817–20. 2 Tufan ZK, Yigit H, Kacar M, Bulut C, Canpolat G, Hatipoglu CA, et al. Sonographic findings in patients with CrimeanCongo hemorrhagic fever. J Ultrasound Med. 2014;33(11):1999–2003.
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3 Clement J, Colson P, Mc Kenna P. Hantavirus pulmonary syndrome in New England and Europe. N Eng J Med. 1994;331:545–546. [Discussion 547–8]. 4 Bateman WA, Clement JP, Solano RK, Vanherweghem JL, van der Groen G. Hemorrhagic fever with renal syndrome in a Canadian serviceman. CMAJ. 1990;143:38–40. 5 Gizzi M, Delaere B, Weynand B, Clement J, Maes P, Vergote V, et al. Another case of ‘‘European hantavirus pulmonary syndrome’’ with severe lung, prior to kidney, involvement, and diagnosed by viral inclusions in lung macrophages. Eur J Clin Microbiol Infect Dis. 2013;32(10):1341–5. 6 Clement J, Maes P, Van Ranst M. Hemorrhagic fever with renal syndrome in the new, and hantavirus pulmonary syndrome in the old world: Paradi(se)gm lost or regained? Virus Res. 2014;187:55–8. 7 Clement J, Maes P, Van Ranst M. Acute kidney injury in emerging, non-tropical infections. Acta Clin Belg. 2007;62:387–95. 8 Keyaerts E, Ghijsels E, Lemey P, Maes P, Zache´e P, Daelemans R, et al. Plasma exchange-associated immunoglobulin m-negative hantavirus disease after a camping holiday in southern France. Clin Infect Dis. 2004;38(10):1350–6. 9 Fro¨hlich R, Ro¨mmele U. Acalculous cholecystitis in hantavirus infections. Dtsch Med Wochenschr. 2013;138(23):1255–8. 10 Kim YO, Chun KA, Choi JY, Yoon SA, Yang CW, Kim KT, et al. Sonographic evaluation of gallbladder-wall thickening in hemorrhagic fever with renal syndrome: prediction of disease severity. J Clin Ultrasound. 2001;29(5):286–9. 11 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(1):35–49.
Acalculous cholecystitis associated with hantavirus infection
12 Ma Y, Liu B, Yuan B, Wang J, Yu H, Zhang Y, et al. Sustained high level of serum VEGF at convalescent stage contributes to the renal recovery after HTNV infection in patients with hemorrhagic fever with renal syndrome. Clin Dev Immunol. 2012;2012:812386. 13 Mackow ER, Gavrilovskaya IN. Hantavirus regulation of endothelial cell functions. Thromb Haemost. 2009;102(6):1030–41. 14 Tseng CS, Lo HW, Teng HC, Lo WC, Ker CG. Elevated levels of plasma VEGF in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol. 2005;43(1):99–102. 15 Sathupan P, Khongphattanayothin A, Srisai J, Srikaew K, Poovorawan Y. The role of vascular endothelial growth factor leading to vascular leakage in children with dengue virus infection. Ann Trop Paediatr. 2007;27(3):179–84. 16 Hooper JW, Larsen T, Custer DM, Schmaljohn CS. A lethal disease model for hantavirus pulmonary syndrome. Virology. 2001;289:6–14. 17 Damoiseaux P, Brisbois J, Duvivier E, Levecque P, Roger JM, Bouilliez DJ, et al. Epidemic of hantavirus disease in EntreSambre-et-Meuse: year 1992-1993. Clinical and biological aspects. Act Clin Belg. 1995;50:197–205. 18 Zhu Y, Chen YX, Zhu Y, Liu P, Zeng H, Lu NH. A retrospective study of acute pancreatitis in patients with hemorrhagic fever with renal syndrome. BMC Gastroenterol. 2013;13:171. 19 Park KH, Kang YU, Kang SJ, Jung YS, Jang HC, Jung SI. Short report: experience with extrarenal manifestations of hemorrhagic fever with renal syndrome in a tertiary care hospital in South Korea. Am J Trop Med Hyg. 2011;13:229–33.
Acalculous cholecystitis associated with hemorrhagic fever with renal syndrome J. B. Nicolas Department of General Internal Medicine, CHU Dinant Godinne UCL Namur, Yvoir, Belgium Hantaviruses are responsible for various types of hemorrhagic fevers depending on the involved subtype. In Europe, Puumala virus is responsible for an epidemic nephropathy. This infection can be complicated by severe abdominal pain. A rarely reported cause of this presenting symptom is acalculous cholecystitis, which must be integrated in the clinicobiological spectrum and should not lead to a surgical sanction. Its presence seems to be correlated with the severity of the disease, whose main pathophysiological phenomenon is plasma leakage induced by a microvascular endothelial dysfunction. We report the case of a young male patient who presented with severe hantavirus infection complicated by acalculous cholecystitis. Keywords: Epidemic nephropathy, Hemorrhagic fever, Hantavirus pulmonary syndrome, Puumala, Acalculous cholecystitis, Plasma leakage, Endothelial dysfunction
Introduction Hantaviruses belong to the Bunyaviridae family. In Europe, the most prevalent subtype is Puumala virus (PUUV), which is mainly transmitted to humans by the red bank vole (Myodes glareolus) living in forests, copses and hedges. It causes a mild form of hemorrhagic fever with renal syndrome (HFRS), whose spectrum of severity is very wide, going from unapparent infection (in the vast majority of cases), over different grades of acute but transient kidney injury (AKI) and in exceptional cases, even up to death in multi-organ failure. Cardiopulmonary syndrome is less frequent with the PUUV subtype. PUUV infection, like any other form of hantavirus disease (HTVD), is often accompanied by severe abdominal pain as presenting symptom before AKI installs. A rarely reported cause of these is acalculous cholecystitis, which is defined by a thickening of the gallbladder wall over 4 mm without associated lithiasis and of spontaneous resolution.
Case Description An 18-year-old male patient presented to emergency room in October 2012, in a context of flu-like syndrome with fever, chills and frontal headache that began 6 days ago [ 5 day 0, corresponding to the onset of symptoms, the following clinical hallmarks and lab data will thus be expressed in days Correspondence to: Dr Jean-Baptiste Nicolas, Department of General Internal Medicine, CHU Dinant Godinne UCL Namur, Yvoir, Belgium. Email: [email protected].
ß Acta Clinica Belgica 2015
post-onset of symptoms (POS)]. On 3 days POS appeared disabling pain in the right upper quadrant. Systematic history found an anorexia without any other digestive complaint, disappearance of fever since the day before, a notion of transient and recent blurred vision without photo-phonophobia, absence of cardio-respiratory and urinary complaint, except of a darker urine colour, absence of recent abroad travel, animal bite or sting. We did not note any walk in the woods, no passage in a cellar, attic, stable, lodge or other poorly ventilated space. He, however, had a picnic in the park of a castle 6 days earlier, in the Belgian Condroz, near the city of Ciney. The patient had no remarkable medical or surgical history. He was neither taking any medication nor illicit drug. Physical examination on admission (6 days POS) found a blood pressure at 125/65 mmHg, heart rate at 98/min, temperature at 37.6uuC, pulse oxygen saturation in ambient air at 98% and weight at 84 kg. The patient presented signs of extracellular dehydration with dry mucous membranes and lazy skin fold. Cardiopulmonary auscultation was unremarkable. The abdomen was painful to deep palpation in the right upper quadrant with a positive Murphy’s sign without clinical signs of peritoneal irritation. Peristalsis was slowed. Lumbar percussion was painful on the right side. The admission blood sample objectified the following pathologic results: C-reactive protein increased to 43.5 mg/l, leukocytosis at 11 770/ml with 3190 lymphocytes and 2272 monocytes, platelets significantly
Nicolas
Acalculous cholecystitis associated with hantavirus infection
lowered to 48 000/ml, fibrinogen increased to 463 mg/ dl, mild hyponatremia at 136 mEq/l, impaired renal function with urea at 65 mg/dl and creatinine at 2.1 mg/dl (or a calculated estimation of glomerular filtration rate using MDRD at 43.94 ml/min/ 1.73 m2), total and direct bilirubin slightly increased to, respectively, 1.44 and 0.64 mg/dl, serum iron was lowered to 47 mg/dl and ferritin increased to 2914 mg/dl. A urine dipstick performed at admission showed an estimated proteinuria and haematuria at three z, confirmed by microscopic analysis (10–20 RC/field). The rest of the urinary sediment was unremarkable. A urinary sample performed by the GP on 4 days POS already showed pathologic proteinuria at 0.45 g/l (nlv0.1 g/l). A chest X-ray upon admission was unremarkable. An abdominal ultrasound performed in emergency room (Fig. 1) showed a thickened gallbladder wall measured at 5 mm and characterised by a discreetly laminated appearance, the so-called reticular pattern.1,2 No dilatation of intrahepatic or extrahepatic biliary ducts was noted. Millimetric hyperechogenic rounded structure was noted up to its front wall (cholesterol granuloma in the first hypothesis). Pancreas looked banal. There was no dilatation of the pyelocaliceal cavities. We noted a discreetly dedifferentiation of both kidneys, which were not swollen (bipolar axial echographic length measured at 12 cm for the right kidney and at 11 cm for the left one). A small liquid blade on the lower side of the right kidney was observed. The patient was then admitted to the general internal medicine service for further support. Differential diagnosis arose between hantavirus infection and leptospirosis. For acute and/or convalescent seroconfirmation of a recent PUUV hantavirus
infection, specific anti-PUUV IgM, and respectively IgG antibodies were scheduled in ELISA screening technique. A treatment with ceftriaxone 2 g/day and metronidazole 500 mg 3 times/day was started empirically pending serology and clinicobiological evolution. Further evolution has been marked by a rapid deterioration of renal function (creatininemia at 5.6 mg/dl on 7 days POS, 8.7 mg/dl on 8 days POS, 11.3 mg/dl on 9 days POS, nl v1.25 mg/dl), reaching a plateau of 11.8 mg/dl on 10 days POS (with urea at 156 mg/dl). At this time, the level of bicarbonate was 17 mEq/l. The patient did neither develop hypo- or hyperkaliemia nor clinical fluid overload. A blood gas analysis on 10 days POS showed arterial pH 7.30, paO2 90 mmHg, paCO2 38 mmHg and base excess – 7.1 mmol/l; this slight hypoxaemia implies an indeniable component of transient acute lung injury (ALI), often seen together with AKI, as in this case report.3–6 Creatinine level then decreased rapidly without the need for recourse to renal replacement therapy, falling to 1.1 mg/dl (urea 24 mg/dl) on 16 days POS, day of hospital discharge. In parallel, platelet count (initially 48 000/ml, nl 150 000–400 000/ml) gradually increased to correct on 10 days POS (170 000/ml). C-reactive protein reached a maximum of 106 mg/l on 9 days POS (nl v5 mg/l) and normalised on 16 days POS. Plasma sodium reached a minimum of 130 mEq/l on 8 days POS (nl 137–145 mEq/l) (due to diminished sodium reabsorption in the proximal tubule7) and a maximum of 146 mEq/l on 15 days POS (context of osmotic polyuria). Albuminaemia fell rapidly until 23.20 g/l on 9 days POS, in a context of nephrotic range proteinuria over 4 g/24 hours. Lactate dehydrogenase (LDH) levels also increased significantly until 1133 IU/l on 10 days POS (nl 313–618 IU/l)
Figure 1 Thickened gallbladder wall measured at 5 mm and characterised by a discreetly laminated appearance.
Nicolas
and were still high at 989 IU/l at discharge. Lipase level, normal at admission, increased until 886 IU/l on 16 days POS (nl 23–300 IU/l) and even remained high at 974 IU/l on a control sample made on 25 days POS, while the patient was asymptomatic. Urinary outflow measured by 24 hours found a minimum of 650 ml on 9 days POS, then increased rapidly to 4900 ml on 13 days POS, with an in–out balance at – 2200 ml over the 24 hours and a weight loss of 1.7 kg in 24 hours, occurring in a context of osmotic polyuria. Minimum blood pressure was measured at 120/ 70 mmHg on 6 days POS and maximum at 180/ 110 mmHg on 13 days POS, this last value justifying a short treatment with amlodipine 5 mg, given the concomitant appearance of headache without meningeal signs. Body weight found a maximum of 86.3 kg on 10 days POS and a minimum of 80.2 kg on 25 days POS. Maximum tympanic temperature was measured at 37.9uuC on 6 days POS. Comparative evolution of major biological and clinical parameters is summarised in Table 1. In terms of treatment, no renal replacement therapy was initiated. The patient benefitted from fluid restriction adapted to in–out balance (balance between 0 and z500 ml over the 24 hours) during the oliguric phase and from hyperhydration during the polyuric phase. Antibiotherapy by ceftriaxone and metronidazole was interrupted on 8 days POS due to lack of sufficient arguments to continue. Puumala virus serology returned positive for IgG (ratio 6.74, positive w1.50) and IgM (ratio 9.26, positive w2.00) on 11 days POS. Leptospirosis serology was cancelled.
Acalculous cholecystitis associated with hantavirus infection
Patient had invalidating pain in the right upper quadrant related to acalculous cholecystitis initially described. Pain was relieved by the administration of IV pethidine until 400 mg/24 h. Pethidine could be stopped on 13 days POS and pain persisted until 15 days POS. Administration of morphine derivatives led to multiple side effects like several episodes of urinary retention, nausea and obstinate constipation. There was no need for cholecystectomy, since no criterion was met. Patient was discharged on 16 days POS and reviewed in consultation 25 days POS. Clinical examination was quite normal at that time.
Discussion This case is remarkable from several points of view. First, it reports a case of acalculous cholecystitis associated with hantavirus infection, which is a rarely described entity. To the best of our knowledge, there are two case reports8,9 and a South Korean series10 relating the association misunderstood. These suggested that a gallblader wall thickening greater than or equal to 4 mm was significantly associated with more severe disease (platelet count and albumin significantly lower, significantly higher levels of aspartate aminotransferase (ASAT) and LDH, higher incidence of severe renal failure requiring haemodialysis), and that this thickening could therefore be useful in predicting the severity of HTVD. This is true in our patient, apart from the fact that the severe acute renal failure did not meet the criteria of renal replacement therapy. But, we know that only 5% of hospitalised PUUV-infected patients require dialysis and some prolonged intensive-care treatment.11
Table 1 Comparative evolution of biological and clinical parameters. Days POS
3
6
7
8
9
11
13
15
16
25
Creatinine (mg/dl) nl 0.66–1.25 Urea (mg/dl) nl 19–43 Cl Creat (mL/min) nl w90 Na (mEq/l) nl 137–145 K (mEq/l) nl 3.5–5.1 HCO{ 3 (mmol/l) nl 22–30 P (mg/dl) nl 2.5–4.5 Mg (mg/dl) nl 1.6–2.3 Platelets (|103/ml) nl 150–400 CRP (mg/l) nl v5.0 Albumin (g/l) nl 37.00–53.00 LDH (IU/l) nl 313–618 Lipases (IU/l) nl 23–300 Amylases (IU/l) nl 30–110 Urinary outflow (ml/24 hours) Weight (kg) Max BP (mmHg) 140/100 Max Tuu (uuC) Abdominal pain (max AVS)
0.81 35 126
2.1 65 68 136
263 16.4
220 8.4
1.0 26 143 141 4.6 28.0 4.2 1.8 256 v1.0
923 879 163
11.7 155 12 134 3.9 19.0 8.2 2.4 196 60.0 25.73 814
1.1 24 130 145 4.3 27.0 3.8 1.2 220 5.0
804 44 55
11.3 143 13 130 3.9 20.0 7.3 2.2 124 106.4 23.20 729 157 84
1.3 28 110 146 4.3 26.0
48 43.5
8.7 119 16 130 3.6 20.0 6.1 2.1 81 95.5 25.05 824 243 125 650
3.2 83 45 144 4.7 24.0
40
5.6 97 25 135 4.2 24.0 4.8 2.2 53 89.1
833
989 886
470 974
2750
3300
1700
37.4 0/10
84 120/70
130/80
170/120
150/110
145/85
180/110
5000 83 180/100
37.9 3/10
36.9 8/10
36.7 5/10
36.9 6/10
37.1 3/10
37.6 0/10
37.5 3/10
80.2 160/100
0/10
POS: post-onset of symptoms; nl: normal values; Cl Creat: estimated creatinine clearance by Cockroft–Gault formula; Na: sodium; K: potassium; HCO{ 3 : bicarbonates; P: phosphorus; Mg: magnesium; CRP: C-reactive protein; LDH: lactate dehydrogenase; Max BP: highest value of blood pressure over the 24 hours; Max Tuu: highest value of auricular body temperature over the 24 hours; Max AVS: highest value of visual analogue scale over the 24 hours.
Nicolas
Acalculous cholecystitis associated with hantavirus infection
These acalculous cholecystitis occurring in the context of viral infection usually resolve spontaneously and should not lead to unnecessary surgery. In terms of pathophysiology, the most likely and the most frequently cited mechanism is a phenomenon of plasma leakage, leading to oedematous swelling of various organs, especially the kidneys.8,12–15 Serositis is also possible in severe cases with pleural and/or peritoneal effusion. It is very likely that the thickening of the gallbladder wall is the consequence of the same mechanism. This hypothesis should be confirmed if possible on surgical or autopsy pieces, by identifying deposit of immune complexes, oedema, hantavirus perinuclear inclusions in endothelial cells, P-bodies, ... South American Andes virus (ANDV) infection of Syrian hamsters is currently the only animal model of hantavirus pathogenesis that closely mimics human disease, but it causes hantavirus pulmonary syndrome (HPS), and is not suitable for the study of HFRS. However, it should be interesting to observe the gallbladder of these infected hamsters.16 The plasma leakage is secondary to the occurrence of endothelial dysfunction predominant in microvascular beds of lungs and kidneys. This endothelial dysfunction seems to be the consequence of a particular tropism of hantavirus for endothelial cells, which internalise it, especially via a beta-3 integrin turned inactive, this one losing its ability to interact with the vascular endothelial growth factor receptor (VEGF receptor).13 This results in a powerful increase of the effect of VEGF on endothelial cell permeability. Indeed, several studies have shown internalisation of vascular endothelial-cadherins (VE-cadherins),13 essential molecules to the formation of the junction between endothelial cells, as a result of interaction between VEGF and receptor VEGFR2. The result is a disassembly of intercellular junctions and hyperpermeability of the endothelial barrier. This is really a dysfunction, most of the time reversible and not cell destruction. Several studies also suggest an increase in VEGF levels during the acute phase of the disease, with a peak corresponding to the peak serum creatinine, but also during the recovery phase, and especially in severely ill patients, suggesting also a protective role of VEGF, especially in kidney recovery.12 Several therapeutic interventions targetting endothelial protection have yet to be investigated, in particular, the way of microRNAs.13 Thrombocytopaenia, almost invariably described in the first phase of infection, should also come from the interaction of platelets with endothelial cells covered with hantavirus through inactivated beta-3 integrins.13 Another noteworthy element in our patient is the occurrence of a biological pancreatitis, with elevated
lipase more than three times the norm, with this elevation predominating on 25 days POS, or at a time when the patient became asymptomatic. Exactly the same unexplained phenomenon of so-called ‘‘late onset chemical, but not clinical pancreatitis’’ was already observed in 2/62 cases of the 1993 HFRS (PUUV) outbreak in South-Belgium.17 Real pancreatitis, i.e. also confirmed by typical changes on medical imaging, has only very rarely been documented so far. Zhu et al. reported two cases of severe, medical imaging-confirmed, pancreatitis, in which the striking particularity was that serum amylases started rising only after all other (including renal) parameters were normalising, as in our case report.18 It is possible that this results from the same mechanism of endothelial hyperpermeability, with plasma leakage causing transient slight oedematous pancreatitis.19 We therefore believe that the severity of HTVD is correlated with the intensity of the plasma leakage, which can, as we have seen, be apprehended by the clinical and some simple additional tests, i.e. biology, abdominal ultrasound and chest radiography. It would be interesting to elaborate a severity score that would take into account, e.g. platelet count at admission, presence or absence of serositis or thickened gallbladder wall, LDH level, possibly levels of albumin and lipases. This could be predictive of the severity of the disease, including the possible need of renal replacement therapy or intensive-care admission.
Conclusion This case relates the occurrence of acalculous cholecystitis and acute biological pancreatitis in a patient with HFRS, this association supporting the hypothesis of endothelial dysfunction with plasma leakage as the main pathophysiological mechanism of HTVD. The development of a severity score at admission, based, in particular, on the presence of a thickened gallbladder wall and biological parameters, could help in predicting the need and duration of hospitalisation and the possible need of renal replacement therapy.
Disclaimer Statements Funding None. Conflicts of interest None. Ethics approval None required.
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