Mats Linderholm

Prevalence of serum IgG antibodies to Puumala virus (haemorrhagic fever with renal syndrome) in northern Sweden.

A stratified and randomly-selected population sample was identified in 1990 in order to study the seroprevalence of nephropathia epidemica (haemorrhagic fever with renal syndrome) in Northern Sweden. Sera from 1538 subjects (750 men, 788 women), 25-64 years of age, were analysed for the presence of Puumala virus (PUV) specific-IgG by the indirect immunofluorescence antibody test. Specific IgG was detected in sera from 83 subjects (5.4%). Men and women had similar seroprevalence rates. The highest seroprevalences were found in subjects 55 years or older (8.0%) and among farmers and forestry workers (15.9%). The geographic distribution of seropositive individuals was uneven and there were significantly more seropositive persons in rural than in urban areas (P < 0.05).

Pulmonary involvement in nephropathia epidemica as demonstrated by computed tomography

SummaryIn a prospective study 19 adult patients with nephropathia epidemica were examined in the acute phase of disease with computed tomography (CT) of the lungs and conventional chest radiography. Infiltrates and/or pleural effusions were seen in ten of 19 patients. In two of the patients, abnormalities were disclosed only by CT. Patients with pathologic radiography findings had a more pronounced inflammatory response, as measured by C-reactive protein and leukocyte count, than did those with normal radiography findings. It is concluded that radiological evidence of pulmonary involvement is a common finding early in the course of nephropathia epidemica. The possibility that the lung may be a site of viral replication merits further investigation.ZusammenfassungNeunzehn erwachsene Patienten in der akuten Phase von Nephropathia epidemica wurden mit computertomographischem (CT) und konventionellem Thoraxröntgen untersucht. Infiltrate und/oder Pleuraergüsse wurden bei 10/19 der Patienten beobachtet. Bei zwei Patienten konnten pathologische Befunde nur mit Hilfe der CT erhoben werden. Patienten mit pathologischen Radiogrammen wiesen, verglichen mit normalen radiographischen Befunden, eine ausgeprägtere Entzündungsreaktion gemessen durch C-reaktives Protein und Leukozytenzahlen auf. Unsere Resultate zeigen, daß in der Frühphase der Nephropathia epidemica röntgenologisch häufig eine Lungenbeteiligung nachgewiesen werden kann. Die Möglichkeit, der Lunge als eine Lokalisation der viralen Replikation sollte weiter untersucht werden.In a prospective study 19 adult patients with nephropathia epidemica were examined in the acute phase of disease with computed tomography (CT) of the lungs and conventional chest radiography. Infiltrates and/or pleural effusions were seen in ten of 19 patients. In two of the patients, abnormalities were disclosed only by CT. Patients with pathologic radiography findings had a more pronounced inflammatory response, as measured by C-reactive protein and leukocyte count, than did those with normal radiography findings. It is concluded that radiological evidence of pulmonary involvement is a common finding early in the course of nephropathia epidemica. The possibility that the lung may be a site of viral replication merits further investigation. Neunzehn erwachsene Patienten in der akuten Phase von Nephropathia epidemica wurden mit computertomographischem (CT) und konventionellem Thoraxröntgen untersucht. Infiltrate und/oder Pleuraergüsse wurden bei 10/19 der Patienten beobachtet. Bei zwei Patienten konnten pathologische Befunde nur mit Hilfe der CT erhoben werden. Patienten mit pathologischen Radiogrammen wiesen, verglichen mit normalen radiographischen Befunden, eine ausgeprägtere Entzündungsreaktion gemessen durch C-reaktives Protein und Leukozytenzahlen auf. Unsere Resultate zeigen, daß in der Frühphase der Nephropathia epidemica röntgenologisch häufig eine Lungenbeteiligung nachgewiesen werden kann. Die Möglichkeit, der Lunge als eine Lokalisation der viralen Replikation sollte weiter untersucht werden.

Clinical Characteristics of Hantavirus Infections on the Eurasian Continent

In 1933 and 1934 two Swedish physicians, working in northern Sweden independently of each other, observed a previously undescribed disease (Myhrman 1934; Zetterholm 1934). It was characterized by a rapid onset of high fever, malaise, chills, headache, abdominal, back and often generalized pain, and a renal syndrome with proteinuria and oliguria followed by a diuretic phase. A spontaneous recovery followed all cases described. In 1945 Myhrman proposed nephropathia epidemica (NE) as the name for this disease. During the subsequent decades, a large number of cases of this disease were reported from Scandinavia and Finland (Myhrman 1945, 1951; Lahdevirta 1971).

A swedish fatal case of nephropathia epidemica

A previously healthy 55-year-old man with nephropathia epidemica (NE) developed disseminated intravascular coagulation, anuria and shock and died on day 6 of his disease. By use of indirect immunofluorescence technique and ELISA, specific serum IgM antibodies against Puumala virus could be detected, thus confirming the clinical diagnosis. This case demonstrates that NE in Scandinavia is a potentially lethal disease.

Central nervous system and ophthalmic involvement in nephropathia epidemica (European type of haemorrhagic fever with renal syndrome)

Central nervous system (CNS) - related symptoms occur in haemorrhagic fever with renal syndrome (HFRS). To study the CNS and ophthalmic involvement in nephropathia epidemica (NE), the European type of HFRS, we included 26 patients in a prospective study. Most common CNS-related symptoms were headache (96%), insomnia (83%), vertigo (79%), nausea (79%), and vomiting (71%). Ophthalmic symptoms were reported by 82% of patients; 41% had photophobia and 50% had impaired vision. A transient loss of vision was recorded in one patient, who also had a generalized seizure. Minor white matter lesions were found in about half of the patients investigated with brain magnetic resonance imaging (MRI). Electroencephalography (EEG) showed severe alterations in only one patient, and slight and reversible patterns in another two patients. Neopterin, interleukin-6 and interferon-gamma levels in the cerebrospinal fluid (CSF) were elevated, which may indicate immune activation. However, we found no evidence of intrathecal NE virus replication. We conclude that CNS-related symptoms are common in NE, and transient ophthalmic involvement can be demonstrated in about half of the patients.

The clinical usefulness of a Puumalavirus recombinant nucleocapsid protein based enzyme-linked immunosorbent assay in the diagnosis of nephropathia epidemica as compared with an immunofluorescence assay

BACKGROUND Nephropathia epidemica (NE), a hemorrhagic fever with renal syndrome (HFRS) predominantly encountered in northern Europe, is a febrile disease, commonly associated with acute renal impairment. A rapid and reliable serological diagnosis is required to differentiate NE from other acute febrile illnesses in endemic areas. OBJECTIVE To evaluate a Puumala (PUU) virus recombinant nucleocapsid protein (rN) based enzyme-linked immunosorbent assay (ELISA) for the serological diagnosis of NE as compared with an immunofluorescence assay (IFA) in a clinically relevant patient sample. STUDY DESIGN During a four-month period, 618 serum samples from 512 patients with an illness suggestive of NE, sent to the Department of Clinical Virology for serological analysis, were included in the study. All sera were tested by PUU rN ELISA for presence of specific IgG, IgM and IgA antibodies and by IFA using PUU virus infected cells as antigen for presence of IgG and IgM antibodies. Patients with discordant results by IFA and rN ELISA were further serologically and/or clinically evaluated to assess the probability of NE. RESULTS Compared to IFA, the specificities of the IgM and IgG rN ELISA were 100% and the corresponding sensitivities were 94.0%. The positive and negative predictive values of the PUU IgM rN ELISA in diagnosing NE infection was 100 and 98.6%, respectively. The positive predictive values for present NE infection of IgG rN ELISA and IFA were 68.3 and 71.4%, respectively. The positive predictive value of IgA rN ELISA was 95.8% and the negative 92.7%. CONCLUSIONS The demonstration of specific IgM by rN ELISA is a highly specific and reliable method for the serological confirmation of NE. Detection of IgG antibodies by rN ELISA or IFA has a low predictive value to diagnose NE in an endemic area. The diagnostic value of IgA determination is in between IgM and IgG determinations.

Evaluation of six commercially available kits using purified heterophile antigen for the rapid diagnosis of infectious mononucleosis compared with Epstein-Barr virus-specific serology.

BACKGROUND Novel commercial kits based on antibody reactivity to purified heterophile antigens have recently been introduced for the diagnosis of Epstein-Barr (EB) virus-associated infectious mononucleosis (IM). It is important to determine possible improvements in the performance and reliability of such tests for the diagnosis of IM. OBJECTIVE To evaluate the reliability of six commercially available kits for the rapid diagnosis of IM in comparison to EB-virus-specific serology. STUDY DESIGN In total, 100 sera, 53 from patients with serologically verified primary EB virus infection and 47 from EB-virus-immune or -susceptible patients, were used to evaluate the six rapid test kits: Monolatex, Mono-Latex, Mono-Lex (latex agglutination-based kits), Mono-Plus, IM-Check and Clearview IM (solid-phase-based kits). EB-virus-specific serologies including detection of viral capsid antigen IgM and IgG and EB nuclear antigen-1 IgG, were used as reference methods. RESULTS Compared with the reference methods, the sensitivities and specificities of the heterophile antibody test kits were 70-92% and 96-100%, respectively. IM-Check had a low sensitivity and was difficult to read. The remaining kits performed well. CONCLUSION Monolatex, Mono-Latex, Mono-Lex, Mono-Plus and Clearview IM can be recommended for the confirmation of EB-virus-associated infectious mononucleosis. Clearview IM combined a high sensitivity and specificity with very simple one-step solid-phase-based procedure.

Local Host Response in the Lower Respiratory Tract in Nephropathia Epidemica

Various lines of evidence suggest a respiratory route of transmission of nephropathia epidemica (NE). To study the response of the respiratory tract in NE, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed in 5 patients in the acute phase of the disease. Compared to a reference group of 15 healthy individuals, BAL fluid of NE patients contained significantly higher total numbers of cells (p < 0.05) and significantly higher numbers of lysozyme-positive macrophages (p < 0.01), CD8+ T cells (p < 0.01), and natural killer (NK) cells (p < 0.01). There was no significant difference in numbers of CD4+ T cells, B cells, or neutrophils. When blood samples of 16 patients were examined at various intervals after onset of NE, a significant decrease in the number of NK cells (p < 0.01) was found in the acute phase of the disease. The findings are compatible with the presence of a local host response in the lower respiratory tract to NE virus infection.

Increased production of nitric oxide in patients with hemorrhagic fever with renal syndrome — Relation to arterial hypotension and tumor necrosis factor

SummaryIn 15 consecutive subjects hospitalized with nephropathia epidemica, a European form of hemorrhagic fever with renal syndrome, the plasma concentrations of nitrate plus nitrite, stable metabolites of nitric oxide, were determined. From day 3 of onset of disease the concentrations increased, peak levels being reached on days 5 to 7. Maximal plasma concentrations of nitrate plus nitrite were correlated to the degree of hypotension (r=−0.64, p=0.02) and levels of tumor necrosis factor (TNF)-α (r=0.51, p=0.05) and soluble TNF receptors p55 and p75 (r=0.58, p=0.03 and r=0.54, p=0.04, respectively) but not to levels of interferon-γ or interleukin-10 (p>0.05). The results are compatible with the well-known capacity of TNF-α to enhance production of nitric oxide, and suggest that nitric oxide may be of physiologic importance in hemorrhagic fever with renal syndrome.ZusammenfassungBei 15 aufeinanderfolgenden, stationär eingewiesenen Patienten mit Nephropathia epidemica, einer europäischen Form des hämorragischen Fiebers mit renalen Syndrom, wurden die Plasmakonzentrationen von Nitrat plus Nitrit, den stabilen Metaboliten von Stickoxid, gemessen. Von dem dritten Tag nach Ausbruch der Krankheit an begannen die Konzentrationen anzusteigen. Höchstwerte wurden am Tag 5–7 beobachtet. Maximale Plasmakonzentrationen von Nitrat plus Nitrit waren mit dem Grad der Hypotension korreliert (r = −0.64, p = 0.02) und auch mit der Konzentration Tumor-Nekrose-Faktor (TNF)-α (r = 0.51, p = 0.05) und löslichen TNF Rezeptoren p55 und p75 (r = 0.58, p = 0.03 und r = 0.54, p = 0.04), aber nicht mit den Interferon-γ oder Interleukin-10 Werten (p>0.05). Die TNF-α-abhängige Produktion von Stickoxiden könnte von pathophysiologischer Bedeutung bei Nephropathia epidemica sein.

Autologous and allogeneic stem cell transplantation in adult ALL: the Swedish Adult ALL Group experience

Summary:Adult patients with acute lymphoblastic leukaemia (ALL) have been treated according to national protocols in Sweden since 1986. Stem cell transplantation (SCT) has been recommended in first remission for patients with risk factors for relapse, and for standard risk patients only after relapse. In this retrospective study, the results of autologous and allogeneic SCT in these populations were evaluated. In total, 187 patients with a median age of 34 years (17–66 years) underwent SCT. The 5-year disease-free survival (DFS), for all patients, was 26% (Confidence intervals (CI) 20–32%). The 5-year DFS was higher for patients transplanted in first remission 32% (CI 24–40%) compared to 14% (CI 5–23%; P<0.0001) in patients transplanted beyond first remission. No significant differences in DFS (P=0.06) were determined between autologous, related donor and unrelated donor SCT in the whole cohort. A lower relapse rate was counterbalanced by higher treatment-related mortality in patients undergoing allogeneic SCT. In Philadelphia-positive ALL, allogeneic SCT was superior to autologous SCT, with a 5-year DFS of 30% (CI 12–47%) vs 0% (P=0.04). Limited chronic graft-versus-host-disease (GVHD) was associated with an improved DFS of 53% (CI 38–69%) compared to no chronic GVHD of 22% (CI 10–36%; P=0.0008), indicating a clinically important graft-versus-leukaemia effect.