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      Hypopituitarism after Orthohantavirus Infection: What is Currently Known?

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          Several case reports have described hypopituitarism following orthohantavirus infection, mostly following Puumala virus. The pathogenesis of this seemingly rare complication of orthohantavirus infection remains unknown. This review explores the possible pathophysiological mechanisms of pituitary damage due to orthohantavirus infection. In only three out of the 28 reported cases, hypopituitarism was detected during active infection. In the remaining cases, detection of pituitary damage was delayed, varying from two months up to thirteen months post-infection. In these cases, hypopituitarism remained undetected during the acute phase of infection or only occurred weeks to months post infection. Both ischemic and hemorrhagic damage of the pituitary gland have been detected in radiographic imaging and post-mortem studies in the studied case reports series. Ischemic damage could be caused by hypotension and/or vasospasms during the acute phase of hemorrhagic fever with renal syndrome (HFRS) while hemorrhage could be caused by thrombocytopenia, thrombopathy, and other known causes of coagulation disorders during orthohantavirus infection. Also, hypophysitis due to the presence of auto-antibodies have been suggested in the literature. In conclusion, a significant number of case reports and series describe hypopituitarism after orthohantavirus infection. In most cases hypopituitarism was diagnosed with a delay and therefore could very well be underreported. Clinicians should be aware of this potential endocrine complication, with substantial morbidity, and if unrecognized, significant mortality.

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          Most cited references 47

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          A global perspective on hantavirus ecology, epidemiology, and disease.

          Hantaviruses are enzootic viruses that maintain persistent infections in their rodent hosts without apparent disease symptoms. The spillover of these viruses to humans can lead to one of two serious illnesses, hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome. In recent years, there has been an improved understanding of the epidemiology, pathogenesis, and natural history of these viruses following an increase in the number of outbreaks in the Americas. In this review, current concepts regarding the ecology of and disease associated with these serious human pathogens are presented. Priorities for future research suggest an integration of the ecology and evolution of these and other host-virus ecosystems through modeling and hypothesis-driven research with the risk of emergence, host switching/spillover, and disease transmission to humans.
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            Hantavirus infections in Europe.

            Hantaviruses are enveloped RNA viruses each carried by a specific rodent species. Three hantaviruses, Puumala, Dobrava, and Saaremaa viruses, are known to cause haemorrhagic fever with renal syndrome. In Europe. Puumala causes a generally mild disease, nephropathia epidemica, which presents most commonly with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision, whereas Dobrava infections often also have haemorrhagic complications. There are few available data about the clinical picture of confirmed Saaremaa infections, but epidemiological evidence suggests that it is less pathogenic than Dobrava, and that Saaremaa infections are more similar to nephropathia epidemica caused by Puumala. Along with its rodent host, the bank vole (Clethrionomys glareolus), Puumala is reported throughout most of Europe (excluding the Mediterranean region), whereas Dobrava, carried by the yellow-necked mouse (Apodemus flavicollis), and Saaremaa, carried by the striped field mouse (Apodemus agrarius), are reported mainly in eastern and central Europe. The diagnosis of acute hantavirus infection is based on the detection of virus-specific IgM. Whereas Puumala is distinct, Dobrava and Saaremaa are genetically and antigenically very closely related and were previously thought to be variants of the same virus. Typing of a specific hantavirus infection requires neutralisation antibody assays or reverse transcriptase PCR and sequencing.
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              Incidence and prevalence of hypopituitarism are estimated to be 4.2 per 100,000 per year and 45.5 per 100,000, respectively. Although the clinical symptoms of this disorder are usually unspecific, it can cause life-threatening events and lead to increased mortality. Current research has refined the diagnosis of hypopituitarism. Identification of growth hormone and corticotropin deficiency generally requires a stimulation test, whereas other deficiencies can be detected by basal hormones in combination with clinical judgment. Newly developed formulations of replacement hormones are convenient and physiological. Work has shown that many patients with brain damage--such as traumatic brain injury or aneurysmal subarachnoid haemorrhage--are at high risk of (sometimes unrecognised) hypopituitarism. Thus, a much increased true prevalence of this disorder needs to be assumed. As a result, hypopituitarism is not a rare disease and should be recognised by the general practitioner.

                Author and article information

                10 April 2019
                April 2019
                : 11
                : 4
                [1 ]Department of Viroscience, Erasmus MC, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; b.s.Bhoelan@ (S.B.); Thomas.langerak@ (T.L.); d.noack@ (D.N.); e.vangorp@ (E.C.M.v.G.); b.rockx@ (B.R.)
                [2 ]Department of Internal Medicine, Erasmus MC, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; l.gribling-vanschinkel@ (L.v.S.); e.vannood@ (E.v.N.)
                Author notes
                [* ]Correspondence: m.goeijenbier@ ; Tel.: +00-3110-404-3300
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (


                Microbiology & Virology

                hfrs, orthohantavirus, hypopituitarism, endocrine disturbances, review


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