Hypopituitarism after Orthohantavirus Infection: What is Currently Known?

Abstract

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.

A Rare Case of SARS-CoV-2 Infection Associated With Pituitary Apoplexy Without Comorbidities

“…This occurs often as the majority of nonfunctional macroadenomas are diagnosed when they present with pituitary apoplexy [ 9-11 ]. Infection-induced thrombocytopenia, platelet dysfunction, coagulopathy, and immune-mediated hypophysitis have been documented as precipitants for pituitary apoplexy [ 2 , 3 , 12 , 13 ]. Wildemberg et al [ 13 ] claimed dengue infection to be a novel condition for pituitary apoplexy.…”

“…Wildemberg et al [ 13 ] claimed dengue infection to be a novel condition for pituitary apoplexy. Although SARS-CoV-2 infection is associated with thrombosis and coagulopathies at the same time and is often treated with unfractionated or low-molecular-weight heparins [ 14 ], a risk factor for pituitary apoplexy [ 2 ], they were not administered in our patient because the serial D-dimer levels were only minimally elevated. Among the numerous hematological complications induced by SARS-CoV-2 infection, thrombocytopenia, coagulopathy, and platelet dysfunction have been reported [ 14-18 ].…”

“…Hemorrhagic viral fevers have long been associated with hypopituitarism, the majority being orthohantavirus and dengue infection [ 2 , 3 ]. In the case of orthohantavirus infection, ischemic damage to pituitary could be caused by hypotension and/or vasospasms during the acute phase, while thrombocytopenia, thrombopathy, and other coagulation disorders can cause hemorrhage [ 2 ]. Further, hypophysitis due to the presence of autoantibodies has been suggested [ 2 ].…”

“…In the case of orthohantavirus infection, ischemic damage to pituitary could be caused by hypotension and/or vasospasms during the acute phase, while thrombocytopenia, thrombopathy, and other coagulation disorders can cause hemorrhage [ 2 ]. Further, hypophysitis due to the presence of autoantibodies has been suggested [ 2 ]. Leow et al [ 4 ] reported postinfectious hypophysitis with related transient hypocortisolism in patients who survived the previous severe acute respiratory syndrome (SARS) epidemic.…”

Orthohantavirus Pathogenesis and Cell Tropism

“…These organ systems were chosen as multiple studies have demonstrated viral presence in these organs in human cases. While there are a variety of studies discussing orthohantavirus infection in other organs, such as intestines (Zaki et al, 1995 ; Green et al, 1998 ; Latus et al, 2014 ), endocrine system (Zaki et al, 1995 ; Green et al, 1998 ; Bhoelan et al, 2019 ), and brain (Zaki et al, 1995 ) in humans, but also brown adipose tissue (Botten et al, 2002 ) in reservoir rodents, these were not included due to lack of mechanistic studies. Of note, transmission via saliva is suggested to be even more relevant than urine among naturally infected hosts as SEOV and ANDV have been detected more often in either saliva (and salivary glands) compared to urine samples (Padula et al, 2004 ; Maas et al, 2019 ).…”