hand , foot , and mouth disease ( hfmd ) is a common , acute , and mostly self - limiting enteroviral infection that presents with fever and vesicular lesions on the hands , feet , mouth , and frequently buttocks as characteristic features1,2,3,4 ) .
although patients with hfmd recover without any sequelae within about 1 week , severe complications occur in a few cases , some of which are life threatening .
severe complications accompanying hfmd include encephalitis , pulmonary edema / hemorrhage , cardiopulmonary collapse , and myocarditis1,2 ) .
enterovirus 71 can often lead to a more severe clinical course accompanied by neurologic and cardiopulmonary complications and may rapidly lead to death1,2,3 ) .
enterovirus 71-induced hfmd developed in korea in 2000 but it was not an epidemic and fatal until 20081,4,5 ) . in the spring of 2009 , a large nationwide outbreak of hfmd caused by enterovirus 71 occurred in korea , and a few cases with encephalitis were fatal1,4,6 ) . a multicenter study in korea performed by the enterovirus complication working group revealed that encephalitis with cardiopulmonary complications of hfmd occurred in 2.4% of patients , including 2 patients ( 1.2% ) who expired1 ) .
pulmonary hemorrhage in enterovirus 71-infected hfmd patients has been reported in taiwan , china , and malaysia2,7,8,9 ) .
however , to our knowledge , no cases of hfmd with sudden - onset massive pulmonary hemorrhage have been reported in korea . here
, we report a fatal case of enterovirus 71-induced hfmd that progressed rapidly with massive pulmonary hemorrhage and convulsion .
a 12-month - old , previously healthy boy with hfmd was referred to inje university ilsan paik hospital because of 3 episodes febrile convulsions .
he was born at full term weighing 3.87 kg through normal vaginal delivery by a vietnamese mother .
he was admitted to a primary hospital with high fever ( up to 39 ) , throat vesicles , and vesicular rashes on his hands and feet for 2 days . on the second hospital day , he had 3 generalized tonic - clonic and atonic convulsions with vertical eyeball deviation within 5 minutes of each other .
his chest radiography was normal . within 5 hours after admission , he vomited 3 times after meals . besides a body temperature of 38.3 , his other vital signs were stable and he remained conscious .
desaturation to 76% percutaneous blood oxygen saturation ( spo2 ) and tachycardia to 176 beats / min accompanied by perioral cyanosis occurred suddenly 6 hours after admission .
his respiration rate was 34 breaths / min , and auscultation disclosed rales on the whole lung field .
an endotracheal tube was inserted immediately , and a large amount of blood from a pulmonary hemorrhage came out through it .
comparison of laboratory test results between his initial and pulmonary hemorrhagic status revealed that his hemoglobin decreased from 9.6 to 8.3 mg / dl and his white blood cell count increased from 13,090 to 17,450 cells/l .
erythrocyte sedimentation rate was slightly increased from 15 to 32 mm / hr , but c - reactive protein level decreased from 1.06 to 0.2 mg / dl .
prothrombin time ( pt ) and pt international normalized ratio were slightly prolonged ( 16.5 and 1.39 seconds , respectively ) .
meanwhile , d - dimer ( 2,375.91 ng / ml ) and fibrin degradation product ( 5 - 20 g / ml ) were elevated .
eight hours after admission , his blood pressure decreased to 82/41 mmhg and heart rate increased to 220 beats / min .
his body temperature ranged from 38.8 to 40.2. the patient was diagnosed as fatal hfmd with massive pulmonary hemorrhage .
intravenous immunoglobulin ( ivig , 1 g / kg / dose ) , dexamethasone ( 0.3 mg / kg / day in divided doses every 6 hours ) , and cefotaxime ( 150 mg / kg / day in divided doses every 6 hours ) were administered immediately .
in addition , leukocyte - depleted red blood cells and fresh frozen plasma were transfused , and intravenous vitamin k and endotracheal epinephrine were administered .
lumbar puncture was scheduled but was ultimately not performed because of the patient 's unstable vital signs .
the patient expired 15 hours after admission , and it was within 3 days of fever onset and within 9 hours after intubation .
we reported it to the korea centers for disease control and prevention ( kcdc ) , sending his urine , serum , nasopharyngeal swab , and endotracheal aspirate .
enterovirus genome detection was attempted by realtime reverse transcription - polymerase chain reaction ( rt - pcr ) using a taqman system ( applied biosystems , foster city , ca , usa ) . for genotyping ,
seminested rt - pcr was used to amplify part of the viral protein 1 ( vp1 ) gene of enteroviruses according to the kcdc protocol , and sequencing analysis for the vp1 amplicon was performed by an automatic sequencer and the dnastar software package ( dnastar inc . , madison , wi , usa ) .
the kcdc isolated enterovirus 71 with subgenotype c4a from the patient 's serum and nasopharyngeal swab .
bocavirus was also isolated from his nasopharyngeal swab by real - time rt - pcr at our hospital .
to our knowledge , this is the first reported case of hfmd with sudden - onset massive pulmonary hemorrhage in korea .
pulmonary edema / hemorrhage is the mysterious hallmark symptom of enteroviral hfmd and can kill a child within 1 day2 ) .
an epidemic study conducted in taiwan from 1998 to 2005 reported that pulmonary edema / hemorrhage occurred in 43% of patients with severe culture - proven enteroviral hfmd / herpangina2 ) .
this discrepancy maybe due to different enterovirus virulence or subgenotypes , or differences in susceptibility with respect to ethnicity .
pulmonary edema / hemorrhage is characterized by respiratory distress , tachypnea , tachycardia , hemoptysis , and rapidly progressing diffuse infiltration or congestion on a chest film2 ) .
a study on the outbreak in taiwan in 1998 reported that enterovirus 71-infected hfmd patients with pulmonary edema had suddenonset tachypnea , tachycardia , and cyanosis within 1 - 3 days after disease onset , and pulmonary edema led to a rapid death within 12 hours after intubation10 ) .
the present patient exhibited a change in consciousness , respiratory distress , tachypnea , tachycardia , hemoptysis , rapidly progressing infiltration on a chest film , hypoxemia , and hypotension .
this patient ultimately expired within 3 days of fever onset and within 9 hours after intubation . in this report , we had applied pulse oxymetry from the beginning , so we could find his desaturation immediately after pulmonary hemorrhage .
we suggest saturation monitoring for hfmd patients with central nervous system ( cns ) involvements for early detection .
it may be caused by increased pulmonary vascular permeability as a result of either brainstem encephalitis or a systemic inflammatory response caused by excessive cytokine release2,6 ) .
cns involvement of enterovirus 71-induced hfmd may also trigger a sympathetic storm , resulting in vasoconstriction with high systemic vascular resistance , passive pulmonary volume loading , and pulmonary edema / hemorrhage8 ) .
the present patient had several episodes of convulsions , lethargy , and loss of consciousness .
therefore , we suspected encephalitis , although we were unable to perform a cerebrospinal fluid study because of his unstable vital signs . his suspected encephalitis may be a possible cause of the pulmonary hemorrhage . however , pulmonary edema / hemorrhage without cns involvement occurred in 11% of patients with severe culture - proven enteroviral hfmd / herpangina in an epidemic study in taiwan from 1998 to 20052 ) .
another possible explanation for the pathogenesis is coinfection with a second virus2 ) , as bocavirus coinfection was detected in the patient .
however , the presence of both viruses would not result in increased mortality due to hfmd , according to a previous study2 ) . a multicenter study performed by the enterovirus complication working group investigating enterovirus 71-induced hfmd in korea in 2009 reported that an hfmd rash pattern , fever longer than 4 days , peak body temperature > 39 , vomiting , headache , neurologic signs , leukocytosis , serum glucose > 100 mg / dl , and isolated enterovirus 71 may be indicative of poor prognosis during hfmd epidemic periods1,10 ) .
in addition , young age at disease onset and a history of lethargy are associated with an increased risk of severe hfmd11 ) .
the present patient was young and presented with hfmd rashes and vesicles , fever up to 39 , vomiting , lethargy , and convulsions as neurologic signs as well as leukocytosis , high serum glucose level , and isolated enterovirus 71 as poor prognostic factors .
hfmd patients are very frequently approximately 1 year of age , and deaths were reported to occur at around 1 year of age in other studies12,13,14,15 ) . in the 2009 outbreak ,
2 patients around 1 year of age expired , and the present patient was a 12-month - old baby .
the gold standard for the diagnosis of enteroviral infection is viral culture and isolation in 2 or more specimens of cerebrospinal fluid , blood , nasopharyngeal swab or secretion , vesicular fluid , or stool to increased diagnostic sensitivity1,4,6,11 ) . in the present report ,
enterovirus 71 was isolated from both the patient 's serum and nasopharyngeal swab . in the 2009 korean outbreak ,
the subgenotype of enterovirus 71 was c4a , which was prevalent in china in 2008 . in the present case , the subgenotype of enterovirus 71 was also c4a .
the administration of high - dose ivig is recommended for severe hfmd as optional treatment , because ivig therapy was effective in many reports4,5,6,7,11 ) .
ivig neutralizes the virus and has nonspecific antiinflammatory properties11 ) ; this would significantly reduce mortality by attenuating sympathetic activity and cytokine production5 ) .
furthermore , fluid restriction , inotropic agents , and early intubation with positive - pressure mechanical ventilation are recommended for severe hfmd with pulmonary edema or hemorrhage8 ) .
pulmonary hemorrhage in enterovirus 71-infected hfmd is very rare ; the present case is likely the first to have occurred in korea .
the present case of fatal hfmd was rapidly aggravated and the patient expired within 3 days from fever onset .
therefore , all physicians should pay special attention to infants and young children with hfmd , particularly in enterovirus 71 epidemic areas such as korea , to enable early detection and management of severe hfmd .
above all , keeping the infected child at home until full recovery and controlling the preschool with infected child are very important for reducing infection6 ) .
in addition , the development of antiviral agents and vaccines is necessary especially for the control of severe hfmd with complication .
 hand , foot , and mouth disease ( hfmd ) is an acute , mostly self - limiting infection . 
 patients usually recover without any sequelae 
 . however , a few cases are life threatening , especially those caused by enterovirus 71 ( ev71 ) . 
 a 12-month - old boy was admitted to a primary hospital with high fever and vesicular lesions of the mouth , hands , and feet . 
 after 3 days , he experienced 3 seizure episodes and was referred to our hospital . on admission , he was conscious and his chest radiograph was normal . however , 6 hours later , he suddenly lost consciousness and had developed a massive pulmonary hemorrhage that continued until his death . 
 he experienced several more intermittent seizures , and diffuse infiltration of both lung fields was observed on chest radiography . 
 intravenous immunoglobulin , dexamethasone , cefotaxime , leukocyte - depleted red blood cells , fresh frozen plasma , inotropics , vitamin k , and endotracheal epinephrine were administered . 
 the patient died 9 hours after intubation , within 3 days from fever onset . 
 ev71 subgenotype c4a was isolated retrospectively from serum and nasopharyngeal swab by real - time reverse transcription - polymerase chain reaction . here , 
 we report a fatal case of ev71-associated hfmd with sudden - onset massive pulmonary hemorrhage and suspected encephalitis . 
Introduction
Case report
Discussion