Table 4.

Studies related to the complications of HFMD

Study	Results	Conclusions
Ooi et al. Sarawak, Malasia 2009 [7]	725 HFMD cases  Risk factors: fever ≥3 days (1), fever ≥38.5 °C (2), lethargy history (3)  ≥2 factors present in 65 % of children with pleocytosis in CSF, compared to 30 % without it  2–3: S 28 %, E 89 %, PPV 79 %, NPV 50 %  1: S 75 %, E 59 %, PPV 75 %, NPV 59 %	There are three risk factors to identify children with possible neurological disorders that are easily identifiable:  Fever ≥3 days duration  Fever ≥38.5 °C  History of lethargy
Cho et al. Seoul, Korea 2010 [23]	16 HFMD cases associated with: meningitis (10), Guillain–Barré syndrome (3), meningoencephalitis (2), poliomyelitis associated with acute flaccid paralysis (1) myoclonus (1) 11 positive cases for C4aEV71	Most neurological manifestations are caused by C4eEV71
Guimbao et al. Zaragoza, Spain 2010 [20]	27 Onychomadesis cases 24 had previously submitted HFMD Virus CVB1 and 2	Strong association between HFMD and onychomadesis. Microbiological results inconclusive
Davia et al. Valencia, Spain 2011 [19]	221 Onychomadesis cases associated with HFMD: 61 % CVA10 present in 49 % Other viruses: CVA5, 6, 16, B1 and B3, echovirus 3, 4, and 9, and EV71	The 2008 onychomadesis outbreak in Spain was associated with HFMD caused primarily by the CVA10 virus
Tian et al. China 2011 [38]	147 HFMD cases. Majority <3 years. 69.4 % males Rashes and fever ≥38.5 °C 100 % 100 % CNS involvement (lethargy 84.4 %, myoclonus 51.7 %, drowsiness 23.1 %), tachypnea 76.2 %, bradypnea 14.3 %, hypertension 15.5 %, increased chest 51.7 %, consolidation of the thorax 29.9 %, hyperglycemia 86.4 %, high levels of lactic acid 88.4 %, positive EV71 76.9 % Treatment: mechanical ventilation for 61.2 ± 12.8 h (range 40–96 h), mannitol, dexamethasone, gamma globulin, ribavirin, dopamine (58.5 %), dobutamine (51.0 %), amrinone (21.8 %) 2 % Died during hospitalization. Everyone else had a full recovery and were discharged after 14.2 ± 1.6 days (range, 12–17)	The central nervous system and cardiac system are involved in patients with severe HFMD. Fasting blood sugar and increased lactic acid levels in the majority of patients Mechanical ventilation support and drug treatment are associated with good clinical outcome of these patients
Wei et al. Taiwan, China 2011 [21]	130 HFMD cases by CVA6  Perioral rash (22 %), rash on body and/or neck (30 %), general rash (5 %), hand-foot-mouth rash (51 %), peeling of palms and soles of the feet (37 %), onychomadesis (5 %)	Patients with CVA6 associated HFMD symptoms of infection saw a broader spectrum of the destruction to the skin and deeper tissues, such as nail abnormalities and peeling
Chang et al. Taiwan. [45]	219 enterovirus 71 case subjects and 97 control children  74 % (163 of 219 cases) were complicated cases, 57 % (125 of 219 cases) are complicated cases with central nervous system involvement, and 17 % (38 of 219 cases) involved cardiopulmonary failure after central nervous system involvement  Necrosis factor α promoter type II (-308 A allele), HLA-A33, and HLA-DR17 were significantly associated with enterovirus 71 susceptibility  HLA-A33 was the gene most significantly susceptible to enterovirus 71. HLA-A2 was associated with the development of cardiopulmonary failure	HLA-A33, which is a common phenotype in Asian populations but is rare in white populations, was most significantly associated with enterovirus 71 infection, compared with the other candidate genes studied, whereas HLA-A2 was significantly related to cardiopulmonary failure

HFMD hand, foot and mouth disease, S sensitivity, E specificity, PPV positive predictive value, NPV negative predictive value