Epidemiology

EV-D68 was first isolated in 1962 in California and had been rare with occasional reports of clusters. Since the late 2000s, EV-D68 has been increasingly reported in various parts of the world. In August 2014, the US Centers for Disease Control and Prevention (CDC) reported cases beginning in the Midwest, with more than 1000 cases reported in 49 states in 2014.

Etiology

EV-D68 is a single-stranded, nonenveloped RNA virus. It belongs to the genus Enteroviruses and family Picornaviridae. It is one of the five EV-D serotypes identified so far. It has virologic characteristics including the ability to bind to α-2, 6-linked sialic acids that are present in the upper respiratory tract, which facilitate respiratory infections ( Table 28.1 ).

Pathology/Pathogenesis

The pathogenesis of EV-D68 has been studied in animal models. Schieble and colleagues noted that the Rhyne strain demonstrated a neurotropic virulence with paralysis of mice. However, despite the predominant respiratory symptoms seen in humans, no effective animal models have been established. Humans are at the moment the only known natural reservoirs of the disease.

Clinical Features

The incubation period for EV-D68 is between 1–5 days, similar to many other viral respiratory infections, and the infectious period lasts from a day prior to symptom onset to about 5 days after onset. Spread of infection occurs by droplet transmission and through the fecal-oral route or indirect contact with contaminated surfaces, as with other enteroviruses.

Symptoms

EV-D68 primarily causes acute respiratory symptoms, unlike other enteroviruses. Presenting symptoms range from mild upper respiratory symptoms such as rhinorrhea, sore throat, fever, and rash to severe pneumonia. Most reported cases were associated with difficulty breathing and wheezing, but this may affected by reporting bias.

Patients can also present with aseptic meningitis or encephalitis. EV-D68 infection has been reported to have a predilection for patients with a personal or family history of atopy. The respiratory symptoms have also been reported to be more severe in those with underlying respiratory illnesses such as asthma, often requiring intensive care treatment. Prior to virological diagnosis, many of these cases were often discharged with a diagnosis of asthma exacerbation.

During the outbreak in California and Colorado, a significant group of children was reported to have presented with acute flaccid myelitis, symptoms of sudden asymmetric limb weakness, facial weakness, ophthalmoplegia, or bulbar signs; they were found to be positive for EV-D68 in their nasopharyngeal swabs. However, the spectrum of neurologic disease associated with EV-D68 has not been fully characterized.

Physical Findings

The physical findings for infected patients are similar to those associated with most respiratory viral infections and are not specific to the disease. However, a significant number of EV-D68 patients have been reported with wheezing as the main clinical feature. Patients with more severe EV-D68 respiratory infections present with tachypnea and retractions. As already mentioned, neurologic symptoms including flaccid myelitis have also been associated with EV-D68 infections.

Imaging, Pulmonary Function Tests, Laboratory Findings

Chest radiographs often demonstrate peribronchial thickening and infiltrates, often with areas of atelectasis.

Diagnosis and Differential Diagnosis

EV-D68 can be identified using molecular methods, polymerase chain reaction (PCR), or viral cultures of fluid samples from the nasopharynx, oropharynx, and serum. Most commercially available respiratory multiplex PCR assays may not be able to distinguish enteroviruses from rhinoviruses, so specific assays for EV-D68 may be needed to identify infections with EV-D68 if the clinical suspicion is high.

Management and Treatment

Supportive care remains the mainstay of treatment. No specific treatment is currently available. Pleconaril has not been shown to be effective for EV-D68 to date.

Prevention

There are currently no available vaccines. Good hand hygiene and prompt diagnosis with subsequent isolation of cases is the main approach to containing the spread of these infections.

Prognosis

Initial studies had suggested that patients with EV-D68 infection, compared with other pulmonary pathogens such as rhinoviruses or non EV-D68 enteroviruses, were more likely to have severe respiratory symptoms and to require hospitalization. However, in a more recent retrospective analysis of the outbreak at the St. Louis Children’s Hospital, the cases analyzed have shown no significant difference in severity of illness in EV-D68 patients compared with those with other viral etiologies. This may have been due to ascertainment bias, as more severely affected children were tested and thus the case fatality rate appeared to be much higher than it probably really was. This has happened with a number of respiratory viruses, including influenza A H1N1 in 2009, when it was first recognized.

In most cases of EV-D68 infection, with supportive care recovery is expected over a few days. Fatalities have been associated with neurologic complications or occasionally cardiac events.

Epidemiology

First reported in April 2012 in Jordan, MERS-CoV spread rapidly to the Middle East, including the Kingdom of Saudi Arabia (KSA), the United Arab Emirates (UAE), and Qatar. Subsequent imported cases were then reported in European countries including France, the United Kingdom, Italy, and Germany and in North Africa (Tunisia). After the 2012 outbreak, there were only sporadic cases and nosocomial outbreaks reported from the Middle East until 2015, when a large outbreak occurred in Korea and Guangdong (China) involving 184 cases and 33 deaths. Since 2012, according to statistics from the World Health Organization (WHO), there have been 1365 laboratory-confirmed cases of MERS-CoV infection, including 487 related deaths.

Etiology

MERS-CoV is an enveloped single-stranded RNA virus belonging to the family Coronaviridae. As with most coronaviruses, the reservoir of infection is thought to originate from animals. MERS-CoV is postulated to have originated from the dromedary camels within the Arabian Peninsula. Molecular isolation of several alphacoronaviruses and betacoronaviruses from bats in Saudi Arabia and other parts of the world has suggested the involvement of bats in human infection as well. The actual route of zoonotic transmission has not been clearly defined despite the publication of a large case-control study.

Pathology/Pathogenesis

The exact pathogenesis of MERS-CoV is being elucidated. Studies looking at ex vivo infected hepatoma cells demonstrate severe cytopathic effects. Hocke and colleagues have demonstrated, through spectral microscopy, significant MERS-CoV antigen expression in type I and II alveolar cells, ciliated bronchial epithelium, and unciliated cuboidal cells of terminal bronchioles as well as pulmonary vessel endothelial cells. Evidence of alveolar epithelial damage with detachment of type II alveolar epithelial cells and associated disruption of tight junctions, chromatin condensation, nuclear fragmentation, and membrane blebbing were seen on electron microscopy. The receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4) (CD26), an exopeptidase, which has been demonstrated in cells on spectral microscopy.

MERS-CoV infection causes significant host immune dysregulation with downregulation of genes involved in the antigen-presenting pathway, leading to subsequent impaired adaptive immune responses, possibly explaining the rapid progression of the illness and the high mortality rate.

Clinical Features

Most of the MERS-CoV infections were spread via travel to or residence in countries near the Arabian Peninsula. Infection occurs via droplet transmission from patients to close contacts. The risk of person-to-person transmission is generally low, but superspreading events have been identified similar to the severe acute respiratory syndrome (SARS) coronavirus, in which single individuals have been associated with transmission to large numbers of others. The median incubation period for secondary cases of human-to-human transmission is about 5 days (range 2–14 days).

Symptoms

In adults, infection results in fever as well as upper and lower respiratory tract symptoms including cough and breathlessness, which can rapidly deteriorate to severe acute respiratory distress syndrome. Other symptoms of myalgia and gastrointestinal symptoms of diarrhea, vomiting, and abdominal pain were commonly present. However, two case series from the Middle East have reported that MERS-CoV infection ran a milder course in children, with the majority being asymptomatic carriers who were contacts of symptomatic adult cases. Severe respiratory symptoms occurred more commonly in those with existing comorbidities.

The reported patients’ age range has been from below 1 year to 99 years of age, although children have formed a minority of cases. This may be due to limited exposure to animals or health care settings where most infections have occurred.

The respiratory symptoms in symptomatic cases are rapidly progressive, with the median time from onset of symptoms to hospitalization being about 4 days and from onset to intensive care admission for severe cases approximately 5 days. Complications include acute respiratory failure, acute respiratory distress syndrome, refractory hypoxemia, and extrapulmonary complications (ischemic hepatitis, septic shock, hypotension, acute renal failure). The median time from onset to death was about 12 days.

Physical Findings

Patients presenting with symptomatic MERS-CoV infection have mainly lower respiratory findings, including tachypnea, rhonchi, and retractions, although upper respiratory symptoms have been reported.

Imaging, Pulmonary Function Tests, Laboratory Findings

Reported chest x-ray findings have included unilateral or bilateral patchy opacities, consolidation, interstitial infiltrates, and pleural effusions.

Diagnosis and Differential Diagnosis

Laboratory confirmation of active MERS-coV infection is based on real-time reverse transcription PCR (RT-PCR) detection of at least two specific genomic targets or a single positive target with sequencing of a second target. Confirmation with nucleic acid sequencing may be required for epidemiologic investigation of the origin and spread of the disease. Specimen collection sites for RT-PCR include lower respiratory samples (bronchoalveolar lavage, tracheal, or sputum aspirates) and upper respiratory samples (nasopharyngeal and oropharyngeal swabs) as well as serum and stool specimens, although the highest yield has been from respiratory samples.

Serologic testing by enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay (IFA) or microneutralization assay is available for the detection of previous infection and is used mainly for surveillance purposes; it should not be used as a diagnostic tool as there is a risk of cross-reactivity with other coronaviruses.

A single negative result on a recommended specimen sent is sufficient to demonstrate no active MERS-CoV infection according to the definition of the US CDC. However, if the clinical suspicion remains, more samples should be sent, as false-negatives do occur.

Patients who have been diagnosed with MERS-CoV are considered clear of active infection and can be deisolated when two consecutive specimen tests are negative on RT-PCR.

Other infectious etiologies presenting similarly with acute, rapidly progressive respiratory distress syndrome include SARS and influenza virus (H5N1). Noninfective causes of acute respiratory distress syndrome (ARDS) should be considered as well. The epidemiologic history and a high index of clinical suspicion are critical.

Management and Treatment

No specific antivirals have developed at this point, and the mainstay of treatment remains supportive care.

Prevention

Currently no vaccine is available against MERS-CoV. Strict infection control measures, including standard, contact, and droplet precautions, with airborne precautions for aerosol-generating procedures, must be taken when care is being provided for suspected or confirmed cases. These have been shown to be effective in controlling nosocomial outbreaks in both the KSA and South Korea. Continued vigilant epidemiologic surveillance, good hand hygiene, and cough etiquette remain the mainstays of prevention for areas not affected by outbreaks.

Prognosis

The prognosis is guarded in symptomatic cases, especially in adults, with 3–4 of every 10 patients reported to have died. The number of children infected has been small, so it remains to be seen if the disease runs a more benign course in the pediatric age group. In the adult population, patients admitted to the intensive care unit had a 58% mortality rate at 90 days post admission.