Atypical Presentations of Respiratory Syncytial Virus Infection Case series

The respiratory syncytial virus (RSV) usually causes a lower respiratory tract infection in affected patients. RSV has also been infrequently linked to extrapulmonary diseases in children. We report four children who had unusually severe clinical manifestations of RSV infections requiring critical care admission. These patients presented to the Royal Hospital, Muscat, Oman, in December 2013 with acute necrotising encephalopathy (ANE), acute fulminant hepatic failure with encephalopathy, pneumatoceles and croup. A unique presentation of ANE has not previously been reported in association with an RSV infection. All patients had a positive outcome and recovered fully with supportive management.

A nasopharyngeal swab viral multiplex polymerase chain reaction (PCR) test revealed a positive result for RSV and a negative result for other respiratory viruses, including influenza A and B, coronaviruses, parainfluenza viruses, rhinoviruses, adenoviruses, enteroviruses, paraechoviruses, human metapneumovirus, bocavirus and Mycoplasma pneumoniae.Plasma PCR tests were negative for herpes simplex virus and human immunodeficiency virus.Hepatitis E immunoglobulin (Ig) M, hepatitis A IgG and IgM, hepatitis B surface antigen and hepatitis C virus antibodies were negative.No growth was observed on blood and urine cultures.The metabolic work-up showed normal ammonia and urine organic acid with mildly elevated levels of methionine and phenylalanine; these were likely secondary to the hepatic dysfunction.
Five days after admission, a repeat CBC showed leukocytosis with lymphocytosis.A chest X-ray (CXR) revealed right upper lobe consolidation [Figure 1A].Computed tomography (CT) of the head was normal.
The patient was stabilised in the Paediatric Intensive Care Unit (PICU) and did not require ventilation.She was prescribed cefotaxime and acyclovir empirically.Five days later, her AST levels dropped to 1,500 IU/L.She improved gradually and regained a normal level of consciousness.Within seven days her liver had returned to a normal size and her CXR showed complete resolution of the consolidation [Figure 1B].

Case Two
A nine-year-old boy diagnosed with a recurrent medulloblastoma was admitted to the Royal Hospital in December 2013 with a two-day history of fever,  day.The endotracheal secretion showed positive Haemophilus influenzae growth.A nasopharyngeal swab viral multiplex PCR test was positive for RSV and negative for other viruses.For a period of two weeks, he received intravenous ceftriaxone and clindamycin followed by oral clindamycin.A repeat CXR on the 12 th day of admission showed resolved pneumonia and a pneumatocele.On the 14 th day of admission, another CXR showed complete resolution of the pneumatoceles [Figure 3B].On the same day, he was discharged on oral clindamycin to complete the fourweek course of treatment.

Case Four
A previously healthy six-year-old female was admitted to a peripheral hospital in Oman in December 2013 with a one-day history of fever, runny nose, cough and lethargy, followed by altered sensorium and an inability to walk.One day prior to admission, she received an oral antibiotic from a local health centre.On examination, she was drowsy, mute, febrile and unable to stand or walk without support.She did not have any meningeal signs, although a lumbar puncture showed significant leukocytosis (red blood cell count [RBC]: 10,000/UL; white blood cell count [WBC]: 50/UL; neutrophils: 70%).Her cerebrospinal fluid (CSF) glucose level was 4.5 mmol/L and her protein level was 0.4 g/L.Her CSF Gram stain, bacterial antigen and culture stains were negative.A viral study was not performed.A nasopharyngeal swab viral multiplex PCR test was positive for RSV and negative for other viruses and Mycoplasma.The patient was suspected to have meningoencephalitis and was prescribed ceftriaxone, vancomycin and acyclovir empirically.On the same day, the patient developed recurrent abnormal movements-sudden twisting of the head to the right side, blankness in the eyes and generalised stridor, a barking cough and respiratory distress.On examination, he was febrile with bilateral equal breath sounds and an expiratory wheeze.He had received high-dose chemotherapy seven days prior to admission.His investigations showed high levels of C-reactive protein.A nasopharyngeal swab viral multiplex PCR test was positive for RSV and negative for other viruses.The patient's CBC showed severe leukopenia 0.1 x 10 9 /L (normal range: 1.4-9.0x 10 9 /L) with no neutrophils.His CXR showed a narrowing of the upper third of the trachea [Figure 2A] with compensatory hyperinflation and no consolidation.The patient was diagnosed with croup and was prescribed adrenaline and dexamethasone.He had severe stridor requiring intubation [Figure 2B] and a three-day course of ventilation.Six days later, a repeat CBC, neck X-ray and CXR showed resolution of the aforementioned signs.He completely recovered and was discharged seven days after admission.

Case Three
A 33-day-old male infant was admitted to the PICU at the Royal Hospital in December 2013 with a twoday history of fever, cough and poor feeding.On examination, he was febrile, tachycardic, tachypnoeic and required 3 L of oxygen via nasal prongs for maintained saturation.Investigations showed a normal CBC, urea electrolyte panel, bone profile and urine analysis.A CXR revealed bronchopneumonia with multiple pneumatoceles [Figure 3A].The day after admission, he became distressed and was found to be hypotensive with right pneumothorax.He required intubation, ventilation, intercostal drainage (ICD) catheter insertion and inotropic support for three days.He began to improve on the fourth day of admission and the ICD catheter was removed and the inotropic support discontinued.He was extubated on the same body stiffness which would last for a few seconds.These movements were eased by the administration of diazepam.When assessed, the patient scored between 8-11 on the Glasgow coma scale.
On the subsequent day, the patient was transferred to the PICU at the Royal Hospital for further evaluation and management.On arrival, she was obtunded, only opened her eyes to painful stimuli, did not respond to verbal commands and showed some withdrawal of the flexor response of the limbs to deep painful stimuli.There were bilateral pyramidal tract signs involving both the upper and lower limbs.She was ventilated due to her low Glasgow coma score and a depressed gag reflex.She developed a severe allergic skin reaction to ceftriaxone and was subsequently prescribed meropenem instead, although she continued to receive acyclovir.Upon her admission to the PICU, results of a brain CT scan were normal.Fluidattenuated inversion recovery magnetic resonance T2 imaging of the brain on the second day of admission revealed multiple subcortical white matter hyperintense lesions involving the periventricular white matter, internal capsule, left anterior midbrain, corpus callosum, posterior brainstem tract, cerebellar peduncles and left optic nerve [Figure 4].This was suggestive of acute necrotising encephalopathy (ANE).She was treated with intravenous methylprednisolone pulse therapy for five days.As no improvement was seen from the methylprednisolone treatment, this was followed by intravenous immunoglobulin at a dosage of 2 g/kg over the next five days.
The patient had multiple episodes of generalised tonic posturing and was treated with phenytoin and levetiracetam.As there were no clinical signs of improvement, a lumbar puncture was repeated on day nine of admission, which showed a negative culture with normal analysis (WBC: 5/UL; RBC: 20/UL; glucose: 4.6 mmol/L; proteins: 0.2 g/L).The patient's CSF viral PCR study was negative for herpes simplex viruses 1 and 2, enteroviruses, varicella zoster virus and mumps virus.Blood serology showed positive Mycoplasma IgG and negative IgM and IgA.On the 11 th day of admission, the patient received five sessions of plasmapheresis over the following seven days.She showed dramatic clinical improvement and was extubated at the end of the third week of admission.
With an extensive rehabilitation programme, the patient made excellent progress.When she was discharged, despite mild left upper limb weakness, she had normal speech, cognitive function and could walk with support.She was advised to continue physiotherapy.Three months after discharge, she was seen in a paediatric neurology outpatient clinic and was found to have no neurological deficits.

Discussion
Almost all children acquire a RSV infection by the second year of life.A minority (0.5-2.0%) of infected children will require admission and most of them will be less than six months old. 5 All of the patients in this case series were asymptomatic apart from upper respiratory tract infections for two days prior to admission.Three of the children were unique in that they had a complicated course with an extrapulmonary manifestation of RSV infection, while the remaining patient had such a severe lower respiratory tract infection that he was found to have a pneumatocele in association with RSV.Only one child was known to be immunocompromised; the other three had no known risk factors.
Pneumatoceles are caused primarily by Staphylococcus aureus, although they may also be associated with other pathogens like Streptococcus pneumoniae, H. influenzae and Klebsiella pneumoniae. 10Pneumatoceles are a very rare complication of RSV bronchiolitis. 11It has been shown that treatments for ANE have limited efficacy. 17A recent report showed that treatment with steroids within the first 24 hours for three children without brainstem involvement improved outcomes, whereas the use of non-steroidal anti-inflammatory drugs has been associated with a poor prognosis and increased mortality rates. 17Methylprednisolone pulse therapy and high-dose γ-globulin treatment have been used to modulate immune-mediated neurovascular and cell injury. 17Plasma exchange can be used in patients who respond poorly to corticosteroids in order to modulate immune-mediated neurovascular and cell injuries.Although no data from randomised trials are available, successful treatment with plasma exchange has been reported. 17,22,23lternative treatments for RSV infections that have been initiated in an attempt to improve mitochondrial function include carnitine, coenzyme Q 10 and pyridoxine; hypothermia has also been tried as a treatment modality. 17The use of these interventions has been associated with a decrease in mortality rate (30% to 15%). 17Currently, there is no clear evidence that the use of ribavirin improves the clinical outcome of critically ill infants with RSV infections. 24ne patient in this case series (case four) had encephalopathy which rapidly progressed within 48 hours preceded by an upper respiratory tract infection.The respiratory viral panel showed positive RSV PCR results with negative findings for other viruses and M. pneumoniae.The patient was managed with methylprednisolone, plasmapheresis and extensive physiotherapy.She improved gradually and had fully recovered within three months.In this case, the most likely cause of ANE was the RSV infection.It is very difficult to confirm that ANE is caused only by RSV in the absence of a brain biopsy.A brain biopsy was not performed on this patient as it was thought to be an invasive procedure and the patient was in an unstable condition.Clinicians should consider ANE in cases of RSV infection with rapid progressive encephalopathy and start aggressive management accordingly.

Conclusion
In healthy children, an RSV infection usually causes a mild respiratory tract infection; however, some patients present with rare atypical and severe manifestations.Testing for RSV in these cases is therefore indicated.Clinicians should have a high suspicion of ANE when treating a patient with a respiratory infection and acute neurological manifestations.Early recognition of ANE is important for the initiation of effective supportive treatment in order to improve patient outcomes.Almost 85% of RSV pneumatoceles resolve completely and spontaneously. 12Lobar emphysema may also be associated with RSV pneumonia. 12One patient (case three) had symptoms of a viral infection with a runny nose and cough, then developed pneumonia and a pneumatocele which completely resolved within two weeks.Endotracheal secretions were positive for RSV PCR findings and H. influenzae non-type B culture, but his blood culture was negative.In this patient, it is likely that RSV was the primary infection; H. influenzae may have been a colonisation or secondary infection.Previous research has shown that serious bacterial infections are present in 0.6-1.2% of children admitted with RSV infections. 13To determine the aetiology of the pneumatoceles and pneumonia in the previously reported patient (case three), a lung biopsy was necessary.However, it was not carried out as the patient had improved; as such, a biopsy would not have added to the clinical management of the case.
Acute laryngeal croup is most often associated with parainfluenza viruses, RSV, rhinoviruses and enteroviruses. 14Usually croup presents in children of five years of age or younger.Unusually, one patient in this case series (case two) had severe croup due to RSV at the age of nine years; this can be explained by his secondary immunodeficiency following chemotherapy.Acute fulminant hepatic failure with encephalopathy is another rare atypical manifestation of RSV infection. 15Acute hepatitis can be a manifestation of other viruses such as the hepatitis, Epstein-Barr, cytomegalovirus and influenza viruses.One patient in this series (case one) had acute fulminant hepatic failure with encephalopathy and deranged coagulation.A liver biopsy was not performed; with supportive management, she recovered both clinically and biochemically within one week.

Figure 1 A&B:
Figure 1 A&B: Chest X-rays of an 11-month-old female infant (case one) with respiratory syncytial virus infection showing (A) right upper lobe consolidation and (B) complete consolidation resolution five days after admission.

Figure 2
Figure 2 A&B: Chest X-rays of a nine-year-old boy (case two) with respiratory syncytial virus infection showing (A) upper airway narrowing which required (B) intubation.

Figure 3
Figure 3 A&B: Chest X-rays of a 33-day-old male infant (case three) with respiratory syncytial virus infection showing (A) right-side pneumatoceles on admission and (B) the resolution of the pneumatoceles four days after admission.

Figure 4 A&B:
Figure 4 A&B: Axial fluid-attenuated inversion recovery magnetic resonance images of the brain in a six-year-old female (case four) with respiratory syncytial virus infection showing (A) non-confluent white matter hyperintense foci involving the centrum semiovale, periventricular white matter and internal capsules, (B) hyperintense lesions involving the anterior midbrain and (C) hyperintense lesions involving the cerebellar peduncles.