Severe Complicated Adenovirus Infection in Previously Healthy Infant

Adenovirus are highly contagious viruses that is responsible for febrile illness in children. These viruses group is mostly associated with respiratory tract infections, but also have a role in gastrointestinal, genitourinary, ophthalmologic and to lesser extent neurological manifestations [1]. The spectrum of illness severity of adenovirus ranges from subclinical and self-limited to severe and lethal disease [2, 3]. Adenoviruses has 51 serotypes, out of which, 15 serotypes play a role in human disease. Adenovirus serotypes have a variable clinical and epidemiology presentations, for instances, serotypes 3 and 7 are usually associated with respiratory illness, while serotypes 40 and 41 frequently cause acute gastroenteritis [4-7].


Introduction
Adenovirus are highly contagious viruses that is responsible for febrile illness in children.These viruses group is mostly associated with respiratory tract infections, but also have a role in gastrointestinal, genitourinary, ophthalmologic and to lesser extent neurological manifestations [1].The spectrum of illness severity of adenovirus ranges from subclinical and self-limited to severe and lethal disease [2,3].Adenoviruses has 51 serotypes, out of which, 15 serotypes play a role in human disease.Adenovirus serotypes have a variable clinical and epidemiology presentations, for instances, serotypes 3 and 7 are usually associated with respiratory illness, while serotypes 40 and 41 frequently cause acute gastroenteritis [4][5][6][7].

Case Presentations
Six months old child, previously healthy, presented to us with history of 3 days fever and cough.He was born by LSCS at term, with uneventful perinatal history, fully vaccinated.His development was appropriate to age.Unremarkable family history.Upon admission his growth parameters showed weight (10th-50th centile), Height; (50th centile) and Head Circumference; (3rd-10th centile).He was feverish with temperature 38°C, tachycardia; pulse was 158 b/m, respiratory rate 36/m, blood pressure 94/44 mmhg and O 2 saturation was 92% on 4L/m oxygen.
Respiratory virology panel PCR showed positive Adenovirus and Bocavirus.Chest x-ray showed opacification of right upper lobe, right lower lobe and left lower lobe-retro-cardiac.Initially, the child was managed with salbutamol and ipratropium nebulization in addition to IV antibiotics amoxicillin clavulanic acid.He was in need for oxygen supplementation to maintain saturation.
On Day 3 of admission the child developed generalized edema with hepatomegaly (liver was 5-6 cm below costal margin).He was tachypneic and tachycardic.On day 4 sputum culture showed MRSA positive antibiotic changed accordingly to vancomycin in addition to ceftriaxone.On day 5, child was sick looking, remained febrile, with shallow breathing, grunting, reduced air entry mainly on the right side and recessions muffed heart sound and hepatomegaly.Abnormal movements in right arm noted.Liver function showed elevated ALT (842 U/L (N; 0-56 U/L) and hypoalbuminemia 2.2 gm/dl (N; 3.8-5.4g/dL).Disturbed coagulation where PT 17.7 secs (N: 11-14 Secs), PTT: 72 secs (N; 28.0-41.0Secs).Procalcitonin 60 ng/mL, platelets reduced to 126 × 10 3 ul.Repeated chest x-ray showed worsen on right side with mild pleural effusion.Abdominal ultrasound showed ascites with hepatomegaly and mild pleural effusion.Child was shifted to PICU, hepatitis markers (Hepatitis A, B and C) were negative, and brain ultrasound was unremarkable.Hemoglobin dropped to 7.2 mg/dl.Child was on 2 liter oxygen by nasal prong received fresh frozen plasma, packed RBCS, albumin and continue on antibiotics.Child developed respiratory acidosis and was ventilated, in view of worsen chest x-ray, child had acute respiratory distress syndrome.He was unresponsive to the above management, so first dose of immunoglobulin was given as well as corticosteroids.
T. spot tuberculosis test was not reactive, no acid fast bacilli in the sputum was detected.HIV was negative, Immune status showed; IgA: 0.69 g/l (N; 0.08-0.67g/L), IgG 19.24 g/l (N:2.06-6.76g/L), IgM: 0.97 g/l (N; 0.33-0.97g/L).On day 9 the child was put on high frequency ventilator, corticosteroid was discontinue in view of persistent hypertension.Second dose of IVIG was given on day 11.On day 17, sputum culture showed negative MRSA, and stenotrophomonous maltophilia was present.Boca virus negative, but adenovirus PCR was still positive.Chest Xray was worsen.At this point: Meropenam and Linezolid added in addition to fluconazole.On day 27, there were moderate improvement in chest x-ray but the child was drowsy, brain ultrasound was unremarkable.Although the patient stay in the hospital, parents refused to do CT chest.On day 30, the child had muffled heart sound, with increased ascites and edema.ECHO showed pulmonary hypertension with moderate ventricular dysfunction.

Al-total
Milirinone and sildenafil were added.Repeated ECHO showed volume overload dopamine was added in addition to peritoneal dialysis which was kept for 13 days.
Adenovirus was the only persistent organism to be positive, with the clinical manifestation of ARDS and multisystem involvement.Child started to gradually improved was extubated on day 49, he was started on oral feeds, which was increased gradually, he was shifted to general ward on day 57.On day 69, the child discharged home in a stable; he continued to have mild tachypnea with bilateral diffuse wheezes and crackles.So he was kept on nebulization, with tapered prednisolone.One month after discharge, the child had mild tachypnea, with bilateral rhonchi.Chest x-ray was improving with only residual bilateral consolidation.Still parents refused to go for CT chest.

Discussion
In view of the above-mentioned condition, severe unresolved complicated adenovirus infection was the first possible diagnosis.Our patient has the clinical criteria which highly suggestive of Hemophagocytic lymphohistocytosis (HLH), most probably secondary to severe adenovirus infection.These include the fever, low hemoglobin and platelets, initial fibrinogen was low, triglycerides were mildly elevated (232 mg/dl), high ferritin level, initial low NK activity which was improved.Though it is difficult to know whether a patient has primary or secondary HLH on the basis of symptoms, which may be very similar.Therefore, genetic testing is usually recommended in order to make the proper diagnosis, regardless of age, which was not done.But secondary HLH was considered, or viral associated hemophagocytic syndrome.Oncology team was involved who suggested steroid course.
Tuberculosis was ruled out the child was previously healthy, no history of contact with tuberculous patient, no weight loss, Loss of appetite or night sweats.As well as, sputum acid-fast bacilli and T. Spot test: negative.Primary immune deficiency could be a possibility but it was ruled out as B and T lymphocytes revealed CD4 cell count moderately reduced.CD8 cell count and NK cells severely suppressed.Pan T cell suppression: suggesting common variable immune deficiency REPEATED: showed improvement in T, B, NK cells.

Conclusion
Adenovirus is a common viral pathogen affecting the respiratory tract in pediatric age group, which is usually selflimiting.Severe adenovirus complications unusual in immunocompetent children yet they have been rarely reported.
Herein we are reporting an unusual sequalae of the adenovirus infection to draw the attention of the pediatrician to such complications for early interference and management.