Life-Threatening Human Requiring Extracorporeal Membrane Oxygenation in a Preterm Infant

Rolando Ulloa-Gutierrez, MD*; Peter Skippen, FRCPC‡; Anne Synnes, MDCM, MHSc§; Michael Seear, MD‡; Nathalie Bastien, PhD࿣; Yan Li, PhD࿣; and John C Forbes, MBChB*

ABSTRACT. We present the first report in the literature the previous 12 hours, he had developed poor feeding, lethargy, of a child with human metapneumovirus pneumonia increasing , respiratory distress, and cyanosis. No history of who required extracorporeal membrane oxygenation for was documented. The patient’s father and 2 young siblings survival. This was a 3-month-old premature boy from each had experienced an uncomplicated, brief, nonfebrile, upper respiratory tract in the previous 3 weeks. British Columbia, Canada, who developed severe respi- This infant was born at 27 weeks of gestation (through cesarean ratory failure, experienced failure of high-frequency os- section, because of preterm labor), with a birth weight of 1200 g cillatory mechanical ventilation, and required extracor- and Apgar scores of 1 and 8 at 1 and 5 minutes, respectively. He poreal membrane oxygenation support for 10 days. This developed hyaline membrane disease and had a persistently case illustrates the importance of including this newly patent ductus arteriosus, which was treated with indomethacin. discovered pathogen among the causes of childhood Mechanical ventilation was required for 3 weeks. The patient was pneumonia. Pediatrics 2004;114:e517–e519. URL: www. discharged from the hospital at 2 months of age. Palivizumab was pediatrics.org/cgi/doi/10.1542/peds.2004-0345; human administered at 1 and 2 months of age, and the patient was metapneumovirus, , prematurity, respira- scheduled to receive a third dose when he became ill. Routine immunizations were given at 2 months, except for pneumococcal tory failure, ECMO, mechanical ventilation. conjugate (Prevnar; Wyeth Pharmaceuticals, Philadelphia, PA). At the time of arrival at the local community hospital emer- ABBREVIATIONS. hMPV, human metapneumovirus; ECMO, ex- gency department, the child was sick-looking, with an axillary tracorporeal membrane oxygenation; PICU, pediatric intensive temperature of 34.9°C, a heart rate of 140 beats per minute, and a care unit; RSV, respiratory syncytial ; CMV, cytomegalovi- respiratory rate of 30 breaths per minute. An intermittent dry rus; PCR, polymerase chain reaction. cough was present. Bilateral pulmonary rales and decreased breath sounds were noted. Cardiac examination results were nor- mal, but weak femoral pulses and mottled extremities were found. uman metapneumovirus (hMPV) is a newly Repeated episodes of apnea led to endotracheal intubation and discovered cause of acute respiratory tract mechanical ventilation. Blood was taken for cultures, and cefo- infection among children and adults that taxime and vancomycin were administered intravenously. Two H 1 boluses of normal saline solution were required to improve circu- was first reported in the Netherlands. The spectrum of disease ranges from mild upper respiratory symp- lation. The initial complete blood count revealed a hemoglobin level of 11.4 g/dL, a leukocyte count of 6800 cells per mm3 (40% toms to severe lower respiratory tract disease with neutrophils, 56% lymphocytes, 3% monocytes, and 1% eosino- respiratory failure necessitating mechanical ventila- phils), and a platelet count of 402 000 platelets per mm3. The tion.1 To date, no reports of human patients requir- C-reactive protein level, serum electrolyte levels, and urinalysis ing extracorporeal membrane oxygenation (ECMO) results were normal. An initial chest radiograph showed a diffuse, bilateral, interstitial infiltrate suggesting viral pneumonia, with no support for severe hMPV or pneumonia focal consolidations or effusions. The patient was transferred to have been published. We describe a premature infant the pediatric intensive care unit (PICU) at British Columbia’s from British Columbia, Canada, with hMPV-associ- Children’s Hospital. ated life-threatening pneumonia who required Twenty-four hours after admission to the PICU, a repeat chest ECMO support for survival. radiograph revealed bilateral patchy infiltrates involving the right upper and middle lobes and the left perihilar region, with areas of atelectasis in the right upper lobe. No pleural pathologic lesions or CASE REPORT air leaks were visible. The patient received high-frequency oscil- A 3-month-old boy was admitted to an urban hospital in March latory mechanical ventilation for 4 days, with no significant clin- 2003, with a 3- day history of and mild dry cough. In ical or radiologic improvement. Nitric oxide was administered with no clinical effect, and dopamine was required for systemic blood pressure support. Serial chest radiographs revealed wors- From the *Infectious Diseases Division, ‡Pediatric Critical Care Division, ening bilateral infiltrates with air bronchograms (Fig 1). The re- and §Neonatology Division, Department of Pediatrics, University of British sults of an echocardiogram were normal except for a small patent Columbia and British Columbia’s Children’s Hospital, Vancouver, British ductus arteriosus. Respiratory failure progressed despite maximal Columbia, Canada; and ࿣National Microbiology Laboratory, Canadian Sci- conventional critical care support; by day 4, the child exhibited ence Center for Human and Animal Health, Winnipeg, Manitoba, Canada. oxygen saturation values ranging from 77% to 88%, with hyper- Accepted for publication May 7, 2004. capnia, and the oxygenation index had increased from 13 to 26. An doi:10.1542/peds.2004-0345 arterial blood gas analysis performed on the morning of day 4 of This work was presented in part as an abstract at the 4th Pediatric Infectious hospitalization showed a pH of 7.28, an arterial partial pressure of Diseases Society Conference; October 12–14, 2003; Rancho Bernardo, Cali- oxygen of 45 mm Hg, an arterial partial pressure of carbon dioxide fornia. of 82 mm Hg, and a bicarbonate level of 37 mEq/L. Diffuse, Address correspondence to Rolando Ulloa-Gutierrez, MD, Pediatric Infec- bilateral, pulmonary opacification was observed at that time. After tious Diseases Division, British Columbia’s Children’s Hospital, 4480 Oak discussion with the family, venovenous ECMO was initiated. St, Room K4-166, Vancouver, BC, Canada V6H 3V4. E-mail: [email protected] Liver enzyme levels were normal, and initial blood cultures PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- were negative. Nasopharyngeal aspirates, repeated 4 days apart, emy of Pediatrics. were negative for Bordetella pertussis in polymerase chain reaction

www.pediatrics.org/cgi/doi/10.1542/peds.2004-0345Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 25, 114 2021 No. 4 October 2004 e517 tions, which was performed at the National Microbiology Labo- ratory (Winnipeg, Manitoba, Canada), was positive for hMPV. The primers used for amplification and sequencing were based on the hMPV F gene sequence, ie, MPVF1f (5Ј-CTTTGGACTTAATGA- CAGATG-3Ј) and MPVF1r (5Ј-GAGAAGAGCTGGGTAGAAG- 3Ј), which were used to amplify a 450-base pair fragment of the F gene.2 Appropriate positive and negative control assays were performed, and the amplified PCR product was confirmed with sequence analysis. Phylogenetic analysis of the F gene sequence from the infant’s isolate revealed that the causative virus was similar to previous Canadian isolates of hMPV (Fig 2). The child was successfully decannulated from ECMO after 10 days and required an additional 5 days of conventional mechan- ical ventilation. After 20 days in the PICU and 1 month of hospi- talization, the patient was discharged from the hospital with bron- chodilators for 1 month and no supplemental oxygen. He has been monitored in the respiratory and neonatal follow-up clinics, cur- rently receives no medications, and has no respiratory or definite neurologic sequelae to date.

DISCUSSION The complete clinical spectrum of hMPV disease is not fully defined. Most occur in the winter Fig 1. Chest radiograph, showing bilateral pneumonic infiltrates months, as happened for this infant. Clinical mani- and air bronchograms. festations produced by this new member of the family resemble those of RSV dis- (PCR) assays and were negative for in direct immunoflu- ease and include fever, cough, rhinorrhea, sore orescence tests and cultures; tested viruses included adenovirus, throat, wheezing, and bronchiolitis.1,2,4 Other mani- respiratory syncytial virus (RSV), A and B, and parain- festations are tachypnea, retractions, flaring, hoarse- fluenza types 1, 2, and 3. A bronchoalveolar lavage specimen ness, and stridor. Less commonly, pneumonia devel- contained epithelial cells and occasional neutrophils, histiocytes, and Gram-positive cocci, but no organisms were isolated. No ops and leads to respiratory failure necessitating 1,5 Pneumocystis jiroveci (previously Pneumocystis carinii) or fungus mechanical ventilation. However, no reports of pa- was recovered. Tracheal viral cultures and PCR assays for cyto- tients requiring ECMO because of hMPV respiratory megalovirus (CMV) and types 1 and 2 were infections have been published. negative, as was a CMV early antigen test. Cultures from tracheal Lower respiratory tract infections that progress to aspirates were negative for Ureaplasma urealyticum, Chlamydia tra- chomatis, Mycoplasma hominis, and Mycoplasma pneumoniae. Serum respiratory failure and necessitate ECMO support was negative for immunoglobulin M antibodies to M pneumoniae, are associated with increased morbidity and mortal- CMV, and herpes simplex virus. Urine and stool cultures were ity rates. ECMO support has been used in the treat- negative for bacteria. No adenovirus, , or was ment of life-threatening infections caused by viruses, detected in the stools with enzyme-linked immunosorbent assays or cultures. After 5 days of treatment with cefotaxime and vanco- bacteria, fungi, mycobacteria, and atypical organ- 6–12 mycin and negative bacterial culture findings, antibiotics were isms. The success of this respiratory support discontinued. A -PCR assay of tracheal secre- mode has been variable, ranging from no effect to

Fig 2. Phylogenetic tree of the hMPV iso- lates. Nucleotide sequences were deter- mined for nucleotides 688 to 1032 of the F gene. The corresponding gene sequences from previously reported Canadian and Dutch isolates were also included. Phyloge- netic analysis was performed by using the Neighbor-Joining method of the MEGA2 program, with 100 bootstraps.3 Numbers on the tree represent bootstrap values (statisti- cal values indicating the reliability of the branch length), which statistically support the tree. The Canadian isolates are indicated by CAN followed by the year of collection and the isolate number. The infant’s isolate is identified as CAN03-421 and is marked with an arrow. A Netherlands’ isolate is in- dicated as NDL00-1.

e518 hMPV PNEUMONIADownloaded AND ECMOfrom www.aappublications.org/news SUPPORT by guest on September 25, 2021 complete recovery. A key consideration is whether the emerging hMPV in the list of infectious causes of lung injury is reversible during the limited period in childhood pneumonia. The clinical suspicion should which ECMO support can be maintained. In this be higher for patients lacking evidence of other com- case, hMPV-induced lung injury resolved substan- mon respiratory pathogens. ECMO support may be tially during 10 days of lung rest with ECMO sup- necessary for survival for some of these patients and port. should be considered, because pulmonary injury Repeated tests for common causes of pneumonia may be reversible. were performed and yielded negative results. These tests for other common pathogens, including direct immunofluorescence tests for RSV, are sensitive and ACKNOWLEDGMENTS the results support hMPV as the etiologic agent in We thank Dr David Scheifele, British Columbia’s Children’s this case. The possible source of infection for this Hospital, for critical review of the manuscript. infant might have been 1 of his 3 sick household contacts, none of whom was screened for respiratory REFERENCES viruses. The patient did not meet the diagnostic cri- 1. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered teria for severe acute respiratory syndrome and was human pneumovirus isolated from young children with respiratory not screened for it. To date, no pediatric cases of tract disease. Nat Med. 2001;7:719–724 severe acute respiratory syndrome have been docu- 2. Bastien N, Ward D, Van Caeseele P, et al. Human metapneumovirus in mented in British Columbia. the Canadian population. 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