Eur J Pediatr (1992) 151 : 697-700
EuropeanJournalof
Pediatrics
9 Springer-Verlag1992
Acute deteriorations in neonatal chronic lung disease B. Yuksel and A. Greenough Department of Child Health, King's College Hospital, London, SE5 9RS, United Kingdom Received October 24, 1991 / Accepted after revision January 14, 1992
Abstract. Preterm infants with chronic lung disease (CLD) have frequent respiratory relapses. The aim of this study was to assess the aetiology of such deteriorations and in particular the proportion due to viral infections. During the study period 118 p r e t e r m infants with birth weight < 1500 g were consecutively admitted to the neonatal intensive care unit; 22 (18.6%) developed C L D . At the onset of all respiratory deteriorations, infants were examined for the presence of patent ductus arteriosus, apnoea or aspiration; they were also carefully screened for both viral and bacterial infection. The 22 infants had a total of 74 episodes of respiratory deterioration; median 3 per b a b y (range 1.-8). Two episodes were associated with patent ductus arteriosus, 18 with apnoea and 5 with aspiration. Infection was suspected or proven in association with all other episodes. On ten occasions the infants had positive blood cultures and on a further eight, bacteria were isolated only from. the endotracheal or nasopharyngeal secretions. On the remaining 31 occasions, 27 associated with chest X-ray film abnormalities, infection was suspected, but no bacteria isolated. Viral infections were identified in association with 8 (11%) of these episodes. We conclude viral infection should be considered as a cause of otherwise unexplained respiratory deteriorations in infants with neonatal C L D .
Key words: Chronic lung disease - Viruses - Prematurity - Patent ductus arteriosus - A p n o e a
Introduction Premature infants with chronic lung disease (CLD), even while remaining on the neonatal intensive care unit, have frequent deteriorations in respiratory status. These episodes may be associated with aspiration, apnoea or patent ductus arteriosus ( P D A ) and clinical experience Correspondence to: A. Greenough Abbreviations: CLD = chronic lung disease; PDA = patent
ductus arteriosus; RSV = respiratory syncytial virus
suggests that infection is also an important cause [15]. Infants with C L D are particularly at risk of infection as they are usually born very p r e t e r m [3, 19], hence their defence systems against infection are p o o r [2, 4, 28, 29] and they are likely to undergo repeated invasive procedures such as intubation or intravenous catheterisation. Frequently, however, although infant's clinical condition and chest X-ray film appearance are strongly suggestive of infection, bacterial agents are not isolated. Neonatal units operate an " o p e n - d o o r " policy regarding visiting, which is likely to increase the infant's exposure to persons who, although not systemically unwell, could be suffering from viral infections. Thus viral infections m a y be responsible for certain of the acute respiratory deteriorations in infants with CLD. As antiviral therapy is now available [16], it is important to test this hypothesis and assess which infants, if any, are predisposed to develop viral infections. Our aim, therefore, was to determine the frequency and aetiology of respiratory deteriorations in p r e t e r m infants who had C L D and were still resident on the neonatal intensive care unit.
Patients Of 118 very low birth weight infants consecutively admitted to the neonatal intensive care unit at King's College Hospital and followed prospectively, 22 developed CLD. The median gestational age of the infants with CLD was 26 weeks (range 23-32) and birth weight 907 g (600-1494). Their median duration of ventilation was 19 days (4-80) and of oxygen dependency was 59 days (range 28240). Their median duration of admission on the neonatal unit was 76.5 days (30-235), 3 died on the neonatal unit. This study was approved by the King's College Hospital Ethics Committee.
Methods All infants with birth weight < 1500 g admitted to the unit were eligible for entry into the study. On admission all such infants were screened for infection, which included venepuncture to obtain blood for culture. At this venepuncture a further aliquot of blood was taken for viral serology and the results used to identify congenital infection and document passively transferred maternal antibodies.
698 All infants who remained oxygen dependent at 21 days of age with an abnormal chest X-ray film were diagnosed as suffering from CLD [7] and recruited into the study. All respiratory deteriorations in such infants were then documented. A respiratory deterioration was denoted by an increase of more than 0.1 in the inspired oxygen concentration (FiO2) and/or an increase in peak pressure of 5 cm H20 which persisted for at least 12 h. At the onset of each deterioration infants were examined for the presence of a PDA, apnoea or aspiration, screened for bacterial and viral infection and a chest X-ray film was taken. A clinically significant PDA was diagnosed if the infant had systolic murmur with bounding peripheral pulses and the chest film demonstrated an enlarged heart with pulmonary plethora [7]. The presence of a PDA was confirmed by 2D cross-sectional echocardiography. Apnoea was defined as a respiratory pause of more than 20 s accompanied by a bradycardia (a heart rate less than 100 bpm). This was determined to be the cause of the infant's respiratory deterioration if the change in the infant's condition coincided with the onset of frequent apnoeas, no bacterial or viral infection was identified nor was there a new abnormality of the chest X-ray film appearance. Aspiration was diagnosed if milk was aspirated from the upper airway following a choking episode related to feeding. The diagnosis was supported by demonstration of localised or diffuse atelectasis predominantly affecting the right upper lobe on the chest X-ray film. The infection screen included obtaining surface swabs, nasopharyngeal or endotracheal aspirate as relevant and samples of blood and urine for microscopy and culture. A lumbar puncture was only performed if clinically indicated. Bacterial infection was divided into those episodes which were associated with a positive blood culture (proven infection) and those in which bacteria were isolated from the endotracheal tube or nasopharyngeal aspirate but not blood culture (probable colonisation). A blood culture was defined as positive if a known pathogen was isolated from the blood culture bottles. If coagulase-negative staphylococci were isolated this was considered only to be a significant infection if the organism was isolated from both bottles and the organisms had identical sensitivities. Urine was sent for culture of cytomegalovirus and conjunctival scrapings to asses for evidence for Chlamydia. Immunofluorescence was performed, using specific antisera towards respiratory syncytial virus (RSV) and influenza virus, on the nasopharyngeal and endotracheal aspirates. Serum was sent for serological determination of the occurrence of rubella, cytomegalovirus, RSV, adenovirus or parainfluenza infection. Serology was considered positive if there had been at least a fourfold increase in antibody titre from the level measured at birth or, in the absence of the specific antibody at birth, an antibody titre of greater than 1 in 32 at the time of the acute episode. Infants who had temperature instability, a raised white blood cell count and a metabolic acidosis, but neither bacteria nor viral infections were identified, were described as suffering from suspected infection.
Statistical analysis Infants who developed a viral infection were compared to the rest of the cohort and differences between the two groups assessed for statistical significance using the Wilcoxon rank sum test.
Results T h e 22 infants h a d a t o t a l of 74 e p i s o d e s o f d e t e r i o r a tion, a m e d i a n o f 3 p e r infant ( r a n g e 1 - 8 ) at a m e d i a n p o s t n a t a l age of 35 days ( r a n g e 2 4 - 1 7 4 days). O n t h e m a j o r i t y o f e p i s o d e s i n f e c t i o n was p r o v e n o r s u s p e c t e d , b u t a p n o e a a c c o u n t e d for 18 e p i s o d e s ( 2 4 % ) ( T a b l e 1). T e n e p i s o d e s w e r e a s s o c i a t e d with positive b l o o d cultures: Staphylococcus epidermidis (four); Enterococcus faecalis (two); Klebsiella pneumoniae (two); Staphylococcus aureus ( o n e ) ; Escherichia coli ( o n e ) . I n all t h e s e
Table 1. Probable causes of deterioration Number of episodes PDA Apnoea Aspiration Bacterial infection positive blood culture isolated from endotracheal tube or nasopharyngeal aspirate Viral infection Suspected infection
2 18 5 10 8 8 23
Table 2. Results of viral screening Patient number
Investigation
1 2 3 4 5 5 6 7
+ +
RSV RSV RSV Adenovirus Adenovirus Influenza A Influenza A Influenza B
IF
+
FAT
CFA
+ + + + + +
IF, immunofluorescence; FAT, fluorescent antibody test; CFA, complement fixing antibody test +; positive test result
episodes the infants h a d suffered from a m e t a b o l i c acidosis a n d t e m p e r a t u r e instability at t h e t i m e o f t h e d e t e r i o r a tion. I n a n o t h e r eight cases the infants w e r e p r o b a b l y c o l o n i s e d [S. epidermidis ( t h r e e ) E. faecalis ( o n e ) ; S. aureus (one); E. coli (one); Pseudomonas aeruginosa (two)]. In a f u r t h e r 31 e p i s o d e s , 27 w i t h o u t chest X - r a y film abn o r m a l i t i e s , i n f e c t i o n was s t r o n g l y s u s p e c t e d b u t n o bact e r i a was i s o l a t e d . O n 8 o f t h e s e e p i s o d e s , in seven infants, viral infections w e r e i d e n t i f i e d ( T a b l e 2). T h r e e o f the seven babies were boys a n d four non-caucasian. T h e r e was no clustering of e p i s o d e s d u e to viral infection. T h e m e d i a n g e s t a t i o n a l age o f t h e i n f e c t e d infants was 26 w e e k s ( r a n g e 2 4 - 3 0 ) , a n d t h e i r p o s t n a t a l age 32 days ( r a n g e 2 4 - 4 9 ) which d i d n o t differ significantly f r o m t h e rest o f the c o h o r t (26 w e e k s , r a n g e 2 3 - 3 2 a n d 38 days, r a n g e 2 6 - 1 7 4 ) r e s p e c t i v e l y . T h e r e was no significant diff e r e n c e in t h e v e n t i l a t o r y r e q u i r e m e n t s o r o x y g e n dep e n d e n c y of t h e two g r o u p s ( i n t e r m i t t e n t p o s i t i v e pressure v e n t i l a t i o n m e d i a n 18 days, r a n g e 5 - 3 8 C o m p a r e d to 20 days, r a n g e 4 - 8 0 a n d o x y g e n d e p e n d e n c y 53 days, r a n g e 2 8 - 9 4 c o m p a r e d to 60 days, r a n g e 3 0 - 2 4 0 , infants with a n d w i t h o u t viral infections r e s p e c t i v e l y ) . N o n e o f the seven infants w h o h a d viral infections w e r e receiving b r e a s t milk at the t i m e o f t h e a c u t e d e t e r i o r a t i o n . F i v e o f t h e 18 infants w h o s e a c u t e d e t e r i o r a t i o n was d u e to a p n o e a w e r e r e - v e n t i l a t e d , the o t h e r 13 r e s p o n d e d to an i n c r e a s e in t h e i r i n s p i r e d o x y g e n c o n c e n t r a t i o n ; all 18 r e c e i v e d antibiotics for at least 48 h. O f the two infants with s y m p t o m a t i c P D A , o n e was successfully t r e a t e d with i n d o m e t h a c i n a n d t h e o t h e r r e q u i r e d surgical liga-
699 tion of the PDA. The five infants who had aspiration episodes were treated with antibiotics, appropriate positioning to prevent gastro-oesophageal reflux and thickening of their feeds. In all 49 episodes in which infection was suspected, antibiotics were given for at least 48 h and until culture results were known to be negative. In addition, 12 infants received Ribavirin, in two cases this was because of identification of RSV infection by immunofluorescence and in the other 10 infants viral infection had been suspected. Influenza A infection was subsequently identified in one of these 10 patients. On all but 2 of the 74 episodes the infants responsed to the therapy outlined above. Two infants died during the acute episodes both had been chronically ventilatordependent for many months and died of respiratory failure, neither had a viral infection.
Discussion
We were able to document probable cause of deterioration in respiratory status in the majority of episodes. Apnoea unrelated to infection was a common cause of deterioration, despite all infants included in the study receiving theophylline. It is our routine policy to treat all ventilated infants with theophylline to facilitate weaning [8], maintenance therapy is then continued until at least 3 months of age. The present results and those of others [25] demonstrate that theophylline may be ineffective in preventing apnoea in certain very immature infants. Gastro-oesophageal reflux, is increased in infants with CLD [6]. Reflux could have been responsible for the aspiration episodes we documented, this hypothesis is supported by our prevention of recurrence of such episodes by institution of thicking of feeds and positioning the infant to lessen the likelihood of reflux. Only two infants had symptomatic PDAs, but we only included infants who were older than 21 days of age. It is, however, possible that certain of our clinical policies may also have influenced this low incidence, in particular fluid restriction during the acute stage of the respiratory illness [9] and use of an artificial rather than a natural surfactant for replacement therapy [22]. Infection, proven or suspected, was associated with the majority of episodes of respiratory deterioration. This is perhaps not surprising, as nosocomial infection is unfortunately common on neonatal units [15] and 30% of nosocomial infection presents as pneumonia [15]. Infants with CLD are particularly at risk of nosocomial infection as, despite the use of home oxygen therapy, they usually have prolonged admissions [11]. In certain episodes however, although infection was strongly suspected, organisms were not isolated or isolated only from the endotracheal tube or nasopharyngeal aspirate. Certain of these episodes may have been due to organisms which we were unable to detect, in particular Mycoplasma horninis and Ureaplasrna urealyticum. Both organisms have been implicated in the development of CLD [23] and may be responsible for deteriorations in CLD. We did, however, examine the infants for the presence of viral
infection and found this to be associated with eight episodes. The viruses we identified have been associated with nosocomial infection in the neonatal unit. It has been suggested that adenovirus is the most common virus to be isolated [20], but that study [20], surprisingly, failed to identify any of the common respiratory pathogens such as RSV or influenza which together, in the present series, accounted for the majority of virus isolates. RSV infection was identified on three occasions. We felt it unlikely that we underdiagnosed RSV infection, as nasopharyngeal or endotracheal aspirates were always sent for immunofluorescent staining, which is a more sensitive test than viral culture [18]. A further major advantage to using immunofluorescence is that results are available within 2-4 h whereas the results of viral culture are available only after some days [13]. Thus, use of immunofluorescence facilitates prompt institution of infection control measures and may prevent, as in our series, nosocomial spread which has previously been documented with RSV infection [18]. The majority of infants in the present series with viral infection were non-caucasian and none were receiving breast milk; these factors may have put them at increased risk [26]. The episodes we identified as due to viral infection were sporadic. Previous influenza infection on an neonatal intensive care unit has occurred as an epidemic associated with an outbreak in the community [17]. Although we did not isolate patients with viral infection our strict handwashing policy may have prevented nosocomial spread [12, 27]. We did prescribe Ribavirin for a small number of patients and this may have limited virus shedding and hence nosocomial spread, but this is controversial [5] and not all infants in the present series with viral infection received Ribavirin. Morbidity following infection is dependent on the type of virus. RSV is associated with marked morbidity and prolongation of hospitalisation [14] and adenoviral infection is frequently disseminated and generally fatal with symptoms of fever, hypothermia, hepatomegaly and bleeding as well as progressive pneumonia [1]. In contrast, influenza infection has not been associated with any sequelae [17]. The numbers in the present study are too small to make meaningful statements regarding the morbidity associated with different viral infections but all of our patients recovered. Preterm infants frequently suffer from wheeze and cough at follow up [10]. These symptoms are responsive to bronchodilator therapy [32]. Plethysmographic studies of lung function have demonstrated that such infants have a high airways resistance [31], which is at least partially improved by nebulised bronchodilator [33]. Such studies suggest preterm infants may have increased bronchial hyperreactivity. Infants born at term who during infancy and early childhood suffer from viral infection have increased bronchial hyperreactivity [21, 24, 26]. Viral infection and parental smoking synergistically increase recurrent wheeze in such infants [30]. It is thus tempting to speculate viral infections in infants with CLD may, in part, account for the bronchial hyperreactivity seen at follow up in such infants.
700
References 1. Abzug MJ, Levin MJ (1991) Neonatal adenovirus infection: four patients and review of the literature. Pediatrics 87 : 890896 2. Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C (1986) Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentration of plasma immunoglobulins and patterns of infection. Pediatr Res 20: 899-904 3. Bowman E, Yu V (1989) Continuing morbidity in extremely low birthweight infants. Early Hum Dev 18 : 165-174 4. Cairo MS (1989) Neonatal neutrophil host defense. Prospects for immunologic enhancement during neonatal sepsis. Am J Dis Child 143 : 40-46 5. Conrad DA, Christenson JC, Warier JL, Marks MI (1987) Aerosolized ribavirin treatment of respiratory syncytial virus infection in infants hospitalized during an epidemic. Pediatr Infect Dis J 6 : 152-158 6. Giuffre RM, Rubin S, Mitchel I (1987) Antireflux surgery in infants with bronchopulmonary dysplasia. Am J Dis Child 141 : 648-651 7. Grennough A, Roberton NRC (1985) Morbidity and survival in neonates ventilated for the respiratory distress syndrome. BMJ 290 : 597-600 8. Greenough A, Elias Jones A, Pool J, Morley CJ, Davis J (1985) The therapeutic actions of theophylline in preterm ventilated infants. Early Hum Dev 12:15-22 9. Greenough A, Gamsu HR, Greenall F (1989) Investigation of the effects of paralysis by pancuronium on heart rate variability, blood pressure and fluid balance. Acta Paediatr Scand 78 : 829-834 10. Greenough A, Maconochie I, Yuksel B (1990) Recurrent respiratory symptoms in the first year of life following preterm delivery. J Perinat Med 18 : 489-494 11. Greenough A, Hird MF, Gamsu HR (1991) Home oxygen therapy following neonatal intensive care. Early Hum Dev 26 : 29-35 12. Hall CB (1977) The shedding and spreading of respiratory syncytial virus. Pediatr Res 11:236-240 13. Hall CB, Douglas RG (1975) Clinically useful method for the isolation of respiratory syncytial virus. J Infect Dis 131 : 1-4 14. Hall CB, Douglas RG, German JM (1975) Nosocomial respiratory syncytial virus infections. N Engl J Med 293 : 1343-1346 15. Hemming VG, Overall JC, Britt MR (1976) Nosocomial infections in a newborn intensive-care unit. Results of forty-one months of surveillance. N Engl J Med 294:1310-1316 16. Herzog KD, Long SS, McGuigan M, Fisher MC, Deforest A (1990) Impact of treatment guidelines on use of Ribavirin. Am J Dis Child 144 : 1001-1004 17. Meibalane R, Sedmak GV, Sasidharan P, Garg P, Grauz JP (1977) Outbreak of influenza in a neonatal intensive care unit. J Pediatr 91 : 974-976
18. Mintz L, Ballard RA, Sniderman SH, Roth RS, Drew WL (1979) Nosocomial respiratory syncytial virus infection in an intensive care nursery: rapid diagnosis by direct immunofluorescence. Pediatrics 64 : 149-153 19. Palta M, Gabberd D, Weinstein MR, Ellen Peters M (1991) Multivariate assessment of traditional risk factors for chronic lung disease in very low birth weight neonates. J Pediatr 119 : 285-292 20. Piedra PA, Kasel JA, Norton HJ, Gruber WC, Garcia-Prats JA, Baker CJ (1990) Evaluation of an intravenous immunoglobulin preparation for the prevention of viral infection among hospitalised low birth weight infants. Pediatr Infect Dis J 9: 470-475 21. Pullan CR, Hey EN (1982) Wheezing, asthma and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. BMJ 284 : 1665-1669 22. Raju TNK, Vidyasagar D, Bhat R, et al. (1987) Double-blind controlled trial of single dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet I : 651-656 23. Rudd PT, Carrington D (1984) A prospective study of chlamydial, mycoplasmal and viral infections in a neonatal intensive care unit. Arch Dis Child 59 : 120-125 24. Sly PD, Hibbert ME (1989) Childhood asthma following hospitalization with acute viral bronchiolitis in infancy. Pediatr Pulmonol 7:153-158 25. Upton CJ, Milner Ad, Stokes GM (1991) Apnoea, bradycardia and oxygen saturation in preterm infants. Arch Dis Child 66 : 381-385 26. Welliver RC, Wong DT, Sun M, McCarthy N (1986) Parainfluenza virus bronchiolitis: epidemiology and pathogenesis. Am J Dis Child 40 : 34-40 27. Wenzel RP, Deal EC, Hendley JO (1977) Hospital-acquired viral respiratory illness on a pediatric ward. Pediatrics 60 : 367371 28. Whitelaw A (1990) Treatment of sepsis with IgG in very low birthweight infants. Arch Dis Child 65 : 347-348 29. Whitelaw A, Parkin J (1988) Development of immunity. In: Whitelaw A, Cooke R (eds) The very immature infant - less than 28 weeks' gestation. Churchill Livingstone, Edinburgh, pp 1037-1051 30. Wright AL, Holberg C, Martinez FD, Taussig LM and group health medical associates (1991) Relationship of parental smoking to wheezing and non-wheezing lower respiratory tract illness in infancy. J Pediatr 118:207-214 31. Yuksel B, Greenough A (1991) Neonatal respiratory distress and lung function at follow-up. Respir Med 85 : 235-237 32. Yuksel B, Greenough A, Maconochie I (1990) Effective bronchodilator therapy by a simple spacer device for wheezy premature infants in the first two years of life. Arch Dis Child 65 : 782-785 33. Yuksel B, Greenough A, Green S (1991) Paradoxical response to nebulised ipratropium bromide in preterm infants. Respir Med 85 : 189-194
EuropeanJournalof
Pediatrics
9 Springer-Verlag1992
Acute deteriorations in neonatal chronic lung disease B. Yuksel and A. Greenough Department of Child Health, King's College Hospital, London, SE5 9RS, United Kingdom Received October 24, 1991 / Accepted after revision January 14, 1992
Abstract. Preterm infants with chronic lung disease (CLD) have frequent respiratory relapses. The aim of this study was to assess the aetiology of such deteriorations and in particular the proportion due to viral infections. During the study period 118 p r e t e r m infants with birth weight < 1500 g were consecutively admitted to the neonatal intensive care unit; 22 (18.6%) developed C L D . At the onset of all respiratory deteriorations, infants were examined for the presence of patent ductus arteriosus, apnoea or aspiration; they were also carefully screened for both viral and bacterial infection. The 22 infants had a total of 74 episodes of respiratory deterioration; median 3 per b a b y (range 1.-8). Two episodes were associated with patent ductus arteriosus, 18 with apnoea and 5 with aspiration. Infection was suspected or proven in association with all other episodes. On ten occasions the infants had positive blood cultures and on a further eight, bacteria were isolated only from. the endotracheal or nasopharyngeal secretions. On the remaining 31 occasions, 27 associated with chest X-ray film abnormalities, infection was suspected, but no bacteria isolated. Viral infections were identified in association with 8 (11%) of these episodes. We conclude viral infection should be considered as a cause of otherwise unexplained respiratory deteriorations in infants with neonatal C L D .
Key words: Chronic lung disease - Viruses - Prematurity - Patent ductus arteriosus - A p n o e a
Introduction Premature infants with chronic lung disease (CLD), even while remaining on the neonatal intensive care unit, have frequent deteriorations in respiratory status. These episodes may be associated with aspiration, apnoea or patent ductus arteriosus ( P D A ) and clinical experience Correspondence to: A. Greenough Abbreviations: CLD = chronic lung disease; PDA = patent
ductus arteriosus; RSV = respiratory syncytial virus
suggests that infection is also an important cause [15]. Infants with C L D are particularly at risk of infection as they are usually born very p r e t e r m [3, 19], hence their defence systems against infection are p o o r [2, 4, 28, 29] and they are likely to undergo repeated invasive procedures such as intubation or intravenous catheterisation. Frequently, however, although infant's clinical condition and chest X-ray film appearance are strongly suggestive of infection, bacterial agents are not isolated. Neonatal units operate an " o p e n - d o o r " policy regarding visiting, which is likely to increase the infant's exposure to persons who, although not systemically unwell, could be suffering from viral infections. Thus viral infections m a y be responsible for certain of the acute respiratory deteriorations in infants with CLD. As antiviral therapy is now available [16], it is important to test this hypothesis and assess which infants, if any, are predisposed to develop viral infections. Our aim, therefore, was to determine the frequency and aetiology of respiratory deteriorations in p r e t e r m infants who had C L D and were still resident on the neonatal intensive care unit.
Patients Of 118 very low birth weight infants consecutively admitted to the neonatal intensive care unit at King's College Hospital and followed prospectively, 22 developed CLD. The median gestational age of the infants with CLD was 26 weeks (range 23-32) and birth weight 907 g (600-1494). Their median duration of ventilation was 19 days (4-80) and of oxygen dependency was 59 days (range 28240). Their median duration of admission on the neonatal unit was 76.5 days (30-235), 3 died on the neonatal unit. This study was approved by the King's College Hospital Ethics Committee.
Methods All infants with birth weight < 1500 g admitted to the unit were eligible for entry into the study. On admission all such infants were screened for infection, which included venepuncture to obtain blood for culture. At this venepuncture a further aliquot of blood was taken for viral serology and the results used to identify congenital infection and document passively transferred maternal antibodies.
698 All infants who remained oxygen dependent at 21 days of age with an abnormal chest X-ray film were diagnosed as suffering from CLD [7] and recruited into the study. All respiratory deteriorations in such infants were then documented. A respiratory deterioration was denoted by an increase of more than 0.1 in the inspired oxygen concentration (FiO2) and/or an increase in peak pressure of 5 cm H20 which persisted for at least 12 h. At the onset of each deterioration infants were examined for the presence of a PDA, apnoea or aspiration, screened for bacterial and viral infection and a chest X-ray film was taken. A clinically significant PDA was diagnosed if the infant had systolic murmur with bounding peripheral pulses and the chest film demonstrated an enlarged heart with pulmonary plethora [7]. The presence of a PDA was confirmed by 2D cross-sectional echocardiography. Apnoea was defined as a respiratory pause of more than 20 s accompanied by a bradycardia (a heart rate less than 100 bpm). This was determined to be the cause of the infant's respiratory deterioration if the change in the infant's condition coincided with the onset of frequent apnoeas, no bacterial or viral infection was identified nor was there a new abnormality of the chest X-ray film appearance. Aspiration was diagnosed if milk was aspirated from the upper airway following a choking episode related to feeding. The diagnosis was supported by demonstration of localised or diffuse atelectasis predominantly affecting the right upper lobe on the chest X-ray film. The infection screen included obtaining surface swabs, nasopharyngeal or endotracheal aspirate as relevant and samples of blood and urine for microscopy and culture. A lumbar puncture was only performed if clinically indicated. Bacterial infection was divided into those episodes which were associated with a positive blood culture (proven infection) and those in which bacteria were isolated from the endotracheal tube or nasopharyngeal aspirate but not blood culture (probable colonisation). A blood culture was defined as positive if a known pathogen was isolated from the blood culture bottles. If coagulase-negative staphylococci were isolated this was considered only to be a significant infection if the organism was isolated from both bottles and the organisms had identical sensitivities. Urine was sent for culture of cytomegalovirus and conjunctival scrapings to asses for evidence for Chlamydia. Immunofluorescence was performed, using specific antisera towards respiratory syncytial virus (RSV) and influenza virus, on the nasopharyngeal and endotracheal aspirates. Serum was sent for serological determination of the occurrence of rubella, cytomegalovirus, RSV, adenovirus or parainfluenza infection. Serology was considered positive if there had been at least a fourfold increase in antibody titre from the level measured at birth or, in the absence of the specific antibody at birth, an antibody titre of greater than 1 in 32 at the time of the acute episode. Infants who had temperature instability, a raised white blood cell count and a metabolic acidosis, but neither bacteria nor viral infections were identified, were described as suffering from suspected infection.
Statistical analysis Infants who developed a viral infection were compared to the rest of the cohort and differences between the two groups assessed for statistical significance using the Wilcoxon rank sum test.
Results T h e 22 infants h a d a t o t a l of 74 e p i s o d e s o f d e t e r i o r a tion, a m e d i a n o f 3 p e r infant ( r a n g e 1 - 8 ) at a m e d i a n p o s t n a t a l age of 35 days ( r a n g e 2 4 - 1 7 4 days). O n t h e m a j o r i t y o f e p i s o d e s i n f e c t i o n was p r o v e n o r s u s p e c t e d , b u t a p n o e a a c c o u n t e d for 18 e p i s o d e s ( 2 4 % ) ( T a b l e 1). T e n e p i s o d e s w e r e a s s o c i a t e d with positive b l o o d cultures: Staphylococcus epidermidis (four); Enterococcus faecalis (two); Klebsiella pneumoniae (two); Staphylococcus aureus ( o n e ) ; Escherichia coli ( o n e ) . I n all t h e s e
Table 1. Probable causes of deterioration Number of episodes PDA Apnoea Aspiration Bacterial infection positive blood culture isolated from endotracheal tube or nasopharyngeal aspirate Viral infection Suspected infection
2 18 5 10 8 8 23
Table 2. Results of viral screening Patient number
Investigation
1 2 3 4 5 5 6 7
+ +
RSV RSV RSV Adenovirus Adenovirus Influenza A Influenza A Influenza B
IF
+
FAT
CFA
+ + + + + +
IF, immunofluorescence; FAT, fluorescent antibody test; CFA, complement fixing antibody test +; positive test result
episodes the infants h a d suffered from a m e t a b o l i c acidosis a n d t e m p e r a t u r e instability at t h e t i m e o f t h e d e t e r i o r a tion. I n a n o t h e r eight cases the infants w e r e p r o b a b l y c o l o n i s e d [S. epidermidis ( t h r e e ) E. faecalis ( o n e ) ; S. aureus (one); E. coli (one); Pseudomonas aeruginosa (two)]. In a f u r t h e r 31 e p i s o d e s , 27 w i t h o u t chest X - r a y film abn o r m a l i t i e s , i n f e c t i o n was s t r o n g l y s u s p e c t e d b u t n o bact e r i a was i s o l a t e d . O n 8 o f t h e s e e p i s o d e s , in seven infants, viral infections w e r e i d e n t i f i e d ( T a b l e 2). T h r e e o f the seven babies were boys a n d four non-caucasian. T h e r e was no clustering of e p i s o d e s d u e to viral infection. T h e m e d i a n g e s t a t i o n a l age o f t h e i n f e c t e d infants was 26 w e e k s ( r a n g e 2 4 - 3 0 ) , a n d t h e i r p o s t n a t a l age 32 days ( r a n g e 2 4 - 4 9 ) which d i d n o t differ significantly f r o m t h e rest o f the c o h o r t (26 w e e k s , r a n g e 2 3 - 3 2 a n d 38 days, r a n g e 2 6 - 1 7 4 ) r e s p e c t i v e l y . T h e r e was no significant diff e r e n c e in t h e v e n t i l a t o r y r e q u i r e m e n t s o r o x y g e n dep e n d e n c y of t h e two g r o u p s ( i n t e r m i t t e n t p o s i t i v e pressure v e n t i l a t i o n m e d i a n 18 days, r a n g e 5 - 3 8 C o m p a r e d to 20 days, r a n g e 4 - 8 0 a n d o x y g e n d e p e n d e n c y 53 days, r a n g e 2 8 - 9 4 c o m p a r e d to 60 days, r a n g e 3 0 - 2 4 0 , infants with a n d w i t h o u t viral infections r e s p e c t i v e l y ) . N o n e o f the seven infants w h o h a d viral infections w e r e receiving b r e a s t milk at the t i m e o f t h e a c u t e d e t e r i o r a t i o n . F i v e o f t h e 18 infants w h o s e a c u t e d e t e r i o r a t i o n was d u e to a p n o e a w e r e r e - v e n t i l a t e d , the o t h e r 13 r e s p o n d e d to an i n c r e a s e in t h e i r i n s p i r e d o x y g e n c o n c e n t r a t i o n ; all 18 r e c e i v e d antibiotics for at least 48 h. O f the two infants with s y m p t o m a t i c P D A , o n e was successfully t r e a t e d with i n d o m e t h a c i n a n d t h e o t h e r r e q u i r e d surgical liga-
699 tion of the PDA. The five infants who had aspiration episodes were treated with antibiotics, appropriate positioning to prevent gastro-oesophageal reflux and thickening of their feeds. In all 49 episodes in which infection was suspected, antibiotics were given for at least 48 h and until culture results were known to be negative. In addition, 12 infants received Ribavirin, in two cases this was because of identification of RSV infection by immunofluorescence and in the other 10 infants viral infection had been suspected. Influenza A infection was subsequently identified in one of these 10 patients. On all but 2 of the 74 episodes the infants responsed to the therapy outlined above. Two infants died during the acute episodes both had been chronically ventilatordependent for many months and died of respiratory failure, neither had a viral infection.
Discussion
We were able to document probable cause of deterioration in respiratory status in the majority of episodes. Apnoea unrelated to infection was a common cause of deterioration, despite all infants included in the study receiving theophylline. It is our routine policy to treat all ventilated infants with theophylline to facilitate weaning [8], maintenance therapy is then continued until at least 3 months of age. The present results and those of others [25] demonstrate that theophylline may be ineffective in preventing apnoea in certain very immature infants. Gastro-oesophageal reflux, is increased in infants with CLD [6]. Reflux could have been responsible for the aspiration episodes we documented, this hypothesis is supported by our prevention of recurrence of such episodes by institution of thicking of feeds and positioning the infant to lessen the likelihood of reflux. Only two infants had symptomatic PDAs, but we only included infants who were older than 21 days of age. It is, however, possible that certain of our clinical policies may also have influenced this low incidence, in particular fluid restriction during the acute stage of the respiratory illness [9] and use of an artificial rather than a natural surfactant for replacement therapy [22]. Infection, proven or suspected, was associated with the majority of episodes of respiratory deterioration. This is perhaps not surprising, as nosocomial infection is unfortunately common on neonatal units [15] and 30% of nosocomial infection presents as pneumonia [15]. Infants with CLD are particularly at risk of nosocomial infection as, despite the use of home oxygen therapy, they usually have prolonged admissions [11]. In certain episodes however, although infection was strongly suspected, organisms were not isolated or isolated only from the endotracheal tube or nasopharyngeal aspirate. Certain of these episodes may have been due to organisms which we were unable to detect, in particular Mycoplasma horninis and Ureaplasrna urealyticum. Both organisms have been implicated in the development of CLD [23] and may be responsible for deteriorations in CLD. We did, however, examine the infants for the presence of viral
infection and found this to be associated with eight episodes. The viruses we identified have been associated with nosocomial infection in the neonatal unit. It has been suggested that adenovirus is the most common virus to be isolated [20], but that study [20], surprisingly, failed to identify any of the common respiratory pathogens such as RSV or influenza which together, in the present series, accounted for the majority of virus isolates. RSV infection was identified on three occasions. We felt it unlikely that we underdiagnosed RSV infection, as nasopharyngeal or endotracheal aspirates were always sent for immunofluorescent staining, which is a more sensitive test than viral culture [18]. A further major advantage to using immunofluorescence is that results are available within 2-4 h whereas the results of viral culture are available only after some days [13]. Thus, use of immunofluorescence facilitates prompt institution of infection control measures and may prevent, as in our series, nosocomial spread which has previously been documented with RSV infection [18]. The majority of infants in the present series with viral infection were non-caucasian and none were receiving breast milk; these factors may have put them at increased risk [26]. The episodes we identified as due to viral infection were sporadic. Previous influenza infection on an neonatal intensive care unit has occurred as an epidemic associated with an outbreak in the community [17]. Although we did not isolate patients with viral infection our strict handwashing policy may have prevented nosocomial spread [12, 27]. We did prescribe Ribavirin for a small number of patients and this may have limited virus shedding and hence nosocomial spread, but this is controversial [5] and not all infants in the present series with viral infection received Ribavirin. Morbidity following infection is dependent on the type of virus. RSV is associated with marked morbidity and prolongation of hospitalisation [14] and adenoviral infection is frequently disseminated and generally fatal with symptoms of fever, hypothermia, hepatomegaly and bleeding as well as progressive pneumonia [1]. In contrast, influenza infection has not been associated with any sequelae [17]. The numbers in the present study are too small to make meaningful statements regarding the morbidity associated with different viral infections but all of our patients recovered. Preterm infants frequently suffer from wheeze and cough at follow up [10]. These symptoms are responsive to bronchodilator therapy [32]. Plethysmographic studies of lung function have demonstrated that such infants have a high airways resistance [31], which is at least partially improved by nebulised bronchodilator [33]. Such studies suggest preterm infants may have increased bronchial hyperreactivity. Infants born at term who during infancy and early childhood suffer from viral infection have increased bronchial hyperreactivity [21, 24, 26]. Viral infection and parental smoking synergistically increase recurrent wheeze in such infants [30]. It is thus tempting to speculate viral infections in infants with CLD may, in part, account for the bronchial hyperreactivity seen at follow up in such infants.
700
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