Original Article

23/03/2005
Surfactant treatment for neonatal pneumonia

Egbert Herting, MD, PhD
Director of the Department of Child and Adolescent Health
University Hospital Schleswig-Holstein - Lübeck, Germany

Introduction
During the last decade surfactant administration has became standard for treatment of premature neonates with severe respiratory distress syndrome (RDS). Randomised controlled trials and meta-analyses clearly demonstrate improved gas exchange following surfactant instillation as well as significantly reduced neonatal morbidity and mortality (1).
More than 30 years ago Ashbaugh and coworkers described a form of severe respiratory failure in adults similar to neonatal RDS (2). However, in contrast to RDS caused by primary surfactant deficiency due to immaturity, the adult form of the disease, now called acute respiratory distress syndrome (ARDS), is caused by secondary surfactant dysfunction (see Figure 1) due to the liberation of surfactant inhibitors or leakage of plasma proteins into the bronchoalveolar space (3, 4).
Pulmonary or systemic infections are the major etiological factor for ARDS in all age groups including childhood (3). Proteins or enzymes and reactive oxygen metabolites released by leukocytes and/or bacteria inhibit surfactant function (see Figure 1) both in vitro and in animal studies (5, 7). Recent clinical trials demonstrated improved gas exchange following surfactant treatment in newborn infants with bacterial pneumonia or meconium aspiration syndrome (8, 10).

Figure 1: Pathophysiology of neonatal pneumonia and surfactant dysfunction (11)

The large alveolar surface of the lung is constantly exposed to air polluted with microbial agents, dust and other foreign particles. In the last decade it has been realized that surfactant and its major components, both the lipids and specific proteins, play an important role in the pulmonary host defense system (for review see Ref. 12). These “non-biophysical” (“non-surfactant”) functions of the surfactant film seem to be of importance both in directly limiting bacterial growth, but also in controlling the immune response and avoiding hypersensitivity reactions in the lung.

Neonatal pneumonia
Neonatal pneumonia comprises a variety of entities from prenatal over perinatal to postnatal disease (see Table 1). Neonatal pneumonia occurs in 0,5-1% of all newborns and up to 10% of all prematurely born infants (13).

Group B streptococci (GBS) are the organisms that are most commonly cultured from infants with early onset disease (13). In many neonates the disease starts already in utero with the ascension of bacteria from the intestinal or the vaginal tract. Maternal risk factors (e. g. prolonged rupture of membranes) are often observed (see Figure 2).

Figure 2: Schematic of drawing of perinatally acquired bacterial infections

Ablow and colleagues (14) were the first to realise that surfactant deficiency was difficult to differentiate from severe pneumonia on clinical grounds (Figure 3), laboratory investigations and x-ray findings (Figure 4, Table 2).

Figure 3: Term newborn infant with septicemia and respiratory failure. Note the skin colour and the signs of impairedmicrocirculation.

Figure 4: Chest radiograph of a term neonate with GBS-sepsis and pneumonia. Note the diffuse opaque appearance of both lungs and the infiltrate and pleural effusion on the right side.

Pathologists had also noted the similarity to neonatal hyaline membrane disease in some patients dying from ARDS (2) or severe pneumonia. Often pneumonia is observed in combination with septicaemia and/or meningitis. Initial clinical symptoms include greyish appearance, apnoea, a feeding intolerance and tachy(dys)pnoea (see Figure 3).

Surfactant replacement for GBS pneumonia
In a European multicenter study (9) we were able to demonstrate that surfactant improved gas exchange both in term and preterm neonates with GBS-infection. The study comprised 118 babies with respiratory failure, clinical and/or laboratory signs of acute inflammatory disease, and GBS infection proven by culture results. They were recruited retrospectively from a data base of patients treated with surfactant at 28 neonatology units participating in European multicenter trials (1987-1993) and prospectively from the same units in the following years. A non-randomised control group of 236 non-infected babies was selected from the same data base. Main parameters evaluated were oxygen requirement, ventilator settings and incidence of complications. Median birth weight in the GBS study group was 1468 g (25th - 75th percentile: 1015 – 2170 g), median gestational age 30 weeks (27 - 33) Thirty-one percent of the infants weighed >2000 g. Median age at surfactant treatment was 6 h. The mean initial surfactant dose was 142 ± 53 (SD) mg/kg bw. Ninety of the infants were treated with Curosurf®, 13 with Survanta®, 12 with Alveofact® and 3 with Exosurf®. Within one hour of surfactant treatment median FiO2 was reduced from 0.84 (25th - 75th percentile: 0.63 - 1.0) to 0.50 (0.35 - 0.80) (p <0.01). The reponse to surfactant was slower than in babies with RDS and repeated surfactant doses were often needed. Term infants and neonates with GBS septicemia demonstrated a slower response to surfactant treatment (Figure 5a). This might be due to a larger amount of surfactant inhibitors in the bronchoalveolar space. Probably, circulatory problems and a certain degree of pulmonary hypertension contributed to the disease severity in this subgroup of patients.
The mortality and morbidity were substantial considering the relatively high mean birth weight of the treated infants. In our study mortality in the group of infants with GBS septicemia was as high as 49% and the overall incidence of intracerebral hemorrhage was 42%, indicating that other problems than surfactant deficiency play a decisive role for the outcome of the disease. Even following adjustment for confounding variables by means of the prospensity score technique the relative risk for GBS infected infants to die or develop intracranial hemorrhage or chronic lung disease was more than doubled. Our results underline that the systemic inflammatory response is not only a pulmonary problem, but equally affects the cerebral perfusion. Perinatal infections constitute an important risk factor for an adverse neurological outcome (15).

Figure 5a: Oxygen demand (FiO2 = fraction of inspiratory oxygen) in term (n = 23) and preterm (n = 95) neonates with respiratory failure and GBS-infection following surfactant treatment (9). Values are are median and 25th/75th percentile.

Figure 5b: Reduction in oxygen demand (FiO2 = fraction of inspiratory oxygen) 1 h following surfactant treatment in neonates with respiratory failure and GBS-infection in relation to initial surfactant dose. From Ref. 9.

Possibly a higher dose of surfactant and/or earlier treatment could have improved these results. In a recent study on multiple-dose surfactant treatment for meconium aspiration syndrome initiated before the age of 6 h, a good effect on oxygenation was only observed after a cumulative surfactant dose of 300 mg/kg bw had been instilled into the airways (10). An initial surfactant dose of 300 mg/kg bw was also effective in adult patients with ARDS due to sepsis (16). Early treatment with large doses of surfactant may be required to counterbalance the presence of intraalveolar surfactant inhibitors in this category of patients and to prevent ventilator induced lung injury. 100 mg/kg bw of surfactant is widely used as the standard initial dose to treat neonatal RDS. In infants with GBS-infection, the improvement in oxygenation was more marked with a treatment dose of 200 mg/kg bw (Figure 5b).

Conclusion:
There is increasing evidence that surfactant improves gas exchange in neonates with severe respiratory failure due to pneumonia. However, larger controlled trials are necessary to determine whether the improved oxygenation is associated with a better outcome. Due to the presence of surfactant inhibitors in the bronchoalveolar space, larger surfactant doses than those administered for the treatment of RDS seem to be necessary. Studies evaluating surfactant lavage are under way. Future developments might lead to production of artificial surfactant preparations that are safe and hopefully less expensive as they need not be extracted from animal lungs. In addition, it seems possible to design synthetic surfactants suitable for treatment of ARDS that are more resistant to inactivation (17).
Looking at the complication rate of affected neonates, prophylactic measures are of prime importance. Rather than optimizing postnatal therapy alone e.g. by surfactant replacement, perinatal antibiotic treatment given to GBS colonized mothers has significantly reduced morbidity and mortality related to invasive GBS-infections in the newborn (18).
There is increasing evidence that surfactant is not only important for the “stability”, but also for the “sterility” of the lung. The porcine surfactant preparation Curosurf® has antibacterial properties that seem to be partly related to the presence of an antibacterial peptide, the so called prophenin that was recently discovered in this preparation (19, 20). It seems possible that surfactant might be used in patients with inflammatory lung disease as a carrier for antimicrobial peptides (20), antibiotics (21) or immunoglobulins (22, 23) in the future.

References

1. Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328:861.
2. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2: 319-23.
3. Möller JC. Surfactant therapy for acute respiratory distress syndrome. In: Wauer R (ed): Surfactant Therapy. Basic Principles, Diagnosis, Georg Thieme Verlag, Stuttgart-New York, 1998:133-145.
4. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Eng J Med 2000; 342 (18):1334-1349.
5. Kobayashi T, Tashiro K, Cui X, Konzaki T, Xu Y, Kabata C, Yamamoto K. Experimental models of acute respiratory distress syndrome: clinical relevance and response to surfactant therapy. Biol Neonate 2001; 80(suppl 1): 26-28 (PubMed)
6. Bouhafs R KL, Rauprich P, Herting E, Schröder A, Robertson B, Jarstrand C. Direct and phagocyte mediated lipid peroxidation of lung surfactant by group B streptococci. Lung 2000; 178:317-329 (PubMed)
7. Herting E, Jarstrand C, Rasool O, Curstedt T, Sun B, Robertson B. Experimental neonatal group B streptococcal pneumonia. Effect of a modified porcine surfactant on bacterial proliferation in ventilated near-term rabbits. Pediatr Res 1994; 36:784-791 (PubMed)
8. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr 1998; 132:40-47 (PubMed)
9. Herting E, Gefeller O, Land M, van Sonderen L, Harms K, Robertson B and members of the Collaborative European Multicenter Study Group. Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Pediatrics 2000; 106:957-964 (Free Full Text)
10. Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996; 97:48-52 (PubMed)
11. Herting E. Surfactant Treatment in Neonatal Group B Streptococcal Pneumonia (Ph. D.-Thesis). Karolinska Institut Stockholm, Sweden 1999; ISBN – 91-628-3691-9 (Abstract)
12. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol 2005; 5: 58-68 (PubMed)
13. Webber S, Wilkinson AR, Lindsell D, Hope PL, Dobson SR, Isaacs D. Neonatal pneumonia. Arch dis Child 1990; 65: 207-211 (PubMed)
14. Ablow RC, Driscoll S, Effmann EL, Gross I, Jolles CJ, Uauy R, Washaw JB. A comparison of early onset group B streptococcal neonatal infection and the respiratory distress syndrome. N Engl J Med 1976; 294:65-70 (PubMed)
15. Yoon BH, Romero R, Kim CJ, et al. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997; 177:406-411 (PubMed)
16. Walmrath D, Günther A, Ghofrani HA, Schermuly R, Schneider T, Grimminger F, Seeger W. Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis. Am J Respir Crit Care Med 1996; 154:57 62 (PubMed)
17. Herting E, Rauprich P, Stichtenoth G, Walter G, Johansson J, Robertson B. Resistance of different surfactant preparations to inactivation by meconium. Pediatr Res 2001; 50:44-49 (Free Full Text)
18. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revise guidelines from CDC. MMWR Recomm Rep 2002; 51 (RR-11): 1-22 (Free Full Text)
19. Wang Y, Griffiths WJ, Curstedt, Johansson J. Porcine pulmonary surfactant preparations contain the antibacterial peptide prophenin and a C-terminal 18-residue fragment thereof. FEBS Letters 1999; 460:257-262 (PubMed)
20. Wang Y, Herting E, Agerberth B, Johansson J. Antibacterial activity of the cathelicidins prophenin (62-79) and LL-37 in the presence of a lung surfactant preparation. Antimicrob Agents Chemotherapy 2004; 48:2097-2100 (Free Full Text)
21. van’t Veen AJ, Mouton W, Gommers D, Lachmann B. Pulmonary surfactant as vehicle for intratracheally instilled tobramycin in mice infected with Klebsiella pneumoniae. Br J Pharmacol 1996; 119:1145-1148 (PubMed)
22. Herting E, Gan XZ, Rauprich P, Jarstrand C, Robertson B. Combined treatment with surfactant and specific immunoglobulin reduces bacterial proliferation in experimental neonatal group B-streptococcal pneumonia. Am J Respir Crit Care Med 1999; 159:1862-1867 (Free Full Text)
23. Gan XZ, Jarstrand C, Herting E, Berggren P, Robertson B. Effect of surfactant and specific antibody on bacterial proliferation and lung function in experimental pneumococcal pneumonia. Int J Infect Dis 2001; 5:9-18 (PubMed)

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