Correspondence

Acute Lower Respiratory Tract Infection

N Engl J Med 2008; 358:2413-2414May 29, 2008

Article

To the Editor:

In his review of inflammatory responses in infected lungs, Mizgerd (Feb. 14 issue)1 notes that animal models of influenza A virus pneumonia indicate that neither neutrophil leukocytes nor cytokine signaling seems to be important in the case of the highly pathogenic influenza virus infections that cause global pandemics. However, this influenza virus directly inhibits pulmonary epithelial sodium transport, which removes water from the alveolar space by osmosis: Viral hemagglutinin binds to receptors on respiratory epithelial cells, inhibiting epithelial sodium-channel–mediated clearance of pulmonary fluid through a pathway involving phospholipase and protein kinase C.2,3 Reduced epithelial sodium transport also occurs in pulmonary edema associated with septicemia4 and is a potential target for treatment of lung injury by beta-agonists.5

Michael Eisenhut, M.D.
Luton and Dunstable Hospital National Health Service Foundation Trust, Luton LU4 0DZ, United Kingdom
michael_eisenhut@yahoo.com

5 References

1. 1

   Mizgerd JP. Acute lower respiratory tract infection. N Engl J Med 2008;358:716-727
   Full Text | Web of Science | Medline

2. 2

   Kunzelmann K, Beesley AH, King NJ, Karupiah G, Young JA, Cook DI. Influenza virus inhibits amiloride-sensitive Na+ channels in respiratory epithelia. Proc Natl Acad Sci U S A 2000;97:10282-10287
   CrossRef | Web of Science | Medline

3. 3

   Chen XJ, Seth S, Yue G, et al. Influenza virus inhibits ENaC and lung fluid clearance. Am J Physiol Lung Cell Mol Physiol 2004;287:L366-L373
   CrossRef | Web of Science | Medline

4. 4

   Eisenhut M, Sidaras D, Barton P, Newland P, Southern KW. Elevated sweat sodium associated with pulmonary oedema in meningococcal sepsis. Eur J Clin Invest 2004;34:576-579
   CrossRef | Web of Science | Medline

5. 5

   Perkins GD, McAuley DF, Thickett DR, Gao F. The Beta-Agonist Lung Injury Trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 2006;173:281-287
   CrossRef | Web of Science | Medline

Author/Editor Response

The pathophysiology of highly pathogenic influenza virus infections is at present poorly understood. The lack of lifesaving effects from depleting neutrophils or individually interrupting any of several different cytokines in studies of H5N1 avian influenza infections in mice, as described and further expanded by Salomon et al.,1 does not rule out the possibility that cytokines or neutrophils exacerbate the pathogenesis of H5N1 or other severe influenza infections, because of the necessarily limited scope of these early experiments. Studies cited by Eisenhut demonstrate that an influenza virus is capable of impairing epithelial fluid transport, but whether such impairment is necessary for edema accumulation during infection is unknown. Notably, those epithelial-transport studies did not examine highly pathogenic viruses. Finally, the significance of alveolar edema as compared with that of other pulmonary and extrapulmonary pathological features2-4 has not been determined and may well vary among different influenza virus infections. Thus, it is premature to rule out roles for cytokines and neutrophils or to rule in roles for impaired epithelial fluid transport. The interesting point raised by Eisenhut is one of many important avenues for further investigation.

Joseph P. Mizgerd, Sc.D.
Harvard School of Public Health, Boston, MA 02115
jmizgerd@hsph.harvard.edu

4 References

1. 1

   Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 2007;104:12479-12481
   CrossRef | Web of Science | Medline

2. 2

   de Jong MD, Van Cam B, Qui PT, et al. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med 2005;352:686-691
   Full Text | Web of Science | Medline

3. 3

   Gu J, Xie Z, Gao Z, et al. H5N1 infection of the respiratory tract and beyond: a molecular pathology study. Lancet 2007;370:1137-1145
   CrossRef | Web of Science | Medline

4. 4

   Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol 2008;3:499-522
   CrossRef | Web of Science | Medline