Behr syndrome

Fibroblastic Foci in Usual Interstitial Pneumonia

To the Editor.

The article by Flaherty and colleagues (1) reveals significant differences in the profusion of fibroblastic foci in usual interstitial pneumonia (UIP) and UIP associated with collagen vascular disease. In addition, the authors have shown a dramatically better prognosis in the patients with collagen vascular diseases. Although it docs seem clear that the behavior of the interstitial pneumonia is different in these two circumstances, the authors have not commented on the treatment that their patients received. When a specific diagnosis of UIP has been made, immunosuppressivc therapy is usually withheld. In contrast, many patients with collagen vascular diseases continue on diseasemodifying drugs, including steroids and cytotoxics. Can the authors comment on whether this may have contributed anything to the differences they observed?

Conflict of Interest Statement: T.K.R. has no declared conflict of interest.

TREVOR K. ROGERS

Doncaster and Bassetlaw Hospitals NHS Trust

Doncaster, United Kingdom

Reference

1. Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J, Murray S, Thannickal VJ, Kazerooni EA, Gross BH, Lynch JP III, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. am J Respir Crit Care Med 2003;167:1410-1415.

From the Authors:

We appreciate the comments by Dr. Rogers. The patients reported in our article (1) were treated with various combinations of immunosuppressive therapies (Table 1). It is unlikely that the difference in survival between patients with idiopathic usual interstitial pneumonia, compared with patients with collagen vascular disease-associated usual interstitial pneumonia, was because of a lack of treatment for the patients with idiopathic usual interstitial pneumonia. As treatments were prescribed by individual physicians and were not prescribed according to a predefined, prospective treatment protocol, we did not include type of treatment as a covariate in our survival models. Interestingly, there is a trend for more patients with collagen vascular disease-associated usual interstitial pneumonia to have received combination therapy with a cytotoxic agent (cyclophosphamide, azathioprine, mycophenolate, methotrexate) combined with prcdnisone (p = 0.06, Fisher's Exact test). Prospective studies are needed to clarify the optimal treatment of patients with usual interstitial pneumonia with or without an associated collagen vascular disease.

Conflict in Interest Statement: K.R.F. and F.J.M. have no declared conflict of interest.

KEVIN R. FLAHERTY

FERNANDO J. MARTINEZ

University of Michigan Health System

Ann Arbor, Michigan

Reference

1. Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J, Murray S, Thannickal VJ, Kazerooni RA, Gross BH, Lynch JP III, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med 2003;167:1410-1415.

Azithromycin and Bronchiolitis Obliterans

To the Editor.

We read with interest the recent report on the pilot study by Gerhardt and colleagues (1). They investigated the effect of azithromycin on bronchiolitis obliterans syndrome after lung transplantation. Because they administered azithromycin for antiinflammatory long-term drug therapy, they found that azithromycin was effective for bronchiolitis obliterans syndrome after lung transplantation. An antiinflammatory action of macrolides has been detected in diffuse panbronchiolitis (2). Inflammatory cells and cytokines/chemokines seem to play an important role in the flu-like reaction to bronchoscopy. We measured the plasma interleukin-6 (IL-6) and soluble CD14 levels in patients who underwent bronchoscopy with or without administration of azithromycin. In patients who were not administered azithromycin, there was a significant increase of IL-6 at 4 hours after bronchoscopy (15.477 ± 28.896 vs. 44.763 ± 69.315, p 0.05, n = 10; soluble CD14: 4.396 ± 1.232 vs. 4.522 ± 1.288, p > 0.05, n = 10; monocytes: 341 ± 120 vs. 385 ± 215, p > 0.05, n = 8; vs. 328 ± 165, p > 0.05, n = 8). CD14 is localized on the surface of monocytes and acts as a receptor for lipopolysaccharide (3). Soluble CD14 is increased in several allergic diseases, infectious diseases, autoimmune diseases, and in bronchiolitis obliterans syndrome after lung transplantation (4). It also seems to be a marker that indicates the activation of monocytes. Conversely, Cercek and colleagues (5) reported that in the Azithromycin in Acute Coronary Syndrome trial, the antimicrobial effect of azithromycin did not prevent recurrent thrombus in the coronary arteries, because they administered azithromycin by the regimen for short-term antichlamydia therapy. The extent to which activated monocytes are involved in coronary artery thrombosis is uncertain. However, the findings of Gerhardt and colleagues (1) and our own data suggest that activated monocytes/macrophages are heavily involved in bronchial events. The antiinflammatry effect of azithromycin, especially on monocytes/macrophages, may help to prevent for both bronchial events and coronary events in which activated monocytes have a role.

Conflict of Interest Statement: S.K., S.N., M.M., K.Y., and S.F. have no declared conflict of interest.

S. KANAZAWA

S. NOMURA

M. MURAMATSU

K. YAMAGUCHI

S. FUKUHARA

First Department of Internal Medicine

Kansai Medical University

Osaka, Japan

References

1. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168: 121-125.

2. Culic O, Erakovic V, Parnham MJ. Review: anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol 2001;429:209-229.

3. Wright SD, Rainos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990;249:1431-1433.

4. Ward C, Walters EH, Zheng L, Whitford H, William TJ, Snell GI. Increased soluble CD14 in bronchoalveolar lavage fluid of stable lung transplant recipients. Eur Respir J 2002;19:472-478.

5. Cercek B, Shah PK, Noc M, Zahger D, Zeymer U, Matetzky S, Maurer G, Mahrer P, for the AZACS Investigators. Effect of short-term treatment with azithromycin on recurrent ischemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomized controlled trial. Lancet 2003;361: 809-813.

From the Authors:

We would like to thank Dr. Nomura and colleagues for their interest in our recent article (1).

Our study documented improved lung function in lung transplant recipients diagnosed with bronchiolitis obliterans syndrome (BOS) after treatment with maintenance oral azithromycin. However, the pathophysiologic mechanism(s) leading to this improvement in FEV^sub 1^ remain unclear. One hypothesis is that azithromycin exerts antiinflammatory effects that may partially account for our clinical observations.

Dr. Nomura and colleagues' findings support this hypothesis. They report observing increases in levels of interleukin (IL)-6, soluble CD14, neutrophils, and monocytes in patients who had undergone bronchoscopy. They also report that when patients were pretreated with azithromycin before bronchoscopy, the measured levels of IL-6, soluble CD14, and peripheral blood monocytes counts were attenuated. Interestingly, they did not observe changes in peripheral neutrophilia; however, they did not report assessing bronchoalveolar lavage (BAL) fluid for neutrophils. BAL neutrophilia has been shown to be increased in patients with BOS and may correlate with disease severity (2). In preliminary in vitro studies from our center, we have observed inhibition of IL-8 production from LPS-stimulated monocytes when exposed to azithromycin. IL-8 levels in BAL fluid have also been shown to be increased in patients with BOS and IL-8 is a potent inducer of neutrophil chemotaxis (3, 4). Currently, we are investigating whether chronic azithromycin therapy alters BAL neutrophilia in patients with BOS.

Although azithromycin therapy may exert antiinflammatory effects that potentially improve BOS, the specific mechanism(s) remain unclear. We agree with Dr. Nomura and colleagues that the Azithromycin in Acute Coronary Syndrome trial may have been a negative study because the subjects were only treated with azithromycin for 5 days (5). Our study subjects were treated for an average of 14 weeks. However, Dr. Nomura and colleagues report treating their patients with a one-time dose of azithromycin before bronchoscopy, and yet detected changes in several inflammatory markers. It is clear that further studies are needed to clarify the potential mechanisms and outcomes in patients treated with azithromycin for BOS and other inflammatory processes.

Conflict of Interest Statement: S.G.G., J.F.M., R.J.C, and J.B.O. have no declared conflict of interest.

SUSAN G. GERHARDT

JOHN F. MCDYER

RHETT J. CUMMINGS

JONATHAN B. ORENS

The Johns Hopkins University School of Medicine

Baltimore, Maryland

References

1. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168: 121-125.

2. Devouassoux G, Drouet C, Pin I, Bramhilla C, Brambilla E, Colle P, Pison C. Alveolar neutrophilia is a predictor for the bronchiolitis obliterans syndrome, and increases with severity. Transpl Immunol 2002;10:303-310.

3. Elssner A, Jaumann F, Dobmann S, Behr J, Schwaiblmair M, Reichenspurner H, Furst H, Briegel J, Vogelmeier C. Elevated levels of interleukin-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant Group. Transplantation 2()00;70:362-367.

4. DiGiovine B, Lynch JP III, Martinez FJ, Flint A, Whyte RI, Iannettoni MD, Arenberg DA, Burdick MD, Glass MC, Wilke CA, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of 1L-8. J Iminnnol 1996;157: 194-202.

5. Cercek B, Shah PK, Noc M, Zahger D, Zeymer U, Matetzky S, Maurer G, Mahrer P, for the AZACS Investigators. Effect of short-term treatment with azithromycin on recurrent ischacmic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003;361: 809-813.

Balance of Inflammation in Sepsis

To the Editor:

In their study, Sherwood and colleagues (1) look at mainly the proinflammatory cytokines in addition to CD8^sup +^ T cells and natural killer cell activity. Despite its expense, modulation of proinflammatory response alone in sepsis has not shown any benefit on mortality rate in septic patients (2). Compensatory antiinflammatory response leads to monocyte/macrophage hyporesponsiveness, resulting in the suppression of proinflammatory cytokines. Inflammatory cytokines, such as IFN-[gamma], interleukin (IL)-12, and granulocyte colony-simulating factor, have been tried in the past to overcome this (3). Therefore, there remains a balance between the proinflammatory and antiinflammatory cytokines in regulating the outcome in sepsis. This balance seems crucial because failure to achieve this balance can lead to multiorgan failure and poor outcome in sepsis, either because of the uncontrolled inflammation or the profound antiinflammation and downregulation of antigen-presenting cells (4).

Although Sherwood and colleagues (1) looked at the CD8^sup +^ T cells and natural killer cells along with Th1 cylokines, it certainly would have been interesting to know the levels of IL-10, a potent immunomodulalory cytokine, and IL-4, the index cytokine of Th2 cell activity. IL-10 not only limits and halts the inflammatory response, but it also regulates the proliferation of T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes (5).

Heidecke and colleagues (6) showed that unbalanced production of proinflammalory and antiinflammatory cytokines occur in patients with severe intraabdominal infection, with severe suppression of tumor necrosis factor-[alpha] in nonsurvivors. Hence, there must be cautious optimism in postulating therapies in sepsis, directed either at proinflammatory or antiinflammatory cytokines alone.

Conflict of Interest Statement: E.P. has no declared conflict of interest.

EGBERT PRAVINKUMAR

Institute of Medical Sciences

Aberdeen, Scotland, United Kingdom

References

1. Sherwood ER, Lin CY, Tao W, Hartmann CA, Dujon JE, French AJ, Varma TK. [beta]2 Microglobulin knockout mice are resistant to lethal intraabdominal sepsis. Am J Respir Crit Care Med 2003;167:1641-1649.

2. Nalanson C, Esposito CJ, Banks SM. The sirens' songs of confirmatory sepsis trials: selection bias and sampling error. Crit Care Med 1998;26: 1927-1931.

3. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Peinke P, Volk HD, Kox W. Monocyte deactivation in septic patients: restoration by IFN-[gamma] treatment. Nat Med 1997;3:678-681.

4. Bone RC. Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 1996; 24:1125-1128.

5. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy: review of a new approach. Pharmacol Rev 2003;55:241-269.

6. Heidecke CD, Hensler T, Weighardt H, Zantl N, Wagner H, Siewert JR, Holzmann B. Selective defects of T lymphocyte function in patients with lethal intraabdominal infection. Am J Surg 1999;178:288-292.

From the Authors:

I read Dr. Pravinkumar's letter with great interest and appreciate his comments. Our recent article (1) examined the response of [beta]2 microglobulin knockout mice to acute intraabdominal sepsis. We found that [beta]2 microglobulin knockout mice treated with anti-asialoGM1 exhibit greater than 70% long-term survival after cecal ligation and puncture. The improved survival was associated with decreased production of proinflammatory cytokines, less hypothermia, and improved acid-base balance. The novel finding of our work is that CD8^sup +^ T and natural killer cells contribute to the proinflammatory response associated with acute peritonitis. Most prior investigations have focused on macrophage function during the early proinflammatory phase of sepsis (2).

The model of sepsis used in our studies is rapidly lethal and causes mortality of wild-type mice within 24 to 30 hours. This mimics the clinical presentation of patients with severe acute peritonitis. Clinically, most patients with acute peritonitis can be effectively treated during this early inflammatory phase with fluid resuscitation, surgery, and antibiotics. However, our findings provide a better understanding of the underlying mechanisms mediating the systemic inflammatory response during acute peritonitis.

There are many underlying causes of sepsis, all of which have differences in pathophysiology. Furthermore, individual patients are likely to pass through different phases of sepsis ranging from an early proinflammatory phase (systemic inflammatory response syndrome) to later immunoparalysis (compensatory antiinflammatory response) (3). Some have speculated that these phases may coexist. The factors that have been classically used to define sepsis are physiologic (4), yet much of the pathogenesis of sepsis is caused by immunologic alterations. Many investigators are working to identify markers that will define the immunologic status of the septic patient (5, 6). On the basis of immunologic conditions, targeted immunotherapy could be provided. For example, antiinflammatory therapies may be beneficial in patients exhibiting a proinflammatory phenotype, whereas they may worsen immunosuppression and increase the risk for mortality in patients with immunoparalysis.

Therefore, I fully agree with Dr. Pravinkumar. The pathogenesis of sepsis is dependent on a complex interplay of proinflammatory and antiinflammatory mediators that change over time. Our study addresses factors that are important during the early proinflammatory phase of septic peritonitis. Hopefully, treatment of clinical sepsis will improve as our understanding of this complex disease process advances.

Conflict of Interest Statement: E.R.S. has no declared conflict of interest.

EDWARD R. SHEERWOOD

The University of Texas Medical Branch

Galveston, Texas

References

1. Sherwood ER, Lin CY, Tao W, Hartmann CA, Dujon JE, French AJ, Varma TK. [beta]2 Microglobulin knockout mice are resistant to lethal intraabdominal sepsis. Am J Respir Cat Care Med 2003;167:1641-1649.

2. Haziot A, Ferrero E, Kontgen F, Hijiya N, Yaraamoto S, Silver J, Stewart CL, Goyert SM. Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity 1996; 4:407-414.

3. Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 2001;16:83-96.

4. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-1655.

5. Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 2002; 17:463-467.

6. Hynninen M, Pettila VV, Takkunen O, Orko R, Jansson SE, Kuusela P, Renkonen R, Valtonen M. Predictive value of monocyte histocompalibility leukocyte antigen-dr expression and plasma interleukin-4 and -10 levels in critically ill patients with sepsis. Shock 2003;20:1-4.

Erratum: ATS/ERS Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency

To the Editor:

We wish to make corrections to the 2003 ATS/ERS Statement on Alpha-1 Antitrypsin Deficiency (1). On page 835, right-hand column, there are incorrect reference numbers in the paragraph immediately below the heading "Intravenous Human Plasmaderived Augmentation Therapy." In the third line from the bottom of that paragraph, the reference numbers "(240-242)" should correctly appear as "(240, 242)." In the second line from the bottom of the paragraph, "(240)" should be "(241)."

We apologize for any inconvenience these errors may have caused.

JAMES K. STOLLER

Chair, ATS/ERS Statement on Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency

References

1. American Thoracic Society/European Respiratory Society. American Thoracic Society/European Respiratory Society Statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818-900.

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