Imatinib and Chronic-Phase Leukemias

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Correspondence

1. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56. 2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63. 3. Safar PJ, Kochanek PM. Therapeutic hypothermia after cardiac arrest. N Engl J Med 2002;346:612-3. 4. Longstreth WT Jr, Diehr P, Inui TS. Prediction of awakening after outof-hospital cardiac arrest. N Engl J Med 1983;308:1378-82. 5. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253:1420-6.

Therapeutic Hypothermia after Cardiac Arrest To the Editor: The results of two studies reported in the Journal (Feb. 21 issue)1,2 suggest that therapeutic hypothermia has a beneficial effect on neurologic outcome in survivors of out-of-hospital cardiac arrest. The authors of the accompanying editorial3 support the conclusions of these studies and firmly recommend the use of hypothermia for at least 12 hours after cardiac arrest. Before this complex intervention becomes accepted as standard therapy, a closer examination of these studies is warranted. The authors of both studies cite problems in study design and in the interpretation of their results, but neither they nor the authors of the editorial acknowledge a flaw in both studies that should cast considerable doubt on the results and conclusions. Factors known to be of prognostic importance after cardiac arrest are the brain-stem reflexes and motor responses immediately after resuscitation.4,5 In this regard, neither study presents data reflecting the depth or severity of coma before randomization. Without these data, there is no reassurance that the hypothermia and normothermia groups were well matched according to the severity of the neurologic insult, thus raising the possibility of bias. Although arrest and resuscitation times correlate with the severity of the neurologic insult and with mortality, they cannot be used as proxies for the neurologic examination. Furthermore, the small number of patients in these trials precludes any assumption that randomization would compensate for the noted deficiencies. It is premature to conclude that therapeutic hypothermia is effective or that it can be recommended for use in comatose survivors of cardiac arrest. JOSEPH M. DARBY, M.D. University of Pittsburgh Pittsburgh, PA 15213 [email protected]

To the Editor: The Hypothermia after Cardiac Arrest Study Group and Bernard et al. report a promising application of therapeutic hypothermia after cardiac arrest. In both studies, however, only highly selected subgroups of patients were enrolled: ventricular fibrillation as the initial cardiac rhythm and a return of spontaneous circulation were prerequisites for enrollment. In addition, the investigators enrolled only patients who had had a witnessed cardiac arrest. Previous analyses of long-term outcomes after cardiac arrest reported according to the Utstein guidelines, however, have revealed that only 13 to 19 percent of all patients with out-of-hospital cardiac arrest belong to these subgroups.1 Therefore, more than 80 percent of all patients with cardiac arrest will not be able to benefit from therapeutic hypothermia. STEPHAN A. PADOSCH, M.D. University of Heidelberg 69120 Heidelberg, Germany

KARL B. KERN, M.D. University of Arizona College of Medicine Tucson, AZ 85724

BERND W. BÖTTIGER, M.D. University of Heidelberg 69120 Heidelberg, Germany [email protected] 1. Böttiger BW, Grabner C, Bauer H, et al. Long term outcome after outof-hospital cardiac arrest with physician staffed emergency medical services: the Utstein style applied to a midsized urban/suburban area. Heart 1999; 82:674-9.

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

To the Editor: Both Bernard and colleagues and the Hypothermia after Cardiac Arrest Study Group report that therapeutic hypothermia has significant neurologic benefits in patients who survive out-of-hospital cardiac arrest. We use moderate hypothermia to treat selected patients after cardiac arrest, ischemic brain injury, and severe head injury. Our experience has been highly favorable, but we wish to sound a note of caution. We have reported that therapeutic hypothermia can have a number of severe side effects,1-3 including severe electrolyte disorders, which may be accompanied by a high risk of cardiac arrhythmias, and hypothermia-induced polyuria, which may cause hypovolemia and hypotension. These occur especially in the initial phase of cooling, when severe disruptions in fluid balance, blood pressure, and electrolyte levels are most likely to occur.2,3 We emphasize that these side effects, although potentially severe, are easily preventable by the administration of appropriate amounts of electrolytes and, if necessary, early administration of antiarrhythmic agents.2 In our opinion, the beneficial effects of hypothermia will be more pronounced if side effects are treated actively. KEES H. POLDERMAN, M.D., PH.D. ARMAND R.J. GIRBES, M.D., PH.D. Vrije Universiteit Medical Center 1007 MB Amsterdam, the Netherlands [email protected] 1. Polderman KH, Girbes ARJ. Mechanisms of hypothermia-induced phosphate depletion. Crit Care Med (in press). 2. Polderman KH, Peerdeman SM, Girbes ARJ. Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J Neurosurg 2001;94:697-705. 3. Polderman KH, Girbes ARJ, Peerdeman SM, Vandertop WP. Hypothermia. J Neurosurg 2001;94:853-8.

TABLE 1. POTASSIUM LEVELS VARIABLE

FLUID BALANCE.*

NORMOTHERMIA

HYPOTHERMIA

median (interquartile range)

Potassium (mmol/liter) Admission 3.6 (3.2–4.0) 3.7 (3.3–4.1) 12 hr 3.9 (3.6–4.2) 3.8 (3.5–4.1) 48 hr 4.0 (3.8–4.4) 4.4 (4.0–4.8) Fluid balance over 48-hr period (liters) Fluid administered 8.8 (5.5–10.9) 10.7 (7.8–13.8) Urine output 4.7 (3.4–6.3) 5.0 (3.2–7.0) Total fluid balance 4.2 (2.5–5.9) 5.6 (3.1–7.9) *Data were available for 103 patients in the hypothermia group and 100 in the normothermia group.

Drs. Polderman and Girbes’s comments give us an opportunity to share our clinical experiences. Potassium levels (Table 1) and magnesium levels were similar between the groups over time. However, we did not assess whether electrolytes were administered differently in the two groups. Patients with mild hypothermia received more fluids during the 48hour period after cardiac arrest than patients with normothermia (P32 µg per



milliliter). Cerebrospinal fluid obtained after the initiation of treatment with ceftriaxone was purulent, with a white-cell count of 5170 per cubic millimeter, 81 percent polymorphonuclear leukocytes, and negative cultures for bacterial pathogens. The patient died on the 17th hospital day. Our experience supports the recommendation of Davidson et al. that microbiology laboratories routinely test S. pneumoniae for susceptibility to fluoroquinolones. Given the deaths of our patient and Patient 3 in the report by Davidson et al., we suggest that if a fluoroquinolone is used to treat bacteremic pneumococcal pneumonia, a beta-lactam antibiotic, such as ceftriaxone, also be administered until the results of tests for susceptibility to fluoroquinolones are available. JOHN J. ROSS, M.D. MICHAEL G. WORTHINGTON, M.D. SHERWOOD L. GORBACH, M.D. Saint Elizabeth’s Medical Center Boston, MA 02135 [email protected]

Editor’s note: Dr. Gorbach has served as a consultant to Bayer. 1. Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002; 346:747-50.

To the Editor: Davidson et al. emphasize that routine susceptibility testing should be more widely implemented, but routine testing is unlikely to detect resistant strains, particularly if they represent a minority of the pathogen population. Furthermore, the use of susceptibility breakpoints can cause the accumulation of strains with intermediate resistance to go unrecognized. This is important in the development of resistance to fluoroquinolones because bacterial species contain two intracellular targets (DNA gyrase and DNA topoisomerase IV). The first mutation increases the probability of a second mutation by several orders of magnitude. Thus, we lack an early-warning system for the development of levofloxacin-resistant pneumococci. As the use of levofloxacin increases, it is likely, for pharmacodynamic reasons, to result in the selection of strains with first-step mutations, thus decreasing the avidity of the newer fluoroquinolones for DNA gyrase and topoisomerase IV. The resultant double-mutation strains will be difficult to treat with any of the available fluoroquinolones.1 The increase in mutant pneumococcal strains with the widespread use of levofloxacin will ultimately reduce the usefulness of the new compounds, thus further decreasing the efficacy of this class of antibiotics. GLENN S. TILLOTSON, M.SC. XILIN ZHAO, PH.D. KARL DRLICA, PH.D. Public Health Research Institute New York, NY 10066 [email protected]

Editor’s note: Dr. Tillotson has served as a consultant to Bayer, Bristol-Myers Squibb, Pharmacia, Johnson and

Johnson, and Anbics. Drs. Zhao and Drlica have served as consultants to Bayer and Bristol-Myers Squibb. 1. Li X, Zhao X, Drlica K. Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin. Antimicrob Agents Chemother 2002;46:522-4.

To the Editor: Davidson et al. report that the S. pneumoniae isolated from Patient 1 had a mutation in both parC (S79F) and gyrA (S81F) and was resistant to levofloxacin (MIC, 8 µg per milliliter). The authors state that this organism had intermediate resistance to gatifloxacin (MIC, 2 µg per milliliter) and was susceptible to moxifloxacin (MIC, 1 µg per milliliter). It is surprising that an S. pneumoniae isolate with both parC S79F and gyrA S81F mutations was found not to have either intermediate or full resistance to all the new fluoroquinolones (i.e., levofloxacin, gatifloxacin, and moxifloxacin). The available evidence to date indicates that any fluoroquinolone-resistant S. pneumoniae strain with both parC S79F and gyrA S81F must be considered to have intermediate or full resistance to levofloxacin, gatifloxacin, and moxifloxacin and that no fluoroquinolone will effectively eradicate these strains.1-4 The implication that a fluoroquinolone-resistant S. pneumoniae strain with both parC S79F and gyrA S81F is susceptible to moxifloxacin but is resistant to levofloxacin and has intermediate resistance to gatifloxacin may give clinicians the impression that moxifloxacin may be used in this setting. GEORGE G. ZHANEL, PH.D. DARYL J. HOBAN, PH.D. University of Manitoba Winnipeg, MB R3A 1R9, Canada [email protected]

CHARLES K. CHAN, M.D. University of Toronto Toronto, ON M5G 2C4, Canada

Editor’s note: Dr. Zhanel has received research support from Bayer, Bristol-Myers Squibb, and Janssen-Ortho/ Ortho-McNeil. Dr. Hoban has received research support from Bayer, Bristol-Myers Squibb, and Janssen-Ortho/ Ortho-McNeil. Dr. Chan has received research support from Bayer and Janssen-Ortho/Ortho-McNeil. 1. Weigel LM, Anderson GJ, Facklam RR, Tenover FC. Genetic analyses of mutations contributing to fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001;45: 3517-23. 2. Brueggemann AB, Coffman SL, Rhomberg P, et al. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995. Antimicrob Agents Chemother 2002;46:680-8. 3. Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs 2002;62:13-59. 4. Zhanel GG, Roberts D, Waltky A, et al. Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. J Antimicrob Chemother 2002;49:807-12.

To the Editor: Canadians were already liberal consumers of fluoroquinolones when levofloxacin became available in 1998. The level of consumption of drugs in the fluoroquin-

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olone category of the Anatomical Therapeutical Chemical classification was 1.38 defined daily doses per 1000 inhabitants per day in 1997; by 2001, this rate had risen to 2.28 defined daily doses per 1000 per day — a 65 percent increase (Rhodes D, IMS Health: personal communication). In contrast, the rate in Denmark has been quite stable, averaging 0.19 defined daily dose per 1000 inhabitants per day during the same period (Sorenson T: personal communication). In hospitals, the use of fluoroquinolones has increased even more dramatically. On the medical service of a 300bed, university-affiliated community hospital in my area, the rate of use of fluoroquinolones rose from 8.6 defined daily doses per 100 bed-days in the first quarter of 2001 to 24.4 defined daily doses per 100 in the fourth quarter. Fluoroquinolones are now the most commonly used class of antimicrobial agents. This phenomenon is probably widespread in Canadian hospitals, since there has been very aggressive marketing focused on the recommendations in the updated Canadian Guidelines for treating community-acquired pneumonia.1 A “respiratory” fluoroquinolone is recommended as the “first choice” for all patients admitted to a hospital. I urge more caution with recommendations for empirical treatment for community-acquired respiratory tract infections. The majority of antibiotics are prescribed for these indications, many inappropriately. Widespread promotion of fluoroquinolones for the treatment of community-acquired pneumonia will undoubtedly result in large increases in overall consumption and therefore in rates of resistance. This remarkable class of antimicrobial agents may be squandered within 20 short years of use.

acin, with susceptibility defined as a MIC of no more than 1 µg per milliliter.4 Zhanel et al. question the wisdom of our reporting a pneumococcal isolate as susceptible to moxifloxacin when it had amino acid substitutions in both parC and gyrA. Their concern is warranted, especially in the case of an infection with a high biomass, such as pneumococcal pneumonia (i.e., more than 1010 infecting organisms), when spontaneous mutations occur at a frequency of 1 in 106 to 1 in 109. We have previously described three such isolates that were susceptible to moxifloxacin yet had amino acid substitutions in parC and gyrA.4 For 99 percent of susceptible pneumococci, the MIC of levofloxacin is no more than 1 µg per milliliter.5 These isolates are proportionately much less likely to have type II topoisomerase substitutions than isolates with a MIC of 2 µg per milliliter. Therefore, one possible solution would be to lower the susceptibility breakpoint for levofloxacin to a MIC of 1 µg per milliliter. Such a change would not be as effective for moxifloxacin or gatifloxacin in identifying isolates with first-step mutations in the susceptible category, emphasizing the need for alternative testing methods. Being able to identify first-step mutations not only is important for detecting the emergence of low-level resistance but also may be important for making decisions about the management of infection. DONALD E. LOW, M.D. JOYCE DE AZAVEDO, PH.D. DARRIN BAST, PH.D.

JIM HUTCHINSON, M.D.

Mount Sinai Hospital Toronto, ON M5G 1X5, Canada

Memorial University of Newfoundland St. John’s, NF A1B 3V6, Canada [email protected]

Editor’s note: Drs. Azavedo and Bast have received research support from Bayer.

1. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000;31:383-421.

The authors reply: To the Editor: Both Tillotson et al. and Zhanel et al. provide compelling arguments for the ability to detect the presence of amino acid substitutions in the fluoroquinoloneresistance–determining region of parC or gyrA, or both, in pneumococci, which current in vitro susceptibility testing does not reliably do.1 Tillotson et al. raise the additional concern that the current category of pathogens that are susceptible to levofloxacin, with susceptibility defined as a MIC of no more than 2 µg per milliliter,2 includes isolates with amino acid substitutions in the fluoroquinolone-resistance– determining region of parC, thereby eliminating the possibility of an early-warning system for the emergence of resistance and resulting in an increase in strains with low-level resistance that favor secondary selection for more resistant strains in treated patients.3 We previously characterized pneumococcal isolates for which the MIC of ciprofloxacin was more than 2 µg per milliliter and found first-step mutations in isolates that were susceptible to levofloxacin and also in isolates that were susceptible to gatifloxacin and moxiflox-

1. Richardson DC, Bast D, McGeer A, Low DE. Evaluation of susceptibility testing to detect fluoroquinolone resistance mechanisms in Streptococcus pneumoniae. Antimicrob Agents Chemother 2001;45:1911-4. 2. Performance standards for antimicrobial susceptibility testing: twelfth informational supplement. Wayne, Pa.: National Committee for Clinical Laboratory Standards, 2002. (NCCLS document M100-S12.) 3. Baquero F. Low-level antibacterial resistance: a gateway to clinical resistance. Drug Resist Updat 2001;4:93-105. 4. Bast DJ, Low DE, Duncan CL, et al. Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob Agents Chemother 2000;44:3049-54. 5. Low DE, de Azavedo J, Weiss K, et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob Agents Chemother 2002;46:1295-301.

Imatinib and Chronic-Phase Leukemias To the Editor: Savage and Antman (Feb. 28 issue)1 summarize the pathogenesis of BCR-ABL–positive chronicphase leukemias that are responsive to imatinib mesylate therapy. The authors point out that the mechanism of the antiproliferative action of imatinib lies in its effective control of BCR-ABL tyrosine kinase activity, thus interfering with the promotion of the phosphorylation of multiple substrates of mitogenic signaling pathways. The precise oncogenic mechanism of BCR-ABL is still unknown.



There are important changes in the metabolic profile of BCR-ABL–positive cells after their reversion as a result of imatinib mesylate treatment. Hematopoietic cells transfected with BCR-ABL express the high-affinity GLUT-1 glucose transporter and increase their glucose uptake — the metabolic hallmark of their transformation.2 This transformation also involves the activation of glucose-metabolizing enzymes, hexokinase type II and glucose-6-phosphate 1-dehydrogenase.3 Imatinib mesylate effectively controls these enzymes, which limits the uptake, phosphorylation, and use of glucose with respect to the synthesis of the nucleic acid precursor ribose as well as of NADP+ by means of the oxidative branch of the pentose cycle.4 This effect of imatinib is dose dependent and directed to the kinase activity of BCR-ABL, since negative control cells did not have a similar metabolic profile. The changes in metabolicenzyme activity are also opposite to those induced by hydroxyurea, a potent inhibitor of DNA and RNA synthesis in patients with chronic myelogenous leukemia. The control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib mesylate and occurs downstream from the genetic and signaling effects of this drug, as described by Savage and Antman. The actions of imatinib on the genome, proteome, and metabolome may be used to identify direct enzyme targets, the inhibition of which would trigger similar metabolic modifications and thus control other cancers.5 LASZLO G. BOROS, M.D. WAI-NANG PAUL LEE, M.D. UCLA School of Medicine Torrance, CA 90502-2910 [email protected]

MARTA CASCANTE, PH.D. University of Barcelona 08028 Barcelona, Spain 1. Savage DG, Antman KH. Imatinib mesylate — a new oral targeted therapy. N Engl J Med 2002;346:683-93. 2. Bentley J, Walker I, McIntosh E, Whetton AD, Owen-Lynch PJ, Baldwin SA. Glucose transport regulation by p210 Bcr-Abl in a chronic myeloid leukaemia model. Br J Haematol 2001;112:212-5. 3. Osawa H, Sutherland C, Robey RB, Printz RL, Granner DK. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem 1996;271:16690-4. 4. Boren J, Cascante M, Marin S, et al. Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. J Biol Chem 2001;276:37747-53. 5. Boros LG, Cascante M, Paul Lee W-N. Metabolic profiling of cell growth and death in cancer: applications in drug discovery. Drug Discov Today 2002;7:364-72.

Blood and Disaster To the Editor: Dr. Schmidt (Feb. 21 issue)1 appears not to appreciate the powerful need people have to give blood when a tragedy strikes or the potent symbolism involved. When America’s Blood Centers, whose community-based network provides nearly half of the nation’s blood supply, learned that there was little need for blood after the September 11, 2001, terrorist attacks, we asked the public on September 12 to donate blood in the weeks ahead. Many, although not all, were satisfied to schedule memorial do-

nations, but most of our centers collected little blood that was not transfused into patients. Schmidt notes that in one instance, up to 40 percent of new donors responding to a disaster gave blood again within six months, although his conclusion was based on the conduct of donors in the disaster area. Recent widespread blood shortages are reminders that September 11 did not create a sustained motivation for blood donation. LOUIS KATZ, M.D. America’s Blood Centers Washington, DC 20005 1. Schmidt PJ. Blood and disaster — supply and demand. N Engl J Med 2002;346:617-20.

To the Editor: Schmidt’s Sounding Board commentary reminds us that mass appeals for blood can be inefficient and unsafe. However, the impulse to bolster blood supplies in the hours that followed the disasters on September 11 was understandable and reasonable. The initial appeals came from the affected areas and were based on the predictions by hospitals in New York and New Jersey that there would be between 5000 and 10,000 casualties.1 Even when the number of casualties turned out to be far smaller, no one could predict what acts of terror might occur in other areas during the succeeding days. Transport of blood nationwide had been curtailed in a way that no contingency plan had anticipated. Prudence dictated preparing for the worst. One positive outcome of the confusion surrounding the need for blood was the formation of a task force to improve the national response to the need for blood during domestic disasters and acts of terrorism. Under the auspices of the American Association of Blood Banks, more than 15 governmental, not-for-profit, and commercial organizations prepared a plan that designates a single coordinating center for national emergencies and provides for local assessments of the need for blood, transportation, and communication with the public. The Advisory Committee on Blood Safety and Availability of the Department of Health and Human Services endorsed this plan at its meeting in February. Finally, Schmidt’s contention that “none of the reports” credited the blood contributed before the disaster with saving lives is incorrect. In fact, the commentary by the American Association of Blood Banks that he cites states that “blood for today’s tragedy is taken from yesterday’s inventory. . . . The question is not whether to donate but when to donate,” and it calls for a sustained national blood program.2 That message was reiterated in the September 12 press release issued by the association, which reported that inventory levels were meeting hospital needs,3 and this was and remains the stated position of the American Association of Blood Banks. Schmidt’s central thesis is that the best preparation for the next disaster is to ensure that sufficient blood is “on the shelf.” The message is not new, but it cannot be repeated often enough.


HARVEY G. KLEIN, M.D. KAREN SHOOS LIPTON, J.D. American Association of Blood Banks Bethesda, MD 20814-2749

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1. AABB responds to needs for blood. Press release of the American Association of Blood Banks, Bethesda, Md., September 11, 2001. 2. Klein HG. Earthquake in America. Transfusion 2001;41:1179-80. 3. AABB applauds Americans’ spirit to help. Press release of the American Association of Blood Banks, Bethesda, Md., September 12, 2001.

To the Editor: Schmidt’s statement that “medical facilities usually have a three-day supply of blood on hand” is clearly wrong, given that shortages and blood emergencies are declared frequently. The summer of 2001 witnessed one of the worst shortages in 20 years, and more recently, early this year in New York City, supplies were again limited and another shortage was declared. Had the terrorist attack occurred a few weeks earlier, even the limited demand would clearly have outstripped the supply. The use of data on supply and demand from disasters that are smaller by an order of magnitude than the September 11 attacks is of dubious value. This disaster was unique in that the ratio of the number of persons injured to the number killed was dramatically skewed, with few crush injuries and amputations, as well as in that the emergency transportation system remained intact. A ratio of the number injured to the number killed of less than 1:20 makes this event unlike those Schmidt lists in his Table 1. Similar figures for transfusion demands from the recent earthquakes in Japan and Turkey would have had greater validity for comparison, had such data been available. What was lost in the aftermath of September 11 was the opportunity to break the monopolistic hold on the blood supply of the American Red Cross and the regional blood centers. Claims of excessive costs to freeze units of blood are really just excuses to perpetuate the status quo. If the federal government could establish a strategic reserve of 100,000 units, the monopoly on blood would be broken. There is minimal competition within regions, and the price of blood has climbed by 20 percent since September 11. The concept that local supplies will always suffice is clearly too optimistic for the realities of asymmetric warfare. Had the terrorists released persistent agents or hit a nuclear facility in the vicinity of the attack, the transport system would not have functioned. Unfortunately, in planning to fight asymmetric warfare, repeatedly making conventional and outmoded assumptions is a recipe for disaster. Large supplies of frozen blood, as well as other medical supplies, need to be positioned in advance. These blood reserves would also have the immediate economic advantage of constraining future price increases. CLIFFORD GEVIRTZ, M.D., M.P.H. Mt. Sinai School of Medicine New York, NY 10029 [email protected]

Gevirtz proposes that we build a strategic reserve of frozen blood for disasters. With the current technology, three hours are required to process each unit of thawed red cells, one by one in its own machine. Transfusions for 50 disaster victims would require a waiting battery of sterile machines and trained operators. Transfusions for 1000 victims would require systems that are not yet available. Frozen stored red cells are discarded whenever blood banks are required to obtain a new type of information about the donor’s history. Despite its 10-year shelf life, blood frozen after September 11 should not be used after May 31, 2002, the effective date of the call by the Food and Drug Administration for the rejection — because of the risk of “mad cow disease” — of blood donors who have lived in the United Kingdom for three months or in France for five years since 1980.1 New requirements are always under review. Using up stored blood just before the implementation of new requirements would be unethical. When the AIDS crisis began, such a decision in France led to charges of involuntary manslaughter against the minister of health and the prime minister, and the head of the national blood service was sent to prison.2 Constant turnover of a stockpile would double the cost of blood to hospitals. What is required now is not the stockpiling of frozen blood but the proper encouragement of the walking blood reserves that exist in every community. Like politics, all blood donation is local, and Klein and Lipton are correct in calling for local assessments of the system. More is needed. A single, local voice must be established for blood emergencies in every community. That voice must be recognized as speaking for the disparate interests of donors, recipients, and collectors and to the demands of competing hospitals. The supply and demand of blood for disasters must be controlled by the authority in charge of emergency preparedness in each community, under commitments like those obtained from the competing fire, rescue, and police departments. Local cooperation regarding the collection and use of blood donations must be forged now, while the lessons from September 11 are fresh. PAUL J. SCHMIDT, M.D. University of South Florida Tampa, FL 33620 [email protected] 1. Guidance for industry: revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jakob disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products. Rockville, Md.: Food and Drug Administration, Center for Biologics Evaluation and Research, January 2002. 2. Steffen M. The nation’s blood: medicine, justice, and the state in France. In: Feldman EA, Bayer R, eds. Blood feuds: AIDS, blood, and the politics of medical disaster. New York: Oxford University Press, 1999:95126.

Dr. Schmidt replies: To the Editor: Katz properly cites the symbolism of blood donation. A half-million people gave blood after September 11 because they had been conditioned to respond in this way to tragedy. The less than 300 units actually transfused into the victims were donated before September 11 in regular volunteer programs. Such disparities are expected by those involved with blood banks but not by the general public.

Pulmonary Alveolar Microlithiasis To the Editor: Pulmonary alveolar microlithiasis is a rare disease of unknown pathogenesis, characterized by widespread laminated calcispherites in alveolar spaces in the absence of any known disorder of calcium metabolism.1 It usually occurs in a sporadic form, but an autosomal recessive



form has been described, especially in patients from the Mediterranean countries.2-5 We report on two initially asymptomatic, nonsmoking siblings: a 38-year-old woman and her 41-year-old brother, both of whom were given a diagnosis of pulmonary alveolar microlithiasis. In both patients, chest x-ray films and a computed tomographic scan (Fig. 1) showed diffusely scattered, bilateral, micronodular areas of radiopacity of calcific densities throughout the lungs with the classic “sandstorm” pattern. The sister subsequently had a mild restrictive respiratory

Figure 1. Computed Tomographic Scan of the Chest of a 41-YearOld Man, Showing Bilateral Calcific, Micronodular Opacities.

defect, but she is still alive and her condition is unchanged after 13 years of follow-up. Her brother’s clinical condition worsened rapidly, and he died of respiratory failure 10 years after diagnosis, despite bilateral lung transplantation. The parents of the patients were unaffected. Examination of open-lung–biopsy specimens from both patients revealed intraalveolar and interstitial deposits of concentrically laminated calcified bodies. Numerous macrophages surrounded the microliths, and there was interstitial fibrosis. Microradiology showed microliths (measuring 50 to 750 µm in diameter) that were almost spherical in shape and were sometimes completely surrounded by woven bone or by lamellar structured bone containing typical ellipsoidal osteocytes. In this case, the microliths were highly indented owing to peripheral osteoclastic activity. X-ray microanalysis showed that the microliths consisted of calcium and phosphorus and a small amount of magnesium. The ratio of calcium to phosphorus indicates that the microliths may consist of hydroxyapatite-like material, similar to bone. Ultrastructural examinations showed that groups of multinucleated osteoclast-like macrophages were always present in the areas surrounding the calcified tissue, and many of them displayed shrinkage necrosis. The nuclear chromatin and cytoplasm of modified type II alveolar pneumocytes also included apoptotic bodies. Moreover, this apoptotic activity was confirmed by immunohistochemical expression of BAX protein (Fig. 2) and bcl-2 protein and by the terminal deoxynucleotidyl transferase–uridine triphosphate nicked-end labeling technique. On the one hand, our observations appear to support previous suggestions that a genetic trait is involved in a great proportion of patients with pulmonary alveolar microlithiasis. On the other hand, we first would stress that, by promoting the formation of calcified lamellar bodies, apoptosis has a crucial role in the pathogenesis of pulmonary alveolar microlithiasis. Finally, microliths act like autologous osteoconductive material when they are implanted in pulmonary parenchyma and serve as a substrate on which bone is easily formed. GIUSEPPE BARBOLINI, M.D. GIULIO ROSSI, M.D. University of Modena and Reggio Emilia I-41100 Modena, Italy [email protected]

ALBERTO BISETTI, M.D. University La Sapienza I-00151 Rome, Italy

Figure 2. Detected by Immunohistochemical Staining Showing Overexpression of BAX Protein in the Alveolar Macrophages of a 41-Year-Old Man (Rabbit Polyclonal Anti-BAX Protein, ¬100).

1. Moran CA, Hochholzer L, Hasleton PS, Johnson FB, Koss MN. Pulmonary alveolar microlithiasis: a clinicopathologic and chemical analysis of seven cases. Arch Pathol Lab Med 1997;121:607-11. 2. Esguerra Gómez G, Lichtemberger E, Santamaría A, et al. Familial pulmonary alveolar microlithiasis: four cases from Colombia, S.A.: is microlithiasis also an environmental disease? Radiology 1959;72:550-61. 3. Mariotta S, Guidi L, Papale M, Ricci A, Bisetti A. Pulmonary alveolar microlithiasis: review of Italian reports. Eur J Epidemiol 1997;13:587-90. 4. ˘enyi g˘ it A, Yarami≥ A, Gürkan F, et al. Pulmonary alveolar microlithiasis: a rare familial inheritance with report of six cases in a family: contribution of six new cases to the number of case reports in Turkey. Respiration 2001;68:204-9. 5. Uçan ES, Keyf AI, Aydilek R, et al. Pulmonary alveolar microlithiasis: review of Turkish reports. Thorax 1993;48:171-3.


Correspondence Copyright © 2002 Massachusetts Medical Society.