Infection in Organ-Transplant Recipients

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

Correspondence

HMOs: The Good and the Bad To the Editor: Mr. Kuttner is seriously misinformed when he describes the Health Insurance Plan of Greater New York (HIP) as “notorious for poor management” (May 21 issue).1 HIP is led by chairman and chief executive officer Anthony L. Watson, who is a presidential appointee to the recently formed National Commission on the Future of Medicare. HIP received the 1998 Sachs Group seal of excellence for health care consumer loyalty. HIP was 1 of only 16 health maintenance organizations (HMOs) nationwide to receive the award. During its 50th anniversary in 1997, year-long attention was focused on HIP as one of the nation’s leading HMOs. Before Mr. Watson’s presidential appointment, the National Committee for Quality Assurance granted HIP full accreditation for three years. HIP was ranked first in the New York metropolitan area in patient care, doctor training, and member satisfaction by U.S. News and World Report in its 1997 national survey. A 1997 survey of Medicare HMOs by CareData Resources ranked HIP first in New York. The mayor of New York City, Rudolph Giuliani, honored HIP for its leadership in forming and helping to fund an alliance with Victim Services to establish a program to identify and provide medical services and social referrals to victims of domestic violence. HIP was ranked second among 11 HMO plans in New York State by health care purchasers surveyed by Watson Wyatt Worldwide, one of the world’s leading humanresources and risk-management consulting companies. The study, “Measuring Value: 1997 Tri-State HMO Valuation,” was based on purchasers’ experience in 1996. The study noted that the purchasers gave HIP the second-highest relative

value score primarily on the basis of their perception of HIP’s quality and provider reimbursement. HIP was one of only three HMOs to join with the American Association of Retired Persons in calling for increased regulation of managed health care, because it believes that all health plans should be subject to legally enforceable national standards. HIP is a not-for-profit, prepaid group-model HMO. The groups are privately owned by the physicians who practice together in state-of-the-art medical centers. HIP contracts with the groups to provide its members with comprehensive health care. To offer its members greater choice and an even wider selection of physicians, HIP has built an expanded health care delivery system of 12,000 to 14,000 qualified physicians who practice out of their own offices. In addition to its plan in New York, HIP has developed highly rated health plans in New Jersey, Pennsylvania, and Florida. Mr. Kuttner owes HIP an apology. DANIEL T. MCGOWAN Health Insurance Plan of Greater New York New York, NY 10001 1. Kuttner R. Must good HMOs go bad? The commercialization of prepaid group health care. N Engl J Med 1998;338:1558-63.

Mr. Kuttner replies: To the Editor: Different HMO rankings produce different results. HIP does not score as well as most nonprofit HMOs on many rankings. Its Health Plan Employer Data and Information Set (HEDIS) statistics are mixed; HEDIS scores HIP below the national average on patient satisfaction. Consumers Union’s most recent member survey of HMOs gave HIP an overall rating of 65, on a scale that ranged from 61 to 85. New York State’s assessment scored HIP above average in a few categories, but well below average in several others that should be among the strengths of a nonprofit HMO, such as childhood immunizations, first-trimester prenatal care, and some types of cancer screening. The report of the New York City public advocate found that HIP had the worst record on unresolved patient complaints; it ranked HIP last among 12

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HMOs on telephone access, and 9th on spending on physicians per member. Yes, HIP did score well on some rankings, and it may well be that HIP’s management is on an upswing. In fairness, I do regret that my mention of HIP was so abbreviated. I did not have space to do a complete profile of every HMO and simply wanted to suggest in this context that the quality of management of both for-profit and nonprofit HMOs varies, but I should not have been quite so categorical about HIP in so few words. ROBERT KUTTNER The American Prospect Cambridge, MA 02138

Death after Exposure to Dimethylmercury To the Editor: In the report by Nierenberg et al. (June 4 issue)1 of a tragic case of fatal dimethylmercury toxicity, the patient’s history, supported by laboratory records, revealed exposure to the toxin on only one day, with a small spill of several drops onto the dorsum of a latex-gloved hand. It was postulated that toxic tissue levels resulted from transdermal absorption through permeable latex gloves, with possible inhalation despite the use of a fume hood. There appears to be little doubt regarding the diagnosis; however, we would be interested in more details of the investigation of the possible sources of the toxin. As the accompanying editorial comments, “it remains possible that the patient had unrecognized mercury exposure before the single spill reported.”2 Specifically, we would like to know more about the evaluation of the laboratory by the Occupational Safety and Health Administration after the exposure. More information is needed about the amount of dimethylmercury involved. Several drops from a pipette is not 0.44 ml, and even if it were, almost complete permeation of the skin would have had to occur, which seems unlikely. Was the skin intact in the area of exposure? How was the possibility of nonaccidental administration of the toxin excluded, given the astounding amount of neurologic damage that occurred from so small a dose? Was there a formal police or medicolegal investigation? Were traces of other toxins or drugs looked for at the time of hospital admission? ROGER W. BYARD, M.D. RICHARD COUPER, F.R.A.C.P. Women’s and Children’s Hospital North Adelaide, SA 5006, Australia 1. Nierenberg DW, Nordgren RE, Chang MB, et al. Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 1998;338:1672-6. 2. Kulig K. A tragic reminder about organic mercury. N Engl J Med 1998; 338:1692-4.

To the Editor: The recent report of the death of a researcher after exposure to dimethylmercury and the companion editorial serve as grim reminders of the dangers associated with exposure to compounds that contain mercury. Mercury cycles through the environment as a consequence of natural and human activity. It is concentrated by preda-

tion among aquatic species, reaching the highest levels at the top of the food chain. It causes a variety of effects in humans, primarily through damage to the nervous system. Although Kulig correctly listed incinerators as a major anthropogenic source of mercury pollution, he stopped short of identifying the specific role of medical-waste incinerators. The Environmental Protection Agency (EPA) ranks medical-waste incinerators as the fourth leading source of mercury contamination of the environment.1 According to the EPA, medical-waste incinerators discharge more mercury into the environment than all manufacturing processes combined.1 Medical-waste incinerators are also a leading source of dioxin production and discharge.2 Although a recent survey of leading hospitals suggests that many are moving away from incineration as a method of disposal, 40 percent still incinerate waste that could be disposed of more safely.2 The maxim “first, do no harm” is the fundamental guiding principle of the practice of medicine. We have an obligation to apply this principle to the disposal of medical waste and to work toward a better solution to the complex problem of medical-waste management. ALAN H. LOCKWOOD, M.D. State University of New York at Buffalo School of Medicine and Biomedical Sciences Buffalo, NY 14215

PHILLIP J. LANDRIGAN, M.D., M.SC. Mount Sinai Medical Center New York, NY 10029-6574 1. Office of Air Quality Planning and Standards. Mercury study report to Congress. Washington, D.C.: Environmental Protection Agency, 1997. 2. Environmental Working Group. “Greening” hospitals: an analysis of pollution prevention in America’s top hospitals. Washington, D.C.: Environmental Working Group, 1998.

To the Editor: Dimethylmercury is a spontaneously nonreactive, lipophilic mercurial whose physicochemical properties predict what was in fact observed in the only study of its effects in vivo.1 Its rapid metabolic conversion in the liver creates the toxic species methylmercuric ion. If liquid dimethylmercury was in fact the causative agent, and if the fatal toxicity was caused by a single exposure, then the volume coming in contact with the patient’s skin should have been something like 10 times that calculated by Nierenberg et al., assuming that dimethylmercury behaves in the same way in humans as Ostlund observed in mice.1 With no evidence to the contrary, it is reasonable to make such an assumption, since the initial distribution of dimethylmercury in vivo should be dictated by its physicochemical properties alone. Assuming that the patient’s death was the result of a single transdermal dose of dimethylmercury, one would expect neurologic symptoms to appear much earlier than five months after exposure. In the two cases of fatal dimethylmercury poisoning in the 1860s,2 both persons were symptomatic shortly after exposure (one died within a few weeks). I can find no data on dimethylmercury toxicity in animal studies: however, single toxic doses of methylmercuric ion given to rats, hamsters, and squirrel monkeys resulted in the appearance of symptoms within a few hours to a few days.3 Humans ingesting methylmercuric ion through multiple exposures (in bread) also manifested tox-

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ic effects much sooner than five months,4 as did those consuming pork over a three-month period.5 These points raise questions about the timing, amount, and manner of exposure and the specific mercurial dimethylmercury or methylmercuric ion to which the patient was exposed. Given the circumstances of this case, it is unfortunate that determinations of the presence or absence of methylmercuric ion and inorganic mercury were not made in brain tissues. DAVID P. HANLON, PH.D. 51 E. Wheelock St. Hanover, NH 03755 1. Ostlund K. Studies on the metabolism of methyl mercury and dimethyl mercury in mice. Acta Pharmacol Toxicol 1969;27:Suppl 1:1-132. 2. Dewhurst F. Edward Franklin and COSHH. Chem Br 1989;25:702-5. 3. Hoskins BB, Hupp EW. Methylmercury effects in rat, hamster, and squirrel monkey. Environ Res 1978;15:5-19. 4. Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science 1973;181:230-41. 5. Davis LE, Kornfeld M, Mooney HS, et al. Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family. Ann Neurol 1994;35:680-8.

The authors reply: To the Editor: In response to Drs. Byard and Couper: our patient had worked previously with other mercury compounds, but not with dimethylmercury. Although the content of mercury in her hair before the date of the accident was slightly high (Fig. 2 of our report),1 this finding may reflect external contamination of the hair after the accident. Other accidental exposures were not suggested by the patient, laboratory notebooks, hair analysis, or memories of coworkers. Wipe tests and air sampling of the patient’s laboratory, office, automobile, and home conducted by a certified industrial-hygiene consultant were remarkable only for elevated airborne mercury levels immediately around the sealed storage can inside the chemical-fume hood. This information, along with the results of the glove-permeation studies, was reviewed by the Occupational Safety and Health Administration. Information from Dartmouth about personal protective equipment for uncommon and highly toxic compounds has been made widely available.2 The patient recalled no skin problems. A comparison of the amount of dimethylmercury purchased with the amount remaining several months after the accident, as well as clinical data, supported the hypothesis of a single exposure through some combination of transdermal absorption and inhalation. Given the density of dimethylmercury (278 mg of mercury per 0.1 ml), just 0.48 ml of dimethylmercury contains 1344 mg of mercury, the net amount that we estimate the patient absorbed.1 By comparison, the minimal lethal dose of methylmercury in an epidemic of mercury poisoning in Iraq was 200 to 312 mg of mercury, and the median lethal dose was 400 to 600 mg.3 Since the patient’s history and physical-examination results were consistent with a diagnosis of methylmercury neurotoxicity, and since she had no history of exposure to other drugs or toxins, we did not pursue a “drug screen.” The chief medical examiner of New Hampshire conducted the autopsy. No grounds were found to suspect suicidal or homicidal intent; the case was ruled an accidental death, with no reason for police investigation.

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Drs. Lockwood and Landrigan support Dr. Kulig’s comment that incinerators (including hospital incinerators) are a major source of mercury contamination of the environment.4,5 Elemental mercury can be a problematic pollutant and workplace contaminant. In addition to limiting the incineration of contaminated medical waste, we urge the minimization or elimination of mercury and use of substitutes whenever possible in the medical workplace. In response to Dr. Hanlon: we pointed out in our report that some dimethylmercury is exhaled unchanged after intravenous administration to mice or after inhalation.5 By extension, our patient may have initially absorbed more than 1344 mg of mercury, and then lost some through exhalation. On the other hand, there appear to be marked interspecies differences in the kinetics and toxicity of methylmercury chloride.6 In monkeys, the onset of neurotoxicity is later than in rats and hamsters, and delayed, severe neurotoxicity, similar to that seen in our patient, can develop in monkeys. Moreover, slight differences in single toxic doses given to monkeys can produce rapid death, delayed but fatal neurotoxicity, or transient minor neurotoxicity with full recovery.6 In short, there appear to be important but not fully understood interspecies and interpatient differences in the pace and severity of the development of neurotoxicity after exposure to methylmercury or dimethylmercury. DAVID W. NIERENBERG, M.D. Dartmouth–Hitchcock Medical Center Lebanon, NH 03756-0001

MICHAEL B. BLAYNEY, PH.D. Dartmouth College Hanover, NH 03755

THOMAS W. CLARKSON, PH.D. University of Rochester School of Medicine Rochester, NY 14642 1. Nierenberg DW, Nordgren RE, Chang MB, et al. Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 1998;338:1672-6. 2. Lewis R. Researchers’ deaths inspire actions to improve safety. Scientist 1997;11(21):1, 4. 3. Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science 1973;181:230-41. 4. Office of Air Quality Planning and Standards. Mercury study report to Congress. Washington, D.C.: Environmental Protection Agency, 1997. 5. Ostlund K. Studies on the metabolism of methyl mercury and dimethyl mercury in mice. Acta Pharmacol Toxicol 1969;27:Suppl 1:1-132. 6. Hoskins BB, Hupp EW. Methylmercury effects in rat, hamster, and squirrel monkey. Environ Res 1978;15:5-19.

Infection in Organ-Transplant Recipients To the Editor: In the excellent review of infection in organ-transplant recipients by Fishman and Rubin (June 11 issue),1 we were surprised that human herpesvirus 6 (HHV-6) and herpesvirus 8 (HHV-8) infections were not addressed. HHV-8 is involved in the development of all forms of Kaposi’s sarcoma; HHV-8 DNA has been found in nearly all Kaposi’s sarcomas from transplant recipients who have been examined for it,2 and an angiogenesiscausing HHV-8 oncogene has been identified.3 This com-

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plication develops an average of 21 months after transplantation (so it would be included in the third period of the timetable proposed by the authors), and it is directly related to the amount of immunosuppression. On the other hand, HHV-6 has been recognized as a cause of myelosuppression, interstitial pneumonitis, encephalitis, and fever during the first four months after transplantation. In view of its pathogenicity and the availability of effective treatment, most authors believe that a diagnostic workup is warranted.4,5 Furthermore, there is evidence of a role for HHV-6 as an immunomodulator,4 so it is involved to a still undetermined extent with the net state of immunosuppression. Thus, we believe it should be included in Fishman and Rubin’s list of factors affecting the net state of immunosuppression. JOSÉ GÓMEZ-MORENO, M.D. VALENTÍN CUERVAS-MONS, PH.D. Clínica Puerta de Hierro 28035 Madrid, Spain 1. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741-51. 2. Alkan S, Karcher DS, Ortiz A, Khalil S, Akhtar M, Ali MA. Human herpesvirus-8/Kaposi’s sarcoma-associated herpesvirus in organ transplant patients with immunosuppression. Br J Haematol 1997;96:412-4. 3. Bais C, Santomasso B, Coso O, et al. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998;391:86-9. [Nature, 1998;392:210.] 4. Singh N, Carrigan DR. Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996;124:1065-71. 5. Singh N, Carrigan DR, Gayowski T, Marino IR. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity. Transplantation 1997;64:674-8.

To the Editor: As organ transplantation becomes an increasingly common part of medical care, clinicians need to be acquainted with the infectious complications that result from long-term immunosuppressive therapy. Data have shown that in the face of human immunodeficiency virus infection and other conditions of immunosuppression, there is a greatly increased risk of the reactivation of Mycobacterium tuberculosis infection.1,2 In areas of the world where tuberculosis is highly endemic, large proportions of the population are estimated to be infected with M. tuberculosis.3 As organ transplantation becomes available in these settings, the detection of M. tuberculosis infection and the prevention of disease will become increasingly important. In their review of the infectious complications of organ transplantation, Fishman and Rubin make recommendations for the management of M. tuberculosis infection that are not consistent with the current recommendations of the American Thoracic Society.2 According to the society’s recommendations, all organ-transplant candidates should be screened for M. tuberculosis infection with tuberculin skin testing by the Mantoux method with 5 TU of purified protein derivative, as well as a history-taking to identify prior exposure to tuberculosis. Persons with »10 mm of induration on skin tests or a history of a positive test without treatment who are receiving or are scheduled to receive immunosuppressive therapy should undergo chest radiography and an evaluation for active disease. If no disease is found, preventive therapy with isoniazid should be given for 6 to 12 months. Serial chest radiographs are not recommended for the detection of the disease. Unless there is

documented exposure to a patient with isoniazid-resistant tuberculosis, rifampin is not recommended as preventive therapy. As a result of its interaction with the cytochrome P-450 system, rifampin decreases serum levels of cyclosporine and tacrolimus, which require dose adjustment to avoid rejection of the graft. Although isoniazid does inhibit certain cytochrome P-450 enzymes, serious interactions with cyclosporine and tacrolimus have not been reported. Appropriate use of isoniazid alone as preventive therapy in these high-risk patients can avert the complications of active disease, such as the need for treatment with multiple antituberculosis agents, including rifampin, and adjustments in the dose of immunosuppressive drugs. RENÉE RIDZON, M.D. IDA M. ONORATO, M.D. Centers for Disease Control and Prevention Atlanta, GA 30333 1. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545-50. 2. American Thoracic Society, Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-74. 3. Raviglione MC, Snider DE Jr, Kochi A. Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA 1995; 273:220-6.

To the Editor: We commend Fishman and Rubin for their outstanding review of infectious complications after organ transplantation. However, we disagree with their suggestion that infections with respiratory viruses usually occur at least one to two months after solid-organ transplantation. Respiratory viruses such as influenzavirus, respiratory syncytial virus, and adenovirus are now increasingly recognized to cause nosocomial infections in the early postoperative period, especially in certain populations of transplant recipients. For example, in a series of 17 pediatric liver-transplant recipients with respiratory syncytial virus infection, over 75 percent of infections (13 of 17) were nosocomial, and the median time to the diagnosis of infection was only 24 days after transplantation.1 Similarly, in a series of adult lung-transplant recipients, 30 percent of respiratory viral infections (3 of 10) were nosocomial, including a fatal postoperative adenovirus pneumonia.2 These results are consistent with the finding that respiratory syncytial virus and other respiratory viruses are increasingly being recognized as nosocomial pathogens in a variety of immunocompromised or critically ill patients.3 Nosocomial transmission of respiratory viruses often mirrors community outbreaks. In some cases, early infection after transplantation may reflect direct transmission through an infected allograft.4 Given the serious morbidity and mortality that can be associated with respiratory viral infections, these pathogens must be considered in the differential diagnosis of early postoperative respiratory tract complications in recipients of solid-organ transplants, and appropriate diagnostic studies should be pursued. SCOTT M. PALMER, M.D. VICTOR F. TAPSON, M.D. Duke University Medical Center Durham, NC 27710


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1. Pohl C, Green M, Wald ER, Ledesma-Medina J. Respiratory syncytial virus infections in pediatric liver transplant recipients. J Infect Dis 1992; 165:166-9. 2. Palmer SM Jr, Henshaw NG, Howell DN, Miller SE, Davis RD, Tapson VF. Community respiratory viral infection in adult lung transplant recipients. Chest 1998;113:944-50. 3. Holladay RC, Campbell GD Jr. Nosocomial viral pneumonia in the intensive care unit. Clin Chest Med 1995;16:121-33. 4. Myerowitz RL, Stalder H, Oxman MN, et al. Fatal disseminated adenovirus infection in a renal transplant recipient. Am J Med 1975;59:591-8.

To the Editor: Fishman and Rubin describe listeriosis as an infection that occurs one month or more after organ transplantation. This is incorrect. In a review of 102 cases of listeriosis in renal-transplant recipients, the time of the infection was reported in 80, and in 13 cases (16 percent), the infection appeared within the first month after transplantation.1 In seven cases (9 percent) listeriosis developed within two weeks after transplantation.

are technically correct. In transplant recipients, however, skin testing is often unrevealing and isoniazid often poorly tolerated.2-4 As described by Dr. Burt Meyers at the World Congress of Transplantation Infectious Disease,4 the incidence of clinically important hepatic dysfunction in organ-transplant recipients is significantly increased after the initiation of therapy with isoniazid, rifampin, or both, particularly in view of the fact that there is a high prevalence of coexisting viral hepatitis in these patients. Alternative approaches are needed for this population, with agents such as quinolones and ethambutol being useful alternatives to traditional programs of prophylaxis and therapy. Tuberculosis is important in these patients. However, standard recommendations are not always applicable. The best approach to these patients has yet to be established through rigorous study — a problem that merits attention.

ALAN M. STAMM, M.D.

JAY A. FISHMAN, M.D. ROBERT H. RUBIN, M.D.

University of Alabama at Birmingham Birmingham, AL 35294

Massachusetts General Hospital Boston, MA 02114

1. Stamm AM, Dismukes WE, Simmons BP, et al. Listeriosis in renal transplant recipients: report of an outbreak and review of 102 cases. Rev Infect Dis 1982;4:665-82.

1. Stamm AM, Dismukes WE, Simmons BP, et al. Listeriosis in renal transplant recipients: report of an outbreak and review of 102 cases. Rev Infect Dis 1982;4:665-82. 2. Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis among renal transplant recipients in India. Transplantation 1996;61:211-5. 3. Schluger LK, Sheiner PA, Jonas M, et al. Isoniazid hepatotoxicity after orthotopic liver transplantation. Mt Sinai J Med 1996;63:364-9. 4. Meyers B. Tuberculosis in organ transplant patients. Presented at: World Congress of Transplantation Infectious Disease, Orlando, Fla., April 1-3, 1998.

The authors reply: To the Editor: A central tenet of the care of transplant recipients is the relation between two variables that determine the risk of infection after transplantation: the net state of immunosuppression and the level of exposure (epidemiologic risk). In the first month after transplantation, the net state of immunosuppression is usually too low for “nontechnical” forms of infection to occur. However, if the level of exposure is great enough, then infections occur despite relatively intact host defenses. This context is useful in considering the comments of Drs. Palmer and Tapson. They are correct to emphasize the nosocomial transmission of respiratory viruses, particularly in children, in the differential diagnosis of pulmonary syndromes after transplantation. Nosocomial outbreaks of a variety of respiratory tract pathogens, from viruses to fungi, are of great importance in the post-transplantation period. One of the clues to a major nosocomial hazard, as we emphasize, is the occurrence of infection in the first month after transplantation. The importance of early infection is also noted by Stamm in relation to infection by Listeria monocytogenes. Without trimethoprim–sulfamethoxazole prophylaxis and with a high enough level of exposure, early listeriosis may occur. Early clustering of cases, as previously described, suggests an excessive nosocomial hazard.1 More commonly, listeriosis reflects simultaneous cytomegalovirus infection or heavy doses of immunosuppression used in patients with a poor result of transplantation. The comments of Drs. Gómez-Moreno and CuervasMons are, we believe, going to be proved correct in that these viruses, true emerging pathogens, are likely to be of increasing importance in organ-transplant recipients. The comments of Drs. Ridzon and Onorato are timely. Their recommendations regarding isoniazid prophylaxis

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Treatment of Cutaneous Larva Migrans To the Editor: Blaum and Omura (June 11 issue)1 report that they treated a case of cutaneous larva migrans with topical liquid-nitrogen cryotherapy. Apart from cryotherapy, various other therapeutic approaches have been used for this condition, including topical administration of thiabendazole and systemic administration of albendazole, thiabendazole, and ivermectin.2-5 Since freezing is often ineffective and not devoid of side effects,3,4 we conducted a prospective study of ivermectin, administered as a single oral dose of 12 mg, to travelers who had returned from various tropical or subtropical destinations. From 1993 to 1997, we treated 67 consecutive outpatients who had one or more cutaneous larva migrans lesions. Data from 51 patients (28 men and 23 women; age range, 1 to 69 years; median age, 30 years) were available for evaluation. The lesions in 48 patients (94 percent) healed within five days (Fig. 1). Two patients were cured after 7 and 10 days. There were no side effects. Two of the patients in whom the lesions healed had relapses, but were cured within two days after a second round of treatment with the same dose of ivermectin. One other patient had an initial improvement but subsequently had repeated relapses, notwithstanding additional treatments (high-dose ivermectin and prolonged administration of albendazole). Her concurrent use of corticosteroids and azathioprine for Crohn’s disease might have had a role in the repeated relapses. Ivermectin has a good safety profile,5 and we con-

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Enden et al., suggesting an expanded indication for the drug, is welcome.

No. of Patients

30 25 20

JANE MCCLURE BLAUM, M.D. EMILY F. OMURA, M.D.

15

University of Alabama School of Medicine Birmingham, AL 35294

10 5 0

1

2

3

4

5

6

7

8

9

10

1. Drugs for parasitic infections. Med Lett Drug Ther 1998;40(1017):112.

Days until Cure Figure 1. Healing Time for 50 Patients with Cutaneous Larva Migrans Treated with a Single Dose of 12 mg of Ivermectin.

clude that it should be seriously considered as an alternative to cryotherapy for the treatment of cutaneous larva migrans. ERWIN VAN DEN ENDEN, M.D. ANN STEVENS, M.D. ALPHONS VAN GOMPEL, M.D. Institute of Tropical Medicine 2000 Antwerp, Belgium 1. Blaum JM, Omura EF. Cutaneous larva migrans. N Engl J Med 1998; 338:1733. 2. Caumes E, Carrière J, Guermonprez G, Bricaire F, Danis M, Gentilini M. Dermatoses associated with travel to tropical countries: a prospective study of the diagnosis and management of 269 patients presenting to a tropical disease unit. Clin Infect Dis 1995;20:542-8. 3. Wolf P, Ochsendorf FR, Milbradt R. Aktuelle Therapiemöglichkeiten bei Larva migrans cutanea. Hautarzt 1993;44:462-5. 4. Davies HD, Sakuls P, Keystone JS. Creeping eruption: a review of clinical presentation and management of 60 cases presenting to a tropical disease unit. Arch Dermatol 1993;129:588-91. 5. Alexander NDE, Bockarie MJ, Kastens WA, Kazura JW, Alpers MP. Absence of ivermectin-associated excess deaths. Trans R Soc Trop Med Hyg 1998;92:342.

The authors reply: To the Editor: Both albendazole and thiabendazole have long been available for the treatment of cutaneous larva migrans (although albendazole has not been approved by the Food and Drug Administration [FDA] for this indication). Both drugs must be administered in multiple doses or applications. Cryotherapy for the single lesion in our patient was both effective and expedient. Because of the potential for cryotherapy to leave a small focus of altered pigmentation, particularly in persons with darker skin, it may not be a cosmetically acceptable approach in a patient with dozens of larvae. Our patient was seen and his photograph submitted to the Journal in 1993, three years before the FDA approved ivermectin for clinical use in the United States. Ivermectin was therefore not a therapeutic option for him. Although ivermectin is currently approved by the FDA for the treatment of strongyloidiasis and onchocerciasis, it may be beneficial in the treatment of other parasitic infections, including cutaneous larva migrans, scabies, and infestation with lice.1 The information provided by Van den

Merkel-Cell Carcinomas in Patients Treated with Methoxsalen and Ultraviolet A Radiation To the Editor: Merkel-cell carcinoma is a very rare smallcell carcinoma of the skin.1 Probably derived from Merkel cells, the mechanoreceptors located in the basal layer of the epidermis, these tumors are asymptomatic, solitary, small red-purple subcutaneous nodules.2 Most are found in elderly persons at sites exposed to the sun. The twoyear survival rate is about 50 percent.3 As is the case for non-melanoma skin cancers, especially squamous-cell cancers, exposure to ultraviolet radiation and, possibly, ionizing radiation are risk factors for Merkel-cell carcinoma. Since 1975, we have prospectively studied 1380 patients with psoriasis who were treated with oral methoxsalen (psoralen) and ultraviolet A photochemotherapy at 16 university centers to assess the long-term risks and benefits of ultraviolet A radiation.4 Merkel-cell carcinomas have developed in three of these patients (0.2 percent), suggesting that ultraviolet A photochemotherapy increases the risk of these rare tumors (Table 1). All three patients were elderly and had had non-melanoma skin cancers after exposure to ultraviolet A photochemotherapy. Only one patient reported exposure to ionizing radiation for the treatment of psoriasis. Two had received more than 300 treatments with ultraviolet A radiation. In two of the three, Merkel-cell carcinoma developed more than 20 years after they had started ultraviolet A photochemotherapy. In this cohort, the incidence of Merkel-cell carcinoma is about 100 times higher than that expected in the general population.1 Although we cannot exclude other causes of these tumors in the three patients, including exposure to other potential carcinogens for the treatment of psoriasis,

WITH

PATIENT NO.

TABLE 1. CHARACTERISTICS OF THREE PATIENTS MERKEL-CELL CARCINOMA IN THE FOLLOW-UP STUDY OF ULTRAVIOLET A PHOTOCHEMOTHERAPY. AGE (YR)/ SEX

OTHER SKIN TUMORS SQUAMOUS-

OUTCOME

BASAL-

CELL

CELL

CANCER

CANCER

no. of tumors

1 2 3

69/F 80/M 80/M

1 35 0

5 25 3


Death from unrelated causes Death from metastatic disease Death from metastatic disease

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our findings argue that long-term ultraviolet A photochemotherapy at high doses increases the risk of Merkelcell carcinoma of the skin. In addition to melanoma and squamous-cell cancer, Merkel-cell carcinoma is yet another risk of ultraviolet A photochemotherapy that should be weighed against the benefits of this treatment.4,5 ELISSA J. LUNDER, M.D. ROBERT S. STERN, M.D. Beth Israel Deaconess Medical Center Boston, MA 02215 1. The SEER histology monograph: supplemental tables. Histology of cancer incidence and prognosis. SEER population based data, 1973–1987. Version 1.0. Bethesda, Md.: National Cancer Institute, June 1995. (CD-ROM.) 2. Yiengpruksawan A, Coit DG, Thaler HT, Urmacher C, Knapper WK. Merkel cell carcinoma: prognosis and management. Arch Surg 1991;126: 1514-9. 3. Kokoska ER, Kokoska MS, Collins BT, Stapleton DR, Wade TP. Early aggressive treatment for Merkel cell carcinoma improves outcome. Am J Surg 1997;174:688-93. 4. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Cancer 1994;73:2759-64. 5. Stern RS, Nichols KT, Väkevä LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997;336:1041-5.

included acute schistosomiasis. Schistosoma haematobium is now endemic in the area where Alexander died, and clinical syndromes consistent with chronic S. haematobium infection had been documented for more than a millennium before that time.1 Acute schistosomiasis is most common in natives of temperate areas where the disease is not endemic who travel to areas where it is endemic. As a traveler with a penchant for freshwater bathing and swimming, Alexander could arguably have been exposed to S. haematobium for the first time in the weeks preceding his final illness. Acute febrile syndromes in association with S. haematobium infection have been well documented, although they are more frequent with infection by other schistosomal species. Symptoms generally include fever, myalgias, diaphoresis, and fatigue and may also include anorexia and pain in the right upper quadrant. These symptoms correspond fairly closely to the clinical presentation described by Oldach et al. Egg deposition in the central nervous system has been documented, and it may result in cerebral or spinal cord disease (including transverse myelitis) with coma and distal weakness.2 Finally, acute schistosomal infection may complicate, as well as resemble, typhoid fever. AMY J. BEHRMAN, M.D. ROBERT B. WILSON, M.D., PH.D.

A Mysterious Death To the Editor: Oldach et al. (June 11 issue)1 try to identify the disease that caused the death of Alexander the Great. They conclude that the diagnosis was “Salmonella typhi enteritis, complicated by bowel perforation and ascending paralysis.” The authors fail to mention what any physician who has treated patients with typhoid fever and most old textbooks2,3 and even more recent ones4 assert — namely, that perforation of the intestine in patients with typhoid fever occurs late in the course of the disease, most often during the 3rd week or the beginning of the 4th week (between the 15th and 25th days) or even during convalescence. Necrosis of the intestine is also a pathological finding in the third week. Furthermore, perforation usually occurs near the end of the ileum, according to old autopsy reports.2 Plutarch, in his description of Alexander’s last days, specifically denies that he was taken by a sudden pain. Severe malaria, explaining the recurring chills and high fever as well as the final comatose state (cerebral malaria) mentioned by Plutarch, may still be a more accurate guess. S.D. MOULOPOULOS, M.D., SC.D. National University of Athens School of Medicine Athens 10672, Greece 1. Oldach DW, Richard RE, Borza EN, Benitez RM. A mysterious death. N Engl J Med 1998;338:1764-9. 2. Dieulafoy G. Manuel de pathologie interne. Paris: Masson, 1907. 3. Krehl L, ed. Lehrbuch der inneren Medizin. Jena, Germany: Fisher, 1921. 4. Wyngaarden JB, Smith LH Jr, eds. Cecil textbook of medicine. 16th ed. Philadelphia: W.B. Saunders, 1982.

University of Pennsylvania School of Medicine Philadelphia, PA 19104 1. Farooq M. Historical development. In: Epidemiology and control of schistosomiasis (Bilharziasis). Basel, Switzerland: Karger, 1973. 2. Scrimgeour EM, Gajdusek DC. Involvement of the central nervous system in Schistosoma mansoni and S. haematobium infection: a review. Brain 1985;108:1023-38.

To the Editor: The 32-year-old man described by Oldach et al. was suffering from repeated, self-limiting episodes of acute abdominal pain, precipitated by the consumption of large amounts of alcohol. In addition, he had mental agitation, bouts of high temperature, and rapidly progressing tetraparesis, including respiratory-muscle weakness.1 This clinical evolution suggests the diagnosis of acute porphyria (acute intermittent or variegate porphyria).2,3 Attacks of acute porphyria are triggered by the ingestion of alcohol or by certain medications, and patients typically present with acute abdominal pain, mental symptoms, and autonomic instability (including high fever), with severe polyneuropathy. This predominantly motor polyneuropathy can result in tetraplegia and may lead to respiratory failure.3 Hyponatremia, another complication of acute intermittent porphyria,4 can lead to pontine and extrapontine myelinolysis,5 especially in patients who abuse alcohol. Central pontine myelinolysis may thus have contributed to the tetraparesis, which was so severe that the patient was “unable to speak, and could make only slight movements of his eyes and hands.”1 HANS SCHNORF, M.D. Rarotonga Hospital Rarotonga, Cook Islands

To the Editor: Oldach et al. present a convincing and enjoyable discussion of the probable cause of Alexander the Great’s death. The differential diagnosis could also have

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1. Oldach DW, Richard RE, Borza EN, Benitez RM. A mysterious death. N Engl J Med 1998;338:1764-9.

Octo b er 2 2 , 19 9 8 The New England Journal of Medicine Downloaded from nejm.org on November 4, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved.

C ORR ES POND ENCE

2. Grandchamp B. Acute intermittent porphyria. Semin Liver Dis 1998; 18:17-24. 3. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 1998;18:43-52. 4. Usalan C, Erdem Y, Altun B, et al. Severe hyponatremia due to SIADH provoked by acute intermittent porphyria. Clin Nephrol 1996;45:418. 5. Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Ann Intern Med 1997;126:57-62.

The authors reply: To the Editor: Dr. Moulopoulos correctly points out that Alexander’s episode of pain in the right upper quadrant, as we reported it, is not universally agreed on. Bosworth’s masterly review1 showed how the loss of ancient primary documents led to the 2000-year-old controversy regarding Alexander’s death and how competing propaganda interests may have influenced the divergent accounts by contemporary observers. Thus, on reviewing the historical records available at the time, Plutarch,2 Diodorus,3 and Arrian4 noted accounts of severe abdominal pain; Plutarch went on to reject these accounts as fanciful, whereas Diodorus and Arrian did not. Furthermore, the time course of Alexander’s final illness is debated. The most detailed accounts in ancient sources are taken from the Royal Ephemerides, as presented by Plutarch2 and Arrian,4 and these accounts date the beginning of Alexander’s final illness to the time of his dinner with Medius. However, Aristobolus (cited by Bosworth) suggests that Alexander already had a raging fever before dining with Medius (the evening of the onset of the disputed abdominal pain). Although we agree with Dr. Moulopoulos that ileal perforation is a complication of typhoid fever that is seen in the later stages of the illness, the ambi-

guity of the historical record easily accommodates this diagnosis. However, as we discussed in our presentation, cerebral malaria is a leading alternative diagnosis, and we respect Dr. Moulopoulos’s opinion in this regard. Drs. Behrman and Wilson suggest that Alexander died of Katayama fever. Although we believe that death due to acute schistosomal infection is far less likely than death due to typhoid, their argument is plausible. Finally, Dr. Schnorf reminds us, in a creative tour de force, of the manifestations of acute intermittent porphyria, including the association of acute episodes with alcohol consumption, polyneuropathy, and possibly pontine myelinolysis. Bravo! Although we are troubled by the absence of a history of such episodes, this remains an intriguing hypothesis. Alexander’s death remains mysterious, shrouded in legend and myth, yet an enduring subject of fascination. We are delighted to have had the opportunity to share our views and to consider others. DAVID W. OLDACH, M.D. R. MICHAEL BENITEZ, M.D. University of Maryland School of Medicine Baltimore, MD 21201 1. Bosworth AB. The death of Alexander the Great: rumour and propaganda. Classical Q 1971;21:112-36. 2. Plutarch. Lives: Alexander. Cambridge, Mass.: Harvard University Press, 1994:431-3. 3. Diodorus Siculus. Historical library. Cambridge, Mass.: Harvard University Press, 1954:17.117.1. 4. Arrian (Flavius Arrianus). Anabasis of Alexander. Cambridge, Mass.: Harvard University Press, 1983:289-97. ©1998, Massachusetts Medical Society.


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