Letters and Corrections
Letters submitted for possible publication must be identified as such and submitted with a signed transfersf-copyright form (see page 1-5 for location of form). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request. Toxic Agoraphobia To the Editor: K a h n and Letz's recent editorial (1) on clinical ecology noted that the American College of Physician's position paper and studies by Brodsky, Stewart, and Terr suggest that clinical ecology methods can lead to intense fear of injury from various chemicals or foods associated with increased symptoms or to withdrawal from normal human activities. Our independent medical assessments of significant numbers of clinical ecology patients strongly support this concept. In addition to instructions for avoidance of exposure to chemicals deemed offensive, clinical ecology patients often are given ethanol injections or intravenous sodium bicarbonate to "neutralize" their reactions. Detoxification treatment may include large doses of intravenous vitamin C, physical therapy in the form of bicycle exercise, herbal wraps, massage, and baths. Large quantities of vitamin and mineral supplements, desensitization injections to be self-administered on a regular basis at home, and water and air purifiers often are recommended. The patient may be encouraged to move to a distant wilderness location to live in a form of permanent disability. During total immersion in a belief and treatment system that includes dieticians and psychologists, some patients become severely isolated. Patients and their families can become nonproductive or disabled and psychologically crippled.
Progressively severe episodes of fear of chemicals may at least partially account for the increased symptoms and withdrawal behavior noted. Panic attacks and agoraphobia have become better understood in recent years ( 2 ) . The American Psychiatric Association has clearly defined panic disorders with and without agoraphobia (300.21 and 300.01) and agoraphobia without a history of panic disorders (300.22) in its Diagnostic Criteria from DSM-III-R ( 3 ) . Many psychologically disabled ecology patients appear to have a form of agoraphobia. Although medical assessment of clinical ecology awaits credible evidence of efficacy and safety ( 1 ) , recent court decisions have begun to set formal boundaries on the admissibility of declarations by clinical ecologists. Opinions based solely on patient recollections and scientifically unsubstantiated attitudes have been ruled outside a legal definition of expert medical testimony and are, therefore, inadmissible (4, 5 ) . With the current public focus on toxic exposures, Agent Orange, Love Canal, Three Mile Island, and Chernobyl have become household words. Announcements from the Environmental Protection Agency generate concern about radon in houses, lead in water pipes, asbestos in schools, and daminozide (Alar, Uniroyal Chemical Company, Bethany, Connecticut) in apples. Concern about health risks associated with toxic hazards is appropriate. Clinical ecology methods, however, may expand appropriate concerns about chemicals to nonspecific fears, resulting in iatrogenic phobia. We call this syndrome to our colleagues' attention and propose the term "toxic agoraphobia" to describe the phenomenon. Thomas L. Kurt, MD, MPH North Texas Poison Center Parkland Memorial Hospital University of Texas Southwestern Medical Center at Dallas Dallas, T X 75235 Timothy J. Sullivan, HI, MD University of Texas Southwestern Medical Center at Dallas Dallas, T X 75235 References 1. Kahn E, Letz G. Clinical ecology: environmental medicine or unsubstantiated theory? [Editorial]. Ann Intern Med. 1989;111:104-5. 2. Sheehan DV. Panic attacks and phobias. AT Engl J Med. 1982;307:156-8. 3. American Psychiatric Association. Diagnostic Criteria from DSMIII-R. Washington, D.C.: American Psychiatric Association; 1987.
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4. Rea W, et al. v. The Aetna Life Insurance Company and the Prudential Insurance Companies of America. Civil Action No. 2-84-0219-H. U.S. Dist. Ct., N. Dist. Texas, Dallas Div. Feb. 25, 1985. 5. Schickele S, Rhodes D, et al. Re: Motion in limine regarding A Levin. Civil Action No. C-451843. Sup. Ct. Arizona, Maricopa County. Jul. 16, 1986.
Increased Blood Leukocytes in Patients with Campylobacter pylori To the Editor: Campylobacter pylori infection is strongly associated with chronic gastritis, but its systemic effects are unknown. We have studied the relation between C pylori-associated gastritis and peripheral leukocyte count. We studied 105 randomly chosen outpatients with dyspepsia (from 40 to 71 years of age) ( 1 ) . WarthinStarry stain was used to search for curved rods in eight biopsy specimens taken systematically from the antrum and corpus. The quantity of inflammatory cells was estimated in specimens from the antrum stained with haematoxylin and eosin, using a 4-point scale (0 = normal; 3 = heavy increase). Leukocyte counts were done on samples from 104 patients. Campylobacter pylori was present in 62 patients ( 5 9 % ) , and the scores for mucosal inflammatory cells were higher in these patients (mononuclear cells: median, 1.7, range, 0.5 to 2; granulocytes: median, 1.3, range, 0 to 2) than in the C pylori-negative patients (mononuclear cells: median, 0, range, 0 to 2; granulocytes: median, 0, range, 0 to 2; P < 0.001, MannWhitney U-test). The mean leukocyte count was 5.86 ± 1.5 ( + SD) in the C pylori-negative patients and 6.4 + 1.5 in the C pylori-positive patients (P = 0.03; M e s t ) . The scores for mucosal inflammatory cells showed a significant correlation with leukocyte count (mononuclear cells: correlation coefficient, 0.21; P = 0.03 [Spearman rank correlation]; granulocytes: 0.23; P = 0.02). The results suggest that inflammation in the gastric mucosa associated with C pylori may result in an increased peripheral leukocyte count and that this infection may have systemic effects. Campylobacter pylori infection is common (2) and chronic ( 3 ) . Whether an inflammation of this kind has any harmful effects in the body beyond the gastroduodenal mucosa is, therefore, important. Possible effects could include consumption of defense mechanisms, effects of possible antigen-antibody complexes, and distant effects of mediators such as cytokines. It has been suggested that chronic low-grade bacterial infections may be implicated in the pathogenesis of atherosclerosis (4, 5). No evidence of such an effect or of any other clinically significant systemic manifestation of C pylori infection is available at present. Tuomo Karttunen, MD University of Oulu Oulu, Finland Seppo Niemela, MD Oulu University Hospital Oulu, Finland
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References 1. Karttunen T, Niemela S, Lehtola J, Heikkila J, Maentausta O, Rasanen O. Campylobacter-hke organisms and gastritis: histopathology, bile reflux, and gastric fluid composition. Scand J Gastroenterol. 1987;22:478-86. 2. Jones D M , Eldridge J, Fox AJ, Sethi P , Whorwell P J . Antibody to the gastric campylobacter-like organism {"Campylobacter pyloridis")-clinical correlations and distribution in the normal population. J Med Microbiol. 1986;22:57-62. 3. Langenberg W, Rauwss EA, Houthoff H J , et al. Follow-up study of individuals with untreated Campylobacter pylori-associated gastritis and of noninfected persons with non-ulcer dyspepsia. / Infect Dis. 1988;157:1245-9. 4. Virella G, Lopes-Virella M F . Infections and atherosclerosis. Transplant Proc. 1987;19:(Suppl 5):26-35. 5. Mattila KJ, Nieminen M S , Valtonen VV, et al. Association between dental health and myocardial infarction. Br Med J [Clin Res J. 1989;298:779-81.
See the short editorial coming up in the IS February issue on the official change in genus designation for Campylobacter pylori-The Editor. High Frequency of Antibodies to the Hepatitis C Virus among Patients with Hepatocellular Carcinoma To the Editor: Although evidence implicates the hepatitis B virus in the pathogenesis of hepatocellular carcinoma ( 1 ) , other factors such as alcohol or chronic infection by non-A, non-B hepatitis agents have also been implicated, particularly in developed countries. Several documented cases of hepatocellular carcinoma following chronic non-A, non-B hepatitis have been reported in developed countries ( 2 ) . The isolation of the major bloodborne non-A, non-B hepatitis agent, hepatitis C virus ( H C V ) , by cloning (3) has led to the development of assays for the detection of specific antibodies ( 4 ) . In a previous report ( 5 ) , we showed that HCV infection is present in a significant proportion of patients with chronic liver disease, even in the absence of a history of parenteral exposure. To assess the potential role of HCV in the development of hepatocellular carcinoma, we tested three groups of patients with enzyme-linked immunosorbent assay ( E L I S A ) (Ortho Diagnostic Systems, Raritan, New Jersey), for anti-HCV. Group 1 included 81 patients (68 men and 13 women) with hepatocellular carcinoma. Their mean age was 62.9 + 10 years, and 59 ( 7 3 % ) of them had histories of alcohol abuse, 42 ( 5 2 % ) had received blood transfusions, and 38 ( 4 7 % ) had HBV markers (anti-HBc positive). Group 2 consisted of 33 patients with alcoholic cirrhosis and without evidence of hepatocellular carcinoma (negative ultrasound examination and normal alphafetoprotein level). Twenty-six were men and 7, women, with a mean age of 58.3 ± 11.8 years. Group 3 consisted of 2915 volunteer blood donors. The prevalence of anti-HCV in patients with hepatocellular carcinoma was 5 4 % (44 of 81) higher than in patients with alcoholic cirrhosis alone ( 2 4 % [8 of 33]) and higher than in blood donors ( 1 % [28 of 2915] ). These differences were significant (P < 0.02), and they persisted when only those patients with hepatocellular carcinoma and a history of alcohol abuse ( 5 1 % [30 of 59] anti-HCV positive) were compared
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with patients with alcoholic cirrhosis alone ( 2 2 % [8 of 23] anti-HCV positive) ( P = 0.02). The presence of anti-HCV in patients with hepatocellular carcinoma was independent of history of blood transfusion or presence of HBV markers. Of 41 patients with hepatocellular carcinoma, 22 ( 5 4 % ) had been transfused. Of 40 patients who had not been transfused, 22 ( 5 5 % ) were anti-HCV positive (P = not significant); twenty-five of thirty-eight ( 6 6 % ) patients with hepatocellular carcinoma who were anti-HBV positive compared with 19 of 43 ( 4 4 % ) patients with hepatocellular carcinoma and without anti-HBV were anti-HCc positive (P = not significant). Although the exact meaning of a positive antibody test for HCV is not completely understood, all data suggest that most anti-HCV-positive patients have persistent infection. Accordingly, although the oncogenic potential of HCV remains unknown, the high frequency of anti-HCV among our patients with hepatocellular carcinoma suggests that chronic infection by this agent plays a role in the development of liver cancer in our area. Such infection may induce a smoldering active cirrhosis that provides the appropriate setting in which another factor triggers malignant transformation. Comparing the frequency of antiHCV in patients with hepatocellular carcinoma with that in blood donors, we estimate the relative risk for liver cancer to be 124 times higher among seropositive subjects than in the general population. Victor Vargas, MD Luis Castells, MD Juan I. Esteban, MD Hospital Vail d'Hebron Universitat Autonoma Barcelona, Spain References 1. Lieberman H M , Shafritz D. Persistent hepatitis B virus infection and hepatocellular carcinoma. In: Popper H, Schaffner F, eds. Progress in Liver Diseases, v 8. Orlando, Florida: Grune & Stratton, Inc.; 1986:395-415. 2. Tabor E. Hepatocellular carcinoma: possible etiologies in patients without serologic evidence of hepatitis B virus infection. / Med Virol. 1989;27:1-6. 3. Choo Q L , Kuo G, Weiner AJ , Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244:359-62. 4. Kuo G, Choo QL, Alter H J , et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989;244:362-4. 5. Esteban J I , Esteban R, Viladomiu L, et al. Hepatitis C virus antibodies among risk groups in Spain. Lancet. 1989;2:294-7.
Immunosuppressive Therapy for Factor VIII Inhibitors To the Editor: Lian and colleagues (1) reported 12 patients and reviewed the literature for the use of combination immunosuppressive therapy and factor VIII administration to treat FVIII antibodies. They credited Green (2) with originating the idea that patients will respond to steroids or cytotoxic agents or both after factor VIII concentration is infused. The ratio-
nale that Green (2) promulgated is that factor VIII stimulates the antibody-producing cells, allowing more effective killing of cells by cytotoxic agents. However, the authors neglected a study in which I participated ( 3 ) , which appeared in 1970, 1 year before Green's article. We treated two patients with an amount of factor VIII calculated to achieve levels in excess of the amount of antibody to achieve antigen excess over the circulating antibody. In one case we infused azathioprine and prednisone and in the other, azathioprine alone. In both patients the antibody disappeared during immunosuppressive therapy. We then postulated that "immunologic tolerance of paralysis was induced in a previously sensitized individual," as has been shown in experimental animals ( 4 ) . This approach is potentially useful, but we feel that to optimize it antigen excess probably must be achieved, which may be difficult in high-titer antibodies. In our report we emphasized the importance of pretitering the antibody in vitro to predict the responses. We compliment Dr. Lian and colleagues for extending our observations to 12 patients. Their study clearly strengthens the validity of this approach. Robert W. Colman, MD Temple University School of Medicine Philadelphia, P A 19140 References 1. Lian EC, Larcada AF, Chiu AY. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med. 1989;110:774-8. 2. Green D. Suppression of an antibody to factor VIII by a combination of factor VIII and cyclophosphamide. Blood. 1971;37:381-7. 3. Robboy S J , Lewis E J , Schur P H , Colman RW. Circulating anticoagulants to factor VIII: immunochemical studies and clinical response to factor VIII concentrates. Am J Med. 1970;49:742-52. 4. Dvorak H F , Flax M H . Immunologic unresponsiveness in the adult guinea pig. II. The kinetics of unresponsiveness. / Immunol. 1966;96:546.
Nimesulide, Thrombocytopenic Purpura, and Human Immunodeficiency Virus (HIV) Infection To the Editor: A 29-year-old man has been followed since 1987 at the Infectious Diseases Institute for a HIV infection contracted by intravenous drug abuse. His hematology values were always within the normal range, with the exception of a slight decrease of C D 4 lymphocytes (0.478 X 1 0 V L ) . His follow-up was uneventful until April 1989 when the patient developed purpuric lesions on the legs after 2 days of nimesulide therapy. When the drug was withdrawn, the lesions subsided completely. Two months later the patient was hospitalized at the Infectious Diseases Institute because of thrombocytopenic purpura. At admission, he had purpuric lesions on the lower third of the legs. The platelet count was 12 X 10VL; other hematology values, morphology, and chemistry, including liver function tests, were within the normal range. A bone marrow biopsy showed an increased number of megakaryocytes. An ultrasound abdominal scan showed a slight increase in the size of liver and spleen without portal hypertension. The patient had received nimesu-
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lide, 100 mg twice a day, for a periodontal abscess for 3 days before the admission. The drug was immediately withdrawn; the purpura resolved and the platelet count increased to normal values (285 X \09/L) within 5 days. Thrombocytopenia is a common feature in HIV-infected patients (1) but the acute, rapidly resolving purpura in our patient suggests a drug-related phenomenon. Antiplatelet antibodies could not be detected either in serum using a suspension immunofluorescence test (2) or in plasma in the presence of the drug using platelet aggregometry ( 3 ) . Our patient met three of the four diagnostic criteria (4) for drug-induced platelet destruction: a clinical history compatible with a drug effect, the exclusion of other causes, and a positive in-vivo rechallenge, the latter inadvertently done by the patient. The lack of positivity to an in-vitro test is not unusual; in addition, we cannot exclude that the mechanism of nimesulide-induced thrombocytopenia is not simply immunologic ( 4 ) . Nimesulide is a nonsteroidal anti-inflammatory agent with antipyretic, analgesic, and antiplatelet activity. The drug is usually well tolerated; pyrosis, nausea, and gastralgia have been observed. Like other nonsteroidal anti-inflammatory agents, nimesulide has been associated with vertigo, somnolence, peptic ulcer and gastrointestinal bleeding (5) but, to our knowledge, this case represents the first report of nimesulide-related thrombocytopenia. M.B. Pasticci, MD F. Menichetti, MD F. Di Candilo, MD Universita di Perugia Perugia, Italy References 1. Morris L, Distenfeld A, Amorosi E, Karpatkin S. Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med. 1982;96:714-8. 2. Von dem Borne AE, Helmerhorst FM, Van Leeuwen EF, Pegels HG, Von Riesz E, Engelfriet CP. Autoimmune thrombocytopenia: detection of platelet autoantibodies with the suspension immunofluorescence test. Br I Haematol. 1980;45:319-27. 3. Deykin D, Hellerstein LJ. The assessment of drug-dependent and isoimmune antiplatelet antibodies by the use of platelet aggregometry. J Clin Invest. 1972;51:3142-53. 4. Hackett T, Kelton JG, Powers P. Drug-induced platelet destruction. Semin Thromb Hemostas. 1982;8:116-37. 5. Biscarini L, Patoia L, Del Favero A. Nimesulide. Drugs of Today. 1988;24:23-7.
Acute Co-infection with Human Immunodeficiency Virus (HIV) and Cytomegalovirus To the Editor: Bonetti and colleagues (1) recently presented two cases of simultaneous human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus seroconversion in intravenous drug users. We wish to report such a co-infection after a single sexual contact. A 30-year-old woman requested termination of a 6week pregnancy. At that time, she was totally asymptomatic; cytomegalovirus and HIV-1 antibodies were absent and HIV-1 p24 antigen was negative. Seven days later, she had sexual intercourse with a bisexual, HIV-1-seropositive man. Eight days later, she devel-
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oped fatigue, fever, chills, myalgia, headache, nausea, cough, and pharyngitis. The leukocyte count was 8.4 X 10VL with 6 3 % lymphocytes. She was first seen 1 month later, with persistent fever (38.2° C ) and asthenia; the spleen and liver were enlarged. The leukocyte count was 11.1 X 10 9 /L with 2 6 % neutrophils, 5 2 % lymphocytes, and 9 % large hyperbasophilic cells. Serum transaminase levels were 5 times the upper normal value. Symptoms then spontaneously resolved, with the duration of fever 41 days. Serologic testing showed a negative heterophile agglutinin test, previous hepatitis A and B infection, and HIV-1 and cytomegalovirus seroconversion: anticytomegalovirus IgG titers were 1:600 by enzyme-linked immunosorbent assay ( E L I S A ) at week 5 and 1:2500 at week 7, anticytomegalovirus IgM being positive; HIV-1 antibodies were absent by ELISA at week 3 after contamination but were present (by both ELISA and Western blot) on subsequent samples, with core antibodies appearing first at week 5 and envelope antibodies at week 7. The test for HIV-1 p24 antigen was negative on all sera tested. The follow-up at 2 years showed that the patient had remained asymptomatic; however, the C D 4 + lymphocyte count dropped at month 18 (0.365 X 10VL) and even more at month 24 (0.14 X 10VL) with appearance of positive HIV-1 p24 antigen in the serum. This case, like that reported by Bonetti and colleagues ( 1 ) , was characterized by a mononucleosislike illness with prolonged fever and marked symptoms. It demonstrates that simultaneous HIV-1 and cytomegalovirus primoinfection can occur after only one high-risk sexual contact. Damaged endometrial mucosa secondary to recent abortion might have facilitated simultaneous transmission of both viruses. The short incubation period of 1 week might have been due to virus inoculum, route of introduction, or acceleration of HIV-1 expression by cytomegalovirus ( 2 ) . Occurrence of cytomegalovirus-mononucleosis has been shown to have unfavorable prognostic significance in the course of HIV-1 infection ( 3 ) . Reappearance of HIV-1 p24 antigen and the decline of C D 4 + lymphocytes 18 months after HIV-1 transmission in our patient might also indicate a particularly rapid course of patients with simultaneous primary infection with HIV-1 and cytomegalovirus toward symptomatic forms of HIV infection. Francois Raffi, MD Daniel Boudart, PhD Sylviane Billaudel, PhD Hotel-Dieu F 44035 Nantes Cedex, France References 1. Bonetti A, Weber R, Vogt MW, Wundeli W, Siegenthaler W, Liithy R. Co-infection with human immunodeficiency virus-type 1 (HIV-1) and cytomegalovirus in two intravenous drug users. Ann Intern Med. 1989;111:293-6. 2. Skolnik PR, Kosloff BR, Hirsch MS. Bidirectional interactions between human immunodeficiency virus type 1 and cytomegalovirus. I Infect Dis. 1988;157:508-14.
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3. Leport C, Harzic M, Pignon JM, et al. Benign cytomegalovirus mononucleosis in non-AIDS, HIV infected patients [Letter]. Lancet. 1987;2:214.
Measles and Immune Globulin Prophylaxis for Travelers and Hepatitis A To the Editor: I fully agree with Drs. Hill and Pearson (1) that revaccination with measles vaccine is advisable for all travelers born in or after 1957 and is particularly important for travelers to areas of high endemicity for measles. These areas occur particularly in the developing world where hepatitis A transmitted via fecal contamination is also a high risk to nonimmune travelers. Hepatitis A can be protected against very well with an injection of immune globulin, which is usually given just before departure because of its relatively short half-life. According to the Centers for Disease Control recommendations for foreign travelers, live attenuated vaccine viruses might not successfully replicate and antibody response could be diminished when the vaccine is given with immune globulin preparations. In general, parenterally administered live vaccines (such as measles, mumps, and rubella) should not be given for at least 6 weeks and preferably 3 months, after immune globulin administration. Because of imminent exposure to hepatitis A, administration of immune globulin may be necessary after a live vaccine has been given, and interference may occur. Vaccine virus replication and stimulation of immunity under normal conditions will occur within 7 to 10 days. If the interval between vaccine and immune globulin is less than 14 days, the vaccine should be readministered at least 3 months after the immune globulin was given, unless serologic testing for measles indicates that antibodies have been produced; if the interval was longer, vaccine need not be readministered. If administration of immune globulin becomes necessary because of imminent exposure to disease, live virus vaccine may be administered simultaneously, with the recognition that vaccine-induced immunity may be compromised. The vaccine should be administered in a site remote from that chosen for the immune globulin inoculation. The vaccination should be repeated about 3 months later unless serologic testing indicates measles antibodies have been produced ( 2 ) . An estimated 4 0 % of Americans have been infected with and are immune to hepatitis A ( 3 ) . The prevalence of hepatitis A virus antibody in the U.S. population equals approximately 10% per decade of life up to age 50. Thus, many of the same adults who should be revaccinated for measles are already immune to hepatitis A, and do not require immune globulin with its attendant risk of possibly masking measles antibody production. Because many adults traveling to the developing world often do not begin their immunizations long enough in advance to space measles and immune globulin inoculations properly, it would be worthwhile to screen for hepatitis A antibodies before giving these inoculations in this group of travelers. The cost for this screening should be approximately $25 to $50, but
the potential savings from not requiring immune globulin, measles serology, or another measles vaccination in 3 months could balance out this cost. Martin S. Wolfe, MD Traveler's Medical Service Washington, D.C. 20037 References 1. Hill DR, Pearson RD. Measles prophylaxis for international travel. Ann Intern Med. 1989;111:699-701. 2. Health Information for International Travel. Atlanta: Centers for Disease Control; 1989:71, 105. 3. Szumness W, Dienstag JL, Purcell RH, et al. Distribution of antibody to hepatitis A antigen in urban adult populations. N Engl J Med. 1976;295:755-9.
Single-Dose Phenytoin Infusion To the Editor: As a neurologist who treats patients with status epilepticus, I disagree strongly with the suggestion by Blaser and colleagues (1) that their loading regimen for intravenous phenytoin, even when combined with intravenous diazepam, should be used to treat those with this condition. Status epilepticus can cause brain damage (2) and permanent memory impairment (3) in humans. Irreversible brain damage has been documented after a seizure period as short as 90 minutes in the baboon ( 4 ) . In some instances seizures will continue even after phenytoin and diazepam have been given, and other anticonvulsants or even general anesthesia may be necessary. For these reasons, phenytoin should be given as rapidly as possible, consistent with patient safety. With the widely accepted dosage of 18 m g / k g body weight intravenously, at a rate not exceeding 50 jxg/ min, serum phenytoin levels of 80 to 120 jmmol/L (20 to 30 jLig/mL) are reached in 30 minutes ( 5 ) . The three-dose regimen recommended by Blaser and colleagues (5 m g / k g intravenously every 2 hours) takes much too long (6 hours) to reach a serum concentration of phenytoin (40 to 80 jxmol/L [10 to 20 u.g/ m L ] ) that has been recommended for chronic maintenance therapy, but that may not be adequate for status epilepticus. The accepted single-dose loading regimen for intravenous phenytoin should not be abandoned in this situation. Denson G. Fujikawa, MD Veterans Affairs Medical Center Sepulveda, CA 91343 U C L A School of Medicine Los Angeles, C A 90024 References 1. Blaser KU, Vozeh S, Landolt H, Kaufmann G, Romppainen J, Gratzl O. Intravenous phenytoin: a loading scheme for desired concentrations. Ann Intern Med. 1989;110:1029-31. 2. Softer D, Melamed E, Assaf Y, Cotev S. Hemispheric brain damage in unilateral status epilepticus. Ann Neurol. 1986;20:737-40. 3. Treiman DM, Delgado-Escueta AV. Complex partial status epilepticus. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Advances in Neurology, v 34. New York: Raven Press; 1983:69-81. 4. Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates:
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ischemic cell change and its relation to ictal physiological events. Arch Neurol. 1973;28:10-7. 5. Crawford RE, Leppik IE, Patrick B, Anderson CB, Kostick B. Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology. 1978;28:874-80.
Oxygen, Food, and Air Travel To the Editor: I enjoyed reading Dr. Hansen's clever letter (1) regarding the article by Dillard and colleagues (2) on the oxygen requirements of patients with lung disease who must travel by airplane. I am a bit concerned, however, about his unqualified recommendation that patients with borderline hypoxemia should drink or eat a carbohydrate-rich diet before and during flights. Dr. Hansen is essentially correct in stating that in a patient with a partial pressure of arterial carbon dioxide (Pacc>2) of 40 mm Hg, increasing the respiratory quotient ( R q ) value from 0.75 to 0.95 would result in an increase in the partial pressure of arterial oxygen (Pac>2) of about 11 m m Hg. However, it is crucial to realize that such an increase will occur only if the PaC02 is kept constant. Usually, in response to a higher rate of CO2 production, (higher Rq value), a normal person will proportionally increase his or her minute ventilation to maintain a stable Pacc>2 level. Under these circumstances the higher Rq value does translate into a higher Pa02- However, a theoretical concern is that for a patient with chronic lung disease and limited ventilatory reserve, increasing the minute ventilation as demanded by the higher Rq may not always be feasible. Thus, an increase in CO2 production could result in a higher PaC02, and under these circumstances, the resulting Pac>2 would not be significantly higher, and may in fact be lower, than the baseline Pao 2 . Using Dr. Hansen's own example, if the Pacc>2 of his imaginary patient had risen from 40 to 47 mm Hg, the P a o 2 corresponding to the Rq of 0.95 would have been only around 58 m m Hg. If the Pacc>2 had risen to 55 mm Hg, the final Pac>2 would have been about 50 mm Hg. Furthermore, even if the Pacc>2 does not rise, the increase in minute ventilation required to prevent such a rise would have to be achieved in the setting of lung- disease and decreased "ventilatory efficiency," and thus the additional work-of-breathing may be perceived by some patients as increased dyspnea or difficulty in breathing. Although not necessarily serious or life-threatening, a feeling of increased dyspnea would certainly spoil anyone's trip. Although it is fairly well established that increased CO2 production resulting from carbohydrate-rich continuous parenteral feeding can precipitate respiratory
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failure in patients with severe ventilatory limitation or pre-existent respiratory failure ( 3 ) , it is not clear whether this concern should also apply to stable ambulatory patients or to oral feedings. Some authors have failed to show any deleterious effect ( 4 ) , whereas others have claimed improvement from restricting carbohydrate intake in these patients ( 5 ) . Thus, until more definite data become available, I believe that some caution is justified in recommending the intentional ingestion of an unusually large amount of carbohydrates, particularly for patients whose daily diet does not normally include such a fare. Rolando Berger, MD University of Kentucky Medical Center Lexington, K Y 40536 References 1. Hansen JE. Diet and flight hypoxemia. Ann Intern Med. 1989;111:859-60. 2. Dillard TA, Berg BW, Rajagopal KR, Dooley JW, Mehm WJ. Hypoxemia during air travel in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1989;111:362-7. 3. Covelli HD, Black JW, Olasen MW, Beekman JF. Respiratory failure precipitated by high carbohydrate loads. Ann Intern Med. 1981;95:579-85. 4. Gieske T, Gurnshanthaigh G, Glauser FL. Effects of carbohydrates on carbon dioxide excretion in patients with airway disease. Chest. 1977;71:55-8. 5. Kwan R, Afzal M. Beneficial effects of dietary carbohydrate restriction in chronic cor pulmonale. Am J Med. 1987;82:751-8.
Correction: Table 2 in National Study of Internal Medicine Manpower: XV To the Editor: There is an error in Table 2 of National Study of Internal Medicine Manpower: XV. A decade of change in Residency Training in Internal Medicine ( 1 ) . In Table 2, the data in the first column (headed "Total, n " ) should be under the heading " M D . " The data in the second column (headed " M D " ) should be under the heading " D O . " The data in the third column (headed " D O " ) should be under the heading "Total, n." Christian M. Schmidt National Study of Internal Medicine Manpower The University of Chicago Chicago, IL 60637 Reference 1. Andersen RM, Lyttle C, Kohrman C, Levey G, Glen C. National Study of Internal Medicine Manpower: XV. A decade of change in residency training in internal medicine. Ann Intern Med. 1989;110:922-9.
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Letters submitted for possible publication must be identified as such and submitted with a signed transfersf-copyright form (see page 1-5 for location of form). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request. Toxic Agoraphobia To the Editor: K a h n and Letz's recent editorial (1) on clinical ecology noted that the American College of Physician's position paper and studies by Brodsky, Stewart, and Terr suggest that clinical ecology methods can lead to intense fear of injury from various chemicals or foods associated with increased symptoms or to withdrawal from normal human activities. Our independent medical assessments of significant numbers of clinical ecology patients strongly support this concept. In addition to instructions for avoidance of exposure to chemicals deemed offensive, clinical ecology patients often are given ethanol injections or intravenous sodium bicarbonate to "neutralize" their reactions. Detoxification treatment may include large doses of intravenous vitamin C, physical therapy in the form of bicycle exercise, herbal wraps, massage, and baths. Large quantities of vitamin and mineral supplements, desensitization injections to be self-administered on a regular basis at home, and water and air purifiers often are recommended. The patient may be encouraged to move to a distant wilderness location to live in a form of permanent disability. During total immersion in a belief and treatment system that includes dieticians and psychologists, some patients become severely isolated. Patients and their families can become nonproductive or disabled and psychologically crippled.
Progressively severe episodes of fear of chemicals may at least partially account for the increased symptoms and withdrawal behavior noted. Panic attacks and agoraphobia have become better understood in recent years ( 2 ) . The American Psychiatric Association has clearly defined panic disorders with and without agoraphobia (300.21 and 300.01) and agoraphobia without a history of panic disorders (300.22) in its Diagnostic Criteria from DSM-III-R ( 3 ) . Many psychologically disabled ecology patients appear to have a form of agoraphobia. Although medical assessment of clinical ecology awaits credible evidence of efficacy and safety ( 1 ) , recent court decisions have begun to set formal boundaries on the admissibility of declarations by clinical ecologists. Opinions based solely on patient recollections and scientifically unsubstantiated attitudes have been ruled outside a legal definition of expert medical testimony and are, therefore, inadmissible (4, 5 ) . With the current public focus on toxic exposures, Agent Orange, Love Canal, Three Mile Island, and Chernobyl have become household words. Announcements from the Environmental Protection Agency generate concern about radon in houses, lead in water pipes, asbestos in schools, and daminozide (Alar, Uniroyal Chemical Company, Bethany, Connecticut) in apples. Concern about health risks associated with toxic hazards is appropriate. Clinical ecology methods, however, may expand appropriate concerns about chemicals to nonspecific fears, resulting in iatrogenic phobia. We call this syndrome to our colleagues' attention and propose the term "toxic agoraphobia" to describe the phenomenon. Thomas L. Kurt, MD, MPH North Texas Poison Center Parkland Memorial Hospital University of Texas Southwestern Medical Center at Dallas Dallas, T X 75235 Timothy J. Sullivan, HI, MD University of Texas Southwestern Medical Center at Dallas Dallas, T X 75235 References 1. Kahn E, Letz G. Clinical ecology: environmental medicine or unsubstantiated theory? [Editorial]. Ann Intern Med. 1989;111:104-5. 2. Sheehan DV. Panic attacks and phobias. AT Engl J Med. 1982;307:156-8. 3. American Psychiatric Association. Diagnostic Criteria from DSMIII-R. Washington, D.C.: American Psychiatric Association; 1987.
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4. Rea W, et al. v. The Aetna Life Insurance Company and the Prudential Insurance Companies of America. Civil Action No. 2-84-0219-H. U.S. Dist. Ct., N. Dist. Texas, Dallas Div. Feb. 25, 1985. 5. Schickele S, Rhodes D, et al. Re: Motion in limine regarding A Levin. Civil Action No. C-451843. Sup. Ct. Arizona, Maricopa County. Jul. 16, 1986.
Increased Blood Leukocytes in Patients with Campylobacter pylori To the Editor: Campylobacter pylori infection is strongly associated with chronic gastritis, but its systemic effects are unknown. We have studied the relation between C pylori-associated gastritis and peripheral leukocyte count. We studied 105 randomly chosen outpatients with dyspepsia (from 40 to 71 years of age) ( 1 ) . WarthinStarry stain was used to search for curved rods in eight biopsy specimens taken systematically from the antrum and corpus. The quantity of inflammatory cells was estimated in specimens from the antrum stained with haematoxylin and eosin, using a 4-point scale (0 = normal; 3 = heavy increase). Leukocyte counts were done on samples from 104 patients. Campylobacter pylori was present in 62 patients ( 5 9 % ) , and the scores for mucosal inflammatory cells were higher in these patients (mononuclear cells: median, 1.7, range, 0.5 to 2; granulocytes: median, 1.3, range, 0 to 2) than in the C pylori-negative patients (mononuclear cells: median, 0, range, 0 to 2; granulocytes: median, 0, range, 0 to 2; P < 0.001, MannWhitney U-test). The mean leukocyte count was 5.86 ± 1.5 ( + SD) in the C pylori-negative patients and 6.4 + 1.5 in the C pylori-positive patients (P = 0.03; M e s t ) . The scores for mucosal inflammatory cells showed a significant correlation with leukocyte count (mononuclear cells: correlation coefficient, 0.21; P = 0.03 [Spearman rank correlation]; granulocytes: 0.23; P = 0.02). The results suggest that inflammation in the gastric mucosa associated with C pylori may result in an increased peripheral leukocyte count and that this infection may have systemic effects. Campylobacter pylori infection is common (2) and chronic ( 3 ) . Whether an inflammation of this kind has any harmful effects in the body beyond the gastroduodenal mucosa is, therefore, important. Possible effects could include consumption of defense mechanisms, effects of possible antigen-antibody complexes, and distant effects of mediators such as cytokines. It has been suggested that chronic low-grade bacterial infections may be implicated in the pathogenesis of atherosclerosis (4, 5). No evidence of such an effect or of any other clinically significant systemic manifestation of C pylori infection is available at present. Tuomo Karttunen, MD University of Oulu Oulu, Finland Seppo Niemela, MD Oulu University Hospital Oulu, Finland
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References 1. Karttunen T, Niemela S, Lehtola J, Heikkila J, Maentausta O, Rasanen O. Campylobacter-hke organisms and gastritis: histopathology, bile reflux, and gastric fluid composition. Scand J Gastroenterol. 1987;22:478-86. 2. Jones D M , Eldridge J, Fox AJ, Sethi P , Whorwell P J . Antibody to the gastric campylobacter-like organism {"Campylobacter pyloridis")-clinical correlations and distribution in the normal population. J Med Microbiol. 1986;22:57-62. 3. Langenberg W, Rauwss EA, Houthoff H J , et al. Follow-up study of individuals with untreated Campylobacter pylori-associated gastritis and of noninfected persons with non-ulcer dyspepsia. / Infect Dis. 1988;157:1245-9. 4. Virella G, Lopes-Virella M F . Infections and atherosclerosis. Transplant Proc. 1987;19:(Suppl 5):26-35. 5. Mattila KJ, Nieminen M S , Valtonen VV, et al. Association between dental health and myocardial infarction. Br Med J [Clin Res J. 1989;298:779-81.
See the short editorial coming up in the IS February issue on the official change in genus designation for Campylobacter pylori-The Editor. High Frequency of Antibodies to the Hepatitis C Virus among Patients with Hepatocellular Carcinoma To the Editor: Although evidence implicates the hepatitis B virus in the pathogenesis of hepatocellular carcinoma ( 1 ) , other factors such as alcohol or chronic infection by non-A, non-B hepatitis agents have also been implicated, particularly in developed countries. Several documented cases of hepatocellular carcinoma following chronic non-A, non-B hepatitis have been reported in developed countries ( 2 ) . The isolation of the major bloodborne non-A, non-B hepatitis agent, hepatitis C virus ( H C V ) , by cloning (3) has led to the development of assays for the detection of specific antibodies ( 4 ) . In a previous report ( 5 ) , we showed that HCV infection is present in a significant proportion of patients with chronic liver disease, even in the absence of a history of parenteral exposure. To assess the potential role of HCV in the development of hepatocellular carcinoma, we tested three groups of patients with enzyme-linked immunosorbent assay ( E L I S A ) (Ortho Diagnostic Systems, Raritan, New Jersey), for anti-HCV. Group 1 included 81 patients (68 men and 13 women) with hepatocellular carcinoma. Their mean age was 62.9 + 10 years, and 59 ( 7 3 % ) of them had histories of alcohol abuse, 42 ( 5 2 % ) had received blood transfusions, and 38 ( 4 7 % ) had HBV markers (anti-HBc positive). Group 2 consisted of 33 patients with alcoholic cirrhosis and without evidence of hepatocellular carcinoma (negative ultrasound examination and normal alphafetoprotein level). Twenty-six were men and 7, women, with a mean age of 58.3 ± 11.8 years. Group 3 consisted of 2915 volunteer blood donors. The prevalence of anti-HCV in patients with hepatocellular carcinoma was 5 4 % (44 of 81) higher than in patients with alcoholic cirrhosis alone ( 2 4 % [8 of 33]) and higher than in blood donors ( 1 % [28 of 2915] ). These differences were significant (P < 0.02), and they persisted when only those patients with hepatocellular carcinoma and a history of alcohol abuse ( 5 1 % [30 of 59] anti-HCV positive) were compared
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with patients with alcoholic cirrhosis alone ( 2 2 % [8 of 23] anti-HCV positive) ( P = 0.02). The presence of anti-HCV in patients with hepatocellular carcinoma was independent of history of blood transfusion or presence of HBV markers. Of 41 patients with hepatocellular carcinoma, 22 ( 5 4 % ) had been transfused. Of 40 patients who had not been transfused, 22 ( 5 5 % ) were anti-HCV positive (P = not significant); twenty-five of thirty-eight ( 6 6 % ) patients with hepatocellular carcinoma who were anti-HBV positive compared with 19 of 43 ( 4 4 % ) patients with hepatocellular carcinoma and without anti-HBV were anti-HCc positive (P = not significant). Although the exact meaning of a positive antibody test for HCV is not completely understood, all data suggest that most anti-HCV-positive patients have persistent infection. Accordingly, although the oncogenic potential of HCV remains unknown, the high frequency of anti-HCV among our patients with hepatocellular carcinoma suggests that chronic infection by this agent plays a role in the development of liver cancer in our area. Such infection may induce a smoldering active cirrhosis that provides the appropriate setting in which another factor triggers malignant transformation. Comparing the frequency of antiHCV in patients with hepatocellular carcinoma with that in blood donors, we estimate the relative risk for liver cancer to be 124 times higher among seropositive subjects than in the general population. Victor Vargas, MD Luis Castells, MD Juan I. Esteban, MD Hospital Vail d'Hebron Universitat Autonoma Barcelona, Spain References 1. Lieberman H M , Shafritz D. Persistent hepatitis B virus infection and hepatocellular carcinoma. In: Popper H, Schaffner F, eds. Progress in Liver Diseases, v 8. Orlando, Florida: Grune & Stratton, Inc.; 1986:395-415. 2. Tabor E. Hepatocellular carcinoma: possible etiologies in patients without serologic evidence of hepatitis B virus infection. / Med Virol. 1989;27:1-6. 3. Choo Q L , Kuo G, Weiner AJ , Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244:359-62. 4. Kuo G, Choo QL, Alter H J , et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989;244:362-4. 5. Esteban J I , Esteban R, Viladomiu L, et al. Hepatitis C virus antibodies among risk groups in Spain. Lancet. 1989;2:294-7.
Immunosuppressive Therapy for Factor VIII Inhibitors To the Editor: Lian and colleagues (1) reported 12 patients and reviewed the literature for the use of combination immunosuppressive therapy and factor VIII administration to treat FVIII antibodies. They credited Green (2) with originating the idea that patients will respond to steroids or cytotoxic agents or both after factor VIII concentration is infused. The ratio-
nale that Green (2) promulgated is that factor VIII stimulates the antibody-producing cells, allowing more effective killing of cells by cytotoxic agents. However, the authors neglected a study in which I participated ( 3 ) , which appeared in 1970, 1 year before Green's article. We treated two patients with an amount of factor VIII calculated to achieve levels in excess of the amount of antibody to achieve antigen excess over the circulating antibody. In one case we infused azathioprine and prednisone and in the other, azathioprine alone. In both patients the antibody disappeared during immunosuppressive therapy. We then postulated that "immunologic tolerance of paralysis was induced in a previously sensitized individual," as has been shown in experimental animals ( 4 ) . This approach is potentially useful, but we feel that to optimize it antigen excess probably must be achieved, which may be difficult in high-titer antibodies. In our report we emphasized the importance of pretitering the antibody in vitro to predict the responses. We compliment Dr. Lian and colleagues for extending our observations to 12 patients. Their study clearly strengthens the validity of this approach. Robert W. Colman, MD Temple University School of Medicine Philadelphia, P A 19140 References 1. Lian EC, Larcada AF, Chiu AY. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med. 1989;110:774-8. 2. Green D. Suppression of an antibody to factor VIII by a combination of factor VIII and cyclophosphamide. Blood. 1971;37:381-7. 3. Robboy S J , Lewis E J , Schur P H , Colman RW. Circulating anticoagulants to factor VIII: immunochemical studies and clinical response to factor VIII concentrates. Am J Med. 1970;49:742-52. 4. Dvorak H F , Flax M H . Immunologic unresponsiveness in the adult guinea pig. II. The kinetics of unresponsiveness. / Immunol. 1966;96:546.
Nimesulide, Thrombocytopenic Purpura, and Human Immunodeficiency Virus (HIV) Infection To the Editor: A 29-year-old man has been followed since 1987 at the Infectious Diseases Institute for a HIV infection contracted by intravenous drug abuse. His hematology values were always within the normal range, with the exception of a slight decrease of C D 4 lymphocytes (0.478 X 1 0 V L ) . His follow-up was uneventful until April 1989 when the patient developed purpuric lesions on the legs after 2 days of nimesulide therapy. When the drug was withdrawn, the lesions subsided completely. Two months later the patient was hospitalized at the Infectious Diseases Institute because of thrombocytopenic purpura. At admission, he had purpuric lesions on the lower third of the legs. The platelet count was 12 X 10VL; other hematology values, morphology, and chemistry, including liver function tests, were within the normal range. A bone marrow biopsy showed an increased number of megakaryocytes. An ultrasound abdominal scan showed a slight increase in the size of liver and spleen without portal hypertension. The patient had received nimesu-
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lide, 100 mg twice a day, for a periodontal abscess for 3 days before the admission. The drug was immediately withdrawn; the purpura resolved and the platelet count increased to normal values (285 X \09/L) within 5 days. Thrombocytopenia is a common feature in HIV-infected patients (1) but the acute, rapidly resolving purpura in our patient suggests a drug-related phenomenon. Antiplatelet antibodies could not be detected either in serum using a suspension immunofluorescence test (2) or in plasma in the presence of the drug using platelet aggregometry ( 3 ) . Our patient met three of the four diagnostic criteria (4) for drug-induced platelet destruction: a clinical history compatible with a drug effect, the exclusion of other causes, and a positive in-vivo rechallenge, the latter inadvertently done by the patient. The lack of positivity to an in-vitro test is not unusual; in addition, we cannot exclude that the mechanism of nimesulide-induced thrombocytopenia is not simply immunologic ( 4 ) . Nimesulide is a nonsteroidal anti-inflammatory agent with antipyretic, analgesic, and antiplatelet activity. The drug is usually well tolerated; pyrosis, nausea, and gastralgia have been observed. Like other nonsteroidal anti-inflammatory agents, nimesulide has been associated with vertigo, somnolence, peptic ulcer and gastrointestinal bleeding (5) but, to our knowledge, this case represents the first report of nimesulide-related thrombocytopenia. M.B. Pasticci, MD F. Menichetti, MD F. Di Candilo, MD Universita di Perugia Perugia, Italy References 1. Morris L, Distenfeld A, Amorosi E, Karpatkin S. Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med. 1982;96:714-8. 2. Von dem Borne AE, Helmerhorst FM, Van Leeuwen EF, Pegels HG, Von Riesz E, Engelfriet CP. Autoimmune thrombocytopenia: detection of platelet autoantibodies with the suspension immunofluorescence test. Br I Haematol. 1980;45:319-27. 3. Deykin D, Hellerstein LJ. The assessment of drug-dependent and isoimmune antiplatelet antibodies by the use of platelet aggregometry. J Clin Invest. 1972;51:3142-53. 4. Hackett T, Kelton JG, Powers P. Drug-induced platelet destruction. Semin Thromb Hemostas. 1982;8:116-37. 5. Biscarini L, Patoia L, Del Favero A. Nimesulide. Drugs of Today. 1988;24:23-7.
Acute Co-infection with Human Immunodeficiency Virus (HIV) and Cytomegalovirus To the Editor: Bonetti and colleagues (1) recently presented two cases of simultaneous human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus seroconversion in intravenous drug users. We wish to report such a co-infection after a single sexual contact. A 30-year-old woman requested termination of a 6week pregnancy. At that time, she was totally asymptomatic; cytomegalovirus and HIV-1 antibodies were absent and HIV-1 p24 antigen was negative. Seven days later, she had sexual intercourse with a bisexual, HIV-1-seropositive man. Eight days later, she devel-
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oped fatigue, fever, chills, myalgia, headache, nausea, cough, and pharyngitis. The leukocyte count was 8.4 X 10VL with 6 3 % lymphocytes. She was first seen 1 month later, with persistent fever (38.2° C ) and asthenia; the spleen and liver were enlarged. The leukocyte count was 11.1 X 10 9 /L with 2 6 % neutrophils, 5 2 % lymphocytes, and 9 % large hyperbasophilic cells. Serum transaminase levels were 5 times the upper normal value. Symptoms then spontaneously resolved, with the duration of fever 41 days. Serologic testing showed a negative heterophile agglutinin test, previous hepatitis A and B infection, and HIV-1 and cytomegalovirus seroconversion: anticytomegalovirus IgG titers were 1:600 by enzyme-linked immunosorbent assay ( E L I S A ) at week 5 and 1:2500 at week 7, anticytomegalovirus IgM being positive; HIV-1 antibodies were absent by ELISA at week 3 after contamination but were present (by both ELISA and Western blot) on subsequent samples, with core antibodies appearing first at week 5 and envelope antibodies at week 7. The test for HIV-1 p24 antigen was negative on all sera tested. The follow-up at 2 years showed that the patient had remained asymptomatic; however, the C D 4 + lymphocyte count dropped at month 18 (0.365 X 10VL) and even more at month 24 (0.14 X 10VL) with appearance of positive HIV-1 p24 antigen in the serum. This case, like that reported by Bonetti and colleagues ( 1 ) , was characterized by a mononucleosislike illness with prolonged fever and marked symptoms. It demonstrates that simultaneous HIV-1 and cytomegalovirus primoinfection can occur after only one high-risk sexual contact. Damaged endometrial mucosa secondary to recent abortion might have facilitated simultaneous transmission of both viruses. The short incubation period of 1 week might have been due to virus inoculum, route of introduction, or acceleration of HIV-1 expression by cytomegalovirus ( 2 ) . Occurrence of cytomegalovirus-mononucleosis has been shown to have unfavorable prognostic significance in the course of HIV-1 infection ( 3 ) . Reappearance of HIV-1 p24 antigen and the decline of C D 4 + lymphocytes 18 months after HIV-1 transmission in our patient might also indicate a particularly rapid course of patients with simultaneous primary infection with HIV-1 and cytomegalovirus toward symptomatic forms of HIV infection. Francois Raffi, MD Daniel Boudart, PhD Sylviane Billaudel, PhD Hotel-Dieu F 44035 Nantes Cedex, France References 1. Bonetti A, Weber R, Vogt MW, Wundeli W, Siegenthaler W, Liithy R. Co-infection with human immunodeficiency virus-type 1 (HIV-1) and cytomegalovirus in two intravenous drug users. Ann Intern Med. 1989;111:293-6. 2. Skolnik PR, Kosloff BR, Hirsch MS. Bidirectional interactions between human immunodeficiency virus type 1 and cytomegalovirus. I Infect Dis. 1988;157:508-14.
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3. Leport C, Harzic M, Pignon JM, et al. Benign cytomegalovirus mononucleosis in non-AIDS, HIV infected patients [Letter]. Lancet. 1987;2:214.
Measles and Immune Globulin Prophylaxis for Travelers and Hepatitis A To the Editor: I fully agree with Drs. Hill and Pearson (1) that revaccination with measles vaccine is advisable for all travelers born in or after 1957 and is particularly important for travelers to areas of high endemicity for measles. These areas occur particularly in the developing world where hepatitis A transmitted via fecal contamination is also a high risk to nonimmune travelers. Hepatitis A can be protected against very well with an injection of immune globulin, which is usually given just before departure because of its relatively short half-life. According to the Centers for Disease Control recommendations for foreign travelers, live attenuated vaccine viruses might not successfully replicate and antibody response could be diminished when the vaccine is given with immune globulin preparations. In general, parenterally administered live vaccines (such as measles, mumps, and rubella) should not be given for at least 6 weeks and preferably 3 months, after immune globulin administration. Because of imminent exposure to hepatitis A, administration of immune globulin may be necessary after a live vaccine has been given, and interference may occur. Vaccine virus replication and stimulation of immunity under normal conditions will occur within 7 to 10 days. If the interval between vaccine and immune globulin is less than 14 days, the vaccine should be readministered at least 3 months after the immune globulin was given, unless serologic testing for measles indicates that antibodies have been produced; if the interval was longer, vaccine need not be readministered. If administration of immune globulin becomes necessary because of imminent exposure to disease, live virus vaccine may be administered simultaneously, with the recognition that vaccine-induced immunity may be compromised. The vaccine should be administered in a site remote from that chosen for the immune globulin inoculation. The vaccination should be repeated about 3 months later unless serologic testing indicates measles antibodies have been produced ( 2 ) . An estimated 4 0 % of Americans have been infected with and are immune to hepatitis A ( 3 ) . The prevalence of hepatitis A virus antibody in the U.S. population equals approximately 10% per decade of life up to age 50. Thus, many of the same adults who should be revaccinated for measles are already immune to hepatitis A, and do not require immune globulin with its attendant risk of possibly masking measles antibody production. Because many adults traveling to the developing world often do not begin their immunizations long enough in advance to space measles and immune globulin inoculations properly, it would be worthwhile to screen for hepatitis A antibodies before giving these inoculations in this group of travelers. The cost for this screening should be approximately $25 to $50, but
the potential savings from not requiring immune globulin, measles serology, or another measles vaccination in 3 months could balance out this cost. Martin S. Wolfe, MD Traveler's Medical Service Washington, D.C. 20037 References 1. Hill DR, Pearson RD. Measles prophylaxis for international travel. Ann Intern Med. 1989;111:699-701. 2. Health Information for International Travel. Atlanta: Centers for Disease Control; 1989:71, 105. 3. Szumness W, Dienstag JL, Purcell RH, et al. Distribution of antibody to hepatitis A antigen in urban adult populations. N Engl J Med. 1976;295:755-9.
Single-Dose Phenytoin Infusion To the Editor: As a neurologist who treats patients with status epilepticus, I disagree strongly with the suggestion by Blaser and colleagues (1) that their loading regimen for intravenous phenytoin, even when combined with intravenous diazepam, should be used to treat those with this condition. Status epilepticus can cause brain damage (2) and permanent memory impairment (3) in humans. Irreversible brain damage has been documented after a seizure period as short as 90 minutes in the baboon ( 4 ) . In some instances seizures will continue even after phenytoin and diazepam have been given, and other anticonvulsants or even general anesthesia may be necessary. For these reasons, phenytoin should be given as rapidly as possible, consistent with patient safety. With the widely accepted dosage of 18 m g / k g body weight intravenously, at a rate not exceeding 50 jxg/ min, serum phenytoin levels of 80 to 120 jmmol/L (20 to 30 jLig/mL) are reached in 30 minutes ( 5 ) . The three-dose regimen recommended by Blaser and colleagues (5 m g / k g intravenously every 2 hours) takes much too long (6 hours) to reach a serum concentration of phenytoin (40 to 80 jxmol/L [10 to 20 u.g/ m L ] ) that has been recommended for chronic maintenance therapy, but that may not be adequate for status epilepticus. The accepted single-dose loading regimen for intravenous phenytoin should not be abandoned in this situation. Denson G. Fujikawa, MD Veterans Affairs Medical Center Sepulveda, CA 91343 U C L A School of Medicine Los Angeles, C A 90024 References 1. Blaser KU, Vozeh S, Landolt H, Kaufmann G, Romppainen J, Gratzl O. Intravenous phenytoin: a loading scheme for desired concentrations. Ann Intern Med. 1989;110:1029-31. 2. Softer D, Melamed E, Assaf Y, Cotev S. Hemispheric brain damage in unilateral status epilepticus. Ann Neurol. 1986;20:737-40. 3. Treiman DM, Delgado-Escueta AV. Complex partial status epilepticus. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Advances in Neurology, v 34. New York: Raven Press; 1983:69-81. 4. Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates:
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ischemic cell change and its relation to ictal physiological events. Arch Neurol. 1973;28:10-7. 5. Crawford RE, Leppik IE, Patrick B, Anderson CB, Kostick B. Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology. 1978;28:874-80.
Oxygen, Food, and Air Travel To the Editor: I enjoyed reading Dr. Hansen's clever letter (1) regarding the article by Dillard and colleagues (2) on the oxygen requirements of patients with lung disease who must travel by airplane. I am a bit concerned, however, about his unqualified recommendation that patients with borderline hypoxemia should drink or eat a carbohydrate-rich diet before and during flights. Dr. Hansen is essentially correct in stating that in a patient with a partial pressure of arterial carbon dioxide (Pacc>2) of 40 mm Hg, increasing the respiratory quotient ( R q ) value from 0.75 to 0.95 would result in an increase in the partial pressure of arterial oxygen (Pac>2) of about 11 m m Hg. However, it is crucial to realize that such an increase will occur only if the PaC02 is kept constant. Usually, in response to a higher rate of CO2 production, (higher Rq value), a normal person will proportionally increase his or her minute ventilation to maintain a stable Pacc>2 level. Under these circumstances the higher Rq value does translate into a higher Pa02- However, a theoretical concern is that for a patient with chronic lung disease and limited ventilatory reserve, increasing the minute ventilation as demanded by the higher Rq may not always be feasible. Thus, an increase in CO2 production could result in a higher PaC02, and under these circumstances, the resulting Pac>2 would not be significantly higher, and may in fact be lower, than the baseline Pao 2 . Using Dr. Hansen's own example, if the Pacc>2 of his imaginary patient had risen from 40 to 47 mm Hg, the P a o 2 corresponding to the Rq of 0.95 would have been only around 58 m m Hg. If the Pacc>2 had risen to 55 mm Hg, the final Pac>2 would have been about 50 mm Hg. Furthermore, even if the Pacc>2 does not rise, the increase in minute ventilation required to prevent such a rise would have to be achieved in the setting of lung- disease and decreased "ventilatory efficiency," and thus the additional work-of-breathing may be perceived by some patients as increased dyspnea or difficulty in breathing. Although not necessarily serious or life-threatening, a feeling of increased dyspnea would certainly spoil anyone's trip. Although it is fairly well established that increased CO2 production resulting from carbohydrate-rich continuous parenteral feeding can precipitate respiratory
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failure in patients with severe ventilatory limitation or pre-existent respiratory failure ( 3 ) , it is not clear whether this concern should also apply to stable ambulatory patients or to oral feedings. Some authors have failed to show any deleterious effect ( 4 ) , whereas others have claimed improvement from restricting carbohydrate intake in these patients ( 5 ) . Thus, until more definite data become available, I believe that some caution is justified in recommending the intentional ingestion of an unusually large amount of carbohydrates, particularly for patients whose daily diet does not normally include such a fare. Rolando Berger, MD University of Kentucky Medical Center Lexington, K Y 40536 References 1. Hansen JE. Diet and flight hypoxemia. Ann Intern Med. 1989;111:859-60. 2. Dillard TA, Berg BW, Rajagopal KR, Dooley JW, Mehm WJ. Hypoxemia during air travel in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1989;111:362-7. 3. Covelli HD, Black JW, Olasen MW, Beekman JF. Respiratory failure precipitated by high carbohydrate loads. Ann Intern Med. 1981;95:579-85. 4. Gieske T, Gurnshanthaigh G, Glauser FL. Effects of carbohydrates on carbon dioxide excretion in patients with airway disease. Chest. 1977;71:55-8. 5. Kwan R, Afzal M. Beneficial effects of dietary carbohydrate restriction in chronic cor pulmonale. Am J Med. 1987;82:751-8.
Correction: Table 2 in National Study of Internal Medicine Manpower: XV To the Editor: There is an error in Table 2 of National Study of Internal Medicine Manpower: XV. A decade of change in Residency Training in Internal Medicine ( 1 ) . In Table 2, the data in the first column (headed "Total, n " ) should be under the heading " M D . " The data in the second column (headed " M D " ) should be under the heading " D O . " The data in the third column (headed " D O " ) should be under the heading "Total, n." Christian M. Schmidt National Study of Internal Medicine Manpower The University of Chicago Chicago, IL 60637 Reference 1. Andersen RM, Lyttle C, Kohrman C, Levey G, Glen C. National Study of Internal Medicine Manpower: XV. A decade of change in residency training in internal medicine. Ann Intern Med. 1989;110:922-9.
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