LETTERS
Letters that report new clinical or laboratory observations; cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. A Survey of Hospital Pharmacists' Knowledge of the Content of Drug Combinations Two YEARS AGO, one of us reported the results of a preliminary survey suggesting that the knowledge of physicians about the exact content of the drug combinations they are prescribing is somewhat limited ( 1 ) . The purpose of the present study was to find out hospital pharmacists' knowledge concerning the content of the same drug combinations that the physicians were previously asked to identify. During the semiannual meeting of the Quebec Hospital Pharmacists Association held in September 1973 in TroisRivieres, Quebec, the 71 pharmacists present in the conference room were asked, without warning, to fill out the questionnaire, whose answers appeared in the 7 July 1973 issue of the Canadian Medical Association Journal ( 1 ) . The percentage of correct answers for each drug was computed in the same manner as previously described, that is, the numerator was the number of correct answers (exact number of ingredients and correct nature of each ingredient), and the denominator was the number of pharmacists queried minus those who mentioned that they had not recently dispensed that particular drug. All results are in Table 1. The commercial names are those used in Canada, and some combinations may not have their exact counterpart in the United States. The physicians' survey had resulted in correct answer percentages ranging from 66% for Pentrium®, 6 5 % for Diazyde®, and 60% for Aldactazide®, to 0% for combinations containing more than 4 single ingredients ( 1 ) . On the whole, pharmacists fared slightly better than the physicians for drug combinations containing up to 3 ingredients, but this difference diminished when more ingredients were present. The correlation between the number of ingredients in a preparation and the percentage of correct answers was negative and highly significant in both professional groups, r = —0.65 (P < 0.001 for physicians and r = —0.60 (P < 0.005) for pharmacists. Such results prove that the knowledge is inversely proportional to the number of ingredients contained in a combination. We are aware that the questionnaire was more difficult for the pharmacists than for the physicians, because the physicians were asked to choose combination drugs that 680
they were used to prescribing. The pharmacists, however, were imposed with the present list of combinations; the large majority of Quebec hospitals have ceased to deliver most of these combinations since the implementation of the Quebec Health Insurance Board List of Drugs ( 2 ) . If neither physicians nor pharmacists attach too much importance to the exact constituents of fixed-drug combinations, then there is something wrong somewhere in our pharmacotherapy system. And the wrong does not necessarily lie with these professionals. If neither physicians nor pharmacists care to remember the exact content of combinations containing several ingredients, it may simply result from the fact that, consciously or unconsciously, they feel that these ingredients are either [1] active products but present in subtherapeutic concentrations or [2] pharmacologically inactive. It would seem that pharmacists consider the presence of certain ingredients as superfluous and not worth remembering. We would not go as far as MacCannell ( 3 ) , who condemned combinations in the following terms: "Many combination drugs can be the darling of the inadequate or the lazy physician, or the less-than-ethical pharmaceutical company." However, we agree that a drug combination may be judged to be effective only if each active ingredient makes a contribution to the effect of the combination ( 3 ) . When such is the case, "no excuse can be offered for the physician who prescribes a combination without even knowing what drugs are in the combination" ( 4 ) , and we could add "no excuses either for the pharmacist who fills the prescription." But the present survey showed that only a small minority of pharmacists failed to recall, for example, the entire content of Pentrium ( 9 % ) or Etrafron (13%). The drug industry developed and marketed fixed-drug combinations, and physicians have for too long believed that the brain trust of these industries knew best what ingredients were good for the welfare of patients; now is the time to learn the names of these ingredients, to question their presence, dosage, effectiveness, and usefulness. Brainwashed by some shrewd promotion, we have prescribed enough combinations to make these constitute 40% of our prescriptions ( 3 ) . Who knows, maybe the time is ripe to go back to magistral prescribing again—at least both physicians and pharmacists would know exactly what they prescribe and dispense! JACQUES GAGNE, P H . D .
Faculty of Pharmacy PIERRE BIRON, M . S C . RICHARD MOISAN, M . S C .
Department of Pharmacology Faculty of Medicine University of Montreal P.O. Box 6128 Montreal 101, Canada Received 16 December 1974. [Continued on pp. 681-682]
May 1975 • Annals of Internal Medicine • Volume 82 • Number 5
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
Table 1. Survey of Hospital Pharmacists' Knowledge of the Content of Drug Combinations Drug Preparation
Number of Ingredients
Librax®
2
Pentrium®
2
Etrafon®
2
Aldactazide®
2
Azogantrisin®
2
Mandrax®
2
Supres®
2
Complamin®
Correct Answers
Acceptable Answers
1 or 2 (still controversial)
Diazyde®
2
Mexaform®
2
Hydergine®
3
222®
3
292®
3
Ornade®
3
Fiorinal® (tablet)
4
Percodan®
4
Tedral® (elixir)
4
Donnatal®
4
Ornex®
4
Donnalate®
5
Name of Ingredients *
Chlordiazepoxide (Librium®, Solium®) Clidinium Pentaerythritol tetranitrate Chlordiazepoxide (Librium®, Solium®) Perphenazine (Trilafon®) Amitriptyline (Elavil®, Elatrol®) Spironolactone (Aldactone®) Hydrochlorothiazide (Hydrodiuril®, Esidrix®) Phenazopyridine (Pyridium®) Sulfisoxazol (Gantrisin®) Methaqualone (Tualone®) Diphenhydramine (Benadryl®) Methyldopa (Aldomet®) Chlorothiazide (Diuril®) Xanthinol niacinate, or Xanthine Niacinate Triamterene (Dyrenium®) Hydrochlorothiazide (Esidrix®, Hydrodiuril®) Phanquone Iodochlorhydroxiquin (Entero-Vioform®) Dihydroergocristine Dihydroergokryptine Dihydroergocornine Acetylsalicylic acid (ASA), aspirin Codeine phosphate, codeine Caffeine, caffeine citrate Acetylsalicylic acid (ASA), aspirin Codeine phosphate, codeine Caffeine citrate, caffeine Chlorpheniramine Phenylpropanolamine Isopropamide iodide, isopropamide Butalbital, itobarbital, allylbarbituric acid Caffeine Acetylsalicylic acid (ASA), aspirin Phenacetin Oxycodone salts, oxycodone, etc. Acetylsalicylic acid (ASA), aspirin Phenacetin Caffeine Theophylline Ephedrine Alcohol, ethanol Phenobarbital Hyoscine hydrobromide, scopolamine hydrobromide, hyoscine, scopolamine Hyoscyamine sulfate (levorotary isomer of atropine), hyoscyamine Atropine, atropine sulfate Phenobarbital Acetaminophen Acetylsalicylic acid (ASA), aspirin Caffeine Phenylpropanolamine Dihydroxyaluminium aminoacetate, aluminium salt Phenobarbital Hyoscyamine sulfate, hyoscyamine Hyoscine hydrobromide, scopolamine hydrobromide, hyoscine, scopolamine Atropine sulfate, atropine
54 91 87 86 61 86 15 35 86 8 4 76 92 3 37
29
29
18
8
4
Letters
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
681
Table 1. (Continued) Drug
Acceptable Answers
Preparation
Number of Ingredients
Correct Answers
Name of Ingredients *
% Plexonal®
5
Cystalgine®
6
Cheracol® (syrup)
7
Sodium barbital, barbital, itobarbital Phenobarbital Butalbital, sodium butalbital Dihydroergotamine, dihydroergotamine methanesulfonate Scopolamine, scopolamine chlorhydrate Sodium phosphate acid Hyoscyamine sulfate, scopolamine Atropine sulfate, atropine Hyoscine hydrobromide, hyoscine Phenobarbital Hexamine Codeine, codeine phosphate Chloroform Guaiacolate Antimony, antimony tartrate Potassium, potassium tartrate Ethanol, alcohol Ammonium chloride
0
0
0
* When more than two commercial names exist, they are not listed but were of course considered acceptable answers. REFERENCES
1. BIRON P: A hopefully biased pilot survey of physicians knowledge of the content of drug combinations. Can Med Assoc J 109:35-39, 1973 2. Quebec Health Insurance Board List of Drugs, 4th ed., 1974 3. MACCANNELL K: The case against combination drugs, in Proceedings of the 5th International Congress of Pharmacology, vol. 3. Basel, S. Karger AG, 1973, pp. 18-22 4. CARR EA JR: Report of the discussion on combination drug therapy—good or bad. See Reference 3, pp. 28-32 Pulmonary Aspergillosis, Inhalation of Contaminated Marijuana Smoke, Chronic Granulomatous Disease INCREASED
S U S C E P T I B I L I T Y to
infection
is a h a l l m a r k
of
chronic g r a n u l o m a t o u s disease of childhood ( 1 ) , a n inherited disorder in which phagocytic cells a r e u n a b l e to kill certain types of ingested organisms ( 2 ) . W e present a case of Aspergillus fumigatus pneumonitis in a 17-year-old b o y with c h r o n i c g r a n u l o m a t o u s disease, whose infection m a y have been acquired t h r o u g h inhalation of s m o k e from m a r i j u a n a c o n t a m i n a t e d with fungi. A 17-year-old boy was admitted to the National Institutes of Health with fever and exertional dyspnea. Two weeks before admission, he noted the onset of malaise 12 hours after smoking several pipefulls of marijuana that had been buried in the earth for "aging." One week before admission, while continuing heavy marijuana use, he developed a nonproductive cough and night sweats. On admission, physical examination was unremarkable except for a respiratory rate of 32/min. N o rales, rhonchi, or wheezes were heard during the chest examination. Temperature was 38.3 °C [101 °F]. Leukocyte count was 8500/mm 3 with 6 5 % segmented neutrophils, 8% bands, and 5 % eosinophils. Erythrocyte sedimentation rate was 50 m m / m i n . Admission chest X ray showed a panlobular diffuse reticular infiltrate, which progressed to a reticulonodular appearance. Repeated sputum and blood cultures showed negative results for bacterial and fungal pathogens, and a purified protein derivative of tuberculin (5 units) was nonreactive. An open thoracotomy and right middle lobe lung biopsy were done. Material obtained 582
grew catalase-positive Aspergillus fumigatus. Histopathologic examination showed marked granulomatous reaction typical of chronic granulomatous disease, and methenamine silver stain showed septate hyphae consistent with Aspergillus. Intravenous amphotericin B (0.5 mg/kg body weight • 24 h ) and methylprednisolone, 40 mg every 8 hours, were administered. Within 5 days the patient, whose Po 2 had been as low as 38 m m Hg, had normal blood gas determinations, and methylprednisolone was withdrawn. He received a total of 2 grams of amphotericin B over a 2-month period, and his chest X ray showed a return to normal. Culture of the patient's marijuana and pipe grew various fungi. Heavy growth of Aspergillus fumigatus was noted after inhibition of more rapidly growing species with cyclohexamide. An acute specimen of patient serum had heavy precipitin lines against Aspergillus fumigatus by an immunodiffusion method, while convalescent serum had marked diminution of these precipitins. An intradermal skin test of purified Aspergillus fumigatus antigen (Hollister-Stier, Yeadon, Pennsylvania) resulted in a positive immediate reaction with wheal and flare reaching 15 m m of induration. A mild Arthus-like reaction was noted at 6 hours, but 24- and 48-hour readings showed negative results. Serum IgE level on admission was 1430 n g / ml and 484 ng/ml during convalescence (normal, < 6 0 0 n g / ml). T h e phagocytes of patients with chronic g r a n u l o m a t o u s disease ingest microorganisms normally b u t fail t o u n d e r g o the burst of oxidative metabolism that follows phagocytosis. T h e resultant lack of h y d r o g e n peroxide p r o d u c t i o n impairs the ability of these cells to kill catalase-producing m i c r o organisms t h r o u g h the h y d r o g e n peroxide-myeloperoxidasehalide system ( 3 ) . Aspergillosis h a s been described in a n u m b e r of patients with chronic g r a n u l o m a t o u s disease usually as p n e u m o n i t i s or osteomyelitis. T h e source of infection in previous cases has n o t been apparent, except for o n e case described b y G o o d ( 1 ) in which overwhelming p u l m o n a r y aspergillosis occurred after inhalation of h a y dust. Because Aspergillus species a r e found in soil, air, a n d vegetable m a t t e r such as t o b a c c o ( 4 ) , inadvertent exposure is likely. Additionally,
May 1975 • Annals of Internal Medicine • Volume 82 • Number 5
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
of 10 samples of confiscated marijuana that we obtained through the Department of Justice Drug Enforcement Agency, Washington, D. C , 2 grew Aspergillus fumigatus on fungal culture and all showed heavy growth of a variety of saprophytic fungi. Our patient's clinical course was atypical for either allergic bronchopulmonary or invasive aspergillosis. Patients with allergic bronchopulmonary aspergillosis usually produce copious amounts of sputum and coarse green-brown sputum plugs containing numerous Aspergillus hyphae. Other frequent findings include wheezing, hemoptysis, and chest pain, as well as an atopic history ( 5 ) . None of the above was noted in the present case. This patient's course was also atypical for invasive aspergillosis. Lobar or asymmetric pulmonary infiltrates are usually seen in this condition rather than the homogenous densities noted in our patient. However, definite parenchymal invasion was documented by open lung biopsy. Our patient may have inhaled an inoculum of Aspergillus fumigatus in the smoke of marijuana that had been in close contact with soil. This presumably resulted in a progressive alveolitis that worsened when the patient was unable to clear the fungus because of his fungicidal defect. This may also have permitted direct parenchymal invasion by fungal organisms. The present case shows that marijuana may at times be
contaminated with Aspergillus fumigatus, and is thus a potential hazard to individuals predisposed to Aspergillus infection. For normal individuals such exposure is probably of little practical significance. M I C H A E L J. C H U S I D , M . D . J E F F R E Y A. GELFAND, M . D . CATHY NUTTER, B.S. A N T H O N Y S. F A U C I , M . D .
Laboratory of Clinical Investigation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland 20014 Received 29 October
1974.
REFERENCES 1. GOOD
RA, QUIE
PG, WINDHORST
DB, et al: Fatal
(chronic)
granulomatous disease of childhood: a hereditary defect of leukocyte function. Semin Hematol 5:215-254, 1968 2. QUIE
PG, WHITE JG, HOLMES B, et al: In vitro bactericidal
capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. / Clin Invest 46:668-679, 1967 3. PINCUS SH, KLEBANOFF SJ: Quantitative leukocyte iodination. N Engl J Med 284:744-750, 1971 4. WELTY RE: Fungi isolated from flue-cured tobacco sold in Southeast United States, 1968-1970. Appl Microbiol 24:518-520, 1972 5. MCCARTHY DS, PEPYS J: Allergic bronchopulmonary aspergillosis. Clin Allergy 1:261-286, 1971
Letters
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
683
Letters that report new clinical or laboratory observations; cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. A Survey of Hospital Pharmacists' Knowledge of the Content of Drug Combinations Two YEARS AGO, one of us reported the results of a preliminary survey suggesting that the knowledge of physicians about the exact content of the drug combinations they are prescribing is somewhat limited ( 1 ) . The purpose of the present study was to find out hospital pharmacists' knowledge concerning the content of the same drug combinations that the physicians were previously asked to identify. During the semiannual meeting of the Quebec Hospital Pharmacists Association held in September 1973 in TroisRivieres, Quebec, the 71 pharmacists present in the conference room were asked, without warning, to fill out the questionnaire, whose answers appeared in the 7 July 1973 issue of the Canadian Medical Association Journal ( 1 ) . The percentage of correct answers for each drug was computed in the same manner as previously described, that is, the numerator was the number of correct answers (exact number of ingredients and correct nature of each ingredient), and the denominator was the number of pharmacists queried minus those who mentioned that they had not recently dispensed that particular drug. All results are in Table 1. The commercial names are those used in Canada, and some combinations may not have their exact counterpart in the United States. The physicians' survey had resulted in correct answer percentages ranging from 66% for Pentrium®, 6 5 % for Diazyde®, and 60% for Aldactazide®, to 0% for combinations containing more than 4 single ingredients ( 1 ) . On the whole, pharmacists fared slightly better than the physicians for drug combinations containing up to 3 ingredients, but this difference diminished when more ingredients were present. The correlation between the number of ingredients in a preparation and the percentage of correct answers was negative and highly significant in both professional groups, r = —0.65 (P < 0.001 for physicians and r = —0.60 (P < 0.005) for pharmacists. Such results prove that the knowledge is inversely proportional to the number of ingredients contained in a combination. We are aware that the questionnaire was more difficult for the pharmacists than for the physicians, because the physicians were asked to choose combination drugs that 680
they were used to prescribing. The pharmacists, however, were imposed with the present list of combinations; the large majority of Quebec hospitals have ceased to deliver most of these combinations since the implementation of the Quebec Health Insurance Board List of Drugs ( 2 ) . If neither physicians nor pharmacists attach too much importance to the exact constituents of fixed-drug combinations, then there is something wrong somewhere in our pharmacotherapy system. And the wrong does not necessarily lie with these professionals. If neither physicians nor pharmacists care to remember the exact content of combinations containing several ingredients, it may simply result from the fact that, consciously or unconsciously, they feel that these ingredients are either [1] active products but present in subtherapeutic concentrations or [2] pharmacologically inactive. It would seem that pharmacists consider the presence of certain ingredients as superfluous and not worth remembering. We would not go as far as MacCannell ( 3 ) , who condemned combinations in the following terms: "Many combination drugs can be the darling of the inadequate or the lazy physician, or the less-than-ethical pharmaceutical company." However, we agree that a drug combination may be judged to be effective only if each active ingredient makes a contribution to the effect of the combination ( 3 ) . When such is the case, "no excuse can be offered for the physician who prescribes a combination without even knowing what drugs are in the combination" ( 4 ) , and we could add "no excuses either for the pharmacist who fills the prescription." But the present survey showed that only a small minority of pharmacists failed to recall, for example, the entire content of Pentrium ( 9 % ) or Etrafron (13%). The drug industry developed and marketed fixed-drug combinations, and physicians have for too long believed that the brain trust of these industries knew best what ingredients were good for the welfare of patients; now is the time to learn the names of these ingredients, to question their presence, dosage, effectiveness, and usefulness. Brainwashed by some shrewd promotion, we have prescribed enough combinations to make these constitute 40% of our prescriptions ( 3 ) . Who knows, maybe the time is ripe to go back to magistral prescribing again—at least both physicians and pharmacists would know exactly what they prescribe and dispense! JACQUES GAGNE, P H . D .
Faculty of Pharmacy PIERRE BIRON, M . S C . RICHARD MOISAN, M . S C .
Department of Pharmacology Faculty of Medicine University of Montreal P.O. Box 6128 Montreal 101, Canada Received 16 December 1974. [Continued on pp. 681-682]
May 1975 • Annals of Internal Medicine • Volume 82 • Number 5
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
Table 1. Survey of Hospital Pharmacists' Knowledge of the Content of Drug Combinations Drug Preparation
Number of Ingredients
Librax®
2
Pentrium®
2
Etrafon®
2
Aldactazide®
2
Azogantrisin®
2
Mandrax®
2
Supres®
2
Complamin®
Correct Answers
Acceptable Answers
1 or 2 (still controversial)
Diazyde®
2
Mexaform®
2
Hydergine®
3
222®
3
292®
3
Ornade®
3
Fiorinal® (tablet)
4
Percodan®
4
Tedral® (elixir)
4
Donnatal®
4
Ornex®
4
Donnalate®
5
Name of Ingredients *
Chlordiazepoxide (Librium®, Solium®) Clidinium Pentaerythritol tetranitrate Chlordiazepoxide (Librium®, Solium®) Perphenazine (Trilafon®) Amitriptyline (Elavil®, Elatrol®) Spironolactone (Aldactone®) Hydrochlorothiazide (Hydrodiuril®, Esidrix®) Phenazopyridine (Pyridium®) Sulfisoxazol (Gantrisin®) Methaqualone (Tualone®) Diphenhydramine (Benadryl®) Methyldopa (Aldomet®) Chlorothiazide (Diuril®) Xanthinol niacinate, or Xanthine Niacinate Triamterene (Dyrenium®) Hydrochlorothiazide (Esidrix®, Hydrodiuril®) Phanquone Iodochlorhydroxiquin (Entero-Vioform®) Dihydroergocristine Dihydroergokryptine Dihydroergocornine Acetylsalicylic acid (ASA), aspirin Codeine phosphate, codeine Caffeine, caffeine citrate Acetylsalicylic acid (ASA), aspirin Codeine phosphate, codeine Caffeine citrate, caffeine Chlorpheniramine Phenylpropanolamine Isopropamide iodide, isopropamide Butalbital, itobarbital, allylbarbituric acid Caffeine Acetylsalicylic acid (ASA), aspirin Phenacetin Oxycodone salts, oxycodone, etc. Acetylsalicylic acid (ASA), aspirin Phenacetin Caffeine Theophylline Ephedrine Alcohol, ethanol Phenobarbital Hyoscine hydrobromide, scopolamine hydrobromide, hyoscine, scopolamine Hyoscyamine sulfate (levorotary isomer of atropine), hyoscyamine Atropine, atropine sulfate Phenobarbital Acetaminophen Acetylsalicylic acid (ASA), aspirin Caffeine Phenylpropanolamine Dihydroxyaluminium aminoacetate, aluminium salt Phenobarbital Hyoscyamine sulfate, hyoscyamine Hyoscine hydrobromide, scopolamine hydrobromide, hyoscine, scopolamine Atropine sulfate, atropine
54 91 87 86 61 86 15 35 86 8 4 76 92 3 37
29
29
18
8
4
Letters
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
681
Table 1. (Continued) Drug
Acceptable Answers
Preparation
Number of Ingredients
Correct Answers
Name of Ingredients *
% Plexonal®
5
Cystalgine®
6
Cheracol® (syrup)
7
Sodium barbital, barbital, itobarbital Phenobarbital Butalbital, sodium butalbital Dihydroergotamine, dihydroergotamine methanesulfonate Scopolamine, scopolamine chlorhydrate Sodium phosphate acid Hyoscyamine sulfate, scopolamine Atropine sulfate, atropine Hyoscine hydrobromide, hyoscine Phenobarbital Hexamine Codeine, codeine phosphate Chloroform Guaiacolate Antimony, antimony tartrate Potassium, potassium tartrate Ethanol, alcohol Ammonium chloride
0
0
0
* When more than two commercial names exist, they are not listed but were of course considered acceptable answers. REFERENCES
1. BIRON P: A hopefully biased pilot survey of physicians knowledge of the content of drug combinations. Can Med Assoc J 109:35-39, 1973 2. Quebec Health Insurance Board List of Drugs, 4th ed., 1974 3. MACCANNELL K: The case against combination drugs, in Proceedings of the 5th International Congress of Pharmacology, vol. 3. Basel, S. Karger AG, 1973, pp. 18-22 4. CARR EA JR: Report of the discussion on combination drug therapy—good or bad. See Reference 3, pp. 28-32 Pulmonary Aspergillosis, Inhalation of Contaminated Marijuana Smoke, Chronic Granulomatous Disease INCREASED
S U S C E P T I B I L I T Y to
infection
is a h a l l m a r k
of
chronic g r a n u l o m a t o u s disease of childhood ( 1 ) , a n inherited disorder in which phagocytic cells a r e u n a b l e to kill certain types of ingested organisms ( 2 ) . W e present a case of Aspergillus fumigatus pneumonitis in a 17-year-old b o y with c h r o n i c g r a n u l o m a t o u s disease, whose infection m a y have been acquired t h r o u g h inhalation of s m o k e from m a r i j u a n a c o n t a m i n a t e d with fungi. A 17-year-old boy was admitted to the National Institutes of Health with fever and exertional dyspnea. Two weeks before admission, he noted the onset of malaise 12 hours after smoking several pipefulls of marijuana that had been buried in the earth for "aging." One week before admission, while continuing heavy marijuana use, he developed a nonproductive cough and night sweats. On admission, physical examination was unremarkable except for a respiratory rate of 32/min. N o rales, rhonchi, or wheezes were heard during the chest examination. Temperature was 38.3 °C [101 °F]. Leukocyte count was 8500/mm 3 with 6 5 % segmented neutrophils, 8% bands, and 5 % eosinophils. Erythrocyte sedimentation rate was 50 m m / m i n . Admission chest X ray showed a panlobular diffuse reticular infiltrate, which progressed to a reticulonodular appearance. Repeated sputum and blood cultures showed negative results for bacterial and fungal pathogens, and a purified protein derivative of tuberculin (5 units) was nonreactive. An open thoracotomy and right middle lobe lung biopsy were done. Material obtained 582
grew catalase-positive Aspergillus fumigatus. Histopathologic examination showed marked granulomatous reaction typical of chronic granulomatous disease, and methenamine silver stain showed septate hyphae consistent with Aspergillus. Intravenous amphotericin B (0.5 mg/kg body weight • 24 h ) and methylprednisolone, 40 mg every 8 hours, were administered. Within 5 days the patient, whose Po 2 had been as low as 38 m m Hg, had normal blood gas determinations, and methylprednisolone was withdrawn. He received a total of 2 grams of amphotericin B over a 2-month period, and his chest X ray showed a return to normal. Culture of the patient's marijuana and pipe grew various fungi. Heavy growth of Aspergillus fumigatus was noted after inhibition of more rapidly growing species with cyclohexamide. An acute specimen of patient serum had heavy precipitin lines against Aspergillus fumigatus by an immunodiffusion method, while convalescent serum had marked diminution of these precipitins. An intradermal skin test of purified Aspergillus fumigatus antigen (Hollister-Stier, Yeadon, Pennsylvania) resulted in a positive immediate reaction with wheal and flare reaching 15 m m of induration. A mild Arthus-like reaction was noted at 6 hours, but 24- and 48-hour readings showed negative results. Serum IgE level on admission was 1430 n g / ml and 484 ng/ml during convalescence (normal, < 6 0 0 n g / ml). T h e phagocytes of patients with chronic g r a n u l o m a t o u s disease ingest microorganisms normally b u t fail t o u n d e r g o the burst of oxidative metabolism that follows phagocytosis. T h e resultant lack of h y d r o g e n peroxide p r o d u c t i o n impairs the ability of these cells to kill catalase-producing m i c r o organisms t h r o u g h the h y d r o g e n peroxide-myeloperoxidasehalide system ( 3 ) . Aspergillosis h a s been described in a n u m b e r of patients with chronic g r a n u l o m a t o u s disease usually as p n e u m o n i t i s or osteomyelitis. T h e source of infection in previous cases has n o t been apparent, except for o n e case described b y G o o d ( 1 ) in which overwhelming p u l m o n a r y aspergillosis occurred after inhalation of h a y dust. Because Aspergillus species a r e found in soil, air, a n d vegetable m a t t e r such as t o b a c c o ( 4 ) , inadvertent exposure is likely. Additionally,
May 1975 • Annals of Internal Medicine • Volume 82 • Number 5
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
of 10 samples of confiscated marijuana that we obtained through the Department of Justice Drug Enforcement Agency, Washington, D. C , 2 grew Aspergillus fumigatus on fungal culture and all showed heavy growth of a variety of saprophytic fungi. Our patient's clinical course was atypical for either allergic bronchopulmonary or invasive aspergillosis. Patients with allergic bronchopulmonary aspergillosis usually produce copious amounts of sputum and coarse green-brown sputum plugs containing numerous Aspergillus hyphae. Other frequent findings include wheezing, hemoptysis, and chest pain, as well as an atopic history ( 5 ) . None of the above was noted in the present case. This patient's course was also atypical for invasive aspergillosis. Lobar or asymmetric pulmonary infiltrates are usually seen in this condition rather than the homogenous densities noted in our patient. However, definite parenchymal invasion was documented by open lung biopsy. Our patient may have inhaled an inoculum of Aspergillus fumigatus in the smoke of marijuana that had been in close contact with soil. This presumably resulted in a progressive alveolitis that worsened when the patient was unable to clear the fungus because of his fungicidal defect. This may also have permitted direct parenchymal invasion by fungal organisms. The present case shows that marijuana may at times be
contaminated with Aspergillus fumigatus, and is thus a potential hazard to individuals predisposed to Aspergillus infection. For normal individuals such exposure is probably of little practical significance. M I C H A E L J. C H U S I D , M . D . J E F F R E Y A. GELFAND, M . D . CATHY NUTTER, B.S. A N T H O N Y S. F A U C I , M . D .
Laboratory of Clinical Investigation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland 20014 Received 29 October
1974.
REFERENCES 1. GOOD
RA, QUIE
PG, WINDHORST
DB, et al: Fatal
(chronic)
granulomatous disease of childhood: a hereditary defect of leukocyte function. Semin Hematol 5:215-254, 1968 2. QUIE
PG, WHITE JG, HOLMES B, et al: In vitro bactericidal
capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. / Clin Invest 46:668-679, 1967 3. PINCUS SH, KLEBANOFF SJ: Quantitative leukocyte iodination. N Engl J Med 284:744-750, 1971 4. WELTY RE: Fungi isolated from flue-cured tobacco sold in Southeast United States, 1968-1970. Appl Microbiol 24:518-520, 1972 5. MCCARTHY DS, PEPYS J: Allergic bronchopulmonary aspergillosis. Clin Allergy 1:261-286, 1971
Letters
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19497/ by a University of California San Diego User on 05/01/2017
683
