Rapid Oral Desensitization to Isoniazid and Rifampin* Christine L. HoUand, M.D.;t Charlotte Malasky, M.D.;t Adenyt OgunkQ!P, M.D.;t and Lecmard Bielory, M.D.t
A 45-yeaJ'oOid black woman, sputum positive for acid-fast bacilli, developed hypersensitivity to both isoniazid and rifampin. She was admitted to the hospital and desensitized to both medications using modi6ed penicillin protocols. Skin testing was negative to both drugs. Desensitization to isoniazid was complicated by a drug fever that was controlled by prednisone. The patient was able to maintain once-a-day dosing without incident even with steroid taper. To our knowledge, this is the 6rst reported case of dual isoniazid and rifampin hypersensitivity with rapid oral desensitization. (Chest 1990; 98:1518-19) PZA = pyrizinamide; INH =isoniazid; RIF = rifampin; EPI =epinephrine; DIP= diphenhydramine; PRED = prednisone; PEN= peniciUin
H
ypersensitivity reactions to antituberculosis agents are seen in 4-5 percent of the general population which usually leads to cessation of and switching of therapy. Modification of an oral penicillin desensitization protocol allowed us to successfully administer isoniazid (INH) and rifampin (RIF) to a patient with documented dual hypersensitivity. CASE REPORT
A 45-yeaN>Id black female pulmonary function technician with a 15-year history of sarcoidosis noted fevers and night sweats. Chest roentgenogram showed a new left upper lobe infiltrate; PPD and anergy panel were negative, while sputum was positive for acid-fast bacilli. She was started on a regimen of pyrazinamide (PZA) 1,500 mgday, INH 300 mgday, and rifampin (RIF) 600 mgday. After 12 days of therapy, she developed a measles-like rash and arthralgia; treatment with all medications was stopped. She was challenged with 500 mg of PZA without effect. Three hours after 150 mg of RIF, the patient noted pruritus, urticaria, angioedema, chest heaviness, shortness of breath, and she was treated with epinephrine (EPI) and diphenhydramine (DIP); however, several hours later she developed a fever to 40"C, chills, and arthralgia. Five days later, a drug regimen of INH 300 mg, PZA 1,500 mg, ethambutol 700 mg day, and streptomycin 1 g intramuscularly was started; 15 minutes after the first dose, she had pruritus, urticaria, angioedema, and chest heaviness. Treatment with all medication was stopped. The patient had a subsequent challenge with INH 100 mg and developed generalized pruritus. She was referred for evaluation and possible desensitization. There was no history of atopic disease, other antibiotic sensitivity, or previous treatment with antituberculosis medications; an antinuclear antibody was negative, and lgE was 5.0 IU/ml (normal, 0 to 180 IU/ml). She was admitted to the hospital, and informed consent was obtained. Intravenous access was placed, EPI, DIP, hydrocortisone, and an emergency cart were kept at the bedside while a physician was present throughout the desensitization procedure. Skin testing to INH and RIF was negative (Thble 1). Rapid oral desensitization using INH elixir (50 mw'5ml) diluted with *From the Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark. tDivision of Allergy and Immunology. tDivision of Pulmonary Medicine.
1518
Table 1-Skin Tming• Prick (Wheal/Flare)
Intradermal (Wheal/Flare)
Saline solution 0.9 NS (-) Histamine 111,000 ( +9116) Sorbital 70% (-) INH injectable 0.1 mgml 0.9 NS (-) 1.0 mgml 0.9 NS (-) RIF oral 0.1 mgml sorbital (-) 1.0 mgml sorbital (-)
Saline solution 0.9 NS 0.05 ml (-) Histamine 1110,000 0.50 ml ( + 15129) Sorbital70% NDt INH injectable: 0.1 mgml 0.9 NS 0.05 ml (-) 1.0 mgml 0.9 NS 0.05 ml (-) RIF NDt NDt
*INH =isoniazid; RIF = rifampin. tND =not done. sorbital 70 percent was done (Thble 2). Nine hours into desensitization, a fever of 38.8•c and mild chest heaviness developed that was treated with DIP and metaproterenol inhalation. She was able to continue desensitization without further symptoms except for persistent fever. Prednisone (PRED) 40 mg was given and the patient defervesced six hours later. She was maintained on a regimen of PRED to suppress her fever; there was no later development of fever, rash, arthralgias, angioedema, or chest complaints. The next day, rapid oral desensitization to RIF was done (Thble 3) without adverse reaction. The patient was discharged from the hospital on a regimen of INH 150 mg and RIF 300 mg twice daily and PRED 40 mgday. Pyrizinamide 1,500 mgday was added three days later, without incident. The patient was to maintain twice daily dosing of INH and RIF; however, she subsequently missed an evening dose of INH and RIF. The next morning, the full dose of INH 300 mg, followed one hour later by RIF 600 mg was given under hospital supervision without incident. Once-a-day dosing was continued without complications. After one month of PRED 40 mgday, the dose was tapered to 5 mg every other day. The patient has continued treatment with her medication without problems and has now completed treatment. DISCUSSION
To our knowledge, this patient is the first reported case of dual INH and RIF hypersensitivity with successful rapid oral desensitization. Adverse reactions to INH are estimated to occur in approximately 5.4 percent of exposed patients, with hyersensitivity reactions of fever and morbilliform, Table 2-180fliazid Deamsitization Protocol Time
Dose, mg
7:00 7:15 7:30 7:45 8:00 8:30 9:00 9:30 10:30
0.1 0.5 1.0 2.0 4.0 8.0 16.0 32.0 50
AM
PM
12:30 2:30 3:00
100 150 150
AM
12:30 150 Continue 150 mg every 12 hours. Rapid Oral Deeensllizalion 10 INH and Rlfampln (Holland et Ill)
Table 3-Rifampin Deserllitization Protocol Tune
Dose, mg
7:00 7:15 7:30 7:45 8:00 8:15 8:30 8:45 9:15 10:15
0.1 0.5 1 2 4 8 16 32 50 75
AM
PM
12:15 4:15
100 150
AM
12:15 300 Continue 300 mg every 12 hours.
maculopapular, or urticarial rashes being the most common reactions. 1"" Isoniazid is metabolized in the liver to form major and minor metabolites. Whether INH or the metabolites are responsible for hypersensitivity reactions is unknown.1Skin testing in our patient was negative as previously reported.• This suggests either a non-IgE-mediated reaction," a metabolite is responsible as is seen with penicillin (PEN),• or that a more sensitive skin test reagent is needed. A subsequent investigation of a patient with INH occupational asthma noted positive skin tests to INH-protein conjugates suggesting that IgE to INH is responsible for hypersensitivity reactions. 7 Previous desensitization to INH has been done over a period of 50 days with fever or rash noted in four of 12 patients successfully desensitized.• This patient's sarcoidosis, poor pulmonary function, and concern of resistant organisms from occupational exposure or a long desensitization led us to develop rapid oral desensitization•·• (Table 2) with twice daily dosing as maintenance.u The patient was able to tolerate daily dosing without incident. The use of corticosteroids as the primary desensitizing agent or to suppress drug fever from INH has been described. 10 Thper of the corticosteroid dose after one month was possible while a more rapid taper has been associated with recurrence of symptoms. 10 A report of fever and prolonged hypotension in a patient receiving a P-blocker challenged with INH . 11 is consistent with severe anaphylaxis seen in patients receiving P-blockers with the recommendation that treatment with them be stopped prior to diagnostic challenge or desensitization.12 Rifampin is a semisynthetic derivative of rifamycin B; an active metabolite is formed through deacetylation in the liver. Hypersensitivity reactions of rash and fever occur in less than 4.0 percent of patients, while a "ftu-like syndrome" occurs in 20 percent taking an intermittent dosage.1·13 A recent abstract noted reactions in 9/19 (47 percent) patients with acquired immunodeficiency syndrome. 14 Skin testing has not been described with RIF and our negative results (Thble 1) suggest further work is needed to clarify this. Intradermal testing was not performed as there is no Food and Drug Administration approved intravenous preparation and RIF is insoluble in saline solution, so a skin test reagent
could not be prepared. Desensitization to RIF has been described with a reduction of dose or an incremental dosage increase over several days. 10 Our protocol was similar to others described for PENM (Thble 3). The use of corticosteroids as an adjunct to RIF desensitization has not been described (to our knowledge). Rapid oral desensitization to INH and RIF was successfully completed using accepted desensitization procedures. These include admission to the hospital (preferably in an intensive care unit or with resuscitation equipment at bedside), informed consent, intravenous access, and desensitization performed by someone other than the prescribing physician and who is familiar with desensitization protocols. 15 Patients receiving p-blockers should be removed from treatment with these medications before attempting a challenge or desensitization. The use of corticosteroids during INH desensitization was successful for the control of drug fever. ACKNOWLEDGMENT: The authors wish to thank Lee Reichman, M.D., for his review of this manuscript; they also thank the patient. REFERENCES 1 Mandell GL, Sande MA. Antimicrobial agents (continued): drugs used in the chemotherapy of tuberculosis and leprosy. In: Gilman AG , Goodman LS, Theodue WR, Murad F, eds. The pharmacological basis of therapeutics, 7th ed. New York, NY: Macmillan; 1985:1199-1218 2 Berte SJ, DiMase JD, Christianson GS. Isoniazid, para-aminosalicylic acid and streptomycin and intolerance in 1, 744 patients. Am Rev Respir Dis 1964; 90:598-606 3 Goldman AL, Braman SS . Isoniazid: a review with emphasis on adverse effects. Chest 1972; 62:71-7 4 Kalinowski SZ, Lloyd Tw, Moyes EN. Complications in the chemo-ther of tuberculosis. Amer Rev Respir Dis 1961; 83:35968
5 Bousquet J. In vivo methods for study of aUergy: skin tests, techniques and interpretation. In: Middleton E, Reed CD, Ellis EF, Adkinson NF, Yuninger Jw. eds. Allergy: principles and practice, 3rd ed. St Louis, MO: CV Mosby Co; 1988:419-36 6 SullivanT. Drug allergy. In: Middleton E, Reed CD, Ellis EF, Adkinson NF, Yuninger Jw. eds. Allergy: principles and practice, 3rd ed. St Louis, MO: CV Mosby Co; 1988:1523-36 7 Asai S, Shimoda T, Hara H, Fujiwara K. Occupational asthma caused by isonicotinic acid hydrazide (IN H) inhalation. J Allergy Clin Immunol1987; 80:578-82 8 Stark BJ, Earl HS, Gross GN, Lumry WR, Goodman EL, Sullivan T. Acute and chronic desensitization of penicillinallergic patients using oral penicillin. J Allergy Clin Immunol 1987; 79:523-32 9 Brown LA, Goldberg ND, Shearer WT. Long term ticarcillin desensitization by the continuous oral administration of penicillin. J Allergy Clin Immunol 1982; 69:51-4 10 Thompson J. The management of hypersensitivity to antituberculosis drugs. Med J Aust 1969:1058-63 11 Gabrail N. Severe febrile reaction to isoniazid. Chest 1987; 91:620-21 12 Toogood JH. Anaphylaxis in patients receiving . beta-blocker drugs. J Allergy Clin Immunoll988; 81:1-5 13 Girling D, Hitze KL. Adverse reactions to rifampicin. Bull WHO 1979; 57:45-9 14 Ricketti AJ, Webb J, Coutant R, Porwancher R. Adverse reaction to rifampin in AIDS in a prison population. J Allergy Clin lmmunoll989; 79:199 15 Patterson R. Diagnosis and treatment of drug allergy. J Allergy Clin Immunoll988; 81 :~ CHEST I 98 I 6 I DECEMBER, 1990
1519
A 45-yeaJ'oOid black woman, sputum positive for acid-fast bacilli, developed hypersensitivity to both isoniazid and rifampin. She was admitted to the hospital and desensitized to both medications using modi6ed penicillin protocols. Skin testing was negative to both drugs. Desensitization to isoniazid was complicated by a drug fever that was controlled by prednisone. The patient was able to maintain once-a-day dosing without incident even with steroid taper. To our knowledge, this is the 6rst reported case of dual isoniazid and rifampin hypersensitivity with rapid oral desensitization. (Chest 1990; 98:1518-19) PZA = pyrizinamide; INH =isoniazid; RIF = rifampin; EPI =epinephrine; DIP= diphenhydramine; PRED = prednisone; PEN= peniciUin
H
ypersensitivity reactions to antituberculosis agents are seen in 4-5 percent of the general population which usually leads to cessation of and switching of therapy. Modification of an oral penicillin desensitization protocol allowed us to successfully administer isoniazid (INH) and rifampin (RIF) to a patient with documented dual hypersensitivity. CASE REPORT
A 45-yeaN>Id black female pulmonary function technician with a 15-year history of sarcoidosis noted fevers and night sweats. Chest roentgenogram showed a new left upper lobe infiltrate; PPD and anergy panel were negative, while sputum was positive for acid-fast bacilli. She was started on a regimen of pyrazinamide (PZA) 1,500 mgday, INH 300 mgday, and rifampin (RIF) 600 mgday. After 12 days of therapy, she developed a measles-like rash and arthralgia; treatment with all medications was stopped. She was challenged with 500 mg of PZA without effect. Three hours after 150 mg of RIF, the patient noted pruritus, urticaria, angioedema, chest heaviness, shortness of breath, and she was treated with epinephrine (EPI) and diphenhydramine (DIP); however, several hours later she developed a fever to 40"C, chills, and arthralgia. Five days later, a drug regimen of INH 300 mg, PZA 1,500 mg, ethambutol 700 mg day, and streptomycin 1 g intramuscularly was started; 15 minutes after the first dose, she had pruritus, urticaria, angioedema, and chest heaviness. Treatment with all medication was stopped. The patient had a subsequent challenge with INH 100 mg and developed generalized pruritus. She was referred for evaluation and possible desensitization. There was no history of atopic disease, other antibiotic sensitivity, or previous treatment with antituberculosis medications; an antinuclear antibody was negative, and lgE was 5.0 IU/ml (normal, 0 to 180 IU/ml). She was admitted to the hospital, and informed consent was obtained. Intravenous access was placed, EPI, DIP, hydrocortisone, and an emergency cart were kept at the bedside while a physician was present throughout the desensitization procedure. Skin testing to INH and RIF was negative (Thble 1). Rapid oral desensitization using INH elixir (50 mw'5ml) diluted with *From the Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark. tDivision of Allergy and Immunology. tDivision of Pulmonary Medicine.
1518
Table 1-Skin Tming• Prick (Wheal/Flare)
Intradermal (Wheal/Flare)
Saline solution 0.9 NS (-) Histamine 111,000 ( +9116) Sorbital 70% (-) INH injectable 0.1 mgml 0.9 NS (-) 1.0 mgml 0.9 NS (-) RIF oral 0.1 mgml sorbital (-) 1.0 mgml sorbital (-)
Saline solution 0.9 NS 0.05 ml (-) Histamine 1110,000 0.50 ml ( + 15129) Sorbital70% NDt INH injectable: 0.1 mgml 0.9 NS 0.05 ml (-) 1.0 mgml 0.9 NS 0.05 ml (-) RIF NDt NDt
*INH =isoniazid; RIF = rifampin. tND =not done. sorbital 70 percent was done (Thble 2). Nine hours into desensitization, a fever of 38.8•c and mild chest heaviness developed that was treated with DIP and metaproterenol inhalation. She was able to continue desensitization without further symptoms except for persistent fever. Prednisone (PRED) 40 mg was given and the patient defervesced six hours later. She was maintained on a regimen of PRED to suppress her fever; there was no later development of fever, rash, arthralgias, angioedema, or chest complaints. The next day, rapid oral desensitization to RIF was done (Thble 3) without adverse reaction. The patient was discharged from the hospital on a regimen of INH 150 mg and RIF 300 mg twice daily and PRED 40 mgday. Pyrizinamide 1,500 mgday was added three days later, without incident. The patient was to maintain twice daily dosing of INH and RIF; however, she subsequently missed an evening dose of INH and RIF. The next morning, the full dose of INH 300 mg, followed one hour later by RIF 600 mg was given under hospital supervision without incident. Once-a-day dosing was continued without complications. After one month of PRED 40 mgday, the dose was tapered to 5 mg every other day. The patient has continued treatment with her medication without problems and has now completed treatment. DISCUSSION
To our knowledge, this patient is the first reported case of dual INH and RIF hypersensitivity with successful rapid oral desensitization. Adverse reactions to INH are estimated to occur in approximately 5.4 percent of exposed patients, with hyersensitivity reactions of fever and morbilliform, Table 2-180fliazid Deamsitization Protocol Time
Dose, mg
7:00 7:15 7:30 7:45 8:00 8:30 9:00 9:30 10:30
0.1 0.5 1.0 2.0 4.0 8.0 16.0 32.0 50
AM
PM
12:30 2:30 3:00
100 150 150
AM
12:30 150 Continue 150 mg every 12 hours. Rapid Oral Deeensllizalion 10 INH and Rlfampln (Holland et Ill)
Table 3-Rifampin Deserllitization Protocol Tune
Dose, mg
7:00 7:15 7:30 7:45 8:00 8:15 8:30 8:45 9:15 10:15
0.1 0.5 1 2 4 8 16 32 50 75
AM
PM
12:15 4:15
100 150
AM
12:15 300 Continue 300 mg every 12 hours.
maculopapular, or urticarial rashes being the most common reactions. 1"" Isoniazid is metabolized in the liver to form major and minor metabolites. Whether INH or the metabolites are responsible for hypersensitivity reactions is unknown.1Skin testing in our patient was negative as previously reported.• This suggests either a non-IgE-mediated reaction," a metabolite is responsible as is seen with penicillin (PEN),• or that a more sensitive skin test reagent is needed. A subsequent investigation of a patient with INH occupational asthma noted positive skin tests to INH-protein conjugates suggesting that IgE to INH is responsible for hypersensitivity reactions. 7 Previous desensitization to INH has been done over a period of 50 days with fever or rash noted in four of 12 patients successfully desensitized.• This patient's sarcoidosis, poor pulmonary function, and concern of resistant organisms from occupational exposure or a long desensitization led us to develop rapid oral desensitization•·• (Table 2) with twice daily dosing as maintenance.u The patient was able to tolerate daily dosing without incident. The use of corticosteroids as the primary desensitizing agent or to suppress drug fever from INH has been described. 10 Thper of the corticosteroid dose after one month was possible while a more rapid taper has been associated with recurrence of symptoms. 10 A report of fever and prolonged hypotension in a patient receiving a P-blocker challenged with INH . 11 is consistent with severe anaphylaxis seen in patients receiving P-blockers with the recommendation that treatment with them be stopped prior to diagnostic challenge or desensitization.12 Rifampin is a semisynthetic derivative of rifamycin B; an active metabolite is formed through deacetylation in the liver. Hypersensitivity reactions of rash and fever occur in less than 4.0 percent of patients, while a "ftu-like syndrome" occurs in 20 percent taking an intermittent dosage.1·13 A recent abstract noted reactions in 9/19 (47 percent) patients with acquired immunodeficiency syndrome. 14 Skin testing has not been described with RIF and our negative results (Thble 1) suggest further work is needed to clarify this. Intradermal testing was not performed as there is no Food and Drug Administration approved intravenous preparation and RIF is insoluble in saline solution, so a skin test reagent
could not be prepared. Desensitization to RIF has been described with a reduction of dose or an incremental dosage increase over several days. 10 Our protocol was similar to others described for PENM (Thble 3). The use of corticosteroids as an adjunct to RIF desensitization has not been described (to our knowledge). Rapid oral desensitization to INH and RIF was successfully completed using accepted desensitization procedures. These include admission to the hospital (preferably in an intensive care unit or with resuscitation equipment at bedside), informed consent, intravenous access, and desensitization performed by someone other than the prescribing physician and who is familiar with desensitization protocols. 15 Patients receiving p-blockers should be removed from treatment with these medications before attempting a challenge or desensitization. The use of corticosteroids during INH desensitization was successful for the control of drug fever. ACKNOWLEDGMENT: The authors wish to thank Lee Reichman, M.D., for his review of this manuscript; they also thank the patient. REFERENCES 1 Mandell GL, Sande MA. Antimicrobial agents (continued): drugs used in the chemotherapy of tuberculosis and leprosy. In: Gilman AG , Goodman LS, Theodue WR, Murad F, eds. The pharmacological basis of therapeutics, 7th ed. New York, NY: Macmillan; 1985:1199-1218 2 Berte SJ, DiMase JD, Christianson GS. Isoniazid, para-aminosalicylic acid and streptomycin and intolerance in 1, 744 patients. Am Rev Respir Dis 1964; 90:598-606 3 Goldman AL, Braman SS . Isoniazid: a review with emphasis on adverse effects. Chest 1972; 62:71-7 4 Kalinowski SZ, Lloyd Tw, Moyes EN. Complications in the chemo-ther of tuberculosis. Amer Rev Respir Dis 1961; 83:35968
5 Bousquet J. In vivo methods for study of aUergy: skin tests, techniques and interpretation. In: Middleton E, Reed CD, Ellis EF, Adkinson NF, Yuninger Jw. eds. Allergy: principles and practice, 3rd ed. St Louis, MO: CV Mosby Co; 1988:419-36 6 SullivanT. Drug allergy. In: Middleton E, Reed CD, Ellis EF, Adkinson NF, Yuninger Jw. eds. Allergy: principles and practice, 3rd ed. St Louis, MO: CV Mosby Co; 1988:1523-36 7 Asai S, Shimoda T, Hara H, Fujiwara K. Occupational asthma caused by isonicotinic acid hydrazide (IN H) inhalation. J Allergy Clin Immunol1987; 80:578-82 8 Stark BJ, Earl HS, Gross GN, Lumry WR, Goodman EL, Sullivan T. Acute and chronic desensitization of penicillinallergic patients using oral penicillin. J Allergy Clin Immunol 1987; 79:523-32 9 Brown LA, Goldberg ND, Shearer WT. Long term ticarcillin desensitization by the continuous oral administration of penicillin. J Allergy Clin Immunol 1982; 69:51-4 10 Thompson J. The management of hypersensitivity to antituberculosis drugs. Med J Aust 1969:1058-63 11 Gabrail N. Severe febrile reaction to isoniazid. Chest 1987; 91:620-21 12 Toogood JH. Anaphylaxis in patients receiving . beta-blocker drugs. J Allergy Clin Immunoll988; 81:1-5 13 Girling D, Hitze KL. Adverse reactions to rifampicin. Bull WHO 1979; 57:45-9 14 Ricketti AJ, Webb J, Coutant R, Porwancher R. Adverse reaction to rifampin in AIDS in a prison population. J Allergy Clin lmmunoll989; 79:199 15 Patterson R. Diagnosis and treatment of drug allergy. J Allergy Clin Immunoll988; 81 :~ CHEST I 98 I 6 I DECEMBER, 1990
1519
