- Email: [email protected]
Severe Febrile Reaction to Isoniazid
possibility of occult sepsis. Results of abdominal ultrasound and KUB were normal. The transplanted kidney functioned normally throughout his course, with good urine output and a steadily decreasing serum creatinine level during the first days ofhis ARDS. His sensorium remained clear, and no abnormalities in hepatic enzyme tests occurred. A Doppler 2-dimensional echocardiogram done one day after onset of symptoms demonstrated left ventricular hypertrophy, but normal left ventricular function. He required mechanical ventilation for two weeks, but was then successfully extubated and eventually returned home free of symptoms. He was not rechallenged with ALG. DISCUSSION
Our patient developed pulmonary edema due to abnormal alveolar-eapillary membrane permeability, as documented by his failure to respond to fluid removal by dialysis, high protein concentration in the pulmonary edema fluid, 3 and the low pulmonary capillary wedge pressure. No known causes of ARDS were present at the time he developed respiratory failure. His symptoms developed in association with fever, which occurs in one third of patients receiving ALG and may be related to leukocyte destruction by infused antibody and complement, with release of endogenous pyrogens." The hemodynamic pattern ofhigh cardiac output and low systemic vascular resistance persisted through the period that the pulmonary artery catheter was in place, and may have been related to the patient's arteriovenous dialysis shunt. This hemodynamic pattern is also seen in sepsis; however, this is very unlikely because all cultures were negative and no identifiable source of infection was present. Also, the patient did not have evidence of other end-organ dysfunction, as usually seen in sepsis severe enough to cause ARDS. Lance et al' noted that dyspnea is ccoccasionally" seen after intravenous ALG in conjunction with bradycardia and hypotension, of unclear etiology. We were unable to find any documented cases of ARDS related to ALG. However, transfusion-related acute lung injury is well described, and has been attributed to leukoagglutinating and lymphocytotoxic antibodies in the transfused serum." Cases of transfusionrelated ARDS have been reported four" and five6 hours after completion of the last transfusion. ALG causes massive leukocyte destruction when infused, and likely causes bystander destruction of platelets." In 10 percent of treated patients, leukopenia «5000 WBe/cu mm) and thrombocytopenia «100, OOO/cu mm) OCCUI: s.g It is possible that ARDS related to ALG is a variant of transfusion associated lung injury. Experimental evidence suggests that ALG could cause acute lung injury. Greco et al' demonstrated that ALG binds to virtually all circulating lymphocytes, granulocytes, and platelets. They also found that ALG binds to nuclear and cytoplasmic components of lung in vitro. Haefen et all demonstrated that heterologous anti-rat thymocyte serum can produce an acute hemorrhagic pulmonary lesion. This effect may be dependent on complement, since complement depletion by prior administration of a human gamma globulin fraction protected the animals from the development of lung toxicity. Absorption of serum with homologous tissue suspensions of lung and thymus also eliminated toxicity. The results of this study suggest that anti-rat thymocyte serum (and by extension, human ALG) may be directly toxic to the lung. Given the theoretical basis for acute lung injury with ALG, 820
it is unclear why other cases have not been reported. It is possible that this case was related to a single batch of ALG with unusual white blood cell or pulmonary cytotoxicity. Two other patients given the same batch of ALG developed dyspnea and rales, but they did not become ill enough to require pulmonary artery catheterization, or allow collection of pulmonary edema fluid. We therefore are uncertain if other, milder episodes of ARDS occurred in patients given the same batch of ALG. High pressure pulmonary edema is common in renal transplant patients, and it could be that concurrent fluid overload has made it difficult to attribute pulmonary edema to abnormal alveolar-capillary membrane permeability alone. A single case report does not prove that ALG can cause acute lung injury. Occult sepsis or aspiration of gastric contents can never be completely excluded as alternative explanations for the development of ARDS. Additional cases of ARDS related to ALG use are needed to determine if there is a causal association. However; clinicians should be aware that the potential for acute lung injury exists in patients receiving ALG. REFERENCES
1 Cosimi AB. The clinical usefulness of antilymphocyte antibodies. 'Irans Proc 1983; 15:583-89 2 Haefen UH, Martins AC, Aranjo MA, Ferraz AS, Ciconelli J, Bohm GM. Diffuse immunologische lungenschadigung durch heterologes antithymozytenserum. Langenbecks Arch Coo 1975; Suppl:153-56 3 Matthay M, Eschenbacher WC, Goetzl E. Elevated concentrations ofleukotriene D4 in pulmonary edema 8uid of patients with the adult respiratory distress syndrome. J Clio Immun 1984; 4: 479-83 4 Lance EM, Medawar PB, Taub RN. Antilymphocyte serum. Adv Immunoll973; 17:1-95 5 Popovsky MA, Abel MD, Moore SB. Thmsfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 1983; 128:185-89 6 Ward HN. Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann Intern Med 1970; 73:689-94 7 Greco B, Bielory L, Stephany D, Hsu SM, Gascon ~ Nienhuis A, et ale Antithymocyte globulin reacts with many normal human cell types. Blood 1983; 62:1047-54 8 Monaco AE Antilymphocyte globulin: a clinical transplantation research opportunity. Am J Kidney Dis 1982; 2:67-78 9 Gratama jw Brand A, Jansen J, Zwaan FE, Valentijn RM, Eernisse JG. Factors influencing platelet survival during antilymphocyte globulin treatment. Br J Haematoll984; 57:5-15
Severe febrile Reaction to lsonlazld* Nashat ~ Gabrail, M.D.
A case of severe febrile reaction to INH is described. The patient had a mild febrile reaction two weeks following INH prophylaxis. Isoniazid was discontinued. 1Wo weeks later and on rechaUenge with INH she developed a severe febrile *From the Department of Medicine, Hematology-Medical Oncology, University of Missouri School of Medicine, Columbia. Reprint requests: Dr. Gabrail, Department of Medicine, N407
MedicalCenter; Columbia, MO 65212
Severe FebrileAeacIIon to INH (Nashat ~ GabraII)
reaction with protracted hypotension. An initial mild febrile reaction to INH is a warning sign that recballenge can result in a life-threatening situation.
T
hree cases offebrile reactions to isoniazid (INH) used as chemoprophylaxis for tuberculosis have been reported. 1,1 This report presents the fourth case which resembles the other three. However, this patient manifested more prolonged febrile reaction and severe protracted hypotension. CASE REPORT
This 56-year-old white woman was admitted to the hospital on August 30, 1985, because of sudden onset of fever, nausea, and vomiting which occurred less than two hours after taking isoniazid, 300 mg orally. On August 1, 1985, the patient was started on INH chemoprophylaxis, 300 mg daily plus pyridoxine, 50 mg daily based on recent tuberculin test conversion. On August 15, 1985, the patient reported to her family physician with symptoms of nausea, vomiting, and fever of 38. SOC. An INH reaction was suspected and INH was discontinued. The patient was advised not to take INH for two weeks and to reinstitute INH therapy on September 1. She complied with instructions and fever subsided within24 hours of discontinuation of the INH. The patient had no history of allergies to any drugs. She drinks wine almost on a daily basis. She is known to be hypertensive and she takes metoprolol (Lopressor), 50 mg twice daily. On admission and two hours after the readministration of INH, her temperature was 4O.SOC. Blood pressure was 70140 mm Hg and pulse rate was 80 per minute. The patient was drowsy, confused and disoriented. Physical examination did not reveal any focus of infection. Isoniazid was discontinued and IV fluids were started at the rate of250 ml per hour. In spite of aggressive use of IV fluids, the blood pressure failed to rise. Six hours later, while the patient was still oliguric, she was given methyl prednisolone (Solu-medrol), 250 mg IV single dose. Within 60 minutes of injection of Solumedrol, the blood pressure rose to 100160 mm Hg and urine output went back to normal levels. The second day of admission, IV fluids were stopped, blood pressure was maintained about 120180 mm Hg with a pulse rate in the range of 70 to 80 beats per minute. . The patient remained febrile for the subsequent four days. On the second hospitalization day, her SCOT level was 69, SCPT was 160, LDH was 372. Bilirubin was .6 and alkaline phosphatase was 90. CBC was unremarkable. There was no eosinophilia. She was discharged home on the fifth day when she became afebrile. Repeat liver enzyme assays done in the subsequent four weeks revealed normalization of all of the liver enzyme abnormalities. DISCUSSION
Febrile reactions to INH have been reported before in three patients. 1.1 Severe reactions such as described herein have never been observed before. In all the reported cases, the febrile reaction developed ten to 20 days after the initiation of isoniazid chemoprophylaxis. However, in all the cases, on rechallenge with INH, the patient became febrile within two hours of therapy. The severe hypotension observed in our case is probably due to a combination of the very high fever; as well as p-blocker therapy. Liver enzyme abnormalities were not reported in previous cases. We think these abnormalities are the result of a prolonged hypotensive episode producing liver ischemia. The amount of alcohol the patient was taking would not be enough to cause liver
dysfunction. Furthermore, the liver enzymes went back to normal after discharge, although she continued to drink the wine as previously. Interactions between isoniazid and wine have been observed before, but the usual presentation is hypertension rather than hypotension.Y The explanation for those reactions are probably related to MAO inhibition by the isoniazid with accumulation of tyramine and histamines derived from the wine. The mechanism of febrile reactions to INH are still unclear; but the temporal relationship suggests an immunologic phenomenon, since in all reported cases, patients developed initial febrile reaction within ten to 20 days after initiation of IN H therapy which is the exact time required for antibody formation. Rechallenge in all reported cases resulted in prompt febrile reaction within two hours of rechallenge. We strongly recommend that an initial febrile reaction to INH should preclude subsequent therapy with this drug, since this may result in a confusing clinical picture and could well be a life-threatening situation as well. REFERENCES
1 Dasta ], Prior}A, Kurzrok S. Isoniazid induced fever. Chest 1979; 75:196-97 2 Davis R. Febrile reactions to INH. N Engl J Med 1977; 297:337 3 Toutoungi M. Cheese, wine and isoniazid. Lancet 1985; 2:671 4 Mithal A. Cheese, wine and isoniazid. Lancet 1985; 2:1074
Obstructive Sleep Apnea Initiated by a Lax Epiglottis· A Contraindication for Continuous Positive Airway Pressure A P. D. Anclenen, M.D.;}. Alving, M.D.; I Uldholdt, M.D., Ph.D.; and C. H. Wulff, M.D.
Treatment with nasal continuous positive airway pressure (CPAP) was attempted in a patient with severe obstructive sleep apnea. However, application of nasal CPAP gave the patient a feeling of being suffocated. This was later documented by cine-8uoroscopic examinations of the upper airways with and without nasal CPAP. The epiglottis was large and lax, and upon positive pressure inspiration, it was literally blown down so it occluded the hypopharyngeal airway.
C
ontinuous positive airway pressure (CPAP) through the nose as treatment for obstructive sleep apnea was introduced by Sullivan et all in 1981. Although this type of treatment may be a disadvantage to some patients, J-4 most reports confirm the beneficial effect of CPAP in this particular disorder: 3.5.& We report a case where the airway obstruction during
*From
the Departments of Anesthesiology, Clinical Neurophysiology and Ear, Nose and Throat Diseases, Odense Hospital, Odense, Denmark. R~rint requests: Dr. Wulff, Department of Clinical Neurophysiology, Odense HOlfJital, DK-5000 Odense C, Denmark CHEST I 91 I 4 I APRIL, 1987
821
Our patient developed pulmonary edema due to abnormal alveolar-eapillary membrane permeability, as documented by his failure to respond to fluid removal by dialysis, high protein concentration in the pulmonary edema fluid, 3 and the low pulmonary capillary wedge pressure. No known causes of ARDS were present at the time he developed respiratory failure. His symptoms developed in association with fever, which occurs in one third of patients receiving ALG and may be related to leukocyte destruction by infused antibody and complement, with release of endogenous pyrogens." The hemodynamic pattern ofhigh cardiac output and low systemic vascular resistance persisted through the period that the pulmonary artery catheter was in place, and may have been related to the patient's arteriovenous dialysis shunt. This hemodynamic pattern is also seen in sepsis; however, this is very unlikely because all cultures were negative and no identifiable source of infection was present. Also, the patient did not have evidence of other end-organ dysfunction, as usually seen in sepsis severe enough to cause ARDS. Lance et al' noted that dyspnea is ccoccasionally" seen after intravenous ALG in conjunction with bradycardia and hypotension, of unclear etiology. We were unable to find any documented cases of ARDS related to ALG. However, transfusion-related acute lung injury is well described, and has been attributed to leukoagglutinating and lymphocytotoxic antibodies in the transfused serum." Cases of transfusionrelated ARDS have been reported four" and five6 hours after completion of the last transfusion. ALG causes massive leukocyte destruction when infused, and likely causes bystander destruction of platelets." In 10 percent of treated patients, leukopenia «5000 WBe/cu mm) and thrombocytopenia «100, OOO/cu mm) OCCUI: s.g It is possible that ARDS related to ALG is a variant of transfusion associated lung injury. Experimental evidence suggests that ALG could cause acute lung injury. Greco et al' demonstrated that ALG binds to virtually all circulating lymphocytes, granulocytes, and platelets. They also found that ALG binds to nuclear and cytoplasmic components of lung in vitro. Haefen et all demonstrated that heterologous anti-rat thymocyte serum can produce an acute hemorrhagic pulmonary lesion. This effect may be dependent on complement, since complement depletion by prior administration of a human gamma globulin fraction protected the animals from the development of lung toxicity. Absorption of serum with homologous tissue suspensions of lung and thymus also eliminated toxicity. The results of this study suggest that anti-rat thymocyte serum (and by extension, human ALG) may be directly toxic to the lung. Given the theoretical basis for acute lung injury with ALG, 820
it is unclear why other cases have not been reported. It is possible that this case was related to a single batch of ALG with unusual white blood cell or pulmonary cytotoxicity. Two other patients given the same batch of ALG developed dyspnea and rales, but they did not become ill enough to require pulmonary artery catheterization, or allow collection of pulmonary edema fluid. We therefore are uncertain if other, milder episodes of ARDS occurred in patients given the same batch of ALG. High pressure pulmonary edema is common in renal transplant patients, and it could be that concurrent fluid overload has made it difficult to attribute pulmonary edema to abnormal alveolar-capillary membrane permeability alone. A single case report does not prove that ALG can cause acute lung injury. Occult sepsis or aspiration of gastric contents can never be completely excluded as alternative explanations for the development of ARDS. Additional cases of ARDS related to ALG use are needed to determine if there is a causal association. However; clinicians should be aware that the potential for acute lung injury exists in patients receiving ALG. REFERENCES
1 Cosimi AB. The clinical usefulness of antilymphocyte antibodies. 'Irans Proc 1983; 15:583-89 2 Haefen UH, Martins AC, Aranjo MA, Ferraz AS, Ciconelli J, Bohm GM. Diffuse immunologische lungenschadigung durch heterologes antithymozytenserum. Langenbecks Arch Coo 1975; Suppl:153-56 3 Matthay M, Eschenbacher WC, Goetzl E. Elevated concentrations ofleukotriene D4 in pulmonary edema 8uid of patients with the adult respiratory distress syndrome. J Clio Immun 1984; 4: 479-83 4 Lance EM, Medawar PB, Taub RN. Antilymphocyte serum. Adv Immunoll973; 17:1-95 5 Popovsky MA, Abel MD, Moore SB. Thmsfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 1983; 128:185-89 6 Ward HN. Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann Intern Med 1970; 73:689-94 7 Greco B, Bielory L, Stephany D, Hsu SM, Gascon ~ Nienhuis A, et ale Antithymocyte globulin reacts with many normal human cell types. Blood 1983; 62:1047-54 8 Monaco AE Antilymphocyte globulin: a clinical transplantation research opportunity. Am J Kidney Dis 1982; 2:67-78 9 Gratama jw Brand A, Jansen J, Zwaan FE, Valentijn RM, Eernisse JG. Factors influencing platelet survival during antilymphocyte globulin treatment. Br J Haematoll984; 57:5-15
Severe febrile Reaction to lsonlazld* Nashat ~ Gabrail, M.D.
A case of severe febrile reaction to INH is described. The patient had a mild febrile reaction two weeks following INH prophylaxis. Isoniazid was discontinued. 1Wo weeks later and on rechaUenge with INH she developed a severe febrile *From the Department of Medicine, Hematology-Medical Oncology, University of Missouri School of Medicine, Columbia. Reprint requests: Dr. Gabrail, Department of Medicine, N407
MedicalCenter; Columbia, MO 65212
Severe FebrileAeacIIon to INH (Nashat ~ GabraII)
reaction with protracted hypotension. An initial mild febrile reaction to INH is a warning sign that recballenge can result in a life-threatening situation.
T
hree cases offebrile reactions to isoniazid (INH) used as chemoprophylaxis for tuberculosis have been reported. 1,1 This report presents the fourth case which resembles the other three. However, this patient manifested more prolonged febrile reaction and severe protracted hypotension. CASE REPORT
This 56-year-old white woman was admitted to the hospital on August 30, 1985, because of sudden onset of fever, nausea, and vomiting which occurred less than two hours after taking isoniazid, 300 mg orally. On August 1, 1985, the patient was started on INH chemoprophylaxis, 300 mg daily plus pyridoxine, 50 mg daily based on recent tuberculin test conversion. On August 15, 1985, the patient reported to her family physician with symptoms of nausea, vomiting, and fever of 38. SOC. An INH reaction was suspected and INH was discontinued. The patient was advised not to take INH for two weeks and to reinstitute INH therapy on September 1. She complied with instructions and fever subsided within24 hours of discontinuation of the INH. The patient had no history of allergies to any drugs. She drinks wine almost on a daily basis. She is known to be hypertensive and she takes metoprolol (Lopressor), 50 mg twice daily. On admission and two hours after the readministration of INH, her temperature was 4O.SOC. Blood pressure was 70140 mm Hg and pulse rate was 80 per minute. The patient was drowsy, confused and disoriented. Physical examination did not reveal any focus of infection. Isoniazid was discontinued and IV fluids were started at the rate of250 ml per hour. In spite of aggressive use of IV fluids, the blood pressure failed to rise. Six hours later, while the patient was still oliguric, she was given methyl prednisolone (Solu-medrol), 250 mg IV single dose. Within 60 minutes of injection of Solumedrol, the blood pressure rose to 100160 mm Hg and urine output went back to normal levels. The second day of admission, IV fluids were stopped, blood pressure was maintained about 120180 mm Hg with a pulse rate in the range of 70 to 80 beats per minute. . The patient remained febrile for the subsequent four days. On the second hospitalization day, her SCOT level was 69, SCPT was 160, LDH was 372. Bilirubin was .6 and alkaline phosphatase was 90. CBC was unremarkable. There was no eosinophilia. She was discharged home on the fifth day when she became afebrile. Repeat liver enzyme assays done in the subsequent four weeks revealed normalization of all of the liver enzyme abnormalities. DISCUSSION
Febrile reactions to INH have been reported before in three patients. 1.1 Severe reactions such as described herein have never been observed before. In all the reported cases, the febrile reaction developed ten to 20 days after the initiation of isoniazid chemoprophylaxis. However, in all the cases, on rechallenge with INH, the patient became febrile within two hours of therapy. The severe hypotension observed in our case is probably due to a combination of the very high fever; as well as p-blocker therapy. Liver enzyme abnormalities were not reported in previous cases. We think these abnormalities are the result of a prolonged hypotensive episode producing liver ischemia. The amount of alcohol the patient was taking would not be enough to cause liver
dysfunction. Furthermore, the liver enzymes went back to normal after discharge, although she continued to drink the wine as previously. Interactions between isoniazid and wine have been observed before, but the usual presentation is hypertension rather than hypotension.Y The explanation for those reactions are probably related to MAO inhibition by the isoniazid with accumulation of tyramine and histamines derived from the wine. The mechanism of febrile reactions to INH are still unclear; but the temporal relationship suggests an immunologic phenomenon, since in all reported cases, patients developed initial febrile reaction within ten to 20 days after initiation of IN H therapy which is the exact time required for antibody formation. Rechallenge in all reported cases resulted in prompt febrile reaction within two hours of rechallenge. We strongly recommend that an initial febrile reaction to INH should preclude subsequent therapy with this drug, since this may result in a confusing clinical picture and could well be a life-threatening situation as well. REFERENCES
1 Dasta ], Prior}A, Kurzrok S. Isoniazid induced fever. Chest 1979; 75:196-97 2 Davis R. Febrile reactions to INH. N Engl J Med 1977; 297:337 3 Toutoungi M. Cheese, wine and isoniazid. Lancet 1985; 2:671 4 Mithal A. Cheese, wine and isoniazid. Lancet 1985; 2:1074
Obstructive Sleep Apnea Initiated by a Lax Epiglottis· A Contraindication for Continuous Positive Airway Pressure A P. D. Anclenen, M.D.;}. Alving, M.D.; I Uldholdt, M.D., Ph.D.; and C. H. Wulff, M.D.
Treatment with nasal continuous positive airway pressure (CPAP) was attempted in a patient with severe obstructive sleep apnea. However, application of nasal CPAP gave the patient a feeling of being suffocated. This was later documented by cine-8uoroscopic examinations of the upper airways with and without nasal CPAP. The epiglottis was large and lax, and upon positive pressure inspiration, it was literally blown down so it occluded the hypopharyngeal airway.
C
ontinuous positive airway pressure (CPAP) through the nose as treatment for obstructive sleep apnea was introduced by Sullivan et all in 1981. Although this type of treatment may be a disadvantage to some patients, J-4 most reports confirm the beneficial effect of CPAP in this particular disorder: 3.5.& We report a case where the airway obstruction during
*From
the Departments of Anesthesiology, Clinical Neurophysiology and Ear, Nose and Throat Diseases, Odense Hospital, Odense, Denmark. R~rint requests: Dr. Wulff, Department of Clinical Neurophysiology, Odense HOlfJital, DK-5000 Odense C, Denmark CHEST I 91 I 4 I APRIL, 1987
821