Influenza A Viral Infection Associated with Acute Renal Failure
ADEL SHENOUDA,
M.D.’
FRED E. HATCH, M.D. Memphis, Tennessee
From the Division of Nephrology, Department of Medicine, University of Tennessee Center for the Health Sciences, Memphis, Tennessee. Requests for reprints should be addressed to Dr. Fred E. Hatch, 353 D, 951 Court Avenue, Memphis, Tennessee 38183. Manuscript accepted March 5, 1976. Present address: Department of Nephrology, Baroness Erlanger Hospital, Chattanooga, Tennessee 37493. l
The clinical and laboratory findings in four cases of acute renal failure following the onset of Influenza A viral infection (Port Chalmers/l/73) are presented. Although the pathophysiologic mechanisms affecting the kktney in these cases varled, the ensuing renal failure In each patient was severe. Findings suggestive of acute myogloblnurla developed In one patient, and disseminated Intravascular coagulation (DE) occurred in another. The role of viruses in the pathogenesis of renal dlsease Is reviewed. Desptte inconclusive evidence that the influenza virus can cause human renal disease, the secondary pathways that can be triggered by viral infections may be even more significant in produclng various dagrees of renal dysfunctbn. The occurreixe of renal failure during an eplsode of influenza represents a serlous compllcation which may Influence slgnifkantly the morbidity and mortaltty of patients with this viral Infection. The development of acute renal failure subsequent to the onset of influenza viral infection has been the subject of sporadic reports in various areas of the world in recent years [ l-61. When viral or serologic identification has been possible, influenza A infections (London/72, Hong Kongl68, Englandl42172) have provided the closest association with renal disease [l-6]. Inherent difficulties in viral isolation in renal tissue have hampered attempts to demonstrate a direct etiologic role. Other well defined pathogenetic mechanisms, however, appear to have been responsible for the renal failue in many of these cases. Acute myoglobinuria has developed in several patients [ 561, and. disseminated intravascular coagulation (DC) has occurred in others [2-41. Myking and Schreiner [l] reported a case of severe renal failure following an influenza virus A infection in which a possible immunologic mechanism was suggested. Until the definitive role of viruses in the pathogenesis of renal disease has been fully established, additional observations on the course of viral-associated renal failure continue to be of clinical interest. In this study we report four cases of acute renal failure following influenza A/Port Chalmers/l/73 viral infection during a recent midwinter epidemic. Although the pathophysiologic mechanisms affecting the kidney in these cases varied, the ensuing renal failure in each patient was severe. This report serves to emphasize that the occurrence of renal failure during an episode of influenza represents a serious complication which may influence significantly the morbidity and mortality of the patient with this viral infection.
November 1976
The American Journal of Medicine
Volume 61
697
INFLUENZA
TABLE
A INFECTION WITH RENAL FAILURE-SHENOUDA,
Clinical
I
HATCH
Data in Patients with Acute Renal Failure Following Influenza
Arterial Blood Gasses
0,
Age (yr)
No. and Sex
Clinical Presentation
Status on Admission
pC0, (mm’
pH
Hg)
Hg)
(%I
(mu/ml) 5.084
tion
-
SGOT
Enzymes
LDH (mLJ/ml)
CPK (mU/ml)
5,310
>50,000
Outcome Recovery
1
26.F
Dyspnea, cyanosis
Anuria
7.38
35
34
66
2
33,F
Dyspnea, cyanosis, confusion
Normal
7.42
55
25
88
140
1,200
200
Death
3
47.F
Dyspnea, peripheral edema
Oliguria
7.36
62
21
90
135
940
690
Death
4
28.M
Cough, peripheral edema
Oiiguria
7.47
75
24
94
70
480
300
Chronic renal failure
NOTE:
p0,
= oxygen tension; pC0,
= carbon dioxide
tension; 0,
CASE REPORTS An upper respiratory tract infection, characterized by low grade fever, nonproductive cough and myalgia, developed in a 26 year old white woman. During the second week of her illness, she began to have moderate respiratory distress that resulted in mild cyanosis of all extremities. Profound generalized muscle weakness occurred, and she became unable to walk. Two days before admission, her urine became dark brown and decreased in amount. She was known to have had normal renal function previously and had no history of kidney disease. Because of increasing respiratory distress and progressive cyanosis, she was admitted to a local hospital. Physical examination revealed an acutely ill woman without palpable blood pressure. Her fingers and toes, lips and face were cyanotic (Table I). The lungs were clear, and a chest film was within normal limits. A white blood cell count was 26,900/mm3, hematocrit value 44 per cent and blood urea nitrogen 40 mg/iOO ml. She was treated with intravenous saline solutions, intermittent intravenous hydrocortisone and antibiotics. Her vital signs returned to normal, and the cyanosis showed marked diminution. The urinary output was low and did not respond to the intravenous administration of mannitol or furosemide. The urine was dark brown in color, with a specific gravity of 1.023, pH 6.5, albumin 4-t and orthotolidin (Hemate&) 4+; microscopic examination showed an occasional white blood cell and red blood cell/hpf. Serum enzyme levels were markedly elevated (Table I). Because of the renal failure, the patient was transferred to the City of Memphis Hospital. Physical examination on admission revealed a critically ill but alert young woman in moderate respiratory distress. The vital signs were stable, but the extremities were cold and mildly cyanotic. Examination of the chest showed diffuse rales and rhonchi throughout both lung fields. The cardiac size was normal; the heart rate was 150 beats/min with a gallop rhythm. Laboratory values included a blood urea nitrogen of 72 mg/lOO ml, creatinine 7.5 mg/lOO ml, calcium 5.3 Case 1.
696
Serum
PO,a (mm
Renal Case
Satura-
November 1976
The American Journal of Medicine
= oxygen.
mg/lOO ml, phosphorus 7.6 mg/lOO ml, and sputum and blood cultures that were negative. Treatment was started with 6 liters of nasal oxygen. The arterial blood gases showed persistent hypoxia, however (Table I), and a volume-controlled ventilator and positive end-expiratory pressure were employed for ventilatory assistance. A Swan-Ganz catheter was inserted into the pulmonary artery for monitoring pressure. The intravenous administration of hydrocortisone was continued (400 mg/day), and the administration of aqueous penicillin G (8 million units/day) was begun. Because of continued renal failure, hemodialysis was performed regularly over a two week period. The patient showed marked clinical improvement with these measures, and all mechanical assistance was discontinued by the third week. She underwent a spontaneous diuresis during the recovery phase of acute renal failure, and renal function slowly returned to normal. Attempts to identify myoglobinuria during the diuretic phase by 80 per cent saturation with ammonium sulfate were unsuccessful. Serum was obtained during the acute and convalescent phases for influenza virus antibody determinations. The serologic response to A/Hong Kong/68 and Port Chalmers/if73 influenza viruses was measured by hemagglutination inhibition as described by Fazekas and Webster [7]. An increase in hemagglutination inhibiting antibody titers to 1: 10,000 dilution was detected (Table II). Extreme soreness and weakness persisted in the quadriceps muscles and prevented ambulation without assistance. Intensive physiotherapy produced gradual improvement in muscle strength. The patient was discharged on the 38th hospital day. Case 2.
A 33 year old white woman was admitted to the City of Memphis Hospital in acute respiratory distress (Table I). Three days earlier, she had been treated for symptoms of an upper respiratory tract infection. One day prior to admission, she became disoriented and progressive dyspnea developed.
Volume 61
INFLUENZA A INFECTION WITH RENAL FAILURE-SHENOUDA,
Physical examination revealed a well developed, slender woman who was confused and agitated. She had a temperature of 100.4’ F, blood pressure 118/70 mm Hg, pulse rate 120 beats/min and respiratory rate 48/min. Pertinent physical findings included cyanotic lips, coarse rales heard in bases of both lungs, a normal-sized heart without murmurs or gallop, and a neurologic examination within normal limits except for the altered mentation. Laboratory studies showed a hematocrit value of 43 per cent and a white blood cell count of 26,900/mm3; blood urea nitrogen was 16 mg/lOO ml and creatinine 0.8 mg/lOO ml. Arterial blood gases indicated severe hypoxia (Table I). The urine was yellow in color, with a specific gravity of 1.019, pH 6 and albumin negative; microscopic examination showed 0 to 4 white blood cells/hpf. Dther pertinent laboratory values included a direct platelet count of 417,000/mm3, negative protamine sulfate test and fibrinogen 460 mg/lOO ml. Serum enzyme levels were moderately elevated (Table I). Gram-stain of the tracheal aspirate revealed rare gram-positive diplococci. Blood and sputum cultures were negative. A chest film showed bilateral diffuse infiltrates consistent with pulmonary edema. The impression on admission was influenza viral pneumonitis with severe respiratory failure. The hypoxia did not diminish with oxygen administration, and positive end-expiratory pressure was begun. In addition, penicillin (8 million units/day) and gentamicin (120 mg/day) were administered. The patient’s condition improved clinically over the next 48 hours, but subsequently a persistent fever developed with a temperature of 103’F. A lumbar puncture was performed which was within normal limits. Acute renal failure developed as manifested by a decreased urine output and progressive azotemia. Repeat laboratory studies revealed a white blood cell count of 54,000/mm3; the red blood cell morphology showed many fragmented cells, burr cells and target cells; the platelet count was 152,000/mm3, fibrinogen 365 mg/lOO ml; protamine sulfate test was positive. The patient received intravenous heparin therapy for DIC, and hemodialysis was started. The platelet count fell subsequently to 44,200/mm3 and the fibrinogen was 265 mg/lOO ml. Bleeding developed subcutaneously and in the gastrointestinal tract. The patient had a cardiac arrest, but cardiac resuscitation was unsuccessful. Permission for an autopsy was not obtained. Blood was obtained for assays of influenza antibodies shortly before the patient’s death (Table II). Values determined during convalescence could not be obtained for comparison. Case 3. A 47 year old white woman had been in good health until two weeks prior to admission when fever, cough, malaise and a sinus infection developed. Four days later, she noticed progressive dyspnea, weight gain, and edema of her feet and ankles (Table I). She was admitted to a I& hospital where she was found to be in moderate respiratory distress. A 20 pound weight gain was documented, and her urinary output was diminished. Laboratory data included a hematocrit value of 20.5 per cent and a white blood cell count of 11 ,700/mm3; the blood urea nitrogen was 114 mg/iOO ml, serum creatinine 7.5 mg/lOO ml and creatinine clearance 7.7 ml/min. The patient
TABLE
Case No. 1 2+ 3 4
II
HATCH
Serologic Response to A/Hong Kong/68 and A/Port Chalmers/l/73 Influenza Viruses as Measured by Hemagglutination Inhibition No. of Days After Admission 9 22 8 7 19 15 32 53
Antibody Titers to Viral Antigens* Hong Kong/68 1:9,300 >1:10,000
ADEL SHENOUDA,
M.D.’
FRED E. HATCH, M.D. Memphis, Tennessee
From the Division of Nephrology, Department of Medicine, University of Tennessee Center for the Health Sciences, Memphis, Tennessee. Requests for reprints should be addressed to Dr. Fred E. Hatch, 353 D, 951 Court Avenue, Memphis, Tennessee 38183. Manuscript accepted March 5, 1976. Present address: Department of Nephrology, Baroness Erlanger Hospital, Chattanooga, Tennessee 37493. l
The clinical and laboratory findings in four cases of acute renal failure following the onset of Influenza A viral infection (Port Chalmers/l/73) are presented. Although the pathophysiologic mechanisms affecting the kktney in these cases varled, the ensuing renal failure In each patient was severe. Findings suggestive of acute myogloblnurla developed In one patient, and disseminated Intravascular coagulation (DE) occurred in another. The role of viruses in the pathogenesis of renal dlsease Is reviewed. Desptte inconclusive evidence that the influenza virus can cause human renal disease, the secondary pathways that can be triggered by viral infections may be even more significant in produclng various dagrees of renal dysfunctbn. The occurreixe of renal failure during an eplsode of influenza represents a serlous compllcation which may Influence slgnifkantly the morbidity and mortaltty of patients with this viral Infection. The development of acute renal failure subsequent to the onset of influenza viral infection has been the subject of sporadic reports in various areas of the world in recent years [ l-61. When viral or serologic identification has been possible, influenza A infections (London/72, Hong Kongl68, Englandl42172) have provided the closest association with renal disease [l-6]. Inherent difficulties in viral isolation in renal tissue have hampered attempts to demonstrate a direct etiologic role. Other well defined pathogenetic mechanisms, however, appear to have been responsible for the renal failue in many of these cases. Acute myoglobinuria has developed in several patients [ 561, and. disseminated intravascular coagulation (DC) has occurred in others [2-41. Myking and Schreiner [l] reported a case of severe renal failure following an influenza virus A infection in which a possible immunologic mechanism was suggested. Until the definitive role of viruses in the pathogenesis of renal disease has been fully established, additional observations on the course of viral-associated renal failure continue to be of clinical interest. In this study we report four cases of acute renal failure following influenza A/Port Chalmers/l/73 viral infection during a recent midwinter epidemic. Although the pathophysiologic mechanisms affecting the kidney in these cases varied, the ensuing renal failure in each patient was severe. This report serves to emphasize that the occurrence of renal failure during an episode of influenza represents a serious complication which may influence significantly the morbidity and mortality of the patient with this viral infection.
November 1976
The American Journal of Medicine
Volume 61
697
INFLUENZA
TABLE
A INFECTION WITH RENAL FAILURE-SHENOUDA,
Clinical
I
HATCH
Data in Patients with Acute Renal Failure Following Influenza
Arterial Blood Gasses
0,
Age (yr)
No. and Sex
Clinical Presentation
Status on Admission
pC0, (mm’
pH
Hg)
Hg)
(%I
(mu/ml) 5.084
tion
-
SGOT
Enzymes
LDH (mLJ/ml)
CPK (mU/ml)
5,310
>50,000
Outcome Recovery
1
26.F
Dyspnea, cyanosis
Anuria
7.38
35
34
66
2
33,F
Dyspnea, cyanosis, confusion
Normal
7.42
55
25
88
140
1,200
200
Death
3
47.F
Dyspnea, peripheral edema
Oliguria
7.36
62
21
90
135
940
690
Death
4
28.M
Cough, peripheral edema
Oiiguria
7.47
75
24
94
70
480
300
Chronic renal failure
NOTE:
p0,
= oxygen tension; pC0,
= carbon dioxide
tension; 0,
CASE REPORTS An upper respiratory tract infection, characterized by low grade fever, nonproductive cough and myalgia, developed in a 26 year old white woman. During the second week of her illness, she began to have moderate respiratory distress that resulted in mild cyanosis of all extremities. Profound generalized muscle weakness occurred, and she became unable to walk. Two days before admission, her urine became dark brown and decreased in amount. She was known to have had normal renal function previously and had no history of kidney disease. Because of increasing respiratory distress and progressive cyanosis, she was admitted to a local hospital. Physical examination revealed an acutely ill woman without palpable blood pressure. Her fingers and toes, lips and face were cyanotic (Table I). The lungs were clear, and a chest film was within normal limits. A white blood cell count was 26,900/mm3, hematocrit value 44 per cent and blood urea nitrogen 40 mg/iOO ml. She was treated with intravenous saline solutions, intermittent intravenous hydrocortisone and antibiotics. Her vital signs returned to normal, and the cyanosis showed marked diminution. The urinary output was low and did not respond to the intravenous administration of mannitol or furosemide. The urine was dark brown in color, with a specific gravity of 1.023, pH 6.5, albumin 4-t and orthotolidin (Hemate&) 4+; microscopic examination showed an occasional white blood cell and red blood cell/hpf. Serum enzyme levels were markedly elevated (Table I). Because of the renal failure, the patient was transferred to the City of Memphis Hospital. Physical examination on admission revealed a critically ill but alert young woman in moderate respiratory distress. The vital signs were stable, but the extremities were cold and mildly cyanotic. Examination of the chest showed diffuse rales and rhonchi throughout both lung fields. The cardiac size was normal; the heart rate was 150 beats/min with a gallop rhythm. Laboratory values included a blood urea nitrogen of 72 mg/lOO ml, creatinine 7.5 mg/lOO ml, calcium 5.3 Case 1.
696
Serum
PO,a (mm
Renal Case
Satura-
November 1976
The American Journal of Medicine
= oxygen.
mg/lOO ml, phosphorus 7.6 mg/lOO ml, and sputum and blood cultures that were negative. Treatment was started with 6 liters of nasal oxygen. The arterial blood gases showed persistent hypoxia, however (Table I), and a volume-controlled ventilator and positive end-expiratory pressure were employed for ventilatory assistance. A Swan-Ganz catheter was inserted into the pulmonary artery for monitoring pressure. The intravenous administration of hydrocortisone was continued (400 mg/day), and the administration of aqueous penicillin G (8 million units/day) was begun. Because of continued renal failure, hemodialysis was performed regularly over a two week period. The patient showed marked clinical improvement with these measures, and all mechanical assistance was discontinued by the third week. She underwent a spontaneous diuresis during the recovery phase of acute renal failure, and renal function slowly returned to normal. Attempts to identify myoglobinuria during the diuretic phase by 80 per cent saturation with ammonium sulfate were unsuccessful. Serum was obtained during the acute and convalescent phases for influenza virus antibody determinations. The serologic response to A/Hong Kong/68 and Port Chalmers/if73 influenza viruses was measured by hemagglutination inhibition as described by Fazekas and Webster [7]. An increase in hemagglutination inhibiting antibody titers to 1: 10,000 dilution was detected (Table II). Extreme soreness and weakness persisted in the quadriceps muscles and prevented ambulation without assistance. Intensive physiotherapy produced gradual improvement in muscle strength. The patient was discharged on the 38th hospital day. Case 2.
A 33 year old white woman was admitted to the City of Memphis Hospital in acute respiratory distress (Table I). Three days earlier, she had been treated for symptoms of an upper respiratory tract infection. One day prior to admission, she became disoriented and progressive dyspnea developed.
Volume 61
INFLUENZA A INFECTION WITH RENAL FAILURE-SHENOUDA,
Physical examination revealed a well developed, slender woman who was confused and agitated. She had a temperature of 100.4’ F, blood pressure 118/70 mm Hg, pulse rate 120 beats/min and respiratory rate 48/min. Pertinent physical findings included cyanotic lips, coarse rales heard in bases of both lungs, a normal-sized heart without murmurs or gallop, and a neurologic examination within normal limits except for the altered mentation. Laboratory studies showed a hematocrit value of 43 per cent and a white blood cell count of 26,900/mm3; blood urea nitrogen was 16 mg/lOO ml and creatinine 0.8 mg/lOO ml. Arterial blood gases indicated severe hypoxia (Table I). The urine was yellow in color, with a specific gravity of 1.019, pH 6 and albumin negative; microscopic examination showed 0 to 4 white blood cells/hpf. Dther pertinent laboratory values included a direct platelet count of 417,000/mm3, negative protamine sulfate test and fibrinogen 460 mg/lOO ml. Serum enzyme levels were moderately elevated (Table I). Gram-stain of the tracheal aspirate revealed rare gram-positive diplococci. Blood and sputum cultures were negative. A chest film showed bilateral diffuse infiltrates consistent with pulmonary edema. The impression on admission was influenza viral pneumonitis with severe respiratory failure. The hypoxia did not diminish with oxygen administration, and positive end-expiratory pressure was begun. In addition, penicillin (8 million units/day) and gentamicin (120 mg/day) were administered. The patient’s condition improved clinically over the next 48 hours, but subsequently a persistent fever developed with a temperature of 103’F. A lumbar puncture was performed which was within normal limits. Acute renal failure developed as manifested by a decreased urine output and progressive azotemia. Repeat laboratory studies revealed a white blood cell count of 54,000/mm3; the red blood cell morphology showed many fragmented cells, burr cells and target cells; the platelet count was 152,000/mm3, fibrinogen 365 mg/lOO ml; protamine sulfate test was positive. The patient received intravenous heparin therapy for DIC, and hemodialysis was started. The platelet count fell subsequently to 44,200/mm3 and the fibrinogen was 265 mg/lOO ml. Bleeding developed subcutaneously and in the gastrointestinal tract. The patient had a cardiac arrest, but cardiac resuscitation was unsuccessful. Permission for an autopsy was not obtained. Blood was obtained for assays of influenza antibodies shortly before the patient’s death (Table II). Values determined during convalescence could not be obtained for comparison. Case 3. A 47 year old white woman had been in good health until two weeks prior to admission when fever, cough, malaise and a sinus infection developed. Four days later, she noticed progressive dyspnea, weight gain, and edema of her feet and ankles (Table I). She was admitted to a I& hospital where she was found to be in moderate respiratory distress. A 20 pound weight gain was documented, and her urinary output was diminished. Laboratory data included a hematocrit value of 20.5 per cent and a white blood cell count of 11 ,700/mm3; the blood urea nitrogen was 114 mg/iOO ml, serum creatinine 7.5 mg/lOO ml and creatinine clearance 7.7 ml/min. The patient
TABLE
Case No. 1 2+ 3 4
II
HATCH
Serologic Response to A/Hong Kong/68 and A/Port Chalmers/l/73 Influenza Viruses as Measured by Hemagglutination Inhibition No. of Days After Admission 9 22 8 7 19 15 32 53
Antibody Titers to Viral Antigens* Hong Kong/68 1:9,300 >1:10,000
