Severe illness with influenza B

Severe Illness with Influenza B

WILLIAM B. BAINE. M.D. JAMES P. LUBY. M.D.

Dallas. Texas STANLEY

M. MARTIN,

MS

Atlanta, Georgia

Fifteen patients with recent influenza B infection were admitted to three Dallas hospitals in the first 11 weeks of 1977. The patitints’ ages ranged from five to 73 years, with a median of 18 years. Most had no significant underlying disease. The spectrum of clinical illness included postinfluenzal bacterial pneumonia (three cases), other severe chest disease (two cases), hyperpyrexia and possible rhabdomyolysis in the elderly (two cases), onset of toxemia of pregnancy, thyroid dysfunction, Stevens-Johnson syndrome, neurologic disorders (two cases), and Reye’s syndrome (three cases). Two patients died. Two elderly men with high fever and weakness entered the hospital within three days of illness and two of three patients with Reye’s syndrome were admitted four days after the onset of influenza, but the 11 other patients gave a history of seven to 31 days of symptoms before being hospitalized. Morbidity and mortality with influenza B are neither trivial nor restricted to debilitated hosts. Current concepts of clinical influenza have largely developed from studying influenza A which enjoys a unique status because it can cause pandemic disease. Influenza B is relegated to the position of a perennial afterthought. This series of 15 cases of severe illness associated with influenza B diagnosed in one laboratory during a single outbreak emphasizes the varied manifestations of influenza B and its ability to cause severe illness. MATERIALS AND METHODS

From the Department of Internal Medicine, University of Texas Southwestern Medical School, and the Virology Laboratory, Parkland Memorial Hospital, Dallas, Texas: and the Bureau of Epidemiology, Center for Disease Control, Public Health Service, U. S. Department of Health, Education, and Welfare, Atlanta, Georgia. This study was presented in part at the 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, October 13, 1977, and at the Workshop on Influenza B Viruses, National Institutes of Health, Bethesda, July 30,1979. Request for reprints should be addressed to Dr. James P. Luby, Department of Internal Medicine, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Manuscript accepted July 24.1979.

During the winter of 1976-1977, visits to the Parkland Memorial Hospital emergency room by adults with temperatures llOl’F in whom the physician made a probable diagnosis of viral respiratory tract infection were tallied on a weekly basis. Syccimens of serums were solicited from patients at three Dallas hospitals in whom the diagnosis of influenza was considered. In some patients with recent onset, cultures of material from the respiratory tract for viral isolation were also obtained. Determination of complement-fixation (CF) titers for influenza B and hemagglutination-inhibition (HI] titers using B Hong Kong/5/72 antigen were performed by standard techniques [1,2]. Isolation of influenza virus from culture swabs transported in tryptose phosphate broth with 0.5 per cent gelatin was performed by standard methods after inoculation of lo-, to II-day embryonated chicken eggs. Confirmation of an isolate as influenza B was performed by standard methods [3]. A confirmed case of influenza B was defined by a fourfold or greater rise in CF or HI titer to influenza B alone or by isolation of influenza B virus from the patient. A presumptive case was defined by one or more serum specimens positive by CF testing at 11:128 to influenza B alone (and a majority had titers L1:256]. The validation of this criterion is given in the appendix to this paper.

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I8 25 December

I

8

15 22 29

5

12 19 26

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January

5

12 19 26

March

I April

WEEK ENDING Figure 1. Cases of presumably viral respiratory tract infection with temperatures 1 10l°F in adults by week of visit to Parkland Memorial Hospital Emergency Room, Dallas, 1976-1977.

Medical records of confirmed and presumptive cases were reviewed, and supplemental data and serum specimens were obtained by contacting patients or their relatives.

domyolysis, (4) onset of toxemia of pregnancy, dysfunction, (6) Stevens-Johnson syndrome, logic disorders and (8) Reye’s syndrome.

(5) thyroid (7) neuro-

RESULTS Visits by adults to the Parkland Memorial Hospital emergency room for febrile presumably viral respiratory tract infection reached a peak during the week ending February 19 (Figure l]. Influenza B virus was obtained from the throat culture of a patient seen in the emergency room on February 18. Five patients with confirmed cases and 10 with presumptive influenza B were admitted to Parkland Memorial Hospital, the Dallas Veterans Administration Hospital or Children’s Medical Center. The epidemic curve of the 15 cases by date of onset (Figure 2Aj indicates a peak during the week ending February 12. The epidemic curve of cases by date of hospitalization (Figure 2B) more closely parallels the curve of emergencyroom visits (Figure l), reflecting the substantial interval in many cases between the onset of influenza1 symptoms and presentation for admission to the hospital. This interval ranged from one to 31 days, with a median of 10 days. There were eight male and seven female patients. Their ages ranged from five to 73 years with a median of 18 years. The distribution of cases by race, socioeconomic status and place of residence was comparable in each hospital to that of the usual patient population. The 15 cases comprised eight clinical categories: (1) postinfluenzal bacterial pneumonia, (2) other severe chest disease, (3) hyperpyrexia and possible rhab-

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REPORT OF CASES In three patients Postinfluenzal Bacterial Pneumonia. bacterial pulmonary infections developed seven to 31 days after the onset of presumed influenza B. One of these patients died, and the other two required drainage of empyemas. Patient 1. A 32 year old black woman with a history of diabetes mellitus was hospitalized with ketoacidosis and bilateral pneumonia two weeks after the onset of a dry cough. Despite vigorous therapy, she died 31 hours after arriving at the hospital. Postmortem examination revealed bilateral bronchopneumonia with extensive abscess formation. Staphylococcus aureus and group B streptococcus were cultured from the lungs. Influenza B serology determined on admission revealed a CF titer of 1:128 and an HI titer of 1:320. Patient 2, A 22 year old Mexican laborer was admitted with staphylococcal pneumonia and empyema after having been ill for one week. He made a satisfactory recovery after the institution of chest-tube drainage and two weeks’ treatment with methicillin. A serum specimen drawn on the 16th hospital day revealed a CF titer of l:l28 to influenza B. Patient 3. A 65 year old white man with a history of previous alcoholism was admitted to the hospital with an involved history of respiratory complaints of one month’s duration, culminating in pneumococcal pneumonia and empyema with bacteremia. He required therapeutic bronchoscopy and

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CONFIRMATION

SEROLOGIC

CONFIRMATION

42PRESUMPTIVE I

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-

I8 25

b BY DATE

I

8

15 22

29

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OF HOSPlTALlZATlON

18 25 December

I

8

15 22 29

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I9

26

5

12 19 26

March

WEEK ENDING J Cases of influenza B infection hospitalized at Parkland Memorial Hospital, Children’s Medical Center, or the Dallas Veterans Administration Hospital in 1976-1977: A, by week of onset; B, by week of hospitalization.

Figure2.

by chest tube, and then rib resection, but he demonstrated a steady defervescence with antibiotic therapy and

drainage

was well on subsequent outpatient visits. An influenza B CF titer determined on blood drawn on the fifth hospital day was positive at 1:128.

Other Severe Pulmonary Disease. Two patients were hospitalized with pulmonary complaints after illnesses of two weeks’ duration without evidence of bacterial infection. One died of pneumonia with virologically proved influenza B. Patient 4. A 45 year old black woman receiving prednisone for long-standing systemic lupus erythematosus died one day after she was hospitalized with bilateral pneumonia. No autopsy was performed, but a specimen aspirated from her endotracheal tube before her death yielded a virus resembling B Hong Kong/5/72. Patient 5. In a 35 year old white mechanic dyspnea and substernal pleurisy developed after a two-week respiratory illness. While breathing room air, the patient had arterial oxygen tension [PaO,] of 56 mm Hg with an unremarkable chest film. Pulmonary perfusion and ventilation scans were interpreted as indicating a high probability of pulmonary embolism, and the patient was given heparin until pulmonary angiography showed only changes consistent with emphysema. Influenza B serology determined on the fourth day of hospitalization revealed a CF titer of 1:128. The patient returned 41 days after discharge, complaining of substernal pressing pain aggravated by coughing, inspiration or lying supine. Three examiners noted a transient, soft, onecomponent precordial rub. His electrocardiogram was un-

changed, but echocardiography suggested a small pericardial effusion. His condition improved spontaneously. Two serum specimens drawn on this admission yielded CF titers to influenza B virus of 1:64and 1:128. Microneutralization antibody titers to Coxsackie B virus, types 1 through 6, showed no significant change when compared to the findings in serum drawn on the previous admission. The influenza B CF titer in a serum specimen drawn five months later was <1:8.

Hyperpyrexia and Possible Rhabdomyolysis,

Two

elderly men required hospitalization soon after the acute onset of high fever and weakness. In both cases, laboratory studies suggested the possibility of rhabdomyolysis, but renal failure did not occur. Patient 6. A 73 year old man had been homebound

for four years because of dementia. One day before admission he had watery stools and could not arise from bed. He then became confused, with a high fever and rigors. Physical examination on admission reuealed a stiff, shivering, incoherent, elderly black man with abdominal guarding and a temperature of 105.2'F. The chest film disclosed no abnormalities. The serum creatine phosphokinase (CPK) was not measured immediately, but a serum specimen obtained on the ninth hospital day yielded 262 IU/liter (normal range 40 to 180W/liter), with 100 per cent as isoenzyme MM. Culture of material from the nasopharynx obtained on admission yielded influenza B virus. The patient gradually became afebrile, his laboratory tests and strength returned to normal, and he was discharged after 33 days of hospitalization. Patient 7. A 61 year old man was hospitalized with a three day history of sore throat, dyspnea, myalgias, weakness and

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fever, with temperatures to 104’F. On admission he was a lethargic black man in mild respiratory distress with rales in the lower lobes of both lungs and occasional wheezes, but roentgen films of the chest disclosed only chronic-appearing changes without infiltrates. Serum CPK measured on the third hospital day was 948 IU/liter. Isoenzyme determination on a specimen obtained on the next day showed 100 per cent isoenzyme MM. The patient rapidly became afebrile and was discharged after 14 days. Serum drawn on the 11th hospital day revealed a CF titer of >1:256 to influenza B virus.

of Pregnancy. Although no causeand-effect relationship was shown, one patient with serologically proved influenza B required pharmacologic induction of labor because of hypertension and azotemia. Onset of Toxemia

Patient 8. A 17 year old previously healthy primigravida presented at eight months’ gestation with a three-day history of sore throat and coryza with subsequent fever. She was a pregnant black woman with a blood pressure of 160/106 mm Hg and a temperature of 103’F. Her lungs were described as clear, but an infiltrate was visible on roentgenogram in the lower lobe of the left lung. She was treated with penicillin and admitted to monitor her blood pressure and renal function. Because of intermittently elevated blood pressure readings as high as 142/110 mm Hg and a serum creatinine reaching 1.6 mg/dl, labor was induced with an infusion of oxytocin, with the uneventful delivery of a 2,030-g infant. Between the fifth and 12th hospital days, her titer of CF antibody to influenza B virus rose from 1:8 to 11:256.

Thyroid function was abnormal in a patient with serologic evidence of influenza B, who still had subclinical hyperthyroidism five months later. Inasmuch as the diagnosis of viral disease of the thyroid was considered only in retrospect, neither 1311-uptake measurement ?or biopsy to confirm or exclude thyroiditis was performed.

Thyroid Dysfunction.

Patient 9. An 18 year old white woman was hospitalized with pulmonary infiltrates three weeks after onset of a dry cough followed by a temperature of 106’F, shaking chills, left-sided pleurisy and hemoptysis. On admission, she had a temperature of 97.8’F and coarse rales in the lower lobes of both lungs. There was no thyromegaly. The x-ray film of the chest showed bilateral infiltrates. An influenza B CF titer determined on the day after admission was 1:128. She was discharged after three days of observation in the hospital. Thyroid function tests reported back after the patient’s discharge showed the triiodothyronine (Ts) resin uptake to be 38.6 per cent (normal range: 33.5 to 46.5 per cent); Ts resin uptake ratio, 0.96 (normal: 0.84 to 1:16); serum thyroxine, 12 rg/dl (normal: 4.8 to 10.4 rg/dl); and free thyroxine index, 7.57 (normal: 3.3 to 6.5). When re-examined five months later she had no signs or symptoms of hyperthyroidism, but her thyroid function tests were still somewhat abnormal (Ts resin uptake, 41.1 per cent; T3 resin uptake ratio, 1.03; thyroxine, 10.8 pg/dl; free thyroxine index, 7.22). An influenza B CF titer measured at this time was <1:8.

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Syndrome. An incapacitating mucocutaneous eruption developed in one patient with serologically confirmed influenza B infection. Stevens-Johnson

Patient 10. An 18 year old waitress presented to the hospital with a history of respiratory symptoms and with temperatures to 104°F.Seven days before admission ulcers had developed on her vagina, followed by oral blisters, a punctate exanthem, spreading from her upper limbs to her trunk and lower extremities but sparing the plantar surfaces, hoarseness, dysuria and hematuria. Her mouth had become swollen and sore, and she had lost 10 pounds in six days due to inanition. She denied having taken any medications or other drugs prior to the onset of her rash. Physical examination on admission revealed an acutely ill white woman with a cough and a temperature of 102.4”F [Figure 3). She had a hemorrhagic conjunctivitis with secondary blepharoconjunctivitis. The tympanic membranes were injected, the nostrils were clogged with inspissated exudate, the lips were swollen and ulcerated, and the oral mucosa was inflamed. She had diffuse rhonchi. The vagina was ulcerated. The trunk and extremities revealed numerous well-circumscribed 0.5 to 2 cm erythematous maculopapular lesions, including some with central darkening, vesiculation or bullae. She was given prednisone and tetracycline, and a diagnosis of erythema multiforme, possibly due to Mycoplasma pneumoniae infection was made. No evidence of mycoplasmal infection was demonstrated, but the patient showed steady improvement and was discharged after nine days’ hospitalization. Paired serums drawn on the second and ninth days in hospital revealed influenza B CF titers of 1:32 and 1:128, respectively. Disorders. In two patients disturbances of the central nervous system developed as apparent sequelae to influenza B infection. Neurologic

11. In a nine year old boy the Guillain-Barr& syndrome developed during the second week after a febrile respiratory illness.and intubation was accomplished on admission. On admission to the intensive-care unit physical examination revealed a Hispanic boy receiving assisted ventilation. There was evidence of dysfunction of the fifth, sixth, ninth, tenth and eleventh cranial nerves, but the patient retained some abduction of the left eye, and a weak gag reflex was present. There was limb weakness, greatest in the lower extremities. Deep tendon reflexes were weak in the upper extremities and absent in the lower. The cerebrospinal fluid showed 1 polymorphonuclear leukocyte and 2 mononuclear cells/mm3; the protein was 46 mg/dl, and the glucose was 92 mg/dl. The patient was discharged after a complicated course covering 34 days in the hospital: his pulmonary function test results and phonation were normal. A serum specimen obtained on admission revealed a CF titer of 11:256 to influenza B.

Patient

Patient 12. A 16 year old girl came to the hospital complaining of visual disturbances. A week earlier she had noted a bifrontal headache and then fever and chills over four days. Three days before admission, she had experienced vomiting and diarrhea. Two days prior to admission, the headache had worsened, and

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Figure 3.

A, Stevens-Johnson syndrome with serologically proved influenza B in Patient 10. B, view of face demonstrating involvement of conjunctivas and mouth.

she had noted periorbital swelling and a stiff neck. The day before admission, she had experienced syncope, dysuria, urgency and lower abdominal pain. On admission, she was an agitated black girl with a temperature of 101.4°F. Her eyelids were swollen and tender, and the conjunctivas were injected. There was nuchal rigidity, and Brudzinski’s and Kernig’s signs were elicited. There was weakness of abduction of the eyes, particularly on the left, and Babinski’s sign was present bilaterally. An ophthalmologic consultant noted papilledema in the form of central disk elevation in the right eye, no spontaneous venous pulsations and questionable venous engorgement. Visual acuity, measured with a Rosenbaum 14-inch scale, was 20/50 in both eyes. At the time of lumbar puncture, the cerebrospinal fluid overflowed the top of the manometer-however, the patient did not lie still during the procedure. The final pressure was 25 cm HzO. Cell count, glucose and protein were within normal limits. The patient was treated with acetaminophen and by the next day was markedly better. The ophthalmologic consultant saw complete resolution of the papilledema. She was discharged completely recovered after one more day. A nasopharyngeal culture obtained on admission was subsequently positive for influenza B virus.

Reye’s Syndrome. Three cases of Reye’s syndrome presumptively associated with influenza B virus were seen at Children’s Medical Center and Parkland. Patient 13. In a five year old girl “flu-like” symptoms developed four days before her admission. Thirty-six hours before admission she began to vomit. The findings on a liver biopsy and blood chemistry studies were consistent with Reye’s syndrome. She required intracerebral pressure monitoring, intubation and assisted ventilation, but she was discharged

recovered after 12 days. Serum specimens obtained one and two weeks after discharge showed a CF titer of 11:256 to influenza B. The HI titer on the first specimen was ?1:1280. Patient 14. A 15 year old white boy was hospitalized for lethargy and confusion after four days’ sore throat, three days’ nausea and abdominal cramps, and two days’ vomiting. The findings on liver biopsy and blood chemistry studies were compatible with Reye’s syndrome. The patient required intracranial pressure monitoring, intubation and assisted ventilation but was discharged recovered after seven days. Serum specimens drawn one and two weeks after discharge showed CF titers of 11:256 to influenza B. The HI titer in the first specimen was 21:1280. Patient 15. In a nine year old white girl fever and coryza developed nine days after a transient episode of respiratory distress. Three days thereafter she had headache, vomiting and abdominal pain. The next day she awoke crying, disoriented, ataxic, confused and combative. She was hospitalized and found to have a serum glutamic oxaloacetic transaminase @GOT) of 248 U/ml (normal range, 6 to 25 U/ml]. On the following day, she was transferred to Dallas. She received intravenous glucose but did not require other supportive measures. A blood ammonia determination was 84 fig/d1 on the fourth hospital day. She was discharged recovered after four days. The CF titer to influenza B in serum drawn on the second hospital day was 11:256.

COMMENTS The epidemiology of influenza B is characterized by discrete outbreaks, without virologically identifiable cases in interepidemic periods [4-181. The greatest apB as a cause of clinically signifpreciation of influenza

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children [l&12,19-211, even though pneumonia as a complication of influenza B in adults has been recognized since the 1940’s [5,22-271. Although respiratory illness predominates quantitatively in any outbreak of influenza B, other manifestations of this infection contribute to its role as a cause of mortality and serious morbidity. Previous reports have dealt with muscular [28-311, neurologic [32-351, gastrointestinal [11,29], mucocutaneous [36], thyroid [37] and hematologic [38] disorders, and Reye’s syndrome [39-471. Influenza B can have a catastrophic effect on immunologically virgin populations [17], but in the United States it does not rival influenza as a cause of morbidity and mortality [48]. Precisely because influenza A is SO important, the significance of influenza B is apt to be underestimated. We were able to identify 15 patients with influenza B infection who required hospitalization. Only five fell into the categories for which the Public Health Service recommended immunization against influenza B, and most were healthy children or young adults. They were hospitalized a total of 184 man-days. Five required assisted ventilation, and two of these patients died. Also during their stay they were subjected to a formidable list of invasive diagnostic and therapeutic procedures, including placement of an intracranial transducer (two instances), bronchoscopy, thoracocentesis (two instances], chest-tube placement (three instances), rib resection and placement of an empyema tube, Swan-Ganz catheterization, pulmonary angiography, liver biopsy (two instances), peritoneal dialysis and lumbar puncture [five instances). One patient had labor induced with oxytocin, and another was treated with anticoagulants. Few of the patients in this series were suspected by the admitting physicians of having influenza or a complication thereof. Most cases were identified by active surveillance during the epidemic or as a result of requests to screen serologic specimens for a battery of viral agents. In most cases, respiratory complaints due to influenza or superimposed bacterial pneumonia were not the reason for hospitalization. Hochberg et al. have pointed out that surveillance of morbidity and mortality from respiratory disease, a sensitive monitor of influenza A activity [15], ignores the problem of influenza B-associated Reye’s syndrome [43]. A more general statement can be made: Quantitatively rare, but qualitatively severe, complications or sequelae outside the respiratory system may be the most significant contributors to morbidity and mortality in outbreaks of influenza B. Evidence strongly supporting this concept already exists [48]. These complications in all age groups, as well as viral and postinfluenzal bacterial pneumonia in adults, will not be identified without alert hospital-based surveillance. Prompt attention to the possibility of identifying underlying or antecedent influenza B infection in patients presenting with a wide variety of syndromes during an outbreak with this virus in the community should broaden the clinical spectrum

186

of disease associated with type B influenza well beyond that of just “the flu” in school children. ACKNOWLEDGMENT We thank Ms. Becky Frank and Ms. Sandra Butler for expert technical assistance, Donna Dryer, R.N., for compiling emergency-room surveillance data, and Geraldine Murphy, R.N., for obtaining follow-up specimens and information. The cases of Reye’s syndrome will be reported in greater detail in a separate publication by Daniel L. Levin, M.D., and his associates. F. Kevin Murphy, M.D., generously provided photographs of Patient 10. APPENDIX Validation of a Minimal Serologic Titer for the Presumptive Diagnosis of Influenza B. A fourfold or

greater rise in titer using the CF or HI test is the basis for the serodiagnosis of influenza [49], but this does not imply that serologic data are worthless in the absence of optimally timed paired specimens, Members of a population who have recently had influenza should, as a group, have higher titers of antibody than their unaffected counterparts. This concept is the basis for the established seroepidemiologic method for rapid confirmation of the existence of an outbreak of influenza [501. Unpaired specimens of serum can also be used to support a diagnosis of influenza in an individual case when “antibody titers proved to be statistically higher than expected” are demonstrated [51]. Data supporting the use of high CF titers in paired serums in the diagnosis of influenza are available from studies of outbreaks of both influenza A [52] and B [22,53]. Hoyle regards a CF titer 132 as “practically diagnostic of recent infection” with influenza B virus [54]. A CF titer 2128 was used to establish a presumptive diagnosis of influenza B during the 1976-1977 outbreak in Dallas from a statistical evaluation of serologic data TABLE I

Antibody Titers* to Influenza B CF Antigen Among Patients with Serum Specimens Tested December lg754arch 1976

Patients (no.)

Class (r)+

f

Expected Patients (no.)

16 32 64 128 1256

142 22 7 1 0 0

0 1 2 3 4 5

0.8237 0.1378 0.0296 0.0068 0.0016 0.0005

142 23.7 5.1 1.2 .2a .OQ

Total

172

..

1.000

172

CF liter (1)

18

There were 267 specimens tested from 172 patients. When more than one specimen was received from a given patient, the one with the highest titer was tabulated. + r = logpt - 3. l

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from the Virology Laboratory, Parkland Memorial Hospital. During December 1975 through March 1976, when no influenza B activity was detected in the community, antibody titers to influenza B CF antigen were measured in 172 patients. None showed seroconversion, and only one patient had a titer as high as 64 (Table I). To facilitate computation, the titers, t, were transformed to classes

ILLNESS

The negative binomial distribution was then fitted to the serologic data from December 1975 through March 1976 [561.

(Equation

1).

The parameters m and p can be approximated by the moment estimators ?ii and is. For a sample, n, of large size, YR=ml’

(Equation

Z),

[Equation

3),

and ml

p=

12

m2 - ml’ where ml’ and m2 represent variance, respectively. Thus,

the sample

mean

and

, _ Z4iri ml z4i =

0.2267,

and

= 0.2933,

TABLE II

Antibody Titers* to Influenza B CF Antigen Among Patients with Serum Specimens Tested December 1976~March 1977

CF Tftsr

Class (r)+

18 la 32 64 128 1256

0 1 2 3 4 5

Total

f*

Patients (W

Expected Patients (no.1

0.8237 0.1378 0.0296 0.0068 0.0016 0.0005

80 15 7 7 6 6

99.7 16.7 3.6 0.82 0.19 0.06

1.000

121

121

There were 201 specimens tested from 121 patients. When more than one specimen was received from a given patient, the one with the highest titer was tabulated. + r = logst - 3. + Based on data from previous year (Table I).

B-BAINE

ET AL.

where r represents the titers after the logarithmic transformation given here, and 4 is the number of patients with titer r. Using these values, from Equation 2 and 3 one obtains m = 0.2267, and fs = 0.7723.

[551! r = logzt - 3 (Table I].

WITH INFLUENZA

These values can be substituted into Equation 1 to obtain values of f for each r. For this study, values of f were calculated with a computer, adopting an iterative solution using more efficient estimators, as described by Sichel [56] (Table I]. In each class, multiplication of the total number of patients, 172, by the appropriate value for f gives the number of patients expected in each class on the basis of the negative binomial (Table I]. The observed and expected frequencies are in good agreement. That is, the distribution of titers during the period from December 1975 through March 1976 was closely approximated by the negative binomial. A year later, from December 1976 through March 1977, the Virology Laboratory tested 201 specimens from 121 patients for antibody to influenza B CF antigen. Applying the frequency distribution given by the negative binomial based on data from the year before to these 121 patients yields the expected distribution of titers for these four months in 1976-1977 (Table II). Assuming no changes in testing procedures, the population from which specimens are submitted to the Virology Laboratory, or the prevalence of influenza B in that population, only 0.25 patients with a titer 2128 would have been expected from December 1976 through March 1977. Since testing procedures and the referral population did not change, a titer 2128 would have suggested recent influenza B infection even under endemic conditions. Since an outbreak of influenza B was documented in the community at that time, and since the predictive value of a positive test is increased by an increase in the prevalence of disease in the population [57], there is particular reason to be confident that cases of influenza B diagnosed on the basis of a CF titer 2128 represented true positives. With regard to the cases described in the body of the article that were diagnosed on the basis of high CF titers without virus isolation or documented seroconversion, what is the likelihood that any represent false-positive cases? The values of f for each titer can be taken to represent the probability that a person from the population in question would have a titer at that level. The probability of false positives can be calculated using the binomial distribution. For a titer 1256. the probability of finding one or more positives in a sample of 121 patients is

l

1 -

(1 - o.ooo5)1”1

= 0.059.

For a titer 2128, the probability of finding positives in a sample of 121 patients is

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1 - (1- (0.0016 + 0.0005)]121 = 0.22. The probability of finding two or more false positives at a cutoff of 2128 in a sample of 121patients is the difference between the aforementioned number and the probability of finding exactly one false positive, that is 1 - (1- o.oo21)1~1 - lfl (0.0021)(0.9979)120 = 0.027. (1

Thus, even ignoring the existence of an outbreak of influenza B infection in the commmunity, it is unlikely that any of the patients diagnosed as having an infection on the basis of a CF titer 1256 did not have recent influenza B.Similarly, it is very unlikely that more than one of the patients diagnosed as having an infection on the basis of a CF titer of 128did not have recent influenza B,and it is more probable that there were no false positives.

REFERENCES 1. National Communicable Disease Center: A guide to the oerformance of the standardized diagnostic comolement fixation method and adaptation to micro test. ‘Atlanta: Public Health Service, U. S. Department of Health, Education, and Welfare, 1969. 2. Center for Disease Control: The hemagglutination inhibition test for influenza viruses. Atlanta: Public Health Service, LJ. S. Denartment of Health. Education. and Welfare, 1975.

3.

4.

5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

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Robinson RO. Dowdle WR: Influenza viruses. In: Lennette EO. Schmrdt NJ, eds. Procedures for viral and rickettsial infections. 4th ed. New York: American Public Health Association, 1969. Philip RN, Bell JA, Davis DJ: Epidemiologic studies on influenza in familial and general population groups, 1951-1956. II. Characteristics of occurrence. Am J Hyg 1961; 73: 123. Commission on Acute Respiratory Diseases: Endemic influenza. Am J Hyg 1948; 47: 290. Jordan WS Jr, Badger GF. Dingle JH: A study of illness in a group of Cleveland families. XVI. The epidemiology of influenza, 1948-1953. Am J Hyg 1958; 68: 169. Hall CE. Coonev MK, Fox JP: The Seattle virus watch. IV. Comparative epidemiologic observations of infections with influenza A and B viruses, 1965-1969, in families with young children. Am J Epidemiol1973; 98: 365. Monto AS, Kioumehr F: The Tecumseh study of respiratory illness. IX. Occurrence of influenza in the community, 1966-1971. Am 1Enidemioll975; 102: 553. Chin TDY, Mosley WH, Poland JD. et al.: Epidemiologic studies of tvne B influenza in 1961-1962. Am J Pub Health ‘1963;53: 1068. Clark PS, Feltz ET, List-Young B, et al.: An influenza B epidemic within a remote Alaska community. JAMA 1970;214: 507. Moffet HL, Cramblett HG, Middleton GK Jr, et al.: Outbreak of influenza B in a children’s home. JAMA 1962; 182: 834. Klein JD, Collier AM, Glezen WP: An influenza B epidemic amone children in dav-care. Pediatrics 1976; 58: 340. Francis T Jr: A new type of virus from epidemic influenza. Science 1940; 92: 405. Craighead JE. Shelokov A, Vogel JE. et al.: An outbreak of influenza B in Panama. Am J Trop Med Hyg 1961; 10: 71. Rubin RI. Grenr! MB: Influenza surveillance in the United States:i972-y974. Am J Epidemio11975; 102: 225. Pokoski MO, Boudreault A, Pavilanis V: An epidemic of influenza B in the province of Quebec in the spring of 1966: laboratory studies. Can Med Assoc J 1967; 96: 457. Warbuton F. Barnes R. Gajdusek DC: Unpublished data cited in Brown P, Gajdusek DC, Morris JA: Epidemic Az influenza in isolated Pacific island populations without pre-epidemic antibody to influenza virus types A and B, and the discovery of other still unexposed populations. Am J Epidemiol1966; 83: 176.

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18. Zhdanov VM: The 1967 outbreak of influenza B in the U.S.S.R. Lancet 1967; 1: 263. 19. Parrott RH, Kim HW, Vargosko AJ, et al.: Serious respiratory tract illness as a result of Asian influenza and influenza B infections in children. J Pediatr 1962; 61: 205. 20. Poland JD, Welton ER. Chin TDY: Influenza virus B as cause of acute croup syndrome. Am J Dis Child 1964; 107: 54. 21. Caul EO, Waller DK, Clarke SKI? A comparison of influenza and respiratory syncytial virus infections among infants admitted to hospital with acute respiratory infections. J Hyg (Camb) 1976; 77: 383. 22. Nigg C, Eklund CM, Wilson DE, et al.: Study of an epidemic of influenza B. Am J Hyg 1942; 35: 265. 23. Hare R, Hamilton J, Feasby WR: Influenza and similar respiratory infections in a military camp over a period of three years. Can J Pub Health 1943; 34: 453. 24. Himmelweit F: Influenza virus B isolated from a fatal case of pneumonia. Lancet 1943; 2: 793. 25. Mufson MA, Chang V, Gill V, et al.: The role of viruses, mycoplasmas and bacteria in acute pneumonia in civilian adults. Am J Epidemiol 1967; 86: 526. 26. Hornsleth A, Siggaard-Andersen J, Hjort L: Epidemiology of herpes virus and respiratory virus infections. Part 1. Serologic findings. Geriatrics 1975; 30 (8): 61. 27. Siggaard-Andersen J, Hjort L, Hornsleth A: Epidemiology of herpesvirus and respiratory virus infections. Part 2. Clinical findings. Geriatrics 1975; 30 (8): 73. 28. Middleton PJ, Alexander RM, Szymanski MT: Severe myositis during recovery from influenza. Lancet 1970; 2: 533. 29. Kerr AA, Downham MA, McQuillin J, et al.: Gastric ‘flu: influenza B causing abdominal symptoms in children. Lancet 1975: 1: 291. 30. Dietzman DE, Schaller JG, Ray CG, et al.: Acute myositis associated with influenza B infection. Pediatrics 1976; 57: 255. 31. Cars 0, Friman G, Nordbring F, et al.: Myalgia nuchae as a manifestation of epidemic influenza. Stand J Infect Dis 1977; 9: 1971. 32. Leigh AD: Infections of the nervous system occurring during an eoidemic of influenza B. Br Med 1 1946: 2: 936. 33. Colonnello F, Signorini C, Di Natale M: Isolamento di virus influenzale B da1 polmone e da1 cervello di un paziente deceduto per meningoencefalite. G Ma1 Infett Parassit 1966; 18: 811. 34. Stevens D, Burman D, Clarke KR, et al.: Temporary paralysis in childhood after influenza B. Lancet 1974; 2: 1354. 35. Kruger H, Franke M: Eine postgrippale, chronisch verlaufende Polyradiculoneuritis Guillain-Barre mit oligoclonaler Gammopathie und generalisierter Amyloidose. Psychiatr Neurol Med Psycho1 (Leipz) 1974; 26: 492. 36. Neumann D, Lengsfeld C: Exanthematischer Verlauf der Influenza-B-Virus-Grippe bei Kindern. Dtsch Med Wochenschr 1972; 97: 263. 37 Joasoo A, Robertson P, Murray IPC: Viral antibodies in thyrotoxicosis. Lancet 1975; 2: 125.

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38. Puxeddu A, Colonna A, Nenci GG, et al.: Su di un rare case di.anemia emolitica autoimmune da virus influenzale B. Haematologica (Pavia] 1965; 50: 1073. 39. Reye RDK, Morgan G, Baral J: Encephalopathy and fatty degeneration of the viscera: a disease entity in childhood. Lancet 1963; 2: 749. 40. Johnson GM, Scurletis TD. Carroll NB: A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. North Carolina Med J 1963,24: 464. 41. Norman MG, Lowden JA, Hill DE, et al.: Encephalopathy and fatty degeneration of the viscera in childhood. II. Report of a case with isolation of influenza B virus. Can Med Assoc ]1968;99:549.

42. 43. 44. 45. 46. 47.

Reynolds DW, et al.: An outbreak of Reye’s syndrome associated with influenza B. J Pediatr 1972; 80: 429. Hochberg FH, Nelson K. Janzen W: Influenza type B-related encephalopathy. The 1971 outbreak of Reye syndrome in Chicago. JAMA 1975; 231817. Ruben FL, Michaels RH: Reye syndrome with associated influenza A and B infection. JAMA 1975; 234: 410. Corey L. Rubin RJ, Hattwick MAW, et al.: A nationwide outbreak of Reye’s syndrome: its epidemiologic relationship to influenza B. Am J Med 1976; 61: 615. Corey L, Rubin RJ. Thompson TR, et al.: Influenza B-associated Reye’s syndrome: incidence in Michigan and potential for prevention. J Infect Dis 1977; 135: 398. Center for Disease Control: Reye syndrome-United States. Morbidity Mortality Weekly Rep 1978: 27: 15.

ET AL.

48. Housworth J, Langmuir AD: Excess mortality from epidemic influenza 1957-1966.Am J Epidemiol1974; 100: 40. 49. Dowdle WR, Coleman MT: Influenza virus, chap 72. In: Lennette EH, Spaulding EH. Truant JP, eds. Manual of clinical microbiology, 2nd ed, Washington: American Society for Microbiology, 1974. 50. Palmer DF, Dowdle WR, Coleman MT, et al.: Advanced Laboratory Techniques for Influenza Diagnosis, Atlanta, Center for Disease Control, 1975. 51. Dowdle WR: Influenza virus, chap 57. In: Rose NR, Friedman H. eds. Manual of clinical immunology. Washington: American Society for Microbiology, 1976. 52. Schwarzmann SW, Adler JL, Sullivan RJ Jr, et al.: Bacterial pneumonia during the Hong Kong influenza epidemic of 1968-1969. Arch Intern Med 1971; 127: 1037. 53. Hoyle L. Fairbrother RW: Serological diagnosis of epidemic influenza by the the complement-fixation reaction. Br Med J 1947; 2: 991. 54. Hoyle L: The influenza viruses. 28. Immunity and antibody production in influenza. Virol Monogr 1968,4: 205. 55. White C: Statistical methods in serum surveys, chap 3. Serological Epidemiology [Paul JR, White C, eds). New York, Academic Press, 1973. 56. Sichel HS: The estimation of the parameters of a negative binomial distribution with special reference to psychological data. Psychometrika 1951; 16: 107. 57. Feinstein AR: Clinical Biostatistics, St. Louis, C.V. Mosby, 1977,~216.

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