Rapid Diagnosis of Primary Influenza Pneumonia

Rapid Diagnosis of Primary Influenza Pneumonia* Douglas B. Bogart, M.D.;oO Chien uc. M.D.;t William E. Ruth, M.D., F.C.C.P.;t Gerald R. Kerby, M.D., F.C.C.P.;§ and Clyde H. Williams, M.D.11

Primary influenza pneumonia is a disease of high mortality. Differentiation between a bacterial and viral etiology for the pulmonary inftltrates frequently presents a diagnostic dilemma. Rapid diagnosis is essential; and once estabUshed, the patient requires careful supportive therapy. This report describes two patients with primary Inftuenza pneumonia compHcated by severe respiratory faDore. Early diagnosis of the pulmonary Infiltrates was accomplished by obtaining bronchial secretions with

fiberoptic bronchoscopy and staining tbem with influenza-A fluorescent conjugate. One patient died of the compUcations of this iDness, despite maximal supportive therapy. The other patient survived the illness and at tbe time of hospital discharge was showing marked improvement in his exercise tolerance. There was subsequent gradual return of ventilation and gas transport functioD to normal values.

he occurrence of pneumonia in patients with T influenza infections has been well described.v"

of infected respiratory epithelial cells provides a method for rapid diagnosis. If one is to accurately assess the pulmonary pathologic findings, it is essential to obtain bronchial secretions free from upper respiratory tract contamination. Both of the patients presented in this report had nasotracheal tubes in place because of severe respiratory failure. These tubes provided a ready means of access to the lower respiratory tract by passing a catheter. When nasotracheal suction yielded only scanty secretions, both patients underwent fiberoptic bronchoscopy. This was done through the nasotracheal tube. Under such circumstances, fiberoptic bronchoscopy has proved to be a useful means of obtaining material for culture and microscopic examination." Using a combination of these two procedures, bronchial epithelial cells and sputum free from upper respiratory tract secretions may be obtained and studied. Once the etiologic .agent is established, appropriate therapy may be undertaken. If the infiltrate is due to bacterial infection, specific chemotherapy should be instituted. However, if a primary influenza pneumonia is found, careful supportive therapy should be undertaken for the adult respiratory distress syndrome. Furthermore, should effective antiviral therapy become available, it may be used to augment the supportive measures." This report describes two patients with primary influenza pneumonia. The diagnosis was established rapidly by immunofluorescent staining of bronchial aspirates.

These lesions can be caused by the influenza virus alone or by secondary bacterial invaders, or both. Since the therapy of pneumonia depends on the etiologic agent responsible, each patient with a pulmonary infiltrate developing during an influenza infection or influenza epidemic must be carefully evaluated. Confirmatory diagnosis of an influenza infection is based on the isolation of the influenza virus from nasal or pharyngeal secretions, tissue specimens from the respiratory tract obtained by biopsy or postmortem examination, and/ or by a rise of the serum antibody titer. All of these methods require considerable time to establish the diagnosis, and they do not provide a rapid basis for clinicians to render immediate therapy to their patients. In addition, neither the isolation of influenza virus from the upper respiratory tract nor a rising serologic titer proves that the patient's pulmonary disease is due to the influenza virus. The immunofluorescent technique developed by Liu? for detecting specific influenza viral antigens in the cytoplasm and nucleus ·From the Department of Medicine, School of Medicine, University of Kansas, Kansas City. o·Chief Resident, Department of Medicine. tProfessor of Medicine and Pediatrics, and Director, Division of Infectious Diseases. tProfessor of Medicine and Director, Division of Pulmonary Diseases. §Associate Professor of Medicine. IIResident in Medicine. Manuscript received January 30; revision accepted March 25. Reprint requests: Dr. Liu" University of Kansas Medical C enter Kansas City, Kansas 66103

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RAPID DIAGNOSIS OF PRIMARY INFLUENZA PNEUMONIA 513

obtained for microscopic examination and for bacterial, fungal, acid-fast bacilli, and viral cultures, as well as for a smear preparation for immunofluorescent staining. When smears from the bronchial aspirates were stained with influenza-A fluorescent conjugate, many ciliated epithelial cells containing specific influenza viral antigen were seen, and a positive diagnosis of influenza infection was established within one hour after the specimen was obtained (Fig 2). This diagnosis was subsequently confirmed by the isolation in tissue culture of influenza A2 virus from the same bronchial aspirates and a marked rise of the hemagglutination-inhibition antibody titer to influenza A2 virus in the patient's serum collected on the 24th day of his hospitalization. Acid-fast bacilli and fungal cultures and smears were negative. In addition, no bacteria were seen on microscopic examination of the bronchial aspirates, and none was grown from the cultures. With this information plus the positive immunofluorescent smear, a diagnosis of primary influenza pneumonia was made. With this diagnosis, supportive measures were undertaken. These included management directed at the adult respiratory distress syndrome. In an effort to provide hetter oxygenation, the patient was given digitalis, corticosteroids, and furosemide. Because of the possibility of a diffuse bacterial pneumonia prior to fiberoptic bronchoscopy, the patient initially FIGURE 1. Admission posteroanterior chest roentgenogram demonstrating hilateral pneumonia with some sparing of left upper lobe . CASE REPORTS CASE

1

A 48-year-old white man was in his usual state of health until four days prior to his appearance at the University of Kansas Medical Center on Feb 3, 1972 . At this time the patient noted onset of fever, diffuse myalgia, rhinorrhea, and cough. He became confused and combative and was taken to his local physician, who then referred him to the University of Kansas Medical Center. His past medical history was si~nificant in that the patient had a 100-pack-per-year history of cigarette consumption. On admission, the patient complained of severe dyspnea and was producing a small amount of clear sputum. Physical examination revealed that the patient was cyanotic, confused, and combative. His vital signs included a respiratory rate of 60 per minute, blood pressure of 120/70 mm Hg, a pulse of 120 beats per minute, and a temperature of 38.3°C (101°F). Diffuse inspiratory and expiratory rales were noted in all lung fields. The rest of the examination was within normal limits . On admission, blood gas analyses showed an arterial oxygen tension (Pa02) of 19 mm Hit, an arterial carbon dioxide tension (PaC0 2) of 40 mm Hit, and pH of 7.31. The remainder of the admission laboratory results were within normal limits, except for a blood urea nitrogen (BUN) level of 40 mg/l00 ml and a urinalysis which showed 2+ protein and was packed with granular casts . His chest x-ray film revealed a diffuse alveolarnodular pattern sparing only the left upper lobe (Fig 1) . The electrocardiogram showed a sinus tachycardia and positional changes consistent with diffu se pulmonary disease. Initial therapy for this patient was directed at improving his severe hypoxemia. This required nasotracheal intubation and the use of a volume cycled respirator (MA-l) . Following this , diagnostic fiberoptic bronchoscopy was performed which showed changes compatible with severe bronchitis, but only minimal secretions were present. Bronchial aspirates were

514 BOGART ET At

FIGURE 2. Ciliated columnar epithelial cells from bronchial aspirate obtained by fiberoptic bronchoscopy on day of admission (upper, case 1; lower, case 2). These cells contained specific fluorescence representing influenza antigen when stained by influenza A fluorescent conjugate ( X 600) .

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FIGURE 3. Improvement in chest roentgenograms at six weeks (left) and 14 weeks (right) after onset of illne ss. did receive cephaloth in and gentamicin. As soon as the diagnosis of influenza pneumonia was established, the gentamicin therapy was discontinued. Cephalothin therapy was continued because the patient had a history of chronic bronchitis and because the initial Gram sta in of the expectorated sputum showed a mixed bacterial flora. This medication was stopped on the tenth hospital day when a drug eruption appeared. At this time the sputum cultures showed a growth of Serratia marcescens that was resistant to cephalothin. However, the patient had no apparent symptoms nor any increase in his pulmonary infiltrations attributable to this organism. No other pathogenic bacteria were cultured from the sputum . His pulmonary disease responded to th is supportive therapy, and the patient was weaned off the respirator by the 19th hospital day. He was slowly tapered off oxygen therapy and was able to maintain an adequate oxygen tension on room air at the time of discharge from the hospital. Figure 3 shows the improvement in the chest x-ray films during the course of the illness . In addition to the chest x-ray films, the patient's pulmonary function also improved dramatically. Initially, a restrictive pattern was seen with a decrease in the forced vital capacity (76 percent of predicted) ; the gas transport factor was also markedly decreased (7 ml of carbon monoxide per minute) . However, these defects gradually improved, and the values were essentially normal six months after the onset of the illness . These changes were associated with a marked increase in exercise tolerance. Similar changes in pulmonary function have been seen in patients with influenza infections.!" Two da ys aft er admission, the patient developed progressive oliguria and azotemia. This was felt to represent acute tubular necrosis from prolonged hypoxia. Because of progressive azotemia and hyperkalemia, peritoneal dialysis was undertaken on the sixth and 12th hospital days. By the 16th hospital day the urine output had returned with a progressive fall in the BUN and creatinine levels . At the time of discharge, the pat ient had a creatinine clearance of 70 ml/rnm, During the peritoneal dialysis, the patient had acute upper gastrointestinal bleeding (site undetermined) , which required six units of packed red blood cells and hourly antacid therapy to control. The patient had no sequelae from this at the time of discharge.

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Despite the se complications, the patient was discharged after 50 days of hospitalization with essentially normal renal and pulmonary functions. CASE

2

A 53-year-old white woman was in good health until one week prior to admission at the University of Kansas Med ical Center. While returning from vacation in San Juan, PR, she noted the onset of a sore throat, generalized myalgia, and fever to 38 .9°C (102°F). The patient consulted her local physician who treated her with penicillin. On the following day the patient began to produce sputum and had hemoptysis. Over the next three days the patient became progressively short of breath and was persistently febrile to 39.4°C to 40 .0°C (103°F to 104°F). At this time the chest x-ray film showed a five-lobe pulmonary infiltrate. The patient was treated with gentamicin and cephalothin. Because of progressive respiratory distress, the patient was intubated and transferred to the University of Kansas Medical Center. Her past medical history was negative for heart disease. The patient did have a history of a chronic productive cough, but she did not smoke cigarettes. Physical examination on admission revealed an obese white woman who was responsive only to painful stimuli and who had an endotracheal tube in place. Vital signs showed blood pressure of 170 /90 mm Hg , a heart rate of 120 beats per minute, a respiratory rate of 40 per minute, and a temperature 38.5°C (101.3°F). Inspiratory and expiratory rales were heard in all lung fields. The finding s from the rest of the physical examination were within normal limits . Pertinent initial laboratory studies showed a leukocytosis of 13,400 / cu mm with a normal hemoglobin level and hematocrit reading. The blood glucose level was 222 mg /loo ml, and the urinalysis showed 2+ glycosuria. The results of renal and liver function studies were normal. At admission, blood gas analyses on 100 percent oxygen via Arnbu-bag and endotracheal tube showed a Pa02 of 21 mm Hg, a PaC0 2 of 44 mm HI'(, and pH of 7.38. The chest x-ray film showed alveolar infiltrates in all five lobes. Soon after admission to this hospital, bronchoscopy was performed through the endotracheal tube. Diffuse airway erythema was noted, and watery secretions were present. The

RAPID DIAGNOSIS OF PRIMARY INFLUENZA PNEUMONIA 515

Table l-Re.ul'. 0/ J'irolopc Studi~ in Cue 2

Study Smear of bronchial aspirate Bronchial aspirate Serum for HAl test against influenza A 2 Serum for HAl test against influenza A 2 Autopsy tissues (blood, spleen, kidney, heart, liver, brain, and lung)

Date

Results

4/18/74

FA positive for influenza A Positive isolation of A2 influenza virus (England) Titer, 1/10

5/2/74

Titer, 1/160

5/2/74

No virus isolated

4/16/74 4/16/74

positive immunofluorescent smear for influenza A on the bronchial aspirates (Fig 2) coupled with negative smears and cultures for acid-fast bacilli, bacteria, and fungi established a diagnosis of influenza pneumonia. This diagnosis was later confirmed by the isolation of influenza A2 virus ( England) from the bronchial washings and a 16-fold rise in the titer of hemagglutination-inhibition antibody in the acute vs convalescent sera (Table 1). The therapy in this patient was also directed at the adult respiratory distress syndrome. Dehydration measures, corticosteroid therapy, and positive end-expiratory pressure ( PEEP) therapy were all used. The patient did show some temporary improvement, but at no time could she be weaned off the PEEP therapy. Her course was further complicated by disseminated intravascular coagulation, and she died on the 18th hospital day. At autopsy, the lungs showed the typical findings of primary influenza pneumonia. These changes included interstitial pneumonia, hyaline membrane formation, and intra-alveolar hemorrhage. Neither bacteria nor virus could be cultured from the lungs at autopsy. COMMENT

A pulmonary infiltrate appearing in a patient with a suspected influenza infection presents a diagnostic challenge. Differentiation between primary influenza and secondary bacterial pneumonia is difficult, as there are no specific clinical signs nor a characteristic roentgenographic picture in either condition. Louria et all described the following four patterns which characterize the lower respiratory tract involvement among patients with Asian influenza: (1) physical signs of lower respiratory tract involvement without x-ray film evidence of pneumonia (this is thought to indicate bronchiolitis caused by the virus ); (2) influenza complicated by secondary bacterial pneumonia; (3 ) primary influenza viral pneumonia which is characterized by being diffuse and hemorrhagic; and (4) combined influenza viral and bacterial pneumonias. It is apparent that this scheme provides only a general outline of the pulmonary pathologic findings which may follow an influenza infection but gives no clues for the specific diagnosis of a pulmonary infiltrate. Lindsay et al4 were able to separate their patients

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with pneumonia and Hong Kong influenza into two categories based on their roentgenograms. The localized pneumonia was felt to be either bacterial or viral in etiology and was associated with a low mortality. In contrast, the patients with bilateral diffuse pneumonia had a high mortality, and this was thought to represent primary influenza pneumonia. However, in both groups, bacterial pathogens were frequently isolated, making it difficult to assess the pathogenic role of these organisms. No diagnostic approach was outlined to clearly establish the etiologic agent in this series of patients. Two other series from the Hong Kong influenza pandemic of 1968 to 1969 stress the incidence of pneumonia in these patients.v" Bisno et al6 found that the Pneumococcus organism was the most common pathogen isolated. The low mortality in this series was attributed to a low incidence of both primary influenza pneumonia and staphylococcal pneumonia. In contrast, Schwarzmann et al 3 found that 26 percent of their influenza patients with pneumonia had Staphylococcus during this same epidemic. From these studies, it is apparent that there is a wide range of presentation in patients with influenza and pneumonic infiltrates. Neither the clinical picture nor the roentgenographic appearance establishes with certainty the etiologic agent involved. The approach to the patients presented here provides a means for a rapid specific diagnosis in patients with suspected influenza and pneumonic infiltrates. It is suggested that each of these patients be evaluated with adequate sputum samples for bacterial, fungal, and acid-fast bacilli smears and cultures, plus viral cultures and immunofluorescent studies. In those patients who are unable to produce sputum, transtracheal aspiration or fiberoptic bronchoscopy may facilitate obtaining these specimens. When this tissue is subjected to immunofluorescent staining, an accurate diagnosis can be established within an hour. With such information, either specific chemotherapy for bacterial infection or careful supportive therapy for primary influenza infection can be undertaken. It is hoped that this approach will help reduce the high mortality rate in this group of patients. REFERENCES

I Louria DE, Blumfeld HL, Ellis JI, et al: Studies on influenza in the pandemic of 1957-1958: 2. Pulmonary complications of influenza. J Clin Invest 38:213-265, 1959 2 Burk RF, Schaffner W, Koenig MG: Severe influenza virus pneumonia in the pandemic of 1968 to 1969. Arch Intern Med 127:1122-1128, 1971 3 Schwarzmann SW, Alder JL, Sullivan RJ, et al: Bacterial pneumonia during the Hong. Kong influenza epidemic of

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1968 to 1969. Arch Intern Med 127:1037-1041, 1971 4 Lindsay MI, Hermann EC, Morrow GW, et al: Hong Kong influenza: Clinical, microbiological, and pathological features in 127 cases. JAMA 214:1825-1832, 1970 5 Kaye D, Rosenbluth M, Hook EW, et al: Endemic influenza: 2. The nature of the disease in the post-pandemic period. Am Rev Respir Dis 85:9-21, 1962 6 Bisno AL, Griffin JP, Van Epps KA, et al: Pneumonia and Hong Kong influenza: Prospective study of the 1968-1969 epidemic. Am J Med Sci 261:251-263, 1971 7 Liu C: Diagnosis of influenza infection by means of

fluorescent antibody staining. Am Rev Respir Dis 83: 130138,1961 8 Renz LE, Smiddy]W, Rauscher CR, et al: Bronchoscopy in respiratory failure. JAMA 219:619, 1972 9 Galbrath AW, Oxford JS, Schild GC, et al: Therapeutic effect of l-adamantanamine hydrochloride in naturally occurring influenza A2/Hong Kong infection: Controlled double blind study. Lancet 2:113-115, 1971 10 Johanson WG, Pierce AK, Sanford JP: Pulmonary function in uncomplicated influenza. Am Rev Respir Dis 100:141-146, 1969

Notre-Dame de Paris Two hundred years in the building, Notre-Dame was never really completed according to the scheme of the original designers. By the fifteenth century the cathedral was already considered outdated; to men of the dawning Renaissance it was but a grotesque symbol of the barbarian past, a hulking, gloomy pile to which the epithet "Gothic" was contemptuously affixed. Later, baroque additions would destroy much of the original harmony, all in the name of modernization. Then, an inspired and dedicated architect of the mid-nineteenth century,

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Eugene Emmanuel Violet-Le-Duc, began the painstaking work of restoration; and only in the present decade, with the cleansing of all Parisian monuments, has the cathedral been revealed in its pristine elegance. To reverent believers, to students of history, even idly curious tourists, Notre-Dame de Paris is now more than ever, the supremely beautiful sight in what is widely regarded as the world's supremely beautiful city. Winston, R and Winston, C: Notre-Dame de Paris, New York, Newsweek, 1971

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