The relationship between the aetiology of pneumonia in adults and certain clinical and radiographic findings

Brit. o7. Dis. Chest Q969) 63, I4o.

The Relationship between the Aetiology of Pneumonia in Adults and Certain Clinical and Radiographic Findings M. E. SGHONELL 1, W. CRAY 2, MARGARET A. J. MOFFAT 2, MARGARET A. C A L D E R 2 AND S H E I L A M . STEWART 3 x Department of Respiratory Diseases, University of Edinburgh 2 City Hospital, Edinburgh s Department of Bacteriology, University of Edinburgh (Medical Research Council Research Assistant)

I T has been suggested that in patients with pneumonia the presence of mucoid sputum, a normal white blood count and a segmental or lobular abnormality in the chest radiograph may indicate a viral infection (Crofton I953; R u s b y 1965). Biberfeld et al. (1965) and Alexander et al. (i 966) reported that patients with pneumonia from whom Mycoplasma pneumoniae had been isolated suffered an illness characterized by systemic symptoms and a normal white blood cell count. Few workers have considered the effect of concurrent or secondary bacterial infection in viral or mycoplasma pneumonia. In such cases bacterial infection might influence the clinical and radiographic features. The present study consisted of a retrospective analysis of pneumonia to determine to what extent the presence of infections with viruses, mycoplasma and bacteria could be related to certain clinical and radiographic findings. Patients One hundred and six adult patients with pneumonia were reviewed. The 'p0sitive ' group consisted of 53 patients over the age of 12 years secn during the period 1960 to 1965 with complement fixation tests showing evidence of current or recent infection with a virus or with M. pneumoniae. Current and recent infection is defined below. For convenience, infections with CoxieUa burnetii and psittacosis are referred to as viral infections. Forty-three (81 ~o) of the patients were admitted to hospital; the remainder were seen as outpatients. From the serological results the cases were grouped as follows: (I) Thirty-two patients with current or recent viral infection. (2) Fourteen patients with current or recent infection with M. pneumoniae. (3) Seven patients with current or recent infection with both viruses and

M. pneumoniae. A further 53 patients with pneumonia and negative serological results were selected as a control group in such a way that the numbers of cases in the positive and control groups were similar in any one year of the investigation. Fifty (Reaeivedfor publication, September x968)

RELATIONSHIP

BETWEEN

PNEUMONIA

AND CLINICAL FINDINGS

I4I

(94~o) of the controls were admitted to hospital; the remainder were outpatients. The ratio of males to females was 2 to i in the positive and control groups. The average age in patients with viral infections was 52 years, in those with M. pneumoniae infections 39 years and in the control group 53 years, with age ranges of i6 to 97, I3 to 82 and 14 to 88 years respectively. Methods

Serological methods Sera taken on admission and after an interval of 14 to 21 days were tested for complement-fixing antibodies according to the technique of Bradstreet and Taylor (1962) using the following antigens:influenza A,B,C, para-influenza I, adenovirus group antigen, respiratory syncytial virus, C. burnetii, psittacosis group antigen and M. pneumoniae. Most of the complement fixing antigens were obtained from the Standards Laboratory for Serological Reagents, Central Public Health Laboratory, Colindale Avenue, London NW9. Parainfluenza I antigen was originally obtained from Colindale but later from Burroughs Wellcome. Respiratory syncytial antigen was at first prepared in this laboratory from the Randall strain but more recently was obtained from Colindale. The M. pneumoniae antigen was prepared at Colindale using washed and heat-killed organisms; a chloroform-methanol extract of M. pneumoniae was not used.

Definition of current and recent infections Patients were considered to have had a current infection if there was a 4-fold rise in antibody titre between the paired sera. A diagnosis of recent infection was made on the basis of the following raised titres : influenza A I/512, influenza B I [ 128, influenza C i/256, para-influenza I I [ 128, adenovirus I/256, respiratory syncytial virus 1/128, C. burnetii 1/128, psittacosis I/I28 and M. pneumoniae I [ 16o. The viral titres were selected because they were above the level consistently found in patients from whom repeated specimens had been tested in the same laboratory at intervals over a period of 4 years (Moffat & Sutherland 1967). The titres for C. burnetii and psittacosis were selected arbitrarily. Titres signifying recent infection with M. pneumoniae were at least 4 times the m a x i m u m titres found in a group of i 15 patients without respiratory infection.

Bacteriological methods Sputum or laryngeal swabs were collected on admission. In 25 (47%) patients in the positive group and 32 (6O~o) in the control group the sputum was homogenized by agitating for 3o minutes in a mechanical shaker with an equal quantity of sterile distilled water and a small number of glass beads. Loopfuls of the homogenized sputum were inoculated on to blood agar and heated blood agar plates which were incubated at 37°C for I8 hours in an atmosphere of iO~o carbon dioxide. Intraperitoneal mouse inoculation

SCHONELL~ GRAYz MOFFAT~ C A L D E R AND S T E W A R T

I42

was also carried out. In the remaining patients with sputum a loopful of sputum was inoculated on to blood agar and incubated for 18 hours at 37°C. Gram films were made from all specimens of sputum. In each group there were 4 patients from w h o m sputum was not available; in these cases laryngeal swabs were examined. In 14 patients no bacteriological examinations were made.

Twenty-four strains of Streptococcus pneumoniae were sero-typed using typing sera from the State Serum Institute, Copenhagen.

Clinical methods The following information was recorded: duration of illness before presentation, antibiotic therapy before admission, purulence of sputum and maximum erythrocyte sedimentation rate and white blood cell count. A chest radiograph taken at the patient's first attendance was read on two separate occasions. At the time of reading the clinicians were unaware of the results of the laboratory findings. Abnormalities were classified as lobar, segmental or lobular. A lobular abnormality involving one or two radiological zones of the lung was recorded as localized lobular; if more than two zones were involved it was recorded as diffuse lobular. Results

Serological results The results of the serological tests in the 53 patients in the positive group are shown in Table I. Thirty-two patients had current or recent viral infection. Two of the patients with raised titres to psittacosis also had raised fitres to one or more viruses. In 14 patients there was current or recent infection with M. pneumoniae. A further 7 patients had evidence of infection with both virus TABLE I. RESULTS OF COMPLEMENT-FIXATIONTESTS ON 53 PATIENTS IN THE POSITIVE GROUP

Total no. o f patients Influenza A Influenza B Influenza C

Para-influenza I R e s p i r a t o r y syncytial (2. burnetii Psittacosis M , pneumoniae Virus a n d M . pneumoniae Total

r

Wo. o f patients with ~" # f o l d rise Raised titre* in titre

io 2 4

6 I I

4 I 3

6

3

3

I I 8 14 7

o I I 8 7

I o 7I" 6 o

53

~8

25

* For criteria see text O n e p a t i e n t in this group h a d raised titres to influenza B a n d influenza C; one p a t i e n t h a d a raised titre to para-influenza I

R E L A T I O N S H I P B E T W E E N P N E U M O N I A AND C L I N I C A L FINDINGS

I43

and M. pneumoniae; in these cases the viruses involved were influenza A (2 eases), para-influenza I (4 cases) and a combination of para-influenza I, respiratory syncytial virus and psittacosis (I case).

Bacteriological results The potential bacterial pathogens isolated from patients in the positive and control groups are shown in Table II. Potential pathogens were isolated from TABLE

II. P O T E N T I A L

B A C T E R I A L P A T H O G E N S ISOLATED POSITIVE A N D C O N T R O L G R O U P S

FROM

PATIENTS

IN T H E

Patients with positive serological results Bacterial pathogen

Virus positive

Str. pneumoniae H. influenzae Staph. aureus H. influenzae with Str. pneumoniae H. influenzae with Staph. aureus

M . pneumoniae Virus and positive M . pneumoniae positive

Total

Patients in control group

5 o o

i i 2

4 2 o

io 3 2

i8 4 4

~

o

I

3

I

o

o

o

o

I

T o t a l no. of patients with pathogens No pathogens isolated Bacteriology not done

7 17 8

4 9 I

7 o o

18 (35~o) 26 (4870) 9 (I77o)

Total no. of patients

32

I4

7

53

28 (5270) 2o (3870) 5 (IoTo)

(10070)

53

(10070)

35~0 of patients in the positive groups compared with 5 2 ~ in the control group. The organisms isolated were similar in all groups, the commonest organism being Str. pneumoniae; the types of Str. pneumoniae are shown in Table III. Type 3 was isolated more frequently from patients with negative seroTABLE

IlL TYPES

OF Str. pneumoniae I S O L A T E D IN T H E POSITIVE AND CONTROL GROUPS

Patients with positive serological results z Virus and Virus M . pneumoniae M . pneumoniae positive positive positive No. of Str. pneumoniae isolated No. of Sir. pneumoniae typed Types

7 5 3, 4, 8, 9, 20

I o --

5 3 3, 8, 14

Patients in control group I9 I6 3 (9 strains), 5, 8 (2 strains), x2, 19 (2 strains), 20

SCHONELL~ GI~AY~ MOFFAT~ C A L D E R AND S T E W A R T

144

logical results (56~o) than from patients with positive results (25~o). The numbers were small and the difference was not statistically significant. The rate of isolation of potential bacterial pathogens and the history of previous antibiotic therapy are shown as histograms in Fig. z. Although potential No bacteriat pnthogens, pQthogens ~ previous F'7 No previous chemotllerapy', chemotherapy given or not known Controt Virus H.pneumoniae Virus and positive positive H...:pneumonioe group positive Ho bacterial

~

BocteriM pothogens isototed

100

21

80 Percentage of

60

///

/// //// //

¢ o c

15

/ / /

on oo'

~oo°¢

o~

/ / / iii / / /

"~'t¢ ~L I t

:joo:

'50: >

t,O

I

III

on

patients

15

o c

,°o%, ~oo° ,~%~

20

o o .

//~/

)58:

;31;

~//~

Z /1

Total no. of ntients 2~

/ / /

i/I i// F/I

13

7

48

FIO. I. Potential bacterial pathogens or previous antibacterial therapy in the positive and control groups. Cases in which sputum or laryngeal swabs were not examined have been excluded. Figures within the columns represent the percentage of patients in each sub-group

bacterial pathogens were isolated less frequently from those patients with current or recent infection with a virus or M. pneumoniae, the proportion of patients with known or possible previous antibacterial therapy was greatest in these groups; the lower isolation rate of bacteria may have been due to previous therapy. The percentage of patients who had not had previous chemotherapy and from whom no bacterial pathogens were isolated was similar in all groups. Potential bacterial pathogens were isolated 7 times more frequently from sputum which had been cultured in IO~o carbon dioxide and inoculated into mice compared with specimens which had been cultured only on blood agar.

Sputum purulence Seventy-five per cent of the patients in the positive group had muco-purulent sputum compared with 7O~o in the control group. All the patients from whom potential bacterial pathogens were isolated had muco-purulent sputum.

RELATIONSHIP

BETWEEN

PNEUMONIA

AND GLINICAL FINDINGS

I45

Duration of illness before presentation Patients with a 4-fold rise in antibody titre to a virus, to M. pneumoniae or to both a virus and M. pneumoniae had been ill for a shorter duration before being first seen (mean durations 5"8, 7"9 and 8.6 days respectively) than those with a raised titre to a virus or M. pneumoniae (mean durations 23"3 and 21 "7 days respectively). The mean duration of illness in the control group was 11.3 days. The mean duration of illness in those patients from w h o m Str. pneumoniae was isolated was less than in those from whom Str. pneumoniae was not isolated (9.i days compared with I6" 4 days in the serological positive group; 9"9 days compared to 12"I days in the control group).

Erythrocyte sedimentation rate and white blood cell count The erythrocyte sedimentation rate and white blood cell count in the patients in the positive and control groups are shown in Table IV. Patients in T A B L E IV. E R Y T H R O C Y T E SEDIMENTATION R A T E A N D W H I T E B L O O D C E L L C O U N T IN T H E POSITIVE A N D C O N T R O L G R O U P S

Patients with positive serological results )k

,

M . pneu- Virus and Virus moniae M . pneupositive positive moniae positive

Total

Patients in control group

Erythrocyte sedimentation rate Less than 20 m m / h r 2o-50 m m / h r Greater than 5 ° m m / h r Not known

3 7 15 7

3 5 6 o

o 2 3 2

6 I4 24 9

(I I~o) (26070) (4670) (I707o)

8 6 33 6

(I5%) (1 I°7o) (63°70) (1107o)

White blood cell count Less than I2,ooo m m 3 12,ooo-I8,ooo m m 3 Greater than 18,ooo m m s Not known

23 4 3 2

9 3 2 o

4 3 o o

36 lO 5 2

(68070) (I907o) (9%) (4070)

29 15 8 I

(55~o) (28~o) (I5%) (2%)

T o t a l no, of patients

32

14

7

53 (IOO07o)

T A B L E V. R A D I O G R A P H I C A P P E A R A N C E S IN T H E POSITIVE A N D C O N T R O L

Radiographic abnormality

t

6 I2 9 5

5 5 3 i

3 i o 3

14 18 I2 9

T o t a l no. of patients

32

I4

7

53 (lOO07o)

3

GROUPS

Patients with positive serological results ~..- • Patients in Virus and control group Virus M . pneumoniae M . pneumoniae Total positive positive positive

Diffuse lobular Localized lobular Segmental LObar

VOL. LXIII

53 (1oo7o)

(26070) (34070) (23°7o) (1707o)

12 IO x6 I5

(23°~o) (19°7o) (30°70) (28~o)

53 (IOO07o) 3

146

SCHONELL, GRAY~ MOFFAT~ C A L D E R A N D S T E W A R T

the positive serological group tended to have a lower erythrocyte sedimentation rate and a lower white blood cell count than those in the control group. The differences were not significant.

Radiographicfindings The radiographic appearances in the positive and control groups are shown in Table V. There was no significant difference in the type of radiographic abnormality in the various groups.

Discussion

Mufson and his co-workers (1967) investigated the role of viruses, mycoplasma and bacteria in acute pneumonia in civilian adults admitted to hospital. They found evidence of more than one aetiological agent in 21 of 427 cases. In 12 of these patients there was a viral infection and Str. pneumoniae was also isolated from throat swabs or sputa. In 3 patients there was combined infection with a virus, M. pneumoniae and Str. pneumoniae. They also found that Str. pneumoniae was the only bacterial pathogen that occurred significantly more frequently in patients with pneumonia than in a control group of i, 134 patients without respiratory tract disease. The present series suggests that in patients with positive viral or mycoplasmal serology it is extremely difficult to determine the relative aetiological importance of bacteria, viruses or mycoplasma. It is possible that the virus or mycoplasma may predispose to the pneumonia without actually causing it. On the other hand, it is known that respiratory bacterial pathogens may be carried in the naso-pharynx of healthy individuals and isolation of a pathogen does not necessarily imply that it is playing a pathogenic role. Few patients in the present series had evidence of only a viral or mycoplasmal infection. In the majority of the patients with positive viral or mycoplasmal serology and of those with negative serological results, either a potential bacterial pathogen was isolated or the patient had received antibiotic therapy which would have made detection of pathogenic bacteria unlikely. It is of interest that in 7 patients there was a 4-fold rise in antibody titre to a virus and to M. pneumoniae and that in 5 of these Str. pneurnoniae was also isolated from the sputum. Str. pneumoniae was the bacterium most commonly isolated in both groups. Type 3 was isolated slightly more frequently from those patients with negative serology than from those in the positive group. To obtain the maximal isolation rate of Str. pneumoniae special bacteriological techniques, including mouse inoculation, must be used, otherwise the extent of bacterial infection may be underestimated (Crofton et al. 1951). The commonest viral infections were due to the influenza group of viruses. This is in keeping with previous reports (Holland et al. 196o; Mufson et al. 1967). There were no adenovirus infections i n the present scries, confirming the findings of Fraser and Hatch (1959) and van der Veen (1963) that this virus is an infrequent predisposing or causative factor in pneumonia in adults

RELATIONSHIP

BETWEEN

PNEUMONIA

AND CLINICAL FINDINGS

I47

in hospital. It is appreciated that in some of the patients with negative serological results there may have been infection with viruses that were not detected by the methods used. No specific clinical or radiographic appearance was found in patients with viral or mycoplasmal infections, possibly because in m a n y cases there was superadded bacterial infection. This may also explain why muco-purulent sputum occurred as frequently in patients with viral or mycoplasmal infections as in the control group. There was a suggestion that patients with viral or mycoplasmal infections tended to have a lower erythrocyte sedimentation rate and white blood cell count, but the differences compared with the control group were not significant. Oswald et al. (1958), in a review of pneumonia complicating Asian influenza, concluded that the white blood cell count was of little value in differentiating a predominantly viral infection from one with secondary invasion by a pyogenic organism. TyrreU (1952) stated that the white blood cell count was of no value in distinguishing influenzal pneumonia from non-influenzal pneumonia. In the present study half of the patients in the positive group had a raised antibody titre to a virus or M. pneumoniae in the first specimen of serum. This is accepted as evidence of a recent infection. Infections with M. pneumoniae respond to tetracycline and erythromycin but are insusceptible to the penicillins (Kingston et al. 1961 ; Smith et al. 1967). C. burnetii and the psittacosis group are also susceptible to tetracycline. It would seem helpful to the clinician for the results of serological tests on the first specimen of serum to be available immediately rather than to wait Iff to 21 days before the second serum is tested. I f the results suggest a recent infection with these agents the clinician may wish to use an antibiotic to which the organism is susceptible. This will also apply to the results of viral serology when anti-viral agents become available. Our results suggest that m a n y adult patients with a viral or mycoplasmal infection, who develop pneumonia and become ill enough to be admitted to hospital, m a y also have a bacterial infection. This may explain why there was relatively little difference in the radiographic and haematological findings in patients with or without evidence of a viral or mycoplasmal infection. Most reported series of pneumonia presumed to be viral or mycoplasmal in origin have not included careful bacteriological studies, but the frequency of multiple aetiology in pneumonia is now being increasingly recognized. It m a y be that specific features of viral or mycoplasmal pneumonia might emerge in patients with milder illness treated at home, or in the armed forces where men are admitted to hospital more readily than in civilian life. O u r results m a y only reflect the situation in a civilian hospital, but this is the context in which most severe pneumonias are treated.

Summary One hundred and six adults with pneumonia were reviewed to determine to what extent the presence of infections with viruses, mycoplasma and bacteria could be related to certain clinical and radiographic findings. Fifty-three

148

SCHONELL, GRAY, MOFFAT~ CALDER AND STEWART

patients with serological evidence of a recent infection with a virus or M. pneumoniae were compared with 53 patients in whom serological tests were negative. In a high proportion of both groups either potential bacterial pathogens were isolated or there was a history of antibacterial therapy before bacteriological examination. The findings suggest that in pneumonia associated with viral or mycoplasmal infections in adults ill enough to be admitted to hospital there is frequently an accompanying bacterial infection. There was no significant difference in the proportion of patients in each group with mucoid sputum or raised erythrocyte sedimentation rate or white blood cell count. Nor was there any difference in the proportion of patients with different types of radiographic abnormality. It is possible that bacterial infection affected the clinical and radiographic findings in patients with viral or mycoplasmal infections.

Acknowledgements The authors wish to thank Professors J. W. Crofton and B. P. M a r = i o n and Drs I. W. B. Grant and N. W. H o m e for their advice and criticism. They also wish to thank the techniciam in the Wellcome Laboratory, City Hospital, Edinburgh for their assistance and the secretaries for typing the manuscript. The cases investigated were under the care of Professor J. W. Crofton and Drs A. C. Douglas, I. W. B. Grant, N. W. Home, J. McC. Murdoch and G. Sangster. The study was supported by grants from the Wellcome Trust, the Scottish Hospitals Endowment Research Trust, the Royal Victoria Hospital Tuberculosis Trust and the Medical Research Council. The authors are grateful to the Standards Laboratory for Serological Reagents, Colindale, London N W 9 for the supply of antigens.

References ALEXANDER, E. R., FoY, H. M., KENNY, G. E., KRONMAL, R. A., M C M A H A N , RUTH, CLARKE, E. R., MAcCoLL, W. A. ~ GRAYSTON, J. r. (i966) Pneumonia due to Mycoplasma pneumoniae. New Engl. 07. Med., =75, 13 I. BIBERFELD, G.,JoHNSSON, T. &JONSSON, J. (1965) Studies on Mycoplasmapneumoniae infection in Sweden. Acta. path. microbiol, scan&, 63, 469 • BRADSTREET, C. M. PATRIClA & TAYLOR, C. E. D. (1962) Technique of complementfixation test applicable to the diagnosis of virus diseases. Mth. Bull. Minist. Hlth Lab. Serv., rex, 9 6. CROFTON, J. W. (i953) Pneumonia. Edinb. reed. 07, 60, 113. CROFTON, J. W., FAWCETT, J. W., JAMES, D. G., SCADDING, J. G., MACRAE, A. D. & MARMION, B. P. (I951) Pneumonia in West London. Brit. med. ft, m, 1368. FRASER, P. K. & HATCH, L. A. (1959) Outbreak of adenovirus infection in the Portsmouth naval command, 1958. Brit. reed. o7., I, 47 o. HOLLAND, W. W., TANNER, ELIZABETH I.,PEREIRA, MARGUERITE S. & TAYLOR, C. E. D. (196o) A study of the aetiology of respiratory disease in a general hospital. Brit. med. 07., x, 19I 7. KINGSTON, J. R., CHANOCK, R. M., MUFSON, M. A., HELLMAN, L. P., JAMES, W. D., F o x , H. H., MANKO, M. A. &BOYERS, J. (i96i) Eaton agent pneumonia. 07. Amer. reed. Assoc., x76, 118. MOFFAT, MAROARET A. J. & SUTHERLAND, J. A. W. (I967) Persistence of viral antibodies in patients with chronic bronchitis. Brit. med. 07, i, 6Ol. MUFSON, M. A., CHANG,V., GILL, V.; WOOD,S. C., ROMANSKY,M.J. & CHANOCK,R. M. (I967) The role of viruses, mycoplasmas and bacteria in acute pneumonia in civilian adults. Amer. 07. Epidem., 86, 526.

RELATIONSHIP BETWEEN PNEUMONIA AND CLINICAL FINDINGS

I49

OSWALD,NEVILLE C., SHOOTER,R. A. & CURWEN, 1VL P. (1958) Pneumonia complicating Asian influenza. Brit. reed. 3:., 2, 13o5. I~USBY, N. LLOYD (1965) Antibiotics and sulphonamides in respiratory infections. Practitioner, x95, 735. SMITH, C. B., FRIEDWALD, W. T. & CHANOCK, R. M. (1967) Shedding of Mycoplasrna pneumoniae after tetracycline and erythromycin therapy. Wew Engl. 07. Med., 276, 1172. TYRRELL, D' A . J . (i95~) The pulmonary complications of influenza as seen in Sheffield in I949. Quart. 07. Med., N.S. 2x, 29 I. VAN DER VEEN, J. (1963) The role of adenoviruses in respiratory disease. Arner. Rev. resp. Dis., 88 (suppl.), 167.