ACUTE
RESPIRATORY
DISEASES
Etiologic,
Diagnostic
and
Therapeutic
Considerations
By John M. Adams, M.D.
Department of Pediatrics, School of Medicine, University of California, Los Angeles
ADDRESS: University of California Medical Center, Los Angeles 24, California.
129
REVIEW
ARTICLE
LTHOUGH some real advances have been made recently in our basic knowledge of acute respiratory tract infections, there
still remain many practical problems of
diagnosis and treatment of these common
diseases. The diagnosis of influenza and
measles, particularly during epidemics, is
not considered difficult. During an epi-demic these diseases might represent a fairly
large proportion of all patients with acute
respiratory disease the physician is called
upon to treat. However, in periods between
epidemics, which make up the great
por-tion of the year, the problem of accurate
diagnosis of acute respiratory disease is an
extremely difficult one. The term “virus in-fection” has become widely employed and represents little more than a guess in most
instances. Such anatomic terms as
naso-pharyngitis, tonsillitis or bronchitis
like-wise provide little or no help when it comes
to intelligent management of the patient. A high premium therefore must be placed
on diagnostic considerations which will
help one to arrive at a wise decision for
the treatment of a patient.
Considerable confusion still reigns in the
field of classification of acute respiratory
illnesses of man, but for practical purposes
more and more pieces of the “pie” are being
identified and serve as diagnostic “handles.”
An attempt has been made to arrange the acute respiratory tract infections with prime
consideration being given to the etiology of these diseases. Although the identifica-tion and isolation of the etiobogic agent in most patients with acute respiratory disease would be next to impossible for the
prac-ticing physician, it still is the only logical
approach he can make in arriving at a
working diagnosis. Diagnostic and
tilera-peutic considerations will be emphasized in the brief discussions of the various
respiratory tract infections which follow. In
general, it should be pointed out that we still must rely on the clinical history and
phys-ical examination, plus the laboratory for help in a few selected instances. However, a knowledge of the clinical features of these
diseases, the epidemiology and etiology, will
go a bong way toward developing a wise
diagnostic and therapeutic decision.
Before highlighting some of the newer
advances in certain specific respiratory tract
infections, it seems important to become
fully aware of the concept that most of
the infectious diseases manifest themselves
by a wide range of symptoms and signs.
The majority of these relate to the
respima-tory passages, but the severity may vary
from the mildest of symptoms, such as sneezing and slight cough, to severe
re-spiratory distress, cyanosis and death. In
pediatrics it is particularly important that we recognize the influence differences in age has on the clinical severity of disease,
particularly as they might reveal them-selves in a single family epidemic. It hardly needs to be mentioned that many infections are much more severe in prematurely born
babies than they are in older children or
adults. This does not, of course, always
ap-ply to all infections for we are aware that
certain so-cabled childhood diseases, such as
measles, chicken pox and poliomyebitis, may manifest themselves in a severe fashion in
the adult patient. Little is known of the
basic factors underlying the differences
ani-130
mal experiments : newborn mice may be quite susceptible to certain types of infec-tion, such as Coxsackie viruses, whereas
older animals are much more resistant. The
opposite may be stated for experimental
poliomyelitis in mice; the newborn being
relatively resistant as compared with mice
which are 3 to 6 weeks of age.
Another important and basic concept
which the clinician must constantly keep in mind relates to the pathogenesis of
respiratory tract infections. We now
recog-nize the importance of mixed infections and the role of secondary complicating
or-ganisms. It is important to keep in mind that these complications may occur in
con-cert with or follow closely a mild primary illness. The whole nature of an epidemic in a family or community may be influenced
by the complicating secondary organisms.
Man is known to be a common carrier of
many bacteria, and, since the advent of
an-tibiotics it has become evident that we
also carry many fungab organisms. Recently
it has become apparent that there are many viruses in the respiratory and gastrointes-tinal tracts not obviously responsible for acute illness in man. It is conceivable that almost any sequence of events might occur to initiate infection, but careful study has
revealed that the majority of the primary
respiratory tract infections are probably
due to viruses. This is most obvious at the times of epidemics of influenza, measles and certain of the newly discovered me-spiratory viruses which cause epidemic dis-ease among new recruits in the military
service.14
A careful and detailed study of families
carried on by 1)n. John H. Dingle and his
associates5 in Cleveland, Ohio, has revealed
that the etiobogic factors in common
respira-tory diseases are probably nonbactenial
for the most part. The measles viruses and the various types of influenza viruses have been recognized for some time as primary respiratory tract infections commonly corn-plicated by secondary bacterial infection. The pathogenesis of respiratory tract in-fection is not completely understood. In the
first place, it would seem illogical to
con-tinue to refer to upper and lower respiratory tract infections. The dividing line would be difficult to determine in most patients,
and a thorough clinical appraisal usually reveals that rarely is any infection con-fined to the upper respiratory passages
alone. Cough, which is frequently a mani-festation of mild respiratory tract infection, usually indicates some irritation in the middle or lower respiratory passages. Ex-perimental studies have fairly clearly es-tablished that the basic mechanism in the
pathogenesis of pneumonia is aspiration.6 This in itself would imply that infection in other parts of the respiratory tree may be aspirated and thus produce disease. The lung is an internal organ constantly
ex-posed to the outside air. The sticky mucus
in the respiratory passages catches many or-ganisms which, in turn, are moved out of the respiratory tract by the cilia. Many
or-ganisms are swallowed and thus destroyed in the stomach or intestinal tract. The con-junctiva is considered a common portal of entry. The tears are known to have a high lysozyme content, and this bacteriostatic
mechanism undoubtedly serves to rid the conjunctiva of many of the organisms that
come in contact with it. The epigbottis is considered an important defense organ, but incompletely so during chilling or
anes-thesia. Lower in the respiratory tree, mucus secretions undoubtedly act, along with coughing, as an essential mechanism for eliminating foreign material. Phago-cytosis and lymphatic drainage in the low-est parts are considered significant
mech-anisms of defense. The lungs, which are
normally sterile, undoubtedly tend to be kept so by these various mechanisms. The factors, then, which underlie the develop-ment of respiratory tract infections are indeed many, and probably one of the most important is specific immunity. Many
factors in the host’s defense are undoubt-edly influenced by environmental
situa-Lions producing stress, such as fatigue,
combina-of
REVIEW ARTICLE
tions of agents or factors undoubtedly play an important robe in the pathogenesis or development of respiratory disease.
Evidence indicates that congestion and irritation resulting from respiratory tract
infections interfere with elimination
mech-anmisms and favor the development of
5cc-ondary infections. When obstruction is
pro-duced by congestion and local irritation
caused by primary respiratory disease,
sec-ondary involvement of the sinuses, inner
ears, bymphatics and lymph glands, and
the lower pulmonary passages may
corn-monly occur. Experimentally, Hamburger
and Robertson8 have demonstrated that bacteria-laden fluid escaping past the epi-glottic barrier plays a much more important mole in the inception of pulmonary disease than does. inhalation of infective droplets.
Transmission through the air is fairly well established in influenza and would appear to be the important factor in the spread of measles and other primary respiratory tract infections caused by viruses.9 These many
complex and interrelated factors must be kept in mind by the clinician attempting
to evaluate a patient. The frequency and
relative mildness of many respiratory tract
infections leads to a careless attitude toward diagnosis and consequently toward treat-ment. Recently, the use of antibiotics and
chemotherapeutic agents in the treatment of measles has shown that complications
may not be prevented, but may even be enhanced. In Weinstein’s recent report,’#{176}
the organism considered responsible for most of the complications in treated
pa-tients was Hemophilus influenzae. An cdi-tonal in the same journal re-emphasized the need for a critical review of “the rou-tine prophylactic use of antibiotics in simple
nonbacterial infections-notably, the corn-mon cold-and influenza, and indeed in many other situations in which such
prophylaxis is frequently advocated.”h1 Those conditions for which a specific
etiology is probable or known are listed in the accompanying table. With the excep-tion of primary streptococcal infection, there is increasing evidence that primary infection of the respiratory tract by bacteria
does not commonly occur. For this reason,
the bacterial pneumonias are not included in the table.
Acirr RESPIRATORY TRACT INFECTIONS
Di.sease
Epidemic influenza
Common cold and acute respira-tory disease (ARD)
Exudative tonsillitis and/or
pharyn-gitis
Vesicular pharyngitis Scarlet fever
Measles Poliemyeitis
Lymphocytic choriomeningitis
Infectious mononucleosis
Q
feverOmithesis
Tuberculosis Memliasis
Histepbasmosis Coccidioidomycosis
Undifferentiated respiratory disease
Type
Influenza A Influenza B
Influenza C
Coryza, and sore throat
Streptococcic, and nenstrep-tecoccic
Herpangina With rash
Without rash Rubeola
Respiratory symptoms Respiratory
Pharyngeal
Rickettsial disease
Psittacosis, etc.
Respiratory symptoms Respiratory symptoms Respiratory symptoms Respiratory symptoms
Respiratory symptoms
Etiology
Influenza A virus Influenza B virus
Influenza C virus, and adeneviruses
Undetermined
Beta-hemelytic streptococcus, and adeneviruses
Cocksackie A viruses
Beta-hemolytic streptococcus, Ejythregenic toxin-producing
Beta-hemolytic streptococcus Rubeoba virus
Peliomyebitis viruses Lymphocytic choriomeningitis
virus
Undetermined Coxiella bumnetii
Psittacosis-ornithesis group viruses
Mycebacterium Tuberculosis
Candida albicans
Histoplasma capsulatum
132
EPIDEMIC INFLUENZA
Over the past several years our
knowb-edge of respiratory disease has increased
significantly, primarily as a result of clinical
and experimental studies of influenza. For
many years this disease, which has
prob-ably been responsible for five major
pan-demics, was considered to be due to
bac-tenia. Several workers upheld the idea that
a bacillus, Hemophilus influenzae, was the
primary factor in this disease until the
dis-covery of the viral etiology in 1933. The
cause of this disease is well defined and
the various types and strains of viruses are
continuously under study in various
me-search laboratories. Excellent laboratory methods now exist in many city and state
health departments for the accurate
diag-nosis of influenza.
It is important to recognize that
epi-demiobogically the influenzas are cyclic
dis-eases which occur most commonly in the
winter months as distinct epidemics. The
onset of the disease and of epidemics is
usually sudden. Children with influenza
frequently have high fever, 39.5#{176}to 40.5#{176}C
are not uncommon on the first day of
ill-ness.1#{176} Signs of toxicity and marked
lassi-tude are striking symptoms. Older patients
frequently complain of sore throat, and
hyperemia of the nasopharyngeal
mem-branes is a very common finding. The
fe-bribe reactions in these patients,
particu-larly infants during their first infections
with influenza, tend to be high and
irregu-bar and often have a bi-phasic character.
Unless complications intervene, the febribe course is usually terminated by a crisis and the patient, although often markedly weak-ened, is clearly in the recovery phase of
the disease. The leukocyte count may be normal or low, occasionally leukopenia will be manifest, but in our experience in a proved epidemic in infants and children
due to influenza A leukopenia was not a striking diagnostic feature.12 Probably the most practical diagnostic feature of
influ-enza is its cyclic epidemic character. This
has been illustrated over and over again
in the past, and we have every reason to
believe will continue to be the pattern of this disease for some time to come. In other words, during a known influenza epidemic
the majority of all respiratory disease is probably due to one of the influenza
vi-ruses. Between epidemics the diagnosis of
influenza should probably never be made
except by means of laboratory studies, as the occurrence of influenza in nonepidemic periods is rare indeed.
The laboratory diagnosis of this disease
involves an attempt at isolation of the
vi-rus from throat washings by means of
embryonated chicken eggs. After 48-hours
incubation, the amniotic fluid is mixed with
chicken erythrocytes which are aggluti-nated by the influenza viruses. Known antiserum set up against this agglutination phenomenon will inhibit the reaction. This constitutes the agglutination-inhibition test. Complement fixation tests are also em-pboyed; a blood specimen drawn early in
the illness is compared with one drawn after 10 days or 2 weeks. A fourfold rise in titer
or more indicates that the patient has been
recently infected by influenza virus.
Influenza vaccines have been employed
in civilian and military populations and have been shown to be effective against certain types of influenza. Their wide ac-ceptance has not occurred because the changing types and strains of virus found in certain epidemics are antigenically dif-ferent from those which have been em-ployed in the vaccines. However, use of a
wide variety of antigenic strains, and at-tempts at hyperimmunization, will un-doubtedly serve in the future to make
in-fiuenza vaccine more effective and thus more widespread in its application.
Al-though in any individual patient the use
of vaccine might appear to be unwarranted,
its use on a wide scale in epidemic areas would undoubtedly prevent many of the severe complications and deaths which
fre-quently result. Prevention of this disease
early in pregnancy may be important in
preg-nancy. Experimental studies in chick
em-bryos1 14 and pregnant animals have
in-dicated that the influenza A virus may be
a serious cause of abortion and damage to
the fetus. The death rate in infants and
elderly I)eoPle during epidemics may be an
important public health problem. The true
incidence of complicating illnesses, such as
tuberculosis and the many secondary
in-fections, can hardly be appraised by any
methods now available. However, the
high-est death rates recorded in all of the cities
in the United States follow in the wake of
known influenza epidemics. Although
them-apy will be discussed in a separate section
of this review, at the present time no
anti-microbial agent is known to be effective
against infections with influenza viruses.
NEW RESPIRATORY TRACT VIRUSES
Recent discovery by Rowe, Huebnen,
Gil-more, Parrott and Ward,’#{176} and at
appmoxi-mately the same time by Hilleman and Werner,1 of respiratory tract viruses has revealed many new types of agents
pre-viously unidentified as causes of respiratory
tract infections. Rowe et al.16 originally
re-ported the isolation of a number of strains of viruses from the cultivation of adenoid
tissue removed at operation. When this
tis-sue is grown in tissue culture preparations a degeneration takes place in the cells, if a
virus is present. The degenerative process
is referred to as cytopathogenesis. When
material is passed to other tissue culture
preparations such as HeLa cells,
follow-ing a period of incubation, destruction will
again take place in the tissue cultures
(cytopathogenesis) and this process then
may be continued and the virus studied as
to its type and histopathologic character-istics. When first isolated the relationship of these viruses to clinical disease was not
clear. However, Hilleman and Werner’ me-ported the isolation in tissue culture of an agent from recruits at Fort Leonard Wood,
Missouri who were ill with acute
respira-tory disease. They named the agent RI 67 (Respiratory Infection 67) and showed that
this agent was related etiobogically to the
illness of the patients. This agent was later
identified as one of the adenovirus family
of viruses, namely type 4, and was found to be related to cases of acute respiratory disease reported by Dingle and associates#{176}
during World War II. Serum from patients studied by them was found to neutralize the RI 67 virus. Many types of adenoviruses,
formerly known as adenoidal-pharyngeal.
conjunctival (APC) viruses, have been idtn tified in both humans and monkeys, but xL cept for three or four types of these, no
clear-cut illness has been attributed to them.
Studies with human volunteers have
incrim-mated adenoviruses types 3 and 4 as
produc-ing clinically recognizable disease in sus-ceptible individuals. Huebner and
associ-ates17 produced a pharyngeal-conjunctival
fever in human volunteers known to have
no pre-existing antibodies. In a recent article
by Hilleman, Werner and Stuart18 the
vi-muses of the RI family, which include certain of the adenoviruses, may be responsible for undifferentiated acute respiratory disease, nonstreptococcal exudative pharyngitis, a
pnimary atypical pneumonia unassociated
with cold hemagglutinins, pharyngeab-con-junctival fever, mesenteric lymphadenitis and inapparent infections.
All of the adenoviruses have a common
complement-fixing antigen and are most clearly identified by this means. All of the
viruses recovered from patients belong to ty pes 3, 4, or 7, and little or no response was found against the other types of agents
which were recovered from human adenoid
or tonsil tissue by tissue culture. A study of
military personnel in the Eastern, Central and Western areas of the United States#{176}8 has revealed types 4 and 7 viruses more
commonly than type 3; the latter appears to be the agent most commonly responsible for epidemics in children, and consequently
may be one of the reasons why it is seen
less frequently in recruits in military
popu-lations.
Epidemic respiratory disease which was not due to influenza has been previously recognized, but only as a result of recent
hospitalized type of patient represents an individual with an acute febnile illness who
is suffering from constitutional symptoms of malaise, anorexia, some hoarseness, throat irritation and cough. The physical
examination reveals an acutely ill individual
with moderate injection of the pharyn-geal area and lymphoid hyperplasia. Some
mild cervical adenopathy is usually pres-ent. The acute febrile phase of the illness lasts from 3 to 7 days and convalescence
usually requires 1 to 2 weeks. Dingle and
associates#{176}9 have designated this disease as
acute respiratory disease (ARD) and
ab-though well described during World War
II, it remained for Hilleman and Werner’
to discover the etiobogic agent responsible for this epidemic disease.
In experimental studies of transmission,
the incubation period was found to be 4 or 5 days, and recovery from the disease
produced resistance against reinoculation.
Studies with human volunteers indicated
that this entity was distinct from the com-mon cold and from the primary atypical pneumonia characterized by cold
hemag-glutinins. Berge et a!.’ in California
re-ported an epidemic respiratory illness in recruits due to another adenovirus, namely
type 7. It is clearly apparent that two types,
4 and 7, may cause acute respiratory dis-ease in military populations, particularly among new recruits.
The agents which produce acute
respira-tory disease appear to be good antigens and
already work on vaccines is progressing. Huebner et al.20 recently reported on vac-cines made from type 3 virus in adult
vol-unteers. They report that among 45 volun-teers injected, 35 subsequently exhibited antibodies against type 3. When challenged
by this virus, 10 of the 35 individuals with antibodies developed illnesses, similar to
the illnesses which developed in all 10 of the individuals who failed to develop
anti-bodies. Of volunteers not vaccinated, 18 of 21 who had no antibodies developed ill-nesses. In striking contrast, only 4 of 17 who had naturally acquired antibiodies de-veboped typical illness. It would appear
that these early and preliminary vaccina-tion studies offer hope for immunization against certain strains of the adenoviruses.
Dingle and Feller19 suggest that con-sideration might be given to the use of pas-sive immunization, especially in recruit
populations during the winter months. 5ev-crab lots of human gamma globulin have
been shown to contain high titer of neu-trabizing antibodies for the epidemic RI 67
strain or for type 4 adenovirus. A study among medical students by Adams and
Smith” reported in 1946 reveals that gamma globulin was effective in reducing the occurrence of acute respiratory disease in the winter months in a selected popula-tion group which was in close contact with one another. A significant reduction took place not only in the incidence of disease,
but as subjectively evaluated by the
pa-tient, there was an apparent sharp reduc-tion in the severity of those respiratory
in-fections which did occur as compared to the controls. Therapeutically, at the pmes-ent time no specific antimicrobial agent has been found to be effective against this group of viruses.
A
type 1 strain of adenovirus has been me-covered from the pharyngeal secretions of a 2-year-old infant on the first day of anacute febnile illness which clinically ap-peared identical with exudative pharyngitis.
A
type 5 adenovirus has been demonstrated in a laboratory technician suffering from acute sore throat and earache, but with-out apparent fever.’ Neva and Enders” have reported a patient with an illnessre-sembling roseola infantum in which a type
3
virus was obtained. This same agent has been isolated in an epidemic in Northern Virginia from the throats, conjunctivae andanal excretions of 76 patients.17 At the same time similar isolation attempts in 85 con-trol patients who were not ill were unsuc-cessful. Conjunctivitis was the striking
fea-hire of this epidemic and, although it was associated with swimming pool contacts, no evidence of inclusion blennorrhea was ob-tamed. The type 1 and 2 agents appear to
chil-dren, and serological studies indicate that
they appear early in the preschool years.
Jawetz”
has isolated type 8 virus frompa-tients with keratoconjunctivitis, similar in all respects to the epidemic disease in
ship-yards during World War II involving the
conjunctivae. Isolations of 14 different types of adenovinus have been reported, two of
these from monkeys.
COXSACKIE VIRUS INFECTIONS
Zahorsky’5 in 1924 pointed out for the
first time an acute febrile disease of chil-dren which was characterized by tiny
vesi-des 011 the pharynx and soft palate which
later became ulcerated. In the last few
years, the Coxsackie or C viruses have been
recognized commonly, and are now
con-sidered to be the cause of vesicular
pharyn-gitis or herpangina, which is included as
one of the acute respiratory diseases. Hueb-ncr and associates,’6 as well as others, have
clearly shown that vesicular pharyngitis
is caused by the group A Coxsackie viruses.
The patients with this illness often have
high fever at the onset, frequently
as-sociated with vomiting, anorexia and sore
throat. The disease runs a limited course of a few days with recovery occurring
un-eventfully. The characteristic physical
find-ings, the limited febrile period and the lack
of a stiff neck and back help to
differenti-ate these summer illnesses from
poliomye-litis. The association, however, of illness of
this type in patients and poliomyelitis viruses has been recorded; Dingle and Feller’9 make the statement that, “It has
been impossible to determine whether
symptoms referrable to the upper
respira-tory tract were due to the pobiomyebitis
viruses or were caused by co-existing
in-fections with a respiratory tract agent.”
The first phase of poliomyelitis illness is
frequently characterized by mild
respira-tory symptoms and the patients often corn-plain of sore throat. If we are to main-tam an etiologic approach to acute
respira-tory disease, it would appear to be
impor-tant for us to recognize that acute
respira-tory symptoms, particularly in the summer
months, may be caused by many different
viruses, including the Coxsackie A group
and poliomyelitis, and that only by special studies can an accurate differentiation be made. Jordan, Stevens, Katz and Dingle27 have found families infected with
polio-myelitis or Coxsackie virus who were ill
with symptoms of acute respiratory disease
only. They state, “The grippe-like illnesses
were consistent with severe colds or acute
respiratory disease.”
LYMPHOCYTIC CHORIOMENINGITIS
VIRUS INFECTIONS
A brief discussion of lymphocytic chorio-meningitis virus as a cause of respiratory tract infections is included because there
is evidence that this virus may produce a disease in man with symptoms and signs
similar to those of influenza. This virus re-ceived its name because experimentally it produced inflammatory lesions in the
choriomeninges of monkeys,28 but it is conceivable that this phase of the disease merely represents a complication similar to the central nervous system involvement which we recognize in many other viral in-fections. There is evidence from studies of
random samples of blood that specific
anti-bodies occur against lymphocytic
chorio-meningitis virus in 11% of such samples.
Our knowledge of this virus as a cause of
respiratory tract infection is extremely
limited. However, early in the history of
lymphocytic choriomeningitis a grippe-like
illness was recognized in laboratory
work-ems. In 106 serums tested from individuals
who had recently recovered from
respira-tory infection, a positive complement-fixa-tion test was found in 28%.29 Armstrong’#{176} has pointed out that less than 100 proved
cases of this disease have been studied and because of the lack of pathologic studies, little is known of the systemic forms. A
laboratory worker who had no known
cx-posure to the virus of lymphocytic
chorio-meningitis had an illness characterized by fever, malaise, general aches, sore throat,
there were no signs of meningitis, cho-noiditis or encephalitis. However, the nec-ropsy did reveal patches of pneumonia which were characterized by mononuclear
cell inflammation. The lymphocytic chorio-meningitis virus was isolated from the
blood and brain of this patient. A second patient reported by Smadell et al.’
as-sisted at the necropsy of the first patient and
8 days later developed fever, leukopenia
and mild pharyngitis. He was hospitalized for a respiratory illness which progressed to death 17 days later due to an acute necrotizing pharyngitis and pneumonia. In neither of these patients was a lumbar puncture performed during life, as appar-ently it was not indicated. The lymphocytic
choriomeningitis virus was isolated from the lung and brain tissues of this second
patient.
This virus occurs naturally in several
species, including mice, guinea pigs, monkeys and dogs. It is known to be elimi-nated in the nasal secretions, semen, urine and feces of animals. Further study of the clinical manifestations of this disease will be required before the physician will be able to recognize what may be one of the common respiratory tract infections of man.
INFECTIOUS MONONUCLEOSIS
Recent studies of infectious
mononucbeo-sis have shown that the prominent clinical features of this disease frequently include acute respiratory symptoms. Hoagland32
re-porting in 1952, pointed out that 80% of the patients with this disease were found to have acute tonsillitis and/on pharyngitis. This disease is probably due to a virus, and
the acute respiratory aspects are clearly demonstrated by sore throat, frequently
ac-companied by a membrane which may be-come solid and confluent. An associated
cervical adenitis may be severe, and the
combination of sore throat with membrane and marked cervical adenitis frequently suggests the diagnosis of diphtheria. The patient fails to respond to antibiotic drugs, and the blood usually reveals a
bymphocyto-sis with abnormal cells of the Downey
type. A positive hetemophib agglutination test is frequently of great aid in arriving at an accurate diagnosis. The liver and spleen may be slightly enlarged and the
patient often suffers from generalized malaise and anorexia. Cervical adenitis
was present in
100%
of Hoagland’s series ofpatients, and it seems thoroughly justi-fled to include this disease in a discussion of acute respiratory tract infections. No specific treatment for infectious mono-nucleosis has been found, but the use of large doses of gamma globulin has been advocated.
THE RICKETTSIAL DISEASES
Certain of the rickettsial diseases, the
most striking of which is
Q
fever, may pro-duce respiratory tract infections oftenchar-acterized by an atypical form of pneu-monitis. A history of contact with dairies or meat packing plants may bead one to suspect this disease in the earliest phases. The cause of
Q
fever is Coxiella burnetli. In 1950 Sigel and associates’3 reported anoutbreak of
Q
fever, which occurred in the first 3 months of 1948 and involved about30 employees of a wool processing plant
in Philadelphia. This epidemic was
char-acterized as an acute respiratory illness which was generally referred to as “flu” or “grippe.” A study of blood from the em-pboyees revealed that 67 individuals showed
positive reactions indicating
Q
fever. Theywere able to conclude from their studies
that the cause of this acute respiratory epi-demic disease was probably the rickettsia of
Q
fever. Antimicrobial therapy is bene-ficial in certain of these diseases and isdis-cussed in more detail later in this paper.
ORNITHOSIS
The ornithosis viruses which are car-ned and spread by many different types of birds, including the common barnyard
fowl, pigeons and canaries, as well as the
REVIEW
ARTICLEcause of this disease is the coccoid
dc-mentary body, Miyagawanella psittaci,
which is considered to be intermediate be-tween rickettsia and filtrable viruses.
Winter epidemics predominate, but the
disease may occur at any time of the
year. The greatest incidence is in women
who are bird fanciers and engage in
breed-ing birds.’ The respiratory passages
un-(loubtedly provide the main portal of entry
ill man, and person to person spread of
this disease is reported. It is important to remember that many patients with acute respiratory illness who may not give a
history of known exposure to sick birds may be victims of ornithosis. The spectrum of
manifestations of infection is important as
many mild ambulatory patients are being
recognized increasingly as having an
ill-ness due to this viral agent. The onset of
the disease may be abrupt; anorexia, sore throat, headache, backache, photophobia and chills being the principal symptoms.
The wide spectrum antibiotics are effec-tive in the treatment of omnithosis and will be discussed in more detail later in this
paper.
THE COMMON COLD
Recent advances in our knowledge of the common cold have been scanty, in spite of considerable study. Most of our infor-mation has been derived from studies in-volving human volunteers, and it appears
evident that some of the common colds are due to transmissible agents of a
nonbac-teriab nature which produce mild
respira-tory symptoms. Respiratory secretions, rendered bacteria free, have produced
respiratory disease in man and chimpan-zees, but attempts to cultivate this virus in animals or tissue cultures have not been
widely confirmed. The newly isolated
adeno-viruses, discussed previously, do not ap-pear to be present in the respiratory tracts of patients with common colds. It has been most difficult to define the common cold,
and no general agreement seems to exist for diagnostic criteria. Confusion with hay fever, allergic rhinitis and other vasomotor
reactions adds to the difficulty. Emotional
factors undoubtedly play a role in the sub-jective evaluation of symptoms. Dingle and Fellem’#{176}point out that the problems sum-rounding this common disease probably will not be solved until the viruses have
been definitely isolated and characterized. However, recent progress in the field of
respiratory tract infections as a whole would seem to offer considerable hope for better understanding of the many causes of respiratory tract infections. The impor-tance of keeping in mind the wide
varia-bility and symptomatobogy cannot be over-emphasized. It is conceivable that certain
of the known respiratory viruses may pro-duce such mild manifestations,
particu-larly in patients who have suffered from
them before, that the symptoms are de-scnibed by the patient as those of the corn-mon cold. We recognize that the individual who reports having a severe cold, may fre-quently have lesions in his chest
character-.istic of those commonly referred to as atypical pneumonia. As our knowledge of
respiratory tract infections increases, there
is every hope that the problems of the
common cold will be better understood.
TREATMENT
This discussion of treatment will be limited to a few of the acute respiratory tract infections for which some rather
spe-cific drugs are considered to be effective therapeutic agents. In addition, brief men-tion of the role of certain antimicrobial
agents in prophylaxis of respiratory infec-tions and treatment of complications will be made.
Ricketisial Diseases
Chloramphenicob, tetracycline and its derivatives are the best agents and appear to be about equally effective for the
treat-ment of all rickettsial 637 The
schedule employed consists of an initial oral loading dose of 50 mg/kg body weight,
followed by a daily dose of 50 mg/kg di-vided into equal doses at approximately
treatment continue until the patient has
been afebrile for 2 to 3 days. A clinical
me-sponse may require several days, but usually can be expected to be evident in 3 to 4 days. Recrudescence of disease may
occur in 5 to 7 days after antibiotic therapy
is discontinued. The incidence of relapse decreases progressively with the duration of illness prior to the onset of treatment.
It is suggested that if treatment is begun during the first week of illness, relapses
may be prevented by administering an
ad-ditional loading dose of 50 mg/kg about the fourth day after completion of the in-itiab course of treatment.
Ornithosis
Although penicillin in high dosage has been reported to be of some value in this disease, chboramphenicol and the tetracy-dines are probably the most effective drugs for treatment of these ‘#{176}They
should be administered in a manner similar
to that outlined for rickettsial diseases, and
various combinations may be employed in
severely ill patients.
Primary Respiratory Diseases
In the preceding part of this paper the etiology of these diseases was discussed and the therapeutic considerations will be considered briefly here. The true viral
dis-eases per se are not influenced by any of the presently available therapeutic agents, with the possible exception of primary
atypical pneumonia, concerning which
there is controversy regarding the efficacy of antimicrobial agents-there appears to be a rather general opinion that they are not
effective. The cause of primary atypicab pneumonia is not clear, and this disease or syndrome may be caused by many different viral agents. Although considerable enthu-siasm existed for the use of the broad spectrum antibiotics in the atypical pneu-monias, this enthusiasm has subsided
con-siderably in the past few years. Recent carefully controlled studies have shown that they have little or no effect on the
course of the disease. Because of the
prob-bern of mixed infection, however, the seri-ously ill patient should undoubtedly have
a trial of the tetracycline drugs.
Certain antibiotics, such as penicillin or the sulfonamides, have been used widely for the prevention of bacterial
complica-tions of primary respiratory diseases.404’ However, recent studies, by Weinstein’0 have thrown considerable doubt on the wisdom of using these drugs
prophybacti-cabby for the prevention of bacterial corn-plications of acute primary respiratory tract
diseases. In the case of measles, the use of
antimicrobial agents resulted in a higher rate of complications than in untreated pa-tients. The problem seems to center about
the fact that the complications are not caused commonly by pneumococci or beta-hemolytic streptococci, but by H.
influ-enzae, M. pyogenes, E. coli, proteus, and other antibiotic-resistant organisms. It is recommended, therefore, that careful
obser-vation for the appearance of secondary
corn-plications is the wisest course, with early treatment of a complication if it occurs.
Bacterial Infections
When a specific bacterial pneumonia or other complication can be diagnosed and
sensitivity tests on the etiobogic agent can
be determined, the antibiotic may be Se-bected wisely. By means of a gram-strained
smear and culture, as well as a blood cul-ture, the causative agent may frequently be revealed, and when these determinations have been initiated there is no
contraindi-cation to commencing specific therapy. In
the presence of severe pulmonary infection, penicillin and streptomycin or penicillin
and tetracycline should be administered at once. In mild infections or moderately Se-vere infections, tetracycline alone may be an adequate drug for use in the vast ma-jority of patients. A more specific drug may be selected when the results of the pre-biminary laboratory studies become known.
Concerning the secondary bacterial
in-fections associated with epidemic influenza,
that obtained in patients who do not have viral disease. He further points out that
the most severe complicating organisms are staphylococcus or Friedlander bacillus, and advocates the prompt institution of
anti-microbial therapy. For staphybococcal
pneumonia complicating infection by the
influenza virus, Honsfall” recommends
mas-sive (loses of penicillin along with maxi-mum tolerated doses of streptomycin,
con-tinning treatment for 3 to 4 weeks or more. As to their use in influenza as prophylactic
agents, he advises against such a procedure
as a routine in healthy individuals, but
does recommend it in the previously ill,
malnourished or debilitated patient. He
prefers the use of penicillin to broad
spec-trum antibiotics which are more toxic and
tend to disturb the balance of the bacterial
flora in the respiratory tract. Although Horsfall” comments that, with the
excep-tion of psittacosis, the effect of currently available antimicrobial substances on viral
diseases of the respiratory tract has been a
recitation of discouraging failures, he goes
on to point out that there is hope for
de-vebopment of the chemotherapeutic ap-proach to therapy of these diseases. He
sug-gests that development of effective agents
xviiI not come through a direct action upon
virus, but rather by interfering with basic
potentials for growth and multiplication.
He suggests that the most effective way to
interrupt the reproduction of viruses is to alter the metabolism of either nucleic acids or proteins.
Although admittedly there is little to
of-fer a patient by way of specific antimicro-bial agents in most respiratory tract
infec-tions, some consideration must be given to nonspecific methods of therapy. We recog-nize the importance of humidification of
the atmosphere, particularly in patients with acute respiratory disease manifested
by attacks of croup. Controlling the
tem-penature in the room is frequently impor-tant in order to increase humidity
with-out the drying effects of heat. Room tern-peratures between 21 and 25#{176}Care de-sirable. Water may be vaporized from a
large vessel or special apparatus, such as
tents equipped with nebulizing devices, are often extremely valuable. Sometimes the
use of an expectorant such as syrup of
ipecac in small doses may be indicated. Atropine is contraindicated in the
manage-ment of all acute infections of the
respira-tory passages.
The etiobogic agent should be sought
by all means at our disposal. Appropriate
specific therapy may usually be found if
the complicating agent is suspected and the patient’s condition properly diagnosed. Mild sedation of the patient is often helpful in the acute cases. In infants and in some
older children we have found the prone position an excellent way to treat cough and promote rest. Special attention should always be given to the general nutrition, although in the management of the acute problem no special recommendations are considered vital, and the patient may often
eat about what he wishes and according to his appetite. Contrary to statements in the medical literature, the forcing of fluids has
no place in the management of acute
re-spiratory tract infections, and may on
oc-casion be actually harmful. The fluid in-take should be noted, but it may be
sur-prisingly low in many patients, particu-larly infants with pneumonitis, without ap. parent ill effects.
SUMMARY
This review might well be regarded as a summary of present knowledge of the barge field of respiratory diseases and a brief
me-view of the salient features, concerned pri-manly with the etiobogic, pathogenic and therapeutic considerations. The etiobogic, rather than the anatomic, approach to
diag-nosis is emphasized in order that an intel-ligent attitude towards therapy might be developed. The recent advances in
dis-covery of new etiobogic agents, e.g., adenovi-ruses, is discussed in some detail.
nickettsial diseases. Specific use of
anti-microbial drugs for certain viral infections is emphasized. Dosage of available themapeu-tic drugs is detailed for the diseases in which they blave been shown to be effec-t:x’e, such as nickettsial diseases, ornithosis,
1fl(l complicating bacterial infections.
Pro-phylactic uses are outlined and a warning
against the uncritical use of such therapy is given. Many problems remain unsolved, but rapid progress is being made.
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