[Comments on the Diagnosis of Mycoplasmal Pneumonia of Swine
(MPS)](../02N-0027_ts00006_02_vol2.ppt)

# Kent J Schwartz, DVM, MS

Until influenza virus entered swine populations in 1918, the
differential diagnosis of swine pneumonia was either "enzootic
pneumonia" (later shown to be *Mycoplasma hyopneumoniae* (Mh)) or
demonstrating the effects of ascarid migration in lung. Even then, the
US swine population was large but herds were reared outdoors in small,
relatively isolated farms. Innovations of mechanization, farrowing
crates, nutritious rations, and confinement production developed in the
1930's fueled the relentless technology-driven consolidation of pork
production. New pathogens emerged as technology altered the ecology of
host and parasite within swine populations. During the 1960's*,
Mycoplasma hyopneumoniae* was isolated and characterized. A host of
other agents, including *Actinobacillus pleuropneumoniae* (App),
*Streptococcus suis, Hemophilus parasuis, Pasteurella multocida* (Pm*)*,
and *Bordetella bronchiseptica* were recognized as pathogens.
Antimicrobials and a potpourri of vaccination products have been used to
control respiratory and systemic diseases since the 1950's. The value of
hybrid genetics in pursuit of lean over lard encouraged widespread
movement of pigs across broad geographic areas thus assuring widespread
distribution of disease agents. Genotype shifts may have also affected
susceptibility and immunity. A resurgence of consolidation with yet
larger farms resulted from research on segregated rearing techniques and
all-in/all-out production. Optimism that large populations of pigs could
be "weaned away" from infection with respiratory pathogens was largely
misguided for two major reasons: 1, infections and immunity are neither
stable nor predictable in large herds; and 2, the widespread
introduction of the troublesome porcine reproductive and respiratory
virus (PRRSV) into swine populations.

Respiratory disease remains the primary impediment to the healthy
production of swine in the US herd and is associated with a complex of
infectious agents, hence the term [P]{.underline}orcine
[R]{.underline}espiratory [D]{.underline}isease [C]{.underline}omplex
(PRDC). Throughout a century of astounding changes in swine production
(nutrition, housing, genotypes, larger populations, wide-spread swine
movement), Mh has remained a ubiquitous challenge to swine health and
continues to play a central role in swine respiratory disease.

Mh has a central role in swine respiratory disease:

Some of the reasons that Mh has maintained its role in pathogenesis of
swine respiratory disease include:

1.  Mh infection is extremely common with \>95% US swine herd
    prevalence.

2.  Mh infection persists for at least 3 months, probably up to a year,
    ensuring its continuing presence in swine herds.

3.  The long Mh incubation period (2 to \>4 weeks) and the fact that all
    swine in a group are not infected simultaneously ensures that all
    stages of infection and/or disease will be present in groups of
    grow-finish swine which hinders effective intervention at critical
    control points.

4.  Mh compromises lung function to create niches for secondary
    pathogens to thrive. Mh infection has been shown experimentally to
    predispose swine to pneumonia caused by Pm and App and to magnify
    severity of disease associated PRRSV.

5.  Mh alters or misdirects some aspects of the immune response further
    compromising effective immune clearance of Mh and other agents, most
    notably viruses.

6.  Mh presence on cilia sequesters it from most effective immune
    mechanisms as well as many antimicrobials.

7.  Large populations of pigs, in spite of age segregation, vary in
    individual infection and immune status. Infection of most pigs may
    not occur until maternal immunity has completely waned. Disease is
    more severe and the infective pressure in these environments is
    likely high. The stage is thus set for PRDC, with multiple
    permutations of infectious agents contributing to the final outcome.

Mh-associated disease is often relatively mild but is a precursor to
enzootic pneumonia and PRDC:

Mh-associated lesions of enzootic pneumonia in slaughter pigs have high
prevalence with some surveys demonstrating up to 100% herd prevalence.
Mh infection herd prevalence by CF or ELISA serology is at least 80%.
Economic loss attributable to MPS in the form of reduced rate of gain
and feed efficiency is well recognized. Ten to 15% decrease in both
average daily gain and feed efficiency during the 1-2 month period of
active disease in grow-finish swine is well documented and widely
accepted.

The appearance of field cases of Mh-associated disease varies
tremendously in both clinical signs and lesions. Clinical signs of
uncomplicated Mh infection are of a chronic disease with high morbidity
and low mortality. Following infection and a highly variable incubation
period of at least 2 weeks, chronic nonproductive cough gradually
increases in frequency and intensity in the group. Cough persists in
individuals for at least several weeks and groups for several months.
Deaths do not occur with a pure Mh infection nor are fever, prostration
and dyspnea features. These signs are associated with common secondary
bacterial infections that a common sequel of Mh infection. Lesions
include clearly demarcated cranioventral distribution of
bronchopneumonia, a location that implies "bronchogenic" origin.
Historically, Mh is by far the most likely primary agent to initiate
such lesions but Mh is not a prerequisite for all cases of
bronchopneumonia. Secondary bacterial pneumonia can follow ascarid
migration, SIV, or PRRSV and bronchogenic pneumonia in individual pigs
can occur with bacterial agents alone. As a general rule, cranioventral
distribution of an enzootic, chronic respiratory disease process on a
herd basis will have Mh as part of the etiology. The probability of
secondary bacterial pneumonia in field cases of Mh-associated PRDC is
high and greatly enhanced by large dense populations and concurrent
infection with respiratory viruses such as PRRSV, SIV, and likely PCV.

***[Lesions are typical of but not always specific for
Mh:]{.underline}***

The lesions of uncomplicated Mh infection and disease are quite typical
but vary depending upon stage of disease. Lesions result from a strong
but misdirected immune response and from compromise of pulmonary
clearance of debris and other pathogens. Cilia of trachea, bronchi, and
bronchioles colonized early in infection appear "clumped"
microscopically which undoubtedly hinders pulmonary clearance of
inflammatory debris and bacteria. Early gross lesions, 2-4 weeks
following infection, consist of well-demarcated cranioventral lobular or
lobar distribution (apical, middle, accessory lobes) of purplish
discoloration, congestion, edema, and are firm to the touch. As the
disease progresses, the affected lung tissue remains edematous, becomes
more grayish in color, and cloudy mucus (mucopus) exudes from airways on
cut surface. By 3-5 weeks, small airways become grossly visible as small
white foci because of peribronchiolar inflammation. Uncomplicated Mh
lesions resolve over a several month period with affected lung gradually
becoming gray, firm, and atelectatic while maintaining a
sharply-demarcated cranioventral location. Later, gray fissures are seen
as the lung progresses to complete resolution. Mh lesions complicated by
bacteria persist and expand, the character of which is somewhat
dependant upon the particular bacteria involved. *Arcanobacterium
pyogenes* tends to form abscesses whereas *Pasteurella multocida* and
*Streptococcus suis* contribute to more typical bronchopneumonia.
*Actinobacillus pleuropneumoniae* also capitalizes on Mh-induces lung
compromise but the severe necrohemorrhagic pneumonia and pleuritis
induced by this organism are recognized apart from typical enzootic
pneumonia.

Microscopically, the early lesions of uncomplicated Mh infection have
scattered neutrophils in affected airways and adjacent alveoli. Clumping
of cilia is not always discernible but IHC or FAT will demonstrate
abundant organisms at this stage. Lymphocytes are present in
perivascular and peribronchiolar connective tissue as well as lamina
propria of airways. By 2 weeks following infection, loose
lymphohistiocytic peribronchiolar cuffs are recognized, along with
mucopus in airways and adjacent alveoli. By 3 weeks there may be
peribronchiolar-associated lymphoid tissue (BALT) hyperplasia
detectable. Later, plugs of suppurative debris create localized
atelectasis and the loose cuffs and lymphoid hyperplasia gradually are
seen as nodular hyperplasia of BALT. With passage of time in cases of
uncomplicated Mh pneumonia, lungs resolve and fewer airway plugs and
less inflammation is observed. Complete resolution by gross examination
will still have peribronchiolar lymphoid nodules remaining in otherwise
normal lung. The process of resolution is variable and depends on the
initial size and severity of the lesion as well as the presence of
co-infections, immune response, inflammatory response, lesion location,
and therapeutic intervention. The process of resolution is likely
hastened by procedures (vaccination, medication) that minimize the
extent of the lesions early in the course of disease.

The gross lesions of field cases of MPS are difficult to interpret
critically because of the common presence of multiple confounding
agents, chronic pathologic changes, and specimen quality. Because the
magnitude, types, and extent of inflammatory responses are limited,
lesions from combined or chronic infections may not be definitive for a
particular etiologic agent but they still can offer etiologic clues.
Most gross lesions of cranioventral bronchopneumonia encountered in the
field will need further characterization for accurate diagnosis.
Cranioventral distribution of pneumonia in pigs less than 6 weeks of age
may be singular bacterial (example: *Streptococcus suis*) infection.
Subacute swine influenza virus (SIV) infection may have gross lesions
that resemble acute Mh-associated pneumonia. Techniques to detect viral
and bacterial agents are frequently warranted to accurately identify the
agents present. Serology can be helpful to detect infection with agents
that are rapidly cleared or are obscured by more severe, aggressive
processes. However seroconversion only confirms infection by an agent,
not causation of disease, in the absence of corroborating lesions and
clinical signs. Clearly, interpretation of gross lesions should consider
clinical presentation of disease and herd history, as well as
supplemental diagnostic testing, to assure that all observations "make
sense" in the context of herd diagnosis. If the diagnosis does not make
sense it probably is either not complete or is not accurate. Yet, if the
pneumonia observed is chronic, occurs on a herd basis on a rather
consistent basis, lesions are consistently cranioventral consolidation,
and Mh is known to be present in the herd, it is highly likely that Mh
is present as part of the disease process.

Field cases of MPS present similar difficulties in interpretation of
microscopic lesions. Later stages of SIV can resemble early stages of Mh
infection. Secondary bacterial pneumonia expand lesions and change the
character such that "chronic-active suppurative bronchopneumonia" is the
only interpretation possible. Chronic pneumonia of mixed etiology may
have severe lesions but none of the lesions may be of etiology-specific
significance. The locations from which histologic sections are taken can
have a marked effect on the types of changes observed microscopically.
Different sections from the same lung can vary from acute to chronic,
from normal to hemorrhagic necrosis, from suppurative to nonsuppurative,
etc. Again, interpretation of microscopic lesions should consider the
gross lesions, location of sections, clinical signs, and herd history.
Most honest histologic evaluations will offer statements such as
"lesions compatible with but not specific for" a particular etiology in
the absence of additional testing.

The diagnosis of swine respiratory disease can occur at several levels.
The diagnosis of disease and etiology in a single pig may or may not
accurately represent the disease processes occurring at the herd level.
Similarly, herd diagnosis often does not account for all afflictions of
individual pigs in a herd. Reasonable confidence in the accuracy of a
disease diagnosis of MPS is by consistently demonstrating typical gross
and microscopic lesions in similar groups of pigs with typical clinical
signs and history. An *etiologic* diagnosis requires demonstrating the
presence of the causal agent, Mh, by detection of agent (isolation),
antigen (IHC, FAT, ELISA) or specific nucleic acid (PCR, RT-PCR).
Isolation of Mh for routine diagnosis is highly impractical. Antigen
detection methods are quite useful for diagnosis of early stages of
disease. There is considerable variability in quantity and location of
antigen at different stages of disease so specimen selection from early
in the MPS disease process is critical for accurate results. These
methods (FAT, IHC) have limitations of sensitivity, particularly in
complicated infections or chronic disease but are quite specific and
useful when properly performed. False negative IHC and FAT tests are
frequent. Detecting antigen by these methods in several pigs is
sufficient to imply that infection is present in most cohorts and that
lesions compatible with MPS are likely associated with Mh. Demonstrating
the presence of an agent (Mh) with highly sensitive methods (PCR)
confirms infection but demonstration of compatible lesions is necessary
to confirm actual disease.

In field cases of MPS, it is important to confirm the presence of agents
within compatible lesions. Typical gross or microscopic lesions have a
high probability of Mh involvement but cannot be considered
pathognomonic. Similarly, typical microscopic lesions are highly
suggestive of but not specific for Mh. A prudent final herd diagnosis
must use all of the available data of diagnostic significance. A final
herd diagnosis should be the responsibility of a qualified,
knowledgeable, objective veterinarian after evaluating production data,
serologic data, clinical signs, lesions, and specific diagnostic data.

**Summary:**

1.  Mh infection is widespread in swine populations. Pneumonia
    associated with Mh infection occurs both consistently and
    predictably in most modern swine production systems.

2.  Mh infection depresses growth rate and feed efficiency, particularly
    during the 4 weeks following onset of disease, and has a central
    role in PRDC.

3.  Mh infection alone is a chronic disease manifested clinically as
    cough, ill-thrift, decreased growth rate, and decreased feed
    efficiency. Fever, and death are not features of Mh infection but
    frequently occur because of the ability of Mh to augment other
    bacterial and viral diseases of the swine respiratory tract.

4.  Uncomplicated Mh infections have rather typical clinical course of
    cough and ill-thrift and rather typical gross and microscopic
    lesions during the early, active, and resolving stages of the
    disease process. In the field, groups of pigs may have individuals
    with uncomplicated Mh infection as well as cohorts simultaneously
    with severe clinical signs or deaths as a complication (secondary
    bacterial infection) of Mh infection.

5.  Field cases of Mh-associated pneumonia almost always have a portion
    of the population complicated by bacterial co-infections (e.g.
    *Pasteurella multocida, Streptococcus suis, Hemophilus parasuis,
    Actinobacillus sp.)* that seems to be a progressive process through
    the group. This disease is commonly referred to as enzootic
    pneumonia or mycoplasmal pneumonia of swine (MPS). Enzootic
    pneumonia or MPS with multiple bacterial co-infections and/or with
    concurrent viral (e.g. PRRSV, SIV, PCV) involvement is often quite
    severe and referred to as porcine respiratory disease complex
    (PRDC).

6.  Diagnosis of early stages of MPS is by demonstrating typical gross
    and microscopic lesions and by detecting organisms by FAT, IHC, or
    perhaps PCR.

7.  To confirm infection in the lesions of later stages of MPS or in
    mixed infections, highly sensitive diagnostic methods (PCR) are
    preferred. Specific serology (CF, ELISA) is helpful to confirm the
    presence of Mh infection in the herd but is not definitive for
    etiologic diagnosis of field cases of pneumonia.

8.  Efficacious therapy or intervention to control Mh disease expression
    does significantly alter the course of respiratory disease in swine.
    Decreasing the duration of Mh insult and lung compromise as well as
    mitigating deleterious effects of Mh on pulmonary clearance and
    immune response appear to be sufficient to decrease the impact
    severity enzootic pneumonia without totally eliminating the
    infection. Intervention efficacy specific for Mh can be evaluated in
    current, well-respected Mh disease models.