Contagious Bovine Pleuropneumonia: A Review

 
Contagious bovine pleuropneumonia (CBPP),  foot and mouth disease (FMD) and rinderpest, are three major cattle plagues in history. Cattle have been at risk from enzootic illnesses ever since they were domesticated. Nocard and Raux were the first to isolate the causative agent of CBPP (Prosperi and Pini 1991). The first unambiguous description of the disease may well be that of B de Haller in Switzerland in 1773. (Haller B 1773). Reported 1^st in 1693 in Germany. 
 
CBPP-India- In India, particularly in Assam there were, 30 cattle deaths reported in 1932, were the first confirmed cases of CBPP. Illness that is locally referred to as “Brahmaputra Valley Disease.” However, the mycoplasma was not isolated or found because there were insufficient culture capabilities.  (Shirlaw and Iver, 1946). Acute, subacute, clinically imperceptible, or chronic CBPP disease is defined by the development of extensive pathological alterations in the thoracic organs, particularly the lungs and pleura. Significant interlobular septal edema, widespread pneumonia and sero-fibrinous pleuritis are among the abnormalities (Chakravarthy, 2007).
 
Etiology
 
Mycoplasma mycoides subsp. mycoides small colony (MmmSC) is the cause of contagious bovine pleuropneumonia (CBPP) (Belinda et al., 2018). The pleomorphic organisms, some of which are filterable, are easily maintained in special culture media and in the eggs of embryonated hens. The ‘Mycoplasma mycoides cluster’ comprises 6 important ruminant mycoplasmas, of which only 2 are known to cause disease in cattle: Mycoplasma bovine group 7 (Bg7), which can cause bovine mastitis and arthritis and two subspecies of Mycoplasma mycoides species. The other 4 are responsible for respiratory and other ailments in goats (Radostits et al., 2007). Although Mmm requires certain medium to develop, it is not thought of as a sensitive mycoplasma. Although various reference laboratories use different media compositions, all of them should fundamentally include a basic medium, such as PPLO broth (pleuropneumonia-like organisms) or heart-infusion broth, 1-2.5% yeast extract, 10%-20% inactivated horse serum, 0.1% glucose, 1% tryptose and 0.0024% DNA (WOAH Terrestrial Manual, 2021). Disinfectants, acidic and alkaline pHs, heat and a brief environmental survival period (up to 2 weeks) can all readily deactivate Mmm. Two (2) epidemio-geographically separate clusters of Mmm strains were identified in 1995: one (1) cluster included strains isolated from several European nations and the other cluster had strains from Australia and Africa (Vilei et al., 2000). Epidemiological and clinical investigations revealed that CBPP outbreaks of European origin are less virulent when compared with those observed in Africa.  (Alhaji et al., 2020). Because mycoplasmas lack cell walls, they are vulnerable to the environment and resistant to antimicrobials that damage cell walls. Their mutation rates are higher than those for typical bacteria, establishing that they can quickly become resistant to antimicrobials such tylosin and oxytetracyclines (Ayling 2013) (Masiga and Read 1972). PCR tests have revealed that three primary lineages are distinct from Europe, Southern Africa and the remainder of Africa. (Belinda et al., 2018).
 
March et al. (2000) assessed the doubling time of bacteria Mmm and concluded to obtain a more quantitative estimate of the growth rate of strain M375 (Africa, recent isolate), growth curves with GB were performed and the doubling times of various strains were measured. Strain M375 grew significantly more slowly than the other strains (P<0.01 with the exception of KH3J (Africa, vaccine strain), for which P<0.05), with a mean doubling time of 346 min. For most other strains the doubling times were in the range of 168 to 229 min. The only exception was Gladysdale (Australia, challenge strain), with a mean doubling time of 101 min, significantly faster than the other strains (P<0.01).
 
Epidemiology
 
Occurrence and prevalence
  There have been documented sporadic outbreaks in the Middle East, most likely caused by the importation of livestock from Africa. In 1892, the CBPP was eliminated in the United States; in 1904, Zimbabwe; in 1924, South Africa; in 1972, Australia and in the 1980s, China. (Recognising Cbpp FAO, 2002). While some suggested the disease might have been present approximately the start of the 20^th century, Rao conjectured that it might have existed in Assam as early as 1919 (Rao, 1969).
 
The Index case of CBPP was recorded in Golpara district of Assam in 1942. About 7.500 km² of cattle in Asom were afflicted by the CBPP infection, out of a total population of 1.25 million. It caused a significant percentage of the northeastern region’s cow population to die, resulting in significant financial losses. Approximately 12,000 cattle perished between 1951 and 1978, posing a threat to the lives of all cattle in the northeastern states of the nation. (Singh and Rana, 2014). India was proclaimed to be temporarily free of the illness, with effect from October 2003. In accordance with OIE decision number 17 (Nicholas, 2023), the WOAH proclaimed India free of CBPP infection on May 26, 2007, seven years later.
 
Source of transmission
 
The primary means of transmission for contagious bovine pleuropneumonia is inhalation of aerosolized respiratory tract droplets from diseased animals; close and frequent contact is usually necessary. Additionally, the organism may be transmitted tran-splacentally and can be detected in the saliva, urine, foetal membranes, or uterine secretions of infected animals (Belinda et al., 2018). CBPP is common in elderly animals may be caused by the likelihood that older animals may be exposed to infections for longer periods of time, a lower level of immunity as people age and the persistence of sequestrum in older animals relative to younger ones, which may benefit somewhat from maternal protection (Dar et al., 2017; Geetha et al., 2015).
 
The causative agent is present in liquid droplets in breath and urine. Although the CBPP organisms are killed rapidly in hot dry environments, airborne transmission appears possible over distances of up to 200 metres. (Recognizing cbpp FAO, 2002). Closely stabled or trucked animals are more likely to contract Mmm infection, the more than hundred metres transmission is seldom observed.  (Marobela-Raborokgwe et al., 2003). (Nicholas et al., 2007).

The organism was found in the semen and preputial washings of two young bulls that were intended for introduction into a breeding facility. The bulls were the offspring of frozen embryos transplanted into Portuguese cows. (Radostitis et al., 2007).
 
Transplacental transmission has been suggested with the isolation of Mmm from the foetus of an infected dam Masiga et al., (1975). Urine has been proposed as a potential method of transmission, particularly in temperate European countries where cattle are intensively raised in confined areas and multiple herds share a single stream (Grieco et al., 2001). It has been documented that an infection can spread from the cow to the foetus (Gladon et al., 2006).
 
Economic importance
 
Being the only bacterial illness included in the old world Organization for Animal Health (OIE) List “A” Diseases grouping that required urgent outbreak reporting. It is a disease of great economic significance that has the potential to jeopardize food security in endemic areas (Tambi et al., 2006). In endemic African countries, the projected cost of CBPP due to mortality, decreased livestock production and disease management efforts is €44.8 million/year (€3.7 million per country) (FAO, 2002) (Muuka et al., 2013).
 
Pathogenesis
 
For naturally infected animals, the incubation period might be anywhere from 3 weeks to 6 months. (WOAH Terrestrial Manual, 2021). Cattle that are infected with the organism experience substantial morbidity and death rates due to mycoplasmemia, which is caused by the invasion of the lungs and subsequent localization in the brain and kidneys, among other places. A crucial aspect of the disease’s pathophysiology involves thrombosis in the pulmonary arteries, most likely occurring before pneumonic lesions manifest (Radostitis et al., 2007). Teodoro et al. (2020) segmented the CBPP pathogenesis into consecutive, interconnected stages.
 
Adhesion to and Invasion of the Host’s Cells and Tissues
 
Animals inhale droplets containing the CBPP etiological agent, which is the main way that illnesses spread. Consequently, the initial pathogenetic stage, which is essential for the host’s successful colonization, is represented by Mmm adherence to the airway cells (Nicholas et al., 2007) (Pilo et al., 2007).
 
Mmm prefers to attach itself to the non-ciliated cells that line the alveoli and the bronchioles, which are the first areas to become infected (Teodoro et al., 2018).

Pilo et al. (2007) explained and represented the virulence pathways of M. mycoides subsp. mycoides SC (Fig 1), as represented above, according to which there are main pathway or upper pathway is based on glycerol import and metabolism.


 
There is no concrete proof of the bypass mechanism that permits glycerol to diffuse through the glycerol facilitator factor (GlpF) and be phosphorylated by the glycerol kinase (GlpK). The key player in this virulence pathway is the membrane-located L-aglycerophosphate oxidase (GlpO) (Fig 2).


 
Variable surface antigen (Vmm) elude’s the host’s immune system. Mycoplasma species generate capsular polysaccharide and trigger the production of cytokines. Due to its superantigen-like characteristics, lipoprotein LppQ is extremely antigenic and appears to be involved in the development of inflammatory processes.  African strains of Mmm are more likely to be virulent than European strains, as evidenced by their greater GtsABC efficiency and higher ROS production (Abdo et al., 1998). It is well known that mycoplasmas cause phagocytic cells to produce reactive oxygen species (ROS), which may intensify tissue and cell damage (Fig 2) (Koppel et al., 1984).
 
Inflammation and collateral damage
 
One of the most crucial and initial lines of defence against bacteria that invade the lower respiratory tract are alveolar macrophages. Alveolar macrophages produce a variety of chemical mediators that help regulate the inflammatory response in addition to their phagocytic and microbicidal actions (Grommes and Soehnlein, 2011).
 
There are currently insufficient and contradictory data available regarding Mmm. In fact, following in vitro stimulation with Mmm or galactan, respectively, macrophages can create pro-inflammatory (TNF-a) or anti-inflammatory (interleukin [IL]-10) cytokines. (Jungi et al., 1996; Tott´eet_al2015).
 
Immune-Mediated Mechanisms in the Pathogenesis of CBPP
 
Lymphoid proliferation, often arranged as follicles (so-called “tertiary lymphoid follicles”), is among the main features of mycoplasma infections (Teodoro et al., 2020).
 
Mycoplasmas have been found to cause mucosal infiltration of lymphocytes in a well-organized manner: B lymphocyte infiltration occurs and becomes dominant later, with the antigenic variation of mycoplasma lipoproteins likely inducing a long-term stimulation of the immune response; CD4+/ TCR helper T cells and CB8+/TCR cytotoxic T lymphocytes arrive at 2 to 3 weeks pi (Castro-Alonso et al., (2009).  Helper T cells significantly contribute to the synthesis of interferon-g (IFN-g), which is thought to be protective during CBPP (Dedieu et al., (2006). 
 
Clinical signs
 
There are four ways that CBPP might present itself: hyperacute, acute, subacute and chronic. Up to 10% of the infected herd may be affected by the hyperacute type, which manifests at the beginning of disease outbreaks and frequently results in abrupt death without other clinical symptoms. The acute type, which typically lasts five to seven days and is marked by fever, self-isolation from the herd, anorexia and painful, laborious breathing and dyspnea is noticed (Fig 3), affects about 20% of the affected cattle. Additional symptoms that could be seen include “grunting” on expiration and breathing from the abdomen. Cattle that are impacted may experience a harsh, dry and shallow cough, edema (Fig 4) which is frequently noticed when they exercise. When pressure is placed between the ribs, affected animals may cry out in agony and occasionally may respond violently (FAO, 2002).




 
Belinda et al. (2018) also concluded that for CBPP, the incubation time varies from a few weeks to many months. Depression, anorexia, pyrexia, dyspnea, tachypnea, nasal discharge, coughing and open-mouth breathing are examples of clinical symptoms. Adult animals that are affected may stand with their necks extended and their elbows bent, arthritis is also evident (Fig 5). Rales, friction rubs (Radostitis et al. 2007; Nehra et al., 2018) and crepitant noises can all be detected by thoracic auscultation. The degree of lung involvement and fluid accumulation can also affect lung sounds, causing dull sounds to be auscultated upon percussion over more ventral parts of the thorax. After recovering from pneumonia, some animals may develop persistent shedding as asymptomatic carriers (Belinda et al., 2018).


 
Necropsy finding and histopathology
 
The evaluation of ad hoc lung lesion scoring systems is desirable due to the distinct pathological characteristics of CBPP. A particular technique to score CBPP lesions in this regard created to evaluate the efficacy of vaccination against CBPP wherein, the scoring system had been developed where researcher allotted two points for acute or necrotic lesions; one point for healing process. Such scores were multiplied by a severity factor (1 to 3) according to the size of the lesions. Possible scores = 0, 1, 2, 4. and 6 (Turner, 1961).
 
Provvido et al. (2018) evaluated a novel lung score system for the CBPP, as there are number of lung affections, such as straw-coloured fluid accumulation and marbled appearance of lungs (Fig 6 and Fig 7) as well as lymph node affections such as hyperthrophy, lymphadenopathy as well as infarction (Fig 8, Fig 9 and  Fig 10) is observed. Turner system only partially separates CBPP lesions; for instance, an animal with a big sequestrum (diameter greater than 20 cm) receives the highest possible score of 6 points, in the same manner as a patient with widespread, bilateral, acute-to-subacute pneumonia. To negate these lacunae created the current lung lesion score system, which is thought to be helpful in quantifying CBPP lesions. It compiles the scores that have been published previously by different writers. Method similar with the “consolidation lung lesion score,” and is presently advised by the European Pharmacopeia for pleuropneumonia in pigs (Sibila et al., 2014).










 
Diagnosis
 
For diagnosis, samples can be collected (Table 1) and diagnostic test based on patho, micro, molecular biology, or serology can be utilized to examine CBPP. Abattoir surveillance for CBPP, which involves lung examination.                         

Suspected animals can be isolated and below mentioned samples can be used for diagnosis of CBPP outbreak. In situations when blood is unavailable and mycoplasma culture from the lung is problematic, immunohistochemistry (IHC) is the preferred test (Fig 11, 12, 13) when a carcass with lung lesions suggestive of CBPP is reported to the diagnostic laboratory. Fresh or previously formalin-fixed and paraffin-wax-embedded samples are obtained from lung lymph nodes or lung tissue suspected of having macroscopic lesion (Noordhuizen et al., 2001).






 
Tests using the polymerase chain reaction (PCR) have shown to be incredibly helpful in quickly identifying Mmm.  (Bashiruddin et al., 1999). In a fluid medium, a uniform cloudiness (Fig 14) that is characteristic of Mmm typically arises in three to five days and is sometimes accompanied by a delicate, silky filament known as a “comet/ fried egg form (Fig 15). While immunohistochemistry is merely a supplemental diagnostic tool for CBPP, it can be extremely helpful in chronic cases, instances where Mmm isolation may be hampered by suspected antibiotic treatment and particularly in renal tissues where Mmm isolation can be challenging.  (Bashiruddin et al., 1999).




 
Serological tests
 
Test results should be weighed as farm result and not interpreted on individual animal level because there will be lot of false positives or false negatives. Tests conducted on a single animal may be deceptive if the animal is in the chronic stage of the disease, when very few animals are seropositive, or if the animal is in the early stage of the disease, which can linger for several months before specific antibodies are generated. False-positive results can happen (2% of the time) and one major reason for this is serological cross-reactions with different mycoplasmas, especially those in the M. mycoides cluster. The most effective technique for identifying infection is still the complement fixation test (CFT) on serum. It is quick, straightforward to execute and outcomes are simple to understand.  Although it is less sensitive for serum samples with extremely low antibody levels than ELISA testing, it is more selective than other tests. (Marobela-Raborokgwe et al., 2003).
 
Although the CF has a low sensitivity and might overlook animals that are critically ill or have persistent lesions, it is useful for identifying infected groups of animals at the herd level (Belinda et.al, 2018).
 
Differential diagnosis
 
Infectious causing consolidated pleuropneumonia, such as Histophilus somni and Mannheimia haemolytica, are possible differentials (Belinda et al., 2018).
 
Acute and chronic respiratory conditions, including pneumonic pasteurellosis and Mycoplasma bovis infection are other differentials In acute cases, the diagnosis might be aided by the lungs’ marbled appearance, the pleural surfaces’ persistent involvement and the presence of vasculitis histopathologically (Teodoro et al., 2020).
 
CBPP should also be differentiated from Haemorrhagic septicaemia (HS). Development of edematous swelling within 6-72 hrs is common finding in (HS). Pasteurella species can also be cultivated, which will aid in differential diagnosis.
 
East Coast fever, or theileriosis - Coughing, discharge from the nose and eyes, diarrhea and abomasal ulcers. But no lesions in the lungs.
 
Treatment
 
Mycoplasma don’t react well to antibiotic treatment was notion; in fact, use was discouraged because threat of carrier animal. Previously demonstrated in experiments that giving the antibiotic danofloxacin (Advocin; 2011) to calves affected by CBPP might dramatically lower the amount of mycoplasma that spreads to other cattle. Therefore, we used the antibiotic in accordance with the manufacturer’s guidelines to treat all clinically afflicted or seropositive herds in the Caprivi. Following treatment, there were no more overt instances and only three animal deaths in the first three months, marking an instantaneous decrease in the number of new cases (Hubschle et al., 2006b).
 
In a comparative study conducted by Muuka et al., (2019) wherein, 2.5 mg/kg of tulathromycin, 6 mg/kg of a commercially available gamithromycin was compared with 24 mg/kg of a commercial oxytetracycline formulation. The study concluded that, tulathromycin protected 82%, gamithromycin 56% and oxytetracycline 80% of the animals in Kenya whereas in Zambia, tulathromycin protected 98%, gamithromycin 94% and oxytetracycline 80%. 
 
The development of Mmm was effectively inhibited by oxytetracycline, danofloxacin and tulathromycin (Mitchell et al., 2012).
 
In vitro study with five widely used antibiotics revealed that tilmicosin and danafloxacin were efficacious in both mycoplasmastatic and mycoplasmacidal action (Ayling, 2013). A synthetic fluoroquinolone authorized for SC injection in cattle is danofloxacin mesylate (Advocin, 2011) efficient distribution and highly bioavailable. In cattle, danofloxacin has a 3-6 hours half-life and very little accumulation (Zeng et al., 2011).
 
Broad spectrum antibiotic, targets bacteria’s 50S ribosome is called flufenicol. Following I.M injection, the medication is only moderately bioavailable (79%) in cattle (Papich and Riviere, 2009; Plumb, 2016).
 
Control and prevention
 
Issues- Movement control, implementation of policies, dearth of pen-side diagnostic testing speed, ineffective vaccine, strained finances, Drought and civil unrest (Radostitis et al., 2007).
 
Mmm has low environmental resistance; its survival is entirely dependent on the infection of animals that are susceptible, (OIE-WOAH 2018). defending the claim that the “CBPP walks on the feet of cattle.” Given this, the following strategies are used to control the disease in CBPP-free areas: (1) prohibiting the import of cattle from infected nations; (2) enforcing border controls; (3) instituting quarantine; and (4) detecting outbreaks early and enforcing tight stamping-out procedures (FAO, 2002).
 
Serologic screening in disease-free areas and to eliminate any positive and in-contact animals. Immunization against CBPP is widely used and essential to control in endemic areas.
 
T1/44 and T1sr are the two strains against which vaccines CBPP have been produced. While T1sr is an avirulent strain, T1/44 is a moderate strain. Compared to T1/44, T1sr offers a shorter duration of immunity; nevertheless, T1/44 has the additional risk of causing postvaccinal responses, which may require antibiotic treatment after vaccination (Belinda et al., 2018).
 
Vaccination campaigns must target all cattle within a specified geographic and epidemiological area in order to be effective. The vaccination must be given again, first at short intervals and then once a year for a number of years, or at least three to five years (FAO, 2002).
 
2 attenuated vaccines, T1/sr and T1/44, derived from the Tanzanian T1 strain, are advised by the OIE. T1/44 IS more effective after 44 passes on chicken embryos, although it only offers a brief immunological shield (less than a year). The “Willems’ reaction” is an invasive edema that appears two to four weeks after injection. (Sheriff and Piercy, 1952; Revell, 1973; Rweyemamu et al.,1995; Mbulu et al., 2004; Muuka et al., 2014, OIE-WOAH, 2018). China was able to eradicate CBPP with the help of the attenuated strain Ben-1 (Xin et al., 2012). More research on CBPP immunology and protective response as well as more effective, safer and less expensive vaccine formulations are required to potentially enable the distinction between infected and vaccinated animals (DIVA vaccines). (Dedieu-Engelmann, 2008). The development of vaccinations against the ISCOM protein component has shown promising early results. A significant surface antigen and pathogenicity factor of MmmSC is capsular polysaccharide (CPS), formerly called as galactan. Capsular polysaccharide conjugate vaccines against CBPP provide a protective immunological response in mice, suggesting that humoral immunity is not the primary mechanism of protection against MmmSC mycoplasmemia (Waite and March, 2002).
 

CBPP is an important bacterial infectious illness that primarily threatens the cattle industry and the financial well-being of pastoralists in Africa. India, especially the northeastern region, appears to be particularly vulnerable to CBPP. Among the drawbacks are the restricted diagnostic options for identifying CBPP in suspected cases and the challenging implementation of control strategies. After rinderpest, CBPP is the second most serious transboundary disease in Africa. Notable mortality and morbidity rates in CBPP. In addition to Sub-Saharan Africa, other countries with sizable bovine populations and husbandry practices are also susceptible to CBPP infection and suffer significant economic losses during epidemics. CBPP is crucial contagious disease, with posing threat to, africa’s pastoralists’ socioeconomic well-being as well as the livestock business. Limited diagnostic modalities to diagnose CBPP in suspected case is presented are also limited, difficult to implement control approaches. CBPP is 2^nd most significant transboundary illness in Africa, after rinderpest. Significant of morbidity and mortality in CBPP. Beside Sub-Saharan Africa, countries in the world wherein there is huge amount of bovine population and husbandry practices, those nations as well, are vulnerable to CBPP infection and the economic losses which occurs after outbreaks are enormous. 
 

The author declares that they have no conflicts of interest related to the research, authorship, or publication of this manuscript.