Introduction

Pasteurella species are commonly present in the oral, nasal, and respiratory cavities of animals they are recognized as one of the most prevalent and opportunistic pathogens globally in both domestic and wild animals (1). Pasteurella multocida (P. multocida) is a microorganism that commonly resides in the nasopharynx of domestic and wild animals. Humans can acquire P. multocida infections through contact with animals or mucous secretions. Despite its infrequent occurrence in clinical settings, P. multocida is classified as a zoonotic pathogen (2). The World Organization for Animal Health (OIE) (www.oie.int), states that pasteurellosis, a symptomatic infection caused by Pasteurella, is a highly impactful disease in livestock. Both animals and humans can be affected by Pasteurella species, especially P. multocida, which can cause chronic and acute effects such as pasteurellosis, pneumonia, atrophic rhinitis, dermatosis, cellulitis, abscesses, meningitis, hemorrhagic septicemia (3), and even mortality in animals (4).

 Pasteurella spp. are coccobacilli that are gram-negative, non-motile, and facultatively anaerobic.  Alifragki et al. state that Pasteurella spp. are frequently present in the oral cavity and gastrointestinal tract of specific animals, potentially leading to infections (5). This species belongs to the Pasteurellaceae family, encompassing various other genera such as Haemophilus, Actinobacillus, Mannheimia, and Aggregatibacter. The length of Pasteurella spp. is 1 to 2 micrometers (6). Louis Pasteur was the first to confirm that P. multocida was responsible for fowl cholera in 1881 (1). To distinguish between various strains of P. multocida, five serogroups (A-F) based on capsular antigens and 16 serovars (1-16) based on somatic antigens are utilized, with certain strains being more frequently found in infected humans (7). There are over 30 species of Pasteurella, with P. multocida being the primary cause of human pasteurellosis due to its connection with the pharyngeal flora of domestic animals (8). Pasteurella multocida is very similar to Brucella in its biochemical and serological properties, but it causes different diseases from Brucella (8).  Pasteurella does not have spores and has a bipolar state in isolation from a fresh. Pasteurella multocida is known to cause rabbit septicemia, swine plague (with severe mortality), and bovine pneumonia. Pasteurella multocida and Mannheimia hemolytica (M. haemolytica) have several hosts. Pasteurellosis in livestock is mostly caused by P. multocida and sometimes M. haemolytica or pastorellas close to these two.   The predominant species of Pasteurella that causes disease in dogs and particularly cats is P. multocida, although other species such as P. canis, P. dagmatis, and P. stomatis may also be involved. These Pasteurella species are often present with other bacteria, including Streptococcus canis, other gram-negative bacteria, or anaerobes (9).

Pathogenesis

Pasteurella. multocida is a variety of bacteria that can be spread to humans using bites or scratches from cats and dogs (Fig. 1), or by coming into contact with their bodily fluids. However, there have been rare cases where the bacteria has been transmitted vertically from an infected mother to her newborn (10, 11). It is not always necessary for the bacteria to penetrate the skin for transmission, as there have been cases of infection after being licked by an infected animal (12). Pasteurella. multocida is a frequently occurring microbe that inhabits the oropharynx and upper respiratory tract of rabbits. The microorganism that causes this infection can be transmitted to humans through scratches, bites, licks, or inhaling air particles. Individuals with weakened immune systems or respiratory problems are more susceptible to contracting the infection. Infected rabbits may carry the microorganism without clinical symptoms (13). Several genes that could affect the pathogenicity of P. multocida include those related to fimbriae, adhesion, and colonization (such as ptfa, fimA, pfhA, and tadD), as well as genes involved in iron regulation and protein acquisition (exbB, exbD, tonB, hgbA, hgbB, tbpA, and fur). Other factors include superoxide dismutase (sodA and sodC), dermonecrotic toxins (toxA), various outer membrane proteins (OMPs) acting as protective agents (ompA, ompH, omp87, and plpB), and neuraminidase (nanB and nanH) (14-18). Currently, researchers are investigating how these small organisms can enter the mucous membrane, evade natural immunity, and cause widespread sickness. Important factors contributing to their ability to cause disease include the capsule and lipopolysaccharide.  The bacterial capsule prevents phagocytosis and resists complement, while complete lipopolysaccharide is crucial for bacterial survival in the host. Other factors that contribute to virulence have been discovered through targeted and random mutagenesis, including P. multocida toxin (PMT), potential surface adhesins, and iron acquisition proteins. Probably, there are still numerous important factors that contribute to the virulence of P. multocida, including those necessary for attaching to and attacking host cells, as well as surviving in a harsh and nutrient-poor environment (1). This bacterium is responsible for bovine respiratory disease (BRD), which has a complex pathogenesis involving various infectious agents, environmental and stress factors, and the host's immune response (19). Although there has been significant investigation into the clinical, pathological, hematological, and biochemical characteristics of goats contaminated with P. multocida, the molecular mechanisms involved in such contamination remain largely unclear (20). Pasteurella. multocida is known to cause inflammation and cell death. When injected into mice, it triggers the production of proinflammatory cytokines such as TNF-α, IL-6, IL-1, IL-8, and IL-12, and increases the number of neutrophils (21). It is worth noting that Honnorat et al. found cases of septic arthritis caused by P. multocida that did not involve bite or scratch injuries (22). Respiratory disease resulting from P. multocida infection typically manifests with symptoms such as coughing, fever, shortness of breath, and chest pain. Although pneumonia is the most common type of P. multocida infection, tracheobronchitis, empyema, and lung abscesses are also possible outcomes (23). Pasteurella is part of the mucous flora of the respiratory system and the disease often follows stress such as the accumulation of livestock, cold, transportation, or simultaneous infections.  Pasteurella can be pathogenic when it enters the body initially, and in these cases, transmission between animals is often through small droplets or contaminated water and food.  While organisms such as ticks, lice, and flies have been found to harbor the bacterium P. multocida, they are not currently recognized as vectors for transmission to humans (23, 24). Unlike mammals, this bacterium is not the natural flora of birds and its presence in the bird is a sign of acute or chronic disease. Most respiratory diseases outbreaks in cattle and pigs are due to bacterial invasion from internal (endogenous) sources. Hemorrhagic septicemic diseases of cattle and sheep and fowl cholera are caused by highly invasive species (i.e. they are secondary infections) and bacteria cause disease in the first place. Studies have shown that particular OMPs present in P. multocida play a role in the onset of disease and possess characteristics that activate the immune system and eliminate bacteria (24-28).

Epidemiology, ways of transmission, and risk factors

Pasteurella multocida, initially discovered after a cat bite in 1930, is now regarded as the most significant microorganism of its kind in clinical settings. However, Pasteurella spp. was first isolated in 1878 from fowls with cholera (6). According to Iaria and Cascio, P. multocida infects around 20-50% of the 1-2 million individuals who suffer from dog and cat bites or scratches in the United States annually (29). Pasteurella multocida is widespread in cats and dogs but can also harm humans, primarily resulting in soft-tissue infections following animal bites or scratches. Immunocompromised individuals or those with chronic illnesses may experience invasive diseases from P. multocida infections (30). Pregnant women and immunocompromised individuals are at a higher risk of contracting pet-induced zoonoses (3, 30).

Clinical signs in human

The clinical symptoms of Pasteurellosis in humans typically occur when an animal bites and leads to a skin and soft tissue infection. Although infective endocarditis is rare, it can be difficult to diagnose and treat due to its infrequency.  According to a recent study by Alifragki et al., 28 patients with infective endocarditis caused by Pasteurella spp. exhibited common clinical symptoms such as fever, sepsis, septic shock, and heart failure (5). The aorta was frequently impacted within the heart, and approximately 21.4% of patients had a valve replacement. These microorganisms are often present in the oral and digestive tracts of specific animals and can lead to infections such as septicemia (6). Pasteurella multocida is commonly linked to skin and soft tissue infections but can cause several human diseases, such as meningitis, urinary tract infections, pneumonia, endocarditis, brain abscesses, conjunctivitis, and epiglottitis. However, the incidence of reported cases is restricted (30). Breen et al. found that P. multocida contamination was only diagnosed 23 times in a major teaching hospital laboratory in Australia over a decade (31). While P. multocida is not a common cause of prosthetic joint infections, other microorganisms like Staphylococcus aureus, coagulase-negative staphylococci, and Streptococcus species are often responsible (32). Christenson et al. reported a case of severe P. multocida sepsis in a renal transplant patient caused by cat-licking venous stasis ulcers on the patient's legs (33). In humans, P. multocida infections are linked to respiratory symptoms such as pneumonia, tracheobronchitis, lung abscesses, and pulmonary emphysema (34).

Clinical signs of pasteurellosis in animals

According to some studies, pasteurellosis is a common illness in both wild and domestic animals. It typically appears as upper respiratory symptoms such as nasal inflammation and discharge, as well as lower respiratory problems like pneumonia. The severity of symptoms can vary from mild to severe (34-37). Non-toxic capsular strains of P. multocida can cause Pneumonic Pasteurellosis without any signs of atrophic rhinitis.

Symptoms of pasteurellosis in ruminants

Respiratory illness is commonly caused by P. multocida in hoofed mammal animals such as cattle. This pathogen, along with other bacteria like M. haemolytica, Histophilus somni (H. somni), Mycobacterium bovis (M. bovis), and Trueperella pyogenes (T. pyogenes), is frequently linked to Bovine respiratory disease (BRD) or "shipping fever," which is a complicated form of non-septic pneumonia (38, 39). Bovine respiratory disease is a complex condition that results in high mortality rates among young calves and significant financial losses for the global cattle industry (40). The most common cause of BRD cases is M. haemolytica, which leads to severe pleuropneumonia with hemorrhage or coagulative necrosis due to extreme inflammation caused by LPS and the production of a leukotoxin specific to ruminants (38). According to Wang et al., BRD results in negative impacts on animal health, carcass weight, welfare, and financial costs due to increased expenses for treatment and vaccination in affected herds (41). Pasteurella multocida species are known as secondary invaders of respiratory injuries in cattle, sheep, and goats, viral and mycoplasmic infections favor the occurrence of Pneumonic Pasteurellosis (32, 41).  Cows can be infected at any age, but at 6 to 24 months (2 years), it has a higher sensitivity.

Clinical symptoms of hemorrhagic septicemia in cows and buffaloes

The disease occurs due to introduction of bacteria into the blood in an acute and sub-acute manner. Clinical signs are high fever (42 to 41 ˚C), lethargy, excessive salivation, bloody diarrhea, and subcutaneous edema. In advanced cases of cyanosis (bruising) of mucous membranes Rapid death is one of the important symptoms (such as enterotoxemia and heartburn). Sometimes, there is bleeding from the pores of the body (same as scalding, but it should not be confused with scalding) (42). Sadeghian et al. state that goats can suffer from two major illnesses caused by pasteurellosis, namely systemic pasteurellosis and pneumonic pasteurellosis (42). Pneumonic pasteurellosis is characterized by symptoms such as fever, lethargy, loss of appetite, swelling, excessive salivation, tearing, nasal discharge, coughing, and dullness. These symptoms quickly progress to respiratory distress, septic shock with severe bleeding, and ultimately death  (42, 43).

Septicemia

Manhemia hemolytica is the cause of septicemia in sheep, which can be seen in two forms. One occurs in lambs less than three months old, characterized by swelling of the pleural membrane and pericarditis, and type A bacterium is responsible for it. The other occurs in lambs aged 5-12 months and is caused by type T. Young lambs acquire the bacteria from the mother, and the bacteria are replaced in the tonsils in the first few weeks of life. The spread of disease often follows a change in the diet from poor to rich. Bacteria multiply in the tonsils and then invade the adjacent tissues of the digestive system. A group of bacteria enters the bloodstream and causes embolism in the vessels of the lung, liver, and spleen, due to the release of endotoxin and the proliferation of bacteria in the lungs, liver, and spleen; the animal dies suddenly. According to Wilson et al. and Dabo et al., livestock, especially cattle, and buffalo, in tropical areas like Asia, India, Africa, southern Europe, and the Middle East can suffer from a serious and potentially deadly acute disease called hemorrhagic septicemia (3, 44, 45). The disease is primarily caused by P. multocida serotypes B: 2 and E: 2 and is commonly observed in the later stages of pasteurellosis disease. While Hemorrhagic septicemia )HS( is less frequently seen in pigs, sheep, goats, and deer, it is more commonly associated with serotype B:2 strain (46). Hemorrhagic septicemia can go unnoticed until the acute phase, which starts suddenly and progresses quickly within a few hours. Symptoms typically involve fever, fatigue, and swelling, along with excessive salivation, watery eyes, and nasal discharge. Soon after, the affected person experiences issues with breathing, septic shock accompanied by heavy bleeding, and passes away within 1-3 days. Even though there has been thorough research, there is limited understanding of the factors that lead to the disease or how it progresses from a mild chronic state to a severe disseminated condition. The pasteurellosis agent in sheep and goats (M. haemolytica) causes two distinct syndromes: pneumonia and septicemia. In addition, a kind of gangrenous mastitis also occurs near the end of the lactation period in ewes. One of its characteristics is one-sidedness and necrotic inflammation of the mammary gland (5, 46).

Pasteurella pneumonia in sheep

Endemic and sporadic pneumonia in sheep is similar to transportation fever in calves. Although transportation is not a significant factor in the pathogenesis of sheep, since the sheep are constantly moving, other stressors are important in this context. Biotype A is the causative agent of sheep pneumonia (Fig. 2). The onset of the disease is rapid (such as enterotoxemia and hemorrhagic septicemia). In addition, it often causes the death of one or two lambs and respiratory diseases of different severity in the rest of the lambs. In acute disease, fever, cough, nasal and eye discharge, and diarrhea occur (15, 47).

Symptoms of mastitis caused by Pasteurella species

It is common in ewes and manifests as a super-acute, dangerous, and fatal gangrene. However, it occurs relatively rarely and in isolated cases in cattle and goats, where the cause is M. hemolytica and P. multocida (12, 18, 47). The infected teat becomes extremely swollen, and the milk becomes watery with blood. Calves can contract pasteurellosis through contaminated milk, but the disease is not fatal in cattle.

Clinical signs of pasteurellosis in rabbits

The wide range of microorganisms is evident in the different clinical presentations related to pasteurellosis in rabbits. These presentations majorly affect the respiratory system (Fig. 3), but may also involve otitis, pyometra, mastitis, orchitis, abortions, subcutaneous abscesses, and intense septicemic forms (47). Infected rabbits might not show any symptoms or may experience severe symptoms. The pathogenicity of P. multocida is impacted by different virulence factors, including capsule proteins and lipopolysaccharides. These factors are more widespread when there is immunosuppression, stress, or unfavorable environmental conditions (1, 17).

Clinical signs of pasteurellosis in dogs and cats

Pasteurella species have been linked to various disease manifestations, including pyothorax, upper respiratory tract infections (often resulting from viral infections or chronic rhinosinusitis), bronchopneumonia, urinary tract infections, ocular surface infections, wound infections, cutaneous abscesses, otitis externa, bacteremia, and, infrequently, infective endocarditis (9).

Clinical signs of bird pasteurellosis or fowl cholera

Poultry infected with P. multocida can develop fowl cholera, which is a significant economic concern in commercial production. It can manifest in various forms, including peracute, acute, and chronic infections (48). The histological features, clinical signs, and macroscopic lesions linked to P. multocida infections in poultry and pigs are not distinctive and can be mistaken for other respiratory system infections that are characterized by inflammation of the upper respiratory tract, pneumonia, airsacculitis, polyserositis, and septicemia. Therefore, it is crucial to accurately detect the causative organism to make a proper diagnosis (49, 50).

Laboratory diagnosis

The ailment agent is present in the lung and tracheal secretions, and the diagnosis is established by culture and isolation of the agent.  Pasteurella multocida can grow on different culture media, such as sheep and chocolate agar, but generally not on MacConkey agar. Furthermore, most strains give a positive outcome for indole, catalase, and oxidase tests (6). According to Townsend et al., P. multocida colonies typically display a smooth, blue, and iridescent appearance on standard growth media (Fig. 4, 5). However, encapsulated isolates may exhibit a mucoid appearance (7). Currently, molecular techniques such as 16SrRNA are commonly used instead of serotyping  to distinguish between various types of Pasteurella spp. (30, 51).

Autopsy findings

Pneumonic Pasteurellosis in ruminants

In sheep, Lesions in acute cases are hemorrhagic bronchopneumonia with pneumonia (pneumonia and pericarditis). Lung lesions are limited to anterior and abdominal regions. Autopsy and pathological signs of pasteurellosis hemorrhagic septicemia in cows and buffaloes are observed in all the organs of the body, from mucous membranes to different parts. Due to the rapid progress of the disease and the rapid loss of animals, the lesions are limited to bleeding points in the serous areas, accumulation of blood in the chest and abdomen, swelling of the intestine, and swelling of subcutaneous tissues (in subacute forms) (16, 51).

Pathological signs of pulmonary pasteurellosis or transportation fever in cows and buffaloes

Pulmonary pasteurellosis manifests with hepatization of the lung. The stages of pneumonia are different in different parts of the lung, starting with hyperemia and goes through different stages of liver development and is associated with the accumulation of mucous and fibrinous secretions in the space between the lobes of the lung. In chronic cases, pleural membrane adhesion is present, which causes severe shortness of breath and prevents inhalation and exhalation. It also becomes a place of infection (51).

Differential diagnosis

It is crucial to take into account other pathogens besides P. multocida, which is the most commonly detected pathogen when diagnosing animal bites or scratches. These additional pathogens comprise Bartonella henselae, Clostridium tetani, Staphylococcus aureus, and Rabies lyssavirus (52).

Treatment

Penicillin is the preferred treatment for P. multocida infections as they are usually responsive. However, in uncommon instances of penicillin resistance, alternative antibiotics like cephalosporins, fluoroquinolones, or tetracyclines may be utilized (52). For prophylaxis or local infections, amoxicillin-clavulanate is the first-line antibiotic. Other treatment options may involve using a blend of antibiotics that have anti-Pasteurella properties, like doxycycline, trimethoprim-sulfamethoxazole, penicillin V, cefuroxime, ciprofloxacin, or levofloxacin, along with an anti-anaerobic agent such as metronidazole or clindamycin to address other bacteria in the mouth. During the initial stages of treatment, antibiotics can be given through injection and may consist of ampicillin-sulbactam, piperacillin-tazobactam, or a carbapenem such as imipenem-cilastatin, meropenem, or ertapenem. Another option is to use ceftriaxone or fluoroquinolone in conjunction with an anti-anaerobic medication like metronidazole or clindamycin. It is crucial to modify antibiotic therapy based on culture and sensitivity test results when appropriate. Antibiotics that are ineffective against Pasteurella, such as cephalexin, dicloxacillin, and erythromycin, should be avoided (53). Enrofloxacin was selected as a treatment option due to its effectiveness in controlling P. multocida in rabbits and authorization for use in pets. In a recent study, enrofloxacin was administered through drinking water at a concentration of 200 mg/L for 15 days. This resulted in a reduction of rhinitis and conjunctivitis symptoms in rabbits and an improvement of symptoms in adults (13). Non-steroidal anti-inflammatory drugs are used as auxiliary drugs in severe cases of the disease.

Prognosis

Soft-tissue infections caused by P. multocida, usually have a simple course and can be cured with proper treatment. In severe cases like bacteremia, meningitis, and endocarditis, the outlook is significantly poorer. Mortality rates range from 25% to 30% in such situations (30).

Prevention and control

Creating vaccines based on Pasteurella is crucial for reducing major economic and domestic wildlife losses caused by pasteurellosis. Different vaccines have been developed for Pneumonic Pasteurellosis, and their efficiencies are different from each other (54). New vaccines are required to combat P. multocida, the primary cause of infections in farm animals, as commercial vaccines only offer temporary immunity. Studies have revealed that both the DNA vaccine and inactivated vaccines lead to a substantial rise in serum antibody levels in rats with infections. DNA vaccine provides better protection than the live attenuated vaccine, although it only offers partial protection. Yassein et al. have reported that the recombinant vaccine shows high immunogenicity and has the potential for use as a vaccine in the future (55). DNA vaccine designed for P. multocida toxin (PMT) can protect animals from infections caused by P. multocida. The vaccineeffectively protects against avian pasteurellosis using two different outer membrane proteins (OMPs), OmpH and OmpA, resulting in the highest level of protection (56, 57). There is another DNA vaccine called pVAX1-ABA392 that has demonstrated potential for use as a vaccine by producing significant levels of anti-HS antibodies against P. multocida (58). This vaccine has a good chance of being selected to serve as a strong candidate for vaccination. Over 30 vaccines have been created for P. multocida. Vaccines for pasteurellosis should be investigated for short-term or long-term serious side effects (Table 1).

Conclusion

Pasteurella multocida can cause illness in various species of animals and birds. It is a significant cause of respiratory infections in animals and is also an important zoonotic disease. If an elderly patient with a chronic lung condition has a history of exposure to cats or dogs, the clinician should be aware that Pasteurella could potentially be a cause of their pulmonary illness.

Acknowledgments

Not applicable.

Ethical approval

Not applicable.

Conflict of interest

There is no conflict of interest in conducting this research.