Virulent  P. gingivalis  further modulates leukocyte recruitment by proteolysis of  cytokines  and  chemokines  that are secreted by the host cells. The arg-gingipain and lys-gingipains are responsible for this proteolysis. In a study using a mouse model,  P. gingivalis  was specifically found to down-regulate  IL-8  induction, causing delayed  neutrophil  recruitment. Prevention of neutrophil recruitment may inhibit the clearance of the bacterium from the site of infection allowing for colonization. [ 29 ]   P. gingivalis  is able to evade opsonophagocytosis from  granulocytes  by using Gingipain K (Kgp) to cleave  IgG  1 and 3. This further modulates immune response by impairing signaling. [ 17 ]  Other studies have found that  P. gingivalis  can subvert the  complement  pathway through C5αR and C3αR, which modulates the killing capacity of leukocytes, allowing for uncontrolled bacterial growth. [ 29 ] [ 30 ] [ 31 ]   P. gingivalis  was also found to inhibit pro inflammatory and antimicrobial responses in human monocytes and mouse macrophages by fimbrial binding to CXCR4, inducing  PKA  signaling and inhibiting  TLR-2 -mediated immune response. [ 32 ]


Once in the host cells,  P. gingivalis  is capable of inhibiting  apoptosis  by modulating the  JAK/Stat  pathway that controls mitochondrial apoptotic pathways. [ 33 ] [ 15 ]  A proliferative phenotype may be beneficial to the bacterium as it provides nutrients, impairs host cell signaling, and compromises the integrity of the epithelial cell layer, allowing for  invasion and colonization. [ 15 ]


P. gingivalis  plays an important role in the onset of chronic adult periodontitis. [ 34 ]  Though it is found in low abundance in the oral cavity, it causes a microbial shift of the oral cavity, allowing for uncontrolled growth of the  commensal  microbial community. This leads to periodontitis through the disruption of the host tissue homeostasis and adaptive immune response. [ 35 ]  After using laser capture microdissection plus qRT-PCR to detect  P. gingivalis  in human biopsies, colocalization of  P. gingivalis  with CD4+ T cells was observed. [ 36 ]  However, the infection mechanism of T cells by  P. gingivalis  remains unknown. [ citation needed ]


P. gingivalis  has been associated with increasing the virulence of other commensal bacteria in both  in vivo  and  in vitro  experiments.  P. gingivalis  outer membrane vesicles  were found to be necessary for the invasion of epithelial cells of  Tannerella forsythia . [ 37 ]   P. gingivalis  short fimbriae were found to be necessary for coculture biofilm formation with  Streptococcus gordonii . [ 26 ]  Interproximal and horizontal alveolar bone loss in mouse models are seen in coinfections involving  P. gingivalis  and  Treponema denticola . [ 38 ]  The role of  P. gingivalis  in periodontitis is studied using specific pathogen-free mouse models of periodontal infections. In these models,  P. gingivalis  inoculation causes significant bone loss, which is a significant characteristic of the disease. In contrast, germ free mice inoculated with a  P. gingivalis  monoinfection incur no bone loss, indicating that  P. gingivalis  alone cannot induce periodontitis. [ 29 ]


While  P. gingivalis  is a part of the typical microbiotic ecosystem of the oral cavity in humans, it can also become pathogenic is provided with sufficient opportunity. When this occurs, the resultant infection is known as  gingivitis  or  periodontitis .


Periodontal disease, which an infection of the gum tissue driven primarily by  P. gingivalis , has been theorized to be linked with other systemic diseases, including  Alzheimer’s ,  atherosclerosis  and other  cardiovascular diseases . Though there exists no scientific consensus on the mechanism by which these disease processes are linked, evidence for the connection between periodontal disease and cardiovascular diseases including atherosclerosis has been found in both statistical study of human populations, [ 39 ]  and  in vivo  studies using a mouse model. [ 40 ]


It is thought that periodontitis is linked to cardiovascular disease due to  inflammation  pathways, which the two pathologies have in common. The inflammation pathway of periodontitis is such that as the infection grows, bacteria, including  P. gingivalis  are targeted by neutrophils and natural killer immune cells. These cells phagocytize the bacteria, while simultaneously  cytokine  molecules in the area lead to a proinflammatory environment. This proinflammatory environment is also rich in intercellular signaling molecules including  tumor necrosis factor-alpha ,  interleukins  ( interleukin 1 ,  interleukin 4 ,  interleukin 10 ),  interferons  and  transforming growth factor beta . These molecules recruit more enzymes and transcription factors, which then in turn recruit more immune cells, forming a positive feedback loop which can make the immune response, and therefore the inflammation become chronic and systemic. Chronic inflammation of gum tissue can lead to a loss of this tissue and of bone tissue as well. The inflammation upregulates production of  RANKL , an intercellular signaling molecule that promotes bone tissue dissolution, leading to a gradual loss of bony tissue.  P. gingivalis  infection is also thought to lead to oxidative stress. Both chronic systemic inflammation and oxidative stress are factors associated with the onset of cardiovascular disease, and are proposed mechanisms by which periodontal disease may, if it indeed is causationally linked to cardiovascular disease, accelerate the disease process of a cardiovascular disease. [ 41 ]


While invasive  P. gingivalis  is associated with various forms of cardiovascular disease, including  stroke ,  coronary artery disease ,  atrial fibrillation , and  heart failure , the best evidence of a direct causational link is between invasive  P. gingivalis  (periodontal disease) and atherosclerosis. In vivo and in vitro animal models have found that the fimbriae of  P. gingivalis  promote host cell entry and  atherothrombotic lesion  formation once the bacteria enter the bloodstream, such as through lesions in the mouth.  P. gingivalis  has been shown to accelerate the atherosclerosis disease pathway in mice, as well as being found in human atherosclerotic plaque lesions. [ 42 ]


Prevotella intermedia  (formerly  Bacteroides intermedius ) is a  gram-negative ,  obligate anaerobic   pathogenic  bacterium involved in periodontal infections, including  gingivitis  and  periodontitis , and often found in  acute necrotizing ulcerative gingivitis . It is commonly isolated from  dental abscesses , where obligate anaerobes predominate.


Prevotella intermedia  is thought to be more prevalent in patients with  noma .
 [ 1 ]


Prevotella intermedia  use  steroid hormones  as growth factors, so their numbers are higher in pregnant women. [ citation needed ]  It has also been isolated from women with  bacterial vaginosis . [ 2 ]


This  Bacteroidota -related article is a  stub . You can help Wikipedia by  expanding it .


Slackia  is a genus of  Actinomycetota , in the family  Coriobacteriaceae . [ 1 ] [ 2 ]   Slackia  is named after the microbiologist  Geoffrey Slack . [ 3 ]


The currently accepted taxonomy is based on the  List of Prokaryotic names with Standing in Nomenclature  (LPSN) [ 1 ]  and  National Center for Biotechnology Information  (NCBI). [ 4 ]


S. isoflavoniconvertens


S. exigua


S. heliotrinireducens


S. equolifaciens


S. faecicanis


S. piriformis


S. exigua   (Poco et al. 1996) Wade et al. 1999


S. heliotrinireducens   corrig. (Lanigan 1983) Wade et al. 1999


S. isoflavoniconvertens   Matthies, Blaut & Braune 2009


S. equolifaciens   Jin et al. 2010


S. faecicanis   Lawson et al. 2005


S. piriformis   Nagai, Watanabe & Morotomi 2010


Tannerella forsythia  is an  anaerobic ,  Gram-negative  bacterial species of the  Bacteroidota  phylum. It has been implicated in  periodontal diseases  and is a member of the  red complex  of  periodontal pathogens . [ 1 ]   T. forsythia  was previously named  Bacteroides forsythus  and  Tannerella forsythensis . [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Tannerella forsythia  was discovered by and named after Anne Tanner, who works at  The Forsyth Institute  located in Cambridge, Massachusetts. [ 6 ]


T. forsythia  has been identified in atherosclerotic lesions. Lee et al. found that infecting mice with  T. forsythia  induced foam cell formation and accelerated the formation of atherosclerotic lesions. [ 7 ]   It has also been isolated from women with  bacterial vaginosis . [ 8 ]   The presence of oral  T. forsythia  has been found to be associated with an increased risk of esophageal cancer. [ 9 ]


Treponema denticola  is a  Gram-negative ,  obligate anaerobic , motile and highly proteolytic  spirochete  bacterium. It is one of four species of oral spirochetes to be reliably cultured, the others being  Treponema pectinovorum,  Treponema socranskii  and  Treponema vincentii [ 2 ] .      T. denticola  dwells in a complex and diverse microbial community within the oral cavity and is highly specialized to survive in this environment.  T. denticola  is associated with the incidence and severity of human  periodontal disease .   Treponema denticola  is one of three bacteria that form the Red Complex, the other two being  Porphyromonas gingivalis  and  Tannerella forsythia . Together they form the major virulent pathogens that cause chronic  periodontitis . [ 3 ]  Having elevated  T. denticola   levels in the mouth is considered one of the main etiological agents of  periodontitis . [ 4 ] [ 5 ]   T. denticola  is related to the syphilis-causing obligate human pathogen,  Treponema pallidum  subsp.  pallidum . It has also been isolated from women with  bacterial vaginosis . [ 6 ]


The first genome of  T. denticola  to be sequenced was strain 35405 which was initially isolated and designated as the type strain by Chan et al. [ 7 ]  The 2,843,201-bp genome sequence encodes 2,786􏴲  open reading frames   (ORFs) as well a 6  rRNAs  and 44  tRNAs . This is in stark contrast to the minimal genome of  Treponema pallidum  which encodes only 1,040 ORFs. [ 8 ]


Tightly organized bundles of periplasmic flagella were observed in the periplasm, a characteristic of spirochetes. The presence of the periplasmic flagella is widely regarded as being responsible for the microorganism's ability to rotate and flex, in addition to its translational movement. [ 2 ]   Spirochetes , including  Treponema denticola  , are therefore able to navigate through particularly viscous environments, unlike that of other prokaryotes. [ 2 ]


The tapering of the cell ends, conserved between cells, encompass a patella-shaped structure observed in the periplasm at the cell tip. This structure might be involved in the polar attachment of the cells. [ 9 ]


The main site for  T. denticola  habitation in the oral cavity is the  gingival crevice . These spirochetes attach to proteins (including  fibronectin  and  collagen ) of local gingival fibroblasts, binding to their plasma membrane. A 53-kDa surface protein on  T. denticola  is responsible for transporting its components into the host cell, exhibiting a cytotoxic effect. Accumulation of  T. denticola  in this manner facilitates the disease-causing process, including membrane blebbing and red blood cell lysis. [ 2 ]


Periodontal disease  is a type of gum disease caused by the accumulation of plaque on the teeth due to poor oral hygiene.  Plaque  is a sticky substance that contains bacteria which can harden into a substance called  calculus , irritating the gums. [ 10 ]


[ 11 ] Treponema denticola , a subgingival oral spirochete has been associated with many  periodontal disease  conditions such as: the early stage of periodontitis, acute pericoronitis (infection under the gum tissue covering a partially erupted tooth) 3 , as well as necrotising ulcerative gingivitis (severe inflammation of the gum more common in immunocompromised patients). It relates to lesions limited to  gingival tissue . [ 12 ]


Clinical evidence and research shows that periodontal pockets contain large numbers of  treponema denticola  together with other proteolytic  gram negative bacteria , playing an important role in the development of  periodontal disease . The toxic products of these bacteria, especially  treponema denticola  may damage the surface lining periodontal cells making them more prone to damage as well as lysis.  Treponema denticola  attaches to  fibroblasts  and epithelial cells as well as to extracellular matrix components which are found in periodontal tissues and release its own bacterial contents. The bacterial components are: [ citation needed ]


A number of studies have observed an increase of  T. denticola  in patients with orthodontic appliances, particularly the fixed type. [ 13 ]


Treponema denticola  is a potential etiological bacterial agent for  oral cancer . [ 14 ]  It encourages  oncogenesis  (process in which healthy cells become cancer cells) and therefore the progression of oral cancer through chronic inflammation advancing invasiveness of the cancer cells. This results in the ceasing of cell  apoptosis  (inhibition of controlled cell death – a safety mechanism within cells to stop more damage from occurring), resulting in rapid growth and multiplication of cancer cells. This suppresses the immune system stopping the body from recognising the cancerous cells and as a result more cancer-promoting substances are produced. [ 14 ]   The presence of  T. denticola  along with other periodontal pathogens and bacterial diversity within the oral cavity are important factors contributing to cancerous cells (including precancerous gastric lesions). [ 15 ]


Atherosclerotic vascular disease  is chronic inflammatory disease of large arteries distinguished by invasion, proliferation and accumulation of cells from arterial smooth muscle cells, and the circulating blood in the intimal layer with deposition of connective tissue and lipids, if left to get worse atherosclerotic vascular disease can result in cardiovascular disease.  Cardiovascular disease  (including angina, heart attack, arrhythmias, heart failure, strokes) is the leading cause of death globally.   [ citation needed ]


Substantial evidence between inflammation from infectious agents and development of  atherosclerosis  – periodontal pathogens prominent contenders due to chronic inflammation related with  periodontal disease . [ citation needed ]


Treponema denticola  bacteria can penetrate gingival tissues and circulate through blood vessels, with opportunity to invade the heart and cardiovascular epithelium in medium to large arteries – including aorta, coronary and carotid arteries. [ 16 ]


It has been recognised that there is an association between oral and intestinal cancer related deaths and chronic  periodontitis . This is based on the high amounts of tumor suppressor gene p53 mutations and k-ras arginine mutations found in patients with pancreatic cancer. Peptidylarginine deiminases from oral bacteria are thought to be responsible for these mutations. This means that there could be a causative link between oral bacteria, particularly the red complex, and pancreatic cancer. [ 3 ]


Ureaplasma urealyticum  is a  bacterium  belonging to the  genus   Ureaplasma  and the  family   Mycoplasmataceae [ 1 ]  in the  order   Mycoplasmatales . This family consists of the genera  Mycoplasma  and  Ureaplasma . Its  type strain  is T960. There are two known  biovars  of this species; T960 and 27.  These strains of bacteria are commonly found as  commensals  in the  urogenital tracts  of human beings, but overgrowth can lead to infections that cause the patient discomfort. Unlike most bacteria,  Ureaplasma urealyticum  lacks a  cell wall  making it unique in physiology and medical treatment.


The six recognised  Ureaplasma   species  have a  GC content  of 27 to 30 percent and a  genome size  ranging from 0.76 to 1.17 million  base pairs , and  cholesterol  is required for  growth . [ 2 ]  A defining characteristic of the genus is that they perform  urea   hydrolysis , which creates ammonia as a product. Some strains originally classified as  U. urealyticum  should be treated as a new species,  U. parvum . [ 3 ]  Both strains of U reaplasma urealyticum  have had their DNA sequenced, using a PCR amplification and dideoxy termination method. [ 4 ]  Their sequences can be accessed through public records and databases. Most of the16S rDNA sequence of the two strains constitute the exact same nucleotides bases (97.3% homology), yet small differences have been acknowledged. [ 4 ]  Due to the direct similarity and the increased variation in other species of  Ureaplasma , it is thought that the two strains of  Ureaplasma urealyticum  (T960 and 27) have evolutionary diverged together. In the same study conducted, using the same 16s rDNA aligned sequences, they concluded all the mammalian strains diverged and coevolved with their corresponding species (canine, feline, human, bovine) during the Cretaceous period. It was found that the most closely related species strain of  Ureaplasma  to  Ureaplasma urealyticum  was  Ureaplasma diversum  (isolated from bovine). [ 4 ]


U. urealyticum represents one of the 14 distinct types within the Ureaplasma genus. Classified within the Mollicutes class, Ureaplasma species have undergone significant evolutionary adaptations from their Gram-positive bacterial ancestors, a phenomenon termed degenerative evolutions (Kallapur, Suhas G, et al 2013 [ 2 ] ). This evolutionary trajectory has resulted in the loss of the peptidoglycan cell wall, a hallmark characteristic of Gram-positive bacteria. Despite this evolutionary divergence, instances have been reported where U. urealyticum, upon gram staining, exhibited the same characteristics as Gram-negative bacteria. Notably, despite such staining outcomes, it is imperative to recognize that the U. urealyticum remains a Gram-Positive bacterium, This discrepancy underscores the importance of discerning between staining outcomes and bacterial classification (“Ureaplasma Urealyticum.” Microbewiki [ 5 ] ).


As stated previously, since these bacteria are still considered Gram-positive, and lack a cell wall, the most versatile antibiotic that can’t be used is penicillin. Since these antibiotics attack the cell wall of a bacterium, they can not be used for this type of infection. The reason that many individuals get this infection can be damage to the uterus wall lining, causing the bacteria to thrive in a carbon-rich environment.


Unfortunately, it was found from trials that many of the antibiotics that we utilize on a day-to-day basis for urinary tract infections do not affect the bacteria due to lacking a cell wall. Yet, the types of antibiotics that can be used are quinolones, tetracyclines, and macrolides, since they affect a large part of the mycoplasma family of bacteria where U. urealyticum falls under.


Yet, it is not recommended to be used a lot because these bacteria can develop resistance to these antibiotics fairly fast. Secondly, other drugs that have β-lactamases are infective to treat infection because of how fast the bacteria's circular genome can mutate (Fan et al. 2023 [ 6 ] ). However, there are new movements to use Azithromycin to treat these infections. This is a therapeutic that can be taken orally, once ingested our macrophages, which are part of our immune system, take up the antibiotic and deliver it to the sites of infection (Fan et al. 2023 [ 7 ] ). This helps control the infection where the bacteria grows, additionally, it is also a great alternative to when a mother is pregnant so it does not cause harm to the fetus since It's using our immune system to help defend the fetus and the mother's body.


To test for this bacterium, an agar plate, which is 10B broth, should be used on U. urealyticum. Since these bacteria love to grow in mostly acidic places, the bacteria should go under microdilution MIC dilution to get a pH color change. If the dilution color changes to red it indicates that there is presence of U. urealyticum in the sample. After this, it should be transferred to the 10B Broth, where once placed it will turn yellow, but then slowly change the color to pink. This helps to indicate the growth of the bacterium(Waites, Ken B, et al 2012 [ 8 ] ). The reason it can grow on this 10B Broth is because it has a lot of nutrients that let the bacteria grow from heart infusion to yeast extract, yet, it also has urea to help the bacteria to hydrolyze it and with hydrolyzing it causes the release of ammonia that causes the broth to change to a pink color ( 10B Broth - Thermo Fisher Scientific ). The reason for this is that it loves to live in urea-rich environments. It's the same reason why in clinics, they take urine samples or vaginal swabs to be sent to the labs to run this test on 10B broth.


Ureaplasma urealyticum  can cause  urethritis  and may cause  bacterial vaginosis . [ 9 ]   Infection  can occur in extragenital sites. [ 3 ]  A common symptom associated with these infections is the "fishy" smell that is created due to the production of ammonia by the hydrolysis of urea. Patients should confirm diagnosis with a doctor. The bacterium has high correlations with the Human Papillomavirus (HPV). [ citation needed ]  It has also been linked to  infertility  in both males and females. [ 9 ]   In addition, this pathogen may latently infect the  chorionic villi  tissues of pregnant women, thereby impacting pregnancy outcome. [ 5 ]  Issues that arise from  Ureaplasma urealyticum  infections during pregnancy include preterm birth and impacted embryonic development. Some patients have given birth to children subjected to  bronchopulmonary dysplasia ,  Intraventricular hemorrhage , and  necrotizing enterocolitis . [ 10 ]  Patients can evolve resistances to normal  antibiotic  treatments due to the distinctive physiology of these organisms. In the Western World, approximately 40% of  Ureaplasma  species are resistant to fluoroquinolones (i.e. ciprofloxacin). [ 6 ]  Patients who are pregnant have further limitations on the treatment course of a  Ureaplasma urealyticum  infection, making it far harder to successfully cure. [ citation needed ]


Vaginal discharge  is a mixture of liquid, cells, and bacteria that lubricate and protect the  vagina . [ 1 ] [ 2 ]  This mixture is constantly produced by the cells of the vagina and  cervix , and it exits the body through the vaginal opening. The composition, quality, and amount of discharge varies between individuals, and can vary throughout the  menstrual cycle  and throughout the stages of sexual and reproductive development. [ 3 ]  Normal vaginal discharge may have a thin, watery consistency or a thick, sticky consistency, and it may be clear or white in color. [ 1 ] [ 2 ]  Normal vaginal discharge may be large in volume but typically does not have a strong odor, nor is it typically associated with itching or pain. [ 3 ]


While most discharge is considered physiologic (represents normal functioning of the body), some changes in discharge can reflect  infection  or other pathological processes. [ 4 ] [ 5 ]  Infections that may cause changes in vaginal discharge include  vaginal yeast infections ,  bacterial vaginosis , and  sexually transmitted infections . [ 6 ] [ 2 ]  The characteristics of abnormal vaginal discharge vary depending on the cause, but common features include a change in color, a foul odor, and associated symptoms such as itching, burning, pelvic pain, or pain during  sexual intercourse . [ 7 ]


Normal vaginal discharge is composed of cervical mucus, vaginal fluid, shedding vaginal and cervical cells, and bacteria. [ 1 ]


The majority of the liquid in vaginal discharge is  mucus  produced by glands of the  cervix . [ 1 ] [ 4 ]  The rest is made up of  transudate  from the vaginal walls and secretions from glands ( Skene's  and  Bartholin's ). [ 4 ]  The solid components or elements are exfoliated epithelial cells from the vaginal wall and cervix as well as some of the bacteria that inhabit the vagina. [ 1 ]  These bacteria that live in the vagina do not typically cause disease. In fact, they can protect the individual from other infectious and invasive bacteria by producing substances such as lactic acid and hydrogen peroxide that inhibit the growth of other bacteria. [ 6 ]  The normal composition of bacteria in the vagina ( vaginal flora ) can vary, but is most commonly dominated by  lactobacilli . [ 1 ]  On average, there are approximately 10 8  to 10 9  bacteria per milliliter of vaginal discharge. [ 1 ] [ 4 ]


Normal vaginal discharge is clear, white, or off-white. [ 1 ]  The consistency can range from milky to clumpy, and odor is typically mild to non-existent. [ 1 ]  The majority of the discharge pools in the deepest portion of the vagina (the  posterior fornix ) [ 3 ]  and exits the body over the course of a day with the force of gravity. [ 1 ] [ 4 ]  A typical reproductive-age woman produces 1.5 grams (half to one teaspoon) of vaginal discharge every day. [ 1 ]


During sexual arousal and sexual intercourse, the amount of fluid in the vagina  increases due to engorgement  of blood vessels surrounding the vagina. This engorgement of blood vessels increases the volume of transudate from the vaginal walls. [ 4 ]  Transudate has a neutral pH, so increases in its production can temporarily shift vaginal pH to be more neutral. [ 4 ]  Semen has a basic pH and can neutralize the acidity of the vagina for up to 8 hrs. [ 4 ]


The composition and amount of vaginal discharge changes as an individual goes through the various stages of sexual and reproductive development. [ 4 ]


However, some individuals may experience changes in vaginal discharge due to underlying conditions such as stress, diabetes, inflammatory disorders, lactation, certain medications, or autoimmune diseases. [ 8 ]


In  neonates , vaginal discharge sometimes occurs in the first few days after birth. This is due to exposure to  estrogen  while in utero. Neonatal vaginal discharge may be white or clear with a mucous texture, or it may be bloody from normal transient shedding of the  endometrium . [ 9 ]


The vagina of girls before puberty is thinner and has a different bacterial flora. [ 1 ] [ 4 ]  Vaginal discharge in pre-pubertal girls is minimal with a neutral to alkaline pH ranging from 6 to 8. [ 10 ]    The composition of the bacterial population in pre-pubertal girls is dominated by  staphylococcus  species, in addition to a range of anaerobes, enterococci,  E. coli , and lactobacillus. [ 10 ]


During  puberty , the hormone estrogen begins to be produced by the ovaries. [ 3 ]  Even before the beginning of menses (up to 12 months before  menarche , typically at the same time as the development of  breast buds [ 4 ] ) vaginal discharge increases in amount and changes in composition. [ 10 ]  Estrogen matures vaginal tissues and causes increased production of  glycogen  by epithelial cells of the vagina. [ 1 ]  These higher levels of glycogen in the vaginal canal support the growth of lactobacilli over other bacterial species. [ 1 ] [ 3 ]  When lactobacilli use glycogen as a food source, they convert it to lactic acid. [ 1 ] [ 3 ] [ 4 ]  Therefore, the predominance of lactobacilli in the vaginal canal creates a more acidic environment. In fact, the pH of the vagina and vaginal discharge after puberty ranges between 3.5 and 4.7. [ 1 ]


The amount and consistency of vaginal discharge change with the  menstrual cycle . [ 11 ]  In the days right after menstruation, vaginal discharge is minimal, and its consistency is thick and sticky. [ 12 ]  When approaching  ovulation , the rising  estrogen  levels cause a concomitant increase in vaginal discharge. [ 12 ]  The amount of discharge produced at ovulation is 30 times greater than the amount produced directly following menstruation. [ 12 ]  The discharge also changes in color and consistency during this time, becoming clear with an elastic consistency, often likened to the colour and texture of egg whites. [ 12 ]  After ovulation the body's  progesterone  levels increase, which causes a decrease in the amount of vaginal discharge. [ 12 ]  The consistency of the discharge once again becomes thick and sticky and opaque in color. [ 12 ]  The discharge continues to decrease from the end of ovulation until the end of menstruation, and then after menstruation, it begins its rise again. [ 12 ]


During pregnancy, vaginal discharge volume increases as a result of the body's increased levels of estrogen and progesterone. [ 13 ] [ 2 ] The discharge is usually white or slightly gray, and may have a musty smell. [ 13 ] [ 2 ]  The normal discharge of pregnancy does not contain blood or cause itching. [ 13 ]  The pH of the vaginal discharge in pregnancy tends to be more acidic than normal due to increased production of lactic acid. [ 13 ]  This acidic environment helps to provide protection from many infections, though conversely it also makes women more susceptible to vaginal yeast infections. [ 13 ] [ 2 ]


Discharge may be red and heavy for the first few days as it consists of blood and the superficial mucous membrane that lined the uterus during pregnancy. This discharge normally begins to taper and should become more watery and change in color from pinkish brown to yellowish white. [ 14 ]


With the drop in estrogen levels that comes with  menopause , the vagina returns to a state similar to pre-puberty. [ 9 ]  Specifically, the vaginal tissues thin, and become less elastic; blood flow to the vagina decreases; the surface epithelial cells contain less glycogen. [ 9 ]  With decreased levels of glycogen, the vaginal flora shifts to contain fewer lactobacilli, and the pH subsequently increases to a range of 6.0-7.5. [ 9 ]  The overall amount of vaginal discharge decreases in menopause. While this is normal, it can lead to symptoms of dryness [ 8 ]  and pain during penetrative sexual intercourse. [ 15 ]  These symptoms can often be treated with vaginal  moisturizers/lubricants  or  vaginal hormone creams . [ 16 ]


Abnormal discharge can occur in a number of conditions, including infections and imbalances in  vaginal flora  or  pH . Sometimes, abnormal vaginal discharge may not have a known cause. In one study looking at women presenting to clinic with concerns about vaginal discharge or a foul smell in their vagina, it was found that 34% had  bacterial vaginosis  and 23% had  vaginal candidiasis  (yeast infection). [ 7 ]  32% of patients were found to have sexually transmitted infections including  Chlamydia ,  Gonorrhea ,  Trichomonas , or  Genital Herpes . [ 7 ]  Diagnosing the cause of abnormal vaginal discharge can be difficult, though a  potassium hydroxide  test or vaginal pH analysis may be used. When abnormal discharge occurs with burning, irritation, or itching on the  vulva , it is called  vaginitis . [ 9 ]


It is important to seek care when abnormal vaginal discharge or changes to vaginal discharge are noticed. Associated symptoms with pathological causes of vaginal discharge include: itching of the exterior genitalia, irritation or inflammation of the external genitalia, green or foam-like discharge, bloody discharge not associated with menstruation, different odors, new or worsening pain associated with the discharge, or pain with sex or urination. [ 17 ]  Self-treatment is not recommended and can worsen symptoms. [ 18 ]


Upon the diagnosis of vaginitis, a speculum exam is performed to evaluate the vagina, vaginal discharge, and the cervix. The physician will insert the speculum into the vagina while the patient lies on their back to exam for foreign bodies, vaginal warts, inflammation, as well as rashes/bruises. A sample of the vaginal discharge is then collected using a cotton-swab and tested for pH and under microscopy. [ 19 ]  The most common causes of pathological vaginal discharge in adolescents and adults are described below. [ citation needed ]


Bacterial vaginosis  (BV) is an infection caused by a change in the vaginal flora, which refers to the community of organisms that live in the vagina. [ 20 ]  It is the most common cause of pathological vaginal discharge in women of childbearing age and accounts for 40–50% of cases. [ 21 ]  In BV, the vagina experiences a decrease in a bacterium called lactobacilli, and a relative increase in a multitude of anaerobic bacteria with the most predominant being  Gardnerella vaginalis . [ 22 ]  This imbalance results in the characteristic vaginal discharge experienced by patients with BV. [ 20 ]  The discharge in BV has a characteristic strong fishy odor, which is caused by the relative increase in anaerobic bacteria.[1] The discharge is typically thin and grey, or occasionally green. [ 20 ] [ 22 ]  It sometimes is accompanied by burning with urination. Itching is rare. [ 23 ]  The exact reasons for the disruption of vaginal flora leading to BV are not fully known. [ 24 ]  However, factors associated with BV include antibiotic use, unprotected sex, douching, and using an intrauterine device (IUD). [ 25 ]  The role of sex in BV is unknown, and BV is not considered an STI. [ 20 ]  The diagnosis of BV is made by a health care provider based on the appearance of the discharge, discharge pH > 4.5, presence of clue cells, when viewing the collected discharge from speculum exam under the microscope, and a characteristic fishy odor when the discharge is placed on a slide and combined with potassium hydroxide ("whiff test"). [ 20 ] [ 22 ]  The gold standard for diagnosis is a  gram stain  showing a relative lack of lactobacilli and a polymicrobial array of gram negative rods, gram variable rods, and cocci. BV may be treated with oral or intravaginal antibiotics, such as  metronidazole , [ 26 ]  or lactobacillus. [ 27 ]


Vaginal yeast infection  or vaginal candidiasis results from overgrowth of candida albicans, or yeast, in the vagina. [ 28 ]  This is a relatively common infection, with over 75% of women having experienced at least one yeast infection at some point in their life. [ 29 ]  Risk factors for yeast infections include recent antibiotic use,  diabetes mellitus , immunosuppression, increased estrogen levels, and use of certain contraceptive devices including intrauterine devices, diaphragms, or sponges. [ 28 ] [ 30 ]  It is not a sexually transmitted infection. [ 30 ]  Vaginal discharge is not always present in yeast infections, but when occurring it is typically odorless,  thick, white, and clumpy. [ 28 ]  Vaginal itching is the most common symptom of candida vulvovaginitis. [ 28 ]  Women may also experience burning, soreness, irritation, pain during urination, or pain during sex. [ 30 ]  The diagnosis of Candida vulvovaginitis is made by looking at a sample taken during speculum exam under the microscope that shows hyphae (yeast), or from a culture. [ 31 ]  The symptoms described above may be present in other vaginal infections, so microscopic diagnosis or culture is needed to confirm the diagnosis. [ 30 ]  Treatment is with intra-vaginal or oral anti-fungal medications. [ 30 ]


Trichomonas vaginitis  is an infection acquired through sex that is associated with vaginal discharge. [ 28 ]  It can be transmitted by way of the penis to the vagina, the vagina to the penis, or from vagina to vagina. [ 32 ]  The discharge in Trichomonas is typically yellowish-green in color. [ 28 ]   It sometimes is frothy and can have a foul smell. [ 33 ]   Other symptoms may include vaginal burning or itching, pain with urination, or pain with sexual intercourse. [ 32 ]  Trichomonas is diagnosed by looking at a sample of discharge under the microscope showing trichomonads moving on the slide. [ 28 ]   However, in women with trichomonas the organism is typically detected in only 60-80% of cases. [ 28 ]  Other testing, including a culture of the discharge or a PCR assay, are more likely to detect the organism. [ 28 ]  Treatment is with a one time dose of oral  antibiotics , most commonly metronidazole or tinidazole. [ 28 ]


Chlamydia  and  gonorrhea  can also cause vaginal discharge, though more often than not these infections do not cause symptoms. [ 33 ]  The vaginal discharge in chlamydia is typically pus-filled, but it is important to note that in around 80% of cases chlamydia does not cause any discharge. [ 33 ]   Gonorrhea can also cause pus-filled vaginal discharge, but gonorrhea is similarly asymptomatic in up to 50% of cases. [ 33 ]   If the vaginal discharge is accompanied by pelvic pain, this is suggestive of  pelvic inflammatory disease  (PID), a condition in which the bacteria have moved up the reproductive tract. [ 33 ]


Foreign objects can cause a chronic vaginal discharge with a foul odor. [ 34 ]   Common foreign objects found in adolescents and adults are tampons, toilet paper, and objects used for sexual arousal. [ 34 ]


The most common reason pre-pubertal females go to the gynecologist is concern about vaginal discharge and vaginal odor. [ 35 ]   The causes of abnormal vaginal discharge in pre-pubertal girls are different than in adults and are usually related to lifestyle factors such as irritation from harsh soaps or tight clothing. [ 35 ]   The vagina of pre-pubertal girls (due to lack of estrogen) is thin-walled and has a different microbiota; additionally, the vulva in pre-pubertal girls lacks pubic hair. These features makes the vagina more prone to bacterial infection. [ 35 ]   The bacteria that are more commonly responsible for vaginal discharge in pre-pubertal girls are distinct from those in other age groups, and include  Bacteroides ,  Peptostreptococcus , and  Candida  (yeast). These can derive from the colonization of the vagina with oral or fecal bacteria. [ 36 ]   Another cause of vaginal discharge in pre-pubertal girls is the presence of a foreign object such as a toy or a piece of toilet paper. [ 34 ]  In the case of a foreign body, the discharge is often bloody or brown. [ 34 ]


The  vaginal flora in pregnancy , or  vaginal microbiota in pregnancy , is different from the  vaginal flora  (the population of microorganisms that resides in the vagina) before  sexual maturity , during reproductive years, and after  menopause . A description of the vaginal flora of pregnant women who are  immunocompromised  is not covered in this article. The composition of the vaginal flora significantly differs in  pregnancy . [ 1 ]  Bacteria or viruses that are infectious most often have no symptoms.


In normal pregnancy, the resident vaginal flora is thought to provide protection against infection. The microbiota during pregnancy are predominantly  Lactobacillus  species. Microbiota composition can change during the course of the pregnancy. If the microbiota populations become more diverse, indicating that the normal  Lactobacillus -dominated population has changed to a bacterial vaginosis population, risks of adverse pregnancy outcomes increase. [ 2 ]  Vaginal discharge is common during pregnancy but is not an indicator of bacterial vaginosis or abnormal microbiota. [ 3 ]  The treatment of abnormal vaginal microbiota populations with lactobacilli and estriol during pregnancy was found to restore the microbiota to a normal state. [ 4 ]


During pregnancy, the vaginal microbiome can contribute and play an important role in spontaneous and preterm labor. The transmission of the flora from mother to children occurs via the vagina, breast milk, and the maternal gut. After the mother has given birth to her child, the  Lactobacillus -rich microbiome drops significantly, and it becomes more diverse during the postpartum period. [ 5 ]


During pregnancy, the pH is altered due to excessive vaginal discharge, and this alters the microbiota that is present in the vagina. The bacterial species  Firmicutes  and  Actinobacteria  are identified in dysbiotic states such as this one. [ 5 ]


Bacterial vaginosis  in pregnancy is an alteration of the normal vaginal microbiota of pregnancy. Intrauterine infections in pregnancy are caused by bacteria that cause inflammation. The women may experience few or no symptoms. This sometimes leads to  chorioamnionitis  and other negative pregnancy outcomes. Chorioamnionitis is due to the presence of bacteria such as  Ureaplasma parvum  and  Mycoplasma  species this generates the release of proinflammatory cytokines and chemokines, IL-8 which causes cervical ripening and can result in premature birth. [ citation needed ]  When there are high bacterial counts in of the vagina during pregnancy is typically due to the presence of the following organisms: [ 3 ]


A major portion of the vaginal microbiome also includes vaginal viral virome. According studies that have been done so far, it can be seen that there are an abundance of ds DNA viruses, ss DNA viruses and some unidentified viruses that are part of the vaginal microbiome. Only few eukaryotic viruses were detected. Out of the ones that were detected, the pathogenic viruses were  Herpesvirales  and  Papillomaviridae . [ 5 ]


There are racial variations that are present in microbiomes between women of different races. Women who belong to Asian, White, and Caucasian race have be observed to have more anaerobic flora. The dominant member in the microbiome of these women is  Lactobacillus . Women who are Hispanic and Black have anaerobic bacteria, but the dominant member of their microbiomes is not  Lactobacillus . Black females are seen to have single-species dominant cluster, while Caucasian women have multiple species of  Lactobacillus  present in their microbiome. [ 5 ]


Racial diversity is just of the few factors that is known to influence the variation in microbiomes in women. Other factors that also influence the variation in microbiomes are health, sexual partner, mother being a diabetic or not, and variation between monozygotic and dizygotic twins. All of different modes of delivery of microbiome from the mother to the infant, vaginal delivery can be seen to be the most favorable. [ 5 ] [ 6 ]


Vaginal microbiomes are affected and influenced by many exogenous and endogenous factors. These factors can include contraceptive agents, using antibiotics, vaginal douching, and pregnancy. Abnormal vaginal flora (AVF) is when there is an overgrowth and colonization of pathogenic microorganisms. This includes microorganisms that cause infections such as vulvo-vaginal candidiasis (VVC), bacterial vaginosis (BV), cytolytic vaginosis (CV), intermediate flora and mixed vaginitis, and trichomoniasis. [ 6 ]


Studies shows that AVF can be one of the contributing risk factors in gynecological complications. There complications include sexually transmitted diseases and pelvic inflammatory disease. AVF has also been associated with issues such as premature rupture of membranes, preterm birth, ascending intrauterine infections, and other adverse outcomes of pregnancy. [ 6 ]


Investigations into reproductive-associated microbiomes began around 1885 by  Theodor Escherich . He wrote that  meconium  from the newborn was free of bacteria. This was interpreted as the uterine environment was sterile. Other investigations used sterile diapers for meconium collection. No bacteria were able to be cultured from the samples. Bacteria were detected and were directly proportional to the time between birth and the passage of meconium. [ 7 ]


Veillonella parvula  is a strictly anaerobic, Gram-negative, coccus-shaped bacterium in the genus  Veillonella . [ 2 ]  It is a normal part of the oral flora but can be associated with diseases such as  periodontitis  and  dental caries  as well as various systemic infections, including meningitis and osteomyelitis. [ 3 ]  It has also been isolated from women with  bacterial vaginosis  and has been associated with  hypertension  together with  Campylobacter rectus  and  Prevotella melaninogenica . [ 4 ]


V. parvula  is unable to feed on carbohydrates, but can feed on lactate provided by  Streptococcus  species also found in the oral cavity. [ 5 ]  Specifically,  Streptococcus mutans  and  V. parvula  can form multispecies  biofilms  that lead to a lower susceptibility to antimicrobial treatments, resulting in periodontitis and dental caries. [ 6 ]


V. parvula  bacteria are susceptible to and typically treated with  metronidazole  and  penicillin  in clinical reports. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  Other antibiotics that have been shown to be active against  V. parvula  include  cephalosporin ,  clindamycin , and  chloramphenicol . [ 7 ]


There have been several reports of  antibiotic resistance  in  V. parvula  isolates in different countries. [ 11 ] [ 12 ] [ 13 ]  In Greece,  V. parvula  isolates were found to be somewhat resistant to penicillin,  ampicillin ,  piperacillin/tazobactam , clindamycin, and  moxifloxacin , with no reported resistance to metronidazole. [ 13 ] [ 14 ]  In Taiwan,  V. parvula  isolates were found to be resistant against metronidazole. [ 15 ]  These findings represent the growing issue of antibiotic resistance worldwide. [ citation needed ]


Mashima I, Nakazawa F (August 2014). "The influence of oral Veillonella species on biofilms formed by Streptococcus species".  Anaerobe .  28 :  54– 61.  doi : 10.1016/j.anaerobe.2014.05.003 .  PMID   24862495 .


Ebola , also known as  Ebola virus disease  ( EVD ) and  Ebola hemorrhagic fever  ( EHF ), is a  viral hemorrhagic fever  in humans and other  primates , caused by  ebolaviruses . [ 1 ]  Symptoms typically start anywhere between two days and three weeks after infection. [ 3 ]  The first symptoms are usually  fever ,  sore throat ,  muscle pain , and  headaches . [ 1 ]  These are usually followed by  vomiting ,  diarrhoea ,  rash  and decreased  liver  and  kidney  function, [ 1 ]  at which point some people begin to  bleed  both  internally  and externally. [ 1 ]  It kills between 25% and 90% of those infected – about 50% on average. [ 1 ]  Death is often due to  shock from fluid loss , and typically occurs between six and 16 days after the first symptoms appear. [ 2 ]  Early treatment of symptoms increases the survival rate considerably compared to late start. [ 4 ]  An  Ebola vaccine  was approved by the US FDA in December 2019.


The virus spreads through direct contact with  body fluids , such as  blood  from infected humans or other animals, [ 1 ]  or from contact with items that have recently been contaminated with infected body fluids. [ 1 ]  There have been no documented cases, either in nature or under laboratory conditions, of spread through the air between humans or other  primates . [ 5 ]  After recovering from Ebola,  semen  or  breast milk  may continue to carry the virus for anywhere between several weeks to several months. [ 1 ] [ 6 ] [ 7 ]   Fruit bats  are believed to be the normal  carrier in nature ; they are able to spread the virus without being affected by it. [ 1 ]  The symptoms of Ebola may resemble those of several other diseases, including  malaria ,  cholera ,  typhoid fever ,  meningitis  and other viral hemorrhagic fevers. [ 1 ]  Diagnosis is confirmed by testing blood samples for the presence of viral  RNA , viral  antibodies  or the virus itself. [ 1 ] [ 8 ]


Control of outbreaks requires coordinated medical services and community engagement, [ 1 ]  including rapid detection,  contact tracing  of those exposed, quick access to laboratory services, care for those infected, and proper disposal of the dead through  cremation  or burial. [ 1 ] [ 9 ]  Prevention measures involve wearing proper protective clothing and  washing hands  when in close proximity to patients and while handling potentially infected  bushmeat , as well as thoroughly cooking bushmeat. [ 1 ]  An  Ebola vaccine  was approved by the US FDA in December 2019. [ 10 ]  While there is no approved treatment for Ebola as of 2019 [update] , [ 11 ]  two treatments ( atoltivimab/maftivimab/odesivimab  and  ansuvimab ) are associated with improved outcomes. [ 12 ]  Supportive efforts also improve outcomes. [ 1 ]  These include  oral rehydration therapy  (drinking slightly sweetened and salty water) or giving  intravenous fluids , and treating symptoms. [ 1 ]  In October 2020, atoltivimab/maftivimab/odesivimab (Inmazeb) was approved for medical use in the United States to treat the disease caused by  Zaire ebolavirus . [ 13 ]


Ebola was first identified in 1976, in two simultaneous outbreaks, one in  Nzara  (a town in  South Sudan ) and the other in  Yambuku  ( the Democratic Republic of the Congo ), a village near the  Ebola River , for which the disease was named. [ 1 ]   Ebola outbreaks  occur intermittently in tropical regions of  sub-Saharan Africa . [ 1 ]  Between 1976 and 2012, according to the  World Health Organization , there were 24 outbreaks of Ebola resulting in a total of  2,387 cases, and 1,590 deaths . [ 1 ] [ 14 ]  The largest Ebola outbreak to date was an  epidemic in West Africa  from December 2013 to January 2016, with 28,646 cases and 11,323 deaths. [ 15 ] [ 16 ] [ 17 ]  On 29 March 2016, it was declared to no longer be an emergency. [ 18 ]  Other outbreaks in Africa began in the Democratic Republic of the Congo in May 2017, [ 19 ] [ 20 ]  and 2018. [ 21 ] [ 22 ]  In July 2019, the World Health Organization declared the Congo Ebola outbreak a  world health emergency . [ 23 ]


The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, [ 1 ] [ 24 ]  and usually between 4 and 10 days. [ 25 ]  However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. [ 26 ]


Symptoms usually begin with a sudden  influenza -like stage characterised by  fatigue ,  fever ,  weakness ,  decreased appetite ,  muscular pain ,  joint pain , headache, and sore throat. [ 1 ] [ 25 ] [ 27 ] [ 28 ]  The fever is usually higher than 38.3 °C (101 °F). [ 29 ]  This is often followed by nausea, vomiting,  diarrhoea , abdominal pain, and sometimes  hiccups . [ 28 ] [ 30 ]  The combination of severe vomiting and diarrhoea often leads to severe  dehydration . [ 31 ]  Next,  shortness of breath  and  chest pain  may occur, along with  swelling ,  headaches , and  confusion . [ 28 ]  In about half of the cases, the skin may develop a  maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. [ 25 ] [ 29 ]


In some cases, internal and external bleeding may occur. [ 1 ]  This typically begins five to seven days after the first symptoms. [ 32 ]  All infected people show some  decreased blood clotting . [ 29 ]  Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. [ 33 ]  This may cause  vomiting blood ,  coughing up of blood , or  blood in stool . [ 34 ]  Bleeding into the skin may create  petechiae ,  purpura ,  ecchymoses  or  haematomas  (especially around needle injection sites). [ 35 ]   Bleeding into the whites of the eyes  may also occur. [ 36 ]  Heavy bleeding is uncommon; if it occurs, it is usually in the  gastrointestinal tract . [ 37 ]  The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, [ 38 ]  but in the 2014–15 outbreak in the US it was ~18%, [ 39 ]  possibly due to improved prevention of  disseminated intravascular coagulation . [ 31 ]


Recovery may begin between seven and 14 days after first symptoms. [ 28 ]  Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to  shock from fluid loss . [ 2 ]  In general, bleeding often indicates a worse outcome, and blood loss may result in death. [ 27 ]  People are often in a  coma  near the end of life. [ 28 ]


Those who survive often have ongoing muscular and joint pain,  liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. [ 28 ] [ 40 ]  Problems with vision may develop. [ 41 ]  It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. [ 42 ]


Survivors develop  antibodies  against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. [ 43 ]


EVD in humans is caused by four of six viruses of the genus  Ebolavirus . The four are  Bundibugyo virus  (BDBV),  Sudan virus  (SUDV),  Taï Forest virus  (TAFV) and one simply called  Ebola virus  (EBOV, formerly Zaire Ebola virus). [ 44 ]  EBOV, species  Zaire ebolavirus , is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks. [ 45 ]  The fifth and sixth viruses,  Reston virus  (RESTV) and  Bombali virus  (BOMV), [ 46 ]  are not thought to cause disease in humans, but have caused disease in other primates. [ 47 ] [ 48 ]  All six viruses are closely related to  marburgviruses . [ 44 ]


Ebolaviruses contain single-stranded, non-infectious  RNA   genomes . [ 49 ]   Ebolavirus  genomes contain seven  genes  including  3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . [ 35 ] [ 50 ]  The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in  sequence  and the number and location of gene overlaps. As with all  filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. [ 50 ] [ 51 ]  In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. [ 52 ]


Their  life cycle  is thought to begin with a virion attaching to specific  cell-surface receptors  such as  C-type lectins ,  DC-SIGN , or  integrins , which is followed by fusion of the  viral envelope with cellular membranes . [ 53 ]  The virions taken up by the cell then travel to acidic  endosomes  and  lysosomes  where the viral envelope glycoprotein GP is cleaved. [ 53 ]  This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral  nucleocapsid . [ 53 ]  The  Ebolavirus  structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. [ 54 ]  The viral  RNA polymerase , encoded by the  L  gene, partially uncoats the nucleocapsid and  transcribes  the genes into positive-strand  mRNAs , which are then  translated  into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. [ 55 ]  Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the  cell membrane . Virions  bud  off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. [ 56 ]


It is believed that between people, Ebola disease spreads only by direct contact with the blood or other  body fluids  of a person who has developed symptoms of the disease. [ 57 ] [ 58 ] [ 59 ]  Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and  semen . [ 6 ] [ 43 ]  The WHO states that only people who are very sick are able to spread Ebola disease in  saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood,  feces  and vomit. [ 60 ]  Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. [ 43 ]  Ebola may be spread through large  droplets ; however, this is believed to occur only when a person is very sick. [ 61 ]  This contamination can happen if a person is splashed with droplets. [ 61 ]  Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. [ 62 ] [ 63 ]  The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. [ 43 ] [ 64 ]


The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via  sexual intercourse . [ 6 ] [ 65 ] [ 66 ]  Virus persistence in semen for over a year has been recorded in a national screening programme. [ 67 ]  Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. [ 7 ]  The virus was also found in the eye of  one patient ,  in 2014, two months after it was cleared from his blood. [ 68 ]  Otherwise, people who have recovered are not infectious. [ 62 ]


The potential for  widespread infections  in countries with medical systems capable of observing correct medical isolation procedures is considered low. [ 69 ]  Usually when someone has symptoms of the disease, they are unable to travel without assistance. [ 70 ]


Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as  embalming  are at risk. [ 69 ]  Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. [ 71 ] [ 72 ]


Health-care workers treating people with Ebola are at greatest risk of infection. [ 62 ]  The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. [ 62 ]  This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. [ 73 ]  There has been transmission  in hospitals  in some African countries that reuse hypodermic needles. [ 74 ] [ 75 ]  Some health-care centres caring for people with the disease do not have running water. [ 76 ]  In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. [ 77 ]


Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, [ 5 ]  and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to  primates , but not from primates to primates. [ 57 ] [ 63 ]  Spread of EBOV by water, or food other than bushmeat, has not been observed. [ 62 ] [ 63 ]  No spread by mosquitos or other insects has been reported. [ 62 ]  Other possible methods of transmission are being studied. [ 64 ]


Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. [ 78 ]  A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. [ 79 ]  Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. [ 80 ]  By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. [ 80 ]  It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. [ 79 ] [ 80 ]


Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. [ 62 ]  Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as  baboons ,  great apes  ( chimpanzees  and  gorillas ), and  duikers  (a species of  antelope ). [ 84 ]


Animals may become infected when they eat fruit partially eaten by bats carrying the virus. [ 85 ]  Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. [ 85 ]


Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. [ 86 ]  Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. [ 86 ]  Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. [ 86 ]


The  natural reservoir  for Ebola has yet to be confirmed; however,  bats  are considered to be the most likely candidate. [ 63 ]  Three types of fruit bats ( Hypsignathus monstrosus ,  Epomops franqueti  and  Myonycteris torquata ) were found to possibly carry the virus without getting sick. [ 87 ]  As of 2013 [update] , whether other animals are involved in its spread is not known. [ 86 ]  Plants,  arthropods ,  rodents , and birds have also been considered possible viral reservoirs. [ 1 ] [ 31 ]


Bats were known to roost in the cotton factory in which the  first cases  of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. [ 88 ]  Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. [ 89 ]  The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from  Gabon  and the  Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. [ 90 ]  Antibodies against Zaire and Reston viruses have been found in fruit bats in  Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. [ 91 ]


Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and  arthropods  sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species  Mus setulosus  and  Praomys ) and one  shrew  ( Sylvisorex ollula ) collected from the  Central African Republic . [ 88 ] [ 92 ]  However, further research efforts have not confirmed rodents as a reservoir. [ 93 ]  Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. [ 88 ]


Deforestation  has been mentioned as a possible contributor to recent outbreaks, including the  West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. [ 94 ] [ 95 ]


Like other  filoviruses , EBOV replicates very efficiently in many  cells , producing large amounts of virus in  monocytes ,  macrophages ,  dendritic cells  and other cells including  liver cells ,  fibroblasts , and  adrenal gland cells . [ 96 ]  Viral replication triggers  high levels of inflammatory chemical signals  and leads to a  septic state . [ 40 ]


EBOV is thought to infect humans through contact with mucous membranes or skin breaks. [ 57 ]  After infection,  endothelial cells  (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as  macrophages, monocytes , and dendritic cells are the main targets of attack. [ 57 ]  Following infection, immune cells carry the virus to nearby  lymph nodes  where further reproduction of the virus takes place. [ 57 ]  From there the virus can enter the bloodstream and  lymphatic system  and spread throughout the body. [ 57 ]  Macrophages are the first cells infected with the virus, and this infection results in  programmed cell death . [ 52 ]  Other types of  white blood cells , such as  lymphocytes , also undergo programmed cell death leading to an abnormally  low concentration of lymphocytes  in the blood. [ 57 ]  This contributes to the weakened immune response seen in those infected with EBOV. [ 57 ]


Endothelial cells may be infected within three days after exposure to the virus. [ 52 ]  The breakdown of endothelial cells leading to  blood vessel  injury can be attributed to EBOV  glycoproteins . This damage occurs due to the synthesis of Ebola virus  glycoprotein  (GP), which reduces the availability of specific  integrins  responsible for cell adhesion to the intercellular structure and causes liver damage, leading to  improper clotting . The widespread  bleeding  that occurs in affected people causes  swelling  and  shock due to loss of blood volume . [ 97 ]  The  dysfunctional bleeding and clotting  commonly seen in EVD has been attributed to increased activation of the  extrinsic pathway  of the  coagulation cascade  due to excessive  tissue factor  production by macrophages and monocytes. [ 25 ]


After infection, a secreted  glycoprotein , small soluble glycoprotein (sGP or GP) is synthesised. EBOV replication overwhelms protein synthesis of infected cells and the host immune defences. The GP forms a  trimeric complex , which tethers the virus to the endothelial cells. The sGP forms a  dimeric protein  that interferes with the signalling of  neutrophils , another type of white blood cell. This enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. [ medical citation needed ]  Furthermore, the virus is capable of hijacking cellular metabolism. Studies have shown that Ebola virus-like particles can reprogram metabolism in both vascular and immune cells. [ 98 ]


Filoviral infection also interferes with proper functioning of the  innate immune system . [ 53 ] [ 55 ]  EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as  interferon-alpha ,  interferon-beta , and  interferon gamma . [ 54 ] [ 99 ]


The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's  cytosol  (such as  RIG-I  and  MDA5 ) or outside of the cytosol (such as  Toll-like receptor 3 (TLR3) ,  TLR7 ,  TLR8  and  TLR9 ) recognise  infectious molecules  associated with the virus. [ 54 ]  On TLR activation, proteins including  interferon regulatory factor 3  and  interferon regulatory factor 7  trigger a signalling cascade that leads to the expression of  type 1 interferons . [ 54 ]  The type 1 interferons are then released and bind to the  IFNAR1  and  IFNAR2  receptors expressed on the surface of a neighbouring cell. [ 54 ]  Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins  STAT1  and  STAT2  are activated and move to the  cell's nucleus . [ 54 ]  This triggers the expression of  interferon-stimulated genes , which code for proteins with antiviral properties. [ 54 ]  EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. [ 54 ]  The VP35 protein directly inhibits the production of interferon-beta. [ 99 ]  By inhibiting these immune responses, EBOV may quickly spread throughout the body. [ 52 ]


When EVD is suspected, travel, work history, and exposure to wildlife are important factors with respect to further diagnostic efforts. [ 100 ]


Possible non-specific laboratory indicators of EVD include a  low platelet count ; an initially  decreased white blood cell count  followed by an  increased white blood cell count ; elevated levels of the liver enzymes  alanine aminotransferase  (ALT) and  aspartate aminotransferase  (AST); and abnormalities in blood clotting often consistent with  disseminated intravascular coagulation  (DIC) such as a prolonged  prothrombin time ,  partial thromboplastin time , and  bleeding time . [ 101 ]  Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with  electron microscopy . [ 102 ]


The specific diagnosis of EVD is confirmed by isolating the virus, detecting its  RNA  or proteins, or detecting  antibodies  against the virus in a person's blood. [ 103 ]  Isolating the virus by  cell culture , detecting the viral RNA by  polymerase chain reaction  (PCR) [ 8 ] [ 25 ]  and detecting proteins by  enzyme-linked immunosorbent assay  (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. [ 8 ] [ 103 ]  Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. [ 103 ]   IgM antibodies  are detectable two days after symptom onset and  IgG antibodies  can be detected six to 18 days after symptom onset. [ 25 ]  During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are  real-time PCR  and ELISA. [ 104 ]  In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. [ 105 ]  In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. [ 106 ]  It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. [ 106 ]


Early symptoms of EVD may be similar to those of other diseases common in Africa, including  malaria  and  dengue fever . [ 27 ]  The symptoms are also similar to those of other viral haemorrhagic fevers such as  Marburg virus disease ,  Crimean–Congo haemorrhagic fever , and  Lassa fever . [ 107 ] [ 108 ]


The complete  differential diagnosis  is extensive and requires consideration of many other infectious diseases such as  typhoid fever ,  shigellosis ,  rickettsial diseases ,  cholera ,  sepsis ,  borreliosis ,  EHEC enteritis ,  leptospirosis ,  scrub typhus ,  plague ,  Q fever ,  candidiasis ,  histoplasmosis ,  trypanosomiasis ,  visceral   leishmaniasis ,  measles , and  viral hepatitis  among others. [ 109 ]


Non-infectious diseases that may result in symptoms similar to those of EVD include  acute promyelocytic leukaemia ,  haemolytic uraemic syndrome ,  snake envenomation ,  clotting factor  deficiencies/platelet disorders,  thrombotic thrombocytopenic purpura ,  hereditary haemorrhagic telangiectasia ,  Kawasaki disease , and  warfarin  poisoning. [ 104 ] [ 110 ] [ 111 ] [ 112 ]


An  Ebola vaccine ,  rVSV-ZEBOV , was approved in the United States in December 2019. [ 10 ]  It appears to be fully effective ten days after being given. [ 10 ]  It was studied in Guinea between 2014 and 2016. [ 10 ]  More than 100,000 people have been vaccinated against Ebola as of 2019 [update] . [ 113 ]  The WHO reported that approximately 345,000 people were given the vaccine during the  Kivu Ebola epidemic  from 2018 to 2020. [ 114 ]


Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control  [ 4 ]


People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. [ 115 ]  The U.S.  Centers for Disease Control  (CDC) recommend that the protective gear leaves no skin exposed. [ 116 ]  These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. [ 117 ]  In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of  personal protective equipment  (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. [ 116 ]  In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. [ 118 ]
In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop.  [ 4 ]


The infected person should be in  barrier-isolation  from other people. [ 115 ]  All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be  disinfected . [ 117 ]  During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as  chlorine powder  and other cleaning supplies. [ 119 ]  Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of  Doctors Without Borders . [ 120 ]


Ebolaviruses can be  eliminated  with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To  disinfect  surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or  calcium hypochlorite  (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. [ 84 ] [ 121 ]


Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the  World Health Organization . [ 1 ]  These measures include avoiding direct contact with infected people and regular  hand washing  using soap and water. [ 122 ]


Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. [ 1 ]  Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. [ 123 ]


If a person with Ebola disease dies, direct contact with the body should be avoided. [ 115 ]  Certain  burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. [ 124 ] [ 125 ] [ 126 ]  Social anthropologists may help find alternatives to traditional rules for burials. [ 127 ]


Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. [ 128 ]  As of August 2014 [update] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. [ 70 ]  In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. [ 129 ]  In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: [ 129 ]


The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. [ 129 ]


In laboratories where diagnostic testing is carried out,  biosafety level 4-equivalent containment  is required. [ 130 ]  Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. [ 130 ]


Isolation refers to separating those who are sick from those who are not.  Quarantine  refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. [ 131 ]  Quarantine, also known as enforced isolation, is usually effective in decreasing spread. [ 132 ] [ 133 ]  Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. [ 134 ]  In the United States, the law allows quarantine of those infected with ebolaviruses. [ 135 ] [ 136 ]


Contact tracing  is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. [ 137 ] [ 138 ]


As of 2019 [update]  two treatments ( atoltivimab/maftivimab/odesivimab  and  ansuvimab ) are associated with improved outcomes. [ 11 ] [ 12 ]  The U.S.  Food and Drug Administration  (FDA) advises people to be careful of advertisements making unverified or fraudulent claims of benefits supposedly gained from various anti-Ebola products. [ 139 ] [ 140 ]


In October 2020, the U.S.  Food and Drug Administration  (FDA) approved atoltivimab/maftivimab/odesivimab with an  indication  for the treatment of infection caused by  Zaire ebolavirus . [ 13 ]


Treatment is primarily  supportive  in nature. [ 141 ]  Early supportive care with rehydration and symptomatic treatment improves survival. [ 1 ]  Rehydration may be via the  oral  or  intravenous  route. [ 141 ]  These measures may include  pain management , and treatment for  nausea ,  fever , and  anxiety . [ 141 ]  The  World Health Organization  (WHO) recommends avoiding  aspirin  or  ibuprofen  for pain management, due to the risk of bleeding associated with these medications. [ 142 ]


Blood products such as  packed red blood cells ,  platelets , or  fresh frozen plasma  may also be used. [ 141 ]  Other regulators of coagulation have also been tried including  heparin  in an effort to prevent  disseminated intravascular coagulation  and  clotting factors  to decrease bleeding. [ 141 ]   Antimalarial medications  and  antibiotics  are often used before the diagnosis is confirmed, [ 141 ]  though there is no evidence to suggest such treatment helps. Several  experimental treatments are being studied . [ 143 ]


Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. [ 144 ]


Intensive care  is often used in the developed world. [ 35 ]  This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. [ 35 ]   Dialysis  may be needed for  kidney failure , and  extracorporeal membrane oxygenation  may be used for lung dysfunction. [ 35 ]


EVD has a  risk of death in those infected  of between 25% and 90%. [ 1 ] [ 145 ]  As of September 2014 [update] , the average risk of death among those infected is 50%. [ 1 ]  The highest risk of death was 90% in the 2002–2003  Republic of the Congo  outbreak. [ 146 ]
Early admission significantly increases survival rates  [ 4 ]


Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to  low blood pressure from fluid loss . [ 2 ]  Early supportive care to prevent dehydration may reduce the risk of death. [ 143 ]


If an infected person survives, recovery may be quick and complete. [ 25 ] [ 147 ]  However, a large portion of survivors develop  post-Ebola virus syndrome  after the acute phase of the infection. [ 148 ]


Prolonged cases are often complicated by the occurrence of long-term problems, such as  inflammation of the testicles ,  joint pains , fatigue, hearing loss, mood and sleep disturbances,  muscular pain , abdominal pain,  menstrual abnormalities ,  miscarriages ,  skin peeling , or  hair loss . [ 25 ] [ 147 ]   Inflammation and swelling of the uveal layer of the eye  is the most common eye complication in survivors of Ebola virus disease. [ 147 ]  Eye symptoms, such as  light sensitivity ,  excess tearing , and  vision loss  have been described. [ 149 ]


Ebola can stay in some body parts like the eyes, [ 150 ]  breasts, and testicles after infection. [ 6 ] [ 151 ]  Sexual transmission after recovery has been suspected. [ 152 ] [ 153 ]  If sexual transmission occurs following recovery it is believed to be a rare event. [ 154 ]  One case of a condition similar to  meningitis  has been reported many months after recovery, as of October 2015 [update] . [ 155 ]


The disease typically occurs in outbreaks in tropical regions of  Sub-Saharan Africa . [ 1 ]  From 1976 (when it was first identified) through 2013, the WHO reported 2,387 confirmed cases with 1,590 overall fatalities. [ 1 ] [ 14 ]  The largest outbreak to date was the  Ebola virus epidemic in West Africa , which caused a large number of deaths in  Guinea ,  Sierra Leone , and  Liberia . [ 16 ] [ 17 ]


The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in  Nzara, South Sudan [ 44 ] [ 156 ]  (then part of  Sudan ), and was caused by  Sudan virus  (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in  Nzara , who was hospitalised on 30 June and died on 6 July. [ 35 ] [ 157 ]  Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in  Zaire . [ 157 ]


On 26 August 1976, the second outbreak of EVD began in  Yambuku , a small rural village in  Mongala District  in northern  Zaire  (now known as the  Democratic Republic of the Congo ). [ 158 ] [ 159 ]  This outbreak was caused by EBOV, formerly designated  Zaire ebolavirus , a different member of the  genus   Ebolavirus  than in the first Sudan outbreak. The  first person infected with the disease  was the village school's headmaster  Mabalo Lokela , who began displaying symptoms on 26 August 1976. [ 160 ]  Lokela had returned from a trip to Northern Zaire near the border of the  Central African Republic , after visiting the  Ebola River  between 12 and 22 August. He was originally believed to have  malaria  and was given  quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. [ 161 ] [ 162 ]


Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President  Mobutu Sese Seko  declared the entire region, including Yambuku and the country's capital,  Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under  martial law . Schools, businesses and social organisations were closed. [ 163 ]  The initial response was led by Congolese doctors, including  Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by  Peter Piot  to identify the previously unknown Ebola virus. [ 164 ]  Muyembe was also the first scientist to come into direct contact with the disease and survive. [ 165 ]  Researchers from the  Centers for Disease Control and Prevention  (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." [ 166 ] [ 167 ] [ 168 ]


Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. [ 163 ]


During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in  Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F),  haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." [ 169 ]


The virus responsible for the initial outbreak, first thought to be the  Marburg virus , was later identified as a new type of virus related to the genus  Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the  Ebola River , near the first-identified viral outbreak site in Zaire. [ 35 ]  Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team [ 170 ]  or Belgian researchers. [ 171 ]  Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. [ 160 ]  In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. [ 172 ]  Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. [ 159 ]


The second major outbreak occurred in Zaire (now the  Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. [ 1 ]


In 2000,  Uganda  had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. [ 1 ]


In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a  genus   Ebolavirus  outbreak to date. [ 173 ]


In 2004, a Russian scientist died from Ebola after  sticking  herself with an infected needle. [ 174 ]


Between April and August 2007, a fever epidemic [ 175 ]  in a four-village region [ 176 ]  of the DRC was confirmed in September to have been cases of Ebola. [ 177 ]  Many people who attended the recent funeral of a local village chief died. [ 176 ]  The 2007 outbreak eventually infected 264 individuals and killed 187. [ 1 ]


On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the  Bundibugyo District  in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of  genus   Ebolavirus , which was tentatively named Bundibugyo. [ 178 ]  The WHO reported 149 cases of this new strain and 37 of those led to deaths. [ 1 ]


The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. [ 1 ]


On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant [ 179 ]  in the eastern region. [ 180 ] [ 181 ]  Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted  bush meat  hunted by local villagers around the towns of  Isiro  and Viadana. [ 1 ] [ 182 ]


In 2014, an outbreak occurred in the DRC.  Genome-sequencing  showed that this outbreak was not related to the  2014–15 West Africa Ebola virus outbreak , but was the same  EBOV  species, the Zaire species. [ 183 ]  It began in August 2014, and was declared over in November with 66 cases and 49 deaths. [ 184 ]  This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as  Zaire . [ 185 ]


In March 2014, the  World Health Organization  (WHO) reported a major Ebola outbreak in  Guinea , a West African nation. [ 186 ]  Researchers traced the outbreak to a one-year-old child who died in December 2013. [ 187 ] [ 188 ]  The disease rapidly spread to the neighbouring countries of  Liberia  and  Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. [ 186 ]  On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." [ 189 ]  By mid-August 2014,  Doctors Without Borders  reported the situation in Liberia's capital,  Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. [ 190 ]  In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a  biosafety level  four pathogen infected so many people so quickly, over such a broad geographical area, for so long." [ 191 ]


Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases.


It caused significant mortality, with a considerable  case fatality rate . [ 192 ] [ 193 ] [ 194 ] [ note 1 ]  By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. [ 195 ]  As of 8 May 2016 [update] , 28,646 suspected cases and 11,323 deaths were reported; [ 15 ] [ 196 ]  however, the WHO said that these numbers may be underestimated. [ 197 ]  Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. [ 198 ]


In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. [ 199 ]  On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. [ 200 ]  On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. [ 201 ]


On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. [ 202 ]  At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. [ 203 ]  A new case was detected in Sierra Leone on 14 January 2016. [ 204 ]  However, the outbreak was declared no longer an emergency on 29 March 2016. [ 18 ]


On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. [ 205 ]


In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. [ 206 ]  Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. [ 207 ]


On 12 October, the  Centers for Disease Control and Prevention  (CDC) confirmed that a nurse in Texas,  Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. [ 208 ]  On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. [ 77 ] [ 209 ]  Both of these people recovered. [ 210 ]  An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with  Médecins Sans Frontières  and tested positive for Ebola on 23 October. [ 211 ]  The person recovered and was discharged from  Bellevue Hospital  on 11 November. [ 210 ]  On 24 December 2014, a laboratory in  Atlanta , Georgia reported that a technician had been exposed to Ebola. [ 212 ]


On 29 December 2014,  Pauline Cafferkey , a British nurse who had just returned to  Glasgow  from Sierra Leone, was diagnosed with Ebola at Glasgow's  Gartnavel General Hospital . [ 213 ]  After initial treatment in Glasgow, she was transferred by air to  RAF Northolt , then to the specialist  high-level isolation unit  at the  Royal Free Hospital  in  London  for longer-term treatment. [ 214 ]


On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. [ 215 ]


On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." [ 216 ]  Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the  Bikoro , Iboko, and  Wangata  areas in  Equateur  province, [ 216 ]  including in the large city of  Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. [ 217 ] [ 218 ] [ 219 ]  On 13 May 2018, WHO Director-General  Tedros Adhanom Ghebreyesus  visited Bikoro. [ 220 ]  Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as  epidemiologists  and officials trying to assess the outbreak and containment efforts. [ 221 ]  The 2018 outbreak in the DRC was declared over on 24 July 2018. [ 22 ]


On 1 August 2018, the world's 10th Ebola outbreak was declared in  North Kivu  province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. [ 222 ] [ 223 ]  By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of  Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. [ 224 ]


By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. [ 225 ] [ 226 ]  As of 4 June 2019 [update] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. [ 227 ]  In June 2019, two people died of Ebola in neighbouring  Uganda . [ 228 ]


In July 2019, an infected man travelled to  Goma , home to more than two million people. [ 229 ]  One week later, on 17 July 2019, the WHO declared the Ebola outbreak a  global health emergency , the fifth time such a declaration has been made by the organisation. [ 230 ]  A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. [ 231 ]


On 25 June 2020, the second biggest EVD outbreak ever was declared over. [ 232 ]


On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in  Mbandaka ,  Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. [ 233 ]  By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. [ 234 ]  The 11th EVD outbreak was officially declared over on 19 November 2020. [ 235 ]  By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths.


On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. [ 236 ] [ 237 ]


On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. [ 238 ]  A day after, a third case was detected in Butembo. [ 239 ]


On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. [ 240 ] [ 241 ]  Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. [ 240 ]


In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. [ 242 ]  On 14 February, the Guinean government declared an Ebola epidemic. [ 243 ]  The outbreak may have started following reactivation of a  latent case  in a survivor of an earlier outbreak. [ 244 ] [ 245 ]  As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. [ 240 ]  A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. [ 240 ] [ 246 ]


On 14 August 2021, The Ministry of Health of  Cote d’Ivoire  confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of  Abidjan , after arriving from Guinea. [ 247 ]