\r\n\t \r\n\tThis knowledge gap is due in part to the lack of a preclinical small animal model which can faithfully recapitulate EBV infection and immune control and would allow testing of EBV specific vaccine candidates. With the advent of mice with reconstituted human immune system compartments (HIS mice) during the past decade, this is changing. The complex interplay between host and virus has made it difficult to elaborate useful vaccine strategies to protect against the EBV-associated diseases (including chronic diseases like MS) or to find efficient drugs specifically targeting EBV malignancies. \r\n\t \r\n\tOne challenge is that the EBV expresses very different proteins during its lytic and its latent phases. To address this, vaccine candidates have been designed to include proteins from both phases. As EBV is associated with nearly 200,000 new malignancies each year worldwide, an EBV vaccine to prevent these diseases is needed. Parallel to this needs one could propose priorities for future research: (i) Identification of surrogate markers that predict the development of EBV-related malignancies. (ii) Definition of a goal for an EBV vaccine and criteria for licensure (iii), investigation of the potential usefulness of targeting certain lytic proteins in the context of drug discovery.
",isbn:"978-1-83968-490-6",printIsbn:"978-1-83968-489-0",pdfIsbn:"978-1-83968-491-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a2128c53becb6064589570cbe8d976f8",bookSignature:"Prof. Emmanuel Drouet",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9619.jpg",keywords:"Epstein-Barr Virus, Multiple Sclerosis, Breast Cancer, Breast Carcinoma, Epstein-Barr Virus Reactivation, Stress, Animal Model, Human Gammaherpesvirus, Infectious Mononucleosis, Nasopharyngeal Carcinoma, Latent Proteins, Central Nervous System",numberOfDownloads:396,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 3rd 2019",dateEndSecondStepPublish:"March 6th 2020",dateEndThirdStepPublish:"May 5th 2020",dateEndFourthStepPublish:"July 24th 2020",dateEndFifthStepPublish:"September 22nd 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.jpg",biography:"Expertise : Human Virology & Microbiology - \r\nNAME : DROUET\r\nGiven name : Emmanuel\r\nDegree : PhD, PharmD\r\nCurrent position : Full Professor CEX1\r\nTeaching & Education Professor at School of Pharmacy, UGA\r\nhttp://www.univ-grenoble-alpes.fr/en/\r\nResearch :Institut de Biologie Structurale (IBS), Univ. Grenoble Alpes, CEA, CNRS, http://www.ibs.fr/\r\nPostal address CIBB-IBS 38044 Grenoble, France 71 Rue des Martyrs, 38000 Grenoble, France\r\n\r\nPrincipal investigator in more than 20 research projects in virology since 2000\r\nMember of the CNU ('Conseil National des Universités” nominated by Ministère de l’Enseignement Supérieur et Recherche, France or French ministry of higher education and research, 87th section)) (2012-) – Expert at the AERES (Evaluation Agency for Research and Higher Education, France) \r\nCollaborations: University Medical Center, Utrecht (NL), University of Heidelberg (D)\r\n\r\nResearch interest :\r\n\r\nMain activities : Research as group leader in the French Institution CNRS and european EMBL. Principal investigator in more than 20 research projects since 1994 \r\n\r\nSubjects : (i) Pathobiology of the viruses belonging to the Flaviviridae family (Hepatitis C Virus) (ii) Innovative diagnosis markers for Herpesviruses and immune response (iii) Virus- associated Cancers \r\n\r\nTeaching in Medical Microbiology (Bacteriology, Virology, and Immunity) (School of Pharmacy students of bachelor & master level)\r\n\r\n5 main publications (key-words: Hepatitis C Virus, Epstein-Barr Virus, Cancer biomarkers)\r\n\r\nHabib M, et al., Morand P, Drouet E (2017) Lytic EBV infection investigated by detection of Soluble Epstein-Barr virus ZEBRA in the serum of patients with PTLD Nature Sci Rep 7: 10479 | DOI:10.1038/s41598-017-09798-7 1\r\n\r\nLe Berre L, Rousse J, Gourraud PA, Imbert-Marcille BM, Salama A, Evanno G, Semana G, Nicot A, Dugast E, Guérif P, Adjaoud C, Freour T, Brouard S, Agbalika F, Marignier R, Brassat D, Laplaud DA, Drouet E, Van Pesch V, Soulillou JPDecrease of blood anti-α1,3 Galactose Abs levels in multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients. Clin Immunol. 2017 Jul;180:128-135. \r\n\r\nFallecker C, et al. Petit MA, Drouet E (2017) New insights into HCV replication in original cells from Aedes mosquitoes Virology Journal 14:161 DOI 10.1186/s12985-017-0828-z\r\n\r\nSouii A, Elargoubi A, Fallecker C, Mastouri M, Drouet EHepatitis C Genotype Prevalence in Monastir Region, Tunisia: Correlation between 5' Untranslated Region (5'UTR), Non-structural 5B (NS5B), and Core Sequences in HCV Subtyping. Curr Microbiol. 2016 Sep;73(3):324-334. doi: 10.1007/s00284-016-1064-2. Epub 2016 May 17.\r\n\r\nMarrão G, et al., Drouet E (2014). Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-α/IFN-γ response. BMC Cancer. Sep 11;14:665. doi: 10.1186/1471-2407-14-665\r\n\r\nPérard J, et al., Drouet E, Jamin M (2013). Structure of the full-length HCV IRES in solution. Nature Comm. 4: 1612. doi: 10.1038/ncomms2611\r\n\r\nRothe R, et al. Drouet E, Lenormand J-L. (2010). Characterization of the Cell-penetrating Properties of the Epstein-Barr Virus ZEBRA trans-Activator. J. Biol. Chem. 285:20224–20233.\r\n\r\nBook chapter (most recent)\r\nhttps://www.intechopen.com/online-first/the-role-of-the-epstein-barr-virus-lytic-cycle-in-tumor-progression-consequences-in-diagnosis-and-th",institutionString:"Université Grenoble-Alpes",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Grenoble Alpes University",institutionURL:null,country:{name:"France"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:[{id:"73462",title:"Ocular Manifestation in Epstein Barr Virus Infection",slug:"ocular-manifestation-in-epstein-barr-virus-infection",totalDownloads:88,totalCrossrefCites:0,authors:[{id:"228998",title:"Dr.",name:"Andi Arus",surname:"Victor",slug:"andi-arus-victor",fullName:"Andi Arus Victor"}]},{id:"73024",title:"EBV Genome Mutations and Malignant Proliferations",slug:"ebv-genome-mutations-and-malignant-proliferations",totalDownloads:126,totalCrossrefCites:0,authors:[null]},{id:"72835",title:"Genome-Wide Profiling of Epstein–Barr Virus (EBV) Isolated from EBV-Related Malignancies",slug:"genome-wide-profiling-of-epstein-barr-virus-ebv-isolated-from-ebv-related-malignancies",totalDownloads:129,totalCrossrefCites:0,authors:[null]},{id:"73437",title:"Epstein-Barr Virus in Myasthenia Gravis: Key Contributing Factor Linking Innate Immunity with B-Cell-Mediated Autoimmunity",slug:"epstein-barr-virus-in-myasthenia-gravis-key-contributing-factor-linking-innate-immunity-with-b-cell-",totalDownloads:55,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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1. Introduction
Syphilis is an infectious sexually transmitted disease caused by the spirochete microorganism Treponema pallidum. Syphilis is transmissible by sexual contact with infectious lesions, from mother to fetus in utero, via blood product transfusion, and occasionally through breaks in the skin that come into contact with infectious lesions. Unprotected sex is the major risk factor for the acquisition of syphilis, especially among men who have sex with men (MSM). It is an intermittently active disease with primary, secondary, latent, and tertiary stages.
Syphilis is a disease with great historical importance and has played a major role in medicine for over a century. The disease was named after an afflicted shepherd named Syphilus in 1530. It is known to be “the great impostor,” particularly because the manifestations can mimic many other infections and immune-mediated diseases. For this reason, the historical Sir William Osler once remarked “The physician who knows syphilis knows medicine.” Many famous people throughout the history are thought to have suffered from syphilis, including Bram Stoker, Henry VIII, and Vincent van Gogh. After the discovery of penicillin in the twentieth century, the spread of the disease has been largely controlled, but up to now, it has not been fully eradicated.
The responsible microorganism T. pallidum is a fragile spiral bacterium. It can survive only briefly outside of the body; thus, transmission almost always requires direct contact with the infectious lesions. Incubation time from exposure to development of primary lesions, which occur at the primary site of inoculation, is approximately 3 weeks but can range from 10 to 90 days. Regardless of the stage of disease and location of lesions, histopathologic hallmarks of syphilis include endarteritis and a plasma cell-rich infiltrate. Secondary syphilis develops about 4–10 weeks after the primary lesion. During this stage, the spirochetes multiply and spread throughout the body, and variable mucocutaneous lesions and systemic manifestations may be observed. During the secondary infection, the immune reaction is at its peak, and antibody titers are high.
Latent syphilis is a stage at which the features of secondary syphilis have subsided, but the patient is still seropositive. About one-third of untreated patients at this stage develop tertiary syphilis, whereas the rest remain asymptomatic. Tertiary syphilis is rather rare and mainly involves the cardiovascular and central nervous system, developing over months to years and involving slow inflammatory damage to tissues.
The morbidity of syphilis ranges from minor symptoms of the early stages to the more significant systemic symptoms of secondary syphilis and neurological and cardiovascular consequences of tertiary disease. Latent syphilis can persist for years, causing significant morbidity and mortality if left untreated. The prevalence of the disease continues to increase due to the emergence of the AIDS epidemic, since genital ulcers may facilitate the sexual transmission of HIV, and HIV-seropositive patients have an increased risk for rapid progression to neurosyphilis. Approximately one-third of patients left untreated will develop late complications such as cardiovascular, neurosyphilis, or gummatous syphilis. Mortality rates are higher among these groups, up to 20% for tertiary syphilis, and late complications appear more commonly in men than in women [1]. On the other hand, for primary and secondary syphilis, the prognosis is rather good with appropriate treatment since T. pallidum is highly sensitive to penicillins.
2. Epidemiology
Syphilis is a worldwide-distributed disease and is particularly encountered in countries with low socioeconomic status. The rates of primary and secondary syphilis decreased dramatically worldwide with the introduction of penicillin treatment after the Second World War. It is estimated that worldwide in 2012, there were 18 million prevalent cases of syphilis in adolescents and adults aged 15–49 and 5.6 million new cases [2]. The global incidence rate was 1.5 cases per 1000 females and 1.5 cases per 1000 males. According to the same report, the highest prevalence was in the African region, followed by the Southeast Asian and Western Pacific regions. In the United States, from 2005 to 2014, the overall number of reported primary and secondary syphilis cases increased significantly from 8724 to 19,999 [3, 4]. In 2015, a total of 23,872 primary and secondary syphilis cases were reported, and the national rate increased by 19% to 7.5 cases per 100,000 population [5]. The rise in the rate of reported syphilis cases is primarily attributable to increased cases among men who have sex with men (MSM). The increasing incidence of syphilis in this population is due in part to rising rates of risky sexual behaviors, such as anonymous sex, unprotected sex (oral and anal), sex with multiple partners, and/or sex under the influence of drugs, especially methamphetamine. Concomitant HIV and syphilis infections are prevalent since they have similar modes of transmission, and infection with one may enhance the acquisition and transmission of the other among MSM. Available data suggest that approximately 50% of MSM with primary and secondary syphilis are HIV-infected, compared with 10% of men who have sex with women and 3.9% of women [6]. One long-term study conducted among US military personnel found that 5.8% of 4239 patients with newly diagnosed HIV infection also had serologic evidence of syphilis [7]. The rate of reported primary and secondary syphilis cases remains highest among Blacks, with the overall rate of syphilis being highest in Black men. As an example, in 2015, the rate of reported cases per 100,000 population was 39.0 in Black men, 16.6 in Hispanic men, and 7.6 in White men. Similar ethnical percentages apply among women as well [5].
Congenital syphilis is also a significant public health problem, complicating an estimated one million pregnancies per year throughout the world [8]. The incidence of congenital syphilis reflects the rate of syphilis in women of childbearing age who received no prenatal care or treatment for syphilis before or during pregnancy. In the United States, the rate of congenital syphilis among infants <1 year of age fluctuated between 8 and 12 cases per 100,000 live births between 2005 and 2015 [9]. The rate of congenital syphilis is increased among infants born to mothers with HIV infection. However, the contribution of maternal coinfection with syphilis and HIV to vertical transmission of either syphilis or HIV is not completely understood.
3. Pathophysiology
T. pallidum, the causative organism of syphilis, was first identified in 1905 by Schaudinn and Hoffmann [10]. It is a bacterium from the order Spirochaetales, a treponeme which causes human disease. T. pallidum is approximately 6–20 microns long and 0.1–0.18 microns in width, making it impossible to be visualized under direct light microscopy. With dark-field microscopy, casting an oblique light, T. pallidum is a corkscrew-shaped organism with wound spirals. It exhibits a characteristic rotary motion with flexing and back-and-forth movement, all of which are considered to be diagnostic. It cannot survive outside an animal host, nor can it be cultured in vitro for extended time period.
The organism has lipid-rich outer membrane with uniform-sized transmembrane proteins and periplasmic flagella. Inoculation and penetration of the microorganism occur via mucosal surfaces and abraded skin, followed by attachment to host cells and multiplication. Despite a slow estimated dividing time of 30 hours, the spirochete evades early host immune responses and establishes the initial ulcerative lesion, the chancre, disseminating to the regional lymph nodes and internal organs [11, 12].
3.1. Primary stage
The primary lesion develops 10–90 days after infection (3 weeks on average) as a papule, followed by necrosis and well-circumscribed ulceration that is firm to palpation (chancre), as well as enlarged regional lymph nodes. T. pallidum elicits innate and adaptive cellular immune responses in the skin and blood. At this stage, Th1-predominant cellular response with activation of macrophages is observed around the lesion [13]. Compared with peripheral blood, lesional fluids were enriched with CD4+ and CD8+ T cells, activated monocytes, macrophages, and dendritic cells. Many of these dendritic cells also express HIV coreceptors (e.g., CCR5 and DC-SIGN), which may help explain the epidemiologic link between syphilis and HIV transmission [14]. Several pathogenic mechanisms including an antigenically inert treponemal cell surface, resistance to phagocytosis, and downregulation of the local host immune response have been considered for this stage. After acquisition of T. pallidum, humoral immune responses also lead to the development of a variety of antibodies, effectively providing the resolution of the primary chancre, even in the absence of therapy, while widespread dissemination of spirochetes occurs at the same time, leading to subsequent clinical manifestations of secondary or tertiary syphilis.
3.2. Secondary stage
The secondary stage is characterized by dissemination and multiplication of the microorganism in different tissues in up to 6 months after the local lesion. This stage follows primary syphilis in almost every patient in the absence of appropriate treatment. Various lesions may occur due to circulating immune complexes, human fibronectin, antibodies, and complements with accompanying systemic signs [15].
3.3. Latency
Latency is the period between healing of the clinical lesions and appearance of late manifestations, lasting for many years. Weakened immunity with aging may result in the reactivation of a small number of treponemes that had survived in sequestered sites. Alternatively, a partially immune hypersensitive host may react to the presence of treponemes, causing a chronic inflammatory response. About 70% of untreated individuals will remain in this stage for the rest of their lives and are immune to new primary infection. This period is divided into early (1 year or less) and late (more than 1 year) latency with positive serology for specific antibodies without clinical signs or symptoms. Infectivity may occur intermittently due to the presence of treponemes in the peripheral bloods, and thus pregnant women at this stage may infect the fetus in utero.
3.4. Tertiary stage
At this stage the number of organisms decrease, but a high cellular immune response arises. Signs of late syphilis can be observed in approximately one-third of untreated individuals several months to years after being infected. The microorganisms may invade the central nervous and cardiovascular systems as well as other organs characterized pathologically by the presence of granulomas, a result of delayed-type cellular hypersensitivity reaction. Studies with human subjects who were inoculated cutaneously with small numbers of live T. pallidum found that gummas developed only in those who had previous syphilis [16]. This suggests that development of gummas requires an immune response insufficient to be protective but substantial enough to cause tissue damage and granuloma formation in the reinfected host. Small vessel vasculitis is also a common manifestation of this stage with the presence of lymphocytes and plasma cells infiltrating blood vessels and perivascular tissues.
4. Clinical features
Syphilis is an intermittent disease with primary, secondary, and tertiary stages as well as a latent period of variable length, preceding the onset of tertiary syphilis. According to the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO), early syphilis includes the primary and secondary stages (CDC, acquired <1 year previously; WHO, acquired <2 years previously), and late syphilis extends from late latency (CDC, acquired >1 year previously; WHO, acquired >2 years previously) through the tertiary stage.
4.1. Primary syphilis
Following acquisition of T. pallidum, the chancre usually begins as a painless papule and progresses to a round or oval ulcer with raised and indurated margin. (Picture 1) The ulcer generally has a non-exudative base and is associated with mild to moderate regional, usually bilateral lymphadenopathy. The median incubation period before the chancre appears is 21 days [17]. Untreated chancres heal in 3–6 weeks with the help of local immune responses. The lesions usually occur on the genitalia (Picture 2), but occasionally patients may develop chancres at other sites of inoculation. Cervical, anal, perianal, rectal, or posterior pharynx chancres may go unrecognized, and thus in these cases, syphilis is more frequently diagnosed during the secondary stage. The chancre represents an initial local infection, but syphilis quickly becomes systemic with widespread dissemination of the spirochete. The presence of treponemes by dark-field microscopic examination of fluid from the surface of the chancre is the most sensitive and specific method for the diagnosis of primary syphilis. Cardiolipin, a component of mammalian cells, is modified by treponemes, and antibodies to cardiolipin can be measured by the rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) assay in about 80% of individuals at the onset of clinical symptoms. Alternatively, antibodies to surface proteins of T. pallidum detected by hemagglutination assays (T. pallidumhemagglutination assay [TPHA], micro-hemagglutination assay for antibodies to T. pallidum [MHA-TP]) or fluorescent treponemal antibody absorption (FTA-ABS) assay are present in 90% of patients with primary syphilis. Since antibodies usually remain positive for life, a differentiation between primary syphilis and an earlier infection may not be possible, and dark-field examination should be performed.
Picture 1.
Primary syphilis chancre with indurated margin.
Picture 2.
Syphilis chancre in subacute phase with crusts and desquamation.
4.2. Secondary syphilis
The secondary stage of the disease results from the hematogenous and lymphatic dissemination of treponemes in 3–10 weeks, observed in approximately 25% of individuals with untreated infection [18]. It is characterized by both mucocutaneous and systemic manifestations. Prodromal symptoms include fever, malaise, anorexia, sore throat, lymphadenopathy, weight loss, myalgia, and headache. These clinical manifestations probably reflect the immunologic response resulting from widespread dissemination of T. pallidum.
Secondary syphilis has a vast variety of signs and symptoms. Most commonly encountered clinical presentation is generalized, non-pruritic papulosquamous eruption. The rash is very characteristic; however, in one series of 105 patients with secondary syphilis, more than 20% of the patients did not notice their lesions [19]. It is a diffuse, symmetric macular or papular eruption involving the entire trunk and extremities, including the palms and soles (Picture 3 and 4). Involvement of the palms and soles is an important clue for the diagnosis of secondary syphilis [20]. Individual lesions are discrete copper, red, or reddish-brown and measure 0.1–2 cm in diameter, with or without scales. (Picture 5) Pustular syphilis can be seen as small pustular syphilis, large pustular syphilis, flat pustular syphiloderm, or pustular-ulcerative syphilis. Superficial, painless aphthae-like lesions or gray plaques may be observed in mucosal areas. Large, raised, gray to white lesions called “condylomata lata” are often observed in the moist mucosal regions of the anogenital area or the mouth. These lesions occur most often in areas near to the primary chancre and may show direct spread of organisms from the primary ulcer. Malignant syphilis (lues maligna) is a rare entity with disseminated chancre-like lesions, particularly observed in case of immunodeficiency states such as AIDS [21]. Additional clinical findings include annular or figurate plaques with central hyperpigmentation on the face; non-scarring and reversible “moth-eaten” alopecia on the scalp, eyebrows, or beard; granulomatous nodules and plaques, or crusted necrotic lesions. Lesions resolve over weeks to months without treatment, except for lues maligna. Occasionally, about 20% of untreated patients experience relapsing episodes of secondary syphilis, which can occur for up to 5 years after their initial infection.
Picture 3.
Symmetrical plantar eruptions of secondary stage syphilis.
Picture 4.
Red to brownish papules on the extensor face of extremities, in secondary stage disease.
Picture 5.
Brown to purple macules and papules, scattered in flexor or extensor face of distal extremities.
Most patients with secondary syphilis have lymph node enlargement with palpable nodes present in the posterior cervical, axillary, inguinal, and femoral regions. Epitrochlear lymphadenopathy is particularly characteristic for the diagnosis. These nodes are generally minimally tender, firm, and rubbery in consistency. Systemic findings of secondary syphilis include syphilitic hepatitis, extensive ulceration of gastrointestinal tract, synovitis, osteitis, periostitis, transient albuminuria, nephrotic syndrome, or acute nephritis with hypertension and acute renal failure [22, 23].
For the detection of secondary syphilis, dark-field examination of serous exudates from skin or mucosal lesions could be performed. On the other hand, serological tests are more useful at this stage. Cardiolipin and specific antibodies are always positive in patients with secondary syphilis, except for a temporary negative non-treponemal test in case of prozone phenomenon or HIV infection.
4.3. Latent syphilis
After a period of 3–12 weeks, untreated secondary syphilis typically resolves spontaneously, followed by an asymptomatic state called latent syphilis. The diagnosis at this stage can only be made based on a positive serology. About 90% of relapses occur within the first year, referred as early latent stage. After 1 year, the patients enter the late latent stage, lasting for months to years.
About one-third of infected individuals have a nonreactive RPR test and no reactivation for the rest of their lives, and only the specific antibody assays (e.g., MHA-TP, FTA-ABS) remain positive. For another one-third of patients, antibodies against cardiolipin (e.g., RPR, VDRL) persist together with a positive MHA-TP or FTA-ABS assay without any symptoms. The remaining one-third, however, progresses to tertiary syphilis. For the cases without any medical history regarding the presence of clinical symptoms in the past weeks or months and previous treatments, differentiation between early and late latency is not possible. This group of patients is accepted as having late latent syphilis. This distinction is particularly important because patients with late latent disease are not considered infectious to their recent sexual contacts since they do not have lesions that can transmit disease. In contrast, patients with early latent syphilis may have transmitted T. pallidum to their sexual partners through lesions that were recently active, but are no longer present. Differentiating early from late latent disease also has implications for treatment approaches. Response of latent syphilis to treatment is indicated by a decline in the RPR or VDRL titer.
4.4. Tertiary (late) syphilis
Approximately 25–40% of patients with untreated syphilis can develop late disease, and symptoms may appear at any time from 1 to 30 years after primary infection [24]. Tertiary syphilis has a variable range of manifestations that appear months to years after initial infection. Involvement of the skin, bones, CNS, heart, and major vessels is pathognomonic. Half of the patients with tertiary syphilis develop only gummatous lesions, while the remaining have either cardiovascular disease or neurological manifestations. A confirmed case of late syphilis with clinical manifestations requires the demonstration of T. pallidum in late syphilitic lesions by special stains, polymerase chain reaction, or equivalent direct molecular methods. A probable case is diagnosed when characteristic abnormalities or lesions are noted along with a reactive treponemal serological test. All patients with a suspicion of tertiary syphilis should undergo lumbar puncture and CSF examination for detection of neurosyphilis.
4.4.1. Gummatous syphilis
The most common feature of late syphilis is gummas, which are locally destructive lesions in the skin, bones, liver, and other organs. The gummas in the skin are nodular or noduloulcerative granulomatous lesions with a round, irregular, or serpiginous shape, remaining for weeks to months, and eventually heal with scar tissue. A subcutaneous gumma may become necrotic, resulting in ulceration of the skin or mucous membranes as well as destruction of underlying bones. Gummatous lesions of the bones are usually accompanied by periostitis and osteitis. Clinical manifestations include pain, swelling, and limited range of motion. Other sites that can be affected by gummas include the tongue and oral cavity, upper respiratory tract, myocardium, and gastrointestinal and nervous systems.
4.4.2. Cardiovascular syphilis
Cardiovascular syphilis has a late onset, with a latent period of 15–30 years. During the early stage of the disease, vasa vasorum of the proximal aorta is affected, and transmural inflammatory lesions leading to endarteritis of the vessels develop. The disease typically involves the ascending thoracic aorta resulting in dilatation and aortic valve regurgitation. Vasculitis of the vasa vasorum leads to weakening of the wall of the aortic root [25]. The onset is insidious, and most patients present with an asymptomatic murmur or with left heart failure. Syphilis may also involve the coronary arteries, resulting in narrowing and thrombosis.
4.4.3. Neurosyphilis
Neurosyphilis is the infection of the central nervous system by T. pallidum, and although it is typically a manifestation of tertiary syphilis, it can occur at any stage of the disease. It was common in the pre-antibiotic era, occurring in 25–35% of patients with syphilis; however, nowadays, it is most frequently seen in patients with HIV infection [26–28]. Within this group of patients, lower peripheral CD4+ T cell counts are closely linked to have symptomatic neurosyphilis [29]. Early in the course, the disease involves cerebrospinal fluid, meninges, and vasculature, while later on brain and spinal cord parenchyma are also affected.
4.4.3.1. Early neurosyphilis
The disease process begins with the invasion of the cerebrospinal fluid; however, this does not always result in persistent infection, and spontaneous resolution may occur after transient meningitis. Failure to clear organisms from the CSF results in “asymptomatic neurosyphilis,” and individuals with this form of neurosyphilis are at risk for subsequent forms of symptomatic neurosyphilis [30]. The diagnosis of asymptomatic neurosyphilis is based on the identification of CSF abnormalities, including a lymphocytic pleocytosis, elevated protein concentration, and a reactive CSF-VDRL. Patients with asymptomatic neurosyphilis, regardless of CSF-VDRL reactivity, should be treated for neurosyphilis to prevent progression to symptomatic disease. Symptomatic meningitis occurs mostly within the first year after infection, and patients may have headache, confusion, nausea and vomiting, and stiff neck. Visual acuity may be impaired if there is concomitant uveitis, vitritis, retinitis, or optic neuropathy. The CSF abnormalities are more severe than those seen in asymptomatic meningitis. Cerebrovascular syphilis is, on the other hand, an infarction secondary to syphilitic endarteritis, which can result in hemiparesis or hemiplegia. This form of neurosyphilis may present as an ischemic stroke in a young person.
4.4.3.2. Late neurosyphilis
Parenchymatous neurosyphilis is observed at this stage, which is due to the direct invasion of the cerebrum by treponemes. General paresis and tabes dorsalis are the hallmarks of late neurosyphilis, and if untreated it can progress to death. General paresis (paretic neurosyphilis) is a progressive condition, usually developing 10–25 years after the infection. Initial findings include deficits in memory, judgment, and personality changes, and severe dementia may be seen in progression [31]. Common abnormal neurological findings include dysarthria; facial and limb hypotonia; intentional tremors of the face, tongue, and hands; and reflex abnormalities. Tabes dorsalis is a disease of the posterior columns of the spinal cord and dorsal roots. It has the longest latent period between primary infection and onset of symptoms with the interval averaging about 20 years. Most frequent symptoms are sensory ataxia and lancinating pains, which are sudden pain attacks affecting the limbs, back, or face. Pupillary irregularities are among the most common signs in patients with tabes dorsalis, and the Argyll Robertson pupil accounts for approximately half of these. Diplopia, loss of vibratory and position sense, reduced reflexes in the legs, ataxia, and sphincter dysfunction are other symptoms of tabes dorsalis.
In patients with known syphilis, a lumbar puncture with CSF examination should be performed if neurologic or ophthalmic signs or symptoms appear in any stage of the disease, if there is evidence of active tertiary syphilis affecting other parts of the body, and if there is a treatment failure including the failure of serum non-treponemal tests to fall appropriately. In addition to the clinical findings, the diagnosis of neurosyphilis is based upon reactive blood and CSF serologies, which are almost always positive with elevation of pressure, protein concentration, and immunoglobulin levels as well as a mononuclear pleocytosis. The presence of specific antitreponemal antibodies in the CSF is mandatory, but the specificity is low since IgG antibodies can diffuse into the CSF or result from contamination of the CSF by blood. CSF to serum IgG ratio divided by CSF to serum albumin ratio gives the CSF-IgG index, and a value of greater than 0.7 indicates IgG synthesis in the brain due to local inflammation. The presence of nonspecific antibodies, e.g., a positive VDRL test or RPR assay in CSF, is observed in most cases.
4.5. Congenital syphilis
Congenital syphilis occurs when the spirochete T. pallidum is transmitted from a pregnant woman to her fetus. Infection can result in stillbirth, prematurity, or a wide spectrum of clinical manifestations, and only severe cases are clinically apparent at birth. If a child has physical, laboratory, or radiographic signs of congenital syphilis and was born to a mother with untreated, inadequately, or suboptimally treated syphilis, this condition is defined as congenital syphilis. It is a significant public health problem, complicating an estimated one million pregnancies per year throughout the world [8]. Most cases develop because the mother received no prenatal care or treatment for syphilis before or during pregnancy. Among women with untreated early syphilis, 40% of pregnancies result in spontaneous abortion [32]. Congenital syphilis is generally acquired through transplacental transmission of spirochetes in the maternal bloodstream or, occasionally, through direct contact with an infectious lesion during birth [33].
4.5.1. Early congenital syphilis
Infants generally present with symptoms during the neonatal period or within the first 3 months of life. Typical manifestations are cachexia and skin lesions similar to those of acquired secondary syphilis. Bloody or purulent mucinous nasal discharge, perioral and perianal fissures, anemia, thrombocytopenia, syphilitic pneumonitis, hepatitis, nephropathy, lymphadenopathy, and hepatosplenomegaly may also be observed. Osteochondritis of skeletal bones may result in pseudoparalysis of Parrot due to reduced movement of the extremities due to pain.
4.5.2. Late congenital syphilis
This clinical entity of childhood or adolescent period corresponds to tertiary syphilis in adults. In about one-third of children, an interstitial keratitis is seen; this finding together with typical dental abnormalities (Hutchinson’s teeth) and neural deafness forms the Hutchinson triad.
The initial evaluation for congenital syphilis in infants and children should include a quantitative VDRL or RPR titer, physical examination for evidence of congenital syphilis, dark-field microscopic examination or direct fluorescent antibody staining of suspicious lesions or body fluids, and, for newborns, pathologic examination of the placenta and umbilical cord with specific fluorescent antitreponemal antibody staining. IgG antibodies which are present in the bloodstream of the child may have been acquired transplacentally from the mother. A serum titer for a non-treponemal test that is fourfold higher than the mother’s titer is suggestive of infection, but infected neonates may have lower titers. FTA-ABS-19S-IgM test to detect 19S-antibodies and IgM-capture ELISA test have high sensitivity for these cases. Additionally, detection of spirochetemia by PCR can improve the sensitivity of the diagnosis of congenital syphilis in neonates. In late congenital syphilis, diagnosis is based on clinical findings in association with reactive serologic tests.
5. Syphilis and pregnancy
Syphilis remains an important health concern for women at childbearing age. Failure to detect or adequately treat maternal disease often results in serious consequences for the fetus. Clinical features and diagnostic approaches are similar to normal population. All pregnant women should be screened for syphilis at the first prenatal visit, and the test should be repeated during the third trimester (28–32 weeks of gestation) and again at delivery in women who are at high risk for syphilis. Vertical transmission of syphilis can occur at any time during pregnancy and at any stage of the disease. Treatment of maternal syphilis at least 30 days before delivery is the most important factor influencing the risk of congenital infection. Penicillin remains the gold standard for the treatment of syphilis in pregnant patients as well. Penicillin desensitization is indicated for infected pregnant women with documented penicillin allergy as alternative drugs are not as safe or effective as penicillin.
6. Syphilis and HIV
Genital ulcerative diseases, such as syphilis, can increase the risk of both sexual and perinatal HIV transmission [34]. This is mostly because of the lack of an epithelial barrier due to ulceration of the skin or mucous membranes, large numbers of macrophages and T cells with receptors for HIV, and production of cytokines by macrophages stimulated by treponemal lipoproteins. Patients with HIV are at increased risk for neurosyphilis, especially if they have a CD4 count <350 cells/ml and/or a RPR titer of ≥1:32; however, unless neurologic symptoms are present, CSF examination in HIV patients has not been associated with improved clinical outcomes [35]. Clinical manifestations of syphilis and treatment approaches are similar for HIV-infected and HIV-noninfected patients; however, serologic responses appear slower in these patient groups.
7. Workup and laboratory diagnosis
Patients presenting with suspicious signs and symptoms of syphilis, pregnant women, commercial sex workers, sexually active men who have sex with men, and HIV-infected individuals should be routinely screened for syphilis. All patients with positive syphilis serology should also be tested for HIV infection.
The diagnosis of syphilis is based on the direct detection of treponemes or treponemal DNA by microscopy or molecular biologic techniques as well as various serologic tests. There are two types of serologic tests for syphilis: against cardiolipin (non-treponemal tests) antigens and treponemal antigens (treponemal tests). These tests rely upon a humoral immune response to infection. Thus, the use of serologic testing may be limited in patients with advanced immunosuppression or early disease.
7.1. Direct detection of T. pallidum
T. pallidum cannot be routinely cultured in vitro; thus, microscopic examination or molecular assays are used to detect the microorganism directly. With careful collection of serous fluid containing specimens, movement of spirochetes can be visualized by dark-field microscopy. Direct fluorescent antibody (DFA) testing can be also used to detect the organism; however, neither of these complex tests is routinely performed nor available in clinical settings. Alternatively, some laboratories have developed polymerase chain reaction (PCR)-based assays to detect T. pallidum DNA target sequences from clinical specimens. According to various studies, the sensitivity and specificity of PCR method from lesional specimens are relatively high, up to 95 and 98%, respectively [36–40]. However, PCR tests are not suitable for screening asymptomatic individuals, since the sensitivity of PCR testing tends to be much lower in blood and cerebrospinal fluid specimens (approximately 24–32%) [36].
7.2. Non-treponemal tests
They are based upon the reactivity of serum from infected patients to a cardiolipin-cholesterol-lecithin antigen and include venereal disease research laboratory (VDRL), rapid plasma regain (RPR), unheated serum reagin (USR), reagin screen test (RST), and toluidine red unheated serum test (TRUST). All these tests measure IgG and IgM antibodies against this lipoprotein-like material released from damaged host cells and treponemes. Titers of these antibodies correlate with disease activity and are used for screening and monitoring the treatment. These quantitative tests are performed even in case of a positive dark-field examination, to obtain a baseline for the follow-up of the treatment process. A fourfold decrease in the antibody titer indicates successful treatment, while a fourfold increase indicates relapse or reinfection. In the case of early and efficacious treatment, non-treponemal assays usually become negative over time. Although these screening tests are nonspecific, and therefore not definitive, they have traditionally been used for initial syphilis screening due to their relatively low cost and ease of performance.
7.3. Treponemal tests
The major indication for treponemal tests is confirmation of reactive non-treponemal tests. However, nowadays, they have been automated, with fast and easy use, and as a result, these tests are increasingly used as an initial screening test rather than as confirmatory tests. They are based upon the detection of antibodies directed against specific treponemal antigens and thus tend to be more specific than non-treponemal tests. The sensitivity varies with the stage of syphilis: between 70 and 100% in primary syphilis, 100% in secondary and latent syphilis, and about 95% in late syphilis [41]. Treponemal tests are qualitative only and are reported as “reactive” or “nonreactive.” These tests cannot differentiate between antibodies to T. pallidum and other treponemes or spirochetes, and they generally remain positive for lifetime; thus, they are not used for monitoring the response to treatment.
T. pallidum hemagglutination assay (TPHA), micro-hemagglutination assay for T. pallidum (MHA-TP), and T. pallidum particle agglutination (TPPA) tests: these tests measure antibodies directed against surface proteins of T. pallidum attached to rabbit erythrocytes as antigen carriers. Positive result shows previous or active syphilis but disease activity cannot be determined.
Fluorescent treponemal antibody absorption (FTA-ABS): This test shows the reaction of serum and whole treponeme and forming of antigen-antibody complexes with the help of fluorescein isothiocyanate. IgM and IgG can be selectively differentiated.
FTA-ABS-19S-IgM test: Fraction of IgM antibody is measured, with a higher specificity. This test is used for differentiation of relapsing disease from reinfection or in case of congenital syphilis.
Solid-phase hemadsorption assay (SPHA) or IgM ELISA: This test is used for the detection of specific IgM antibodies that attach to the solid phase of microtiter plates by reacting with the treponemal antigen on rabbit erythrocytes as antigen carriers. IgM antibodies can also be measured by the ELISA technology. They are used for the diagnosis of congenital syphilis, neurosyphilis, and reinfection.
T. pallidum enzyme immunoassay (TP-EIA)
In late 2014, the US Food and Drug Administration granted a Clinical Laboratory Improvement Amendments waiver permitting the use of a rapid (10-minute) finger-stick treponemal-based antibody test called the Syphilis Health Check (SHC) [42]. But exact sensitivity and specificity of this test have not been established yet. In Table 1 types and different properties of both treponemal and non-treponemal tests are summarized.
Treponemal tests
Non-treponemal tests
Treponema pallidum hemagglutination assay (TPHA)
Micro-hemagglutination assay for Treponema pallidum (MHA-TP)
Possible false positivity (autoimmune diseases, HIV infection, hypergammaglobulinemia)
High sensitivity and specificity
Venereal disease research laboratory (VDRL)
Rapid plasma regain (RPR)
Unheated serum reagin (USR)
Reagin screen test (RST)
Toluidine red unheated serum test (TRUST)
Possible false negativity in early-stage disease
Useful for monitoring treatment response
May become negative with early treatment
Possible false negativity (prozone phenomenon, HIV)
Possible false positivity (pregnancy, autoimmune diseases, drug use, lymphomas, malaria, vaccinations, cirrhosis, antiphospholipid syndrome)
Low cost and ease of performance
Table 1.
Serological tests for diagnosis of syphilis.
Serologic testing to diagnose syphilis should include the use of both non-treponemal and treponemal tests [43]. Traditional serologic testing algorithms for syphilis involve initial screening with a non-treponemal test. A reactive result is then confirmed with a treponemal test, such as FTA-ABS. If the non-treponemal test is negative and patient is asymptomatic, no further testing is necessary. If both tests are reactive and the patient has no history of previous disease, the results are consistent with a new infection, and appropriate treatment should be prompted. However, for patients with a history of treated syphilis in the past with positive treponemal and non-treponemal results, the need for treatment depends upon the patient’s clinic and the non-treponemal titer. This may indicate a new infection, an evolving response to recent treatment, treatment failure, or the presence of a serofast state. In case of a new infection, non-treponemal test reveals a fourfold or greater increase in titer from the individual’s prior posttreatment test. If the patient has persistently reactive but low titer non-treponemal test despite adequate treatment, it is considered as a serofast state. All other cases are regarded as treatment failures and should be retreated properly.
Alternatively, a popular novel approach uses treponemal tests such as TP-EIA as a screening method, followed by a non-treponemal test for confirmation. With this reverse order, there is an increase in false positivity rates but also an increase likelihood of catching patients with very early or late latent syphilis.
In case of a positive but usually low titer non-treponemal test followed by a negative one during screening, the patient is generally considered to have a false-positive syphilis result. It is estimated that 1–2% of the United States population has false-positive non-treponemal test results [44]. False-positive tests may be observed during pregnancy, acute febrile illness such as endocarditis or rickettsial disease, recent immunization, autoimmune disorders (particularly systemic lupus erythematosus), intravenous drug use, chronic liver disease, and in case of HIV disease [41].
If the patient has a positive treponemal and negative non-treponemal test, clinical symptoms should be investigated, and treatment should be administered in case of a positive finding. However, if there are no clinical signs or symptoms and repeated treponemal test is also positive, treatment for late latent syphilis is recommended. Another possibility is false-positive treponemal test which can be seen in case of spirochetal infections, malaria, and leprosy [45].
Negative non-treponemal test together with possible clinical signs and symptoms may point out early syphilis, prior to antibody formation or can be due to prozone effect [46]. In such cases of early primary syphilis, fluorescent treponemal antibody absorption (FTA-ABS) is thought to be the most sensitive method. Prozone reaction is also a major cause of a false-negative non-treponemal test. High titers of antibodies, usually in secondary syphilis, interfere with clumping of antigen-antibody complexes and make the visualization of the agglutination impossible. This phenomenon is usually associated with pregnancy, HIV coinfection, and neurosyphilis [47].
8. Pathology
Ulceration and dermal infiltrate of plasma cells, lymphocytes, and histiocytes are observed in primary syphilis. Spirochetes may also be detected with Warthin-Starry stain. In case of secondary syphilis, dermal infiltrates can be perivascular, lichenoid, diffuse, or nodular, with necrotic or ulcerated epidermis. In tertiary syphilis, tuberculoid granulomas, endothelial swelling, and vascular proliferation are present together with plasma cells.
9. Differential diagnosis
For primary syphilis, all conditions causing genital ulcers should be taken into consideration. These most commonly include genital herpes, chancroid, lymphogranuloma venereum, Behçet’s disease, and fixed drug eruption. In case of secondary syphilis, cutaneous findings may resemble viral exanthems, guttate psoriasis, pityriasis rosea, lichen planus, pityriasis lichenoides chronica, maculopapular drug eruptions, or nonspecific nummular eczema. Recurrent aphthous stomatitis, oral lichen planus, herpangina, candidiasis, and hand,foot, and mouth disease should be considered in case of mucosal involvement. Genital mucosa findings of secondary stage may mimic HPV-related lesions such as condyloma lata, bowenoid papulosis, or squamous cell carcinoma. Gummatous lesions of tertiary syphilis can be mistaken for lupus vulgaris, leishmaniasis, deep fungal infections, mycosis fungoides, and sarcoidosis.
10. Treatment
A non-treponemal serologic test should be obtained before initiating therapy (preferably on the first day of treatment) to establish the pretreatment titer and adequacy of serological response. Parenteral penicillin G is the treatment of choice for all stages of the disease [16, 43, 48]. A penicillin level of >0.018 mcg/l is considered treponemicidal, and this level of antimicrobial should be present in serum and/or CSF [49]. The dosage and duration of treatment depend upon the stage of the disease. For patients without neurosyphilis, penicillin G benzathine is the preferred formulation, and it is given via intramuscular route. In case of penicillin allergy, rechallenging or desensitization can be tried initially. Alternative antimicrobial agents include tetracyclines and cephalosporins. Azithromycin should be used only if other agents are not available, because treatment failures due to macrolide-resistant T. pallidum have been reported [50, 51]. The CDC and International Union against Sexually Transmitted Infections (IUSTI) currently recommend that HIV-infected individuals receive the same syphilis regimens as HIV-negative patients. Stage of the disease and treatment options are summarized in Table 2.
Clinical stage
Recommended treatment regimen
Alternative treatment regimen
Early syphilis
Primary
Secondary
Early latent (acquired <1 year previously)
Penicillin G benzathine 2.4 million units IM, single dose
Procaine penicillin, 1.2 million units, for 10 days
Doxycycline 100 mg orally twice daily for 14 days
Ceftriaxone 1–2 g daily IM or IV for 10–14 days
Tetracycline 500 mg orally four times daily for 14 days
Azithromycin, 2 g orally, single dose
Amoxicillin 3 g plus probenecid 500 mg, orally twice daily for 14 days
Late syphilis
Late latent (acquired >1 year previously or of unknown duration)
Cardiovascular and gummatous syphilis
Retreatment of primary, secondary, or latent syphilis after treatment failure
Penicillin G benzathine 2.4 million units IM once weekly for 3 weeks
Procaine penicillin, 1.2 million units IM for 20 days
Doxycycline 100 mg orally twice daily for 28 days
Ceftriaxone 2 g daily IM or IV for 10–14 days
Tetracycline, 500 mg orally for 28 days
Neurosyphilis
Early neurosyphilis
Late neurosyphilis
Penicillin G 3–4 million units IV every 4 hours (18–24 million units by continuous infusion) for 10–14 days
Penicillin G procaine 2.4 million units IM daily plus probenecid 500 mg orally four times daily, for 10–14 days
If possible, patients allergic to penicillin should be desensitized and treated with IV penicillin
Ceftriaxone, 2 g IM or IV for 10–14 days
Table 2.
Stage of the disease and treatment options.
10.1. Early syphilis
The goals of treatment are to prevent long-term adverse outcomes and reduce transmission. A diagnosis of early syphilis implies that T. pallidum infection occurred within the previous year and consists of primary, secondary, and early latent syphilis. A single dose of 2.4 million units of penicillin G benzathine (intramuscular) is the standard therapy for early syphilis [48, 50, 52]. No resistance against penicillin G has been reported up to now, and clinical cure rates are 90 to 100% for both HIV-uninfected and HIV-infected persons. First-line alternative to penicillin is doxycycline (100 mg PO twice daily), for 14 days. Oral amoxicillin (3 g) with probenecid (500 mg) can also be used, twice daily for 14 days. One to two grams of parenteral ceftriaxone for 10–14 days and a single 2 g dose of azithromycin are other alternatives [53–55]. Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache and myalgias within the first 24 hours of penicillin treatment and is most common among patients with early syphilis.
10.2. Late syphilis
This includes tertiary and late latent syphilis, with longer duration of treatment. Penicillin G benzathine (2.4 million units intramuscularly) once weekly for three weeks is the standard therapy for late syphilis [43]. If the patient misses a dose or more than 14 days have elapsed since the prior dose, the course should be reinitiated [56]. Patients with gummatous or cardiovascular infection should have a CSF examination prior to therapy to assess for neurosyphilis.Administration of 40–60 mg of prednisolone daily for 3 days beginning 24 hours before treatment for any form of cardiovascular syphilis may be advised [57]. Alternative regimens for late syphilis include doxycycline (100 mg PO twice daily for 28 days) or ceftriaxone (2 g IV or IM daily for 10–14 days); however, as there are limited data on the efficacy of these regimens in late syphilis, close monitoring is mandatory [58].
10.3. Neurosyphilis
These patients should generally be treated with intravenous therapy due to the fact that higher doses are necessary to produce measurable cerebrospinal fluid levels of the drug [59]. Preferred regimen is IV penicillin G (3–4 million units IV every 4 hours or 18–24 million units per day by continuous infusion) for 10–14 days. If the patient has late syphilis, together with neurosyphilis, a single dose or three doses of penicillin G benzathine (2.4 million units IM) may be administered after this course of therapy, for longer duration of effect. If the patient is allergic to penicillin, desensitization or rechallenge is strongly advised, so that the standard IV regimen can be used instead of an alternative regimen. Procaine penicillin plus probenecid, ceftriaxone, oral amoxicillin with probenecid, or doxycycline are other alternatives with limited success rates.
11. Follow-up
Patients should be monitored clinically and with laboratory testing to ensure that they are responding appropriately to therapy. A fourfold decline in the non-treponemal titer, equivalent to a change of two dilutions, is considered as good response to therapy. In a systematic review that included data from 20 studies, a fourfold or greater decline in non-treponemal titers was associated with younger age, higher baseline non-treponemal titers, and earlier syphilis stage [60].
If non-treponemal titers do not decline fourfold or if there is a fourfold increase after initial decline, this is considered as treatment failure. Since drug resistance to penicillin has not been described, treatment failure is likely due to poor adherence with the treatment regimen, treatment with an alternative agent, immunocompromised status, or undiagnosed neurosyphilis. It is also important to distinguish this treatment failure from reinfection.
In patients with early syphilis, serologic testing should be performed 6 and 12 months following treatment and at any time if clinical symptoms recur. Patients with late syphilis should undergo follow-up serologic testing at 6, 12, and 24 months. In case of abnormal CSF findings, a CSF examination is recommended at a 6-month interval until cell counts are normal and the CSF-VDRL is negative.
\n',keywords:"syphilis, clinical stages of syphilis, neurosyphilis, congenital syphilis, diagnosis of syphilis, treatment of syphilis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/56658.pdf",chapterXML:"https://mts.intechopen.com/source/xml/56658.xml",downloadPdfUrl:"/chapter/pdf-download/56658",previewPdfUrl:"/chapter/pdf-preview/56658",totalDownloads:762,totalViews:672,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:null,dateReviewed:"July 3rd 2017",datePrePublished:null,datePublished:"September 6th 2017",dateFinished:null,readingETA:"0",abstract:"Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. It is transmissible by sexual contact, from mother to fetus, via blood transfusion, and occasionally by direct contact with infectious lesions. It has been a major public health problem both before the antibiotic era and now, with the increase of acquired immunodeficiency states and unprotected sex. The clinical manifestations of the disease can mimic many other infections and immune-mediated diseases; thus, it may be difficult to make early diagnosis. After the discovery of penicillin in the twentieth century, the spread of the disease has been largely controlled, but up to now, it has not been fully eradicated. In this chapter, overall information about the disease including the epidemiology, clinical presentation forms, pathophysiological mechanisms, and latest diagnostic and treatment approaches are reviewed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/56658",risUrl:"/chapter/ris/56658",book:{slug:"fundamentals-of-sexually-transmitted-infections"},signatures:"Ayşegül Sevim Keçici",authors:[{id:"215974",title:"Dr.",name:"Aysegul Sevim",middleName:null,surname:"Kecici",fullName:"Aysegul Sevim Kecici",slug:"aysegul-sevim-kecici",email:"aysegul_sevim@hotmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Epidemiology",level:"1"},{id:"sec_3",title:"3. Pathophysiology",level:"1"},{id:"sec_3_2",title:"3.1. Primary stage",level:"2"},{id:"sec_4_2",title:"3.2. Secondary stage",level:"2"},{id:"sec_5_2",title:"3.3. Latency",level:"2"},{id:"sec_6_2",title:"3.4. Tertiary stage",level:"2"},{id:"sec_8",title:"4. Clinical features",level:"1"},{id:"sec_8_2",title:"4.1. Primary syphilis",level:"2"},{id:"sec_9_2",title:"4.2. Secondary syphilis",level:"2"},{id:"sec_10_2",title:"4.3. Latent syphilis",level:"2"},{id:"sec_11_2",title:"4.4. Tertiary (late) syphilis",level:"2"},{id:"sec_11_3",title:"4.4.1. Gummatous syphilis",level:"3"},{id:"sec_12_3",title:"4.4.2. Cardiovascular syphilis",level:"3"},{id:"sec_13_3",title:"4.4.3. Neurosyphilis",level:"3"},{id:"sec_13_4",title:"4.4.3.1. Early neurosyphilis",level:"4"},{id:"sec_14_4",title:"4.4.3.2. Late neurosyphilis",level:"4"},{id:"sec_17_2",title:"4.5. Congenital syphilis",level:"2"},{id:"sec_17_3",title:"4.5.1. Early congenital syphilis",level:"3"},{id:"sec_18_3",title:"4.5.2. Late congenital syphilis",level:"3"},{id:"sec_21",title:"5. Syphilis and pregnancy",level:"1"},{id:"sec_22",title:"6. Syphilis and HIV",level:"1"},{id:"sec_23",title:"7. Workup and laboratory diagnosis",level:"1"},{id:"sec_23_2",title:"7.1. Direct detection of T. pallidum",level:"2"},{id:"sec_24_2",title:"7.2. Non-treponemal tests",level:"2"},{id:"sec_25_2",title:"7.3. Treponemal tests",level:"2"},{id:"sec_27",title:"8. Pathology",level:"1"},{id:"sec_28",title:"9. Differential diagnosis",level:"1"},{id:"sec_29",title:"10. Treatment",level:"1"},{id:"sec_29_2",title:"10.1. Early syphilis",level:"2"},{id:"sec_30_2",title:"10.2. Late syphilis",level:"2"},{id:"sec_31_2",title:"10.3. Neurosyphilis",level:"2"},{id:"sec_33",title:"11. Follow-up",level:"1"}],chapterReferences:[{id:"B1",body:'Woznicova V, Valisova Z. 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The clinical presentation and imaging manifestation of psychosis and dementia in general paresis: A retrospective study of 116 cases. Journal of Neuropsychiatry and Clinical Neurosciences. 2011;23:300'},{id:"B32",body:'Lago EG, Vaccari A, Fiori RM. Clinical features and follow-up of congenital syphilis. Sexually Transmitted Diseases. 2013;40:85'},{id:"B33",body:'Qureshi F, Jacques SM, Reyes MP. Placental histopathology in syphilis. Human Pathology. 1993;24:779'},{id:"B34",body:'Reynolds SJ, Risbud AR, Shepherd ME, et al. High rates of syphilis among STI patients are contributing to the spread of HIV-1 in India. Sexually Transmitted Infections. 2006;82:121'},{id:"B35",body:'Ghanem KG, Moore RD, Rompalo AM, et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008;22:1145'},{id:"B36",body:'Liu H, Rodes B, Chen CY, Steiner B. 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Clinical Infectious Diseases. 2015;61:818'},{id:"B57",body:'Kingston M, French P, Higgins S, et al. UK National Guidelines on the management of syphilis 2015. International Journal of STD & AIDS. 2016;27:421'},{id:"B58",body:'Augenbraun MH. Treatment of syphilis 2001: Nonpregnant adults. Clinical Infectious Diseases. 2002;35:187'},{id:"B59",body:'Polnikorn N, Witoonpanich R, Vorachit M, et al. Penicillin concentrations in cerebrospinal fluid after different treatment regimens for syphilis. British Journal of Venereal Diseases. 1980;56:363'},{id:"B60",body:'Seña AC, Zhang XH, Li T, et al. A systematic review of syphilis serological treatment outcomes in HIV-infected and HIV-uninfected persons: rethinking the significance of serological non-responsiveness and the serofast state after therapy. BMC Infectious Disease. 2015;15:479'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ayşegül Sevim Keçici",address:"aysegul_sevim@hotmail.com",affiliation:'
Department of Dermatology, University of Medical Sciences, Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey
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Yuryev",authors:[{id:"189400",title:"Dr.",name:"Anastasia",middleName:null,surname:"Nesterova",fullName:"Anastasia Nesterova",slug:"anastasia-nesterova"},{id:"205662",title:"Dr.",name:"Anton",middleName:null,surname:"Yuryev",fullName:"Anton Yuryev",slug:"anton-yuryev"}]},{id:"53933",title:"Cicatricial Alopecias",slug:"cicatricial-alopecias",signatures:"Ibrahim Halil Yavuz, Goknur Ozaydin Yavuz and Serap Gunes Bilgili",authors:[{id:"190495",title:"Associate Prof.",name:"Serap Gunes",middleName:null,surname:"Bilgili",fullName:"Serap Gunes Bilgili",slug:"serap-gunes-bilgili"},{id:"191273",title:"Dr.",name:"Goknur",middleName:null,surname:"Ozaydin Yavuz",fullName:"Goknur Ozaydin Yavuz",slug:"goknur-ozaydin-yavuz"},{id:"191275",title:"Dr.",name:"Ibrahim Halil",middleName:null,surname:"Yavuz",fullName:"Ibrahim Halil Yavuz",slug:"ibrahim-halil-yavuz"}]},{id:"53947",title:"Infections, Infestations and Neoplasms of the 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Design and Methodology",doi:"10.5772/intechopen.85731",slug:"research-design-and-methodology",body:'
1. Introduction
Research methodology is the path through which researchers need to conduct their research. It shows the path through which these researchers formulate their problem and objective and present their result from the data obtained during the study period. This research design and methodology chapter also shows how the research outcome at the end will be obtained in line with meeting the objective of the study. This chapter hence discusses the research methods that were used during the research process. It includes the research methodology of the study from the research strategy to the result dissemination. For emphasis, in this chapter, the author outlines the research strategy, research design, research methodology, the study area, data sources such as primary data sources and secondary data, population consideration and sample size determination such as questionnaires sample size determination and workplace site exposure measurement sample determination, data collection methods like primary data collection methods including workplace site observation data collection and data collection through desk review, data collection through questionnaires, data obtained from experts opinion, workplace site exposure measurement, data collection tools pretest, secondary data collection methods, methods of data analysis used such as quantitative data analysis and qualitative data analysis, data analysis software, the reliability and validity analysis of the quantitative data, reliability of data, reliability analysis, validity, data quality management, inclusion criteria, ethical consideration and dissemination of result and its utilization approaches. In order to satisfy the objectives of the study, a qualitative and quantitative research method is apprehended in general. The study used these mixed strategies because the data were obtained from all aspects of the data source during the study time. Therefore, the purpose of this methodology is to satisfy the research plan and target devised by the researcher.
2. Research design
The research design is intended to provide an appropriate framework for a study. A very significant decision in research design process is the choice to be made regarding research approach since it determines how relevant information for a study will be obtained; however, the research design process involves many interrelated decisions [1].
This study employed a mixed type of methods. The first part of the study consisted of a series of well-structured questionnaires (for management, employee’s representatives, and technician of industries) and semi-structured interviews with key stakeholders (government bodies, ministries, and industries) in participating organizations. The other design used is an interview of employees to know how they feel about safety and health of their workplace, and field observation at the selected industrial sites was undertaken.
Hence, this study employs a descriptive research design to agree on the effects of occupational safety and health management system on employee health, safety, and property damage for selected manufacturing industries. Saunders et al. [2] and Miller [3] say that descriptive research portrays an accurate profile of persons, events, or situations. This design offers to the researchers a profile of described relevant aspects of the phenomena of interest from an individual, organizational, and industry-oriented perspective. Therefore, this research design enabled the researchers to gather data from a wide range of respondents on the impact of safety and health on manufacturing industries in Ethiopia. And this helped in analyzing the response obtained on how it affects the manufacturing industries’ workplace safety and health. The research overall design and flow process are depicted in Figure 1.
Figure 1.
Research methods and processes (author design).
3. Research methodology
To address the key research objectives, this research used both qualitative and quantitative methods and combination of primary and secondary sources. The qualitative data supports the quantitative data analysis and results. The result obtained is triangulated since the researcher utilized the qualitative and quantitative data types in the data analysis. The study area, data sources, and sampling techniques were discussed under this section.
3.1 The study area
According to Fraenkel and Warren [4] studies, population refers to the complete set of individuals (subjects or events) having common characteristics in which the researcher is interested. The population of the study was determined based on random sampling system. This data collection was conducted from March 07, 2015 to December 10, 2016, from selected manufacturing industries found in Addis Ababa city and around. The manufacturing companies were selected based on their employee number, established year, and the potential accidents prevailing and the manufacturing industry type even though all criterions were difficult to satisfy.
3.2 Data sources
3.2.1 Primary data sources
It was obtained from the original source of information. The primary data were more reliable and have more confidence level of decision-making with the trusted analysis having direct intact with occurrence of the events. The primary data sources are industries’ working environment (through observation, pictures, and photograph) and industry employees (management and bottom workers) (interview, questionnaires and discussions).
3.2.2 Secondary data
Desk review has been conducted to collect data from various secondary sources. This includes reports and project documents at each manufacturing sectors (more on medium and large level). Secondary data sources have been obtained from literatures regarding OSH, and the remaining data were from the companies’ manuals, reports, and some management documents which were included under the desk review. Reputable journals, books, different articles, periodicals, proceedings, magazines, newsletters, newspapers, websites, and other sources were considered on the manufacturing industrial sectors. The data also obtained from the existing working documents, manuals, procedures, reports, statistical data, policies, regulations, and standards were taken into account for the review.
In general, for this research study, the desk review has been completed to this end, and it had been polished and modified upon manuals and documents obtained from the selected companies.
4. Population and sample size
4.1 Population
The study population consisted of manufacturing industries’ employees in Addis Ababa city and around as there are more representative manufacturing industrial clusters found. To select representative manufacturing industrial sector population, the types of the industries expected were more potential to accidents based on random and purposive sampling considered. The population of data was from textile, leather, metal, chemicals, and food manufacturing industries. A total of 189 sample sizes of industries responded to the questionnaire survey from the priority areas of the government. Random sample sizes and disproportionate methods were used, and 80 from wood, metal, and iron works; 30 from food, beverage, and tobacco products; 50 from leather, textile, and garments; 20 from chemical and chemical products; and 9 from other remaining 9 clusters of manufacturing industries responded.
4.2 Questionnaire sample size determination
A simple random sampling and purposive sampling methods were used to select the representative manufacturing industries and respondents for the study. The simple random sampling ensures that each member of the population has an equal chance for the selection or the chance of getting a response which can be more than equal to the chance depending on the data analysis justification. Sample size determination procedure was used to get optimum and reasonable information. In this study, both probability (simple random sampling) and nonprobability (convenience, quota, purposive, and judgmental) sampling methods were used as the nature of the industries are varied. This is because of the characteristics of data sources which permitted the researchers to follow the multi-methods. This helps the analysis to triangulate the data obtained and increase the reliability of the research outcome and its decision. The companies’ establishment time and its engagement in operation, the number of employees and the proportion it has, the owner types (government and private), type of manufacturing industry/production, types of resource used at work, and the location it is found in the city and around were some of the criteria for the selections.
The determination of the sample size was adopted from Daniel [5] and Cochran [6] formula. The formula used was for unknown population size Eq. (1) and is given as
E1
where n = sample size, Z = statistic for a level of confidence, P = expected prevalence or proportion (in proportion of one; if 50%, P = 0.5), and d = precision (in proportion of one; if 6%, d = 0.06). Z statistic (Z): for the level of confidence of 95%, which is conventional, Z value is 1.96. In this study, investigators present their results with 95% confidence intervals (CI).
The expected sample number was 267 at the marginal error of 6% for 95% confidence interval of manufacturing industries. However, the collected data indicated that only 189 populations were used for the analysis after rejecting some data having more missing values in the responses from the industries. Hence, the actual data collection resulted in 71% response rate. The 267 population were assumed to be satisfactory and representative for the data analysis.
4.3 Workplace site exposure measurement sample determination
The sample size for the experimental exposure measurements of physical work environment has been considered based on the physical data prepared for questionnaires and respondents. The response of positive were considered for exposure measurement factors to be considered for the physical environment health and disease causing such as noise intensity, light intensity, pressure/stress, vibration, temperature/coldness, or hotness and dust particles on 20 workplace sites. The selection method was using random sampling in line with purposive method. The measurement of the exposure factors was done in collaboration with Addis Ababa city Administration and Oromia Bureau of Labour and Social Affair (AACBOLSA). Some measuring instruments were obtained from the Addis Ababa city and Oromia Bureau of Labour and Social Affair.
5. Data collection methods
Data collection methods were focused on the followings basic techniques. These included secondary and primary data collections focusing on both qualitative and quantitative data as defined in the previous section. The data collection mechanisms are devised and prepared with their proper procedures.
5.1 Primary data collection methods
Primary data sources are qualitative and quantitative. The qualitative sources are field observation, interview, and informal discussions, while that of quantitative data sources are survey questionnaires and interview questions. The next sections elaborate how the data were obtained from the primary sources.
5.1.1 Workplace site observation data collection
Observation is an important aspect of science. Observation is tightly connected to data collection, and there are different sources for this: documentation, archival records, interviews, direct observations, and participant observations. Observational research findings are considered strong in validity because the researcher is able to collect a depth of information about a particular behavior. In this dissertation, the researchers used observation method as one tool for collecting information and data before questionnaire design and after the start of research too. The researcher made more than 20 specific observations of manufacturing industries in the study areas. During the observations, it found a deeper understanding of the working environment and the different sections in the production system and OSH practices.
5.1.2 Data collection through interview
Interview is a loosely structured qualitative in-depth interview with people who are considered to be particularly knowledgeable about the topic of interest. The semi-structured interview is usually conducted in a face-to-face setting which permits the researcher to seek new insights, ask questions, and assess phenomena in different perspectives. It let the researcher to know the in-depth of the present working environment influential factors and consequences. It has provided opportunities for refining data collection efforts and examining specialized systems or processes. It was used when the researcher faces written records or published document limitation or wanted to triangulate the data obtained from other primary and secondary data sources.
This dissertation is also conducted with a qualitative approach and conducting interviews. The advantage of using interviews as a method is that it allows respondents to raise issues that the interviewer may not have expected. All interviews with employees, management, and technicians were conducted by the corresponding researcher, on a face-to-face basis at workplace. All interviews were recorded and transcribed.
5.1.3 Data collection through questionnaires
The main tool for gaining primary information in practical research is questionnaires, due to the fact that the researcher can decide on the sample and the types of questions to be asked [2].
In this dissertation, each respondent is requested to reply to an identical list of questions mixed so that biasness was prevented. Initially the questionnaire design was coded and mixed up from specific topic based on uniform structures. Consequently, the questionnaire produced valuable data which was required to achieve the dissertation objectives.
The questionnaires developed were based on a five-item Likert scale. Responses were given to each statement using a five-point Likert-type scale, for which 1 = “strongly disagree” to 5 = “strongly agree.” The responses were summed up to produce a score for the measures.
5.1.4 Data obtained from experts’ opinion
The data was also obtained from the expert’s opinion related to the comparison of the knowledge, management, collaboration, and technology utilization including their sub-factors. The data obtained in this way was used for prioritization and decision-making of OSH, improving factor priority. The prioritization of the factors was using Saaty scales (1–9) and then converting to Fuzzy set values obtained from previous researches using triangular fuzzy set [7].
5.1.5 Workplace site exposure measurement
The researcher has measured the workplace environment for dust, vibration, heat, pressure, light, and noise to know how much is the level of each variable. The primary data sources planned and an actual coverage has been compared as shown in Table 1.
Table 1.
Planned versus actual coverage of the survey.
The response rate for the proposed data source was good, and the pilot test also proved the reliability of questionnaires. Interview/discussion resulted in 87% of responses among the respondents; the survey questionnaire response rate obtained was 71%, and the field observation response rate was 90% for the whole data analysis process. Hence, the data organization quality level has not been compromised.
This response rate is considered to be representative of studies of organizations. As the study agrees on the response rate to be 30%, it is considered acceptable [8]. Saunders et al. [2] argued that the questionnaire with a scale response of 20% response rate is acceptable. Low response rate should not discourage the researchers, because a great deal of published research work also achieves low response rate. Hence, the response rate of this study is acceptable and very good for the purpose of meeting the study objectives.
5.1.6 Data collection tool pretest
The pretest for questionnaires, interviews, and tools were conducted to validate that the tool content is valid or not in the sense of the respondents’ understanding. Hence, content validity (in which the questions are answered to the target without excluding important points), internal validity (in which the questions raised answer the outcomes of researchers’ target), and external validity (in which the result can generalize to all the population from the survey sample population) were reflected. It has been proved with this pilot test prior to the start of the basic data collections. Following feedback process, a few minor changes were made to the originally designed data collect tools. The pilot test made for the questionnaire test was on 10 sample sizes selected randomly from the target sectors and experts.
5.2 Secondary data collection methods
The secondary data refers to data that was collected by someone other than the user. This data source gives insights of the research area of the current state-of-the-art method. It also makes some sort of research gap that needs to be filled by the researcher. This secondary data sources could be internal and external data sources of information that may cover a wide range of areas.
Literature/desk review and industry documents and reports: To achieve the dissertation’s objectives, the researcher has conducted excessive document review and reports of the companies in both online and offline modes. From a methodological point of view, literature reviews can be comprehended as content analysis, where quantitative and qualitative aspects are mixed to assess structural (descriptive) as well as content criteria.
A literature search was conducted using the database sources like MEDLINE; Emerald; Taylor and Francis publications; EMBASE (medical literature); PsycINFO (psychological literature); Sociological Abstracts (sociological literature); accident prevention journals; US Statistics of Labor, European Safety and Health database; ABI Inform; Business Source Premier (business/management literature); EconLit (economic literature); Social Service Abstracts (social work and social service literature); and other related materials. The search strategy was focused on articles or reports that measure one or more of the dimensions within the research OSH model framework. This search strategy was based on a framework and measurement filter strategy developed by the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) group. Based on screening, unrelated articles to the research model and objectives were excluded. Prior to screening, researcher (principal investigator) reviewed a sample of more than 2000 articles, websites, reports, and guidelines to determine whether they should be included for further review or reject. Discrepancies were thoroughly identified and resolved before the review of the main group of more than 300 articles commenced. After excluding the articles based on the title, keywords, and abstract, the remaining articles were reviewed in detail, and the information was extracted on the instrument that was used to assess the dimension of research interest. A complete list of items was then collated within each research targets or objectives and reviewed to identify any missing elements.
6. Methods of data analysis
Data analysis method follows the procedures listed under the following sections. The data analysis part answered the basic questions raised in the problem statement. The detailed analysis of the developed and developing countries’ experiences on OSH regarding manufacturing industries was analyzed, discussed, compared and contrasted, and synthesized.
6.1 Quantitative data analysis
Quantitative data were obtained from primary and secondary data discussed above in this chapter. This data analysis was based on their data type using Excel, SPSS 20.0, Office Word format, and other tools. This data analysis focuses on numerical/quantitative data analysis.
Before analysis, data coding of responses and analysis were made. In order to analyze the data obtained easily, the data were coded to SPSS 20.0 software as the data obtained from questionnaires. This task involved identifying, classifying, and assigning a numeric or character symbol to data, which was done in only one way pre-coded [9, 10]. In this study, all of the responses were pre-coded. They were taken from the list of responses, a number of corresponding to a particular selection was given. This process was applied to every earlier question that needed this treatment. Upon completion, the data were then entered to a statistical analysis software package, SPSS version 20.0 on Windows 10 for the next steps.
Under the data analysis, exploration of data has been made with descriptive statistics and graphical analysis. The analysis included exploring the relationship between variables and comparing groups how they affect each other. This has been done using cross tabulation/chi square, correlation, and factor analysis and using nonparametric statistic.
6.2 Qualitative data analysis
Qualitative data analysis used for triangulation of the quantitative data analysis. The interview, observation, and report records were used to support the findings. The analysis has been incorporated with the quantitative discussion results in the data analysis parts.
6.3 Data analysis software
The data were entered using SPSS 20.0 on Windows 10 and analyzed. The analysis supported with SPSS software much contributed to the finding. It had contributed to the data validation and correctness of the SPSS results. The software analyzed and compared the results of different variables used in the research questionnaires. Excel is also used to draw the pictures and calculate some analytical solutions.
7. The reliability and validity analysis of the quantitative data
7.1 Reliability of data
The reliability of measurements specifies the amount to which it is without bias (error free) and hence ensures consistent measurement across time and across the various items in the instrument [8]. In reliability analysis, it has been checked for the stability and consistency of the data. In the case of reliability analysis, the researcher checked the accuracy and precision of the procedure of measurement. Reliability has numerous definitions and approaches, but in several environments, the concept comes to be consistent [8]. The measurement fulfills the requirements of reliability when it produces consistent results during data analysis procedure. The reliability is determined through Cranach’s alpha as shown in Table 2.
Table 2.
Internal consistency and reliability test of questionnaires items.
K stands for knowledge; M, management; T, technology; C, collaboration; P, policy, standards, and regulation; H, hazards and accident conditions; PPE, personal protective equipment.
7.2 Reliability analysis
Cronbach’s alpha is a measure of internal consistency, i.e., how closely related a set of items are as a group [11]. It is considered to be a measure of scale reliability. The reliability of internal consistency most of the time is measured based on the Cronbach’s alpha value. Reliability coefficient of 0.70 and above is considered “acceptable” in most research situations [12]. In this study, reliability analysis for internal consistency of Likert-scale measurement after deleting 13 items was found similar; the reliability coefficients were found for 76 items were 0.964 and for the individual groupings made shown in Table 2. It was also found internally consistent using the Cronbach’s alpha test. Table 2 shows the internal consistency of the seven major instruments in which their reliability falls in the acceptable range for this research.
7.3 Validity
Face validity used as defined by Babbie [13] is an indicator that makes it seem a reasonable measure of some variables, and it is the subjective judgment that the instrument measures what it intends to measure in terms of relevance [14]. Thus, the researcher ensured, in this study, when developing the instruments that uncertainties were eliminated by using appropriate words and concepts in order to enhance clarity and general suitability [14]. Furthermore, the researcher submitted the instruments to the research supervisor and the joint supervisor who are both occupational health experts, to ensure validity of the measuring instruments and determine whether the instruments could be considered valid on face value.
In this study, the researcher was guided by reviewed literature related to compliance with the occupational health and safety conditions and data collection methods before he could develop the measuring instruments. In addition, the pretest study that was conducted prior to the main study assisted the researcher to avoid uncertainties of the contents in the data collection measuring instruments. A thorough inspection of the measuring instruments by the statistician and the researcher’s supervisor and joint experts, to ensure that all concepts pertaining to the study were included, ensured that the instruments were enriched.
8. Data quality management
Insight has been given to the data collectors on how to approach companies, and many of the questionnaires were distributed through MSc students at Addis Ababa Institute of Technology (AAiT) and manufacturing industries’ experience experts. This made the data quality reliable as it has been continually discussed with them. Pretesting for questionnaire was done on 10 workers to assure the quality of the data and for improvement of data collection tools. Supervision during data collection was done to understand how the data collectors are handling the questionnaire, and each filled questionnaires was checked for its completeness, accuracy, clarity, and consistency on a daily basis either face-to-face or by phone/email. The data expected in poor quality were rejected out of the acting during the screening time. Among planned 267 questionnaires, 189 were responded back. Finally, it was analyzed by the principal investigator.
9. Inclusion criteria
The data were collected from the company representative with the knowledge of OSH. Articles written in English and Amharic were included in this study. Database information obtained in relation to articles and those who have OSH area such as interventions method, method of accident identification, impact of occupational accidents, types of occupational injuries/disease, and impact of occupational accidents, and disease on productivity and costs of company and have used at least one form of feedback mechanism. No specific time period was chosen in order to access all available published papers. The questionnaire statements which are similar in the questionnaire have been rejected from the data analysis.
10. Ethical consideration
Ethical clearance was obtained from the School of Mechanical and Industrial Engineering, Institute of Technology, Addis Ababa University. Official letters were written from the School of Mechanical and Industrial Engineering to the respective manufacturing industries. The purpose of the study was explained to the study subjects. The study subjects were told that the information they provided was kept confidential and that their identities would not be revealed in association with the information they provided. Informed consent was secured from each participant. For bad working environment assessment findings, feedback will be given to all manufacturing industries involved in the study. There is a plan to give a copy of the result to the respective study manufacturing industries’ and ministries’ offices. The respondents’ privacy and their responses were not individually analyzed and included in the report.
11. Dissemination and utilization of the result
The result of this study will be presented to the Addis Ababa University, AAiT, School of Mechanical and Industrial Engineering. It will also be communicated to the Ethiopian manufacturing industries, Ministry of Labor and Social Affair, Ministry of Industry, and Ministry of Health from where the data was collected. The result will also be availed by publication and online presentation in Google Scholars. To this end, about five articles were published and disseminated to the whole world.
12. Conclusion
The research methodology and design indicated overall process of the flow of the research for the given study. The data sources and data collection methods were used. The overall research strategies and framework are indicated in this research process from problem formulation to problem validation including all the parameters. It has laid some foundation and how research methodology is devised and framed for researchers. This means, it helps researchers to consider it as one of the samples and models for the research data collection and process from the beginning of the problem statement to the research finding. Especially, this research flow helps new researchers to the research environment and methodology in particular.
Conflict of interest
There is no “conflict of interest.”
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Population and sample size",level:"1"},{id:"sec_8_2",title:"4.1 Population",level:"2"},{id:"sec_9_2",title:"4.2 Questionnaire sample size determination",level:"2"},{id:"sec_10_2",title:"4.3 Workplace site exposure measurement sample determination",level:"2"},{id:"sec_12",title:"5. Data collection methods",level:"1"},{id:"sec_12_2",title:"5.1 Primary data collection methods",level:"2"},{id:"sec_12_3",title:"5.1.1 Workplace site observation data collection",level:"3"},{id:"sec_13_3",title:"5.1.2 Data collection through interview",level:"3"},{id:"sec_14_3",title:"5.1.3 Data collection through questionnaires",level:"3"},{id:"sec_15_3",title:"5.1.4 Data obtained from experts’ opinion",level:"3"},{id:"sec_16_3",title:"Table 1.",level:"3"},{id:"sec_17_3",title:"5.1.6 Data collection tool pretest",level:"3"},{id:"sec_19_2",title:"5.2 Secondary data collection methods",level:"2"},{id:"sec_21",title:"6. 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New York: John Wiley & Sons Inc; 2000'},{id:"B2",body:'Saunders M, Lewis P, Thornhill A. Research Methods for Business Student. 5th ed. Edinburgh Gate: Pearson Education Limited; 2009'},{id:"B3",body:'Miller P. Motivation in the Workplace. Work and Organizational Psychology. Oxford: Blackwell Publishers; 1991'},{id:"B4",body:'Fraenkel FJ, Warren NE. How to Design and Evaluate Research in Education. 4th ed. New York: McGraw-Hill; 2002'},{id:"B5",body:'Danniel WW. Biostatist: A Foundation for Analysis in the Health Science. 7th ed. New York: John Wiley & Sons; 1999'},{id:"B6",body:'Cochran WG. Sampling Techniques. 3rd ed. New York: John Wiley & Sons; 1977'},{id:"B7",body:'Saaty TL. The Analytical Hierarchy Process. Pittsburg: PWS Publications; 1990'},{id:"B8",body:'Sekaran U, Bougie R. Research Methods for Business: A Skill Building Approach. 5th ed. New Delhi: John Wiley & Sons, Ltd; 2010. pp. 1-468'},{id:"B9",body:'Luck DJ, Rubin RS. Marketing Research. 7th ed. New Jersey: Prentice-Hall International; 1987'},{id:"B10",body:'Wong TC. Marketing Research. Oxford, UK: Butterworth-Heinemann; 1999'},{id:"B11",body:'Cronbach LJ. Coefficient alpha and the internal structure of tests. Psychometrika. 1951;16:297-334'},{id:"B12",body:'Tavakol M, Dennick R. Making sense of Cronbach’s alpha. International Journal of Medical Education. 2011;2:53-55. DOI: 10.5116/ijme.4dfb.8dfd'},{id:"B13",body:'Babbie E. The Practice of Social Research. 12th ed. Belmont, CA: Wadsworth; 2010'},{id:"B14",body:'Polit DF, Beck CT. Generating and Assessing Evidence for Nursing Practice. 8th ed. Williams and Wilkins: Lippincott; 2008'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Kassu Jilcha Sileyew",address:"jkassu@gmail.com",affiliation:'
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
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