But many HPV+OPC present with involvement of the lymph nodes in the neck, and hence a higher stage of disease, generally referred to as locally advanced disease. This group is mostly treated with multimodality therapy, except one of the more favourable subgroups with small primary tumours and lymph node involvement confined to a single node no larger than 3 cm in size, which as noted are considered early-stage disease. The three main options for locally advanced but operable disease are resection, neck dissection, and adjuvant therapy; chemoradiation (with possible  salvage surgery ); induction chemotherapy followed by radiation or chemoradiation. However, the last option has not been supported in clinical trials that tested it. [ r ]  The primary consideration of surgery for locally advanced disease is to obtain adequate negative margins and spare the patient postoperative chemoradiation. But this must be balanced against the morbidity and functional loss from extensive resection, particularly where the tongue base is involved. To avoid such morbidity, primary chemoradiation is preferred. The management of disease within the cervical lymph nodes has to be taken into account in treating locally advanced disease. Guidelines for all OPC dictate that extracapsular extension be given postoperative chemoradiation. Where gross neck disease is evident initially primary chemoradiation is usually given. [ 12 ]


Current guidelines are based on data for OPC as a whole so that patients are generally being treated regardless of HPV status, yet many clinicians and researchers are considering deintensification. [ 195 ]  Treatment of this condition will likely continue to evolve in the direction of deintensification, to minimize loss of function but maintain disease control. [ 196 ]  In the absence of specific clinical trials and guidelines, patient preferences need to be taken into consideration to minimise short- and long-term toxicity and functional loss and optimize quality of life, given the prolonged survival frequently seen. [ 12 ]  This may involve exploring patients' values regarding  trade-offs  of disease control against adverse effects of treatment. Patients who have received CRT as primary treatment for OPC place a high value on survival, and although agreeing that deintensification is desirable, were reluctant to trade off much survival advantage for lower toxicity, though would be more likely to forgo chemotherapy than accept reduced radiation. [ 197 ]


In some situations, HPV+OPC may present with cervical lymph nodes but no evident disease of a primary tumour (T0 N1–3) and is therefore classed as  Squamous Cell Carcinoma of Unknown Primary Origin . This occurs in 2–4% of patients presenting with metastatic cancer in the cervical nodes. The incidence of HPV positivity is increasing at a similar rate to that seen in OPC. In such situations, resection of the lingual and palatine tonsils together with neck dissection may be diagnostic and constitute sufficient intervention, since recurrence rates are low. [ 198 ] [ 199 ] [ 200 ] [ 201 ] [ 202 ] [ 12 ] [ excessive citations ]


The presence of HPV within the tumour has been realised to be an important factor for predicting survival since the 1990s. [ 203 ]


Tumor HPV status is strongly associated with positive therapeutic response and survival compared with HPV-negative cancer, independent of the treatment modality chosen and even after adjustment for the stage. [ 204 ]  While HPV+OPC patients have some favourable  demographic  features compared to HPV-OPC patients, such differences account for only about ten percent of the survival difference seen between the two groups. [ 11 ]  Response rates of over 80% are reported in HPV+ cancer and three-year progression-free survival has been reported as 75–82% and 45–57%, respectively, for HPV+ and HPV- cancer, and improving over increasing time. [ 12 ] [ 205 ] [ 206 ] [ 207 ]  It is likely that HPV+OPC is inherently less malignant than HPV-OPC since patients treated by surgery alone have better survival after adjustment for stage. [ 11 ]


HPV is tested for by the presence of the  biomarker   p16 , which normally increases in the presence of HPV. Some people can have elevated levels of p16 but test negative for HPV and vice versa. This is known as discordant cancer. The 5-year survival for people who test positive for HPV and p16 is 81%, for discordant cancer it is 53 – 55%, and 40% for those who test negative for p16 and HPV. [ 208 ] [ 209 ]


In  RTOG  clinical trial 0129, [ s ]  in which all patients with advanced disease received radiation and chemotherapy, a retrospective analysis ( recursive-partitioning analysis , or RPA) at three years identified three risk groups for survival (low, intermediate, and high) based on HPV status, smoking, T stage, and N stage ( see  Ang et al., Fig. 2). [ 157 ]  HPV status was the major determinant of survival, followed by smoking history and stage. 64% were HPV+ and all were in the low and intermediate-risk groups, with all non-smoking HPV+ patients in the low-risk group. 82% of the HPV+ patients were alive at three years compared to 57% of the HPV- patients, a 58% reduction in the risk of death. [ t ] [ 157 ]  Locoregional failure is also lower in HPV+, being 14% compared to 35% for HPV-. [ 160 ]


HPV positivity confers a 50–60% lower risk of disease progression and death, but the use of tobacco is an independently negative prognostic factor. [ 157 ] [ 210 ]  A pooled analysis of HPV+OPC and HPV-OPC patients with disease progression in RTOG trials 0129 and 0522 showed that although less HPV+OPC experienced disease progression (23 v. 40%), the  median  time to disease progression following treatment was similar (8 months). The majority (65%) of recurrences in both groups occurred within the first year after treatment and were locoregional. Although the rate of failure in the opposite neck following treatment of only one side, is 2.4%, the rate of an isolated recurrence in the opposite neck is 1.7%, and these were mainly where the primary tumour involved the midline. However, the rate of failure in the contralateral neck is also greater for HPV+. [ 211 ]  Of those that recur in this site, nearly all were successfully treated (salvaged) by further local treatment to the opposite neck. [ 133 ]


HPV+ did not reduce the rate of metastases (about 45% of patients experiencing progression), which are predominantly to the lungs (70%), although some studies have reported a lower rate. [ 212 ] [ 161 ]  with 3-year distant recurrence rates of about 10% for patients treated with primary radiation or chemoradiation. [ 213 ]  Even if recurrence or metastases occur, HPV positivity still confers an advantage. [ 12 ] [ 212 ] [ 214 ]
By contrast tobacco usage is an independently negative prognostic factor, with decreased response to therapy, [ 157 ] [ 210 ]  increased disease recurrence rates and decreased survival. [ 215 ]  The negative effects of smoking, increases with the amount smoked, particularly
if greater than 10  pack-years . [ 157 ] [ 210 ]


For patients such as those treated on RTOG 0129 with primary chemoradiation, detailed  nomograms  have been derived from that  dataset  combined with RTOG 0522, enabling prediction of outcome based on a large number of  variables . For instance, a 71-year-old married non-smoking high school graduate with a  performance status  (PS) of 0, and no weight loss or  anaemia  and a T3N1 HPV+OPC would expect to have a  progression-free survival  of 92% at 2 years and 88% at 5 years. A 60-year-old unmarried nonsmoking high school graduate with a PS of 1, weight loss and anaemia, and a T4N2 HPV+OPC  would expect to have a survival of 70% at two years and 48% at five years. [ 216 ]


Less detailed information is available for those treated primarily with surgery, for whom fewer patients are available, [ 121 ]  as well as low rates of recurrence (7–10%), but features that have traditionally been useful in predicting prognosis in other head and neck cancers, appear to be less useful in HPV+OPC. [ 51 ]  These patients are frequently stratified into three risk groups: [ 93 ]


HPV+OPC patients are less likely to develop other cancers, compared to other head and neck cancer patients. [ 30 ]  A possible explanation for the favourable impact of HPV+ is "the lower probability of occurrence of 11q13 gene amplification, which is considered to be a factor underlying faster and more frequent recurrence of the disease" [ 14 ]  Presence of TP53 mutations, a marker for HPV- OPC, is associated with worse prognosis. [ 8 ]  High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response. [ 64 ]


The risk of regional cancer recurrence after neck dissection is often estimated [ 164 ]  from a large series based on all upper aerodigestive squamous cell cancers. In this series, the overall risks at three years by pathological stage (AJCC 7) were: [ 217 ]


In 2015, squamous cell cancer of the head and neck region was the fifth most common cancer other than skin cancer, globally, with an annual incidence of 600,000 cases and about 60,000 cases annually in the United States and Europe. [ 218 ]  The global  incidence  of pharyngeal cancer in 2013 was estimated at 136,000 cases. [ 12 ] [ 219 ] [ 220 ]  For 2008 the  Global Burden of Disease  for OPC in 2008 is estimated at 85,000 cases, of which 22,000 were attributable to HPV, a  population attributable fraction  (PAF) of 26%. Of these, 17,000 were males and 4,400 females, 13,000 (60%) were aged between 50 and 69 years of age, and the majority of cases (15,000) were in  developed regions  compared to  developing regions  (6,400). [ 221 ] [ 2 ]   Age Standardised Incidence Rates  (ASR) differ considerably by region and country ( see  de Martel et al., 2017 Fig. 2b). [ 221 ]  ASRs for 2012 were highest in  Europe (Hungary 3.0) and North America (United States 1.7) but much lower in Africa (≤ 0.3), Asia (≤ 0.6), Latin America (≤ 0.4) and  Oceania  (≤ 0.2) (other than  Australasia , Australia 0.9). [ 222 ] [ 221 ]  Estimated average numbers of cases and ASR for the US in the period 2008–2012 were 15,738 and 4.5 respectively. HPV+OPC was much more common in males than females (12,638, 7.6 and 3,100, 1.7). The highest incidence age group was 60–69 and was higher in  Caucasians  than in other races. [ 223 ]


HPV+OPC patients tend to be younger than HPV- patients in general. [ 224 ]  The clinical presentation is also changing from the "typical" head and neck cancer patient with advanced age and major  substance usage . [ 12 ]  By contrast patients with HPV+ cancer are younger (4th–6th decades), male (ratio 8:1) with no or only a minimum history of smoking, generally Caucasian, reached higher education levels, are married, and have higher income. [ 225 ]  The risk factors for HPV-OPC and HPV+OPC tend to be independent, except for smoking which adversely affects both. [ 11 ]  The presenting features are also different between HPV+ and HPV- OPC. HPV+ tumours have smaller primary lesions (less than 4 cm) but more advanced nodal disease resulting in higher TNM staging. This, in turn, may overestimate the severity of the disease status. [ 226 ] [ 227 ]


There has been a global trend in increasing OPC incidence, particularly in North America and northern Europe, but even in Taiwan, which has a very high rate for all cancers of the head and neck region, OPC rates increased more rapidly between 1995 and 2009 than any other cancer site. [ 228 ] [ 229 ]  The Global Burden of HPV+OPC increased from 22,000 in 2008 to 29,000 by 2012, and the PAF from 26% to 31%, [ 221 ]  and is considered an  epidemic . [ 44 ]  In the United States the estimated number of cases was 12,410 in 2008, [ 230 ]  13,930 in 2013 [ 231 ]  and 17,000 for 2017. [ 232 ]  Of these cases, HPV+ cancer has been increasing compared to HPV- cancer, but the increase in HPV+OPC exceeds the decline in HPV-OPC resulting an overall increase in OPC. [ 11 ]  The rise in pharyngeal cancer incidence contrasts with a marginal decline in other head and neck cancers. [ 233 ]  As a result, the commonest head and neck cancer has shifted from  larynx  to oropharynx. [ 121 ]  A survey of 23 countries between 1983 and 2002 showed an increase in oropharyngeal squamous cell carcinoma that was particularly noticeable in young men in economically  developed  countries. [ 220 ] [ 12 ]  In the United Kingdom the incidence of oral and oropharyngeal cancer in men rose 51%, from 7/100,000 to 11/100,000 between 1989 and 2006. [ 233 ]  In the US there is a growing incidence of HPV associated oropharyngeal cancers, [ 234 ]  In the early 1980s HPV+ accounted for only 7.5% of cases in the US but by 2016 this was 70%, [ 12 ] [ 235 ] [ 236 ] [ 237 ]  perhaps as a result of changing sexual behaviors, decreased popularity of tonsillectomies, improved radiologic and pathologic evaluation, and changes in classification. [ 238 ] [ 239 ] [ 240 ]  Tonsil and oropharyngeal cancers increased in male predominance between 1975 and 2004, despite reductions in smoking. [ 241 ]  HPV-OPC decreased with decreasing smoking rates from 1988 to 2004, while HPV+OPC increased by almost 7.5% per year from about 16% of all cases of OPC in the early 1980s to almost 70% in 2004. [ 225 ] [ 242 ]  The decline in smoking may be linked to the decreasing proportion of HPV negative cancers, while changes in sexual activity may be reflected in increasing proportion of HPV positive cancers. [ 225 ]  Recently, in the US, HPV associated OPC represent about 60% of OPC cases [ 160 ] [ 243 ]  compared with 40% in the previous decade. [ 233 ]  By 2007, in the US,  incidence of general OPC, including non-HPV associated, is 3.2 cases per 100,000 males/year and 1.9 per 100,000 all-sexes/year. [ 244 ]  This makes HPV+OPC one of only five cancers that have increased in incidence in the US since 1975. [ 245 ]  The largest increase in incidence has occurred in patients under age 50. [ 246 ]


The increase in incidence of HPV-associated OPC is also seen in other countries, like  Sweden , with a 2007 incidence of over 80% for cancer in the tonsils, [ 247 ] [ 248 ]   Finland [ 249 ]  and the  Czech Republic . [ 250 ]  Partners of patients with HPV-positive oropharyngeal cancer do not seem to have elevated oral HPV infection compared with the general population. [ 251 ]  In Australia the incidence of HPV-associated OPC was 1.56 cases per 100,000 males/year (2001–2005), rising from 19% (1987–90) to 47% (2001–05) and 63.5% (2006–2010). [ 252 ] [ 253 ]  In Canada the percentage of cases of OPC attributable to HPV increased from 47% in 2000 to 74% in 2012. [ 254 ]


Human T-cell lymphotropic virus type 1  or  human T-lymphotropic virus  ( HTLV-I ), also called the  adult T-cell lymphoma virus type 1 , is a  retrovirus  of the  human T-lymphotropic virus  (HTLV) family.


Most people with HTLV-1 infection do not appear to develop health conditions that can be directly linked to the infection. However, there is a subgroup of people who experience severe complications. The most well characterized are  adult T-cell lymphoma  (ATL) and  HTLV-I-associated myelopathy / Tropical spastic paraparesis  (HAM/TSP), both of which are only diagnosed in individuals testing positive to HTLV-1 infection. The estimated lifetime risk of ATL among people with HTLV-1 infection is approximately 5%, while that of HAM/TSP is approximately 2%. [ 1 ] [ 2 ] [ 3 ]


In 1977, Adult T-cell lymphoma (ATL) was first described in a case series of individuals from Japan. [ 4 ]  The symptoms of ATL were different from other lymphomas known at the time. The common birthplace shared amongst most of the ATL patients was suggestive of an infectious cause, referred to as ATLV. [ 5 ]  Strikingly, ATLV had the transforming activity in vitro. [ 6 ]  These studies established that HTLV-1 was the causitive agent of ATL. The retrovirus is now generally called HTLV-I because later studies proved that ATLV is the same as the firstly identified human retrovirus called HTLV discovered by Bernard Poiesz and Francis Ruscetti and their co-workers in the laboratory of  Robert C. Gallo  at the  National Cancer Institute . [ 7 ]  Persistent lifelong infection is established when HTLV-1 integrates into the host genome as a provirus.  A patient infected with HTLV-1 can be diagnosed when antibodies against HTLV-1 are detected in the  serum . [ 8 ]


HTLV-1 is a  retrovirus  belonging to the family  retroviridae  and the genus  deltaretrovirus . It has a  positive-sense RNA  genome that is  reverse transcribed  into DNA and then integrated into the cellular DNA. Once integrated, HTLV-1 continues to exist only as a  provirus  which can spread from cell to cell through a  viral synapse . Few, if any, free  virions  are produced and there is usually no detectable virus in the blood plasma though the virus is present in genital secretions. Like  HIV , HTLV-1 predominantly infects  CD4+ T cells . [ 8 ]


The viral RNA is packed into the icosahedral  capsid  which is contained inside the protein inner envelope. The lipid outer envelope is of host cell origin but contains viral transmembrane and surface proteins. The virion is spherical in shape with a diameter of about 100 nm. [ 8 ]


HTLV-1 is genetically classified into seven subtypes, each defined by a unique geographic distribution influenced by population migration. The most globally widespread is the cosmopolitan subtype A, which further branches into several subgroups: transcontinental, Japanese, West African, North African, Senegalese, and Afro-Peruvian. [ 9 ]  While subtypes B, D, E, F, and G are localized to distinct regions in Africa, subtype C is predominant in Australia and Oceania. [ 10 ]


HTLV-1 is believed to have originated from the simian T-lymphotropic virus type 1 (STLV-1), a retrovirus prevalent among numerous nonhuman primates in intertropical Africa. This theory is supported by the significant genetic diversity of HTLV-1 subtypes in Africa, potentially arising from repeated zoonotic transmissions during human interactions with STLV-1 endemic nonhuman primates. This correlation is further reinforced by the observation that individuals bitten by nonhuman primates exhibit HTLV-1 strains with sequences remarkably homologous to the STLV-1 found in local primate species. [ 11 ]


The global distribution of HTLV-I is highly heterogeneous, with focal occurrence in diverse regions. Within areas where HTLV-I is found, its occurrence varies considerably, with endemic clusters often situated near populations with lower prevalence. This pattern might be influenced by the founder effect, suggesting prolonged viral transmission within isolated groups, but this theory warrants further investigation. Consistent findings reveal that HTLV-1 prevalence increases with age and is usually higher in adult females than males. Areas broadly regarded as having endemic regions include Japan, Iran, the Americas, the Caribbean, Melanesia, Central and West Africa, and Australia. Globally, there remains a lack of robust data from populous countries like India and Nigeria and most of North and East Africa. As such, current global prevalence estimates, which are based on known endemic regions, likely underestimate the true global prevalence. [ 1 ]


In Australia, HTLV-I has notably high prevalence among Aboriginal communities in Central Australia. Community-based cross-sectional studies from Central Australia report HTLV-1 prevalences exceeding 30%, representing the highest reported prevalence for any population worldwide. [ 12 ]  In Taiwan, in Iran, and in  Fujian  (a Chinese province near Taiwan) the prevalence is 0.1–1%. The infection rate is about 1% in  Papua New Guinea , the  Solomon Islands , and  Vanuatu , where the genotype C predominates. In Europe HTLV-1 is uncommon, although it is present in some populations, generally people who have migrated from known endemic regions. In the Americas HTLV-1 is found in some Indigenous populations and descendants of African ancestry from where it is thought to have originated. Prevalence ranges from 0.1 to 1%. In Africa the prevalence is not well known, but it is about 1% in some countries. [ 8 ]


HTLV-I infection in the United States appears to be about half as prevalent among  IV drug users  and about one-tenth as prevalent in the population at large as HIV infection. [ citation needed ]  Although little serologic data exist, the prevalence of infection is thought to be highest among blacks living in the Southeast. [ citation needed ]  A prevalence rate of 30% has been found among black intravenous drug users in  New Jersey , and a rate of 49% has been found in a similar group in  New Orleans . [ 13 ] [ 14 ] [ citation needed ]


It is also high among the  Inuit  of Northern Canada, in Japan, northeastern Iran, [ 15 ]  Peru, the Pacific coast of Colombia and Ecuador, and the Caribbean. [ citation needed ]


HTLV-1 has three main routes of transmission. Vertical transmission is most common, through which an infected mother transmits the virus to her child. [ citation needed ]  The risk to a fetus while inside the womb is minimal, given the virtual absence of viral particles in human plasma. Most vertical infection occurs through breastfeeding. About 25% of infants who are breastfed by infected mothers are infected, while less than 5% of children born to but not breastfed by infected mothers are infected. Sexual transmission is second-most common, whereby an individual infects another through exchange of bodily fluids. Some evidence has suggested that male-to-female transmission is more efficient than female-to-male transmission. For example, one study in Japan found a 61% transmission rate for males to females vs. a less than 1% rate for females to males. Least common is parenteral transmission through blood transfusion, with an infection rate of 44-63% estimated in one study, and needle sharing among intravenous drug users. With proper prophylaxis (e.g. breastfeeding counseling for mothers, condom use, and donor blood screening), rates of transmission can be effectively reduced. [ 8 ]  The importance of the various routes of transmission is believed to vary geographically. The research in discordant couples showed that probability of sexual transmission is about 0.9 per 100 person-years. [ 8 ]


The term viral tropism refers to which cell types HTLV-I infects. Although HTLV-1 is primarily found in CD4+ T cells, other cell types in the peripheral blood of infected individuals have been found to contain HTLV-1, including CD8+ T cells, dendritic cells and B cells. HTLV-I entry is mediated through interaction of the surface unit of the virion envelope glycoprotein (SU) with its cellular receptor  GLUT1 , a glucose transporter, on target cells. [ 18 ]


HTLV-1 is also associated with  adult T-cell leukemia/lymphoma  and has been quite well studied in Japan. The time between infection and onset of cancer also varies geographically. It is believed to be about sixty years in Japan and less than forty years in the Caribbean. The cancer is thought to be due to the pro-oncogenic effect of viral RNA incorporated into host lymphocyte DNA. Chronic stimulation of the lymphocytes at the cytokine level may play a role in the development of the malignancy. The lymphoma ranges from a very  indolent  and slowly progressive type to a very aggressive and nearly uniformly lethal proliferative type. [ citation needed ]


There is some evidence that HTLV-1 is a causative agent of  cutaneous T-cell lymphoma . [ 8 ]


HTLV-1 is also associated with a progressive demyelinating upper motor neuron disease known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), characterized by sensory and motor deficits, particularly of the lower extremities, incontinence and impotence. [ 19 ]  Only 0.3 to 4% of infected individuals develop HAM/TSP, but this will vary from one geographic location to another. [ 8 ]


Signs and symptoms of HTLV myelopathy include:


Other neurologic findings that may be found in  HTLV  include:


HTLV-1 is associated with a rheumatoid-like  arthropathy , although the evidence is contradictory. In these cases patients have a negative  rheumatoid factor . [ 8 ]


Studies from Japan demonstrated that HTLV-1 infection may be associated with an  intermediate uveitis . At onset the patients present with blurred vision and floaters. The prognosis is favorable—the condition usually resolves within weeks. [ 8 ]


Individuals infected with HTLV-1 are at risk for  opportunistic infections —diseases not caused by the virus itself, but by alterations in the host's immune functions. [ 8 ]


HTLV-1, unlike the distantly related retrovirus HIV, has an immunostimulating effect which actually becomes immunosuppressive. The virus activates a subset of  T-helper cells  called  Th1  cells. The result is a proliferation of Th1 cells and overproduction of Th1 related cytokines (mainly  IFN-γ  and  TNF-α ). Feedback mechanisms of these cytokines cause a suppression of the Th2 lymphocytes and a reduction of Th2 cytokine production (mainly  IL-4 ,  IL-5 ,  IL-10  and  IL-13 ). The result is a reduction in the ability of the infected host to mount an adequate immune response to invading organisms that require a predominantly Th2 dependent response (these include parasitic infections and production of mucosal and humoral antibodies). [ citation needed ]


In the central Australian Aboriginal population, HTLV-1 is thought to be related to their extremely high rate of death from  sepsis . It is also particularly associated with  bronchiectasis , a chronic lung condition predisposing to recurrent  pneumonia . It is also associated with chronic infected  dermatitis , often superinfected with  Staphylococcus aureus  and a severe form of  Strongyloides stercoralis  infection called  hyper-infestation  which may lead to death from polymicrobial sepsis. HTLV-1 infection has also been associated with  Tuberculosis . [ 8 ]


Treatment of opportunistic infections varies depending on the type of disease and ranges from careful observation to aggressive chemotherapy and antiretroviral agents. [ citation needed ]  Adult T cell lymphoma is a common complication of HTLV infection and requires aggressive chemotherapy, typically  R-CHOP . Other treatments for ATL in HTLV infected patients include interferon alpha,  zidovudine  with  interferon alpha  and CHOP with  arsenic trioxide . Treatments for HTLV myelopathy are even more limited and focus mainly on symptomatic therapy. Therapies studied include  corticosteroids ,  plasmapheresis ,  cyclophosphamide , and  interferon , which may produce a temporary symptomatic improvement in myelopathy symptoms. [ 20 ]


Valproic acid  has been studied to determine if it might slow the progression of HTLV disease by reducing viral load. Although in one human study it was effective in reducing viral load, there did not appear to be a clinical benefit. Recently however, a study of valproic acid combined with  zidovudine  showed a major decrease in the viral load of baboons infected with HTLV-1. It is important to monitor HTLV patients for opportunistic infections such as  cytomegalovirus ,  histoplasmosis ,  scabies ,  pneumocystis pneumonia , and  staphylococcal infections .  HIV testing  should also be performed, as some patients may be co-infected with both viruses. [ citation needed ]


Allogenic  bone marrow transplantation  has been investigated in the treatment of HTLV-1 disease with varied results. One case report describes an HTLV-1 infected woman who developed chronic refractory eczema, corneal injury and adult T cell leukemia. She was subsequently treated with allogenic  stem cell transplantation  and had complete resolution of symptoms. One year post-transplant, she has had no recurrence of any symptoms, and furthermore has had a decrease in her proviral load. [ citation needed ]


A  virus  closely related to  HTLV-I ,  human T-lymphotropic virus 2  ( HTLV-II ) shares approximately 70% genomic  homology  (structural similarity) with  HTLV-I.  It was discovered by  Robert Gallo  and colleagues. [ 1 ] [ 2 ]


HTLV-2 is prevalent in  Africa  and among  Indigenous peoples  in  Central and South America , as well as among  drug users  in  Europe  and  North America . [ 3 ]  It can be passed down from  mother to child  through  breast milk , and even genetically from either parent. [ citation needed ]


HTLV-II entry in target cells is mediated by the  glucose transporter   GLUT1 . [ 4 ]


HTLV-1  and HTLV-2 share broad similarities in their overall genetic organization and expression pattern, but they differ substantially in their  pathogenic  properties. [ 3 ]   The virus utilizes the  GLUT-1  and  NRP1  cellular receptors for their entry, although  HTLV-1 , but not HTLV-2, is dependent on  heparan sulfate proteoglycans .  Cell-to-cell transmission  is essential for virus  replication  and occurs through the formation of a  virological synapse . [ 3 ]  The family of Human T-lymphotropic virus (Figure 2) can be further categorized into four sub types. The figure also divides the retroviruses into exogenous and endogenous.  Retroviruses  can exist as two different forms: endogenous which consist of normal genetic components and exogenous which are horizontally transferred genetic components that are usually infectious agents that cause disease i.e.  HIV . In (Figure 3) open reading frames (ORF) are shown which can if translated can predict which genes will be present and this can help to better understand human  retroviruses . Of the four subtypes, HTLV-2 may be linked to  Cutaneous T-cell lymphoma  (CTCL). [ 5 ]  In one study involving cultured lymphocytes from patients with  mycosis fungoides  (Figure 1),  PCR  amplification showed gene sequences of HTLV-II. This finding may suggest a possible correlation with HTLV-2 and CTCL. Further research and studies must be conducted to show a positive relationship. [ 1 ]


Perinatal transmission  and breastfeeding and through  blood transfusion , sexual contact, and use of  intravenous drugs. [ 3 ]


HTLV-1  and HTLV-2 are both involved in actively spreading  epidemics , affecting 15-20 million people worldwide.  [4]  In the  United States , the overall prevalence is 22 per 100,000 population, with HTLV-2 more common than  HTLV-1 . Data collection performed from 2000 to 2009 among US  blood donors  has shown a general decline since the 1990s. [ 6 ]


Human T- leukemia, type 2 (HTLV-2) generally causes no signs or  symptoms . Although HTLV-2 has not been definitively linked with any specific  health problems , scientists suspect that some affected people may later develop  neurological problems  such as: [ 7 ] [ 6 ]


Although evidence is limited, there may also be a link between HTLV-2 and chronic lung infections (i.e.  pneumonia  and  bronchitis ),  asthma  and  dermatitis . [ 8 ]


HTLV-II has not been clearly linked to any disease, but has been associated with several cases of  myelopathy /tropical spastic paraparesis ( HAM/TSP )- like  neurological disease  and may cause  chronic lung problems. [ citation needed ]


An impact on  platelet count  has been observed. [ 9 ]


In the 1980s, HTLV-2 was identified in a patient with an unidentified T cell  lymphoproliferative disease  that was described as having characteristics similar to the  B cell disorder ,  hairy cell leukemia . [ 10 ]   HTLV-2 was identified in a second patient with a T cell lymphoproliferative disease; this patient later developed  hairy cell leukemia , but HTLV-2 was not found in the  hairy cell  clones. [ 11 ]   The cause of  hairy cell leukemia  is not known, but it is no longer believed to be related to  viral infections . [ citation needed ]


There are few  treatments [ 12 ]  including  chemotherapy  and  antiretrovirals  that can slow the  viral load  but no cure or definitive treatment exists for HTLV-2. [ 8 ]


Human T- leukemia, type 2 (HTLV-2) is usually diagnosed based on blood tests that detect to the virus. However, HTLV-2 is often never suspected or  diagnosed  since most people  never develop any signs or symptoms of the infection .  Diagnosis  may occur during  for  blood donation , testing performed due to an  infection , or a  work-up  for an HTLV-2-associated medical problems. [ 8 ]


Due to there being no  cure  for HTLV II the  prevention  is focused on early detection and preventing the spread of HTLV-2 to others.  blood donors, promoting safe sex and discouraging needle sharing can decrease the number of new infections.  Mother-to-child transmission  can be reduced by screening  pregnant  women so infected mothers can avoid  breastfeeding . [ 8 ]


The long-term  outlook  for most people infected with HTLV-2 is good. Infection with HTLV-2 is  lifelong , but 95% of affected people have  no signs or symptoms of the condition . Although, HTLV-2-related health problems tend to be significantly milder than those associated with  HTLV1 . [ 8 ]


The  International Union against Sexually Transmitted Infections  ( IUSTI ) is a  non-governmental organisation  established in 1923, [ 1 ]  and has charitable status in the UK. [ 2 ]  It produces guidelines for Europe on the management of  sexually transmitted infections  and is organisation in consultative status with the  WHO . [ 1 ]  It also provides training and management in the field of STIs, publishes an STI textbook, [ 1 ]  and publishes the journal  Sexual Health . It also runs conferences, such as IUSTI Europe Congress (as of 2024, 36 annual conferences) and the IUSTI World Congress (as of 2024, 24) [ 3 ]  and many other regional meetings. [ 4 ]


This non-governmental organization-related article is a  stub . You can help Wikipedia by  expanding it .


This article about a charitable organisation in the United Kingdom is a  stub . You can help Wikipedia by  expanding it .


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The  Journal of the European Academy of Dermatology and Venereology  is the official journal of the European Academy of Dermatology and Venereology. The journal is  peer-reviewed  monthly that publishes articles of general and practical interest in the field of  dermatology  and  venereology  on clinical and basic science topics, as well as research with practical implications. According to the  Journal Citation Reports , the journal has a 2022  impact factor  of 9.2. [ 1 ]


Kaposi's sarcoma-associated herpesvirus  ( KSHV ) is the ninth known human  herpesvirus ; its formal name according to the  International Committee on Taxonomy of Viruses  (ICTV) is  Human gammaherpesvirus 8 , or  HHV-8  in short. [ 1 ]  Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes  Kaposi's sarcoma , a cancer commonly occurring in  AIDS  patients, [ 2 ]  as well as  primary effusion lymphoma , [ 3 ]   HHV-8-associated multicentric Castleman's disease  and  KSHV inflammatory cytokine syndrome . [ 4 ]  It is one of seven currently known human cancer viruses, or  oncoviruses . [ 2 ]  Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.


In 1872,  Moritz Kaposi  described a blood vessel tumor [ 5 ]  (originally called "idiopathic multiple pigmented sarcoma of the skin") that has since been eponymously named  Kaposi's sarcoma  (KS). KS was at first thought to be an uncommon tumor of Jewish and Mediterranean populations until it was later determined to be extremely common throughout sub-Saharan African populations. This led to the first suggestions in the 1950s that this tumor might be caused by a virus. With the onset of the  AIDS  epidemic in the early 1980s, there was a sudden resurgence of KS affecting AIDS patients, with up to 50% of reported AIDS patients having this tumor—an extraordinary rate of cancer predisposition. [ 6 ]


Careful analysis of epidemiologic data by Valerie Beral, Thomas Peterman and  Harold Jaffe , [ 7 ]  led these investigators to propose that KS is caused by an unknown sexually transmitted virus that rarely causes tumors unless the host becomes  immunosuppressed , as in AIDS. [ citation needed ]


As early as 1984, scientists reported seeing herpesvirus-like structures in KS tumors examined under  electron microscopy . Scientists had been searching for the agent causing KS, and over 20 agents were proposed as the possible cause, including  cytomegalovirus  and  HIV  itself. The pathogen was ultimately identified in 1994 by  Yuan Chang  and  Patrick S. Moore , a wife and husband team at  Columbia University , through the isolation of DNA fragments from a  herpesvirus  found in a KS tumor in an AIDS patient. [ 8 ] [ 9 ] [ 10 ]  Chang and Moore used  representational difference analysis , or RDA, to find KSHV by comparing KS tumor tissue from an AIDS patient to his own unaffected tissue. The idea behind this experiment was that if a virus causes KS, the genomic DNA in the two samples should be precisely identical except for DNA belonging to the virus. In their initial RDA experiment, they isolated two small DNA fragments that represented less than 1% of the actual viral genome. These fragments were similar (but still distinct from) the known herpevirus sequences, indicating the presence of a new virus. Starting from these fragments, this research team was then able to sequence the entire genome of the virus less than two years later. [ citation needed ]


The discovery of this  herpesvirus  sparked considerable controversy and scientific in-fighting until sufficient data had been collected to show that indeed KSHV was the causative agent of Kaposi's sarcoma. [ 11 ]   The virus is now known to be a widespread infection of people living in sub-Saharan Africa; intermediate levels of infection occur in Mediterranean populations (including Lebanon, Saudi Arabia, Italy, and Greece) and low levels of infection occur in most Northern European and North American populations.  Gay and bisexual men are more susceptible to infection (through still unknown routes of sexual transmission) whereas the virus is transmitted through non-sexual routes in developing countries. [ citation needed ]


KSHV is a  herpesvirus , and is a large double-stranded DNA virus with a protein covering that packages its nucleic acids, called the  capsid , which is then surrounded by an amorphous protein layer called the  tegument , and finally enclosed in a lipid envelope derived in part from the cell membrane. KSHV has a  genome  which is approximately 165,000 nucleic acid bases in length. The viral genome consists of a ~145  kilobase -long unique region, encoding all of expressed viral genes, which is flanked by ~20-30 kilobases of terminal repeat sequences. [ 12 ]
Each terminal repeat unit is 801 bp in length, has 85% G+C content and is oriented in a repetitive head-to-tail fashion. KSHV is a  rhadinovirus , a Herpes genus remarkable since it has stolen numerous genes from host cells including, in the case of KSHV, genes that encode for  complement -binding protein,  IL-6 ,  BCL-2 ,  cyclin -D, a  G protein-coupled receptor ,  interferon regulatory factor  and Flice inhibitory protein ( FLIP ), as well as DNA synthesis proteins including  dihydrofolate reductase ,  thymidine kinase ,  thymidylate synthetase , DNA  polymerase  and many others. While no other human tumor virus possesses these same genes, other tumor viruses target the same cellular pathways illustrating that at a basic level, all tumor viruses appear to attack the same cellular control pathways, so-called tumor suppressor pathways. [ citation needed ]


Crucial for the entry of KSHV into cells
 [ 13 ]
are the  EPH receptor A2 , [ 14 ]
Hrs, [ 15 ]
 TSG101 , [ 16 ]
and a few  integrins  (whose identity has yet to be confirmed). [ 17 ]
After infection, the virus enters into lymphocytes via  macropinosomes . [ citation needed ]
Once the virus newly infects a cell, the lipid membrane is shed and the virion travels to the nucleus. The viral genome is released where it circularizes into an  episome  through a poorly understood process that appears to involve  homologous recombination  of the terminal repeats. [ citation needed ]  The viral episome is chromatinized upon entry into the host cell nucleus. [ 18 ]


After entry, the virus typically remains in a latent ("quiet") state. Only a subset of genes that are encoded in the KSHV latency associated region (KLAR) are expressed during latency, including latency-associated nuclear antigen (LANA), vFLIP, vCyclin and 12 microRNAs.  Latency is the hallmark of all KSHV-associated etiologies known to date including all KSHV-associated oncogenesis. It has been shown that both protein coding genes such as LANA and noncoding genes (microRNAs) encoded in KLAR are important for KSHV associated tumorigenesis. To study the functions of microRNAs, a detailed protocol of bacmid mutagenesis and a complete set of cell-lines carrying microRNA deletion mutants have been established and are available as a resource to researchers. [ 19 ]
Additionally, it has been shown that vFLIP and vCyclin interfere with the TGF-β signaling pathway indirectly by inducing the oncogenic host mir17-92 cluster. [ 20 ]  These observations represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS. [ citation needed ]


During latency, LANA is the only viral protein that is required for viral replication, which is carried out by the host replication machinery. LANA tethers the viral DNA to cellular chromosomes, inhibits  p53  and  retinoblastoma protein  and suppresses viral genes needed for full virus production and assembly ("lytic replication"). Why only a subset of virus genes expressed during latency is not fully understood. But it has been shown that the latency associated gene expression can be explained in part by a characteristic  epigenetic  state that KSHV episome acquires during latency. LANA plays an important role during latency, regulating both host and virus transcripts and binding to multiple active promoters; it also associates with the host protein hSET1 that creates  H3K4me3  marks in chromatin. [ 21 ]


Various signals such as inflammation may provoke the virus to enter into lytic replication. The primary viral protein responsible for the switch between latent and lytic replication is known as the ORF50 Replication Transactivation Activator (RTA).  When cell signaling conditions activate the generation of RTA, it in turn activates synthesis of a stereotypic cascade of secondary and tertiary viral proteins that ultimately make components of the virus capsid and also the DNA synthesis enzymes required to replicate the virus genome. [ 22 ]
During lytic replication, it is believed that the virus genome is replicated as a continuous linear molecule off of an episome (so-called  rolling circle model ). As each unit genome is replicated, it is cut within the terminal repeat region, and then packaged into a virus particle (virion). The virus then becomes enveloped with a lipid membrane as it transits the nucleus and the cytoplasm to exit the cell. Thus, whereas KSHV genome is circular in the nucleus of latently infected cells, it is packaged into infectious viruses as a linear molecule. When the virus enters into lytic replication, thousands of virus particles can be made from a single cell, which usually results in death of the infected cell. [ citation needed ]


It was discovered in 2020 that infection with the  SARS-CoV-2  virus, the virus which causes  COVID-19 , may induce the lytic reactivation of KSHV in the human body, causing the herpes virus to cease latency and begin the formation of cancerous cells.  Further, it was discovered that some medications used to treat the infection with SARS-CoV-2, namely  Nafamostat  and  Azithromycin , ended up promoting the production of mature virions, "... potentially inducing KSHV lytic reactivation." [ 23 ]


The mechanisms by which the virus is contracted are not well understood. Healthy individuals can be infected with the virus and show no signs or symptoms, due to the immune system's ability to keep the infection in check. Infection is of particular concern to the  immunocompromised . Cancer patients receiving chemotherapy, AIDS patients, and organ transplant patients are all at a high risk of showing signs of infection. [ citation needed ] .


Recent advances in sequencing technologies have uncovered that virus is chromatinized during latency. It has also been shown that virus encoded microRNA  manipulates and interacts not only with host mRNA but also deregulate host long non-coding RNA (lncRNA). [ 24 ]  More recently, circularRNAs (circRNAs) are recently discovered in both EBV and KSHV  [ 25 ] [ 26 ] [ 27 ]


Infection with this virus is thought to be lifelong, but a healthy immune system will keep the virus in check. Many people infected with KSHV will never show any symptoms. Kaposi's sarcoma occurs when someone who has been infected with KSHV becomes immunocompromised due to AIDS, medical treatment, or, very rarely, aging.


KSHV is a known causative agent of four diseases: [ 4 ] [ 28 ]


In the 1970s, the global prevalence rate for HHV-8 was 2 to 10%. [ 29 ]  The seroprevalence of HHV-8 varies significantly geographically and infection rates in northern European, southeast Asian, and Caribbean countries are between 2-4%, [ 30 ]  in Mediterranean countries at approximately 10%, and in sub-Saharan African countries at approximately 40%. [ 31 ]  In South America, infection rates are low in general but are high among  Amerindians . [ 32 ]  Even within individual countries, significant variation can be observed across different regions, with infection rates of about 19.2% in  Xinjiang  compared to about 9.5% in  Hubei , China. [ 33 ]  Although seroprevalence has been consistently shown to increase with age in a linear manner, [ 33 ] [ 34 ] [ 35 ] [ 36 ]  countries with high infection rates may see higher seroprevalence in younger age groups. [ 37 ]  Educational level has shown an inverse correlation with infection rates. [ 34 ] [ 35 ]  Individuals infected with HIV-1 or genital warts are generally more likely to be co-infected with HHV-8. [ 31 ] [ 33 ] [ 38 ]


In countries with low seroprevalence, HHV-8 is primarily limited to AIDS and KS patients. [ 39 ]  In countries with high seroprevalence, infection is frequent in childhood, [ 40 ]  indicating a likely  mother-to-child transmission  by saliva. [ 41 ] [ 42 ]  In a  Zambian  survey, all children with KS had mothers who were positive for HHV-8, whereas not all children whose mothers had KS were HHV-8 positive. [ 43 ]  In another Zambian survey, 13.8% of children were seropositive for HHV-8 by age 4. [ 44 ]  Seroprevalence has not been shown to vary significantly because of gender or marital status. [ 36 ]


The  most recent common ancestor  of this virus in the Mediterranean, Iran, and Xinjiang, China, has been estimated to have evolved 29,872 years (95% highest probability density 26,851–32,760 years) ago. [ 45 ]  the most recent common ancestor for viruses isolated in Xinjiang was 2037 years (95% highest probability density 1843–2229 years) ago. Given the historical links between the Mediterranean and Xinjiang during the  Roman  period it seems likely that this virus was introduced to Xinjiang along the  Silk Road . The mutation rate was estimated to be   3.44 × 10 −6  substitutions per site per year (95% highest probability density  2.2 × 10 −6  to  4.71 × 10 −6 ). However, the global distribution of different genotypes of KSHV and the potential transmission path need further studies. [ citation needed ]


Typing of isolates is based on the variable K1 membrane protein. Six types are recognised (A–F). [ 46 ]


Since persons infected with KSHV will asymptomatically give the virus, caution should be used by  sex partners  in having  unprotected sex  and activities where saliva might be shared during sexual activity. Prudent advice is to use  condoms  when needed and avoid  deep kissing  with partners who may have  KSHV infections.


Kaposi's sarcoma is usually a localized tumor that can be treated either surgically or through local irradiation. Chemotherapy with drugs such as liposomal  anthracyclines  or  paclitaxel  may be used, particularly for invasive disease. Antiviral drugs, such as  ganciclovir , that target the replication of herpesviruses such as KSHV have been used to successfully prevent development of Kaposi's sarcoma, [ 47 ]  although once the tumor develops these drugs are of little or no use. For patients with AIDS-KS, the most effective therapy is  highly active antiretroviral therapy  to reduce HIV infection. [ 48 ]  AIDS patients receiving adequate anti-HIV treatment may have up to a 90% reduction in Kaposi's sarcoma occurrence.


Although KSHV affects the host immune system, there is ample chance for clinical intervention to recover this change. One challenge is overexpression inhibitory of target cell repress immune. Under longtime inflammation stimulation, the target cell becomes unable to respond, which leads to an exhausted phenotype. The activation immunotherapies can revive and enhance immune cell function. Comparing to other immunotherapies, therapies targeting the anti-programmed cell death protein 1 ( PD-1 )/programmed death-ligand 1 ( PD-L1 ) has been a great success. Because of KSHV infection, the monocytes increase the expression of PD-1, which is an inhibitory molecule, and cause immune escape in many tumor types. There is high PD-1 expression in NK cells from KS-HIV patients and cause exhausted phenotype. The anti-PD-1 antibody, ( nivolumab  or  pembrolizumab ), demonstrated a significant antitumor effect. Nivolumab is currently an ongoing phase I clinical trial, and Pembrolizumab has shown its function in treatment for HIV and KS patients in phase I and is in a phase II trial for treatment. A thalidomide analog medicine –  Pomalidomide  was also granted by the FDA in 2011. Pomalidomide was shown to recover the expression of  MHC-1 , which help cell display intracellular proteins to cytotoxic T cells, and it also can repress the expression of PD-L1 and increase the CD8+ T cell killing. [ 49 ]


KSHV encodes for ~90 genes and multiple non-coding RNAs, such as microRNAs. [ 50 ]  The "ORF" genes are named based on genome position of the homologous genes in the first rhadinovirus described, herpesvirus saimiri. The "K" genes are unique to KSHV, Some KSHV genes have well-characterized functions, while others remain uncharacterized. [ citation needed ]


ORF2 –  dihydrofolate reductase


ORF8 – gB – envelope  glycoprotein  involved in viral entry


ORF9 – Pol8 –  DNA polymerase  required for viral DNA replication


ORF10 – regulates RNA export and responses to type I IFNs


ORF16 – v Bcl2


ORF18, ORF24, ORF30, ORF31, ORF34, ORF66 – viral transcription factors required for the expression of late genes


ORF21 – vTK –  thymidine kinase


ORF22 – gH – envelope  glycoprotein  involved in viral entry


ORF23 – uncharacterized


ORF25, ORF26 and ORF65 –  capsid  proteins


ORF33 – involved in viral particle formation


ORF34 – unclear function


ORF35 – unclear function, mutant does not express early viral genes


ORF36 – vPK – viral protein kinase with multiple roles in replication cycle


ORF37 – SOX – dual function protein –  DNase  activity required for genome packaging and  RNase  activity regulates host gene expression


ORF38 – involved in viral particle formation


ORF39 – gM – envelope  glycoprotein


ORF40 and ORF41 –  helicase  and  primase  – DNA replication


ORF42 – uncharacterized


ORF45 –  tegument  protein, binds and prevents dephosphorylation of p90 ribosomal S6 kinases (RSKs) and ERK for modulate the ERK/RSK  MAPK  signaling pathway


ORF47 – gL – envelope glycoprotein involved in viral entry


ORF49 – may be required for viral gene expression


ORF50 – RTA, replication and transcription activator – the major transcription factor driving lytic KSHV reactivation


ORF52 – KicGAS –  tegument  protein required for formation of virions and inhibition of  cGAS  DNA sensing


ORF53 – gN – envelope glycoprotein


ORF55 – uncharacterized


ORF57 – MTA – regulates RNA stability, export and translation of viral genes


ORF59 – PF–8 – polymerase processivity factor, accessory subunit of viral DNA polymerase


ORF67 and ORF69 – nuclear egress


ORF70 –  thymidylate synthase


ORF72 – v Cyclin


ORF73 –  LANA , latency-associated nuclear antigen– tethers genome to chromosome during latency, also regulates host gene expression. A cytoplasmic form of LANA may inhibit activation of immune responses.


ORF74 – vGPCR


ORF75 – FGARAT


PAN,  polyadenylated  nuclear  RNA  – non–coding linear and circular RNAs


miRNAs  (mirKs) – viral microRNAs expressed during latency to regulate proliferation and cell death


K1 – involved in oncogenesis


K2 –  Interleukin 6  homolog,  Q2HRC7


K3 and K5 –  ubiquitin   E3 ligases  – regulates antigen presentation


K4 – vCCL2 –  chemokine


K4.1 – vCCL3 –  chemokine


K8 – transcriptional repressor – modulates chromatin


K8.1 – envelope  glycoprotein


K9 – v IRF 1, viral  interferon regulatory factor  1


K10 – v IRF 4.  A circular RNA ( circRNA ) is also generated from this  locus .


K10.5 – v IRF 3 (initially designated LANA2), is expressed during latency in PEL cell lines, but is also a bona fide lytic factor, like all of the vIRFs. [ 51 ]


K11 – v IRF 2


K12 – kaposin


K13 – v FLIP


Leukorrhea  or ( leucorrhoea   British English ), also known as  fluor albus , is a thick, whitish, yellowish or greenish  vaginal discharge . [ 1 ] [ 2 ] [ 3 ]
It has also been referred to as " the whites ". [ 4 ]
There are many causes of leukorrhea, the usual one being  estrogen  imbalance. [ citation needed ]  The amount of discharge may increase due to  vaginal infection , and it may disappear and reappear from time to time. This discharge can keep occurring for years, in which case it becomes more yellow and strong-smelling. It is usually a non-pathological symptom secondary to  inflammatory  conditions of the vagina or  cervix . [ 5 ]


Leukorrhea can be confirmed by finding >10  WBC  per  high-power field  under a microscope when examining vaginal fluid. [ 6 ]


Vaginal discharge is normal, and causes of change in discharge include infection, malignancy, and hormonal changes. It sometimes occurs before an adolescent female has her first  period , and is considered a sign of  puberty .


The word leukorrhea comes from Greek  λευκός  (leukós, “white”) +  ῥοία  (rhoía, “flow, flux”). In Latin leukorrhea is  fluor albus  ( fluor , "flow" &  albus , "white").


It is not a major issue but is to be resolved as soon as possible. It can be a natural defense mechanism that the vagina uses to maintain its chemical balance, as well as to preserve the flexibility of the vaginal tissue. The term "physiologic leukorrhea" is used to refer to leukorrhea due to estrogen stimulation. [ 7 ]


Leukorrhea may occur normally during  pregnancy . This is caused by increased bloodflow to the vagina due to increased estrogen. Female  infants  may have leukorrhea for a short time after birth due to their in-uterine exposure to estrogen.


It may also result from  inflammation  or congestion of the vaginal  mucosa . In cases where it is yellowish or gives off an odor, a doctor should be consulted since it could be a sign of several disease processes, including an organic bacterial infection ( aerobic vaginitis ) or  STD . [ 8 ]


After  delivery , leukorrhea accompanied by backache and foul-smelling  lochia  ( post-partum  vaginal discharge, containing blood, mucus, and  placental  tissue) may suggest the failure of  involution  (the  uterus  returning to pre-pregnancy size) due to infection. A number of investigation such as  wet smear ,  Gram stain , culture,  pap smear  and biopsy are suggested to diagnose the condition.


Leukorrhea is also caused by trichomonads, a group of  parasitic   protozoan , specifically  Trichomonas vaginalis . Common symptoms of this disease are burning sensation, itching and discharge of frothy substance, thick, white or yellow mucous. [ 5 ] [ 9 ]


Leukorrhea may be caused by sexually transmitted diseases; therefore, treating the STD will help treat the leukorrhea.


Treatment may include  antibiotics , such as  metronidazole . Other antibiotics common for the treatment of STIs include  clindamycin  or  tinidazole . [ 10 ]


This is the list of healthy  vaginal  microbiota (VMB), which is defined as the group of species and  genera  that generally are found to have lack of symptoms, absence of various infections, and result in good pregnancy outcomes. [ 1 ]  VMB is dominated mainly by Lactobacillus species. This is the list of organisms that are found in the lower  reproductive tract  of  sexually mature  women who are not  immunocompromised . A partial description of  pathogens  that can be found in the lower and upper reproductive tract of women can be found in the article  sexually transmitted infection . The organisms listed below are capable of causing illness if for some reason there is a change in vaginal  pH  or a change in the ratio of one organism to another. For example,  Candida  is a normal inhabitant of a healthy reproductive tract but an overgrowth of this organism can cause  candidiasis . [ 2 ] [ 3 ] [ 4 ]


This is the list of the normal flora that are found in the lower reproductive tract of  sexually mature  women who exhibit no symptoms of illness and who are not  immunocompromised .  Lactobacilli  predominate. [ 4 ] [ 5 ] [ 6 ]  These organisms protect against infection. Vaginal microbiota composition may have a  genetic component . [ 3 ]


These bacteria may be detected as transients or are marginally discernable with PCR techniques. They are also opportunistic pathogens, and their overgrowth is considered an infection though symptoms and signs may be absent.


While the vaginal microbiota is populated predominantly by  Lactobacillus  spp. in 71% of women, 29% of asymptomatic, healthy women possess a microbiota essentially lacking in  Lactobacillus  and instead the following groups have been isolated from this population.  This microbiota is affiliated with ethnicity:


Candida albicans  and other spp. [ 2 ]


Pre-pubescent  girls, women in  menarche , and postmenopausal women have lower populations of  Lactobacillus  spp. in proportion to the other species.  Hormone replacement therapy  in  postmenopausal  women restores the microbiota to that of a reproductive-aged woman. The microbiota populations change in response to the menstrual cycle. Pregnancy alters the microbiota, with a reduction in species/genus diversity. [ 3 ]
Overgrowth of  Candida albicans  or other  Candida  ( yeast infections ) sometimes occurs after antibiotic therapy. [ 2 ]   Bacterial vaginosis  results in altered populations and ratios of the normal microbiota. [ 10 ] [ 3 ] [ 11 ]
There has been no link demonstrated between taking oral  probiotics  and maintaining normal microbiota populations of lactobacilli. [ 4 ]


Microbicides for   sexually transmitted infections  are  pharmacologic  agents and  chemical substances  that are capable of killing or destroying certain  microorganisms  that commonly cause sexually transmitted infection (for example, the  human immunodeficiency virus ).


Microbicides  are a diverse group of  chemical compounds  that exert their activity by a variety of different  mechanisms of action .
Multiple compounds are being developed and tested for their microbicidal activity in  clinical trials . Microbicides can be formulated in various  delivery systems  including  gels ,  creams ,  lotions ,  aerosol sprays ,  tablets  or  films  (which must be used near the time of  sexual intercourse ) and sponges and  vaginal rings  (or other devices that release the  active ingredient (s) over a longer period). Some of these agents are being developed for  vaginal  application, and for  rectal  use by those engaging in  anal sex . [ citation needed ]


Although there are many approaches to preventing sexually transmitted infections in general (and HIV in particular), current methods have not been sufficient to halt the spread of these infections (particularly among women and people in  less-developed nations ).  Sexual abstinence  is not a realistic option for women who want to bear children, or who are at risk of  sexual violence . [ 1 ]  In such situations, the use of microbicides could offer both primary protection (in the absence of  condoms ) and secondary protection (if a condom breaks or slips off during intercourse). It is hoped that microbicides may be safe and effective in reducing the risk of HIV  transmission  during  sexual activity  with an infected partner. [ 2 ] [ 3 ] [ full citation needed ]


Detergent  and  surfactant  microbicides such as  nonoxynol-9 ,  sodium dodecyl sulfate  and Savvy (1.0% C31G), act by disrupting the  viral envelope ,  capsid  or  lipid membrane  of microorganisms. Since detergent microbicides also kill host cells and impair the barrier function of healthy  mucosal  surfaces, they are less desirable than other agents. Additionally, clinical trials have not demonstrated these agents to be effective at preventing HIV transmission. [ citation needed ]  Consequently, laboratory and clinical trials testing this class of products as microbicides have largely been discontinued. [ 4 ]


Healthy vaginal  pH  is typically quite  acidic , with a pH value of around 4. However, the  alkaline  pH of  semen  can neutralize vaginal pH. One potential class of microbicides acts by reducing the pH of vaginal  secretions , which may kill (or otherwise inactivate) pathogenic microorganisms. One such agent is  BufferGel , a  spermicidal  and microbicidal gel formulated to maintain the natural protective acidity of the vagina. Candidates in this category (including BufferGel) have proven to be ineffective in preventing HIV infection. [ 5 ]


The  polyanion  category of microbicides includes the  carrageenans . Carrageenans are a family of linear sulfated  polysaccharides  chemically related to  heparan sulfate , which many microbes utilize as a  biochemical receptor  for initial attachment to the  cell membrane . Thus, carrageenan and other microbicides of its class act as decoy receptors for  viral  binding. [ citation needed ]


Carrageenan  preparations (such as 0.5% PRO 2000 and 3% Carraguard vaginal microbicide gels) have failed to demonstrate  efficacy  in preventing HIV transmission in  phase III  clinical  multicenter trials . PRO 2000 was demonstrated to be safe, but it did not reduce the risk of HIV infection in women (as explained in the MDP 301 trial results, released in December 2009). [ 6 ]  Similarly, the phase III efficacy trial of Carraguard showed that the drug was safe for use but ineffective in preventing HIV transmission in women. [ 7 ]


Cellulose sulfate  is another microbicide found ineffective in preventing the transmission of HIV. On February 1, 2007, the  International AIDS Society  announced that two phase III trials of  cellulose   sulfate  had been stopped because preliminary results suggested a potential increased risk of HIV in women who used the compound. [ 8 ]  There is no satisfactory explanation as to why application of cellulose sulfate was associated with a higher risk of HIV infection than  placebo . According to a review of microbicide drug candidates by the  World Health Organization  on March 16, 2007, a large number of compounds (more than 60 in early 2007) are under development; [ 9 ]  at the beginning of that year, five phase III trials testing different formulations were underway.


VivaGel is a sexual lubricant with antiviral properties manufactured by Australian pharmaceutical company Starpharma. The active ingredient is a  nanoscale   dendrimeric  molecule (which binds to viruses and prevents them from affecting an organism's cells). [ 10 ]  Experimental results with VivaGel indicate 85–100% effectiveness at blocking transmission of both HIV and  genital herpes  in  macaque  monkeys. It has passed the animal-testing phases of the  drug-approval process  in Australia and the United States, which will be followed by initial human safety tests. The  National Institutes of Health  and the  National Institute of Allergy and Infectious Diseases  have awarded grants totaling $25.7 million for VivaGel's development and testing. VivaGel is being developed as a standalone microbicide gel and an intra-vaginal microbicide. [ 11 ]  It is also being evaluated for use in condoms. It is hoped that VivaGel will provide an extra resource to mitigate the  sub-Saharan AIDS pandemic . [ citation needed ]


It is also hoped that microbicides will block the transmission of HIV and other sexually transmitted infections, such as those caused by certain  human papillomaviruses  (HPV) and  herpes simplex viruses  (HSV). In 2009, Starpharma released its results for a study investigating VivaGel's antiviral activity against HIV and HSV in humans by testing cervico-vaginal samples  in vitro  (in a test tube). The compound displayed a high level of efficacy against HIV and HSV. While the results are encouraging, the study did not evaluate VivaGel's effect in the body. It is still unknown what the results mean for women who would use the product in real-life settings; for example, the effect of sexual intercourse (or semen) on the gel (which often affects the protective properties of a drug) is unknown. The  CAPRISA 004  trial demonstrated that topical tenofovir gel provided 51% protection against HSV-2. [ 12 ]


Researchers have begun to focus on another class of microbicides, the  antiretroviral  (ARV) agents. ARVs work either by preventing the HIV virus from entering a human host cell, or by preventing its replication after it has already entered. [ 13 ]  Examples of ARV drugs being tested for prevention include  tenofovir ,  dapivirine  (a  diarylpyrimidine   inhibitor  of HIV  reverse transcriptase ) and UC-781. [ 14 ]  These next-generation microbicides have received attention and support because they are based on the same ARV drugs currently used to extend the survival (and improve the quality of life) of HIV-positive people. ARVs are also used to prevent  vertical transmission  of HIV from mother to child during  childbirth , and are used to prevent HIV infection from developing immediately  after exposure  to the virus. [ 15 ]  Such ARV-based compounds could be formulated into  topical  microbicides to be administered locally in the rectum or vagina or systemically through oral or injectable formulations ( pre-exposure prophylaxis ). ARV-based microbicides may be formulated as long-acting vaginal rings, gels and films. The results of the first efficacy trial of an ARV-based microbicide, CAPRISA 004, tested 1% tenofovir in gel form to prevent male-to-female HIV transmission. The trial showed that the gel (which was applied topically to the vagina), was 39% effective at preventing HIV transmission. [ 15 ]  CAPRISA 004 was the 12th microbicide-efficacy study to be completed, and the first to demonstrate a significant reduction in HIV transmission. The results of this trial are  statistically significant  and offer  proof of concept  that ARVs, topically applied to the vaginal mucosa, can offer protection against HIV (and other)  pathogens . [ 15 ]


Most of the  first generation  microbicides were formulated as semi-solid systems, such as gels, tablets, films, or creams, and were designed to be applied to the vagina before every act of intercourse. However, vaginal rings have the potential to provide long-term controlled release of microbicide drugs. Long-acting formulations, like vaginal rings, are potentially advantageous since they could be easy to use, requiring replacement only once a month. This ease of use could prove very important to make sure that products are used properly. In 2010, the  International Partnership for Microbicides  began the first study in Africa to test the safety and acceptability of a vaginal ring containing dapivirine. [ 16 ]  Drugs might also be administered systemically through injectable or oral formulations known as PrEP. Injectable formulations may be desirable since they could be administered infrequently, possibly once a month. It is likely, however, that such products would need to be monitored closely and would be available only through prescription. This approach also carries the risk of emergence of ARV-resistant strains of HIV. [ 17 ]


Substantial numbers of men who have sex with men in  developed countries  use lubricants containing nonoxynol-9. [ citation needed ]  This suggests that they might be receptive to the concept of using topical rectal microbicides if such products were to become commercially available. [ 18 ]  However, the development of rectal microbicides is not as advanced as that of vaginal microbicides. One reason for this is that the rectum has a thinner epithelium, greater surface area and lower degree of elasticity than that of the vagina. Due to these factors, a microbicidal preparation that is effective when applied vaginally might have a different degree of effectiveness when applied rectally. [ 19 ]  In January 2010, the National Institutes of Health awarded two grants totaling $17.5 million to the  University of Pittsburgh  to fund research into rectal microbicides. [ 20 ]  That research will include investigations into product acceptability of rectal microbicides with  homosexual  men ages 18 to 30 years old. [ citation needed ]


Ultimately, successful topical microbicides might simultaneously employ multiple modes of action. In fact, long-acting formulations such as vaginal rings could provide the technology needed to deliver multiple active ingredients with different mechanisms of action. [ citation needed ]


A major breakthrough in microbicide research, announced in July 2010, reported that an ARV-based microbicide gel could partially prevent HIV. A trial led by the Centre for the AIDS Programme of Research in South Africa (CAPRISA), conducted in South Africa, demonstrated that the ARV tenofovir, when used in a vaginal gel, was 39% effective at preventing HIV transmission from men to women during sex. [ 21 ]


In July 2010 the  Centre for the AIDS Programme of Research in South Africa  (CAPRISA) released results of a study establishing proof of concept that an ARV-based, topical microbicide can reduce the likelihood of HIV transmission. The trial,  CAPRISA 004 , was conducted among 889 women to evaluate the ability of 1% tenofovir gel to prevent male-to-female HIV transmission. The study found a 39% lower HIV infection rate in women using 1% tenofovir gel compared with women using a placebo gel. In addition, tenofovir gel was shown to be safe as tested. [ 21 ]  The results of the  CAPRISA 004  trial provide statistically significant evidence that ARVs, topically applied to the vaginal mucosa, can offer protection against HIV and (potentially) other pathogens. During the study, 38 of the women who used the tenofovir gel acquired HIV and 60 women who used a placebo gel became HIV-infected. No tenofovir-resistant virus was detected in the women who acquired HIV infection during the study. In addition to demonstrating efficacy against HIV, CAPRISA 004 found evidence that tenofovir gel also prevents the transmission of herpes simplex virus type 2 (HSV-2). HSV-2 is a lifelong, incurable infection which can make those infected with the virus two-to-three times more likely to acquire HIV. Data collected during the CAPRISA 004 study indicate that tenofovir gel provided 51% protection against HSV-2. Tenofovir, developed by Gilead Sciences, is a nucleotide reverse-transcriptase inhibitor (NRTI) which interferes with the replication of HIV and is approved in tablet form for use in combination with other ARVs to treat HIV. CAPRISA 004 was a collaboration among CAPRISA,  Family Health International  and  CONRAD . It was funded by the  United States Agency for International Development  (USAID) and the South African Department of Science and Technology's  Technology Innovation Agency . [ citation needed ]


Results released in February 2009 from a clinical trial of PRO 2000 ( Indevus Pharmaceuticals ), a vaginal-microbicide gel (0.5%), sparked hope that it might provide modest protection against HIV. [ 22 ]  The results of a larger trial released in December 2009 showed that PRO 2000 was safe as administered, but was ineffective in reducing the risk of HIV infection. That trial (MDP 301) was sponsored by the Microbicides Development Programme. MDP 301 was conducted in South Africa, Tanzania, Uganda and Zambia with more than 9,300 women volunteers. No significant difference was found in the number of women who contracted HIV in the group given PRO 2000 compared to the group given a placebo. [ 23 ]  While this trial did not result in an effective product, it served as a model for future HIV-prevention trials; it provided scientific information and lessons from its social-science component, community engagement and preparation undertaken by the trial staff. [ 24 ]


Carrageenan may prevent HPV and HSV transmission, but not HIV.  See  Carrageenan#Medical Uses


The phase III clinical trial for carrageenan-based Carraguard showed that it had no statistical effect on HIV infection, according to results released in 2008. The study showed that the gel was safe, with no side effects or increased risks. The trial also provided information about usage patterns in trial participants. [ 25 ] [ 26 ]


Nonoxynol-9 , a  spermicide , is ineffective as a topical microbicide in preventing HIV infection. Although nonoxynol-9 has been shown to increase the risk of HIV infection when used frequently by women at high risk of infection, it remains a contraceptive option for women at low risk. [ 27 ]


Efforts are underway to develop safe and effective topical microbicides. Several different gel formulations are currently undergoing testing in phase III clinical efficacy trials, and about two dozen other products are in various phases of development. [ 28 ] [ 29 ]  Results from CAPRISA 004, while promising, may need to be confirmed by other clinical trials before the microbicide tenofovir gel is made available to the public. [ 30 ]  This decision rests with regulators, particularly in South Africa. In 2013, the VOICE study (MTN 003), another large-scale trial, is scheduled to release results. VOICE is evaluating three different strategies to prevent HIV in women: one ARV-based microbicide and two regimens consisting of oral ARVs on a daily basis. [ 31 ]  The VOICE trial is testing 1% tenofovir vaginal gel in a once-daily formulation. It is not known at this time if VOICE will be considered a  confirmatory trial  for CAPRISA 004, which used a different dosing strategy. [ 32 ]  Products known as Pre-Exposure Prophylaxis, or PrEP, are also being tested at various stages of the development process. These products, administered orally or via injection, would contain ARVs to protect HIV-negative people from becoming infected. Individuals would receive ARVs before they were exposed to HIV, with the goal of lowering their risk or preventing infection. [ 33 ]  One of the potential advantages of PrEP is that an individual could use it autonomously (without the need to negotiate with a partner), and it is not dependent on the time of sex. It is hoped that those unable to negotiate condom use with their sexual partners would be able to reduce their risk of HIV infection with the use of an oral (or injectable) prophylactic drug. Current PrEP candidates in development include tenofovir and Truvada (a combination of two ARV compounds, tenofovir and emtricitabine). [ 34 ]  One potential risk of the PrEP approach is that drugs present in systemic circulation might, over time, create ARV-resistant HIV strains. [ 34 ]


Condoms  are an effective method for blocking the transmission of most sexually transmitted infections (with HPV a notable exception). [ citation needed ]  However, a variety of social factors (including, but not limited to, the sexual disempowerment of women in many cultures) limit the feasibility of condom use. [ 35 ]  Thus, topical microbicides might provide a useful woman-initiated alternative to condoms. [ citation needed ]


Some sub-Saharan African cultures view vaginal lubrication as undesirable. [ 36 ]  Since some topical microbicide formulations currently under development function as lubricants, such "dry sex" traditions may pose a barrier to the implementation of topical microbicidal programs. Recent data on product acceptability, however, show that many men and women enjoy using gels during sex that would contain a microbicidal drug. [ 34 ]


Molluscum contagiosum  ( MC ), sometimes called  water warts , is a  viral infection  of the  skin  that results in small raised pink  lesions  with a dimple in the center. [ 1 ]  They may become itchy or sore, and occur singularly or in groups. [ 1 ]  Any area of the skin may be affected, with  abdomen , legs, arms, neck,  genital area , and face being the most common. [ 1 ]  Onset of the lesions is around seven weeks after infection. [ 3 ]  They usually go away within a year without  scarring . [ 1 ]


The infection is caused by a  poxvirus  called the  molluscum contagiosum virus  (MCV). [ 1 ]  The virus is spread either by direct contact, including  sexual activity , or via contaminated objects such as towels. [ 4 ]  The condition can also be spread to other areas of the body by the person themselves. [ 4 ]  Risk factors include a  weak immune system ,  atopic dermatitis , and crowded living conditions. [ 2 ]  Following one infection, it is possible to get re-infected. [ 9 ]  Diagnosis is typically based on the appearance of the lesions. [ 3 ]


Prevention includes  hand washing  and not sharing personal items. [ 6 ]  While treatment is not necessary, some may wish to have the lesions removed for cosmetic reasons or to prevent spread. [ 7 ]  Removal may occur with  freezing ,  laser therapy , or opening up the lesion and scraping the inside. [ 7 ]  Scraping the lesion can, however, result in  scarring . [ 9 ]  The oral medication  cimetidine , or  podophyllotoxin  cream applied to the skin, may also be used for treatment. [ 7 ]


Approximately 122 million people globally were affected by molluscum contagiosum as of 2010 (1.8% of the population). [ 8 ]  It is more common in children between the ages of one and ten years old. [ 2 ]  The condition has become more common in the United States since 1966. [ 2 ]  Having an infection is not a reason to keep a child out of school or daycare. [ 10 ]


Molluscum contagiosum lesions are flesh-colored, dome-shaped, and pearly in appearance. They are often 1–5 mm in diameter, with a dimpled center. [ 11 ]  Molluscum lesions are most commonly found on the face, arms, legs, torso, and  armpits  in children. Adults typically have molluscum lesions in the genital region and this is considered to be a  sexually transmitted infection ; because of this, if genital lesions are found on a child, sexual abuse should be suspected. [ 3 ]   These lesions are generally not painful, but they may itch or become irritated.  Picking or scratching the bumps may lead to a spread of the viral infection responsible for molluscum contagiosum, an additional bacterial infection, and scarring. [ 3 ] [ 12 ]  In some cases,  eczema  develops around the lesions. [ 13 ]


Individual molluscum lesions may go away on their own within two months and generally clear completely without treatment or scarring in six to twelve months. [ 3 ]  Mean durations for an outbreak are variously reported from eight [ 14 ]  to about 18 months, [ 15 ] [ 16 ]  but durations are reported as widely as six months to five years, lasting longer in  immunosuppressed  individuals. [ 16 ]


As the name implies, molluscum contagiosum is extremely contagious. [ 3 ]  Transmission of the molluscum contagiosum virus can occur many different ways including direct skin contact (e.g., contact sports or sexual activity), contact with an infected surface ( fomite ), or autoinoculation (self-infection) by scratching or picking molluscum lesions and then touching other parts of the skin not previously affected by the virus. [ 3 ]  Children are particularly susceptible to autoinoculation and may have widespread clusters of lesions. [ 17 ]  The viral infection is limited to a localized area on the topmost layer of the  superficial layer of the skin . [ 18 ]   Once the virus-containing head of the lesion has been destroyed, the infection is gone. The central waxy core contains the virus. [ citation needed ]


Diagnosis is made on the appearance; the virus cannot routinely be cultured. The diagnosis can be confirmed by excisional  biopsy . [ citation needed ]


Histologically, molluscum contagiosum is characterized by  molluscum bodies  (also known as Henderson-Patterson bodies) in the  epidermis , above the  stratum basale , which consist of cells with abundant large granular eosinophilic cytoplasmic  inclusion bodies  (accumulated virions) and a small nucleus that has been pushed to the periphery. [ 19 ] [ 20 ]


Because molluscum contagiosum usually resolves without treatment and treatment options can cause discomfort to children, initial recommendations are often to simply wait for the lesions to resolve on their own. [ 21 ]  Of the treatments available, a meta-analysis of randomized controlled trials suggested that there is no difference between treatments in short term improvement, and no single treatment is significantly better than natural resolution of the condition. [ 22 ]


Bumps located in the genital area may be treated in an effort to prevent them from spreading. [ 16 ]  When treatment has resulted in the elimination of all bumps, the infection has been effectively cured and will not reappear unless the person is reinfected. [ 23 ]


For mild cases,  over-the-counter  topical medication, such as  potassium hydroxide  may provide a modest benefit. There is limited evidence for other topical agents including  salicylic acid ,  benzoyl peroxide , and  tretinoin , but none of these agents are recommended above the others to shorten infection duration. [ 24 ]


Studies have found  cantharidin  to be an effective and safe treatment for removing molluscum contagiosum. [ 25 ]  This medication is usually well tolerated though mild side effects such as pain or blistering are common. [ 25 ]
There is no high-quality evidence for  cimetidine . [ 26 ]  However, oral cimetidine has been used as an alternative treatment for the pediatric population as it is generally well tolerated and less invasive. [ 27 ]


Berdazimer sodium , sold under the brand name Zelsuvmi, is a  medication  used for the treatment for molluscum contagiosum. [ 28 ]  Berdazimer sodium is a  nitric oxide  releasing agent. [ 28 ]  It is a polymer formed from sodium 1-hydroxy-3-methyl-3-(3-(trimethoxysilyl)propyl)-1-triazene-2-oxide and  tetraethyl silicate . [ 29 ]


The most common side effects occurred at the drug application site including pain, rash, itch, eczema, swelling, erosion, discoloration, blister, irritation, and infection. [ 30 ]  Other common side effects included fever, vomiting, and upper respiratory infections (common cold). [ 30 ]


Imiquimod  is a form of immunotherapy initially proposed as a treatment for molluscum based on promising results in small case series and clinical trials. [ 34 ]  However, two large  randomized controlled trials , specifically requested by the U.S.  Food and Drug Administration  under the  Best Pharmaceuticals for Children Act  both demonstrated that imiquimod cream applied three times per week was no more effective than placebo cream for treating molluscum after 18 weeks of treatment in a total of 702 children aged 2–12 years. [ 35 ]  In 2007, results from those trials—which remain unpublished—were incorporated into FDA-approved prescribing information for imiquimod, which states: "Limitations of Use: Efficacy was not demonstrated for molluscum contagiosum in children aged 2–12." [ 35 ] [ 36 ]  In 2007, the FDA also updated imiquimod's label concerning safety issues raised in the two large trials and an FDA-requested pharmacokinetic study (the latter of which was published). [ 35 ]  The updated safety label reads as follows:


Surgical treatments include  cryosurgery , in which  liquid nitrogen  is used to freeze and destroy  lesions , as well as scraping them off with a  curette . Application of liquid nitrogen may cause burning or stinging at the treated site, which may persist for a few minutes after the treatment. With liquid nitrogen, a blister may form at the treatment site, but it will slough off in two to four weeks. Cryosurgery and curette scraping can be painful procedures and can result in residual scarring. [ 38 ]


A 2014 systematic review of  case reports  and  case series  concluded that the limited available data suggest  pulsed dye laser  therapy is a safe and effective treatment for molluscum contagiosum and is generally well tolerated by children. [ 38 ]  Side effects seen with pulsed dye laser therapy included mild temporary pain at the site of therapy,  bruising  (lasting up to 2–3 weeks), and temporary discoloration of the treated skin (as long as 1–6 months). [ 38 ]  No cases of permanent scarring have been reported. [ 38 ]  As of 2009, however, there is no evidence for genital lesions. [ 39 ]


Most cases of molluscum contagiosum will clear up naturally within two years (usually within nine months). So long as the skin growths are present, there is a possibility of transmitting the infection to another person. When the growths are gone, the possibility of spreading the infection is ended. [ 23 ]


Unlike  herpesviruses , which can remain inactive in the body for months or years before reappearing, molluscum contagiosum does not remain in the body when the growths are gone from the skin and will not reappear on their own. [ 23 ]


As of 2010, approximately 122 million people were affected worldwide by molluscum contagiosum (1.8% of the population). [ 8 ]


Mycoplasma genitalium  Tully  et al.  1983 [ 2 ]


Mycoplasma genitalium  (also known as  MG [ 3 ] ,   Mgen , or since 2018,  Mycoplasmoides genitalium [ 1 ] ) is a  sexually transmitted , [ 4 ]  small and  pathogenic   bacterium  that lives on the  mucous   epithelial cells  of the  urinary  and  genital tracts  in humans. [ 5 ]  Medical reports published in 2007 and 2015 state that Mgen is becoming increasingly common. [ 6 ] [ 7 ]  Resistance to multiple  antibiotics , including the  macrolide   azithromycin , which until recently was the most reliable treatment, is becoming prevalent. [ 6 ] [ 8 ]  The bacterium was first isolated from the  urogenital tract  of humans in 1981, [ 9 ]  and was eventually identified as a new species of  Mycoplasma  in 1983. [ 2 ]  It can cause negative health effects in men and women. It also increases the risk for  HIV  spread [ 10 ]  with higher occurrences in those previously treated with the  azithromycin   antibiotics . [ 6 ] [ 11 ]


Mgen is a bacterium recognized for causing  urethritis  in both men and women along with  cervicitis  and  pelvic inflammation  in women. [ 12 ]  It presents clinically similar symptoms to that of  Chlamydia trachomatis  infection and has shown higher incidence rates, compared to both  Chlamydia trachomatis  and  Neisseria gonorrhoeae  infections in some populations. [ 13 ]


Infection with Mgen can be symptomatic or  asymptomatic . Both men and women may experience  inflammation  in the  urethra  ( urethritis ), characterized by  mucopurulent discharge  in the  urinary tract , and  burning while urinating . In women, it causes  cervicitis  and  pelvic inflammatory diseases (PID) , including  endometritis  and  salpingitis . [ 12 ]  Women may also experience bleeding after sex and it is also linked with  tubal factor infertility . [ 5 ] [ 14 ] [ 15 ]  For men, the most common signs are painful urination or a watery discharge from the penis. [ 16 ]


There is a consistent association of  M. genitalium  infection and female reproductive tract syndromes.  M. genitalium  infection was significantly associated with increased risk of preterm birth, spontaneous abortion, cervicitis, and pelvic inflammatory disease. In addition, this pathogen may latently infect the  chorionic villi  tissues of pregnant women, thereby impacting pregnancy outcome. [ 17 ]  Infertility risk is also strongly associated with infection with  M. genitalium , although evidence suggests it is not associated with male infertility. [ 18 ]  When  M. genitalium  is a co-infectious agent risk associations are stronger and statistically significant. [ 19 ]


Polymerase chain reaction  analyses indicated that it is a cause of acute  non-gonococcal urethritis  (NGU) and probably chronic NGU. It is strongly associated with persistent and recurring non-gonococcal urethritis (NGU), responsible for 15 percent to 20 percent of  symptomatic  NGU cases in men. [ 20 ]  Unlike other mycoplasmas, the infection is not associated with  bacterial vaginosis . [ 21 ]  It is highly associated with the intensity of HIV infection. [ 22 ]  Some scientists are performing research to determine if Mgen could play a role in the development of  prostate  and  ovarian cancers  and  lymphomas  in some individuals. These studies have yet to find conclusive evidence to suggest a link. [ 23 ]


The genome of  M. genitalium  strain G37 T  consists in one circular DNA molecule of 580,070  base pairs . [ 24 ]  Scott N. Peterson and his team at the  University of North Carolina at Chapel Hill  reported the first genetic map using  pulsed-field gel electrophoresis  in 1991. [ 25 ]  They performed an initial study of the genome using  sequencing  in 1993, by which they found 100,993 nucleotides and 390 protein-coding genes. [ 26 ]  Collaborating with researchers at The  Institute for Genomic Research  (TIGR; now the J. Craig Venter Institute), which included  Craig Venter , they made the complete genome sequence in 1995 using  shotgun sequencing . [ 24 ]  Only 470 predicted  coding regions  were identified in 1995, including  genes  required for  DNA replication ,  transcription  and  translation ,  DNA repair ,  cellular transport , and  energy metabolism . It was the second complete bacterial genome ever sequenced, after  Haemophilus influenzae . [ 24 ]  Later data from  KEGG  reports 476 protein-coding genes and 43  RNA genes , totaling 519. [ 27 ]  It is unclear where the "525" gene count for the G37 T  stems from and what  gene calling  procedure was used. [ 28 ]


In 2006, the team at the J. Craig Venter Institute reported that only 382 genes are essential for biological functions. [ 29 ]  The small genome of  M. genitalium  made it the organism of choice in  The Minimal Genome Project , a study to find the smallest set of genetic material necessary to sustain  life . [ 30 ]


There is limited divergence among clinical strains of  M. genitalium . All strains retain the small genome size. [ 31 ]


Recent research shows that prevalence of Mgen is currently higher than other commonly occurring  sexually transmitted infections  (STIs). [ 32 ]  Mgen is a fastidious organism with prolonged growth durations. This makes detection of the pathogen in clinical specimens and subsequent isolation extremely difficult. [ 33 ]  Lacking a  cell wall ,  Mycoplasma  remains unaffected by commonly used  antibiotics . [ 34 ]  The absence of specific serological assays leaves  nucleic acid amplification tests  (NAAT) as the only viable option for detection of Mgen  DNA  or  RNA . [ 35 ]  However, samples with positive NAAT for the pathogen should be tested for  macrolide  resistance  mutations , which are strongly correlated to  azithromycin  treatment failures, owing to rapid rates of mutation of the pathogen. [ 6 ]  Mutations in the  23S rRNA  gene of Mgen have been linked with clinical treatment failure and high level  in vitro  macrolide resistance. [ 36 ]  Macrolide resistance mediating mutations have been observed in 20-50% of cases in the UK, Denmark, Sweden, Australia, and Japan. [ 6 ]  Resistance is also developing towards the second-line  antimicrobials  like  fluoroquinolone . [ 37 ]


According to the European guidelines, the indication for commencement of diagnosis for Mgen infection are: [ 35 ]


Screening for Mgen with a combination of detection and macrolide resistance mutations will provide the adequate information required to develop personalised antimicrobial treatments, in order to optimise patient management and control the spread of  antimicrobial resistance  (AMR). [ 35 ] [ 38 ]


Owing to the widespread  macrolide resistance , samples that are positive for Mgen should ideally be followed up with an assay capable of detecting mutations that mediate antimicrobial resistance. The European Guideline on Mgen infections recommend complementing the molecular detection of Mgen with an assay capable of detecting macrolide resistance-associated mutations. Furthermore, molecular assays for quinolone resistance-associated mutations are available at specialised laboratories in suspected treatment failure due to treatment with moxifloxacin. [ 39 ]


The U.S.  Centers for Disease Control and Prevention  recommends a step-wise treatment approach for  Mycoplasma genitalium  with  doxycycline  for seven days followed immediately by a seven-day course of  moxifloxacin  as the preferred therapy due to high rates of macrolide resistance. [ 40 ] [ 41 ] [ 42 ]  If resistance assay testing is available, and the Mgen is sensitive to macrolides, the CDC recommends a seven-day course of doxycycline followed by a four-day course of  azithromycin . [ 40 ]   Although the majority of  M. genitalium  strains are sensitive to moxifloxacin, resistance has been reported, and potential for serious, adverse side effects should be considered with this regimen.  [ 43 ]  Floroquinolones, including moxifloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including: [ citation needed ]


and other serious side effects detailed in the FDA black box warning. Moxifloxacin/Avelox should be reserved for use when patients have no other treatment options.  [ 44 ]


In settings without access to resistance testing, or if moxifloxacin cannot be used, the CDC recommends as an alternative regimen: seven days of doxycycline followed by the four-day course of azithromycin, with a test of cure 21 days after treatment being required due to the high rate of macrolide resistance.   Beta lactam antibiotics  are not effective against Mgen as the organism lacks a cell wall. [ 42 ]


In the UK the British Association for Sexual Health and HIV (BASHH) guidelines for treatment are: [ 45 ]


Treatment of  Mycoplasma genitalium  infections is becoming increasingly difficult due to rapidly growing  antimicrobial resistance . [ 46 ]  Diagnosis and treatment is further hampered by the fact that  Mycoplasma genitalium  infections are not routinely tested. [ 47 ]  Studies have demonstrated that a 5-day course of azithromycin has a superior cure rate compared to a single, larger dose. Further, a single dose of azithromycin can lead to the bacteria becoming resistant to azithromycin. [ 48 ]  Among Swedish patients, doxycycline was shown to be relatively ineffective (with a cure rate of 48% for women and 38% for men); and treatment with a single dose of azithromycin is not prescribed due to it inducing antimicrobial resistance. The five-day treatment with azithromycin showed no development of antimicrobial resistance. [ 49 ]  Based on these findings, UK doctors are moving to the 5-day azithromycin regimen. Doxycycline is also still used, and  moxifloxacin  is used as a second-line treatment in case doxycyline and azithromycin are not able to eradicate the infection. [ 50 ] [ 51 ]
In patients where doxycycline, azithromycin and moxifloxacin all failed,  pristinamycin  has been shown to still be able to eradicate the infection. [ 50 ]


Mycoplasma genitalium  was originally isolated in 1980 from  urethral   specimens  of two male patients with  non-gonococcal urethritis  in the genitourinary medicine (GUM) clinic at  St Mary's Hospital, Paddington , London. [ 52 ] [ 53 ]  It was reported in 1981 by a team led by Joseph G. Tully. [ 9 ]  Under  electron microscopy , it appears as a flask-shaped cell with a narrow terminal portion that is crucial for its attachment to the host cell surfaces. [ 54 ]  The bacterial cell is slightly elongated, somewhat like a vase, and measures 0.6–0.7 μm in length, 0.3–0.4 μm at the broadest region, and 0.06–0.08 μm at the tip. The base is broad while the tip is stretched into a narrow neck, which terminates with a cap. The terminal region has a specialised region called nap, which is absent in other mycoplasmas.  Serological tests  indicated that the bacterium was not related to known species of  Mycoplasma . The comparison of genome sequences with other urinogenital bacteria, such as  M. hominis  and  Ureaplasma parvum , revealed that  M. genitalium  is significantly different, especially in the  energy-generating pathways , although it shared a core genome of ~250 protein-encoding genes. [ 55 ]


In 2018, Gupta et al. proposed to change the name of  Mycoplasma genitalium  to  Mycoplasmoides genitalium  on phylogenetic grounds, reflecting the existing knowledge that  M. genitalium  is not very related to other  Mycoplasma . [ 1 ]  The change became  correct name  under the  International Code of Nomenclature of Prokaryotes  (ICNP, "Code") with Validation List 184, published by the  ICSP  ("Committee"). [ 56 ]  Mycoplasmaologists working in the field generally oppose this renaming. In 2019, they published an opinion paper arguing that even though the phylogenetic methods are valid, Gupta's renaming scheme causes too many changes, which is impractical and confusing. [ 57 ]  They cite some essential principles of the Code, such as "no unnecessary new names", "aim at stability of names", and "avoid or reject the use of names which may cause error or confusion". [ 57 ]  However, the 2019 argument for preserving old names was rejected by the Committee in Opinion 122 of 2022, [ 58 ]  where it was ruled that the argument incorrectly cited the Code. [ 56 ]  The Opinion emphasizes that use of an older  validly published name  remains acceptable under the Code. [ 58 ]